Classifications

• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to a method of inhibiting adenosine kinase by administering 5,7-disubstirated-4-aminopyrido[2,3-d]pyri ⁇ dine compounds, to pharmaceutical compositions containing such compounds, as well as to certain 5,7- disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.
• Adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) is a ubiquitous enzyme which catalyzes the phosphorylation of adenosine to AMP, using ATP, preferentially, as the phosphate source.
• Adenosine kinase has broad tissue and species distribution, and has been isolated from yeast, a variety of mammalian sources and certain microorganisms. It has been found to be present in virtually every human tissue assayed including kidney, liver, brain, spleen, placenta and pancreas.
• Adenosine kinase is a key enzyme in the control of the cellular concentrations of adenosine.
• Adenosine is a purine nucleoside that is an intermediate in the pathways of purine nucleotide degradation and salvage. Adenosine also has many important physiologic effects, many of which are mediated through the activation of specific ectocellular receptors, termed Pl receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones,
• adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev. 1992, : 346-360), functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci. 1986, 7: 128- 130) and may have a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445).
• Adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease.
• schizophrenia anxiety, depression and Parkinson's disease.
• Parkinson's disease adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease.
• Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther. 1987, 243: 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13).
• Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, impairment of atrioventricular conduction and endogenous cardioprotection in myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, pp. 289-334).
• the widespread actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes.
• Adenosine via its Al receptor activation on adipocytes, plays a role in diabetes by inhibiting lipolysis [Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551.
• Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions are therefore highly localized.
• adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby minimizing systemic toxicities.
• Pharmacologic compounds directed towards adenosine kinase inhibition provide potentially effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine.
• Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other ' thrombotic and embolic conditions, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal disfunctions such as abnormal gastrointestinal motility.
• ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other ' thrombotic and embolic conditions
• neurological disorders such
• Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside.
• These purine nucleoside analogs represent an important group of antimetabolites which possess cytotoxic, anticancer and antiviral properties. They serve as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form.
• adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogs ⁇ e.g. Bennett, et al., Mol. Pharmacol., 1966, 2: 432-443; Caldwell, et al, Can. J. Biochem., 1967, 45: 735-744; Suttle, et al., Europ. J. Cancer, 1981, 17: 43-51).
• Decreased cellular levels of adenosine kinase have also been associated with resistance to the toxic effects of 2'-deoxyadenosine (Hershfield and Kredich, Proc. Natl. Acad. Sci.
• dATP deoxyadenosine triphosphate
• Chem., 31B: 719-720 (1992) disclose 4-amino-5-(4-chlorophenyl)-7-(4- nitrophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-methoxyphenyl)-7-(4- nitiOphenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity.
• Prakash et al, Pharmazie, 48: 221-222 (1993)) disclose 4-amino-5-phenyl-7-(4- aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3- djpyrimidine, 4-ammo-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, and 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine compounds having antifungal activity.
• the present invention provides for 5,7-disubstituted-4-aminopyrido[2,3- djpyrimidine compounds having utility as adenosine kinase inhibitors.
• the present invention provides a method of inhibiting adenosine kinase by administering a compound of formula (I)
• Ri and R ⁇ are independently selected from H, loweralkyl, Ci-CgalkoxyCi- C ⁇ alkyl, arylC ⁇ -C6alkyl, -C(O)C ⁇ -C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
• R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
• R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained.
• the method of inhibiting adenosine kinase comprises exposing an adenosine kinase to an effective inhibiting amount of a compound of Formula I of the present invention.
• the adenosine kinase is located in vivo, the compound is administered to the organism.
• the present invention provides a method of treating ischemia, neurological disorders, nociperception , inflammation, immunosuppression, gastrointestinal disfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising adiTiinistering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.
• the present invention provides a method of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising adrninistering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.
• the present invention also contemplates the use of pharmaceutically acceptable salts and amides of compounds having Formula I.
• the present invention provides a compound of formula (I)
• Ri and R ⁇ are independently selected from H, loweralkyl, C ⁇ -C6alkoxyCi- C ⁇ alkyl, arylCj-C ⁇ alkyl, -C(O)C ⁇ -C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
• R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
• R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with the proviso that the compound may not be selected from the group consisting of:
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I above in combination with a pharmaceutically acceptable carrier.
• the present invention provides a process for the preparation of adenosine kinase inhibiting compounds having the formula
• the present invention relates to 5,7-disubstituted-4-ammopyrido[2,3-d]pyrimidine compounds that are useful in inhibiting adenosine kinase, to pharmaceutical compositions containing such compounds, to a method of using such compounds for inhibiting adenosine kinase, and to novel 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.
• the present invention provides 5,7-disubstituted-4-aminopyrido[2,3- d]pyrimidine compounds that are adenosine kinase inhibitors.
• An adenosine kinase inhibitor of the present invention is a compound of the Formula I, shown above.
• the present invention relates to a method of inhibiting adenosine kinase comprising administering a compound of formula I 98/46605
• Ri and R2 are independently selected from H, loweralkyl, arylC ⁇ -C6alkyl, - C(O)C ⁇ -C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
• R3 and R ⁇ are independently selected from the group consisting of:
• C3-C8cycloalkyl heteroarylCo-C ⁇ alkyl or substituted heteroarylCo-C ⁇ alkyl, optionally substituted cycloalkyl, arylCo-C ⁇ alkyl or substituted arylC()-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6 ⁇ alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2 ⁇ , cyanoCi-C ⁇ alkyl, heteroarylC()-C6alkyl, heterocyclicCo-C alkyl, Ci-Cgalkyloxy,
• C6alkylacryl R 5 R 6 N(CO)NR 5 , N-formyl(heterocyclic), NO2, NR5R6C ⁇ - C ⁇ alkyl, (R 5 O)(R 6 O)-P(O)- C()-C6alkyl, wherein R ⁇ and R ⁇ are independently selected from H, C ⁇ -C6alkyl, HC(O), C ⁇ -C6alkyloxyC ⁇ -C6alkyl, C ⁇ -C6alkyloxy, C ⁇ - C6alkylC(O), CF3C(O), phthalimidoCi-
• an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R 4 is aryl or heteroaryl and substituted versions thereof.
• an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R 4 is aryl or heteroaryl and substituted versions thereof and R 3 is loweralkyl, aryl, arylalkyl or heteroaryl and substituted versions thereof wherein the substituents are as identified above.
• an adenosine kinase inhibitor of the present invention is a compound of Formula (I) above, wherein R 4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino)- 5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)-5-pyrimidinyl; 2-(l-mo holinyl)-5-pyrimidinyl; 2-(l-pyrrolidinyl)-5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2- oxobenzoxazolin-6-yl; 2-pyridyl; 3-(dimethylamino)phenyl; 3-
• an adenosine kinase inhibitor of the present invention is a compound of Formula (I) above, wherein R 3 is selected from the group consisting of: (thiophene-2-yl)methyl; (thiophene-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophene-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3- bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxypheny
• Exemplary and preferred adenosine kinase inhibitor compounds of the invention utilized in the method recited herein include the compounds listed below wherein Rl and R ⁇ in a compound of formula II are selected from H, the groups identified at the 5-position are included within R3 and the groups identified at the 7-position are included within R ⁇ , R5- R8 are as described in the specific compound: 4-arnino-5-(4-dime ylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrirnidine;
• 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3 pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N- oxide)pyrido[2,3-d]pyrimidine;
• the partially hydrogenated or fully hydrogenated versions wherein the 5,6 and/or the 7,8 double bonds are hydrogenated of the compounds identified above are also included within the scope of the invention.
