U.S. patent application number 13/220843 was filed with the patent office on 2011-12-22 for pharmaceutical use of substituted amides.
This patent application is currently assigned to HIGH POINT PHARMACEUTICALS, LLC. Invention is credited to Henrik Sune Andersen, Soren Ebdrup, Gita Camilla Tejlgaard Kampen, John Paul Kilburn.
Application Number | 20110312949 13/220843 |
Document ID | / |
Family ID | 36072052 |
Filed Date | 2011-12-22 |
United States Patent
Application |
20110312949 |
Kind Code |
A1 |
Kilburn; John Paul ; et
al. |
December 22, 2011 |
PHARMACEUTICAL USE OF SUBSTITUTED AMIDES
Abstract
The use of substituted amides for modulating the activity of
11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1) and the
use of these compounds as pharmaceutical compositions, are
described. Also a novel class of substituted amides, their use in
therapy, pharmaceutical compositions comprising the compounds, as
well as their use in the manufacture of medicaments are described.
The present compounds are modulators and more specifically
inhibitors of the activity of 11.beta.HSD1 and may be useful in the
treatment, prevention and/or prophylaxis of a range of medical
disorders where a decreased intracellular concentration of active
glucocorticoid is desirable.
Inventors: |
Kilburn; John Paul; (Haslev,
DK) ; Andersen; Henrik Sune; (Holte, DK) ;
Kampen; Gita Camilla Tejlgaard; (Naerum, DK) ;
Ebdrup; Soren; (Roskilde, DK) |
Assignee: |
HIGH POINT PHARMACEUTICALS,
LLC
High Point
NC
|
Family ID: |
36072052 |
Appl. No.: |
13/220843 |
Filed: |
August 30, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12092223 |
Oct 23, 2008 |
8053431 |
|
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PCT/EP2006/068017 |
Nov 1, 2006 |
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13220843 |
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Current U.S.
Class: |
514/228.2 ;
514/234.5; 514/314; 514/322; 514/394; 544/143; 544/58.2; 546/164;
546/199; 548/305.1 |
Current CPC
Class: |
C07D 235/06 20130101;
A61P 9/12 20180101; A61P 3/06 20180101; A61P 3/04 20180101; C07D
403/12 20130101; A61P 3/00 20180101; A61P 25/28 20180101; C07D
401/12 20130101; A61P 3/10 20180101; C07D 401/14 20130101; C07D
405/14 20130101; C07D 413/14 20130101; C07D 451/06 20130101; A61K
31/4184 20130101; C07D 403/06 20130101; C07D 209/08 20130101; A61K
31/404 20130101; A61P 25/18 20180101; A61P 43/00 20180101; C07D
401/06 20130101 |
Class at
Publication: |
514/228.2 ;
548/305.1; 546/199; 544/143; 546/164; 544/58.2; 514/394; 514/322;
514/234.5; 514/314 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; C07D 401/14 20060101 C07D401/14; C07D 403/10 20060101
C07D403/10; C07D 413/14 20060101 C07D413/14; C07D 401/10 20060101
C07D401/10; A61P 3/00 20060101 A61P003/00; A61K 31/454 20060101
A61K031/454; A61K 31/5377 20060101 A61K031/5377; A61K 31/4709
20060101 A61K031/4709; A61K 31/541 20060101 A61K031/541; C07D
403/14 20060101 C07D403/14; C07D 405/14 20060101 C07D405/14; C07D
417/14 20060101 C07D417/14 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 1, 2005 |
EP |
05110226.7 |
Claims
1. A compound of Formula IA or a pharmaceutically acceptable salt
thereof: ##STR00127## wherein: R.sup.1 is
--(CH.sub.2).sub.1-2--R.sup.6; R.sup.2 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl, and
--C(.dbd.O)R.sup.13; the ring ##STR00128## R.sup.6 is selected from
the group consisting of cyano, aryl, hetaryl,
-oxoC.sub.1-C.sub.6alkyl-S(.dbd.O).sub.nR.sup.13,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.O)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, --N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.6cycloalkyl, and
--N(R.sup.18)C(.dbd.O)-- (3-6 membered hetcycloalkyl), wherein the
cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted
with 0-3 R.sup.16; R.sup.13 is selected from the group consisting
of --OH, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19; R.sup.15 and R.sup.16
are independently selected from the group consisting of H,
C.sub.1-C.sub.4alkyl, 3-6-membered cycloalkyl, halo, OH, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-1 R.sup.20;
R.sup.18 and R.sup.19 are independently selected from the group
consisting of H, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy,
aryl, hetaryl, arylC.sub.1-C.sub.4alkylene, and
hetarylC.sub.1-C.sub.4alkylene, wherein the alkyl, alkylene, aryl,
and hetaryl groups are independently substituted with 0-1 R.sup.20;
alternatively, R.sup.18 and R.sup.19, together with the nitrogen
atom to which they are attached, form a saturated or partially
saturated monocyclic, bicyclic, or tricyclic ring consisting of the
shown nitrogen, 4-5 carbon atoms, and 0-1 additional heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein this ring is substituted 0-1 times with substituents
selected from the group consisting of C.sub.1-C.sub.4alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.4alkylene,
hetarylC.sub.1-C.sub.4alkylene, hydroxy, and
C.sub.1-C.sub.4alkyloxy; R.sup.20 is selected from the group
consisting of H, OH, oxo, halo, cyano, nitro, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxy, NR.sup.21R.sup.22, trihalomethyl, and
trihalomethyloxy; R.sup.21 and R.sup.22 are independently selected
from the group consisting of H, C.sub.1-C.sub.4alkyl, and
arylC.sub.1-C.sub.4alkyl; R.sup.23 is selected from the group
consisting of H and C.sub.1-C.sub.6alkyl; and n is 2.
2. The compound of claim 1, wherein R.sup.2 is H.
3. The compound of claim 2, wherein R.sup.1 is
--(CH.sub.2).sub.2--R.sup.6.
4. A compound, which is a compound selected from the group
consisting of: Furan-2-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-amide; 1-Acetyl-piperidine-4-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-amide;
2-Methoxy-N-{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-benzoimidazol-1-yl]-ethyl}-acetamide;
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimid-
azol-1-yl]-ethyl}-isonicotinamide;
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimid-
azol-1-yl]-ethyl}-acetamide;
{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-carbamic acid tert-butyl ester;
Isoxazole-5-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoi-
midazol-1-yl]-ethyl}-amide;
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimid-
azol-1-yl]-ethyl}-benzamide;
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benz-
imidazol-1-yl]-propionic acid ethyl ester;
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benz-
imidazol-1-yl]-propionic acid;
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ben-
zimidazol-1-yl]-propionic acid ethyl ester;
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]octane-6-carbonyl)-1H--
benzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl ester;
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]octane-6-carbonyl)-be-
nzimidazol-1-yl]-propionic acid;
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]octane-6-carbonyl)-1H--
benzimidazol-2-yl]-cyclopropanecarboxylic acid;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid ethyl ester;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid;
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-ac-
etic acid tert-butyl ester;
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-ac-
etic acid;
1-Morpholin-4-yl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octa-
ne-6-carbonyl)-indol-1-yl]-propan-1-one;
1-Morpholin-4-yl-2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbo-
nyl)-indol-1-yl]-ethanone;
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-indol-1-yl]-propionic acid ethyl ester;
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-indol-1-yl]-propionic acid;
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ind-
ol-1-yl]-propionic acid methyl ester;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
butyric acid methyl ester;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
butyric acid;
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ind-
ol-1-yl]-propionic acid;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzoic acid;
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzoic acid methyl ester; and
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzoic acid; or a pharmaceutically acceptable salt
thereof.
5.
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-y-
l]-propionic acid ethyl ester or a pharmaceutically acceptable salt
thereof.
6. The compound of claim 5, where the compound is
3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid ethyl ester.
7.
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-y-
l]-propionic acid or a pharmaceutically acceptable salt
thereof.
8. The compound of claim 7, where the compound is
3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid.
9. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising a compound of claim 4
and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising a compound of claim 5
and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising a compound of claim 6
and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a compound of claim 7
and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a compound of claim 8
and a pharmaceutically acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 12/092,223, which is the U.S.
national-stage application, pursuant to 35 U.S.C. .sctn.371, of
international application No. PCT/EP2006/068017, filed Nov. 1,
2006, which claims the benefit of priority of European Patent App.
No. 05110226.7, filed Nov. 1, 2005. Each of the aforementioned
applications is incorporated by reference as though each were fully
set forth herein in its entirety.
FIELD OF INVENTION
[0002] The present invention relates to use of substituted amides
and pharmaceutical compositions comprising the same for treating
disorders where it is desirable to modulate the activity of
11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1). The
present invention also relates to novel substituted amides, to
their use in therapy, to pharmaceutical compositions comprising the
same, to the use of said compounds in the manufacture of
medicaments, and to therapeutic methods comprising the
administration of the compounds. The present compounds modulate the
activity of 11.beta.-hydroxysteroid dehydrogenase type 1
(11.beta.HSD1) and are accordingly useful in the treatment of
diseases in which such a modulation is beneficial, such as the
metabolic syndrome.
BACKGROUND OF THE INVENTION
[0003] The metabolic syndrome is a major global health problem. In
the US, the prevalence in the adult population is currently
estimated to be approximately 25%, and it continues to increase
both in the US and worldwide. The metabolic syndrome is
characterised by a combination of insulin resistance, dyslipidemia,
obesity and hypertension leading to increased morbidity and
mortality of cardiovascular diseases. People with the metabolic
syndrome are at increased risk of developing frank type 2 diabetes,
the prevalence of which is equally escalating.
[0004] In type 2 diabetes, obesity and dyslipidemia are also highly
prevalent and around 70% of people with type 2 diabetes
additionally have hypertension once again leading to increased
mortality of cardiovascular diseases.
[0005] In the clinical setting, it has long been known that
glucocorticoids are able to induce all of the cardinal features of
the metabolic syndrome and type 2 diabetes.
[0006] 11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1)
catalyses the local generation of active glucocorticoid in several
tissues and organs including predominantly the liver and adipose
tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium,
ocular tissue and certain parts of the central nervous system.
Thus, 11.beta.HSD1 serves as a local regulator of glucocorticoid
actions in the tissues and organs where it is expressed (Tannin et
al., J. Biol. Chem., 266, 16653 (1991); Bujalska et al.,
Endocrinology, 140, 3188 (1999); Whorwood et al., J Clin Endocrinol
Metab., 86, 2296 (2001); Cooper et al., Bone, 27, 375 (2000);
Davani et al., J. Biol. Chem., 275, 34841 (2000); Brem et al.,
Hypertension, 31, 459 (1998); Rauz et al., Invest. Ophthalmol. Vis.
Sci., 42, 2037 (2001); Moisan et al., Endocrinology, 127, 1450
(1990)).
[0007] The role of 11.beta.HSD1 in the metabolic syndrome and type
2 diabetes is supported by several lines of evidence. In humans,
treatment with the non-specific 11.beta.HSD1 inhibitor
carbenoxolone improves insulin sensitivity in lean healthy
volunteers and people with type 2 diabetes. Likewise, 11.beta.HSD1
knock-out mice are resistant to insulin resistance induced by
obesity and stress. Additionally, the knock-out mice present with
an anti-atherogenic lipid profile of decreased VLDL triglycerides
and increased HDL-cholesterol. Conversely, mice that overexpress
11.beta.HSD1 in adipocytes develop insulin resistance,
hyperlipidemia and viscera) obesity, a phenotype that resembles the
human metabolic syndrome (Andrews et al., J. Clin. Endocrinol.
Metab., 88, 285 (2003); Walker et al., J. Clin. Endocrinol. Metab.,
80, 3155 (1995); Morton et al., J. Biol. Chem., 276, 41293 (2001);
Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924 (1997);
Masuzaki et al., Science, 294, 2166 (2001)).
[0008] The more mechanistic aspects of 11.beta.HSD1 modulation and
thereby modulation of intracellular levels of active glucocorticoid
have been investigated in several rodent models and different
cellular systems. 11.beta.HSD1 promotes the features of the
metabolic syndrome by increasing hepatic expression of the
rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate
carboxykinase and glucose-6-phosphatase, promoting the
differentiation of preadipocytes into adipocytes thus facilitating
obesity, directly and indirectly stimulating hepatic VLDL
secretion, decreasing hepatic LDL uptake and increasing vessel
contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94,
14924 (1997); Morton et al., J. Biol. Chem. 276, 41293 (2001);
Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al.,
Steroids, 67, 195 (2002), Brindley & Salter, Prog. Lipid Res.,
30, 349 (1991)).
[0009] WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO
01/90094 discloses various thiazol-sulfonamides as inhibitors of
the human 11.beta.-hydroxysteroid dehydrogenase type 1 enzyme, and
further states that said compounds may be useful in treating
diabetes, obesity, glaucoma, osteoporosis, cognitive disorders,
immune disorders and depression.
[0010] We have now found substituted amides that modulate the
activity of 11.beta.HSD1 leading to altered intracellular
concentrations of active glucocorticoid. More specifically, the
present compounds inhibit the activity of 11.beta.HSD1 leading to
decreased intracellular concentrations of active glucocorticoid.
Thus, the present compounds can be used to treat disorders where a
decreased level of active intracellular glucocorticoid is
desirable, such as e.g. the metabolic syndrome, type 2 diabetes,
impaired glucose tolerance (IGT), impaired fasting glucose (IFG),
dyslipidemia, obesity, hypertension, diabetic late complications,
cardiovascular diseases, arteriosclerosis, atherosclerosis,
myopathy, muscle wasting, osteoporosis, neurodegenerative and
psychiatric disorders, and adverse effects of treatment or therapy
with glucocorticoid receptor agonists.
[0011] One object of the present invention is to provide compounds,
pharmaceutical compositions and use of compounds that modulate the
activity of 11.beta.HSD1.
DEFINITIONS
[0012] In the following structural formulas and throughout the
present specification, the following terms have the indicated
meaning. The examples provided in the definitions present in this
application are non-inclusive unless otherwise stated. They include
but are not limited to the recited examples.
[0013] The term "halo" includes fluorine, chlorine, bromine, and
iodine.
[0014] The term "trihalomethyl" includes trifluoromethyl,
trichloromethyl, tribromomethyl, and triiodomethyl.
[0015] The term "trihalomethoxy" includes trifluorometoxy,
trichlorometoxy, tribromometoxy, and triiodometoxy.
[0016] The term "alkyl" includes C.sub.1-C.sub.8 straight chain
saturated and methylene aliphatic hydrocarbon groups and
C.sub.3-C.sub.8 branched saturated hydrocarbon groups having the
specified number of carbon atoms. For example, this definition
includes methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl,
hexyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu),
sec-butyl (s-Bu), isopentyl, and neopentyl.
[0017] The term "alkenyl" includes C.sub.2-C.sub.6 straight chain
unsaturated aliphatic hydrocarbon groups and branched
C.sub.3-C.sub.6 unsaturated aliphatic hydrocarbon groups having the
specified number of carbon atoms. For example, this definition
includes ethenyl, propenyl, butenyl, pentenyl, hexenyl,
methylpropenyl, and methylbutenyl.
[0018] The term "alkynyl" includes C.sub.2-C.sub.6 straight chain
unsaturated aliphatic hydrocarbon groups and C.sub.4-C.sub.6
branched unsaturated aliphatic hydrocarbon groups having the
specified number of carbon atoms. For example, this definition
includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, and
methylbutynyl.
[0019] The term "saturated or partially saturated monocyclic,
bicyclic, or tricyclic ring system" represents but is not limited
to aziridinyl, azepanyl, azocanyl, pyrrolinyl, pyrrolidinyl,
2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl,
piperidinyl, thiomorpholinyl, piperazinyl, phthalimide,
1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl,
1,2,3,4-tetrahydro-quinoxalinyl, indolinyl,
1,6-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[4.1.1]octane,
2-aza-bicyclo[3.2.1]octanyl, 7-aza-bicyclo[4.1.1]octanyl,
9-aza-bicyclo[3.3.2]decanyl,
4-aza-tricyclo[4.3.1.1.sup.3,8]undecanyl,
9-aza-tricyclo[3.3.2.0.sup.3,7]decanyl.
[0020] The term "saturated or partially saturated ring" represents
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
cyclononenyl, cyclodecenyl, tetrahydrofuranyl, and
tetrahydropyranyl.
[0021] The term "saturated or partially saturated aromatic ring"
represents cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,
cyclodecenyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl,
pyridyl, and pyrimidinyl.
[0022] The term "cycloalkyl" represents a saturated, mono-, bi-,
tri- or spirocarbocyclic group having the specified number of
carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,
bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl,
and adamantyl).
[0023] The term "cycloalkylalkyl" represents a cycloalkyl group as
defined above attached through an alkyl group having the indicated
number of carbon atoms or substituted alkyl group as defined above
(e.g., cyclopropylmethyl, cyclobutylethyl, and
adamantylmethyl).
[0024] The term "cycloalkenyl" represents a partially saturated,
mono-, bi-, tri- or spirocarbocyclic group having the specified
number of carbon atoms (e.g., cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and
cyclodecenyl).
[0025] The term "cycloalkylcarbonyl" represents a cycloalkyl group
as defined above having the indicated number of carbon atoms
attached through a carbonyl group (e.g., cyclopropylcarbonyl and
cyclohexylcarbonyl).
[0026] The term "cycloalkylalkylcarbonyl" represents a cycloalkyl
group as defined above attached through an alkyl group having the
indicated number of carbon atoms or substituted alkyl group as
defined above (e.g., cyclohexylmethylcarbonyl and
cycloheptylethylcarbonyl).
[0027] The term "hetcycloalkyl" represents a saturated mono-, bi-,
tri-, or spirocarbocyclic group having the specified number of
atoms with 1-4 of the specified number being heteroatoms or groups
selected from nitrogen, oxygen, sulphur, SO, and SO.sub.2 (e.g.,
tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl,
piperidine, and pyridzine).
[0028] The term "hetcycloalkylalkyl" represents a hetcycloalkyl
group as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., tetrahydrofuranylmethyl,
tetrahydropyranylethyl, and tertahydrothiopyranylmethyl).
[0029] The term "hetcycloalkylcarbonyl" represents a hetcycloalkyl
group as defined above having the indicated number of carbon atoms
attached through a carbonyl group (e.g., 1-piperidin-4-yl-carbonyl
and 1-(1,2,3,4-tetrahydro-isoquinolin-6-yl)carbonyl).
[0030] The term "alkyloxy" represents an alkyl group having the
indicated number of carbon atoms attached through an oxygen bridge
(e.g., methoxy, ethoxy, propyloxy, allyloxy, and
cyclohexyloxy).
[0031] The term "alkyloxyalkyl" represents an alkyloxy group as
defined above attached through an alkyl group having the indicated
number of carbon atoms (e.g., methyloxymethyl).
[0032] The term "aryl" includes a carbocyclic aromatic ring that is
monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl,
naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl,
pentalenyl, azulenyl, and biphenylenyl. Aryl also includes the
partially hydrogenated derivatives of the carbocyclic aromatic
enumerated above. Examples of partially hydrogenated derivatives
include 1,2,3,4-tetrahydronaphthyl and 1,4-dihydronaphthyl.
[0033] The term "aryl1" includes phenyl, biphenyl, naphthyl,
anthracenyl, phenanthrenyl, and fluorenyl.
[0034] The term "aryl2" includes phenyl, biphenyl, and
naphthyl.
[0035] The term "hetaryl" includes pyrrolyl (2-pyrrolyl), pyrazolyl
(3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl,
4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl,
1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl),
oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl
(3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl,
4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl,
4-thiophenyl, 5-thiophenyl), furanyl (2-furanyl, 3-furanyl,
4-furanyl, 5-furanyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl,
5-pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl,
pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl
(2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl,
7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl,
8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl,
3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl,
6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl
(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl),
4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo-[b]furanyl),
6-(2,3-dihydro-benzo-[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)),
1,4-benzodioxin (2-(1,4-benzodioxin), 3-(1,4-benzodioxin),
5-(1,4-benzodioxin), 6-(1,4-benzodioxin)), benzo[b]thiophenyl
(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,
5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),
2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro-benzo[b]thiophenyl),
3-(2,3-dihydro-benzo[b]thiophenyl),
4-(2,3-dihydrobenzo[b]thiophenyl),
5-(2,3-dihydro-benzo[b]thiophenyl),
6-(2,3-dihydro-benzo[b]thiophenyl),
7-(2,3-dihydro-benzo[b]thiophenyl)),
4,5,6,7-tetrahydro-benzo[b]thiophenyl
(2-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
3-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
4-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
5-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
6-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
7-(4,5,6,7-tetrahydro-benzo[b]thiophenyl)),
thieno[2,3-b]thiophenyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl
(4-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl),
5-4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl),
6-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl),
7-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl)), indolyl (1-indolyl,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl),
isoindolyl (1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl), 1,3-dihydro-isoindolyl
(1-(1,3-dihydro-isoindolyl), 2-(1,3-dihydro-isoindolyl),
3-(1,3-dihydro-isoindolyl), 4-(1,3-dihydro-isoindolyl),
5-(1,3-dihydro-isoindolyl), 6-(1,3-dihydro-isoindolyl),
7-(1,3-dihydro-isoindolyl)), indazole (1-indazolyl, 3-indazolyl,
4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl
(1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl,
5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,
8-benzimidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl),
benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl,
4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,
7-benzothiazolyl), benzo-[1,2,5]oxadiazolyl,
(4-benzo[1,2,5]oxadiazole, 5-benzo[1,2,5]oxadiazole), carbazolyl
(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),
piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), and
pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl).
[0036] The term "arylalkyl" represents an aryl group as defined
above attached through an alkyl group having the indicated number
of carbon atoms (e.g., benzyl, phenylethyl, 3-phenylpropyl,
1-naphtylmethyl, and 2-(1-naphtyl)ethyl).
[0037] The term "hetarylalkyl" or "hetaralkyl" represents a hetaryl
group as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., (2-furyl)methyl,
(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,
(2-pyridyl)methyl, and 1-methyl-1-(2-pyrimidyl)ethyl).
[0038] The term "aryloxyhetaryl" represents an aryloxy group as
defined above attached through a hetaryl group (e.g.,
2-phenoxy-pyridyl).
[0039] The term "aryloxy" represents an aryl group as defined above
attached through an oxygen bridge (e.g., phenoxy and
naphthyloxy).
[0040] The term "hetaryloxy" represents a hetaryl group as defined
above attached through an oxygen bridge (e.g., 2-pyridyloxy).
[0041] The term "arylalkyloxy" represents an arylalkyl group as
defined above attached through an oxygen bridge (e.g., phenethyloxy
and naphthylmethyloxy).
[0042] The term "hetarylalkyloxy" represents a hetarylalkyl group
as defined above attached through an oxygen bridge (e.g.,
2-pyridylmethyloxy).
[0043] The term "alkyloxycarbonyl" represents an alkyloxy group as
defined above attached through a carbonyl group (e.g.,
methylformiat and ethylformiat).
[0044] The term "aryloxycarbonyl" represents an aryloxy group as
defined above attached through a carbonyl group (e.g.,
phenylformiat and 2-thiazolylformiat).
[0045] The term "arylalkyloxycarbonyl" represents an "arylalkyloxy"
group as defined above attached through a carbonyl group (e.g.,
benzylformiat and phenyletylformiat).
[0046] The term "alkylthio" represents an alkyl group having the
indicated number of carbon atoms attached through a sulphur bridge
(e.g., methylthio and ethylthio).
[0047] The term "arylthio" represents an aryl group as defined
above attached through a sulphur bridge (e.g., benzenthiol and
naphthylthiol).
[0048] The term "hetarylthio" represents a hetaryl group as defined
above attached through a sulphur bridge (e.g., pyridine-2-thiol and
thiazole-2-thiol).
[0049] The term "arylthioalkyl" represents an arylthio group as
defined above attached through an alkyl group having the indicated
number of carbon atoms (e.g., methylsulfanyl benzene, and
ethylsulfanyl naphthalene).
[0050] The term "hetarylthioalkyl" represents a hetarylthio group
as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., 2-methylsulfanyl-pyridine
and 1-ethylsulfanyl-isoquinoline).
[0051] The term "hetaryloxyaryl" represents a hetaryloxy group as
defined above attached through an aryl group as defined above
(e.g., 1-phenoxy-isoquinolyl and 2-phenoxypyridyl).
[0052] The term "hetaryloxyhetaryl" represents a hetaryloxy group
as defined above attached through a hetaryl group as defined above
(e.g., 1-(2-pyridyloxy-isoquinoline) and
2-(imidazol-2-yloxy-pyridine)).
[0053] The term "aryloxyalkyl" represents an aryloxy group as
defined above attached through an alkyl group having the indicated
number of carbon atoms (e.g., phenoxymethyl and
naphthyloxyethyl).
[0054] The term "aryloxyaryl" represents an aryloxy group as
defined above attached through an aryl group as defined above
(e.g., 1-phenoxy-naphthalene and phenyloxy-phenyl).
[0055] The term "arylalkyloxyalkyl" represents an arylalkyloxy
group as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., ethoxymethyl-benzene and
2-methoxymethyl-naphthalene).
