NZ615283B2 - Asymmetric ureas and medical uses thereof - Google Patents
Asymmetric ureas and medical uses thereof Download PDFInfo
- Publication number
- NZ615283B2 NZ615283B2 NZ615283A NZ61528312A NZ615283B2 NZ 615283 B2 NZ615283 B2 NZ 615283B2 NZ 615283 A NZ615283 A NZ 615283A NZ 61528312 A NZ61528312 A NZ 61528312A NZ 615283 B2 NZ615283 B2 NZ 615283B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- ethyl
- urea
- methyl
- methylpiperidinyl
- dichlorophenyl
- Prior art date
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title claims description 294
- 235000013877 carbamide Nutrition 0.000 title description 104
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 604
- 150000001875 compounds Chemical class 0.000 claims abstract description 231
- 125000001424 substituent group Chemical group 0.000 claims abstract description 104
- 239000011780 sodium chloride Substances 0.000 claims abstract description 67
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 54
- 125000003118 aryl group Chemical group 0.000 claims abstract description 50
- 201000010099 disease Diseases 0.000 claims abstract description 50
- 102000000393 Ghrelin Receptors Human genes 0.000 claims abstract description 44
- 108010016122 Ghrelin Receptors Proteins 0.000 claims abstract description 44
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 150000002367 halogens Chemical class 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 30
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 26
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 21
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 21
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 20
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- 206010012601 Diabetes mellitus Diseases 0.000 claims abstract description 16
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 73
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 72
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 43
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 35
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- 230000000051 modifying Effects 0.000 claims description 15
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 12
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- FBJWCNILPAGKLV-UHFFFAOYSA-N 3-[1-(2,3-dichlorophenyl)ethyl]-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(C)NC(=O)N(C)C1CCN(C)CC1(C)C FBJWCNILPAGKLV-UHFFFAOYSA-N 0.000 claims description 6
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Disclosed are 4-ureido-N-methyl-piperidine derivatives of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R is aryl optionally substituted with one or more independent R103 substituents; R1 is selected from the group consisting of hydroxyalkyl, alkyl, optionally substituted with one or more independent R103 substituents; R4 is selected from the group consisting of alkyl, aryl, arylalkyl, optionally substituted with one or more independent R103 substituents; or R4 is OR103; R6, R7, R8, R9 are selected from the group consisting of hydrogen and alkyl; R103 is selected from the group consisting of hydrogen, cyano, nitro, -OR104, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -C(O)R104, -C(O)OR104, -C(O)NR104R105, -NR104R105, -NR104S(O)2R105, -NR104C(O)R105, -S(O)2R104, -SR104 and -S(O)2NR104R105, and R104 and R105 are each independently selected from the group consisting of hydrogen, cyano, nitro, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl and heteroarylalkyl. Also disclosed are representative compounds such as 1-methyl-3-((R)-1-(naphthalen-1-yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(4-methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(2,3-dichlorophenyl)ethyl)-1-(3-methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(2-methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, 3-(2-cyclopropyl-1-(2,3-dichlorophenyl)ethyl)-1-(3-methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(2-hydroxy-1-(naphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, 1-ethyl-1-(1-methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)-3-(3-(pyridin-3-yloxy)phenyl)propyl)urea, 1-methyl-1-(1-methylpiperidin-4-yl)-3-(3-morpholino-1-(naphthalen-1-yl)propyl)urea and 3-(1-(3-chloro-2-(pyridin-4-yl)phenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea. Also disclosed is a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined above, and one or more pharmaceutically acceptable excipients, for preventing and/or treating a subject having a disease which is pathophysiologically mediated by the ghrelin receptor, including conditions such as obesity, overweight, eating disorder, diabetes, metabolic syndrome, cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric disorder or substance abuse. one or more independent R103 substituents; R4 is selected from the group consisting of alkyl, aryl, arylalkyl, optionally substituted with one or more independent R103 substituents; or R4 is OR103; R6, R7, R8, R9 are selected from the group consisting of hydrogen and alkyl; R103 is selected from the group consisting of hydrogen, cyano, nitro, -OR104, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -C(O)R104, -C(O)OR104, -C(O)NR104R105, -NR104R105, -NR104S(O)2R105, -NR104C(O)R105, -S(O)2R104, -SR104 and -S(O)2NR104R105, and R104 and R105 are each independently selected from the group consisting of hydrogen, cyano, nitro, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl and heteroarylalkyl. Also disclosed are representative compounds such as 1-methyl-3-((R)-1-(naphthalen-1-yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(4-methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(2,3-dichlorophenyl)ethyl)-1-(3-methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(1-(2-methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, 3-(2-cyclopropyl-1-(2,3-dichlorophenyl)ethyl)-1-(3-methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, 3-(2-hydroxy-1-(naphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, 1-ethyl-1-(1-methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)-3-(3-(pyridin-3-yloxy)phenyl)propyl)urea, 1-methyl-1-(1-methylpiperidin-4-yl)-3-(3-morpholino-1-(naphthalen-1-yl)propyl)urea and 3-(1-(3-chloro-2-(pyridin-4-yl)phenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea. Also disclosed is a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined above, and one or more pharmaceutically acceptable excipients, for preventing and/or treating a subject having a disease which is pathophysiologically mediated by the ghrelin receptor, including conditions such as obesity, overweight, eating disorder, diabetes, metabolic syndrome, cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric disorder or substance abuse.
Description
ASYMMETRIC UREAS AND MEDICAL USES THEREOF
CROSS-REFERENCES TO RELATED APPLICATIONS
1. This application claims priority under 35 U.S.C. § 365(b) to PCT Application No.
, filed February 25, 2011, and under 35 U.S.C. § 119(e) to Provisional
U.S. Application No. 61/466,070, filed March 22, 2011. The disclosure of PCT Application
No. and U.S. Application No. 61/466,070 are hereby incorporated by
reference in their entirety.
FIELD OF THE INVENTION
2. The present invention relates to novel compounds based on asymmetric ureas, and
medical uses thereof, particularly in the treatment of medical conditions modulated by the
ghrelin receptor.
BACKGROUND
3. The growth hormone secretagogue receptor (GHS-R) regulates a number of
physiological processes, including growth hormone (GH) release, metabolism, and appetite.
Ghrelin, a circulating hormone produced predominantly by endocrine cells in the stomach, is
its endogenous ligand. Ghrelin is a 28 amino acid peptide with an acyl side chain required
for biological activity (Kojima et al., Nature, 402, 656-660, 1999). Ghrelin has been shown
to stimulate growth hormone (GH) release and to increase food intake when administered
both centrally and peripherally (Wren et al., Endocrinology, 141, 4325-4328, 2000).
4. Endogenous levels of ghrelin rise on fasting and fall on re-feeding in humans
(Cummings et al., Diabetes, 50, 1714-1719, 2001). Ghrelin also appears to play a role in
maintaining long term energy balance and appetite regulation. Chronic administration of
ghrelin in rodents leads to hyperphagia and weight gain that are independent of growth
hormone secretion (Tschop et al., Nature, 407, 908-913, 2000). Circulating ghrelin levels
decrease in response to chronic overfeeding and increase in response to chronic negative
energy balance associated with anorexia or exercise. Obese people generally have low
plasma ghrelin levels (Tschop et al., Diabetes, 50, 707-709, 2001) accordingly to the
physiological response of the body in reducing calories intake. Intravenous ghrelin is
effective in stimulating food intake in humans. A recent study showed a 28% food intake
— 1 —
increase from a buffet meal with a ghrelin infusion compared with saline control (Wren et al.,
J Clin Endocrinology and Metabolism, 86, 5992, 2001).
. In view of the above experimental evidence, compounds that modulate ghrelin
receptor activity have been proposed for preventing and/or treating disorders associated with
ghrelin receptor physiology. For example, antagonists at ghrelin receptor may reduce
appetite, reduce food intake, induce weight loss and treat obesity without affecting or
reducing the circulating growth hormone levels. On the other hand, agonists at ghrelin
receptor may be useful in stimulating food intake and thus be useful in treating eating
disorders, for example anorexia nervosa, or in treating cachexia resulting from cancer, AIDS
or Chronic Obstructive Pulmonary Disease (COPD). Ghrelin agonists may also be useful as
gastroprokinetic agents which can enhance gastrointestinal motility by increasing the
frequency of contractions in the small intestine or making them stronger, but without
disrupting their rhythm. Gastroprokinetic agents are used to relieve gastrointestinal
symptoms such as abdominal discomfort, bloating, constipation, heart burn, nausea, and
vomiting, and are used to treat a number of gastrointestinal disorders, including but not
limiting to, irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and
functional dyspepsia. Furthermore, compounds that modulate ghrelin receptor activity can
also be used to prevent or treat diseases related to substance abuse, for example, alcohol or
drug (e.g., amphetamines, barbiturates, benzodiazepines, ***e, methaqualone, and opioids)
abuse, which refers to a maladaptive pattern of use of a substance that is not considered
dependent.
6. A number of compounds acting on the ghrelin receptor have been reported in the
literature. YIL-781, for example, is a small molecule ghrelin receptor antagonist from Bayer
that reportedly improves glucose tolerance, suppress appetite and promote weigh loss (Esler
et al., Endocrinology 148 (11):5175-5185); LY444711 is an orally active ghrelin receptor
agonist from Lilly that reportedly induces adiposity by stimulating food consumption and
sparing fat utilization (Bioorg. & Med. Chem. Lett., 2004, 14, 5873-5876); Anamorelin is an
orally available ghrelin receptor small molecule agonist from Helsinn Therapeutics that is in
clinical trials for the treatment of anorexia and cachexia in cancer patients. Other small
molecule ghrelin receptor modulators can be found in , US 2009/0253673,
, , US 2007/0270473 and US 2009/0186870.
— 2 —
7. In view of the above, it is desirable to find new compounds which modulate
ghrelin receptor activity with enhanced efficacy and fewer undesirable side effects.
SUMMARY
8. In view of the foregoing, the inventors have developed a novel class of
compounds particularly well-suited for modulating the ghrelin receptor and having the
general formula (I):
with R and R -R as defined herein, and pharmaceutically acceptable salts or adducts thereof.
1 14
8.1. Accordingly, in one aspect the invention provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof,
N R O R
N NH R
Formula (I)
wherein:
R is aryl optionally substituted with one or more independent R substituents;
R is selected from the group consisting of hydroxyalkyl, alkyl, optionally substituted
with one or more independent R substituents;
R is selected from the group consisting of alkyl, aryl, arylalkyl, optionally substituted
with one or more independent R substituents; or R is OR ;
103 4
R , R , R , R are selected from the group consisting of hydrogen and alkyl;
6 7 8 9
103 104
R is selected from the group consisting of hydrogen, cyano, -NO , -OR , hydroxy,
amino, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl,
104, 104 104 105
heterocycloalkyl, heteroaryl, heteroarylalkyl, -C(O)R -C(O)OR , -C(O)NR R , -
— 3 —
104 105 104 105 104 105 104 104 104 105
NR R , -NR S(O) R , -NR C(O)R ,- S(O) R , -SR and -S(O) NR R ,
2 2 2
104 105
R and R are each independently selected from the group consisting of hydrogen,
cyano, NO , hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy,
alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl and heteroarylalkyl.
8.2. In another aspect, the invention provides a compound selected from the group
consisting of:
GA1 1-methyl((R)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA2 1-methyl((S)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA3 1-methyl(1-(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA4 3-(1-(4-methoxynaphthalen
yl)ethyl)methyl(1,3,3-
trimethylpiperidinyl)urea,
GA5 1-benzyl((R)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA6 3-(1-(2,3-dichlorophenyl)ethyl)
(3-methoxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
— 4 —
GA7 3-(1-(2,3-dichlorophenyl)ethyl)
(2-fluorobenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA8 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA9 3-(1-(2,3-dichlorophenyl)ethyl)
methyl(1,3,3-trimethylpiperidin-
4-yl)urea,
GA10 3-((R)(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA11 1-benzyl(1-(2,3-
dichlorophenyl)propyl)(1,3,3-
trimethylpiperidinyl)urea,
GA12 3-((S)(2,3-
dichlorophenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA13 3-((R)(2,3-
dichlorophenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA14 3-(1-(2,3-dichlorophenyl)ethyl)
methyl(1,3,3-trimethylpiperidin-
4-yl)urea,
— 5 —
GA15 1-benzyl((S)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA16 1-benzyl((R)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA17 1-benzyl(1-(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA18 3-(1-(2,3-dichlorophenyl)propyl)-
1-methyl(1,3,3-
trimethylpiperidinyl)urea,
GA19 3-(1-(2,3-difluorophenyl)ethyl)
methyl(1,3,3-trimethylpiperidin-
4-yl)urea,
GA20 1-benzyl(1-(2,3-
dichlorophenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA21 1-benzyl(1-(2,3-
difluorophenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
— 6 —
GA22 1-benzyl(1-(4-
methoxynaphthalenyl)ethyl)
(1,3,3-trimethylpiperidinyl)urea,
GA23 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA26 3-(2-hydroxy(naphthalen
yl)ethyl)methyl(1,3,3-
trimethylpiperidinyl)urea,
GA27 1-(4-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA28 1-benzyl(3,3-diethyl
methylpiperidinyl)((S)
(naphthalenyl)ethyl)urea,
GA29 1-benzyl(3,3-diethyl
methylpiperidinyl)((R)
(naphthalenyl)ethyl)urea,
GA30 1-benzyl(3,3-diethyl
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
— 7 —
GA31 3-(2-(benzyloxy)(naphthalen
yl)ethyl)methyl(1,3,3-
trimethylpiperidinyl)urea,
GA33 3-((R)(2,3-
dichlorophenyl)ethyl)(3-
methoxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA34 3-(2-cyclopropyl(2,3-
dichlorophenyl)ethyl)(3-
methoxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA35 3-(1-(2,3-dichlorophenyl)ethyl)
(3-hydroxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA37 1-benzyl(1-(2,3-
dihydroxyphenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA38 3-((R)(2,3-
dichlorophenyl)ethyl)(3-(2-
hydroxyethoxy)benzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA39 3-(1-(2,3-difluoro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
— 8 —
GA40 3-(1-(2,3-difluoro
hydroxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA46 1-ethyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)ethyl)urea,
GA47 3-(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA48 3-(2-hydroxy(naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA49 3-(2-hydroxy(4-
methoxynaphthalenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA50 1-(1-methylpiperidinyl)(1-
(naphthalenyl)ethyl)(pyridin-
3-ylmethyl)urea,
GA57 1-(cyclohexylmethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA58 1-isopropyl(1-methylpiperidin-
4-yl)(1-(naphthalen
yl)ethyl)urea,
— 9 —
GA59 1-(2-methoxyethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA62 1-(cyclopropylmethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA63 3-(1-(2-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA67 3-(2-methoxy(naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA68 3-(3-methoxy(naphthalen
yl)propyl)methyl(1-
methylpiperidinyl)urea,
GA69 1-methyl(1-methylpiperidin
yl)(1-(naphthalen
yl)propyl)urea,
GA73 (S)(1-methylpiperidinyl)
(1-(naphthalenyl)ethyl)
(pyridinylmethyl)urea,
GA74 (R)(1-methylpiperidinyl)
(1-(naphthalenyl)ethyl)
(pyridinylmethyl)urea,
— 10 —
GA75 1-isobutyl(1-methylpiperidin
yl)(1-(naphthalen
yl)ethyl)urea,
GA76 1-(cyclobutylmethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA77 1-butyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)ethyl)urea,
GA79 1-(1-methylpiperidinyl)(1-
(naphthalenyl)ethyl)(pyridin-
2-ylmethyl)urea,
GA80 1-(1-methylpiperidinyl)(1-
(naphthalenyl)ethyl)(pyridin-
4-ylmethyl)urea,
GA82 (R)ethyl(1-methylpiperidin-
4-yl)(1-(naphthalen
yl)ethyl)urea,
GA83 3-(2-hydroxy(4-
methoxynaphthalenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA84 3-(2-hydroxy(naphthalen
yl)ethyl)(1-methylpiperidin
yl)(pyridinylmethyl)urea,
— 11 —
GA85 3-(2-methoxy(4-
methoxynaphthalenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA86 3-(1-(2,3-dichlorophenyl)ethyl)
(3-hydroxybenzyl)(1-
methylpiperidinyl)urea,
GA87 1-benzyl(1,3-dimethylpiperidin-
4-yl)((R)(naphthalen
yl)ethyl)urea,
GA88 1-(1,3-dimethylpiperidinyl)
methyl((R)(naphthalen
yl)ethyl)urea,
GA89 3-(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA90 (R)(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA91 (S)(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA92 3-(1-(4,8-dimethoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA93 3-(1-(4-
(methoxymethoxy)naphthalen
yl)ethyl)methyl(1-
— 12 —
methylpiperidinyl)urea,
GA94 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA95 (R)(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA96 (S)(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA97 3-(1-(2,3-dichlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA98 1-benzyl(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA99 3-(1-(2,3-dichlorophenyl)ethyl)
(3-fluorobenzyl)(1-
methylpiperidinyl)urea,
GA100 1-(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA101 3-(1-(3,5-difluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
— 13 —
GA102 3-(1-(2-chlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA103 3-(1-(3-fluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA104 3-(1-(4-chlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA105 3-(1-(2,4-difluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA106 1-methyl(1-methylpiperidin
yl)(1-(o-tolyl)ethyl)urea,
GA107 1-methyl(1-methylpiperidin
yl)(1-(4-
(methylsulfonyl)phenyl)ethyl)urea,
GA108 1-(cyclohexylmethyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA109 1-(cyclopropylmethyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA110 3-(1-(2,3-dichlorophenyl)ethyl)
ethyl(1-methylpiperidin
yl)urea,
— 14 —
GA111 3-(1-(2,3-dichlorophenyl)ethyl)
(1-methylpiperidinyl)
(pyridinylmethyl)urea,
GA112 3-(1-(3-chlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA113 1-benzyl(1-(3-
chlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA114 1-(3-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA115 3-(1-(2,3-dichlorophenyl)ethyl)
(2-methoxybenzyl)(1-
methylpiperidinyl)urea,
GA116 3-(1-(2,3-dichlorophenyl)ethyl)
(3-methoxybenzyl)(1-
methylpiperidinyl)urea,
GA117 3-(1-(2,3-dichlorophenyl)ethyl)
(4-fluorobenzyl)(1-
methylpiperidinyl)urea,
— 15 —
GA118 3-(1-(2,3-dichlorophenyl)ethyl)
(2-fluorobenzyl)(1-
methylpiperidinyl)urea,
GA119 1-(4-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA120 3-(1-(3,4-dichlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA121 3-(1-(2,3-dichlorophenyl)ethyl)
(4-methoxybenzyl)(1-
methylpiperidinyl)urea,
GA122 3-(1-(2,3-dichlorophenyl)propyl)-
1-ethyl(1-methylpiperidin
yl)urea,
GA123 1-(cyclohexylmethyl)(1-(2,3-
dichlorophenyl)propyl)(1-
methylpiperidinyl)urea,
GA124 3-(1-(2,3-difluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA125 1-benzyl(1-(2,3-
difluorophenyl)ethyl)(1-
methylpiperidinyl)urea,
— 16 —
GA126 1-(cyclohexylmethyl)(1-(2,3-
difluorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA127 (R)(1-(2,3-
dichlorophenyl)ethyl)ethyl(1-
methylpiperidinyl)urea,
GA128 1-benzyl(1-(2,3-
dichlorophenyl)ethyl)(1,3-
dimethylpiperidinyl)urea,
GA129 3-(1-(2,3-dichlorophenyl)ethyl)
(1,3-dimethylpiperidinyl)
methylurea,
GA130 (S)(1-(2,3-
dichlorophenyl)ethyl)ethyl(1-
methylpiperidinyl)urea,
GA131 (R)(1-(2,3-
dichlorophenyl)ethyl)ethyl(1-
methylpiperidinyl)urea,
GA132 3-(1-(2,3-dichlorophenyl)ethyl)
ethyl(1-methylpiperidin
yl)urea,
GA133 3-((R)(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
— 17 —
GA134 3-((S)(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA135 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA136 3-(1-(2,3-difluorophenyl)ethyl)
(1,3-dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA137 3-(1-(2,3-dichlorophenyl)ethyl)
(4-(hydroxymethyl)benzyl)(1-
methylpiperidinyl)urea,
GA138 methyl 4-((3-(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidin
yl)ureido)methyl)benzoate,
GA139 3-(2-cyclopropyl(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA140 3-(1-(2,3-dichlorophenyl)
hydroxyethyl)methyl(1-
methylpiperidinyl)urea,
GA141 (R)(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
— 18 —
GA142 (S)(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA143 1-(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA144 3-(1-(2,3-dimethoxyphenyl)ethyl)-
1-methyl(1-methylpiperidin
yl)urea,
GA145 3-(1-(2,3-difluoro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA146 3-(1-(2,3-dichlorophenyl)
methoxyethyl)methyl(1-
methylpiperidinyl)urea,
GA147 N-(2,3-dichloro(1-(3-methyl
(1-methylpiperidin
yl)ureido)ethyl)phenyl)acetamide,
GA148 3-(1-(4-amino-2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA149 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
— 19 —
GA150 1-ethyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)(3-
(pyridin
yloxy)phenyl)propyl)urea,
GA151 1-methyl(1-methylpiperidin
yl)(1-(naphthalenyl)
(pyridinyl)propyl)urea,
GA152 1-methyl(1-methylpiperidin
yl)(3-morpholino(naphthalen-
1-yl)propyl)urea,
GA153 1-ethyl(3-(3-methoxyphenyl)
(naphthalenyl)propyl)(1-
methylpiperidinyl)urea,
GA154 3-(3-(3-(benzyloxy)phenyl)
(naphthalenyl)propyl)ethyl
(1-methylpiperidinyl)urea,
GA155 1-ethyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)(pyridin-
3-yl)propyl)urea,
— 20 —
GA156 3-(3-(3-(benzyloxy)phenyl)
(naphthalenyl)propyl)(1-
methylpiperidinyl)(pyridin
ylmethyl)urea,
GA157 3-(3-(3-(benzyloxy)phenyl)(2,3-
dichlorophenyl)propyl)methyl-
1-(1-methylpiperidinyl)urea,
GA158 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA159 3-(2-(benzylamino)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA161 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)(2-
chlorobenzyl)(1-
methylpiperidinyl)urea,
GA162 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)(4-
(hydroxymethyl)benzyl)(1-
methylpiperidinyl)urea,
— 21 —
GA163 3-(1-(2,3-dichlorophenyl)((4-
methoxybenzyl)oxy)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA164 3-(1-(2,3-dichlorophenyl)
(pyridinylmethoxy)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA165 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA166 (S)(1-(2,3-dichloro
methoxyphenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA167 (R)(1-(2,3-dichloro
methoxyphenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA168 1-hydroxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA169 (R)hydroxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA170 (S)hydroxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
— 22 —
GA171 3-(1-(2,3-dichlorophenyl)ethyl)
methoxy(1-methylpiperidin
yl)urea,
GA172 (R)(1-(2,3-
dichlorophenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA173 (S)(1-(2,3-
dichlorophenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA174 1-methoxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA175 (R)methoxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA176 (S)methoxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA177 3-(1-(2,3-dichlorophenyl)ethyl)
hydroxy(1-methylpiperidin
yl)urea,
GA178 (R)(1-(2,3-
dichlorophenyl)ethyl)hydroxy
(1-methylpiperidinyl)urea,
GA179 (S)(1-(2,3-
dichlorophenyl)ethyl)hydroxy
(1-methylpiperidinyl)urea,
GA180 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)hydroxy-
1-(1-methylpiperidinyl)urea,
— 23 —
GA181 (R)(1-(2,3-dichloro
methoxyphenyl)ethyl)hydroxy-
1-(1-methylpiperidinyl)urea,
GA182 (S)(1-(2,3-dichloro
methoxyphenyl)ethyl)hydroxy-
1-(1-methylpiperidinyl)urea,
GA183 3-(1-(2,3-dichloro
(dimethylamino)phenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA184 3-(1-(4-((4-
methoxybenzyl)oxy)naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA185 3-(1-(4-hydroxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA186 3-(1-(4,5-dimethoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA187 3-(1-(2,3-dichlorophenyl)
(pyridinylmethoxy)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA189 3-(1-(2-chloro-3,4-
dimethoxyphenyl)ethyl)methyl-
1-(1-methylpiperidinyl)urea,
— 24 —
GA190 1-methyl(1-methylpiperidin
yl)(1-(2,3,4-
trichlorophenyl)ethyl)urea,
GA191 1-methyl(1-methylpiperidin
yl)(1-(4-(pyridin
ylmethoxy)naphthalen
yl)ethyl)urea,
GA192 3-(1-(6-chloro-[1,1'-biphenyl]
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA193 3-(1-(3-chloro(pyridin
yl)phenyl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA194 3-(1-(2,3-dichloro
methylphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA195 3-(1-(3-chloro
methylphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA196 3-(1-(2,3-dichlorophenyl)((4-
(hydroxymethyl)benzyl)oxy)ethyl)-
1-methyl(1-methylpiperidin
yl)urea,
GA197 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
— 25 —
GA198 (R)(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA199 (S)(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA200 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA201 3-((R)(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA202 3-((S)(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA203 3-(1-(4-(2-
(benzyloxy)ethoxy)naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea.