• the preferred substitution pattern on the R3 group when it is selected from, for example, a substituted aryl group is having at least one substituent at the meta position.
• the preferred substitution pattern on the R ⁇ position when it is selected from, for example, a substituted heteroaryl group is having at least one substituent at the para position.
• the present invention is therefore directed to compounds of formula I or II with the variables recited as above wherein, in the case of R selected from substituted aryl or heteroaryl groups and R ⁇ selected from substituted aryl or heteroaryl groups, the substiuents on the R group are meta and the substituents on the R ⁇ group are para.
• the present invention encompasses pro-drugs of the above compounds which may be active in their own right or are metabolized or converted to the non pro-drug form as exemplified above.
• the invention is not limited to synthetic versions of the claimed compounds and includes the compounds-per-se or pro-drugs or metabolites thereof regardless of how or where they are manufactured or made.
• acyl refers to a moiety attached by a carbonyl linkage, as for example, loweralkyl-carbonyl or aryl-carbonyl, wherein loweralkyl and aryl are as defined herein.
• acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N- Bocglycylimidazoyl, N-phthalimidylglycyl and the like or others as specified herein.
• aryl or “substituted aryl” as used herein, refers to a carbocyclic aromatic radical, including, for example, phenyl and 1- or 2-naphthyl, which may be unsubstituted or substituted respectively by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl- N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups.
• aryl refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, mo ⁇ holinyl, phenyl-loweralkoxy, phenyl-loweralkenyl or cycloalkyl-loweralkyl group.
• aryl radicals include, but are not limited to, 3- bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-propyl)phenyl, 3,4- dimethoxyphenyl, 3-trifluromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-methyl-N- methoxyl)ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4- methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4- methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl, 3-methylsulfonylphenyl, 3- carboxamidopropylphenyl.
• arylalkyl refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl.
• aryloxy refers to a aryl radical which is appended to the molecule via an ether linkage ⁇ i.e., through an oxygen atom), as for example phenoxy, naphthyloxy, 4- chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxypehenoxy, and the like.
• cycloalkyl refers to a cyclic saturated hydrocarbon radical having from 3 to 7 ring atoms.
• examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-C8cycloalkyl.
• cycloalkyl-loweralkyl refers to a loweralkyl radical as defined below substituted with a cycloalkyl group as defined above by replacement of one hydrogen atom.
• examples of cycloalkyl-loweralkyl include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like.
• heteroaryl or “substituted heteroaryl” refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen, oxygen or sulfur; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
• a heteroaryl group may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylarnino), N-loweralkyl-N- loweralkoxyamino, trifluoromethyl or methoxymethyl groups.
• heteroaryl refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, mo ⁇ holinyl, phenyl-loweralkoxy. phenyl-loweralkenyl or cycloalkyl-loweralkyl group.
• a heteroaryl group may be substituted by replacement of any two adjacent hydrogen atoms with a grouping of atoms to form a fused benzene ring, e.g., benz derivatives such as indole, benzoxazole and the like.
• heteroaryl examples include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, 5- methylthiophene-2-yl, 5-nitrothiophene-2-yl, 5-methylfuranyl, benzofuranyl, benzothiophenyl, and the like and those additionally described herein.
• heterocyclic refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen or oxygen; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring carbon atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino (loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amin
• heterocyclic examples include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine, aziridine and azetidine or those additionally described herein.
• heterocyclic-loweralkyl refers to a loweralkyl radical as defined below substituted with a heterocyclic-group as defined above by replacement of one hydrogen atom.
• examples of cycloalkyl-loweralkyl include pyrrolidinylmethyl, piperidinylethyl, and the like.
• loweralkyl refers to saturated, straight- or branched- chain hydrocarbon radicals containing from one to six carbon atoms including, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I. cyano, carboxamido, hydroxy, loweralkoxy, amino, loweralkylamino, iminoloweralkylamino,di(loweralkylamino) or N-loweralkyl-N- loweralkoxyamino groups.
• loweralkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, ⁇ -butyl, tert-butyl. neopentyl, n-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyi, and the like.
• the group "C ⁇ -C6alkyl” is described and has a similar meaning as above for loweralkyl but is more specifically recited.
• the term "Co-C6alkyl” indicates the carbon atoms which may be present in the alkyl chain including zero. These terms are also provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, “arylalkyl” or “heteroarylalkyl”.
• loweralkenyl refers to mono-unsaturated straight- or branched-chain hydrocarbon radicals containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, -butenyl, n-pentenyl, and n-hexenyl. These variables are also recited as, for example, C2-C6alkenyl.
• loweralkoxy refers to a loweralkyl radical which is appended to the molecule via an ether linkage ⁇ i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. This term is also described as Ci-C6alkyloxy.
• loweralkynyl refers to straight- or branched-chain hydrocarbon radicals possessing a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n-butynyl, n-pentynyl, and n- hexynyl. This term is also described as C2-C6alkynyl.
• compositions which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.
• the present invention includes one or more compounds, as set forth above, formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
• diluents for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
• a compound of the present invention can exist in a variety of forms including pharmaceutically-acceptable salts, amides and the like.
• Compositions may be prepared that will deliver the correct amount of a compound or compounds of the invention.
• the following dosages are thought to provide the optimal therapy: iv infusions: 0.1- 250 nmol/kg/minute, preferably from 1-50 nmol/kg/minute; oral: 0.01-250 ⁇ Mol/kg/day, preferably from about 0.1-50 ⁇ Mol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day.
• the preferred route of administration is intravenous; the preferred method of treating chronic disorders is orally by means of a tablet or sustained release formulation.
• “Pharmaceutically-acceptable amide” refers to the pharmaceutically-acceptable, nontoxic amides of the compounds of the present invention which include amides formed with suitable organic acids or with amino acids, including short peptides consisting of from l-to-6 amino acids joined by amide linkages which may be branched or linear, wherein the amino acids are selected independently from naturally-occurring amino acids, such as for example, glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and the like.
• “Pharmaceutically-acceptable salts” refers to the pharmaceutically-acceptable, nontoxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below.
• the compounds of the present invention can be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids.
• These salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulf onate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate
• Appropriate cationic salts are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
• base such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium
• an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine,
• the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
• loweralkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
• dialkyl sulfates long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides
• arylalkyl halides like benzy
• compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
• a coating such as lecithin
• surfactants for example, by the use of surfactants.
• compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged abso ⁇ tion of the injectable pharmaceutical form may be brought about by the use of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
• the compounds may be inco ⁇ orated into slow-release or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
• the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) abso ⁇ tion accelerators, as for example, quaternary ammonium compounds; (g) fillers
• compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
• Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes.
• the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
• inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, eth
• these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
• Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
• suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
• compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
• suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
• Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches.
• Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require admixture with special formulating agents or with special packaging materials to assure proper dosage delivery. In addition, compounds which are very rapidly absorbed through the skin may require formulation with abso ⁇ tion-retarding agents or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
• the present compounds may also be administered in the form of liposomes.
• liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
• the present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.
• the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.
• the compounds of the present invention may be synthesized by methods illustrated in Schemes 1 and 2.
• the 5,7-disubstituted compounds wherein R 4 and R 3 are aryl, heteroaryl, or a heterocyclic group may be prepared by a modification of a method of Kambe et al, Synthesis, 1980, 366-368.
• Suitable aprotic solvents include benzene, toluene, methylene chloride, DMF, THF, dioxane, and the like.
• the reaction may be performed at from about 40 °C to about 200 °C, and preferably at the reflux temperature of the solvent, for from about 1 hour to about 24 hours, preferably about 4 hours to 8 hours.
• the product (3) is preferably purified by chromatography after isolation from the reaction mixture.
• the above reaction may also proceed by contacting the aldehyde (2) with malononitrile and isolating the resulting dicyano R3substituted alkene which is then reacted with the ketone (1) to form, upon addition of ammonium and cyclization, compound (3).
• Aliphatic aldehydes do not work effectively by this route.
• the ketone (1) may, however, include R ⁇ as alkyl groups.
• the acetophenone starting materials (1) may be obtained commercially, or prepared easily by Friedel-Craft acylation of a suitable aromatic substrate, for example.
• the appropriate aldehyde starting materials (2) also may be obtained commercially, or may be prepared easily, for example by reductions of esters or acids with DIBAL or another suitable hydride reducing agent, or oxidation of alcohols under Swem conditions, for example.
• Compound (3) is then treated with excess formamide by heating at reflux. The formation of product is monitored by TLC, and when the reaction is complete (after about 1 to about 8 hours) the reaction mixture is cooled to room temperature.
• the 5,7-disubstituted pyrido[2,3-d]pyrimidine product (I) is then removed by filtration and purified by column chromatography.
• This compound may then be partially or fully reduced by catalytic hydrogenation to the partially saturated or fully saturated version(s) (on the right side of the molecule) of the compounds shown in Scheme 1 or of Formula I.
• Stereoisomers produced during these reduction steps are included within the scope of the invention.
• the present invention also contemplates reductions which produce single bonds between the 5,6 and 7,8 positions and a double bond between the 6,7 carbons.
• the stereoisomers may be isolated and purified by conventional means.
• R 4 is preferrably an aryl, heteroaryl or heterocyclic group
• R 3 is loweralkyl, loweralkenyl, loweralkynyl, or an arylalkyl group.
• R ⁇ may be selected from those additional groups listed in R3.
• Compound (4, the "R 3 Reagent”) may be obtained commercially or prepared from the precursor ester (5) or alcohol (5) by suitable reactions.
• Compound (5) may be reduced with a suitable reducing agent, such as for example, diisobutylaluminum hydride or another similar alkylaluminum hydride, under conditions well known to the art.
• Compound (6) may be oxidized to the aldehyde (4) Swem oxidation conditions, or other reactions known to those skilled in the art.
• the desired compound (4) is freshly prepared before its use in the reaction described below.
• Compound (9), the "R 4 Reagent”)) may be prepared from the precursor alpha-bromo ketone (7) by a two-step procedure.
• Compound (7) is treated with triphenylphosphine in the presence of a base, such as for example, triethyl amine, to give compound (8).
• Compound (8) is then treated with an alkali metal base, such as NaOH or the like, to give compound (9).
• the procedure is normally accomplished by vigorous mixing of a solution of (8) in an organic solvent with an aqueous solution of base.
• the reaction mixture is cooled and added to a mixture of ammonia in ethanol.
• the mixture is stirred for about 12 to 24 hours at 25 °C, then at reflux for from one to 4 hours, and the solvent is removed in vacuo.
• the residue is purified by trituration with chloroform/ethyl acetate, and the product may be converted to a hydrochloride salt by suspension in 3M HCl, followed by lyophilization.
• Scheme 3 illustrates an alternate method for preparing the compounds (I) of the invention.
• Compounds (1), prepared as described above, are reacted with a dicyanoalkene compound (12) by heating with a suitable ammonium salt, such as for example, ammonium acetate, ammonium propionate, ammonium iodide, or the like, at reflux in an alcoholic or aprotic solvent to give the compound (I).
• a suitable ammonium salt such as for example, ammonium acetate, ammonium propionate, ammonium iodide, or the like
• Suitable solvents for the reaction may be easily determined by those skilled in the art, without undue trial and error, and may include, for example, ethanol, propanol, isopropanol, t-butanol, n-butanol, 1,2-dichloroethane, benzene, chloroform, carbon tetrachloride, toluene, dioxane, dimethoxyethane, and the like.
• a preferred solvent is 1,2-dichloroethane.
• the dicyano compounds (12) may be prepared from the precursor aldehyde (4) by treatment with malononitrile in 1 : 1 H2 ⁇ :EtOH in the presence of a catalytic amount of glycine according to the method of Bastus ⁇ Tetrahedron Lett. , 1963: 955), or alternately MgO in dichloromethane or a similar aprotic solvent (cf. Broekhuis, et al., Reel. J. R. Neth. Chem. Soc, 99: 6-12 (1980); Moison, et al. Tetrahedron (1987), 43:537-542).
• R 1 and R 2 are not both hydrogen atoms
• R 1 or R 2 is loweralkyl this may be accomplished by reaction of the free amino group with the appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
• the appropriate alkylating reagent such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
• R 1 or R 2 is arylalkyl this may be accomplished by reaction of the free amino group with the appropriate arylalkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triemylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
• a base such as triemylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
• R 1 or R 2 is acyl this may be accomplished by reaction of the free amino group with the appropriate acid anhydride, acyl chloride or activated acyl group, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
• the compound may be prepared by reacting a precursor compound having a halogen atom in place of the amino group at the 4-position with a 5-7 membered ring compound optionally containing an additional oxygen or nitrogen atom.
• a precursor compound having a halogen atom in place of the amino group at the 4-position with a 5-7 membered ring compound optionally containing an additional oxygen or nitrogen atom.
• examples of such compounds include, but are not limited to, mo ⁇ holine, piperidine, pyrrolidine, piperazine, thiomo ⁇ holine, and the like.
• this alternate procedure may be used to prepare alkyl substituted amino compounds, for example by reacting the chloro compound with a mono- or disubstituted amine, such as for example, diethylamine, allyl amine, dibutylamine.
• a mono- or disubstituted amine such as for example, diethylamine, allyl amine, dibutylamine.
• This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine.
• the precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of triethyl orthoformate for the formamide followed by chlorination of the ring by treatment with phosphorous oxychloride or thionyl chloride in the presence of DMF in Scheme 1 wherein compound (3) is converted to compound (I).
• a process of inhibiting adenosine kinase is disclosed.
• an adenosine kinase enzyme is exposed to an effective inhibiting amount of an adenosine kinase inhibitor compound of the present invention.
• Preferred such compounds for use in the process are the same as set forth above.
• Means for determining an effective inhibiting amount are well known in the art.
• the adenosine kinase to be inhibited can be located in vitro, in situ or in vivo. Where the adenosine kinase is located in vitro, adenosine kinase is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP.