[0056] The term "hetaryloxyalkyl" represents a hetaryloxy group as
defined above attached through an alkyl group having the indicated
number of carbon atoms (e.g., 2-pyridyloxymethyl and
2-quinolyloxyethyl).
[0057] The term "hetarylalkyloxyalkyl" represents a hetarylalkyloxy
group as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., 4-methoxymethyl-pyrimidine
and 2-methoxymethyl-quinoline).
[0058] The term "alkylcarbonyl" represents an alkyl group as
defined above having the indicated number of carbon atoms attached
through a carbonyl group (e.g., octylcarbonyl, pentylcarbonyl, and
3-hexenylcarbonyl).
[0059] The term "arylcarbonyl" represents an aryl group as defined
above attached through a carbonyl group (e.g., benzoyl).
[0060] The term "hetarylcarbonyl" represents a hetaryl group as
defined above attached through a carbonyl group (e.g.,
2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, and
oxazolylcarbonyl).
[0061] The term "carbonylalkyl" represents a carbonyl group
attached through an alkyl group having the indicated number of
carbon atoms (e.g., acetyl).
[0062] The term "alkylcarbonylalkyl" represents an alkylcarbonyl
group as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., propan-2-one and
4,4-dimethyl-pentan-2-one).
[0063] The term "arylcarbonylalkyl" represents a arylcarbonyl group
as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., 1-phenyl-propan-1-one and
1-(3-chloro-phenyl)-2-methyl-butan-1-one).
[0064] The term "hetarylcarbonylalkyl" represents a hetarylcarbonyl
group as defined above attached through an alkyl group having the
indicated number of carbon atoms (e.g., 1-pyridin-2-yl-propan-1-one
and 1-(1-H-imidazol-2-yl)-propan-1-one).
[0065] The term "arylalkylcarbonyl" represents an arylalkyl group
as defined above having the indicated number of carbon atoms
attached through a carbonyl group (e.g., phenylpropylcarbonyl and
phenylethylcarbonyl).
[0066] The term "hetarylalkylcarbonyl" represents a hetarylalkyl
group as defined above wherein the alkyl group is in turn attached
through a carbonyl (e.g., imidazolylpentylcarbonyl).
[0067] The term "alkylcarbonylamino" represents an "alkylcarbonyl"
group as defined above wherein the carbonyl is in turn attached
through the nitrogen atom of an amino group (e.g.,
methylcarbonylamino, cyclopentylcarbonyl-aminomethyl, and
methylcarbonylaminophenyl). The nitrogen atom may itself be
substituted with an alkyl or aryl group.
[0068] The term "alkylcarbonylaminoalkyl" represents an
"alkylcarbonylamino" group attached through an alkyl group having
the indicated number of carbon atoms (e.g. N-propylacetamide and
N-butyl-propionamide).
[0069] The term "arylalkylcarbonylamino" represents an
"arylalkylcarbonyl" group as defined above attached through an
amino group (e.g., phenylacetamide and 3-phenylpropionamide).
[0070] The term "arylalkylcarbonylaminoalkyl" represents an
"arylalkylcarbonylamino" group attached through an alkyl group
having the indicated number of carbon atoms (e.g.,
N-ethyl-phenylacetamide and N-butyl-3-phenyl-propionamide).
[0071] The term "arylcarbonylamino" represents an "arylcarbonyl"
group as defined above attached through an amino group (e.g.,
benzamide and naphthalene-1-carboxylic acid amide).
[0072] The term "arylcarbonylaminoalkyl" represents an
"arylcarbonylamino" group attached through an alkyl group having
the indicated number of carbon atoms (e.g., N-propyl-benzamide and
N-Butyl-naphthalene-1-carboxylic acid amide).
[0073] The term "alkylcarboxy" represents an alkylcarbonyl group as
defined above wherein the carbonyl is in turn attached through an
oxygen bridge (e.g., heptylcarboxy, cyclopropylcarboxy, and
3-pentenylcarboxy).
[0074] The term "arylcarboxy" represents an arylcarbonyl group as
defined above wherein the carbonyl is in turn attached through an
oxygen bridge (e.g., benzoic acid).
[0075] The term "alkylcarboxyalkyl" represents an alkylcarboxy
group as defined above wherein the oxygen is attached via an alkyl
bridge (e.g., heptylcarboxymethyl, propylcarboxy tert-butyl, and
3-pentylcarboxyethyl).
[0076] The term "arylalkylcarboxy" represents an arylalkylcarbonyl
group as defined above wherein the carbonyl is in turn attached
through an oxygen bridge (e.g., benzylcarboxy and
phenylpropylcarboxy).
[0077] The term "arylalkylcarboxyalkyl" represents an
arylalkylcarboxy group as defined above wherein the carboxy group
is in turn attached through an alkyl group having the indicated
number of carbon atoms (e.g., benzylcarboxymethyl and
phenylpropylcarboxypropyl).
[0078] The term "hetarylcarboxy" represents a hetarylcarbonyl group
as defined above wherein the carbonyl is in turn attached through
an oxygen bridge (e.g., pyridine-2-carboxylic acid).
[0079] The term "hetarylalkylcarboxy" represents a
hetarylalkylcarbonyl group as defined above wherein the carbonyl is
in turn attached through an oxygen bridge (e.g.,
(1-H-imidazol-2-yl)-acetic acid and 3-pyrimidin-2-yl-propionic
acid).
[0080] The term "alkylSO.sub.m" represents an alkyl group having
the number of indicated carbon atoms, wherein the alkyl group is in
turn attached through a sulphur bridge wherein the sulphur is
substituted with m oxygen atoms (e.g., ethylsulfonyl and
ethylsulfinyl).
[0081] The term "arylSO.sub.m" represents an aryl group as defined
above, wherein the aryl group is in turn attached through a sulphur
bridge wherein the sulphur is substituted with m oxygen atoms
(e.g., phenylsulfinyl and naphthyl-2-sulfonyl).
[0082] The term "hetarylSO.sub.m" represents a hetaryl group as
defined above, wherein the hetaryl group is in turn attached
through a sulphur bridge wherein the sulphur is substituted with m
oxygen atoms (e.g., thiazol-2-sulfinyl and
pyridine-2-sulfonyl).
[0083] Certain of the above defined terms may occur more than once
in the structural formulae, and upon such occurrence each term
shall be defined independently of the other.
[0084] The term "optionally substituted" as used herein means that
the groups in question are either unsubstituted or substituted with
one or more of the substituents specified. When the groups in
question are substituted with more than one substituent, the
substituents may be the same or different.
[0085] The term "treatment" or "treating" is defined as the
management and care of a patient for the purpose of combating or
alleviating the disease, condition, or disorder, and the term
includes the administration of the active compound to prevent or
delay the onset of the symptoms or complications; alleviating (both
temporary and permanent) the symptoms or complications; and/or
eliminating the disease, condition, or disorder. Thus, "treatment"
or "treating" includes prevention and/or prophylaxis of the
disease, condition, or disorder.
[0086] The term "pharmaceutically acceptable" is defined as being
suitable for administration to humans without adverse events.
[0087] The term "prodrug" is defined as a chemically modified form
of the active drug, said prodrug being administered to the patient
and subsequently being converted to the active drug. Techniques for
development of prodrugs are well known in the art.
DETAILED DESCRIPTION OF THE INVENTION
[0088] [1] Thus in an embodiment, the present invention provides
for the novel use of a substituted amide, a prodrug thereof, or a
salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture or any tautomeric forms, wherein the substituted
amide or a prodrug thereof is of formula I:
##STR00001##
[0089] wherein:
[0090] X is selected from CR.sup.5 and nitrogen;
[0091] R.sup.1 is selected from H and C.sub.1-C.sub.6alkyl-R.sup.6,
wherein the alkyl group is substituted with 0-3 R.sup.7;
[0092] R.sup.2 is selected from hydrogen, halo,
C.sub.1-C.sub.6alkyl, and --C(.dbd.O)R.sup.13;
[0093] alternatively, R.sup.1 and R.sup.2 are, independently,
##STR00002##
[0094] Ring A is a saturated or partially saturated bicyclic or
tricyclic ring consisting of the shown nitrogen, 4-10 carbon atoms,
and 0-2 additional heteroatoms selected from nitrogen, oxygen, and
sulphur;
[0095] Ring A is substituted with 0-3 groups selected from
C.sub.1-C.sub.8alkyl, halo, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14;
[0096] R.sup.5 is selected from hydrogen, C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sup.13, and cyano;
[0097] R.sup.6 is selected from cyano, C.sub.3-C.sub.10cycloalkyl,
3-10 membered hetcycloalkyl, aryl, hetaryl, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, --N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.10cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-10 membered hetcycloalkyl,
--N(R.sup.18)C(.dbd.O)-aryl, --N(R.sup.18)C(.dbd.O)-hetaryl,
wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are
substituted with 0-3 R.sup.16;
[0098] R.sup.7 is selected from halo, hydroxy, oxo, cyano, and
C.sub.1-C.sub.8alkyl;
[0099] R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
independently selected from hydrogen, C.sub.1-C.sub.8alkyl, F,
trihalomethyl, trihalomethoxy, hydroxy, and
C.sub.1-C.sub.6alkyloxy, wherein the C.sub.1-C.sub.8alkyl and
C.sub.1-C.sub.6alkyloxy are substituted with 0-3 R.sup.17;
[0100] alternatively, R.sup.8 and R.sup.9 together with the carbon
atom to which they are attached form a saturated or partially
saturated ring consisting of the carbon atom shown, 2-5 additional
carbon atoms, and 0-2 heteroatoms selected from nitrogen, oxygen,
and sulphur, wherein this ring is substituted with 0-3 groups
selected from halo, trihalomethyl, C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy;
[0101] alternatively, R.sup.10 and R.sup.11 together with the
carbon atom to which they are attached form a saturated or
partially saturated ring consisting of the carbon atom shown, 2-5
additional carbon atoms, and 0-2 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein this ring is substituted
with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy;
[0102] alternatively, R.sup.8 and R.sup.10 together with the two
carbon atoms to which they are attached form a saturated or
partially saturated ring consisting of the two shown carbon atoms,
1-4 additional carbon atoms, and 0-2 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein this ring is substituted
with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy, and
hetarylC.sub.1-C.sub.6alkyloxy;
[0103] R.sup.12 is selected from H, OH, NR.sup.18R.sup.19,
C.sub.3-C.sub.10cycloalkyl, 3-10 membered hetcycloalkyl,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, and
--C(.dbd.NR.sup.15)NR.sup.16; wherein the cycloalkyl and
hetcycloalkyl groups are substituted with 0-3 R.sup.17;
[0104] R.sup.13 is selected from OH, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8alkyloxy,
C.sub.1-C.sub.8alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19;
[0105] R.sup.14 is selected from halo, hydroxy, oxo, and cyano;
[0106] R.sup.15 and R.sup.16 are independently selected from H,
C.sub.1-C.sub.8alkyl, 3-10 membered cycloalkyl, halo, OH, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-3
R.sup.20;
[0107] R.sup.17 is selected from halo, OH, oxo, nitro, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, NR.sup.18R.sup.19,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, and aryloxy;
[0108] R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, and hetarylC.sub.1-C.sub.6alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-3 R.sup.20;
[0109] alternatively, R.sup.18 and R.sup.19, together with the
nitrogen atom to which they are attached, form a saturated or
partially saturated monocyclic, bicyclic, or tricyclic ring
consisting of the shown nitrogen, 4-10 carbon atoms, and 0-2
additional heteroatoms selected from nitrogen, oxygen, and sulfur,
wherein this ring is substituted with 0-3 C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkyl-carboxy, and
hetarylC.sub.1-C.sub.6alkylcarboxy;
[0110] R.sup.20 is selected from H, OH, oxo, halo, cyano, nitro,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, NR.sup.21R.sup.22,
methylendioxo, dihalomethylendioxo, trihalomethyl, and
trihalomethyloxy;
[0111] R.sup.21 and R.sup.22 are independently selected from H,
C.sub.1-C.sub.8alkyl, and arylC.sub.1-C.sub.6alkyl;
[0112] R.sup.23 is selected from H and C.sub.1-C.sub.6alkyl;
[0113] n is selected from 0, 1, and 2;
[0114] Y is selected from O and S;
[0115] or a salt thereof with a pharmaceutically acceptable acid or
base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric forms.
[0116] [2] In another embodiment, the present invention provides
the novel use of compounds of formula I, wherein:
[0117] R.sup.1 is selected from H and C.sub.1-C.sub.4alkyl-R.sup.6,
wherein the alkyl group is substituted with 0-1 R.sup.7;
[0118] R.sup.2 is selected from hydrogen, C.sub.1-C.sub.6alkyl, and
--C(.dbd.O)R.sup.13;
[0119] alternatively, R.sup.1 and R.sup.2 are, independently,
##STR00003##
[0120] Ring A is a saturated or partially saturated bicyclic or
tricyclic ring consisting of the shown nitrogen and 7-10 carbon
atoms;
[0121] Ring A is substituted with 0-3 groups selected from
C.sub.1-C.sub.4alkyl, halo, hydroxy, and
C.sub.1-C.sub.6alkyloxy;
[0122] R.sup.5 is selected from hydrogen and
C.sub.1-C.sub.4alkyl;
[0123] R.sup.6 is selected from cyano, C.sub.3-C.sub.6cycloalkyl,
3-6 membered hetcycloalkyl, aryl, hetaryl, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, --N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.6cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-6 membered hetcycloalkyl,
--N(R.sup.18)C(.dbd.O)-aryl, --N(R.sup.18)C(.dbd.O)-hetaryl,
wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are
substituted with 0-3 R.sup.16;
[0124] R.sup.7 is selected from halo and C.sub.1-C.sub.4alkyl;
[0125] R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
independently selected from hydrogen and C.sub.1-C.sub.4alkyl;
[0126] alternatively, R.sup.8 and R.sup.10 together with the two
carbon atoms to which they are attached form a saturated or
partially saturated ring consisting of the two shown carbon atoms
and 1-4 additional carbon atoms, wherein this ring is substituted
with 0-1 groups selected from halo, trihalomethyl, hydroxyl, and
C.sub.1-C.sub.6alkyl;
[0127] R.sup.12 is selected from H, OH, and NR.sup.18R.sup.19;
[0128] R.sup.13 is selected from OH, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxy,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19;
[0129] R.sup.15 and R.sup.16 are independently selected from H,
C.sub.1-C.sub.4alkyl, 3-6 membered cycloalkyl, halo, OH, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-1
R.sup.20;
[0130] R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.4alkylene, and hetarylC.sub.1-C.sub.4alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-1 R.sup.20;
[0131] alternatively, R.sup.18 and R.sup.19, together with the
nitrogen atom to which they are attached, form a saturated or
partially saturated monocyclic, bicyclic, or tricyclic ring
consisting of the shown nitrogen, 4-5 carbon atoms, and 0-1
additional heteroatoms selected from nitrogen, oxygen, and sulfur,
wherein this ring is substituted with 0-1 C.sub.1-C.sub.4alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.4alkylene,
hetarylC.sub.1-C.sub.4alkylene, hydroxy, and
C.sub.1-C.sub.4alkyloxy;
[0132] R.sup.20 is selected from H, OH, oxo, halo, cyano, nitro,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy, NR.sup.21R.sup.22,
trihalomethyl, and trihalomethyloxy;
[0133] R.sup.21 and R.sup.22 are independently selected from H,
C.sub.1-C.sub.4alkyl, and arylC.sub.1-C.sub.4alkyl;
[0134] R.sup.23 is selected from H and C.sub.1-C.sub.6alkyl;
[0135] n is selected from 0, 1, and 2; and,
[0136] Y is selected from O and S.
[0137] [3] In another embodiment, the present invention provides
the novel use of compounds wherein the substituted amide or prodrug
thereof is of formula IA:
##STR00004##
[0138] [4] In another embodiment, the present invention provides
the novel use of compounds wherein the substituted amide or prodrug
thereof is of formula IB:
##STR00005##
[0139] [5] In another embodiment, the present invention provides
the novel use of compounds wherein the substituted amide or prodrug
thereof is of formula IC:
##STR00006##
[0140] [6] In another embodiment, the present invention provides
the novel use of compounds wherein the substituted amide or prodrug
thereof is of formula ID:
##STR00007##
[0141] [7] In another embodiment, the present invention provides
the novel use of compounds of formula I, wherein:
[0142] Ring A is selected from:
##STR00008##
[0143] Ring A is substituted with 0-2 R.sup.24; and,
[0144] R.sup.24 is selected from C.sub.1-C.sub.8alkyl, halo,
hydroxy, oxo, cyano, and C.sub.1-C.sub.6alkyloxy.
[0145] [8] In another embodiment, the present invention provides
the novel use of compounds of formula I, wherein:
[0146] Ring A is
##STR00009##
[0147] [9] In another embodiment, the present invention provides
the novel use of compounds of formula I, wherein the substituted
amide or a prodrug thereof is of the selected from the group:
TABLE-US-00001 1 Furan-2-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-benzoimidazol-1-yl]ethyl}-amide 1-1
1-Acetyl-piperidine-4-carboxylic acid {2[5-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl-ethyl}-amide
1-2
2-Methoxy-N-{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)- benzoimidazol-1-yl]ethyl}-acetamide 1-3
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]ethyl}-isonicotinamide 1-4
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]ethyl}-acetamide 1-5
{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimi-
dazol- 1-yl]-ethyl}-carbamic acid tert-butyl ester 1-6
Isoxazole-5-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-
6-carbonyl)-benzoimidazol-1-yl]ethyl}-amide 1-7
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]ethyl}-benzamide 2
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzimidazol-1-yl]-propionic acid ethyl ester 3
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzimidazol-1-yl]-propionic acid 4
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-
benzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl ester 5
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-
benzimidazol-2-yl]-cyclopropanecarboxylic acid 5-1
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzimidazol-1-yl]-propionic acid ethyl ester 5-2
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1-
H- benzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl ester 5-3
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzimidazol-1-yl]-propionic acid 5-4
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1-
H- benzimidazol-2-yl]-cyclopropanecarboxylic acid 6
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-
- propionic acid ethyl ester 7
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-
- propionic acid 7-1
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-
-acetic acid tert-butyl ester 7-2
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-
-acetic acid 7-3
1-Morpholin-4-yl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-ca-
rbonyl)- indol-1-yl]-propan-1-one 7-4
1-Morpholin-4-yl-2-[5-(1,3,3-trimethy1-6-aza-bicyclo[3.2.1]octane-6-ca-
rbonyl)- indol-1-yl]-ethanone 7-5
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)- indol-1-yl]-propionic acid ethyl ester 7-6
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)- indol-1-yl]-propionic acid 7-7
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)--
indol-1- yl]-propionic acid methyl ester 7-8
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-y-
l]- butyric acid methyl ester 7-9
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-y-
l]- butyric acid 7-10
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-indol-1- yl]-propionic acid 7-11
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-
yl-methyl]-benzoic acid 7-12
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-
yl-methyl]-benzoic acid methyl ester 7-13
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-
yl]-methyl]-benzoic acid 7-14
3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]undecane-4-carbonyl)-indol-1-yl]-pr-
opionic acid ethyl ester 7-15
3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]undecane-4-carbonyl)-indol-1-yl]-pr-
opionic acid 8
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-
carboxylic acid ethyl ester 9
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-
carboxylic acid
N-Methoxy-N-methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbony)-indol-1-yl]-propionamide
N-Ethoxy-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ind-
ol-1- yl]-propionamide
N-Hydroxy-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-in-
dol- 1-yl]-propionamide
{1-[2-(2H-Tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-1H-indo1-5-yl}-(1,3,3-
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trime-
thyl-6- aza-bicyclo[3.2.1]oct-6-yl)-methanone
N-(1H-Tetrazol-5-yl)-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-yl]-propionamide
{1-[2-(2-Methyl-2H-tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trimethyl--
6-aza- bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(1-Methyl-1H-tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trimethyl--
6-aza- bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-1H-indo1-5-yl}-(1,3,3-trime-
thyl-6- aza-bicyclo[3.2.1]oct-6-yl)-methanone
[0148] or a salt thereof with a pharmaceutically acceptable acid or
base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric forms.
[0149] [10] In another embodiment, the present invention provides
for the novel preparation of a pharmaceutical composition for the
treatment of conditions, disorders, or diseases wherein a
modulation or an inhibition of the activity of 11.beta.HSD1 is
beneficial.
[0150] [11] In another embodiment, the present invention provides
for the novel preparation of a pharmaceutical composition, wherein:
the conditions, disorders, and diseases that are influenced by
intracellular glucocorticoid levels.
[0151] [12] In another embodiment, the present invention provides
for the novel preparation of a pharmaceutical composition, wherein:
the conditions, disorders, or diseases are selected from metabolic
syndrome, insulin resistance, dyslipidemia, hypertension, obesity,
type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting
glucose (IFG), the progression from IGT to type 2 diabetes, the
progression of the metabolic syndrome into type 2 diabetes,
diabetic late complications, neurodegenerative and psychiatric
disorders, and the adverse effects of glucocorticoid receptor
agonist treatment or therapy.
[0152] [13] In another embodiment, the present invention provides
for the novel preparation of a pharmaceutical composition, wherein:
the pharmaceutical composition is suitable for a route of
administration selected from oral, nasal, buccal, transdermal,
pulmonal, and parenteral.
[0153] [14] In another embodiment, the present invention provides a
novel method for the treatment of conditions, disorders, or
diseases wherein a modulation or an inhibition of the activity of
11.beta.HSD1 is beneficial, the method comprising administering to
a subject in need thereof an effective amount of a compound of the
present invention.
[0154] [15] In another embodiment, the present invention provides a
novel method wherein the conditions, disorders, and diseases that
are influenced by intracellular glucocorticoid levels.
[0155] [16] In another embodiment, the present invention provides a
novel method wherein the conditions, disorders, or diseases are
selected from metabolic syndrome, insulin resistance, dyslipidemia,
hypertension, obesity, type 2 diabetes, impaired glucose tolerance
(IGT), impaired fasting glucose (IFG), progression from IGT to type
2 diabetes, progression of metabolic syndrome into type 2 diabetes,
diabetic late complications, neurodegenerative and psychiatric
disorders, and the adverse effects of glucocorticoid receptor
agonist treatment or therapy.
[0156] [17] In another embodiment, the present invention provides a
novel method wherein the administering is via a route selected from
oral, nasal, buccal, transdermal, pulmonal, and parenteral.
[0157] [18] In another embodiment, the present invention provides
for a novel compound of formula I:
##STR00010##
[0158] wherein:
[0159] X is selected from CR.sup.5 and nitrogen;
[0160] R.sup.1 is selected from H and C.sub.1-C.sub.6alkyl-R.sup.6,
wherein the alkyl group is substituted with 0-3 R.sup.7;
[0161] R.sup.2 is selected from hydrogen, halo,
C.sub.1-C.sub.6alkyl, and --C(.dbd.O)R.sup.13;
[0162] alternatively, R.sup.1 and R.sup.2 are, independently,
##STR00011##
[0163] Ring A is a saturated or partially saturated bicyclic or
tricyclic ring consisting of the shown nitrogen, 4-10 carbon atoms,
and 0-2 additional heteroatoms selected from nitrogen, oxygen, and
sulphur;
[0164] Ring A is substituted with 0-3 groups selected from
C.sub.1-C.sub.8alkyl, halo, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14;
[0165] R.sup.5 is selected from hydrogen, C.sub.1-C.sub.6alkyl,
--C(.dbd.O)R.sup.13, and cyano;
[0166] R.sup.6 is selected from cyano, C.sub.3-C.sub.10cycloalkyl,
3-10 membered hetcycloalkyl, aryl, hetaryl, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, --N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.10cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-10 membered hetcycloalkyl,
--N(R.sup.18)C(.dbd.O)-aryl, --N(R.sup.18)C(.dbd.O)-hetaryl,
wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are
substituted with 0-3 R.sup.16;
[0167] R.sup.7 is selected from halo, hydroxy, oxo, cyano, and
C.sub.1-C.sub.8alkyl;
[0168] R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
independently selected from hydrogen, C.sub.1-C.sub.8alkyl, F,
trihalomethyl, trihalomethoxy, hydroxy, and
C.sub.1-C.sub.6alkyloxy, wherein the C.sub.1-C.sub.8alkyl and
C.sub.1-C.sub.6alkyloxy are substituted with 0-3 R.sup.17;
[0169] alternatively, R.sup.8 and R.sup.9 together with the carbon
atom to which they are attached form a saturated or partially
saturated ring consisting of the carbon atom shown, 2-5 additional
carbon atoms, and 0-2 heteroatoms selected from nitrogen, oxygen,
and sulphur, wherein this ring is substituted with 0-3 groups
selected from halo, trihalomethyl, C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy;
[0170] alternatively, R.sup.10 and R.sup.11 together with the
carbon atom to which they are attached form a saturated or
partially saturated ring consisting of the carbon atom shown, 2-5
additional carbon atoms, and 0-2 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein this ring is substituted
with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy;
[0171] alternatively, R.sup.8 and R.sup.10 together with the two
carbon atoms to which they are attached form a saturated or
partially saturated ring consisting of the two shown carbon atoms,
1-4 additional carbon atoms, and 0-2 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein this ring is substituted
with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy, and
hetarylC.sub.1-C.sub.6alkyloxy;
[0172] R.sup.12 is selected from H, OH, NR.sup.18R.sup.19,
C.sub.3-C.sub.10cycloalkyl, 3-10 membered hetcycloalkyl,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, and
--C(.dbd.NR.sup.15)NR.sup.16; wherein the cycloalkyl and
hetcycloalkyl groups are substituted with 0-3 R.sup.17;
[0173] R.sup.13 is selected from OH, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8alkyloxy,
C.sub.1-C.sub.8alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19;
[0174] R.sup.14 is selected from halo, hydroxy, oxo, and cyano;
[0175] R.sup.15 and R.sup.16 are independently selected from H,
C.sub.1-C.sub.8alkyl, 3-10 membered cycloalkyl, halo, OH, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-3
R.sup.20;
[0176] R.sup.17 is selected from halo, OH, oxo, nitro, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, NR.sup.18R.sup.19,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, and aryloxy;
[0177] R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, and hetarylC.sub.1-C.sub.6alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-3 R.sup.20;
[0178] alternatively, R.sup.18 and R.sup.19, together with the
nitrogen atom to which they are attached, form a saturated or
partially saturated monocyclic, bicyclic, or tricyclic ring
consisting of the shown nitrogen, 4-10 carbon atoms, and 0-2
additional heteroatoms selected from nitrogen, oxygen, and sulfur,
wherein this ring is substituted with 0-3 C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkyl-carboxy, and
hetarylC.sub.1-C.sub.6alkylcarboxy;
[0179] R.sup.20 is selected from H, OH, oxo, halo, cyano, nitro,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, NR.sup.21R.sup.22,
methylendioxo, dihalomethylendioxo, trihalomethyl, and
trihalomethyloxy;
[0180] R.sup.21 and R.sup.22 are independently selected from H,
C.sub.1-C.sub.8alkyl, and arylC.sub.1-C.sub.6alkyl;
[0181] R.sup.23 is selected from H and C.sub.1-C.sub.6alkyl;
[0182] n is selected from 0, 1, and 2;
[0183] Y is selected from O and S;
[0184] or a salt thereof with a pharmaceutically acceptable acid or
base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric forms.
