NZ738082B2 - Novel breathing control modulating compounds, and methods of making and using same - Google Patents
Novel breathing control modulating compounds, and methods of making and using same Download PDFInfo
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- NZ738082B2 NZ738082B2 NZ738082A NZ73808216A NZ738082B2 NZ 738082 B2 NZ738082 B2 NZ 738082B2 NZ 738082 A NZ738082 A NZ 738082A NZ 73808216 A NZ73808216 A NZ 73808216A NZ 738082 B2 NZ738082 B2 NZ 738082B2
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- New Zealand
- Prior art keywords
- pyrimido
- bis
- per
- propanol
- compound
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- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000000153 supplemental Effects 0.000 description 1
- 230000000576 supplementary Effects 0.000 description 1
- 229960005126 tapentadol Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present invention includes compounds including 1-(2,6-Bis-methylamino-8-propylamino-pyrimido[5,4-d]pyrimidin-4-yl amino)-2-methyl-propan-2-ol and crystal forms thereof that are useful in the prevention and/or treatment of breathing control diseases or disorders in a subject in need thereof. The present invention also includes a method of preventing and/or treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound and/or composition of the invention. The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound and/or composition of the invention. present invention also includes a method of preventing and/or treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound and/or composition of the invention. The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound and/or composition of the invention.
Description
TITLE OF THE INVENTION
Novel Breathing Control IVIodulating Compounds, and IVIethods of Making and Using Same
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional
Application No. 62/186,468, filed June 30, 2015, and U.S. Provisional Application No.
62/328,277, filed April 27, 2016, all of which are incorporated herein by reference in their
entireties.
BACKGROUND OF THE INVENTION
Normal control of breathing is a complex process that involves, in part, the
body's interpretation and response to chemical stimuli such as carbon dioxide, pH and
oxygen levels in blood, tissues and the brain. Normal breathing control is also affected by
other factors such as wakefulness (ji.e., whether the patient is awake or sleeping), emotion,
posture and vocalization. Within the brain medulla, there are respiratory control centers that
inteipret various feed-forward and feed-back signals that affect respiration by issuing
commands to the muscles that perform the work of breathing. Key muscle groups are located
in the abdomen, diaphragm, pharynx and thorax. Sensors located centrally and peripherally
then provide input to the brain's central respiration control areas that enables response to
changing metabolic requirements.
For example, ventilation sufficient to meet the body's metabolic needs is
maintained primarily by the body's rapid response to changes in carbon dioxide (C02) levels.
Increased C02 levels (hypercapnia) signal the body to increase breathing rate and depth,
resulting in higher blood oxygen levels and subsequent lower blood C02 levels. Conversely,
low C02 levels (hypocapnia) can result in periods ofhypopnea (decreased breathing) or, in
the extreme case, apnea (no breathing) since the stimulation to breathe is diminished.
There are many diseases in which loss of normal breathing control is a
primary or secondary feature of the disease. Examples of diseases with a primary loss of
breathing control are sleep apneas (central, mixed or obstructive; where the breathing
repeatedly stops for 10 to 60 seconds) and congenital central hypoventilation syndrome.
Secondary loss of breathing control may be due to chronic cardio-pulmonary diseases (e.g.,
heart failure, chronic bronchitis, emphysema, and impending respiratory failure), excessive
weight (e.g., obesity -hypoventilation syndrome), certain drugs (e.g., anesthetics, sedatives,
sleeping aids, anxiolytics, hypnotics, alcohol, and narcotic analgesics and/or factors that
affect the neurological system (e.g., stroke, tumor, trauma, radiation damage, and ALS). In
chronic obstructive pulmonary diseases where the body is exposed to chronically high levels
of carbon dioxide, the body adapts to the respiratory acidosis (lower pH) by a kidney
mediated retention ofbicarbonate, which has the effect of partially neutralizing the C02/pH
respiratoiy stimulation. Thus, the patient is unable to mount a normal ventilatory response to
changes in metabolic demand.
Sleep disordered breathing is an example of where abnormalities in the control
of breathing lead to a serious and prevalent disease in humans. Sleep apnea is characterized
by frequent periods of no or partial breathing. Key factors that contribute to these apneas
include anatomical factors (e.g., obesity), decreased hypercapnic and hypoxic ventilatory
responses (e.g., decreased response to high carbon dioxide and low oxygen levels,
respectively) and loss of "wakefulness" (respiratoiy drive to pharyngeal dilator muscles
during sleep). Apneic events result in intermittent hypoxia (and the associated oxidative
stress) and eventually severe cardiovascular consequences (high blood pressure, stroke, heart
attack).
Estimates for U.S. individuals afflicted with conditions wherein there is
compromised respiratoiy control include sleep apneas (15-20 millions); obesity-
hypoventilation syndrome (3-5 millions); chronic heart disease (5 millions); chronic
obstmctive pulmonary disease (COPD)/chronic bronchitis (10 millions); drug-induced
hypoventilation (2-10 millions); and mechanical ventilation weaning (0.5 million).
There is a need in the art for novel compounds useful for restoring all or part
of the body's normal breathing control system in response to changes in C02 and/or oxygen
levels, with minimal side effects. Further, there is a need in the art for novel compounds that
are useful for restoring all or part of the body's normal breathing control system and possess
suitable pharmacokinetic properties, such as oral bioavailability. Further, there is a need in
the art for novel compounds that are useful for restoring all or part of the body's normal
breathing control system and may be administered orally and used in a chronic or acute
manner. Further, there is a need in the art for novel compounds that are useful for restoring
all or part of the body's normal breathing control system and may be administered
parenterally (e.g., intravenously) and used in an acute manner. The present invention
addresses and meets these needs.
BRIEF SUMMARY OF THE INVENTON
The invention provides a compound of formula (I), or a salt, solvate,
R6N'RS
R8^A,^k^Y2
? T T
R7 N^.N
enantiomer, diastereoisomer or tautomer thereof: Y (I), wherein in (I):
one of the substituents selected from the group consisting of Y1 and Y is selected from the
Rn Rn
group consisting of-N(R1)-L-C(R9)(R10)OH, K- R , and
and the other substituent is -N(R1)R2; R1, R5 and R7 are independently selected from the
group consisting of hydrogen and optionally substituted Ci-Cs alkyl; R is selected from the
group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, aiylalkyl,
heteroarylalkyl and heteroaiyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl,
phenylalkyl, aryl, arylalkyl, heteroarylalkyl or heteroaryl group is independently optionally
substituted; R6 and R8 are independently selected from the group consisting of alkyl,
cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aiyl, arylalkyl, heteroarylalkyl and
heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl,
arylalkyl, heteroarylalkyl or heteroaryl group is independently optionally substituted; R9 and
R10 are independently selected from the group consisting of H and optionally substituted Ci-
Cs-alkyl; or R and R combine with the carbon atom to which they are bound so as to form
an optionally substituted €3-06 cycloalkyl group; each instance of R11 is independently
selected from the group consisting of H and optionally substituted Ci-Cs-alkyl; wherein a -
C(R )2-C(R )2- group within ring b is optionally replaced by an optionally substituted 1,2-
phenylene group that is fused with ring b; each occurrence of independently optionally
substituted Ci-Cs alkylene; m and n are independently selected from the group consisting of
1, 2, 3 and 4, such that 2<(m+n)<4; p and q are independently elected from the group
consisting of 0, 1, 2, 3 and 4, such that 2<(p+q)<4; with the proviso that the alkyl group is not
substituted with a hydroxy group.
In certain embodiments, the compound of formula (I) is the compound of
formula (IIa), or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof:
R6...R5
(IIa), wherein in (IIa): one of the substituents selected from the group
consisting of Y' and Y2 is -L-C(R9)(R10)OH, and and the other substituent is -N(R1)R2; R\
R and R are independently selected from the group consisting of hydrogen and optionally
substituted CI-CB alkyl; R is selected from the group consisting ofalkyl, cycloalkyl, alkenyl,
alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl, wherein the
alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroaiylalkyl or
heteroaryl group is independently optionally substituted; R6 and R are independently
selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl,
aryl, arylalkyl, heteroarylalkyl and heteroaiyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl,
phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or heteroaryl group is independently
optionally substituted; R9 and R are independently selected from the group consisting of
hydrogen and optionally substituted Ci-Cs-alkyl; or R9 and R10 combine with the carbon atom
to which they are bound so as to form an optionally substituted Cs-Cg cycloalkyl group; L is
optionally substituted Ci-Cs alkylene; and with the proviso that the alkyl group is not
substituted with a hydroxy group.
In certain embodiments, the compound of formula (I) is the compound of
formula (lib), or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof:
(lib), wherein in (lib):
one of the substituents selected from the group consisting of Yl and Y2 is R R
and the other substituent is -N(R )R ; R , R and R7 are independently selected from the
group consisting of H and optionally substituted Ci-Cs alkyl; R is selected from the group
consisting ofalkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl,
heteroarylalkyl and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl,
phenylalkyl, aryl, aiylalkyl, heteroarylalkyl or heteroaiyl group is independently optionally
substituted;!, is optionally substituted Ci-Cs alkylene; and R and R8 are independently
selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl,
aryl, aiylalkyl, heteroarylalkyl and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl,
phenyl, phenylalkyl, aryl, arylalkyl, heteroaiylalkyl or heteroaryl group is independently
optionally substituted; each instance of R is independently selected from the group
consisting of hydrogen and optionally substituted Ci-Cs-alkyl; L is optionally substituted Ci-
Cs alkylene; m and n are independently selected from the group consisting of 1, 2, 3 and 4,
such that 2<m+n<4; with the proviso that the alkyl group is not substituted with a hydroxy
group.
In certain embodiments, the compound of formula (I) is a compound of
formula (lie), or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof:
(lie), wherein in (lie): one of the substituents selected from the group
Ru Rn
consisting of Y' and Y2 is R'' Rl ] , and the other substituent is -N(R!)R2; R1,
R5 and R7 are independently selected from the group consisting of hydrogen and optionally
substituted Ci-Cs alkyl; R2 is selected from the group consisting ofalkyl, cycloalkyl, alkenyl,
alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroaiylalkyl and heteroaryl, wherein the
alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or
heteroaryl group is independently optionally substituted; R and R8 are independently
selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl,
aryl, aiylalkyl, heteroarylalkyl and heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl,
phenyl, phenylalkyl, aiyl, arylalkyl, heteroarylalkyl or heteroaryl group is independently
optionally substituted; R9 and R10 are independently selected from the group consisting of H
and optionally substituted Ci-C3-alkyl; or R9 and R10 combine with the carbon atom to which
they are bound so as to form an optionally substituted C3-C6 cycloalkyl group; each instance
of R is independently selected from the group consisting of H and optionally substituted Ci-
Cs-alkyl; wherein a -C(Rn)2-C(RU)2- group within ring b is optionally replaced by an
optionally substituted 1,2-phenylene group that is fused with ring b; each occurrence of L is
independently optionally substituted Ci-Cs alkylene; p and q are s independently elected from
the group consisting of 0, 1, 2, 3 and 4, such that 2<p+q<4; with the proviso that the alkyl
group is not substituted with a hydroxy group.
In certain embodiments of compounds of formulas (I), (IIa), (lib) and (lie),
each occurrence of the alkyl group is optionally substituted with one or more substituents
independently selected from the group consisting ofCi-C6 alkyl, F, Cl, Br, I, and CN; each
occurrence of the cycloalkyl, alkenyl or alkynyl group is optionally substituted with one or
more substituents independently selected from the group consisting ofCi-C6 alkyl, F, Cl, Br,
I, and CN; each occurrence of the phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or
heteroaryl group is optionally substituted with one or more substituents independently
selected from the group consisting ofCi-C6 alkyl, Ci-C6 alkoxy, hydroxy, F, Cl, Br, I, nitro, -
NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)(Ci-C6 alkyl), -S(=0)o-2(Ci-C6alkyl), -C(=0)OH and
-C(=0)OCi-C6 alkyl.
In certain embodiments of compounds of formula (I), R1, R5 and R are H. In
certain embodiments of compounds of formula (I), R', R5 and R7 are independently
optionally substituted Ci-Cs alkyl. In certain embodiments of compounds of formula (I), R ,
R5 and R are H; and R9 and R are H. In certain embodiments of compounds of formula (I),
R\ Rs and R7 are H; R9 is H; and R10 are CHs.
In certain embodiments, a compound of formula (I) is selected from the group
consisting of: 2-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (4); 2-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
yl)-methyl-amino]-ethanol (6); 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)-propan-l-ol (8);; l-(2,6-Bis-methylaminopropylamino-
pyrimido[5,4-d]-pyrimidinylamino)-propanol (10); (S)-l-(2,6-Bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidmylamino)-propanol (12); (R)-l-(2,6-Bis-
methylammopropylamino-pyrimido[5,4-d]pyrimidinylamino)-propanol (14); 2-(2,6-
Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)methyl-propan-l-
ol (16); (S)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylammo)-
propanol (18); (R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-propan-l-ol (20); 3-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-
d]pyrimidmylamino)-1,1,1 -trifluoro-propanol (22); 1 -(2,6-Bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (24); 3-(2,6-Bis-methylamino-
8-propylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (26); 2-(2,6-Bis-ethylammo-
8-propylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (27); 2-[8-Propylamino-2,6-
bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]-ethanol (28); 1 -(2,6-
Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)methyl-propan
ol (31); l-(2,6-Bis-ethylaminopropylammo-pyrimido[5,4-d]-pyrimidinylamiao)
methyl-propanol (32); 1 -[2,6-Bis-(2,2-difluoro-ethylamino)propylammo-pyrimido[5,4-
d]-pyrimidinylamino]methyl-propanol (33); 2-Methyl-l-[8-propylamino-2,6-bis-
(2,2,2-trifluoro-ethylammo)-pyrimido[5,4-d]pyrimidmylamino]-propanol (34); 1-[8-
(2,2-difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]
methyl-propanol (36); l-{2,6-bis-methylamino[(pyrimidinylmethyl)-ammo]-
pyrimido[5,4-d]pyrimidmylammo}methyl-propanol (38); l-[8-((R)-s'ec-butylamino)-
2,6-bis-methylammo-pyrimido[5,4-d]-pyrimidinylamino]methyl-propanol (40); 1 -[8-
((S)-5ec-butylamino)-2,6-bis-methylammo-pyrimido[5,4-d]-pyrimidinylamino]methyl-
propanol (42); 1 -(8-benzylamino-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylammo)methyl-propanol (44); l-[8-(cyclopropylmethyl-ammo)-2,6-bis-methylamino-
pyrimido[5,4-d]pyrimidinylamino]methyl-propanol (46); l-[8-(2,2-difluoro-
ethylamino)-2,6-bis-ethylamino-pyrimido[5,4-d]pyrimidinylamino]methyl-propanol
(47); 2-methyl-1 -(2,6,8 -tris-methylamino-pyrimido [5,4-d] -pyrimidinylammo)-propanol
(48); 2-methyl-1 -(2,6,8-tris-ethylamino-pyrimido[5,4-d]-pyrimidmylamino)-propanol
(49); 2-(2,6,8-tris-methylammo-pyrimido[5,4-d]pyrimidinylamino)-ethanol (52); 2-[8-
(cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
ethanol (54); 2-[8-(2-methoxy-ethylammo)-2,6-bis-methylammo-pyrimido[5,4-d]pyrimidin-
4-ylamino]-ethanol (56); 2-(2,6-bis-methylammopropynylamino-pyrimido[5,4-
d]pyrimidinylamino)-ethanol (58); 2-[8-(2,2-difluoro-ethylamino)-2,6-bis-methylamino-
pyrimido[5,4-d]-pyrimidmylamino]-ethanol (60); 2-[2,6-bis-methylamino(2,2,2-
trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]-ethanol (62); 2-(8-benzylamino-
2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-ethanol (64); 3-(8-ethylamino-
2,6-bis-methylammo-pyrimido[5,4-d]-pyrimidinylamino)-propan-l-ol (67); l-(2,6-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinyl)-pyrrolidmol (71); 1 -[(2,6-
bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-methyl]-cyclobutanol
(72); l-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinyl)-methyl-
amino]-propanol (73); 3-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm-
4-ylamino)-methyl]-pentanol (74); l-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinyl)-methyl-amino]methyl-propanol (76); (lR,2S)-l-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-indanol (77);
(lS,2S)-l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
indanol (78); (lS,,2R)-l-(2,6-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin-
4-ylamino)-indanol (79); (lR,2R)-l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-
d]-pyrimidinylamino)-mdanol (80); (2-(2,6-bis-methylaminopropylamino-
pyrimido[5,4-d]-pyrimidinylammo)-indan-l -ol (81); (lR,2S)(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidmylammo)-cyclohexanol (82); (1 S,2S)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol (83);
(lS,2R)(2,6-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-
cyclohexanol (84); (lR,2R)(2,6-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)-cyclohexanol (85); (1 S,2S)(2,6-bis-methylaminopropylammo-
pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol (86); (lR,2R)(2,6-bis-methylamino-
8-propylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol (87); 2-[6-
(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
ethanol (90); 2-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (91); 2-(6-dimethylamino-4,8-bis-methylammo-pyrimido[5,4-d]-pyrimidin
ylammo)-ethanol (92); l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)methyl-propanol (94); l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-
d]-pyrimidmylamino)-propanol (95); 1 -[(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinyl)-methyl-amino]methyl-propanol (96); l-[(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-amino]-propanol
(97); l-[6-((R)-5ec-butylammo)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidmylamino]-
2-methyl-propanol (99); (R)-l-[6-((R)-^ec-butylamino)-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidmylamino]-propanol (100); (S)-1 -[6-((R)-s'ec-butylamino)-4,8-
bis-methylammo-pyrimido[5,4-d]pyrimidinylammo]-propanol (101); l-[6-((S)-sec-
butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidmylamino]methyl-propan
ol (103); (R)-l-[6-((S)-5ec-butylamino)-4,,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino]-propanol (104); (S)-l -[6-((S)-5ec-butylammo)-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinylammo]-propanol(105); l-[6-(2,2-difluoro-ethylamino)-4,8-
bis-methylamino-pyrimido [5,4-d]pyrimidinylamino] methyl-propanol (107); 1-{4,8-
bis-methylamino[(pyrimidinylmethyl)-amino]-pyrimido[5,4-d]pyrimidmylammo}
methyl-propanol (109); 3-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin-
2-ylamino)-1,1,1 -trifluoro-propanol (111); (S)(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylamino)-propanol (113); (R)-l-(4,8-bis-methylamino
propylamino-pyrimido [5,4-d]pyrimidinylamino)-propanol (115); 1 -(4,8-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidmylamino)-butanol (117); 3-(4,8-
Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (119);
(lR,2S)-l-(4,8-bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidmylamino)-
indanol (123); (lS,2S)-l-(4,8-bis-methylammopropylamino-pyrimido[5,4-d]-
pyrimidmylamino)-indanol (125); (lS,2R)-l-(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]-pyrimidinylamino)-mdanol (127); (lR,2R)-l-(4,8-bis-methylamino
propylamino-pyrimido[5,4-d]-pyrimidmylamino)-indanol (129); (lR,2S)(4,8-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol (131);
(1 S,2S)(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylammo)-
cyclohexanol (133); (1 S,2R)(4,8-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylammo)-cyclohexanol (135); (lR,2R)(4,8-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol (137); (1 S,2S)(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol (139);
(lR,2R)(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
cyclopentanol (141); (S)-1 -[6-(cyclopropylmethyl-amino)-4,8-bis-methylammo-
pyrimido[5,4-d]pyrimidinylamino]-propanol (142); (S)-l-(6-allylamino-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidinylamino)-propanol (143); (R)-l-[6-
(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylammo]-
propanol (144); (R)-l-(6-allylammo-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (145); 1 -[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinylamino]-butanol (146); 1 -(6-ethylammo-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidmylamino)-butanol (147); 2-methyl-l-(4,6,8-tris-
methylamino-pyrimido[5,4-d]pyrimidinylamino)-propanol (149); 2-(6-allylamino-4,8-
bis-methylammo-pyrimido[5,4-d]pyrimidinylamino)-ethanol (154); (S)-l-[(6-allylamino-
4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidmyl)-propyl-amino]-propanol (155); (S)-
l-[(6-allylamino-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidmyl)-methyl-ammo]-
propanol (156); (R)-l-[6-(2-methyl-allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidmylamino]-propanol (158); (S)-l-[6-(2-methyl-allylamino)-4,8-bis-
methylamino-pyrimido[5,4-d]-pyrimidinylamino]-propanol (159); 2-(4,8-bis-
ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (162); l-(4,8-bis-
ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)methyl-propanol
(163); (S)-l-(4,6,8-Tris-ethylammo-pyrimido[5,4-d]pyrimidinylamino)-propanol (165);
(S)-l-(4,8-bis-ethylammopropylamino-pyrimido[5,4-d]-pyrimidmylamino)-propanol
(166); (R)-1 -(4,6,8-tris-ethylamino-pyrimido[5,4-d]pyrimidinylamino)-propanol (168);
(R)-l-(4,8-bis-ethylammopropylamino-pyrimido[5,4-d]-pyrimidmylamino)-propanol
(169); (R)-l-[4,8-bis-ethylamino(2-methyl-allylammo)-pyrimido[5,4-d]-pyrimidin
ylamino]-propanol (174); (S)-l-[4,8-bis-ethylamino(2-methyl-allylamino)-
pyrimido[5,4-d]-pyrimidinylamino]-propanol (175); a salt, solvate, enantiomer,
diastereoisomer or tautomer thereof; and any combinations thereof.
In certain embodiments of compounds of formula (I), the salt comprises an
acid addition salt, and the acid is at least one selected from the group consisting of sulfuric,
hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, phosphoric, foiTnic, acetic,
propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, maleic,
glucuronic, fumaric, pymvic, aspartic, glutamic, benzoic, anthi-anilic, mandelic, pamoic, 4-
hydroxybenzoic, phenylacetic, methanesulfonic, ethanesulfonic, alginic, benzenesulfonic,
pantothenic, sulfanilic, stearic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-
toluenesulfonic, cyclohexylaminosulfonic, P-hydroxybutyric, salicylic, galactaric and
galacturonic, and any combinations thereof.
The invention also provides at least one crystalline salt of l-(2,6-Bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl amino)methyl-propanol
(31) selected from the group consisting of:
(i) Crystalline hydrochloride salt (31a), with a XRPD spectrum as per ; XRPD
peaks as per ; and/or DSC spectrum as per ;
(ii) Crystalline bis-hydrochloride salt (31b), with a XRPD spectrum as per ;
XRPD peaks as per ; and/or DSC spectrum as per ;
(iii) Crystalline hydrogen malonate salt (31c), with a XRPD spectrum as per ;
XRPD peaks as per ; and/or DSC spectrum as per ;
(iv) Crystalline hydrogen maleinate salt Foi-m Male-A (31d-l), with a XRPD spectrum as
per ; XRPD peaks as per ; and/or DSC spectrum as per ;
(v) Crystalline hydrogen maleinate salt Form Male-B (31d-2), with a XRPD spectrum as
per ; XRPD peaks as per ; aad/or DSC spectrum as per ;
(vi) Crystalline hydrogen fumarate salt (31e), with a XRPD spectrum as per ;
XRPD peaks as per ; and/or DSC spectrum as per ;
(vii) Crystalline hydrogen L(+)tartrate salt (31f), with a XRPD spectrum as per ;
XRPD peaks as per ; DSC spectrum as per ;
(viii) Crystalline D,L-mandelate salt (31g), with a XRPD spectmm as per OA; XRPD
peaks as per OB; and/or DSC spectrum as per C;
(ix) Crystalline tosylate salt form Tos-A (31h-l), with a XRPD spectrum as per 1A;
XRPD peaks as per B; and/or DSC spectrum as per C;
(x) Crystalline tosylate salt form Tos-B (31h-2), with a XRPD spectrum as per A;
XRPD peaks as per B; and/or DSC spectrum as per C;
(xl) Ciystalline mesylate salt (31i), with a XRPD spectrum as per 3A; XRPD peaks
as per B; and/or DSC spectrum as per C;
(xii) Crystalline saccharinate salt (31 j), with a XRPD spectrum as per A; XRPD
peaks as per B; and/or DSC spectrum as per C;
and any mixtures thereof.
The invention further provides a pharmaceutical composition comprising at
least one compound of formula (I) and at least one pharmaceutically acceptable carrier or
excipient.
In certain embodiments, the pharmaceutical composition further comprises at
least one additional agent selected from the group consisting ofdoxapram, enantiomers of
doxapram, acetazolamide, almitrine, theophylline, caffeine, methylprogesterone and related
compounds, sedatives that increase arousal threshold in sleep disordered breathing patients,
benzodiazepine receptor agonists, orexin antagonists, tricyclic antidepressants, serotonergic
modulators, adenosine and adenosine receptor and nucleoside transporter modulators,
cannabinoids, orexins, melatonin agonists, ampakines, sodium oxybate, modafmil, and
armodafinil. In other embodiments, the compound and the additional agent are physically
mixed or physically separated in the composition. In yet other embodiments the
pharmaceutical composition comprises at least one additional agent that causes changes in
breathing control. In yet other embodiments, the additional agent is at least one selected from
the group consisting of opioid narcotics, benzodiazepines, sedatives, sleeping aids, hypnotics,
propofol, and any combinations thereof.
In certain embodiments, the pharmaceutical composition allows for modified
delivery of the compound following oral administration to a subject. In other embodiments,
the composition minimizes delivery of the compound to the stomach of the subject and
maximizes delivery of the compound to the intestine of the subject.
In certain embodiments, the composition includes an enteric coating. In other
embodiments, the compound is contained in a pharmaceutically suitable capsule. In other
embodiments, the capsule contains granules or powder of the compound, or an admixture of
the compound with the carrier or excipient. In yet other embodiments, the excipient
comprises a binder, disintegrant, diluent, buffer, lubricant, glidant, antioxidant, antimicrobial
preservative, colorant, or flavorant. In yet other embodiments, the capsule is enterically
coated but the granules or powders of the compound are not enterically coated. In yet other
embodiments, the granules or powders of the compound are coated with an enteric coating
before being placed into the capsule. In yet other embodiments, the granules or powders of
the compound are coated with a plurality of enteric coatings, as to provide delivery of drug to
different regions of the intestine of the subject. In yet other embodiments, at least a portion of
the granules or powders of the compound are enterically coated. In yet other embodiments,
the capsule is coated with an enteric coating that is different from the enteric coating that
coats the granules or powders of the compound.
In certain embodiments, the compound is coated onto a base particles so as to
form a core. In other embodiments the base particle is not enterically coated and the
composition is contained in a pharmaceutically acceptable capsule that is enterically coated.
In other embodiments, the core is coated with an enteric coating, thereby forming an
enterically coated bead. In yet other embodiments, the enterically coated bead is contained in
a pharmaceutically acceptable capsule. In yet other embodiments, the capsule contains beads
coated with a plurality ofenteric coatings, so that the capsule provides delivery of the
compound to different regions of the intestine of the subject. In yet other embodiments, the
contents of the capsule are dissolved or suspended in a pharmaceutically acceptable liquid as
to provide a liquid-filled capsule. In yet other embodiments, the capsule is enterically coated
but the liquid foi-mulate on contained within does not comprise an enteric coating.
The invention also provides a method of preventing or treating a breathing
control disorder or disease in a subject in need thereof, the method comprising administering
to the subject an effective amount of at least one compound of the invention or a salt, solvate,
enantiomer, diastereoisomer or tautomer thereof.
In certain embodiments, the breathing control disorder or disease is at least
one selected from the group consisting of respiratory depression, sleep apnea, apnea of
prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome,
dyspnea, altitude sickness, hypoxia, hypercapnia, chronic obstmctive pulmonary disease
(COPD), sudden infant death syndrome (SIDS), congenital central hypoventilation syndrome,
Alzheimer's disease, Parkinson's disease, stroke, Duchenne muscular dystrophy, and brain
and spinal cord traumatic injury. In other embodiments, the respiratory depression is caused
by an anesthetic, a sedative, a sleeping aid, an anxiolytic agent, a hypnotic agent, alcohol or a
narcotic.
In certain embodiments, the subject is further administered at least one agent
useful for treating the breathing disorder or diease. In other embodiments, the agent is at
least one selected from the group consisting of doxapram, acetazolamide, almitrine,
theophylline, caffeine, methylprogesterone and related compounds, sedatives that increase
arousal threshold in sleep disordered breathing patients, benzodiazepine receptor agonists,
orexin antagonists, tricyclic antidepressants, serotonergic modulators, adenosine and
adenosine receptor and nucleoside transporter modulators, cannabinoids, orexins, melatonin
agonists, ampakines, sodium oxybate, modafinil, and aiTnodafmil. In other embodiments, the
compound and the agent are separately administered to the subject. In yet other
embodiments, the compound and the agent are co-administered to the subject, further wherein
the compound and the agent are physically mixed or physically separated when administered
to the subject.
In certain embodiments, the subject is further administered at least one
additional thereapeutic agent that changes normal breathing control in the subject. In other
embodiments, the at least one additional agent is selected from the group consisting of opioid
narcotics, benzodiazepines, sedatives, sleeping aids, hypnotics, propofol, and any
combinations thereof.
In certain embodiments, the compound is administered in conjunction with the
use of a mechanical ventilation device or positive airway pressure device on the subject.
In certain embodiments, the subject is a mammal or bird. In other
embodiments, the mammal is a human.
In certain embodiments, the compound is administered to the subject by at
least one route selected from the group consisting ofnasal, inhalational, topical, oral, buccal,
rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdennal, epidural,
intrathecal and intravenous routes.
The invention also provides a method of preventing destabilization or
stabilizing breathing rhythm in a subject in need thereof, the method comprising
administering to the subject an effective amount of at least one pharmaceutically acceptable
carrier and at least one compound of the invention or a salt, solvate, enantiomer,
diastereoisomer or tautomer thereof.
In certain embodiments, the destabilization is associated with a breathing
control disorder or disease selected from the group consisting ofrespiratoiy depression, sleep
apnea, apnea ofprematurity, obesity-hypoventilation syndrome, primary alveolar
hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia, chronic
obstmctive pulmonary disease (COPD), sudden infant death syndrome (SIDS), congenital
central hypoventilation syndrome, Alzheimer's disease, Parkinson's disease, stroke,
Duchenne muscular dystrophy, and brain and spinal cord traumatic injury. In other
embodiments, the the respiratory depression is caused by an anesthetic, a sedative, a sleeping
aid, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic. In yet other embodiments,
the subject is farther administered at least one agent useful for treating the breathing disorder
or disease. In yet other embodiments, the agent is selected from the group consisting of
doxapram, acetazolamide, almitrine, theophylline, caffeine, methylprogesterone and related
compounds, sedatives that increase arousal threshold in sleep disordered breathing patients,
benzodiazepine receptor agonists, orexin antagonists, tricyclic antidepressants, serotonergic
modulators, adenosine and adenosine receptor and nucleoside transporter modulators,
cannabinoids, orexins, melatonin agonists, ampakines, sodium oxybate, modafinil, and
armodafinil. In other embodiments, the compound and the agent are separately administered
to the subject. In yet other embodiments, the compound and the agent are co-administered to
the subject, further wherein the compound and the agent are physically mixed or physically
separated when administered to the subject.
In certain embodiments, the subject is further administered at least one
additional thereapeutic agent that changes normal breathing control in the subject. In other
embodiments, the at least one additional agent is selected from the group consisting of opioid
narcotics, benzodiazepines, sedatives, sleeping aids, hypnotics, propofol, and any
combinations thereof.
In certain embodiments, the compound is administered in conjunction with the
use of a mechanical ventilation device or positive airway pressure device on the subject.
In certain embodiments, the subject is a mammal or bird. In other
embodiments, the mammal is a human.
In certain embodiments, the compound is administered to the subject by at
least one route selected from the group consisting ofnasal, inhalational, topical, oral, buccal,
rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural,
intrathecal and intravenous routes.
BRIEF DESCRIPTION OF THE DRAWINGS
For the purpose of illustrating the invention, there are depicted in the drawings
certain embodiments of the invention. However, the invention is not limited to the precise
arrangements and instrumentalities of the embodiments depicted in the drawings.
FIGs. 1A-1B are a set of tables summarizing results of a salt form and solvent
screen for 1 -(2,,6-bis-methylammopropylamino-pyrimido [5,4-d]pyrimidmylammo)
methyl-propanol (31) (pKa 2.32, 5.79).
illustrates non-limiting gram scale preparation conditions of selected
salts of 1 -(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (31), as well as differential scanning calorimetry and mass spectroscopy
data.
depicts an illustrative XRPD spectrum of 3 la (hydrochloride salt
form). depicts an illustrative XRPD peak list for 31a (hydrochloride salt foiTn).
depicts an illustrative DSC spectrum of31a (hydrochloride salt form).
depicts an illustrative XRPD of31b (bis-hydrochloride salt form).
depicts an illustrative XRPD peak list for 31b (bis-hydrochloride salt form). depicts an illustrative DSC spectrum for 31b (bis-hydrochloride salt form).
depicts an illustrative XRPD spectrum for 31c (hydrogen malonate
salt form). depicts an illustrative XRPD peak list for 31c (hydrogen malonate salt
form). depicts an illustrative DSC spectrum of31c (hydrogen malonate salt form).
depicts an illustrative XRPD spectrum of31d-l (hydrogen maleinate
salt form Mal-A). depicts an illustrative XRPD peak list of31d-l (hydrogen
maleinate form Mal-A). depicts an illustrative DSC spectrum of31d-l (hydrogen
maleinate salt form Mal-A).
depicts an illustrative XRPD spectrum of31d-2 (hydrogen maleinate
salt form Mal-B). depicts an illustrative XRPD peak list for 31d-2 (hydrogen
maleinate salt form Mal-B). depicts an illustrative DSC spectrum of31d-2
(hydrogen maleinate salt form Mal-B).
depicts an illustrative XRPD spectrum of 31c (hydrogen fumarate salt
form). depicts an illustrative XRPD peak list for 31e (hydrogen fumarate salt form).
depicts an illustrative DSC spectrum for 31e (hydrogen fumarate salt form).
depicts an illustrative XRPD spectmm for 31f(hydrogen-L(+)-
tartrate salt form). depicts an illustrative XRPD peak list for 31f (hydrogen-L(+)-
tartrate salt form). depicts an illustrative DSC spectrum for 31f (hydrogen-L(+)-
tartrate salt form).
A depicts an illustrative XRPD spectmm of31g (D,L-mandelate salt
form). OB depicts an illustrative XRPD Peak List for 31 g (D,L-mandelate salt form).
C depicts an illustrative DSC spectrum for 31g (D,L-mandelate salt form).
A depicts an illustrative XRPD spectrum for 31h-l (tosylate salt form
Tos-A). B depicts an illustrative XRPD peak list for 31h-l (tosylate salt form Tos-
A). C depicts an illustrative DSC spectrum for 31h-l (tosylate salt form Tos-A).
A depicts an illustrative XRPD spectmm for 31h-2 (tosylate salt form
Tos-B). B depicts an illustrative XRPD peak list for 31h-2 (tosylate salt form Tos-B).
C depicts an illustrative DSC spectrum for 31h-2 (tosylate salt form Tos-B).
A depicts an illustrative XRPD spectrum of31i (mesylate salt form).
B depicts an illustrative XRPD peak list 31i (mesylate salt form). C depicts
an illustrative DSC spectrum for 31i (mesylate salt form).
A depicts an illustrative XRPD spectrum for 31j (saccharinate salt
form). B depicts an illustrative XRPD peak list for 31j (saccharinate salt form). C depicts an illustrative DSC spectrum of31j (saccharinate salt form).
depicts a set of graphs illustrating that l-(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinyl amino)methyl-propanol hydrochloride salt
(3 la) reduces apnea-hypopnea index in morphine-tolerant rats (CSA model) without
significantly increasing minute volume.
FIGs. 16A-16C illustrate graphs of the % time spent in each sleep-wake state
(A: Awake, B: REM, C: NREM) during baseline (drug-naive) and
after oral gavage with vehicle and l-(2,6-bis-methylammopropylamino-pyrimido[5,4-
d]pyrimidinyl amino)methyl-propanol hydrochloride salt (31a) (10 mg/kg). Values
are means ± SEM.
FIGs. 17A-17B illustrate a set of graphs illustrating NREM and REM sleep
quality as assessed by measuring the absolute power density (|xV /0.25Hz) and relative power
density (% total power between 0.5 Hz to 30 Hz) during baseline (drug naive), vehicle, and 1-
(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmyl amino)methyl-
propanol hydrochloride salt (31a) (10 mg/kg PO) treatment. The first 2 hours after dosing
were not included in the post-dose measurements because of the strong gavage effect on time
spent asleep that was detected immediately after vehicle and administration of test article.
Values are means ± SEM.
depicts a graph illustrating the reduction of SpOz desaturations after
the administration of l-(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinyl
amino)methyl-propanol hydrochloride salt (3 la).
depicts a graph illustrating the reduction of frequency of obstructive
apneas (OA) after the administration of l-(2,6-bis-methylamiaopropylamino-
pyrimido[5,4-d]pyrimidinyl amino)methyl-propanol hydrochloride salt (31a).
depicts a graph illustrating the reduction of arterial oxygen content
deficit after the administration of l-(2,6-bis-methylammopropylamino-pyrimido[5,4-
d]pyrimidinyl ammo)methyl-propanol hydrochloride salt (31a).
A depicts a graph illustrating increases of airway (genioglossus, or
GG) responses in rats, to evoked obstructions after the administration of l-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl amino)methyl-propanol
hydrochloride salt (3 la). B depicts a graph illustrating insignificant increases of
diapraghm (DIA) responses, in the same rats, to evoked obstructions after the administration
of 1 -(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl amino)methyl-
propanol hydrochloride salt (31a). Red bar-Vehicle; Light blue bar-Middle dose (MD)
cmpd (31a) infusion involved administering 0.008 mg/kg/min for 15 minutes (loading phase)
followed by 0.002 mg/kg/min for 45 minutes (maintenance phase); Dark blue bar- High dose
(HD) cmpd (3 la) infusion entailed administering 0.024 mg/kg/min for 15 minutes (loading
phase) followed by 0.006 mg/kg/min for 45 minutes (maintenance phase).
depicts a graph illustrating the increase in the upper airway (total
genioglossus EMG amplitude) response to spontaneous obstructive apneas in rats after the
administration of 1 -(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl
amino)methyl-propanol hydrochloride salt (31a).
depicts a graph illustrating that l-(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinyl amino)methyl-propanol hydrochloride salt
(3 la) administered by IV infusion dose-dependently increases the upper airway response
(genioglossus activity) to spontaneous obstructive apneas in rats.
is a table illustrating that l-(2,6-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinyl amino)methyl-propanol hydrochloride salt (31a) (10
mg/kg PO) does not produce effects on sleep architecture in rats.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the discoveiy that the compounds of the
invention are orally bioavailable breathing control modulators and useful in the prevention or
treatment of breathing control disorders or diseases. Further, the compounds of the invention
are breathing control modulators suitable in the prevention or treatment of breathing control
disorders or diseases. In certain embodiments, the compounds are orally bioavailable.
In one aspect, the compounds of the invention prevent changes to the body's
normal breathing control system, as a result of disorders and diseases and in response to
changes in C02 and/or oxygen levels, with minimal side effects. In another aspect, the
compounds of the invention decrease the incidence and severity of breathing control
disturbances, such as apneas. In yet another aspect, the compounds of the invention decrease
the incidence ofapneic events and/or decrease the duration ofapneic events. In yet another
aspect, the compounds of the invention have good metabolic stability and oral bioavailability.
In yet another aspect, the compounds of the invention do not interfere with the effectiveness
of therapies that may cause changes to breathing control, such as opioid analgesia. Such
breathing control-altermg therapies benefit from administration of agents that support or
restore normal breathing function.
In certain embodiments, the breathing control disorder or disease is selected
from, but is not limited to, the group consisting of respiratory depression, sleep apnea, apnea
ofprematurity, obesity -hypoventilation syndrome, primary alveolar hypoventilation
syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia, chronic obstructive pulmonary
disease (COPD) and sudden infant death syndrome (SIDS). In other embodiments, the
respiratory depression is caused by an anesthetic, a sedative, a sleeping aid, an anxiolytic
agent, a hypnotic agent, alcohol or a narcotic. In yet other embodiments, the respiratory
depression is caused by genetic factors as manifested in, but not limited to, congenital central
hypoventilation syndrome. In yet other embodiments, the respiratory depression is caused by
neurological conditions such as, but not limited to, Alzheimer's disease, Parkinson's disease,
stroke, Duchenne muscular dystrophy, and brain and spinal cord traumatic injury.
Definitions
As used herein, each of the following terms has the meaning associated with it
in this section.
Unless defined otherwise, all technical and scientific terms used herein
generally have the same meaning as commonly understood by one of ordinary skill in the art
to which this invention belongs. Generally, the nomenclature used herein and the laboratory
procedures in animal pharmacology, pharmaceutical science, separation science and organic
chemistiy are those well-known and commonly employed in the art.
In a non-limiting embodiment, the following terminology used to report blood
gas measurements is well known to those skilled in the art and may be defined as such:
minute ventilation (MV) is a measure of breathing volume per unit time and is given herein
as mL/min; pC02 is partial pressure of carbon dioxide (gas) in (arterial) blood measured in
mm Hg (millimeters ofHg); p02 is partial pressure of oxygen (gas) in (arterial) blood
measured in mmHg (millimeters ofHg); Sa02 is the percentage of oxyhemoglobin saturation
(oxygen gas bound to hemoglobin) that correlates to the percentage ofhemoglobin binding
sites in the bloodstream occupied by oxygen; end-tidal COz is the measurement of exhaled
carbon dioxide gas as detected using calorimetry, capnometry, or capnography techniques.
As used herein, the articles "a" and "an" refer to one or to more than one (;. e.
to at least one) of the grammatical object of the article. By way of example, "an element"
means one element or more than one element.
As used herein, the term "about" is understood by persons of ordinary skill in
the art and varies to some extent on the context in which it is used. As used herein when
referring to a measurable value such as an amount, a temporal duration, and the like, the term
"about" is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even
more preferably ±1%, and still more preferably ±0.1% from the specified value, as such
variations are appropriate to perform the disclosed methods.
In one aspect, the terms "co-administered" and "co-administration" as relating
to a subject refer to administering to the subject a compound of the invention or salt thereof
along with a compound that may also treat breathing control disorders and/or with a
compound that is useful in treating other medical conditions but which in themselves may
alter breathing control. In certain embodiments, the co-administered compounds are
administered separately, or in any kind of combination as part of a single therapeutic
approach. The co-administered compound may be formulated in any kind of combinations as
mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a
solution.
As used herein, the term "CYP450" as applied to enzymes refers to
cytochrome P450 family of enzymes.
As used herein, a "disease" is a state of health of a subject wherein the subject
cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject's
health continues to deteriorate.
As used herein, a "disorder" in a subject is a state of health in which the
subject is able to maintain homeostasis, but in which the subject's state of health is less
favorable than it would be in the absence of the disorder. Left untreated, a disorder does not
necessarily cause a farther decrease in the subject's state of health.
As used herein, the term "EDso" refers to the effective dose of a formulation
that produces 50% of the maximal effect in subjects that are administered that formulation.
As used herein, an "effective amount," "therapeutically effective amount" or
"pharmaceutically effective amount" of a compound is that amount of compound that is
sufficient to provide a beneficial effect to the subject to which the compound is administered.
"Instructional material," as that term is used herein, includes a publication, a
recording, a diagram, or any other medium of expression that can be used to communicate the
usefulness of the composition and/or compound of the invention in a kit. The instructional
material of the kit may, for example, be affixed to a container that contains the compound
and/or composition of the invention or be shipped together with a container that contains the
compound and/or composition. Alternatively, the instructional material may be shipped
separately from the container with the intention that the recipient uses the instructional
material and the compound cooperatively. Delivery of the instructional material may be, for
example, by physical delivery of the publication or other medium of expression
communicating the usefulness of the kit, or may alternatively be achieved by electronic
transmission, for example by means of a computer, such as by electronic mail, or download
from a website.
As used herein, the term "pharmaceutical composition" or "composition"
refers to a mixture of at least one compound useful within the invention with a
pharmaceutically acceptable carrier. The pharmaceutical composition facilitates
administration of the compound to a subject.
As used herein, the term "pharmaceutically acceptable" refers to a material,
such as a carrier or diluent, which does not abrogate the biological activity or properties of
the compound useful within the invention, and is relatively non-toxic, ;". e., the material may
be administered to a subject without causing undesirable biological effects or interacting in a
deleterious manner with any of the components of the composition in which it is contained.
As used herein, the term "pharmaceutically acceptable carrier" means a
pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler,
stabilize!-, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or
encapsulating material, involved in carrying or transporting a compound useful within the
invention within or to the subject such that it may perform its intended function. Typically,
such constructs are carried or transported from one organ, or portion of the body, to another
organ, or portion of the body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation, including the compound useful
within the invention, and not injurious to the subject. Some examples of materials that may
serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and
sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as
sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;
malt; gelatin; tale; excipients, such as cocoa butter and suppositoiy waxes; oils, such as
peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;
glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and
polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such
as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer
solutions; and other non-toxic compatible substances employed in pharmaceutical
formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all
coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that
are compatible with the activity of the compound useful within the invention, and are
physiologically acceptable to the subject. Supplementary active compounds may also be
incorporated into the compositions. The "pharmaceutically acceptable carrier" may further
include a pharmaceutically acceptable salt of the compound useful within the invention.
Other additional ingredients that may be included in the pharmaceutical compositions used in
the practice of the invention are known in the art and described, for example in Remington's
Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is
incorporated herein by reference.
As used herein, the language "pharmaceutically acceptable salt" refers to a salt
of the administered compound prepared from pharmaceutically acceptable non-toxic acids
and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases,
solvates, hydrates, and clathrates thereof.
The term "prevent," "preventing" or "prevention," as used herein, means
avoiding or delaying the onset of symptoms associated with a disease or condition in a
subject that has not developed such symptoms at the time the administering of an agent or
compound commences. Disease, condition and disorder are used interchangeably herein.
By the term "specifically bind" or "specifically binds," as used herein,is
meant that a first molecule preferentially binds to a second molecule (e.g., a particular
receptor or enzyme), but does not necessarily bind only to that second molecule.
As used herein, a "subject" may be a human or non-human mammal or a bird.
Non-human mammals include, for example, livestock and pets, such as ovine, bovine,
porcine, canine, feline and murine mammals. Preferably, the subject is human.
The term "treat," "treating" or "treatment," as used herein, means reducing the
frequency or severity with which symptoms of a disease or condition are experienced by a
subject by virtue of administering an agent or compound to the subject.
As used herein, the term "alkyl," by itself or as part of another substituent
means, unless otherwise stated, a straight or branched chain hydrocarbon having the number
of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes
straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-buty\, pentyl, neopentyl, hexyl, and cyclopropylmethyl.
Most preferred is (Ci-C6)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl,
n-pentyl, n-hexyl and cyclopropylmethyl.
As used herein, the term "alkylene" by itself or as part of another substituent
means, unless otherwise stated, a straight or branched hydrocarbon group having the number
of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes
straight, branched chain, or cyclic substituent groups, wherein the group has two open
valencies. Examples include methylene, 1,2-ethylene, 1,1-ethylene, 1,1-propylene, 1,2-
propylene and 1,3-propylene.
As used herein, the term "cycloalkyl," by itself or as part of another
substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of
carbon atoms designated (i. e. , C3-C6 means a cyclic group comprising a ring group consisting
of three to six carbon atoms) and includes straight, branched chain or cyclic substituent
groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. Most preferred is (C3-C6)cycloalkyl, such as, but not limited to, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "alkenyl," employed alone or in combination with
other terms, means, unless otherwise stated, a stable mono-unsaturated or di-unsaturated
straight chain or branched chain hydrocarbon group having the stated number of carbon
atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-
pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. A functional group
representing an alkene is exemplified by -CH2-CH=CH2.
As used herein, the term "alkynyl," employed alone or in combination with
other terms, means, unless otherwise stated, a stable straight chain or branched chain
hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon
atoms. Non-limiting examples include ethynyl and propynyl, and the higher homologs and
isomers. The term "propargylic" refers to a group exemplified by -CH2-C^CH. The tenn
"homopropargylic" refers to a group exemplified by -CH2CH2-C=CH. The term "substituted
propargylic" refers to a group exemplified by -CR2-C=CR, wherein each occurrence of R is
independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that
at least one R group is not hydrogen. The term "substituted homopropargylic" refers to a
group exemplified by -CR2CR2-C=CR, wherein each occurrence of R is independently H,
alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R
group is not hydrogen.
As used herein, the term "substituted alkyl," "substituted cycloalkyl,"
"substituted alkenyl" or "substituted alkynyl" means alkyl, cycloalkyl, alkenyl or alkynyl, as
defined above, substituted by one, two or three substituents selected from the group
consisting ofhalogen, alkoxy, tetrahydroH-pyranyl, -NN2, -N(€N3)2, (1-methyl-imidazol-
2-yl), pyridinyl, pyridin-3 -yl, pyridinyl, -C(=0)OH, trifluoromethyl, -C=N, -
C(=0)0(Ci-C4)alkyl, -C(=0)NH2, -C(=0)NH(Ci-C4)alkyl, -C(=0)N((Ci-C4)alkyl)2, -
S02NH2, -C(=NH)NH2, and -N02, preferably containing one or two substituents selected
from halogen, -OH, alkoxy, -NHz, trifluoromethyl, -N(€N3)2, and -C(=0)OH, more
preferably selected from halogen, alkoxy and -OH. Examples of substituted alkyls include,
but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl. In
certain embodiments, the substituted alkyl is not substituted with a hydroxy group.
As used herein, the term "alkoxy" employed alone or in combination with
other terms means, unless otherwise stated, an alkyl group having the designated number of
carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom,
such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher
homologs and isomers. Preferred are (Ci-C3)alkoxy, such as, but not limited to, ethoxy and
methoxy.
As used herein, the term "halo" or "halogen" alone or as part of another
substituent means, unless otherwise stated, a fluorine, chlorme, bromine, or iodine atom,
preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
As used herein, the term "heteroalkyl" by itself or in combination with another
term means, unless otherwise stated, a stable straight or branched chain alkyl group
consisting of the stated number of carbon atoms and one or two heteroatoms selected from
the group consisting of 0, N, and S, and wherein the nitrogen and sulfur atoms may be
optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The
heteroatom(s) may be placed at any position of the heteroalkyl group, including between the
rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to
the most distal carbon atom in the heteroalkyl group. Examples include: -O-CHh-CHh-CHb, -
CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=0)-CH3. Up to
two heteroatoms may be consecutive, such as, for example, -CHh-NH-OCHs, or -CHh-CFh-S-
S-CHs.
As used herein, the term "heteroalkenyl" by itself or in combination with
another term means, unless otherwise stated, a stable straight or branched chain
monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of
carbon atoms and one or two heteroatoms selected from the group consisting of 0, N, and S,
and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen
heteroatom may optionally be quaternized. Up to two heteroatoms may be placed
consecutively. Examples include -CH=CHCH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -
CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.
As used herein, the term "aromatic" refers to a carbocycle or heterocycle with
one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2)
delocalized n (pi) electrons, where n is an integer.
As used herein, the term "aryl," employed alone or in combination with other
terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more
rings (typically one, two or three rings) wherein such rings may be attached together in a
pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include
phenyl, anthracyl, and naphthyl. Prefen-ed are phenyl and naphthyl, most prefen-ed is phenyl.
As used herein, the term "aryl-(Ci-C3)alkyl" means a functional group
wherein a one to three carbon alkylene chain is attached to an aryl group, e.g., -CHhCHh-
phenyl or -CHh-phenyl (benzyl). PrefeiTed is aryl-CH2- and aryl-CH(CH3)-. The term
"substituted aryl-(Ci-C3)alkyl" means an aryl-(Ci-C3)alkyl functional group in which the aryl
group is substituted. Preferred is substituted aryl(CH2)-. Similarly, the term "heteroaryl-(Ci-
C3)alkyl" means a functional group wherein a one to three carbon alkylene chain is attached
to aheteroaryl group, e.g.,-CH2CH2-pyridyl. Preferred is heteroaryl-(CH2)-. The term
"substituted heteroaryl-(Ci-C3)alkyl" means a heteroaryl-(Ci-C3)alkyl functional group in
which the heteroaryl group is substituted. Preferred is substituted heteroaryl-(CH2)-.
As used herein, the term "heterocycle" or "heterocyclyl" or "heterocyclic" by
itself or as part of another substituent means, unless otherwise stated, an unsubstituted or
substituted, stable, mono- or multi-cyclic heterocyclic ring system that consists of carbon
atoms and at least one heteroatom selected from the group consisting of N, 0, and S, and
wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen
atom may be optionally quatemized. The heterocyclic system may be attached, unless
otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A
heterocycle may be aromatic or non-aromatic in nature. In certain embodiments, the
heterocycle is a heteroaryl.
As used herein, the term "heteroaryl" or "heteroaromatic" refers to a
heterocycle having aromatic character. A polycyclic heteroaryl may include one or more
rings that are partially saturated. Examples include tetrahydroquinoline and
2,3-dihydrobenzofuryl.
Examples ofnon-aromatic heterocycles include monocyclic groups such as
aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline,
pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuraa,
thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,
morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-
dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-l,3-dioxepin and
hexamethyleneoxide.
Examples ofheteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such
as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl,
thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl,
tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
Examples ofpolycyclic heterocycles include indolyl (such as, but not limited
to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as,
but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl,
quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl,
1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl,
benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-
dihydrobenzofiiryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-
, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-
benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl,
carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.
The aforementioned listing ofheterocyclyl and heteroaryl moieties is intended
to be representative and not limiting.
As used herein, the term "substituted" means that an atom or group of atoms
has replaced hydrogen as the substituent attached to another group.
For aiyl, aryl-(Ci-C3)alkyl and heterocyclyl groups, the term "substituted" as
applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-,
tetra-, or penta-substitution, where such substitution is permitted. The substituents are
independently selected, and substitution may be at any chemically accessible position. In
certain embodiments, the substituents vary in number between one and four. In other
embodiments, the substituents vary in number between one and three. In yet other
embodiments, the substihients vary in number between one and two. In yet other
embodiments, the substituents are independently selected from the group consisting of C 1-6
alkyl, -OH, C 1-6 alkoxy, halo, amino, acetamido and nitro. As used herein, where a
substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic,
with straight being preferred.
The following abbreviations are used herein:
ABG: arterial blood gas; AcOH: acetic acid; ASV: adaptive servo ventilation; AUG: area
under (the) curve; BOP: (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate; BiPAP: bi-level positive airway pressure; nBuOH: n-butanol; C:
carbon atom or elemental carbon; C NMR: carbon-13 nuclear magnetic resonance; CHCls:
chloroform; CDCls: chloroform-d; CHhCb: dichloromethane or methylene dichloride;
CPAP: continuous positive airway pressure; CSA: central sleep apnea; DBU: 1,8-
diazabicyclo[5.4.0]undecene; DC1VI: dichloromethane or methylene dichloride; DIA:
diaphragm (muscle); DIPEA: N,N-diisopropylethylamine; DMAc: N,N-dimethylacetamide;
DMSO: dimethylsulfoxide; DMSO-d6: dimethylsulfoxide-d6; DSC: differential scanning
calorimetry; EPAP: expiratory positive airway pressure; EtOAc: ethyl acetate; EtOH:
ethanol; Et20: (di)ethyl ether; f: frequency (ofrespiration); F (%): bioavailability (percent);
FID: flame ionization detector; GG: genioglossus; H: hydrogen atom or elemental
hydrogen; HNMR: proton or hydrogen-1 nuclear magnetic resonance; HC1: hydrochloric
acid or a hydrochloride salt; HDPE: high-density polyethylene; hERG: human Ether-a-go-
go Related Gene (Kvl 1.1 ion channel); H2S04: sulfuric acid; HLM: human liver
microsomes; HPLC: high pressure liquid chromatography; ICU: intensive care unit; IPA:
isopropanol (or 2-propanol); IPAP: inspiratory positive airway pressure; kPa: kilopascal;
LCMS: liquid chromatography-mass spectrometry; LOQ: limit of quantification; m:
multiplet; MAP: mean arterial blood pressure; mbar: millibar (0.001 bar); MBP: mean
blood pressure; MTBE: methyl tert-butyi ether; MeCN or CHsCN: acetonitrile; MEK:
methyl ethyl ketone; MeOH or CHsOH: methanol; min: minute; mL (or ml): milliliter; MP:
melting point; mpk: mg/kg; MV: inute volume (synonymous with Va); ms: milli-secoad;
MS: mass spectrometry; N: nitrogen atom or elemental nitrogen; NaCl: sodium chloride;
NaHCOs: sodium bicarbonate; NaOH: sodium hydroxide; N02804: sodium sulfate; NAVA:
neurally adjusted ventilatory assist; NIPPV: non-iavasive positive pressure ventilation;
NMR: nuclear magnetic resonance; 0: oxygen atom or elemental oxygen; OA: obstructive
apnea; PA: propargylamine (propargylic amine); PAV: proportional assist ventilation; PE or
pet ether: petroleum ether; PEG: polyethylene glycol; PET: positron emission topography;
ppm: part per million; q: quartet; RLM: rat liver microsomes; RR: respiratory rate; rt:
room (ambient) temperature; s: singlet; Sp02: arterial oxygen saturation; std: standard; t:
triplet; THF: tetrahydrofuran; TV: tidal volume; UPLC: ultra performance liquid
chromatography; VE: minute (expired) volume (synonymous with MV); XRPD: x-ray
powder diffraction (spectrum); 5 (delta): delta (ppm); yL (p.1): microliter.
Throughout this disclosure, various aspects of the invention may be presented
in a range format. It should be understood that the description in range format is merely for
convenience and brevity and should not be construed as an inflexible limitation on the scope
of the invention. Accordingly, the description of a range should be considered to have
specifically disclosed all the possible sub-ranges as well as individual numerical values
within that range and, when appropriate, partial integers of the numerical values within
ranges. For example, description of a range such as from 1 to 6 should be considered to have
specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4,
from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1,
2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
Compounds and Compositions
The invention includes a compound of formula (I), or a salt, solvate,
enantiomer, diastereoisomer or tautomer thereof:
(I), wherein in (I):
one of the substituents selected from the group consisting ofY! and Y2 is selected from the
Rn Ru
m.OH
group consisting of-N(R1)-L-C(R9)(R10)OH, Rli Rlt , and
Rn R11
•^ AP ^OH
Rn Mq Rl
, and the other substituent is -N(R )R ;
Rl, R5 and R7 are independently selected from the group consisting of hydrogen and
optionally substituted Ci-Cs alkyl;
R2 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl,
phenylalkyl, aryl, aiylalkyl, heteroarylalkyl and heteroaryl, wherein the alkyl,
cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or
heteroaryl group is independently optionally substituted;
R6 and R8 are independently selected from the group consisting ofalkyl, cycloalkyl, alkenyl,
alkynyl, phenyl, phenylalkyl, aiyl, arylalkyl, heteroarylalkyl and heteroaryl,
wherein the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl,
heteroarylalkyl or heteroaryl group is independently optionally substituted;
R9 and R10 are independently selected from the group consisting of H and optionally
substituted Ci-Cs-alkyl; or R9 and R10 combine with the carbon atom to which they
are bound so as to form an optionally substituted C3-C6 cycloalkyl group;
each instance of R11 is independently selected from the group consisting of H and optionally
substituted Ci-Cs-alkyl; wherein a -C(RH)2-C(RH)2- group within ring b is optionally
replaced by an optionally substituted 1,2-phenylene group that is fused with ring b;
each occurrence of L is independently optionally substituted Ci-Cs alkylene;
m and n are independently selected from the group consisting of 1, 2, 3 and 4, such that 2<
m+n<4;
p and q are independently selected from the group consisting of 0, 1, 2, 3 and 4, such that 2<
p+q<4;
with the proviso that the alkyl group is not substituted with a hydroxy group.
In certain embodiments, the compound of formula (I) is the compound of
formula (IIa), or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof:
R6N-R5
R8lVTY2
R7 N^N
Y (Ha), wherein in (IIa):
one of the substituents selected from the group consisting of Y' and Y2 is -L-C(R9)(R )OH,
and and the other substituent is -N(R1)R ;
R1, R5 and R7 are independently selected from the group consisting of hydrogen and
optionally substituted Ci-Cs alkyl;
R2 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl,
phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl, wherein the alkyl,
cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or
heteroaryl group is independently optionally substituted;
R6 and R are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl,
alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl, wherein
the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl,
heteroarylalkyl or heteroaryl group is independently optionally substituted;
R9 and R are independently selected from the group consisting of hydrogen and optionally
substituted Ci-Cs-alkyl; or R9 and R10 combine with the carbon atom to which they
are bound so as to form an optionally substituted C3-C6 cycloalkyl group;
L is optionally substituted Ci-Cs alkylene; and
with the proviso that the alkyl group is not substituted with a hydroxy group.
In certain embodiments, the compound of formula (I) is the compound of
formula (lib), or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof:
(lib), wherein in (lib):
one of the substituents selected from the group consisting of Y1 and Y2 is R R ^
and the other substituent is -N(R1)R2;
R , R5 and R are independently selected from the group consisting of H and optionally
substituted Ci-Cs alkyl;
R2 is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, alkynyl, phenyl,
phenylalkyl, aryl, arylalkyl, heteroaiylalkyl and heteroaryl, wherein the alkyl,
cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or
heteroaryl group is independently optionally substituted;L is optionally substituted
Ci-Cs alkylene; and
R and R are independently selected from the group consisting ofalkyl, cycloalkyl, alkenyl,
alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl, wherein
the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl,
heteroarylalkyl or heteroaryl group is independently optionally substituted;
each instance of R11 is independently selected from the group consisting of hydrogen and
optionally substituted Ci-C3-alkyl;
L is optionally substituted Ci-Cs alkylene;
m and n are independently selected from the group consisting of 1, 2, 3 and 4, such that 2<
m+n<4;
with the proviso that the alkyl group is not substituted with a hydroxy group.