• the enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under suitable physiological conditions. Means for determining maintenance times are well known in the art and depend inter aha on the concentrations of enzyme and the physiological conditions.
• Suitable physiological conditions are those necessary to maintain adenosine kinase viability and include temperature, acidity, tonicity and the like. Inhibition of adenosine kinase can be performed, by example, according to standard procedures well known in the art (Yamada, et al, Comp. Biochem. Physiol. 1982, 71B: 367-372).
• adenosine kinase is located in situ or in vivo, is typically administered to a fluid perfusing the tissue containing the enzyme.
• That fluid can be a naturally occuring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution and the like.
• a method of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans.
• Administering an inhibitor compound is typically accomplished by the parenteral ⁇ e.g., intravenous injection or oral) administration of the compound. The amount administered is an effective inhibiting or therapeutic amount.
• a “therapeutically-effective amount” of the compound of the invention is meant a sufficient amount of the compound to treat adenosine kinase related disorders or those conditions or diseases which are ameliorated or modified by local inhibition of the enzyme which results in an increase in the concentration of adenosine. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is to be decided by the attending physician within the scope of sound medical judgment.
• the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with specific compound employed; and the like factors well known in the medical arts and well within the capabilities of attending physicians.
• Compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art.
• cells containing adenosine kinase are cultured in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or externally applied ⁇ C-adenosine by these cells.
• the cells can be intact or broken.
• the specificity of adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine Al and A2 ⁇ receptor binding, adenosine deaminase activity and adenosine transport.
• adenosine kinase inhibitors have been reported to protect rodents ⁇ e.g., mice and rats) from seizures induced by the subcutaneous administration of pentylenetetrazol (PTZ).
• PTZ pentylenetetrazol
• the rodents are injected with various doses of a given inhibitor followed at various times by the subcutaneous administration of from about 10 to about 500 milligrams per kilogram of PTZ, The injected animals are then observed for the onset of seizures.
• the compounds of the invention were tested in vivo in the hot plate test of analgesia in mammals such as mice.
• the compounds of examples 6, 79, 104, 130, 133, 134, 137, 205, 246 and 256 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30 ⁇ mol/kg i.p.) for latency to 10th jump (in seconds). The longer the number of seconds, the more effective the drug at masking the pain felt from the hot plate.
• Compound 6 resulted in 152 seconds relative to the vehicle alone of 72.8 ⁇ 10.5 seconds (average ⁇ standard deviation); compound 79 resulted in 143 seconds; compound 104 resulted in 180 seconds; compound 130 resulted in 158 seconds; compound 133 resulted in 131 seconds; compound 134 resulted in 137 seconds; compound 137 resulted in 159 seconds; compound 205 resulted in 158 seconds, compound 246 resulted in 160 seconds and compound 256 resulted in 143 seconds.
• Compounds of the invention are therefore potent pain relievers as demonstrated in this animal model.
• mice Male CF1 mice (Charles River) of approximately 25-30 g body weight are pretreated with 10 ml/kg of the test compounds, i.p. or p.o, in groups of 8 animals per dose. At the end of the pretreatment period, the mice are placed in an Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) in individual, 9.8 x 7.2 x 15.3 cm (1 x w x h) plastic enclosures on top of a copper plate warmed to 55°C. Infared sensors located near the top of each enclosure record beam crossings that occur as the mice jump off of the heated surface.
• Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor Coldbus, OH; Model AHP16AN
• Latency times for each jump are automatically recorded, and latency to both the first and tenth jumps are used for data analysis. Mice that do not reach the criteria of 10 jumps by 180 seconds are immediately removed from the hotplate to avoid tissue damage, and they are assigned the maximum value of 180 seconds as their latency to tenth jump. Numerous other animal models of adenosine kinase activity have been described
• Nociperception Nociperception (Nociception) (Pain)
• Inflammation including conditions such as Septic Shock due to Sepsis Infection
• a method of treating cerebral ischemia, epilepsy, nociperception or nociception, inflammation including conditions such as septic shock due to sepsis infection in a human or lower mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I with R -R° as defined herein.
• the preferred compounds are those of formula II with the R variables as defined previously.
• the present invention relates to a method of treating the above disorders comprising administering a compound of formula II wherein R3 is a substituted aryl or heteroaryl moiety wherein the substituent (preferrably halogen) is at the meta position relative to the ring attachment and R ⁇ is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment.
• R3 is a substituted aryl or heteroaryl moiety wherein the substituent (preferrably halogen) is at the meta position relative to the ring attachment and R ⁇ is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment.
• R ⁇ is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment.
• Adenosine kinase activity was found to be decreased, relative to normal liver, in a variety of rat hepatomas: activity of the enzyme giving a negative correlation with tumor growth rate (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also diminished in regenerating Uver after partial hepatectomy in experimental animals (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713).
• Erythrocyte Adenosine kinase activity was found to be diminished in patients with gout (Nishizawa, et al, Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and increased in asymptomatic HIY-seropositive and HTV-seronegative high-risk subjects, compared to normal healthy controls (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481).
• HIV human immunodeficiency virus
• adenosine kinase activity may prove useful in monitoring the clinical progress of patients with HIV infection (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481).
• Sepsis infection may lead to a systemic inflammatory syndrome (SIRS), characterized by an increase in cytokine production, neutrophil accumulation, hemodynamic effects, and tissue damage or death.
• SIRS systemic inflammatory syndrome
• the ability of adenosine kinase inhibitor to elevate adenosine levels in tissues has been demonstrated to ameliorate syndrome symptoms, due to the known anti-inflammatory effects of adenosine. (Firestein, et al., J. of Immunology, 1994: 5853-5859).
• adenosine kinase inhibitors to elevate adenosine levels is expected to alleviate pain states, since it has been demonstrated that administration of adenosine or its analogs results in antinociception or antinociperception. (Swaynok, et al, Neuroscience, 1989, 32:557-569).
• Examples 2-156 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 2 below, compounds of Examples 2-156 were prepared. Table 2 Examples 2-156
• step 157a preparation of 3-bromophenylacetaldehyde (the "R 3 reagent")
• step 157b preparation of ⁇ -(triphenylphosphonium)-4-(dimethylamino)phenylethan-l-one chloride
• the ⁇ -bromo-(4-dimethylaminophenyl)ethan-l-one was prepared by bromination with bromine in hydrobromic acid according to the method of Suzuki et al (J. Pharm. Soc. Japan, (1955), 75:54. Removal of solvent and recrystallization from methanol/ethyl acetate/toluene gave the title product as a white powder.
• step 157c preparation of l-(4-(dimethylamino ' )phenyl)-4-(3-bromophenyl)-but-2-en-l-one 20 g of ⁇ -(triphenylphosphonium)-4-(dimethylamino)phenylethan-l-one chloride
• step b was partitioned between dichloromethane and 50 mL of 2N NaOH. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was mixed with 3-bromophenylacetaldehyde (from step a) for 24 hours at 25 °C. The mixture was purified by chromatography to give 8.35 g (61%) of a cis/trans mixture of the title compound. The cis/trans mixture was taken to the next step without separation of the isomers.