[0185] [19] In another embodiment, the present invention provides
the novel compound of formula I, wherein:
[0186] R.sup.1 is selected from H and C.sub.1-C.sub.4alkyl-R.sup.6,
wherein the alkyl group is substituted with 0-1 R.sup.7;
[0187] R.sup.2 is selected from hydrogen, C.sub.1-C.sub.6alkyl, and
--C(.dbd.O)R.sup.13;
[0188] alternatively, R.sup.1 and R.sup.2 are, independently,
##STR00012##
[0189] Ring A is a saturated or partially saturated bicyclic or
tricyclic ring consisting of the shown nitrogen and 7-10 carbon
atoms;
[0190] Ring A is substituted with 0-3 groups selected from
C.sub.1-C.sub.4alkyl, halo, hydroxy, and
C.sub.1-C.sub.6alkyloxy;
[0191] R.sup.5 is selected from hydrogen and
C.sub.1-C.sub.4alkyl;
[0192] R.sup.6 is selected from cyano, C.sub.3-C.sub.6cycloalkyl,
3-6 membered hetcycloalkyl, aryl, hetaryl, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nR.sup.18R.sup.13,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, --N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.6cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-6 membered hetcycloalkyl,
--N(R.sup.18)C(.dbd.O)-aryl, --N(R.sup.18)C(.dbd.O)-hetaryl,
wherein the cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are
substituted with 0-3 R.sup.16;
[0193] R.sup.7 is selected from halo and C.sub.1-C.sub.4alkyl;
[0194] R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
independently selected from hydrogen and C.sub.1-C.sub.4alkyl;
[0195] alternatively, R.sup.8 and R.sup.10 together with the two
carbon atoms to which they are attached form a saturated or
partially saturated ring consisting of the two shown carbon atoms
and 1-4 additional carbon atoms, wherein this ring is substituted
with 0-1 groups selected from halo, trihalomethyl, hydroxyl, and
C.sub.1-C.sub.6alkyl;
[0196] R.sup.12 is selected from H, OH, and NR.sup.18R.sup.19;
[0197] R.sup.13 is selected from OH, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxy,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19;
[0198] R.sup.15 and R.sup.16 are independently selected from H,
C.sub.1-C.sub.4alkyl, 3-6 membered cycloalkyl, halo, OH, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-1
R.sup.20;
[0199] R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.4alkylene, and hetarylC.sub.1-C.sub.4alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-1 R.sup.20;
[0200] alternatively, R.sup.18 and R.sup.19, together with the
nitrogen atom to which they are attached, form a saturated or
partially saturated monocyclic, bicyclic, or tricyclic ring
consisting of the shown nitrogen, 4-5 carbon atoms, and 0-1
additional heteroatoms selected from nitrogen, oxygen, and sulfur,
wherein this ring is substituted with 0-1 C.sub.1-C.sub.4alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.4alkylene,
hetarylC.sub.1-C.sub.4alkylene, hydroxy, and
C.sub.1-C.sub.4alkyloxy;
[0201] R.sup.20 is selected from H, OH, oxo, halo, cyano, nitro,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy, NR.sup.21R.sup.22,
trihalomethyl, and trihalomethyloxy;
[0202] R.sup.21 and R.sup.22 are independently selected from H,
C.sub.1-C.sub.4alkyl, and arylC.sub.1-C.sub.4alkyl;
[0203] R.sup.23 is selected from H and C.sub.1-C.sub.6alkyl;
[0204] n is selected from 0, 1, and 2; and,
[0205] Y is selected from O and S.
[0206] [20] In another embodiment, the present invention provides
the novel compounds of formula IA:
##STR00013##
[0207] [21] In another embodiment, the present invention provides
the novel compounds of formula IB:
##STR00014##
[0208] [22] In another embodiment, the present invention provides
the novel compounds of formula IC:
##STR00015##
[0209] [23] In another embodiment, the present invention provides
the novel compounds of formula ID:
##STR00016##
[0210] [24] In another embodiment, the present invention provides
the novel compounds of formula I, wherein:
[0211] Ring A is selected from:
##STR00017##
[0212] Ring A is substituted with 0-2 R.sup.24; and,
[0213] R.sup.24 is selected from C.sub.1-C.sub.8alkyl, halo,
hydroxy, oxo, cyano, and C.sub.1-C.sub.6alkyloxy.
[0214] [25] In another embodiment, the present invention provides
the novel compounds of formula I, wherein:
[0215] Ring A is
##STR00018##
[0216] [26] In another embodiment, the present invention provides
the novel compounds of formula I, selected from the group:
TABLE-US-00002 1 Furan-2-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
1-1 1-Acetyl-piperidine-4-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
1-2
2-Methoxy-N-{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-benzoimidazol-1-yl]-ethyl}-acetamide 1-3
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]-ethyl}-isonicotinamide 1-4
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]-ethyl}-acetamide 1-5
{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]-ethyl}-carbamic acid tert-butyl ester 1-6
Isoxazole-5-carboxylic acid {2-[5-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)benzoimidazol-1-yl]-ethyl}-amide
1-7
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]-ethyl}-benzamide 2
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-benzimidazol-1-yl]-propionic acid ethyl ester 3
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-benzimidazol-1-yl]-propionic acid 4
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-
benzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl ester 5
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-
benzimidazol-2-yl]-cyclopropanecarboxylic acid 5-1
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-benzimidazol-1-yl]-propionic acid ethyl ester 5-2
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-1H-benzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl
ester 5-3
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-benzimidazol-1-yl]-propionic acid 5-4
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-1H-benzimidazol-2-yl]-cyclopropanecarboxylic acid 6
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
indol-1-yl]-propionic acid ethyl ester 7
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]-octane-6-carbonyl)-
indol-1-yl]-propionic acid 7-1
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-
1-yl]-acetic acid tert-butyl ester 7-2
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-
1-yl]-acetic acid 7-3
1-Morpholin-4-yl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-
6-carbonyl)-indol-1-yl]-propan-1-one 7-4
1-Morpholin-4-yl-2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-
6-carbonyl)-indol-1-yl]-ethanone 7-5
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-yl]-propionic acid ethyl ester 7-6
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-yl]-propionic acid 7-7
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-yl]-propionic acid methyl ester 7-8
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
indol-1-yl]-butyric acid methyl ester 7-9
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
indol-1-yl]-butyric acid 7-10
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-yl]-propionic acid 7-11
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
indol-1-ylmethyl]-benzoic acid 7-12
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
indol-1-ylmethyl]-benzoic acid methyl ester 7-13
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
indol-1-ylmethyl]-benzoic acid 7-14
3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]undecane-4-carbonyl)-indol-
1-yl]-propionic acid ethyl ester 7-15
3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]undecane-4-carbonyl)-indol-
1-yl]-propionic acid 8
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-
indole-2-carboxylic acid ethyl ester 9
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-
indole-2-carboxylic acid
N-Methoxy-N-methyl-3-[5-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionamide
N-Ethoxy-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-
6-carbonyl)-indol-1-yl]-propionamide
N-Hydroxy-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-
6-carbonyl)-indol-1-yl]-propionamide
{1-[2-(2H-Tetrazol-5-yl)-ethyl]-1H-indol-5-yl]-(1,3,3-trimethyl-
6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-1H-indol-5-yl}-
(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-1H-indol-5-yl}-
(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
N-(1H-Tetrazol-5-yl)-3-[5-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionamide
{1-[2-(2-Methyl-2H-tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(1-Methyl-1H-tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
{1-[2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-1H-indol-5-yl}-
(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
[0217] or a salt thereof with a pharmaceutically acceptable acid or
base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric forms.
[0218] In another embodiment, the present invention provides for a
novel compound of formula I:
##STR00019##
wherein: [0219] X is selected from CR.sup.5 and nitrogen; [0220]
R.sup.1 is selected from C.sub.1-C.sub.6alkyl-R.sup.6, wherein the
alkyl group is substituted with 0-3 R.sup.7; [0221] R.sup.2 is
selected from hydrogen, halo, C.sub.1-C.sub.6alkyl, and
--C(.dbd.O)R.sup.13; alternatively, R.sup.1 and R.sup.2 are,
independently,
[0221] ##STR00020## [0222] Ring A is a saturated or partially
saturated bicyclic or tricyclic ring consisting of the shown
nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms
selected from nitrogen, oxygen, and sulphur; [0223] Ring A is
substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14; alternatively,
##STR00021##
[0223] wherein Rx is selected from hydrogen and
C.sub.1-C.sub.6alkyl;
##STR00022##
is substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14; [0224] R.sup.5 is selected from
hydrogen, C.sub.1-C.sub.6alkyl, --C(.dbd.O)R.sup.13, and cyano;
[0225] R.sup.6 is selected from cyano, aryl, hetaryl,
-oxoC.sub.1-C.sub.6alkyl-S(.dbd.O).sub.nR.sup.13,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.n.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, [0226]
--N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.10cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-10 membered hetcycloalkyl, wherein the
cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted
with 0-3 R.sup.16; [0227] R.sup.7 is selected from
C.sub.1-C.sub.6alkyl, halo, hydroxy, oxo and cyano; [0228] R.sup.8,
R.sup.9, R.sup.10 and R.sup.11 are each independently selected from
hydrogen, C.sub.1-C.sub.8alkyl, F, trihalomethyl, trihalomethoxy,
hydroxy, and C.sub.1-C.sub.6alkyloxy, wherein the
C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.6alkyloxy are substituted
with 0-3 R.sup.17; [0229] alternatively, R.sup.8 and R.sup.9
together with the carbon atom to which they are attached form a
saturated or partially saturated ring consisting of the carbon atom
shown, 2-5 additional carbon atoms, and 0-2 heteroatoms selected
from nitrogen, oxygen, and sulphur, wherein this ring is
substituted with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; [0230] alternatively, R.sup.10 and
R.sup.11 together with the carbon atom to which they are attached
form a saturated or partially saturated ring consisting of the
carbon atom shown, 2-5 additional carbon atoms, and 0-2 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein this ring is
substituted with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; [0231] alternatively, R.sup.8 and
R.sup.10 together with the two carbon atoms to which they are
attached form a saturated or partially saturated ring consisting of
the two shown carbon atoms, 1-4 additional carbon atoms, and 0-2
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
this ring is substituted with 0-3 groups selected from halo,
trihalomethyl, C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, hetarylC.sub.1-C.sub.6alkylene,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, and hetarylC.sub.1-C.sub.6alkyloxy;
[0232] R.sup.12 is selected from H, OH, NR.sup.18R.sup.19,
C.sub.3-C.sub.10cycloalkyl, 3-10 membered hetcycloalkyl,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, and
--C(.dbd.NR.sup.15)NR.sup.16; wherein the cycloalkyl and
hetcycloalkyl groups are substituted with 0-3 R.sup.17; [0233]
R.sup.13 is selected from OH, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8alkyloxy,
C.sub.1-C.sub.8alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19; [0234] R.sup.14 is
selected from halo, hydroxy, oxo, and cyano; [0235] R.sup.15 and
R.sup.16 are independently selected from H, C.sub.1-C.sub.8alkyl,
3-10 membered cycloalkyl, halo, OH, cyano, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-3 R.sup.20;
[0236] R.sup.17 is selected from halo, OH, oxo, nitro, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, NR.sup.18R.sup.19,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, and aryloxy; [0237]
R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, and hetarylC.sub.1-C.sub.6alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-3 R.sup.20; [0238] alternatively,
R.sup.18 and R.sup.19, together with the nitrogen atom to which
they are attached, form a saturated or partially saturated
monocyclic, bicyclic, or tricyclic ring consisting of the shown
nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms
selected from nitrogen, oxygen, and sulfur, wherein this ring is
substituted with 0-3 C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, hetarylC.sub.1-C.sub.6alkylene,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkyl-carboxy, and
hetarylC.sub.1-C.sub.6alkylcarboxy; [0239] R.sup.20 is selected
from H, OH, oxo, halo, cyano, nitro, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, NR.sup.21R.sup.22, methylendioxo,
dihalomethylendioxo, trihalomethyl, and trihalomethyloxy; [0240]
R.sup.21 and R.sup.22 are independently selected from H,
C.sub.1-C.sub.8alkyl, and arylC.sub.1-C.sub.6alkyl; [0241] R.sup.23
is selected from H and C.sub.1-C.sub.6alkyl; [0242] n is selected
from 0, 1, and 2; [0243] Y is selected from O and S; or a salt
thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or mixture of optical isomers, including a racemic
mixture, or any tautomeric forms.
[0244] In another embodiment, the present invention provides for a
novel compound of formula I:
##STR00023##
wherein: [0245] X is selected from CR.sup.5 and nitrogen; [0246]
R.sup.1 is selected from C.sub.1-C.sub.6alkyl-R.sup.6, wherein the
alkyl group is substituted with 0-3 R.sup.7; [0247] R.sup.2 is
selected from hydrogen, halo, C.sub.1-C.sub.6alkyl, and
--C(.dbd.O)R.sup.13; alternatively, R.sup.1 and R.sup.2 are,
independently,
[0247] ##STR00024## [0248] Ring A is a saturated or partially
saturated bicyclic or tricyclic ring consisting of the shown
nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms
selected from nitrogen, oxygen, and sulphur; [0249] Ring A is
substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14; alternatively,
##STR00025##
[0249] wherein Rx is selected from hydrogen and
C.sub.1-C.sub.6alkyl;
##STR00026##
is substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14; [0250] R.sup.5 is selected from
hydrogen, C.sub.1-C.sub.6alkyl, --C(.dbd.O)R.sup.13, and cyano;
[0251] R.sup.6 is selected from cyano, aryl, hetaryl,
-oxoC.sub.1-C.sub.6alkyl-S(.dbd.O).sub.nR.sup.13,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, C(.dbd.NR.sup.15)NR.sup.15, [0252]
--N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.10cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-10 membered hetcycloalkyl, wherein the
cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted
with 0-3 R.sup.16; [0253] R.sup.7 is selected from
C.sub.1-C.sub.6alkyl, halo, hydroxy, oxo and cyano; [0254] R.sup.8,
R.sup.9, R.sup.10 and R.sup.11 are each independently selected from
hydrogen, C.sub.1-C.sub.6alkyl, F, trihalomethyl, trihalomethoxy,
hydroxy, and C.sub.1-C.sub.6alkyloxy, wherein the
C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.6alkyloxy are substituted
with 0-3 R.sup.17; [0255] alternatively, R.sup.8 and R.sup.9
together with the carbon atom to which they are attached form a
saturated or partially saturated ring consisting of the carbon atom
shown, 2-5 additional carbon atoms, and 0-2 heteroatoms selected
from nitrogen, oxygen, and sulphur, wherein this ring is
substituted with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; [0256] alternatively, R.sup.10 and
R.sup.11 together with the carbon atom to which they are attached
form a saturated or partially saturated ring consisting of the
carbon atom shown, 2-5 additional carbon atoms, and 0-2 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein this ring is
substituted with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; [0257] alternatively, R.sup.8 and
R.sup.10 together with the two carbon atoms to which they are
attached form a saturated or partially saturated ring consisting of
the two shown carbon atoms, 1-4 additional carbon atoms, and 0-2
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
this ring is substituted with 0-3 groups selected from halo,
trihalomethyl, C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, hetarylC.sub.1-C.sub.6alkylene,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, and hetarylC.sub.1-C.sub.6alkyloxy;
[0258] R.sup.12 is selected from H, OH, NR.sup.18R.sup.19,
C.sub.3-C.sub.10cycloalkyl, 3-10 membered hetcycloalkyl,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, and
--C(.dbd.NR.sup.15)NR.sup.16; wherein the cycloalkyl and
hetcycloalkyl groups are substituted with 0-3 R.sup.17; [0259]
R.sup.13 is selected from OH, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8alkyloxy,
C.sub.1-C.sub.8alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19; [0260] R.sup.14 is
selected from halo, hydroxy, oxo, and cyano; [0261] R.sup.15 and
R.sup.16 are independently selected from H, C.sub.1-C.sub.8alkyl,
3-10 membered cycloalkyl, halo, OH, cyano, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-3 R.sup.20;
[0262] R.sup.17 is selected from halo, OH, oxo, nitro, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, NR.sup.18R.sup.19,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, and aryloxy; [0263]
R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, and hetarylC.sub.1-C.sub.6alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-3 R.sup.20; [0264] alternatively,
R.sup.18 and R.sup.19, together with the nitrogen atom to which
they are attached, form a saturated or partially saturated
monocyclic, bicyclic, or tricyclic ring consisting of the shown
nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms
selected from nitrogen, oxygen, and sulfur, wherein this ring is
substituted with 0-3 C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, hetarylC.sub.1-C.sub.6alkylene,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkyl-carboxy, and
hetarylC.sub.1-C.sub.6alkylcarboxy; [0265] R.sup.20 is selected
from H, OH, oxo, halo, cyano, nitro, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, NR.sup.21R.sup.22, methylendioxo,
dihalomethylendioxo, trihalomethyl, and trihalomethyloxy; [0266]
R.sup.21 and R.sup.22 are independently selected from H,
C.sub.1-C.sub.8alkyl, and arylC.sub.1-C.sub.6alkyl; [0267] R.sup.23
is selected from H and C.sub.1-C.sub.6alkyl; [0268] n is selected
from 0, 1, and 2; [0269] Y is selected from O and S; [0270]
provided that when X is CR.sup.5, then R.sup.6, is
--C(.dbd.O)R.sup.13 wherein R.sup.13 is OH; or a salt thereof with
a pharmaceutically acceptable acid or base, or any optical isomer
or mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0271] In another embodiment, the present invention provides for a
novel compound of formula I, wherein: [0272] X is selected from
CR.sup.5 and nitrogen; [0273] R.sup.1 is selected from
C.sub.1-C.sub.6alkyl-R.sup.6, wherein the alkyl group is
substituted with 0-3 R.sup.7; [0274] R.sup.2 is selected from
hydrogen, halo, C.sub.1-C.sub.6alkyl, and --C(.dbd.O)R.sup.13;
alternatively, R.sup.1 and R.sup.2 are, independently,
[0274] ##STR00027## [0275] Ring A is a saturated or partially
saturated bicyclic or tricyclic ring consisting of the shown
nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms
selected from nitrogen, oxygen, and sulphur; [0276] Ring A is
substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14; alternatively,
##STR00028##
[0276] wherein Rx is selected from hydrogen and
C.sub.1-C.sub.6alkyl;
##STR00029##
is substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14; [0277] R.sup.5 is selected from
hydrogen, C.sub.1-C.sub.6alkyl, --C(.dbd.O)R.sup.13, and cyano;
[0278] R.sup.6 is selected from cyano, aryl, hetaryl,
-oxoC.sub.1-C.sub.6alkyl-S(.dbd.O).sub.nR.sup.13,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, [0279]
--N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.10cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-10 membered hetcycloalkyl, wherein the
cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted
with 0-3 R.sup.16; [0280] R.sup.7 is selected from halo, hydroxy,
oxo and cyano; [0281] R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are
each independently selected from hydrogen, C.sub.1-C.sub.8alkyl, F,
trihalomethyl, trihalomethoxy, hydroxy, and
C.sub.1-C.sub.6alkyloxy, wherein the C.sub.1-C.sub.8alkyl and
C.sub.1-C.sub.6alkyloxy are substituted with 0-3 R.sup.17; [0282]
alternatively, R.sup.8 and R.sup.9 together with the carbon atom to
which they are attached form a saturated or partially saturated
ring consisting of the carbon atom shown, 2-5 additional carbon
atoms, and 0-2 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein this ring is substituted with 0-3 groups selected
from halo, trihalomethyl, C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, hetarylC.sub.1-C.sub.6alkylene,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy or hetarylC.sub.1-C.sub.6alkyloxy;
[0283] alternatively, R.sup.10 and R.sup.11 together with the
carbon atom to which they are attached form a saturated or
partially saturated ring consisting of the carbon atom shown, 2-5
additional carbon atoms, and 0-2 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein this ring is substituted
with 0-3 groups selected from halo, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkylene,
hetarylC.sub.1-C.sub.6alkylene, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; [0284] alternatively, R.sup.8 and
R.sup.10 together with the two carbon atoms to which they are
attached form a saturated or partially saturated ring consisting of
the two shown carbon atoms, 1-4 additional carbon atoms, and 0-2
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
this ring is substituted with 0-3 groups selected from halo,
trihalomethyl, C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, hetarylC.sub.1-C.sub.6alkylene,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, and hetarylC.sub.1-C.sub.6alkyloxy;
[0285] R.sup.12 is selected from H, OH, NR.sup.18R.sup.19,
C.sub.3-C.sub.10cycloalkyl, 3-10 membered hetcycloalkyl,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, and
--C(.dbd.NR.sup.15)NR.sup.16; wherein the cycloalkyl and
hetcycloalkyl groups are substituted with 0-3 R.sup.17; [0286]
R.sup.13 is selected from OH, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8alkyloxy,
C.sub.1-C.sub.8alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19; [0287] R.sup.14 is
selected from halo, hydroxy, oxo, and cyano; [0288] R.sup.15 and
R.sup.16 are independently selected from H, C.sub.1-C.sub.8alkyl,
3-10 membered cycloalkyl, halo, OH, cyano, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-3 R.sup.20;
[0289] R.sup.17 is selected from halo, OH, oxo, nitro, cyano,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, NR.sup.18R.sup.19,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, and aryloxy; [0290]
R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, and hetarylC.sub.1-C.sub.6alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-3 R.sup.20; [0291] alternatively,
R.sup.18 and R.sup.19, together with the nitrogen atom to which
they are attached, form a saturated or partially saturated
monocyclic, bicyclic, or tricyclic ring consisting of the shown
nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms
selected from nitrogen, oxygen, and sulfur, wherein this ring is
substituted with 0-3 C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkylene, hetarylC.sub.1-C.sub.6alkylene,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkyl-carboxy, and
hetarylC.sub.1-C.sub.6alkylcarboxy; [0292] R.sup.20 is selected
from H, OH, oxo, halo, cyano, nitro, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, NR.sup.21R.sup.22, methylendioxo,
dihalomethylendioxo, trihalomethyl, and trihalomethyloxy; [0293]
R.sup.21 and R.sup.22 are independently selected from H,
C.sub.1-C.sub.8alkyl, and arylC.sub.1-C.sub.6alkyl; [0294] R.sup.23
is selected from H and C.sub.1-C.sub.6alkyl; [0295] n is selected
from 0, 1, and 2; [0296] Y is selected from O and S; [0297]
provided that when X is CR.sup.5, then R.sup.6, is
--C(.dbd.O)R.sup.13 wherein R.sup.13 is OH; or a salt thereof with
a pharmaceutically acceptable acid or base, or any optical isomer
or mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0298] In another embodiment, the present invention provides for a
novel compound of formula I, wherein [0299] R.sup.1 is
C.sub.1-C.sub.4alkyl-R.sup.6, wherein the alkyl group is
substituted with 0-1 R.sup.7; [0300] R.sup.2 is selected from
hydrogen, C.sub.1-C.sub.6alkyl, and --C(.dbd.O)R.sup.13;
alternatively, R.sup.1 and R.sup.2 are, independently,
[0300] ##STR00030## [0301] Ring A is a saturated or partially
saturated bicyclic or tricyclic ring consisting of the shown
nitrogen and 7-10 carbon atoms; Ring A is substituted with 0-3
groups selected from C.sub.1-C.sub.4alkyl, halo, hydroxy, oxo,
--COOH, --CONR.sup.18R.sup.19, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19 and C.sub.1-C.sub.6alkyloxy;
alternatively,
##STR00031##
[0301] wherein Rx is selected from hydrogen and
C.sub.1-C.sub.6alkyl;
##STR00032##
is substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14; [0302] R.sup.5 is selected from
hydrogen and C.sub.1-C.sub.4alkyl; [0303] R.sup.6 is selected from
cyano, aryl, hetaryl,
-oxoC.sub.1-C.sub.6alkyl-S(.dbd.O).sub.nR.sup.13,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, --N(R.sup.18)C(.dbd.O)R.sup.13,
--N(R.sup.18)C(.dbd.O)--C.sub.3-C.sub.6cycloalkyl,
--N(R.sup.18)C(.dbd.O)-3-6 membered hetcycloalkyl, wherein the
cycloalkyl, hetcycloalkyl, aryl, and hetaryl groups are substituted
with 0-3 R.sup.16; [0304] R.sup.7 is selected from halo; [0305]
R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each independently
selected from hydrogen and C.sub.1-C.sub.4alkyl; [0306]
alternatively, R.sup.8 and R.sup.10 together with the two carbon
atoms to which they are attached form a saturated or partially
saturated ring consisting of the two shown carbon atoms and 1-4
additional carbon atoms, wherein this ring is substituted with 0-1
groups selected from halo, trihalomethyl, hydroxyl, and
C.sub.1-C.sub.6alkyl; [0307] R.sup.12 is selected from H, OH, and
NR.sup.18R.sup.19; [0308] R.sup.13 is selected from OH,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkylene, aryl, hetaryl,
aryloxy, hetaryloxy, and NR.sup.18R.sup.19; [0309] R.sup.15 and
R.sup.16 are independently selected from H, C.sub.1-C.sub.4alkyl,
3-6 membered cycloalkyl, halo, OH, cyano, --C(.dbd.O)R.sup.13,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13, aryl, and hetaryl, wherein
the alkyl and cycloalkyl groups are substituted with 0-1 R.sup.20;
[0310] R.sup.18 and R.sup.19 are independently selected from H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyloxy, aryl, hetaryl,
arylC.sub.1-C.sub.4alkylene, and hetarylC.sub.1-C.sub.4alkylene,
wherein the alkyl/alkylene, aryl, and hetaryl groups are
independently substituted with 0-1 R.sup.20; [0311] alternatively,
R.sup.18 and R.sup.19, together with the nitrogen atom to which
they are attached, form a saturated or partially saturated
monocyclic, bicyclic, or tricyclic ring consisting of the shown
nitrogen, 4-5 carbon atoms, and 0-1 additional heteroatoms selected
from nitrogen, oxygen, and sulfur, wherein this ring is substituted
with 0-1 C.sub.1-C.sub.4alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.4alkylene, hetarylC.sub.1-C.sub.4alkylene,
hydroxy, and C.sub.1-C.sub.4alkyloxy; [0312] R.sup.20 is selected
from H, OH, oxo, halo, cyano, nitro, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxy, NR.sup.21R.sup.22, trihalomethyl, and
trihalomethyloxy; [0313] R.sup.21 and R.sup.22 are independently
selected from H, C.sub.1-C.sub.4alkyl, and
arylC.sub.1-C.sub.4alkyl; [0314] R.sup.23 is selected from H and
C.sub.1-C.sub.6alkyl; [0315] n is selected from 0, 1, and 2; and,
[0316] Y is selected from O and S; [0317] provided that when X is
CR.sup.5, then R.sup.6, is --C(.dbd.O)R.sup.13 wherein R.sup.13 is
OH; or a salt thereof with a pharmaceutically acceptable acid or
base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric forms.