In certain embodiments, the compound of formula (I) is the compound of
formula (He), or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof:
(lie), wherein in (lie):
one of the substituents selected from the group consisting of Yl and Y is
R.n .Rn
JJ^ A ,OH
, and the other substituent is -N(R')R2;
R', R5 and R7 are independently selected from the group consisting of hydrogen and
optionally substituted Ci-Cs alkyl;
R is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, phenyl,
phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl, wherein the alkyl,
cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl or
heteroaryl group is independently optionally substituted;
R and R are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl,
alkynyl, phenyl, phenylalkyl, aryl, arylalkyl, heteroarylalkyl and heteroaryl,
wherein the alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, phenylalkyl, aryl, arylalkyl,
heteroarylalkyl or heteroaryl group is independently optionally substituted;
R9 and R10 are independently selected from the group consisting of H and optionally
substituted Ci-Cs-alkyl; or R and R10 combine with the carbon atom to which they
are bound so as to form an optionally substituted C3-C6 cycloalkyl group;
each instance of R is independently selected from the group consisting of H and optionally
substituted Ci-Cs-alkyl; wherein a -C(Rl )2-C(RU)2- group within ring b is optionally
replaced by an optionally substituted 1,2-phenylene group that is fused with ring b;
each occurrence of L is independently optionally substituted Ci-Cs alkylene;
p and q are s independently elected from the group consisting of 0, 1, 2, 3 and 4, such that 2<
p+q<4;
with the proviso that the alkyl group is not substitited with a hydroxy group.
In certain embodiments, each occurrence of the alkyl group is independently
optionally substituted with one or more independently selected from the group consisting of
Ci-C6 alkyl, F, Cl, Br, I, and CN.
In certain embodiments, each occurrence of the cycloalkyl, alkenyl or alkynyl
group is independently optionally substituted with one or more independently selected from
the group consisting ofCi-C6 alkyl, F, Cl, Br, I, and CN.
In certain embodiments, each occurrence of the phenyl, phenylalkyl, aryl,
arylalkyl, heteroarylalkyl or heteroaryl group is independently optionally substituted with one
or more independently selected from the group consisting ofCi-C6 alkyl, Ci-C6 alkoxy,
hydroxy, F, Cl, Br, I, nitro, -NN2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)( Ci-C6 alkyl), -S(=0)o-
2(Ci-C6 alkyl), -C(=0)OH and -C(=0)OCi-C6 alkyl.
In certain embodiments, Rl, R5 and R7 are H. In other embodiments, R\ R5
and R7 are H; and R6 and R8 are independently optionally substituted Ci-C6 alkyl. In yet
other embodiments, Rl, R5 and R7 are H; and R6 and R8 are independently optionally
substituted arylalkyl. In yet other embodiments, Rl, R5 and R7 are H; and R and R are
independently optionally substituted alkenyl. In yet other embodiments, R', R5 and R7 are H;
and R and R are independently optionally substituted alkynyl.
In certain embodiments, R , R and R7 are independently optionally
substituted Ci-Cs-alkyl. In other embodiments, R , R5 and R7 are independently optionally
substituted Ci-Cs-alkyl; and R6 and R are independently optionally substituted alkyl. In yet
other embodiments, R1, R5 and R7 are independently optionally substituted Ci-Cs-alkyl; and
R6 and R8 are independently optionally substituted arylalkyl. In yet other embodiments, R*,
R5 and R7 are independently optionally substituted Ci-Cs-alkyl; and R6 and R8 are
independently optionally substituted alkenyl. In yet other embodiments, Rl, R5 and R7 are
independently optionally substituted Ci-Cs-alkyl; and R6 and R are independently optionally
substituted alkynyl.
In certain embodiments, R1, R5 and R7 are H; and R9 and R10 are H. In other
embodiments, Rl, R5 and R7 are H; R9 and R10 are H; and R6 and R8 are independently
optionally substituted alkyl. In yet other embodiments, R*, R5 and R7 are H; R9 and R10 are
H; and R6 and R8 are independently optionally substituted arylalkyl. In yet other
embodiments, R', R5 and R7 are H; R9 and R10 are H; and R6 and R8 are independently
optionally substituted alkenyl. In yet other embodiments, R1, R5 and R7 are H; R9 and R10 are
H; and R6 and R8 are independently optionally substituted alkynyl.
In certain embodiments, R', R5 and R7 are H; and R9 and R10 are CHs. In
other embodiments, R1, R5 and R7 are H; R9 and R10 are CHs; and R6 and R8 are
independently optionally substituted alkyl. In yet other embodiments, R', R5 and R are H;
R9 and R10 are CHs; and R6 and R8 are independently optionally substituted arylalkyl. In yet
other embodiments, Rl, R5 and R7 are H; R9 and R10 are CHs; and R6 and R8 are
independently optionally substituted alkenyl. In yet other embodiments, R , R and R are H;
R9 and R10 are CHs; and R6 and R8 are independently optionally substituted alkynyl.
In certain embodiments, R\ R5 and R7 are H; R9 is H; and R10 is CHa. In other
embodiments, Rl, R5 and R7 are H; R9 is H; R10 is CHs; and R6 and R8 are independently
optionally substituted alkyl. In yet other embodiments, R!, R5 and R7 are H; R9 is H; R10 is
CHb; and R6 and R8 are independently optionally substituted arylalkyl. In yet other
embodiments, Rl, R5 and R7 are H; R9 is H; R10 is CHs; and R6 and R8 are independently
optionally substituted alkenyl. In yet other embodiments, Rl, R5 and R7 are H; R9 is H; R10 is
CHs; and R and R are independently optionally substituted alkynyl.
In certain embodiments, each occurrence of the alkyl group is independently
optionally substituted with one or more independently selected from the group consisting of
Ci-C6 alkyl, F, Cl, Br, I, and CN.
In certain embodiments, each occurrence of the cycloalkyl, alkenyl or alkynyl
group is independently optionally substituted with one or more independently selected from
the group consisting ofCi-C6 alkyl, F, Cl, Br, I, and CN.
In certain embodiments, each occurrence of the phenyl, phenylalkyl, aryl,
arylalkyl, heteroarylalkyl or heteroaryl group is independently optionally substituted with one
or more independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 alkoxy,
hydroxy, F, Cl, Br, I, nitro, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)( Ci-C6 alkyl), -S(=0)o-
2(Ci-C6 alkyl), -C(=0)OH and -C(=0)OCi-C6 alkyl.
In certain embodiments, R1 is selected from the group consisting of H, CHs
and propyl.
In certain embodiments, R is selected from the group consisting of CHs, ethyl,
CH2CHF2 and CHiCFs.
In certain embodiments, R5 is selected from the group consisting of H and
CHs.
In certain embodiments, R6 is selected from the group consisting of CH3,
ethyl, propyl, CHhCHF^ CH2CF3, CH2(cyclopropyl), sec-Bu, CH2(2-pyrimidine),
CHzCH-CHh and CH2C(CH3)=CH2.
In certain embodiments, R7 is selected from the group consisting of H and
CHs.
In certain embodiments, R is selected from the group consisting ofCHb,
ethyl, propyl, CH2CHF2, CH2CF3, CH2(cyclopropyl), sec-Bu, CH2(2-pyrimidine), benzyl,
CH2CH20CH3 and CH2C=CH.
In certain embodiments, R9 and R10 are independently selected from the group
consisting H, CHs, ethyl and CFs.
In certain embodiments, R11 is selected from the group consisting of H and a
fused pheaylene ring.
In certain embodiments, L is selected from the group consisting ofmethylene,
methyl substituted methylene, dimethyl substituted methylene and ethylene.
In certain embodiments, m and n are independently selected from the group
consisting of 1 and 2.
In certain embodiments, p and q are independently selected from the group
consisting of 0, 3 and 4.
In certain embodiments, Y is selected from the group consisting of
H H H H H | H
T T l' T l I T
^N^ ^N^CHF, ^N^CF3 ^N^^^ \N^OH \N^OH
555 9 ?
H CF.-i . .1; I H r" Me ] Me i Pr -3
\N—kOH ^NY^OH \N^OH \N-^OH \N-AOH \N-J~'OH
H OH H OH
^-6 ^
.of\N-
In certain embodiments, Y^ is selected from the group consisting of
H H Me Hi H i HCF
H H Me H| H | HCFs
\N-^OH \N—OH \N—OH \N-^OH \N'~-J<OH \N^'OH
J, I . J, . J, H < H < Me
^°"^Nr'°" \Y-OH\U-OH ^-^OH^OH
H OH
N^^ H OH OH
H OH \'
H OH :i T" 'tL ^\ ? ^N
,N^^ " ^ \N
Tj^vs^ <y"^
,0 \N-Y- -u. - k^. W. -<J.\N-~y „
\N^S)H
In certain embodiments, the compound of formula (I) is selected from the
group consisting of:
2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (4); 2-
[(2,6-Bis-methylaminopropylamiao-pyrimido[5,4-d]pyrimidinyl)-methyl-amino]-
ethanol (6); 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol (8); l-(2,6-Bis-methylammopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-propanol (10); (S)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)-propanol (12); (R)-l-(2,6-Bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-propanol (14); 2-(2,6-Bis-methylamino
propylammo-pyrimido[5,4-d]-pyrimidinylamino)methyl-propan-l-ol (16); (S)(2,6-
Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan-l-ol (18);
(R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan-
l-ol(20);
3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-l, 1,1-
trifluoro-propanol (22); 1 -(2,6-Bis-methylaminopropylammo-pyrimido[5,4-
d]pyrimidmylamino)-butanol (24); 3-(2,6-Bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylamino)-butanol (26); 2-(2,6-Bis-ethylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-ethanol (27); 2-[8-Propylamino-2,6-bis-(2,2,2-
trifluoro-ethylammo)-pyrimido[5,4-d]pyrimidinylamino]-ethanol (28); l-(2,6-Bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)methyl-propanol
(31); l-(2,6-Bis-ethylammopropylamino-pyrimido[5,4-d]-pyrimidinylammo)methyl-
propanol (32); l-[2,6-Bis-(2,2-difluoro-ethylamino)propylamino-pyrimido[5,4-d]-
pyrimidinylamino]methyl-propanol (33); 2-Methyl-l-[8-propylamino-2,6-bis-(2,2,2-
trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]-propanol (34);
l-[8-(2,2-difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylammo]-
2-methyl-propanol (36); l-{2,6-bis-methylamino[(pyrimidmylmethyl)-amino]-
pyrimido[5,4-d]pyrimidmylamino}methyl-propanol (38); l-[8-((R)-5ec-butylamino)-
2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylammo]methyl-propanol (40); 1 -[8-
((S)-5ec-butylammo)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]methyl-
propanol (42); 1 -(8-benzylammo-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)methyl-propanol (44); l-[8-(cyclopropylmethyl-amino)-2,6-bis-methylamino-
pyrimido[5,4-d]pyrimidinylammo]methyl-propanol (46); l-[8-(2,2-difluoro-
ethylamino)-2,6-bis-ethylamino-pyrimido[5,4-d]pyrimidinylamino]methyl-propanol
(47); 2-methyl-l-(2,6,8-tris-methylamino-pyrimido[5,4-d]-pyrimidmylamino)-propanol
(48); 2-methyl-l-(2,6,8-tris-ethylammo-pyrimido[5,4-d]-pyrimidinylamino)-propanol
(49); 2-(2,6,8-tris-methylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (52); 2-[8-
(cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
ethanol (54); 2-[8-(2-methoxy-ethylamino)-2,6-bis-methylammo-pyrimido[5,4-d]pyrimidin-
4-ylamino]-ethanol (56); 2-(2,6-bis-methylaminopropynylamino-pyrimido[5,4-
d]pyrimidinylamino)-ethanol (58); 2-[8-(2,2-difluoro-ethylamino)-2,6-bis-methylamino-
pyrimido[5,4-d]-pyrimidmylamino]-ethanol (60); 2-[2,6-bis-methylammo(2,2,2-
trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]-ethanol (62); 2-(8-benzylamino-
2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-ethanol (64); 3-(8-ethylamino-
2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylammo)-propan-l-ol (67); l-(2,6-bis-
methylammopropylammo-pyrimido[5,4-d]pyrimidinyl)-pyiTolidinol (71); 1 -[(2,6-
bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-methyl]-cyclobutanol
(72); l-[(2,6-bis-methylammopropylammo-pyrimido[5,4-d]-pyrimidinyl)-methyl-
amino]-propanol (73); 3-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin-
4-ylamino)-methyl]-pentanol (74); l-[(2,6-bis-methylaminopropylammo-pyrimido[5,4-
d]pyrimidinyl)-methyl-amino]methyl-propanol (76); (lR,2S)-l-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-indanol (77);
(lS,2S)-l-(2,6-bis-methylammopropylamiao-pyrimido[5,4-d]-pyrimidinylamino)-
indanol (78); (lS,2R)-l-(2,6-bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin-
4-ylammo)-indanol (79); (lR,2R)-l-(2,6-bis-methylaminopropylammo-pyrimido[5,4-
d]-pyrimidinylamino)-indanol (80); (2-(2,6-bis-methylaminopropylamino-
pyrimido[5,4-d]-pyrimidinylammo)-indan-l-ol (81); (lR,2S)(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol (82); (1 S,2S)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)-cyclohexanol (83);
(lS,2R)(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
cyclohexanol (84); (lR,2R)(2,6-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)-cyclohexanol (85); (lS,2S)(2,6-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-cyclopentanol (86); (lR,2R)(2,6-bis-methylamino-
8-propylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol (87); 2-[6-
(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
ethanol(90); 2-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (91); 2-(6-dimethylammo-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-ethanol (92); l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)methyl-propanol (94); l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-
d]-pyrimidinylamino)-propanol (95); 1 -[(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinyl)-methyl-amino]methyl-propanol (96); l-[(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-amino]-propanol
(97); l-[6-((R)-i'ec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidmylamino]-
2-methyl-propanol (99); (R)-l-[6-((R)-5ec-butylamino)-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinylamino]-propanol (100); (S)-l-[6-((R)-5ec-butylamino)-4,8-
bis-methylamino-pyrimido[5,4-d]pyrimidinylammo]-propanol (101); l-[6-((S)->s'ec-
butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]methyl-propan
ol (103); (R)-l -[6-((S)-5ec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-propanol (104); (S)-l-[6-((S)-^ec-butylamino)-4,8-bis-methylammo-
pyrimido[5,4-d]pyrimidiaylamino]-propanol (105); 1 -[6-(2,2-difluoro-ethylamino)-4,8-
bis-methylamino-pyrimido[5,4-d]pyrimidmylamino]methyl-propanol (107); 1-{4,8-
bis-methylamino [(pyrimidinylmethyl)-amino]-pyrimido [5,4-d]pyrimidinylammo}
methyl-propanol (109); 3-(4,8-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin-
2-ylamino)-l,l,l-trifluoro-propanol (111); (S)-l-(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-propanol(113); (R)-l-(4,8-bis-methylamino
propylammo-pyrimido[5,4-d]pyrimidinylamino)-propanol (115); l-(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (117); 3-(4,8-
Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (119);
(lR,2S)-l-(4,8-bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidinylammo)-
indanol (123); (1 S,2S)-l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]-
pyrimidmylamino)-indanol (125); (lS,2R)-l-(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]-pyrimidinylamino)-indanol (127); (lR,2R)-l-(4,8-bis-methylamino
propylammo-pyrimido[5,4-d]-pyrimidmylammo)-indanol (129); (lR,2S)(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol(131);
(lS,2S)(4,8-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidmylamino)-
cyclohexanol (133); (lS,2R)(4,8-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidmylamino)-cyclohexanol (135); (lR,2R)(4,8-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol (137); (1 S,2S)(4,8-bis-
methylamiaopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol (139);
(lR,2R)(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)-
cyclopentanol (141); (S)-1 -[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-
pyrimido[5,4-d]pynmidmylamino]-propanol (142); (S)-l-(6-allylammo-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidinylammo)-propanol (143); (R)-l-[6-
(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
propanol (144); (R)-l-(6-allylamino-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (145); 1 -[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinylammo]-butanol (146); 1 -(6-ethylamino-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (147); 2-methyl-l-(4,6,8-tris-
methylamino-pyrimido[5,4-d]pyrimidinylamino)-propanol (149); 2-(6-allylamino-4,8-
bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (154); (S)-l-[(6-allylamino-
4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinyl)-propyl-amino]-propanol (155); (S)-
l-[(6-allylammo-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-ammo]-
propanol (156); (R)-l-[6-(2-methyl-allylamino)-4,8-bis-methylammo-pyrimido[5,4-d]-
pyrimidmylamino]-propanol (158); (S)-l-[6-(2-methyl-allylamino)-4,8-bis-
methylammo-pyrimido[5,4-d]-pyrimidinylamino]-propanol (159); 2-(4,8-bis-
ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (162); 1 -(4,8-bis-
ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)methyl-propanol
(163); (S)-l-(4,6,8-Tris-ethylammo-pyrimido[5,4-d]pyrimidinylammo)-propanol (165);
(S)-l-(4,8-bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-propanol
(166); (R)-l-(4,6,8-tris-ethylammo-pyrimido[5,4-d]pyrimidmylamino)-propanol (168);
(R)-l-(4,8-bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-propanol
(169); (R)-l-[4,8-bis-ethylamino(2-methyl-allylamino)-pyrimido[5,4-d]-pyrimidm
ylamino]-propanol (174); (S)-l-[4,8-bis-ethylamino(2-methyl-allylammo)-
pyrimido[5,4-d]-pyrimidinylamino]-propanol (175); a salt, solvate, enantiomer,
diastereoisomer or tautomer thereof; and any combinations thereof.
In certain embodiments, the salt comprises an acid that is at least one selected
from the group consisting ofsulfuric, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,
phosphoric, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, mandelic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, pamoic, methanesulfonic,
ethanesulfonic, benzenesulfonic, pantothenic, sulfanilic, stearic, alginic, trifluoromethane
sulfonic, 2-hydroxyethanesulfonic, 7?-toluenesulfonic, cyclohexylaminosulfonic, ?-
hydroxybutyric, salicylic, galactaric, galacturonic, and saccharin, and any combinations
thereof.
In certain embodiments, the at least one compound of the invention is a
component of a pharmaceutical composition further including at least one pharmaceutically
acceptable carrier.
The compounds of the invention may possess one or more stereocenters, and
each stereocenter may exist independently in either the (R) or (S) configuration. In certain
embodiments, compounds described herein are present in optically active or racemic forms.
The compounds described herein encompass racemic, optically-active, regioisomeric and
stereoisomeric forms, or combinations thereof that possess the therapeutically useful
properties described herein. Preparation of optically active forms is achieved in any suitable
manner, including by way ofnon-limiting example, by resolution of the racemic form with
recrystallization techniques, synthesis from optically-active starting materials, chiral
synthesis, or chromatographic separation using a chiral stationary phase. In certain
embodiments, a mixture of one or more isomer is utilized as the therapeutic compound
described herein. In other embodiments, compounds described herein contain one or more
chiral centers. These compounds are prepared by any means, including stereoselective
synthesis, enantioselective synthesis and/or separation of a mixture ofenantiomers and/ or
diastereomers. Resolution of compounds and isomers thereof is achieved by any means
including, by way ofnon-limiting example, chemical processes, enzymatic processes,
fi-actional crystallization, distillation, and chromatography.
The methods and formulations described herein include the use ofN-oxides (if
appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases,
and/or pharmaceutically acceptable salts of compounds having the structure of any compound
of the invention, as well as metabolites and active metabolites of these compounds having the
same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyi
ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the
compounds described herein exist in solvated forms with pharmaceutically acceptable
solvents such as water, and ethanol. In other embodiments, the compounds described herein
exist in unsolvated form.
In certain embodiments, the compounds of the invention exist as tautomers.
All tautomers are included within the scope of the compounds recited herein.
In certain embodiments, compounds described herein are prepared as
prodrugs. A "prodrug" is an agent conveiled into the parent drug in vivo. In certain
embodiments, upon in vivo administration, a prodmg is chemically converted to the
biologically, pharmaceutically or therapeutically active form of the compound. In other
embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to
the biologically, pharmaceutically or thempeutically active form of the compound.
In certain embodiments, sites on, for example, the aromatic ring portion of
compounds of the invention are susceptible to various metabolic reactions. Incorporation of
appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate
this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or
eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example
only, a deuterium, a halogen, or an alkyl group.
Compounds described herein also include isotopically-labeled compounds
wherein one or more atoms is replaced by an atom having the same atomic number, but an
atomic mass or mass number different from the atomic mass or mass number usually found in
nature. Examples ofisotopes suitable for inclusion in the compounds described herein
include and are not limited to 2H, 3H, UC, 13C, 14C, 36C1,18F, 1231,125I, 13N, 15N, 150, 170,180,
P, and S. In certain embodiments, isotopically-labeled compounds are useful in drug
and/or substrate tissue distribution studies. In other embodiments, substitution with heavier
isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo
half-life or reduced dosage requirements). In yet other embodiments, substitution with
positron emitting isotopes, such as UC, F, 150 and N, is useful in Positron Emission
Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled
compounds are prepared by any suitable method or by processes using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
In certain embodiments, the compounds described herein are labeled by other
means, including, but not limited to, the use of chromophores or fluorescent moieties,
bioluminescent labels, or chemiluminescent labels.
Synthesis
The compounds described herein, and other related compounds having
different substituents are synthesized using techniques and materials described herein and as
described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Vol. 1-17 (John
Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vol. 1-5 and
Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Vol. 1-40 (John
Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey & Sundberg,
Advanced Organic Chemistry, 4th Ed., Vols. A and B (Plenum 2000,2001), and Green &
Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are
incorporated by reference for such disclosure). General methods for the preparation of
compound as described herein are modified by the use of appropriate reagents and conditions,
for the introduction of the various moieties found in the formula as provided herein.
Compounds described herein are synthesized using any suitable procedures
starting from compounds that are available from commercial sources, or are prepared using
procedures described herein. See, for example, Northen, et al., 2002, J. Chem. Soc., Perkin
Trans. 1, 108-115; DOI: 10.1039/B102224P.
In non-limiting examples, compounds of formula (I) may be prepared by the
additions of primary alkylamines to a chlorinated pyrimido-pyrimidine intennediate (A), in
which one alkylamine contains a pendant alcohol moiety (Schemes 1-3). The aminoalkanol
can be added at various stages; for example reacted directly with tetrachloro-pyrimido[5,4-
d]pyrimidine (A; Scheme 2) or alternatively, added to a mono-alkylammo-trichloro-
pyrimido[5,4-d]pyrimidine (B; Scheme 1) or alternatively, added to a bis-alkylamino-
dichloro-pyrimido[5,4-d]pyrimidine (F; Scheme 3).
Analogs were also prepared following the general synthetic scheme in which
first an amine is added to tetrachloro-pyrimido[5,4-d]pyrimidine (i); secondly an alcohol is
added to the resultant alkylamino-trichloro-pyrimido[5,4-d]pyrimidme (ii); and lastly, an
amine undergoes bis-addition upon reaction with alkyl-amino-dichloro-pyrimido[5,4-
d]pyrimidinyl-alkanol (iii) (Scheme 4).
R8rH
R3N-L^
N.'^N
N.^N
s ^OH
R8,A^yCi
R7 N^N
N ^RW
Cl B
RVRS
RA^-H
Ni's
RA and RB =
R1 and R2, or
NI%'^'° <1,
R^R^ ^" (1)
R5and R6
Scheme 1.
R3.,.L
N.^N R3
N^N R3
CI^N.
H R9
^L/^. ^N.
N-^CI
R7 N^N ^
Y" R9^R1°
Y ^•1
RA-N-H
N.^N R3
RA and RB = R8N^SrS
R1 and R2, or
NvN R94-.Ri°
R5 and R6
Rl%.
Scheme 2.
R°-N-H RVH
N.^N R3
C'YN-
~N R7
^^\ ^N.
N^CI
R/ N^^N
R6.,/R5
>3 | o10
RYL^°
N.^N R3
R'^YYN~R4
R7 N^N
Scheme 3
N.^N
HgN—R HzN—L—OH
DIPEA
-78°C
R'\.
N"~^N
NHz-R'
[<^N
fsAiArNH-L-OH
R"N^^V OH
n-BuOH
115°C
sealed vial
Scheme 4
In certain embodiments, reactive functional groups, such as hydroxyl, amino,
imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in
reactions. Protecting groups are used to block some or all of the reactive moieties and
prevent such groups from participating in chemical reactions until the protective group is
removed. In other embodiments, each protective group is removable by a different means.
Protective groups that are cleaved under totally disparate reaction conditions fulfill the
requirement of differential removal.
In certain embodiments, protective groups are removed by acid, base, reducing
conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such
as trityl, dimethoxytrityl, acetal and ^7^-butyldimethylsilyl are acid labile and are used to
protect carboxy and hydroxy reactive moieties in the presence ofamino groups protected
with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base
labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups
such as, but not limited to, methyl, ethyl, and acetyl, in the presence ofamines that are
blocked with acid labile groups, such as /er/-butyl carbamate, or with carbamates that are
both acid and base stable but hydrolytically removable.
In certain embodiments, carboxylic acid and hydroxy reactive moieties are
blocked with hydrolytically removable protective groups such as the benzyl group, while
amine groups capable of hydrogen bonding with acids are blocked with base labile groups
such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester
compounds as exemplified herein, which include conversion to alkyl esters, or are blocked
with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-
existing amino groups are blocked with fluoride labile silyl carbamates.
Allyl blocking groups are useful in the presence of acid- and base- protecting
groups since the former are stable and are subsequently removed by metal or pi-acid
catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-
catalyzed reaction in the presence of acid labile tert-butyl carbamate or base-labile acetate
amine protecting groups. Yet another form of protecting group is a resin to which a
compound or intermediate is attached. As long as the residue is attached to the resin, that
functional group is blocked and does not react. Once released from the resin, the functional
group is available to react.
Typically blockmg/protectmg groups may be selected from:
H3C>'
1-CH3
HsC^l
13U CH? 0
methyl
ethyl allyl
acetyl
trimethylsilylethoxycarbonyl allyloxycarbonyl
(TEOC) (AIIOC)
CH-,
-CH.
^-SI-t-Bu
-CH3
CH, '0
tert-butyl
tert-butyldimethylsilyl
tert-butyloxycarbonyl
(t-Bu)
(TBDMSi) (BOC)
trityl
O-CHs
K '0
benzyl para-methoxybenzyl
carboxybenzyl
fluorenylmethyloxycarbonyl
(Bn) (PMB) (Cbz)
(FMOC)
Other protecting groups, plus a detailed description of techniques applicable to
the creation of protecting groups and their removal are described in Greene & Wuts,
Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999,
and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are
incorporated herein by reference for such disclosure.
The compounds of the invention may be prepared according to the general
methodology illustrated in the synthetic schemes described above. The reagents and
conditions described herein may be modified to allow the preparation of the compounds of
the invention, and such modifications are known to those skilled in the art. The schemes
included herein are intended to illustrate but not limit the chemistry and methodologies that
one skilled in the art may use to make compounds of the invention.
Salts
The compounds described herein may form salts with acids and/or bases, and
such salts are included in the present invention. In certain embodiments, the salts are
pharmaceutically acceptable salts. The term "salts" embraces addition salts of free acids
and/or bases that are useful within the methods of the invention. The term "pharmaceutically
acceptable salt" refers to salts that possess toxicity profiles within a range that affords utility
in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess
properties such as high crystallinity, which have utility in the practice of the present
invention, such as for example utility in process of synthesis, purification or formulation of
compounds useful within the methods of the invention.
Suitable pharmaceutically acceptable acid addition salts may be prepared from
an inorganic acid or from an organic acid. Examples ofinorganic acids include sulfate,
hydrogen sulfate, hemisulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic,
sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic,
araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which
include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric,
ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-
hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,
ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-
hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,
alginic, p-hydroxybutyric, salicylic, galactaric, galacturonic acid, glycerophosphonic acids
and saccharin (e.g., saccharinate, saccharate). Salts may be comprised of a fraction of one,
one or more than one molar equivalent of acid or base with respect to any compound of the
invention.
Suitable pharmaceutically acceptable base addition salts of compounds of the
invention include, for example, metallic salts including alkali metal, alkaline earth metal and
transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc
salts. Pharmaceutically acceptable base addition salts also include organic salts made from
basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, cho line,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of
these salts may be prepared from the corresponding compound by reacting, for example, the
appropriate acid or base with the compound.
Acid addition salts are generally formed by combining the target freebase with
a salt former in a solvent, forming a solution, and collecting the salt as a solid. The molar
ratio of salt former to free base may vary (e.g., 1:1,2:1,1:2, etc.). A ratio of 1:1 may be
preferred. Solvents may include, but are not limited to methyl ethyl ketone, methyl isobutyl
ketone, ethyl acetate, isopropyl acetate, water, heptane, methyl tert-butyl ether, cyclohexane,
toluene, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isoamyl alcohol,
tetrahydrofuran and acetonitrile, and mixtures thereof. Mixtures of the freebase and salt
former in a solvent may from a clear solution at temperatures ranging from about room
temperature to the reflux temperature of the solvent or mixture of solvents being used to
prepare the salt. Solid salts may be formed by concentrating the dissolved mixture of salt
former and free base, or by allowing the mixture to stand or stir for a period of time,
optionally including the cooling of the mixture to a temperature lower than that at which the
solution of free base and salt former was initially prepared. Isolated, solid salts may be
characterized for stoichiometiy using titration, elemental analysis and/or 1H NMR, and for
crystallinity using DSC and XRPD and other methodologies known within the art.
In certain embodiments, the salts of the invention are crystalline. In other
embodiments, the salts of the invention are non-crystalline or amorphous. In yet other
embodiment, a crystalline salt of l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinyl amino)methyl-propanol (31) is at least one selected from the group
consisting of:
(i) Crystalline hydrochloride salt (31a), with a XRPD spectrum as per , XRPD
peaks as per , and/or DSC (differential scanning calorimetry) spectrum per
;
(ii) Ciystalline bis-hydrochloride salt (31b), with a XRPD spectrum as per ,
XRPD peaks as per , and/or DSC spectrum per ;
(iii) Crystalline hydrogen malonate salt (31c), with a XRPD spectrum as per ,
XRPD peaks as per , and/or DSC spectrum per ;
(iv) Crystalline hydrogen maleinate salt form Mal-A (31d-l), with a XRPD spectrum as
per , XRPD peaks as per , and/or DSC spectrum per ;
(v) Crystalline hydrogen maleinate salt Form Mal-B (31d-2), with a XRPD spectrum as
per , XRPD peaks as per , and/or DSC spectrum per ;
(vi) Crystalline hydrogen fumarate salt (31e), with a XRPD spectmm as per ,
XRPD peaks as per , and/or DSC spectrum per ;
(vii) Crystalline hydrogen L(+)-tartrate salt (31f), with a XRPD spectrum as per ,
XRPD peaks as per , and/or DSC spectrum per ;
(viii) Crystalline D,L-mandelate salt (31g), with a XRPD spectmm as per OA, XRPD
peaks as per OB, and/or DSC spectrum per C;
(ix) Crystalline tosylate salt form Tos-A (31h-l), with a XRPD spectrum as per 1A,
XRPD peaks as per B, and/or DSC spectrum per C;
(x) Crystalline tosylate salt form Tos-B (31h-2), with a XRPD spectrum as per A,
XRPD peaks as per B, and/or DSC spectrum per C;
(xi) Crystalline mesylate salt (31i), with a XRPD spectrum as per A, XRPD peaks
as per B, and/or DSC spectrum per C;
(xii) Crystalline saccharinate salt (31j), with a XRPD spectmm as per A, XRPD
peaks as per B, and/or DSC spectrum per C;
and any mixtures thereof.
Combination and Concurrent Therapies
In certain embodiments, the compounds of the invention are useful in the
methods of present invention when used concurrently with at least one additional compound
useful for preventing and/or treating breathing control disorders. In certain embodiments, the
compounds of the invention are useful in the methods of present invention in combination
with at least one additional compound useful for preventing and/or treating breathing control
disorders.
These additional compounds may comprise compounds of the present
invention or other compounds, such as commercially available compounds, known to treat,
prevent, or reduce the symptoms of breathing disorders. In certain embodiments, the
combination of at least one compound of the invention, or a salt, solvate, enantiomer,
diastereoisomer or tautomer thereof, and at least one additional compound useful for
preventing and/or treating breathing disorders has additive, complementary or synergistic
effects in the prevention and/or treatment of disordered breathing, and in the prevention
and/or treatment of sleep-related breathing disorders.
In a non-limiting example, the compounds of the invention or a salt thereof
may be used concurrently or in combination with one or more of the following drugs:
doxapram, enantiomers ofdoxapram, acetazolamide, almitrine, theophylline, caffeine,
methylprogesterone and related compounds, sedatives that increase arousal threshold in sleep
disordered breathing patients (such as eszopiclone and zolpidem), benzodiazepine receptor
agonists {e.g., zolpidem, zaleplon, estazolam, flurazepam, quazepam, temazepam, triazolam)
orexin antagonists (e.g., suvorexant), tricyclic antidepressants (e.g., doxepin), serotonergic
modulators, adenosine and adenosine receptor and nucleoside transporter modulators,
cannabinoids (such as, but not limited to, dronabinol), orexins, melatonin agonists (such as
ramelteon), compounds known as ampakines, sodium oxybate, modafinil, and armodafinil.
In a non-limiting example, the compounds of the invention or a salt thereof
may be used concurrently or in combination with inhaled therapeutics such as oxygen and
carbon dioxide as for the treatment of sleep disordered breathing.
Non-limiting examples ofampakines are the pyn-olidine derivative racetam
drugs such as piracetam and aniracetam; the "CX-" series of dmgs which encompass a range
ofbenzoylpiperidine and benzoylpyrrolidine structures, such as CX-516 (6-(piperidin-l-yl-
carbonyl)quinoxaline), CX-546 (2,3-dihydro-1,4-benzodioxinyl-(l -piperidyl)-methanone),
CX-614(2H,3H,6aH-pyrrolidmo(2,l-3\2')-l,3-oxazino-(6',5'-5,4)benzo(e)l,4-dioxan
one), CX-691 (2,l,3-benzoxadiazolyl-piperidin-l-yl-methanone), CX-717, CX-701, CX-
1739, CX-1763, and CX-1837; benzothiazide derivatives such as cyclothiazide and IDRA-21
(7-chloro-3 -methyl-3,4-dihydro-2H-1 ,2,4-benzothiadiazine 1,1 -dioxide);
biarylpropylsulfonamides such as LY-392,098, LY-404,187 (N-[2-(4'-cyanobiphenyl
yl)propyl]propanesulfonamide), LY-451,646 and LY-503,430 (4'-{(lS)-l-fluoro
[(isopropylsulfonyl)amino]-l-methylethyl}-N-methylbiphenylcarboxamide).
In one embodiment, the invention includes a composition comprising a
compound of the invention and at least one agent selected from the group consisting of
doxapram, enantiomers of doxapram, enantiomers of doxapram, acetazolamide, almitrine,
theophylline, caffeine, methylprogesterone and related compounds, sedatives that increase
arousal threshold in sleep disordered breathing patients (such as eszopiclone or zolpidem),
benzodiazepine receptor agonists (such as zolpidem, zaleplon, estazolam, flurazepam,
quazepam, temazepam, or triazolam), orexin antagonists (e.g. suvorexant), tricyclic
antidepressants (such as doxepin), serotonergic modulators, adenosine and adenosine receptor
and nucleoside transporter modulators, carmabinoids (such as but not limited to dronabinol),
orexins, melatonin agonists (such as ramelteon), compounds known as ampakines, sodium
oxybate, modafinil, armodafinil, and inhaled therapeutics such as oxygen and carbon dioxide
gases.
In another non-limiting example, the compounds of the invention, or a salt,
solvate, enantiomer, diastereoisomer or tautomer thereof, may be used concurrently or in
combination with one or more of the following drugs and drug classes known to cause
changes in breathing control: opioid narcotics (such as morphine, fentanyl, codeine,
hydromorphone, hydrocodone, oxymoi-phone, oxycodone, meperidine, butorphanol,
carfentanil, buprenorphine, methadone, nalbuphine, propoxyphene, pentazocine, remifentanil,
alfentanil, sufentanil and tapentadol); benzodiazepines (such as midazolam); and sedatives
(such as zolipidem and eszopiclone); sodium oxybate and propofol. In certain embodiments,
the invention includes a composition comprising a compound of the invention and at least
one agent known to cause changes in breathing control. In certain embodiments, the at least
one agent is selected from the group consisting ofopioid narcotics, benzodiazepines,
sedatives, sleeping aids and propofol.
In another non-limiting example, the compounds of the invention, or a salt,
solvate, enantiomer, diastereoisomer or tautomer thereof, may be used concurrently or in
combination with one or more of the following drugs and drug classes known to either aid the
onset of sleep, maintain sleep and/or alter arousal threshold: zolipidem, zaleplon,
eszopiclone, ramelteon, estazolam, temazepam, doxepin, sodium oxybate, phenobarbital and
other barbiturates, diphenhydramine, doxylamine and related compounds, for example. The
combination of a sleep promoting/stabilizing drug and the compounds of the invention may
act additively or synergistically to improve indices of sleep disordered breathing. In certain
embodiments, the compounds of the invention stabilize respiratory pattern (i.e., decrease
variation in respiratory rate and tidal volume on a breath-by-breath basis) and respiratory
drive (i.e., decrease fluctuations in the neural control of the respiratory muscles), thereby
decreasing the incidence of central and obstructive apneas whilst the sleep
promoting/stabilizing drug prevents patient arousal from sleep if residual apneas persist.
Blood gas derangements associated with a residual apnea may elicit chemoreceptor
stimulation, which in turn elicits generalized central nervous system arousal. Patients with a
low arousal threshold from sleep wake early and often (i.e., experience sleep fragmentation)
and these patients experience a ventilatory overshoot due to the sudden awakening in excess
of the level of chemoreceptor stimulation. Sleep promoting/stabilizing drugs delay cortical
arousal and permit a more appropriate ventilatory response to apnea-induced chemoreceptor
stimulation. The patient benefits from delayed arousal from sleep because sleep
fragmentation decreases and hyperventilation-driven central apneas decrease.
As used herein, combination of two or more compounds may refer to a
composition wherein the individual compounds are physically mixed or wherein the
individual compounds are physically separated. A combination therapy encompasses
administering the components separately to produce the desired additive, complementary or
synergistic effects.
In certain embodiments, the compound and the agent are physically mixed in
the composition. In other embodiments, the compound and the agent are physically separated
in the composition.
In certain embodiments, the compound of the invention is co-administered
with a compound that is used to treat another disorders but incidentally causes loss or
depression of breathing control. In this aspect, the compound of the invention blocks or
otherwise reduces depressive effects on normal breathing control caused by the compound
with which they are co-administered. Such compound that treats another disorder but
depresses breathing control includes but is not limited to anesthetics, sedatives, sleeping aids,
anxiolytics, hypnotics, alcohol, and narcotic analgesics. The co-administered compound may
be administered individually, or a combined composition as a mixture of solids and/or liquids
in a solid, gel or liquid formulation or as a solution, according to methods known to those
familiar with the art.
In certain embodiments, a compound of the present invention is co-
administered with at least one additional compound useful for treating breathing control
disorders and with at least one compound that is used to treat other disorder but causes a loss
of breathing control. In this aspect, the compound of the invention works in an additive,
complementary or synergistic manner with the co-administered breathing control agent to
block or otherwise reduce depressive effects on normal breathing control caused by other
compounds with which they are combined. A synergistic effect may be calculated, for
example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford &
Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation ofLoewe additivity (Loewe
& Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326), the median-effect equation
(Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55), and through the use of
isobolograms (Tallarida & Raffa, 1996, Life Sci. 58: 23-28). Each equation referred to above
may be applied to experimental data to generate a corresponding graph to aid in assessing the
effects of the dmg combination. The corresponding graphs associated with the equations
referred to above are the concentration-effect curve, isobologram curve and combination
index curve, respectively.
In certain embodiments, a compound of the present invention may be
packaged with at least one additional compound useful for treating breathing control
disorders. In other embodiments, a compound of the present invention may be packaged with
a therapeutic agent known to cause changes in breathing control, such as, but not limited to,
anesthetics, sedatives, anxiolytics, hypnotics, alcohol, and narcotic analgesics. A co-package
may be based upon, but not limited to, dosage units.
Methods
In one aspect, the present invention includes a method of preventing or
treating a breathing control disorder or disease in a subject in need thereof. The method
includes administering to the subject an effective amount of at least one compound of the
invention or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof, which is
optionally part of a pharmaceutical formulation further comprising at least a pharmaceutically
acceptable carrier.
In another aspect, the present invention includes a method of preventing
destabilization of or stabilizing breathing rhythm in a subject in need thereof. The method
includes administering to the subject an effective amount of at least one compound of the
invention or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof, which is
optionally part of a pharmaceutical formulation further comprising at least a pharmaceutically
acceptable carrier.
In certain embodiments, administering the formulation of the invention
stabilizes the breathing rhythm of the subject. In other embodiments, administering the
formulation of the invention increases minute ventilation in the subject.
In certain embodiments, the destabilization is associated with a breathing
control disorder or disease.
In certain embodiments, the breathing disorder or disease is selected from the
group consisting ofnarcotic-induced respiratory depression, anesthetic-induced respiratory
depression, sedative-induced respiratory depression, sleeping aid-induced respiratory
depression, anxiolytic-induced respiratory depression, hypnotic-induced respiratory
depression, alcohol-induced respiratory depression, analgesic-induced respiratory depression,
sleep apnea (includes but not limited to mixed central, obstructive, anatomical), apnea of
prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome,
dyspnea, altitude sickness, hypoxia, hypercapnia, chronic obstmctive pulmonary disease
(COPD), sudden infant death syndrome (SIDS), Alzheimer's disease, Parkinson's disease,
stroke, Duchenne muscular dystrophy, and brain and spinal cord traumatic injury. In other
embodiments, the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic
agent, a hypnotic agent, alcohol or a narcotic. In yet other embodiments, the compounds of
the invention or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof may be used
concurrently or in combination with one or more of the following drugs and drug classes
known to either aid the onset of sleep, maintain sleep and/or alter arousal threshold:
zolipidem, zaleplon, eszopiclone, ramelteon, estazolam, temazepam, sodium oxybate,
doxepin, phenobarbital and other barbiturates, diphenhydramine, doxylamine and related
compounds for example.
In certain embodiments, the subject is further administered at least one
additional compound useful for preventing or treating the breathing disorder or disease. In
other embodiments, the at least one additional compound is selected from the group
consisting of doxapram, enantiomers of doxapram, acetazolamide, almitrine, theophylline,
caffeine, methylprogesterone and related compounds, sedatives such as eszopiclone and
zolpidem, sodium oxybate, benzodiazepine receptor agonists (e.g. zolpidem, zaleplon,
eszopiclone, estazolam, flurazepam, quazepam, temazepam, triazolam), orexin antagonists
(e.g. suvorexant), tricyclic antidepressants (e.f. doxepin), serotonergic modulators, adenosine
and adenosine receptor and nucleoside transporter modulators, cannabinoids (such as but not
limited to dronabinol), orexins, melatonin agonists (such as ramelteon) and compounds
known as ampakines.
In yet other embodiments, the formulation is administered to the subject in
conjunction with the use of a mechanical ventilation device or positive airway pressure
device. In certain embodiments, the formulation is administered to the subject by an
inhalational, topical, oral, nasal, buccal, rectal, pleural, peritoneal, vaginal, intramuscular,
subcutaneous, transdermal, epidural, intrathecal or intravenous route. In other embodiments,
the subject is a bird or a mammal including but not limited to mouse, rat, ferret, guinea pig,
non-human primate (such as monkey), dog, cat, horse, cow, pig and other farm animals. In
certain embodiments, the subject is a human.
Pharmaceutical Compositions and Formulations
The invention also encompasses the use of pharmaceutical compositions of at
least one compound of the invention or a salt, solvate, enantiomer, diastereoisomer or
tautomer thereof to practice the methods of the invention. Such a pharmaceutical
composition may consist of at least one compound of the invention or a salt, solvate,
enantiomer, diastereoisomer or tautomer thereof, in a form suitable for administration to a
subject, or the pharmaceutical composition may comprise at least one compound of the
invention or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof, and one or more
pharmaceutically acceptable carriers, one or more additional ingredients, or some
combination of these. The at least one compound of the invention may be present in the
pharmaceutical composition in the form of a physiologically acceptable salt, such as in
combination with a physiologically acceptable cation or anion, as is well known in the art.
In an embodiment, the pharmaceutical compositions useful for practicing the
method of the invention may be administered to deliver a dose of between 1 ng/kg/day and
100 mg/kg/day. In other embodiments, the pharmaceutical compositions useful for practicing
the invention may be administered to deliver a dose of between 1 ng/kg/day and 1,000
mg/kg/day.
The relative amounts of the active ingredient, the pharmaceutically acceptable
carrier, and any additional ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and condition of the subject treated and further
depending upon the route by which the composition is to be administered. By way of
example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.
Pharmaceutical compositions that are useful in the methods of the invention
may be suitably developed for nasal, inhalational, oral, rectal, vaginal, pleural, peritoneal,
parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, epidural,
intrathecal, intravenous or another route of administration. A composition useful within the
methods of the invention may be directly administered to the brain, the brainstem, or any
other part of the central nervous system of a mammal or bird. Other contemplated
formulations include projected nanoparticles, microspheres, liposomal preparations, coated
particles, polymer conjugates, resealed erythrocytes containing the active ingredient, and
immunologically-based formulations.
In certain embodiments, the compositions of the invention are part of a
pharmaceutical matrix, which allows for manipulation of insoluble materials and
improvement of the bioavailability thereof, development of controlled or sustained release
products, and generation of homogeneous compositions. By way of example, a
pharmaceutical matrix may be prepared using hot melt extrusion, solid solutions, solid
dispersions, size reduction technologies, molecular complexes (e.g. cyclodextrins, and
others), microparticulate, and particle and formulation coating processes. Amorphous or
crystalline phases may be used in such processes.
The route(s) of administration will be readily apparent to the skilled artisan
and will depend upon any number of factors including the type and severity of the disease
being treated, the type and age of the veterinary or human patient being treated, and the like.
The formulations of the pharmaceutical compositions described herein may be
prepared by any method known or hereafter developed in the art ofpharmacology and
pharmaceutics. In general, such preparatory methods include the step of bringing the active
ingredient into association with a carrier or one or more other accessoiy ingredients, and then,
if necessary or desirable, shaping or packaging the product into a desired single-dose or
multi-dose unit.
As used herein, a "unit dose" is a discrete amount of the pharmaceutical
composition comprising a predetermined amount of the active ingredient. The amount of the
active ingredient is generally equal to the dosage of the active ingredient that would be
administered to a subject or a convenient fraction of such a dosage such as, for example, one-
half or one-third of such a dosage. The unit dosage form may be for a single daily dose or
one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily
doses are used, the unit dosage form may be the same or different for each dose.
Although the descriptions of pharmaceutical compositions provided herein are
principally directed to pharmaceutical compositions which are suitable for ethical
administration to humans, it will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts. IVlodification of
pharmaceutical compositions suitable for administration to humans in order to render the
compositions suitable for administration to various animals is well understood, and the
ordinarily skilled veterinary pharmacologist can design and perform such modification with
merely ordinary, if any, experimentation. Subjects to which administration of the
pharmaceutical compositions of the invention is contemplated include, but are not limited to,
humans and other primates, mammals including commercially relevant mammals such as
cattle, pigs, horses, sheep, cats, and dogs.
In certain embodiments, the compositions of the invention are formulated
using one or more pharmaceutically acceptable excipients or carriers. In certain
embodiments, the pharmaceutical compositions of the invention comprise a therapeutically
effective amount of at least one compound of the invention and a pharmaceutically
acceptable carrier. Pharmaceutically acceptable carriers, which are useful, include, but are
not limited to, glycerol, water, saline, ethanol, recombinant human albumin (e.g.
Recombumin®), solubilized gelatins (e.g. Gelofusine®), and other pharmaceutically
acceptable salt solutions such as phosphates and salts of organic acids. Examples of these
and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical
Sciences (1991, Mack Publication Co., New Jersey).
The carrier may be a solvent or dispersion medium containing, for example,
water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene
glycol, and the like), recombinant human albumin, solubilized gelatins, suitable mixtures
thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use
of a coating such as lecithin, by the maintenance of the required particle size in the case of
dispersion and by the use ofsurfactants. Prevention of the action ofmicroorganisms may be
achieved by various antibacterial and antifimgal agents, for example, parabens,
chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be
preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols
such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable
compositions may be brought about by including in the composition an agent that delays
absorption, for example, aluminum monostearate or gelatin.
Formulations may be employed in admixtures with conventional excipients,
;". e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral,
parenteral, nasal, inhalational, intravenous, subcutaneous, transdermal enteral, or any other
suitable mode of administration, known to the art. The pharmaceutical preparations may be
sterilized and if desired mixed with auxiliary agents, e.g. , lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers,
coloring, flavoring and/or fragrance-conferring substances and the like. They may also be
combined where desired with other active agents, e.g., other analgesic, anxiolytics or
hypnotic agents. As used herein, "additional ingredients" include, but are not limited to, one
or more ingredients that may be used as a pharmaceutical carrier.
The composition of the invention may comprise a preservative from about
0.005% to 2.0% by total weight of the composition. The preservative is used to prevent
spoilage in the case of exposure to contaminants in the environment. Examples of
preservatives useful in accordance with the invention include but are not limited to those
selected from the group consisting ofbenzyl alcohol, sorbic acid, parabens, imidurea and
combinations thereof. A particularly preferred preservative is a combination of about 0.5%
to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.
The composition preferably includes an antioxidant and a chelating agent
which inhibit the degradation of the compound. Preferred antioxidants for some compounds
are BHT, BHA, alpha-tocopherol and ascorbic acid in the preferred range of about 0.01% to
0.3% and more preferably BHT in the range of 0.03% to 0.1% by weight by total weight of
the composition. Preferably, the chelating agent is present in an amount of from 0.01% to
0.5% by weight by total weight of the composition. Particularly preferred chelating agents
include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about
0.01 % to 0.20% and more preferably in the range of 0.02% to 0.10% by weight by total
weight of the composition. The chelating agent is useful for chelating metal ions in the
composition which may be detrimental to the shelf life of the formulation. While BHT and
disodium edetate are the particularly preferred antioxidant and chelating agent, respectively,
for some compounds, other suitable and equivalent antioxidants and chelating agents may be
substituted therefore as would be known to those skilled in the art.
Liquid suspensions may be prepared using conventional methods to achieve
suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include,
for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily
esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated
vegetable oils, and mineral oils such as liquid paraffm. Liquid suspensions may further
comprise one or more additional ingredients including, but not limited to, suspending agents,
dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts,
flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a
thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup,
hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum
acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not
limited to, naturally-occurring phosphatides such as lecithin, condensation products of an
alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester
derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a
hexitol anhydride {e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol,
polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate,
respectively). Known emulsifying agents include, but are not limited to, lecithin, acacia, and
ionic or non-ionic surfactants. Known preservatives include, but are not limited to, methyl,
ethyl, or n-propyl^ara-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening
agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
Liquid solutions of the active ingredient in aqueous or oily solvents may be
prepared in substantially the same manner as liquid suspensions, the primary difference being
that the active ingredient is dissolved, rather than suspended in the solvent. As used herein,
an "oily" liquid is one which comprises a carbon-containing liquid molecule and which
exhibits a less polar character than water. Liquid solutions of the pharmaceutical
composition of the invention may comprise each of the components described with regard to
liquid suspensions, it being understood that suspending agents will not necessarily aid
dissolution of the active ingredient in the solvent. Aqueous solvents include, for example,
water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl
alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable
oils, and mineral oils such as liquid paraffin.
Powdered and granular formulations of a pharmaceutical preparation of the
invention may be prepared using known methods. Such formulations may be administered
directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an
aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto.
Each of these formulations may further comprise one or more of dispersing or wetting agent,
a suspending agent, ionic and non-ionic surfactants, and a preservative. Additional
excipients, such as filters and sweetening, flavoring, or coloring agents, may also be included
in these formulations.
A pharmaceutical composition of the invention may also be prepared,
packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily
phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin,
or a combination of these. Such compositions may further comprise one or more emulsifying
agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-
occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters
derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate,
and condensation products of such partial esters with ethylene oxide such as polyoxyethylene
sorbitan monooleate. These emulsions may also contain additional ingredients including, for
example, sweetening or flavoring agents.
Methods for impregnating or coating a material with a chemical composition
are known in the art, and include, but are not limited to methods of depositing or binding a
chemical composition onto a surface, methods of incorporating a chemical composition into
the structure of a material during the synthesis of the material (ji.e., such as with a
physiologically degradable material), and methods of absorbing an aqueous or oily solution
or suspension into an absorbent material, with or without subsequent drying. Methods for
mixing components include physical milling, the use of pellets in solid and suspension
formulations and mixing in a transdermal patch, as known to those skilled in the art.
Administration/Dosing
The regimen of administration may affect what constitutes an effective
amount. The therapeutic formulations may be administered to the patient either prior to or
after the onset of a breathing disorder event. Further, several divided dosages, as well as
staggered dosages may be administered daily or sequentially, or the dose may be
continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic
formulations may be proportionally increased or decreased as indicated by the exigencies of
the therapeutic or prophylactic situation.
Administration of the compositions of the present invention to a patient,
preferably a mammal, more preferably a human, may be carried out using known procedures,
at dosages and for periods of time effective to treat a breathing control disorder in the patient.
An effective amount of the therapeutic compound necessary to achieve a therapeutic effect
may vary according to factors such as the activity of the particular compound employed; the
time of administration; the rate ofexcretion of the compound; the duration of the treatment;
other drugs, compounds or materials used in combination with the compound; the state of the
disease or disorder, age, sex, weight, condition, general health and prior medical history of
the patient being treated, and like factors well-known in the medical arts. Dosage regimens
may be adjusted to provide the optimum therapeutic response. For example, several divided
doses may be administered daily or the dose may be proportionally reduced as indicated by
the exigencies of the therapeutic situation. A non-limiting example of an effective dose range
for a therapeutic compound of the invention is from about 0.01 mg/kg to 100 mg/kg of body
weight/per day. One of ordinary skill in the art would be able to study the relevant factors
and make the determination regarding the effective amount of the therapeutic compound
without undue experimentation.
The compound may be administered to an animal as frequently as several
times daily, or it may be administered less frequently, such as once a day, once a week, once
eveiy two weeks, once a month, or even less frequently, such as once every several months or
even once a year or less. It is understood that the amount of compound dosed per day may be
administered, in non-limitiag examples, every day, eveiy other day, every 2 days, every 3
days, every 4 days, or every 5 days. For example, with every other day administration, a 5
mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose
administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday,
and so on. The frequency of the dose will be readily apparent to the skilled artisan and will
depend upon any number of factors, such as, but not limited to, the type and severity of the
disease being treated, the type and age of the animal, etc.
Actual dosage levels of the active ingredients in the pharmaceutical
compositions of this invention may be varied so as to obtain an amount of the active
ingredient that is effective to achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the patient.
A medical doctor, e.g., physician or veterinarian, having ordinaiy skill in the
art may readily determine and prescribe the effective amount of the pharmaceutical
composition required. For example, the physician or veterinarian could start doses of the
compounds of the invention employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect and gradually increase the
dosage until the desired effect is achieved.
In particular embodiments, it is especially advantageous to formulate the
compound in dosage unit form for ease of administration and uniformity of dosage. Dosage
unit form as used herein refers to physically discrete units suited as unitary dosages for the
patients to be treated; each unit containing a predetermined quantity of therapeutic compound
calculated to produce the desired therapeutic effect in association with the required
pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly
dependent on (a) the unique characteristics of the therapeutic compound and the particular
therapeutic effect to be achieved, and (b) the limitations inherent in the art of
compounding/formulating such a therapeutic compound for the treatment of breathing
disorders in a patient.
In certain embodiments, the compositions of the invention are administered to
the patient in dosages that range from one to five times per day or more. In other
embodiments, the compositions of the invention are administered to the patient in range of
dosages that include, but are not limited to, once every day, every two days, every three days
to once a week, and once every two weeks. It will be readily apparent to one skilled in the art
that the frequency of administration of the various combination compositions of the invention
will vary from subject to subject depending on many factors including, but not limited to,
age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the
invention should not be construed to be limited to any particular dosage regime and the
precise dosage and composition to be administered to any patient will be determined by the
attending physician taking all other factors about the patient into account.
Compounds of the invention for administration may be in the range of from
about 1 |^g to about 7,500 mg, about 20 p.g to about 7,000 mg, about 40 p,g to about 6,500
mg, about 80 |j.g to about 6,000 mg, about 100 p,g to about 5,500 mg, about 200 p.g to about
,000 mg, about 400 |^g to about 4,000 mg, about 800 ^ig to about 3,000 mg, about 1 mg to
about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg
to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to
about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to
about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments
there-in-between.
In some embodiments, the dose of a compound of the invention is from about
0.5 p,g and about 5,000 mg. In some embodiments, a dose of a compound of the invention
used in compositions described herein is less than about 5,000 mg, or less than about 4,000
mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or
less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than
about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second
compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less
than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about
300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or
less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about
mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less
than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or
partial increments thereof.
In certain embodiments, the present invention is directed to a packaged
pharmaceutical composition comprising a container holding a therapeutically effective
amount of a compound of the invention, alone or in combination with a second
pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce
one or more symptoms of breathing disorder in a patient.
The term "container" includes any receptacle for holding the pharmaceutical
composition or for managing stability or water uptake. For example, in certain embodiments,
the container is the packaging that contains the pharmaceutical composition, such as liquid
(solution and suspension), semisolid, lyophilized solid, solution and powder or lyophilized
formulation present in dual chambers. In other embodiments, the container is not the
packaging that contains the pharmaceutical composition, i.e., the container is a receptacle,
such as a box or vial that contains the packaged pharmaceutical composition or unpackaged
pharmaceutical composition and the instructions for use of the pharmaceutical composition.
Moreover, packaging techniques are well known in the art. It should be understood that the
instructions for use of the pharmaceutical composition may be contained on the packaging
containing the pharmaceutical composition, and as such the instructions form an increased
functional relationship to the packaged product. However, it should be understood that the
instructions may contain information pertaining to the compound's ability to perform its
intended function, e.g., treating, preventing, or reducing a breathing disorder in a patient.
Administration
Routes of administration of any of the compositions of the invention include
inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g.,
sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally),
(intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical,
intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal,
intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
Suitable compositions and dosage forms include, for example, tablets,
capsules, caplets, pills, gel caps, troches, emulsions, dispersions, suspensions, solutions,
syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges,
creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral
administration, dry powder or aerosolized formulations for inhalation, compositions and
formulations for intravesical administration and the like. It should be understood that the
formulations and compositions that would be useful in the present invention are not limited to
the particular formulations and compositions that are described herein.
Oral Administration
In one embodiment, compounds of the invention may be formulated to prepare
a phannaceutical composition for oral administration. In further embodiments, the
composition for oral administration may be designed to promote a modified release of the
drug, such that the location, extent and rate of exposure of the compound when ingested are
modulated. Factors that affect the target zone for exposure of a drug may be the drug's pH or
enzymatic stability, reactivity with other drugs (e.g., certain antibiotics), solubility as a salt or
free base, ionization behavior, and pharmacodynamic and pharmacokinetic behaviors in
specific environments. Some dmgs are better absorbed in the duodenum or other intestinal
locations.
Delayed release is a particularly useful mode of modified release that delivers
drug in its most concentrated form to the duodenum or other intestinal location. In a
preferred embodiment, compounds of the present invention are formulated to promote
delivery to the duodenum and, optionally, other intestinal locations. Delayed release may be
achieved using compositions that include enteric coatings. Enteric coatings are insoluble in
highly acidic environments, with the polyacidic coating remaining non-ionized and intact at
gastric pH. However, under mildly acidic (> pH 5.5), neutral or mildly alkaline conditions
(pH 6.5-7.6) of the duodenum or other intestinal regions, the coating ionizes, swells and
breaks down, exposing the coated entity to the environment. Coating options exist to allow
ionization at or near a specific pH (e.g. Eudragit L-l 10, ionization threshold pH 6.0; Eudragit
S-100, ionization threshold pH 7.0).
In a further embodiment, compounds of the present invention may be
formulated with an enteric coating which has been modified by adding plasticizers to the
polymer before coating. The plasticizers may be added to adjust resistance to chipping or
cracking of the coating, while also lowering the glass transition temperature of the coating to
enable smooth and even spreadability of the coating during its application. Suitable
plasticizers include polyethylene glycol 8000 (PEG 8000), triethyl citrate (TEC), and
triacetin, which may be incorporated into the polymeric enteric coating agent.
Compounds of the present invention may be enterically formulated under a
variety of dosage forms, including (but not limited to) capsules, granules of the active drug
itself, beads, and tablets. In one embodiment, the composition may comprise a drug
encapsulated in a capsule that is enterically coated to release the drug in the duodenum or
other intestinal environment. In one aspect of the invention, pharmaceutically acceptable
capsules include hard capsules, which may be composed of plant derived polysaccharides,
starches, and cellulose, or gelatin. In another embodiment, pharmaceutically acceptable
capsules include soft gelatin capsules. The gelatin capsule may be composed ofanimal-
derived collagen or from a hypromellose, a modified form of cellulose, and manufactured
using optional mixtures of gelatin, water and plasticizers such as sorbitol or glycerol
In one embodiment, molecules of the invention may be encapsulated in pure
granular or powdered form, with no carriers, excipients or other pharmaceutically acceptable
additives. In other embodiments, molecules of the invention may be encapsulated together
with one or more pharmaceutically acceptable carriers, excipients, antioxidants (e.g., sodium
metabisulfite, butylated hydroxy toluene [BHT]), antifungals, (e.g., benzoic and ascorbic
acids and their salts, and phenolic compounds such as methyl, ethyl, propyl and butyl p-
hydroxybenzoate (parabens)), antimicrobial preservatives (e.g., sodium benzoate, sorbic
acid), colorants, and flavorants. The excipients may aid in capsule-filling behavior, stability,
and in the distribution of the drug when the capsule disintegrates in the body. In another
embodiment, granules and/or powders of compounds of the present invention may be
enterically coated before being placed in a capsule. The enterically coated granules and/or
powders placed in the capsule may feature one or several types of enteric coating to enable
delivery of the drug to different regions of the intestine. The capsule may lack enteric
coating or may be coated with an enteric coating matching or differing entirely from the
coating applied to any of the enterically coated material inside the capsule.