8.3. In another aspect, the invention relates to the use of a compound of formula (I)
according to the invention, or a pharmaceutically acceptable salt thereof in the manufacture of
a medicament for preventing and/or treating a subject having a disease which is
pathophysiologically mediated by the ghrelin receptor.
8.4. In another aspect, the invention provides a pharmaceutical composition for
preventing and/or treating a subject comprising a therapeutically effective amount of a
compound according to the invention, and one or more pharmaceutically acceptable
excipients.
— 26 —
8.5. Certain statements that appear below are broader than what appears in the
statements of the invention above. These statements are provided in the interests of providing
the reader with a better understanding of the invention and its practice. The reader is directed
to the accompanying claim set which defines the scope of the invention.
9. Compounds of formula (I), also known as asymmetric ureas, are particularly
useful for preventing and/or treating diseases that are pathophysiologically related to the
ghrelin receptor in a subject. Accordingly, in another embodiment described is a method of
treating a disease that is mediated by the ghrelin receptor, comprising administering to said
subject a therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or adduct thereof.
. Also disclosed are pharmaceutical compositions for preventing and/or treating
diseases which are pathophysiologically related to ghrelin receptor in a subject, comprising a
therapeutically effective amount of a compound of formula (I), or a pharmaceutically
acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
11. Before the present compounds, compositions, articles, devices, and/or methods
are disclosed and described, it is to be understood that they are not limited to specific
synthetic methods or specific treatment methods unless otherwise specified, or to particular
reagents unless otherwise specified, as such may, of course, vary. It is also to be understood
that the terminology used herein is for the purpose of describing particular embodiments only
and is not intended to be limiting.
Materials
A. Compounds
12. Disclosed are compounds, and pharmaceutically acceptable salts or adducts
thereof, represented by formula (I):
— 27 —
wherein:
R is selected from the group consisting of aryl, arylalkyl, carbocyclic ring,
heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, optionally substituted
with one or more independent R substituents;
13. R is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl,
101 101
amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -C(O)R , -C(O)OR , aryl,
arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each
optionally independently substituted with one or more independent R substituents;
14. R is hydrogen or R and R , together with the atoms connecting the same, form
2 1 2
a fused or non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ring which is
optionally independently substituted with one or more R substituents;
. R is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,
aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(O)R ,
101 101 102 102 101 101 102
-C(O)OR , -C(O)NR R , -S(O) R , -SR and -S(O) NR R , optionally substituted
with one or more independent R substituents;
16. R is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl,
arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -OR ,
101 102 101 101 101 102 101 102 102 101
NR R , -C(O)R , -C(O)OR , -C(O)NR R , -alkylNR R , -S(O) R , -SR
101 102 103
and -S(O) NR R , optionally substituted with one or more independent R substituents;
or R and R , together with the atoms connecting R and R , form a fused or non-fused mono,
3 4 3 4
bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently
substituted with one or more R substituents;
17. R is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl,
101 101
arylalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, oxide (=O), -C(O)R , -C(O)OR , -
101 102 102 101 101 102
C(O)NR R , -S(O) R , -SR and -S(O) NR R ;
18. R , R , R , R , R , R , R , R and R are each independently selected from
6 7 8 9 10 11 12 13 14
the group consisting of hydrogen, cyano, -NO , -OR , hydroxy, amino, alkyl, alkenyl,
cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl,
101 101 101 102
heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(O)R , -C(O)OR , -C(O)NR R , -
101 102 101 102 101 102 102 101 101 102
NR R , -NR S(O) R , -NR C(O)R , -S(O) R , -SR and -S(O) NR R , each
2 2 2
optionally independently substituted with one or more independent R substituents; or any
two or more substituents selected from the group consisting of R , R , R , R , R , R , R ,
6 7 8 9 10 11 12
— 28 —
R and R together with the atoms connecting the same, form a fused or non-fused mono,
13 14
bicyclic or tricyclic heterocyclic or carbocyclic ring which is optionally independently
substituted with one or more R substituents; and
101 102 103
19. R , R and R are each independently selected from the group consisting of
hydrogen, cyano, -NO , -OR , hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy,
alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,
104 104 104 105 104 105 104 105
heteroarylalkyl, -C(O)R , -C(O)OR , -C(O)NR R , -NR R , -NR S(O) R , -
104 105 104 104 104 105
NR C(O)R , -S(O) R , -SR and -S(O) NR R , each optionally independently
103 101 102
substituted with one or more independent R substituents; or R , R , together with the
atoms connecting the same, form a fused or non-fused mono, bicyclic or tricyclic heterocyclic
or carbocyclic ring which is optionally independently substituted with one or more R
substituents; and
104 105
. R and R are each independently selected from the group consisting of
hydrogen, cyano, -NO , hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen,
alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and
heteroarylalkyl.
21. In some forms, the compounds as presently disclosed are compounds of formula
(I), or pharmaceutically acceptable salts or adducts thereof, wherein R is aryl or heteroaryl.
In some other forms, the compounds as presently disclosed are compounds of formula (I), or
pharmaceutically acceptable salts or adducts thereof, wherein R is R is selected from the
group consisting of phenyl, naphthalene, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl,
anthracenyl, phenanthrenyl, benzonaphthenyl, fluorenyl, indolizinyl, pyrindinyl,
pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl,
isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl,
benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl,
benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl,
isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,
benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl, which is optionally independently
substituted with from one to six substituents independently selected from the group
consisting of hydrogen, halogen, alkoxy, haloalkyl, cyano, -NO , -OR , hydroxy, amino,
alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,
— 29 —
101 101 101 102 101 102 101 102
heteroarylalkyl, -C(O)R , -C(O)OR , -C(O)NR R , -NR R , -NR S(O) R , -
101 102 102 101 101 102
NR C(O)R , -S(O) R , -SR and -S(O) NR R .
22. In some forms, the compounds as presently disclosed are compounds of formula
(I), or pharmaceutically acceptable salts or adducts thereof, wherein R is phenyl or
naphthalene which is optionally independently substituted with from one to six substituents
independently selected from the group consisting of hydrogen, chloro, fluoro, bromo,
trifluoromethyl, cyano, methoxy, ethoxy, methyl and ethyl.
23. In some forms, the compounds as presently disclosed are compounds of formula
(I), or pharmaceutically acceptable salts or adducts thereof, wherein R is selected from the
group consisting of hydrogen, alkoxy, alkoxyalkyl, -OR , hydroxy, hydroxyalkyl, amino,
alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl
and heteroarylalkyl. In some other forms, the compounds as presently disclosed are
compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein
R is selected from the group consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl,
arylalkyl and heteroarylalkyl. In some other forms, the compounds as presently disclosed are
compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein
R is selected from the group consisting of methyl, -CH OH, and -CH -O-CH -phenyl.
1 2 2 2
24. In some other forms, the compounds as presently disclosed are compounds of
formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is hydrogen,
alkyl or cycloalkyl.
. In some forms, the compounds as presently disclosed are compounds of formula
(I), or pharmaceutically acceptable salts or adducts thereof, wherein R is selected from the
group consisting of alkyl, cycloalkyl, hydroxy, amino, alkoxy, alkylamino, aryl, arylalkyl,
heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and aminoalkyl. In some
other forms, the compounds as presently disclosed are compounds of formula (I), or
pharmaceutically acceptable salts or adducts thereof, wherein R is methyl, ethyl, benzyl, or
benzyl substituted with from one to five substituents independently selected from the group
consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy.
26. In some forms, the compounds as presently disclosed are compounds of formula
(I), or pharmaceutically acceptable salts or adducts thereof, wherein R is selected from the
group consisting of alkyl, cycloalkyl, oxide (=O), aryl, arylalkyl, heterocycloalkyl,
101 101
heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(O)R , -C(O)OR and -
— 30 —
101 102
C(O)NR R . In some other forms, the compounds as presently disclosed are compounds
of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R is methyl.
27. In some forms, the compounds as presently disclosed are compounds of formula
(I), or pharmaceutically acceptable salts or adducts thereof, wherein R , R , R , R , R , R ,
6 7 8 9 10 11
R , R and R are each independently selected from the group consisting of hydrogen, alkyl,
12 13 14
101 103
cycloalkyl, , -C(O)OR , and -alkylOR . In some other forms, the compounds as presently
disclosed are compounds of formula (I), or pharmaceutically acceptable salts or adducts
thereof, wherein R and R are each independently hydrogen, alkyl, cycloalkyl, -C(O)OR ,
or -alkylOR . In some other forms, the compounds as presently disclosed are compounds of
formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein R and R are
each independently hydrogen, methyl, ethyl, -C(=O)OEt, or –CH OH. In some other forms,
the compounds as presently disclosed are compounds of formula (I), or pharmaceutically
acceptable salts or adducts thereof, wherein R and R , together with the atom connecting
them, form a cycloalkyl ring. In some forms, the compounds as presently disclosed are
compounds of formula (I), or pharmaceutically acceptable salts or adducts thereof, wherein
said cycloalkyl ring as formed by R and R together with the atom connecting them, is
cyclopropane.