[0318] In another embodiment, the present invention provides for a
novel compound of formula IA:
##STR00033##
[0319] In another embodiment, the present invention provides for a
novel compound of formula IB:
##STR00034##
[0320] In another embodiment, the present invention provides for a
novel compound of formula IC:
##STR00035##
[0321] In another embodiment, the present invention provides for a
novel compound of formula ID:
##STR00036##
[0322] In another embodiment, the present invention provides for a
novel compound of formula I wherein R.sup.6 is selected from aryl,
hetaryl, --C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19,
--C(.dbd.NR.sup.15)NR.sup.15, C(.dbd.NR.sup.15)NR.sup.15,
--N(R.sup.18)C(.dbd.O)-aryl, or --N(R.sup.18)C(.dbd.O)-hetaryl,
wherein the aryl, and hetaryl groups are substituted with 0-3
R.sup.16.
[0323] In another embodiment, the present invention provides for a
novel compound of formula I wherein R.sup.6 is selected from aryl,
hetaryl, -oxoC.sub.1-C.sub.6alkyl-S(.dbd.O).sub.nR.sup.13,
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19 or
--C(.dbd.NR.sup.15)NR.sup.15; wherein the aryl, and hetaryl groups
are substituted with 0-3 R.sup.16.
[0324] In another embodiment, the present invention provides for a
novel compound of formula I, wherein R.sup.6 is selected from
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19,
--N(R.sup.18)S(.dbd.O).sub.nR.sup.13,
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19 or
--C(.dbd.NR.sup.15)NR.sup.15.
[0325] In another embodiment, the present invention provides for a
novel compound of formula I wherein R.sup.6 is selected from
--C(.dbd.O)R.sup.13, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19, or
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19.
[0326] In another embodiment, the present invention provides for a
novel compound of formula I, wherein R.sup.6 is selected from
--N(R.sup.23)C(.dbd.Y)NR.sup.18R.sup.19.
[0327] In another embodiment, the present invention provides for a
novel compound of formula I, wherein R.sup.7 is
C.sub.1-C.sub.6alkyl.
[0328] In another embodiment, the present invention provides for a
novel compound of formula I, wherein R.sup.7 is halo.
[0329] In another embodiment, the present invention provides for a
novel compound of formula I, wherein R.sup.7 is hydroxy.
[0330] In another embodiment, the present invention provides for a
novel compound of formula I, wherein R.sup.7 is oxo.
[0331] In another embodiment, the present invention provides for a
novel compound of formula I, wherein R.sup.7 is cyano.
[0332] In another embodiment, the present invention provides for a
novel compound of formula I, wherein Y is oxygen (O).
[0333] In another embodiment, the present invention provides for a
novel compound of formula I, wherein [0334] Ring A is a saturated
or partially saturated bicyclic or tricyclic ring consisting of the
shown nitrogen, 4-10 carbon atoms, and 0-2 additional heteroatoms
selected from nitrogen, oxygen, and sulphur; [0335] Ring A is
substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14.
[0336] In another embodiment, the present invention provides for a
novel compound of formula I, wherein [0337] Ring A is a saturated
or partially saturated bicyclic or tricyclic ring consisting of the
shown nitrogen, 4-10 carbon atoms, and 1-2 additional heteroatoms
selected from nitrogen, oxygen, and sulphur; Ring A is substituted
with 0-3 groups selected from C.sub.1-C.sub.4alkyl, halo, hydroxy,
oxo, --COOH, --CONR.sup.18R.sup.19, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19 and C.sub.1-C.sub.6alkyloxy.
[0338] In another embodiment, the present invention provides for a
novel compound of formula I, wherein Ring A is selected from:
##STR00037##
Ring A is substituted with 0-2 groups selected from
C.sub.1-C.sub.8alkyl, halo, hydroxy, oxo, cyano, --COOH,
--CONR.sup.18R.sup.19, --S(.dbd.O).sub.nR.sup.13,
--S(.dbd.O).sub.nNR.sup.18R.sup.19 and C.sub.1-C.sub.6alkyloxy.
[0339] In another embodiment, the present invention provides for a
novel compound of formula I, wherein Ring A is
##STR00038##
[0340] In another embodiment, the present invention provides for a
novel compound of formula I wherein Ring A is
##STR00039##
[0341] In another embodiment, the present invention provides for a
novel compound of formula I, wherein Ring A is
##STR00040##
[0342] In another embodiment, the present invention provides for a
novel compound of formula I, wherein Ring A is
##STR00041##
[0343] In another embodiment, the present invention provides for a
novel compound of formula I, wherein Ring A is
##STR00042##
[0344] In another embodiment, the present invention provides for a
novel compound of formula I, wherein Ring A is
##STR00043##
[0345] In another embodiment, the present invention provides for a
novel compound of formula I, wherein
##STR00044##
wherein Rx is selected from hydrogen and C.sub.1-C.sub.6alkyl;
##STR00045##
is substituted with 0-3 groups selected from C.sub.1-C.sub.8alkyl,
halo, hydroxy, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 oxo,
cyano, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkylene, and
C.sub.1-C.sub.6alkylcarbonyl, wherein each alkyl/alkylene group is
substituted with 0-3 R.sup.14.
[0346] In another embodiment, the present invention provides for a
novel compound of formula I, wherein
##STR00046##
wherein Rx is selected from hydrogen and C.sub.1-C.sub.6alkyl;
##STR00047##
is substituted with 0-3 groups selected from C.sub.1-C.sub.4alkyl,
halo, hydroxy, oxo, --COOH, --CONR.sup.18R.sup.19,
--S(.dbd.O).sub.nR.sup.13, --S(.dbd.O).sub.nNR.sup.18R.sup.19 and
C.sub.1-C.sub.6alkyloxy.
[0347] In another embodiment, the present invention provides for a
novel compound, wherein the compound is of the selected from the
group: [0348] Furan-2-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-amide [0349] 1-Acetyl-piperidine-4-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-amide [0350]
2-Methoxy-N-{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-benzoimidazol-1-yl]-ethyl}-acetamide [0351]
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimid-
azol-1-yl]-ethyl}-isonicotinamide [0352]
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimid-
azol-1-yl]-ethyl}-acetamide [0353]
{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-carbamic acid tert-butyl ester [0354]
Isoxazole-5-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-amide [0355]
N-{2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimid-
azol-1-yl]-ethyl}-benzamide [0356]
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benz-
imidazol-1-yl]-propionic acid ethyl ester [0357]
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benz-
imidazol-1-yl]-propionic acid [0358]
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzimida-
zol-2-yl]-cyclopropanecarboxylic acid ethyl ester [0359]
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzimida-
zol-2-yl]-cyclopropanecarboxylic acid [0360]
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ben-
zimidazol-1-yl]-propionic acid ethyl ester [0361]
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-b-
enzimidazol-2-yl]-cyclopropanecarboxylic acid ethyl ester [0362]
3-[2-Methyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ben-
zimidazol-1-yl]-propionic acid [0363]
2-[1-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-b-
enzimidazol-2-yl]-cyclopropanecarboxylic acid [0364]
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid ethyl ester [0365]
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid [0366]
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-ac-
etic acid tert-butyl ester [0367]
[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-ac-
etic acid [0368]
1-Morpholin-4-yl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbo-
nyl)-indol-1-yl]-propan-1-one [0369]
1-Morpholin-4-yl-2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbo-
nyl)-indol-1-yl]-ethanone [0370]
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-indol-1-yl]-propionic acid ethyl ester [0371]
2,2-Dimethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-indol-1-yl]-propionic acid [0372]
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ind-
ol-1-yl]-propionic acid methyl ester [0373]
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
butyric acid methyl ester [0374]
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
butyric acid [0375]
2-Methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ind-
ol-1-yl]-propionic acid [0376]
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzoic acid [0377]
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzoic acid methyl ester [0378]
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzoic acid [0379]
3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]undecane-4-carbonyl)-indol-1-yl]-propio-
nic acid ethyl ester [0380]
3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]undecane-4-carbonyl)-indol-1-yl]-propio-
nic acid [0381]
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-car-
boxylic acid ethyl ester [0382]
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-car-
boxylic acid [0383]
[1-(2-Methanesulfonylmethoxy-ethyl)-1H-benzoimidazol-5-yl]-(octahydro-qui-
nolin-1-yl)-methanone [0384]
(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[1-(2-methanesulfonylmethoxy-eth-
yl)-1H-benzoimidazol-5-yl]-methanone [0385]
trans-1-(2-Methanesulfonyl-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic
acid (5-hydroxy-adamantan-2-yl)-amide [0386]
Cis-1-(2-Methanesulfonyl-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic
acid (5-hydroxy-adamantan-2-yl)-amide [0387]
(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[1-(2-methanesulfonylmethoxy-eth-
yl)-1H-benzoimidazol-5-yl]-methanone [0388]
1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide [0389]
(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[1-(2-methanesulfonyl-ethyl)-1H--
benzoimidazol-5-yl]-methanone [0390]
(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[1-(2-methanesulfonyl-ethyl)-1H--
benzoimidazol-5-yl]-methanone [0391]
[1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazol-5-yl]-(octahydro-quinolin-1-
-yl)-methanone [0392]
1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide [0393]
(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{1-[2-(1H-tetrazol-5-yl)-ethyl]--
1H-benzoimidazol-5-yl}-methanone [0394]
(Octahydro-quinolin-1-yl)-{1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-benzoimidazo-
l-5-yl}-methanone [0395]
Trans-1-[2-(1H-Tetrazol-5-yl)-ethyl]-1H-benzoimidazole-5-carboxylic
acid (5-hydroxy-adamantan-2-yl)-amide [0396]
Cis-1-[2-(1H-Tetrazol-5-yl)-ethyl]-1H-benzoimidazole-5-carboxylic
acid (5-hydroxy-adamantan-2-yl)-amide [0397]
3-Hydroxy-pyrrolidine-1-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide [0398] 4-Hydroxy-piperidine-1-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
[0399]
1-{2-[(4-Hydroxy-piperidine-1-carbonyl)-amino]-ethyl}-1H-benzoimid-
azole-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide [0400]
1-{2-[(1,1-Dioxo-thiomorpholine-4-carbonyl)amino]-ethyl}-1H-benzoimidazol-
e-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide [0401]
1,1-Dioxo-thiomorpholine-4-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide [0402]
Cis-1-{2-[(morpholine-4-carbonyl)-amino]-ethyl}-1H-benzo-imidazole-5-carb-
oxylic acid (5-hydroxy-adamantan-2-yl)-amide [0403]
Trans-1-{2-[(Morpholine-4-carbonyl)-amino]-ethyl}-1H-benzo-imidazole-5-ca-
rboxylic [0404] Cis-morpholine-4-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
[0405] Trans-morpholine-4-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
[0406] Morpholine-4-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo-[3.2.1]octane-8-carbonyl)-benzoimidazol-1--
yl]-ethyl}-amide [0407] 1,1-Dioxo-thiomorpholine-4-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
[0408] 3-Hydroxy-pyrrolidine-1-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
[0409]
1-{2-[5-(Octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl-
carbamoyl}-piperidine-4-carboxylic acid [0410]
3-Hydroxy-pyrrolidine-1-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide [0411] Cis-4-hydroxy-piperidine-1-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
[0412] Trans-4-hydroxy-piperidine-1-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
[0413] Endo-4-hydroxy-piperidine-1-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide [0414] Exo-4-hydroxy-piperidine-1-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide [0415]
1-{2-[(1,1-Dioxo-thiomorpholine-4-carbonyl)amino]-ethyl}-1H-benzoimidazol-
e-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide [0416]
1,1-Dioxo-thiomorpholine-4-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]-octane-8-carbonyl)-benzo-imidazol-1-
-yl]-ethyl}-amide [0417]
1-{2-[(4-Hydroxy-piperidine-1-carbonyl)-amino]-ethyl}-1H-benzoimidazole-5-
-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide [0418]
1-{2-[(3-Hydroxy-pyrrolidine-1-carbonyl)-amino]-ethyl}-1H-benzoimidazole--
5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide [0419]
Morpholine-4-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo-[3.2.1]octane-8-carbonyl)-benzoimidazol-1--
yl]-ethyl}-amide [0420]
Cis-1-{2-[5-(5-hydroxy-adamantan-2-ylcarbamoyl)-benzoimidazol-1-yl]-ethyl-
carbamoyl}-piperidine-4-carboxylic acid [0421]
Trans-1-{2-[5-(5-hydroxy-adamantan-2-ylcarbamoyl)-benzoimidazol-1-yl]-eth-
ylcarbamoyl}-piperidine-4-carboxylic acid [0422]
1-{2-[5-(3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-
-yl]-ethylcarbamoyl}-piperidine-4-carboxylic acid [0423]
N-Methoxy-N-methyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-car-
bonyl)-indol-1-yl]-propionamide [0424]
N-Ethoxy-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-ind-
ol-1-yl]-propionamide [0425]
N-Hydroxy-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-in-
dol-1-yl]-propionamide [0426]
{1-[2-(2H-Tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone [0427]
{1-[2-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3--
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone [0428]
{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trime-
thyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone [0429]
N-(1H-Tetrazol-5-yl)-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-c-
arbonyl)-indol-1-yl]-propionamide [0430]
{1-[2-(2-Methyl-2H-tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trimethyl--
6-aza-bicyclo[3.2.1]oct-6-yl)-methanone [0431]
{1-[2-(1-Methyl-1H-tetrazol-5-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trimethyl--
6-aza-bicyclo[3.2.1]oct-6-yl)-methanone [0432]
{1-[2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-1H-indol-5-yl}-(1,3,3-trime-
thyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof
with a pharmaceutically acceptable acid or base, or any optical
isomer or mixture of optical isomers, including a racemic mixture,
or any tautomeric forms.
[0433] In another embodiment, the present invention provides for a
novel compound of formula I, which is an agent useful for the
treatment of conditions, disorders, or diseases wherein a
modulation or an inhibition of the activity of 11.beta.HSD1 is
beneficial.
[0434] In another embodiment, the present invention provides for a
use of a compound of formula I, for the preparation of a
pharmaceutical composition for the treatment of conditions,
disorders, or diseases wherein a modulation or an inhibition of the
activity of 11.beta.HSD1 is beneficial.
[0435] In another embodiment, the present invention provides for a
use of a compound of formula I for the preparation of a
pharmaceutical composition for the treatment of conditions,
disorders, or diseases, wherein the conditions, disorders, and
diseases are influenced by intracellular glucocorticoid levels.
[0436] In another embodiment, the present invention provides for a
use of a compound of formula I for the preparation of a
pharmaceutical composition for the treatment of conditions,
disorders, or diseases, wherein the conditions, disorders, or
diseases are selected from metabolic syndrome, insulin resistance,
dyslipidemia, hypertension, obesity, type 2 diabetes, impaired
glucose tolerance (IGT), impaired fasting glucose (IFG), the
progression from IGT to type 2 diabetes, the progression of the
metabolic syndrome into type 2 diabetes, diabetic late
complications, neurodegenerative and psychiatric disorders, and the
adverse effects of glucocorticoid receptor agonist treatment or
therapy.
[0437] In another embodiment, the present invention provides for a
method for the treatment of conditions, disorders, or diseases
wherein a modulation or an inhibition of the activity of
11.beta.HSD1 is beneficial, the method comprising administering to
a subject in need thereof an effective amount of a compound of
formula I.
[0438] In another embodiment, the present invention provides for a
method for the treatment of conditions, disorders or diseases,
wherein the conditions, disorders, and diseases are influenced by
intracellular glucocorticoid levels, the method comprising
administering to a subject in need thereof an effective amount of a
compound of formula I.
[0439] In another embodiment, the present invention provides for a
method for the treatment of conditions, disorders or diseases,
wherein the conditions, disorders or diseases are selected from
metabolic syndrome, insulin resistance, dyslipidemia, hypertension,
obesity, type 2 diabetes, impaired glucose tolerance (IGT),
impaired fasting glucose (IFG), progression from IGT to type 2
diabetes, progression of metabolic syndrome into type 2 diabetes,
diabetic late complications, neurodegenerative and psychiatric
disorders, and the adverse effects of glucocorticoid receptor
agonist treatment or therapy.
[0440] [27] In another embodiment, the present invention provides a
novel compound, which is an agent useful for the treatment of
conditions, disorders, or diseases wherein a modulation or an
inhibition of the activity of 11.beta.HSD1 is beneficial.
[0441] [28] In another embodiment, the present invention provides a
novel method wherein the conditions, disorders, and diseases that
are influenced by intracellular glucocorticoid levels.
[0442] [29] In another embodiment, the present invention provides a
novel method wherein the conditions, disorders, or diseases are
selected from metabolic syndrome, insulin resistance, dyslipidemia,
hypertension, obesity, type 2 diabetes, impaired glucose tolerance
(IGT), impaired fasting glucose (IFG), progression from IGT to type
2 diabetes, progression of metabolic syndrome into type 2 diabetes,
diabetic late complications, neurodegenerative and psychiatric
disorders, and the adverse effects of glucocorticoid receptor
agonist treatment or therapy.
[0443] [30] In another embodiment, the present invention provides a
novel method pharmaceutical composition comprising, as an active
ingredient, at least one compound according of the present
invention together with one or more pharmaceutically acceptable
carriers or excipients.
[0444] [31] In another embodiment, the present invention provides a
novel pharmaceutical composition, which is suitable for oral,
nasal, buccal, transdermal, pulmonal, or parenteral
administration.
[0445] The compounds of the present invention may have asymmetric
centers and may occur as racemates, racemic mixtures, and as
individual enantiomers or diastereoisomers, with all isomeric forms
being included in the present invention as well as mixtures
thereof.
[0446] The present invention also encompasses pharmaceutically
acceptable salts of the present compounds. Such salts include
pharmaceutically acceptable acid addition salts, pharmaceutically
acceptable base addition salts, pharmaceutically acceptable metal
salts, ammonium and alkylated ammonium salts. Acid addition salts
include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include
hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, and
nitric acids. Representative examples of suitable organic acids
include formic, acetic, trichloroacetic, trifluoroacetic,
propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic,
maleic, malic, malonic, mandelic, oxalic, picric, pyruvic,
salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,
ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,
gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,
p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,
sulphates, nitrates, phosphates, perchlorates, borates, acetates,
benzoates, hydroxynaphthoates, glycerophosphates, and
ketoglutarates. Further examples of pharmaceutically acceptable
inorganic or organic acid addition salts include the
pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2
(1977), which is incorporated herein by reference. Examples of
metal salts include lithium, sodium, potassium, barium, calcium,
magnesium, zinc, and calcium salts. Examples of amines and organic
amines include ammonium, methylamine, dimethylamine,
trimethylamine, ethylamine, diethylamine, propylamine, butylamine,
tetramethylamine, ethanolamine, diethanolamine, triethanolamine,
meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine,
N-benzylphenylethylamine, N-methyl-D-glucamine, and guanidine.
Examples of cationic amino acids include lysine, arginine, and
histidine.
[0447] Further, some of the compounds of the present invention may
form solvates with water or common organic solvents. Such solvates
are encompassed within the scope of the invention.
[0448] The pharmaceutically acceptable salts are prepared by
reacting a compound of the present invention with 1 to 4
equivalents of a base such as sodium hydroxide, sodium methoxide,
sodium hydride, potassium tert-butoxide, calcium hydroxide, and
magnesium hydroxide, in solvents such as ether, THF, methanol,
tert-butanol, dioxane, and isopropanol, ethanol. Mixtures of
solvents may be used. Organic bases such as lysine, arginine,
diethanolamine, choline, guandine and their derivatives etc. may
also be used. Alternatively, acid addition salts wherever
applicable are prepared by treatment with acids such as
hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid,
acetic acid, citric acid, maleic acid salicylic acid,
hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid,
benzoic acid, benzenesulfonic acid, and tartaric acid in solvents
such as ethyl acetate, ether, alcohols, acetone, THF, and dioxane.
Mixture of solvents may also be used.
[0449] The stereoisomers of the compounds forming part of this
invention may be prepared by using reactants in their single
enantiomeric form in the process wherever possible or by conducting
the reaction in the presence of reagents or catalysts in their
single enantiomer form or by resolving the mixture of stereoisomers
by conventional methods. Some of the preferred methods include use
of microbial resolution, enzymatic resolution, resolving the
diastereomeric salts formed with chiral acids such as mandelic
acid, camphorsulfonic acid, tartaric acid, and lactic acid,
wherever applicable or chiral bases such as brucine, (R)- or
(S)-phenylethylamine, cinchona alkaloids and their derivatives.
Commonly used methods are compiled by Jaques et al. in
"Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
More specifically the compound of the present invention may be
converted to a 1:1 mixture of diastereomeric amides by treating
with chiral amines, aminoacids, aminoalcohols derived from
aminoacids; conventional reaction conditions may be employed to
convert acid into an amide; the diastereomers may be separated
either by fractional crystallization or chromatography and the
stereoisomers of compound of formula I may be prepared by
hydrolysing the pure diastereomeric amide.
[0450] Various polymorphs of the compounds forming part of this
invention may be prepared by crystallization of said compounds
under different conditions. For example, using different solvents
commonly used or their mixtures for recrystallization;
crystallizations at different temperatures; various modes of
cooling, ranging from very fast to very slow cooling during
crystallizations. Polymorphs may also be obtained by heating or
melting the compound followed by gradual or fast cooling. The
presence of polymorphs may be determined by solid probe NMR
spectroscopy, it spectroscopy, differential scanning calorimetry,
powder X-ray diffraction or such other techniques.