• step 157d preparation of 3-cvano-4-(3-bromophenyl)methyl-6- (4- fdimethyl)am ophenyl)pyridine-2-amine
• Examples 158-174 Following the procedures of Example 157, except substituting the appropriate reagents for the R 4 and R 3 reagents of Example 157 as indicated in Table 3 below, compounds of Examples 158-174 were prepared. The treatment with aqueous HCl was omitted, and the free bases were obtained except as indicated.
• Examples 167-174 the formamide or formamidine acetate (added periodically until the reaction was complete) treatment was replaced by treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 °C and addition of excess ammonia in ethanol. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2-dichloro benzene at 120-180 °C for 1-8 hours. The reaction mixture was cooled to room temperatureand purified by chromatography, and the product was recrystallized if necessary (chloroform in methanol). Table 3 Examples 158-187
• Examples 190-198 Following the procedures of Example 189, except substituting the appropriate acylating reagent for the acetic anhydride of Example 189 as indicated in Table 5 below, compounds of Examples 190-198 were prepared.
• the product was prepared by treating a solution of 4-chloro-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine in CH2 2-TEA with allylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Si ⁇ 2, EtOAc/hexanes) to provide the title compound IR (KBr) 3437, 1564, 1355, 1195; MS mlz 460/462 (M+H)+.
• the 4-chloro-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido [2,3- dlpyrimidine was prepared as follows. A sample of 4-(4-bromophenyl)-3-cyano-6-(4-(dimethylamino)phenyl)pyridine-2- amine (from Example 1, 5.0 g, 12.7 mmol) in 20 mL of H2SO4 was heated at 80 °C for 30 minutes. Ice was added, and the reaction mixture was neutralized with aqueous NaOH. The resulting crude 3-carboxamide was collected by filtration, triturated with EtOAc- hexanes, then dried under reduced pressure (4.95 g, 95% theoretical).
• the POCl 3 was removed under reduced pressure to provide crude 4-chloro-5-(p-dimethyla ⁇ nophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine.
• the invention therefore relates to intermediate compounds of formula HI wherein X is selected from hydroxyl or halogen and the remaining variables are the same as in formula I or II.
• Example 200 4-(2-(N.N-dimemylamino)ethylamino)-5-(4-bromophenyl)-7-(4-dimethylaminophenyl) pyrido r2,3-dl pyrimidine trihvdrochloride
• the product was prepared by treating a solution of 4-chloro-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine (prepared as in Example 199) in CH2CI2-TEA with the 2-(dimethylamino)ethylamine and heating the resulting mixture at reflux for 1 hour.
• Example 201 4-(4-(N.N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido [2.3-dl pyrimidine tetrahvdrochlori.de
• the product was prepared by treating a solution of 4-amino-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-dlpyrimidine in CH2CI2-TEA with the 4-(dimethylamino)butylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Si ⁇ 2, EtOAc/hexanes).
• the 5-aminopyridine-2-carboxaldehyde starting material was prepared as follows: 204a. 5-amino-2-bromopyridine
• Hg(O2CCF3)2 (11.1 g, 26 mmol) and H2SO4 (72 mmol) were added to the reaction mixture, and the solution was heated at reflux for 2 hours.
• the reaction mixture was cooled to 25 °C and neutralized with saturated aqueous sodium carbonate.
• Example 205 4-am o-5-(3-bromophenyl)-7-(5-dimemylamino-2-pyridyl)pyridor2,3-dlpyrirrudine trihvdrochloride salt
• the 5-dimethylammopyridine-2-carboxaldehyde starting material was prepared as follows:
• Example 206 4-am o-5-(3-bromophenyl)-7-(5-dimethylamino-2-pyrazinyl)- pyrido[2.3-dlpyrimidine hydrochloride
• the 5-dimethylaminopyrazine-2-carboxaldehyde starting material was prepared as follows:
• 2-oxobenzoxazolin-6-ethanone_ was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to prepare the title compound: LRMS m/z 434/436; IR (cm "1 ) 3095, 1760, 1579, 1481, 1350.
• the 2-oxobenzoxazolin-5-ethanone_starting material was prepared as follows:
• the l-methyl-2-oxobenzoxazolin-5-ethanone_starting material was prepared as follows:
• Example 209 4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dimethylam ophenyl)pyridor2.3-dlpyrimidine
• the title compound was prepared from the compound of Example 173 by reaction with 3-methoxyphenylboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions.
• IR (KBr) 3550-3250,3240- 2760,1580,1560,1540,1350; H. Res. MS m/z 496.1902 (M+H)+.
• Example 210 4-ammo-5-((2-bromophenyl)methyl)-7-(4-m ⁇ ethylammophenyl)pyridor2.3-dlpyrirnidine Following the procedures of Example 157, except substituting l-(4- dimethylaminophenyl)-ethanone for the R 4 reagent and 2-(2-bromophenyl)- acetaldehyde for the R 3 reagent of Example 157, the title compound was prepared as shown in Table 6.
• Example 212 4-amino-5-(2-((thiophene-3-yl)phenyl)methyl)-7-(4-diethylaminophenyl)pyridor2.3- dlpyrimidine
• the title compound was prepared from the compound of Example 173 by reaction with 3-thiopheneboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions.
• IR (KBr) 3640-3240, 3240-2800, 1580, 1560, 1540, 1350; H. Res. MS m/z 466.2057 (M+H)+.
• Example 213 *prepared by deformylation of Example 213 with dilute HCl in methanol. **prepared by acylation of Example 213 with 2-methoxyacetyl chloride/pyridine. ***prepared by formylation of the 7-(3-bromophenyl)-2-cyano-5-(4- aminophenyl)pyridine-2-amine intermediate. ****prepared by acylation of Example 213 with the 2-(dimethylamino)acetyl chloride.
• Examples 223-225 Following the procedures of Example 157, except substituting the appropriate reagents for the R 4 and R 3 reagents of Example 157 as indicated in Table 8 below, compounds of Examples 223-225 were prepared. Table 8 Examples 223-225
• Examples 226-228 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 9 below, compounds of Examples 226-228 were prepared.
• Examples 231-243 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 10 below, compounds of Examples 230-243 were prepared. In some cases, the treatment with aqueous HCl was omitted, and the free bases were obtained. Table 10 Examples 231-243
• the title compound was prepared by condensing l,l-dicyano-(3-(3- bromophenyl)propene (the R 3 reagent) with the compound from Step 246c (the R 4 reagent) and ammonium acetate in ethanol according to the procedure of Example 157d.
• the title compound was prepared from the compound of Step 246d according to the procedure of Example 157, except substituting formamide for the ammonium sulfate and triethyl orthoformate thereof.
• step (c) first substituting the appropriate reagent for R 4 as indicated in Table 1 IB below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 249-2 1 were prepared. In some cases, the hydrochloride salts were not prepared. Table 1 IB Examples 249-260
• Step 252a l-(5-bromo-2-pyridyl)ethanone, ethylene ketal
• dibromopyridine 5.2 g, 21.95 mmol
• tributyl(l-ethoxyvinyl)tin 9.11 g, 25.24 mmol
• Pd2(dba)3 0.7 g, 0.8 mmol
• (2-furyl)3P 0.37 g, 1.6 mmol
• the reaction mixture was concenttated, and the crude product was purified by elution through a short column of silica gel.