28. In some forms, the compounds as presently disclosed are compounds of formula
(I), or pharmaceutically acceptable salts or adducts thereof, wherein the compound of formula
(I) is a compound selected from the group consisting of:
Compound Chemical Structure Chemical Name
GA1 1-methyl((R)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA2 1-methyl((S)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
— 31 —
GA3 1-methyl(1-(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA4 3-(1-(4-methoxynaphthalen
yl)ethyl)methyl(1,3,3-
trimethylpiperidinyl)urea,
GA5 1-benzyl((R)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA6 3-(1-(2,3-dichlorophenyl)ethyl)
(3-methoxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA7 3-(1-(2,3-dichlorophenyl)ethyl)
(2-fluorobenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA8 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA9 3-(1-(2,3-dichlorophenyl)ethyl)
methyl(1,3,3-trimethylpiperidin-
4-yl)urea,
GA10 3-((R)(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
— 32 —
GA11 1-benzyl(1-(2,3-
dichlorophenyl)propyl)(1,3,3-
trimethylpiperidinyl)urea,
GA12 3-((S)(2,3-
dichlorophenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA13 3-((R)(2,3-
dichlorophenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA14 3-(1-(2,3-dichlorophenyl)ethyl)
methyl(1,3,3-trimethylpiperidin-
4-yl)urea,
GA15 1-benzyl((S)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA16 1-benzyl((R)(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA17 1-benzyl(1-(naphthalen
yl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA18 3-(1-(2,3-dichlorophenyl)propyl)-
1-methyl(1,3,3-
trimethylpiperidinyl)urea,
— 33 —
GA19 3-(1-(2,3-difluorophenyl)ethyl)
methyl(1,3,3-trimethylpiperidin-
4-yl)urea,
GA20 1-benzyl(1-(2,3-
dichlorophenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA21 1-benzyl(1-(2,3-
difluorophenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA22 1-benzyl(1-(4-
methoxynaphthalenyl)ethyl)
(1,3,3-trimethylpiperidinyl)urea,
GA23 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA24 3-(1-(2,3-dichlorophenyl)ethyl)
methyl(1,2,2,5,5-
pentamethylpiperidinyl)urea,
GA25 methyl 2-(3-methyl(1,3,3-
trimethylpiperidinyl)ureido)
(naphthalenyl)acetate,
GA26 3-(2-hydroxy(naphthalen
yl)ethyl)methyl(1,3,3-
trimethylpiperidinyl)urea,
— 34 —
GA27 1-(4-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA28 1-benzyl(3,3-diethyl
methylpiperidinyl)((S)
(naphthalenyl)ethyl)urea,
GA29 1-benzyl(3,3-diethyl
methylpiperidinyl)((R)
(naphthalenyl)ethyl)urea,
GA30 1-benzyl(3,3-diethyl
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA31 3-(2-(benzyloxy)(naphthalen
yl)ethyl)methyl(1,3,3-
trimethylpiperidinyl)urea,
GA32 ethyl 4-(1-benzyl(1-(2,3-
dichlorophenyl)ethyl)ureido)-1,3-
dimethylpiperidinecarboxylate,
GA33 3-((R)(2,3-
dichlorophenyl)ethyl)(3-
methoxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
— 35 —
GA34 3-(2-cyclopropyl(2,3-
dichlorophenyl)ethyl)(3-
methoxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA35 3-(1-(2,3-dichlorophenyl)ethyl)
(3-hydroxybenzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA36 1-benzyl(1-(2,3-
dichlorophenyl)ethyl)(3-
(hydroxymethyl)-1,3-
dimethylpiperidinyl)urea,
GA37 1-benzyl(1-(2,3-
dihydroxyphenyl)ethyl)(1,3,3-
trimethylpiperidinyl)urea,
GA38 3-((R)(2,3-
dichlorophenyl)ethyl)(3-(2-
hydroxyethoxy)benzyl)(1,3,3-
trimethylpiperidinyl)urea,
GA39 3-(1-(2,3-difluoro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA40 3-(1-(2,3-difluoro
hydroxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
— 36 —
GA41 4-(1-benzyl(1-(2,3-
dichlorophenyl)ethyl)ureido)-1,3-
dimethylpiperidinecarboxylic
acid,
GA42 ethyl 4-(3-(1-(2,3-
dichlorophenyl)ethyl)
methylureido)-1,3-
dimethylpiperidinecarboxylate,
GA43 3-(1-(2,3-dichlorophenyl)ethyl)
(3-(hydroxymethyl)-1,3-
dimethylpiperidinyl)
methylurea,
GA44 4-(3-(1-(2,3-dichlorophenyl)ethyl)-
1-methylureido)-1,3,3-
trimethylpiperidine 1-oxide,
GA45 3-(1-(benzo[d][1,3]dioxol
yl)ethyl)benzyl(1,3,3-
trimethylpiperidinyl)urea,
GA46 1-ethyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)ethyl)urea,
GA47 3-(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA48 3-(2-hydroxy(naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
— 37 —
GA49 3-(2-hydroxy(4-
methoxynaphthalenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA50 1-(1-methylpiperidinyl)(1-
(naphthalenyl)ethyl)(pyridin-
3-ylmethyl)urea,
GA51 1-cyclopentyl(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA52 1-methyl(1-(naphthalen
yl)ethyl)(piperidinyl)urea,
GA53 1-(1-acetylpiperidinyl)
methyl(1-(naphthalen
yl)ethyl)urea,
GA54 1-methyl(1-
(methylsulfonyl)piperidinyl)
(1-(naphthalenyl)ethyl)urea,
GA55 1-methyl(1-(naphthalen
yl)ethyl)(1-(pyridin
ylmethyl)piperidinyl)urea,
GA56 1-cyclohexyl(1-methylpiperidin-
4-yl)(1-(naphthalen
yl)ethyl)urea,
— 38 —
GA57 1-(cyclohexylmethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA58 1-isopropyl(1-methylpiperidin-
4-yl)(1-(naphthalen
yl)ethyl)urea,
GA59 1-(2-methoxyethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA60 1-(1-ethylpiperidinyl)methyl-
3-(1-(naphthalenyl)ethyl)urea,
GA61 1-ethyl(1-methyl(1-
(naphthalen
yl)ethyl)ureido)piperidine 1-oxide,
GA62 1-(cyclopropylmethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA63 3-(1-(2-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA64 1-methyl(1-methylpiperidin
yl)(1-(quinolinyl)ethyl)urea,
GA65 tert-butyl 4-(1-methyl(1-
(naphthalen
yl)ethyl)ureido)piperidine
carboxylate,
— 39 —
GA66 1-(1-formylpiperidinyl)
methyl(1-(naphthalen
yl)ethyl)urea,
GA67 3-(2-methoxy(naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA68 3-(3-methoxy(naphthalen
yl)propyl)methyl(1-
methylpiperidinyl)urea,
GA69 1-methyl(1-methylpiperidin
yl)(1-(naphthalen
yl)propyl)urea,
GA70 1-methyl(1-methylpiperidin
yl)(1-(quinolinyl)ethyl)urea,
GA71 1-methyl(1-methylpiperidin
yl)(2-(naphthalenyl)propan
yl)urea,
GA72 3-(1-(2-chloroquinolinyl)ethyl)-
1-methyl(1-methylpiperidin
yl)urea,
GA73 (S)(1-methylpiperidinyl)
(1-(naphthalenyl)ethyl)
(pyridinylmethyl)urea,
— 40 —
GA74 (R)(1-methylpiperidinyl)
(1-(naphthalenyl)ethyl)
(pyridinylmethyl)urea,
GA75 1-isobutyl(1-methylpiperidin
yl)(1-(naphthalen
yl)ethyl)urea,
GA76 1-(cyclobutylmethyl)(1-
methylpiperidinyl)(1-
(naphthalenyl)ethyl)urea,
GA77 1-butyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)ethyl)urea,
GA78 3-(1-(2-methoxyquinolin
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA79 1-(1-methylpiperidinyl)(1-
(naphthalenyl)ethyl)(pyridin-
2-ylmethyl)urea,
GA80 1-(1-methylpiperidinyl)(1-
(naphthalenyl)ethyl)(pyridin-
4-ylmethyl)urea,
GA81 (S)ethyl(1-(2-
methoxyquinolinyl)ethyl)(1-
methylpiperidinyl)urea,
— 41 —
GA82 (R)ethyl(1-methylpiperidin-
4-yl)(1-(naphthalen
yl)ethyl)urea,
GA83 3-(2-hydroxy(4-
methoxynaphthalenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA84 3-(2-hydroxy(naphthalen
yl)ethyl)(1-methylpiperidin
yl)(pyridinylmethyl)urea,
GA85 3-(2-methoxy(4-
methoxynaphthalenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA86 3-(1-(2,3-dichlorophenyl)ethyl)
(3-hydroxybenzyl)(1-
methylpiperidinyl)urea,
GA87 1-benzyl(1,3-dimethylpiperidin-
4-yl)((R)(naphthalen
yl)ethyl)urea,
GA88 1-(1,3-dimethylpiperidinyl)
methyl((R)(naphthalen
yl)ethyl)urea,
GA89 3-(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
— 42 —
GA90 (R)(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA91 (S)(1-(4-methoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA92 3-(1-(4,8-dimethoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA93 3-(1-(4-
(methoxymethoxy)naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA94 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA95 (R)(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA96 (S)(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA97 3-(1-(2,3-dichlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA98 1-benzyl(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
— 43 —
GA99 3-(1-(2,3-dichlorophenyl)ethyl)
(3-fluorobenzyl)(1-
methylpiperidinyl)urea,
GA100 1-(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA101 3-(1-(3,5-difluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA102 3-(1-(2-chlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA103 3-(1-(3-fluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA104 3-(1-(4-chlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA105 3-(1-(2,4-difluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA106 1-methyl(1-methylpiperidin
yl)(1-(o-tolyl)ethyl)urea,
GA107 1-methyl(1-methylpiperidin
yl)(1-(4-
(methylsulfonyl)phenyl)ethyl)urea,
— 44 —
GA108 1-(cyclohexylmethyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA109 1-(cyclopropylmethyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA110 3-(1-(2,3-dichlorophenyl)ethyl)
ethyl(1-methylpiperidin
yl)urea,
GA111 3-(1-(2,3-dichlorophenyl)ethyl)
(1-methylpiperidinyl)
(pyridinylmethyl)urea,
GA112 3-(1-(3-chlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA113 1-benzyl(1-(3-
chlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA114 1-(3-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA115 3-(1-(2,3-dichlorophenyl)ethyl)
(2-methoxybenzyl)(1-
methylpiperidinyl)urea,
— 45 —
GA116 3-(1-(2,3-dichlorophenyl)ethyl)
(3-methoxybenzyl)(1-
methylpiperidinyl)urea,
GA117 3-(1-(2,3-dichlorophenyl)ethyl)
(4-fluorobenzyl)(1-
methylpiperidinyl)urea,
GA118 3-(1-(2,3-dichlorophenyl)ethyl)
(2-fluorobenzyl)(1-
methylpiperidinyl)urea,
GA119 1-(4-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA120 3-(1-(3,4-dichlorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA121 3-(1-(2,3-dichlorophenyl)ethyl)
(4-methoxybenzyl)(1-
methylpiperidinyl)urea,
GA122 3-(1-(2,3-dichlorophenyl)propyl)-
1-ethyl(1-methylpiperidin
yl)urea,
GA123 1-(cyclohexylmethyl)(1-(2,3-
dichlorophenyl)propyl)(1-
methylpiperidinyl)urea,
— 46 —
GA124 3-(1-(2,3-difluorophenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA125 1-benzyl(1-(2,3-
difluorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA126 1-(cyclohexylmethyl)(1-(2,3-
difluorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA127 (R)(1-(2,3-
dichlorophenyl)ethyl)ethyl(1-
methylpiperidinyl)urea,
GA128 1-benzyl(1-(2,3-
dichlorophenyl)ethyl)(1,3-
dimethylpiperidinyl)urea,
GA129 3-(1-(2,3-dichlorophenyl)ethyl)
(1,3-dimethylpiperidinyl)
methylurea,
GA130 (S)(1-(2,3-
dichlorophenyl)ethyl)ethyl(1-
methylpiperidinyl)urea,
GA131 (R)(1-(2,3-
dichlorophenyl)ethyl)ethyl(1-
methylpiperidinyl)urea,
— 47 —
GA132 3-(1-(2,3-dichlorophenyl)ethyl)
ethyl(1-methylpiperidin
yl)urea,
GA133 3-((R)(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA134 3-((S)(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA135 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)(1,3-
dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA136 3-(1-(2,3-difluorophenyl)ethyl)
(1,3-dimethylpiperidinyl)(3-
methoxybenzyl)urea,
GA137 3-(1-(2,3-dichlorophenyl)ethyl)
(4-(hydroxymethyl)benzyl)(1-
methylpiperidinyl)urea,
GA138 methyl 4-((3-(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidin
yl)ureido)methyl)benzoate,
GA139 3-(2-cyclopropyl(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
— 48 —
GA140 3-(1-(2,3-dichlorophenyl)
hydroxyethyl)methyl(1-
methylpiperidinyl)urea,
GA141 (R)(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA142 (S)(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA143 1-(2-chlorobenzyl)(1-(2,3-
dichlorophenyl)ethyl)(1-
methylpiperidinyl)urea,
GA144 3-(1-(2,3-dimethoxyphenyl)ethyl)-
1-methyl(1-methylpiperidin
yl)urea,
GA145 3-(1-(2,3-difluoro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA146 3-(1-(2,3-dichlorophenyl)
methoxyethyl)methyl(1-
methylpiperidinyl)urea,
GA147 N-(2,3-dichloro(1-(3-methyl
(1-methylpiperidin
yl)ureido)ethyl)phenyl)acetamide,
— 49 —
GA148 3-(1-(4-amino-2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA149 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA150 1-ethyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)(3-
(pyridin
yloxy)phenyl)propyl)urea,
GA151 1-methyl(1-methylpiperidin
yl)(1-(naphthalenyl)
(pyridinyl)propyl)urea,
GA152 1-methyl(1-methylpiperidin
yl)(3-morpholino(naphthalen-
1-yl)propyl)urea,
GA153 1-ethyl(3-(3-methoxyphenyl)
(naphthalenyl)propyl)(1-
methylpiperidinyl)urea,
— 50 —
GA154 3-(3-(3-(benzyloxy)phenyl)
(naphthalenyl)propyl)ethyl
(1-methylpiperidinyl)urea,
GA155 1-ethyl(1-methylpiperidinyl)-
3-(1-(naphthalenyl)(pyridin-
3-yl)propyl)urea,
GA156 3-(3-(3-(benzyloxy)phenyl)
(naphthalenyl)propyl)(1-
methylpiperidinyl)(pyridin
ylmethyl)urea,
GA157 3-(3-(3-(benzyloxy)phenyl)(2,3-
dichlorophenyl)propyl)methyl-
1-(1-methylpiperidinyl)urea,
GA158 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA159 3-(2-(benzylamino)(2,3-
dichlorophenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
— 51 —
GA160 3-(1-(2,3-dichlorophenyl)((3-
(hydroxymethyl)benzyl)oxy)ethyl)-
1-methyl(1-methylpiperidin
yl)urea,
GA161 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)(2-
chlorobenzyl)(1-
methylpiperidinyl)urea,
GA162 3-(2-(benzyloxy)(2,3-
dichlorophenyl)ethyl)(4-
(hydroxymethyl)benzyl)(1-
methylpiperidinyl)urea,
GA163 3-(1-(2,3-dichlorophenyl)((4-
methoxybenzyl)oxy)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA164 3-(1-(2,3-dichlorophenyl)
(pyridinylmethoxy)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA165 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA166 (S)(1-(2,3-dichloro
methoxyphenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
— 52 —
GA167 (R)(1-(2,3-dichloro
methoxyphenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA168 1-hydroxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA169 (R)hydroxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA170 (S)hydroxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA171 3-(1-(2,3-dichlorophenyl)ethyl)
methoxy(1-methylpiperidin
yl)urea,
GA172 (R)(1-(2,3-
dichlorophenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA173 (S)(1-(2,3-
dichlorophenyl)ethyl)methoxy-
1-(1-methylpiperidinyl)urea,
GA174 1-methoxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA175 (R)methoxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
— 53 —
GA176 (S)methoxy(1-(4-
methoxynaphthalenyl)ethyl)
(1-methylpiperidinyl)urea,
GA177 3-(1-(2,3-dichlorophenyl)ethyl)
hydroxy(1-methylpiperidin
yl)urea,
GA178 (R)(1-(2,3-
dichlorophenyl)ethyl)hydroxy
(1-methylpiperidinyl)urea,
GA179 (S)(1-(2,3-
dichlorophenyl)ethyl)hydroxy
(1-methylpiperidinyl)urea,
GA180 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)hydroxy-
1-(1-methylpiperidinyl)urea,
GA181 (R)(1-(2,3-dichloro
methoxyphenyl)ethyl)hydroxy-
1-(1-methylpiperidinyl)urea,
GA182 (S)(1-(2,3-dichloro
methoxyphenyl)ethyl)hydroxy-
1-(1-methylpiperidinyl)urea,
GA183 3-(1-(2,3-dichloro
(dimethylamino)phenyl)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA184 3-(1-(4-((4-
methoxybenzyl)oxy)naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
— 54 —
GA185 3-(1-(4-hydroxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA186 3-(1-(4,5-dimethoxynaphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA187 3-(1-(2,3-dichlorophenyl)
(pyridinylmethoxy)ethyl)
methyl(1-methylpiperidin
yl)urea,
GA188 3-(1-(4-chlorobenzo[d][1,3]dioxol-
-yl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA189 3-(1-(2-chloro-3,4-
dimethoxyphenyl)ethyl)methyl-
1-(1-methylpiperidinyl)urea,
GA190 1-methyl(1-methylpiperidin
yl)(1-(2,3,4-
trichlorophenyl)ethyl)urea,
GA191 1-methyl(1-methylpiperidin
yl)(1-(4-(pyridin
ylmethoxy)naphthalen
yl)ethyl)urea,
GA192 3-(1-(6-chloro-[1,1'-biphenyl]
yl)ethyl)methyl(1-
methylpiperidinyl)urea,
— 55 —
GA193 3-(1-(3-chloro(pyridin
yl)phenyl)ethyl)methyl(1-
methylpiperidinyl)urea,
GA194 3-(1-(2,3-dichloro
methylphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA195 3-(1-(3-chloro
methylphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA196 3-(1-(2,3-dichlorophenyl)((4-
(hydroxymethyl)benzyl)oxy)ethyl)-
1-methyl(1-methylpiperidin
yl)urea,
GA197 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA198 (R)(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA199 (S)(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1-methylpiperidinyl)urea,
GA200 3-(1-(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
— 56 —
GA201 3-((R)(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA202 3-((S)(2,3-dichloro
methoxyphenyl)ethyl)methyl
(1,3,3-trimethylpiperidinyl)urea,
GA203 3-(1-(4-(2-
(benzyloxy)ethoxy)naphthalen
yl)ethyl)methyl(1-
methylpiperidinyl)urea.
1. Isomers
29. When an asymmetric center is present in a compound of formula (I), hereinafter
referred to as the disclosed compounds, the compound may exist in the form of optical
isomers (enantiomers). In some forms, the disclosed compounds and compositions can
comprise enantiomers and mixtures, including racemic mixtures of the compounds of
formula (I). In some forms, for compounds of formula (I) that contain more than one
asymmetric center, the disclosed compounds and compositions can comprise diastereomeric
forms (individual diastereomers and mixtures thereof) of compounds. When a compound of
formula (I) contains an alkenyl group or moiety, geometric isomers may arise.
2. Tautomeric Forms
. The disclosed compositions and compounds comprise the tautomeric forms of
compounds of formula (I). Where structural isomers are interconvertible via a low energy
barrier, tautomeric isomerism (‗tautomerism‘) can occur. This can take the form of proton
tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime
group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It
follows that a single compound may exhibit more than one type of isomerism. The various
ratios of the tautomers in solid and liquid form are dependent on the various substituents on
the molecule as well as the particular crystallization technique used to isolate a compound.
— 57 —
3. Salts
31. The disclosed compositions and compounds can be used in the form of salts
derived from inorganic or organic acids. Depending on the particular compound, a salt of the
compound can be advantageous due to one or more of the salt‘s physical properties, such as
enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable
solubility in water or oil. In some instances, a salt of a compound also can be used as an aid
in the isolation, purification, and/or resolution of the compound.
32. Where a salt is intended to be administered to a patient (as opposed to, for
example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable.
The term ―pharmaceutically acceptable salt‖ refers to a salt prepared by combining a
compound, such as the disclosed compounds, with an acid whose anion, or a base whose
cation, is generally considered suitable for human consumption. Pharmaceutically acceptable
salts are particularly useful as products of the disclosed methods because of their greater
aqueous solubility relative to the parent compound. For use in medicine, the salts of the
disclosed compounds are non-toxic ―pharmaceutically acceptable salts.‖ Salts encompassed
within the term ―pharmaceutically acceptable salts‖ refer to non-toxic salts of the disclosed
compounds which are generally prepared by reacting the free base with a suitable organic or
inorganic acid.
33. Suitable pharmaceutically acceptable acid addition salts of the disclosed
compounds, when possible include those derived from inorganic acids, such as hydrochloric,
hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,
sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric,
ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic,
methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and
trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclylic, carboxylic, and sulfonic classes of
organic acids.
34. Specific examples of suitable organic acids include acetate, trifluoroacetate,
formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid,
citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate,
anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate,
embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,
— 58 —
toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic
acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate,
camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate,
glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate,
pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
. Furthermore, where the disclosed compounds carry an acidic moiety, suitable
pharmaceutically acceptable salts thereof can include alkali metal salts, e.g., sodium or
potassium salts; alkaline earth metal salts, e.g., copper, calcium or magnesium salts; and salts
formed with suitable organic ligands, e.g., quaternary ammonium salts. In some forms, base
salts are formed from bases which form non-toxic salts, including aluminum, arginine,
benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine,
tromethamine and zinc salts.
36. Organic salts can be made from secondary, tertiary or quaternary amine salts, such
as tromethamine, diethylamine, N,N‘-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic
nitrogen-containing groups can be quaternized with agents such as lower alkyl (C1-C6)
halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl
sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl,
lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl
and phenethyl bromides), and others. In some forms, hemisalts of acids and bases can also be
formed, for example, hemisulphate and hemicalcium salts. The disclosed compounds can
exist in both unsolvated and solvated forms. A ―solvate‖ as used herein is a nonaqueous
solution or dispersoid in which there is a noncovalent or easily dispersible combination
between solvent and solute, or dispersion means and disperse phase.
4. Adducts
37. Also disclosed are so-called ―adducts‖ of the disclosed compounds. An
representive type of adduct can be Lewis acid adduct. Lewis acid is a molecular entity (and
the corresponding chemical species) that is an electron-pair acceptor and therefore able to
react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the
Lewis base. An illustrative example is given by the reaction of trimethylboron and ammonia
to give the adduct Me BNH . Typical Lewis acids are boron trihalides, for example, boron
— 59 —
trifluoride. Thus, the disclosed compounds encompass boron trihalides adduct, for example,
boron trifluoride adduct.
. Isotopes
38. Also disclosed are isotopically labeled compounds, which are identical to those
compounds recited in formula (I), but for the fact that one or more atoms are replaced by an
atom having an atomic mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes that can be incorporated into disclosed
compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur,
2 3 13 11 14 15 18 17 31 32 35 18 36
fluorine and chlorine, such as H, H, C, C, C, N, O, O, P, P, S, F, and Cl,
respectively. Disclosed compounds, prodrugs thereof, and pharmaceutically acceptable salts
of said compounds or of said prodrugs which contain the aforementioned isotopes and/or
other isotopes of other atoms are contemplated. Certain isotopically labeled disclosed
3 14
compounds, for example those into which radioactive isotopes such as H and C are
incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., H,
and carbon-14, i.e., C, isotopes are particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as deuterium, i.e., H, can
afford certain therapeutic advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in
some circumstances. Isotopically labeled compounds of formula (I) (and other disclosed
compounds) and prodrugs thereof can generally be prepared by carrying out the procedures
disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a
readily available isotopically labeled reagent for a non-isotopically labeled reagent.
6. General Synthetic Schemes
39. The compounds of the formula (I) (and other disclosed compounds), or their
pharmaceutically acceptable salts or adducts, can be prepared by the methods as illustrated by
examples described in the ―Examples‖ section, together with synthetic methods known in the
art of organic chemistry, or modifications and derivatisations that are familiar to those of
ordinary skill in the art. The starting materials used herein are commercially available or can
be prepared by routine methods known in the art (such as those methods disclosed in
standard reference books such as the Compendium of Organic Synthesis Methods, Vol. I-VI
(published by Wiley-Interscience)). Preferred methods include, but are not limited to, those
described below. During any of the following synthetic sequences it may be necessary and/or
— 60 —
desirable to protect sensitive or reactive groups on any of the molecules concerned. This can
be achieved by means of conventional protecting groups, such as those described in T. W.
Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene
and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons,
1999, and P. G. M. Wuts and T.W.Greene, Protective Groups in Organic Chemistry, John
Wiley & Sons, 2006, which are hereby incorporated by reference. Isolation and purification
of the products is accomplished by standard procedures, which are known to a chemist of
ordinary skill.