In a further embodiment, molecules of the invention may be encapsulated in a
liquid in the form of a solution or suspension in water or various pharmaceutically acceptable
oils or other dispersion medium (e.g., mineral oil, sesame oil, safflower oil, coconut oils),
optionally with such excipients as co-solvents (e.g., propylene glycol, glycerol), solubility
enhancers (e.g., sorbitol, dextrose), wetting agents (e.g.; polysorbates [Tweens], sorbitan
esters [Span], hydrophobic colloids [cellulose derivatives], thickening agents (e.g.,
methylcellulose, microcrystalline cellulose), buffers (e.g., disodium hydrogen phosphate),
antioxidants (e.g., butylated hydroxy toluene [BHT], citric acid, potassium sorbate),
antifungals (e.g., benzoic and ascorbic acids and their salts, and phenolic compounds such as
methyl, ethyl, propyl and butyl p-hydroxybenzoate (parabens)) antimicrobial preservatives
(e.g., sodium benzoate, sorbic acid), colorants and flavorants. In some embodiments,
compounds of the present invention may be formulated for liquid filled capsules in the form
of the pure drug as granules and/or powders in the liquid. In a related embodiment, the
capsule contained the drug in liquid may be enterically coated. In another embodiment,
granules and/or powders of compounds of the invention may be enterically coated before
being placed in a liquid and the combination placed in a capsule. The enterically coated
granules and/or powder may feature one or several types ofenteric coating to enable deliver
of the drug to different regions of the intestine. The capsule may lack enteric coating or may
be coated with an enteric coating matching or differing entirely from the coating applied to
any of the enterically coated material inside the capsule.
In another embodiment, molecules of the present invention may be
encapsulated in a capsule comprised of material which affords post-gastric drug delivery
without the need for the separate application of an enteric coating (e.g., Entericare enteric
softgels). The molecules may be encapsulated in such capsules as granules or powders with
or without excipients, and as solutions or suspensions as described above.
In some embodiments, the solid particles of the compounds of the present
invention, as a variety of particle sizes and particle size distributions, may be admixed with
excipients such as microcrystalline cellulose or lactose and formed as a bead which comprise
the drug-containing core onto which the enteric coating is applied. In some embodiments,
molecules of the current invention may be formed as a suspension or solution including,
optionally, buffers (e.g., aq. 1 N HC1 with tris-hydroxymethyl-aminomethane [TRIS]), and
binders (e.g., Opadry Clear Coat Powder) and coated onto a base particle, for example sugar
beads (e.g.. Sugar Spheres, NF particles) to form a bead. In another embodiment, the beads
may be enterically coated. In yet another embodiment, molecules of the invention may be
formulated as enterically coated beads, as described above, and the beads further formulated
by encapsulation. In a further embodiment, a combination of beads with different types of
enteric coating may be encapsulated, such that once released from the capsule, compounds of
the invention are made available in a controlled manner at different regions ranging from the
duodenum to other parts of the intestine. The capsule may lack enteric coating or may be
coated with an enteric coating matching or differing entirely from the coating applied to any
of the enterically coated material inside the capsule.
In a further embodiment, compounds of the present invention may be
formulated as tablets or caplets which alone or in combination with other formulation
components deliver drug to the duodenum or other intestinal region. In one embodiment,
compounds of the invention are formulated as tablets or caplets which are enterically coated
and which constitute the dosage form administered. In another embodiment, tablets or
caplets of suitable size and shape may be placed inside a capsule. In one such embodiment,
the capsule may be enterically coated and contain non-enterically coated tablets or caplets
which are released from the capsule in the duodenum or other intestinal region. In yet
another such embodiment, the capsule may be designed to disintegrate in the stomach and
release enterically coated tablets or caplets for subsequent delivery to duodenum or other
intestinal regions. In yet another such embodiment, the capsule and tablets or caplets
contained within may both be enterically coated to provide further control over the release of
the tablets or caplets from the capsule, and the subsequent release of the drug from the tablet
or caplet. In a further related embodiment, tablets or caplets featuring a variety of enteric
coating may combined and place in a capsule which itself may optionally be enterically
coated as well. Materials which are useful for enteric coatings for tablets and caplets include
but are not limited to those described above for application to capsules.
Enteric coatings may permit premature drug release in acidic media. In a still
further embodiment, compounds of the present invention may be formulated such that a
subcoating is applied before the enteric coating is applied. The subcoating may comprise
application to the enteric substrate of a soluble subcoating agent, examples of which are
hydroxypropylmethylcellulose, povidone, hydroxypropyl cellulose, polyethylene glycol
3350, 4500, 8000, methyl cellulose, pseudo ethylcellulose and amylopectin. A thin
subcoating layer on the enteric substrate impedes water penetration through the enteric
coating on the capsule shell or into the core where the active ingredient is located, preventing
premature dmg release. The subcoating may also promote the release of the drug in a basic
environment by moderating the acidic microenvironment at the interface between the core
and the enteric coating. In some embodiments, compounds of the present invention are
formulated with a subcoating containing organic acids intended to promote more rapid
polymer dissolution of a capsule as the coating degrades in environments with pH 5-6,
promoting a rapid release of the drug in basic media.
For oral application, particularly suitable are tablets, dragees, liquids, drops,
capsules, caplets and gelcaps. Other formulations suitable for oral administration include, but
are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an
aqueous or oily solution, a paste, a gel, toothpaste, a mouthwash, a coating, an oral rinse, or
an emulsion. The compositions intended for oral use may be prepared according to any
method known in the art and such compositions may contain one or more agents selected
from the group consisting of inert, non-toxic, generally recognized as safe (GRAS)
pharmaceutically excipients which are suitable for the manufacture of tablets. Such
excipients include, for example an inert diluent such as lactose; granulating and disintegrating
agents such as comstarch; binding agents such as starch; and lubricating agents such as
magnesmm stearate.
Tablets may be non-coated or they may be coated using known methods to
achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing
sustained release and absorption of the active ingredient. By way of example, a material such
as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of
example, tablets may be coated using methods described in U.S. Patents Nos. 4,256,108;
4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further
comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some
combination of these in order to provide for pharmaceutically elegant and palatable
preparation. Hard capsules comprising the active ingredient may be made using a
physiologically degradable composition, such as gelatin. The capsules comprise the active
ingredient, and may further comprise additional ingredients including, for example, an inert
solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
Hard capsules comprising the active ingredient may be made using a
physiologically degradable composition, such as gelatin. Such hard capsules comprise the
active ingredient, and may further comprise additional ingredients including, for example, an
inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
Soft gelatin capsules comprising the active ingredient may be made using a
physiologically degradable composition, such as gelatin from animal-derived collagen or
from a hypromellose, a modified form of cellulose, and manufactured using optional mixtures
of gelatin, water and plasticizers such as sorbitol or glycerol. Such soft capsules comprise the
active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid
paraffm, or olive oil.
For oral administration, the compounds of the invention may be in the form of
tablets or capsules prepared by conventional means with pharmaceutically acceptable
excipients such as binding agents; filters; lubricants; disintegrates; or wetting agents. If
desired, the tablets may be coated using suitable methods and coating materials such as
OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g.,
OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A
Type, OY-PM Type and OPADRY™ White, 32K18400). It is understood that similar type
of film coating or polymeric products from other companies may be used.
A tablet comprising the active ingredient may, for example, be made by
compressing or molding the active ingredient, optionally with one or more additional
ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the
active ingredient in a free-flowing form such as a powder or granular preparation, optionally
mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a
dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of
the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to
moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of
tablets include, but are not limited to, inert diluents, granulating and disintegrating agents,
binding agents, and lubricating agents. Known dispersing agents include, but are not limited
to, potato starch and sodium starch glycolate. Known surface-active agents include, but are
not limited to, sodium lauryl sulphate. Known diluents include, but are not limited to,
calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate,
calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating
agents include, but are not limited to, corn starch and alginic acid. Known binding agents
include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch,
polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents
include, but are not limited to, magnesium stearate, stearic acid, silica, and tale.
Granulating techniques are well known in the pharmaceutical art for
modifying starting powders or other particulate materials of an active ingredient. The
powders are typically mixed with a binder material into larger permanent free-flowing
agglomerates or granules referred to as a "granulation." For example, solvent-using "wet"
granulation processes are generally characterized in that the powders are combined with a
binder material and moistened with water or an organic solvent under conditions resulting in
the formation of a wet granulated mass from which the solvent must then be evaporated.
Melt granulation generally consists in the use of materials that are solid or
semi-solid at room temperature (;'. e., having a relatively low softening or melting point range)
to promote granulation of powdered or other materials, essentially in the absence of added
water or other liquid solvents. The low melting solids, when heated to a temperature in the
melting point range, liquefy to act as a binder or granulating medium. The liquefied solid
spreads itself over the surface of powdered materials with which it is contacted, and on
cooling, forms a solid granulated mass in which the initial materials are bound together. The
resulting melt granulation may then be provided to a tablet press or be encapsulated for
preparing the oral dosage form. Melt granulation improves the dissolution rate and
bioavailability of an active (?'. e., drug) by forming a solid dispersion or solid solution.
U.S. Patent No. 5,169,645 discloses directly compressible wax-containing
granules having improved flow properties. The grannies are obtained when waxes are
admixed in the melt with certain flow improving additives, followed by cooling and
granulation of the admixture. In certain embodiments, only the wax itself melts in the melt
combination of the wax(es) and additives(s), and in other cases both the wax(es) and the
additives(s) will melt.
The present invention also includes a multi-layer tablet comprising a layer
providing for the delayed release of one or more compounds useful within the methods of the
invention, and a further layer providing for the immediate release of one or more compounds
useful within the methods of the invention. Using a wax/pH-sensitive polymer mix, a gastric
insoluble composition may be obtained in which the active ingredient is entrapped, ensuring
its delayed release.
Liquid preparation for oral administration may be in the form of solutions,
syrups or suspensions. The liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl
cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-
aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g.,
methyl or propyl para-hydroxy benzoates or sorbic acid). Liquid formulations of a
pharmaceutical composition of the invention which are suitable for oral administration may
be prepared, packaged, and sold either in liquid form or in the form of a dry product intended
for reconstitution with water or another suitable vehicle prior to use.
Parenteral Administration
As used herein, "parenteral administration" of a pharmaceutical composition
includes any route of administration characterized by physical breaching of a tissue of a
subject and administration of the pharmaceutical composition through the breach in the
tissue. Parenteral administration thus includes, but is not limited to, administration of a
pharmaceutical composition by injection of the composition, by application of the
composition through a surgical incision, by application of the composition through a tissue-
penetrating non-surgical wound, and the like. In particular, parenteral administration is
contemplated to include, but is not limited to, subcutaneous, iatravenous, intraperitoneal,
intramuscular, intrastemal injection, and kidney dialytic infusion techniques.
Formulations of a pharmaceutical composition suitable for parenteral
administration comprise the active ingredient combined with a pharmaceutically acceptable
carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared,
packaged, or sold in a form suitable for bolus administration or for continuous administration.
Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in
ampules or in multidose containers containing a preservative. Injectable formulations may
also be prepared, packaged, or sold in devices such as patient-controlled analgesia (PCA)
devices. Formulations for parenteral administration include, but are not limited to,
suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable
sustained-release or biodegradable formulations. Such formulations may further comprise
one or more additional ingredients including, but not limited to, suspending, stabilizing, or
dispersing agents. In one embodiment of a formulation for parenteral administration, the
active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a
suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the
reconstituted composition.
The pharmaceutical compositions may be prepared, packaged, or sold in the
form of a sterile injectable aqueous or oily suspension or solution. This suspension or
solution may be formulated according to the known art, and may comprise, in addition to the
active ingredient, additional ingredients such as the dispersing agents, wetting agents, or
suspending agents described herein. Such sterile injectable formulations may be prepared
using a noa-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol,
for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's
solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-
glycerides. Other parentally-administrable formulations which are useful include those which
comprise the active ingredient in microcrystalline form in a recombinant human albumin, a
fluidized gelatin, in a liposomal preparation, or as a component of a biodegradable polymer
system. Compositions for sustained release or implantation may comprise pharmaceutically
acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a
sparingly soluble polymer, or a sparingly soluble salt.
Topical Administration
An obstacle for topical administration ofpharmaceuticals is the stratum
corneum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of
protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes
cornified and living cells. One of the factors that limit the penetration rate (flux) of a
compound through the stratum comeum is the amount of the active substance that can be
loaded or applied onto the skin surface. The greater the amount of active substance which is
applied per unit of area of the skin, the greater the concentration gradient between the skin
surface and the lower layers of the skin, and in turn the greater the diffusion force of the
active substance through the skin. Therefore, a formulation containing a greater
concentration of the active substance is more likely to result in penetration of the active
substance through the skin, and more of it, and at a more consistent rate, than a formulation
having a lesser concentration, all other things being equal.
Formulations suitable for topical administration include, but are not limited to,
liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil
emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically
administrable formulations may, for example, comprise from about 1% to about 10% (w/w)
active ingredient, although the concentration of the active ingredient may be as high as the
solubility limit of the active ingredient in the solvent. Formulations for topical administration
may further comprise one or more of the additional ingredients described herein.
Enhancers ofpermeation may be used. These materials increase the rate of
penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol
monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like.
Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram,
alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methylpyrrolidone.
One acceptable vehicle for topical delivery of some of the compositions of the
invention may contain liposomes.
In alternative embodiments, the topically active pharmaceutical composition
may be optionally combined with other ingredients such as adjuvants, anti-oxidants, chelating
agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers,
buffering agents, preservatives, and the like. In other embodiments, a permeation or
penetration enhancer is included in the composition and is effective in improving the
percutaneous penetration of the active ingredient into and through the stratum comeum with
respect to a composition lacking the permeation enhancer. Various penneation enhancers,
including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids,
dimethylsulfoxide, polar lipids, or N-methylpyrrolidone, are known to those of skill in the
art. In another aspect, the composition may further comprise a hydrotropic agent, which
functions to increase disorder in the structure of the stratum comeum, and thus allows
increased transport across the stratum corneum. Various hydrotropic agents such as
isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill
in the art.
The topically active pharmaceutical composition should be applied in an
amount effective to affect desired changes. As used herein "amount effective" shall mean an
amount sufficient to cover the region of skin surface where a change is desired. An active
compound should be present in the amount of from about 0.0001% to about 15% by weight
volume of the composition. More preferable, it should be present in an amount from about
0.0005% to about 5% of the composition; most preferably, it should be present in an amount
of from about 0.001% to about 1% of the composition. Such compounds may be
synthetically-or naturally derived.
Buccal Administration
A pharmaceutical composition of the invention may be prepared, packaged, or
sold in a formulation suitable for buccal administration. Such formulations may, for
example, be in the form of tablets or lozenges made using conventional methods, and may
contain, for example, 0.1 to 20% (w/w) of the active ingredient, the balance comprising an
orally dissolvable or degradable composition and, optionally, one or more of the additional
ingredients described herein. Alternately, formulations suitable for buccal administration
may comprise a powder or an aerosolized or atomized solution or suspension comprising the
active ingredient. Such powdered, aerosolized, or aerosolized formulations, when dispersed,
preferably have an average particle or droplet size in the range from about 0.1 to about 200
nanometers, and may further comprise one or more of the additional ingredients described
herein. The examples of fonnulations described herein are not exhaustive and it is
understood that the invention includes additional modifications of these and other
formulations not described herein, but which are known to those of skill in the art.
Rectal Administration
A pharmaceutical composition of the invention may be prepared, packaged, or
sold in a formulation suitable for rectal administration. Such a composition may be in the
form of, for example, a suppository, a retention enema preparation, and a solution for rectal
or colonic irrigation.
Suppository formulations may be made by combining the active ingredient
with a non-imtating pharmaceutically acceptable excipient which is solid at ordinary room
temperature (i.e., about 20°C) and which is liquid at the rectal temperature of the subject (i.e.,
about 37°C in a healthy human). Suitable pharmaceutically acceptable excipients include, but
are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository
formulations may further comprise various additional ingredients including, but not limited
to, antioxidants, and preservatives.
Retention enema preparations or solutions for rectal or colonic irrigation may
be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier.
As is well known in the art, enema preparations may be administered using, and may be
packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema
preparations may further comprise various additional ingredients including, but not limited
to, antioxidants, and preservatives.
Additional Administration Forms
Additional dosage forms of this invention include dosage forms as described
inU.S. Patents Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790.
Additional dosage forms of this invention also include dosage forms as described in U.S.
Patent Applications Nos. 20030147952, 20030104062, 20030104053,20030044466,
20030039688, and 20020051820. Additional dosage forms of this invention also include
dosage forms as described in PCT Applications Nos. WO 03/35041, WO 03/35040, WO
03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO
01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO 97/47285, WO 93/18755, and
WO 90/11757.
Controlled Release Formulations and Drug Delivery Systems
In certain embodiments, the composition is designed to promote controlled
release of the drug, such that the location, extent and rate of exposure of the compound when
administered are modulated. Factors that affect the target zone for exposure of an orally
administered drug may be the drug's pH and enzymatic stability, reactivity with other drugs
(e.g., certain antibiotics), solubility as a salt or free base, ionization behavior, and
pharmacodynamic and pharmacokinetic behaviors in specific environments.
Controlled- or sustained-release formulations of a pharmaceutical composition
of the invention may be made using conventional technology. In some cases, the dosage
forms to be used can be provided as slow or controlled-release of one or more active
ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices,
gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes,
or microspheres or a combination thereof to provide the desired release profile in varying
proportions. Suitable controlled-release formulations known to those of ordinary skill in the
art, including those described herein, can be readily selected for use with the pharmaceutical
compositions of the invention. Thus, single unit dosage forms suitable for oral
administration, such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-
release are encompassed by the present invention.
Most controlled-release pharmaceutical products have a common goal of
improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the
use of an optimally designed controlled-release preparation in medical treatment is
characterized by a minimum of dmg substance being employed to cure or control the
condition in a minimum amount of time. Advantages of controlled-release formulations
include targeted delivery within the gastrointestinal tract upon oral administration, extended
activity of the dmg, reduced dosage frequency, and increased patient compliance. In
addition, controlled-release formulations can be used to affect the time of onset of action or
other characteristics, such as blood level of the drug, and thus can affect the occurrence of
side effects.
Most controlled-release formulations are designed to initially release an
amount of dmg that promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level of therapeutic effect over
an extended period of time. In order to maintain this constant level of drug in the body, the
drug must be released from the dosage form at a rate that will replace the amount of drug
being metabolized and excreted from the body.
Controlled-release of an active ingredient can be stimulated by various
inducers, for example water, pH, temperature, enzymes, bacteria, or other physiological
conditions or compounds. The term "controlled-release component" in the context of the
present invention is defined herein as a compound or compounds, including, but not limited
to, polymers, polymer matrices, gels, pemieable membranes, liposomes, or microspheres or a
combination thereof that facilitates the controlled-release of the active ingredient.
In certain embodiments, the formulations of the present invention may be,but
are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained
release, delayed release and pulsatile release formulations. The active drug substance can
also be coated on an implantable medical device to be eluted or be released using a remotely
activated system.
The term sustained release is used in its conventional sense to refer to a drug
formulation that provides for gradual release of a drug over an extended period of time, and
that may, although not necessarily, result in substantially constant blood levels of a drug over
an extended time period. The period of time may be as long as a month or more and should
be a release that is longer that the same amount of agent administered in bolus form.
For sustained release, the compounds may be formulated with a suitable
polymer or hydrophobic material which provides sustained release properties to the
compounds. As such, the compounds for use the method of the invention may be
administered in the form ofmicroparticles, for example, by injection or in the form of wafers
or discs by implantation (drug embedded in polymeric matrices).
In a preferred embodiment of the invention, the compounds of the invention
are administered to a patient, alone or in combination with another pharmaceutical agent,
using a sustained release formulation.
The term delayed release is used herein in its conventional sense to refer to a
drug formulation that provides for an initial release of the drug after some delay following
drug administration and that may, although not necessarily, includes a delay of from about 10
minutes up to about 24 hours.
The term pulsatile release is used herein in its conventional sense to refer to a
drug formulation that provides release of the drug in such a way as to produce pulsed plasma
profiles of the drug after dmg administration.
The term immediate release is used in its conventional sense to refer to a drug
formulation that provides for release of the drug immediately after drug administration.
As used herein, short-term refers to any period of time up to and including
about 24 hours, about 12 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours,
about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20
minutes, or about 10 minutes and any or all whole or partial increments thereof after dmg
administration after drug administration.
As used herein, rapid-offset refers to any period of time up to and including
about 24 hours, about 12 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours,
about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20
minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug
administration.
A drug may be better absorbed in the duodenum or other intestinal locations.
A particularly useful mode of controlled release is one which minimizes release of drug in the
stomach, while delivering drug in its most concentrated form to the duodenum or other
intestinal locations. In certain embodiments, the compounds of the present invention are
formulated to promote deliveiy to the duodenum and, optionally, other intestinal locations.
Controlled release that delivers drug to the duodenum or other intestinal regions may be
achieved using compositions that include enteric coatings. Enteric coatings are insoluble in
highly acidic environments, often comprising a polyacidic coating that remains non-ionized
and intact at gastric pH. However, under mildly acidic (>pH 5.5) or neutral or mildly
alkaline conditions (pH 6.5-7.6) of the duodenum or other intestinal regions, the coating
ionizes, swells and breaks down, exposing the coated entity to the environment. Coating
options exist to allow ionization at or near a specific pH (e.g. Eudragit L-l 10, ionization
threshold pH 6.0; Eudragit S-100, ionization threshold pH 7.0). It is understood that similar
type or grade of film coating or polymeric products from other companies may be used.
In certain embodiments, compounds of the present invention are formulated
with an enteric coating, which has been modified by adding plasticizers to the polymer before
coating. The plasticizers may be added to adjust resistance to chipping or cracking of the
coating, while also lowering the glass transition temperature of the coating to enable
smoothness and even spreadability of the coating during its application. Suitable plasticizers
include polyethylene glycol 8000 (PEG 8000), triethyl citrate (TEC), and triacetin, which
may be incorporated into the polymeric enteric coating agent.
Compounds of the present invention may be enterically formulated under a
variety of dosage forms, including (but not limited to) capsules, grannies of the active dmg
itself, beads, micro spheres, and tablets. In certain embodiments, the composition comprises
a dmg encapsulated in a capsule enterically coated to release the drug in the duodenum or
other intestinal environment. In other embodiments, pharmaceutically acceptable capsules
include hard capsules. In yet other embodiments, pharmaceutically acceptable capsules
include soft gelatin capsules.
In certain embodiments, a compound of the invention is encapsulated in pure
granular or powdered form, with no carriers, excipients or other pharmaceutically acceptable
additives. In other embodiments, a compound of the invention is encapsulated together with
one or more pharmaceutically acceptable carriers, excipients, antioxidants, antifungals, (e.g.,
benzoic and ascorbic acids and their salts, and phenolic compounds such as methyl, ethyl,
propyl and butyl p-hydroxybenzoate (parabens)), antimicrobial preservatives, colorants, and
flavorants. The excipients may aid in capsule-filling behaviour, stability, and in the
distribution of the drug when the capsule disintegrates in the body. In other embodiments,
granules and/or powders of a compound of the present invention are enterically coated before
being placed in a capsule. The enterically coated granules and/or powders placed in the
capsule may feature one or several types ofenteric coating to enable delivery of the drug to
different regions of the intestine. The capsule may lack enteric coating or may be coated with
an enteric coating that is the same as or distinct from the coating applied to any of the
enterically coated materials inside the capsule.
In certain embodiments, a compound of the invention is encapsulated in a
liquid in the form of a solution or suspension in water or various pharmaceutically acceptable
oils or other dispersion medium , optionally with such excipients as co-solvents (e.g., PEG
300, PEG 400, propylene glycol, glycerol, tween 80, ethanol), solubility enhancers (e.g.,
sorbitol, dextrose), wetting agents (e.g., thickening agents), buffers (e.g., disodium hydrogen
phosphate), antioxidants , antifungals, preservatives, colorants and flavorants. In certain
embodiments, a compound of the present invention is formulated for liquid filled capsules in
the form of the pure drug as granules and/or powders in the liquid. In other embodiments, the
capsule containing the compound in liquid is enterically coated. In yet other embodiments,
granules and/or powders of a compound of the invention are enterically coated before being
placed in a liquid and the combination placed in a capsule. The enterically coated granules
and/or powder may feature one or several types ofenteric coating to enable delivery of the
drug to distinct regions of the intestine. The capsule may lack enteric coating or may be
coated with an enteric coating that is the same as or distinct from the coating applied to any
of the enterically coated materials inside the capsule.
In certain embodiments, a compound of the present invention is encapsulated
in a capsule comprised of material that affords post-gastric drug delivery without the need for
the separate application of an enteric coating (e.g., Entericare enteric softgels). The
compound may be encapsulated in such capsules as granules or powders with or without
excipients, and as solutions or suspensions as described above.
In certain embodiments, the solid particles of a compound of the present
invention, as a variety of particle sizes and particle size distributions, are admixed with
excipients such as microcrystalline cellulose or lactose and formed as a bead that comprises
the drug-containing core onto which the enteric coating is applied. In other embodiments, a
compound of the present invention is fanned as a suspension or solution including,
optionally, buffers (e.g., aq. 1 N HC1 with tris(hydroxymethyl)aminomethane "TRIS"), and
binders (e.g., Opadry Clear Coat Powder) and coated onto a base particle, for example sugar
beads (e.g.. Sugar Spheres, NF particles) to form a bead. In yet other embodiments, the beads
are enterically coated. In yet other embodiments, a compound of the invention is formulated
as enterically coated beads, as described above, and the beads further formulated by
encapsulation. In yet other embodiments, a combination of beads with different types of
enteric coating is encapsulated, such that once released from the capsule, the compound of
the invention is made available in a controlled manner at different regions ranging from the
duodenum to other parts of the intestine. The capsule may lack enteric coating or may be
coated with an enteric coating that is the same as or distinct from the coating applied to any
of the enterically coated materials inside the capsule.
In certain embodiments, a compound of the present invention is formulated as
tablets or caplets which alone or in combination with other formulation components deliver
drug to the duodenum or other intestinal region. In other embodiments, a compound of the
invention is formulated as tablets or caplets that are enterically coated and that constitute the
dosage form administered. In yet other embodiments, tablets or caplets of suitable size and
shape are placed inside a capsule. In yet other embodiments, the capsule is enterically coated
and contains non-enterically coated tablets or caplets, which are released from the capsule in
the duodenum or other intestinal region. In yet other embodiments, the capsule is designed to
disintegrate in the stomach and release enterically coated tablets or caplets for subsequent
delivery to duodenum or other intestinal regions. In yet other embodiments, the capsule and
tablets or caplets contained within are both enterically coated to provide further control over
the release of the tablets or caplets from the capsule, and the subsequent release of the drug
from the tablet or caplet. In yet other embodiments, tablets or caplets featuring a variety of
enteric coating are combined and placed in a capsule which itself may optionally be
enterically coated as well. Materials useful for enteric coatings for tablets and caplets include
but are not limited to those described above for application to capsules.
Enteric coatings may permit premature drug release in acidic media. In
certain embodiments, a compound of the present invention is formulated such that a
subcoating is applied before the enteric coating is applied. The subcoating may comprise
application to the enteric substrate of a soluble subcoating agent, examples of which are
hydroxypropylmethylcellulose, povidone, hydroxypropyl cellulose, polyethylene glycol
3350, 4500, 8000, methyl cellulose, pseudo ethylcellulose and amylopectin. It is understood
that similar type of synthetic and semisynthetic polymeric products from other companies
may be used. A thin subcoating layer on the enteric substrate impedes water penetration
through the enteric coating on the capsule shell or into the core where the active ingredient is
located, preventing premature dmg release. The subcoating may also promote the release of
the drug in a basic environment by moderating the acidic microenvironment at the interface
between the core and the enteric coating. In certain embodiments, a compound of the present
invention is formulated with a subcoating containing organic acids intended to promote more
rapid polymer dissolution of a capsule as the coating degrades in environments with pH 5-6,
promoting a rapid release of the drug in basic media.
Mechanical Devices
In one aspect of the invention, a method of treating a patient without normal
ventilation and normal breathing control comprises administering the composition useful
within the invention as described herein, and additionally treating the patient using a device
to support breathing. Such devices include, but are not limited to, ventilation devices, CPAP
and BiPAP devices.
Mechanical ventilation is a method to mechanically assist or replace
spontaneous breathing. Mechanical ventilation is typically used after an invasive intubation,
a procedure wherein an endotracheal or tracheostomy tube is inserted into the airway. It is
normally used in acute settings, such as in the ICU, for a short period of time during a serious
illness. It may also be used at home or in a nursing or rehabilitation institution, if patients
have chronic illnesses that require long-term ventilation assistance. The main form of
mechanical ventilation is positive pressure ventilation, which works by increasing the
pressure in the patient's airway and thus forcing air into the lungs. Less common today are
negative pressure ventilators (for example, the "iron lung") that create a negative pressure
environment around the patient's chest, thus sucking air into the lungs. Mechanical
ventilation is often a life-saving intervention, but carries many potential complications
including pneumothorax, airway injury, alveolar damage, and ventilator-associated
pneumonia. For this reason the pressure and volume of gas used is strictly controlled, and
discontinued as soon as possible. Types of mechanical ventilation are: conventional positive
pressure ventilation, high frequency ventilation, non-invasive ventilation (non-invasive
positive pressure ventilation or NIPPV), proportional assist ventilation (PA V), adaptive servo
ventilation (ASV) and neurally adjusted ventilatory assist (NAVA).
Non-invasive ventilation refers to all modalities that assist ventilation without
the use of an endotracheal tube. Non-invasive ventilation is primarily aimed at minimizing
patient discomfort and the complications associated with invasive ventilation, and is often
used in cardiac disease, exacerbations of chronic pulmonary disease, sleep apnea, and
neuromuscular diseases. Non-invasive ventilation refers only to the patient interface and not
the mode of ventilation used; modes may include spontaneous or control modes and may be
either pressure or volume cycled modes. Some commonly used modes ofNIPPV include:
(a) Continuous positive airway pressure (CPAP): This kind of machine has been used
mainly by patients for the treatment of sleep apnea at home, but now is in widespread use
across intensive care units as a form ofventilatory support. The CPAP machine stops upper
airway obstruction by delivering a stream of compressed air via a hose to a nasal pillow, nose
mask or full-face mask, splinting the airway open (keeping it open under air pressure) so that
unobstructed breathing becomes possible, reducing and/or preventing apneas and hypopneas.
When the machine is turned on, but prior to the mask being placed on the head, a How of air
comes through the mask. After the mask is placed on the head, it is sealed to the face and the
air stops flowing. At this point, it is only the air pressure that accomplishes the desired result.
This has the additional benefit of reducing or eliminating the extremely loud snoring that
sometimes accompanies sleep apnea.
(b) Bi-level positive airway pressure (BIPAP): Pressures alternate between
inspiratory positive airway pressure (IPAP) and a lower expiratory positive airway pressure
(EPAP), triggered by patient effort. On many such devices, backup rates may be set, which
deliver IPAP pressures even if patients fail to initiate a breath.
(c) Intermittent positive pressure ventilation (IPPV), via mouthpiece or mask.
Those skilled in the art will recognize, or be able to ascertain using no more
than routine experimentation, numerous equivalents to the specific procedures, embodiments,
claims, and examples described herein. Such equivalents were considered to be within the
scope of this invention and covered by the claims appended hereto. For example, it should be
understood, that modifications in reaction conditions, including but not limited to reaction
times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures,
atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-
recognized alternatives and using no more than routine experimentation, are within the scope
of the present application.
It is to be understood that, wherever values and ranges are provided herein, the
description in range format is merely for convenience and brevity and should not be
construed as an inflexible limitation on the scope of the invention. Accordingly, all values
and ranges encompassed by these values and ranges are meant to be encompassed within the
scope of the present invention. Moreover, all values that fall within these ranges, as well as
the upper or lower limits of a range of values, are also contemplated by the present
application. The description of a range should be considered to have specifically disclosed
all the possible sub-ranges as well as individual numerical values within that range and, when
appropriate, partial integers of the numerical values within ranges. For example, description
of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges
such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well
as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This
applies regardless of the breadth of the range.
The following examples further illustrate aspects of the present invention.
However, they are in no way a limitation of the teachings or disclosure of the present
invention as set forth herein.
EXAMPLES
The invention is now described with reference to the following Examples.
These Examples are provided for the purpose of illustration only, and the invention is not
limited to these Examples, but rather encompasses all variations that are evident as a result of
the teachings provided herein.
Materials:
Unless otherwise noted, all remaining starting materials were obtained from
commercial suppliers and used without purification. Final products are typically isolated as
salts unless noted otherwise.
Example 1: 2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (4) and corresponding hydrochloride salt (4a)
HsC^.^H
-13 4
(a) Propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidmyl)-amme (2)
To a suspension of2,4,6,8-tetrachloro-pyrimido[5,4-d]pyrimidine (1) (3.00 g,
11.15 mmol) in THF (40 mL) at -78°C, propylamine (880 \iL, 10.71 mmol) in THF (7 mL)
was added via syringe pump (during ~20 min) followed by DIPEA (2.12 mL, 12.27 mmol) in
THF (7 mL). The reaction mixture was stirred at -78°C for additional 30 min, and then
allowed to reach the room temperature. Water (200 mL) was added and the resulting
suspension was extracted with EtOAc (3 x 200 mL). The combined organic extracts were
washed with brine (250 mL) and dried over solid anhydrous MgS04. After filtration, the
solvent was removed and the residue was purified by flash column chromatography using
gradient elution from PE/EtOAc (99:1) to PE/EtOAc (5:1) to give propyl-(2,6,8-trichloro-
pyrimido[5,4-d]pyrimidmyl)-amine (2) (2.91 g, 93% yield). 300 MHz 'H NMR (CDCb,
ppm): 7.22 (1H, br s) 3.69-3.60 (2H, m) 1.78 (2H, sextet, J=7.4 Hz) 1.05 (3H, t, J=7.4 Hz).
ESI-MS (m/z): 292, 294, 296, 298 [M+H]+.
(b) 2-(2,6-Dichloropropylammo-pyrimido[5,4-d]pyrimidinylamino)-ethanol (3)
2-Amino-ethanol (2.90 mL, 47.85 mmol) (in 10 mL of dichloromethane) was
added in portions to a solution ofpropyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-
amine (2) (5.60 g, 19.14 mmol) in dichloromethane (180 mL) at 0°C. The reaction mixture
was stirred at room temperature for Ih. Saturated NaHCOs (100 mL) was added and the
resulting suspension was extracted with chloroform (3 x 100 mL). After filtration, the
combined organic extracts were washed with water and dried over solid anhydrous MgS04.
After filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from PE/EtOAc (5:1) to PE/EtOAc (1:2) to give 2-
(2,6-dichloropropylamino-pyrimido[5,4-d]pyrimidmylamino)-ethanol (3) (5.53 g, 91%
yield). 300 MHz 'H NMR (CDCk, ppm): 7.30 (1H, t, J=5.7 Hz) 6.91 (1H, t, J=5.7 Hz) 3.96-
3.88 (2H, m) 3.83-3.74 (2H, m) 3.61-3.51 (2H, m) 2.62 (1H. T, J=4.9 Hz) 1.80-1.66 (2H, m)
1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 317, 319, 321 [M+H]+.
(c) 2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol(4)
A mixture of 2-(2,6-dichloropropylamino-pyrimido[5,4-d]pyrimidinyl
amino)-ethanol (3) (5.53 g, 17.43 mmol) and methylamine (40% water solution) (15.00 mL)
in n-butanol (50 mL) was heated at 115°C for 72 h in a closed vial. After cooling, a saturated
NaHCOs solution (100 mL) was added and the resulting suspension was extracted with
EtOAc (3 x 150 mL). The combined organic extracts were washed with water (300 mL),
then with brine (300 mL) and dried over solid anhydrous MgS04. After filtration, the solvent
was removed and the residue was purified by flash column chromatography using gradient
elution from PE/EtOAc (5:1) to PE/EtOAc (1:3) to give 2-(2,6-bis-methylamino
propylamino-pyrimido[5,4-d] pyrimidinylamino)-ethanol (4) (3.39 g, 63% yield). 300
MHz *HNMR (CDCb, ppm): 7.03-6.83 (1H, m) 6.61-6.41 (1H, m) 4.84-4.48 (3H, m) 3.89-
3.83 (2H, m) 3.72-3.64 (2H, m) 3.51-3.41 (2H, m) 2.96 (3H, d, J=4.9 Hz) 2.95 (3H, d, J=4.9
Hz) 1.69 (2H, sextet, J=7.4 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 307 [M+H]+.
(d) 2-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-
ethanol hydrochloride (4a)
A 2M HC1 /diethyl ether solution (4.64 mL, 9.27 mmol) was added to a
solution of 2-(2,6-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidmylammo)-
ethanol (4) (2.84 g, 9.27 rnmol) in diethyl ether (50 mL) and methanol (25 mL). The mixture
was stirred for 1 h at room temperature and the resultant precipitate was filtered, washed with
diethyl ether (20 mL), and dried to give 2-(2,6-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-ethanol hydrochloride (4a) (3.13 g, 98% yield). 300
MHz 'HNMR (D20, ppm): 3.85 (2H, t, J=5.4 Hz) 3.68 (2H, t, J=5.4 Hz) 3.44 (2H, t, J=7.3
Hz) 2.95 (3H, s) 2.94 (3H, s) 1.68 (2H, sextet, J=7.4 Hz) 0.97 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 307 [M+H]+; MP: 201-203 °C.
N^N ^^OH
H,N'
DIPEA
N^.N
-78°C
NHz-CHs
n-BuOH
115°C
sealed vial
Scheme 5
Example 2: 2-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-
methyl-ammo]-ethanol (6) and corresponding hydrochloride salt (6a)
(a) 2-[(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidmyl)-methyl-amino]-
ethanol(5)
2-Methylamino-ethanol (740 [iL, 3.00 mmol) was added to a solution of
propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidmyl)-amine (2) (350 mg, 1.20 mmol) in
dichloromethane (15 mL) at 0°C. The reaction mixture was stirred at room temperature for
2h. After this time, a saturated NaHCOs (30 mL) was added, and the resulting suspension
was extracted with dichloromethane (3x10 mL). The combined organic extracts were
washed with water (30 mL) and dried over solid anhydrous MgS04. After filtration, the
solvent was removed and the residue was purified by flash column chromatography using
gradient elution from PE/EtOAc (9:1) to PE/EtOAc (1:1) to give 2-[(2,6-dichloro
propylamino-pyrimido[5,4-d] pyrimidinyl)-methyl-amino]-ethanol (5) (230 mg, 58%
yield). 300 MHz 1HNMR (CDCb, ppm): 7.08 (1H, br s) 4.39-4.13 (2H, m) 4.05-3.98 (2H,
m) 3.85 (1H, br s) 3.59-3.50 (2H, m) 3.38 (3H, s) 1.72 (2H, sextet, J=7.4 Hz) 1.02 (3H, t,
3=7 A Hz). ESI-MS (m/z): 331, 333, 335 [M+H]+.
(b) 2-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-ethanol (6)
A mixture of 2-[(2,6-dichloropropylamino-pyrimido[5,4-d]pyrimidinyl)-
methyl-amino]-ethanol (5) (210 g mg, 0.63 mmol) and methylamine (40% water solution)
(330 \iL, 4.25 mmol) in n-butanol (3 mL) was heated at 100°C for 40 h in a closed vial. After
cooling, a saturated NaHCOa solution (20 mL) was added and the resulting suspension was
extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water
(30 mL), then with brine (30 mL) and dried over solid anhydrous MgS04. After filtration,
the solvent was removed and the residue was purified by flash column chromatography using
gradient elution from PE/EtOAc (9:1) to PE/EtOAc (1:4) to give 2-[(2,6-bis-methylamino
propylamino-pyrimido [5,4-d]pyrimidinyl)-methyl-amino]-ethanol (6) (80 mg, 40% yield).
400 MHz 1HNMR (CDCk, ppm): 6.86-6.73 (1H, m) 6.5-6.2 (1H, m) 4.72-4.51 (2H, m) 4.18
(2H, t, 3=4.9 Hz) 3.95 (2H, t, J=4.9 Hz) 3.49-3.41 (2H, m) 3.27 (3H, m) 2.96 (3H, d, J=5.1
Hz) 2.96 (3H, d, J=5.1 Hz) 1.74-1.64 (2H, m) 1.00 (3H, t, J==7.4 Hz). ESI-MS (m/z): 321
[M+H]+.
(c) 2-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-ethanol hydrochloride (6a)
A 2M HC1 /diethyl ether solution (115 [XL, 0.23 mmol) was added to the
solution of 2-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-ethanol (6) (74 mg, 0.23 mmol) in diethyl ether (5 mL). The mixture was stirred for
min at room temperature and then the precipitate were filtered, washed with diethyl ether
(3 mL), and dried to give 2-[(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin-
4-yl)-methyl-amino]-ethanol hydrochloride (6a) (81 mg, 99% yield). 400 MHz 1HNMR
(CDCk, ppm): 14.2-13.7 (1H, m) 8.4-7.7 (2H, m) 6.7-6.3 (1H, m) 4.28-3.77 (4H, m) 3.64-
3.49 (2H, m) 3.28 (3H, s) 3.03-2.97 (6H, m) 1.83-1.72 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 321 [M+H]+; MP: 165-167 OC.
Examples: 3-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidmylamino)-
propanol (8) and corresponding hydrochloride salt (8a)
HsC^H
Nl"~~N H
H' 'CH3 8
(a) 3-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-1 -ol (7)
3-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-
l-ol (7) was prepared from propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidmyl)-amine (2)
(300 mg, 1.03 mmol) and 3-amino-propan-l-ol in dichloromethane using procedure described
for compound (5) to give 3-(2,6-dichloropropylamino-pyrimido[5,4-d]pyrimidin
ylammo)-propan-l-ol (7) (260 mg, 77% yield). 400 MHz 1H NMR (CDCb, ppm): 7.17 (1H,
t, J=6.3 Hz) 6.90 (1H, t, J=5.8 Hz) 3.79-3.73 (2H, m) 3.69 (2H, t, J=5.6 Hz) 3.59-3.53 (2H,
m) 3.02 (1H, br s) 1.92-1.84 (2H, m) 1.72 (2H, sextet, J=7.4 Hz) 1.02 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 331, 333, 335 [M+H]+.
(b) 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol (8)
3-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-
l-ol (7) (250 mg, 0.75 mmol) and methylamine (40% water solution) in n-butanol were
reacted using the procedure described for compound (6). The crude product was purified by
flash column chromatography using gradient elution from CHhCb to CHhCb/MeOH (95:5) to
give 3-(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-l-
ol (8) (200 mg, 83% yield). 400 MHz 'HNMR (CDCb, ppm): 6.73 (1H, s) 6.52 (1H, s) 4.88
(1H, s) 4.63 (1H, s) 4.57 (1H, s) 3.73-3.65 (2H, m) 3.59 (2H, t, J=5.5) 3.50-3.43 (2H, m) 2.97
(3H, d, J=5.2 Hz) 2.95 (3H, d, J=5.2 Hz) 1.83-1.75 (2H, m) 1.75-1.64 (2H, m) 1.00 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol hydrochloride (8a)
3-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-propan-l -ol (8) (190 mg, 0.59 mmol) and 2M HC1 /diethyl ether in diethyl ether
were reacted using procedure described for compound (6a) to afford the desired product (208
mg,98% yield). 400 MHz !H NMR (CDsOD, ppm): 3.74-3.66 (4H, m) 3.56 (2H, t, 3=7.2
Hz) 3.00 (6H, d, J=5.2 Hz) 1.97-1.88 (2H, m) 1.79-1.68 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 321 [M+H]+; MP: 178-180 °C.
Example 4: 1 -(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidmylamino)-
propanol (10) and corresponding hydrochloride salt (lOa)
H3C^H
N"^N ^ CHs
^"YSr ^OH
H N<^N
H €N3 ^0
(a) l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylammo)-propanol (9)
A mixture ofpropyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-amine (2)
(350 mg, 1.20 mmol), l-amino-propanol (100 |J,L, 1.25 mmol) and N,N-diisopropylethyl
amine (230 [iL, 1.31 mmol) in dichloromethane (7 mL) was stiiTed at room temperature for
2h. A saturated NaHC03 solution (30 mL) was then added and the resulting suspension was
extracted with dichloromethane (3x10 mL). The combined organic extracts were washed
with water (30 mL) and dried over solid anhydrous MgS04. After filtration, the volatiles
were removed, and the residue was disolved in dichloromethane (5 mL) and filtered through
a pad ofsilica gel. The solvent was evaporated to give l-(2,6-dichloropropylamino-
pyrimido[5,4-d] pyrimidmylamino)-propanol (9) (380 mg (96% yield). 300 MHz 1H
NMR (CDCla, ppm): 7.31 (1H, t, J=5.7 Hz) 6.90 (1H, t, J==5.5 Hz) 4.19-4.08 (1H, m) 3.78
(1H, ddd, J=14.0, 6.6, 3.1 Hz) 3.60-3.51 (2H, m) 3.48 (1H, ddd, J=14.0, 7.8, 5.5 Hz) 2.67
(1H, s) 1.72 (2H, sextet, J=7.4 Hz) 1.30 (3H, d, J=6.3 Hz) 1.02 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 331,333, 335 [M+H]+.
(b) l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (10)
l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-
2-ol (9) (370 mg, 1.12 mmol) and methylamine (40% water solution) were reacted in n-
butanol using procedure described for compound 4 to give l-(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]-pyrimidmylamino)-propanol (10) (230 mg, 64% yield).
400 MHz 1H NMR (CDCb, ppm): 6.96-6.81 (1H, m) 6.59-6.42 (1H, m) 4.90 (1H, s) 4.69-
4.51 (2H, m) 4.11-4.01 (1H, m) 3.64-3.56 (1H, m) 3.50 (1H, dd, J=7.1, 6.0 Hz) 3.47-3.42
(2H, m) 2.96 (3H, d, J=5.1 Hz) 2.95 (3H, d, J=5.1 Hz) 1.74-1.63 (2H, m) 1.23 (3H, d, J=6.4
Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) l-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol hydrochloride (lOa)
l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-propanol (10) (190 mg, 0.59 mmol) and 2M HC1 /diethyl ether in diethyl ether
were reacted using procedure described for compound 6a to afford l-(2,6-bis-methylamino-
8-propylamino-pyrimido[5,4-d]-pyrimidinylamino)-propanol hydrochloride (lOa) (200
mg, 75% yield). 400 MHz 1HNMR (DzO, ppm): 4.18-4.08 (1H, m) 3.63 (1H, dd, J=13.9, 4.1
Hz) 3.52 (1H, dd, J=13.9, 7.6 Hz) 3.47 (2H, t, J=7.2 Hz) 2.97 (3H, s) 2.95 (3H, s) 1.74-1.63
(2H, m) 1.25 (3H, d, J=6.4 Hz) 0.97 (3H, t, 3=7 A Hz). ESI-MS (m/z): 321 [M+H]+; MP:
216-219 °C.
Example 5: (5)-l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (12) and corresponding hydrochloride salt (12a)
HsC^H
N^N CHs
'N^f;^VN^^OH
H €N3 ^^
(a) (S)-1 -(2,6-Dichloropropylamino-pyrimido [5,4-d]pyrimidmylamino)-propan
ol(ll)
Propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-amme (2) (300 mg,
1.03 mmol) and (S)-l-amino-propanol were reacted in dichloromethane (7 ml) using
procedure described for compound 9 to give (S)-l-(2,6-dichloropropylamino-
pyrimido[5,4-d]pyrimidmylamino)-propanol (11) (333 mg, 98% yield). 300 MHz 1H
NMR (CDCb, ppm): 7.32 (1H, t, J=5.8 Hz) 6.90 (1H, t, J=5.5 Hz) 4.19-4.08 (1H, m) 3.78
(1H, ddd, J==14.0, 6.6, 3.1 Hz) 3.60-3.42 (3H, m) 2.74 (1H, s) 1.72 (2H, sextet, J=7.4 Hz)
1.30 (3H, d, J=6.3 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 331, 333, 335 [M+H]+.
(b) (S)-l-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidiaylamino)-
propanol(12)
(S)-l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol (11) (340 mg, 1.03 mmol) and methylamine (40% water solution) were reacted
in n-butanol using procedure described for compound 4. The crude product was purified by
flash column chromatography using gradient elution from CHCb to CHCls/MeOH (9:1) to
give (S)-l-(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylammo)-
propanol (12) (160 mg, 48% yield). 300 MHz 1H NMR (CDCk, ppm): 6.97-6.84 (1H, m)
6.58-6.44 (1H, m) 4.92 (1H, s) 4.74-4.53 (2H, m) 4.13-3.99 (1H, m) 3.60 (1H, ddd, J=14.3,
6.4, 2.4 Hz) 3.53-3.39 (3H, m) 2.96 (3H, d, J=5.1 Hz) 2.94 (3H, d, J=5.1 Hz) 1.68 (2H,
sextet, J=7.4 Hz) 1.22 (3H, d, J=6.4 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) (S)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)-
propanol hydrochloride (12a)
A 2M HC1 /diethyl ether (220 [iL, 0.44 mmol) was added to the solution of
(S)-l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylammo)-propan
ol (12) (140 mg, 0.44 mmol) in diethyl ether (5 mL) and dichloromethane (6 mL). The
mixture was stirred for 30 min at room temperature and then the volatiles were removed in
vacuum. The residue was treated with diethyl ether (5 mL) and the resultant precipitate were
filtered, washed with diethyl ether (3 mL), and dried to give (5)-l-(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinylammo)-propanol hydrochloride (12a) (150
mg, 96% yield). 300 MHz 1HNMR (CDsOD, ppm): 4.14-3.99 (1H, m) 3.69 (1H, dd, J=13.6,
4.0 Hz) 3.57 (2H, t, J=7.2 Hz) 3.48 (1H, dd, J=13.6, 7.6 Hz) 3.00 (3H, s) 2.99 (3H, s) 1.74
(2H, sextet, J=7.4 Hz) 1.24 (3H, d, J==6.3 Hz) 1.01 (3H, t, J=7.4 Hz). ESI- MS (m/z): 321
[M+H]+; MP: 206-208 °C.
Example 6: (R)-l -(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylammo)-propanol (14) and corresponding hydrochloride salt (14a)
H3C^H
N^N CHs
-N^Y^YN^OH
H N^N
H""^CH3 14
(a) (R)-l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidmylamino)-propan
ol(13)
Propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-amine (2) (300 mg,
1.03 rnmol) and (R)-l-amino-propanol were reacted in dichloromethane using procedure
described for compound 9 to give (R)-l-(2,6-dichloropropylamino-pyrimido[5,4-
d]pyrimidinyl amino)-propanol (13) (333 mg, 98% yield). 300 MHz !H NMR (CDCla,
ppm): 7.32 (1H, t, J=5.8 Hz) 6.90 (1H, t, J=5.5 Hz) 4.19-4.08 (1H, m) 3.78 (1H, ddd, J=14.0,
6.6, 3.1 Hz) 3.60-3.42 (3H, m) 2.74 (1H, s) 1.72 (2H, sextet, J=7.4 Hz) 1.30 (3H, d, J=6.3
Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 331, 333, 335 [M+H]+.
(b) (R)-l-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidmylamino)-
propanol (14)
(R)-l-(2,6-Dichloropropylamino-pyrim ido[5,4-d]pyrimidinylamino)-
propanol (13) (311 mg, 0.94mmol) and methylamine (40% water solution) were reacted in
n-butanol using procedure described for compound 4 to produce (R)-l-(2,6-bis-methylamiao-
8-propylamino-pyrimido[5,4-d]pyrimidinylammo)-propanol (14) (190 mg, 63% yield).
300 MHz !H NMR (CDCk, ppm): 6.95-6.82 (1H, m) 6.57-6.41 (1H, m) 4.92 (1H, br s) 4.70-
4.53 (2H, m) 4.13-4.01 (1H, m) 3.61 (1H, ddd, J= 14.3, 6.3, 2.3) 3.54-3.41 (3H, m) 2.96 (3H,
d, J=5.0 Hz) 2.95 (3H, d, J-5.0 Hz) 1.69 (2H, sextet, J=7.4 Hz) 1.23 (3H, d, J=6.4 Hz) 1.0
(3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) (R)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylammo)-
propanol hydrochloride (14a)
(R)-l-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylammo)-propanol (14) (180 mg, 0.56 mmol) and 2M HC1 /diethyl ether were reacted in
dichloromethane using procedure described for compound (12a) to produce (R)-l-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-propanol
hydrochloride (14a) (170 mg, 85% yield). 300 MHz 'HNMR (CDCb, ppm): 14.25-13.60
(1H, m) 8.11-7.88 (1H, m) 7.67-7.46 (1H, m) 6.63-6.24 (1H, m) 4.88 (1H, br s) 4.23-4.10
(1H, m) 3.79-3.34 (4H, m) 3.09-2.86 (6H, m) 1.76 (2H, sextet, J==7.4 Hz) 1.28 (3H, d, J=5.6
Hz) 1.03 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+; MP: 218-220 °C.
Example 7: 2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
2-methyl-propan-l-ol (16) and corresponding hydrochloride salt (16a)
H3C^H
N"^N OH
'NAfSrK-
N^N CH3U"3
H CH3 16
(a) 2-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)methyl-
propanol (15)
Propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-amine (2) (350 mg,
1.20 mmol) and 2-aminomethyl-propan-l-ol were reacted in dichloromethane using
procedure described for compound 5 to give 2-(2,6-dichloropropylamino-pyrimido[5,4-
d]pyrimidinylamino)methyl-propan-l-ol (15) (250 mg, 60% yield). 300 MHz 'H NMR
(CDCb, ppm): 6.97 (1H, s) 6.89 (1H, t, J=5.5 Hz) 4.59 (1H, t, J=6.5 Hz) 3.77 (2H, d, J=6.5
Hz) 3.60-3.50 (2H, m) 1.72 (2H, sextet, J=7.4 Hz) 1.48 (6H, s) 1.02 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 345, 347, 349 [M+H]+.
(b) 2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylammo)
methyl-propan-1 -ol (16)
2-(2,6-Dichloropropylamino-pyrimido[5,,4-d]pyrimidinylamino)
methyl-propanol (15) (250 mg, 0.72 mmol) and methylamine (40% water solution) were
reacted in n-butanol using procedure described for compound 4 to afford 2-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)methyl-propan-l-ol
(16) (120 mg, 50% yield). 300 MHz 1H NMR (CDCk, ppm): 6.96 (1H, s) 6.72 (1H, s) 6.48
(1H, t, J=5.7 Hz) 4.62 (1H, q, J-5.0 Hz) 4.54 (1H, q, J=5.0 Hz) 3.70 (2H, s) 3.51-3.40 (2H,
m) 2.96 (3H, d, J=5.0 Hz) 2.95 (3H, d, J=5.0 Hz) 1.76-1.62 (2H, m) 1.44 (6H, s) 1.00 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
(c) 2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidmylamino)
methyl-propanol hydrochloride (16a)
2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)methyl-propan-l-ol (16) (115 mg, 0.34 mmol) was treated with 2M HC1 /diethyl
ether in dichloromethane using procedure described for compound (12a) to produce 2-(2,6-
bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)methyl-propan-l-
ol hydrochloride (16a) (125 mg, 99% yield). 400 MHz 1H NMR (CDaOD, ppm): 3.82 (2H,
s) 3.56 (2H, t, J=7.1 Hz) 3.00 (3H, s) 2.98 (3H, s) 1.79-1.68 (2H, m) 1.53 (6H, s) 1.01 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
Examples: (S)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-propan-l-ol (18) and corresponding hydrochloride salt (18a)
HsC^H
N^N ^
'K'WT^OH
N<^N CH3
H CH3 ^g
(a) (S)(2,6-Dichloropropylammo-pyrimido[5,4-d]pyrimidinylamino)-propan-l-
ol (17)
(S)(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol (17) was prepared frompropyl-(2,6,8-trichloro-pyrimido[5,4-d] pyrimidinyl)-
amine (2) (350 mg, 1.20 mmol) and (>S)ammopropan-l-ol in dichloromethane using
procedure described for compound 5 to obtain the desired product(280 mg, 70% yield). 300
MHz !H NMR (CDCb, ppm): 7.00 (1H, d, J=7.5 Hz) 6.90 (1H, t, J=5.4 Hz) 4.52-4.38 (1H,
m) 3.90-3.79 (1H, m) 3.77-3.67 (1H, m) 3.60-3.51 (2H, m) 2.48 (1H, s) 1.79-1.66 (2H, m)
1.35 (3H, d, J=6.8 Hz) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 331, 333, 335 [M+H]+.
(b) (S)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidmylamiao)-
propanol (18)
(S)(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-propan-l-ol (18) was prepared from (>S)(2,6-dichloropropylamino-pyrimido
[5,4-d]pyrimidinylamino)-propan-l-ol (17) (280 mg, 0.85 mmol) and methylamine (40%
water solution) in n-butanol using procedure described for compound 4 to obtain the desired
product (160 mg, 59% yield). 300 MHz 'H NMR (CDCk, ppm): 6.61-6.39 (2H, m) 4.86
(1H, br s) 4.69-4.49 (2H, m) 4.30-4.15 (1H, m) 3.79 (1H, dd, J=11.0, 2.8 Hz) 3.67 (1H, dd,
J=11.0, 7.4 Hz) 3.51-3.41 (2H, m) 2.97 (3H, d, J=5.2 Hz) 2.94 (3H, d, J==5.2 Hz) 1.76-1.61
(2H, m) 1.33 (3H, d, J=6.9 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) (S)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol hydrochloride (18a)
(S)(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-propan-l-ol hydrochloride (18a) was prepared from (5)(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]-pyrimidmylamino)-propan-l-ol (18) (150 mg, 0.47 mmol)
and 2M HC1 /diethyl ether in diethyl ether using procedure described for compound 6a to
obtain the desired product (135 mg, 80% yield). 400 MHz )H NMR (CDsOD, ppm): 4.51-
4.40 (1H, m) 3.72 (1H, dd, J=ll.l, 4.8 Hz) 3.67 (1H, dd, J=ll.l, 5.5 Hz) 3.60 (2H,t, J=7.3
Hz) 3.03 (3H, s) 3.00 (3H, s) 1.81-1.70 (2H, m) 1.33 (3H, d, J-6.8 Hz) 1.02 (3H, t, J=7.4 Hz).
ESI-MS (m/z): 321 [M+H]+.
Example 9: (R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylammo)-propan-l-ol (20) and corresponding hydrochloride salt (20a)
HsC^H
'KAA'RT'OH
N^/N CHs
H CHs ^Q
(a) (R)(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-l-
ol (19)
Propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-amine (2) (270 mg,
0.93 mmol) and (R)aminopropan-l-ol were reacted in dichloromethane using procedure
described for compound 9 to give (R)(2,6-dichloropropylamino-pyrimido[5,4-
d]pyrimidinyl amino)-propan-l-ol (19) (275 mg, 90% yield). 300 MHz 'H NMR (CDCk,
ppm): 6.98 (1H, d, J=7.7 Hz) 6.89 (1H, t, J=5.3 Hz) 4.52-4.38 (1H, m) 3.84 (1H, dd, J=11.2,
3.9 Hz) 3.72 (1H, dd, J=11.2, 5.9 Hz) 3.60-3.51 (2H, m) 2.39 (1H, s) 1.79-1.66 (2H, m) 1.36
(3H, d, J=6.8 Hz) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 331, 333, 335 [M+H]+.
(b) (R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (20)
(R)(2,6-dichloropropylammo-pyrimido[5,4-d]pyrimidinylammo)-
propanol (19) (269 mg, 0.81 mmol) and methylamine (40% water solution) were reacted
in n-butanol using procedure described for compound 4 to afford (R)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan-l-ol (20) (180
mg, 69% yield). 300 MHz 'H NMR (CDCb, ppm): 6.67-6.43 (2H, m) 5.0-4.5 (3H, m) 4.30-
4.13 (1H, m) 3.79 (1H, dd, J=11.0, 2.8 Hz) 3.68 (1H, dd, J=11.0, 7.4 Hz) 3.51-3.41 (2H, m)
2.97 (3H,d, J=5.1 Hz) 2.95 (3H, d, J=5.1 Hz) 1.77-1.62 (2H, m) 1.34 (3H, d, J=6.9 Hz) 1.00
(3H, t, 3=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) (R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol hydrochloride (20a)
(R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-propan-l-ol (20) (143 mg, 0.45 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether using procedure described for compound 6a to produce (R)(2,6-bis-methyl
aminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan-l-ol hydrochloride
(20a) (150 mg, 93% yield). 300 MHz 1HNMR (CDsOD, ppm): 4.50-4.38 (1H, m) 3.72 (1H,
dd, J=ll.l, 4.9 Hz) 3.67 (1H, dd, J=ll.l, 5.4 Hz) 3.58 (2H, t, J=7.2 Hz) 3.02 (3H, s) 2.99
(3H, s) 1.81-1.70 (2H, m) 1.33 (3H, d, J=6.8 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321
[M+H]+;MP: 197-199 °C.
Example 10: 3-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-1,1,1 -trifluoro-propanol (22) and corresponding hydrochloride salt (22a)
HsC^H
NI^N H CF3
~-[!'W"AOH
H'""^CH3 22
(a) 3-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-l,l,l-trifluoro-
propanol (21)
A mixture ofpropyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-amine
(2) (250 mg, 0.85 mmol) and 3-amino-l,l,l-trifluoro-propanol (221 mg, 1.71 mmol) in
THF (7 mL) was stirred at room temperature for 18h. A saturated NaHCOs solution (30 mL)
was added, the resulting suspension was extracted with dichloromethane (3x10 mL). The
combined organic extracts were washed with brine (30 mL) and dried over solid anhydrous
Na2S04. After filtering, the solvent was removed and the residue was purified by flash
column chromatography using gradient elution from PE/EtOAc (3:1) to PE/EtOAc (1:9) to
give 3-(2,6-dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-1,1,1 -trifluoro-
propanol (21) (277 mg, 84% yield). ESI-MS (m/z): 385, 387, 389 [M+H]+.
(b) 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-l, 1,1-
tnfluoro-propanol (22)
3-(2,6-Dichloropropylammo-pyrimido[5,4-d]pyrimidinylammo)-l,l,l-
trifluoro-propanol (21) (277 mg, 0.72 mmol) and methylamine (40% water solution) were
reacted in n-butanol at 125 °C using procedure described for compound 4 to give 3-(2,6-bis-
methylaminopropylammo-pyrimido [5,4-d]pyrimidinylamino)-1,1,1 -trifluoro-propan
ol (22) (250 mg, 93% yield). 300 MHz 1H NMR (CDCb, ppm): 6.69-6.87 (2H, m) 6.55-6.46
(1H, m) 4.73-4.58 (2H, m) 4.26-4.14 (1H, m) 3.90-3.74 (2H, m) 3.51-3.40 (2H, m) 2.96 (3H,
d, J-5.0 Hz) 2.95 (3H, d, J=5.0 Hz) 1.69 (2H, sextet, J=7.4 Hz) 1.0 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 375 [M+H]+.