[0451] The invention also encompasses prodrugs of the present
compounds, which on administration undergo chemical conversion by
metabolic processes before becoming active pharmacological
substances. In general, such prodrugs will be functional
derivatives of the present compounds, which are readily convertible
in vivo into the required compound of the present invention.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in "Design
of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0452] It is a well known problem in drug discovery that compounds,
such as enzyme inhibitors, may be very potent and selective in
biochemical assays, yet be inactive in vivo. This lack of so-called
bioavailability may be ascribed to a number of different factors
such as lack of or poor absorption in the gut, first pass
metabolism in the liver and/or poor uptake in cells. Although the
factors determining bioavailability are not completely understood,
there are many examples in the scientific literature--well known to
those skilled in the art--of how to modify compounds, which are
potent and selective in biochemical assays but show low or no
activity in vivo, into drugs that are biologically active.
[0453] It is within the scope of the invention to modify the
compounds of the present invention, termed the `original compound`,
by attaching chemical groups that will improve the bioavailability
of said compounds in such a way that the uptake in cells or mammals
is facilitated.
[0454] Examples of said modifications, which are not intended in
any way to limit the scope of the invention, include changing of
one or more carboxy groups to esters (for instance methyl esters,
ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters
or other acyloxymethyl esters). Compounds of the invention,
original compounds, such modified by attaching chemical groups are
termed `modified compounds`.
[0455] The invention also encompasses active metabolites of the
present compounds.
[0456] The compounds according to the invention alter, and more
specifically, reduce the level of active intracellular
glucocorticoid and are accordingly useful for the treatment of
conditions, disorders, and diseases in which such a modulation or
reduction is beneficial.
[0457] Accordingly, the present compounds may be applicable for the
treatment of the metabolic syndrome, insulin resistance,
dyslipidemia, hypertension, obesity, type 2 diabetes, impaired
glucose tolerance (IGT), impaired fasting glucose (IFG), Latent
Autoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic
late complications including cardiovascular diseases,
cardiovascular disorders, disorders of lipid metabolism,
neurodegenerative and psychiatric disorders, dysregulation of
intraocular pressure including glaucoma, immune disorders,
inappropriate immune responses, musculo-skeletal disorders,
gastrointestinal disorders, polycystic ovarie syndrome (PCOS),
reduced hair growth or other diseases, disorders or conditions that
are influenced by intracellular glucocorticoid levels, adverse
effects of increased blood levels of active endogenous or exogenous
glucocorticoid, and any combination thereof, adverse effects of
increased plasma levels of endogenous active glucocorticoid,
Cushing's disease, Cushing's syndrome, adverse effects of
glucocorticoid receptor agonist treatment of autoimmune diseases,
adverse effects of glucocorticoid receptor agonist treatment of
inflammatory diseases, adverse effects of glucocorticoid receptor
agonist treatment of diseases with an inflammatory component,
adverse effects of glucocorticoid receptor agonist treatment as a
part of cancer chemotherapy, adverse effects of glucocorticoid
receptor agonist treatment for surgical/post-surgical or other
trauma, adverse effects of glucocorticoid receptor agonist therapy
in the context of organ or tissue transplantation or adverse
effects of glucocorticoid receptor agonist treatment in other
diseases, disorders or conditions where glucocorticoid receptor
agonists provide clinically beneficial effects. Also the present
compounds may be applicable for thr treatment of visceral fat
accumulation and insulin resistance in HAART (highly active
antiretroviral treatment)-treated patients.
[0458] More specifically the present compounds may be applicable
for the treatment of the metabolic syndrome, type 2 diabetes,
diabetes as a consequence of obesity, insulin resistance,
hyperglycemia, prandial hyperglycemia, hyperinsulinemia,
inappropriately low insulin secretion, impaired glucose tolerance
(IGT), impaired fasting glucose (IFG), increased hepatic glucose
production, type 1 diabetes, LADA, pediatric diabetes,
dyslipidemia, diabetic dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia,
decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders
of lipid metabolism, obesity, visceral obesity, obesity as a
consequence of diabetes, increased food intake, hypertension,
diabetic late complications, micro-/macroalbuminuria, nephropathy,
retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases,
arteriosclerosis, atherosclerosis, coronary artery disease, cardiac
hypertrophy, myocardial ischemia, heart insufficiency, congestional
heart failure, stroke, myocardial infarction, arrythmia, decreased
blood flow, erectile dysfunction (male or female), myopathy, loss
of muscle tissue, muscle wasting, muscle catabolism, osteoporosis,
decreased linear growth, neurodegenerative and psychiatric
disorders, Alzheimers disease, neuronal death, impaired cognitive
function, depression, anxiety, eating disorders, appetite
regulation, migraine, epilepsia, addiction to chemical substances,
disorders of intraocular pressure, glaucoma, polycystic ovary
syndrome (PCOS), inappropriate immune responses, inappropriate T
helper-1/T helper-2 polarisation, bacterial infections,
mycobacterial infections, fungal infections, viral infections,
parasitic infestations, suboptimal responses to immunizations,
immune dysfunction, partial or complete baldness, or other
diseases, disorders or conditions that are influenced by
intracellular glucocorticoid levels and any combination thereof,
adverse effects of glucocorticoid receptor agonist treatment of
allergic-inflammatory diseases such as asthma and atopic
dermatitis, adverse effects of glucocorticoid receptor agonist
treatment of disorders of the respiratory system e.g., asthma,
cystic fibrosis, emphysema, bronchitis, hypersensitivity,
pneumonitis, eosinophilic pneumonias, pulmonary fibrosis, adverse
effects of glucocorticoid receptor agonist treatment of
inflammatory bowel disease such as Crohn's disease and ulcerative
colitis; adverse effects of glucocorticoid receptor agonist
treatment of disorders of the immune system, connective tissue and
joints e.g., reactive arthritis, rheumatoid arthritis, Sjogren's
syndrome, systemic lupus erythematosus, lupus nephritis,
Henoch-Schonlein purpura, Wegener's granulomatosis, temporal
arteritis, systemic sclerosis, vasculitis, sarcoidosis,
dermatomyositis-polymyositis, pemphigus vulgaris; adverse effects
of glucocorticoid receptor agonist treatment of endocrinological
diseases such as hyperthyroidism, hypoaldosteronism,
hypopituitarism; adverse effects of glucocorticoid receptor agonist
treatment of hematological diseases e.g., hemolytic anemia,
thrombocytopenia, paroxysmal nocturnal hemoglobinuria; adverse
effects of glucocorticoid receptor agonist treatment of cancer such
as spinal cord diseases, neoplastic compression of the spinal cord,
brain tumours, acute lymphoblastic leukemia, Hodgkin's disease,
chemotherapy-induced nausea, adverse effects of glucocorticoid
receptor agonist treatment of diseases of muscle and at the
neuro-muscular joint e.g., myasthenia gravis and heriditary
myopathies (e.g., Duchenne muscular dystrophy), adverse effects of
glucocorticoid receptor agonist treatment in the context of surgery
& transplantation e.g., trauma, post-surgical stress, surgical
stress, renal transplantation, liver transplantation, lung
transplantation, pancreatic islet transplantation, blood stem cell
transplantation, bone marrow transplantation, heart
transplantation, adrenal gland transplantation, tracheal
transplantation, intestinal transplantation, corneal
transplantation, skin grafting, keratoplasty, lens implantation and
other procedures where immunosuppression with glucocorticoid
receptor agonists is beneficial; adverse effects of glucocorticoid
receptor agonist treatment of brain absess, nausea/vomiting,
infections, hypercalcemia, adrenal hyperplasia, autoimmune
hepatitis, spinal cord diseases, saccular aneurysms or adverse
effects to glucocorticoid receptor agonist treatment in other
diseases, disorders and conditions where glucocorticoid receptor
agonists provide clinically beneficial effects.
[0459] Accordingly, in a further aspect the invention relates to a
compound according to the invention for use as a pharmaceutical
composition.
[0460] The invention also relates to pharmaceutical compositions
comprising, as an active ingredient, at least one compound
according to the invention together with one or more
pharmaceutically acceptable carriers or diluents.
[0461] The pharmaceutical composition is preferably in unit dosage
form, comprising from about 0.05 mg/day to about 2000 mg/day,
preferably from about 0.1 mg/day to about 1000 mg/day, and more
preferably from about 0.5 mg/day to about 500 mg/day of a compound
according to the invention.
[0462] In another embodiment, the patient is treated with a
compound according to the invention for at least about 1 week, for
at least about 2 weeks, for at least about 4 weeks, for at least
about 2 months or for at least about 4 months.
[0463] In yet another embodiment, the pharmaceutical composition is
for oral, nasal, buccal, transdermal, pulmonal or parenteral
administration.
[0464] Furthermore, the invention relates to the use of a compound
according to the invention for the preparation of a pharmaceutical
composition for the treatment of disorders and diseases wherein a
modulation or an inhibition of the activity of 11.beta.HSD1 is
beneficial.
[0465] The invention also relates to a method for the treatment of
disorders and diseases wherein a modulation or an inhibition of the
activity of 11.beta.HSD1 is beneficial, the method comprising
administering to a subject in need thereof an effective amount of a
compound according to the invention.
[0466] In a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the
treatment of any diseases and conditions that are influenced by
intracellular glucocorticoid levels as mentioned above.
[0467] Thus, in a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the
treatment of conditions and disorders where a decreased level of
active intracellular glucocorticoid is desirable, such as the
conditions and diseases mentioned above.
[0468] In yet a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the
treatment of metabolic syndrome, insulin resistance, dyslipidemia,
hypertension obesity, type 2 diabetes, impaired glucose tolerance
(IGT), impaired fasting glucose (IFG), progression from IGT to type
2 diabetes, progression of the metabolic syndrome into type 2
diabetes, diabetic late complications (e.g., cardiovascular
diseases, arteriosclerosis, and atherosclerosis), neurodegenerative
and psychiatric disorders, and, the adverse effects of
glucocorticoid receptor agonist treatment or therapy.
[0469] In another embodiment of the present invention, the route of
administration may be any route which effectively transports a
compound according to the invention to the appropriate or desired
site of action, such as oral, nasal, buccal, transdermal, pulmonal,
or parenteral.
[0470] In still a further aspect of the invention the present
compounds are administered in combination with one or more further
active substances in any suitable ratios. Such further active
substances may e.g., be selected from antiobesity agents,
antidiabetics, agents modifying the lipid metabolism,
antihypertensive agents, glucocorticoid receptor agonists, agents
for the treatment and/or prevention of complications resulting from
or associated with diabetes and agents for the treatment and/or
prevention of complications and disorders resulting from or
associated with obesity.
[0471] Thus, in a further aspect of the invention the present
compounds may be administered in combination with one or more
antiobesity agents or appetite regulating agents.
[0472] Such agents may be selected from the group consisting of
CART (cocaine amphetamine regulated transcript) agonists, NPY
(neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin
antagonists, TNF (tumor necrosis factor) agonists, CRF
(corticotropin releasing factor) agonists, CRF BP (corticotropin
releasing factor binding protein) antagonists, urocortin agonists,
.beta.3 agonists, MSH (melanocyte-stimulating hormone) agonists,
MCH (melanocyte-concentrating hormone) antagonists, CCK
(cholecystokinin) agonists, serotonin re-uptake inhibitors,
serotonin and noradrenaline re-uptake inhibitors, mixed serotonin
and noradrenergic compounds, 5HT (serotonin) agonists, bombesin
agonists, galanin antagonists, growth hormone, growth hormone
releasing compounds, TRH (thyreotropin releasing hormone) agonists,
UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists,
DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors,
PPAR (peroxisome proliferator-activated receptor) modulators, RXR
(retinoid X receptor) modulators, TR .beta. agonists, AGRP (Agouti
related protein) inhibitors, H3 histamine antagonists, opioid
antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary
neurotrophic factor.
[0473] In one embodiment of the invention the antiobesity agent is
leptin; dexamphetamine or amphetamine; fenfluramine or
dexfenfluramine; sibutramine; orlistat; mazindol or
phentermine.
[0474] Suitable antidiabetic agents include insulin, insulin
analogues and derivatives such as those disclosed in EP 792 290
(Novo Nordisk A/S), e.g., N.sup..epsilon.B29-tetradecanoyl des
(B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S),
e.g., Asp.sup.B28 human insulin, U.S. Pat. No. 5,504,188 (Eli
Lilly), e.g., Lys.sup.B28 Pro.sup.B29 human insulin, EP 368 187
(Aventis), eg Lantus, which are all incorporated herein by
reference, GLP-1 (glucagon like peptide-1) and GLP-1 derivatives
such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which
is incorporated herein by reference as well as orally active
hypoglycaemic agents.
[0475] The orally active hypoglycaemic agents preferably comprise
sulphonylureas, biguanides, meglitinides, glucosidase inhibitors,
glucagon antagonists such as those disclosed in WO 99/01423 to Novo
Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists,
potassium channel openers such as those disclosed in WO 97/26265
and WO 99/03861 to Novo Nordisk A/S which are incorporated herein
by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors,
inhibitors of hepatic enzymes involved in stimulation of
gluconeogenesis and/or glycogenolysis, glucose uptake modulators,
compounds modifying the lipid metabolism such as antihyperlipidemic
agents and antilipidemic agents as PPAR.alpha. modulators,
PPAR.delta. modulators, cholesterol absorption inhibitors, HSL
(hormone-sensitive lipase) inhibitors and HMG CoA inhibitors
(statins), nicotinic acid, fibrates, anion exchangers, compounds
lowering food intake, bile acid resins, RXR agonists and agents
acting on the ATP-dependent potassium channel of the
.beta.-cells.
[0476] In one embodiment, the present compounds are administered in
combination with insulin or an insulin analogue or derivative, such
as N.sup..epsilon.B29-tetradecanoyl des (B30) human insulin,
Asp.sup.B28 human insulin, Lys.sup.B28 Pro.sup.B29 human insulin,
Lantus.RTM., or a mix-preparation comprising one or more of
these.
[0477] In a further embodiment the present compounds are
administered in combination with a sulphonylurea e.g., tolbutamide,
glibenclamide, glipizide or glicazide.
[0478] In another embodiment the present compounds are administered
in combination with a biguanide e.g., metformin.
[0479] In yet another embodiment the present compounds are
administered in combination with a meglitinide e.g., repaglinide or
senaglinide.
[0480] In still another embodiment the present compounds are
administered in combination with a thiazolidinedione e.g.,
troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds
disclosed in WO 97/41097 such as
5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]th-
iazolidine-2,4-dione or a pharmaceutically acceptable salt thereof,
preferably the potassium salt.
[0481] In yet another embodiment the present compounds may be
administered in combination with the insulin sensitizers disclosed
in WO 99/19313 such as (-)
3-[4-[2-Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a
pharmaceutically acceptable salts thereof, preferably the arginine
salt.
[0482] In a further embodiment the present compounds are
administered in combination with an .alpha.-glucosidase inhibitor
e.g., miglitol or acarbose.
[0483] In another embodiment the present compounds are administered
in combination with an agent acting on the ATP-dependent potassium
channel of the .beta.-cells e.g., tolbutamide, glibenclamide,
glipizide, glicazide or repaglinide.
[0484] Furthermore, the present compounds may be administered in
combination with nateglinide.
[0485] In still another embodiment the present compounds are
administered in combination with an antihyperlipidemic agent or
antilipidemic agent e.g., cholestyramine, colestipol, clofibrate,
gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156,
LY-818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin,
simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
[0486] In a further embodiment the present compounds are
administered in combination with more than one of the
above-mentioned compounds e.g., in combination with a sulphonylurea
and metformin, a sulphonylurea and acarbose, repaglinide and
metformin, insulin and a sulphonylurea, insulin and metformin,
insulin, insulin and lovastatin, etc.
[0487] Further, the present compounds may be administered in
combination with one or more antihypertensive agents. Examples of
antihypertensive agents are .beta.-blockers such as alprenolol,
atenolol, timolol, pindolol, propranolol, metoprolol,
bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol,
betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol,
amusolalul, carvedilol, labetalol, .beta.2-receptor blockers e.g.,
S-atenolol, OPC-1085, ACE (angiotensin converting enzyme)
inhibitors such as quinapril, lisinopril, enalapril, captopril,
benazepril, perindopril, trandolapril, fosinopril, ramipril,
cilazapril, delapril, imidapril, moexipril, spirapril, temocapril,
zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP
00481522), omapatrilat, gemopatrilat and GW-660511, calcium channel
blockers such as nifedipine, felodipine, nicardipine, isradipine,
nimodipine, diltiazem, amlodipine, nitrendipine, verapamil,
lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine,
azelnidipine, barnidipine, efonodipine, iasidipine, iemildipine,
iercanidipine, manidipine, nilvadipine, pranidipine, furnidipine,
.alpha.-blockers such as doxazosin, urapidil, prazosin, terazosin,
bunazosin and OPC-28326, diuretics such as thiazides/sulphonamides
(e.g., bendroflumetazide, chlorothalidone, hydrochlorothiazide and
clopamide), loop-diuretics (e.g., bumetanide, furosemide and
torasemide) and potassium sparing diuretics (e.g., amiloride,
spironolactone), endothelin ET-A antagonists such as ABT-546,
ambrisetan, atrasentan, SB-234551, CI-1034, S-0139 and YM-598,
endothelin antagonists e.g., bosentan and J-104133, renin
inhibitors such as aliskiren, vasopressin V1 antagonists e.g.,
OPC-21268, vasopressin V2 antagonists such as tolvaptan, SR-121463
and OPC-31260, B-type natriuretic peptide agonists e.g.,
Nesiritide, angiotensin II antagonists such as irbesartan,
candesartancilexetil, losartan, valsartan, telmisartan, eprosartan,
candesartan, CL-329167, eprosartan, iosartan, olmesartan,
pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g., fenoldopam
and ketanserin, adenosine A1 antagonists such as naftopidil, N-0861
and FK-352, thromboxane A2 antagonists such as KT2-962,
endopeptidase inhibitors e.g., ecadotril, nitric oxide agonists
such as LP-805, dopamine D1 antagonists e.g., MYD-37, dopamine D2
agonists such as nolomirole, n-3 fatty acids e.g., omacor,
prostacyclin agonists such as treprostinil, beraprost, PGE1
agonists e.g., ecraprost, Na+/K+ ATPase modulators e.g., PST-2238,
Potassium channel activators e.g., KR-30450, vaccines such as
PMD-3117, Indapamides, CGRP-unigene, guanylate cyclase stimulators,
hydralazines, methyldopa, docarpamine, moxonidine, CoAprovel,
MondoBiotech-811.
[0488] Further reference can be made to Remington: The Science and
Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed., Mack
Publishing Co., Easton, Pa., 1995.
[0489] Furthermore, the present compounds may be administered in
combination with one or more glucocorticoid receptor agonists.
Examples of such glucocorticoid receptor agonists are betametasone,
dexamethasone, hydrocortisone, methylprednisolone, prednisolone,
prednisone, beclomethasone, butixicort, clobetasol, flunisolide,
flucatisone (and analogues), momethasone, triamcinolonacetonide,
triamcinolonhexacetonide GW-685698, NXC-1015, NXC-1020, NXC-1021,
NS-126, P-4112, P-4114, RU-24858 and T-25 series.
[0490] It should be understood that any suitable combination of the
compounds according to the invention with one or more of the
above-mentioned compounds and optionally one or more further
pharmacologically active substances are considered to be within the
scope of the present invention.
Pharmaceutical Compositions
[0491] The compounds of the present invention may be administered
alone or in combination with pharmaceutically acceptable carriers
or excipients, in either single or multiple doses. The
pharmaceutical compositions according to the invention may be
formulated with pharmaceutically acceptable carriers or diluents as
well as any other known adjuvants and excipients in accordance with
conventional techniques such as those disclosed in Remington: The
Science and Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed.,
Mack Publishing Co., Easton, Pa., 1995.
[0492] The pharmaceutical compositions may be specifically
formulated for administration by any suitable route such as the
oral, rectal, nasal, pulmonary, topical (including buccal and
sublingual), transdermal, intracisternal, intraperitoneal, vaginal
and parenteral (including subcutaneous, intramuscular, intrathecal,
intravenous and intradermal) route, the oral route being preferred.
It will be appreciated that the preferred route will depend on the
general condition and age of the subject to be treated, the nature
of the condition to be treated and the active ingredient
chosen.
[0493] Pharmaceutical compositions for oral administration include
solid dosage forms such as hard or soft capsules, tablets, troches,
dragees, pills, lozenges, powders and granules. Where appropriate,
they can be prepared with coatings such as enteric coatings or they
can be formulated so as to provide controlled release of the active
ingredient such as sustained or prolonged release according to
methods well-known in the art.
[0494] Liquid dosage forms for oral administration include
solutions, emulsions, suspensions, syrups and elixirs.
[0495] Pharmaceutical compositions for parenteral administration
include sterile aqueous and non-aqueous injectable solutions,
dispersions, suspensions or emulsions as well as sterile powders to
be reconstituted in sterile injectable solutions or dispersions
prior to use. Depot injectable formulations are also contemplated
as being within the scope of the present invention.
[0496] Other suitable administration forms include suppositories,
sprays, ointments, cremes, gels, inhalants, dermal patches,
implants etc.
[0497] A typical oral dosage is in the range of from about 0.001 to
about 100 mg/kg body weight per day, preferably from about 0.01 to
about 50 mg/kg body weight per day, and more preferred from about
0.05 to about 10 mg/kg body weight per day administered in one or
more dosages such as 1 to 3 dosages. The exact dosage will depend
upon the frequency and mode of administration, the sex, age, weight
and general condition of the subject treated, the nature and
severity of the condition treated and any concomitant diseases to
be treated and other factors evident to those skilled in the
art.
[0498] The formulations may conveniently be presented in unit
dosage form by methods known to those skilled in the art. A typical
unit dosage form for oral administration one or more times per day
such as 1 to 3 times per day may contain from 0.05 to about 2000
mg, e.g., from about 0.1 to about 1000 mg, from about 0.5 mg to
about 500 mg., from about 1 mg to about 200 mg, e.g., about 100
mg.
[0499] For parenteral routes, such as intravenous, intrathecal,
intramuscular and similar administration, typically doses are in
the order of about half the dose employed for oral
administration.
[0500] The compounds of this invention are generally utilized as
the free substance or as a pharmaceutically acceptable salt
thereof. Examples are an acid addition salt of a compound having
the utility of a free base and a base addition salt of a compound
having the utility of a free acid. The term "pharmaceutically
acceptable salts" refers to non-toxic salts of the compounds for
use according to the present invention which are generally prepared
by reacting the free base with a suitable organic or inorganic acid
or by reacting the acid with a suitable organic or inorganic base.
When a compound for use according to the present invention,
contains a free base such salts are prepared in a conventional
manner by treating a solution or suspension of the compound with a
chemical equivalent of a pharmaceutically acceptable acid. When a
compounds for use according to the present invention, contains a
free acid such salts are prepared in a conventional manner by
treating a solution or suspension of the compound with a chemical
equivalent of a pharmaceutically acceptable base. Physiologically
acceptable salts of a compound with a hydroxy group include the
anion of said compound in combination with a suitable cation such
as sodium or ammonium ion. Other salts which are not
pharmaceutically acceptable may be useful in the preparation of
compounds for use according to the present invention and these form
a further aspect of the present invention.
[0501] For parenteral administration, solutions of the present
compounds in sterile aqueous solution, aqueous propylene glycol or
sesame or peanut oil may be employed. Such aqueous solutions should
be suitable buffered if necessary and the liquid diluent first
rendered isotonic with sufficient saline or glucose. The aqueous
solutions are particularly suitable for intravenous, intramuscular,
subcutaneous and intraperitoneal administration. The sterile
aqueous media employed are all readily available by standard
techniques known to those skilled in the art.
[0502] Suitable pharmaceutical carriers include inert solid
diluents or fillers, sterile aqueous solution and various organic
solvents. Examples of suitable carriers are water, salt solutions,
alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,
peanut oil, olive oil, syrup, phospholipids, gelatine, lactose,
terra alba, sucrose, cyclodextrin, amylose, magnesium stearate,
talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl
ethers of cellulose, silicic acid, fatty acids, fatty acid amines,
fatty acid monoglycerides and diglycerides, pentaerythritol fatty
acid esters, polyoxyethylene, hydroxymethylcellulose and
polyvinylpyrrolidone. Similarly, the carrier or diluent may include
any sustained release material known in the art, such as glyceryl
monostearate or glyceryl distearate, alone or mixed with a wax. The
formulations may also include wetting agents, emulsifying and
suspending agents, preserving agents, sweetening agents or
flavouring agents.
[0503] The pharmaceutical compositions formed by combining the
compounds of the invention and the pharmaceutically acceptable
carriers are then readily administered in a variety of dosage forms
suitable for the disclosed routes of administration. The
formulations may conveniently be presented in unit dosage form by
methods known in the art of pharmacy.