7. Definition of Terms
40. The term ―alkyl‖ refers to a linear or branched-chain saturated hydrocarbyl
substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen)
containing from one to twenty carbon atoms; in one embodiment from one to twelve carbon
atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from
one to six carbon atoms; and in another embodiment, from one to four carbon atoms.
Examples of such substituents include methyl, ethyl, propyl (including n-propyl and
isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl,
hexyl and the like.
41. The term ―alkenyl‖ refers to a linear or branched-chain hydrocarbyl substituent
containing one or more double bonds and from two to twenty carbon atoms; in another
embodiment, from two to twelve carbon atoms; in another embodiment, from two to six
carbon atoms; and in another embodiment, from two to four carbon atoms. Examples of
alkenyl include ethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and 2-
propenyl) and butenyl (including 1-butenyl, 2-butenyl and 3-butenyl). The term ―alkenyl‖
embraces substituents having ―cis‖ and ―trans‖ orientations, or alternatively, ―E‖ and ―Z‖
orientations.
42. The term ―benzyl‖ refers to methyl radical substituted with phenyl, i.e., the
following structure: .
43. The term ―carbocyclic ring‖ refers to a saturated cyclic, partially saturated cyclic,
or aromatic ring containing from 3 to 14 carbon ring atoms (―ring atoms‖ are the atoms
— 61 —
bound together to form the ring). A carbocyclic ring typically contains from 3 to 10 carbon
ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A ―carbocyclic
ring system‖ alternatively may be 2 or 3 rings fused together, such as naphthalenyl,
tetrahydronaphthalenyl (also known as ―tetralinyl‖), indenyl, isoindenyl, indanyl,
bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as ―phenalenyl‖),
fluorenyl, and decalinyl.
44. The term ―heterocyclic ring‖ refers to a saturated cyclic, partially saturated cyclic,
or aromatic ring containing from 3 to 14 ring atoms (―ring atoms‖ are the atoms bound
together to form the ring), in which at least one of the ring atoms is a heteroatom that is
oxygen, nitrogen, or sulfur, with the remaining ring atoms being independently selected from
the group consisting of carbon, oxygen, nitrogen, and sulfur.
45. The term ―cycloalkyl‖ refers to a saturated carbocyclic substituent having three to
fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon
atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
46. The term ―cycloalkyl‖ also includes substituents that are fused to a C -C
6 10
aromatic ring or to a 5membered heteroaromatic ring, wherein a group having such a
fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group.
When such a fused cycloalkyl group is substituted with one or more substituents, the one or
more substituents, unless otherwise specified, are each bound to a carbon atom of the
cycloalkyl group. The fused C -C aromatic ring or to a 5membered heteroaromatic ring
6 10
may be optionally substituted with halogen, C -C alkyl, C -C cycloalkyl, or =O.
1 6 3 10
47. The term ―cycloalkenyl‖ refers to a partially unsaturated carbocyclic substituent
having three to fourteen carbon atoms, typically three to ten carbon atoms. Examples of
cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
48. A cycloalkyl or cycloalkenyl may be a single ring, which typically contains from 3
to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, 2 or
3 rings may be fused together, such as bicyclodecanyl and decalinyl.
49. The term ―aryl‖ refers to an aromatic substituent containing one ring or two or
three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an
example, the aryl substituent may have six to fourteen carbon atoms. The term ―aryl‖ may
— 62 —
refer to substituents such as phenyl, naphthyl and anthracenyl. The term ―aryl‖ also includes
substituents such as phenyl, naphthyl and anthracenyl that are fused to a C -C carbocyclic
4 10
ring, such as a C or a C carbocyclic ring, or to a 4membered heterocyclic ring, wherein
a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the
aryl group. When such a fused aryl group is substituted with one more substituents, the one
or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the
fused aryl group. The fused C -C carbocyclic or 4membered heterocyclic ring may be
4 10
optionally substituted with halogen, C -C alkyl, C -C cycloalkyl, or =O. Examples of aryl
1 6 3 10
groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as
―tetralinyl‖), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also
known as ―phenalenyl‖), and fluorenyl.
50. In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g.,
alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix ―C -C -,‖ wherein
x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus,
for example, ―C -C -alkyl‖ refers to an alkyl substituent containing from 1 to 6 carbon atoms.
Illustrating further, C -C -cycloalkyl refers to saturated cycloalkyl containing from 3 to 6
carbon ring atoms.
51. In some instances, the number of atoms in a cyclic substituent containing one or
more heteroatoms (e.g., heteroaryl or heterocycloalkyl) is indicated by the prefix ―X-Y-
membered‖, wherein wherein x is the minimum and y is the maximum number of atoms
forming the cyclic moiety of the substituent. Thus, for example, 5membered
heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one ore
more heteroatoms, in the cyclic moiety of the heterocycloalkyl.
52. The term ―hydrogen‖ refers to hydrogen substituent, and may be depicted as -H.
53. The term ―hydroxy‖ refers to –OH. When used in combination with another
term(s), the prefix ―hydroxy‖ indicates that the substituent to which the prefix is attached is
substituted with one or more hydroxy substituents. Compounds bearing a carbon to which
one or more hydroxy substituents include, for example, alcohols, enols and phenol.
54. The term ―hydroxyalkyl‖ refers to an alkyl that is substituted with at least one
hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl,
hydroxypropyl and hydroxybutyl.
55. The term ―nitro‖ means -NO .
— 63 —
56. The term ―cyano‖ (also referred to as ―nitrile‖) -CN, which also may be
depicted: .
57. The term ―carbonyl‖ means -C(O)-, which also may be depicted as: .
58. The term ―amino‖ refers to -NH .
59. The term ―alkylamino‖ refers to an amino group, wherein at least one alkyl chain
is bonded to the amino nitrogen in place of a hydrogen atom. Examples of alkylamino
substituents include monoalkylamino such as methylamino (exemplified by the
formula -NH(CH )), which may also be depicted: and dialkylamino such as
dimethylamino, (exemplified by the formula –N(CH ) ), which may also be depicted:
60. The term ―aminocarbonyl‖ means -C(O)-NH , which also may be depicted
as: .
61. The term ―halogen‖ refers to fluorine (which may be depicted as -F), chlorine
(which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which
may be depicted as -I). In one embodiment, the halogen is chlorine. In another embodiment,
the halogen is a fluorine.
62. The prefix ―halo‖ indicates that the substituent to which the prefix is attached is
substituted with one or more independently selected halogen substituents. For example,
haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. Where
more than one hydrogen is replaced with halogens, the halogens may be the identical or
different. Examples of haloalkyls include chloromethyl, dichloromethyl,
difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl,
— 64 —
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl,
difluoropropyl, dichloropropyl, and heptafluoropropyl. Illustrating further, ―haloalkoxy‖
refers to an alkoxy that is substituted with at least one halogen substituent. Examples of
haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy (also known as ―perfluoromethyloxy‖), and
2,2,2-trifluoroethoxy. It should be recognized that if a substituent is substituted by more
than one halogen substituent, those halogen substituents may be identical or different (unless
otherwise stated).
63. The prefix ―perhalo‖ indicates that each hydrogen substituent on the substituent to
which the prefix is attached is replaced with an independently selected halogen substituent.
If all the halogen substituents are identical, the prefix may identify the halogen substituent.
Thus, for example, the term ―perfluoro‖ means that every hydrogen substituent on the
substituent to which the prefix is attached is replaced with a fluorine substituent. To
illustrate, the term ―perfluoroalkyl‖ refers to an alkyl substituent wherein a fluorine
substituent is in the place of each hydrogen substituent. Examples of perfluoroalkyl
substituents include trifluoromethyl (-CF ), perfluorobutyl, perfluoroisopropyl,
perfluorododecyl, and perfluorodecyl. To illustrate further, the term ―perfluoroalkoxy‖ refers
to an alkoxy substituent wherein each hydrogen substituent is replaced with a fluorine
substituent. Examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF ),
perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy.
64. The term ―oxo‖ refers to =O.
65. The term ―oxy‖ refers to an ether substituent, and may be depicted as -O-.
66. The term ―alkoxy‖ refers to an alkyl linked to an oxygen, which may also be
represented as –O-R, wherein the R represents the alkyl group. Examples of alkoxy include
methoxy, ethoxy, propoxy and butoxy.
67. The term ―alkylthio‖ means -S-alkyl. For example, ―methylthio‖ is -S-CH .
Other examples of alkylthio include ethylthio, propylthio, butylthio, and hexylthio.
68. The term ―alkylcarbonyl‖ means -C(O)-alkyl. For example, ―ethylcarbonyl‖ may
be depicted as: . Examples of other alkylcarbonyl include methylcarbonyl,
propylcarbonyl, butylcarbonyl, pentylcabonyl, and hexylcarbonyl.
— 65 —
69. The term ―aminoalkylcarbonyl‖ means -C(O)-alkyl-NH . For example,
―aminomethylcarbonyl‖ may be depicted as: .
70. The term ―alkoxycarbonyl‖ means -C(O)-O-alkyl. For example,
O CH
―ethoxycarbonyl‖ may be depicted as: . Examples of other
alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
pentoxycarbonyl, and hexyloxycarbonyl. In another embodiment, where the carbon atom of
the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group is
an ester.
71. The terms ―thio‖ and ―thia‖ mean a divalent sulfur atom and such a substituent
may be depicted as -S-. For example, a thioether is represented as ―alkyl-thio-alkyl‖ or,
alternatively, alkyl-S-alkyl.
72. The term ―thiol‖ refers to a sulfhydryl substituent, and may be depicted as -SH.
73. The term ―thione‖ refers to =S.
74. The term ―sulfonyl‖ refers to -S(O) -, which also may be depicted as: .
Thus, for example, ―alkyl-sulfonyl-alkyl‖ refers to alkyl-S(O) -alkyl. Examples of
alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
75. The term ―aminosulfonyl‖ means -S(O) -NH , which also may be depicted
as: .
76. The term ―sulfinyl‖ or ―sulfoxido‖ means -S(O)-, which also may be depicted as:
or .
— 66 —
77. Thus, for example, ―alkylsulfinylalkyl‖ or ―alkylsulfoxidoalkyl‖ refers to
alkyl-S(O)-alkyl. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl,
butylsulfinyl, and hexylsulfinyl.
78. The term ―heterocycloalkyl‖ refers to a saturated or partially saturated ring
structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a
heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being
independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A
heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one
such ring contains a heteroatom as a ring atom (e.g., nitrogen, oxygen, or sulfur). In a group
that has a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that
is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom,
where the ring carbon atom may be in the same ring as the at least one heteroatom or where
the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if
the heterocycloalkyl substituent is in turn substituted with a group or substituent, the group or
substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon
atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or
where the ring carbon atom may be in a different ring from the at least one heteroatom.
79. The term ―heterocycloalkyl‖ also includes substituents that are fused to a C -C
6 10
aromatic ring or to a 5membered heteroaromatic ring, wherein a group having such a
fused heterocycloalkyl group as a substituent is bound to a heteroatom of the
heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. When such a
fused heterocycloalkyl group is substituted with one more substituents, the one or more
substituents, unless otherwise specified, are each bound to a heteroatom of the
heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. The fused C -C
6 10
aromatic ring or to a 5membered heteroaromatic ring may be optionally substituted with
halogen, C -C alkyl, C -C cycloalkyl, or =O.
1 6 3 10
80. The term ―heteroaryl‖ refers to an aromatic ring structure containing from 5 to 14
ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or
sulfur), with the remaining ring atoms being independently selected from the group
consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or
3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents
such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as
— 67 —
triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,
1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents
such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and
anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl,
quinazolinyl, and 1,4-benzoxazinyl. In a group that has a heteroaryl substituent, the ring
atom of the heteroaryl substituent that is bound to the group may be the at least one
heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same
ring as the at least one heteroatom or where the ring carbon atom may be in a different ring
from the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted
with a group or substituent, the group or substituent may be bound to the at least one
heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in
the same ring as the at least one heteroatom or where the ring carbon atom may be in a
different ring from the at least one heteroatom. The term ―heteroaryl‖ also includes pyridyl
N-oxides and groups containing a pyridine N-oxide ring.
81. Examples of single-ring heteroaryls include furanyl, dihydrofuranyl,
tetradydrofuranyl, thiophenyl (also known as ―thiofuranyl‖), dihydrothiophenyl,
tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl,
imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl,
dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,
thiazolidinyl, isothiazolidinyl, thiaodiazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl,
1,2,4-oxadiazolyl (also known as ―azoximyl‖), 1,2,5-oxadiazolyl (also known as ―furazanyl‖),
or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),
dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or
1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1,2-pyranyl or
1,4-pyranyl), dihydropyranyl, pyridinyl (also known as ―azinyl‖), piperidinyl, diazinyl
(including pyridazinyl (also known as ―1,2-diazinyl‖), pyrimidinyl (also known as
―1,3-diazinyl‖ or ―pyrimidyl‖), or pyrazinyl (also known as ―1,4-diazinyl‖)), piperazinyl,
triazinyl (including s-triazinyl (also known as ―1,3,5-triazinyl‖), as-triazinyl (also known
1,2,4-triazinyl), and v-triazinyl (also known as ―1,2,3-triazinyl‖)), oxazinyl (including
1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as ―pentoxazolyl‖), 1,2,6-oxazinyl,
or 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl,
isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl
— 68 —
(including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl,
thiepinyl, and diazepinyl.
82. Examples of 2-fused-ring heteroaryls include, indolizinyl, pyrindinyl,
pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including
pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl,
indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl,
quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl,
anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl,
benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl,
benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.
83. Examples of 3-fused-ring heteroaryls or heterocycloalkyls include
,6-dihydro-4H-imidazo[4,5,1-ij]quinoline, 4,5-dihydroimidazo[4,5,1-hi]indole,
4,5,6,7-tetrahydroimidazo[4,5,1-jk][1]benzazepine, and dibenzofuranyl.
84. Other examples of fused-ring heteroaryls include benzo-fused heteroaryls such as
indolyl, isoindolyl (also known as ―isobenzazolyl‖ or ―pseudoisoindolyl‖), indoleninyl (also
known as ―pseudoindolyl‖), isoindazolyl (also known as ―benzpyrazolyl‖), benzazinyl
(including quinolinyl (also known as ―1-benzazinyl‖) or isoquinolinyl (also known as
―2-benzazinyl‖)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including
cinnolinyl (also known as ―1,2-benzodiazinyl‖) or quinazolinyl (also known as
―1,3-benzodiazinyl‖)), benzopyranyl (including ―chromanyl‖ or ―isochromanyl‖),
benzothiopyranyl (also known as ―thiochromanyl‖), benzoxazolyl, indoxazinyl (also known
as ―benzisoxazolyl‖), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl,
benzofuranyl (also known as ―coumaronyl‖), isobenzofuranyl, benzothienyl (also known as
―benzothiophenyl,‖ ―thionaphthenyl,‖ or ―benzothiofuranyl‖), isobenzothienyl (also known
as ―isobenzothiophenyl,‖ ―isothionaphthenyl,‖ or ―isobenzothiofuranyl‖), benzothiazolyl,
benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including
1,3,2-benzoxazinyl , 1,4,2-benzoxazinyl , 2,3,1-benzoxazinyl , or 3,1,4-benzoxazinyl ),
benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl ,
carbazolyl, xanthenyl, and acridinyl.
85. The term ―heteroaryl‖ also includes substituents such as pyridyl and quinolinyl
that are fused to a C -C carbocyclic ring, such as a C or a C carbocyclic ring, or to a 4
4 10 5 6
membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent
— 69 —
is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl
group. When such a fused heteroaryl group is substituted with one more substituents, the one
or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the
heteroaryl group or to a heteroatom of the heteroaryl group. The fused C -C carbocyclic or
4 10
4membered heterocyclic ring may be optionally substituted with halogen, C -C alkyl,
C -C cycloalkyl, or =O.
3 10
86. The term ―ethylene‖ refers to the group –CH -CH - The term ―ethynelene‖ refers
2 2 .
to the group –CH=CH- The term ―propylene‖ refers to the group –CH -CH -CH - The term
. 2 2 2 .
―butylene‖ refers to the group –CH -CH -CH -CH - The term ―methylenoxy‖ refers to the
2 2 2 2 .
group –CH -O- The term ―methylenethioxy‖ refers to the group –CH -S- The term
2 . 2 .
―methylenamino‖ refers to the group –CH -N(H)- The term ―ethylenoxy‖ refers to the group
–CH -CH -O- The term ―ethylenethioxy‖ refers to the group – CH -CH -S- The term
2 2 . 2 2 .
―ethylenamino‖ refers to the group –CH –CH -N(H)-
2 2 .
87. A substituent is ―substitutable‖ if it comprises at least one carbon, sulfur, oxygen
or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example,
hydrogen, halogen, and cyano do not fall within this definition. If a substituent is described
as being ―substituted,‖ a non-hydrogen substituent is in the place of a hydrogen substituent on
a carbon, oxygen, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl
substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the
place of a hydrogen substituent on the alkyl substituent. To illustrate, monofluoroalkyl is
alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two
fluoro substituents. It should be recognized that if there is more than one substitution on a
substituent, each non-hydrogen substituent may be identical or different (unless otherwise
stated).
88. If a substituent is described as being ―optionally substituted,‖ the substituent may
be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as
being optionally substituted with one or more of a list of substituents, one or more of the
hydrogens on the carbon (to the extent there are any) may separately and/or together be
replaced with an independently selected optional substituent. If a nitrogen of a substituent is
described as being optionally substituted with one or more of a list of substituents, one or
more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with
an independently selected optional substituent. One exemplary substituent may be depicted
— 70 —
as –NR‘R,‖ wherein R‘ and R‖ together with the nitrogen atom to which they are attached,
may form a heterocyclic ring. The heterocyclic ring formed from R‘ and R‖ together with the
nitrogen atom to which they are attached may be partially or fully saturated. In one
embodiment, the heterocyclic ring consists of 3 to 7 atoms. In another embodiment, the
heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl,
triazolyl, tetrazolyl, isoxazolyl, pyridyl and thiazolyl.
89. This specification uses the terms ―substituent,‖ ―radical,‖ and ―group‖
interchangeably. If a group of substituents are collectively described as being optionally
substituted by one or more of a list of substituents, the group may include: (1) unsubstitutable
substituents, (2) substitutable substituents that are not substituted by the optional substituents,
and/or (3) substitutable substituents that are substituted by one or more of the optional
substituents. If a substituent is described as being optionally substituted with up to a
particular number of non-hydrogen substituents, that substituent may be either (1) not
substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or
by up to the maximum number of substitutable positions on the substituent, whichever is less.
Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up
to 3 non-hydrogen substituents, then any heteroaryl with less than 3 substitutable positions
would be optionally substituted by up to only as many non-hydrogen substituents as the
heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one
substitutable position) would be optionally substituted with up to one non-hydrogen
substituent. To illustrate further, if an amino nitrogen is described as being optionally
substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally
substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen,
whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen
substituent if the amino nitrogen is a secondary nitrogen.
90. A prefix attached to a multi-moiety substituent only applies to the first moiety.
To illustrate, the term ―alkylcycloalkyl‖ contains two moieties: alkyl and cycloalkyl. Thus, a
C -C - prefix on C -C -alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl
1 6 1 6
contains from 1 to 6 carbon atoms; the C -C - prefix does not describe the cycloalkyl moiety.
To illustrate further, the prefix ―halo‖ on haloalkoxyalkyl indicates that only the alkoxy
moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If
the halogen substitution may only occur on the alkyl moiety, the substituent would be
— 71 —
described as ―alkoxyhaloalkyl.‖ If the halogen substitution may occur on both the alkyl
moiety and the alkoxy moeity, the substituent would be described as ―haloalkoxyhaloalkyl.‖
91. When a substituent is comprised of multiple moieties, unless otherwise indicated,
it is the intention for the final moiety to serve as the point of attachment to the remainder of
the molecule. For example, in a substituent A-B-C, moiety C is attached to the remainder of
the molecule. In a substituent A-B-C-D, moiety D is attached to the remainder of the
molecule. Similarly, in a substituent aminocarbonylmethyl, the methyl moiety is attached to
the remainder of the molecule, where the substituent may also be be depicted as
. In a substituent trifluoromethylaminocarbonyl, the carbonyl moiety is
attached to the remainder of the molecule, where the substituent may also be depicted as
92. If substituents are described as being ―independently selected‖ from a group, each
substituent is selected independent of the other. Each substituent therefore may be identical
to or different from the other substituent(s).