(c) 3-(2,6-Bis-methylammopropylammo-pyrimido[5,4-d]pyrimidinylammo)-l,l,l-
trifluoro-propanol hydrochloride (22a)
3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylammo)-UJ-trifluoro-propanol (22) (220 mg, 0.59 mmol) was treated with 2M HC1
/diethyl ether in dichloromethane using procedure described for compound 12a to produce 3-
(2,6-bis-methylaminopropylammo-pyrimido [5,4-d]pyrimidinylamino)-1,1,1 -trifluoro-
propanol hydrochloride (22a) (185 mg, 76% yield). 300 MHz 1H NMR (CDCls, ppm):
13.89-13.57 (1H, m) 8.29-8.09 (1H, m) 7.60-7.45 (1H, m) 6.35-6.15 (1H, m) 5.35-5.18 (1H,
m) 4.99-4.86 (1H, m) 4.42-4.27 (1H, m) 3.91-3.69 (2H, m) 3.68-3.57 (2H, m) 3.10-3.02 (3H,
m) 2.96 (3H, d, J=4.8 Hz) 1.76 (2H, sextet, J=7.4 Hz) 1.04 (3H, t, J=7.4 Hz). ESI-MS (m/z):
375 [M+H]+; MP: 230-232 °C.
Example 11: l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-butanol (24) and corresponding hydrochloride salt (24a)
HsC^H
N^N ^ ^CH3
""Yi-^"
H CH3 ^
(a) l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (23)
Propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidmyl)-amine (2) (350 mg,
1.20 mmol) and l-amino-butanol were reacted in butanol using procedure described for
compound 9The product was purified by flash column chromatography using gradient elution
from CHhCh to CH2Cl2/EtOAc (4:1) as eluent to give to give l-(2,6-dichloropropylamino-
pyrimido[5,4-d]pyrimidinylamino)-butanol (23) (350 mg, 84% yield). 300 MHz 1H
NMR (CDCls, ppm): 7.29 (1H, t, J=5.7 Hz) 6.90 (1H, t, J=5.7 Hz) 3.89-3.74 (2H, m) 3.60-
3.45 (3H, m) 2.63 (1H, d, J=3.8 Hz) 1.72 (2H, sextet, J=7.4 Hz) 1.67-1.51 (2H, m) 1.03 (3H,
t, J=7.4 Hz) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 345, 347, 349 [M+H]+.
(b) l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol (24)
l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol (23) (350 mg, 1.01 mmol) and methylamine (40% water solution) were reacted in n-
butanol using procedure described for compound 4. The crude product was purified by flash
column chromatography using gradient elution from CH2Cl2/EtOAc (9:1) to CHhCk/EtOAc
(1:4) as eluent to give l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-butanol (24) (275 mg, 81% yield). 300 MHz 'H NMR (CDCk, ppm): 6.96-6.80
(1H, m) 6.57-6.43 (1H, m) 4.92 (1H, s) 4.72-4.50 (2H, m) 3.84-3.69 (1H, m) 3.63 (1H, ddd,
J=14.3, 6.3, 2.1 Hz) 3.56-3.38 (3H, m) 2.96 (3H, d, J=5.2 Hz) 2.94 (3H, d, J=5.2 Hz) 1.68
(2H, sextet, J=7.4 Hz) 1.60-1.45 (2H, m) 0.99 (6H, t, J=7.4 Hz). ESI-MS (Wz): 335 [M+H]+.
(c) 1 -(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol hydrochloride (24a)
l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-butanol (24) (270 mg, 0.81 mmol) and 2M HC1 /diethyl ether in diethyl ether
were reacted using procedure described for compound 6a to produce l-(2,6-bis-methylamino-
8-propylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol hydrochloride (24a) (240
mg, 80% yield). 300 MHz }H NMR (CDsOD, ppm) 3.85-3.72 (2H, m) 3.58 (2H, t, J=7.1 Hz)
3.49 (1H, dd, J-14.3, 8.3 Hz) 3.00 (6H, s) 1.75 (2H, sextet, J=7.4 Hz) 1.66-1.42 (2H, m) 1.02
(6H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
Example 12: 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmyl
amino)-butanol (26) and corresponding hydrochloride salt (26a)
H3C^H
Nl N HH?H3
'K-YTNt^°H
N^N CH'3-
H CHs ^
(a) 3-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (25)
Propyl-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinyl)-amine (2) (360 mg,
1.23 mmol) and 3-amino-butanol were reacted in n-butanol using procedure described for
compound 21. The product was purified by flash column chromatography using gradient
elution from PE/EtOAc (95:5) to PE/EtOAc (5:95) to give 3-(2,6-dichloropropylamino-
pyrimido[5,4-d]pyrimidinylammo)-butanol (25) (330 mg, 78% yield). 300 MHz *H
NMR (CDCb, ppm): 7.14 (1H, d, J=8.6 Hz) 6.91 (1H, t, J=5.6 Hz) 4.38-4.24 (1H, m) 4.01-
3.89 (1H, m) 3.61-3.49 (2H, m) 2.53 (1H, d, J=3.5 Hz) 1.79-1.65 (2H, m) 1.34 (3H, d, J=6.7
Hz) 1.26 (3H, d, J=6.3 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 345, 347, 349 [M+H]+.
(b) 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol (26)
3-(2,6-Dichloropropylammo-pyrimido[5,4-d]pyrimidmylamino)-butan-
2-ol (25) (330 mg, 0.95 mmol) and methylamine (40% water solution) were reacted in n-
butanol at 120 °C using procedure described for compound 4 to afford 3-(2,6-bis-
methylaminopropyl amino-pyrimido[5,4-d]pyrimidinylamino)-butanol (26) (208 mg,
66% yield). 400 MHz 'H NMR (CDCls, ppm): 6.60 (1H, d, J=6.3 Hz) 6.54-6.48 (1H, m)
4.68-4.54 (2H, m) 4.35 (1H, br s) 4.0 (1H, sextet, J=6.8 Hz) 3.82 (1H, pentet, J=6.2 Hz) 3.49-
3.43 (2H, m) 2.96 (3H, d, J=5.2 Hz) 2.94 (3H, d, J=5.2 Hz) 1.69 (2H, sextet, J=7.4 Hz) 1.32
(3H, d, J=6.8 Hz) 1.23 (3H, d, J=6.2 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
(c) 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)-butan-
2-ol hydrochloride (26a)
3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-butanol (26) (208 mg, 0.62 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether using procedure described for compound 6a to afford 3-(2,6-bis-methylamino-
8-propylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol hydrochloride (26a) (170
mg, 74% yield). 400 MHz IH NMR (CDsOD, ppm): 4.43-4.35 (1H, m) 3.96-3.89 (1H, m)
3.59 (2H, t, J=7.2 Hz) 3.02 (3H, s) 3.01 (3H, s) 1.76 (2H, sextet, J=7.4 Hz) 1.32 (3H, d, J=6.7
Hz) 1.21 (3H, d, J=6.4 Hz) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
Example 13: 2-(2,6-Bis-ethylammopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (27) and corresponding hydrochloride salt (27a)
ll -T H
<?^^N.
'K' T T v 'OH
H""^ 27
(a) 2-(2,6-Bis-ethylammopropylamino-pyrimido[5,4-d]pyrimidinylammo)-ethanol
(27)
A mixture of 2-(2,6-dichloropropylamino-pyrimido[5,4-d]pyrimidmyl
amino)-ethanol (3) (250 mg, 0.79 mmol) and ethylamine (70% water solution) (1.20 mL) in
n-butanol (2 mL) was heated at 120°C for 48 h in a closed vial. After cooling, a saturated
NaCl solution (20 mL) was added and the resulting suspension was extracted with EtOAc (3
x 30 mL). The combined organic extracts were washed with brine (30 mL) and dried over
solid anhydrous N02804. The solvent was removed and the residue was purified by flash
column chromatography using gradient elution from CHzCk/EtOAc (99:1) to CH2Cl2/EtOAc
(9:1) to give 2-(2,6-bis-ethylaminopropylammo-pyrimido[5,4-d]pyrimidmylamino)-
ethanol (27) (220 mg, 83% yield). 400 MHz !H NMR (CDCb, ppm): 6.90 (1H, s) 6.49 (1H,
s) 4.62 (2H, br s) 4.52 (1H, s) 3.88-3.84 (2H, m) 3.71-3.64 (2H, m) 3.50-3.34 (6H, m) 1.69
(2H, sextet, J=7.4 Hz) 1.23 (3H, t, J=7.2 Hz) 1.22 (3H, t, J=7.2 Hz) 1.00 (3H, t, J=7.4 Hz).
ESI-MS (m/z): 335 [M+H]+.
(b) 2-(2,6-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol
hydrochloride (27a)
2-(2,6-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (27) (190 mg, 0.62 mmol) was treated with 2M HC1 /diethyl ether in diethyl ether /
ethanol (2/1) using procedure described for compound 12a to produce 2-(2,6-bis-ethylamino-
8-propylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol hydrochloride (27a) (185 mg,
88% yield). 400 MHz 1H NMR (CDsOD, ppm): 3.82-3.77 (2H, m) 3.76-3.65 (2H, m) 3.56
(2H, t, J=7.0 Hz) 3.53-3.41 (4H, m) 1.79-1.68 (2H, m) 1.30-1.19 (6H, m) 1.01 (3H, t, J=7.4
Hz). ESI-MS (m/z): 335 [M+H]+; MP: 192-194 °C.
Example 14: 2-[8-Propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]
pyrimidinylammo]-ethanol (28) and corresponding hydrochloride salt (28a)
"-N^CFS 2S
(a) 2-[8-Propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinyl
amino]-ethanol (28)
A mixture of 2-(2,6-dichloropropylamino-pyrimido[5,4-d]pyrimidinyl
amino)-ethanol (3) (240 mg, 0.76 mmol) and 2,2,2-trifluoro-ethylamine (726 |^L, 9.12 mmol)
in n-butanol (2 mL) was heated at 120°C for 72 h in a closed vial. The reaction mixture was
cooled and the precipitate were filtered, washed with ethanol (2x5 mL) and dried to give 2-
[8-propyl amino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]-
ethanol (28) (310 mg, 92% yield). 400 MHz !H NMR (DMSO-d6, ppm): 8.3-7.6 (1H, br s)
7.41 (1H, br s) 4.36-4.18 (4H, m) 3.72-3.37 (6H, m, overlapped with water) 1.63 (2H, sextet,
J=7.3 Hz) 0.92 (3H, t, J=7.3 Hz). ESI-MS (m/z): 443 [M+H]+.
(b) 2-[8-Propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinyl
amino]-ethanol hydrochloride (28a)
2-[8-Propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-
d]pyrimidmylamino]-ethanol (28) (250 mg, 0.57 mmol) was treated with 2M HC1 /diethyl
ether in CHhCh using procedure described for compound 6a to produce 2-[8-propylamino-
2,6-bis-(2,2,2-trifluoroethylamino)-pyrimido[5,4-d]pyrimidinylamino]ethanol
hydrochloride (28a) (250 mg, 92% yield). 400 MHz 1HNMR (CDsOD, ppm): 4.28 (2H, q,
J=9.1 Hz) 4.27 (2H, q, J=9.1 Hz) 3.83-3.78 (2H, m) 3.77-3.72 (2H, m) 3.60 (2H, t, J=7.1 Hz)
1.80-1.70 (2H, m) 1 .02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 443 [M+H]+; MP: 254-255 °C.
Example 15: 1 -(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl
amino)methyl-propanol (31) and corresponding hydrochloride salt (31a)
H3C^H
N.^N ^ H3C
^v^,%
H^'^CH,
(a) 2-Methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylamino)-propanol (29)
To a suspension of2,4,6,8-tetrachloro-pyrimido[5,4-d]pyrimidme (1) (3.50 g,
13.01 mmol) in THF (200 mL) at -78°C, l-aminomethyl-propanol (1.17 mL, 12.36
mmol) in THF (20 mL) was added via syringe pump (during about 30 min) followed by
DIPEA (2.93 mL, 1 6.91 mmol) in THF (20 mL). The reaction mixture was stirred at -78°C
for additional 30 min, and then allowed to reach the room temperature. Water (250 mL) was
added and the resulting suspension was extracted with EtOAc (3 x 100 mL). The combined
organic extracts were washed with water (150 mL), then with brine (150 mL) and dried over
solid anhydrous MgS04. After filtration, the solvent was removed and the residue was
purified by flash column chromatography using gradient elution from PE/EtOAc (10:4) to
PE/EtOAc (1:1) to give 2-methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylamino)-
propanol (29)(3.67 g, 92% yield). 300 MHz 1H NMR (CDCb, ppm): 7.70-7.58 (1H, m)
3.70 (2H, d, J=6.1 Hz) 1.80 (1H, s) 1.36 (6H, s). ESI-MS (m/z): 322, 324, 326, 328 [M+H]+.
(b) l-(2,6-Dichloropropylammo-pyrimido[5,4-d]pyrimidinylamino)methyl-
propanol (30)
Propylamine (1.03 mL, 12.50 mmol) and DIPEA (2.56 mL, 14.79 mmol) were
added to a solution of2-methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidmylammo)-
propanol (29) (3.67 g, 11.38 mmol) in dichloromethane (50 mL) at 0°C. The reaction
mixture was stirred at room temperature for 2h. After this time, a saturated NaHCOs (100
mL) was added and the resulting suspension was extracted with dichloromethane (3x50
mL). The combined organic extracts were washed with water (100 mL) and dried over solid
anhydrous MgS04. After filtration, the solvent was removed and the residue was purified by
Hash column chromatography using gradient elution from PE/EtOAc (5:1) to PE/EtOAc (2:1)
to give 1 -(2,6-dichloropropylammo-pyrimido[5,4-d]pyrimidinylammo)methyl-
propanol (30) (3.10 g, 79% yield). 300 MHz 1H NMR (CDCk, ppm): 7.28 (1H, t, J=6.2
Hz) 6.94-6.84 (1H, m) 3.62 (2H, d, J=6.2 Hz) 3.60-3.51 (2H, m) 2.36 (1H, s) 1.72 (2H,
sextet, J=7.4 Hz) 1.32 (6H, s) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 345, 347, 349 [M+H]+.
(c) 1 -(2,6-Bis-methylaminopropylamino-pyrimido [5,4-d]pyrimidinylamino)
methyl-propanol (31)
l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (30) (3.10 g, 8.98 mmol) and methylamine (40% water solution) (7.7
mL) were reacted in n-butanol (20 mL) heated at 1 15°C for 72 h. After cooling, a saturated
NaHCOs solution (100 mL) was added and the resulting suspension was extracted with
EtOAc (3 x 75 mL). The combined organic extracts were washed with water (100 mL), then
with a brine solution (100 mL) and lastly, dried over solid anhydrous MgS04. After
filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from CH2Ck/MeOH (99:1) to CHhCk/MeOH (95:5)
to give 1 -(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (31) (2.30 g, 77% yield). 300 MHz 'H NMR (CDCls, ppm): 6.98-6.83
(1H, m) 6.55-6.45 (1H, m) 5.24-5.06 (1H, m) 4.70-4.53 (2H, m) 3.52 (2H, d, J=6.3 Hz) 3.50-
3.41 (2H, m) 2.97 (3H, d, J=5.1 Hz) 2.94 (3H, d, J=5.1 Hz) 1.76-1.61 (2H, m) 1.27 (6H, s)
1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
(d) l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol hydrochloride (3 1 a)
A 2M HC1 /diethyl ether solution (3.42 mL, 6.84 mmol) was added to the
solution of 1 -(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (31) (2.30 g, 6.88 mmol) in diethyl ether (60 mL) and ethanol (3 mL).
The mixture was stirred for 0.5 h at room temperature and the resultant precipitate were
filtered and washed with diethyl ether (60 mL) to give l-(2,6-bis-methylamino
propylamino-pyrimido[5,4-d] pyrimidinylamino)methyl-propanol hydrochloride
(31a) (2.36 g, 92% yield). 300 MHz }H NMR (CDsOD, ppm): 3.64 (2H, s) 3.57 (2H, t, J=7.2
H) 3.00 (6H, s) 1.82-1.67 (2H, m) 1.27 (6H, s) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335
[M+H]+; MP: 205-208 °C. Anal. Calcd for C^HhpClNgO: C, 48.58; H, 7.34; N, 30.21.
Found: C, 48.33; H, 7.34; N,30.00.
Example 16: 1 -(2,6-Bis-ethylammopropylamino-pyrimido[5,4-d]-pyrimidmylamino)-
2-methyl-propanol (32) and corresponding hydrochloride salt (32a)
Nl N HH3?^CH3
'~KAA'R^""
H^v 32
(a) 1 -(2,6-Bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)
methyl-propanol (32)
l-(2,6-Dichloropropylatnino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (30) (300 mg, 0.87 mmol) was reacted with ethylamine (70% water
solution) in n-butanol using procedure described for compound (27) to afford l-(2,6-bis-
ethylaminopropylamino-pyrimido[5,4-d]-pyrimidmylamino)methyl-propanol (32)
(220 mg, 70% yield). 300 MHz 'H NMR (CDCls, ppm): 6.86 (1H, t, J=6.3 Hz) 6.46 (1H, t,
J=5.8 Hz) 5.21 (1H, s) 4.58 (1H, t, J=5.5 Hz) 4.51 (1H, t, J=5.5 Hz) 3.51 (2H, d, J=6.3 Hz)
3.49-3.33 (6H, m) 1.75-1.61 (2H, m) 1.27 (6H, s) 1.23 (3H, t, 3=7.2 Hz) 1.21 (3H, t, J=7.2
Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 363 [M+H]+.
(b) l-(2,6-Bis-ethylammopropylamino-pyrimido[5,4-d]-pyrimidmylammo)
methyl-propanol hydrochloride (32a)
l-(2,6-Bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
2-methyl-propanol (32) (175 mg, 0.48 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / methanol (1/1) using procedure described for compound 12a to obtain 1-(2,6-
bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)methyl-propanol
hydrochloride (32a) (170 mg, 88% yield). 300 MHz !H NMR (CDsOD, ppm): 3.64 (2H, s)
3.56(2H,t,J=7.1 Hz)3.48(4H,q,J=7.1 Hz) 1.83-1.65 (2H, m) 1.36-1.14 (12H,m) 1.01 (3H,
t, J=7.4 Hz). ESI-MS (m/z): 363 [M+H]+; MP: 199-201 °C.
Example 17: 1 -[2,6-Bis-(2,2-difluoro-ethylamino)propylammo-pyrimido[5,4-d]-
pyrimidinylamino]methyl-propanol (33) and corresponding hydrochloride salt (33a)
F^N'H
N"S , HsC
.-^ 33
(a) l-[2,6-Bis-(2,2-difluoro-ethylammo)propylamino-pyrimido[5,4-d]-pyrimidm
ylammo]methyl-propanol (33)
l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylammo)
methyl-propanol (30) (300 mg, 0.87 mmol) and 2,2-difluoro-ethylamine were reacted in n-
butanol using procedures described elsewhere herein. The product was purified by flash
column chromatography using gradient elution from PE/EtOAc (5:1) to PE/EtOAc (1:1) to
give 1 -[2,6-bis-(2,2-difluoro-ethylamino)propylammo-pyrimido[5,4-d]-pyrimidm
ylamino]methyl-propanol (33) (200 mg, 53% yield). 300 MHz !H NMR (CDC13, ppm):
6.85 (1H, t, J=6.0 Hz) 6.47 (1H, t, J=6.0 Hz) 5.97 (1H, tt, J=56.5, 4.3 Hz) 5.94 (1H, tt,
J=56.5, 4.3 Hz) 4.94-4.80 (2H, m) 3.88-3.68 (5H, m) 3.53 (2H, d, J=6.4 Hz) 3.51-3.42 (2H,
m) 1.76-1.62 (2H, m) 1.29 (6H, s) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 435 [M+H]+.
(b) l-[2,6-Bis-(2,2-difluoro-ethylamino)propylamino-pyrimido[5,4-d]-pyrimidm
ylamino]methyl-propanol hydrochloride (33a)
l-[2,6-Bis-(2,2-difluoro-ethylamino)propylamino-pyrimido[5,4-d]-
pyrimidinyl amino]methyl-propanol (33) (170 mg, 0.39 mmol) was treated with 2M
HC1 /diethyl ether in diethyl ether using procedure described for compound 6a to give 1-[2,6-
bis-(2,2-difluoro-ethylamino)propylamino-pyrimido[5,4-d]-pyrimidinylamino]
methyl-propanol hydrochloride (33a) (170 mg, 92% yield). 400 MHz rH NMR (CDsOD,
ppm): 6.04 (2H, t, J=56.5 Hz) 3.98-3.73 (4H, m) 3.64 (2H, s) 3.62-3.51 (2H, m) 1.81-1.66
(2H, m) 1.28 (6H, s) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 435 [M+H]+; MP: 245-247 °C.
Example 18: 2-Methyl-l-[8-propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-
d] pyrimidinylamino]-propanol (34) and corresponding hydrochloride salt (34a)
FsC" ^N/'
N^^N ,. HaC
H ""T^CHs
^YT^""
N<^N
H-N^-CF3 34
(a) 2-Methyl-l-[8-propylamino-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]
pyrimidmylammo]-propanol (34)
l-(2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinylammo)
methyl-propanol (30) (300 mg, 0.87 mmol) and 2,2,2-trifluoro-ethylamine were reacted in
n-butanol using procedures previously to afford 2-methyl-l-[8-propylamino-2,6-bis-(2,2,2-
trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]-propanol (34) (390 mg, 95%
yield). 300 MHz !H NMR (CDsOD, ppm): 4.34-4.14 (4H, m) 3.66 (2H, s) 3.60 (2H, t, J=6.8
Hz) 1.82-1.66 (2H, m) 1.28 (6H, s) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 471 [M+H]+.
(b) 2-]V[ethyl-l-[8-propylammo-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-
d]pyrimidinylamino]-propanol hydrochloride (34a)
2-Methyl-l-[8-propylammo-2,6-bis-(2,2,2-trifluoro-ethylamino)-
pyrimido[5,4-d]pyrimidinylammo]-propanol (34) (344 mg, 0.73 mmol) was treated
with 2M HC1 /diethyl ether in methanol using procedure described for compound 12a to
produce 2-methyl-l-[8-propylammo-2,6-bis-(2,2,2-trifluoro-ethylamino)-pyrimido [5,4-
d]pyrimidinylammo]-propanol hydrochloride (34a) (255 mg, 69% y). 300 MHz 1H
NMR (DMSO-d6, ppm): 9.6-7.8 (3H, m) 7.68 (1H, s) 7.53 (1H, s) 4.4-3.9 (4H, m, overlapped
with water) 3.58-3.38 (4H, m) 1.72-1.55 (2H, m) 1.17 (6H, s) 0.93 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 471 [M+H]+; MP: 257-259 °C.
Example 19: l-[8-(2,2-Difluoro-ethylamino)-2,6-bis-methylammo-pyrimido[5,4-
d]pyrimidinylamino]methyl-propanol (36) and corresponding hydrochloride salt
(36a)
N^N ^
Fr'KVYK^OH
F " N^N
(a) l-[2,6-Dichloro(2,2-difluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]
methyl-propanol (35)
2-Methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylamino)-propanol
(29) (550 mg, 1.71 mmol) and 2,2-difluoro-ethylamine in THF were reacted using procedures
described elsewhere herein to obtain l-[2,6-dichloro(2,2-dinuoro-ethylamino)-
pyrimido[5,4-d]pyrimidinylammo]methyl-propanol (35) (609 mg, 97% yield). ESI-
MS (m/z): 367, 369, 371 [M+H]+.
(b) I -[8-(2,2-Difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]methyl-propanol (36)
l-[2,6-Dichloro(2,2-difluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylammo]methyl-
propanol (35) (300 mg, 0.82 mmol) and methylamine (40% water solution) were reacted
in n-butanol at 125°C using procedure described for compound (4) to produce 1-[8-(2,2-
difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]methyl-
propanol (36) (172 mg, 59% yield). 400 MHz 'H NMR (CDCk, ppm): 6.89 (1H, t, J=5.0
Hz) 6.63 (1H, t, J=5.0 Hz) 6.0 (1H, tt, J=56.4, 4.4 Hz) 4.84 (1H, s) 4.69-4.56 (2H, m) 3.96-
3.84 (2H, m) 3.54 (2H, d, J=6.4 Hz) 2.97 (3H, d, J=5.2 Hz) 2.94 (3H, d, J=5.2 Hz) 1.28 (6H,
s). ESI-MS (m/z): 357 [M+H]+.
(c) l-[8-(2,2-Difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidm
ylamino]methyl-propanol hydrochloride (36a)
l-[8-(2,2-Difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
2-methyl-propanol (36) (150 mg, 0.42 mmol) and 2M HC1 /diethyl ether were reacted in
CHhCk (7 ml) using procedure described for compound (12a) to give l-[8-(2,2-difluoro-
ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]methyl-propan
ol hydrochloride (36a) (335 mg, 82% yield). 400 MHz 1HNMR (CDCk, ppm): 8.18-7.85
(2H, m) 7.66 (1H, br s) 6.67-6.38 (1H, m) 6.05 (1H, tt, J=56.0, 4.2 Hz) 4.94 (1H, br s) 4.15-
3.85 (2H, m) 3.70-3.52 (2H, m) 3.10-2.89 (6H, m) 1.34 (6H, s). ESI-MS (m/z): 357 [M+H]+;
MP: 223-225 °C.
Example 20: l-{2,6-Bis-methylammo[(pyrimidinylmethyl)-ammo]-pyrimido[5,4-
d]pyrimidinylamino}methyl-propanol (38) and corresponding hydrochloride salt
(38a)
""'NH
Nl""N H
'NY^y^fYN-A:OH
,^N H N^^N
HN- 38
(a) l-{2,6-Dichloro[(pyrimidinylmethyl)-amino]-pyrimido[5,4-d]pyrimidm
ylamino}methyl-propanol (37)
A mixture of 2-methyl-1 -(2,6,8-trichloro-pyrimido [5,4-d]pyrimidin
ylamino)-propanol (29) (250 mg, 0.78 mmol), pyrimidinylmethanamine (114 mg, 0.78
mmol) and N,N-diisopropylethylamine (272 p.L, 1.56 mmol) in n-butanol (4 mL) was heated
at 70 °C for 2h. The reaction mixture was cooled to room temperature, the precipitate were
filtered, washed with n-butanol (3 mL), then ethanol (3 mL) and dried to give 1-{2,6-
dichloro [(pyrimidinylmethyl)-amino] -pyrimido [5,4-d]pyrimidinylamino} methyl-
propanol (37) (300 mg, 97% yield). 300 MHz 'HNMR (CDCb, ppm): 8.78 (2H, d, J=4.9
Hz) 8.09 (1H, t, J=5.0 Hz) 7.33-7.23 (1H, m) 7.27 (1H, t. 3=4.9 Hz) 5.02 (2H, d, J=5.0 Hz)
3.64 (2H, d, J=6.3 Hz) 2.28 (1H, s) 1.33 (6H, s). ESI-MS (m/z): 395, 397, 399 [M+H]+.
(b) l-{2,6-Bis-methylammo[(pyrimidmylmethyl)-amino]-pyrimido[5,4-
d]pyrimidinylamino}methyl-propanol (38)
l-{2,6-Dichloro[(pyrimidmylmethyl)-amino]-pyrimido[5,4-d]pyrimidin-
4-ylamino}methyl-propanol (37) (300 mg, 0.76 mmol) and methylamine (1 mL, 40%
water solution) were heated in DMSO (2 mL) at 115°C for 72 h in a closed vial.. After
cooling, a saturated NaHCOs solution (100 mL) was added and the resulting suspension was
extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water
(10 mL), then with a brine solution (10 mL) and dried over solid anhydrous MgS04. After
filtration, the product was purified by flash column chromatography using gradient elution
from CHbCh to TOCk/EtOH (4:1) to give pure l-{2,6-bis-methylamino[(pyrimidm
ylmethyl)-ammo]-pyrimido[5,4-d]pyrimidinylammo}methyl-propanol (38) (120 mg,
41% yield). 300 MHz 1H NMR (CDCb, ppm): 8.76 (2H, d, J=4.9 Hz) 7.67-7.57 (1H, m)
7.22 (1H, t, J=4.9 Hz) 6.96-6.84 (1H, m) 5.27 (1H, br s) 4.95 (2H, d, J=5.1 Hz) 4.71-4.57
(2H, m) 3.54 (2H, d, J=6.3 Hz) 2.99 (3H, d, J=5.1 Hz) 2.96 (3H, d, J=5.1 Hz) 1.28 (6H, s).
ESI-MS (m/z): 385 [M+H]+.
(c) l-{2,6-Bis-methylamino[(pyrimidinylmethyl)-amino]-pyrimido[5,4-
djpyrimidinylammo} methyl-propanol hydrochloride (38a)
l-{2,6-Bis-methylamino[(pyrimidmylmethyl)-amino]-pyrimido[5,4-
d]pyrimidinylamino}methyl-propanol (38) (110 mg, 0.29 mmol) and 2M HC1
/diethyl ether were reacted in diethyl ether / EtOH (5/1) using procedure described for
compound (6a) to produce l-{2,6-bis-methylamino[(pyrimidinylmethyl)-amino]-
pyrimido[5,4-d]pyrimidinylammo}methyl-propanol hydrochloride (38a) (110 mg,
90% yield). 300 MHz 'H NMR (CDsOD, ppm): 8.78 (2H, d, J=5.0 Hz) 7.42 (1H, t, J=5.0
Hz) 4.99 (2H, s) 3.66 (2H, s) 3.03 (3H, s) 2.86 (3H, s) 1.28 (6H, s). ESI-MS (m/z): 385
[M+H]+; MP: 169-170 °C.
Example 21: l-[8-((R)-^ec-Butylammo)-2,6-bis-methylammo-pyrimido[5,4-d]-pyrimidm
ylamino]methyl-propanol (40) and corresponding hydrochloride (40a)
LMVrK-AOH
N^.N
HN- 40
(a) (R)-l-(8->s'ec-Butylamino-2,6-dichloro-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (39)
A mixture of 2-methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (29) (250 mg, 0.78 mmol) and (R)-butanamine (93 [iL, 0.93 mmol)
and N,N-diisopropylethylamine (202 |J.L, 1.17 mmol) in CHhCk (5 mL) was stirred at room
temperature for 16 h. Water (10 mL) was added and the resulting suspension was extracted
with methylene chloride (3 x 20 mL). The combined organic extracts were washed with
water (30 mL) and dried over solid anhydrous MgS04. After filtration, the solvent was
removed and the product was filtered through a silica gel pad using PE/EtOAc as eluent to
give, after rotary evaporation, (R)-l-(8-5ec-butylamino-2,6-dichloro-pyrimido[5,4-
d]pyrimidinylamino)methyl-propanol (39) (255 mg, 91% yield). 300 MHz 1HNMR
(CDCk, ppm): 7.29 (1H, t, J=6.2 Hz) 6.69 (1H, d, J=8.7 Hz) 4.36-4.20 (1H, m) 3.62 (2H, d,
J=6.2 Hz) 2.36 (1H, s) 1.71-1.58 (2H, m) 1.32 (6H, s) 1.28 (3H,d, J=6.6 Hz) 0.97 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 359, 361, 363 [M+H]+.
(b) l-[8-((R)-5ec-Butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol (40)
(R)-1 -(8 -5ec-Butylamino-2,6-dichloro-pyrimido [5,4-d]pyrimidinylamino)-
2-methyl-propanol (39) (250 mg, 0.70 mmol) and methylamine (40% water solution, 700
j^L)) were reacted in n-butanol (3 mL) at 125 °C for 96 h. A saturated sodium bicarbonate
solution (10 mL) was added and the resulting suspension was extracted with EtOAc (3x15
mL). The combined organic extracts were washed with a brine solution (30 mL) and dried
over solid anhydrous MgS04. After filtration, the solvent was removed and the product was
purified by flash column chromatography using gradient elution from PE/acetone (10:1) to
PE/acetone (4:l)to give l-[8-((R)-^ec-butylammo)-2,6-bis-methylammo-pyrimido[5,4-d]-
pyrimidinylammo]methyl-propanol (40) (176 mg, 73% yield). 300 MHz 1HNMR
(CDCk, ppm): 6.95-6.82 (1H, m) 6.29 (1H, d, J=8.3 Hz) 5.28 (1H, br s) 4.70-4.49 (2H, m)
4.22-4.02 (1H, m) 3.52 (2H, d, J=6.3 Hz) 2.98-2.91 (6H, m) 1.72-1.50 (2H, m) 1.27 (6H, s)
1.26 (3H, t, J=6.7 Hz) 0.96 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+.
(c) l-[8-((R)-sec-Butylamino)-2,6-bis-methylammo-pyrimido[5,4-d]-pyrimidm
ylammo]methyl-propanol hydrochloride (40a)
l-[8-((R)-5ec-Butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylamino]methyl-propanol (40) (176 mg, 0.51 mmol) and 2M HC1 /diethyl ether were
reacted in diethyl ether / EtOH (5/1) using procedure described for compound (6a) to produce
l-[8-((R)-^ec-butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]
methyl-propanol hydrochloride (40a) (170 mg, 87% yield). 300 MHz IH NMR (CD30D,
ppm): 4.40-4.20 (1H, m) 3.65 (2H, s) 3.11-2.86 (6H, m) 1.80-1.58 (2H, m) 1.35-1.22 (3H, m)
1.27 (6H, s) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+; MP: 173-175 °C.
Example 22: l-[8-((S)-^ec-Butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol (42) and corresponding hydrochloride salt (42a)
N^N ^
^AfSr N^)H
"< 42
(a) (S)-l-(8-sec-Butylamino-2,6-dichloro-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (41)
2-Methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidmylamino)-propanol
(29) (250 mg, 0.78 mmol) and (S)-butanamine in CH2Cb were reacted using procedure
described for compound (39) to give (S)-l-(8-5gc-butylammo-2,6-dichloro-pyrimido[5,4-
d]pyrimidinylammo)methyl-propanol (41) (253 mg, 90% yield). 300 MHz !H NMR
(CDCb, ppm): 7.31-7.24 (1H, m) 6.68 (1H, d, J=8.7 Hz) 4.36-4.20 (1H, m) 3.62 (2H, d,
J=6.2 Hz) 2.36 (1H, s) 1.71-1.58 (2H, m) 1.32 (6H, s) 1.28 (3H,d, J=6.6 Hz) 0.97 (3H, t,
3=7 A Hz). ESI-MS (m/z): 359, 361, 363 [M+H]+.
(b) l-[8-((S)-sec-Butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol (42)
(S)-l-(8-5ec-Butylammo-2,6-dichloro-pyrimido[5,4-d]pyrimidinylammo)-
2-methyl-propanol (41) (250 mg, 0.70 mmol) and methylamine (40% water solution) were
reacted in n-butanol at 125 °C using procedure described for compound (4) to give 1-[8-((S)-
5ec-butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]methyl-
propanol (42) (180 mg, 74% yield). 300 MHz 'H NMR (CDCb, ppm): 6.95-6.82 (1H, m)
6.29 (1H, d, J=8.3 Hz) 5.19 (1H, br s) 4.66-4.51 (2H, m) 4.22-4.02 (1H, m) 3.53 (2H, d,
J=6.3 Hz) 2.98-2.91 (6H, m) 1.72-1.50 (2H, m) 1.27 (6H, s) 1.26 (3H, t, J-6.7 Hz) 0.96 (3H,
t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+.
(c) l-[8-((S)-sec-Butylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol hydrochloride (42a)
l-[8-((S)-^ec-Butylamino)-2,6-bis-methylammo-pyrimido[5,4-d]-pyrimidm
ylamino]methyl-propanol (42) (150 mg, 0.43 mmol) and 2M HC1 /diethyl ether were
reacted in diethyl ether / EtOH (5/1) using procedure described for compound (6a) to produce
l-[8-((S)-^ec-butylamino)-2,6-bis-methylammo-pyrimido[5,4-d]-pyrimidinylamino]
methyl-propanol hydrochloride (42a) (155 mg, 94% yield). 300 MHz 1H NMR (CDsOD,
ppm): 4.40-4.20 (1H, m) 3.65 (2H, s) 3.00 (3H, s) 2.98 (3H, s) 1.80-1.58 (2H, m) 1.35-1.22
(3H, m) 1.27 (6H, s) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+; MP: 170-172 °C.
Example 23: l-(8-Benzylamino-2,6-bis-methylammo-pyrimido[5,4-d]pyrimidinylamino)-
2-methyl-propanol (44) and corresponding hydrochloride salt (44a)
""NH
(a) 1 -(8-Benzylamino-2,6-dichloro-pyrimido[5,4-d]pyrimidinylamino)methyl-
propanol (43)
2-Methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylammo)-propanol
(29) (250 mg, 0.78 mmol), benzylamine (102 \iL, 0.93 mmol) andN,N-
diisopropylethylamine (202 p-L, 1.17 mmol) in n-butanol (5 mL) were stirred at room
temperature for 3 h. Water (10 mL) was added and the resulting suspension was extracted
with EtOAc (3 x 20 mL). The combined organic extracts were washed with a brine solution
(30 mL) and dried over solid anhydrous N02804. After filtration, the solvent was removed
and the product was purified by flash column chromatography using gradient elution from
CH2Ck to CHzCk/EtOAc (9:1) to give l-(8-benzylammo-2,6-dichloro-pyrimido[5,4-
d]pyrimidmylamino)methyl-propanol (43) (290 mg, 95% yield). 300 MHz 1H NMR
(CDCb, ppm): 7.40-7.28 (6H, m) 7.14 (1H, t, J=5.9 Hz) 4.78 (2H, d, J=5.9 Hz) 3.63 (2H, d,
J=6.3 Hz) 2.19 (1H, br s) 1.32 (6H, s). ESI-MS (m/z): 393, 395, 397 [M+H]+.
(b) l-(8-Benzylammo-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (44)
l-(8-Benzylammo-2,6-dichloro-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (43) (280 mg, 0.71 mmol) and methylamine (40% water solution, 1,1
mL) were reacted in n-butanol (6 mL) at 120 °C for 72 h. After cooling, a saturated NaHCOs
solution (10 mL) was added, the resulting suspension was extracted with EtOAc (3 x 20 mL).
The combined organic extracts were washed with a brine solution (30 mL) and dried over
solid anhydrous N02804. After filtration, the solvent was removed and the product was
purified by flash column chromatography using gradient elution from CH2Cl2/EtOAc (9:1) to
CHhCk/EtOAc (1:4) as eluentto give pure l-(8-benzylamino-2,6-bis-methylamino-
pyrimido[5,4-d]pyrimidinylammo)methyl-propanol (44) (212 mg, 78% yield). 400
MHz 1HNMR (CDCk, ppm): 7.38-7.24 (5H, m) 6.98-6.89 (1H, m) 6.87-6.79 (1H, m) 5.10
(1H, s) 4.73 (2H, d, J=6.1 Hz) 4.68 (1H, br s) 4.63-4.55 (1H, m) 3.52 (2H, d, J=6.3 Hz) 2.97
(3H, d, J=5.1 Hz) 2.90 (3H, d, J=5.1 Hz) 1.27 (6H, s). ESI-MS (m/z): 383 [M+H]+.
(c) l-(8-Benzylamino-2,6-bis-methylammo-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol hydrochloride (44a)
l-(8-Benzylammo-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)methyl-propanol (44) (175 mg, 0.46 mmol) and 2M HC1 /diethyl ether were
reacted in diethyl ether / MeOH (5/1) using procedure described for compound (6a) to
produce l-(8-benzylamino-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylammo)
methyl-propanol hydrochloride (44a) (155 mg, 80% yield). 400 MHz )H NMR (CDsOD,
ppm): 7.44-7.40 (2H, m) 7.38-7.32 (2H, m) 7.31-7.26 (1H, m) 4.79 (2H, s) 3.65 (2H, s) 3.00
(3H, s) 2.98 (3H, s) 1.28 (6H, s). ESI-MS (m/z): 383 [M+H]+; MP: 227-228 °C.
Example 24: l-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]methyl-propanol (46) and corresponding hydrochloride salt
(46a)
^ N H
'K'Yl"-^0"
(a) l-[2,6-Dichloro(cyclopropylmethyl-amino)-pyrimido[5,4-d]pyrimidmylamino]-
2-methyl-propanol (45)
2-Methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylamino)-propanol
(29) (250 mg, 0.78 mmol) and cyclopropylmethanamine (80 pL, 0.93 mmol) and N,N-
diisopropylethylamine (202 \iL, 1.17 mmol) were stin-ed in n-butanol (5 mL) at ambient
temperature for 3 h. Water (10 mL) was added, the resulting suspension was extracted with
EtOAc (3 x 20 mL). The combined organic extracts were washed with a brine solution (30
mL) and dried over solid anhydrous N02804. After filtration, the solvent was removed and
the product was purified by flash column chromatography using gradient elution from
CH2Cl2/EtOAc (99:1) to CI^Ck/EtOAc (9:1) as eluentto give l-[2,6-dichloro
(cyclopropylmethyl-amino)-pyrimido[5,4-d]pyrimidinylamino]methyl-propanol (45)
(200 mg, 72% yield). ESI-MS (m/z): 357, 359, 361 [M+H]+.
(b) l-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]methyl-propaaol (46)
l-[2,6-Dichloro(cyclopropylmethyl-amino)-pyrimido[5,4-d]pyrimidin
ylamino]methyl-propanol (45) (200 mg, 0.56 mmol) and methylamine (40% water
solution, 870 pL) were heated n-butanol (6 mL) at 120 °C for 72 h. After cooling, a saturated
NaHCOs solution (10 mL) was added and the resulting suspension was extracted with EtOAc
(3 x 20 mL). The combined organic extracts were washed with a brine solution (30 mL) and
dried over solid anhydrous Na2S04. After filtration and removal of solvents, the product was
purified by flash column chromatography using gradient elution from CH2Cl2/EtOAc (9:1) to
CHhCk/EtOAc (1:4) as eluentto give l-[8-(cyclopropylmethyl-amino)-2,6-bis-methylamino-
pyrimido[5,4-d]pyrimidinylamino]methyl-propanol (46) (180 mg, 93% yield). 400
MHz 1H NMR (CDCla, ppm): 6.91 (1H, br s) 6.58 (1H, br s) 5.13 (1H, br s) 4.60 (2H, s) 3.53
(2H, d, J=6.3 Hz) 3.40-3.32 (2H, m) 2.99-2.93 (6H, m) 1.28 (6H, s) 1.18-1.07 (1H, m) 0.59-
0.52 (2H, m) 0.33-0.28 (2H, m). ESI-MS (m/z): 347 [M+H]+.
(c) l-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylammo]methyl-propanolhydrochloride (46a)
l-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]methyl-propanol (46) (180 mg, 0.52 mmol) and 2M HC1
/diethyl ether were reacted in diethyl ether using procedures previously to produce 1-[8-
(cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]
methyl-propanol hydrochloride (46a) (145 mg, 73% yield). 400 MHz 1H NMR (CDaOD,
ppm): 3.66 (2H, s) 3.47 (2H, d, J=7.2 Hz) 3.02 (3H, s) 3.00 (3H, s) 1.28 (s, 6H), 1.26-1.14
(1H, m) 0.63-0.56 (2H, m) 0.39-0.33 (2H, m). ESI-MS (m/z): 347 [M+H]+; MP: 215-216
Example 25: l-[8-(2,2-Difluoro-ethylamino)-2,6-bis-ethylamino-pyrimido[5,4-d]pyrimidin-
4-ylamino]methyl-propanol (47) and corresponding hydrochloride salt (47a)
hr ^N
FV^'NA^VN~~^OH
F " N^^N
HN^/ 47
(a) l-[8-(2,2-Difluoro-ethylamino)-2,6-bis-ethylammo-pyrimido[5,4-d]pyrimidin
ylamino]methyl-propanol (47)
l-[2,6-Dichloro(2,2-difluoro-ethylamino)-pyrimido[5,4-d]pyrimidinyl
amino]methyl-propanol (35) (300 mg, 0.82 mmol) and ethylamine (70% water solution)
were reacted in n-butanol using procedure described for compound (32) to give 1-[8-(2,2-
difluoro-ethylamino)-2,6-bis-ethylamino-pyrimido[5,4-d]pyrimidinylamino]methyl-
propanol (47) (262 mg, 83% yield). 400 MHz !H NMR (CDCla, ppm): 6.92-6.81 (1H, m)
6.66-6.53 (1H, m) 6.0 (1H, tt, J=56.4, 4.4 Hz) 4.89 (1H, s) 4.63 (1H, t, J=5.0 Hz) 4.59-4.52
(1H, m) 3.95-3.83 (2H, m) 3.52 (2H, d, J=6.3 Hz) 3.46-3.35 (4H, m) 1.28 (6H, s) 1.23 (3H, t,
J-7.4 Hz) 1.21 (3H, t, J=7.4 Hz). ESI-MS (m/z): 385 [M+H]+.
(b) l-[8-(2,2-Difluoro-ethylamino)-2,6-bis-ethylammo-pyrimido[5,4-d]pyrimidinyl
amino]methyl-propanol hydrochloride (47a)
l-[8-(2,2-Difluoro-ethylamino)-2,6-bis-ethylammo-pyrimido[5,4-d]pyrimidin-
4-ylamino]methyl-propanol (47) (200 mg, 0.52 mmol) and 2M HC1 /diethyl ether were
reacted in CHhCk using procedures described elsewhere herein to produce l-[8-(2,2-difluoro-
ethylamino)-2,6-bis-ethylamino-pyrimido[5,4-d]pyrimidinylamino]methyl-propanol
hydrochloride (47a) (170 mg, 78% yield). 400 MHz 'H NMR (CDCk, ppm): 8.24-7.97 (1H,
m) 7.89 (1H, br s) 7.61 (1H, br s) 6.71-6.45 (1H, m) 6.20-5.88 (1H, m) 4.95-4.85 (1H, m)
4.12-3.85 (2H, m) 3.69-3.35 (6H, m) 1.34 (6H, s) 1.30-1.20 (6H, m). ESI-MS (m/z): 385
[M+H]+; MP: 233-235 °C.
Example 26: 2-Methyl-l-(2,6,8-tris-methylammo-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (48) and corresponding hydrochloride salt (48a)
~S'YTK~~^OH
HN" 48
(a) 2-Methyl-l-(2,6,8-tris-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan
ol (48)
A mixture of2-methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (29) (400 mg, 1.24 mmol) and methylamine (40% water solution) (1.00
mL, 12.87 mmol) in n-butanol (5 mL) was stirred at room temperature for 2h and then heated
at 120°C for 96 h in the closed vial. After this time, a saturated NaHCOs solution (20 mL)
was added and the resulting suspension was extracted with EtOAc (3 x 25 mL). The
combined organic extracts were washed with water (30 mL), then with a brine solution (30
mL) and lastly dried over solid anhydrous N02804. After filtration, the solvent was removed
and the residue was purified by flash column chromatography using gradient elution from
PE/acetone (5:1) to PE/acetone (1:1) to give 2-methyl-l-(2,6,8-tris-methylamino-
pyrimido[5,4-d]-pyrimidinylammo)-propanol (48) (345 mg, 91% yield). 400 MHz 1H
NMR (CDCb, ppm): 7.21 (1H, s) 6.28 (1H, s) 6.36-5.94 (1H, br s) 4.87 (1H, s) 3.52 (2H, d,
J=6.0 Hz) 3.10 (3H, d, J=5.1 Hz) 2.99 (3H, d, J=5.0 Hz) 2.93 (3H, d, J=5.0 Hz) 1.28 (6H, s).
ESI-MS (m/z): 307 [M+H]+.
(b) 2-Methyl-l-(2,6,8-tris-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan
ol hydrochloride (48a)
2-Methyl-l-(2,6,8-tris-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (62) (310 mg, 1.01 mmol) and 2M HC1 /diethyl ether were reacted in diethyl
ether / MeOH (1/1) using procedures described elsewhere herein to produce 2-methyl-l-
(2,6,8-tris-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-propanolhydrochloride
(48a) (290 mg, 84% yield). 400 MHz 'H NMR (CDsOD, ppm): 3.65 (2H, s) 3.13 (3H, s)
3.09 (3H, s) 2.99 (3H, s) 1.28 (6H, s). ESI-MS (m/z): 307 [M+H]+; MP: 213-215 °C.
Example 27: 2-Methyl-1 -(2,6,8-tris-ethylamino-pyrimido[5,,4-d]-pyrimidmylamino)-
propanol (49) and corresponding hydrochloride salt (49a)
^ N "
'N'^f;:;YN^<OH
HN\/ 49
(a) 2-Methyl-l-(2,6,8-tris-ethylamino-pyrimido[5,4-d]-pyrimidinylamino)-propanol
(49)
2-Methyl-l-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylamino)-propanol
(29) (300 mg, 0.93 mmol) and ethylamine (70% water solution) were reacted in n-butanol (5
mL) using procedures described elsewhere herein. The crude product was purified by flash
column chromatography using gradient elution from PE/EtOAc (5:1) to PE/ EtOAc (1:2) to
give2-methyl-l-(2,6,8-tris-ethylamino-pyrimido[5,4-d]-pyrimidmylamino)-propanol
(49) (210 mg, 65% yield). 300 MHz 1H NMR (CDCls, ppm): 6.92-6.80 (1H, m) 6.45-6.34
(1H, m) 5.24-5.14 (1H, m) 4.64-4.55 (1H, m) 4.55-4.46 (1H, m) 3.58-3.48 (4H, m) 3.48-3.33
(4H, m) 1.32-1.17 (9H, m) 1.27 (6H, s). ESI-MS (m/z): 349 [M+H]+.
(b) 2-Methyl-l-(2,6,8-tns-ethylamiao-pyrimido[5,4-d]-pyrimidinylamino)-propanol
hydrochloride (49 a)
2-Methyl-l-(2,6,8-tris-ethylammo-pyrimido[5,4-d]-pyrimidinylammo)-
propanol (49) (190 mg, 0.55 mmol) and 2M HC1 /diethyl ether were reacted in diethyl
ether / EtOH (1/1) using procedures previously to produce 2-methyl-l-(2,6,8-tris-ethylamino-
pyrimido[5,4-d]-pyrimidinylamino)-propaaol hydrochloride (49a) (205 mg, 97% yield).
300 MHz 1HNMR(CD30D, ppm): 3.69-3.55 (4H, m) 3.55-3.38 (4H, m) 1.27 (6H, s) 1.34-
1.19 (9H, m). ESI-MS (m/z): 349 [M+H]+; MP: 192-194 °C.
Example 28: 2-(2,6,8-Tris-methylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (52)
and corresponding hydrochloride salt (52a)
""NH
'KVr^°H
N^.N
HN, „
(a) 2-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidmylamino)-ethanol (50)
To a suspension of2,4,6,8-tetrachloro-pyrimido[5,4-d]pyrimidine (1) (1.00 g,
3.70 mmol) in THF (50 mL), 2-amino-ethanol (200 ^L, 3.32 mmol) andN,N-
diisopropylethylamine (900 j^L, 5.18 mmol) in THF (5 mL) was added dropwise at -78°C.
The reaction mixture was stirred at -78°C for 2h, and then allowed to reach the room
temperature. Water (50 mL) was added and the resulting suspension was extracted with
EtOAc (3 x 30 mL). The combined organic extracts were washed with water (50 mL), then
with a brine solution (50 mL) and dried over solid anhydrous MgS04. After filtration, the
solvent was removed; the residue was purified by flash column chromatography using
PE/EtOAc (1:1) as eluent to give 2-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (50) (860 mg, 88% yield). 300 MHz 1H NMR (CDCb, ppm): 7.61 (1H, s) 3.99-3.93
(2H, m) 3.91-3.83 (2H, m) 1.99 (1H, s). ESI-MS (m/z): 294, 296, 298, 300 [M+H]+.
(b) 2-(2,6-Dichloromethylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (51)
Methylamine (2M in THF, 2.04 mL, 2.04 mmol) was added to a solution of 2-
(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylammo)-ethanol (50) (300 mg, 1.02 mmol) in
THF (5 mL) at 0°C. The reaction mixture was stirred at room temperature for 2h. After this
time a saturated NaHCOs solution (20 mL) was added and the resulting suspension was
extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water
(50 mL) and dried over solid anhydrous N02804. After filtration, the solvent was removed
and the residue was purified by flash column chromatography using gradient elution from
PE/EtOAc (5:1) to PE/EtOAc (1:1) to give 2-(2,6-dichloromethylamino-pyrimido[5,4-
d]pyrimidinylamino)-ethanol (51) (180 mg, 61% yield). 400 MHz !H NMR (DMSO-d6,
ppm): 8.68 (1H, q, J=4.2 Hz) 8.44 (1H, s) 4.84 (1H, t, J=5.5 Hz) 3.61-3.55 (2H, m) 3.54-3.48
(2H, m) 2.93 (3H, d, J=4.2 Hz). ESI-MS (m/z): 289, 291, 293 [M+H]+.
(c) 2-(2,6,8-Tris-methylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (52)
2-(2,6-Dichloromethylamino-pyrimido[5,4-d]pyrimidinylammo)-ethanol
(51) (171 mg, 0.59 mmol) and methylamine (40% water solution) were reacted in n-butanol
at 125°C using procedure described for compound (4) to give 2-(2,6,8-tris-methylamino-
pyrimido[5,4-d]pyrimidmylamino)-ethanol (52) (112 mg, 68% yield). 300 MHz !H NMR
(CDCb, ppm): 6.99-6.87 (1H, m) 6.54-6.41 (1H, m) 4.73-4.65 (1H, m) 4.63-4.54 (1H, m)
3.89-3.84 (2H, m) 3.72-3.65 (2H, m) 3.07 (3H, d, J=5.1 Hz) 2.97 (3H, d, J=5.1 Hz) 2.96 (3H,
d, J=5.1 Hz). ESI-MS (m/z): 279 [M+H]+.
(d) 2-(2,6,8-Tris-methylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol
hydrochlonde (52a)
2-(2,6,8-Tris-methylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (52)
(112 mg, 0.40 mrnol) and 2M HC1 /diethyl ether in CHzCk were using procedures described
elsewhere herein to produce 2-(2,6,8-tris-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol hydrochloride (52a) (110 mg, 87% yield). 300 MHz 'H NMR (D20, ppm):
3.83 (2H, t, J=5.4 Hz) 3.66 (2H, t, J=5.4 Hz) 3.03 (3H, s) 2.95 (3H, s) 2.90 (3H, s). ESI-MS
(m/z): 279 [M+H]+; MP: 252-254 °C.
Example 29: 2-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-ethanol (54) and corresponding hydrochloride salt (54a)
T~N H
N-WN^OH
HN112-
(a) 2-[2,6-Dichloro(cyclopropylmethyl-amino)-pyrimido[5,4-d]pyrimidinylammo]-
ethanol (53)
2-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidinylamino)-ethanol (50) (300
mg, 1.02 mmol) and cyclopropylmethanamine were reacted in THF using procedures
described elsewhere herein to give 2-[2,6-dichloro(cyclopropylmethyl-amino)-
pyrimido[5,4-d]pyrimidinylamino]-ethanol (53) (244 mg, 73% yield). 400 MHz 'H NMR
(DMSO-d6, ppm): 8.77 (1H, t, J=6.0 Hz) 8.45 (1H, t, J=5.7 Hz) 4.84 (1H, t, J=5.5 Hz) 3.61-
3.55 (2H, m) 3.55-3.48 (2H, m) 3.32-3.27 (2H, m) 1.20-1.09 (1H, m) 0.48-0.40 (2H, m) 0.33-
0.26 (2H, m). ESI-MS (m/z): 329, 331, 333 [M+H]+.
(b) 2-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-ethanol (54)
2-[2,6-Dichloro(cyclopropylmethyl-amino)-pyrimido[5,4-d]pyrimidin
ylamino]-ethanol (53) (244 mg, 0.74 mmol) and methylamine (40% water solution) were
reacted in 1,4-dioxane at 125°C using procedure described for compound (4). The product
was purified by flash column chromatography using gradient elution from EtOAc to EtOAc/
EtOH (9:1) as eluentto give 2-[8-(cyclopropylmethyl-amino)-2,6-bis-methylamino-
pyrimido[5,4-d]pyrimidinylamino]-ethanol (54) (80 mg, 34% yield). 300 MHz 1HNMR
(CDCk, ppm): 6.98-6.87 (1H, m) 6.62-6.52 (1H, m) 4.76-4.54 (3H, m) 3.89-3.84 (2H, m)
3.73-3.66 (2H, m) 3.35 (2H, dd, J=7.7, 5.6 Hz) 2.97 (3H, d, J-5.1 Hz) 2.96 (3H, d, J=5.1 Hz)
1.18-1.07 (1H, m) 0.60-0.52 (2H, m) 0.33-0.27 (2H, m). ESI-MS (m/z): 319 [M+H]+.
(c) 2-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylaminoj-ethanol hydrochloride (54a)
2-[8-(Cyclopropylmethyl-amino)-2,6-bis-methylamino-pyrimido[5,4-
d]pyrimidmylamino]-ethanol (54) (80 mg, 0.25 mmol) and 2M HC1 /diethyl ether were
reacted in CHhCk using procedures described elsewhere herein to produce 2-[8-
(cyclopropylmethyl-amino)-2,6-bis-methylammo-pyrimido[5,4-d]pyrimidinylamino]-
ethanol hydrochloride (54a) (75 mg, 84% yield). 300 MHz !H NMR (DzO, ppm): 3.83 (2H,
t, J=5.4 Hz) 3.67 (2H, t, J=5.4) 3.31 (2H, d, J=7.1 Hz) 2.93 (3H, s) 2.91(3H, s) 1.20-1.06 (1H,
m) 0.62-0.53 (2H, m) 0.34-0.27 (2H, m). ESI-MS (m/z): 319 [M+H]+; MP: 206-208 °C.
Example 30: 2-[8-(2-Methoxy-ethylamino)-2,6-bis-methylammo-pyrimido[5,4-d]pyrimidin-
4-ylamino]-ethanol (56) and corresponding hydrochloride salt (56a)
(a) 2-[2,6-Dichloro(2-methoxy-ethylammo)-pyrimido[5,4-d]pyrimidinylamino]-
ethanol (55)
2-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidmylamino)-ethanol (50) (300
mg, 1.02 rnmol) and 2-methoxy-ethylamine were reacted in THF using procedures described
elsewhere herein to give 2-[2,6-dichloro(2-methoxy-ethylamino)-pyrimido[5,4-
d]pyrimidinylammo]-ethanol (55) (246 mg, 72% yield). 400 MHz 'H NMR (DMSO-d6,
ppm): 8.54 (1H, t, J=5.9 Hz) 8.47 (1H, t, J=5.7 Hz) 4.84 (1H, t, J==5.5 Hz) 3.64-3.56 (4H, m)
3.56-3.48 (4H, m) 3.27 (3H, s). ESI-MS (m/z): 333, 335, 337 [M+H]+.
(b) 2-[8-(2-Methoxy-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidmyl
amino]-ethanol (56)
2-[2,6-Dichloro(2-methoxy-ethylamino)-pyrimido[5,4-d]pyrimidin
ylaminoj-ethanol (55) (240 mg, 0.72 mmol) and methylamine (40% water solution) were
reacted in n-butanol at 125°C using procedure described for compound (4). The crude
product was purified by flash column chromatography using gradient elution from EtOAc to
EtOAc/ EtOH (9:1) as eluent to give pure 2-[8-(2-methoxy-ethylamino)-2,6-bis-
methylammo-pyrimido[5,4-d]pyrimidinylamino]-ethanol (56) (111 mg, 48% yield). 300
MHz 1HNMR (CDCb, ppm): 6.95-6.87 (1H, m) 6.79-6.71 (1H, m) 4.70-4.53 (3H, m) 3.89-
3.84 (2H, m) 3.74-3.65 (4H, m) 3.64-3.58 (2H, m) 3.40 (3H, s) 2.98-2.93 (6H, m). ESI-MS
(m/z): 323 [M+H]+.
(c) 2-[8-(2-Methoxy-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-ethanol hydrochloride (56a)
2-[8-(2-Methoxy-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-
d]pyrimidmylammo]-ethanol (56) (111 mg, 0.34 mmol) and 2M HC1 /diethyl ether were
reacted in CHhCk using procedures described elsewhere herein to produce 2-[8-(2-methoxy-
ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-ethanol
hydrochloride (56a) (115 mg, 93% yield). 300 MHz 1H NMR (D20, ppm): 3.82 (2H, t, J=5.3
Hz) 3.75-3.60 (6H, m) 3.41 (3H, s) 2.93-2.85 (6H, m). ESI-MS (m/z): 323 [M+H]+; MP:
160-162 °C.
Example 31: 2-(2,6-Bis-methylaminopropynylammo-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (58) and corresponding hydrochloride salt (58a)
r -^N ^
'HVr^0"
N^,N
HN- 58
(a) 2-(2,6-Dichloropropynylamino-pyrimido[5,4-d]pyrimidmylamino)-ethanol
(57)
2-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidinylamino)-ethanol (50) (300
mg, 1.02 mmol) and propyn-l-amine were reacted in THF using procedures described
elsewhere herein to give 2-(2,6-dichloropropynylamiao-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (57) (100 mg, 31% yield). 400 MHz 1H NMR (DMSO-d6, ppm): 9.05 (1H,
s) 8.55 1H, t, J=5.7 Hz) 4.84 (1H, t, J=5.5 Hz) 4.18 (2H, s) 3.62-3.55 (2H, m) 3.55-3.49 (2H,
m) 3.13 (1H, t, J=2.4 Hz). ESI-MS (m/z): 313, 315, 317 [M+H]+.
(b) 2-(2,6-Bis-methylaminopropynylamino-pyrimido[5,,4-d]pyrimidinylamino)-
ethanol (58)
A mixture of 2-(2,6-dichloropropynylamino-pyrimido[5,4-d]pyrimidm-
4-ylamino)-ethanol (57) (100 mg, 0.32 mmol) and methylamine (40% water solution) (330
(iL, 4.25 mmol) in n-butanol (3 mL) was heated at 105°C for 18h in a closed vial. After
cooling, a saturated NaHCOs solution (20 mL) was added and the resulting suspension was
extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water
(30 mL), then with a brine solution (30 mL) and dried over solid anhydrous MgS04. After
filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from EtOAc to EtOAc/ EtOH (9:1) to give 2-(2,6-bis-
methylaminopropynylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol (58) (37
mg, 38% yield). 400 MHz 1H NMR (CDCk, ppm): 6.91 (1H, br s) 6.56 (1H, br s) 4.70 (1H,
br s) 4.61 (1H, br s) 4.34-4.29 (2H, m) 3.90-3.84 (2H, m) 3.72-3.66 (2H, m) 2.99-2.94 (6H,
m) 2.27-2.24 (1H, m). ESI-MS (m/z): 303 [M+H]+.