• Step 252c 4-amino-5-(3-bromophenyl)-7-(5-(N.N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2,3-dlpyrimidine ttihvdrochloride
• step (c) first substituting the reagent from Step 252b for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the free base of the title compound was prepared.
• the title compound was prepared from this by treatment with HCL in ether.
• IR (KBr) 3440, 1635, 1605, 1580, 1360 cm" 1 ; MS mlz 466/468, (M+H)+.
• Examples 253-260 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R 4 as indicated in Table 1 IB below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 253-260 were prepared. In some cases, the hydrochloride salts were not prepared.
• the compound was prepared by using the method generally described above in
• Example 262 4-(me ylarruno)-5-(3-bromophenyl)-7-(4-dime ylanjmophenyl)pyridor2.3-d1pyrimidi «e hydrochloride
• the title compound was prepared by using the method described in Example 200, except substituting methylamine for the 2-(dimeftylammo)ethylamine thereof.
• Example 263 4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2.3-dlpyrimidine hydrochloride
• the title compound was prepared by using the method described in Example 200, except substituting 2-methoxyethylamine for the 2-(dimethylamino)ethylamine thereof.
• Step 264a l-(4-(l-Methylimidazol-2-yl)phenyl)ethanone
• N-methyl imidazole (0.90 g, 11.0 mmol) in 12 mL of THF at -78 °C was treated with n-BuLi (7.5 mL, 1.6 M solution in hexanes, 12.0 mmol) for 0.5 hours at - 78 °C.
• ZnCl 2 (20 mL, 1.0 M solution in Et 2 O, 20 mmol) was added, and the solution was warmed to 25°C.
• Step 264b 4-amino-5-(3-bromophenyl)-7-(4-( l-methyl-2-imidazolyl)phenyl)pyrido[2,3- dlpyrimidine ttihvdrochloride
• step (c) Following the procedures of Example 244, except in step (c) first substituting the R 4 reagent from Step 264a for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared.
• Example 265-267 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R 4 as indicated in the Table below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 264-285 were prepared. In Ex. 266, the hydrochloride salt was not prepared.
• Example 268 4-amino-5-( ' 3-bromophenylV7-f4-(3-(dimethylarnino propynyl phenyl)pyridor2.3- dlpyrimidine
• Example 269-271 Following the procedures of Example 268, except substituting the reagent compound shown in the table below for the 3-dimethylaminoprop-l-yne of Example 268, the compounds shown in the table below were prepared.
• Step 273a 7-acetyl-2H-pyridor3.2-b1-1.4-oxazin-3(4H)-one
• Step 273b 7-acetyl-4-methyl-2H-pyrido[3.2-bl-1.4-oxazin-3(4H)-one
• step 273 a The compound from step 273 a was tteated with methyl iodide and Na ⁇ in 1: 1 T ⁇ F/DMF for 6 hours at 0 °C to 25 °C.
• the reaction was quenched with aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane, and the resiue was purified by chromatogaphy to give the tide compound.
• Step 273c 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2 ⁇ -4 ⁇ -pyridor3.2-bl-1.4- oxazinyl)pyrido[2.3-dlpyrimidine
• Example 244 Step c Following the procedure of Example 244 Step c, except first substituting 7-acetyl-4- methyl-2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (the R 4 reagent) from Step 273b for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+ ⁇ ), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700, 1640, 1605, 1590, 1395, 1380, 1345.
• Example 274 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2 ⁇ -4 ⁇ -pyrido[3,2-bl- l,4-oxazin-7-yl)pyridor2.3-dlpyrimidine
• Step 274a 7-acetyl-4-dimethylaminoethyl -2H-pyridor3.2-bl-1.4-oxazin-3(4H)-one
• the compound from Example 273 Step a was treated with 2-chloro-(N,N- dimethyl)ethylamine HCl and K2CO3 in aqueous acetone at reflux.
• the mixture was diluted with water and exttacted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
• Step 274b 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3.2-bl-l,4-oxazin-7-yl)pyrido[2,3-dlpyrimidine
• step c Following the procedures of Example 244 Step c, except in step c first substituting 7-acetyl-4-dimethylaminoethyl -2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (the R 4 reagent, from Step 273b) for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+ ⁇ ), 519 (1 Br); IR (cm-1) 3440, 1685, 1630, 1605, 1580, 1395
• Step 275a 6-acetyl-2-benzoxazolinone Following the procedures of Example 273 Step a, except substituting 2- benzoxazolinone (Aldrich) for the 2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one thereof, the title compound was prepared.
• Step 275b 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazolinone
• the compound from Example 275 Step a was tteated with 2-chloro-(N,N- dimethyl)ethylarnine ⁇ C1 and K2CO3 in aqueous acetone at reflux. The mixture was diluted with water and exttacted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
• Step 275c 4-amino-5-(3-bromophenyl)-7-(2,3-dihvdro-3-(dimethylaminoethyl)-2- oxobenzoxazol-6-yl)pyridor2.3-dlpyrimidine
• Example 244 Step c Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 275a for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+ ⁇ ), 506 (1 Br); IR (cm-1) 3400, 3050, 1630, 1610, 1360.
• Example 276 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-l,4-oxazin-7-yl)pyridor2.3- dlpyrimidine
• Example 275 Step a The compound from Example 275 Step a was tteated with methyl iodide and NaH in 1: 1 THF/DMF for 6 hours at 0 °C to 25 °C. The reaction was quenched with aqueous sodium bicarbonate solution, the mixture was exttacted with dichloromethane, and the resiue was purified by chromatogaphy to give the title compound.
• Step 276b l-(3-hvdroxy-4-methylaminophenyl)-ethanone
• Step 276c 7-acetyl-4-methyl-2H-4H-benzo-l,4-oxazin-3-one
• Step 276d 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-H-benzo- 1 -oxazin-7- yl)pyridor2.3-dlpyrimidine
• step c first substituting the compound from Step 276c for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared.
• Example 277 4-amino-5-(3-bromophenyl)-7-(2.2.4-trimethyl-3-oxo-2H-4H-benzo-1.4-oxazin-7- yl)pyrido[2,3-dlpyrimidine Step 277a. 7-acetyl-2.2.4-trimethyl-2H-4H-benzo-1.4-oxazin-3-one
• Step 277b 4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-1.4- oxazin-7-yl)pyridor2.3-dlpyrimidine
• Example 244 Step c Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 277a for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as die solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 490 (1 Br); IR (cm-1) 3450, 2900-3100, 1680, 1645, 1610, 1515, 1385, 1365, 1 165.
• Example 278 4-an ⁇ ino-5-cvclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo-1.4-oxazin-7- yl)pyridor2.3-dlpyrimidine
• Step 278a l-(3-hvdroxy-4-(2-(dimethylamino)ethyl)phenyl)-ethanone
• Step 278b 7-acetyl-4-(dimethylamino)ethyl)-2H-4H-benzo- 1.4-oxazin-3-one
• step c Following the procedures of Example 244 Step c, except in step c first substituting l,l-dicyano-3-cyclohexylethene (prepared according to die method of Moison, et al. (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane) for the R3 reagent of Example 244 Step c, and substituting the compound from Step 278b for the R 4 reagent of Example 244 Step c, and also performing the condensation with ammonium acetate but also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 447; IR(cm-l) 3400, 2900, 1690, 1610, 1590, 1395.