B. Pharmaceutical Compositions
93. Pharmaceutical compositions for preventing and/or treating a subject are further
provided comprising a therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically
acceptable excipients.
94. A ―pharmaceutically acceptable‖ excipient is one that is not biologically or
otherwise undesirable, i.e., the material can be administered to a subject without causing any
undesirable biological effects or interacting in a deleterious manner with any of the other
components of the pharmaceutical composition in which it is contained. The carrier can be
selected to minimize any degradation of the active ingredient and to minimize any adverse
side effects in the subject, as would be well known to one of skill in the art. The carrier can
be a solid, a liquid, or both.
— 72 —
95. The disclosed compounds can be administered by any suitable route, preferably in
the form of a pharmaceutical composition adapted to such a route, and in a dose effective for
the treatment or prevention intended. The active compounds and compositions, for example,
can be administered orally, rectally, parenterally, ocularly, inhalationaly, or topically. In
particular, administration can be epicutaneous, inhalational, enema, conjunctival, eye drops,
ear drops, alveolar, nasal, intranasal, vaginal, intravaginal, transvaginal, ocular, intraocular,
transocular, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal,
injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular,
intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal,
intraperitoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial,
transdermal, transmucosal, transnasal, inhalational, intracisternal, epidural, peridural,
intravitreal, etc.
96. Suitable carriers and their formulations are described in Remington: The Science
and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton,
PA, 1995. Oral administration of a solid dose form can be, for example, presented in discrete
units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a
predetermined amount of at least one of the disclosed compound or compositions. In some
forms, the oral administration can be in a powder or granule form. In some forms, the oral
dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the
compounds of formula I are ordinarily combined with one or more adjuvants. Such capsules
or tablets can contain a controlled-release formulation. In the case of capsules, tablets, and
pills, the dosage forms also can comprise buffering agents or can be prepared with enteric
coatings.
97. In some forms, oral administration can be in a liquid dose form. Liquid dosage
forms for oral administration include, for example, pharmaceutically acceptable emulsions,
solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art
(e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying,
suspending, flavoring (e.g., sweetening), and/or perfuming agents.
98. In some forms, the disclosed compositions can comprise a parenteral dose form.
―Parenteral administration‖ includes, for example, subcutaneous injections, intravenous
injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be
— 73 —
formulated according to the known art using suitable dispersing, wetting agents, and/or
suspending agents. . Typically, an appropriate amount of a pharmaceutically acceptable
carrier is used in the formulation to render the formulation isotonic. Examples of the
pharmaceutically acceptable carrier include, but are not limited to, saline, Ringer‘s solution
and dextrose solution. Other acceptable excipients include, but are not limited to, thickeners,
diluents, buffers, preservatives, surface active agents and the like.
99. In some forms, the disclosed compositions can comprise a topical dose form.
―Topical administration‖ includes, for example, transdermal administration, such as via
transdermal patches or iontophoresis devices, intraocular administration, or intranasal or
inhalation administration. Compositions for topical administration also include, for example,
topical gels, sprays, ointments, and creams. A topical formulation can include a compound
which enhances absorption or penetration of the active ingredient through the skin or other
affected areas. When the compounds and compositions are administered by a transdermal
device, administration will be accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. Typical formulations for this purpose include
gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams,
films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions.
Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid
petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration
enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin
and Morgan (October 1999).
100. Formulations suitable for topical administration to the eye include, for example,
eye drops wherein the disclosed compound or composition is dissolved or suspended in
suitable carrier. A typical formulation suitable for ocular or aural administration can be in
the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile
saline. Other formulations suitable for ocular and aural administration include ointments,
biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone)
implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a
cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or
methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, can be
— 74 —
incorporated together with a preservative, such as benzalkonium chloride. Such formulations
can also be delivered by iontophoresis.
101. Other carrier materials and modes of administration known in the
pharmaceutical art can also be used. The disclosed pharmaceutical compositions can be
prepared by any of the well-known techniques of pharmacy, such as effective formulation
and administration procedures. The above considerations in regard to effective formulations
and administration procedures are well known in the art and are described in standard
textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington‘s
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al.,
Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et
al., Eds., Handbook of Pharmaceutical Excipients (3 Ed.), American Pharmaceutical
Association, Washington, 1999.
102. The disclosed compounds can be used, alone or in combination with other
therapeutic agents, in the treatment or prevention of various conditions or disease states. The
administration of two or more compounds ―in combination‖ means that the two compounds
are administered closely enough in time that the presence of one alters the biological effects
of the other. The two or more compounds can be administered simultaneously, concurrently
or sequentially.
103. Disclosed are pharmaceutical compositions comprising an effective amount of a
compound of the invention or a pharmaceutically accepted salt, solvate, clathrate, or prodrug
thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions may further
comprise additional agents. These compositions are useful for modulating the activity of
ghrelin receptor, thus to improve the prevention and treatment of ghrelin receptor associated
human diseases such as obesity and/or metabolic disorders.
Methods
104. All of the methods described herein may be practiced with a compound of the
invention alone, or in combination with other agents.
A. Treating
105. The above-described compounds and compositions are useful for the inhibition,
reduction, prevention, and/or treatment of diseases which are pathophysiologically modulated
by the ghrelin receptor. Accordingly, in some forms, disclosed are methods of preventing
and/or treating diseases which are pathophysiologically modulated by the ghrelin receptor,
— 75 —
comprising administering to a subject a therapeutically effective amount of a compound of
formula (I) as disclosed above, or a pharmaceutically acceptable salt or adduct thereof.
106. Suitable subjects can include mammalian subjects. Mammals include, but are
not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs,
primates, and the like, and encompass mammals in utero. In some forms, humans are the
subjects. Human subjects can be of either gender and at any stage of development.
107. Diseases modulated by the ghrelin receptor, and treatable by the methods
disclosed herein, include obesity, overweight, eating disorder, diabetes, metabolic syndrome,
cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS,
chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric
disorder or substance abuse. Metabolic disorders treatable by the instant methods include
diabetes, Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance,
hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart
disease, stroke, hypertension and peripheral vascular disease. Gastric disorders treatable by
the instant methods include post-operative ileus (POI), diabetic gastroparesis, and opioid
induced bowel dysfunction. Gastrointestinal diseases treatable by the instant methods
include irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional
dyspepsia. Substance abuse treatable by the instant methods includes alcohol and drug abuse,
and said drug includes amphetamines, barbiturates, benzodiazepines, ***e, methaqualone,
and opioids.
108. In some methods the compound of Formula (I) is a ghrelin receptor modulator.
In some other methods the compound of Formula (I) is a ghrelin receptor agonist. In some
methods the compound of Formula (I) is a ghrelin receptor antagonist. In some methods, the
compound of Formula (I) or a pharmaceutically acceptable salt or adduct thereof, is
administered by one or more routes selected from the group consisting of rectal, buccal,
sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye
drops, parenteral and topical administration. In some other methods, administration is
accomplished by administering an oral form of the compound of Formula (I) or a
pharmaceutically acceptable salt or adduct thereof.
109. A therapeutically effective amount may vary widely depending on the severity
of the disease, the age and relative health of the subject, the potency of the compound used
— 76 —
and other factors. Therapeutically effective amounts of compounds of Formula (I) may range
from approximately 0.01 microgram per Kg (µg/Kg) body weight per day to about 100
mg/Kg body weight per day, or from about 0.1 µg /Kg/day to about 10 mg/Kg/day, or from
about 1 µg /Kg /day to about 5 mg/ Kg /day, or from about 10 µg /Kg/day to about 5
mg/Kg/day, or from about 100 µg /Kg/day to about 5 mg/Kg/day, or from about 500 µg
/Kg/day to about 5 mg/Kg/day.
110. One of ordinary skill in the art of treating such diseases will be able, without
undue experimentation and in reliance upon personal knowledge and the disclosure of this
application, to ascertain a therapeutically effective amount of a compound of Formula I for a
given disease. In some other forms, disclosed are methods of preventing and/or treating a
subject, further comprising one or more therapeutic agents.
B. More Definitions of Terms
111. Throughout this application, various publications are referenced. The
disclosures of these publications in their entireties are hereby incorporated by reference into
this application in order to more fully describe the state of the art to which this pertains. The
references disclosed are also individually and specifically incorporated by reference herein
for the material contained in them that is discussed in the sentence in which the reference is
relied upon.
1. A, an, the
112. As used in the specification and the appended claims, the singular forms ―a,‖
―an‖ and ―the‖ include plural referents unless the context clearly dictates otherwise. Thus,
for example, reference to ―a pharmaceutical carrier‖ includes mixtures of two or more such
carriers, and the like.
2. Abbreviations
113. Abbreviations, which are well known to one of ordinary skill in the art, may
be used (e.g., ―h‖ or ―hr‖ for hour or hours, ―g‖ or ―gm‖ for gram(s), ―mL‖ for milliliters, and
―rt‖ for room temperature, ―nm‖ for nanometers, ―M‖ for molar, and like abbreviations).
3. About
114. The term ―about,‖ when used to modify the quantity of an ingredient in a
composition, concentrations, volumes, process temperature, process time, yields, flow rates,
pressures, and like values, and ranges thereof, employed in describing the embodiments of
the disclosure, refers to variation in the numerical quantity that can occur, for example,
— 77 —
through typical measuring and handling procedures used for making compounds,
compositions, concentrates or use formulations; through inadvertent error in these procedures;
through differences in the manufacture, source, or purity of starting materials or ingredients
used to carry out the methods; and like considerations. The term ―about‖ also encompasses
amounts that differ due to aging of a composition or formulation with a particular initial
concentration or mixture, and amounts that differ due to mixing or processing a composition
or formulation with a particular initial concentration or mixture. Whether modified by the
term ―about‖ the claims appended hereto include equivalents to these quantities.
4. Comprise
115. Throughout the description and claims of this specification, the word
―comprise‖ and variations of the word, such as ―comprising‖ and ―comprises,‖ means
―including but not limited to,‖ and is not intended to exclude, for example, other additives,
components, integers or steps.
. Ghrelin receptor agonist
A ghrelin receptor agonist is any molecule that binds to and activates the Ghrelin
receptor in the cells.
6. Ghrelin receptor antagonist
116. A ghrelin receptor antagonist is any molecule that binds to and inhibits the
activity of Ghrelin receptor.
7. pathophysiologically mediated to ghrelin receptor
117. Something is ―pathophysiologically mediated by the ghrelin receptor‖ if the
ghrelin receptor is involved in the functional changes in body associated with or resulting
from disease or injury.
8. Obesity
118. Obesity is a medical condition in which excess body fat has accumulated to the
extent that it may have an adverse effect on health, leading to reduced life expectancy and/or
increased health problems. Obesity treatment includes inducing weight loss, reducing
bodyweight, reducing food intake, reducing appetite, increasing metabolic rate, reducing fat
intake, reducing carbohydrate craving; or inducing satiety. The obesity-related disorders
herein are associated with, caused by, or result from obesity. Examples of obesity-related
disorders include overeating, binge eating, and bulimia, hypertension, diabetes, elevated
plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia,
— 78 —
endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea,
cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial
infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic
ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich‘s syndrome, GH-
deficient subjects, normal variant short stature, Turner‘s syndrome, and other pathological
conditions showing reduced metabolic activity or a decrease in resting energy expenditure as
a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia. Further
examples of obesity-related disorders are metabolic syndrome, insulin resistance syndrome,
sexual and reproductive dysfunction, such as infertility, hypogonadism in males and
hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-
esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome
(Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic
inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,
lower back pain, gallbladder disease, gout, and kidney cancer, nicotine addiction, substance
addiction and alcoholism. The compositions of the present invention are also useful for
reducing the risk of secondary outcomes of obesity, such as reducing the risk of left
ventricular hypertrophy.
9. metabolic disorder
119. A metabolic disorder is a disorder of metabolism, such as diabetes, Type I
diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia,
hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia,
obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and
peripheral vascular disease.
. congestive heart failure
120. Congestive heart failure (CHF) is a condition in which the heart‘s function as a
pump to deliver oxygen rich blood to the body is inadequate to meet the body‘s needs.
Congestive heart failure can be caused by diseases that weaken the heart muscle, or diseases
that cause stiffening of the heart muscles, or diseases that increase oxygen demand by the
body tissue beyond the capability of the heart to deliver. Many diseases can impair the
pumping action of the ventricles. For example, the muscles of the ventricles can be weakened
by heart attacks or infections (myocarditis). The diminished pumping ability of the ventricles
due to muscle weakening is called systolic dysfunction. After each ventricular contraction
— 79 —
(systole) the ventricle muscles need to relax to allow blood from the atria to fill the ventricles.
This relaxation of the ventricles is called diastole. Diseases such as hemochromatosis or
amyloidosis can cause stiffening of the heart muscle and impair the ventricles‘ capacity to
relax and fill; this is referred to as diastolic dysfunction. The most common cause of this is
longstanding high blood pressure resulting in a thickened (hypertrophied) heart. Additionally,
in some patients, although the pumping action and filling capacity of the heart may be normal,
abnormally high oxygen demand by the body‘s tissues (for example, with hyperthyroidism)
may make it difficult for the heart to supply an adequate blood flow (called high output heart
failure). In some patients one or more of these factors can be present to cause congestive
heart failure. Congestive heart failure can affect many organs of the body. For example, the
weakened heart muscles may not be able to supply enough blood to the kidneys, which then
begin to lose their normal ability to excrete salt (sodium) and water. This diminished kidney
function can cause to body to retain more fluid. The lungs may become congested with fluid
(pulmonary edema) and the person‘s ability to exercise is decreased. Fluid may likewise
accumulate in the liver, thereby impairing its ability to rid the body of toxins and produce
essential proteins. The intestines may become less efficient in absorbing nutrients and
medicines. Over time, untreated, worsening congestive heart failure will affect virtually every
organ in the body.
11. agonism action
121. Agonism action refers to the binding of a molecule to a receptor that leads to the
activation of the receptor, thus triggering a cellular response similar to the cellular response
for a known agonist for the receptor.
12. antagonism action
122. Antagonism action refers to the binding of a molecule to a receptor that leads to
the inhibition of the receptor.
13. Modulate
123. To modulate, or forms thereof, means either increasing, decreasing, or
maintaining a cellular activity mediated through a cellular target. It is understood that
wherever one of these words is used it is also disclosed that it could be 1%, 5%, 10%, 20%,
50%, 100%, 500%, or 1000% increased from a control, or it could be 1%, 5%, 10%, 20%,
50%, or 100% decreased from a control.
— 80 —
14. Optional
124. ―Optional‖ or ―optionally‖ means that the subsequently described event or
circumstance may or may not occur, and that the description includes instances where said
event or circumstance occurs and instances where it does not.
. Or
125. The word ―or‖ or like terms as used herein means any one member of a
particular list and also includes any combination of members of that list.
16. Publications
126. Throughout this application, various publications are referenced. The
disclosures of these publications in their entireties are hereby incorporated by reference into
this application in order to more fully describe the state of the art to which this pertains. The
references disclosed are also individually and specifically incorporated by reference herein
for the material contained in them that is discussed in the sentence in which the reference is
relied upon.
17. Subject
127. As used throughout, by a ―subject‖ is meant an individual. Thus, the ―subject‖
can include, for example, domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle,
horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.)
mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles,
amphibians, fish, and any other animal. The subject can be a mammal such as a primate or a
human. The subject can also be a non-human.
18. Treating
128. By ―treating‖ or ―treatment‖ is meant the medical management of a patient with
the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or
disorder. These terms include active treatment, that is, treatment directed specifically toward
the improvement of a disease, pathological condition, or disorder, and also includes causal
treatment, that is, treatment directed toward removal of the cause of the associated disease,
pathological condition, or disorder. These terms can mean that the symptoms of the
underlying disease are reduced, and/or that one or more of the underlying cellular,
physiological, or biochemical causes or mechanisms causing the symptoms are reduced. It is
understood that reduced, as used in this context, means relative to the state of the disease,
including the molecular state of the disease, not just the physiological state of the disease. In
— 81 —
certain situations a treatment can inadvertently cause harm. In addition, these terms include
palliative treatment, that is, treatment designed for the relief of symptoms rather than the
curing of the disease, pathological condition, or disorder; preventative treatment, that is,
treatment directed to minimizing or partially or completely inhibiting the development of the
associated disease, pathological condition, or disorder; and supportive treatment, that is,
treatment employed to supplement another specific therapy directed toward the improvement
of the associated disease, pathological condition, or disorder. These terms mean both
treatment having a curing or alleviating purpose and treatment having a preventive purpose.
The treatment can be made either acutely or chronically. It is understood that treatment can
mean a reduction or one or more symptoms or characteristics by at least 5% 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, 99.99%, 100%, relative to a control.
In the context of these terms, preventing refers to the ability of a compound or composition
(such as the disclosed compounds and compositions) to prevent a disease identified herein in
patients diagnosed as having the disease or who are at risk of developing such disease. In
this context, preventing includes the delaying the onset of the disease relative to a control.
These terms do not require that the treatment in fact be effective to produce any of the
intended results. It is enough that the results are intended.
19. Therapeutically effective
129. The term ―therapeutically effective‖ means that the amount of the composition
used is of sufficient quantity to treat a subject as defined herein.
. Toxicity
130. Toxicity is the degree to which a substance, molecule, is able to damage
something, such as a cell, a tissue, an organ, or a whole organism, that has been exposed to
the substance or molecule. For example, the liver, or cells in the liver, hepatocytes, can be
damaged by certain substances. The methods described herein are preferably non-toxic.
Examples
131. The following examples are put forth so as to provide those of ordinary skill in
the art with a complete disclosure and description of how the compounds, compositions,
articles, devices and/or methods claimed herein are made and evaluated, and are intended to
be purely exemplary and are not intended to limit the disclosure. Efforts have been made to
ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors
— 82 —
and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight,
temperature is in C or is at ambient temperature, and pressure is at or near atmospheric.
A. Example 1
1. Preparation of compounds of formula (I)
132. The following are examples of preparation of compounds of formula (I). This
example is intended to be purely exemplary and is not intended to limit the disclosure.
Synthesis of Compound 1 (an intermediate compound)
Me Me
Boc Boc Me Me
N N HN
O NaH O
1b 1c
Me Me
CH NH
MeI N 3 2
H , Pd/C
K CO
2 3 NH Me
Compound 1
Step 1:
133. A solution of 1a (5g, 25 mmol) in dry THF (10 mL) was cooled to 5 °C under
nitrogen atmosphere. 60% NaH (2.4 g, 60 mmol) was added and the resulting mixture was
stirred for 30 min. CH I (8.5 g, 60 mmol) was then added to the mixture and stirred at room
temperature overnight. The solvent was removed under reduced pressure and the residue was
dissolved in ethyl acetate and washed with brine. The organic phase was dried over
anhydrous Na SO and concentrated under reduced pressure. The residue was purified by
column chromatography (silica, ethyl acetate/petroleum ether 1:15, v:v) to provide compound
1b (2.9 g, 51% yield). H-NMR (CDCl , 300 MHz): δ=3.74 (t, 2H), 3.41 (s, 2H), 2.50 (t, 2H),
1.44 (s, 9H), 1.06 (s, 6H). LC-MS: 228 [M+1] .