(c) 2-(2,6-Bis-methylaminopropynylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol hydrochloride (58a)
2-(2,6-Bis-methylaminopropynylamino-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (58) (37 mg, 0.12 mmol) and 2M HC1 /diethyl ether were reacted in CHhClz
using procedures described elsewhere herein to produce 2-(2,6-bis-methylaminoprop
ynylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol hydrochloride (58a) (40 mg, 96%
yield). 300 MHz !HNMR (D20, ppm): 4.35-4.27 (2H, m) 3.90-3.82 (2H, m) 3.78-3.71 (2H,
m) 2.98 (3H,s) 2.97 (3H, s) 2.76-2.72 (1H, m). ESI-MS (m/z): 303 [M+H]+; MP: 240-242
Example 32: 2-[8-(2,2-Difluoro-ethylamino)-2,6-bis-methylammo-pyrimido[5,4-d]-
pyrimidinylammoj-ethanol (60) and corresponding hydrochloride salt (60a)
N-^N
'"""- 60
(a) 2-[2,6-Dichloro(2,2-difluoro-ethylammo)-pyrimido[5,4-d]pyrimidinylammo]-
ethanol (59)
2-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidinylammo)-ethanol(50) (240
mg, 0.81 mmol) and 2,2-difluoro-ethylamine were reacted in THF using procedures described
elsewhere herein to give 2-[2,6-dichloro(2,2-difluoro-ethylamino)-pyrimido[5,4-
d]pyrimidmylamino]-ethanol (59; (190 mg, 69% yield). 300 MHz !H NMR (CDCls,
ppm): 7.31 (1H, s) 7.05 (1H, t, J=6.3 Hz) 6.04 (1H, tt, J=55.5, 4.1 Hz) 4.01 (2H, tdd, J=14.4,
6.5, 4.1 Hz) 3.97-3.89 (2H, m) 3.84-3.76 (2H, m) 2.30 (1H, J=5.1 Hz). ESI-MS (m/z): 339,
341, 343 [M+H]+.
(b) 2-[8-(2,2-Difluoro-ethylammo)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylamino]-ethanol (60)
2-[2,6-Dichloro(2,2-dinuoro-ethylammo)-pyrimido[5,4-d]pyrimidinyl
amino]-ethanol (59) (240 mg, 0.61 mmol) and methylamine (40% water solution) were
reacted in n-butanol using procedure described for compound (4). The product was purified
by flash column chromatography using gradient elution from CH2C12 to CH2Cl2/MeOH
(95:5) to give 2-[8-(2,2-difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylammo]-ethanol (60) (125 mg, 68% yield). 300 MHz 'H NMR (DMSO-d6,
ppm): 7.32 (1H, t, J==6.1 Hz) 7.05 (1H, t, J=5.6 Hz) 6.28 (1H, q, J=4.6 Hz) 6.24 (1H, tt,
J=56.5, 4.3 Hz) 6.16 (1H, q, J=4.6 Hz) 4.84 (1H, t, J=5.1 Hz) 3.93-3.73 (2H, m) 3.63-3.54
(2H, m) 3.53-3.44 (2H, m) 2.81 (3H, d, J=4.6 Hz) 2.79 (3H, d, J=4.6 Hz). ESI-MS (m/z):
329 [M+H]+.
(c) 2-[8-(2,2-Difluoro-ethylammo)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylamino]-ethanol hydrochloride (60a)
2-[8-(2,2-Difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylamino]-ethanol (60) (125 mg, 0.38 mmol) and 2M HC1 /diethyl ether were
reacted in diethyl ether using procedure described for compound (6a) to produce 2-[8-(2,2-
difluoro-ethylamino)-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]-ethanol
hydrochloride (60a) (125 mg, 90% yield). 400 MHz 1H NMR (CDsOD, ppm): 6.14 (1H, tt,
J=56.2, 4.0 Hz) 3.98 (2H, td, J=14.9, 4.0 Hz) 3.84-3.69 (4H, m) 3.03 (3H, s) 2.98 (3H, s).
ESI-MS (m/z): 329 [M+H]+; MP: 213-215 °C.
Example 33: 2-[2,6-Bis-methylamino(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-
d]pyrimidinylammo]-ethanol (62) and corresponding hydrochloride salt (62a)
F N N "
FT"y'VJYN^OH
N^/N
HN- 62
(a) 2-[2,6-Dichloro(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidmylammo]-
ethanol(61)
A mixture of 2-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidinylamino)-ethanol
(50) (295 mg, 1.00 mmol) and 2,2,2-trifluoro-ethylamine (159 [iL, 2.00 mmol) in n-butanol
(2 mL) was stirred at room temperature for 3 h. A saturated NaHCOs solution (10 mL) was
added and the resulting suspension was extracted with EtOAc (3 x 20 mL). The combined
organic extracts were washed with a brine solution (30 mL) and dried over solid anhydrous
Na2S04. After filtration, the solvent was removed and the product was purified by flash
column chromatography using gradient elution from CH2C12 to CHzClz/MeOH (95:5) to give
pure2-[2,6-dichloro(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidinylamino]-
ethanol (61) (300 mg, 84% yield). 300 MHz 1H NMR (CDCb, ppm): 7.38-7.30 (1H, m) 7.05
(1H, t, J=6.4 Hz) 4.31 (2H, qd, J=8.8, 6.8 Hz) 3.96-3.89 (2H, m) 3.85-3.77 (2H, m) 2.26 (1H,
t, J=5.2 Hz). ESI-MS (m/z): 357, 359, 361 [M+H]+.
(b) 2-[2,6-Bis-methylammo(2,2,2-trifluoro-ethylammo)-pyrimido[5,4-d]pyrimidin
ylamino]-ethanol (62)
2-[2,6-Dichloro(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidm
ylamino]-ethanol (61) (290 mg, 0.81 mmol) and methylamine (40% water solution) were
reacted in n-butanol using procedures described elsewhere herein. The product was purified
by flash column chromatography using gradient elution from CHhCb to CH2Cl2/MeOH
(98:25) to give 2-[2,6-bis-methylamino(2,2,2-trifluoro-ethylammo)-pyrimido[5,4-
d]pyrimidinylamino]-ethanol (62) (242 mg, 86% yield). 300 MHz (H NMR (CDCls,
ppm): 6.99-6.86 (1H, m) 6.65 (1H, t, J=5.8 Hz) 4.75-4.58 (2H, m) 4.37 (1H, s) 4.22 (2H, qd,
J=9.1, 6.8 Hz) 3.89-3.84 (2H, m) 3.73-3.67 (2H, m) 2.97 (3H, d, J=5.1 Hz) 2.96 (3H, d, J=5.1
Hz). ESI-MS (m/z): 347 [M+H]+.
(c) 2-[2,6-Bis-methylamino(2,2,2-trifluoro-ethylamino)-pyrimido[5,4-d]pyrimidm
ylaminoj-ethanol hydrochloride (62a)
2-[2,6-Bis-methylammo(2,2,2-trifluoro-ethylammo)-pyrimido[5,4-
d]pyrimidinylamino]-ethanol (62) (125 mg, 0.38 mmol) and 2M HC1 /diethyl ether were
reacted in diethyl ether/ MeOH (1/2) using procedures described elsewhere herein to produce
2-[2,6-bis-methylamino(2,2,2-trifluoro-ethylammo)-pyrimido[5,4-d]pyrimidin
ylamino]-ethanol hydrochloride (62a) (210 mg, 95% yield). 300 MHz 'H NMR (CDaOD,
ppm): 4.38 (2H, q, J=9.3 Hz) 3.85-3.69 (4H, m) 3.04 (3H, s) 2.97 (3H, s). ESI-MS (m/z):
347 [M+H]+; MP: 253-254 °C.
Example 34: 2-(8-Benzylammo-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-ethanol (64) and corresponding hydrochloride salt (64a)
""'NH
(a) 2-(8-Benzylamino-2,6-dichloro-pyrimido[5,4-d]pyrimidinylamino)-ethanol (63)
2-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidinylammo)-ethanol (50) (400
mg, 1.36 mmol) and benzylamine were reacted in dichloromethane using procedures
described elsewhere herein to give 2-(8-benzylammo-2,6-dichloro-pyrimido[5,4-d]pyrimidin-
4-ylamino)-ethanol (63) (380 mg, 77% yield). 300 MHz 1H NMR (CDCb, ppm): 7.41-7.27
(6H, m) 7.15 (1H, t, J=5.7 Hz) 4.77 (2H, d, J=5.9 Hz) 3.95-3.88 (2H, m) 3.82-3.74 (2H, m)
2.49 (1H, s). ESI-MS (m/z): 365, 367, 369 [M+H]+.
(b) 2-(8-Benzylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylammo)-
ethanol (64)
2-(8-Benzylamino-2,6-dichloro-pyrimido[5,4-d]pyrimidinylamino)-ethanol
(63) (370 mg, 1.01 mmol) and methylamine (40% water solution) were reacted in n-butanol
using procedure described for compound (4) to give 2-(8-benzylamino-2,6-bis-methylamino-
pyrimido[5,4-d]-pyrimidmylamino)-ethanol (64) (235 mg, 66% yield). 300 MHz !HNMR
(CDCb, ppm): 7.42-7.27 (5H, m) 6.95 (1H, t, J=6.1 Hz) 6.80 (1H, t, J=6.1 Hz) 4.73 (2H, d,
J=6.1 Hz) 4.68 (1H, q, J=5.1 Hz) 4.58 (1H, q, J=5.1 Hz) 3.90-3.83 (2H, m) 3.73-3.65 (2H, m)
2.97 (3H, d, J=5.1 Hz) 2.92 (3H, d, J=5.1 Hz). ESI-MS (m/z): 355 [M+H]+.
(c) 2-(8-Benzylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-
ethanol hydrochloride (64a)
2-(8-Benzylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-ethanol (64) (180 mg, 0.51 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether/ MeOH (5/1) using the procedure described for compound (6a) to produce 2-(8-
ben2ylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-ethanol
hydrochloride (64a) (198 mg, 99% yield). 300 MHz 1H NMR (CDsOD, ppm): 7.44-7.38
(2H, m) 7.38-7.23 (3H, m) 4.77 (2H, s) 3.83-3.76 (2H, m) 3.77-3.66 (2H, m) 2.98 (6H, s).
ESI-MS (m/z): 355 [M+H]+; MP:181-183 °C.
Example 35: 3-(8-Ethylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidmylamino)-
propanol (67) and corresponding hydrochloride salt (67a)
^~NH
(a) 3-(2,6,8-Trichloro-pyrimido[5,4-d]pyrimidinylammo)-propan-l-ol (65)
To a suspension of 2,4,6,8-tetrachloro-pyrimido[5,4-d]pyrimidme (1) (600 mg,
2.23 mmol) in THF (10 mL) at -78°C, 3-amino-propan-l-ol (158 mg, 2.11 mmol) and N,N-
diisopropylethylamine (500 |J,L, 2.90 mmol) in THF (5 mL) was added via syringe pump
(over about 20 min). The mixture was stirred at -78°C for additional 30 min, and then
allowed to reach the room temperature. Water (40 mL) was added and the resulting
suspension was extracted with EtOAc (3x30 mL). The combined organic extracts were
washed with a brine solution (50 mL) and dried over solid anhydrous MgS04. After
filtration, the solvent was removed and the residue was purified by flash column
chromatography using PE/EtOAc (1:1) as eluent to give 3-(2,6,8-trichloro-pyrimido[5,4-
d]pyrimidinylamino)-propan-l-ol (65) (630 mg, 97% yield). 300 MHz 1HNMR (CDCk,
ppm): 7.77 (1H, s) 3.89-3.78 (4H, m) 2.35 (1H, s) 2.02-1.91 (2H, m). ESI-MS (m/z): 308,
310,312,314[M+H]+.
(b) 3-(2,6-Dichloroethylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-1 -ol (66)
Ethylamine (2 M in THF, 1.5 mL, 3 mmol) was added portionwise to a
solution of3-(2,6,8-trichloro-pyrimido[5,4-d]pyrimidinylammo)-propan-l-ol (65) (300
mg, 0.97 mmol) in n-butanol (3 mL) and chloroform (3 mL) at 0°C. The mixture was stirred
at room temperature for 2h. After this time, a saturated NaHCOs soltuion (20 mL) was added
and the resulting suspension was extracted with chloroform (3 x 20 mL). The combined
organic extracts were washed with water and dried over solid anhydrous MgS04. After
filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from from CH2C12 to CHhCk/MeOH (97:3) to give 3-
(2,6-dichloroethylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-l-ol (66) (275 mg,
89% yield). 300 MHz (H NMR (CDCla, ppm): 7.17 (1H, t, J=5.9 Hz) 6.87 (1H, t, J=5.3 Hz)
3.80-3.72 (2H, m) 3.72-3.66 (2H, m) 3.64 (2H, qd, J=7.3, 5.9 Hz) 3.00 (1H, s) 1.93-1.83 (2H,
m) 1.33 (3H, t, J-7.3 Hz). ESI-MS (m/z): 317, 319, 321 [M+H]+.
(c) 3-(8-Ethylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan-
l-ol(67)
3-(2,6-Dichloroethylamino-pyrimido[5,4-d]pyrimidinylamino)-propan-
l-ol (66) (270 mg, 0.85 mmol) and methylamine (40% water solution) were reacted in n-
butanol using the procedure described for compound (4) to give 3-(8-ethylamino-2,6-bis-
methylammo-pyrimido[5,4-d]-pyrimidinylamino)-propan-l-ol (67) (165 mg, 63% yield).
300 MHz 1H NMR (CDCb, ppm): 6.74 (1H, t, J=6.3 Hz)) 6.46 (1H, t, J=5.8 Hz) 5.2-4.4 (1H,
br s) 4.75-4.64 (1H, m) 4.63-4.52 (1H, m) 3.74-3.66 (2H, m) 3.62-3.55 (2H, m) 3.54 (2H, qd,
3=7.2, 5.8 Hz) 2.97 (3H, d, J=4.9 Hz) 2.95 (3H, d, J-4.9 Hz) 1.84-1.74 (2H, m) 1.29 (3H, t,
J=7.2 Hz). ESI-MS (m/z): 307 [M+H]+.
(b) 3-(8-Ethylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan-
l-ol hydrochloride (67a)
3-(8-Ethylammo-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (67) (170 mg, 0.55 mmol) and 2M HC1 /diethyl ether were reacted in diethyl
ether /EtOH (4/1) using the procedure described for compound (14a) to produce 3-(8-
ethylamino-2,6-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan-l-ol
hydrochloride (67a) (185 mg, 98% yield). 300 MHz !H NMR (CDsOD, ppm): 3.80-3.49
(4H, m) 3.69 (2H, t, J=6.1 Hz) 3.11-2.87 (6H, m) 1.98-1.86 (2H, m) 1.31 (3H, t, J=7.2 Hz).
ESI-MS (m/z): 307 [M+H]+; MP: 179-181 °C.
Example 36: l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-
pyrrolidinol (71) and corresponding hydrochloride salt (71a)
""NH
""'"- 71
(a) 2,6,8-Trichloro-pyrimido[5,4-d]pyrimidinol (68)
A mixture of2,4,6,8-tetrachloro-pyrimido[5,4-d]pyrimidine (1) (10.00 g,
37.05 mmol), water (60 mL) and THF (120 mL) was stirred at room temperature for 24h.
The volatiles were removed in vacua. Water (200 mL) was added and the resulting
suspension was filtered. The collected solid were washed with water (2 x 50 mL) and dried
over P205 in vacuo at 60°C for 48h to give 2,6,8-trichloro-pyrimido[5,4-d]pyrimidmol (68)
(8.47 g, 91% yield).
(b) 2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinol(69)
To a suspension of2,6,8-trichloro-pyrimido[5,4-d]pyrimidinol (68) (8.47 g,
33.68 mmol) in THF (120 mL) at 0 °C, propylamine (7.20 mL, 101.05 mmol) in THF (20
mL) was added dropwise. The mixture was stirred at room temperature for 16h after which
time, the volatiles were removed in vacua and water (200 mL) was added. The resultant
precipitate was filtered, washed with water (3x50 mL) and dried over P20s in vacua at 60°C
for 16hto give 2,6-dichloropropylammo-pyrimido[5,4-d]pyrimidinol (69) (9.00 g, 97%
yield). 300 MHz 1H NMR (CDCls+TFA, ppm): 7.79 (1H, t, J=6.0 Hz) 3.79-3.69 (2H, m)
1.81 (2H, sextet, J=7.4 Hz) 1.06 (3H, t, J=7.4 Hz). ESI-MS (m/z): 274, 276, 278 [M+H]+.
(c) 2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmol (70)
2,6-Dichloropropylamino-pyrimido[5,4-d]pyrimidinol (69) (9.00 g,
32.83 mmol) and methylamine (40% water solution) (23.00 mL) were reacted in ??-butanol
(50 mL) was heated at 105°C for 96 h in a closed vial. After cooling, a saturated NaHCOs
solution (100 mL) was added and the resulting suspension was extracted with CHCls (3 x 150
mL). The combined organic extracts were washed with water (300 mL) and dried over solid
anhydrous MgS04. After filtration, the solvent was removed and the residue was purified by
flash column chromatography using gradient elution from CHCls/MeOH (98:2) to
CHCls/MeOH (1:1) to give 2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin-
4-ol (70) (6.18 g, 71% yield). 300 MHz 'H NMR (DMSO-d6, ppm): 7.18 (1H, s) 6.23 (1H, q,
J==4.7 Hz) 6.10 (1H, q, 3=4.7 Hz) 3.48-3.26 (2H, m, overlapped with water) 3.16 (1H, s) 2.83
(3H, d, J=4.7 Hz) 2.75 (3H, d, J=4.7 Hz) 1.66-1.52 (2H, m) (3H, t, J=7.4 Hz). ESI-MS (m/z):
264 [M+H]+.
(d) l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidmyl)-pyrrolidin
ol(71)
A mixture of 2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin-
4-ol (70) (250 mg, 0.95 mmol), (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP) (548 mg, 1.24 mmol) and l,8-diazabicyclo[5.4.0]undecene
(DBU) (214 fiL, 1.43 mmol) in DMF (5 mL) was stirred at room temperature for Ih. A
mixture ofpyrrolidinol hydrochloride (352 mg, 2.85 mmol) and DBU (426 ^iL, 2.85
mmol) in DMF (2mL) was added, and the resulting reaction mixture was stirred at room
temperature for 18 h. Water (50 mL) was added and the resulting suspension was extracted
with EtOAc (3 x 50 mL). The combined organic extracts were washed with a brine solution
(50 mL) and dried over solid anhydrous N02804. After filtration, the solvent was removed
and the residue was purified by flash column chromatography using gradient elution from
PE/EtOAc (99:1) to PE/EtOAc (1:99) to give l-(2,6-bis-methylaminopropylammo-
pyrimido[5,4-d]pyrimidinyl)-pyrrolidmol (71) (161 mg, 51% yield). 300 MHz !H
NMR (CDCb, ppm): 6.62-6.53 (1H, m) 4.65-4.44 (3H, m) 4.36-3.98 (5H, m) 3.47-3.39 (2H,
m) 2.95-2.89 (6H, m) 2.07-1.98 (2H, m) 1.69 (2H, sextet, 3=7 A Hz) 1.00 (3H, t, J=7.4 Hz).
ESI-MS (m7z): 333 [M+H]+.
(c) l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinyl)-pyrrolidm
ol hydrochloride (71 a)
l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinyl)-
pyrrolidinol (71) (144 mg, 0.43 mmol) and 2M HC1 /diethyl ether were reacted in CH^Ck
using the procedure described for compound (14a) to produce l-(2,6-bis-methylamino
propylammo-pyrimido[5,4-d]pyrimidinyl)-pyrrolidinol hydrochloride (71a) (125
mg,78% yield). 300 MHz !H NMR (CDsOD, ppm): 4.59-4.52 (1H, m) 4.39-4.04 (4H, m)
3.54 (2H, t, J=7.4 Hz) 3.02 (3H, s) 2.97 (3H, s) 2.16-2.0 (2H, m) 1.75 (2H, sextet, J=7.4 Hz)
1.03 (3H, t, J=7.4 Hz). ESI-MS (m/z): 333 [M+H]+; MP:202-204 °C.
Example 37: l-[(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-methyl]-cyclobutanol (72) and corresponding hydrochloride salt (72a)
r ^N
'y^Y OH
N^,N
HN^ ^
(a) l-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
methyl]-cyclobutanol (72)
A mixture of 2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin-
4-ol (70) (250 mg, 0.95 mmol), BOP reagent (548 mg, 1.24 mmol and DBU (214 [iL, 1.43
mmol) in DMF (5 mL) was stirred at room temperature for Ih. 1-Aminomethyl-cyclobutanol
(288 mg, 2.85 mmol) was added and the resulting reaction mixture was stirred at room
temperature for 18 h. Water (50 mL) was added and the resulting suspension was extracted
with EtOAc (3x50 mL). The combined organic extracts were washed with a brine solution
(50 mL) and dried over solid anhydrous N02804. After filtration the solvent was removed
and the residue was purified by flash column chromatography using gradient elution from
PE/EtOAc (99:1) to PE/EtOAc (1:99) to give l-[(2,6-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidmylamino)-methyl]-cyclobutanol (72) (147 mg, 45% yield). 300
MHz 1HNMR (CDCb, ppm): 7.03-6.92 (1H, m) 6.53-6.44 (1H, m) 6.14-5.95 (1H, m) 4.67-
4.60 (1H, m) 4.60-4.52 (1H, m) 3.68 (2H, d, J=6.2 Hz) 3.49-3.41 (2H, m) 2.97 (3H, d, J=5.1
Hz) 2.93 (3H, d, J=5.1 Hz) 2.18-2.02 (4H, m) 1.80-1.60 (3H, m) 1.58-1.41 (1H, m) 0.99 (3H,
t, J=7.4 Hz). ESI-MS (m/z): 347 [M+H]+.
(b) l-[(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylammo)-
methylj-cyclobutanol hydrochloride (72 a)
l-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-methyl]-cyclobutanol (72) (113 mg, 0.33 mmol) and 2M HC1 /diethyl ether were
reaced in CHhCk using procedures described elsewhere herein to produce l-[(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-methyl]-cyclobutanol
hydrochloride (72a) (95 mg, 76% yield). 300 MHz 1H NMR (CD30D, ppm): 3.85 (2H, s)
3.61 (2H, t, J=7.4 Hz) 3.04 (3H, s) 3.03 (3H, s) 2.22-2.04 (4H, m) 1.86-1.60 (2H, m) 1.77
(2H, sextet, J=7.4 Hz) 1.03 (3H, t, J-7.4 Hz). ESI-MS (ni/z): 347 [M+H]+; MP: 248-250 °C.
Example 38: l-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidmyl)-
methyl-amino]-propanol (73) and corresponding hydrochloride salt (73a)
~^NH
^'^iTN"S^^OH
H N^N
HN, 73
(a) 1 - [(2,6-Bis-methylaminopropylamino-pyrimido [5 ,4-d] -pyrimidinyl)-methyl-
aminoj-propanol (73)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol (70) (250
mg, 0.95 mmol) and l-methylamino-propanol were reacted using procedures described
elsewhere herein to obtain l-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]-
pyrimidmyl)-methyl-ammo]-propanol (73) (170 mg, 54% yield). 300 MHz 'HNMR
(CDCb, ppm): 7.0-6.4 (1H, br s) 6.79 (1H, t, J=5.7 Hz) 4.70 (1H, dd, J=14.5, 9.5 Hz) 4.61
(1H, q, J=5.1 Hz) 4.56 (1H, q, J=5.1 Hz) 4.24-4.10 (1H, m) 3.50-3.39 (2H, m) 3.30 (1H, dd,
J=14.5, 2.5 Hz) 3.30 (3H, s) 2.97 (3H, d, J=5.1 Hz) 2.95 (3H, d, J=5.1 Hz) 1.76-1.61 (2H, m)
1.28 (3H, d, J=6.3 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
(b) l-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinyl)-methyl-
amino]-propanol hydrochloride (73a)
l-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidmyl)-
methyl-amino]-propanol (73) (165 mg, 0.49 mmol) and 2M HC1 /diethyl ether were
reacted in diethyl ether using procedures described elsewhere herein to produce l-[(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinyl)-methyl-amino]~propanol
hydrochloride (73a) (160 mg, 88% yield). 300 MHz 1HNMR (CDsOD, ppm): 4.36-4.24
(1H, m) 3.85-3.67 (1H, m) 3.60 (2H, t, J=7.2 Hz) 3.28-3.11 (1H, m) 3.18 (3H, s) 3.03 (3H, s)
2.98 (3H, s) I .83-1.67 (2H, m) 1.31 (3H, d, J=6.3 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z):
335 [M+H]+.
Example 39: 3-[(2,6-Bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-methyl]-pentanol (74) and corresponding hydrochloride salt (74a)
(a) 3-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
methyl]-peatanol (74)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol (70) (300
mg, 1.14 mmol) and 3-aminomethyl-pentanol were reacted using the procedures described
elsewhere herein to obtain 3-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)-methyl]-pentanol (74) (134 mg, 32% yield). 300 MHz 1HNMR
(CDCls, ppm): 6.81 (1H, t, J=6.3 Hz) 6.50 (1H, t, J=5.7 Hz) 5.09-4.73 (1H, br s) 4.69-4.53
(2H, m) 3.53 (2H, d, J=6.3 Hz) 3.49-3.42 (2H, m) 2.96 (3H, d, J=5.1 Hz) 2.94 (3H, d, J=5.1
Hz) 1.69 (2H, sextet, J=7.4 Hz) 1.58-1.51 (4H, m) 1.0 (3H, t, J=7.4 Hz) 0.92 (6H, t, J=7.6
Hz). ESI-MS (m/z): 363 [M+H]+.
(b) 3-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
methyl]-pentanol hydrochloride (74a)
3-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-methyl]-pentanol (74) (134 mg, 0.37 mmol) and 2M HC1 /diethyl ether were
reacted in diethyl ether using procedures described elsewhere herein to produce 3-[(2,6-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-methyl]-pentanol
hydrochloride (74a) (137 mg, 93% yield). 400 MHz 1H NMR (CDsOD, ppm): 3.69 (2H, s)
3.59 (2H, t, J=7.3 Hz) 3.02 (3H, s) 3.02 (3H, s) 1.76 (2H, sextet, 3=7.4 Hz) 1.61-1.53 (4H, m)
1.03 (3H, t, 3=7 A Hz) 0.94 (6H, t, J=7.4 Hz). ESI-MS (m/z): 363 [M+H]+; MP: 219-221 °C.
Comparative Example 40: 3-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-
d]pyrimidinylamino)-propane-l,2-diol (75) and corresponding hydrochloride salt (75a)
(a) 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propane-l,2-diol (75)
2,,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol (70) (263
mg, 1.00 mmol) and 3-amino-propane-l,2-diol were reacted using the procedures described
elsewhere herein. The crude product was purified by flash column chromatography using
gradient elution from CH2C12 to CH2Cl2/EtOAc (4:1) as eluent to give pure 3-(2,6-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-propane-l,2-diol (75)
(175 mg, 52% yield). 400 MHz 1H NMR (CDCb, ppm): 6.86 (1H, br s) 6.52 (1H, br s) 4.66
(1H, br s) 4.63-4.53 (1H, m) 3.98-3.81 (3H, m) 3.72-3.65 (2H, m) 3.61 (1H, dd, J=11.7, 4.0
Hz) 3.56 (1H, dd, J=11.7, 4.5 Hz) 3.51-3.42 (2H, m) 2.97 (3H, d, J=5.1 Hz) 2.95 (3H, J=5.1
Hz) 1.69 (2H, sextet, J=7.4 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 337 [M+H]+.
(b) 3-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propane-l,2-diol hydrochloride (75a)
3-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-propane-l,2-diol (75) (165 mg, 0.49 mmol) and 2M HC1 /diethyl ether were reacted
in diethyl ether/ MeOH (6/1) using the procedure described for compound 6a to produce 3-
(2,6-bis-methylammopropylammo-pyrimido[5,4-d]pyrimidinylamino)-propane-l,2-diol
hydrochloride (75a) (135 mg, 74% yield). 400 MHz }H NMR (CDsOD, ppm): 3.97-3.89
(1H, m) 3.83 (1H, dd, J=13.8, 4.1 Hz) 3.59 (2H, d, J=5.4 Hz) 3.63-3.51 (3H, m) 3.00 (6H, s)
1.74 (2H, sextet, J=7.4 Hz) 1.01 (3H, J=7.4 Hz). ESI-MS (m/z): 337 [M+H]+; MP: 166-167
°C.
Example 41: l-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmyl)-
methyl-amino]methyl-propanol (76) and corresponding hydrochloride salt (76a)
"""NH
N.' ^N
^'^f^YN^<OH
N^,N
HN- 76
(a) 1 -[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]methyl-propanol (76)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol (70) (300
mg, 1.14 mmol) and 2-methyl-l-methylamino-propanol were reacted using the procedures
previously described to obtain l-[(2,6-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinyl)-methyl-amino]methyl-propanol (76) (235 mg, 59% yield). 300 MHz
1H NMR (CDCk, ppm); 6.79 (1H, t, J=5.0 Hz) 4.62-4.49 (2H, m) 4.06 (2H, s) 3.49-3.39 (2H,
m) 3.41 (3H, s) 2.98-2.92 (6H, m) 1.68 (2H, sextet, J=7.4 Hz) 1.30 (6H, s) 0.99 (3H, t, J=7.4
Hz). ESI-MS (m/z): 349 [M+H]+.
(b) l-[(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
ammo]methyl-propanol hydrochloride (76a)
l-[(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-
methyl-amino]methyl-propanol (76) (233 mg, 0.67 mmol) and 2M HC1 /diethyl ether
were reacted in diethyl ether using the procedure described for compound 6a to produce 1-
[(2,6-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinyl)-methyl-amino]
methyl-propanol hydrochloride (76a) (160 mg, 62% yield). 400 MHz 1HNMR (CDsOD,
ppm): 3.71-3.63 (2H, br s) 3.60 (2H, t, J=7.4 Hz) 3.29-3.22 (3H, br s) 3.02 (3H, s) 2.97 (3H,
s) 1.74 (2H, sextet, J=7.4 Hz) 1.41 (6H, s) 1.0 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+;
MP: 161-163 °C.
Example 42: (lR,2S)-l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidm
ylamino)-indanol (77) and corresponding hydrochloride salt (77a)
""NH
N-^N
(a) (lR,2S)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (77)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol (70) (250
mg, 0.95 mmol) and (lR,2S)-l-amino-mdanol were reacted using the procedure described
for compound (71). The crude product was purified by flash column chromatography using
gradient elution j&om CH2Cl2/MeOH (98:2) to CH2Ck/MeOH (96:4) as eluent to give
(lR,2S)-l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
indanol (77) (180 mg, 48% yield). 300 MHz 1HNMR (CDCls, ppm): 7.38-7.33 (1H, m)
7.33-7.27 (2H,m) 7.25-7.19 (1H, m) 7.04 (1H, br s) 6.61 (1H, br s) 5.60 (1H, dd, J=7.4, 5.1
Hz) 4.87-4.54 (2H, m) 4.80 (1H, td, J=5.1, 2.8 Hz) 3.53-3.43 (2H, m) 3.23 (1H, dd, J=16.4,
.3 Hz) 3.09 (1H, dd, J=16.4, 2.8 Hz) 2.97 (3H, d, J=5.1 Hz) 2.92 (3H, d, J=5.1 Hz) 1.78-1.63
(2H, m) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+.
(b) (lR,2S)-l-(2,,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidm
ylamino)-indanol hydrochloride (77a)
(lR,2S)-l-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidin-
4-ylamino)-indanol (77) (145 mg, 0.37 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether/ MeOH (6/1) using procedures described elsewhere herein to produce (1R,2S)-
l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-indanol
hydrochloride (77a) (155 mg, 98% yield). 300 MHz !HNMR (CDsOD, ppm): 7.37-7.17
(4H, m) 5.83 (1H, d, J=5.1 Hz) 4.76 (1H, td, J=5.1, 1.8 Hz) 3.61 (2H, t, 3=7.2 Hz) 3.24 (1H,
dd, J=16.6, 5.1 Hz) 3.06-2.91 (1H, m) 3.01 (3H, s) 2.99 (3H, s) 1.84-1.68 (2H, m) 1.03 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+; MP: 281-283 °C.
Using the procedures described herein, and variations readily available and
known to those skilled in the art, the following pyrimido[5,4-d]-pyrimidmyl-amino
cycloalkanols were prepared.
Example 43: (lS,2S)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (78) and corresponding hydrochloride salt (78a)
'""^ ^^ 78
(a) (lS,2S)-l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (78)
2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinol (70) (250
mg, 0.95 mmol) and (l<S',25)-l-amino-indanol were reacted using the procedure described
for compound (71). The cmde product was purified by flash column chromatography using
gradient elution from CHCb to CHCk/MeOH (99:1) as eluent to give (lS,2S)-l-(2,6-bis-
methylaminopropylammo-pyrimido[5,4-d]-pyrimidinylamino)-indanol (78) (140
mg, 37% yield). 300 MHz 1HNMR (CDCk, ppm) 7.42-7.35 (1H, m) 7.35-7.27 (3H, m) 7.12
(1H, s) 6.55 (1H, s) 6.27 (1H, br s) 5.30 (1H, t, J=5.9 Hz) 4.66 (2H, s) 4.58-4.47 (1H, m)
3.53-3.44 (2H, m) 3.37 (1H, dd, J=15.6, 7.9 Hz) 3.05-2.92 (1H, m) 2.98 (3H, d, J=5.1 Hz)
2.95 (3H, d, J=5.1 Hz) 1.78-1.63 (2H, m) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395
[M+H]+.
(b) (1 S,2S)-1 -(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-mdanol hydrochloride (78a)
(l<S',2<Sr)-l-(2,6-bis-methylammopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (78) (140 mg, 0.35 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether/ MeOH (6/1) using the procedure described for compound 6a to produce
(lS,2S)-l-(2,6-Bis-methylammopropylammo-pyrimido[5,4-d]-pyrimidmylamino)-
indanol hydrochloride (78a) (120 mg, 80% yield). 300 MHz 1H NMR (CDaOD, ppm):
7.32-7.25 (3H, m) 7.25-7.19 (1H, m) 5.67 (1H, d, J-5.5 Hz) 4.63-4.54 (1H, m) 3.62 (2H, t,
J==7.1 Hz) 3.36 (1H, dd, J=15.9, 7.0 Hz) 3.01 (3H, s) 3.00 (3H, s) 2.91 (1H, dd, J=15.9, 6.3
Hz) 1.85-1.69 (2H, m) 1.03 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+; MP: 290-292 °C.
Example 44: (15',21?)-l-(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-indanol (79) and corresponding hydrochloride salt (79a)
N^N , OH
(a) (lS,2R)-l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-indanol (79)
2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinol (70) (300
mg, 1.14 mmol) and (lS,2R)-l-amino-mdanol were reacted using procedures described
above. The crude product was purified by flash column chromatography using gradient
elution from CH2Ck to CH2Cl2/EtOAc (4:1) as eluent to give (lS,2R)-l-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-indanol (79) (380 mg,
84% yield). 400 MHz 1H NMR (CDCb, ppm): 7.36-7.32 (1H, m) 7.32-7.20 (3H, m) 7.01
(1H, d, J=7.1 Hz) 6.58-6.51 (1H, m) 5.59 (1H, dd, J=7.3, 5.3 Hz) 4.80 (1H, td, J-5.2, 2.6 Hz)
4.75-4.56 (2H, m) 3.54-3.40 (2H, m) 3.22 (1H, dd, J=16.4, 5.3 Hz) 3.06 (1H, dd, J=16.4, 2.5
Hz) 2.96 (3H, d, J=5.0 Hz) 2.91 (3H, d, J=5.0 Hz) 1.70 (2H, sextet, J=7.4 Hz) 1.01 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+.
(b) (lS,2R)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-indanol hydrochloride (79a)
(lS,2R)-l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (79) (310 mg, 0.35 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether/ MeOH (1/1) using the procedure described for compound 6a to produce
(lS,2R)-l-(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylammo)-
indanol hydrochloride (79a) (300 mg, 88% yield). 300 MHz 1H NMR (CDsOD, ppm):
7.40-7.15 (4H, m) 5.87-5.75 (1H, m) 4.78-4.70 (1H, m) 3.68-3.50 (2H, m) 3.33-3.16 (1H, m)
3.10-2.85 (7H, m) 1.76 (2H, sextet, J=7.4 Hz) 1.03 (3H, J=7.4 Hz). ESI-MS (m/z): 395
[M+H]+; MP: 286 °C (dec.).
Example 45: (l^,27?)-l-(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidm
ylammo)-indanol (80) and corresponding hydrochloride salt (80a)
"""NH
N-^N , OH
(a) (lR,2R)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidm
ylamino)-indanol (80)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol (70) (250
mg, 0.95 mmol) and (11?,2J?)-l-amino-indanol were reacted using procedures described
elsewhere herein. The crude product was purified by flash column chromatography using
gradient elution from CHhCk/EtOH (99:1) to CHhCk/EtOH (9:1) to obtain (1R,2R)(2,6-
bis-methy laminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-indanol (80) (144
mg, 38% yield). 300 MHz IHNMR (CDCb, ppm): 7.42-7.35 (1H, m) 7.35-7.26 (3H, m)
7.08 (1H, d, J=4.6 Hz) 6.57-6.45 (1H, m) 6.28 (1H, s) 5.33-5.24 (1H, m) 4.71-4.58 (2H, m)
4.58-4.47 (1H, m) 3.53-3.43 (2H, m) 3.37 (1H, dd, J=15.7, 7.9 Hz) 3.05-2.95 (1H, m) 2.98
(3H, d, J=5.1 Hz) 2.95 (3H, d, J=5.1) 1.78-1.61 (2H, m) 1.01 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 395 [M+H]+.
(b) (lR,2R)-l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol hydrochloride (80a)
(17?,27?)-l-(2,6-bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidia
ylamino)-indanol (80) (130 mg, 0.33 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether using the procedure described for compound 6a to produce (lR,2R)-l-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-indanol
hydrochloride (80a) (120 mg, 84% yield). 300 MHz 1H NMR (CDsOD, ppm): 7.32-7.24
(3H, m) 7.24-7.16 (1H, m) 5.65 (1H, d, J=5.5 Hz) 4.62-4.50 (1H, m) 3.61 (2H, t, J=7.0 Hz)
3.35 (1H, dd, J=16.0, 7.0 Hz) 2.99 (3H, s) 2.98 (3H, s) 2.90 (1H, dd, J=16.0, 6.4 Hz) 1.84-
1.68 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+.
Example 46: rac(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indan-l-ol (81) and corresponding hydrochloride salt (81a)
N"^N ^ OH
(a) 2-(2,6-Bis-methylammo- 8-propylamino-pyrimido [5,4-d] -pyrimidinylamino)-
indanol (81)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmol (70) (220
mg, 0.84 mmol) and 2-amino-indan-l-ol were reacted using procedures described elsewhere
herein. The crude product was purified by flash column chromatography using gradient
elution from CHhCk/EtOH (99:1) to CH2Cl2/EtOH (9:1) to obtain (2-(2,6-bis-methylamino-
8-propylammo-pyrimido[5,4-d]-pyrimidinylammo)-indan-l-ol (81) (200 mg, 61% yield).
300 MHz 1H NMR (CDCb, ppm): 7.48-7.39 (1H, m) 7.34-7.20 (3H, m) 7.00-6.90 (1H, m)
6.85 (1H, br s) 6.53 (1H, t, J=5.5 Hz) 5.19 (1H, d, J=6.7 Hz) 4.72-4.55 (2H, m) 4.49-4.35
(1H, m) 3.56-3.40 (3H, m) 3.06 (1H, dd, J-15.5, 10.2 Hz) 2.98 (3H, d, J=5.1 Hz) 2.97 (3H, d,
J-5.1 Hz) 1.78-1.63 (2H, m) 1.01 (3H, t, 3=7 A Hz). ESI-MS (m/z): 395 [M+H]+.
(b) 2-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
indanol hydrochloride (81a)
2-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indan-l-ol (81) (200 mg, 0.51 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether using the procedure described elsewhere herein to produce 2-(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylammo)-indan-l-ol
hydrochloride (81a) (200 mg, 91% yield). 300 MHz 'H NMR (CDsOD, ppm): 7.44-7.37
(1H, m) 7.33-7.22 (3H, m) 5.26 (1H, d, J=5.8 Hz) 4.80-4.68 (1H, m) 3.60 (2H, t, J=7.2 Hz)
3.54 (1H, dd, J=15.8, 7.9 Hz) 3.02 (3H, s) 2.98 (3H, s) 2.92 (1H, dd, J=15.8, 7.2 Hz) 1.83-
1.67 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+; MP: 181-183 °C.
Example 47: (lR,2S)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol (82) and corresponding hydrochloride salt (82a)
hT ^N OH
•H'WT
N^.N
HN- 82
(a) (lR,2S)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol (82)
2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinol (70) (250
mg, 0.95 mmol) and (lR,2S)aminocyclohexanol hydrochloride were reacted using
procedures described elsewhere herein to obtain (lR,2S)(2,6-bis-methylamino
propylamino-pyrimido[5,4-d]pyrimidinylammo)-cyclohexanol (82) (190 mg, 56% yield).
300 MHz 1HNMR (CDCb, ppm): 6.76 (1H, d, J=6.7 Hz) 6.50 (1H, t, J=5.2 Hz) 4.76-4.63
(1H, m) 4.58 (1H, q, J=5.2 Hz) 4.25-4.16 (1H, m) 4.05-3.99 (1H, m) 3.50-3.41 (2H, m) 2.97
(3H, d, J=5.2 Hz) 2.94 (3H, d, J=5.2 Hz) 1.95-1.35 (10H, m) 0.99 (3H, J=7.4 Hz). ESI-MS
(m/z): 361 [M+H]+.
(b) (lR,2S)(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol hydrochloride (82a)
(lR,2S)(2,6~Bis-methylammopropylammo-pyrimido[5,,4-d]pyrimidin
ylamino)-cyclohexanol (82) (190 mg, 0.53 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether using the procedure described for compound 6a to produce (lR,2S)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol
hydrochloride (82a) (165 mg, 79% yield). 400 MHz !H NMR (CDsOD, ppm): 4.28-4.21
(1H, m) 4.13-4.08 (1H, m) 3.58 (2H, t, J=7.4 Hz) 3.01 (3H, s) 2.99 (3H, s) 1.93-1.58 (8H, m)
1.53-1.37 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361 [M+H]+; MP: 249-251 °C.
Example 48: (15',25)(2,6-Bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-(83) and corresponding cyclohexanol hydrochloride salt (83a)
(a) (lS,2S)(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol (83)
2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinol (70) (300
mg, 1.14 mmol) and (lS,2S)aminocyclohexanol were reacted using procedures described
elsewhere herein. The crude product was purified by flash column chromatography using
gradient elution from CHbCk to CH2Cl2/EtOAc (4:1) as eluent to give (lS,2S)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol(83) (269
mg, 65% yield). 300 MHz 'H NMR (CDCk, ppm): 6.6-6.3 (2H, br s) 5.42 (1H, s) 4.7-4.4
(2H, br s) 3.84-3.66 (1H, m) 3.58-3.38 (3H, m) 3.06-2.85 (6H, m) 2.18-2.02 (2H, m) 1.84-
1.62 (2H, m) 1.69 (2H, sextet, J=7.4 Hz) 1.51-1.17 (4H, m) 1.00 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 361 [M+H]+.
(b) (lS,2S)(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylammo)-cyclohexanol hydrochloride (83a)
(lS,2S)(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamiao)-cyclohexanol (83) (230 mg, 0.64 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether using the procedure described for compound 6a to produce (1 S,2S)(2,6-bis-
methylammopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol
hydrochloride (83a) (215 mg, 85% yield). 300 MHz rH NMR (CDsOD, ppm): 4.15-4.00
(1H, m) 3.69-3.51 (1H, m) 3.59 (2H, t, J=7.4 Hz) 3.02 (3H, s) 2.99 (3H, s) 2.20-2.03 (2H, m)
1.86-1.68 (2H, m) 1.75 (2H, sextet, J=7.4 Hz) 1.49-1.29 (4H, m) 1.02 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 361 [M+H]+; MP: 236-238 °C.
Example 49: (liS',2I?)(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (84) and corresponding hydrochloride salt (84a)
(a) (lS,2R)(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylammo)-cyclohexanol (84)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol (70) (250
mg, 0.95 mmol) and (lS,2R)aminocyclohexanol hydrochloride were reacted procedures
described elsewhere herein to obtain (lS,2R)(2,6-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-cyclohexanol (84) (190 mg, 63% yield). 300 MHz 1H
NMR (CDCk, ppm): 6.75 (1H, d, J=7.0 Hz) 6.50 (1H, t, J=5.2 Hz) 4.72-4.62 (1H, m) 4.58
(1H, q, J=5.2 Hz) 4.25 (1H, m) 4.06-3.98 (1H, m) 3.50-3.41 (2H, m) 2.96 (3H, d, J=5.2 Hz)
2.94 (3H, d, J-5.2) 1.94-1.58 (8H, m) 1.57-1.36 (2H, m) 0.99 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 361 [M+H]+.
(b) (lS,2R)(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol hydrochloride (84a)
(lS,2R)(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidm
ylammo)-cyclohexanol (84) (215 mg, 0.60 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether using the procedure described for compound 6a to produce (lS,2R)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol
hydrochloride (84a) (180 mg, 76% yield). 300 MHz 1HNMR (CDsOD, ppm): 4.30-4.19
(1H, m) 4.13-4.06 (1H, m) 3.58 (2H, t, J=7.4 Hz) 3.0 (3H, s) 2.99 (3H, s) 1.95-1.55 (8H, m)
1.54-1.34 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361 [M+H]+; MP: 242-244 °C.
Example 50: (l^,27?)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (85) and corresponding hydrochloride salt (85a)
N' ^N ^ OH
.N-V^R.
N^,N
HN- 85
(a) (lR,2R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (85)
2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinol(70) (300
mg, 1.14 mmol) and (lR,2R)aminocyclohexanol were reacted using procedures described
elsewhere herein. The crude product was purified by flash column chromatography using
gradient elution from CH2C12 to CH2Cl2/EtOAc (4:1) as eluent to give (lR,2R)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol (85) (205
mg, 55% yield). 300 MHz 1H NMR (CDCk, ppm): 6.59-6.40 (2H, m) 4.70-4.53 (2H, m)
3.82-3.71 (1H, m) 3.57-3.41 (3H, m) 2.98-2.91 (6H, m) 2.16-2.05 (2H, m) 1.82-1.72 (2H, m)
1.69 (2H, sextet, 3=7.4 Hz) 1.51-1.24 (4H, m) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361
[M+H]+.
(b) (lR,2R)(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol hydrochloride (85a)
(lR,2R)(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
yl amino)-cyclohexanol (85) (195 mg, 0.54 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether using the procedure described for compound 6a to produce (lR,2R)(2,6-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol
hydrochloride (85a) (200 mg, 93% yield). 400 MHz 1HNMR (CDsOD, ppm): 4.12-4.01
(1H, m) 3.67-3.54 (1H, m) 3.58 (2H, t, J=7.4 Hz) 3.02 (3H, s) 2.99 (3H, s) 2.19-2.06 (2H, m)
1.84-1.70 (2H, m) 1.74 (2H, sextet, J=7.4 Hz) 1.46-1.32 (4H, m) 1.01 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 361 [M+H]+; MP: 212-213 °C.
Example 51: (1 S,2S)(2,6-Bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (86) and corresponding hydrochloride salt (86a)
""NH
^TN H PH
.N/V-yR,,,^
HN- 86
(a) (1 S,2S)(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (86)
2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinol (70) (300
mg, 1.14 mmol) and (lS,2S)aminocyclopentanol hydrochloride were reacted using
procedures previously. The cmde product was purified by flash column chromatography
using gradient elution from CHhCb to CH2Cl2/EtOAc (4:1) as eluent to obtain (1S,2S)(2,6-
bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylammo)-cyclopentanol (86)
(275 mg, 73% yield). 300 MHz 1H NMR (CDCls, ppm): 6.68-6.59 (1H, m) 6.57-6.44 (1H,
m) 6.2-6.0 (1H, br s) 4.75-4.47 (2H, m) 4.13-3.91 (2H, m) 3.53-3.40 (2H, m) 2.97 (3H, d,
J=5.2 Hz) 2.95 (3H, d, J=5.2 Hz) 2.36-2.22 (1H, m) 2.20-2.04 (1H, m) 1.94-1.51 (4H, m)
1.69 (2H, sextet, J=7.4 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 347 [M+H]+.
(b) (lS,2S)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol hydrochloride (86a)
(lS,2S)(2,6-bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (86) (235 mg, 0.68 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether/ MeOH (15/1) using the procedure described for compound 6a to produce
(lS,2S)(2,6-bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
cyclopentanol hydrochloride (86a) (230 mg, 88% yield). 300 MHz 1H NMR (CDsOD, ppm):
4.38-4.26 (1H, m) 4.24-4.13 (1H, m) 3.60 (2H, t, J=7.4 Hz) 3.03 (3H, s) 3.01 (3H, s) 2.37-
2.22 (1H, m) 2.11-1.97 (1H, m) 1.92-1.58 (4H, m) 1.75 (2H, sextet, J=7.4 Hz) 1.02 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 347 [M+H]+; MP: 257-259 °C.
Example 52: (lI?,2^)(2,6-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidm
ylamino)-cyclopentanol (87) and corresponding hydrochloride salt (87a)
""NH
^ H ?H
^-JIYJYN^
N^,N
HN-- 87
(a) (lR,2R)(2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (87)
2,6-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidmol (70) (300
mg, 1.14 mmol) and (lR,2R)ammocyclopentanol hydrochloride were reacted using
procedures described elsewhere herein. The crude product was purified by flash column
chromatography using gradient elution from CH2C12 to CHhCb/EtOAc (4:1) as eluent to
obtain (lR,2R)(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclopentanol (87) (210 mg, 55% yield). 300 MHz 'H NMR (CDCls, ppm): 6.68-
6.57 (1H, m) 6.55-6.43 (1H, m) 6.2-6.1 (1H, br s) 4.67-4.49 (2H, m) 4.12-3.91 (2H, m) 3.51-
3.42 (2H, m) 2.96 (3H, d, J=5.1 Hz) 2.95 (3H, d, J=5.0 Hz) 2.36-2.22 (1H, m) 2.20-2.04 (1H,
m) 1.94-1.51 (4H, m) 1.69 (2H, sextet, J=7.4 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 347
[M+H]+.
(b) (lR,2R)(2,6-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclopentanol hydrochloride (87a)
(lR,2R)(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (87) (235 mg, 0.68 mmol) and 2M HC1 /diethyl ether were reacted in
diethyl ether/ MeOH (15/1) using procedure described for compound 6a to produce (1R,2R)-
2-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol
hydrochloride (87a) (160 mg, 80% yield). 300 MHz rH NMR (CDsOD, ppm): 4.38-4.26
(1H, m) 4.24-4.13 (1H, m) 3.60 (2H, t, J=7.4 Hz) 3.03 (3H, s) 3.00 (3H, s) 2.38-2.22 (1H, m)
2.11-1.97 (1H, m) 1.92-1.56 (4H, m) 1.75 (2H, sextet, J=7.4 Hz) 1.02 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 347 [M+H]+; MP: 255-257 °C.
Example 53: 2-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylammo-pyrimido[5,4-
d]pyrimidinylammo]-ethanol (90) and corresponding hydrochloride salt (90a)
HN----"0"
"tfVSr^
N^,N
HN^/^90
(a) 2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamine (88)
2M Methylamine/THF (42 mL, 84.00 mmol) was added dropwise to a solution
of2,4,6,8-tetrachloro-pyrimido[5,4-d]pyrimidine (1) (5.00 g, 18.52 mmol) in THF (300 mL)
at 0°C. The reaction mixture was stirred at room temperature for 2 h and then the volatiles
were removed. The residue was suspended in water (50 mL) and the precipitate was filtered,
washed with water (2x30 mL) and dried over solid anhydrous P205 to give 2,6-dichloro-
N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamine (88) (4.61 g, 96% yield). 400 MHz
1H NMR (CDCls, ppm): 6.90 (2H, br s) 3.16 (6H, d, J=5.0 Hz). ESI-MS (m/z): 259, 261,263
[M+H]+.
(b) 2-(6-Chloro-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidinylamino)-ethanol (89)
A mixture of2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (600 mg, 2.32 mmol) and 2-amino-ethanol (700 \iL, 11.60 mmol) in 1,4-
dioxane (5 mL) was heated at 100°C for 18h in a closed vial. After cooling, a saturated
NaHCOs solution (20 mL) was added and the resulting suspension was extracted with EtOAc
(3x30 mL). The combined organic extracts were dried over solid anhydrous NazS04. After
filtration, the volatiles were evaporated, and the residue was crystallized from EtOAc /
petroleum ether (1/1) to give 2-(6-chloro-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (89) (500 mg, 76% yield). 300 MHz 'H NMR (CDCb, ppm): 6.68-6.54
(2H, m) 5.36 (1H, t, J=5.7 Hz) 3.87-3.82 (2H, m) 3.62 (2H, dt, J=5.7, 4.6 Hz) 3.46 (1H, br s)
3.13 (3H, d, J-5.2 Hz) 3.04 (3H, d, J=5.2 Hz). ESI-MS (m/z): 284, 286 [M+H]+.
(c) 2-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-ethanol (90)
A mixture of 2-(6-chloro-4,8-bis-methylamino-pyrimido [5 ,4-d]pyrimidin
ylamino)-ethanol (89) (250 mg, 0.81 mmol) and cyclopropylmethanamine (176 |J.L, 3.53
mmol) in n-butanol (4.0 mL) was heated at 125°C for 72 h in a closed vial. The reaction
mixture was cooled, and a saturated NaHCOs solution (20 mL) was added. The resulting
suspension was extracted with EtOAc (3 x 30mL). The combined organic extracts were
washed with a brine solution (50 mL) and dried over solid anhydrous N02804. After
filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from PE / i-PrOH (2/1) to PE / i-PrOH (1/1) to give 2-
[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
ethanol (90) (159 mg, 57% yield). 400 MHz !H NMR (CDC13, ppm): 6.62-6.54 (1H, m)
6.27-6.19 (1H, m) 5.10 (1H, t, J=6.0 Hz) 4.84 (1H, t, J=5.0 Hz) 4.56 (1H, s) 3.85-3.81 (2H,
m) 3.60-3.55 (2H, m) 3.24 (2H, dd, J=7.0, 5.2 Hz) 3.06 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2
Hz) 1.14-1.03 (1H, m) 0.55-0.49 (2H, m) 0.26-0.22 (2H, m). ESI-MS (m/z): 319 [M+H]+.
(d) 2-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-ethanol hydrochloride (90a)
2-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-ethanol (90) (159 mg, 0.50 mmol) was treated with 2M HC1 /diethyl
ether in dichloromethane using procedures described elsewhere herein to produce 2-[6-
(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
ethanol hydrochloride (90a) (177 mg, 87% yield). 300 MHz !H NMR (DiO, ppm): 3.78 (2H,
t, J=5.5 Hz) 3.55 (2H, t, J=5.5 Hz) 3.26 (2H, d, J=7.0 Hz) 3.05 (3H, s) 3.01 (3H, s) 1.19-1.08
(1H, m) 0.62-0.53 (2H, m) 0.34-0.26 (2H, m). ESI-MS (m/z): 319 [M+H]+; MP: 214-216
Example 54: 2-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (91) and corresponding hydrochloride (91a)
HN--OH
Nl N "
^VYS'
N^.N
HN^^ 91
(a) 2-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)-
ethanol (91)
2-(6-Chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-
ethanol (89) (250 mg, 0.81 mmol) and propylamine were reacted in n-butanol using
procedure described for compound (90) to obtain 2-(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-ethanol (91) (129 mg, 48% yield). 400 MHz 'H NMR
(CDCb, ppm): 6.64-6.54 (1H, m) 6.26-6.18 (1H, m) 5.09 (1H, t, J=6.0 Hz) 4.75-4.65 (1H, m)
4.64-4.48 (1H, br s) 3.85-3.81 (2H, m) 3.60-3.55 (2H, m) 3.38-3.32 (2H, m) 3.06 (3H, d,
J=6.5 Hz) 3.05 (3H, d, J=6.5 Hz) 1.63 (2H, sextet, J=7.4 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 307 [M+H]+.
(b) 2-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol hydrochloride (9 1 a)
2-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (91) (125 mg, 0.41 mmol) was treated with 2M HC1 /diethyl ether in
dichloromethane using procedures described elsewhere herein to produce 2-(4,8-bis-
methylaminopropylamino-pyrimido [5,4-d]pyrimidmylamino)-ethanol hydrochloride
(91a) (128 mg, 92% yield). 300 MHz IH NMR (DiO, ppm): 3.78 (2H, t, J=5.5 Hz) 3.55 (2H,
t, J=5.5 Hz) 3.35 (2H, t, J=7.0 Hz) 3.05 (3H, s) 3.01 (3H, s) 1.64 (2H, sextet, J=7.3 Hz) 0.96
(3H, t, J=7.3 Hz). ESI-MS (m/z): 307 [M+H]+; MP: 224-226 °C.
Example 55: 2-(6-Dimethylamino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylammo)-ethanol (92) and corresponding hydrochloride salt (92a)
HN-—OH
11 N H
N^.N
^-N\ 92
(a) 2-(6-Dimethylamino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-
ethanol (92)
A mixture of 2-(6-chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol (89) (300 mg, 1.06 rnmol) and dimethylamine (40% water solution) (1.00
mL) in n-butanol (3.0 mL) was heated at 110°C for 18h in a closed vial. The reaction mixture
was cooled, the precipitate was filtered, washed with water (2x10 mL) and dried over solid
anhydrous P205 to give 2-(6-dimethylamino-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylamino)-ethanol (92) (200 mg, 65% yield). 300 MHz 1H NMR (CDCl3-d6,
ppm): 6.68-6.51 (1H, m) 6.22-6.04 (1H, m) 5.06 (1H, t, J=6.1 Hz) 4.75 (1H, s) 3.88-3.78 (2H,
m) 3.62-3.51 (2H, m) 3.16 (6H, s) 3.08 (3H, d, J=5.1 Hz) 3.07 (3H, d, J=5.1 Hz). ESI-MS
(m/z): 293 [M+H]+.
(b) 2-(6-Dimethylammo-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-
ethanol hydrochloride (92a)
2-(6-Dimethylamino-4,8-bis-methylammo-pyrimido[5,4-d]-pyrimidinyl
amino)-ethanol (92) (140 mg, 0.48 mmol) was treated with 2M HC1 /diethyl ether in diethyl
ether / MeOH (4/1) using procedure described for compound 6a to produce 2-(6-
dimethylamino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-ethanol
hydrochloride (92a) (145 mg, 92% yield). 300 MHz 1HNMR (CDsOD, ppm): 3.81-3.70
(2H, m) 3.68-3.55 (2H, m) 3.19 (6H, s) 3.15 (3H, s) 3.07 (3H, s). ESI-MS (m/z): 293
[M+H]+; MP: 264-266 °C.
Example 56: l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylammo)methyl-propanol (94) and corresponding hydrochloride salt (94a)
N^N ^
Wvi<
N^,N
HN^OH 94
(a) 6-Chloro-N4,N8-dimethyl-N2-propylpyrimido[5,4-d]pyrimidine-2,4,8-triamine (93)
A mixture of 2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (4.00 g, 15.44 mmol) and propylamine (5.1 mL, 61.75 mmol) in n-butanol (40
mL) was heated at 90°C for 20 h. After cooling, a saturated NaHCOs solution (200 mL) was
added and the resulting suspension was extracted with EtOAc (3 x 100 mL). The combined
organic extracts were washed with water (200 mL), then with a brine solution (200 mL) and
dried over solid anhydrous N02804. After filtration, the solvent was removed to give 6-
chloro-N4,N8-dimethyl-N2-propylpyrimido[5,4-d]pyrimidine-2,4,8-triamine (93) (4.32 g, 99%
yield). 400 MHz 1H NMR (CDCls, ppm): 6.72 (1H, br s) 6.49 (1H, br s) 4.97 (1H, t, J=5.4
Hz) 3.42-3.35 (2H, m) 3.14 (3H, d, J=5.2 Hz) 3.04 (3H, d, J=5.1 Hz) 1.69-1.59 (2H, m) 0.99
(3H, t, J=7.4 Hz). ESI-MS (m/z): 282, 284 [M+H]+.
(b) l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (94)
A mixture of 6-chloro-N4,N8-dimethyl-N2-propylpyrimido[5,4-d]pyrimidine-
2,4,8-triamine (93) (253 mg, 0.90 mmol) and l-aminomethyl-propanol (340 ^L, 3.60
mmol) in n-butanol (4.0 mL) was heated at 125°C for 48h in a closed vial. A second portion
of l-aminomethyl-propanol (340 |J.L, 3.60 mmol) was added and the mixture was
heated for 100 h. The reaction mixture was cooled and a saturated NaHCOs solution (20 mL)
was added. The resulting suspension was extracted with EtOAc (3 x 30mL). The combined
organic extracts were washed with brine (50 mL) and dried over solid anhydrous N02804.
After filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from PE / EtOAc (1/1) to PE / EtOAc (1/99) to give
l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)methyl-
propanol (94) (263 mg, 87% yield). 300 MHz 1HNMR (CDCb, ppm): 6.65-6.53 (1H, m)
6.19-6.11 (1H, m) 5.33 (1H, br s) 5.09 (1H, t, J=5.1 Hz) 4.69 (1H, t, J=5.1 Hz) 3.43-3.31 (2H,
m) 3.39 (2H, d, J=6.4 Hz) 3.06 (3H, d, J=5.1 Hz) 3.04 (3H, d, J=5.1 Hz) 1.62 (2H, sextet,
J=7.4 Hz) 1.27-1.24 (6H, m) 0.98 (3H, t, 3=7 A Hz). ESI-MS (m/z): 335 [M+H]+.