[0504] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules
or tablets, each containing a predetermined amount of the active
ingredient, and which may include a suitable excipient. These
formulations may be in the form of powder or granules, as a
solution or suspension in an aqueous or non-aqueous liquid, or as
an oil-in-water or water-in-oil liquid emulsion.
[0505] Compositions intended for oral use may be prepared according
to any known method, and such compositions may contain one or more
agents selected from the group consisting of sweetening agents,
flavouring agents, colouring agents, and preserving agents in order
to provide pharmaceutically elegant and palatable preparations.
Tablets may contain the active ingredient in admixture with
non-toxic pharmaceutically-acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be for
example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch or
alginic acid; binding agents, for example, starch, gelatine or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the techniques described in
U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated
herein by reference, to form osmotic therapeutic tablets for
controlled release.
[0506] Formulations for oral use may also be presented as hard
gelatine capsules where the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or a soft gelatine capsule wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin, or olive oil.
[0507] Aqueous suspensions may contain the active compounds in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide such as
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more colouring agents, one or more flavouring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[0508] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as a liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavouring agents may be added
to provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0509] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
compound in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavouring, and colouring agents may also be
present.
[0510] The pharmaceutical compositions comprising a compound for
use according to the present invention may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example, olive oil or arachis oil, or a mineral oil, for example a
liquid paraffin, or a mixture thereof. Suitable emulsifying agents
may be naturally-occurring gums, for example gum acacia or gum
tragacanth, naturally-occurring phosphatides, for example soy bean,
lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and
condensation products of said partial esters with ethylene oxide,
for example polyoxyethylene sorbitan monooleate. The emulsions may
also contain sweetening and flavouring agents.
[0511] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, preservative and
flavouring and colouring agent. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known methods using suitable dispersing or wetting agents and
suspending agents described above. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conveniently employed as solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed using synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
[0512] The compositions may also be in the form of suppositories
for rectal administration of the compounds of the present
invention. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will thus
melt in the rectum to release the drug. Such materials include
cocoa butter and polyethylene glycols, for example.
[0513] For topical use, creams, ointments, jellies, solutions of
suspensions, etc., containing the compounds of the present
invention are contemplated. For the purpose of this application,
topical applications shall include mouth washes and gargles.
[0514] The compounds for use according to the present invention may
also be administered in the form of liposome delivery systems, such
as small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes may be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[0515] In addition, some of the compounds for use according to the
present invention may form solvates with water or common organic
solvents. Such solvates are also encompassed within the scope of
the present invention.
[0516] Thus, in a further embodiment, there is provided a
pharmaceutical composition comprising a compound for use according
to the present invention, or a pharmaceutically acceptable salt,
solvate, or prodrug thereof, and one or more pharmaceutically
acceptable carriers, excipients, or diluents.
[0517] If a solid carrier is used for oral administration, the
preparation may be tabletted, placed in a hard gelatine capsule in
powder or pellet form or it can be in the form of a troche or
lozenge. The amount of solid carrier will vary widely but will
usually be from about 25 mg to about 1 g. If a liquid carrier is
used, the preparation may be in the form of a syrup, emulsion, soft
gelatine capsule or sterile injectable liquid such as an aqueous or
non-aqueous liquid suspension or solution.
[0518] A typical tablet which may be prepared by conventional
tabletting techniques may contain:
TABLE-US-00003 Core: Active compound (as free compound or salt
thereof) 5.0 mg Lactosum PH. Eur. 67.8 mg Cellulose, microcryst.
(Avicel) 31.4 mg Amberlite .RTM.IRP88* 1.0 mg Magnesii stearas PH.
Eur. q.s. Coating: Hydroxypropyl methylcellulose approx. 9 mg
Mywacett 9-40 T** approx. 0.9 mg *Polacrillin potassium NF, tablet
disintegrant, Rohm and Haas. **Acylated monoglyceride used as
plasticizer for film coating.
[0519] The compounds of the invention may be administered to a
patient which is a mammal, especially a human in need thereof. Such
mammals include also animals, both domestic animals, e.g.,
household pets, and non-domestic animals such as wildlife.
[0520] Any novel feature or combination of features described
herein is considered essential to this invention.
[0521] The present invention also relate to the below methods of
preparing the compounds of the invention.
[0522] The present invention is further illustrated in the
following representative examples which are, however, not intended
to limit the scope of the invention in any way.
EXAMPLES
[0523] The following examples and general procedures refer to
intermediate compounds and final products for general formula (I)
identified above. The preparation of the compounds of general
formula (I) of the present invention is described in detail using
the following examples. Occasionally, the reaction may not be
applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this
occurs will be readily recognised by those skilled in the art. In
these cases the reactions can be successfully performed by
conventional modifications known to those skilled in the art, which
is, by appropriate protection of interfering groups, by changing to
other conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. The structures of the compounds are
confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in
the title compounds are presented where appropriate. .sup.1H NMR
shifts (.delta..sub.H) are given in parts per million (ppm) down
field from tetramethylsilane as internal reference standard. M.p.:
is melting point and is given in .degree. C. and is not corrected.
Column chromatography was carried out using the technique described
by W. C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck
silica gel 60 (Art. 9385). HPLC analyses are performed using 5
.mu.m C18 4.times.250 mm column eluted with various mixtures of
water and acetonitrile, flow=1 ml/min, as described in the
experimental section.
[0524] Microwave oven synthesis: The reaction was heated by
microwave irradiation in sealed microwave vessels in a single mode
Emrys Optimizer EXP from PersonalChemistry.RTM..
[0525] Preparative HPLC: Column: 1.9.times.15 cm Waters XTerra
RP-18. Buffer: linear gradient 5-95% in 15 min, MeCN, 0.1% TFA,
flow rate of 15 ml/min. The pooled fractions are either evaporated
to dryness in vacuo, or evaporated in vacuo until the MeCN is
removed, and then frozen and freeze dried.
ABBREVIATIONS
[0526] d=day(s)
[0527] g=gram(s)
[0528] h=hour(s)
[0529] Hz=hertz
[0530] L=liter(s)
[0531] M=molar
[0532] mg=milligram(s)
[0533] min=minute(s)
[0534] mL=milliliter(s)
[0535] mmol=millimole(s)
[0536] mol=mole(s)
[0537] ppm=parts per million
[0538] psi=pounds per square inch
[0539] ESI=electrospray ionization
[0540] m/z=mass to charge ratio
[0541] mp=melting point
[0542] MS=mass spectrometry
[0543] HPLC=high pressure liquid chromatography
[0544] RP=reverse phase
[0545] HPLC-MS=high pressure liquid chromatography-mass
spectrometry
[0546] NMR=nuclear magnetic resonance spectroscopy
[0547] rt=room temperature
[0548] TLC=thin layer chromatography
[0549] DCM=dichloromethane, CH.sub.2Cl.sub.2, methylenechloride
[0550] DIPEA=N,N-diisopropylethylamine
[0551] DMF=N,N-dimethylformamide
[0552] DMSO=dimethylsulfoxide
[0553] EDAC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride
[0554] Et.sub.2O=diethyl ether
[0555] EtOAc=ethyl acetate
[0556] HOBt=1-hydroxybenzotriazole
[0557] MeCN=acetonitrile
[0558] MeOH=methanol
[0559] NMP=N-methylpyrrolidin-2-one
[0560] TEA=triethylamine
[0561] TFA=trifluoroacetic acid
[0562] THF=tetrahydrofuran
[0563] CDCl.sub.3=deuterio chloroform
[0564] CD.sub.3OD=tetradeuterio methanol
[0565] DMSO-d.sub.6=hexadeuterio dimethylsulfoxide
[0566] Analysis
[0567] NMR
[0568] NMR spectra were recorded at 300 and 400 MHz on a Bruker
DRX300, DRX400 or AV400 instrument equipped with 5 mm
selective-inverse (SEI, .sup.1H and .sup.13C), 5 mm broadband
inverse (BBI, .sup.1H, broad-band) and 5 mm quadro nuclear (QNP,
.sup.1H, .sup.13C) probeheads, respectively. Shifts (.delta.) are
given in parts per million (ppm) down field from tetramethylsilane
as internal reference standard.
[0569] HPLC-MS
[0570] HPLC-MS Method
[0571] The RP-analysis was performed on an Agilent HPLC system
(1100 degasser, 1100 pump, 1100 injector and a 1100 DAD) fitted
with an Agilent MS detector system Model VL (MW 0-1000) and a
S.E.D.E.R.E Model Sedex 55 ELS detector system using a Waters
X-terra MS C18 column (5 .mu.m, 3.0 mm.times.50 mm) with gradient
elution, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent
A (0.05% TFA in water) within 3 min, 2.7 mL/min, temperature
40.degree. C.
[0572] Preparative Techniques
[0573] HPLC
[0574] HPLC Method Z3
[0575] The RP-purification was performed on a Gilson system (3
Gilson 306 pumps, Gilson 170 DAD detector and a Gilson 215 liquid
handler) using a Waters X-terra RP (10 .mu.m, 30 mm.times.150 mm)
with gradient elution, 5% to 95% solvent B (0.05% TFA in
acetonitrile) in solvent A (0.05% TFA in water) within 15 min, 40
mL/min, detection at 210 nm, temperature rt. The pooled fractions
are either evaporated to dryness in vacuo, or evaporated in vacuo
until the acetonitrile is removed, and then frozen and freeze
dried.
[0576] General
[0577] The following examples and general procedures refer to
intermediate compounds and final products for general formula (I)
identified in the specification and in the synthesis schemes. The
preparation of the compounds of general formula (I) of the present
invention is described in detail using the following examples.
Occasionally, the reaction may not be applicable as described to
each compound included within the disclosed scope of the invention.
The compounds for which this occurs will be readily recognised by
those skilled in the art. In these cases the reactions can be
successfully performed by conventional modifications known to those
skilled in the art, which is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or
by routine modification of reaction conditions. Alternatively,
other reactions disclosed herein or otherwise conventional will be
applicable to the preparation of the corresponding compounds of the
invention. In all preparative methods, all starting materials are
known or may be prepared by a person skilled in the art in analogy
with the preparation of similar known compounds or by the General
procedures A through D described herein. The structures of the
compounds are confirmed by either elemental analysis or nuclear
magnetic resonance (NMR), where peaks assigned to characteristic
protons in the title compounds are presented where appropriate.
[0578] General Procedures
[0579] General Procedure (A)
[0580] Compounds of the formula (Ia) according to the invention
wherein R.sup.1, R.sup.3, and R.sup.4 are as defined for formula
(I), with NR.sup.3R.sup.4 corresponding to ring A, can be prepared
as outlined below:
##STR00048##
[0581] A benzimidazole of formula (II) wherein NR.sup.3R.sup.4
corresponds to ring A defined above may be reacted with a
carboxylic acid in the presence of coupling reagents (e.g., EDAC
and HOBt) or an activated carboxylic acid of the formula (III)
wherein R.sup.1 is as defined above. This reaction may be carried
out in a suitable solvent (e.g., dichloromethane) in the presence
of a base (e.g., DIPEA) at ambient temperature.
[0582] General Procedure (B)
[0583] Compounds of the formula (Ib) according to the invention
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, and R.sup.12 are as defined for formula (I), with
NR.sup.3R.sup.4 corresponding to ring A, can be prepared as
outlined below:
##STR00049##
[0584] 4-Fluoro-3-nitrobenzoic acid may be reacted with an amine of
formula (IV) wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11 and
R.sup.12 are as defined above. This reaction may be carried out in
a suitable solvent (e.g., ethanol) in the presence of a base (e.g.,
DIPEA) at ambient temperature forming the secondary aniline of
formula (V). The carboxylic acid of formula (V) then can be
activated with HOBT and EDAC and reacted with an amine of the
formula (VI) wherein NR.sup.3R.sup.4 is ring A as defined above.
This reaction may be carried out in a suitable solvent (e.g., THF)
in the presence of a base (e.g., DIPEA) at ambient temperature
forming the compound of formula (VII). The nitro group of compounds
of formula (VII) may be reduced by hydrogen under pressure in a
suitable solvent (e.g., methanol/dichloromethane) in presence of a
catalyst (e.g., palladium on activated carbon) at ambient
temperature to form the diamine of formula (VIII). Compounds of
formula (VIII) may be reacted with an aldehyde of formula (IX)
wherein R.sup.2 is as defined above. This reaction may be carried
out in a suitable solvent (e.g., NMP) in the presence of a drying
agent (e.g., molecular sieve 4 .ANG.) at 50.degree. C. to form
compounds of formula (Ib).
[0585] General Procedure (C)
[0586] Compounds of the formula (Ic) according to the invention
wherein R.sup.2, R.sup.3, and R.sup.4 are as defined for formula
(I), with NR.sup.3R.sup.4 corresponding to ring A, can be prepared
as outlined below:
##STR00050##
[0587] 4-Amino-3-nitrobenzoic acid can be activated with HOBT and
EDAC and reacted with an amine of the formula (VI) wherein
NR.sup.3R.sup.4 is ring A as defined above. This reaction may be
carried out in a suitable solvent (e.g., THF) in the presence of a
base (e.g., DIPEA) at ambient temperature to form the compound of
formula (X). The nitro group of the formula (X) may be reduced by
hydrogen under pressure in a mixture of methanol and
dichloromethane in presence of a catalyst (e.g., palladium on
activated carbon) at ambient temperature to form the diamine of the
formula (XI). (XI) may be reacted with an aldehyde of the formula
(IX) wherein R.sup.2 is as defined above. This reaction may be
carried out in NMP in the presence of a drying agent (e.g.,
molecular sieve 4 .ANG.) at 50.degree. C. to form target product
(Ic).
[0588] General Procedure (D)
[0589] Compounds of the formula (Id) according to the invention
wherein R.sup.1, R.sup.3, R.sup.4, and R.sup.5 are as defined for
formula (I), with NR.sup.3R.sup.4 corresponding to ring A, can be
prepared as outlined below:
##STR00051##
[0590] An indole of formula (XII) wherein R.sup.3, R.sup.4, and
R.sup.5 are as defined above, with NR.sup.3R.sup.4 corresponding to
ring A, may be reacted with an alky/benzyl halide of the formula
(XIII) wherein R.sup.1 is as defined above in the presence of base
(e.g., sodium hydride). This reaction may be carried out in a
suitable solvent (e.g., DMF) at a temperature of up to reflux.
Example 1
General Procedure (A)
Furan-2-carboxylic acid
{2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoimidaz-
ol-1-yl]-ethyl}-amide
##STR00052##
[0592] To a solution of 2-furoic acid (37 mg, 0.33 mmol) in dry THF
(2 mL) at room temperature under an inert atmosphere of nitrogen
were added HOBt (49 mg, 0.36 mmol) and EDAC (82 mg, 0.43 mmol), and
the resulting solution was stirred for 30 min.
[1-(2-Aminoethyl)-1H-benzoimidazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3-
.2.1]oct-6-yl)-methanone trifluoroacetate (150 mg, 0.33 mmol) was
added to the solution followed by TEA (0.184 mL, 1.32 mmol), and
the reaction mixture was stirred for 16 h at room temperature. The
volatiles were evaporated in vacuo and the resulting solid was
purified by preparative HPLC, dried in vacuo at 50.degree. C.
affording 100 mg (70%) of the title compound as a solid. MS-ESI m/z
435; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.88-0.99 (m, 6H),
1.07 (d, 3H), 1.29-1.41 (m, 4H), 1.50-1.52 (m) and 2.10-2.11 (m,
1H), 1.76-1.79 (m, 1H), 3.02 (d), 3.13 (d), 3.32 (d) and 3.47 (d,
2H), 3.69 (t, 2H), 3.87-3.89 (m) and 4.39-4.41 (m, 1H), 4.56 (t,
2H), 6.58 (s, 1H), 6.98 (d, 1H), 7.48 (dd, 1H), 7.77-7.82 (m, 2H),
7.89 (t, 1H), 8.54-8.58 (m, 1H), 9.07 (d, 1H).
[0593] The following compounds were synthesised employing a similar
method to the one described in Example 1 above:
TABLE-US-00004 MS-ESI Ex. Structure MW IUPAC Name m/z 1-1
##STR00053## 493.65 1-Acetyl-piperidine-4- carboxylic acid
{2-[5-(1,3,3- trimethyl-6-aza-bicyclo- [3.2.1]octane-6-carbonyl)-
benzoimidazol-1-yl]-ethyl}- amide 494 1-2 ##STR00054## 412.53
2-Methoxy-N-{2-[5-(1,3,3- trimethyl-6-aza-bicyclo-
[3.2.1]octane-6-carbonyl)- benzoimidazol-1-yl]-ethyl}- acetamide
413 1-3 ##STR00055## 445.57 N-{2-[5-(1,3,3-Trimethyl-6-
aza-bicyclo[3.2.1]octane-6- carbonyl)-benzoimidazol-1-
yl]-ethyl}-isonicotinamide 446 1-4 ##STR00056## 382.51
N-{2-[5-(1,3,3-Trimethyl-6- aza-bicyclo[3.2.1]octane-6-
carbonyl)-benzoimidazol-1- yl]-ethyl}-acetamide 383 1-5
##STR00057## 440.59 {2-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-benzoimidazol-1-
yl]-ethyl}-carbamic acid tert- butyl ester 441 1-6 ##STR00058##
435.53 Isoxazole-5-carboxylic acid {2-[5-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-benzoimidazol-1- yl]-ethyl}-amide
436 1-7 ##STR00059## 444.58 N-{2-[5-(1,3,3-Trimethyl-6-
aza-bicyclo[3.2.1]octane-6- carbonyl)-benzoimidazol-1-
yl]-ethyl}-benzamide 445
Example 2
General Procedure (B)
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzi-
midazol-1-yl]-propionic acid ethyl ester
##STR00060##
[0595] To a solution of
3-[2-amino-4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phen-
ylamino]-propionic acid ethyl ester (250 mg, 0.645 mmol) in dry NMP
(10 mL) at room temperature under an inert atmosphere of nitrogen
was added approx. 200 mg of molecular sieve 4 .ANG. followed by
acetaldehyde (93 uL, 1.29 mmol). The mixture was stirred for 16 hrs
at 50.degree. C. The reaction was quenched by the addition of water
(100 mL) followed by extraction with diethyl ether (3.times.100
mL). The combined organic phases were washed with brine
(4.times.200 mL), dried (MgSO.sub.4), filtered, and evaporated in
vacuo. The resulting oil was purified by preparative HPLC, dried in
vacuo at 50.degree. C. affording 104 mg (38%) of the title compound
as brown oil. MS-ESI m/z 426; .sup.1H NMR (400 MHz, CDCl3) .delta.
0.88-1.06 (m, 6H), 1.11-1.23 (m, 7H), 1.24-1.28 (m) and 1.55-1.65
(m, 1H), 1.36-1.45 (m, 2H), 1.50 (t, 3H), 1.74-1.81 (m, 1H),
2.23-2.30 (m) and 3.12-3.20 (m, 1H), 2.81 (t, 2H), 2.96 (q, 2H),
3.22-3.35 (m, 1H), 3.32 (dd) and 3.62 (dd, 1H), 4.03-4.07 (m) and
4.63-4.67 (m, 1H), 4.13 (q, 2H), 4.45 (dt, 2H), 7.32-7.46 (m, 2H),
7.84 (d, 1H).
Example 3
3-[2-Ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzi-
midazol-1-yl]-propionic acid
##STR00061##
[0597] To a solution of
3-[2-ethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benz-
imidazol-1-yl]-propionic acid ethyl ester (104 mg, 0.244 mmol) in
96% ethanol (5 mL) at room temperature under an inert atmosphere of
nitrogen was added 1N NaOH (aq) (0.3 mL, 0.3 mmol). The mixture was
stirred for 2 hrs at room temperature. The reaction was quenched by
the addition of water (5 mL) and acidified to pH 2 with 1N HCl
followed by extraction with diethyl ether (2.times.10 mL). The
combined organic phases were washed with water (2.times.10 mL),
brine (10 mL), dried (MgSO.sub.4), filtered, and evaporated in
vacuo affording 11 mg (11%) of the title compound as yellow oil.
MS-ESI m/z 398; .sup.1H NMR (400 MHz, CDCl3) .delta. 0.83-1.06 (m,
6H), 1.12-1.22 (m, 7H), 1.24-1.28 (m) and 1.46-1.54 (m, 1H),
1.30-1.39 (m, 2H), 1.33 (t, 3H), 1.63-1.74 (m, 1H), 2.22-2.32 (m)
and 3.15-3.27 (m, 1H), 2.26 (t, 2H), 2.85 (t, 2H), 3.51 (q, 2H),
7.25-7.35 (m, 2H), 7.56 (d) and 7.74 (d, 1H).
Example 4
General Procedure (C)
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzimidaz-
ol-2-yl]-cyclopropanecarboxylic acid ethyl ester
##STR00062##
[0599] To a solution of
(3,4-diaminophenyl)-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-methano-
ne (500 mg, 1.74 mmol) in dry NMP (25 mL) at room temperature under
an inert atmosphere of nitrogen was added approx. 500 mg of
molecular sieve 4 .ANG. followed by ethyl
2-formyl-1-cyclopropanecarboxylate (0.51 mL, 3.86 mmol). The
mixture was stirred for 16 hrs at 50.degree. C. The reaction was
quenched by the addition of water (100 mL) followed by extraction
with diethyl ether (3.times.100 mL). The combined organic phases
were washed with water (3.times.100 mL), brine (100 mL), dried
(MgSO.sub.4), filtered, and evaporated in vacuo. The resulting oil
was purified by preparative HPLC, dried in vacuo at 50.degree. C.
affording 60 mg (8%) of the title compound as a solid. MS-ESI m/z
410; .sup.1H NMR (400 MHz, CDCl3) .delta. 0.88-1.06 (m, 6H),
1.07-1.20 (m, 4H), 1.25 (t, 3H), 1.27-1.34 (m) and 1.49-1.66 (m,
3H), 1.36-1.48 (m, 2H), 1.72-1.84 (m, 2H), 2.36-2.48 (m, 1H),
2.66-2.76 (m, 1H), 3.18-3.27 (m, 1H), 3.30 (d) and 3.65 (d, 1H),
4.00-4.06 (m) and 4.57-4.65 (m, 1H), 4.14 (q, 2H), 7.18-7.30 (m,
2H), 7.57 (d, 1H), 10.37 (br s, 1H).
Example 5
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzimidaz-
ol-2-yl]-cyclopropanecarboxylic acid
##STR00063##
[0601] To a solution of
2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzimida-
zol-2-yl]-cyclopropanecarboxylic acid ethyl ester (60 mg, 0.147
mmol) in 96% ethanol (3 mL) at room temperature under an inert
atmosphere of nitrogen was added 1N NaOH (aq) (0.36 mL, 0.36 mmol).
The mixture was stirred for 16 hrs at 50.degree. C. The reaction
was quenched by the addition of water (3 mL) and acidified to pH 2
with 1N HCl followed by extraction with diethyl ether (2.times.5
mL). The combined organic phases were washed with water (2.times.5
mL), brine (5 mL), dried (MgSO.sub.4), filtered, and evaporated in
vacuo affording 49 mg (88%) of the title compound as a solid.
MS-ESI m/z 382; .sup.1H NMR (400 MHz, CDCl3) .delta. 0.87-1.06 (m,
6H), 1.08-1.20 (m, 4H), 1.30-1.38 (m, 1H), 1.39-1.45 (m) and
1.48-1.64 (m, 3H), 1.70-1.90 (m, 2H), 1.91-2.01 (m, 1H), 2.18-2.30
(m) and 2.43-2.61 (m) and 2.85-3.02 (m, 2H), 3.15 (t) and 3.66 (t,
1H), 3.20-3.34 (m, 1H), 3.88-4.01 (m) and 4.54-4.65 (m, 1H),
7.39-7.50 (m, 1H), 7.69-7.85 (m, 2H).
[0602] The following compounds were synthesised employing a similar
method to the ones described in Examples 2, 3, 4 and 5 above:
TABLE-US-00005 MS-ESI Ex. Structure MW IUPAC Name m/z 5-1
##STR00064## 411.54 3-[2-Methyl-5-(1,3,3-trimethyl-
6-aza-bicyclo[3.2.1]octane-6- carbonyl)-benzimidazol-1-yl]-
propionic acid ethyl ester 412 5-2 ##STR00065## 437.58
2-[1-Ethyl-5-(1,3,3-trimethyl- 6-aza-bicyclo-[3.2.1]octane-6-
carbonyl)-1H-benzimidazol-2- yl]-cyclopropanecarboxylic acid ethyl
ester 438 5-3 ##STR00066## 383.49 3-[2-Methyl-5-(1,3,3-trimethyl-
6-aza-bicyclo-[3.2.1]octane-6- carbonyl)-benzimidazol-1-yl]-
propionic acid 384 5-4 ##STR00067## 409.53
2-[1-Ethyl-5-(1,3,3-trimethyl- 6-aza-bicyclo-[3.2.1]octane-6-
carbonyl)-1H-benzimidazol-2- yl]-cyclopropanecarboxylic acid
410
Example 6
General Procedure (D)
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-p-
ropionic acid ethyl ester
##STR00068##
[0604] To a solution of
(1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(250 mg, 0.84 mmol) in dry DMF (5 mL) at room temperature under an
inert atmosphere of nitrogen was added sodium hydride (30 mg, 1.26
mmol, 60% dispersion in oil), and after stirring for 30 min ethyl
bromopropionate (168 mg, 0.93 mmol) was added, and the reaction
mixture was stirred for 16 h at 60.degree. C. The reaction was
quenched by the addition of water (20 mL) followed by extraction
with DCM (3.times.100 mL). The combined organic phases were dried
(MgSO.sub.4), filtered and evaporated in vacuo. The resulting solid
was purified by silica gel chromatography using a mixture of ethyl
acetate and heptane (1:1) as eluent. Pure fractions were collected,
the solvent evaporated in vacuo and dried in vacuo at 50.degree. C.
affording 125 mg (37%) of the title compound as a solid. MS-ESI m/z
397; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.95 (d, 3H), 1.03
(d, 3H), 1.13-1.22 (m, 7H), 1.25-1.43 (m, 2H), 1.45 (s, 1H),
1.62-1.68 (m, 1H), 1.76-1.80 (m, 1H), 2.29-2.33 (m, 1H), 2.82 (t,
2H), 3.28-3.35 (m) and 3.63 (d), 1H), 4.12-4.14 and 4.64-4.66 (m,
1H), 4.11 (q, 2H), 4.47 (t, 2H), 6.52 (d, 1H), 7.18 (d, 1H),
7.32-7.39 (m, 2H), 7.74 (d, 1H).