• Step 279a l-(5-methvethyl-2-pyridyl)ethanone
• Step 279b 4-amino-5-(3-bromophenyl)-7-(5-( l-methylethyl)-2-pyridyl)pyridor2,3- dlpyrimidine
• Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting the compound from Step 279a for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroetfiane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 421 (IBr); IR (cm-1) 3489, 2940, 1545, 1482, 1357.
• Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting die compound shown below for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds shown in the table below were prepared.
• Step 282a 4-cyanoacetophenone. acetal with 2.2-dimethylpropylene glycol
• Step 282b 4-(aminomethyl)acetophenone. acetal with 2.2-dimethylpropylene glycol
• Step 282c l-(4-(BOC-aminomethyl)phenyl)ethanone
• THF 20 mL
• IN HCl 20 mL
• d-tibutyl dicarbonate 2.18 g, 10 mmol
• the mixture was stirred at room temperature over a weekend.
• the solution was diluted with water, and the mixture was exttacted with ether and ethyl acetate.
• the organic extracts were dired (MgSO4), and the solvent was remove under vacuum to give the title compound.
• step c substituting the compound from Step 282c for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate but also substituting dichloroethane as die solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared.
• Step 283a 4-(l -amino- l-methylethyl)acetophenone
• Step 283b 4-(l-(N-BOC- amino)- l-methylethyl)acetophenone
• Step 283a The compound from Step 283a (2.32 g, 8.77 mmol) was tteated sequentially with HCl and di-t-butyl dicarbonate according to the procedure of Example 282 Step c to give the title compound (1.60 g). MS (M+H) 278.
• Step 283c 4-amino-5-(3-bromophenylV7-(4-(l-(N-formylamino)-l- methylethyl)phenyl)pyridor2.3-dlpyrimidine
• Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting the compound from Step 283b for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate but also substituting dichloroetiiane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared.
• Step 284a 4-(l-(dimemylamino)-l-methylemyl)acetophenone
• the compound from Step 283a (1.18 g, 5 mmol) was dissolved in 5 mL formic acid, and 5 mL of formalin (37% ) was added. The mixture was heated at reflux for 4 hours, then cooled and neuttalized widi 2N Na 3 CO 3 . The mixture was exttacted with dichloromethane. The solution was dried (MgSO 4 ), and the solvent was removed to give the title compound (0.94 g).
• IR (cm-1) 3520, 1640, 1610, 1580, 1375.
• Examples 285-286 Following die procedures of Example 157, except substituting die appropriate reagents for the R 3 and R 4 reagents of Example 157 as indicated in the Table below, compounds of Examples 285-286 were prepared. For Example 286, treatment with aqueous HCl was omitted, and the free base was obtained.
• Examples 287-300 Following the procedures of Example 157, except substituting the appropriate R 3 and R 4 reagents as indicated in die Table below and replacing the formamide or formamidine acetate treatment with treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 °C and addition of excess ammonia in ethanol, compounds of Examples 287-300 were prepared. . After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2-dichloroethane at reflux for 1-8 hours. The reaction mixture was cooled to room temperature and purified by chromatography, and die product was recrystallized if necessary. The treatment with aqueous HCl was omitted in some cases, and the free bases were obtained.
• the l,l-dicyano-3-cyclohexyled ⁇ ene was prepared according to the method of Moison, et al (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde witii malononitrile in the presence of finely powdered magnesium oxide in dichloromethane.
• the reagents for the following examples were prepared by this method substituting the compound shown below for the cyclohexane carboxaldehyde used to prepare the reagent of Example 290.
• Example 298, N-(phenylmethoxylcarbony)piperidine-4-carboxaldehyde (this material was prepared from N-(carbobenzyloxy)-4-(2-hydroxyethyl)piperidine (Brehm et al., Helv.Chim.Acta, 70; (1987), 1981-1987 by treatment with TEMPO (2,2,6,6-tetramethylpiperidinyloxy radical) and potassium bromide in dichloromethane at 0 °C to which was added commercial bleach (Clorox) containing sodium bicarbonate).
• TEMPO 2,2,6,6-tetramethylpiperidinyloxy radical
• Example 303 the compounds of Examples 301-305 were prepared.
• the condensation solvent was DMSO instead of etfianol and dimetiioxyethane.
• Example 306 4-amino-5-cvclohexyl-7-(6-(4-acetvIpiperazinyl)-3-pyridyl)pyrido[2.3-dlpyrimidine
• a mixture of 679 mg (2 mmol) of the compound from Example 298 and 1.28 g (10 mmol) of N-acetylpiperazine in 5 mL of DMSO was heated at 110 °C for 5 hours. On cooling a precipitate was deposited, which was collected and washed with 20% metiianol and dried to give 647 mg of the product as orange flakes:
• IR (cm-1) 3522, 3306, 3110, 2925, 2854, 1670, 1650, 1586, 1506.
• Example 307-322 Follwing the procedure of Example 306, except substituting the reagent shown in the table below for the N-acetylpiperazine of Example 306, the compounds shown in the table were prepared. The compounds were purified by HPLC chromatography.
• Example 323 4-an ⁇ mo-5-(l-(2-bromophenyl)ethyl)-7-(l-memyl-5-indolyl)pyridor2.3-dlpyrimidine
• the procedures of Example 157 were followed, except substituting l',l'-dicyano-3- bromostyrene for the R 3 reagent and l-(l-methyl-5-indolyl)-ethanone for the R 4 reagent .
• the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum.
• the amidine compound was tiien heated in 1,2-dichloroethane at reflux for 1-8 hours.
• Example 324 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2.3-dioxo-5-indolyl)pyrido[2.3- dlpyrimidine
• the tide compound was prepared from the compound of Example 323 by oxidation with CrO3 in sulfuric acid.
• Examples 325-326 Following the procedures of Example 157, except substituting the appropriate R 3 and R 4 reagents as indicated in the Table below, compounds of Examples 325-326 were prepared. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2- dichloroediane at reflux for 1-8 hours. The reaction mixture was cooled to room temperature and purified by chromatography, and the product was recrystallized if necessary. The treatment with aqueous HCl was omitted in some cases, and the free bases were obtained.
• Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting the compound resulting from the reaction of 2-acetyl-5-chloropyridine in refluxing edianol with the precursor reagent compound (4-piperidinone ethylene ketal) shown below for the R 4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compound shown in the table below was prepared.
• Example 328 4-ammo-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2.3-dlpyrimidine Treating the compound of Example 327 with dilute HCl, die title compound was prepared.
• Example 329-331 Following the procedures of Example 244 Step c, except in step c substituting die compound resulting from the reaction of 2-acetyl-5-chloropyridine in refluxing etiianol with the precursor reagent compound shown below for the R 4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds shown in the table below were prepared.
• Example 332 4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomo ⁇ hohnyl)-3-pyridyl)pyrido[2,3- dlpyrimidine
• the compound of Example 331 was treated with 4-chloroperbenzoic acid in metiianol and dichloromethane to give the tide compound.