(c) l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol hydrochloride (94a)
l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)methyl-propanol (94) (207 mg, 0.62 mmol) was treated with 2M HC1 /diethyl
ether in dichloromethane using procedures previously to produce l-(4,8-bis-methylamino
propyl amino-pyrimido[5,4-d]pyrimidmylamino)methyl-propanol hydrochloride
(94a) (200 mg, 87% yield). 400 MHz 1HNMR (CDsOD, ppm): 3.52 (2H, s) 3.46 (2H, t,
J=7.1 Hz) 3.15 (3H, s) 3.13 (3H, s) 1.69 (2H, sextet, J=7.4 Hz) 1.27 (6H, s) 1.01 (3H, t, J=7.4
Hz). ESI-MS (m/z): 335 [M+H]+; MP: 191-193 °C.
Example 57: l-(4,8-Bis-methylamiaopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-propanol (95) and corresponding hydrochloride salt (95a)
'OH 95
(a) l-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (95)
6-Chloro-N ,N -dimethyl-N -propylpyrimido[5,4-d]pyrimidine-2,4,8-triamine
(93) (200 mg, 0.71 mmol) and l-amino-propanol were reacted in n-butanol using
procedure described for compound (94) to obtain l-(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]-pyrimidinylamino)-propanol (95) (110 mg, 48% yield). 400 MHz rH
NMR (CDCb, ppm): 6.57 (1H, s) 6.18 (1H, s) 5.10-4.90 (2H, m) 4.75-4.61 (1H, m) 4.08-3.99
(1H, m) 3.50 (1H, ddd, J=14.4, 6.3, 2.3 Hz) 3.41-3.30 (3H, m) 3.07 (3H, d, J=5.2 Hz) 3.05
(3H, d, J=5.2 Hz) 1.68-1.56 (2H, m) 1.22 (3H, d, J=6.3 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 321 [M+H]+.
(b) 1 -(4,8-Bis-methylaminopropylamino-pyrimido [5,4-d] -pyrimidinylamino)-
propanol hydrochloride (95a)
l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-propanol (95) (105 mg, 0.33 mmol) was treated with 2M HC1 /diethyl ether in
dichloromethane using procedures described elsewhere herein to produce l-(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-propanol
hydrochloride (95a) (110 mg, 94% yield). 400 MHz 1H NMR (CDaOD, ppm): 4.03-3.93 (1H,
m) 3.53 (1H, dd, J=13.7, 4.6 Hz) 3.48-3.37 (3H, m) 3.13 (3H, s) 3.11 (3H, s) 1.74-1.63 (2H,
m) 1.23 (3H, d, J=6.3 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+; MP: 217-219
Example 58: l-[(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidmyl)-
methyl-amino]methyl-propanol (96) and corresponding hydrochloride salt (96a)
N^N ^
^A^k^
H N^N
^N^^OH 96
(a) l-[(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]methyl-propanol (96)
A mixture of 6-chloro-N ,N8-dimethyl-N2-propylpyrimido [5,4-d]pyrimidine-
2,4,8-triamine (93) (285 mg, 1.01 mmol) and2-methyl-l-methylamino-propanol (238 p.L,
2.02 mmol) in n-butanol (4.0 mL) was heated at 125°C for 120 h in a closed vial. The
reaction mixture was cooled and a saturated NaHCOs solution (20 mL) was added. The
resulting suspension was extracted with EtOAc (3 x 20mL). The combined organic extracts
were washed with a brine solution (50 mL) and then dried over solid anhydrous N02804.
After filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/99) to give
l-[(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-amino]
methyl-propanol (96) (250 mg, 71% yield). 400 MHz !H NMR (CDCb, ppm): 6.8-6.5
(1H, br s) 6.55 (1H, s) 6.27 (1H, s) 4.70-4.63 (1H, m) 3.56 (2H, s) 3.38-3.31 (2H, m) 3.22
(3H, s) 3.07 (3H, d, J=5.2 Hz) 3.07 (3H, d, J=5.2 Hz) 1.63 (2H, sextet, J=7.4 Hz) 1.27 (6H, s)
0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+.
(b) l-[(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]methyl-propanol hydrochloride (96a)
l-[(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinyl)-
methyl-amino]methyl-propanol (96) (182 mg, 0.52 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether using procedure described for compound 6a to produce 1-[(4,8-
bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-amino]methyl-
propanol hydrochloride (96a) (191 mg, 95% yield). 400 MHz 1H NMR: (CDaOD, ppm)
3.74 (2H, s) 3.46 (2H, t, J=7.4 Hz) 3.30 (3H, s) 3.15 (3H, s) 3.09 (3H, s) 1.70 (2H, sextet,
J=7.4 Hz) 1.25 (6H, s) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+; MP: 213-215 °C.
Example 59: l-[(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmyl)-
methyl-amino]-propanol (97) and corresponding hydrochloride salt (97a)
"OH 97
(a) l-[(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-propanol (97)
6-Chloro-N4,N8-dimethyl-N2-propylpyrimido[5,4-d]pyrimidine-2,4,8-triamine
(93) (280 mg, 0.99 mmol) and l-methylamino-propanol were reacted in n-butanol using
procedure described for compound (94) to obtain l-[(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinyl)-methyl-amino]-propanol (97) (215 mg, 64% yield). 400
MHz 1HNMR (CDCb, ppm): 6.54 (1H, br s) 6.29 (1H, br s) 5.65 (1H, br s) 4.66 (1H, s)
4.18-4.07 (1H, m) 3.74 (1H, dd, J=14.7, 7.4 Hz) 3.47 (1H, d, J=14.7 Hz) 3.41-3.30 (2H, m)
3.21 (3H, s) 3.11-3.01 (6H, m) 1.63 (2H, sextet, J=7.4 Hz) 1.23 (3H, d, J=6.1 Hz) 0.99 (3H, t,
J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+. ESI-MS (m/z): 335 [M+H]+.
(b) l-[(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-propanol hydrochloride (97a)
l-[(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmyl)-
methyl-amino]-propanol (97) (175 mg, 0.52 mmol) was treated with 2M HC1 /diethyl ether
in diethyl ether using procedure described for compound 6a to produce l-[(4,8-bis-
methylaminopropylamino-pyrimido [5,4-d]pyrimidmyl)-methyl-ammo] -propanol
hydrochloride (97a) (159 mg, 82% yield). 400 MHz 1H NMR (CDsOD, ppm): 4.17-4.07
(1H, m) 3.64 (2H, s) 3.46 (2H, t, J=7.4 Hz) 3.25 (3H, s) 3.16 (3H, s) 3.07 (3H, s) 1.70 (2H,
sextet, J=7.4 Hz) 1.20 (3H, d, J=6.1 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+;
MP: 236-237 °C. Anal. Calcd for Ci5H27ClN80: C, 48.58; H, 7.34; N, 30.21. Found: C,
48.47; H, 7.33; N,30.22.
Example 60: 1 -[6-((R)-5ec-Butylamino)-4,8-bis-methylammo-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol (99) and corresponding hydrochloride salt (99a)
N N "
WYR"
H Vi
HN--J<OH 99
(a) (R)-N2-^ec-butylchloro-N ,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-triamine
(98)
A mixture of 2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (350 mg, 1.35 mmol), (R)-(-)-s'ec-butylamine (216 [XL, 2.16 mmol) andN-
diisopropyl ethylamine (234 \\L, 1.35 mmol) in n-butanol (5 mL) was heated at 80°C for 72h.
After cooling, a saturated NaHCOs solution (20 mL) was added and the resulting suspension
was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with
water (30 mL), then with a brine solution (30 mL) and dried over solid anhydrous ]V[gS04.
After filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (2/1) to give
(R)-N2-5ec-butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-triamme(98)
(330 mg, 83% yield). 300 MHz 1H NMR (CDCb, ppm) 6.77-6.63 (1H, m) 6.54-6.41 (1H, m)
4.79 (1H, d, J=8.2 Hz) 4.09-3.94 (1H, m) 3.14 (3H, d, J=5.1 Hz) 3.04 (3H, d, J=5.1 Hz) 1.63-
1.49 (2H, m) 1.21 (3H, d, J=6.6 Hz) 0.96 (3H, t, J=7.5 Hz). ESI-MS (m/z): 296, 298 [M+H]+.
(b) l-[6-((R)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol (99)
(R)-N2-5ec-Butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-
triamine (98) (330 mg, 1.12 mmol) and l-aminomethyl-propanol were reacted in n-
butanol using procedure described for compound (94) to l-[6-((R)-s'ec-butylamino)-4,8-bis-
methyl amino-pyrimido[5,4-d]-pyrimidmylamino]methyl-propanol (99) (160 mg,
41% yield). 300 MHz 1HNMR (CDCb, ppm): 6.62-6.49 (1H, m) 6.20-6.06 (1H, m) 5.6-5.2
(1H, br s) 5.07 (1H, t, J=6.3 Hz) 4.52 (1H, d, J=8.3 Hz) 4.04-3.89 (1H, m) 3.39 (2H, d, J=6.3
Hz) 3.06 (3H, d, J=5.2 Hz) 3.04 (3H, d, J=5.2 Hz) 1.66-1.43 (2H, m) 1.26 (6H, s) 1.19 (3H, d,
J=6.5 Hz) 0.96 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+.
(c) l-[6-((R)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylammo]methyl-propanol hydrochloride (99a)
l-[6-((R)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol (99) (140 mg, 0.40 mmol) was treated with 2M HC1 /diethyl
ether in diethyl ether using procedure described for compound 6a to produce l-[6-((R)-^ec-
butylammo)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]methyl-propan
ol hydrochloride (99a) (145 mg, 94% yield). 300 MHz 'H NMR (CDaOD, ppm): 4.19-4.06
(1H, m) 3.51 (2H, s) 3.13 (3H, s) 3.12 (3H, s) 1.70-1.55 (2H, m) 1.26 (6H, s) 1.25 (3H, d,
J==6.4 Hz) 0.98 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+: MP: 174-176 °C.
Example 61: (R)-l-[6-((R)-^ec-Butylammo)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-propanol (100) and corresponding hydrochloride salt (lOOa)
N-^N
"KVT"'
N^,N
HN-^OH 100
(a) (R)-l-[6-((R)->s'ec-Butylammo)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-propanol (100)
(R)-N2-5ec-butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-
triamine (98) (168 mg, 0.57 mmol) and (^')-l-amino-propanol were reacted in n-butanol
using procedures described elsewhere herein to obtain (R)-l-[6-((R)-5gc-butylamino)-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidinylamino]-propanol (100) (109 mg, 67% yield).
300 MHz 1HNMR (CDCb, ppm): 6.61-6.51 (1H, m) 6.24-6.14 (1H, m) 5.07 (1H, t, J=5.8
Hz) 4.54 (1H, d, J=8.3 Hz) 4.09-3.90 (2H, m) 3.49 (1H, ddd, J=14.4, 6.3, 2.5 Hz) 3.35 (1H,
ddd, J=14.4, 6.9, 6.2 Hz) 3.06 (3H, d, J=5.1 Hz) 3.04 (3H, d, J=5.1 Hz) 1.69-1.46 (2H, m)
1.22 (3H, d, J=6.3 Hz) 1.19 (3H, d, J=6.5 Hz) 0.95 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335
[M+H]+.
(b) (R)-1 -[6-((R)-j'ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylaminoj-propanol hydrochloride (lOOa)
(R)-l-[6-((R)-5'ec-Butylammo)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-propanol (100) (109 mg, 0.33 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether using procedure described for compound 6a to produce (R)-l-
[6-((R)-^ec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-propan-
2-ol hydrochloride (lOOa) (95 mg, 78% yield). 400 MHz 'HNMR (CDsOD, ppm): 4.17-4.06
(1H, m) 4.02-3.93 (1H, m) 3.51 (1H, dd, J=13.7, 4.5 Hz) 3.40 (1H, dd, J=13.7, 6.9 Hz) 3.12
(3H, s) 3.10 (3H, s) 1.62 (2H, pentet, J=7.4 Hz) 1.25 (3H, d, J=6.6 Hz) 1.22 (3H, d, J=6.3 Hz)
0.98 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+; MP: 186-188 °C.
Example 62: (S)-l -[6-((R)-^ec-Butylamino)-4,8-bis-methylammo-pyrimido[5,4-
d]pyrimidinylamino]-propanol (101) and corresponding hydrochloride salt (lOla)
fl N H
•HVr"'
HN-^OH 101
(a) (S)-1 -[6-((R)-5ec-Butylamino)-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino]-propanol (101)
(S)-N2-^ec-butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-
triamine (98) (168 mg, 0.57 mmol) and (S)-l-amino-propanol were reacted in n-butanol
using procedures described elsewhere herein to obtain (S)-l-[6-((R)-5ec-butylamino)-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidinylamino]-propanol (101) (100 mg, 52% yield).
300 MHz 1HNMR (CDCb, ppm): 6.61-6.51 (1H, m) 6.24-6.14 (1H, m) 5.07 (1H, t, J=5.8
Hz) 4.54 (1H, d, J=8.3 Hz) 4.09-3.90 (2H, m) 3.49 (1H, ddd, J=14.4, 6.3, 2.5 Hz) 3.35 (1H,
ddd, J=14.4, 6.9, 6.2 Hz) 3.06 (3H, d, J=5.1 Hz) 3.04 (3H, d, J==5.1 Hz) 1.69-1.46 (2H, m)
1.22 (3H, d, J=6.3 Hz) 1.19 (3H, d, J=6.5 Hz) 0.95 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335
[M+H]+.
(b) (S)-l-[6-((R)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinyl
amino]-propanol hydrochloride (lOla)
(S)-l-[6-((R)->s'ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylammo]-propanol (101) (90 mg, 0.27 mmol) was treated with 2M HC1
/diefhyl ether in diethyl ether using procedure described for compound 6a to produce (S)-l-
[6-((R)-5ec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-propan-
2-ol hydrochloride (lOla) (85 mg, 85% yield). 400 MHz 1HNMR (CDaOD, ppm): 4.16-4.06
(1H, m) 4.02-3.93 (1H, m) 3.51 (1H, dd, J=13.7, 4.6 Hz) 3.40 (1H, dd, J-13.7, 6.9 Hz) 3.12
(3H, s) 3.10 (3H, s) 1.62 (2H, pentet, J=7.4 Hz) 1.25 (3H, d, J=6.6 Hz) 1.22 (3H, d, J=6.3 Hz)
0.98 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+; MP: 167-169 °C.
Example 63: l-[6-((S)->yec-Butylamino)-4,8-bis-methylammo-pyrimido[5,4-d]-pyrimidm
ylamino]methyl-propanol (103) and corresponding hydrochloride salt (103a)
1i N tl
-tlVr"'
HN-^OH 103
(a) (S)-N2->s'ec-butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-triamine
(102)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamme (88)
(350 mg, 1.35 mrnol) and (S)-(+)-5ec-butylamine were reacted in n-butanol using procedures
described elsewhere herein to obtain (S)-N -.yec-butylchloro-N ,N -dimethylpyrimido[5,4-
d]pyrimidine-2,4,8-triamine (102) (250 mg, 63% yield). 300 MHz 'H NMR (CDCls, ppm):
6.77-6.63 (1H, m) 6.54-6.41 (1H, m) 4.79 (1H, d, J=8.2 Hz) 4.09-3.94 (1H, m) 3.14 (3H, d,
J=5.1 Hz) 3.04 (3H, d, J=5.1 Hz) 1.65-1.49 (2H, m) 1.21 (3H, d, J=6.5 Hz) 0.96 (3H, t, J=7.5
Hz). ESI-MS (m/z): 296, 298 [M+H]+.
(b) l-[6-((S)->s'ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol(103)
(S)-N2-5ec-Butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-
triamine (102) (250 mg, 0.85 mmol) and l-aminomethyl-propanol were reacted in n-
butanol using procedures described elsewhere herein to obtain l-[6-((S)-5ec-butylamino)-4,8-
bis-methylamino-pyrimido[5,4-d]-pyrimidmylamino]methyl-propanol (103) (180
mg, 61% yield). 300 MHz 1H NMR (CDCk, ppm): 6.62-6.49 (1H, m) 6.20-6.06 (1H, m)
.41 (1H, s) 5.06 (1H, t, J=6.3 Hz) 4.51 (1H, d, J=8.3 Hz) 4.04-3.89 (1H, m) 3.39 (2H, d,
J=6.3 Hz) 3.07 (3H, d, J=5.2 Hz) 3.04 (3H, d, J=5.2 Hz) 1.66-1.43 (2H, m) 1.26 (6H, s) 1.19
(3H, d, J=6.5 Hz) 0.96 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+.
(c) l-[6-((S)-^ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylammo]methyl-propanol hydrochloride (103a)
l-[6-((S)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidin
ylamino]methyl-propanol (103) (140 mg, 0.40 mmol) was treated with 2M HC1 /diethyl
ether in diethyl ether using procedure described for compound 6a to produce l-[6-((S)-sec-
butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]methyl-propan
ol hydrochloride (103a) (140 mg, 91% yield). 300 MHz 1H NMR (CDsOD, ppm): 4.19-4.06
(1H, m) 3.50 (2H, s) 3.12 (3H, s) 3.11 (3H, s) 1.70-1.55 (2H, m) 1.26 (6H, s) 1.25 (3H,d,
J=6.5 Hz) 0.98 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+: MP: 182-184 °C.
Example 64: (R)-l-[6-((S)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-propanol (104) and corresponding hydrochloride salt (104a)
N-^N
~HVTR'
N^.N
HN-^OH 104
(a) (R)-l-[6-((S)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-propanol (104)
(S)-N2-^ec-Butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidme-2,4,8-
triamine (102) (185 mg, 0.63 mmol) and (^)-l-ammo-propanol were reacted in n-butanol
using procedures described elsewhere herein to obtain (R)-l-[6-((S)-^ec-butylamino)-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidinylamino]-propanol (104) (95 mg, 45% yield).
300 MHz 1HNMR (CDCb, ppm): 6.56 (1H, s) 6.18 (1H, s) 5.20-4.85 (2H, m) 4.63-4.42 (1H,
m) 4.10-3.90 (2H, m) 3.50 (1H, ddd, J=14.4, 6.3, 2.5 Hz) 3.35 (1H, ddd, J=14.4, 6.9, 6.2 Hz)
3.09-3.02 (6H, m) 1.67-1.48 (2H, m) 1.22 (3H, d, J=6.3 Hz) 1.20 (3H, d, J=6.5 Hz) 0.96 (3H,
t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
(b) (R)-l-[6-((S)-5ec-Butylamino)-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino]-propanol hydrochloride (104a)
(R)-l-[6-((S)-5ec-Butylammo)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-propanol (104) (95 mg, 0.28 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether using procedure described for compound 6a to produce (R)-l-
[6-((S)-^ec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-propan-
2-ol hydrochloride (104a) (70 mg, 66% yield). 300 MHz 'H NMR (CDsOD, ppm): 4.20-4.06
(1H, m) 4.05-3.92 (1H, m) 3.53 (1H, dd, J=13.7, 4.6 Hz) 3.41 (1H, dd, J=13.7, 6.9 Hz) 3.13
(3H, s) 3.12 (3H, s) 1.69-1.56 (2H, m) 1.26 (3H, d, J=6.6 Hz) 1.23 (3H, d, J=6.3 Hz) 0.99
(3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
Example 65: (S)-l-[6-((S)-^ec-Butylamino)-4,8-bis-methylammo-pyrimido[5,4-
d]pyrimidinylamino]-propanol (105) and corresponding hydrochloride salt (105a)
if^N
-KVr"'
HN—OH ,05
(a) (S)-l-[6-((S)-5ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-propanol (105)
(S)-N2-^ec-Butylchloro-N4,N8-dimethylpyrimido[5,4-d]pyrimidine-2,4,8-
triamine (102) (185 mg, 0.63 mmol) and (S)-l-amino-propanol were reacted in n-butanol
using procedures described elsewhere herein to afford (S)-l-[6-((S)-^-ec-butylammo)-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidmylamino]-propanol (105) (110 mg, 52% yield).
300 MHz 'HNMR (CDCls, ppm): 6.56 (1H, s) 6.18 (1H, s) 5.16-4.90 (2H, m) 4.60-4.45 (1H,
m) 4.10-3.90 (2H, m) 3.50 (1H, ddd, J=14.4, 6.3, 2.5 Hz) 3.35 (1H, ddd, J=14.4, 6.9, 6.2 Hz)
3.06 (3H, d, J=5.1 Hz) 3.05 (3H, d, J=5.1 Hz) 1.66-1.45 (2H, m) 1.22 (3H, d, J=6.3 Hz) 1.19
(3H, d, J=6.5 Hz) 0.96 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+.
(b) (S)-l-[6-((S)-5ec-Butylamino)-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino]-propanol hydrochloride (105a)
(S)-l-[6-((S)-^ec-Butylamino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidmylamino]-propanol (105) (I 10 mg, 0.33 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether using procedure described for compound 6a to produce (S)-l-
[6-((S)-5ec-butylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino]-propan-
2-ol hydrochloride (105a) (85 mg, 69% yield). 300 MHz 'H NMR (CDsOD, ppm): 4.20-4.08
(1H, m) 4.05-3.91 (1H, m) 3.54 (1H, dd, J=13.7, 4.6 Hz) 3.41 (1H, dd, J=13.7, 6.9 Hz) 3.14
(3H, s) 3.12 (3H, s) 1.69-1.56 (2H, m) 1.26 (3H, d, J=6.6 Hz) 1.23 (3H, d, J=6.3 Hz) 0.99
(3H, t, J-7.4 Hz). ESI-MS (m/z): 335 [M+H]+; MP: 178-180 °C.
Example 66: 1 -[6-(2,2-Difluoro-ethylammo)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]methyl-propanol (107) and corresponding hydrochloride salt
(107a)
HN^V
N-^N
~KVTN"~
HN^<°H 107
(a) 6-Chloro-N2-(2,2-difluoro-ethyl)-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (106)
A mixture of2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (250 mg, 0.96 mmol) and 2,2-difluoro-ethylamine (157 mg, 1.93 mmol) in 1,4-
dioxane (4 mL) was heated at 100°C for 18h in a closed vial. After cooling, a saturated
NaHCOs solution (20 mL) was added and the resulting suspension was extracted with EtOAc
(3 x 30 mL). The combined organic extracts were dried over solid anhydrous N02804. After
filtration, the volatiles were evaporated and the residue was purified by flash column
chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/2) to give 6-
chloro-N2-(2,2-difluoro-ethyl)-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamme
(106) (105 mg, 36% yield). ESI-MS (m/z): 304, 306 [M+H]+.
(b) l-[6-(2,2-Difluoro-ethylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinyl
amino]methyl-propanol (107)
A mixture of 6-chloro-N2-(2,2-difluoro-ethyl)-N4,N8-dimethyl-pyrimido[5,4-
d] pyrimidine-2,4,8-tnamine (106) (105 mg, 0.35 mmol) and l-aminomethyl-propanol
(340 p.L, 3.60 mmol) in n-butanol (4.0 mL) was heated at 125°C for 48 h in a closed vial.
The reaction mixture was cooled, and a saturated NaHCOa solution (20 mL) was added. The
resulting suspension was extracted with EtOAc (3 x 30mL). The combined organic extracts
were washed with a brine solution (50 mL) and dried over solid anhydrous N02804. After
filtration, the solvent was removed; the residue was purified by flash column chromatography
using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/99) to give l-[6-(2,2-difluoro-
ethylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]methyl-propan
ol (107) (95 mg, 76% yield). 300 MHz 1H NMR (CDCb, ppm): 6.54-6.43 (1H, m) 6.30-6.20
(1H, m) 5.97 (1H, tt, J=57.0, 4.5 Hz) 5.12 (1H, t, J=6.4 Hz) 4.88 (1H, t, J=6.4 Hz) 3.86-3.71
(2H, m) 3.41 (2H, d, J=6.4 Hz) 3.07 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz) 1.27 (6H, s).
ESI-MS (m/z): 357 [M+H]+.
(c) l-[6-(2,2-Difluoro-ethylamino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylammo]methyl-propanol hydrochloride (107a)
l-[6-(2,2-Difluoro-ethylamino)-4,8-bis-methylammo-pyrimido[5,4-
d]pyrimidinylamino]methyl-propanol (107) (95 mg, 0.27 mmol) was treated with
2M HC1 /diethyl ether in dichloromethane using procedures described elsewhere herein to
produce l-[6-(2,2-difluoro-ethylamino)-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino]methyl-propanol hydrochloride (107a) (90 mg, 85% yield). 400 MHz rH
NMR (CD30D, ppm): 6.02 (1H, tt, J=57.0, 4.2 Hz) 3.84 (2H, dd, J=14.7, 4.2 Hz) 3.52 (2H, s)
3.16 (3H, s) 3.09 (3H, s) 1.28 (6H, s). ESI-MS (m/z): 357 [M+H]+; MP: 223-225 °C.
Example 67: 1 - {4,8-Bis-methylamino [(pyrimidinylmethyl)-amino] -pyrimido [5,4-d]
pyrimidinylamino}methyl-propanol (109) and corresponding hydrochloride salt
(109a)
"OH 109
(a) 6-Chloro-N4,N8-dimethyl-N2-pyrimidinylmethyl-pyrimido[5,4-d]pyrimidme-2,4,8-
triamine (109)
A mixture of2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (259 mg, 1.00 mmol), pyrimidmylmethanamine hydrochloride (218 mg, 1.50
mmol) and N,N-diisopropylethylamine (435 |J.L, 2.50 mmol) in n-butanol (3 mL) was heated
at 90°C for 72 h. The reaction mixture was cooled, the precipitate were filtered, washed with
water (2x10 mL) and dried over P205 to afford 6-chloro-N4,N8-dimethyl-N -pyrimidin
ylmethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine (108) (260 mg, 79% yield). 300 MHz 1H
NMR (DMSO-d6+TFA, ppm): 8.76 (2H, d, J=4.8 Hz) 7.92 (1H, q, J=4.9 Hz) 7.77 (1H, q,
J=4.9 Hz) 7.38 (1H, t, J-4.8 Hz) 7.02 (1H, br s) 4.83 (2H, s) 2.91 (3H, d, J=4.9 Hz) 2.90-2.80
(3H, m). ESI-MS (m/z): 332, 334 [M+H]+.
(b) 1 - {4,8-Bis-methylamino [(pynmidinylmethyl)-amino] -pyrimido [5 ,4-
d]pyrimidinylamino}methyl-propanol (109)
A mixture of6-chloro-N4,N8-dimethyl-N2-pyrimidinylmethyl-
pyrimido[5,4-d]pyrimidine-2,4,8-triamine (108) (125 mg, 0.38 mmol) and l-aminomethyl-
propanol (180 |^L, 1.90 mmol) in DMSO (1.5 mL) was heated at 115°C for 48 h. After
cooling, the reaction mixture was cooled and water (20 mL) was added. The resulting
suspension was extracted with CHhCk (3 x 15mL). The combined organic extracts were
washed with water (20 mL) and dried over solid anhydrous N02804. After filtration, the
solvent was removed and the residue was purified by flash column chromatography using
gradient elution from CH2C12 to CHzCk / EtOAc (4/1) to give l-{4,8-bis-methylamino
[(pyrimidinylmethyl)-amino] -pyrimido [5,4-d]pyrimidmylamino } methyl-propanol
(109) (70 mg, 48% yield). 300 MHz 'H NMR (CDCk, ppm): 8.72 (2H, d, J=4.9 Hz) 7.18
(1H, t, J=4.9 Hz) 6.60 (1H, br s) 6.17 (1H, br s) 5.95-5.77 (1H, m) 5.34 (1H, br s) 5.09 (1H,
br s) 4.87 (2H, d, J=5.2 Hz) 3.39 (2H, d, J=6.2 Hz) 3.06 (3H, d, J=5.1 Hz) 3.05 (3H, d, J=5.1
Hz) 1.26 (6H, s). ESI-MS (m/z): 385 [M+H]+.
(c) 1 - {4,8-Bis-methylamino[(pyrimidmylmethyl)-ammo]-pyrimido[5,4-
d]pyrimidinylamino}methyl-propanolhydrochloride (109a)
l-{4,8-Bis-methylammo[(pyrimidinylmethyl)-amino]-pyrimido[5,4-
d]pyrimidinylamino}methyl-propanol (109) (65 mg, 0.17 mmol) was treated with
2M HC1 /diethyl ether in diethyl ether / MeOH (2/1) using procedures described elsewhere
herein to produce l-{4,8-bis-methylammo[(pyrimidmylmethyl)-amino]-pyrimido[5,4-
d]pyrimidmylamino}methyl-propanol hydrochloride (109a) (63 mg, 88% yield).
400 MHz 1HNMR (CDsOD, ppm): 8.80 (2H, d, J=5.0 Hz) 7.44 (1H, t, J=5.0 Hz) 4.87 (2H, s)
3.50 (2H, s) 3.13 (3H, s) 3.00 (3H, s) 1.27 (6H, s). ESI-MS (nVz): 385 [M+H]+; MP: 159-
160°C.
Example 68: 3-(4,8-Bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-l,l,l-trifluoro-propanol (111) and corresponding hydrochloride salt (llla)
Nl N H
"N'VVN~-
'OH in
(a) 3 -(6-Chloro-4,8-bis-methylamino-pyrimido [5,4-d]pyrimidinylammo)-1,1,1-
trifluoro-propanol (110)
A mixture of2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (250 mg, 0.96 mmol), 3-amino-l,l,l-trifluoropropanol (249 mg, 1.93 mmol)
and N,N-diisopropylethylamine (166 pL, 0.96 mmol) in 1,4-dioxane (4 mL) was heated at
90°C for 18 h. After cooling, a saturated NaHCOs solution (20 mL) was added and the
resulting suspension was extracted with EtOAc (3 x 20 mL). The combined organic extracts
were washed with brine (30 mL) and dried over solid anhydrous N02804. After filtration, the
solvent was removed and the residue was purified by flash column chromatography using
gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/4) to give 3-(6-chloro-4,8-bis-
methylamino-pyrimido [5,4-d]pyrimidinylamino)-1,1,1 -trifluoro-propanol (110) (151
mg, 45% yield). 400 MHz !H NMR (CDCla, ppm): 6.75 (1H, q, J=5.2 Hz) 6.45 (1H, s) 5.90
(1H, br s) 5.39-5.29 (1H, m) 4.25-4.17 (1H, m) 3.83 (1H, ddd, J=15.0, 6.8, 2.6 Hz) 3.72 (1H,
ddd, J= 15.0, 7.4, 6.0 Hz) 3.15 (3H, d, J=5.2 Hz) 3.07 (3H, d, J=5.2 Hz). ESI-MS (m/z): 352,
354 [M+H]+.
(b) 3-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-l, 1,1-
trifluoro-propanol (111)
3-(6-Chloro-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidmylamino)-l,l,l-
trifluoro-propanol (110) (151 mg, 0.43 mmol) and propylamine (212 yiL, 2.58 mmol) in n-
butanol (4.0 mL) was heated at 120°C for 100 h in a closed vial. After cooling, the reaction
mixture was cooled, and a saturated NaHCOs solution (20 mL) was added. The resulting
suspension was extracted with EtOAc (3 x 30 mL). The combined organic extracts were
washed with a brine solution (50 mL) and dried over solid anhydrous N02804. After
filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/9) to give 3-
(4,8-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidmylammo)-l,l,l-trifluoro-
propanol (111) (150 mg, 93% yield). 300 MHz 1HNMR (CDCk, ppm): 6.73-6.63 (1H,
m) 6.09-5.99 (1H, m) 5.04 (1H, t, J=5.3 Hz) 4.73 (1H, t, J=5.3 Hz) 4.22-4.11 (1H, m) 3.75-
3.69 (2H, m) 3.40-3.31 (2H, m) 3.08 (3H, d, J=5.3 Hz) 3.06 (3H, d, J=5.3 Hz) 1.63 (2H,
sextet, J-7.4 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 375 [M+H]+.
(c) 3-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylamino)-l,l,l-
trifluoro-propanol hydrochloride (111)
3-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-l,l,l-trifluoro-propanol (111) (150 mg, 0.40 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether to produce 3-(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylamino)-l,l,l-trifluoro-propanol hydrochloride (11 la) (110
mg, 67% yield). 400 MHz !H NMR (CDsOD, ppm): 4.28-4.19 (1H, m) 3.88 (1H, dd, J-4.2
,14.3 Hz) 3.56-3.49 (1H, m) 3.46 (2H, t, J=7.10 Hz) 3.14 (3H, s) 3.09 (3H, s) 1.70 (2H,
sextet, J=7.4 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 375 [M+H]+; MP: 236-240 °C.
Example 69: (S)-l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylammo)-propanol (113) and corresponding hydrochloride salt (113a)
^A^Sr-^
HN^^
'OH H3
(a) (S)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)propan
ol (112)
A mixture of 2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamiae (88) (1.50, 5.79 mmol) and (S)-l-amino-propanol (869 mg, 11.78 mmol) in n-
butanol (20 mL) was heated at 100°C for 18 h in a closed vial. After cooling, a saturated
NaHCOs solution (20 mL) was added and the resulting suspension was extracted with EtOAc
(3 x 30 mL). The combined organic extracts were dried over solid anhydrous N02804. After
filtration, the volatiles were evaporated and the residue was purified by flash column
chromatography using gradient elution from PE / acetone (5/1) to PE / acetone (1/1) to give
(>Sf)-l-(6-chloro-4,8-bis(methylammo)pyrimido[5,4-d]pyrimidinylammo)propanol (112)
(1.33 g, 77% yield). 300 MHz 'H NMR (CDCk, ppm): 6.69-6.49 (2H, m) 5.35 (1H, t, J=6.0
Hz) 4.05 (1H, dqd, J=7.2, 6.3, 2.8 Hz) 3.77 (1H, br s) 3.56 (1H, ddd, J=14.2, 6.5, 2.8 Hz)
3.38 (1H, ddd, J=14.2, 7.2, 6.0 Hz) 3.13 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz) 1.24 (3H, d,
J=6.3 Hz). ESI-MS (m/z): 298, 300 [M+H]+.
(b) (S)-l-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol (113)
(S)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylammo)
propanol (112) (213 mg, 0.72 mmol) and propylamine were reacted in n-butanol as
described above to afford (S)-l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-
djpyrimidinyl amino)-propanol (113) (108 mg, 47% yield). 300 MHz 1H NMR
(CDCk, ppm): 6.63-6.52 (1H, m) 6.23-6.12 (1H, m) 5.04 (1H, br s) 5.04 (1H, t, J-5.3 Hz)
4.69 (1H, t, J=5.3 Hz) 4.09-3.96 (1H, m) 3.50 (1H, ddd, J=14.4, 6.3, 2.5 Hz) 3.41-3.30 (3H,
m) 3.07 (3H, d, J==5.3 Hz) 3.05 (3H, d, J=5.3 Hz) 1.63 (2H, sextet, J=7.4 Hz) 1.22 (3H, d,
J=6.3 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) (S)-l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylammo)-
propanol hydrochloride (113a)
(S)-l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinyl
amino)-propanol (113) (108 mg, 0.34 mmol) was treated with 2M HC1 /diethyl ether in
dichloromethane using procedures described elsewhere herein to produce (>Sr)-l-(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-propanol
hydrochloride (113a) (90 mg, 75% yield). 300 MHz 'H NMR (CDsOD, ppm): 4.03-3.89
(1H, m) 3.59-3.34 (4H, m) 3.21-2.93 (6H, m) 1.75-1.58 (2H, m) 1.22 (3H, d, J=6.3 Hz) 1.0
(3H, t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+; MP: 218-220 °C.
Example 70: (R)-l -(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (115) and corresponding hydrochloride salt (115a)
N^^N
"N-VV"-
N^.N
'OH 115
(a) (R)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)propan
ol (114)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamme (88)
(250 mg, 0.96 mmol) and (7?)-l-ammo-propanol were reacted in 1,4-dioxane using
procedures described elsewhere herein. The crude product was purified by flash column
chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/2) to afford
the desired (R)-1 -(6-chloro-4,8-bis(methylamino)pyrimido [5,4-d]pyrimidm
ylamino)propanol (114) (224 mg, 78% yield). 300 MHz 1H NMR (CDCb, ppm): 6.69-
6.49 (2H, m) 5.37-5.28 (1H, m) 4.11-4.00 (1H, m) 3.77 (1H, br s) 3.56 (1H, ddd, J=14.2, 6.5,
2.8 Hz) 3.38 (1H, ddd, J=14.2,7.2, 6.0 Hz) 3.13 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz)
1.25 (3H, d, J=6.3 Hz). ESI-MS (m/z): 298, 300 [M+H]+.
(b) (R)-l-(4,8-Bis-methylamiaopropylamino-pyrimido[5,4-d]pyrimidmylammo)-
propanol (115)
(R)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidmylamino)
propanol (114) (224 mg, 0.75 mmol) and propylamine were reacted in n-butanol using
procedures described elsewhere herein to afford (R)-l-(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylammo)-propanol (115) (88 mg, 37% yield). 400 MHz 1H
NMR (CDCk, ppm): 6.57 (1H, br s) 6.18 (1H, br s) 5.04 (1H, br s) 4.96 (1H, br s) 4.68 (1H,
br s) 4.08-4.0 (1H, m) 3.50 (1H, ddd, J=14.3, 6.2, 2.4 Hz) 3.40-3.32 (3H, m) 3.07 (3H, d,
J=5.3 Hz) 3.05 (3H, d, J=5.3 Hz) 1.63 (2H, sextet, J=7.4 Hz) 1.23 (3H, d, J=6.2 Hz) 0.99 (3H,
t, J=7.4 Hz). ESI-MS (m/z): 321 [M+H]+.
(c) (R)-l-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidinylamiao)-
propanol hydrochloride (115a)
(R)-l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-propanol (115) (69 mg, 0.22 mmol) was treated with 2M HC1 /diethyl ether in
dichloromethane using procedures described elsewhere herein to produce (7?)-l-(4,8-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-propanol
hydrochloride (115a) (75 mg, 97% yield). 400 MHz 1H NMR (CDsOD, ppm): 4.02-3.93
(1H, m) 3.51 (1H, dd, J=13.7, 4.6 Hz) 3.47-3.40 (2H, m) 3.41 (1H, dd, J=13.7, 6.9 Hz) 3.13
(3H, s) 3.10 (3H, s) 1.68 (2H, sextet, J=7.4 Hz) 1.22 (3H, d, J=6.3 Hz) 1.01 (3H, t, 3=7 A Hz).
ESI-MS (m/z): 321 [M+H]+; MP: 215-217 °C.
Example 71: l-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-butanol (117) and corresponding hydrochloride salt (117a)
N^N ^
"N-VVK-
'OH 117
(a) l-(6-Chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-butanol
(116)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamme(88)
(1.40, 5.40 mmol) and l-aminobutanol were reacted in n-butanol as described elsewhere
herein. The cmde product was purified by flash column chromatography using gradient
elution from CH2C12 / EtOAc (9/1) to CI^Ck / EtOAc (1/2) to afford l-(6-chloro-4,8-bis-
methylamino-pyrimido[5,4-d]pyrimidmylamino)-butanol (116) (1.48 g, 88% yield).
300 MHz 1HNMR (CDCla, ppm): 6.67-6.50 (2H, m) 5.37-5.27 (1H, m) 3.81-3.71 (1H, m)
3.69 (1H, br s) 3.62 (1H, ddd, J=14.3, 6.5, 2.4 Hz) 3.44-3.33 (1H, m) 3.13 (3H, d, J=5.2 Hz)
3.05 (3H, d, J=5.2 Hz) 1.63-1.50 (2H, m) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 312,314
[M+H]+.
(b) l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol (117)
l-(6-Chloro-4,,8-bis-methylammo-pyrimido[5,4-d]pyrimidinylamino)-
butanol (116) (325 mg, 1.04 mmol) and propylamine were reacted in n-butanol as
described elsewhere herein. The crude product was purified by flash column chromatography
using gradient elution from CH2C12 / EtOAc (9/1) to mCb / EtOAc (1/2) to afford 1 -(4,8-
bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylammo)-butanol (117) (230
mg, 66% yield). 300 MHz 1H NMR (CDCk, ppm): 6.56 (1H, s) 6.18 (1H, s) 5.08-4.94 (1H,
m) 4.94-4.81 (1H, m) 4.74-4.58 (1H, m) 3.79-3.68 (1H, m) 3.62-3.51 (1H, m) 3.43-3.30 (3H,
m) 3.07 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz) 1.74-1.43 (4H, m) 0.99 (6H, t, J=7.4 Hz).
ESI-MS (m/z): 335 [M+H]+.
(c) l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol hydrochloride (117a)
l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-butanol (117) (220 mg, 0.66 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / MeOH (10/1) to produce l-(4,8-bis-methylaminopropylammo-
pyrimido[5,4-d]pyrimidinylamino)-butanol hydrochloride (117a) (190 mg, 78% yield).
400 MHz 1HNMR (CDsOD, ppm): 3.75-3.66 (1H, m) 3.59 (1H, dd, J==13.8, 4.0 Hz) 3.48-
3.40 (2H, m) 3.40 (1H, dd, J=13.8, 7.2 Hz) 3.13 (3H, s) 3.11 (3H, s) 1.68 (2H, sextet, J=7.2
Hz) 1.64-1.54 (1H, m) 1.54-1.43 (1H, m) 1.01 (3H, t, J=7.4 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 335 [M+H]+; MP: 189-190 °C.
Example 72: 3-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidm
ylamino)-butanol (119) and corresponding hydrochloride salt (119a)
N-^N
(a) 3-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)butanol
(118)
A mixture of 2,6-dichloro-N,N8-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (300 mg, 1.16 mmol) and 3-amino-butanol (206 mg, 2.32 mmol) in n-butanol
(4 mL) was heated at 100°C for 120 h. After cooling, a saturated NaHCOs solution (20 mL)
was added and the resulting suspension was extracted with EtOAc (3x30 mL). The
combined organic extracts were dried over solid anhydrous N02804. After filtration, the
volatiles were evaporated and the residue was purified by flash column chromatography
using gmdient elution from PE / EtOAc (9/1) to PE / EtOAc (1/2) to afford 3-(6-chloro-4,8-
bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)butanol (118) (251 mg, 69% yield).
400 MHz !HNMR (CDCls, ppm): 6.67-6.53 (2H, m) 5.03 (1H, d, J=8.3 Hz) 4.06-3.96 (1H,
m) 3.80 (1H, pentet, J=6.2 Hz) 3.4-3.1 (1H, br s) 3.13 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.1
Hz) 1.25 (3H, d, J=6.2 Hz) 1.24 (3H, d, J=6.6 Hz). ESI-MS (m/z): 312, 314 [M+H]+.
(b) 3-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol (119)
3-(6-Chloro-4,8-bis(methylammo)pyrimido[5,4-d]pyrimidinylamino)butan-
2-ol (118) (251 mg, 0.81 mmol) and propylamine were reacted in n-butanol as described
elsewhere herein to afford 3-(4,8-Bis-methylammopropylamino-pyrimido[5,4-
d]pyrimidmylamino)-butanol (119) (80 mg, 30% yield). 300 MHz 1H NMR (CDCb,
ppm): 6.54 (1H, q, J=5.2 Hz) 6.24 (1H, q, J=5.2 Hz) 4.75-4.60 (2H, m) 4.42 (1H, br s) 3.88
(1H, sextet, J=7.1 Hz) 3.73 (1H, pentet, J=6.4 Hz) 3.40-3.31 (2H, m) 3.06 (3H, d, J=5.1 Hz)
3.04 (3H, d, J=5.1 Hz) 1.62 (2H, sextet, 3=7.4 Hz) 1.25-1.20 (6H, m) 0.98 (3H, t, J=7.4 Hz).
ESI-MS (m/z): 335 [M+H]+.
(c) 3-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-butan-
2-ol hydrochloride (119a)
3-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-butanol (119) (80 mg, 0.24 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / EtOH (2/1 to produce 3-(4,8-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)-butanol hydrochloride (119a) (85 mg, 96% yield). 400 MHz 'H
NMR (CDaOD, ppm): 4.21-4.13 (1H, m) 3.88-3.82 (1H, m) 3.49-3.44 (2H, m) 3.15 (3H, s)
3.14 (3H, s) 1.69 (2H, sextet, J=7.4 Hz) 1.26 (3H, d, J=6.8 Hz) 1.20 (3H, d, J=6.4 Hz) 1.01
(3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+; MP: 179-181 °C.
Comparative Example 73: 3-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-
d]pyrimidinylamino)-propane-l,2-diol (121) and corresponding hydrochloride salt (121a)
N-^N
.N/V^K.,
N^,N ,OH
HN^°" 121
(a) 3-(6-Chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-propane-l,2-
diol (120)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamine (88)
(300 mg, 1.16 nunol) and 3-aminopropane-l,2-diol were reacted in n-butanol using the
procedures described elsewhere herein. The cmde product was purified by flash column
chromatography using gradient elution from CHzCk / EtOAc (9/1) to CH2C12 / EtOAc (1/2)
to afford3-(6-chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-propane-
1,2-diol (120) (260 mg, 71% yield). 400 MHz 'H NMR (CDCb, ppm): 6.67 (1H, br s) 6.50
(1H, br s) 5.34-5.25 (1H, m) 3.95-3.88 (1H, m) 3.66 (2H, d, J=5.0 Hz) 3.65-3.60 (2H, m)
3.15 (3H, d, J=5.2 Hz) 3.06 (3H, d, J=5.2 Hz). ESI-MS (m/z): 314, 316 [M+H]+.
(b) 3-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)-
propane-l,2-diol (121)
3-(6-Chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-
propane-l,2-diol (120) (260 mg, 0.83 mmol) and propylamine were reacted in n-butanol as
described elsewhere herein. The crude product was purified by flash column
chromatography using gradient elution from CH2C12 / EtOAc (9/1) to CHhCh / EtOAc (1/2)
to afford 3-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propane-l,2-diol (121) (119 mg, 43% yield). 400 MHz 'H NMR (CDCb, ppm): 6.65 (1H, br
s) 6.13 (1H, br s) 5.02 (1H, t, J=6.4 Hz) 4.78-4.67 (1H, m) 3.89-3.83 (1H, m) 3.66 (1H, dd,
J=11.3, 4.9 Hz) 3.61 (1H, dd, J=11.3, 5.0 Hz) 3.61-3.56 (2H, m) 3.39-3.31 (2H, m) 3.07 (3H,
d, J=5.2 Hz) 3.05 (3H, d, J=5.1 Hz) 1.63 (2H, sextet, J=7.4 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 337 [M+H]+.
(c) 3-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
propane-l,2-diolhydrochloride (121a)
3-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylammo)-propane-l,2-diol (121) (115 mg, 0.34 mmol) was treated with 2M HC1 /diethyl
ether in diethyl ether to produce 3-(4,8-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)-propane-l,2-diol hydrochloride (121a) (120 mg, 94% yield). 400
MHz *HNMR (CDaOD, ppm): 3.89-3.81 (1H, m) 3.66 (1H, dd, J=14.0, 4.5 Hz) 3.60-3.57
(2H, m) 3.47 (1H, dd, J=14.0, 6.8 Hz) 3.47-3.41 (2H, m) 3.12 (3H, s) 3.10 (3H, s) 1.68 (2H,
sextet, J=7.4 Hz) 1.01 (3H, J=7.4 Hz). ESI-MS (m/z): 337 [M+H]+; MP: 232-234 OC.
Example 74: (lR,2S)-l-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidm
ylamino)-mdanol (123) and corresponding hydrochloride salt (123a)
HOV 123
(a) (lR,2S)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidmylamino)-
indanol (122)
A mixture of 2,6-dichloro-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (250 mg, 0.96 mmol), (1R,2S)-1 -amino-mdanol (215 mg, 1.44 mmol) and
N,N-diisopropylethylamine (166 |J.L, 0.96 mmol) in /i-butanol (3 mL) was heated at 100°C
for 72 h. The reaction mixture was cooled, the precipitate was filtered, washed with water (2
x 10 mL) and dried over solid P205 to afford (lR,2S)-l-(6-chloro-4,8-
bis(methylamino)pyrimido [5,4-d]pyrimidinylammo)- indanol (122) (260 mg, 73%
yield). 300 MHz 'HNMR (CDCb, ppm): 7.38-7.32 (1H, m) 7.32-7.18 (3H, m) 6.72-6.56
(2H, m) 5.58-5.45 (2H, m) 4.81-4.73 (1H, m) 3.23 (1H, dd, J=16.5, 5.3 Hz) 3.14 (3H, d,
J=5.2 Hz) 3.06 (3H, d, J=5.1 Hz) 3.04 (1H, dd, J=16.5, 2.5 Hz) 2.56 (1H, br s). ESI-MS
(m/z): 372, 374 [M+H]+.
(b) (lR,2S)-l-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (123)
(l^,25r)-l-(6-chloro-4,8-bis(methylammo)pyrimido[5,4-d]pyrimidm
ylamino)- indanol (122) (250 mg, 0.67 mmol) and propylamine were reacted in n-butanol
as described elsewhere herein. The cmde product was purified by flash column
chromatography using gradient elution from PE / acetone (5/1) to PE / acetone (1/1) to obtain
(lR,2S)-l-(4,8-bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidmylamino)-
indanol (123) (140 mg, 53% yield). 300 MHz 1HNMR (CDCls, ppm): 7.38-7.32 (1H, m)
7.30-7.25 (2H, m) 7.25-7.17 (1H, m) 6.58 (1H, br s) 6.36 (1H, br s) 5.46 (1H, ddd, J=7.0, 5.1,
0.8 Hz) 5.14 (1H, br s) 4.84-4.63 (2H, m) 3.43-3.33 (2H, m) 3.19 (1H, dd, J=16.5, 5.4 Hz)
3.08-3.01 (1H, m) 3.07 (3H, d, J=5.1 Hz) 3.06 (3H, d, J=5.1 Hz) 1.72-1.56 (2H, m) 1.00 (3H,
t, J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+.
(c) (1 R,2S)-1 -(4,8-Bis-methylaminopropylamino-pyrimido [5,4-d] -pyrimidin
ylamino)-indanol hydrochloride (123a)
(l^,2<Sr)-l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (123) (130 mg, 0.33 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether to produce (l^,2<S)-l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]-
pyrimidmylammo)-indanol hydrochloride (123a) (110 mg, 77% yield). 300 MHz rH
NMR (CDsOD, ppm): 7.33-7.26 (2H, m) 7.26-7.16 (2H, m) 5.68 (1H, d, J=4.9 Hz) 4.70 (1H,
td, J=5.0, 1.5 Hz) 3.48 (2H, t, J=7.1 Hz) 3.22 (1H, dd, J=16.5, 4.9 Hz) 3.14 (3H, s) 3.13 (3H,
s) 2.98 (1H, d, J=16.5 Hz) 1.78-1.63 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395
[M+H]+.
Using the procedures described herein, and variations readily available and
known to those skilled in the art, the following pyrimido[5,4-d]-pyrimidinyl-ammo
cycloalkanols were prepared.
Example 75: (liS',2,S)-l-(4,8-Bis-methylammopropylammo-pyrimido[5,4-d]-pyrimidm
ylamino)-mdanol (125) and corresponding hydrochloride salt (125a)
HO- 125
(a) (lS,2S)-l-(6-Chloro-4,8-bis(methylammo)pyrimido[5,4-d]pyrimidinylammo)-2,3-
dihydro-lH-indanol (124)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamine(88)(250
mg, 0.96 mmol) and (l,S',2<Sf)-l-amino-indanol were reacted in n-butanol using procedures
described elsewhere herein. The crude product was purified by flash column
chromatography using gradient elution from PE / EtOAc (3/1) to PE / EtOAc (1/1) to afford
(lS,28)-l-(6-chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)-2indanol
(124) (230 mg, 64% yield). 300 MHz 1H NMR (CDCb, ppm): 7.35-7.23 (4H, m) 6.74 (1H,
s) 6.51 (1H, br s) 5.7-5.1 (1H, br s) 5.46 (1H, d, J=6.0 Hz) 5.39-5.31 (1H, m) 4.55-4.45 (1H,
m) 3.34 (1H, dd, J=15.5, 7.7 Hz) 3.15 (3H, d, J=5.2 Hz) 3.09 (3H, d, J=5.2 Hz) 2.96 (1H, dd,
J=15.5, 8.7 Hz). ESI-MS (m/z): 372, 374 [M+H]+.
(b) (1 S,2S)-l-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-mdanol (125)
(lS,2S)-l-(6-chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidm
ylamino)- -indanol (124) (225 mg, 0.61 mmol) and propylamine were reacted in n-butanol
using procedures described elsewhere herein. The crude product was purified by flash
column chromatography using gradient elution from PE / acetone (5/1) to PE / acetone (2/1)
to obtain (lS,2S)-l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidm
ylamino)-mdanol (125) (125 mg, 52% yield). 300 MHz 1HNMR (CDCls, ppm): 7.38-
7.31 (1H, m) 7.31-7.22 (3H, m) 6.78-6.60 (1H, m) 6.49-6.04 (2H, m) 5.31-5.19 (2H, m) 4.73
(1H, t, J=5.7 Hz) 4.53-4.42 (1H, m) 4.42-3.27 (3H, m) 3.10 (3H, d, J=5.2 Hz) 3.07 (3H, d,
J-5.2 Hz) 2.95 (1H, dd, J=15.3, 8.9 Hz) 1.72-1.56 (2H, m) 1.00 (3H, t, J=7.4 Hz). ESI-MS
(m/z): 395 [M+H]+.
(c) (lS,2S)-l-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-mdanol hydrochloride (125a)
(15',2>Sr)-l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-mdanol (125) (125 mg, 0.32 mmol) was treated with 2M HC1 /diethyl ether to
produce (liS',2>Sr)-l-(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylammo)-indanol hydrochloride (125a) (115 mg, 84% yield). 300 MHz 1H NMR
(CDsOD, ppm): 7.28-7.14 (4H, m) 5.47 (1H, d, J=5.9 Hz) 4.51-4.38 (1H, m) 3.47 (2H, t,
J=7.0 Hz) 3.35-3.23 (1H, m, overlapped with methanol) 3.14 (3H, s) 3.06 (3H, s) 2.86 (1H,
dd, J=15.6, 6.7 Hz) 1.79-1.61 (2H, m) 1.02 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395 [M+H]+.
Example 76: (1 S,2R)-1 -(4,8-Bis-methylaminopropylamino-pyrimido [5,4-d] -pyrimidin
ylamino)-indanol (127) and corresponding hydrochloride salt (127a)
HO' 127
(a) (lS,2R)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylammo)-
indanol (126)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamme (88)
(300 mg, 1.16 mmol) and (l<S',27?)-l-amino-mdanol were reacted in n-butanol using
procedures described elsewhere herein. The crude product was purified by flash column
chromatography using gradient elution from CH2C12 / EtOAc (99/1) to CH2C12 / EtOAc (1/4)
to afford (lS,2R)-l-(6-chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylammo)-
indanol (126) (300 mg, 70% yield). 300 MHz !H NMR (CDCk, ppm): 7.37-7.31 (1H, m)
7.31-7.19 (3H, m) 6.73-6.55 (2H, m) 5.58-5.49 (2H, m) 4.83-4.73 (1H, s) 3.23 (1H, dd,
J=16.4, 5.3 Hz) 3.13 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz) 3.04 (1H, dd, J=16.4, 2.2 Hz)
2.66 (1H, br s). ESI-MS (m/z): 372, 374 [M+H]+.
(b) (lS,2R)-l-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (127)
(lS,2R)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidin
ylamino)- indanol (126) (300 mg, 0.81 mrnol) and propylamine were reacted in n-butanol
using procedures described elsewhere herein. The crude product was purified by flash
column chromatography using gradient elution fi-om CH2C12 / EtOAc (99/1) to CHbCk/
EtOAc (1/4) to produce (lS,2R)-l-(4,8-bis-methylammopropylamino-pyrimido[5,4-d]-
pyrimidinylammo)-mdanol (127) (170 mg, 53% yield). 300 MHz !H NMR (CDCb,
ppm): 7.38-7.33 (1H, m) 7.30-7.18 (3H, m) 6.61-6.47 (1H, m) 6.39-6.27 (1H, m) 5.49-5.42
(1H, m) 5.10 (1H, d, J=6.4 Hz) 4.80-4.65 (1H, m) 4.77 (1H, td, J=5.2, 3.3 Hz) 3.42-3.32 (2H,
m) 3.19 (1H, dd, J=16.4, 5.4 Hz) 3.07 (3H, d, J-5.1 Hz) 3.05 (3H, d, J=5.0 Hz) 3.05 (1H, dd,
J-16.4, 3.3 Hz) 1.64 (2H, sextet, J=7.4 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 395
[M+H]+.
(c) (1 S,2R)-1 -(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-mdanol hydrochloride (127a)
(lS,2R)-l-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidin-
2-ylamino)-indanol (146) (167 mg, 0.42 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / MeOH (10/1) produce (151,21?)-l-(4,8-bis-methylaminopropylamino-
pyrimido [5,4-d]-pyrimidinylamino)-indanol hydrochloride (127'a) (130 mg, 71%
yield). 300 MHz 1H NMR (CDsOD, ppm): 7.35-7.15 (4H, m) 5.69 (1H, d, J=4.2 Hz) 4.73-
4.67 (1H, m) 3.47 (2H, t, J=7.0 Hz) 3.22 (1H, dd, J=16.5, 4.7 Hz) 3.14 (3H, s) 3.12 (3H, s)
2.98 (1H, d, J=16.5 Hz) 1.71 (2H, sextet, J=7.4 Hz) 1.03 (3H, J=7.4 Hz). ESI-MS (m/z): 395
[M+H]+; MP: 210-211 °C.
Example 77: (lR,2R)-l-(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (129) and corresponding hydrochloride salt (129a)
N-^N
HO' 129
(a) (lR,2R)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)-
indanol (128)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidme-4,8-diamine (88)
(250 mg, 0.96 mmol) and (lJ?,27?)-l-ammo-indanol were reacted in n-butanol using
procedures described elsewhere herein to afford (lR,2R)-l-(6-chloro-4,8-bis
(methylamino)pyrimido[5,4-d]pyrimidinylamino)- indanol (128) (230 mg, 64% yield).
300 MHz 1H NMR (CDCb, ppm): 7.35-7.23 (4H, m) 6.74 (1H, s) 6.50 (1H, br s) 5.6-5.1 (1H,
br s) 5.46 (1H, d, J=6.1 Hz) 5.39-5.31 (1H, m) 4.55-4.45 (1H, m) 3.34 (1H, dd, J=15.6, 7.7
Hz) 3.15 (3H, d, J=5.2 Hz) 3.09 (3H, d, J=5.2 Hz) 2.96 (1H, dd, J=15.6, 8.7 Hz). ESI-MS
(m/z): 372, 374 [M+H]+.
(b) (lR,2R)-l-(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol (129)
(lR,2R)-l-(6-Chloro-4,8-bis(methylammo)pyrimido[5,4-d]pyrimidin
ylamino)- indanol (128) (230 mg, 0.62 mmol) and propylamine were reacted in n-butanol
using procedures described elsewhere herein. The crude product was purified by flash
column chromatography using gradient elution from PE / acetone (5/1) to PE / acetone (2/1)
to obtain (lR,2R)-l-(4,8-bis-methylaminopropylamino-pyrimido [5,4-d]-pyrimidin
ylamino)-indanol (129) (120 mg, 49% yield). 300 MHz 'H NMR (CDCls, ppm): 7.40-
7.32 (1H, m) 7.32-7.22 (3H, m) 6.74-6.59 (1H, m) 6.24 (1H, br s) 6.18-6.06 (1H, m) 5.31-
.25 (1H, m) 5.22 (1H, d, J=5.9 Hz) 4.72 (1H, t, J=5.5 Hz) 4.47 (1H, ddd, J=9.0, 7.7, 6.8 Hz)
3.41-3.33 (2H, m) 3.33 (1H, dd, J=15.5, 7.7 Hz) 3.10 (3H, d, J=5.1 Hz) 3.07 (3H, d, J=5.1
Hz) 2.95 (1H, dd, J=15.5, 9.0 Hz) 1.72-1.57 (2H, m) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z):
395 [M+H]+.
(c) (lR,2R)-l-(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-indanol hydrochloride (129a)
(1 R,2R)-1 -(4,8-Bis-methylaminopropylamino-pyrimido [5,4-d]-pyrimidm-
2-ylamino)-indanol (129) (I 15 mg, 0.29 mmol) was treated with 2M HC1 /diethyl ether in
diethyl to produce (lR,2R)-l-(4,8-bis-methylammopropylamino-pyrimido[5,4-d]-
pyrimidinylamino)-mdanol hydrochloride (129a) (110 mg, 88% yield). 300 MHz 1H
NMR (CDsOD, ppm): 7.30-7.14 (4H, m) 5.47 (1H, d, J=6.1 Hz) 4.50-4.37 (1H, m) 3.47 (2H,
t, J=7.1 Hz) 3.35-3.24 (1H, m, overlapped with methanol) 3.14 (3H, s) 3.07 (3H, s) 2.86 (1H,
dd, J=15.6, 6.7 Hz) 1.79-1.62 (2H, m) 1.02 (3H, t, 3=7 A Hz). ESI-MS (m/z): 395 [M+H]+.
Example 78: (17?,2iS)(4,8-Bis-methylaminopropylamino-pyrimido [5,4-d]pyrimidin
ylamino)-cyclohexanol (131) and corresponding hydrochloride salt (131a)
Ni N H
-N-VYN-
H NVNOH
HN"0,
(a) (lR,2S)(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)
cyclohexanol (130)
A mixture of 2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (250 mg, 0.96 mmol), (lR,2S)aminocyclohexanol hydrochloride (146 mg,
0.96 mmol) and N,N-diisopropylethylamine (319 \\L, 1.92 mmol) in n-butanol (4 mL) was
heated at 110°C for lOOh. The mixture was cooled, and a saturated NaHCOs solution (20
mL) was added. The resulting suspension was extracted with EtOAc (3 x 30mL). The
combined organic extracts were washed with a brine solution (50 mL) and dried over solide
anhydrous N02804. The solvent was removed and the residue was purified by flash column
chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/99) to afford
(lR,2S)(6-chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)cyclohexanol
(130)(140 mg, 43% yield). 300 MHz 'H NMR (CDCb, ppm): 6.63-6.52 (2H, m) 5.20 (1H, d,
J=7.1 Hz) 4.19-4.08 (1H, m) 4.06-3.98 (1H, m) 3.3-3.0 (1H, br s) 3.14 (3H, d, J=5.2 Hz) 3.05
(3H, d, J=5.1 Hz) 1.84-1.57 (6H, m) 1.57-1.36 (2H, m). ESI-MS (ni/z): 338, 340 [M+H]+.