Example 7
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-p-
ropionic acid
##STR00069##
[0606] To a solution of
3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid ethyl ester (80 mg, 0.2 mmol) in ethanol (2 mL) was
added 1N aqueous sodium hydroxide solution (2 mL), and the
resulting solution stirred for 2 h. The solution was acidified with
1N hydrochloric acid solution before the organic volatiles were
removed in vacuo, and the aqueous residues were extracted with DCM
(3.times.5 mL). The combined organic phases were dried
(MgSO.sub.4), filtered, and evaporated in vacuo. The resulting
solid was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 55 mg (74%) of the title compound as a
solid. MS-ESI m/z 369; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
0.94 (d, 3H), 1.04 (d, 3H), 1.13-1.17 (m, 4H), 1.28-1.38 (m, 2H),
1.43-1.45 (m, 1H), 1.60-1.63 (m, 1H), 1.75-1.79 (m, 1H), 2.24-2.32
and 3.25-3.26 (m, 1H), 2.74 (t, 2H), 3.27-3.35 (m) and 3.62-3.65
(m), 1H), 4.08-4.10 and 4.62-4.63 (m, 1H), 4.39 (t, 2H), 6.47-6.48
(m, 1H), 7.17-7.23 (m, 3H), 7.70 (d, 1H).
[0607] The following compounds were synthesised employing a similar
method to the ones described in examples 6 and 7 above:
TABLE-US-00006 MS-ESI Ex. Structure MW IUPAC Name m/z 7-1
##STR00070## 410.56 [5-(1,3,3-Trimethyl-6-aza-bicyclo-
[3.2.1]octane-6-carbonyl)-indol-1- yl]-acetic acid tert-butyl ester
411 7-2 ##STR00071## 354.45 [5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-yl]-acetic acid 355 7-3
##STR00072## 437.58 1-Morpholin-4-yl-3-[5-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-yl]-propan-1-one 438 7-4
##STR00073## 423.56 1-Morpholin-4-yl-2-[5-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-yl]-ethanone 424 7-5
##STR00074## 424.58 2,2-Dimethyl-3-[5-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-yl]-propionic acid ethyl
ester 425 7-6 ##STR00075## 396.53 2,2-Dimethyl-3-[5-(1,3,3-
trimethyl-6-aza-bicyclo[3.2.1]- octane-6-carbonyl)-indol-1-yl]-
propionic acid 397 7-7 ##STR00076## 396.53
2-Methyl-3-[5-(1,3,3-trimethyl-6- aza-bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-yl]-propionic acid methyl ester 397 7-8
##STR00077## 396.53 3-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-yl]-butyric acid methyl
ester 397 7-9 ##STR00078## 382.50 3-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-yl]-butyric acid 383 7-10
##STR00079## 382.50 2-Methyl-3-[5-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]octane-6- carbonyl)-indol-1-yl]-propionic acid
383 7-11 ##STR00080## 430.55 3-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-ylmethyl]-benzoic acid
431 7-12 ##STR00081## 444.57 4-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- indol-1-ylmethyl]-benzoic acid
methyl ester 445 7-13 ##STR00082## 430.55
4-[5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-carbonyl)-
indol-1-ylmethyl]-benzoic acid 431 7-14 ##STR00083## 394.51
3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]-
undecane-4-carbonyl)-indol-1-yl]- propionic acid ethyl ester 395
7-15 ##STR00084## 366.46 3-[5-(4-Aza-tricyclo[4.3.1.1*3,8*]-
undecane-4-carbonyl)-indol-1-yl]- propionic acid 367
Example 8
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-carb-
oxylic acid ethyl ester
##STR00085##
[0609] To a solution of 1H-Indole-2,5-dicarboxylic acid 2-ethyl
ester (890 mg, 3.8 mmol) in dry DMF (10 mL) at room temperature
under an inert atmosphere of nitrogen was added HOBt (570 mg, 4.2
mmol) and EDAC (951 mg, 4.9 mmol), and the resulting solution was
stirred for 30 min. 1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane
hydrochloride (796 mg, 4.2 mmol) was added to the solution followed
by DIPEA (1.98 mL, 11.4 mmol), and the reaction mixture was stirred
for 16 h at room temperature. The reaction was quenched by the
addition of water (20 mL) followed by extraction with DCM
(3.times.50 mL). The combined organic phases were dried
(MgSO.sub.4), filtered, and evaporated in vacuo. The resulting
solid was purified by silica gel chromatography using a mixture of
ethyl acetate and heptane (1:2) as eluent. Pure fractions were
collected, the solvent evaporated in vacuo and dried in vacuo at
50.degree. C. affording 800 mg (57%) of the title compound as a
solid. MS-ESI m/z 369; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.94 (d, 3H), 1.04 (d, 3H), 1.14-1.19 (m, 4H), 1.24-1.29 (m, 2H),
1.39-1.45 (m, 4H), 1.58-1.63 (m, 1H), 1.76-1.79 (m, 1H), 3.25-3.30
(m, 1H), 3.35 (d) and 3.65 (d, 1H), 4.06-4.09 (m) and 4.64-4.67 (m,
1H), 4.42 (q, 2H), 7.27 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (d, 1H),
9.05 (s, 1H).
Example 9
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-carb-
oxylic acid
##STR00086##
[0611] To a solution of
5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-car-
boxylic acid ethyl ester (500 mg, 1.35 mmol) in ethanol (10 mL) was
added 1N aqueous sodium hydroxide solution (10 mL), and the
resulting solution stirred for 16 h. The solution was acidified
with 1N hydrochloric acid solution before the organic volatiles
were removed in vacuo and the aqueous residues were extracted with
DCM (3.times.5 mL). The combined organic phases were dried
(MgSO.sub.4), filtered and evaporated in vacuo. The resulting solid
was dried in vacuo at 50.degree. C. affording 460 mg (100%) of the
title compound as a solid. MS-ESI m/z 341; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.88-0.99 (m, 6H), 1.07 (d, 3H), 1.16-1.19
(m, 1H), 1.27-1.50 (m, 4H), 1.74-1.77 (m, 1H), 3.10-3.19 (m, 1H),
3.40-3.48 (m, 1H), 3.99-4.07 (m) and 4.38-4.40 (m, 1H), 7.16 (s,
1H), 7.32-7.37 (m, 1H), 7.42-7.48 (m, 1H), 7.77 (d, 1H), 11.93 (s,
1H), 13.04 (s, 1H).
Example 10
[1-(2-Methanesulfonylmethoxy-ethyl)-1H-benzoimidazol-5-yl]-(octahydro-quin-
olin-1-yl)-methanone
##STR00087##
[0612] Step-A
4-(2-Hydroxyethylamino)-3-nitro-benzoic acid methyl ester
[0613] 4-Fluoro-3-nitro-benzoic acid methyl ester (3 g, 15.64 mmol)
was dissolved in DMF (20 ml) and DIPEA (5.8 g, 18.07 mmol) was
added. 2-Aminoethanol (1.1 g, 18.07 mmol) was then added slowly by
maintaining the temperature<20.degree. C. Stirring continued at
ambient temperature for 1 h. After checking the completion of
reaction by TLC, the reaction mixture was added onto the ice cold
water. The yellow solid which separated out was filtered, washed
with cold water and finally washed with hexane affording 3.3 g
(92%) of 4-(2-hydroxyethylamino)-3-nitro-benzoic acid methyl ester.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.5 (q, 2H), 3.7 (q, 2H),
3.9 (s, 3H), 5.1 (t, 1H), 7.2 (d, 1H), 8.0 (d, 1H), 8.6 (s,
1H).
Step-B
3-Amino-4-(2-hydroxy-ethylamino)-benzoic acid methyl ester
[0614] To a solution of 4-(2-hydroxy-ethylamino)-3-nitro-benzoic
acid methyl ester (3.0 g, 12.4 mmol) in methanol was added 10% Pd/C
(800 mg). The mixture was hydrogenated at 1 atmospheric pressure
for 2 h. The catalyst was filtered off and the methanol evaporated
to give 2.6 g (99%) of 3-amino-4-(2-hydroxyethylamino)-benzoic acid
methyl ester.
Step-C
1-(2-Hydroxyethyl)-1H-benzoimidazole-5-carboxylic acid methyl
ester
[0615] 3-Amino-4-(2-hydroxy-ethylamino)-benzoic acid methyl ester
(2.6 g, 12.0 mmol) was dissolved in formic acid (20 mL). The
solution was heated at 45.degree. C. for 1 h. After checking the
completion of reaction by TLC, formic acid was evaporated at
<40.degree. C. under reduced pressure and the resulting solid
was recrystallized from EtOAc. The above solid was dissolved in 3N
HCl, stirred at ambient temperature for 1 h, basified back with
saturated sodium bicarbonate solution and extracted with EtOAc. The
organic layer was evaporated to give 2.1 g (78%) of
1-(2-hydroxy-ethyl)-1H-benzoimidazole-5-carboxylic acid methyl
ester. MS-ESI m/z 221 (M+1): .sup.1H NMR (300 MHz, DMSO-d6) .delta.
3.7 (q, 2H), 3.9 (s, 3H), 4.3 (t, 3H), 5.0 (t, 1H), 7.7 (d, 1H),
7.9 (dd, 1H), 8.25 (s, 1H), 8.35 (s, 1H)
Step-D
1-(2-Methylsulfanylmethoxy-ethyl)-1H-benzoimidazole-5-carboxylic
acid methyl ester
[0616] A solution of
1-(2-hydroxyethyl)-1H-benzimidazole-5-carboxylic acid methyl ester
(0.5 g. 2.27 mmol) in a mixture of dry THF:DME (25 mL:15 mL) was
cooled to 5.degree. C. NaH (0.081 g, 3.4 mmol) was added and
stirred for 30 min at the same temperature. A mixture of
chloromethyl methyl sulphide (0.285 g, 2.95 mmol) and NaI (0.408 g,
2.95 mmol) was then added slowly followed by TBAl (0.087 g, 0.22
mmol). The reaction was allowed to stir for overnight at ambient
temperature. It was then quenched with saturated ammonium chloride
solution and extracted with EtOAc. The organic layer was evaporated
to give 0.53 g (83%) of
1-(2-methylsulfanylmethoxyethyl)-1H-benzimidazole-5-carboxylic acid
methyl ester. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.9 (s,
3H), 3.9 (t, 2H), 3.95 (s, 3H), 4.4 (t, 2H), 4.6 (s, 2H), 7.45 (d,
1H), 8.05 (m, 2H), 8.5 (d, 1H)
Step-E
1-(2-Methanesulfonylmethoxy-ethyl)-1H-benzoimidazole-5-carboxylic
acid methyl ester
[0617] A solution of
1-(2-methylsulfanylmethoxyethyl)-1H-benzimidazole-5-carboxylic acid
methyl ester (3.0 g. 10.7 mmoles) in methanol (30 mL) was cooled to
0.degree. C. and to this was added a solution of oxone (4.88 g,
7.94 mmoles) in water. The solution was stirred at the ambient
temperature for 12 h. It was quenched with 5% sodium bicarbonate
solution and extracted with EtOAc. Removal of solvent gave 2.0 g
(60%) of
1-(2-methane-sulfonylmethoxy-ethyl)-1H-benzoimidazole-5-carboxylic
acid methyl ester. MS-ESI m/z 313 (M+1): .sup.1H NMR (300 MHz,
DMSO-d6) .delta. 2.9 (s, 3H), 4.0 (s, 3H), 4.25 (t, 2H), 4.65 (t,
2H), 4.75 (s, 2H), 7.85 (d, 2H), 8.0 (dd, 1H), 8.35 (s, 1H), 8.5
(s, 1H)
Step-F
1-(2-Methanesulfonylmethoxy-ethyl)-1H-benzoimidazole-5-carboxylic
acid
[0618]
1-(2-Methanesulfonylmethoxyethyl)-1-H-benzimidazole-5-carboxylic
acid methyl ester (1.0 g, 3.2 mmoles) was dissolved in THF (5 mL).
A solution of LiOH (0.38 g, 16 mmol) in water was added and the
mixture stirred vigorously for 1 h. The reaction was acidified with
2N HCl to pH 2 at 5-10.degree. C. It was then filtered to give 0.8
g (84%) of
1-(2-methanesulfonylmethoxy-ethyl)-1H-benzoimidazole-5-carboxylic
acid. .sup.1H NMR (300 MHz, DMSO-d6) .delta. 2.9 (s, 3H), 4.2 (t,
2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.75 (d, 1H), 7.9 (dd, 1H), 8.25
(d, 1H), 8.35 (s, 1H), 12.7 (s, 1H)
Step-G
[1-(2-Methanesulfonylmethoxy-ethyl)-1H-benzoimidazol-5-yl]-(octahydro-quin-
olin-1-yl)-methanone
[0619] To a solution of
1-(2-methanesulfonylmethoxyethyl)-1H-benzimidazole-5-carboxylic
acid (0.5 g, 1.677 mmol) in DMF (5 mL) was added decahydroquinoline
(0.257 g, 1.845 mmol) followed by HOBt (0.25 g, 1.845 mmol) and
DIPEA (0.65 g, 5 mmol). The reaction mixture was cooled to
0.degree. C. and EDCl.HCl (0.354 g, 1.845 mmol) was added. It was
gradually raised to ambient temperature and stirring continued for
12 h. The solvent was then evaporated, the residue diluted with
water (5 mL) and extracted with CH.sub.2Cl.sub.2 (3.times.25 mL).
The combined organic phases were washed with brine solution, dried
(Na.sub.2SO.sub.4) and the solvent evaporated affording the crude
amide which was purified by preparative HPLC to give 0.3 g (43%) of
[1-(2-methanesulfonylmethoxy-ethyl)-1H-benzimidazol-5-yl]-(octahydroquino-
lin-1-yl)-methanone. MS-ESI m/z 420 (M+1): .sup.1H NMR (300 MHz,
DMSO-d6) .delta. 1.1-1.9 (br, 13H), 2.8 (s, 3H), 3.0-3.3 (m, 2H),
4.15 (t, 2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.3 (m, 1H), 7.6 (m, 1H),
7.7 (d, 1H), 8.3 (s, 1H)
[0620] The following compounds were synthesised employing a similar
method to the ones described in example 10 above:
TABLE-US-00007 MS-ESI Ex. Structure MW IUPAC Name m/z 10-1
##STR00088## 407.49 (3-Hydroxy-8-aza-bicyclo-
[3.2.1]oct-8-yl)-[1-(2-methane- sulfonylmethoxy-ethyl)-1H-
benzoimidazol-5-yl]-methanone 408 10-2 ##STR00089## 447.56
trans-1-(2-Methanesulfonyl- methoxy-ethyl)-1H-benzo-
imidazole-5-carboxylic acid (5- hydroxy-adamantan-2-yl)- amide 448
10-3 ##STR00090## 447.56 Cis-1-(2-Methanesulfonyl-
methoxy-ethyl)-1H-benzo- imidazole-5-carboxylic acid (5-
hydroxy-adamantan-2-yl)- amide 448 10-4 ##STR00091## 407.49
(3-Hydroxy-8-aza-bicyclo- [3.2.1]oct-8-yl)-[1-(2-methane-
sulfonylmethoxy-ethyl)-1H- benzoimidazol-5-yl]-methanone 408
Example 11
1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide
##STR00092##
[0621] Step A
2-(2-Methylsulfanylethyl)isoindol-1,3-dione
[0622] To a solution of N-bromoethylphthalimide (1 g, 3.953 mmol)
in methanol (25 mL), was added NaSMe (0.415 g, 5.929 mmol) under
N.sub.2 atmosphere at 0.degree. C. The reaction mixture was allowed
to stir at ambient temperature for 2 h. The reaction mass was
concentrated, diluted with water and extracted with EtOAc
(3.times.25 mL). The organic layer was washed with brine solution
and dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give
2-(2-Methylsulfanylethyl)isoindol-1,3-dione (0.88 g, 80%). MS-ESI
m/z 222 (M+1); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.7 (m,
2H), 7.9 (m, 2H), 3.9 (t, 1H), 2.8 (t, 2H), 2.2 (s, 3H).
Step-B
2-(2-Methanesulfonyl-ethyl)-isoindole-1,3-dione
[0623] To a solution of
2-(2-methylsulfanylethyl)-isoindole-1,3-dione (2.5 g, 11.30 mmol)
in acetic acid (10 mL) was added 30% hydrogen peroxide (6 mL) at
0.degree. C. The reaction mixture was brought to room temp and
stirred for 2 h. Excess hydrogen peroxide in the reaction mixture
was quenched with a saturated solution of sodium sulphite, and the
resulting solution extracted with CHCl.sub.3. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to
give 2-(2-Methanesulfonyl-ethyl)-isoindole-1,3-dione (2.3 g, 83%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.9 (m, 2H), 7.8 (m, 2H),
4.2 (t, 1H), 3.4 (t, 1H), 3.1 (s, 3H).
Step-C
2-Methanesulfonyl-ethylamine
[0624] Hydrazine hydrate (15 mL) was added to a solution of
2-(2-methanesulfonylethyl)-isoindole-1,3-dione (3.123 g, 12.344
mmol) in a mixture of CHCl.sub.3-ethanol (:1) at 0.degree. C. It
was then stirred overnight at room temperature. It was filtered and
the filtrate concentrated to give 2-Methanesulfonylethylamine (1.2
g, 80%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.05 (t, 2H),
3.15 (t, 2H), 3.0 (s, 3H).
Step-D
4-(2-Methanesulfonyl-ethylamino)-3-nitro-benzoic acid methyl
ester
[0625] To a solution of 2-methanesulfonylethylamine (1.3 g, 10.56
mmol) and DIPEA (3.5 mL, 31.69 mmol) in DMF (15 mL) was added
4-fluoro-3-nitro-benzoic acid methyl ester (1.2 g, 15.84 mmol) in
portions. The reaction mixture was allowed to stir for 15 h at room
temperature. It was then diluted with water and extracted with
EtOAc. The organic layers were washed with water, brine and
concentrated to give
4-(2-methanesulfonyl-ethylamino)-3-nitrobenzoic acid methyl ester
(83%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.9 (d, 1H), 8.6
(t, 1H), 8.2 (d, 1H), 6.9 (d, 1H), 4.0 (q, 2H), 3.9 (s, 3H), 3.4
(t, 2H), 3.0 (s, 3H).
Step-E
1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid
methyl ester
[0626] 4-(2-Methanesulfonyl-ethylamino)-3-nitro-benzoic acid methyl
ester (1.63 g, 5.40 mmol) was dissolved in methanol, and 10% Pd/C
(150 mg) was added to it under N.sub.2 atmosphere. The reaction
mixture was then hydrogenated at 1 atmospheric pressure at room
temp for 2 h. It was filtered through celite and the filtrate
concentrated to yield the desired product. The crude material (1.32
g, 4.85 mmol) was taken in formic acid (10 mL) and allowed to stir
at 50.degree. C. for 4 h. The reaction mass was concentrated,
diluted with water and extracted with EtOAc. The organic layers
were washed with saturated NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4 and concentrated to give
1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid
methyl ester (77%). .sup.1H NMR (300 MHz, DMSO-d.sub.6).
[0627] .delta. 8.45 (s, 1H), 8.3 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H),
4.75 (t, 2H), 3.9 (s, 3H), 3.8 (t, 2H), 3.0 (s, 3H).
Step F
1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid
[0628] To a solution of
1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid
methyl ester (0.2 g, 7.09 mmol) in methanol was added LiOH (50 mg)
followed by water (1 mL). The reaction mixture was allowed to stir
at room temp for 2 h. it was then concentrated to remove methanol
and the aqueous layer was acidified with citric acid. The
precipitated product was filtered to give
1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid
(90%). MS-ESI m/z 269 (M+1); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.6 (br, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.8
(d, 1H), 4.8 (t, 2H), 3.8 (t, 2H), 3.0 (s, 3H).
Step G
1-(2-Methanesulfonyl-ethyl)-1H-benzoimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide
[0629] To a solution of
1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid (0.2
g, 0.74 mmol) in DMF (5 mL) was added HOBt (0.15 g, 0.89 mmol),
DIPEA (0.4 mL, 2.23 mmol), 4-aminoadamantan-1-ol (0.15 g 0.89 mmol)
and EDCl (0.21 g, 1.11 mmol) successively under N.sub.2 atmosphere.
The reaction mixture was allowed to stir over night at room
temperature. It was diluted with water and extracted with
CHCl.sub.3. The organic layer was washed with saturated NaHCO.sub.3
solution, brine and dried over anhydrous Na.sub.2SO.sub.4.
Concentration of the organic layer gave
1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid
(5-hydroxyadamantan-2-yl)-amide (0.05 g). MS-ESI m/z 418 (M+1);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.2 (s, 1H), 8.1 (s, 1H),
7.9 (d, 1H), 7.5 (d, 1H), 6.4 (d, 1H), 4.8 (t, 2H), 4.2 (m, 1H),
3.6 (t, 2H), 2.7 (s, 3H), 2.4 (s, 2H), 2.3 (m, 1H), 1.8 (m,
1H).
[0630] The following compounds were synthesised employing a similar
method to the ones described in example 11 above:
TABLE-US-00008 MS-ESI Ex. Structure MW IUPAC Name m/z 11-1
##STR00093## 377.47 (3-Hydroxy-8-aza-
bicyclo[3.2.1]oct-8-yl)-[1-(2- methanesulfonyl-ethyl)-1H-
benzoimidazol-5-yl]- methanone 378 11-2 ##STR00094## 377.47
(3-Hydroxy-8-aza- bicyclo[3.2.1]oct-8-yl)-[1-(2-
methanesulfonyl-ethyl)-1H- benzoimidazol-5-yl]- methanone 378 11-3
##STR00095## 389.52 [1-(2-Methanesulfonyl-ethyl)-
1H-benzoimidazol-5-yl]- (octahydro-quinolin-1-yl)- methanone 390
11-4 ##STR00096## 417.53 1-(2-Methanesulfonyl-ethyl)-
1H-benzoimidazole-5- carboxylic acid (5-hydroxy-
adamantan-2-yl)-amide 418
Example 12
(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{1-[2-(1H-tetrazol-5-yl)-ethyl]-1-
H-benzoimidazol-5-yl}-methanone
##STR00097##
[0631] Step-A
4-(2-Cyano-ethylamino)-3-nitro-benzoic acid methyl ester
[0632] To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester
(4.95 g, 24.8 mmol) in DMF (25 ml) was added 3-aminopropionitrile
fumarate (3.18 g, 12.4 mmol) and DIPEA (15 ml, 84.3 mmol). The
mixture was stirred at room temperature for 2 h. The solvent was
evaporated under vacuum and the residue diluted with water (50 mL).
It was extracted with EtOAc (3.times.100 mL) and the organic phase
washed with brine solution and dried (Na.sub.2SO.sub.4). Removal of
solvent gave 4-(2-cyanoethylamino)-3-nitro-benzoic acid methyl
ester (6.19 g, 98.5%). MS-ESI m/z 250 (M+1); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 2.8 (t, 2H), 3.8 (m, 2H), 6.9 (d, 1H), 8.2 (m,
1H), 8.5 (t, 1H), 8.9 (s, 1H)
Step-B
3-Amino-4-(2-cyanoethylamino)-benzoic acid methyl ester
[0633] To a solution of ammonium chloride (21.7 g, 406.3 mmol) in
water (200 mL) was added 4-(2-cyanoethylamino)-3-nitro-benzoic acid
methyl ester (6.1 g, 24.5 mmol) followed by zinc powder (42.8 g,
655.9 mmol). The mixture was heated to 60.degree. C. for 3 h. It
was filtered hot and washed with EtOAc. The filtrate was further
extracted with EtOAc and the combined organic phase washed with
brine solution. The organic layer was evaporated to give 4.1 g
(75%) of 3-amino-4-(2-cyano-ethylamino)-benzoic acid methyl ester.