Step 2:
134. A solution of 1b (2.0 g, 8.8 mmol) in THF (30 mL) was treated with 1.5 mL of
conc. HCl at room temperature. The resulting mixture was heated at 60 °C for 3h, then
cooled to room temperature. A white precipitate resulted and was collected by filtration and
dried to obtain compound 1c (1.1 g, 78% yield) as HCl salt. This product was used in the
next step without further purification.
Step 3:
— 83 —
135. To a mixture of 1c (1.0 g, 6.1 mmol) and K CO (2.5 g, 18.3 mmol) in dry
CH CN (20 mL) was added CH I (0.95 g, 6.7 mmol) dropwise under N atmosphere. The
3 3 2
mixture was stirred at room temperature overnight. The solvent was removed under reduced
pressure and the residue dissolved in ethyl acetate, washed with brine, dried over anhydrous
Na SO and concentrated. The residue was purified by column chromatography (silica, ethyl
acetate/ petroleum ether 1:10, v:v) to provide compound 1d (0.69 g, 81% yield). H-NMR
(CDCl , 300 MHz): δ=2.65 (t, 2H), 2.50 (t, 2H), 2.38 (s, 2H), 2.32 (s, 3H), 1.14 (s, 6H). LC-
MS: 142 [M+1] .
Step 4:
136. A mixture of 1d (0.5 g, 3.5 mmol) and methyl amine (30% in MeOH, 5 mL)
was hydrogenated (50 psi, 60 °C) in the presence of 5% Pd/C (50 mg) in MeOH (5 mL).
After cooling, the reaction mixture was filtered, the solvent evaporated under reduced
pressure and the residue purified by column chromatography (silica, MeOH/CH Cl 1:15, v:v)
to provide Compound 1 (0.21 g, 39 % yield). H-NMR (CDCl , 300 MHz): δ=2.65 (t, 2H),
2.56 (d, 3H), 2.51 (t, 2H), 2.38 (s, 2H), 2.32 (s, 3H), 1.14 (s, 6H). LC-MS: 157 [M+1] .
Synthesis of Compound 2 (an intermediate compound)
NaBH
Me Cl
2a 2b
NPhth
N H .H O
2 4 2
Compound 2
Step 1:
137. To a solution of AlCl (800 mg, 6 mmol) in dry CH Cl (12 mL) was added acyl
3 2 2
chloride (236 mg, 3 mmol) at 0 °C under N . The mixture was stirred for 10 min at room
temperature, then compound 2a was added (474 mg, 3 mmol) and the resulting mixture
stirred at room temperature overnight. Following water quench, the organic phase was
separated, dried with anhydrous Na SO and concentrated. The residue was purified by
— 84 —
column chromatography (silica, ethyl acetate/petroleum ether 1:15, v:v) to provide compound
2b (338 mg, 56% yield) as a white solid. H-NMR (CDCl , 300 MHz): δ= 9.01-9.96 (m, 1H),
8.32-8.35 (m, 1H), 8.03 (d, 1H), 7.63-7.65 (m, 1H), 7.53-7.58 (m, 1H), 6.79 (d, 1H), 4.07 (s,
3H), 2.72 (s, 3H). LC-MS: 201 [M+1] .
Step 2:
138. To a solution of compound 2b (167 mg, 0.84 mmol) in MeOH (5 mL) at 0 °C
was added NaBH (127 mg, 3.34 mmol). The mixture was stirred at room temperature for 2h
then the reaction was quenched with water. The reaction mixture was concentrated and
partitioned between ethyl acetate and water. The organic phase was separated, dried with
anhydrous Na SO and concentrated under reduce pressure to give 2c (170 mg, 100% yield)
which was used in the next step without further purification. H-NMR (CDCl , 300 MHz):
δ= 8.30-8.33 (m, 1H). 8.12-8.16 (m, 1H), 7.52-7.58 (m, 3H), 6.80 (d, 1H), 5.59 (q, 1H), 4.00
(s, 3H), 1.66 (d, 3H). LC-MS: 203 [M+1] .
Step 3:
139. To a mixture of 2c (170 mg, 0.84 mmol), phtalimide (186 mg, 1.26 mmol) and
PPh (441 mg, 1.68 mmol) in dry THF (12 mL) was added DIAD (340 mg, 1.68 mmol) at
room temperature under N . The mixture was stirred at room temperature overnight and then
concentrated. The residue was purified by column chromatography (silica, ethyl
acetate/petroleum ether 1:15, v:v) to provide compound 2d (113 mg, 41% yield). H-NMR
(CDCl , 300 MHz): δ= 8.28-8.30 (m, 1H),. 8.12 (d, 1H), 7.92 (d, 1H), 7.74-7.76 (m, 2H),
7.65-7.68 (m, 2H), 7.52-7.56 (m, 1H), 7.43-7.45(m, 1H), 6.87 (d, 1H), 6.24 (q, 1H), 4.01 (s,
3H), 2.01 (d, 3H).
Step 4:
140. A solution of compound 2d (113 mg, 0.34 mmol) in MeOH (4 mL) was treated
with hydrazine hydrate (98%, 68 mg, 1.36 mmol) under reflux for 2h. The mixture was then
cooled and concentrated. The residue was partitioned between CH Cl and water. The
organic phase was separated, dried with anhydrous Na SO and concentrated to give
Compound 2 (65 mg, 95% yield) as a yellow oil. H-NMR (CDCl , 300 MHz): δ= 8.32 (d,
1H), 8.08 (d, 1H), 7.46-7.56 (m, 3H), 6.79 (d, 1H), 4.86 (q, 1H), 3.96 (s, 3H), 1.64 (s, 2H),
1.52 (d, 3H). LC-MS: 202 [M+1] .
Synthesis of Compound 3 (an intermediate compound)
— 85 —
Cl Cl OH
NaBH
Cl 4
Me Cl
3a 3b
Cl NH
Cl NPhth
N H .H O Cl
O 2 4 2
Compound 3
141. Compound 3 was prepared using a synthetic procedure analogous to that of
Compound 2 to yield the target compound as a light-yellow oil (8.6 g, 55% yield). H NMR
(CDCl , 300 MHz,): δ= 7.42 (d, 1H), 6.87 (d, 1H), 4.52 (q, 1H), 3.90 (s, 3H), 1.66 (s, 2H),
1.36 (d, 3H). LC-MS: 220 [M+1] .
Synthesis of Compound 4
Step 1:
142. To a solution of 4a (1 g, 5 mmol) in MeOH (50 mL) was added acetic acid (0.5
mL, 8.7 mmol), sodium acetate (0.5 g, 6 mmol) and hydroxylamine hydrochloride (340 mg, 5
mmol), followed by NaBH CN (640 mg, 10 mmol). The mixture was stirred at room
temperature overnight. The solvent was removed under reduced pressure and the residue
washed with aqueous NaHCO solution and the mixture extracted with CH Cl (3 ×30). The
3 2 2
combined organic phases were dried over anhydrous Na SO and concentrated under reduced
pressure. The residue was purified by column chromatography (silica, ethyl acetate/petroleum
ether 1:1, v:v) to provide compound 4b (650 mg, 60% yield). H-NMR (CDCl , 300 MHz):
— 86 —
δ= 4.03-4.07 (m, 2H), 2.91-3.01 (m, 1H), 2.76-2.84 (m, 2H), 1.83-1.88 (m, 2H), 1.41 (s, 9H),
1.23-1.35 (m,2H). LC-MS: 217 [M+1] .
Step 2:
143. To a solution of compound 2 (45 mg, 0.72 mmol) in CH Cl (30 mL) at 0 °C
was added TEA (1.5 mL, 10.4 mmol) and triphosgene (210 mg, 0.72 mmol). The mixture
was stirred for 15 min, then 4b (155 mg, 0.72 mmol) was added. The resulting mixture was
warmed to room temperature and stirred for 30 min. Following concentration, the residue
was washed with an aqueous solution of NaHCO and extracted with CH Cl . The combined
3 2 2
organic phases were dried with Na SO and concentrated to provide crude urea 4c, which was
used in the next step without further purification. LC-MS: 444 [M+1] .
Step 3:
144. To a solution of 4c (300 mg 0.92 mmol) in MeOH (20 mL) at 0 °C was added
anhydrous HCl in MeOH (2N, 10 mL). The mixture was stirred at room temperature for 2 h.
After concentration, the residue was dissolved in MeOH (30 mL) and sodium acetate (0.5 g,
6 mmol), acetic acid (0.5 mL, 8.7 mmol) and 38% formaldehyde solution (2 mL, 25 mmol)
were added, followed by NaBH CN (87 mg, 1.3 mmol). The resulting mixture was stirred at
room temperature overnight and then concentrated under reduced pressure. The residue was
washed with saturated aqueous NaHCO (40 mL) solution, and extracted with CH Cl (3 × 50
3 2 2
mL) The combined organic phases were dried with anhydrous Na SO and concentrated
. 2 4
under reduced pressure to yield a residue that was purified by column chromatography (silica,
MeOH/CH Cl 1:20, v:v) to provide Compound 4 (130 mg, 50% yield) as a white solid. H-
NMR (300 MHz, CDCl ): δ= 8.26-8.29 (m, 1H); 8.03-8.06 (m, 1H), 7.36-7.52 (m, 3H), 6.72-
6.74 (d, 1H), 6.26-6.29 (d, 1H), 5.64-5.69 (m, 1H), 4.06-4.08 (m, 1H), 3.98 (s, 3H), 2.89-2.93
(m, 2H), 1.93-2.20 (m, 4H), 2.08 (s, 3H) 1.53-1.68 (m, 2H), 1.57 (d, 3H). LC-MS: 358
[M+1]
Synthesis of Compound 5
Step 1:
— 87 —
145. To a solution of 5a (5.65 g, 50 mmol) and methoxyamine (5 g, 60 mmol) in
MeOH (150 mL) was added acetic acid (5 mL, 87.5 mmol), sodium acetate (5.0 g, 60 mmol),
followed by NaBH CN (640 mg, 10 mmol). The mixture was stirred at room temperature for
48 h, then quenched with aqueous sat. NaHCO (add volume). The aqueous layer was
extracted with CH Cl (3 × 160 mL). The combined organic phase was dried over anhydrous
Na SO and evaporated to provide product 5b (21% crude yield) as a colorless oil, which was
used in the next step without further purification. LC-MS: 145 [M+1] .
Step 2:
146. To a solution of Compound 3 (250 mg, 1.14 mmol) in CH Cl (60 mL) at 0 C
was added TEA (3.5 ml, 25.21 mmol) and triphosgene (203 mg, 0.68 mmol). The mixture
was stirred for 15 min, then crude 5b (329 mg, 2.28 mmol) was added. The resulting mixture
was stirred for 30 min and evaporated. The residue was purified by column chromatography
(silica, MeOH/CH Cl 1:20, v:v) to afford Compound 5 (100 mg, 22% yield) as a white
solid . H-NMR (CDCl , 300 MHz): δ= 7.17 (d, 1H); 6.84 (d, 1H), 6.21-6.30 (m, 1H), 5.16-
.24 (m, 1H), 4.00-4.16 (m, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.18-3.29 (m, 2H), 2.53 (s, 3H),
2.21-2.50 (m, 4H), 1.69-1.90 (m, 2H), 1.50 (d, 3H). LC-MS: 390 [M+1] .
Synthesis of Compound 6
147. An analogous procedure to the last step of the synthesis of Compound 5
provided the target Compound 6 (120 mg, 61% yield) as a yellow solid. H-NMR (CDCl
300 MHz): δ= 8.14 (d, 1H); 7.91 (t, 1H), 7.78 (d, 1H), 7.47-7.56 (m, 4H), 6.57 (d, 1H), 5.63-
.72 (m, 1H), 3.83-3.97 (m, 1H), 3.16 (q, 2H), 2.75 (d, 2H), 2.12 (s, 3H), 1.84-1.91 (m, 2H),
1.55-1.66 (m, 2H), 1.49 (d, 3H), 1.40-1.48 (m, 2H), 0.99 (t, 3H). LC-MS: 340 [M+1] .
Synthesis of Compound 7
— 88 —
148. Following an analogous synthetic procedure to the last step in the preparation of
Compound 5, compound 7 (140 mg, 91% yield) was obtained as a yellow solid. H-NMR
(300 MHz, CDCl ): δ= 7.32-7.35 (m, 1H); 7.16-7.23 (m, 2H), 5.22-5.36 (m, 1H), 4.82 (d,
1H), 4.04-4.17 (m, 1H), 2.82-2.92 (m, 2H), 2.77 (s, 3H), 2.25 (s, 3H), 1.96-2.03 (m, 2H),
1.61-1.74 (m, 4H), 1.46 (d, 3H). LC-MS: 344 [M+1] .
Synthesis of Compound 8
149. Following an analogous synthetic procedure to the last step in the preparation of
Compound 5, compound 8 (101 mg, 28% yield) was obtained as a yellow solid. H-NMR
(CDCl , 300 MHz): δ= 8.30-8.32 (m, 1H), 8.09 (t, 1H), 7.43-7.48 (m, 3H), 6.77 (d, 1H),
.72-5.76 (m, 1H), 4.56 (t, 1H), 4.36-4.38 (m, 1H), 4.00 (s, 3H), 3.12-3.15 (m, 2H), 2.64 (s,
3H), 2.36-2.39 (m, 5H), 2.00-2.03 (m, 2H), 1.60-1.66 (m, 5H); LC-MS: 356 [M+1] .
Synthesis of Compound 9
150. Following an analogous synthetic procedure to the last step in the preparation of
Compound 5, compound 9 (100 mg, 64% yield) was obtained as a white solid. H- NMR
(CDCl , 300 MHz): δ=7.40-7.25 (m, 6H); 7.06-7.01 (t, 1H), 6.75-6.72 (m, 1H), 5.28-5.23 (m,
1H), 4.70-4.68 (d, 1H), 4.40-4.38 (m, 3H), 2.87-2.83 (m, 2H), 2.23 (s, 3H), 2.05-2.01 (m,
2H), 1.74-1.61 (m, 4H) , 1.22-1.19 (d, 3H). LC-MS: 420 [M+1] .
— 89 —
Synthesis of Compound 10
151. Following an analogous synthetic procedure to the last step in the preparation of
Compound 5, compound 10 (176 mg, 76% yield) was obtained as a white solid. H-NMR
(CDCl , 300 MHz): δ= 7.28-7.37 (m, 2H); 6.97-7.11 (m, 4H), 6.81-6.85 (m, 1H), 5.24-5.29
(m, 1H), 4.67-4.70 (m, 1H), 4.30-4.47 (m, 3H), 2.90-2.98 (m, 2H), 2.16 (s, 3H), 2.10-2.21 (m,
2H), 1.31-1.98 (m, 4H), 1.22 (d, 3H). LC-MS: 438 [M+1] .
Synthesis of Compound 11
152. Following an analogous synthetic procedure to the last step in the preparation of
Compound 5, compound 11 (105 mg, 35% yield) was obtained as a white solid. H -NMR
(CDCl , 300 MHz): δ= 7.40-7.42 (m, 1H), 7.29-7.31 (m, 1H), 7.25-7.27 (m, 3H), 7.05-7.10
(m, 1H), 6.89-6.92 (m, 1H), 5.29-5.20 (m, 1H), 4.64 (d, 1H), 4.37-4.44 (m, 3H), 2.91-3.01 (m,
2H), 2.32 (s, 3H), 2.17-2.23 (m, 2H), 1.65-1.82 (m, 4H), 1.33 (d, 3H). LC-MS: 454 [M+1] .
Synthesis of Compound 12
153. Following an analogous synthetic procedure to the last step of the preparation of
Compound 5, compound 12 (120 mg, 46% yield) was obtained as a white solid. H-NMR
(CDCl , 300 MHz): δ= 7.32-7.36 (m, 1H); 7.13-7.25 (m, 2H), 5.28-5.35 (m, 1H), 4.82-4.92
(m, 1H), 4.07-4.12 (m, 1H), 2.94-3.00 (m, 1H), 2.85 (s, 3H), 2.40-2.47 (m, 1H), 2.22 (s, 3H),
— 90 —
2.02-2.12 (m, 2H), 1.86-1.91 (m, 1H), 1.41-1.49 (m, 3H), 1.33-1.37 (m, 1H), 1.07 (s, 3H),
0.82 (d, 3H). LC-MS: 372.1 [M+1] .
Synthesis of Compound 13
154. Following an analogous synthetic procedure to the last step of the preparation of
Compound 5, compound 13 (70 mg, 36% yield) was obtained as a light yellow solid. H
NMR (CDCl , 300 MHz): δ= 8.28-8.31 (m, 1H), 8.09 (d, 1H), 7.26-7.54 (m, 3H), 6.77 (d,
1H), 5.70-5.79 (m, 1H), 4.56 (q, 1H), 4.16-4.28 (m, 1H), 4.00 (d, 3H), 2.96-3.00 (m, 1H),
2.67 (d, 3H), 2.45 (d, 1H), 2.25-2.26 (m, 3H), 1.92-2.11 (m, 3H), 1.63 -1.67 (m, 3H), 1.40-
1.48 (m, 1H), 1.05 (d, 3H), 0.90 (d, 3H); LC-MS: 384 [M+1]
Synthesis of Compound 14
Step 1:
155. A mixture of 1d (0.5 g, 3.5 mmol) and benzyl amine (0.34 g, 3.19 mmol) in
MeOH (30 mL) as stirred at room temperature for 3 h. Then NaBH CN (0.45 g, 7.0 mmol)
was added and the reaction mixture was stirred at room temperature overnight. The solvent
was removed under reduce pressure and the residue was dissolved in CH Cl (50 mL). The
mixture was washed with 100 mL of brine (100 mL) and the organic phases dried over
Na SO and concentrated. The residue was purified by column chromatograph (silica,
MeOH:CH Cl 1:20 to 1:10) to provide intermediate 11a (0.2 g, 27% yield) as a light yellow
oil. LC-MS: 234 [M+1] .
— 91 —
Step 2:
156. This procedure is analogous to the final step of the synthesis of Compound 5
and provided Compound 14 (80 mg, 20% yield) as a white solid. H-NMR (CDCl , 300
MHz,): δ=8.05-8.10 (m, 1H); 7.76-7.85 (m, 2H), 7.64-7.66 (m, 2H), 6.33-7.79 (m, 7H), 5.73-
.79 (m, 1H), 4.31-4.67 (m, 4H), 3.00-3.05 (m, 1H), 2.51-2.55 (m, 1H), 1.97-2.30 (m, 6H),
1.59-1.69 (m, 1H), 1.29-1.33 (m, 3H), 0.95-1.15 (m, 6H). LC-MS: 430 [M+1] .
Synthesis of Compound 15
Step 1:
157. Analogous to the preparation of 11a, compound 12b was obtained (2.1 g, 63%
yield) and used without further purification in the following step. LC-MS: 263 [M+1] .
Step 2:
158. This step is analogous to the final step in the synthesis of Compound 5 and
provided Compound 15 (140 mg, 57% yield) as a white solid. H-NMR (CDCl , 300 MHz):
δ= 7.22-7.31 (m, 2H); 7.09 (t, 1H), 6.79-6.95 (m, 4H), 5.15-5.30 (m, 1H), 4.64-4.78 (m, 1H),
4.36-4.46 (m, 3H), 3.76-3.79 (d, 3H), 3.94-3.96 (m, 1H), 2.39-2.42 (m, 1H), 2.19 (s, 3H),
1.98-2.05 (m, 2H), 1.20-1.25 (m, 2H), 1.07-1.09 (m, 6H), 0.86-0.97 (m, 3H). LC-MS: 378
[M+1] .
Synthesis of Compound 16
— 92 —
Step 1:
159. The synthesis is similar to that of 11b and provided 13b (1.0g, 46% yield)
which was used in the following step without further purification . LC-MS: 251 [M+1] .