(b) (lR,2S)(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol (131)
(lR,2S)(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidin
ylamino) cyclohexanol (130) (140 mg, 0.41 mmol) and propylamine were reacted in n-
butanol using procedures described elsewhere herein to obtain (lR,2S)(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylammo)-cyclohexanol(131) (121
mg, 81% yield). 300 MHz 1HNMR (CDCk, ppm): 6.60-6.50 (1H, m) 6.36-6.21 (1H, m)
4.90 (1H, d, J==5.6 Hz) 4.76 (1H, t, J=5.2 Hz) 4.17-4.09 (1H, m) 3.99-3.92 (1H, m) 3.39-3.30
(2H, m) 3.06 (3H, d, J=5.2 Hz) 3.04 (3H, d, J=5.2 Hz) 1.86-1.34 (10H, m) 0.98 (3H, t, J=7.4
Hz). ESI-MS (m/z): 361 [M+H]+.
(c) (lR,2S)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol hydrochloride (131a)
(lR,2S)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (130) (121 mg, 0.34 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether produce (lR,2S)(4,8-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylammo)-cyclohexanol hydrochloride (131a) (85 mg, 64% yield). 300 MHz
1H NMR (CDsOD, ppm): 4.15-4.06 (1H, m) 4.03-3.97 (1H, m) 3.43 (2H, t, J=7.4 Hz) 3.11
(3H, s) 3.11 (3H, s) 1.90-1.57 (8H, m) 1.53-1.36 (2H, m) 1.0 (3H, t, J-7.4 Hz). ESI-MS
(m/z): 361 [M+H]+.
Example 79: (1 S,2S)(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (133) and corresponding hydrochloride salt (133a)
N-^N
(a) (lS,2S)(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidin
ylamino)cyclohexanol (132)
2,6-Dichloro-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamine(88)
(300 mg, 1.16 mmol) and (lS,2S)aminocyclohexanol were reacted in n-butanol using
procedures described elsewhere herein. The crude product was purified by flash column
chromatography using gradient elution from CH2C12 / EtOAc (99/1) to CH2C12 / EtOAc (1/4)
to afford (1 S,2S)(6-chloro-4,8-bis(methylammo)pyrimido[5,4-d]pyrimidin
ylamino)cyclohexanol (132) (290 mg, 74% yield). 300 MHz !H NMR (CDCls, ppm): 6.69-
6.59 (1H, m) 6.57-6.47 (1H, m) 4.93 (1H, d, J=6.7 Hz) 4.76 (1H, s) 3.79-3.65 (1H, m) 3.52-
3.41 (1H, m) 3.14 (3H, d, J=5.2 Hz) 3.06 (3H, d, J=5.1 Hz) 2.16-1.99 (2H, m) 1.82-1.70 (2H,
m) 1.48-1.18 (4H, m). ESI-MS (m/z): 338, 340 [M+H]+.
(b) (lS,2S)(4,8-Bis-methylaminopropylamiao-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol (133)
(lS,2S)(6-chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidin
ylamino) cyclohexanol (132) (290 mg, 0.86 mmol) and propylamine were reacted in n-
butanol using procedures described elsewhere herein. The crude product was purified by
flash column chromatography using gradient elution from CHhCk / EtOAc (99/1) to CH2C12 /
EtOAc (1/4) to obtain (lS,2S)(4,8-bis-methylaminopropylammo-pyrimido[5,4-
d]pyrimidmylamino)-cyclohexanol (133) (180 mg, 58% yield). 300 MHz 1H NMR
(CDCk, ppm): 6.66-6.49 (1H, m) 6.23-6.06 (1H, m) 5.89-5.69 (1H, m) 4.75-4.57 (2H, m)
3.69-3.55 (1H, m) 3.50-3.40 (1H, m) 3.39-3.30 (2H, m) 3.07 (3H, d, J=5.2 Hz) 3.05 (3H, d,
J=5.2 Hz) 2.16-1.95 (2H, m) 1.81-1.68 (2H, m) 1.63 (2H, sextet, J=7.4 Hz) 1.43-1.19 (4H, m)
0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361 [M+H]+.
(c) (lS,2S)(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol hydrochloride (133a)
(lS,2S)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol (133) (142 mg, 0.39 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether produce (lS,2S)(4,8-bis-methylaminopropylammo-pyrimido[5,4-
d]pyrimidinylamino)-cyclohexanol hydrochloride (133a) (135 mg, 86% yield). 300 MHz
1HNMR (CDsOD, ppm): 3.89-3.75 (1H, m) 3.56-3.39 (1H, m) 3.44 (2H, t, J=7.4 Hz) 3.13
(3H, s) 3.12 (3H, s) 2.12-1.98 (2H, m) 1.84-1.72 (2H, m) 1.67 (2H, sextet, J-7.4 Hz) 1.52-
1.25 (4H, m) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361 [M+H]+; MP: 163-165 °C.
Example 80: (1 S,2R)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (135) and corresponding hydrochloride salt (135a)
(a) (lS,2R)(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)
cyclohexanol (134)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidme-4,8-diamine (88) (250
mg, 0.96 mmol) and (lS,2R)aminocyclohexanol hydrochloride were reacted in n-butanol
to afford (1 S,2R)(6-chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)
cyclohexanol (134) (221 mg, 68% yield). 300 MHz 1H NMR (CDCk, ppm): 6.64-6.50 (2H,
m) 5.20 (1H, d, J=7.3 Hz) 4.19-4.09 (1H, m) 4.05-3.98 (1H, m) 3.3-3.0 (1H, br s) 3.14 (3H,
d, J=5.2 Hz) 3.05 (3H, d, J=5.1 Hz) 1.84-1.36 (8H, m). ESI-MS (m/z): 338, 340 [M+H]+.
(b) (lS,2R)(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (135)
(lS,2R)(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidm
ylamino) cyclohexanol (134) (221 mg, 0.65 mmol) and propylamine were reacted in n-
butanol to obtain (lS,2R)(4,8-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin-
2-ylammo)-cyclohexanol (135) (155 mg, 66% yield). 300 MHz 1H NMR (CDCk, ppm):
6.60-6.49 (1H, m) 6.28-6.16 (1H, m) 4.83 (1H, d, J=6.0 Hz) 4.68 (1H, t, J=6.0 Hz) 4.18-4.10
(1H, m) 3.99-3.93 (1H, m) 3.39-3.30 (2H, m) 3.07 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz)
1.87-1.32 (8H, m) 1.63 (2H, sextet, J=7.4 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361
[M+H]+.
(c) (lS,2R)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol hydrochloride (134a)
(lS,2R)(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidm
ylamino)-cyclohexanol (135) (131 mg, 0.36 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether to produce (l<S',21?)(4,8-bis-methylaminopropylamino-pyrimido[5,4-d]
pyrimidinylamino)-cyclohexanol hydrochloride (135a) (110 mg, 76% yield). 300 MHz !H
NMR (CDsOD, ppm) 4.19-4.09 (1H, m) 4.03-3.96 (1H, m) 3.47 (2H, t, J=7.1 Hz) 3.15 (6H,
s) 1.88-1.59 (8H, m) 1.53-1.37 (2H, m) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361 [M+H]+.
Example 81: (lR,2R)(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (137) and corresponding hydrochloride salt (137a)
(a) (lR,2R)(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)
cyclohexanol (136)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamme (88)
(300 mg, 1.16 mmol) and (lR,2R)aminocyclohexanol were reacted in n-butanol and the
crude product was purified by flash column chromatography using gradient elution from
CH2C12 / EtOAc (99/1) to mCk / EtOAc (1/4) to afford (lR,2R)(6-chloro-4,8-
bis(methylamino) pyrimido[5,4-d]pyrimidinylamino)cyclohexanol (136) (225 mg, 58%
yield). 300 MHz 1HNMR (CDCb, ppm): 6.65 (1H, s) 6.53 (1H, s) 5.1-4.6 (1H, br s) 5.00-
4.88 (1H, m) 3.80-3.62 (1H, m) 3.53-3.38 (1H, m) 3.14 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.1
Hz) 2.17-1.98 (2H, m) 1.83-1.70 (2H, m) 1.45-1.18 (4H, m). ESI-MS (m/z): 338, 340
[M+H]+.
(b) (lR,2R)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (137)
(lR,2R)(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidm
ylamino) cyclohexanol (136) (220 mg, 0.65 mmol) and propylamine were reacted in n-
butanol and the cmde product was purified by flash column chromatography using gradient
elution from CHzCk / EtOAc (99/1) to CH2Cl2 / EtOAc (1/4) to afford (lR,2R)(4,8-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol (137) (165
mg, 70% yield). 300 MHz 'HNMR (CDCb, ppm): 6.59 (1H, br s) 6.15 (1H, br s) 5.79 (1H,
br s) 4.74-4.60 (2H, m) 3.69-3.55 (1H, m) 3.50-3.40 (1H, m) 3.39-3.30 (2H, m) 3.07 (3H, d,
J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz) 2.16-1.95 (2H, m) 1.81-1.68 (2H, m) 1.63 (2H, sextet, J=:7.4
Hz) 1.47-1.19 (4H, m) 0.99 (3H, t, 3=7.4 Hz). ESI-MS (m/z): 361 [M+H]+.
(c) (lR,2R)(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol hydrochloride (137a)
(lR,2R)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclohexanol (137) (160 mg, 0.44 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / MeOH (20/1) to produce (17?,21?)(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylamino)-cyclohexanol hydrochloride (137a) (140 mg, 79%
yield). 300 MHz 'H NMR (CDsOD, ppm): 3.87-3.75 (1H, m) 3.53-3.37 (1H, m) 3.43 (2H, t,
J=7.4 Hz) 3.11 (3H, s) 3.10 (3H, s) 2.11-1.98 (2H, m) 1.84-1.72 (2H, m) 1.67 (2H, sextet,
J=7.4 Hz) 1.50-1.25 (4H, m) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361 [M+H]+; MP: 170-
171 °C.
Example 82: (18,2S)(4,8-Bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (139) and corresponding hydrochloride salt (139a)
N-^N
"NAfSrR"
HN/,^.
(a) (lS,2S)((6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidmyl)amino)-
cyclopentanol (138)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamine (88)
(300 mg, 1.16 mmol) and (lS,2S)aminocyclopentanol hydrochloride were reacted in n-
butanol and the crude product was purified by flash column chromatography using gradient
elution from CHzCk / EtOAc (99/1) to CH2C12 / EtOAc (1/4) to afford (lS,2S)((6-chloro-
4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinyl)amino)-cyclopentanol (138) (310 mg,
83% yield). 300 MHz !H NMR (CDCb, ppm): 66.61 (1H, m) 6.47 (1H, br s) 5.30 (1H,
br s) 5.14 (1H, d, J=3.8 Hz) 4.14-3.95 (2H, m) 3.12 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz)
2.28-2.02 (2H, m) 1.94-1.61 (3H, m) 1.61-1.43 (1H, m). ESI-MS (m/z): 324, 326 [M+H]+.
(b) (lS,2S)(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (139)
(lS,2S)((6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidin
yl)amino)-cyclopentanol (138) (310 mg, 0.96 mmol) and propylamine were reacted in n-
butanol and the crude product was purified by flash column chromatography using gradient
elution from CH2C12 / EtOAc (99/1) to CH2C12 / EtOAc (1/4) to obtain (18,2S)(4,8-bis-
methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol (139) (135
mg, 41% yield). 300 MHz IH NMR (CDCb, ppm): 6.69-6.55 (1H, m) 6.4-6.2 (1H, br s)
6.13-5.98 (1H, m) 4.86 (1H, d, J=3.6 Hz) 4.69 (1H, t, J=5.4 Hz) 4.08-3.86 (2H, m) 3.41-3.29
(2H, m) 3.07 (3H, d, J=5.2 Hz) 3.04 (3H, d, J=5.1 Hz) 2.24-2.03 (2H, m) 1.90-1.44 (6H, m)
0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 347 [M+H]+.
(c) (1 S,2S)(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol hydrochloride (139a)
(lS,2S)(4,8-Bis-methylammopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (139) (134 mg, 0.39 mmol) was treated with 2M HC1 /diethyl ether
in diethyl ether / MeOH (6/1) to produce (15',25r)(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol hydrochloride (l39a) (85 mg,57%
yield). 300 MHz 1HNMR (CDsOD, ppm) 4.21-4.04 (2H, m) 3.46 (2H, t, J=7.4 Hz) 3.16 (3H,
s) 3.13 (3H, s) 2.31-2.14 (1H, m) 2.07-1.92 (1H, m) 1.92-1.74 (2H, m) 1.74-1.52 (4H, m)
1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 347 [M+H]+; MP: 215-217 °C.
Example 83: (lR,2R)(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (141) and corresponding hydrochloride salt (141a)
fl N H
"N-VV"-
H .1. [I
HNr>
(a) (lR,2R)((6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinyl)amino)-
cyclopentanol (140)
2,6-Dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-diamme (88)
(300 mg, 1.16 mmol) and (lJ?,2J?)aminocyclopentanol hydrochloride were reacted in n-
butanol and the crude product was purified by flash column chromatography using gradient
elution from CHbCk / EtOAc (99/1) to TOCk / EtOAc (1/4) to afford (lR,2R)((6-chloro-
4,8-bis(methyl amino)pyrimido[5,4-d]pyrimidinyl)ammo)-cyclopentanol (140) (270 mg,
72% yield). 300 MHz 1HNMR (CDCls, ppm): 66.62 (1H, m) 6.45 (1H, br s) 5.31 (1H,
br s) 5.17-5.08 (1H, m) 4.12-3.95 (2H, m) 3.13 (3H, d, J=5.2 Hz) 3.06 (3H, d, J=5.2 Hz)
2.28-2.02 (2H, m) 1.94-1.62 (3H, m) 1.62-1.45 (1H, m). ESI-MS (m/z): 324, 326 [M+H]+.
(b) (lR,2R)(4,8-Bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (141)
(lR,2R)((6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinyl)
ammo)-cyclopentanol (140) (270 mg, 0.83 mmol) and propylamine were reacted in n-butanol
and the crude product was purified by flash column chromatography using gradient elution
from CH2Cb / EtOAc (99/1) to TOCb / EtOAc (1/4) to obtain (lR,2R)(4,8-bis-
methylaminopropylammo-pyrimido[5,4-d]pyrimidinylammo)-cyclopentanol (141) (160
mg, 55% yield). 300 MHz 'HNMR (CDCla, ppm): 6.69-6.55 (1H, m) 6.31 (1H, s) 6.14-5.98
(1H, m) 4.87 (1H, d, J=3.6 Hz) 4.69 (1H, t, J=5.4 Hz) 4.08-3.98 (1H, m) 3.98-3.86 (1H, m)
3.41-3.30 (2H, m) 3.07 (3H, d, J=5.2 Hz) 3.04 (3H, d, J=5.1 Hz) 2.24-2.04 (2H, m) 1.92-1.44
(6H, m) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 347 [M+H]+.
(c) (lR,2R)(4,8-Bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol hydrochloride (141a)
(lR,2R)(4,8-Bis-methylammopropylammo-pyrimido[5,4-d]pyrimidin
ylamino)-cyclopentanol (141) (160 mg, 0.46 mmol) was treated with 2M. HC1 /diethyl ether
in diethyl ether / MeOH (6/1) to produce (17?,27?)(4,8-bis-methylaminopropylamino-
pyrimido[5,4-d]pyrimidinylamino)-cyclopentanol hydrochloride (141a) (115 mg, 65%
yield). 300 MHz 1HNMR (CDsOD, ppm): 4.22-4.03 (2H, m) 3.43 (2H, t, J=7.4 Hz) 3.15
(3H, s) 3.12 (3H, s) 2.30-2.14 (1H, m) 2.07-1.91 (1H, m) 1.91-1.74 (2H, m) 1.74-1.52 (4H,
m) 1.01 (3H, t, 3=7.4 Hz). ESI-MS (m/z): 347 [M+H]+; MP: 209-210 °C.
Example 84: (S)-l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-propanol (142) and corresponding hydrochloride salt (142a)
'OH 142
(a) (S)-1 -[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin-
2-ylamino]-propanol (142)
(S)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylamino)
propanol (112) (220 mg, 0.74 mmol) and cyclopropylmethanamine were reacted in n-
butanol obtain (5)-1 -[6-(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylammo]-propanol (142) (130 mg, 53% yield). 300 MHz 1H NMR (CDCk,
ppm): 6.63-6.51 (1H, m) 6.25-6.14 (1H, m) 5.08-4.99 (1H, m) 4.86-4.76 (1H, m) 4.07-4.0
(1H, m) 3.55-3.44 (1H, m) 3.41-3.30 (1H, m) 3.28-3.21 (2H, m) 3.09-3.06 (6H, m) 1.22 (3H,
d, J=6.3 Hz) 1.15-1.01 (1H, m) 0.56-0.48 (2H, m) 0.29-0.19 (2H, m). ESI-MS (m/z): 333
[M+H]+.
(b) (S)-l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidm-
2-ylamino]-propanol hydrochloride (142a)
(S)-l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]
pyrimidinylamino]-propanol (142) (126 mg, 0.38 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether / EtOH (2/1) to produce (>S)-l-[6-(cyclopropylmethyl-amino)-
4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-propanolhydrochloride
(142a) (90 mg, 64% yield). 300 MHz 1HNMR (CDsOD, ppm): 4.06-3.92 (1H, m) 3.56-3.49
(1H, m) 3.46-3.37(1H, m) 3.31 (2H, d, J=7.1 Hz) 3.14 (3H, s) 3.12 (3H, s) 1.23 (3H, d, J=6.4
Hz) 1.22-1.10 (1H, m) 0.60-0.51 (2H, m) 0.36-0.27 (2H, m). ESI-MS (m/z): 333 [M+H]+;
MP: 211-213 °C.
Example 85: (S)-l-(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidm
ylamino)-propanol (143) and corresponding hydrochloride salt (143a)
^ N H
"uAArN"
N^,N
HN—°" 143
(a) (S)-l-(6-Allylammo-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol (143)
(S)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidinylammo)
propanol (112) (1.33 g, 4.47 mmol) and allylamine (2.0 mL. 26.80 mmol) were heated in
n-butanol at 105 °C for 8 days. The mixture was cooled, and a saturated NaHCOs solution
(40 mL) was added. The resulting suspension was extracted with EtOAc (3 x 30mL). The
combined organic extracts were washed with a brine solution (50 mL) and dried over solid
anhydrous MgS04. After filtration, the solvent was removed and the residue was purified by
flash column chromatography using gradient elution from PE / EtOAc (1/1) to PE / EtOAc
(99/1) to afford (5)-l-(6-allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (143) (820 mg, 58% yield). 300 MHz 'H NMR (CDCb, ppm): 6.62-
6.48 (1H, m) 6.26-6.14 (1H, m) 5.99 (1H, ddt, J=17.2, 10.2, 5.5 Hz) 5.25 (1H, ddt, J=17.2,
1.6, 1.6 Hz) 5.12 (1H, ddt, J=10.2, 1.6, 1.6 Hz) 5.04 (1H, t, J=6.3 Hz) 4.90 (1H, br s) 4.74
(1H, t, J=5.9 Hz) 4.09-3.98 (3H, m) 3.50 (1H, ddd, J=14.4, 6.3, 2.4 Hz) 3.36 (1H, ddd,
J-14.4, 7.0, 6.3 Hz) 3.06 (3H, d, J=5.1 Hz) 3.05 (3H, d, J=5.1 Hz) 1.23 (3H, d, J=6.3 Hz).
ESI-MS (m/z): 319 [M+H]+.
(b) (S)-l-(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol hydrochloride (143a)
(S)-l-(6-Allylammo-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidm
ylamino)-propanol (143) (820 mg, 2.58 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / MeOH (2/1) to produce (S)-l-(6-allylamino-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinylamino)-propanol hydrochloride (143a) (870 mg,95%
yield). 400 MHz 1HNMR (CDaOD, ppm): 5.97 (1H, ddd, J=17.2, 10.3, 5.4 Hz) 5.29 (1H,
ddt, J=17.2, 1.6, 1.6 Hz) 5.16 (1H, ddt, J-10.3, 1.6, 1.6 Hz) 4.13 (2H, dt, J=5.4, 1.6 Hz) 4.00
(1H, dqd, J=7.0, 6.3, 4.3 Hz) 3.56 (1H, dd, J=13.8, 4.3 Hz) 3.42 (1H, dd, J=13.8, 7.0 Hz) 3.14
(3H, s) 3.13 (3H, s) 1.23 (3H, d, J=6.3 Hz). ESI-MS (m/z): 319 [M+H]+; MP: 192-193 °C.
Example 86: (R)-l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-propanol (144) and corresponding hydrochloride salt (144a)
'KVTR'
N^.N
HN-A'OH 144
(a) (R)-1 -[6-(Cyclopropylmethyl-amino)-4,8-bis-methylammo-pyrimido[5,4-
d]pyrimidinylamino]-propanol (144)
(R)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidmylamino)
propanol (114) (210 mg, 0.71 mmol) and cyclopropylmethanamine were reacted in n-
butanol and the crude product was purified by flash column chromatography using gradient
elution from PE / acetone (10/1) to PE / acetone (1/1) to afford (R)-l-[6-(cyclopropylmethyl-
amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino]-propanol (144) (110
mg, 47% yield). 300 MHz 1H NMR (CDCb, ppm): 6.63-6.49 (1H, m) 6.24-6.12 (1H, m)
.04 (1H, t, J=6.0 Hz) 4.93 (1H, s) 4.82 (1H, t, J=5.6 Hz) 4.09-3.98 (1H, m) 3.56-3.44 (1H,
m) 3.42-3.29 (1H, m) 3.28-3.21 (2H, m) 3.07 (3H, d, J=5.2 Hz) 3.06 (3H, d, J=5.2 Hz) 1.23
(3H, d, J=6.3 Hz) 1.16-1.02 (1H, m) 0.56-0.46 (2H, m) 0.28-0.20 (2H, m). ESI-MS (m/z):
333 [M+H]+.
(b) (R)-1 -[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidinylamino]-propanol hydrochloride (144a)
(I?)-l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylammo-pyrimido[5,4-d]
pyrimidmylamino]-propanol (144) (110 mg, 0.33 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether / MeOH (2/1) to produce (1?)-l-[6-(cyclopropylmethyl-amino)-
4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-propanolhydrochloride
(144a) (120 mg, 98% yield). 300 MHz 1H NMR (CDaOD, ppm): 4.05-3.91 (1H, m) 3.58-
3.45 (1H, m) 3.45-3.34 (1H, m) 3.34-3.27 (2H, m, overlapped with methanol) 3.11 (3H, s)
3.09 (3H, s) 1.22 (3H, d, J=6.2 Hz) 1.19-1.07 (1H, m) 0.61-0.49 (2H, m) 0.35-0.24 (2H, m).
ESI-MS (m/z): 333 [M+H]+; MP: 224-226 °C.
Example 87: (R)-l-(6-Allylamino-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (145) and corresponding hydrochloride salt (145a)
tfl N H
H Vi
HN^°" 145
(a) (R)-l-(6-Allylamino-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidmylammo)-
propanol (145)
(R)-l-(6-Chloro-4,8-bis(methylamino)pyrimido[5,4-d]pyrimidmylamino)
propanol (114) (210 mg, 0.71 mmol) and allylamine were reacted in n-butanol to obtain
(R)-l-(6-allylammo-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidinylammo)-propanol
(145) (125 mg, 55% yield). 300 MHz 'HNMR (CDCb, ppm): 6.63-6.48 (1H, m) 6.27-6.13
(1H, m) 5.99 (1H, ddt, J=17.2, 10.2, 5.6 Hz) 5.25 (1H, ddt, J=17.2, 1.6, 1.6 Hz) 5.11 (1H, ddt,
J=10.2, 1.6, 1.4 Hz) 5.05 (1H, t, J=6.0 Hz) 4.90 (1H, s) 4.74 (1H, t, J=6.0 Hz) 4.10-3.98 (3H,
m) 3.50 (1H, ddd, J=14.4, 6.3, 2.4 Hz) 3.42-3.29 (1H, m) 3.06 (3H, d, J=5.1 Hz) 3.05 (3H, d,
J=5.1 Hz) 1.23 (3H, d, J=6.3 Hz). ESI-MS (m/z): 319 [M+H]+.
(b) (R)-l-(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol hydrochloride (145a)
(R)-l-(6-Allylammo-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)-propanol (145) (120 mg, 0.38 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / MeOH (2/1) to produce (R)-l-(6-allylamino-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinylamino)-propanol hydrochloride (145a) (120 mg, 90%
yield). 400 MHz 'HNMR (CDsOD, ppm): 5.97 (1H, ddt, J-17.2, 10.3, 5.4 Hz) 5.28 (1H,
ddt, J=17.2, 1.6, 1.6 Hz) 5.15 (1H, ddt, J=10.3, 1.6, 1.5 Hz) 4.12 (2H, dt, J=5.4, 1.6 Hz) 4.04-
3.95 (1H, m) 3.54 (1H, dd, J= 13.7, 4.4 Hz) 3.42 (1H, dd, J=13.7, 7.0 Hz) 3.13 (3H, s) 3.12
(3H, s) 1.23 (3H, d, J=6.3 Hz). ESI-MS (m/z): 319 [M+H]+; MP: 205-207 °C.
Example 88: l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-
d]pyrimidmylamino]-butanol (146) and corresponding hydrochloride salt (146a)
••"'^\^ 146
(a) l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino]-butanol (146)
l-(6-Chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylammo)-
butanol (116) (350 mg, 1.12 mmol) and cyclopropylmethanamine were reacted in n-
butanol and the cmde product was purified by flash column chromatography using gradient
elution from CH^Ch / EtOAc (9/1) to mCk / EtOAc (1/4) to afford 1-[6-
(cyclopropylmethyl-amino)-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino]-
butanol (146) (210 mg, 54% yield). 400 MHz 1H NMR (CDCk, ppm): 6.66-6.50 (1H, m)
6.28-6.15 (1H, m) 5.04 (1H, t, J=6.0 Hz) 4.90 (1H, s) 4.87-4.77 (1H, m) 3.77-3.69 (1H, m)
3.57 (1H, ddd, J=14.4, 6.3, 2.4 Hz) 3.41-3.32 (1H, m) 3.24 (2H, dd, J=7.0, 5.5 Hz) 3.06 (3H,
d, J=5.1 Hz) 3.05 (3H, d, J=5.1 Hz) 1.64-1.47 (2H, m) 1.15-1.03 (1H, m) 0.99 (3H, t, J=7.4
Hz) 0.54-0.48 (2H, m) 0.27-0.21 (2H, m). ESI-MS (m/z): 347 [M+H]+.
(b) l-[6-(Cyclopropylmethyl-amino)-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidin
ylamino]-butanol hydrochloride (146a)
l-[6-(Cyclopropylmethyl-amino)-4,,8-bis-methylammo-pyrimido[5,4-
d]pyrimidinylammo]-butanol (146) (150 mg, 0.43 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether / MeOH (4/1) to produce l-[6-(cyclopropylmethyl-amino)-4,8-
bis-methylamino-pyrimido[5,4-d]pyrimidinylammo]-butanol hydrochloride (146a) (145
mg, 87% yield). 400 MHz 'H NMR (CDsOD, ppm): 3.75-3.66 (1H, m) 3.60 (1H, dd, J-13.8,
3.9 Hz) 3.40 (1H, dd, J=13.8, 7.2 Hz) 3.35 (2H, d, J=7.0 Hz) 3.13 (3H, s) 3.11 (3H, s) 1.67-
1.54 (1H, m) 1.54-1.42 (1H, m) 1.21-1.09 (1H, m) 1.01 (3H, t, J=7.4 Hz) 0.59-0.52 (2H, m)
0.34-0.28 (2H, m). ESI-MS (m/z): 347 [M+H]+; MP: 208-209 °C.
Example 89: l-(6-Ethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-
butanol (147) and corresponding hydrochloride salt (147a)
(a) l-(6-Ethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-butan
ol (147)
l-(6-Chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-
butanol (116) (325 mg, 1.04 mmol) and ethylamine (70% water solution) (0.8 mL) were
reacted in n-butanol and the crude product was purified by flash column chromatography
using gradient elution from CH2C12 / EtOAc (9/1) to CHhCb / EtOAc (1/4) to afford 1-(6-
ethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-butanol (147)
(150 mg, 45% yield). 400 MHz 1HNMR (CDCk, ppm): 6.62 (1H, s) 6.25 (1H, s) 5.14-4.98
(1H, m) 4.97-4.53 (1H, m) 4.68 (1H, s) 3.77-3.70 (1H, m) 3.57 (1H, ddd, J=14.5, 6.3, 2.4 Hz)
3.43 (2H, qd, J=7.2, 5.7 Hz) 3.41-3.33 (1H, m) 3.07 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz)
1.64-1.47 (2H, m) 1.23 (3H, t, J=7.2 Hz) 0.99 (3H, t, J=7.5 Hz). ESI-MS (m/z): 321 [M+H]+.
(b) l-(6-Ethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-butan
ol hydrochloride (147a)
l-(6-Ethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-
butanol (147) (140 mg, 0.44 mmol) was treated with 2M HC1 /diethyl ether in diethyl ether
/ MeOH (3/1) to produce l-(6-ethylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)-butanol hydrochloride (147a) (120 mg, 77% yield). 400 MHz 1H NMR
(CDsOD, ppm): 3.76-3.64 (1H, m) 3.64-3.34 (4H, m) 3.11 (3H, s) 3.09 (3H, s) 1.67-1.54 (1H,
m) 1.54-1.42 (1H, m) 1.26 (3H, t, J=6.5 Hz) 1.01 (3H, t, J=7.4 Hz). ESI-MS (m/z): 321
[M+H]+; MP: 190-191 °C.
Example 90: 2-Methyl-l -(4,6,8-tris-methylamino-pyrimido[5,4-d]pyrimidinylamino)-
propanol (148) and corresponding hydrochloride salt (148a)
Nl N H
vVv"-
'OH 149
(a) l-(6-Chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)methyl-
propanol (148)
A mixture of2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (1.50 g, 5.79 mmol) and l-aminomethyl-propanol (1.65 mL, 17.37 mmol)
in n-butanol (10 mL) was heated at 90°C for 40 h in a closed vial. Water (20 mL) was added
and the resulting suspension was extracted with EtOAc (3 x 30 mL). The combined organic
extracts were dried over solid anhydrous N02804. After filtration, the solvent was removed
and the residue was purified by flash column chromatography using gradient elution ixom
CHbCb / EtOAc (9/1) to CHzCk / EtOAc (1/4) to afford l-(6-chloro-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinylammo)methyl-propanol (148) (1.47 g, 81% yield). 300
MHz 1H NMR (CDCls, ppm): 6.69-6.58 (1H, m) 6.58-6.46 (1H, m) 5.36 (1H, t, J=6.4 Hz)
4.02 (1H, s) 3.45 (2H, d, J=6.4 Hz) 3.13 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.1 Hz) 1.28 (6H,
s). ESI-MS (m/z): 312, 314 [M+H]+.
(b) 2-Methyl-l-(4,6,8-tris-methylamino-pyrimido[5,4-d]pyrimidmylamino)-propan
ol (149)
A mixture of l-(6-chloro-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmyl
amino)methyl-propanol (148) (312 mg, 1.00 mmol) and methylamine (40% water
solution) (2.30 mL) in n-butanol (7 mL) was heated at 120°C for 48 h in a closed vial. Water
(20 mL) was added and the resulting suspension was extracted with EtOAc (3x15 mL).
Combined organic extracts were washed with water (30 mL), brine (30 mL) and dried over
solid anhydrous N02804. After filtration, the solvent was removed; the residue was purified
by flash column chromatography using gradient elution from CKhCk / EtOAc (9/1) to
CH2C12 / EtOAc (1/4) to afford 2-methyl-l -(4,6,8-tris-methylamino-pyrimido[5,4-
d]pyrimidinylammo)-propanol (149) (230 mg, 75% yield). 400 MHz 'H NMR (CDCb,
ppm): 6.71-6.55 (1H, m) 6.24-6.09 (1H, m) 5.37 (1H, s) 5.09 (1H, t, J=6.3 Hz) 4.72-4.61 (1H,
m) 3.40 (2H, d, J=6.3 Hz) 3.07 (3H, d, J=5.1 Hz) 3.04 (3H, d, J=5.1 Hz) 2.96 (3H, d, J=5.1
Hz) 1.26 (6H, s). ESI-MS (m/z): 307 [M+H]+.
(c) 2-Methyl-l-(4,6,8-tris-methylamino-pyrimido[5,4-d]pyrimidinylamino)-propan
ol hydrochloride (149a)
2-Methyl-l-(4,6,8-tris-methylammo-pyrimido[5,4-d]pyrimidinylamino)-
propanol (149) (180 mg, 0.59 mmol) was treated with 2M HC1 /diethyl ether in diethyl
ether / MeOH (10/1) to produce 2-methyl-l -(4,6,8-tris-methylamino-pyrimido[5,4-
d]pyrimidinylammo)-propanol hydrochloride (149a) (145 mg, 72% yield). 400 MHz
1HNMR (CDsOD, ppm): 3.51 (2H, s) 3.14 (3H, s) 3.13 (3H, s) 3.04 (3H, s) 1.26 (6H, s).
ESI-MS (m/z): 307 [M+H]+; MP: 214-215 °C.
Comparative Example 91: (R)-l-(6-Amino-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylamino)-propanol (151) and corresponding hydrochloride salt (151a)
N Hz
~OH 151
(a) 6-Chloro-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine(150)
A mixture of2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (800 mg, 3.09 mmol) and aqueous ammonia (25% solution) (1.00 mL) in n-
butanol (10 mL) was heated at 100°C for 48 h in a closed vial. An additional portion of
aqueous ammonia (25% solution) (1.00 mL) was added and the heating was continued for
another 48 h. The reaction mixture was cooled, and the precipitate were filtered, washed with
water (2 x 30 mL) and dried over solid P205 to give 6-chloro-N4,N8-dimethyl-pyrimido[5,4-
d]pyrimidine-2,4,8-triamine (150) (590 mg, 80% yield). 300 MHz 'H NMR (CDCb, ppm):
6.69 (1H, s) 6.59 (1H, s) 4.83 (2H, s) 3.13 (3H, d, J==5.2 Hz) 3.06 (3H, d, J=5.1 Hz). ESI-MS
(m/z): 240, 242 [M+H]+.
(b) (R)-l-(6-Ammo-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidmylammo)-propan-
2-ol(151)
6-Chloro-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamme(150)
(280 mg, 1.17 mmol) and (R)-l-amino-propanol were reacted in n-butanol and the crude
product was purified by flash column chromatography using gradient elution from CHCb /
EtOH (98/2) to CHCb / EtOH (96/4) to afford (R)-l-(6-amino-4,8-bis-methylamino-
pyrimido[5,4-d]-pyrimidmylammo)-propanol (151) (170 mg, 52% yield). 300 MHz !H
NMR (CDCb, ppm): 6.61-6.46 (1H, m) 6.39-6.21 (1H, m) 5.31 (1H, t, J=5.9 Hz) 4.9-4.4 (1H,
br s) 4.60 (2H, s) 4.04 (1H, dqd, J=7.1, 6.3, 2.5 Hz) 3.51 (1H, ddd, J=14.3, 6.3, 2.5 Hz) 3.36
(1H, ddd, J=14.3, 7.1, 6.1 Hz) 3.06 (3H, d, J=5.1 Hz) 3.04 (3H, d, J=5.1 Hz) 1.23 (3H, d,
J=6.3 Hz). ESI-MS (m/z): 279 [M+H]+.
(c) (R)-l-(6-Ammo-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidmylammo)-propan-
2-ol hydrochloride (151a)
(R)-l-(6-Amino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (151) (170 mg, 0.61 mmol) was treated with 2M HC1 /diethyl ether in diethyl
ether / MeOH (10/1) to produce (R)-l-(6-amino-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidmylamino)-propanol hydrochloride (151a) (150 mg, 78% yield). 300 MHz 'H
NMR (CDaOD, ppm): 4.03-3.90 (1H, m) 3.51 (1H, dd, J=13.7, 4.7 Hz) 3.40 (1H, dd, J=13.7,
6.9 Hz) 3.14 (3H, s) 3.09 (3H, s) 1.22 (3H, d, J-6.3 Hz). ESI-MS (rn/z): 279 [M+H]+; MP:
229-231°C.
Comparative Example 92: (S)-l-(6-Amino-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylamino)-propanol (152) and corresponding hydrochloride salt (152a)
N^N ^
HN—°" 152
(a) (S)-l-(6-Ammo-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylammo)-propan-
2-ol(152)
6-Chloro-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamme(150)
(280 mg, 1.17 mmol) and (S)-l-amino-propanol were reacted in n-butanol and the crude
product was purified by flash column chromatography using gradient elution from CHhCk /
EtOH (99/1) to CH2C12 / EtOH (9/1) to afford (S)-l-(6-amino-4,8-bis-methylamino-
pyrimido[5,4-d]-pyrimidmylamino)-propanol (152) (165 mg, 51% yield). 300 MHz 1H
NMR (CDCb, ppm): 6.59-6.48 (1H, m) 6.38-6.25 (1H, m) 5.16-5.04 (1H, m) 4.72 (1H, br s)
4.58 (2H, s) 4.09-3.98 (1H, m) 3.51 (1H, ddd, J=14.4, 6.3, 2.5 Hz) 3.36 (1H, ddd, J=14.4, 7.1,
6.1 Hz) 3.06 (3H, d, J=5.1 Hz) 3.04 (3H, d, J=5.1 Hz) 1.23 (3H, d, J=6.3 Hz). ESI-MS (m/z):
279 [M+H]+.
(b) (S)-l-(6-Amino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidmylamino)-propan-
2-ol hydrochloride (152a)
(S)-l-(6-Amino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylammo)-
propanol (152) (165 mg, 0.59 mmol) was treated with 2M HC1 /diethyl ether in diethyl
ether / MeOH (10/1) to produce (S)-l-(6-amino-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylammo)-propanol hydrochloride (152a) (150 mg, 80% yield). 400 MHz 1H
NMR (CDsOD, ppm): 4.00 (1H, dqd, J=7.0, 6.3, 4.3 Hz) 3.58 (1H, dd, J=13.7, 4.3 Hz) 3.44
(1H, dd, J=13.7, 7.0 Hz) 3.17 (3H, s) 3.16 (3H, s) 1.24 (3H, d, J=6.3 Hz). ESI-MS (m/z): 279
[M+H]+; MP: 227-230 °C.
Example 93: 2-(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-
ethanol (154) and corresponding hydrochloride salt (154a)
N'^N
-NA^-R.
N^,N
'OH 154
(a) N -Allylchloro-N ,N -dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine (153)
A mixture of 2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (750 mg, 2.89 mmol) and allylamine (433 |^L, 5.78 inmol) in 1,4-dioxane (5
mL) was heated at 100°C for 18 h in a closed vial. After cooling, a saturated NaHCOs
solution (20 mL) was added and the resulting suspension was extracted with EtOAc (3x30
mL). The combined organic extracts were dried over solid anhydrous N02804. After
filtration, the volatiles were evaporated, and the residue was purified by flash column
chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/2) to give
N2-allylchloro-N ,N -dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine (153) (760 mg,
94% yield). 300 MHz 'H NMR (CDCls, ppm): 6.79-6.65 (1H, m) 6.58-6.45 (1H, m) 5.97
(1H, ddt, J-17.2, 10.3, 5.4 Hz) 5.26 (1H, ddt, J=17.2, 1.6, 1.6 Hz) 5.14 (1H, ddt, J=10.3, 1.4,
1.4 Hz) 5.04 (1H, t, J=5.4 Hz) 4.11-4.04 (2H, m) 3.14 (3H, d, J-5.2 Hz) 3.04 (3H, d, J=5.1
Hz). ESI-MS (m/z): 280, 282 [M+H]+.
(b) 2-(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidmylamino)-ethanol
(154)
N2-Allylchloro-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine
(153) (250 mg, 0.89 mmol) and 2-amino-ethanol were reacted in n-butanol to afford 2-(6-
allylamino-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidinylammo)-ethanol (154) (120
mg, 44% yield). 300 MHz 1HNMR (CDCk, ppm): 6.62-6.51 (1H, m) 6.31-6.17 (1H, m)
.99 (1H, ddt, J=17.1, 10.3, 5.7 Hz) 5.25 (1H, ddt, J=17.1, 1.7, 1.7 Hz) 5.15-5.05 (2H, m)
4.76 (1H, t, J=5.7 Hz) 4.08-4.02 (2H, m) 3.86-3.80 (2H, m) 3.62-3.54 (2H, m) 3.06 (3H, d,
J=5.2 Hz) 3.05 (3H, d, J=5.2 Hz). ESI-MS (m/z): 305 [M+H]+.
(c) 2-(6-Allylammo-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol
hydrochloride (154a)
2-(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (154) (120 mg, 0.39 mmol) was treated with 2M HC1 /diethyl ether in diethyl ether /
IVIeOH (1/1) to produce 2-(6-allylammo-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol hydrochloride (154a) (110 mg, 83% yield). 300 MHz 1H NMR (CDsOD,
ppm): 5.98 (1H, ddt, 3=17.1, 10.3, 5.7 Hz) 5.31-5.21 (1H, m) 5.17-5.10 (1H, m) 4.15-4.04
(2H, m) 3.77-3.71 (2H, m) 3.63-3.55 (2H, m) 3.09 (6H, s). ESI-MS (m/z): 305 [M+H]+.
Example 94: (S)-l-[(6-Allylamino-4,8-bis-methylammo-pyrimido[5,4-d]-pyrimidmyl)-
propyl-amino]-propanol (155) and corresponding hydrochloride salt (155a)
Nl N "
'KVrFk-
-N-^OH 155
(a) (S)-1 -(propylamino)propanol
Propionaldehyde (274 p,L, 3.76 mmol) was added to the solution of(S)-l-
amino-propanol in EtOH (5.0 mL) at 0 °C, and the mixture was stin-ed at 0 °C for 45 min.
After this time, NaBH4 (259 mg, 6.84 mmol) was added in portions at 0 °C. The reaction
mixture was stirred for 18 h at room temperature. Water (4 mL) was added and the resulting
suspension was extracted with EtOAc (3x10 mL). The combined organic extracts were
washed with brine (20 mL) and dried over solid anhydrous N02804. After filtration, the
solvent was removed to give (5)-l-(propylamino)propanol (336 mg, 84% yield). 400 MHz
1HNMR (CDCla, ppm): 3.79-3.70 (1H, m) 3.21 (1H, br s) 2.70 (1H, dd, J=12.1, 3.2 Hz)
2.65-2.62 (1H, dt, J=11.6, 7.1 Hz) 2.55 (1H, dt, J=11.6, 7.1 Hz) 2.38 (1H, dd, J=12.1, 9.5 Hz)
1.49 (2H, sextet, J=7.4 Hz) 1.14 (3H, d, J=6.3 Hz) 0.92 (3H, t, J=7.4 Hz). ESI-MS (m/z): 118
[M+H]+.
(b) (S)-l-[(6-Allylamino-4,8-bis-methylamiao-pyrimido[5,4-d]-pyrimidinyl)-propyl-
amino]-propanol (155)
A mixture ofN2-allylchloro-N ,N8-dimethyl-pyrimido[5,4-d]pyrimidine-
2,4,8-triamine (153) (250 mg, 0.89 mmol), (S)-l-(propylamino)propanol (313 mg, 2.67
mmol) and N,N-diisopropylethylamine (295 \\L, 1.78 mmol) in n-butanol (5 mL) was heated
at 125 °C for 100 h. After cooling, saturated NaHCOs solution (20 mL) was added and the
resulting suspension was extracted with EtOAc (3 x 20 mL). The combined organic extracts
were washed with water (30 mL), then with a brine solution (30 mL) and dried over solid
anhydrous MgS04. After filtration, the solvent was removed and the residue was purified by
flash column chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc
(2/1) to obtain (S)-l-[(6-allylammo-4,8-bis-methylammo-pyrimido[5,4-d]-pyrimidinyl)-
propyl-ammo]-propanol (155) (135 mg, 42% yield). 300 MHz 1H NMR (CDCk, ppm):
6.49 (1H, br s) 6.21 (1H, br s) 6.06-5.90 (2H, m) 5.30-5.20 (1H, m) 5.15-5.07 (1H, m) 4.76-
4.66 (1H, m) 4.17-3.99 (3H, m) 3.78 (1H, dd, J=14.8, 7.9 Hz) 3.73-3.59 (1H, m) 3.54-3.42
(1H, m) 3.37 (1H, dd, J= 14.8, 1.2 Hz) 3.07 (6H, d, J=5.1 Hz) 1.75-1.60 (2H, m) 1.22 (3H, d,
J=6.3 Hz) 0.93 (3H, t, J=7.4 Hz). ESI-MS (m/z): 361 [M+H]+.
(c) (S)-l-[(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinyl)-propyl-
amino]-propanol hydrochloride (155a)
(S)-l-[(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinyl)-
propyl-aminoj-propanol (155) (125 mg, 0.35 mmol) was treated with 2M HC1 /diethyl
ether in diethyl ether to produce (5)-l-[(6-allylammo-4,8-bis-methylammo-pyrimido[5,4-d]-
pyrimidinyl)-propyl-amino]-propanol hydrochloride (155a) (120 mg, 86% yield). 300
MHz 1HNMR (CDsOD, ppm): 5.98 (1H, ddt, J=17.2, 10.4, 5.1 Hz) 5.29 (1H, ddt, J=17.2,
1.5, 1.5 Hz) 5.18 (1H, ddt, J=10.4, 1.5, 1.5 Hz) 4.22-4.08 (3H, m) 3.76-3.50 (4H, m) 3.15
(3H, s) 3.09 (3H, s) 1.78-1.61 (2H, m) 1.22 (3H, d, J=6.4 Hz) 0.95 (3H, t, J=7.4 Hz). ESI-
MS (m/z): 361 [M+H]+; MP: 198-200 °C.
Example 95: (S)-l-[(6-Allylamino-4,8-bis-methylammo-pyrimido[5,4-d1|pyrimidmyl)-
methyl-amino]-propanol (156) and corresponding hydrochloride salt (156a)
N^N ^
'tiY-r^
^N^^OH 156
(a) (S)-ethyl 2-((2-hydroxypropyl)amino)acetate
To the solution of(S)-l-amino-propanol (414 j^L, 5.26 mmol) in 1,4-
dioxane (5.0 mL) 5M NaOH (1.18 mL, 5.92 mmol) and ethyl chloroformate (564 j^L, 5.92
mmol) were added and the mixture was stirred at room temperature for 30 min. Water (15
mL) was added and the resulting suspension was extracted with EtOAc (3x10 mL). The
combined organic extracts were washed with a brine solution (20 mL) and dried over solid
anhydrous N02804. After filtration, the solvent was removed to give (S)-ethyl 2-((2-
hydroxypropyl)amino)acetate (734 mg, 95% yield). 300 MHz rH NMR (CDCk, ppm): 5.12
(1H, br s) 4.16-4.06 (2H, m) 3.96-3.83 (1H, m) 3.31 (1H, ddd, J=14.0, 6.5, 3.1 Hz) 3.03 (1H,
ddd, J=14.0, 7.5, 5.5 Hz) 2.7-2.2 (1H, br s) 1.28-1.20 (6H, m) 1.17 (3H, d, J=6.3 Hz). ESI-
MS (m/z): 148 [M+H]+.
(b) (S)-l -(methylamino)propanol
UA1H4 (379 mg, 9.97 mmol) was added to a solution of(S)-ethyl 2-((2-
hydroxypropyl)-ammo)acetate (734 mg, 4.99 mmol) in THF (10 mL). The mixture was
refluxed for 2h and after cooling, a 15% NaOH water solution (1.2 mL) was added. The
resultant precipitate was filtered and washed successively with THF, CHhCh and diethyl
ether (each 10 mL). The filtrate was evaporated to give (S)-l-(methylamino)propanol
(289 mg, 65% yield). 300 MHz 'H NMR (CDCk, ppm): 3.86-3.74 (1H, m) 2.64 (1H, dd,
J=12.0, 3.1 Hz) 2.44 (3H, s) 2.4 (1H, dd, J-12.0, 9.4 Hz) 1.16 (3H, d, J=6.3 Hz). ESI-MS
(m/z): 90 [M+H]+.
(c) (S)-1 -[(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-propanol (156)
N -Allylchloro-N4,N8-dimethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine
(153) (253 mg, 0.90 mmol) (5)-l-(methylamino)propanol were reacted in n-butanol to
afford (S)-1 -[(6-allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-propanol (156) (130 mg, 43% yield). 300 MHz 1H NMR (CDCb, ppm): 6.68-6.46
(1H, br s) 6.43-6.27 (1H, br s) 5.98 (1H, ddt, J=17.4, 10.3, 5.6 Hz) 5.26 (1H, ddt, J=17.4, 1.7,
1.7 Hz) 5.12 (1H, ddt, J=10.3, 1.5, 1.5 Hz) 4.93-4.65 (1H, br s) 4.17-4.09 (1H, m) 4.08-4.03
(2H, m) 3.75 (1H, dd, J=14.7, 7.4 Hz) 3.47 (1H, dd, J=14.7, 2.2 Hz) 3.21 (3H, s) 3.07 (6H, d,
J=5.1 Hz) 1.23 (3H, d, J=6.3 Hz). ESI-MS (m/z): 333 [M+H]+.
(d) (S)-l-[(6-Allylamino-4,8-bis-methylammo-pyrimido[5,4-d]pyrimidinyl)-methyl-
amino]-propanol hydrochloride (156a)
(S)-l-[(6-Allylamino-4,8-bis-methylamino-pyrimido[5,4-d]pyrimidinyl)-
methyl-ammo]-propanol (156) (130 mg, 0.39 mmol) was treated with 2M HC1 /diethyl
ether in diethyl ether /ethanol (5/2) to produce (S)-l-[(6-allylamino-4,8-bis-methylamino-
pyrimido[5,4-d]pyrimidinyl)-methyl-amino]-propanol hydrochloride (156a) (110 mg,
76% yield). 300 MHz 'H NMR (CDsOD, ppm): 5.98 (1H, ddt, J=17.2, 10.3, 5.4 Hz) 5.29
(1H, ddt, J=17.2, 1.7, 1.7 Hz) 5.18 (1H, ddt, J=10.3, 1.5, 1.5 Hz) 4.17-4.10 (3H, m) 3.71-3.61
(2H, m) 3.28 (3H, s) 3.15 (3H, s) 3.09 (3H, s) 1.22 (3H, d, J=6.3 Hz). ESI-MS (m/z): 333
[M+H]+; MP: 218-220 °C.
Example 96: (R)-l-[6-(2-Methyl-allylamino)-4,8-bis-methylammo-pyrimido[5,4-d]-
pyrimidinylamino]-propanol (158) and corresponding hydrochloride salt (158a)
^N-^-r^S---^
~OH 158
(a) 6-Chloro-N4,N8-dimethyl-N2-(2-methylallyl)pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (157)
A mixture of 2,6-dichloro-N,N'-dimethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (88) (700 mg, 2.70 mmol), 2-methyl-allylamine (294 [iL, 3.24 mmol) and N,N-
diisopropyl ethylamine (560 [iL, 3.24 mmol) in n-butanol (8 mL) was heated at 90°C for 48
h. An additional portion of2-methyl-allylamine (100 pL, 1.10 mmol) was added and the
mixture was heated at 90°C for 24 h. After cooling, water (30 mL) was added and the
resulting suspension was extracted with EtOAc (3x30 mL). The combined organic extracts
were washed with a brine solution (30 mL) and dried over solid aahydrous MgS04. After
filtration, the solvent was removed; the residue filtered through silica gel using PE / EtOAc
(1/1) to give 6-chloro-N4,N8-dimethyl-N2-(2-methylallyl)pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (157) (650 mg, 82% yield). 300 MHz 1H NMR (CDCb, ppm): 6.77-6.63 (1H, m)
6.58-6.45 (1H, m) 5.06 (1H, t, J=6.0 Hz) 4.96-4.91 (1H, m) 4.87-4.83 (1H, m) 4.03-3.98 (2H,
m) 3.14 (3H, d, J=5.2 Hz) 3.05 (3H, d, J=5.1 Hz) 1.81-1.78 (3H, m). ESI-MS (m/z): 294, 296
[M+H]+.
(b) (R)-1 -[6-(2-Methyl-allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylamino]-propanol (158)
6-Chloro-N4,N8-dimethyl-N2-(2-methylallyl)pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (157) (325 mg, 1.11 mmol) and (R)-l-amino-propanol were reacted in n-butanol
and the crude product was purified by flash column chromatography using gradient elution
from CHCk / MeOH (99/1) to CHCb / EtOH (97/3) to obtain (R)-l-[6-(2-methyl-
allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]-propanol (158)
(185 mg, 50% yield). 300 MHz 'HNMR (CDCb, ppm): 6.63-6.48 (1H, m) 6.29-6.12 (1H,
m) 5.11-5.01 (1H, m) 4.96-4.91 (1H, m) 4.86-4.81 (1H, m) 4.81-4.73 (1H, m) 4.09-3.95 (1H,
m) 3.98 (2H, d, J-6.0 Hz) 3.50 (1H, ddd, J-14.4, 6.3, 2.5 Hz) 3.41-3.30 (1H, m) 3.06 (3H, d,
J=5.2 Hz) 3.05 (3H, d, J-5.2 Hz) 1.80 (3H, s) 1.22 (3H, d, J-6.3 Hz). ESI-MS (m/z): 333
[M+H]+.
(c) (R)-l-[6-(2-Methyl-allylammo)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylaminoj-propanol hydrochloride (158a)
(R)-l-[6-(2-Methyl-allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylamino]-propanol (158) (180 mg, 0.54 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether /methanol (2/1) to produce (R)-l-[6-(2-methyl-allylamino)-4,8-
bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]-propanol hydrochloride (158a)
(175 mg, 88% yield). 300 MHz 1H NMR (D^O, ppm): 4.97-4.90 (2H, m) 4.14-4.04 (1H, m)
4.04-3.99 (2H, m) 3.52 (1H, dd, J=14.0, 4.5 Hz) 3.44 (1H, dd, J=14.0, 7.0 Hz) 3.08 (3H, s)
3.07 (3H, s) 1.81 (3H, s) 1.25 (3H, d, J=6.4 Hz). ESI-MS (m7z): 333 [M+H]+.
Example 97: (S)-l-[6-(2-Methyl-allylammo)-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidmylamino]-propanol (159) and corresponding hydrochloride salt (159a)
N-^N ^
"!fVSrp"
N^ ,N
HN—OH ,„
(a) (S)-l-[6-(2-Methyl-allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylamino]-propanol (159)
6-Chloro-N4,N8-dimethyl-N2-(2-methylallyl)pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (157) (325 mg, 1.11 mmol) and (S)-l-amino-propanol were reacted in n-butanol
and the cmde product was purified by flash column chromatography using gradient elution
from CHCb / MeOH (99/1) to CHCls / EtOH (97/3) to afford (S)-l-[6-(2-methyl-allylamino)-
4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidinylamino]-propanol (159) (185 mg, 50%
yield). 300 MHz 1H NMR (CDCb, ppm): 6.62-6.47 (1H, m) 6.26-6.13 (1H, m) 5.05 (1H, t,
J=6.1 Hz) 4.96-4.91 (1H, m) 4.85-4.81(1H, m) 4.78 (1H, t, J=5.9 Hz) 4.09-3.95 (1H, m) 3.98
(2H, d, J=6.1 Hz) 3.50 (1H, ddd, J=14.3, 6.3, 2.5 Hz) 3.41-3.30 (1H, m) 3.06 (3H, d, 3=5.2
Hz) 3.05 (3H, d, J-5.2 Hz) 1.81-1.78 (3H, m) 1.22 (3H, d, J=6.3 Hz). ESI-MS (m/z): 333
[M+H]+.
(b) (S)-l-[6-(2-Methyl-allylammo)-4,8-bis-methylamino-pyrimido[5,4-d]-pyrimidm
ylamino]-propanol hydrochloride (159a)
(S)-l-[6-(2-Methyl-allylamino)-4,8-bis-methylamino-pyrimido[5,4-d]-
pyrimidinylammo]-propanol (159) (180 mg, 0.54 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether /methanol (2/1) to produce (S)-l-[6-(2-methyl-allylamino)-4,8-
bis-methylamino~pyrimido[5,4-d]-pyrimidinylamino]-propanolhydrochloride (159a)
(185 mg, 93% yield). 300 MHz 1HNMR (D20, ppm): 4.97-4.90 (2H, s) 4.13-4.03 (1H, m)
4.03-3.95 (2H, m) 3.55-3.35 (2H, m) 3.05 (6H, s) 1.81 (3H, s) 1.25 (3H, d, J=6.3 Hz). ESI-
MS (m/z): 333 [M+H]+; MP: 201-203 °C.
Example 98: 2-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)-
ethanol (162) and corresponding hydrochloride salt (162a)
Nl N H
-N-VV""
'OH 162
(a) 2,6-Dichloro-N,N'-diethyl-pyrimido[5,4-d]pyrimidine-4,8-diamine (160)
2M Ethylamine/THF (27 mL, 54.00 mmol) was added dropwise to a solution
of2,4,6,8-tetrachloro-pyrimido[5,4-d]pyrimidine (1) (3.00 g, 11.15 mmol) in THF (150 mL)
at 0°C. The reaction mixture was stirred at room temperature for 2 h. The volatiles were
removed and the residue was suspended in water (50 mL). The resultanthe precipitate were
filtered, washed with water (2x30 mL) and dried over solid PzOs to give 2,6-dichloro-N,N'-
diethyl-pyrimido [5,4-d]pyrimidine-4,8-diamine (160) (2.93 g, 92% yield). 300 MHz 1H
NMR (DMSO-d6, ppm): 8.68 (2H, t, J=5.9 Hz) 3.52-3.40 (4H, m) 1.16 (6H, t, J=7.1 Hz).
ESI-MS (m/z): 287, 289, 291 [M+H]+.
(b) 6-Chloro-N4,N8-diethyl-N2-propyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine(161)
A mixture of2,6-dichloro-N,N'-diethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (160) (420 mg, 1.46 mmol) and propylamine (720 pL, 8.76 mmol) in n-butanol (5
mL) was heated at 90°C for 24 h. After cooling, a saturated NaHCOs solution (15 mL) was
added and the resulting suspension was extracted with EtOAc (3 x 20 mL). The combined
organic extracts were washed with water (30 mL), then with a brine (30 mL) solution and
dried over solid anhydrous N02804. After filtration, the solvent was removed to give 6-
chloro-N ,N8-diethyl-N2-propylpyrimido[5,4-d]pyrimidine-2,4,8-triamine (161) (450 mg,
99% yield). 300 MHz 1H NMR (CDCk, ppm): 6.66 (1H, t, J=5.9 Hz) 6.46 (1H, t, J=5.9 Hz)
4.93 (1H, t, J=6.0 Hz) 3.61 (2H, qd, J=7.3, 5.9 Hz) 3.52 (2H, qd, J=7.3, 5.9 Hz) 3.38 (2H, td,
J=7.1, 6.0 Hz) 1.71-1.55 (2H, m) 1.32 (3H, t, J=7.3 Hz) 1.28 (3H, t, J=7.3 Hz) 1.00 (3H, t,
J=7.5 Hz). ESI-MS (m/z): 310, 312 [M+H]+.
(c) 2-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol
(162)
A mixture of 6-chloro-N ,N8-diethyl-N2-propyl-pyrimido[5,4-d]pyrimidine-
2,4,8-triamine (161) (225 mg, 0.73 mmol) and 2-amino-ethanol (176 ^iL, 2.92 mmol) in n-
butanol (3 mL) was heated at 120°C for 24h in a closed vial. An additional portion of 2-
amino-ethanol (176 [iL, 2.92 mmol) was added and heating was continued for another 24 h.
After cooling, water (10 mL) and a saturated NaHCOs solution (10 mL) was added. The
resulting suspension was extracted with EtOAc (3 x 20 mL). The combined organic extracts
were washed with a brine solution (30 mL) and dried over solid anhydrous N02804. After
filtration, the solvent was removed and the residue was purified by flash column
chromatography using gradient elution fi-om CH2C12 / EtOH (99/1) to CHzCk / EtOH (97/3)
to give2-(4,8-bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol
(162) (165 mg, 68% yield). 300 MHz 1H NMR (CDCk, ppm): 6.53 (1H, br s) 6.18 (1H, br s)
.04 (1H, t, J=5.0 Hz) 4.76-4.46 (2H, m) 3.86-3.80 (2H, m) 3.61-3.46 (6H, m) 3.36 (2H, td,
J=7.0, 6.1 Hz) 1.70-1.55 (2H, m) 1.30 (3H, t, J=7.2 Hz) 1.28 (3H, t, J=7.2 Hz) 0.99 (3H, t,
J=7.3 Hz). ESI-MS (m/z): 335 [M+H]+.
(d) 2-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-ethanol
hydrochloride (162a)
2-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
ethanol (162) (155 mg, 0.46 mmol) was treated with 2M HC1 /diethyl ether in diethyl ether /
ethanol (2/1) to produce 2-(4,8-bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidin
ylamino)-ethanol hydrochloride (162a) (165 mg, 97% yield). 300 MHz 1H NMR (CDsOD,
ppm): 3.73 (2H, t, J=5.6 Hz) 3.69-3.56 (6H, m) 3.44 (2H, t, J=7.1 Hz) 1.68 (2H, sextet, J=7.4
Hz) 1.32 (6H, t, 3=7.2 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 335 [M+H]+; MP: 1 83-184
Example 99: 1 -(4,8-Bis-ethylammopropylammo-pyrimido[5,4-d]pyrimidinylammo)-
2-methyl-propanol (163) and corresponding hydrochloride salt (163a)
Nl N H
"KVr"'-
H Vi
HN~^°" 163
(a) l-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)
methyl-propanol (163)
A mixture of 6-chloro-N4,N -diethyl-N -propyl-pyrimido[5,4-d]pyrimidine-
2,4,8-triamine (161) (200 mg, 0.65 mmol) and l-aminomethyl-propanol (232 mg, 2.60
mmol) in n-butanol (4 mL) was heated at 120°C for 48 h in a closed vial. An additional
portion of 1-aminomethyl-propanol (232 mg, 2.60 mmol) was added and heating was
continued for another 48 h. After cooling, a saturated NaHCOs solution (20 mL) was added
and the resulting suspension was extracted with EtOAc (3 x 20 mL). The combined organic
extracts were washed with a brine (30 mL) solution and dried over solid anhydrous N02804.