• Example 333 4-amino-5-(2-bromophenyl)-7-(6-mo ⁇ holinyl-3-pyridyl)pyrido[2,3-d1pyrimidine
• Step 333a r,r-dievano-2-bromostyrene
• the tide compound was prepared by condensation of 2-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. ⁇ Reel J. R. Neth. Chem. Soc, 99: 6-12 (1980)).
• Step 333b 5-acetyl-2-mo ⁇ holinylpyridine
• the title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with mo ⁇ holine in refluxing ethanol.
• the tide compound was prepared by condensation of r,l'-dicyano-2-bromostyrene with 5-acetyl-2-mo ⁇ holinylpyridine and ammonium acetate in dichloroethane at reflux. After the reaction was complete (TLC), the mixture was cooled, and the solvent was removed. The residue was triturated with methanol to give the product
• Step 333d 4-amino-5-(2-bromophenyl)-7-(6-mo ⁇ holinyl-3-pyridyl)pyrido[2.3- dlpyrimidine
• Examples 334-336 FoUowing the procedures of Example 333, except in Step a substituting the precursor aldehyde reagent shown below for the 2- bromobenzaldehyde of Example 333 Step a, and carrying the product forward as in procedures 333 Stepbs b-d, the compounds shown in the table below were prepared. Examples 334-336
• Step b substituting 5-acety 1-2,3- dichloropyridine for the 5-acetyl-2-chloropyridine to give 5-acetyl-3-chloro-2- mo ⁇ holinylpyridine, and substituting 5-acetyl-3-chloro-2-mo ⁇ holinylpyridine for the 5- acetyl-2-mo ⁇ hohnylpyridine in step c, then the carrying the product forward as in Example 333 Step d, the title compound was prepared.
• Example 338 4-an ⁇ ino-5-(3-bromophenyl)-7-(6-(N-oxidomo ⁇ holinyl)-3-pyridyl)pyrido[2.3-d1pyrimidine
• the tide compound was prepared by treating die compound of Example 134 witii hydrogen peroxide in acetic acid according to standard procedures.
• Step 339a .r-dicvano-3-bromostyrene
• the tide compound was prepared by condensation of 3-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. ⁇ Reel J. R. Neth. Chem. Soc, 99: 6-12 (1980)).
• the tide compound was prepared by the reaction of 5-acetyl-2-chloropyridine with 2-ed ⁇ oxyeti ⁇ ylamine in refluxing ethanol.
• Step 339c 4-(3-bromophenyl)-3-cvano-6-(N-(2-ethoxyethyl)amino)pyridine-2-amine
• the tide compound was prepared by condensation of ,l'-dicyano-2-bromostyrene with 5-acetyl-2-mo ⁇ holinylpyridine and ammonium acetate in dichloroethane at reflux. After the reaction was complete (TLC), the mixture was cooled, and the solvent was removed. The residue was triturated witii methanol to give the product.
• Step 339d 4-amino-5-(2-bromophenyl)-7-(6-(N-(2-ed ⁇ oxyethyl)amino)-3- pyridyl)pyrido[2.3-dlpyrimidine
• Example 340 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hvdroxyethoxyethyl)-N-formyla ⁇ rino)-3- pyridyl)pyridor2,3-dlpyrimidine This compound was isolated by chromatography as a product of the reaction described in Example 239 Step d.
• Example 341 4-amino-5-(3-bromophenv -7-(6-(N-(2-hvdroxyethoxyethyl)-3-pyridyl-N- oxide)pyridor2.3-dlpyrimidine
• the tide compound was prepared by treating the compound of Example 341 with hydrogen peroxide in acetic acid according to standard procedures.
• IR (microscope) 3296, 1628, 1560, 141 1, 1353 cm ' 1 ; MS mlz 497 (M+H)+.
• Example 342 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)mo ⁇ holinyl)-3-pyridyl)pyrido[2.3- dlpyrimidine
• the tide compound was prepared from the compound of Example 328 by reduction witii (Lithium Aluminum Hydride, and subsequent workup acccording to standard procedures).
• Example 343 l-(5-(4-ammo-5-(3-bromophenyl)pyrido[2,3-dlpyrimidin-7-yl)-2-pyridyl)-piperidine-4- phosphate, disodium salt
• the title compound was prepared from the compound of Example 342 by treatment with POCI3, and subsequent workup acccording to standard procedures.
• Example 344 4-amino-5-(3-bromophenyl)-7-(6-(2-hvdroxy)mo ⁇ holinyl)-3-pyridyl)pyridor2.3- dlpyrimidine
• the tide compound was prepared from the compound of Example 339 by oxidation of the free hydroxy group to an aldehyde with TEMPO reagent. During workup of the mixture, the compound self-condensed to give die tide compound.
• Example 346 4-amino-5-(3-bromophenyl)-7-(4-hvdroxy-4-(hvdroxymethvDpiperidinyl)-3- p yrid yl)p yridor ⁇ .3 -dlpyrimidine
• the title compound was prepared from the compound of Example 345 by treatment with Os ⁇ 4 in DMSO at room temperature. After quenching, the title compound was extracted, then purified by chromatography.
• Step 347a l.l-dicvano-3-cvclohexylethene
• the l,l-dicyano-3-cyclohexylethene was prepared according to the method of Moison, et al. (Tetrahedron (1987), 43:537-542) by tteating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane.
• Step 347c 4-amino-5-cvclohexyl-7-(6-(4.4-ethylenedioxypiperidinyl)-3- pyridyl)pyridor2.3-d1pyrimidine
• Example 349 4-ammo-5-cvclohexyl-7-(6-(4-me ylenylpiperidinyl)-3-pyridv pyridor2.3-dlp ii ⁇ idirie
• the tide compound was prepared from the compound of Example 348 by treatment with methyl triphenylphosphine bromide at -78 °C in DMSO. After quenching and warming the mixture to room temperature, the title compound was exttacted, then purified by chromatography.

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• 1998
  • 1998-04-14 IL IL13161898A patent/IL131618A0/xx unknown
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  • 1998-04-14 KR KR1019997009599A patent/KR20010006509A/ko not_active Application Discontinuation
  • 1998-04-14 CN CN98804151A patent/CN1252070A/zh active Pending
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  • 1998-04-14 CA CA002286909A patent/CA2286909A1/en not_active Abandoned
  • 1998-04-14 HU HU0001434A patent/HUP0001434A3/hu unknown
  • 1998-04-14 AU AU71083/98A patent/AU7108398A/en not_active Abandoned
  • 1998-04-14 WO PCT/US1998/007207 patent/WO1998046605A1/en not_active Application Discontinuation
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  • 1998-04-14 BR BR9809055-0A patent/BR9809055A/pt not_active Application Discontinuation
  • 1998-04-14 EP EP98918093A patent/EP0989986A1/en not_active Withdrawn
  • 1998-04-14 JP JP54408898A patent/JP2001520655A/ja active Pending
  • 1998-04-15 AR ARP980101733A patent/AR012436A1/es unknown
  • 1998-04-15 ZA ZA983177A patent/ZA983177B/xx unknown
  • 1998-04-16 CO CO98020979A patent/CO4940446A1/es unknown
• 1999
  • 1999-10-15 NO NO995036A patent/NO995036D0/no not_active Application Discontinuation
  • 1999-10-29 BG BG103842A patent/BG103842A/xx active Pending

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