Step 2:
160. Compound 16 was synthesized using a procedure similar to the final step in the
preparation of Compound 5. Compound 16 was obtained as a white solid (195 mg, 49%
yield). H NMR (CDCl , 300 MHz): δ= 7.25-7.40 (m, 6H); 7.01-7.06 (m, 3H), 6.72-6.75 (m,
1H), 5.25-5.28 (m, 1H), 4.70 (d, 1H), 4.38-4.40 (m, 3H), 2.83-2.87 (m, 2H), 2.24 (s, 3H),
2.01-2.05 (m, 2H), 1.67-1.74 (m, 4H), 1.21 (d, 3H). LC-MS: 466 [M+1] .
Synthesis of Compound 17
Step 1:
161. A mixture of 1b (2 g, 8.8 mmol) and methyl amine (30% in MeOH, 4 mL) was
hydrogenated (50 psi, 60 °C) in the presence of 5% Pd/C (2000 mg) in MeOH (25 mL)
overnight. After cooling the mixture was filtered and the filtrate was concentrated under
— 93 —
reduced pressure. The residue was purified by column chromatography (silica, ethyl
acetate/petroleum ether 1:10, v:v) to provide compound 14a (1.0 g, 48% yield) as a light
yellow oil. H-NMR (CDCl , 300 MHz): δ= 4.07-4.09 (m, 1H) ,2.65 (t, 2H), 2.51 (t, 2H),
2.43 (s, 3H), 2.38 (s, 2H), 1.41 (s, 9H), 1.14 (s, 6H). LC-MS: 243 [M+1] .
Step 2:
162. To a solution of Compound 3 (382 mg, 1.74 mmol) in CH Cl (50 mL) was
added TEA (351 mg) and triphosgene (309 mg, 1.04 mmol). The mixture was stirred for 15
min at 0 °C, then 14a (407 mg, 1.92 mmol) was added. The resulting mixture was stirred for
min at 0 °C and then concentrated under reduced pressure. The residue was purified by
column chromatography (silica, MeOH/CH Cl 1:20, v:v) to afford 14b (701 mg, 82% yield).
LC-MS: 488 [M+1] .
Step 3:
163. To a solution of 14b (701 mg, 1.44 mmol) in THF (20 mL) was added conc.
HCl (2 mL). The mixture was heated at 75 °C for 2h, then the solvent was evaporated to
obtain crude 14c (580 mg) , which was used in next step without further purification.
Step 4:
164. To the solution of crude 14c (580 mg) in MeOH (15 mL) was added aqueous
formaldehyde (38%, 4 mL, 24 mmol,), sodium acetate (200 mg, 2.4 mmol) and acetic acid (2
mL, 26 mmol), followed by NaBH CN (135 mg, 2.9 mmol). The mixture was stirred at room
temperature overnight, then concentrated under reduced pressure. The residue was purified
by column chromatography (silica, MeOH/CH Cl 1:20, v:v) to afford Compound 17 (262
mg, 38% yield) as a white solid. H-NMR (CDCl , 300 MHz): δ= 7.17-7.22 (m, 1H); 6.81-
6.84 (m, 1H), 5.21-5.26 (m, 1H), 4.81-4.92 (m, 1H), 4.07-4.10 (m, 1H), 3.88-3.91 (m, 3H),
2.90-2.93 (m, 1H), 2.81-2.82 (m, 3H), 2.38-2.42 (m, 1H), 2.21-2.22 (m, 3H), 1.85-2.05 (m,
4H), 1.42-1.50 (m, 3H), 1.06-1.07 (m, 3H) , 0.77-0.87 (m, 3H). LC-MS: 402 [M+1] .
Synthesis of Compound 18
— 94 —
Step 1:
165. To a solution of 15a (5.04 g, 26.8 mmol) in CH Cl (80 mL) at 0 °C was
added dropwise a solution of Br (3.81g, 24.1 mmol) in CH Cl . The solution was stirred at
2 2 2
room temperature overnight. The reaction mixture was washed with aqueous Na SO
solution, NaHCO solution and water successively. The organic phase was dried with
anhydrous Na SO and concentrated under reduced pressure. The residue was purified by
silica column chromatography (silica, ethyl acetate/petroleum ether 1:60, v:v) to provide
compound 15b (7.1 g, quantitative yield).
Step 2:
166. To a solution of compound 15b (3 g, 11.2 mmol) in MeOH (90 mL) at –20 °C
to –10 °C was added NaBH (936 mg, 24.5 mmol). The reaction mixture was warmed up to
room temperature and stirred for 1.5h, then the solvent was evaporated and the residue was
partitioned between ethyl acetate and water. The organic phase was separated, dried with
anhydrous Na SO , and concentrated under reduced pressure. The residue was purified by
column chromatography (silica, ethyl acetate/petroleum ether 1:30, v:v) to provide compound
15c (2.2 g, 73% yield). H-NMR (CDCl , 300 MHz): δ=7.54-7.57 (m, 1H), 7.42-7.46 (m,
1H), 7.24-7.29 (m, 1H), 5.29-5.34 (m, 1H), 3.81 (dd, 1H), 3.43 (dd, 1H), 2.84 (d, 1H).
Step 3:
167. To a solution of compound 15c (1.0 g, 3.72 mmol) in THF (100 mL) was added
1N KOH (5.6 mL, 5.58 mmol). The reaction was stirred at room temperature overnight. Ethyl
— 95 —
acetate (100 mL) was added and the organic phase was washed with brine, dried with
anhydrous Na SO and concentrated under reduced pressure. The residue was purified by
column chromatography (silica, petroleum ether) to provide compound 15d (432 mg, 62%
yield). H-NMR (CDCl , 300 MHz): δ=7.38-7.42 (m, 1H), 7.16-7.23 (m, 2H), 4.19-5.21 (m,
1H), 3.20 (dd, 1H), 2.63 (dd, 1H).
Step 4:
168. Metallic sodium (11 mg, 0.53 mmol) was added to benzyl alcohol (2 mL) at
room temperature under N and the mixture was stirred until sodium was completely
dissolved. Compound 15d (100 mg, 0.53 mmol) was then added to the solution, which was
then stirred at 70 °C overnight. The reaction was concentrated under reduced pressure and
the residue was purified by column chromatography (silica, ethyl acetate/petroleum ether 1:4,
v:v) to provide compound 15e (44 mg, 28% yield). H-NMR (CDCl , 300 MHz): δ= 7.53-
7.56 (m, 1H), 7.30-7.35 (m, 6H), 7.24-7.26 (m, 1H), 5.35 (q, 1H), 4.61 (q, 2H), 3.78 (q, 1H),
3.38 (q, 1H), 3.00 (s, 1H).
Step 5:
169. To a solution of compound 15e (480 mg, 1.6 mmol), phtalimide (286 mg, 1.9
mmol) and PPh (629 mg, 2.4 mmol) in dry THF (20 mL) at room temperature under N , was
added DIAD (485 mg, 2.4 mmol). The mixture was stirred at room temperature overnight
and then concentrated under reduced pressure. The residue was purified by column
chromatography (silica, ethyl acetate/petroleum ether 1:30, v:v) to provide 15f (570 mg, 83%
yield). H-NMR (CDCl , 300 MHz): δ= 7.79-7.85 (m, 2H), 7.70-7.74 (m, 2H), 7.58 (dd, 1H),
7.40 (dd, 1H), 7.24-7.27 (m, 5H), 7.19 (t, 1H), 6.07 (dd, 1H), 4.59 (d, 2H), 4.46 (t, 1H), 4.00
(dd, 1H).
Step 6:
170. A solution of compound 15h (570 mg, 1.34 mmol) and hydrazine hydrate (98%)
(270 mg, 5.36 mmol) in MeOH (10 mL) was heated under reflux for 2h. The mixture was
then concentrated under reduced pressure, the residue was dissolved in CH Cl and washed
with water. The aqueous phase was back extracted with CH Cl (3 × 30 mL) and the
combined organic phases were dried with anhydrous Na SO and concentrated to give 15g
(350 mg, 88% yield). LC-MS: 296 [M+1] .
Step 7:
171. To a solution of 15g (350 mg, 1.19 mmol) in dry CH Cl (10 mL) at room
temperature under nitrogen was added triphosgene (353 mg, 1.19 mmol). The reaction was
— 96 —
stirred at room temperature for 10 min, followed by the addition of 7a (235 mg, 1.43 mmol).
The reaction mixture was stirred at room temperature for 1h, then concentrated under reduced
pressure. The residue was purified by column chromatography (silica, MeOH/CH Cl 1:20,
v:v) to provide compound Compound 18 (450 mg, 84% yield) as a white solid. H-NMR
(CDCl , 300 MHz): δ= 7.28-7.36 (m, 8H), 5.43-5.48 (m, 2H), 4.50 (q, 2H), 4.26-4.30 (m,
1H), 3.79 (q, 1H), 3.62 (q, 1H), 3.10 (t, 2H), 2.81 (s, 3H), 2.43 (s, 3H), 2.30-2.36 (m, 2H),
2.10-2.17 (m, 2H), 1.65-1.70 (m, 2H). LC-MS: 450 [M+1] .
Synthesis of Compound 19
172. A solution of 5a (115mg, 0.584mmol), 5b (98mg, 0.596mmol) and TEA (0.5mL)
in dry DCM (20mL) was stirred at room temperature under N for 30min. After the reaction
was complete, water (10mL) was added. The organic phase was separated, dried with
Na SO and concentrated. The residue was purified by column chromatography (silica,
MeOH:DCM=1:20) to afford Compound 19 (108 mg, 57% yield). H NMR (300 MHz,
DMSO-d ): δ=8.14 (d, 1H), 7.92 (t, 1H), 7.78 (d, 1H), 7.57-7.45 (m, 4H), 6.71 (d, 1H), 5.71-
.60 (m, 1H), 4.16-4.08 (m, 1H), 3.17 (br, 2H); 2.72-2.61 (m, 5H), 2.50 (s, 3H), 1.93-1.87 (m,
2H), 1.58-1.51 (m, 5H). LC-MS: 326 [M+1]
Synthesis of Compound 20
173. To a solution of 6a (100 mg, 0.584mmol), TEA (1.5mL) in dry DCM (20 mL)
was added triphosgene (104 mg, 0.350 mmol) at room temperature under N . The mixture
was stirred at room temperature for 30 min, then 5b (98mg, 0.596mmol) was added. The
— 97 —
resulted mixture was stirred at room temperature for 30min. Water (10mL) was added and
the organic phase was separated, dried with Na SO and concentrated. The residue was
purified by column chromatography (silica, MeOH:DCM=1:20) to provide Compound 20
(109 mg, 57% yield). H NMR (300 MHz, DMSO-d ): δ=8.13 (d, 1H), 7.95 (t, 1H), 7.78 (d,
1H), 7.56-7.45 (m, 4H), 6.70-6.68 (d, 1H), 5.70-5.61 (m, 1H), 4.02-3.94 (m, 1H), 2.93 (br,
2H), 2.70 (s, 3H), 2.27 (s, 3H), 2.16 (br, 2H), 1.76-1.63 (m, 2H), 1.50-1.35 (m, 5H). LC-MS:
326 [M+1] .
2. Materials and methods
i. Calcium FLIPR assay
174. The intracellular calcium assay was carried out in a 384-well format FLIPR
(Molecular Device) HEK293/GHSR1a cell line. Cells were seeded 24 hr prior to the
experiments at an optimal density per well. Preincubation with selected calcium dye lasted
for 30-60 min at room temperature or 37 °C. Test compounds, dissolved in DMSO, were
added at the appropriate time and incubated for 15 min followed by the addition of ghrelin
with FlexStation or FLIPR. Relative fluorescence was monitored by the FLIPR Molecular
Device. EC and IC values were estimated from dose-response data using GraphPad Prism
50 50
software. To check for GHSR-1a agonism the compound was added at t=20 sec. and the
calcium response was followed for 2 minutes. To check forGHSR-1a antagonism the
compound and Ghrelin (10 nM) were added to the cells at t=20 sec. and the calcium response
was measured for 2 minutes. The potency of the antagonist was calculated by its ability to
reduce the ghrelin response. Dose-response curves were made for relevant antagonists.
ii. Evaluation of GHSR1a antagonists on food intake test in mouse
175. Male C57BL/6J mice, 18-22 g body weight, were fasted overnight (16h before
compound administration) and placed in a regular light dark cycle (6:00-18:00 light/18:00-
6:00 dark). After 1 wk acclimation, animals were sorted into two groups (n=6 each, 2 per
cage) based on body weight. Animals in group one were be treated with vehicle and animals
in group 2 were treated with the test agent (n=6 for each group). The cumulative food intake
was evaluated at 1, 2, 4, 8 and 24 hrs after drug or vehicle treatment. Food intake was
measured by subtracting uneaten food from the initial premeasured food.
3. Results
176. The following table presents representative compounds of formula (I) with
biological data including the ghrelin antagonist/agonist activity in vitro and mouse food
— 98 —
intake results. The data clearly demonstrates that compounds of formula (I) are ghrelin
receptor modulators and are useful in preventing and/or treating diseases associated with
ghrelin receptor, for example, obesity.
Table 1.
Mouse Food
IC FLIPR EC FLIPR
50 50
Intake
antagonist agonist
Structure (% inhibition.
Activity Activity
Doses as mg/kg
( M) ( M/Emax)
i.p.
N O CH
47% inhib. at 4 h,
0.021 0.009/1081 activity up to 8 hrs
(30 mg/kg)
3 CH
N 3 O CH
0.005 0.006/1268 NSE (30 mg/kg)
N O CH
28% inhibition at 1 hr,
0.320 30/124 activity up to 24hrs
(30 mg/kg)
N O CH Cl
N N 0.120 0.009/138 NSE (10mg/kg)
NSE(10mg/kg),
N O CH
70% increase food
intake at 1 hr, activity
0.040 0.030/2316
O up to 24 hrs(30
mg/kg).
27% inhibition at to 24
0.910 0.49/689
hrs (10mg/kg)
N O CH Cl
47% inhibition at 1hr
0.022 16.76/497
(10mg/kg)
74% inhibition at 1 hr,
N O 0.075 18.70/118.5 activity up to 24 hrs
(10mg/kg)
H C OH
47% inhibition at 1hr
0.066 0.020/3945
(10mg/kg)
— 99 —
Mouse Food
IC FLIPR EC FLIPR
50 50
Intake
antagonist agonist
Structure (% inhibition.
Activity Activity
Doses as mg/kg
( M) ( M/Emax)
i.p.
N O CH Cl
44% inhibition at 1hr
0.065 30/NA
(10mg/kg)
H C CH
N O CH Cl
26% inhibition at 1hr
0.012 30/260
(10mg/kg)
NSE(3mg/kg), 40%
inhibition at 1 hr,
N O Cl
activity up to 4
hrs(10mg/kg),
0.070 30/1573
50% inhibition at 1
hrs, activity up to 2
hrs(30mg/kg)
39% inhibition at 1 hr,
N O CH Cl
no activity up to follow
hrs.(3mg/kg),
95% inhibition at 1 hr,
activity up to 24
0.038 30/NA
hrs(10mg/kg),
70% inhibition at 2 hr,
activity up to 24 hrs
(30mg/kg)
N CHO CH Cl
NSE (10 mg/kg)
0.005 30/NA
H C CH
N O CH
NSE (10 mg/kg)
0.012 0.010/3208
H C CH
N O CH Cl
NSE (10 mg/kg)
0.003 0.010/2921
N CHO CH Cl
NSE (10 mg/kg)
0.007 30/NA
N O CH Cl
CH N N
NSE (10 mpk)
0.005 30/NA
— 100 —
Mouse Food
IC FLIPR EC FLIPR
50 50
Intake
antagonist agonist
Structure (% inhibition.
Activity Activity
Doses as mg/kg
( M) ( M/Emax)
i.p.
N O CH Cl
0.0082/4239 N/A
0.004
CH O
N O CH
n/a 0.0021/4203 N/A
OH CH
* NSE: not significant effect.
The term ‗comprising‘ as used in this specification and claims means ‗consisting at
least in part of‘. When interpreting statements in this specification and claims which
includes the ‗comprising‘, other features besides the features prefaced by this term in
each statement can also be present. Related terms such as ‗comprise‘ and ‗comprised‘
are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose
of providing a context for discussing the features of the invention. Unless specifically
stated otherwise, reference to such external documents is not to be construed as an
admission that such documents, or such sources of information, in any jurisdiction,
are prior art, or form part of the common general knowledge in the art.
— 101 —
Claims (27)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, N R O R N NH R Formula (I) wherein: R is aryl optionally substituted with one or more independent R substituents; R is selected from the group consisting of hydroxyalkyl, alkyl, optionally substituted with one or more independent R substituents; R is selected from the group consisting of alkyl, aryl, arylalkyl, optionally substituted with one or more independent R substituents; or R is OR ; 103 4 R , R , R , R are selected from the group consisting of hydrogen and alkyl; 6 7 8 9 103 104 R is selected from the group consisting of hydrogen, cyano, -NO , -OR , hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, 104, 104 104 105 heterocycloalkyl, heteroaryl, heteroarylalkyl, -C(O)R -C(O)OR , -C(O)NR R , - 104 105 104 105 104 105 104 104 104 105 NR R , -NR S(O) R , -NR C(O)R ,- S(O) R , -SR and -S(O) NR R , and 2 2 2 104 105 R and R are each independently selected from the group consisting of hydrogen, cyano, NO , hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl and heteroarylalkyl.
2. A compound of formula (I) according to claim 1 wherein: 103 103 when R is optionally substituted with R , then R is halogen or alkoxy; 103 103 when R is alkyl, aryl, arylalkyl optionally substituted with R , then R is halogen or alkoxy; 103 103 or when R is OR , then R is hydrogen or alkyl. — 102 —
3. The compound of claim 1, wherein R is selected from the group consisting of phenyl, naphthalene, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl, fluorenyl.
4. The compound of claim 1, wherein R is phenyl or naphthalene which is optionally independently substituted with from one to six substituents independently selected from the group consisting of chloro, fluoro, bromo, methoxy and ethoxy.
5. The compound of claim 1, wherein R is selected from the group consisting of methyl, - CH OH, and -CH -O-CH -phenyl. 2 2 2
6. The compound of claim 1, wherein R is methyl, ethyl, benzyl, or benzyl substituted with from one to five substituents independently selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy.