After filtration, the solvent was removed; the residue was purified by flash column
chromatography using gradient elution from CH2C12 to CHhCk / EtOH (98/2) to obtain 1-
(4,8-bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)methyl-propan-
2-ol (163) (180 mg, 76% yield). 300 MHz 1HNMR (CDCk, ppm): 6.53 (1H, s) 6.15 (1H, s)
.24 (1H, br s) 5.09-4.97 (1H, m) 4.70-4.60 (1H, m) 3.58-3.46 (4H, m) 3.39 (2H,d, J=6.4 Hz)
3.39-3.31 (2H, m) 1.63 (2H, sextet, J=7.4 Hz) 1.34-1.23 (6H, m) 1.26 (6H, s) 0.99 (6H, t,
J=7.4 Hz). ESI-MS (m/z): 363 [M+H]+.
(b) l-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidin-2~ylamino)
methyl-propanol hydrochloride (163a)
l-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)-
2-methyl-propanol (163) (170 mg, 0.47 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / MeOH (20/1) to produce l-(4,8-bis-ethylaminopropylamino-pyrimido[5,4-
d] pyrimidiaylamino)methyl-propanol hydrochloride (163a) (145 mg, 77% yield).
300 MHz 'H NMR (CDsOD, ppm): 3.70-3.53 (4H, m) 3.48 (2H, s) 3.42 (2H, t, J=7.2 Hz)
1.75-1.60 (2H, m) 1.35-1.27 (6H, m) 1.25 (6H, s) 1 .00 (3H, t, J=7.4 Hz). ESI-MS (m/z): 363
[M+H]+; MP: 182-183 °C.
Example 100: (S)-l-(4,6,8-Tris-ethylamino-pyrimido[5,4-d]pyrimidmylamino)-propan
ol (165) and corresponding hydrochloride salt (165a)
.HrroH
N.^N
-yW-
""^ 165
(a) (S)-l-((6-Chloro-4,8-bis(ethylamino)pyrimido[5,4-d]pyrimidmyl)amino)propan
ol (164)
A mixture of 2,6-dichloro-N,N'-diethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (160) (500 mg, 1.74 mmol), (S)-l-amino-propanol (207 mg, 2.76 mmol) and N,N-
diisopropyl ethylamine (301 j^L, 1.74 mmol) in n-butanol (5 mL) was heated at 75°C for 48
h. After cooling, a saturated NaHCOs solution (20 mL) was added and the resulting
suspension was extracted with EtOAc (3 x 20 mL). The combined organic extracts were
washed with a brine solution (30 mL) and dried over solid anhydrous MgS04. After
filtration, the solvent was removed; the residue was purified by flash column chromatography
using gradient elution from PE / acetone (9/1) to PE / acetone (3/1) to give (S)-l-((6-chloro-
4,8-bis(ethylammo)pyrimido[5,4-d]pyrimidinyl)amino)propanol (164) (330 mg, 58%
yield). 300 MHz lHNMR(CDCl3, ppm): 6.63-6.47 (2H, m) 5.30 (lH,t, J=6.1 Hz) 4.11-3.99
(1H, m) 3.70 (1H, br s) 3.60 (2H, qd, J=7.3, 5.9 Hz) 3.59-3.52 (1H, m) 3.52 (2H, qd, J=7.3,
.8 Hz) 3.36 (1H, ddd, J=14.2, 7.2, 6.1 Hz) 1.31 (3H, t, J=7.3 Hz) 1.29 (3H, t, J=7.3 Hz) 1.25
(3H, d, 3=6.3 Hz). ESI-MS (m/z): 326, 328 [M+H]+.
(b) (S)-1 -(4,6,8-Tris-ethylammo-pyrimido[5,4-d]pyrimidmylamino)-propanol (165)
A mixture of (S)-l-((6-chloro-4,8-bis(ethylammo)pyrimido[5,4-d]pyrimidm-
2-yl)amino)propanol (164) (160 mg, 0.49 mmol) and ethylamine (70% water solution) (0.8
mL) in n-butanol (3 mL) was heated at 120°C for 48 h in a closed vial. After cooling, a
saturated NaHC03 solution (10 mL) was added and the resulting suspension was extracted
with EtOAc (3 x 20 mL). The combined organic extracts were washed with a brine solution
(30 mL) and dried over solid anhydrous N02804. After filtration, the solvent was removed;
the residue was purified by flash column chromatography using gmdient elution from PE /
acetone (9/1) to PE / acetone (1/1) to obtain (S)-l-(4,6,8-Tris-ethylammo-pyrimido[5,4-
d]pyrimidinylamino)-propanol (165) (95 mg, 58% yield). 300 MHz 'H NMR (CDCb,
ppm): 6.61-6.43 (1H, m) 6.25-6.10 (1H, m) 5.10-4.87 (2H, m) 4.67-4.53 (1H, m) 4.08-3.97
(1H, m) 3.59-3.27 (8H, m) 1.30 (3H, t, J=7.0 Hz) 1.27 (3H, t, J=7.0 Hz) 1.23 (3H, t, J=7.2
Hz) 1.22 (3H, d, J=6.3 Hz). ESI-MS (m/z): 335 [M+H]+.
(c) (S)-1 -(4,6,8-Tris-ethylamino-pyrimido [5,4-d]pyrimidinylamino)-propanol
hydrochloride (165a)
(S)-l-(4,6,8-Tris-ethylamino-pyrimido[5,4-d]pyrimidinylammo)-propan
ol (165) (95 mg, 0.28 mmol) was treated with 2M HC1 /diethyl ether in diethyl ether / EtOH
(1/1) to produce (S)-l-(4,6,8-tris-ethylammo-pyrimido[5,4-d]pyrimidmylamino)-propan
ol hydrochloride (165a) (105 mg, -100% yield). 300 MHz 'H NMR (CDsOD, ppm): 4.04-
3.91 (1H, m) 3.65 (2H, q, J-7.3 Hz), 3.63 (2H, q, J=7.3 Hz) 3.5.7-3.46 (3H, m) 3.40 (1H, dd,
J=13.7, 7.0 Hz) 1.33 (6H, t, J=7.3 Hz) 1.27 (3H, t, J=7.2 Hz) 1.24 (3H, d, J=6.3 Hz). ESI-MS
(m/z): 335 [M+H]+; MP: 193-195 °C.
Example 101: (S)-l-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidin
ylamino)-propanol (166) and corresponding hydrochloride salt(166a)
."0"
N.^N
^Yr"-
HN^ 166
(a) (S)-l-(4,8-Bis-ethylammopropylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol (166)
A mixture of (S)-l -((6-chloro-4,8-bis(ethylamino)pyrimido[5,4-d]pyrimidin-
2-yl)amino)propanol (164) (160 mg, 0.49 mmol) and propylamine (403 [XL, 4.90 mmol) in
n-butanol (3 mL) was heated at 120°C for 24h in a closed vial. An additional portion of
propylamine (200 p.L, 2.45 mmol) was added and heating was continued for another 24h.
After cooling, a saturated NaHCOs solution (10 mL) was added and the resulting suspension
was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with a
brine solution (30 mL) and dried over solid anhydrous N02804. After filtration, the solvent
was removed; the residue was purified by flash column chromatography using gradient
elution from PE / acetone (9/1) to PE / acetone (1/1) to obtain (S)-l-(4,8-bis-ethylamino
propylammo-pyrimido[5,4-d]-pyrimidmylammo)-propanol (166) (110 mg, 64% yield).
300 MHz 1H NMR (CDCk, ppm): 6.60-6.46 (1H, m) 6.24-6.12 (1H, m) 5.10-4.90 (2H, m)
4.72-4.60 (1H, m) 4.10-3.96 (1H, m) 3.58-3.45 (5H, m) 3.40-3.25 (3H, m) 1.71-1.55 (2H, m)
1.30 (3H, t, 3=7.2 Hz) 1.27 (3H, t, J=7.2 Hz) 1.22 (3H, d, J-6.3 Hz) 0.99 (3H, t, J=7.4 Hz).
ESI-MS (m/z): 349 [M+H]+.
(b) (S)-l-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidmylammo)-
propanol hydrochloride (166a)
(S)-l-(4,8-Bis-ethylammopropylamino-pyrimido[5,4-d]-pyrimidm
ylamino)-propanol (166) (100 mg, 0.29 mmol) was treated with 2M HC1 /diethyl ether in
diethyl ether / EtOH (1/1) to produce (S)-l-(4,8-bis-ethylaminopropylammo-pyrimido[5,4-
d]-pyrimidmylammo)-propanol hydrochloride (166a) (100 mg, 90% yield). 300 MHz
1H NMR (CDsOD, ppm): 4.04-3.90 (1H, m) 3.69-3.55 (4H, m) 3.55-3.34 (4H, m) 1.76-1.59
(2H, m) 1.31 (6H, t, J=7.3 Hz) 1.22 (3H, d, J=6.4 Hz) 1.00 (3H, t, J=7.4 Hz). ESI-MS (m/z):
349 [M+H]+.
Example 102: (R)-l-(4,6,8-Tris-ethylamino-pyrimido[5,4-d]pyrimidinylammo)-propan-
2-ol (168) and corresponding hydrochloride salt (168a)
HN^V°"
IH N H
S?^S^'N'
'K' T 1
HN-^ 168
(a) (R)-l-((6-Chloro-4,8-bis(ethylamino)pyrimido[5,4-d]pyrimidinyl)amino)propan
ol (167)
A mixture of2,6-dichloro-N,N'-diethyl-pyrimido[5,4-d]pyrimidme-4,8-
diamine (160) (300 mg, 1.04 mmol), (R)-l-amino-propanol (157 mg, 2.09 mmol) in n-
butanol (5 mL) was heated at 100°C for 18 h. After cooling, a saturated NaHCOs solution
(20 mL) was added and the resulting suspension was extracted with EtOAc (3 x 20 mL). The
combined organic extracts were washed with a brine solution (30 mL) and dried over solid
anhydrous N02804. After filtration, the solvent was removed; the residue was purified by
flash column chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc
(1/4) to give (R)-l-((6-chloro-4,8-bis(ethylamino)pyrimido[5,4-d]pyrimidm
yl)amino)propanol (167) (222 mg, 66% yield). 300 MHz 1H NMR (CDCb, ppm): 6.59
(1H, t, J=5.8 Hz) 6.54 (1H, t, J=5.8 Hz) 5.32 (1H, t, J=6.0 Hz) 4.05 (1H, dqd, J=7.2, 6.4, 2.8
Hz) 3.76 (1H, br s) 3.60 (2H, qd, 3=7.3, 5.8 Hz) 3.59-3.53 (1H, m) 3.51 (2H, qd, J=7.3, 5.8
Hz) 3.36 (1H, ddd, J=14.2, 7.2, 6.0 Hz) 1.30 (3H, t, J=7.3 Hz) 1.28 (3H, J=7.3 Hz) 1.24 (3H,
d, J=6.4 Hz). ESI-MS (m/z): 326, 328 [M+H]+.
(b) (R)-l-(4,6,8-Tris-ethylamino-pyrimido[5,4-d]pyrimidmylammo)-propanol (168)
(R)-l-((6-Chloro-4,8-bis(ethylamino)pyrimido[5,4-d]pyrimidm
yl)amino)propanol (167) (222 mg, 0.68 mmol) and ethylamine (70% water solution) were
reacted in n-butanol. The cmde product was purified by flash column chromatography using
gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/4) to obtain (R)-l-(4,6,8-tris-
ethylammo-pyrimido[5,4-d]pyrimidinylamino)-propanol (168) (128 mg, 56% yield).
300 MHz JHNMR (CDCk, ppm) 6.57-6.49 (1H, m) 6.23-6.14 (1H, m) 5.01 (1H, t, J=6.0 Hz)
4.90 (1H, br s) 4.60 (1H, t, J=5.0 Hz) 4.10-3.96 (1H, m) 3.58-3.27 (8H, m) 1.33-1.19 (12H,
m). ESI-MS (m/z): 335 [M+H]+.
(c) (R)-l-(4,6,8-Tris-ethylamino-pyrimido[5,4-d]pyrimidinylammo)-propanol
hydrochloride (168a)
(R)-l-(4,6,8-Tris-ethylamino-pyrimido[5,4-d]pyrimidmylamino)-propan
ol (168) (110 mg, 0.33 mmol) was treated with 2M HC1 /diethyl ether in CHhCk to produce
(R)-1 -(4,6,8-tris-ethylamino-pyrimido [5,4-d]pyrimidinylamino)-propanol
hydrochloride (168a) (122 mg, -100% yield). 400 MHz !H NMR (CDsOD, ppm): 4.02-3.94
(1H, m) 3.65 (2H, q, J=7.3 Hz) 3.62 (2H, q, J=7.3 Hz) 3.55-3.48 (3H, m) 3.40 (1H, dd,
J=13.7, 7.0 Hz) 1.32 (6H, t, J-7.3 Hz) 1.26 (3H, t, J=7.2 Hz) 1.22 (3H, d, J=:6.3 Hz). ESI-MS
(m/z): 335 [M+H]+; MP: 194-196 °C.
Example 103: (R)-l-(4,8-Bis-ethylammopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-propanol (169) and corresponding hydrochloride salt (169a)
HN-VOH
fl N "
>rVvK-~
HN^^ ^9
(a) (R)-1 -(4,8-Bis-ethylaminopropylamino-pyrimido [5 ,4-d] -pyrimidmylamino)-
propanol (169)
(R)-l-((6-Chloro-4,8-bis(ethylamino)pyrimido[5,4-d]pyrimidm
yl)amino)propanol (167) (160 mg, 0.49 mmol) and propylamine were reacted in n-butanol
using procedures described elsewhere herein. The cmde product was purified by flash
column chromatography using gradient elution from PE / EtOAc (9/1) to PE / EtOAc (1/4) to
obtain (R)-l-(4,8-bis-ethylaminopropylamino-pyrimido [5,4-d]-pyrimidinylamino)-
propanol (169) (123 mg, 72% yield). 400 MHz (H NMR (CDCls, ppm): 6.53 (1H, br s)
6.18 (1H, br s) 5.04-4.97 (1H, m) 4.91 (1H, br s) 4.69-4.60 (1H, br s) 4.07-3.99 (1H, m) 3.56-
3.47 (5H, m) 3.39-3.29 (3H, m) 1.63 (2H, sextet, J=7.4 Hz) 1.30 (3H, t, J=7.3 Hz) 1.28 (3H,
t, 3=7.3 Hz) 1.22 (3H, d, J=6.3 Hz) 0.99 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+.
(b) (R)-l-(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidmylamino)-
propanol hydrochloride (169a)
(R)-1 -(4,8-Bis-ethylaminopropylamino-pyrimido[5,4-d]-pyrimidm
ylamino)-propanol (169) (100 mg, 0.29 mmol) was treated with 2M HC1 /diethyl ether in
CHhCk to produce (R)-l-(4,8-bis-ethylaminopropylammo-pyrimido[5,4-d]-pyrimidin
ylamino)-propanol hydrochloride (169a) (105 mg, 95% yield). 400 MHz 1H NMR
(CDsOD, ppm): 4.02-3.93 (1H, m) 3.67-3.57 (4H, m) 3.50 (1H, dd, J=13.7, 4.6 Hz) 3.46-3.39
(2H, m) 3.40 (1H, dd, J=13.7, 6.9) 1.68 (2H, sextet, J=7.4) 1.31 (6H, t, J=7.3 Hz) 1.22 (3H, d,
J=6.3 Hz) 1.0 (3H, t, J=7.4 Hz). ESI-MS (m/z): 349 [M+H]+.
Comparative Example 104: (R)-l-(6-Ammo-4,8-bis-ethylamino-pyrimido[5,4-d]-
pyrimidinylamino)-propanol (171) and corresponding hydrochloride salt (171a)
HN—OH
N.^N
"K-W-
H N^
NH2 171
(a) 6-Chloro-N4,N8-diethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamine(170)
A mixture of 2,6-dichloro-N ,N8-diethyl-pyrimido[5,4-d]pyrimidine-4,8-
diamine (160) (800 mg, 2.79 mmol) and ammonium hydroxide (NHs, 25% water solution,
1.00 mL) in n-butanol (5 mL) was heated at 95°C for 72 h. An additional portion of
ammonium hydroxide (NHb, 25% water solution, 1.00 mL) was added and heating was
continued for 96 h. After cooling, a saturated NaHC03 solution (20 mL) was added and the
resulting suspension was extracted with CHCk (3 x 20 mL). The combined organic extracts
were washed with water (30 mL) and dried over solid anhydrous ]V[gS04. After filtration, the
solvent was removed; the residue was purified by flash column chromatography using
gradient elution fi-om CHCls / MeOH (99/1) to CHCls / MeOH (95/5) to give 6-chloro-N4,N8-
diethyl-pyrimido[5,4-d]pyrimidme-2,4,8-triamine (170) (380 mg, 51% yield). 300 MHz !H
NMR (CDCb, ppm): 6.70-6.60 (1H, m) 6.60-6.50 (1H, m) 4.80 (2H, s) 3.59 (2H, qd, J=7.2,
.8 Hz) 3.53 (2H, qd, J=7.2, 5.8 Hz) 1.31 (3H, t, J=7.2 Hz) 1.28 (3H, t, J=7.2 Hz). ESI-MS
(m/z): 268, 270 [M+H]+.
(b) (R)-l-(6-Ammo-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidinylamino)-propan
ol (171)
A mixture of 6-chloro-N4,N8-diethyl-pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (170) (150 mg, 0.56 mrnol) and (R)-l-amino-propanol (170 mg, 2.24 nunol) in n-
butanol (3 mL) was heated at 110°C for 120 h. After cooling, a saturated NaHCOs solution
(20 mL) was added and the resulting suspension was extracted with EtOAc (3 x 20 mL). The
combined organic extracts were washed with brine (30 mL) and dried over solid anhydrous
MgS04. After filtration, the solvent was removed; the residue was purified by flash column
chromatography using gradient elution from CH2C12 / EtOH (99/1) to CHhCb / EtOH (9/1) to
obtain (R)-l-(6-amino-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidmylammo)-propan
ol (171) (115 mg, 67% yield). 300 MHz 1HNMR (CDCb, ppm): 6.55-6.41 (1H, m) 6.32-
6.19 (1H, m) 5.05 (1H, t, J=5.8 Hz) 4.70 (1H, br s) 4.54 (2H, s) 4.09-3.98 (1H, m) 3.59-3.45
(5H, m) 3.34 (1H, ddd, J=14.2, 6.7, 6.2 Hz) 1.29 (3H, t, J=7.3 Hz) 1.28 (3H, t, J=7.3 Hz) 1.23
(3H, d, J=6.3 Hz). ESI-MS (m/z): 307 [M+H]+.
(c) (R)-l-(6-Amino-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidinylammo)-propan
ol hydrochloride (171a)
(R)-l-(6-Ammo-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidinylammo)-
propanol (171) (105 mg, 0.34 mmol) was treated with 2M HC1 /diethyl ether in diethyl
ether to produce (R)-l-(6-amino-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidinylamino)-
propanol hydrochloride (171a) (105 mg, 90% yield). 300 MHz ZH NMR (CDsOD, ppm)
4.02-3.89 (1H, m) 3.64 (2H, q, J=7.2 Hz) 3.58 (2H, q, J=7.2 Hz) 3.52-3.34 (2H, m) 1.31 (3H,
t, J=7.2 Hz) 1.30 (3H, t, J=7.2 Hz) 1.21 (3H, d, J=6.3 Hz). ESI-MS (m/z): 307 [M+H]+; MP:
178-180 °C.
Comparative Example 105: (S)-l-(6-Amino-4,8-bis-ethylamino-pyrimido[5,4-d]-
pyrimidinylamino)-propanol (172) and corresponding hydrochloride salt (172a)
N.^N
NHs ^2
(a) (S)-l-(6-Amino-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidinylammo)-propan
ol (193)
6-Chloro-N4,N8-diethyl-pyrimido[5,4-d]pyrimidine-2,4,8-triamme (170) (150
mg, 0.56 mmol) and (S)-l-amino-propanol were reacted in n-butanol to obtain (S)-l-(6-
amino-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidmylammo)-propanol (172) (115 mg,
67% yield). 300 MHz 'H NMR (CDCb, ppm): 6.48 (1H, s) 6.27 (1H, s) 5.05 (1H, t, J=5.8
Hz) 4.9-4.3 (1H, br s) 4.54 (2H, s) 4.09-3.98 (1H, m) 3.59-3.45 (5H, m) 3.41-3.25 (1H, m)
1.29 (3H, t, J=7.3 Hz) 1.28 (3H, t, J=7.3 Hz) 1.23 (3H, d, J=6.3 Hz). ESI-MS (m/z): 307
[M+H]+.
(b) (S)-1 -(6-Amino-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidmylamino)-propan
ol hydrochloride (172a)
(S)-l-(6-Amino-4,8-bis-ethylammo-pyrimido[5,4-d]-pyrimidmylammo)-
propanol (172) (105 mg, 0.34 mmol) was treated with 2M HC1 /diethyl ether in diethyl
ether to produce (S)-l-(6-amino-4,8-bis-ethylamino-pyrimido[5,4-d]-pyrimidinylammo)-
propanol hydrochloride (172a) (100 mg, 86% yield). 300 MHz 1H NMR (CDsOD, ppm):
4.02-3.89 (1H, m) 3.64 (2H, q, J=7.2 Hz) 3.58 (2H, q, J=7.2 Hz) 3.48 (1H, dd, J=13.6, 4.6
Hz) 3.38 (1H, dd, J=13.6, 6.7 Hz) 1.31 (3H, t, J=7.2 Hz) 1.30 (3H, t, J=7.2 Hz) 1.21 (3H, d,
J=6.3 Hz). ESI-MS (m/z): 307 [M+H]+; MP: 180-182 °C.
Example 106: (R)-l -[4,8-Bis-ethylamino(2-methyl-allylamino)-pyrimido[5,4-d]-
pyrimidinylammo]-propanol (174) and corresponding hydrochloride salt (174a)
HN-YOH
N.^N
'rW-
H ¥11
HN^< 174
(a) 6-Chloro-N4,N8-diethyl-N2-(2-methyl-allyl)-pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (173)
A mixture of 2,6-dichloro-N,N8-diethyl-pyrimido[5,4-d]pyrimidme-4,8-
diamine (160) (700 mg, 2.44 mmol), 2-methyl-allylamine (270 [iL, 2.93 mmol) and N,N-
diisopropyl ethylamine (334 p.L, 2.93 mmol) in n-butanol (8 mL) was heated at 80°C for 24
h. An additional portion of2-methyl-allylamine (130 \\L, 1.43 mmol) was added and the
mixture was heated at 90°C for 24 h. After cooling, water (30 mL) was added and the
resulting suspension was extracted with CHCls (3x30 mL). The combined organic extracts
were washed with water (30 mL) and dried over solid anhydrous MgS04. After filtration, the
solvent was removed; the residue was purified by flash column chromatography using
gradient elution from PE / EtOAc (9/1) to PE / EtOAc (5/1) to give 6-chloro-N4,N8-diethyl-
N2-(2-methyl-allyl)-pyrimido[5,4-d] pyrimidme-2,4,8-triamine (173) (570 mg, 73% yield).
300 MHz (H NMR (CDCk, ppm): 6.64 (1H, t, J=5.9 Hz) 6.49 (1H, t, J=5.9 Hz) 5.03 (1H, t,
J=6.1 Hz) 4.96-4.91 (1H, m) 4.88-4.83 (1H, m) 4.01 (2H, d, J=6.1 Hz) 3.60 (2H, qd, J=7.2,
.9 Hz) 3.53 (2H, qd, J=7.2, 5.9 Hz) 1.80 (3H, s) 1.31 (3H, t, J=7.2 Hz) 1.28 (3H, t, J=7.2
Hz). ESI-MS (m/z): 322, 324 [M+H]+.
(b) (R)-l-[4,8-Bis-ethylammo(2-methyl-allylamino)-pyrimido[5,4-d]-pyrimidin
ylaminoj-propanol (174)
6-Chloro-N4,N8-diethyl-N2-(2-methyl-allyl)-pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (173) (285 mg, 0.89 mmol) and (R)-l-ammo-propanol were reacted in n-butanol
and the crude product was purified by flash column chromatography using gradient elution
from PE / EtOAc (5/1) to PE / EtOAc (1/1) to obtain (R)-l-[4,8-bis-ethylammo(2-methyl-
allylammo)-pyrimido[5,4-d]-pyrimidinylamino]-propanol (174) (150 mg, 47% yield).
300 MHz !H NMR (CDCla, ppm): 6.50 (1H, t, J=5.6 Hz) 6.20 (1H, t, J=5.6 Hz) 5.01 (1H, t,
J==6.0 Hz) 4.95-4.92 (1H, m) 4.90 (1H, br s) 4.85-4.81 (1H, m) 4.75 (1H, t, J=6.1 Hz) 4.07-
3.94 (3H, m) 3.57-3.45 (5H, m) 3.33 (1H, ddd, J=14.4, 6.9, 6.1) 1.80 (3H, s) 1.29 (3H, t,
J=7.2 Hz) 1.27 (3H, t, J=7.2 Hz) 1.22 (3H, d, J=6.3 Hz). ESI-MS (m/z): 361 [M+H]+.
(c) (R)-l-[4,8-Bis-ethylamino(2-methyl-allylammo)-pyrimido[5,4-d]-pyrimidm
ylamino]-propanol hydrochloride (174a)
(R)-l-[4,8-Bis-ethylamino(2-methyl-allylamino)-pyrimido[5,4-d]-
pyrimidmylamino]-propanol (174) (150 mg, 0.42 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether to produce (R)-l-[4,8-bis-ethylamino(2-methyl-allylamino)-
pyrimido[5,4-d]-pyrimidinylamino]-propanol hydrochloride (174a) (145 mg,88%
yield). 300 MHz 'H NMR (CDsOD, ppm): 4.92 (1H, s) 4.85 (1H, s, overlapped with water)
4.04 (2H, s) 4.02-3.92 (1H, m) 3.62 (2H, q, 3=7.2 Hz) 3.61 (2H, q, J=7.2 Hz) 3.52 (1H, dd,
J=13.7, 4.5 Hz) 3.39 (1H, dd, J=13.7, 6.9 Hz) 1.79 (3H, s) 1.31 (3H, t, J=7.2 Hz) 1.30 (3H, t,
3=7.2 Hz) 1.22 (3H, d, J=6.3 Hz). ESI-MS (m/z): 361 [M+H]+; MP: 148-150 °C.
Example 107: (S)-l-[4,8-Bis-ethylamino(2-methyl-allylamino)-pyrimido[5,4-d]-
pyrimidinylamino]-propanol (175) and corresponding hydrochloride salt (175a)
.Hrr°H
H ¥u
HN^< ^
(a) (S)-l-[4,8-Bis-ethylamino(2-methyl-allylamino)-pyrimido[5,4-d]-pyrimidm
ylaminoj-propanol (175)
6-Chloro-N4,N8-diethyl-N2-(2-methyl-allyl)-pyrimido[5,4-d]pyrimidine-2,4,8-
triamine (173) (285 mg, 0.89 mmol) and (S)-l-amino-propanol were reacted in n-butanol.
The crude product was purified by flash column chromatography using gradient elution from
PE / EtOAc (5/1) to PE / EtOAc (1/1) to obtain (S)-l-[4,8-bis-ethylamino(2-methyl-
allylamino)-pyrimido[5,4-d]-pyrimidinylamino]-propanol (175) (160 mg, 50% yield).
300 MHz 1H NMR (CDCb, ppm): 6.50 (1H, t, J=5.6 Hz) 6.20 (1H, t, J=5.6 Hz) 5.01 (1H, t,
J=6.0 Hz) 4.95-4.92 (1H, m) 4.90 (1H, br s) 4.85-4.81 (1H, m) 4.75 (1H, t, J=6.1 Hz) 4.07-
3.94 (3H, m) 3.57-3.45 (5H, m) 3.33 (1H, ddd, J=14.4, 6.9, 6.1) 1.80 (3H, s) 1.29 (3H, t,
J=7.2 Hz) 1.27 (3H, t, J=7.2 Hz) 1.22 (3H, d, J=6.3 Hz). ESI-MS (m/z): 361 [M+H]+.
(b) (S)-l-[4,8-Bis-ethylamino(2-methyl-allylamino)-pyrimido[5,4-d]-pyrimidm
ylamino]-propanol hydrochloride (175a)
(S)-l-[4,8-Bis-ethylammo(2-methyl-allylamino)-pyrimido[5,4-d]-
pyrimidinylammo]-propanol (175) (160 mg, 0.44 mmol) was treated with 2M HC1
/diethyl ether in diethyl ether to produce (S)-l-[4,8-bis-ethylamino(2-methyl-allylamino)-
pyrimido[5,4-d]-pyrimidinylamino]-propanol hydrochloride (175a) (150 mg, 85%
yield). 300 MHz !H NMR (CDsOD, ppm): 4.92 (1H, s) 4.85 (1H, s, overlapped with water)
4.04 (2H, s) 4.02-3.92 (1H, m) 3.62 (2H, q, J=7.2 Hz) 3.61 (2H, q, J=7.2 Hz) 3.52 (1H, dd,
J=13.7, 4.5 Hz) 3.39 (1H, dd, J=13.7, 6.9 Hz) 1.79 (3H, s) 1.31 (3H, t, J=7.2 Hz) 1.30 (3H, t,
J=7.2 Hz) 1.22 (3H, d, J-6.3 Hz). ESI-MS (m/z): 361 [M+H]+; MP: 151-153 °C.
Example 108: Salt Screen
The salt formers (i.e., acids) and solvents evaluated in a salt screen for 1-(2,6-
bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidinylamino)methyl-propanol
(31) are illustrated in l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidmylamino)methyl-propanol free base (31) was combined with 1 or 2 molar
equivalents of salt former in a variety of solvents at room temperature and heated as
necessary for form a clear solution. The solution was concentrated to dryness and the
resulting solid was evaluated for solubility at room temperature and under reflux at 50
mg/mL in the solvents listed in . Any solutions which formed were allowed to cool to
as low as 0°C to induce crystallization. Mixtures from which solids were formed were noted.
Only select salts were prepared in larger quantities (i.e., those in which solids were formed);
however the lack of solid formation from any given experiment do not imply that a salt was
not formed.
Example 109: General Procedure to Prepare Gram Quantities of Selected Salts of 31 (FIG.
The indicated quantity l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinylamino)methyl-propanol (31) free base was mixed with the indicated
solvent and appropriate molar equivalents of salt former was added; the mixture was heated
as needed to form a solution, cooled to room temperature in cases where heated to form a
solution, then stirred overnight at room temperature. Crystallized product was collected by
filtration, rinsed with diethyl ether (for salts formed from EtOH/Et20) or otherwise with the
same solvent or solvent mixture as used to form the salt. The rinsed product was briefly dried
on the filter, then in air at 65°C. Salts were characterized by melting point (SRS OptiMelt) or
DSC endothermic behavior, LC/MS, H NMR, elemental analysis and XRPD. Elemental
analysis and H NMR confirmed the stoichiometry for all initially obtained salts as prepared
by combining free base and salt former in the column C solvent or solvent mixture.
For the XRPD spectrum, XRPD peaks listing and DSC spectrum for:
Hydrochloride salts of31a, see FIGs. 3A-3C; Bis-Hydrochloride salts of31a, see FIGs. 4A-
4C; Hydrogen Malonate salts of31a, see FIGs. 5A-5C; Hydrogen Malonate Male-A salts of
31a, see FIGs. 6A-6C; Hydrogen Maleinate Male-B salts of31a, see FIGs. 7A-7C;
Hydrogen Fumarate salts of31a, see FIGs. 8A-8C; Hydrogen-L(+)Tartrate salts of31a, see
FIGs. 9A-9C; D,L-Mandelate salts of31a, see FIGs. 10A-10C; Tosylate salts of31a, see
FIGs. 11A-11C and 12A-12C; Mesylate salts of31a, see FIGs. 13A-13C; Saccharinate salts
of 31a, seeFIGs.l4A.14C.
Example 110: Polymorphic Transformation by Exposure to Humidity
Approximately 10 mg of the solid as its initially obtained polymorphic form
were placed in a 4 mL open vial. In a 20 mL vial, about 5 mL of distilled water were added
and heated to about 50°C, then the vial was capped, and the contents were cooled for about
minutes at ambient temperature. Then the 20 mL vial was uncapped, the smaller vial was
placed inside the bigger vial, the bigger vial was recapped, and the sample in the smaller vial
was exposed and aged in an environment of approximately 80-95% relative humidity at
ambient temperature for 3 days. Polymorphic transformation was confirmed by XRPD and
DSC vs. that for the initially obtained polymorphic form.
The maleinate salt 31d was initially obtained as form Mal-A (31d-l)and was
converted to form Mal-B (31d-2) after exposure to >80% humidity for three days at ambient
temperature as described above.
The tosylate salt 31h was initially obtained as form Tos-A (31h-l) and was
converted to form Tos-B (31h-2) after exposure to >80% humidity for three days at ambient
temperature.
See for a summary of the gram scale preparation of selected salts of 1-
(2,6-bis-methylaminopropylammo-pyrimido[5,4-d]pyrimidinylamino)methyl-
propanol (31).
See FIGs. 3A-14C for XRPD spectra, XRPD peak listings and DSC spectra of
the salts of l-(2,6-bis-methylaminopropylamino-pyrimido[5,4-d]pyrimidmylamino)
methyl-propanol (31).
Analytical Characterization
X-ray powder diffraction patterns were obtained using a Bruker D 8 Advance
X-Ray Diffractometer equipped with a Cu Ka radiation source (X=l.54060 °A) in
locked/coupled mode. A 9-position sample changer and LYNXEYE high speed detector
were used. Samples were placed on zero-background, silicon plate holders. The step was
0.05°. Count times were 1.3 second per step.
DSC data were collected using a TA Instruments Q 1000 DSC equipped with
auto-sampler. Typically, samples (5 mg) were placed in hermetic alodined aluminum
sample pans and scanned from 30 to 300 °C at a rate of 10°C/min under a nitrogen purge of
50 mL/min. Then the pan was cooled to 25°C at a rate of20°C/min.
Example 111: Effect on respiratory rate (RR), tidal volume (VT), and product minute
volume (MV) using an anesthetized rat spirometry screening assay
Anesthetized rats provide a quick method of screening compounds for
respiratory and cardiovascular activity.
Method outline:
Rats were initially anesthetized with 3% isoflurane (inhaled) and femoral
artery and vein cannulas were surgically inserted. Once cannulated, the rats were transitioned
to urethane anesthesia (1.5 g/kg; i.v.) and a tracheal cut-down was performed. After placing
the tracheal cannula, it was connected to a pneumotachometer to record respiratory airflow
from which respiratoiy rate (RR), tidal volume (VT), and their product minute volume (MV,
also termed Va) were derived. After the surgical preparation was complete, animals were
allowed to stabilize for 30 minutes while respiratory rate, tidal volume, minute volume, blood
pressure and heart rate were recorded continuously. Arterial blood gases (ABG) were
obtained from arterial blood collected from the femoral artery. ABG measurements were
taken before and 6 minutes after vehicle and each dose of compound administered.
Compounds being screened were administered via bolus injections through the venous
cannula followed by a saline flush (total time of administration is approximately 30 seconds),
and the animal was monitored for at least 6 minutes for changes in cardiovascular efforts.
Compounds were prepared in formulations identified to ensure optimal solubility. As such,
vehicle controls were matched for the formulation of each compound tested. Dosing of the
compounds being screened was conducted at 0.1 and/or 0.3 mg/kg and/or 3 mg/kg The next
dose was not administered until all cardiovascular and respiratory measures had returned to
baseline levels. The positive control compounds used were N-[4,6-di-(n-propylamino)-
[l,3,5]triazmyl]-N,0-dimethyl-hydroxylamineorN-[2,6-di-(n-propylamino)-
[l,3]pyrimidinyl]-N,0-dimethyl-hydroxylamine (both administered at the end of each
screening experiment (0.3 mg/kg dose) to validate the experiment and also to serve as a
measure with which the compound being screened could be compared.
Data Analysis:
Data were analyzed by collecting cardiovascular and respiratory data in 30
second averages (BINs). Data were plotted 2 minutes before challenge and then 6 minutes
after challenge.
Table 1. Ventilatory activity.
Compound
VE%Inc Peak ratio
VE%Inc
Peak ratio
@ 0.3 mg/kg IV (% 0.3 dose*
@ 3.0 mg/kg IV (% 3.0 dose *
0.55
6a 37
0.29
31 0.22
lOa 93
0.47
114 0.70
0.46
0.53
18a 50
0.38
0.68
22a 102
0.85
24a 100
0.87 121
1.05
26a 39
0.26
0.95
0.87
28a 16
0.12
69 0.58
32a 201
0.69
23 0.14
0.71
0.01
0.20
38a 18
0.14
0.22
79 0.64
158 1.28
42a 76
0.60
1.17
0.95 132
1.02
46a 79
0.34
0.88
0.25
48a 20
0.12
0.45
0.73
1.05
52a 26
0.16
0.96
2 0.02
0.08
60a 15
0.10
0.79
0.25
64a 32
0.17
0.83
0.04
136 0.74
71a 17
0.16
0.78
72a 132 0.94 150 1,07
73a 16 0.11 79 0.53
74a 153 0.77 208 1.05
75a 158 0.79 180 0.90
37 0.22 71 0.42
77 135
0.55 170 0.77
78 173 0.79 180
0.82
79 56 0.30 162
0.89
80 71 0.36 95
0.48
81 50 0.41 72
0.60
82 102 0.70 132
0.90
83 176 0.86 153 0.75
84 169 1.04 184 1.13
85 69 0.62 83 0.74
86 26 0.20 92 0.78
87 39 0.17 129 0.57
90 26
0.16
91 16
0.12
92 49 0.36 148
1.10
94 18 0.13 130
0.91
95 138 0.90
96 70 0.43 96 0.58
97 49 0.26 140 0.75
99 0.13 61 0.32
100 33
0.20 139 0.86
101 20 129
0.08 0.52
103 5 0.03 99
0.52
104 33 0.17 98
0.50
105 14 0.07 120
0.63
107 14 0.11 95 0.74
109 21 0.10 10 0.05
Ill 18 0.15 105 0.90
113 Ill 0.49 190 0.84
115 60
0.33 151 0.83
117 150 162
0.82 0.88
119 10 0.05
151 0.82
121 0 0.00 38
0.20
123 11 0.07 129 0.87
125 38 0.26 84 0.57
127 81 0.48 108 0.64
129 0.01 68 0.48
131 18
0.08 142 0.62
133 35
0.18 Ill 0.58
135 22 0.11 142
0.68
0.10
0.48
0.41 114
0.51
0.32
0.67
142 2
0.01
0.45
0.51
0.94
0.08
0.50
0.22
0.75
0.06
0.76
31 0.20
0.93
0.10
0.30
0.00
0.00
0.44
0.04
0.52
0.35
0.90
0.05
0.30
156 16
0.11
0.68
0.44
0.78
159 61
0.36
0.95
0.88
1.01
88 0.49
0.80
0.61
0.93
88 0.84
0.87
0.26
0.62
169 113
0.88
1.10
0.08 175
0.84
0.03
0.90
174 72
0.47
0.75
75 0.40
0.71
Ratio compared to N-(2,6-Bis-propylamino-pyrimidinyl)-O^N-dimethyl-hydroxylamine
hydrogen sulfate
Example 112: Effects on the apnea hypopnea index and ventilation during sleep in rats
receiving chronic morphine
Central sleep apnea (CSA) and hypopnea are especially prevalent in people on
chronic opioid therapy. Accordingly, a novel rodent model of chronic opioid-induced sleep
disordered breathing that mimics many features of the condition in people was developed.
Morphine was administered chronically to rats in their drinking water at a dose
and duration that elicited morphine tolerance. Morphine sulfate was added to the drinking
water of individually housed rats beginning at 0.1 mg/ml morphine and increasing the
concentration in increments so that a final concentration of 0.6 mg/ml was achieved within 2
weeks of beginning morphine exposure. During the first three weeks after starting moiphine
administration, rats were acclimated to whole body plethysmography chambers.
Respiratory rate (/R), tidal volume (VT), minute volume (VE), and CSA and
hypopnea frequency and length (;'. e., duration of each apnea) were measured continuously
while animals were unrestrained in whole-body plethysmography chambers. Animals
breathed room air for the duration of the study, except where indicated for the hyperoxia
validation study. A bias chamber air flow of at least 2 L/min was generated by connecting
the chambers to a constant flow vacuum source. A period of at least 1 hour was permitted for
animals to acclimate to the chamber before data collection began. In general, most rats
would enter into a normal sleep-wake cycle within that time frame. On occasion, more time
was needed until the rat was restful.
A respiratory waveform was generated from the expansion and contraction of
the air that was exchanged between the animal and the chamber. The cyclic change in air
volume during the respiratory cycle elicited oscillating airflow across a calibrated
pneumotachometer in the wall of the plethysmograph chamber. Each pneumotachometer was
calibrated (5.0 mL volume delivered in triplicate) on each study day prior to placing the
animals in the chambers. The airflow signal was amplified and continuously recorded using
PowerLab and LabChart 7.0.
Respiratory pattern (tidal volume, respiratory rate) and minute volume (the
product of tidal volume and respiratory rate), and the number and length of central sleep
apneas and number ofhypopneas were measured using whole-body plethysmography before
and after administration of either vehicle or test compound (10 mg/kg PO) in a cross over
design. The coefficient of variation for respiratory period, an index ofventilatory instability,
was also calculated. Epochs of time were classified as either "sleep" or "awake" based on the
presence or absence of movement artifact in the air flow waveform recorded from a
pneumotachometer attached to the wall of the plethysmograph chamber. The total number of
CSA and hypopneas were summed per hour to provide an apnea hypopnea index (AHI).
Methods:
All surgical and plethysmographic studies were approved by the IACUC
committee ofGalleon Pharmaceuticals. The study used rats implanted with dual biopotential
electrodes that permitted continuous and simultaneous telemetric recordings of
electroencephalogram (EEG) and electromyogram (EMG) waveforms. Three treatment
conditions were assessed for their effects on sleep quantity, architecture, and quality: baseline
(drug-naive), (31a) (10 mg/kg PO) and vehicle (equal volume PO). Baseline and (31a)
treatment study days were randomized. However, vehicle alone was assessed after each rat
had completed drug naive and compound (31a) evaluations.
EEG, EM^G and temperature implantation surgeries:
Standard aseptic technique was used for all surgical procedures. Adult male
Sprague Dawley rats were premedicated with dexmedetomidine (0.1 mg/kg subcutaneously)
for sedation and analgesia, carprofen (5 mg/kg subcutaneously) for analgesia, and ceftriaxone
(33 mg/kg subcutaneously or intravenously) as a prophylactic antibiotic. Anesthesia was
induced and maintained with isoflurane in oxygen. The body of the telemetry implant was
sutured to the parietal peritoneum via a midline laparotomy. The 4 electrode leads (each pair
used as one biopotential) exited the abdomen via the midline incision and were tunneled
subcutaneously to the dorsum of the neck. For EEG lead placement, the electrodes were
attached to two screws that penetrated the thickness of the cranium (coordinates first
electrode: at ~5 mm caudal to the bregma and ~5 mm to the left of the midline; second
electrode: ~5 mm caudal to the bregma and ~2 mm to the right of the midline) and anchored
with dental cement. For EMG lead placement, the electrodes were secured to neck muscles
with nylon suture. Surgical wounds were closed using standard techniques. Buprenorphine
(0.05 mg/kg subcutaneously or intravenously) was administered at the end of surgery and
before recovery from anesthesia. Atipamezole (0.4 mg/kg subcutaneously or intravenously)
was administered at the end of surgery to reverse the effects ofdexmedetomidine.
Antibiotics and analgesics were continued for 3 days post-surgery, as necessary. At least 1
week (7-10 days) was permitted post-surgery before animals were used in further studies.
EEC, EMG and temperature telemetry data collection:
Rats with implanted telemeters were allowed to remain in their home cages
during data collection. Signals from the telemeters were wirelessly transmitted to receivers
that were placed directly under the home cages. EEG and EMG waveforms were recorded
between 8 am and 3 pm each study day. Only data collected between the hours of 10:00 am
to 3:00 pm was used in the final analysis. For each rat, the three telemetiy signals (EEG,
EMG, and temperature) were routed from the receiver to the PowerLab and recorded using
LabChart. EEG/EMG signal conditioning is described in the Data Analysis section.
Data Analysis and Statistical Methods:
Sleep Scoring:
EEG, EMG, and temperature signals were calibrated within LabChart software
according to the telemeter manufacturer's recommendations. The sampling frequency for
each signal was 1 K/s. The EEG signal was digitally band-pass filtered between 0.3 to 30 Hz.
The EMG signal was filtered using a high pass filter of 25 Hz, rectified, and moving averaged
(100 ms). All sleep scoring analysis was performed using Sleep Sign (Kissei Comtec). This
software was developed and validated, and its ability to identify sleep states in rats is based
on previous studies (www dot sleepsign dot com/bibliography dot html).
The principal aspects of these analyses were to quantify the magnitude of the
EMG signal (i.e., the animals activity level) and the relative densities ofEEG delta waves
(0.5 to 4 Hz; predominant in NREM sleep) and EEG theta waves (6 to 10 Hz; predominant in
REM sleep) during each 4-second epoch. The relative wave densities allowed one to
template each sleep/awake state (NREM, REM & AWAKE) in the Sleep Sign analysis
software as AWAKE (relatively high frequency and low amplitude EEG, with high EMG
activity), NREM (low frequency and high amplitude EEG, with low EMG activity), and
REM (high frequency and low amplitude EEG, with generally lower EMG activity than
NREM sleep). Once templated the software automatically assigned a sleep/awake state to
each 4 second epoch based on a minimum percentage of time the epoch spent in each state.
After completing the automated analysis, each 4 second epoch for each file used in the final
data analysis was visually assessed by the investigator to ensure accuracy of epoch scoring.
Any epochs that were scored incorrectly by Sleep Sign were manually corrected by the same
investigator. Hypnograms were then exported to Excel to permit analysis of relative time in
NREM/REM/AWAKE per hour, awakening index, number of awake bouts/hour sleep,
arousals/hour sleep, number ofNREM/REM bouts/hr, number ofNREM/REM: epochs/hr,
NREM/REM bout length, and NREM/REM epoch length.
Statistical Analysis
A sleep bout was defined as 3 or more continuous epochs (4-s periods) ofNREM
or REM sleep. Wake bouts were defined as 4 or more epochs ofwakefulness preceded by
one or more bouts of sleep. An arousal was defined as 3 or less epochs of wakefulness
preceded by at least 3 epochs of sleep. For each animal, the sleep quantity, architecture and
quality parameters were averaged between the periods of 10:00 am and 3:00 pm and
compared between vehicle control and test compound treatment groups using two way
ANOVA and Dunnett's post hoc tests (comparison to the drug naive state).
Sleep architecture was assessed by quantifying: the percent time spent in awake,
NREM sleep, and REM sleep, the number of awake bouts per hr sleep, the number of arousal
per hr sleep, awakening index (sum of awake bouts and arousals per hour), number ofNREM
bouts per hr, number ofNREM epochs per hr, NREM bout length, NREM epoch length,
number ofREM bouts per hr, number ofREM epochs per hr, REM bout length, and REM
epoch length.
Sleep quality was evaluated by measuring the EEG spectral power density
(|j.V2/0.25Hz) and relative power density (across the 0.5 - 30 Hz spectrum) during NREM
and REM sleep. See Figure 24..
Results:
The effects of vehicle and (3 la) (10 mg/kg PO) on indices of sleep architecture.
For each animal, these parameters were averaged between the periods of 10:00 am - 3:00 pm
and compared between vehicle and (31a) treatment groups using Student-Neuman-Keuls post
hoc tests. No significant differences in sleep architecture were detected comparing baseline
to the (31a) groups (Fig. 24).
Oral administration of l-(2,6-Bis-methylaminopropylamino-pyrimido[5,4-
d]pyrimidinyl amino)methyl-propanol hydrochloride salt (31a) at 10 mg/kg PO was
not associated with any statistically significant effects on sleep quantity, architecture, or
quality. A vehicle effect on REM sleep architecture was likely related to non-randomization
of treatment study days and subsequent anticipation of oral gavage as an adverse stimulus.
Example 113: Effects on obstructive sleep apnea
Two rodent models of obstructive apnea were used: one that modeled
spontaneous obstructions (spontaneous obstmctive apnea model) which become
progressively worse over time, and another (evoked obstructive apnea model) where the
investigator retained control over the variables that define OSA severity, such as apnea
frequency (/ OA) and apnea duration (OA f).
The majority of studies were conducted using the spontaneous obstruct! ve
apnea model, where rats were positioned in dorsal recumbency (supine), and permitted to
breathe spontaneously on room air. Air flow was measured continuously by whole-body
plethysmography. Most anesthetized and supine rats exhibit a eupneic breathing pattern, and
to elicit spontaneous recurring obstructions, the neck of each rat was ventroflexed and
maintained at 25° to 30° above the horizontal plane. OA were defined as periods of no air
flow for more than 2 respiratory cycles accompanied by efforts to breathe (e.g., increased
transthoracic esophageal inspiratory pressure). After neck flexion, eupnea became
increasingly interrupted by clusters of upper airway obstructions (/ OA 30 ± 3 hr-l (mean ±
SEM), range: 13 to 94 hi-'1; OA /11 ±3 s, range: 6 to 15 s). OA severity was further
quantified by the peak change in hemoglobin oxygen saturation during an obstruction
(ASp02: -20 ± 1%, range: -11 to -31%). Clustered OAs were often separated by long
periods of eupneic breathing, which presumably returned when activation of a relevant
afferent/effector reflex (e.g., chemoreceptor driven increased motor drive to the genioglossus
muscle) reached a threshold necessary to reestablish a patent upper airway.
Methods:
All animal experiments were performed according to protocols approved by
the Institutional Animal Care and Use Committee (IACUC) at Galleon Pharmaceuticals, Inc.
All experimental procedures were performed under general anesthesia. All experiments were
non-survival procedures and animals were euthanized at the conclusion of the experiment
prior to the animal recovering from anesthesia. Two rodent models ofobstmctive apnea were
used, one that modeled spontaneous obstructions that become progressively worse over time
(Spontaneous Obstructive Apnea Model), and another where the investigator retained control
over the parameters that defined OSA severity, such as / OA, and OA /, and by controlling
these directly also controlling of the magnitude of oxy-hemoglobin desaturation (Evoked
Obstmctive Apnea Model).
Anesthesia common to all spontaneous obstructive apnea models:
Rats were initially anesthetized in a rodent anesthesia induction chamber using
3% (dial setting) isoflurane in 97% oxygen (02) for surgical instrumentation. When rats had
become recumbent they were removed from the chamber and placed in dorsal recumbency
(supine) on a heating pad. Anesthesia was maintained with 2% isoflurane in 98% oxygen and
rats were permitted to breathe spontaneously on room air. After instrumentation, isoflurane
was slowly discontinued and urethane (1.5 to 1.8 g/kg, IV) administered to maintain
anesthesia without interruption. Supplemental oxygen was discontinued at this time.
Instrnmentation common to all models:
The femoral artery was cannulated to permit continuous recording of arterial
blood pressure and intermittent sampling of blood for pH and blood gas analyses, and single
time point quantification of test article plasma concentrations. The femoral vein was
cannulated to permit test compound administration and fluid support. The arterial cannula
was connected to a heparinized saline filled pressure transducer. The arterial pressure
waveforms were sampled at 2K/second and band-pass filtered between 0 - 1000 Hz. The
cyclic measurement function in LabChart was used to calculate heart rate and the average of
the weighted ratio 1/3 max + 2/3 min was used to calculate mean arterial blood pressure
(MAP).
Spontaneous obstructive apnea model:
After femoral vessel cannulation, rats were positioned in dorsal recumbency
within a head-out plethysmography chamber to permit continuous recording of respiratory air
flow waveforms. The arterial and venous lines were exteriorized by threading each line
through a port in the chamber. The cervical segment of the esophagus was exposed by
surgical cut down and gently dissociated away the surrounding tissue. A small incision was
made into the esophagus to allow the insertion of saline filled PE-205 tubing and attached to
a saline-filled pressure transducer. The tubing was advanced into the thoracic segment of the
esophagus to a level that detected maximal inspiratory pressure fluctuations without affecting
the respiratory pattern. Bipolar EMG electrodes were inserted into the genioglossus muscle
immediately cranial to the hyoid bone and a ground lead was attached to nearby skin. EMGoo
activity was digitized and sampled at 4 K/s, amplified, filtered (Band-pass: high cut-off
frequency: 2500 Hz Low cut-off frequency 120 Hz), and rectified and moving time averaged
(60 ms). An intravenous infusion of 50% Hetastarch/50% saline was administered at a rate of
5 mL/kg/min as fluid support.
One hour elapsed to allow physiological stabilization before starting the period
of baseline data recording. Most anesthetized and supine rats exhibit a eupneic breathing
pattern, so to elicit spontaneous recurring OA, the neck of each rat was slightly ventroflexed
and maintained between 25° to 30° above the horizontal plane at the start of the stabilization
period. OA were defined as periods of no air flow for more than 2 respiratory cycles
accompanied by evidence that inspiratory efforts were occurring during the apnea (e.g.
increased trans-esophageal inspiratory pressure (PTP) and EM[GGG inspiratory burst
amplitude).
Study parameters to quantify OA severity:
OA severity was quantified by the number of OA per hour (/ OA hr-l), mean
duration of each apnea (OA /, seconds), and mean decrease in hemoglobin oxygen saturation
(ASp02, %) associated with an apnea. The response to an obstruction was quantified by
measuring the peak change in the moving time averaged (100 ms) EMGGG burst amplitude
during an apnea (nV.s).
Study parameters to assess physiological state:
Study parameters that were measured to evaluate physiological state during
and between apneic periods, but not quantitate OA severity, were arterial blood pressure
(mmHg), respiratory air flow (L/s), FTP (mmHg), percutaneous hemoglobin oxygen
saturation (Pulse oximetry, Sp02» %)• These parameters were recorded continuously as
waveforms throughout each experiment. The study variables that were derived from these
waveforms and also considered "continuously measured", were MAP, /H, /1R, VT, VE, and
APTP during each inspiration. Intermittently measured study parameters were rectal
temperature (°C), and arterial pH, PaC02 (nunHg), PaOz (rnmHg), Sp02 (%) derived from
arterial blood gas analyses.
Model validation with continuous positive airway pressure (CPAP):
Continuous positive airway pressure (CPAP) is a first line treatment for
patients with OSA and was administered to a subset of rats as a positive control. Rats were
fitted with a custom made mask positioned to cover the nose without covering the mouth.
Thus, a circuit for positive pressure flow was created with forced air entering the upper
airway via the nares and exiting through the mouth. Constant positive pressure was applied
throughout the respiratory cycle producing a steady state bias flow from which each rat
ventilated using normal inspiratory pressures. The objectives for the first experiment were to
validate the model as a tool with sufficient sensitivity to detect an incremental decrease in /
OA while incrementally increasing the level of CPAP support. The level of CPAP was
controlled using a custom made valve with a resolution of ± 0.1 cmHhO. CPAP pressure was
slowly increased (0, 0.5, 1.0, 1.5, 2.0, and 4.0 cmHhO). Rats was allowed to remain at each
pressure for 30 minutes while the study parameters were recorded. In a second study, the
objective was to determine if the positive effects ofCPAP on OA severity were indeed
temporary, as described for humans. The study parameters were recorded during baseline
conditions, 30 minutes ofCPAP support at 4 cm HhO, then a final 30 minutes offCPAP
support (FIGs. 18-25).
The disclosures of each and every patent, patent application, and publication
cited herein are hereby incorporated herein by reference in their entirety. While this
invention has been disclosed with reference to specific embodiments, it is apparent that other
embodiments and variations of this invention may be devised by others skilled in the art
without departing from the tme spirit and scope of the invention. The appended claims are
intended to be construed to include all such embodiments and equivalent variations.
Claims (27)
1. A compound that is 1-(2,6-Bis-methylaminopropylamino- pyrimido[5,4-d]pyrimidinyl amino)methyl-propanol (31) or at least one crystalline salt selected from the group consisting of: (i) Crystalline hydrochloride salt (31a), with a XRPD spectrum as per ; XRPD peaks as per ; and/or DSC spectrum as per ; (ii) Crystalline bis-hydrochloride salt (31b), with a XRPD spectrum as per ; XRPD peaks as per ; and/or DSC spectrum as per ; (iii) Crystalline hydrogen malonate salt (31c), with a XRPD spectrum as per ; XRPD peaks as per ; and/or DSC spectrum as per ; (iv) Crystalline hydrogen maleinate salt Form Male-A (31d-1), with a XRPD spectrum as per ; XRPD peaks as per ; and/or DSC spectrum as per ; (v) Crystalline hydrogen maleinate salt Form Male-B (31d-2), with a XRPD spectrum as per ; XRPD peaks as per ; and/or DSC spectrum as per ; (vi) Crystalline hydrogen fumarate salt (31e), with a XRPD spectrum as per ; XRPD peaks as per ; and/or DSC spectrum as per ; (vii) Crystalline hydrogen L(+)tartrate salt (31f), with a XRPD spectrum as per ; XRPD peaks as per ; DSC spectrum as per ; (viii) Crystalline D,L-mandelate salt (31g), with a XRPD spectrum as per A; XRPD peaks as per B; and/or DSC spectrum as per C; (ix) Crystalline tosylate salt form Tos-A (31h-1), with a XRPD spectrum as per A; XRPD peaks as per B; and/or DSC spectrum as per C; (x) Crystalline tosylate salt form Tos-B (31h-2), with a XRPD spectrum as per A; XRPD peaks as per B; and/or DSC spectrum as per C; (xi) Crystalline mesylate salt (31i), with a XRPD spectrum as per A; XRPD peaks as per B; and/or DSC spectrum as per C; (xii) Crystalline saccharinate salt (31j), with a XRPD spectrum as per A; XRPD peaks as per B; and/or DSC spectrum as per C; and any mixtures thereof.
2. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier or excipient.
3. The composition of claim 2, further comprising at least one additional agent selected from the group consisting of doxapram, enantiomers of doxapram, acetazolamide, almitrine, theophylline, caffeine, methylprogesterone, sedatives that increase arousal threshold in sleep disordered breathing patients, benzodiazepine receptor agonists, orexin antagonists, tricyclic antidepressants, serotonergic modulators, adenosine and adenosine receptor and nucleoside transporter modulators, cannabinoids, orexins, melatonin agonists, ampakines, sodium oxybate, modafinil, and armodafinil.
4. The composition of claim 3, wherein the compound and the additional agent are physically mixed or physically separated in the composition.
5. The composition of claim 2, further comprising at least one additional agent that causes changes in breathing control.
6. The composition in claim 5, wherein the additional agent is at least one selected from the group consisting of opioid narcotics, benzodiazepines, sedatives, sleeping aids, hypnotics, propofol, and any combinations thereof.
7. The composition of claim 2, wherein the compound is coated onto a base particle so as to form a core.
8. The composition of claim 7, wherein the base particle is not enterically coated and the composition is contained in a pharmaceutically acceptable capsule that is enterically coated.
9. The composition of claim 7, wherein the core is coated with an enteric coating, thereby forming an enterically coated bead.
10. The composition of claim 9, wherein the enterically coated bead is contained in a pharmaceutically acceptable capsule.
11. The composition of claim 10, wherein the capsule contains beads coated with a plurality of enteric coatings, so that the capsule provides delivery of the compound to different regions of the intestine of the subject.
12. The composition of claim 10, wherein the contents of the capsule are dissolved or suspended in a pharmaceutically acceptable liquid as to provide a liquid-filled capsule.
13. The composition of claim 12, wherein the capsule is enterically coated but the liquid formulation contained within does not comprise an enteric coating.
14. Use of at least one compound of claim 1 or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof, in the manufacture of a medicament for inhibiting or treating a breathing control disorder or disease in a subject, or for inhibiting destabilization or stabilizing breathing rhythm associated with a breathing control disorder or disease, in a subject in need thereof.
15. Use of claim 14, wherein the breathing control disorder or disease is at least one selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia, chronic obstructive pulmonary disease (COPD), sudden infant death syndrome (SIDS), congenital central hypoventilation syndrome, Alzheimer’s disease, Parkinson’s disease, stroke, Duchenne muscular dystrophy, and brain and spinal cord traumatic injury.
16. Use of claim 15, wherein the respiratory depression is caused by an anesthetic, a sedative, a sleeping aid, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic.
17. Use of claim 14, wherein the medicament is formulated for administration with at least one agent useful for treating the breathing disorder or disease.
18. Use of claim 17, wherein the agent is at least one selected from the group consisting of doxapram, acetazolamide, almitrine, theophylline, caffeine, methylprogesterone, sedatives that increase arousal threshold in sleep disordered breathing patients, benzodiazepine receptor agonists, orexin antagonists, tricyclic antidepressants, serotonergic modulators, adenosine and adenosine receptor and nucleoside transporter modulators, cannabinoids, orexins, melatonin agonists, ampakines, sodium oxybate, modafinil, and armodafinil.
19. Use of claim 17, wherein the medicament and the agent are formulated for separate administration to the subject.
20. Use of claim 17, wherein the medicament and the agent are formulated for co-administration to the subject, as a mixture or separately.
21. Use of claim 14, wherein the medicament is formulated for administration with at least one additional therapeutic agent that changes normal breathing control in the subject.
22. Use of claim 21, wherein that at least one additional agent is selected from the group consisting of opioid narcotics, benzodiazepines, sedatives, sleeping aids, hypnotics, propofol, and any combinations thereof.
23. Use of claim 14, wherein the medicament is formulated for administration in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject.
24. Use of claim 14, wherein the subject is a mammal or bird.
25. Use of claim 24, wherein the mammal is a human.
26. Use of claim 14, wherein the medicament is formulated for administration to the subject by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal and intravenous routes.
27. Use of claim 14, wherein the salt comprises an acid addition salt, and the acid is at least one selected from the group consisting of sulfuric, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, phosphoric, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, pamoic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, sulfanilic, stearic, alginic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, β-hydroxybutyric, salicylic, galactaric and galacturonic, and any combinations thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562186468P | 2015-06-30 | 2015-06-30 | |
US62/186,468 | 2015-06-30 | ||
US201662328277P | 2016-04-27 | 2016-04-27 | |
US62/328,277 | 2016-04-27 | ||
PCT/US2016/039032 WO2017003822A1 (en) | 2015-06-30 | 2016-06-23 | Novel breathing control modulating compounds, and methods of making and using same |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ738082A NZ738082A (en) | 2020-10-30 |
NZ738082B2 true NZ738082B2 (en) | 2021-02-02 |
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