7. The compound of claim 1, wherein R and R are each independently hydrogen, methyl, or ethyl.
8. A compound selected from the group consisting of: GA1 1-methyl((R)(naphthalen yl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA2 1-methyl((S)(naphthalen yl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA3 1-methyl(1-(naphthalen yl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA4 3-(1-(4-methoxynaphthalen yl)ethyl)methyl(1,3,3- trimethylpiperidinyl)urea, — 103 — GA5 1-benzyl((R)(naphthalen yl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA6 3-(1-(2,3-dichlorophenyl)ethyl) (3-methoxybenzyl)(1,3,3- trimethylpiperidinyl)urea, GA7 3-(1-(2,3-dichlorophenyl)ethyl) (2-fluorobenzyl)(1,3,3- trimethylpiperidinyl)urea, GA8 3-(1-(2,3-dichloro methoxyphenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA9 3-(1-(2,3-dichlorophenyl)ethyl) methyl(1,3,3-trimethylpiperidin- 4-yl)urea, GA10 3-((R)(2,3-dichloro methoxyphenyl)ethyl)(1,3- dimethylpiperidinyl)(3- methoxybenzyl)urea, GA11 1-benzyl(1-(2,3- dichlorophenyl)propyl)(1,3,3- trimethylpiperidinyl)urea, — 104 — GA12 3-((S)(2,3- dichlorophenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA13 3-((R)(2,3- dichlorophenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA14 3-(1-(2,3-dichlorophenyl)ethyl) methyl(1,3,3-trimethylpiperidin- 4-yl)urea, GA15 1-benzyl((S)(naphthalen yl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA16 1-benzyl((R)(naphthalen yl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA17 1-benzyl(1-(naphthalen yl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA18 3-(1-(2,3-dichlorophenyl)propyl)- 1-methyl(1,3,3- trimethylpiperidinyl)urea, GA19 3-(1-(2,3-difluorophenyl)ethyl) methyl(1,3,3-trimethylpiperidin- 4-yl)urea, — 105 — GA20 1-benzyl(1-(2,3- dichlorophenyl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA21 1-benzyl(1-(2,3- difluorophenyl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA22 1-benzyl(1-(4- methoxynaphthalenyl)ethyl) (1,3,3-trimethylpiperidinyl)urea, GA23 3-(1-(2,3-dichloro methoxyphenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA26 3-(2-hydroxy(naphthalen yl)ethyl)methyl(1,3,3- trimethylpiperidinyl)urea, GA27 1-(4-chlorobenzyl)(1-(2,3- dichlorophenyl)ethyl)(1,3,3- trimethylpiperidinyl)urea, GA28 1-benzyl(3,3-diethyl methylpiperidinyl)((S) (naphthalenyl)ethyl)urea, — 106 — GA29 1-benzyl(3,3-diethyl methylpiperidinyl)((R) (naphthalenyl)ethyl)urea, GA30 1-benzyl(3,3-diethyl methylpiperidinyl)(1- (naphthalenyl)ethyl)urea, GA31 3-(2-(benzyloxy)(naphthalen yl)ethyl)methyl(1,3,3- trimethylpiperidinyl)urea, GA33 3-((R)(2,3- dichlorophenyl)ethyl)(3- methoxybenzyl)(1,3,3- trimethylpiperidinyl)urea, GA34 3-(2-cyclopropyl(2,3- dichlorophenyl)ethyl)(3- methoxybenzyl)(1,3,3- trimethylpiperidinyl)urea, GA35 3-(1-(2,3-dichlorophenyl)ethyl) (3-hydroxybenzyl)(1,3,3- trimethylpiperidinyl)urea, GA37 1-benzyl(1-(2,3- dihydroxyphenyl)ethyl)(1,3,3- trimethylpiperidinyl)urea, — 107 — GA38 3-((R)(2,3- dichlorophenyl)ethyl)(3-(2- hydroxyethoxy)benzyl)(1,3,3- trimethylpiperidinyl)urea, GA39 3-(1-(2,3-difluoro methoxyphenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA40 3-(1-(2,3-difluoro hydroxyphenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA46 1-ethyl(1-methylpiperidinyl)- 3-(1-(naphthalenyl)ethyl)urea, GA47 3-(1-(4-methoxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA48 3-(2-hydroxy(naphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA49 3-(2-hydroxy(4- methoxynaphthalenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA50 1-(1-methylpiperidinyl)(1- (naphthalenyl)ethyl)(pyridin- 3-ylmethyl)urea, — 108 — GA57 1-(cyclohexylmethyl)(1- methylpiperidinyl)(1- (naphthalenyl)ethyl)urea, GA58 1-isopropyl(1-methylpiperidin- 4-yl)(1-(naphthalen yl)ethyl)urea, GA59 1-(2-methoxyethyl)(1- methylpiperidinyl)(1- (naphthalenyl)ethyl)urea, GA62 1-(cyclopropylmethyl)(1- methylpiperidinyl)(1- (naphthalenyl)ethyl)urea, GA63 3-(1-(2-methoxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA67 3-(2-methoxy(naphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA68 3-(3-methoxy(naphthalen yl)propyl)methyl(1- methylpiperidinyl)urea, GA69 1-methyl(1-methylpiperidin yl)(1-(naphthalen yl)propyl)urea, — 109 — GA73 (S)(1-methylpiperidinyl) (1-(naphthalenyl)ethyl) (pyridinylmethyl)urea, GA74 (R)(1-methylpiperidinyl) (1-(naphthalenyl)ethyl) (pyridinylmethyl)urea, GA75 1-isobutyl(1-methylpiperidin yl)(1-(naphthalen yl)ethyl)urea, GA76 1-(cyclobutylmethyl)(1- methylpiperidinyl)(1- (naphthalenyl)ethyl)urea, GA77 1-butyl(1-methylpiperidinyl)- 3-(1-(naphthalenyl)ethyl)urea, GA79 1-(1-methylpiperidinyl)(1- (naphthalenyl)ethyl)(pyridin- 2-ylmethyl)urea, GA80 1-(1-methylpiperidinyl)(1- (naphthalenyl)ethyl)(pyridin- 4-ylmethyl)urea, GA82 (R)ethyl(1-methylpiperidin- 4-yl)(1-(naphthalen yl)ethyl)urea, — 110 — GA83 3-(2-hydroxy(4- methoxynaphthalenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA84 3-(2-hydroxy(naphthalen yl)ethyl)(1-methylpiperidin yl)(pyridinylmethyl)urea, GA85 3-(2-methoxy(4- methoxynaphthalenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA86 3-(1-(2,3-dichlorophenyl)ethyl) (3-hydroxybenzyl)(1- methylpiperidinyl)urea, GA87 1-benzyl(1,3-dimethylpiperidin- 4-yl)((R)(naphthalen yl)ethyl)urea, GA88 1-(1,3-dimethylpiperidinyl) methyl((R)(naphthalen yl)ethyl)urea, GA89 3-(1-(4-methoxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA90 (R)(1-(4-methoxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, — 111 — GA91 (S)(1-(4-methoxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA92 3-(1-(4,8-dimethoxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA93 3-(1-(4- (methoxymethoxy)naphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA94 3-(2-(benzyloxy)(2,3- dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA95 (R)(2-(benzyloxy)(2,3- dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA96 (S)(2-(benzyloxy)(2,3- dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA97 3-(1-(2,3-dichlorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA98 1-benzyl(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA99 3-(1-(2,3-dichlorophenyl)ethyl) (3-fluorobenzyl)(1- methylpiperidinyl)urea, — 112 — GA100 1-(2-chlorobenzyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA101 3-(1-(3,5-difluorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA102 3-(1-(2-chlorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA103 3-(1-(3-fluorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA104 3-(1-(4-chlorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA105 3-(1-(2,4-difluorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA106 1-methyl(1-methylpiperidin yl)(1-(o-tolyl)ethyl)urea, GA107 1-methyl(1-methylpiperidin yl)(1-(4- (methylsulfonyl)phenyl)ethyl)urea, GA108 1-(cyclohexylmethyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, — 113 — GA109 1-(cyclopropylmethyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA110 3-(1-(2,3-dichlorophenyl)ethyl) ethyl(1-methylpiperidin yl)urea, GA111 3-(1-(2,3-dichlorophenyl)ethyl) (1-methylpiperidinyl) (pyridinylmethyl)urea, GA112 3-(1-(3-chlorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA113 1-benzyl(1-(3- chlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA114 1-(3-chlorobenzyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA115 3-(1-(2,3-dichlorophenyl)ethyl) (2-methoxybenzyl)(1- methylpiperidinyl)urea, GA116 3-(1-(2,3-dichlorophenyl)ethyl) (3-methoxybenzyl)(1- methylpiperidinyl)urea, — 114 — GA117 3-(1-(2,3-dichlorophenyl)ethyl) (4-fluorobenzyl)(1- methylpiperidinyl)urea, GA118 3-(1-(2,3-dichlorophenyl)ethyl) (2-fluorobenzyl)(1- methylpiperidinyl)urea, GA119 1-(4-chlorobenzyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA120 3-(1-(3,4-dichlorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA121 3-(1-(2,3-dichlorophenyl)ethyl) (4-methoxybenzyl)(1- methylpiperidinyl)urea, GA122 3-(1-(2,3-dichlorophenyl)propyl)- 1-ethyl(1-methylpiperidin yl)urea, GA123 1-(cyclohexylmethyl)(1-(2,3- dichlorophenyl)propyl)(1- methylpiperidinyl)urea, GA124 3-(1-(2,3-difluorophenyl)ethyl) methyl(1-methylpiperidin yl)urea, — 115 — GA125 1-benzyl(1-(2,3- difluorophenyl)ethyl)(1- methylpiperidinyl)urea, GA126 1-(cyclohexylmethyl)(1-(2,3- difluorophenyl)ethyl)(1- methylpiperidinyl)urea, GA127 (R)(1-(2,3- dichlorophenyl)ethyl)ethyl(1- methylpiperidinyl)urea, GA128 1-benzyl(1-(2,3- dichlorophenyl)ethyl)(1,3- dimethylpiperidinyl)urea, GA129 3-(1-(2,3-dichlorophenyl)ethyl) (1,3-dimethylpiperidinyl) methylurea, GA130 (S)(1-(2,3- dichlorophenyl)ethyl)ethyl(1- methylpiperidinyl)urea, GA131 (R)(1-(2,3- dichlorophenyl)ethyl)ethyl(1- methylpiperidinyl)urea, GA132 3-(1-(2,3-dichlorophenyl)ethyl) ethyl(1-methylpiperidin yl)urea, — 116 — GA133 3-((R)(2,3-dichloro methoxyphenyl)ethyl)(1,3- dimethylpiperidinyl)(3- methoxybenzyl)urea, GA134 3-((S)(2,3-dichloro methoxyphenyl)ethyl)(1,3- dimethylpiperidinyl)(3- methoxybenzyl)urea, GA135 3-(1-(2,3-dichloro methoxyphenyl)ethyl)(1,3- dimethylpiperidinyl)(3- methoxybenzyl)urea, GA136 3-(1-(2,3-difluorophenyl)ethyl) (1,3-dimethylpiperidinyl)(3- methoxybenzyl)urea, GA137 3-(1-(2,3-dichlorophenyl)ethyl) (4-(hydroxymethyl)benzyl)(1- methylpiperidinyl)urea, GA138 methyl 4-((3-(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidin yl)ureido)methyl)benzoate, GA139 3-(2-cyclopropyl(2,3- dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA140 3-(1-(2,3-dichlorophenyl) hydroxyethyl)methyl(1- methylpiperidinyl)urea, — 117 — GA141 (R)(2-chlorobenzyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA142 (S)(2-chlorobenzyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA143 1-(2-chlorobenzyl)(1-(2,3- dichlorophenyl)ethyl)(1- methylpiperidinyl)urea, GA144 3-(1-(2,3-dimethoxyphenyl)ethyl)- 1-methyl(1-methylpiperidin yl)urea, GA145 3-(1-(2,3-difluoro methoxyphenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA146 3-(1-(2,3-dichlorophenyl) methoxyethyl)methyl(1- methylpiperidinyl)urea, GA147 N-(2,3-dichloro(1-(3-methyl (1-methylpiperidin yl)ureido)ethyl)phenyl)acetamide, GA148 3-(1-(4-amino-2,3- dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea, — 118 — GA149 3-(1-(2,3-dichloro methoxyphenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA150 1-ethyl(1-methylpiperidinyl)- 3-(1-(naphthalenyl)(3- (pyridin yloxy)phenyl)propyl)urea, GA151 1-methyl(1-methylpiperidin yl)(1-(naphthalenyl) (pyridinyl)propyl)urea, GA152 1-methyl(1-methylpiperidin yl)(3-morpholino(naphthalen- 1-yl)propyl)urea, GA153 1-ethyl(3-(3-methoxyphenyl) (naphthalenyl)propyl)(1- methylpiperidinyl)urea, GA154 3-(3-(3-(benzyloxy)phenyl) (naphthalenyl)propyl)ethyl (1-methylpiperidinyl)urea, — 119 — GA155 1-ethyl(1-methylpiperidinyl)- 3-(1-(naphthalenyl)(pyridin- 3-yl)propyl)urea, GA156 3-(3-(3-(benzyloxy)phenyl) (naphthalenyl)propyl)(1- methylpiperidinyl)(pyridin ylmethyl)urea, GA157 3-(3-(3-(benzyloxy)phenyl)(2,3- dichlorophenyl)propyl)methyl- 1-(1-methylpiperidinyl)urea, GA158 3-(2-(benzyloxy)(2,3- dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA159 3-(2-(benzylamino)(2,3- dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA161 3-(2-(benzyloxy)(2,3- dichlorophenyl)ethyl)(2- chlorobenzyl)(1- methylpiperidinyl)urea, — 120 — GA162 3-(2-(benzyloxy)(2,3- dichlorophenyl)ethyl)(4- (hydroxymethyl)benzyl)(1- methylpiperidinyl)urea, GA163 3-(1-(2,3-dichlorophenyl)((4- methoxybenzyl)oxy)ethyl) methyl(1-methylpiperidin yl)urea, GA164 3-(1-(2,3-dichlorophenyl) (pyridinylmethoxy)ethyl) methyl(1-methylpiperidin yl)urea, GA165 3-(1-(2,3-dichloro methoxyphenyl)ethyl)methoxy- 1-(1-methylpiperidinyl)urea, GA166 (S)(1-(2,3-dichloro methoxyphenyl)ethyl)methoxy- 1-(1-methylpiperidinyl)urea, GA167 (R)(1-(2,3-dichloro methoxyphenyl)ethyl)methoxy- 1-(1-methylpiperidinyl)urea, GA168 1-hydroxy(1-(4- methoxynaphthalenyl)ethyl) (1-methylpiperidinyl)urea, GA169 (R)hydroxy(1-(4- methoxynaphthalenyl)ethyl) (1-methylpiperidinyl)urea, — 121 — GA170 (S)hydroxy(1-(4- methoxynaphthalenyl)ethyl) (1-methylpiperidinyl)urea, GA171 3-(1-(2,3-dichlorophenyl)ethyl) methoxy(1-methylpiperidin yl)urea, GA172 (R)(1-(2,3- dichlorophenyl)ethyl)methoxy- 1-(1-methylpiperidinyl)urea, GA173 (S)(1-(2,3- dichlorophenyl)ethyl)methoxy- 1-(1-methylpiperidinyl)urea, GA174 1-methoxy(1-(4- methoxynaphthalenyl)ethyl) (1-methylpiperidinyl)urea, GA175 (R)methoxy(1-(4- methoxynaphthalenyl)ethyl) (1-methylpiperidinyl)urea, GA176 (S)methoxy(1-(4- methoxynaphthalenyl)ethyl) (1-methylpiperidinyl)urea, GA177 3-(1-(2,3-dichlorophenyl)ethyl) hydroxy(1-methylpiperidin yl)urea, GA178 (R)(1-(2,3- dichlorophenyl)ethyl)hydroxy (1-methylpiperidinyl)urea, GA179 (S)(1-(2,3- dichlorophenyl)ethyl)hydroxy (1-methylpiperidinyl)urea, — 122 — GA180 3-(1-(2,3-dichloro methoxyphenyl)ethyl)hydroxy- 1-(1-methylpiperidinyl)urea, GA181 (R)(1-(2,3-dichloro methoxyphenyl)ethyl)hydroxy- 1-(1-methylpiperidinyl)urea, GA182 (S)(1-(2,3-dichloro methoxyphenyl)ethyl)hydroxy- 1-(1-methylpiperidinyl)urea, GA183 3-(1-(2,3-dichloro (dimethylamino)phenyl)ethyl) methyl(1-methylpiperidin yl)urea, GA184 3-(1-(4-((4- methoxybenzyl)oxy)naphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA185 3-(1-(4-hydroxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA186 3-(1-(4,5-dimethoxynaphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea, GA187 3-(1-(2,3-dichlorophenyl) (pyridinylmethoxy)ethyl) methyl(1-methylpiperidin yl)urea, — 123 — GA189 3-(1-(2-chloro-3,4- dimethoxyphenyl)ethyl)methyl- 1-(1-methylpiperidinyl)urea, GA190 1-methyl(1-methylpiperidin yl)(1-(2,3,4- trichlorophenyl)ethyl)urea, GA191 1-methyl(1-methylpiperidin yl)(1-(4-(pyridin ylmethoxy)naphthalen yl)ethyl)urea, GA192 3-(1-(6-chloro-[1,1'-biphenyl] yl)ethyl)methyl(1- methylpiperidinyl)urea, GA193 3-(1-(3-chloro(pyridin yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea, GA194 3-(1-(2,3-dichloro methylphenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA195 3-(1-(3-chloro methylphenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA196 3-(1-(2,3-dichlorophenyl)((4- (hydroxymethyl)benzyl)oxy)ethyl)- 1-methyl(1-methylpiperidin yl)urea, — 124 — GA197 3-(1-(2,3-dichloro methoxyphenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA198 (R)(1-(2,3-dichloro methoxyphenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA199 (S)(1-(2,3-dichloro methoxyphenyl)ethyl)methyl (1-methylpiperidinyl)urea, GA200 3-(1-(2,3-dichloro methoxyphenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA201 3-((R)(2,3-dichloro methoxyphenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA202 3-((S)(2,3-dichloro methoxyphenyl)ethyl)methyl (1,3,3-trimethylpiperidinyl)urea, GA203 3-(1-(4-(2- (benzyloxy)ethoxy)naphthalen yl)ethyl)methyl(1- methylpiperidinyl)urea. — 125 —
9. Use of a compound of formula (I) according to any one of claims 1- 8, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and/or treating a subject having a disease which is pathophysiologically mediated by the ghrelin receptor.
10. The use of claim 9, wherein said disease is obesity, overweight, eating disorder, diabetes, metabolic syndrome, cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric disorder or substance abuse.
11. The use of claim 10, wherein said metabolic disorder is selected from the group consisting of diabetes, Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.
12. The use of claim 10, wherein said gastric disorder is selected from the group consisting of Post-operative ileus (POI), diabetic gastroparesis, and opioid induced bowel dysfunction.
13. The use of claim 10, wherein said gastrointestinal disease is selected from the group consisting of irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.
14. The use of claim 10, wherein said substance abuse is alcohol or drug abuse.
15. The use of claim 14, wherein said drug is selected from the group consisting of amphetamines, barbiturates, benzodiazepines, ***e, methaqualone, and opioids.
16. The use of any one of claims 9 to 15, wherein said compound or a pharmaceutically acceptable salt thereof, is a ghrelin receptor modulator.
17. The use of any one of claims 9 to 16, wherein said compound or a pharmaceutically acceptable salt thereof, is a ghrelin receptor agonist.
18. The use of any one of claims 9 to 17, wherein said compound or a pharmaceutically acceptable salt thereof, is a ghrelin receptor antagonist.
19. The use of any one of claims 9 to 18, wherein said medicament is in a form suitable to be administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, ocular, parenteral and topical administration.
20. The use of any one of claims 9 to 19, wherein said medicament is to be administered to provide said compound or a pharmaceutically acceptable salt thereof in an amount of from about 0.01 microgram per Kg (µg/Kg) body weight per day to about 100 mg/Kg body weight per day, from about 0.1 µg /Kg/day to about 10 mg/Kg/day, from about 1 µg/Kg /day to about 5 mg/ Kg /day, from about 10 µg /Kg/day to about 5 mg/Kg/day, from about 100 µg /Kg/day to about 5 mg/Kg/day, or from about 500 µg /Kg/day to about 5 mg/Kg/day. — 126 —
21. The use of any one of claims 9 to 20, wherein the medicament is to be further administered with one or more therapeutic agents.
22. The use of any one of claims 9 to 21, wherein the subject is a human.
23. The use of any one of claims 9 to 22, wherein the subject has been identified as needing treatment for the disease or the administration.
24. A pharmaceutical composition for preventing and/or treating a subject comprising a therapeutically effective amount of a compound according to any one of claims 1-8, and one or more pharmaceutically acceptable excipients.
25. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, substantially as herein described with reference to any example thereof.
26. A use as claimed in any one of claims 9 to 23, substantially as herein described with reference to any example thereof.
27. A pharmaceutical composition as claimed in claim 24, substantially as herein described with reference to any example thereof. — 127 —
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2011/000298 WO2012113103A1 (en) | 2011-02-25 | 2011-02-25 | Asymmetric ureas and medical uses thereof |
CNPCT/CN2011/00298 | 2011-02-25 | ||
US201161466070P | 2011-03-22 | 2011-03-22 | |
US61/466,070 | 2011-03-22 | ||
PCT/US2012/026315 WO2012116176A2 (en) | 2011-02-25 | 2012-02-23 | Asymmetric ureas and medical uses thereof |
Publications (2)
Publication Number | Publication Date |
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NZ615283A NZ615283A (en) | 2015-09-25 |
NZ615283B2 true NZ615283B2 (en) | 2016-01-06 |
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