MS-ESI m/z 220 (M+1); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.7
(t, 2H), 3.6 (m, 2H), 3.8 (s, 3H), 4.3 (bs, 1H), 6.6 (d, 1H), 7.45
(d, 1H), 7.6 (d, 1H)
Step-C
1-(2-Cyano-ethyl)-1H-benzoimidazole-5-carboxylic acid methyl
ester
[0634] To 3-amino-4-(2-cyano-ethylamino)-benzoic acid methyl ester
(4.0 g) was added formic acid (25 ml) and the mixture heated to
50.degree. C. for 3 h. It was then concentrated and the residue
recrystallised from EtOAc to afford 4.0 g (95%) of
1-(2-cyanoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester.
MS-ESI m/z 230 (M+1); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
2.95 (t, 2H), 4.0 (s, 3H), 4.55 (t, 2H), 7.4 (d, 1H), 8.1 (m, 1H),
8.15 (s, 1H), 8.55 (s, 1H)
Step-D
1-(2-Cyanoethyl)-1H-benzoimidazole-5-carboxylic acid
[0635] To a solution of
1-(2-cyanoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester
(4.0 g, 17.4 mmol) in THF (30 mL) was added LiOH (1.67 g, 69.79
mmol) in water (8 mL) followed by MeOH (2 mL). Stirring continued
at the ambient temperature for 1 h. It was then concentrated and
acidified with 2N HCl. The solids formed were filtered and dried
which afforded 1-(2-cyanoethyl)-1H-benzoimidazole-5-carboxylic acid
(3.5 g, 95%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.1 (t,
2H), 4.6 (t, 2H), 7.8 (d, 1H), 7.9 (dd, 1H), 8.25 (d, 1H), 8.42 (s,
1H)
Step-E
3-[5-(3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-
-propionitrile
[0636] To a solution of
1-(2-cyanoethyl)-1H-benzoimidazole-5-carboxylic acid (0.25 g, 1.16
mmol) in DMF (2.5 mL) was added with stirring HOBt (0.17 g, 1.27
mmol) followed by exo-nortropinol hydrochloride (0.21 g, 1.27
mmol), DIPEA (0.45 g, 3.48 mmol). EDCl.HCl was then added and it
was stirred at room temperature for 12 h. The solvent was then
evaporated and to the residue diluted with water (5 mL) and
extracted with CH.sub.2Cl.sub.2. The organic phase was washed with
brine solution, dried (Na.sub.2SO.sub.4) and the solvent
evaporated. The residue was purified by preparative HPLC which
afforded 0.26 g (67%) of
3-[5-(3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl-
]-propionitrile. MS-ESI m/z 325 (M+1).
Step-F
3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-
-benzoimidazol-5-yl}-methanone
[0637] To a solution of
3-[5-(3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl-
]-propionitrile (250 mg, 0.7 mmol) in DMF (5 mL) was added sodium
azide (184 mg, 2.83 mmol) and ammonium chloride (152 mg, 2.83 mmol)
and heated to 100.degree. C. for 12 h. The solvent was evaporated
completely; methanol (20 mL) was added and filtered. The filtrate
was concentrated and the residue purified by preparative HPLC to
give 36 mg (13%) of
3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{1-[2-(1H-tetrazol-5-yl)-ethyl]-1-
H-benzoimidazol-5-yl}-methanone. MS-ESI m/z 368 (M+1); .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.3-2.0 (m, 8H), 3.15 (s, 1H), 3.5
(t, 2H), 3.9-4.0 (m, 2H), 4.6 (br, 1H), 4.75 (t, 2H), 7.4 (dd, 1H),
7.6-7.7 (m, 2H), 8.25 (s, 1H).
[0638] The following compounds were synthesised employing a similar
method to the ones described in example 11 above:
TABLE-US-00009 MS-ESI Ex. Structure MW IUPAC Name m/z 12-1
##STR00098## 379.41 (Octahydro-quinolin-1-yl)-{1-
[2-(1H-tetrazol-5-yl)-ethyl]-1H- benzoimidazol-5-yl}- methanone 380
12-2 ##STR00099## 407.48 Trans-1-[2-(1H-Tetrazol-5-yl)-
ethyl]-1H-benzoimidazole-5- carboxylic acid (5-hydroxy-
adamantan-2-yl)-amide 355 12-3 ##STR00100## 477.48
Cis-1-[2-(1H-Tetrazol-5-yl)- ethyl]-1H-benzoimidazole-5- carboxylic
acid (5-hydroxy- adamantan-2-yl)-amide 438
Example 13
3-Hydroxy-pyrrolidine-1-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide
##STR00101##
[0639] Step-A
4-Fluoro-3-nitro-benzoic acid methyl ester
[0640] To a solution of 4-fluoro-3-nitrobenzoic acid (16.0 g,
0.0864 mol) in dry DMF (100 mL) was added with stirring potassium
carbonate (59.0 g, 0.43 mol) followed by methyl iodide (24.5 g,
0.173 mol) and the mixture was stirred for 3 h at ambient
temperature. The reaction mixture was diluted with ice water (500
mL), extracted with EtOAc (3.times.100 mL) and the combined organic
phases were washed with water (3.times.100 mL) and saturated brine
solution (100 mL). The organic phase was dried (Na.sub.2SO.sub.4)
and the solvent evaporated affording 17.0 g (99%) of
4-fluoro-3-nitro-benzoic acid methyl ester.
Step-B
4-(2-Chloroethylamino)-3-nitro-benzoic acid methyl ester
[0641] To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester
(10.0 g, 0.0502 mol) in dry DMF (100 mL) was added with stirring
potassium carbonate (59.0 g, 0.43 mol) followed by
2-chloroethylamine hydrochloride (8.7 g, 0.075 mol) and the mixture
was stirred for 15 h at ambient temperature. The reaction mixture
was diluted with ice water (500 mL) and the solid precipitated was
filtered, washed with water and dried under vacuum to get a yellow
solid (12.7 g, 98%). MS-ESI m/z 259 (M+1).
Step-C
3-Amino-4-(2-chloroethylamino)-benzoic acid methyl ester
[0642] To a solution of 4-(2-chloroethylamino)-3-nitro-benzoic acid
methyl ester (12.7 g, 0.0492 mol) in methanol (500 mL) was added
10% Pd/C (1.3 g) under a N.sub.2 atmosphere. The reaction mixture
was hydrogenated in a Parr apparatus at 3 kg pressure for 2 h. The
catalyst was filtered over celite and the filtrate was concentrated
affording 11.0 g (98%) of 3-amino-4-(2-chloroethylamino)-benzoic
acid methyl ester as a solid.
Step-D
1-(2-Chloroethyl)-1H-benzimidazole-5-carboxylic acid methyl
ester
[0643] To 3-amino-4-(2-chloroethylamino)-benzoic acid methyl ester
(11.0 g, 0.0482 mol) was added HCO.sub.2H (30 mL) and heated at
100.degree. C. for 1 h. The reaction was cooled to ambient
temperature and diluted with ice water (100 mL). The pH of the
reaction mixture was adjusted to 7 with NaHCO.sub.3 and the solid
precipitated was filtered, washed with water and dried under vacuum
to get a pale green solid (9.9 g, 86%) of
1-(2-chloroethyl)-1H-benzimidazole-5-carboxylic acid methyl ester.
MS-ESI m/z 239 (M+1).
Step-E
1-(2-Azidoethyl)-1H-benzimidazole-5-carboxylic acid methyl
ester
[0644] To a solution of
1-(2-chloroethyl)-1H-benzimidazole-5-carboxylic acid methyl ester
(9.9 g, 0.0416 mol) in dry DMSO (90 mL) was added with stirring
NaN.sub.3 (5.4 g, 0.0832 mol) and the mixture was stirred for 15 h
at 75.degree. C. The reaction mixture was cooled to ambient
temperature and diluted with ice water (500 mL) and the solid
precipitated was filtered, washed with water and dried under vacuum
affording 9.3 g (91%) of
1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester as
a solid. MS-ESI m/z 246 (M+1); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 3.8 (t, 2H), 3.9 (s, 3H), 4.5 (t, 2H), 7.8 (d, 1H), 7.9
(dd, 1H), 8.25 (s, 1H), 8.4 (s, 1H).
Step-F
1-(2-Azido-ethyl)-1H-benzimidazole-5-carboxylic acid
[0645] To a solution of
1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester
(5.0 g, 0.0204 mol) in THF/water 1:1 (100 mL) was added with
stirring LiOH (0.73 g, 0.0306 mol) and the mixture was stirred for
5 h at ambient temperature. The solvent was evaporated and to the
residue was added ice water (100 mL). The pH of the reaction
mixture was adjusted to 5 with 1N HCl and the mixture extracted
with EtOAc (5.times.100 mL). The combined organic phases were
washed with saturated brine solution (100 mL), dried
(Na.sub.2SO.sub.4) and the solvent evaporated affording 4.2 g (89%)
of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid as an ash
coloured solid. MS-ESI m/z 232 (M+1); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 3.8 (t, 2H), 4.5 (t, 2H), 7.8 (d, 1H), 7.9
(d, 1H), 8.25 (s, 1H), 8.4 (s, 1H).
Step-G
[1-(2-Azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct--
8-yl)methanone
[0646] To a solution of
1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.82 g,
0.00357 mol) in dry DMF (8.0 mL) was added with stirring HOBt
(0.578 g, 0.00428 mol), DIPEA (1.9 mL, 0.0107 mol),
8-azabicyclo[3.2.1]octan-3-ol (0.5 g, 0.00393 mol) and the mixture
was cooled to 0.degree. C. To the resulting mixture was added EDCl
(0.82 g, 0.00428 mol) and stirred for 15 h at ambient temperature.
The reaction mixture was then diluted with ice water (100 mL),
extracted with EtOAc (3.times.50 mL) and the combined organic
phases were washed with water (3.times.50 mL) and saturated brine
solution (50 mL). The organic phase was dried (Na.sub.2SO.sub.4)
and the solvent evaporated affording (1.1 g, 98%) of
[1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3-
.2.1]oct-8-yl)methanone. MS-ESI m/z 341 (M+1).
Step-H
[1-(2-Amino-ethyl)-1H-benzoimidazol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2.1]o-
ct-8-yl)-methanone
[0647] To a solution of
[1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2.1]oc-
t-8-yl)methanone (1.1 g, 0.0035 mol) in methanol (15 mL) was added
10% Pd/C (0.17 g) and the mixture hydrogenated at 3 kg pressure for
1 h. The catalyst was filtered over celite and the filtrate was
concentrated to give
[1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2-
.1]oct-8-yl)methanone (0.87 g, 86%). MS-ESI m/z 315 (M+1).
Step-I
3-Hydroxypyrrolidine-1-carboxylic acid
{2-[5-(3-hydroxy-8-azabicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl-
]ethyl}amide
[0648] A) 3-Hydroxypyrrolidine-1-carbonyl chloride:
[0649] To a solution of pyrrolidin-3-ol (0.083 g, 0.955 mmol) in
dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) and cooled
0.degree. C. To the resulting mixture was added triphosgene (0.127
g, 0.429 mmol) and the mixture was stirred for 2 h at an ambient
temperature.
[0650] B) To a solution of
[1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2.1]oc-
t-8-yl)methanone (0.25 g, 0.79 mmol) in dry THF (5 mL) was added
DIPEA (0.3 mL, 1.91 mmol) at 0.degree. C. To this reaction mixture
was added compound A slowly and stirred for 3 days at an ambient
temperature. The solvent was evaporated and the residue purified by
preparative HPLC to afford 175 mg (54%) of
3-hydroxy-pyrrolidine-1-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide. MS-ESI m/z 428 (M+1); .sup.1H-NMR (300 MHz,
CD.sub.3OD) .delta. 1.5 (t, 1H), 1.9 (m, 6H), 2.1 (m, 3H), 3.2 (m,
2H), 3.5 (t, 2H), 4.2 (m, 2H), 4.4 (m, 1H), 4.5 (t, 2H), 4.8 (s,
1H), 7.45 (dd, 1H), 7.7 (d, 1H), 7.8 (s, 1H), 8.25 (s, 1H),
Example 14
4-Hydroxy-piperidine-1-carboxylic acid
{2-[5-(octahydro-quinoline-1-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide
##STR00102##
[0652] Steps A-F is similar to those used in example 13 above.
Step-G
[1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone
[0653] To a solution of
1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (1 g, 0.00433
mol) in dry DMF (7.0 mL) was added with stirring HOBt (0.876 g,
0.00649 mol), DIPEA (2.25 mL, 0.0129 mol), decahydroquinoline
(0.902 g, 0.00649 mol) at 0.degree. C. To the resulting mixture was
added EDCl (1.24 g, 0.00649 mol) and stirred for 15 h at an ambient
temperature. The reaction mixture was diluted with ice water (100
mL) and extracted with EtOAc (3.times.50 mL). The combined organic
phases were washed with water, dried (Na.sub.2SO.sub.4) and the
solvent evaporated to give
[1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)meth-
anone (1.5 g, 98%).
Step-H
[1-(2-Aminoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone
[0654] To a solution of
[1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone
(1.8 g, 0.0051 mol) in methanol (10 mL) was added 10% Pd/C (0.2 g).
The reaction mixture was hydrogenated at 3 kg pressure for 2 h. The
catalyst was filtered over celite and the filtrate was concentrated
to give
[1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone
(1.5 g, 90%).
Step-I
4-Hydroxypiperidine-1-carboxylic acid
{2-[5-(octahydroquinoline-1-carbonyl)benzimidazol-1-yl]ethyl}amide
[0655] A) 4-Hydroxypiperidine-1-carbonyl chloride:
[0656] To a solution of piperidin-4-ol (0.074 g, 0.73 mmol) in dry
THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0.degree. C. To
the resulting mixture was added triphosgene (0.076 g, 2.1 mmol) and
stirred for 2 h at ambient temperature.
[0657] B) To a solution of
[1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone
(0.2 g, 0.613 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91
mmol) at 0.degree. C. To this reaction mixture was added compound A
slowly and stirred for 2 h at ambient temperature. The solvent was
evaporated and the residue purified by preparative HPLC affording
cis and trans isomers of 4-hydroxypiperidine-1-carboxylic acid
{2-[5-(octahydroquinoline-1-carbonyl)-benzimidazol-1-yl]ethyl}amide.
[0658] Isomer I (12 mg): MS-ESI m/z 454 (M+1); .sup.1H-NMR (300
MHz, CD.sub.3OD) .delta. 1.30-1.80 (m, 13H), 2.0 (m, 3H), 2.9 (m,
2H), 3.2 (m, 2H), 3.55 (t, 2H), 3.7 (m, 3H), 4.5 (t, 2H), 7.35 (d,
1H), 7.7 (m, 2H), 8.25 (s, 1H). HPLC (VERYPOL.M): tr=7.73 min
(95%).
[0659] Isomer II (8 mg): MS-ESI m/z 454 (M+1); .sup.1H-NMR (300
MHz, CD.sub.3OD) .delta. 1.2 (m, 3H), 1.4 (m, 8H), 1.7 (m, 6H), 3.0
(m, 2H), 3.6 (t, 2H), 3.7 (m, 3H), 4.4 (t, 2H), 7.4 (dd, 1H), 7.65
(d, 1H), 7.7 (s, 1H), 8.3 (s, 1H). HPLC (VERYPOL.M): tr=7.86 min
(94%).
Example 15
1-{2-[(4-Hydroxy-piperidine-1-carbonyl)-amino]-ethyl}-1H-benzoimidazole-5--
carboxylic acid (5-hydroxy-adamantan-2-yl)-amide
##STR00103##
[0661] Steps A-F is similar to those used in example 14 above.
Step-G
1-(2-Azidoethyl)-1H-benzimidazole-5-carboxylic acid
(5-hydroxyadamantan-2-yl)-amide
[0662] To a solution of
1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.65 g, 0.0028
mol) in dry DMF (5.0 mL) was added with stirring HOBt (0.46 g,
0.0034 mol), DIPEA (2.5 mL, 0.014 mol), 4-aminoadamantan-1-ol
(0.685 g, 0.0034 mol) at 0.degree. C. To the resulting mixture was
added EDCl (0.65 g, 0.0034 mol) and stirred for 15 h at ambient
temperature. The reaction mixture was diluted with ice water (100
mL) and extracted with EtOAc (3.times.50 mL) and the combined
organic phases were washed with water, dried (Na.sub.2SO.sub.4) and
the solvent evaporated affording (1.0 g, 93.5%) of
1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid
(5-hydroxyadamantan-2-yl)-amide. MS-ESI m/z 381 (M+1).
Step-H
1-[(2-Aminoethyl)-1H-benzimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)]-amide
[0663] To a solution of
1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid
(5-hydroxyadamantan-2-yl)-amide (1.0 g, 0.00263 mol) in methanol
(20 mL) was added 10% Pd/C (200 mg). The reaction mixture was
hydrogenated at 3 kg pressure for 1 h. The catalyst was filtered
over celite and the filtrate was concentrated to give
1-(2-aminoethyl)-1H-benzimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide (0.7 g, 75%).
Step-I
1-{2-[(4-Hydroxypiperidine-1-carbonyl)-amino]ethyl}
H-benzoimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide
[0664] To a solution of
1-(2-aminoethyl)-1H-benzimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide (0.35 g, 0.988 mmol) in dry THF (5
mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0.degree. C. To this
reaction mixture was added 4-hydroxypiperidine-1-carbonyl chloride
slowly and stirred for 2 h at ambient temperature. The solvents
were evaporated and the residue purified by preparative HPLC cis
and trans isomers of
1-{2-[(4-hydroxypiperidine-1-carbonyl)-amino]-ethyl}-1H-benzimidazole-5-c-
arboxylic acid (5-hydroxyadamantan-2-yl)-amide.
[0665] Isomer I (0.008 g): MS-ESI m/z 482 (M+1); .sup.1H-NMR (300
MHz, CD.sub.3OD): .delta. 1.4 (m, 3H), 1.6 (d, 3H), 1.8 (m, 9H),
2.0 (d, 2H), 2.2 (s, 1H), 2.4 (s, 2H), 2.9 (m, 2H), 3.5-3.8 (m,
5H), 4.0 (s, 1H), 4.5 (t, 2H), 7.65 (d, 1H), 7.8 (d, 1H), 7.95 (d,
1H), 8.15 (s, 1H), 8.25 (s, 1H). HPLC (VERYPOL.M): tr=6.59 min
(95%).
[0666] Isomer II (0.022 g): MS-ESI m/z 482 (M+1); .sup.1H-NMR (300
MHz, CD.sub.3OD): .delta. 1.4 (m, 3H), 1.5 (d, 2H), 1.8 (m, 5H),
1.9 (d, 2H), 2.1 (d, 2H), 2.2 (brs, 1H), 2.3 (d, 2H), 2.9 (m, 2H),
3.55 (t, 2H), 3.7 (m, 3H), 4.1 (s, 1H), 4.4 (t, 2H), 4.6 (s, 1H),
7.65 (d, 1H), 7.8 (dd, 1H), 8.15 (d, 1H), 8.25 (s, 1H). HPLC
(VERYPOL.M): tr=6.12 min (98%).
Example 16
1-{2-[(1,1-Dioxo-thiomorpholine-4-carbonyl)amino]-ethyl}-1H-benzoimidazole-
-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide
##STR00104##
[0668] Steps A-F is similar to those used in example 15 above.
Step-I
[0669] A) 1,1-Dioxo-thiomorpholine-4-carbonyl chloride:
[0670] To a solution of thiomorpholine 1,1-dioxide (0.181 g,
0.00105 mol) in dry THF (5 mL) was added DIPEA (0.3 mL, 0.00191
mol) at 0.degree. C. To the resulting mixture was added triphosgene
(0.11 g, 0.00037 mol) and the mixture was stirred for 2 h at
ambient temperature.
[0671] B) To a solution of
1-(2-aminoethyl)-1H-benzimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2-yl)-amide (0.25 g, 0.706 mmol) in dry THF (5
mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0.degree. C. To this
reaction mixture was added compound A slowly and stirred for 2 h at
ambient temperature. The solvents were evaporated and the residue
purified by preparative HPLC affording cis and trans isomers of
1-{2-[(1,1-dioxo-thiomorpholine-4-carbonyl)-amino]-ethyl}-1H-benzimidazol-
e-5-carboxylic acid (5-hydroxyadamantan-2-yl)-amide.
[0672] Isomer I (15 mg): MS-ESI m/z 516 (M+1); .sup.1H-NMR (300
MHz, CD.sub.3OD) .delta. 1.5 (d, 2H), 1.8 (d, 4H), 1.9 (d, 2H), 2.1
(m, 3H), 2.3 (s, 2H), 2.7 (t, 4H), 3.6 (t, 2H), 4.1 (s, 1H), 4.5
(t, 2H), 7.6 (d, 1H), 7.8 (d, 1H), 8.2 (s, 1H), 8.35 (s, 1H). HPLC
(VERYPOL.M): tr=6.54 min (98%).
[0673] Isomer II (17 mg): MS-ESI m/z 516 (M+1); .sup.1H-NMR (300
MHz, CD.sub.3OD) .delta. 1.6 (d, 2H), 1.8 (d, 6H), 2.1 (d, 2H), 2.2
(m, 1H), 2.4 (s, 2H), 2.7 (t, 4H), 3.6 (t, 2H), 3.7 (t, 4H), 4.0
(s, 1H), 4.5 (t, 2H), 7.6 (d, 1H), 7.8 (dd, 1H), 8.2 (s, 1H), 8.3
(s, 1H). HPLC (VERYPOL.M): tr=6.84 min (94%).
Example 17
1,1-Dioxo-thiomorpholine-4-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide
##STR00105##
[0675] Steps A-F is similar to those used in example 16 above.
Step-I
[0676] To a solution of
[1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-
-8-yl)-methanone (0.2 g, 0.636 mmol) in dry THF (5 mL) was added
DIPEA (0.3 mL, 1.91 mmol) at 0.degree. C. To this reaction mixture
was added 1,1-dioxo-thiomorpholine-4-carbonyl chloride slowly and
stirred for 2 h at ambient temperature. The solvents were
evaporated and the residue purified by preparative HPLC to afford
1,1-dioxo-thiomorpholine-4-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-y-
l]-ethyl}-amide (0.007 g, 2.3%). MS-ESI m/z 476 (M+1); .sup.1H-NMR
(300 MHz, CD.sub.3OD) .delta. 1.5 (t, 1H), 1.8 (m, 4H), 2.1 (brs,
3H), 2.8 (s, 4H), 3.6 (t, 2H), 3.8 (s, 4H), 4.2 (m, 2H), 4.5 (t,
2H), 4.7 (s, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 7.85 (s, 1H), 8.3 (s,
1H). HPLC (VERYPOL.M): tr=6.24 min (97%).
[0677] The following compounds were synthesised employing a similar
method to the ones described in examples 13-17 above:
TABLE-US-00010 MS-ESI Ex. Structure MW IUPAC Name m/z 17-1
##STR00106## 467.57 Cis-1-{2-[(morpholine-4-
carbonyl)-amino]-ethyl}-1H- benzo-imidazole-5-carboxylic acid
(5-hydroxy-adamantan-2- yl)-amide 458 17-2 ##STR00107## 467.57
Trans-1-{2-[(morpholine-4- carbonyl)-amino]-ethyl}-1H-
benzo-imidazole-5-carboxylic acid (5-hydroxy-adamantan-2- yl)-amide
458 17-3 ##STR00108## 439.56 Cis-morpholine-4-carboxylic acid
{2-[5-(octahydro- quinoline-1-carbonyl)-
benzoimidazol-1-yl]-ethyl}- amide 440 17-4 ##STR00109## 439.56
Trans-morpholine-4-carboxylic acid {2-[5-(octahydro-
quinoline-1-carbonyl)- benzoimidazol-1-yl]-ethyl}- amide 440 17-5
##STR00110## 427.51 Morpholine-4-carboxylic acid
{2-[5-(3-hydroxy-8-aza-bicyclo- [3.2.1]octane-8-carbonyl)-
benzoimidazol-1-yl]- ethyl}-amide 428 17-6 ##STR00111## 487.63
1,1-Dioxo-thiomorpholine-4- carboxylic acid {2-[5-
(octahydro-quinoline-1- carbonyl)-benzoimidazol-1-yl]- ethyl}-amide
488 17-7 ##STR00112## 439.56 3-Hydroxy-pyrrolidine-1- carboxylic
acid {2-[5- (octahydro-quinoline-1- carbonyl)-benzoimidazol-1-yl]-
ethyl}-amide 440 17-8 ##STR00113## 481.60
1-{2-[5-(Octahydro-quinoline- 1-carbonyl)-benzoimidazol-1-
yl]-ethylcarbamoyl}-piperidine- 4-carboxylic acid 482 17-9
##STR00114## 427.51 3-Hydroxy-pyrrolidine-1- carboxylic acid
{2-[5-(3- hydroxy-8-aza-bicyclo[3.2.1] octane-8-carbonyl)-benzo-
imidazol-1-yl]-ethyl}- amide 428 17-10 ##STR00115## 453.59
Cis-4-hydroxy-piperidine-1- carboxylic acid {2-[5-
(octahydro-quinoline-1- carbonyl)-benzoimidazol-1-yl]- ethyl}-amide
454 17-11 ##STR00116## 453.59 Trans-4-hydroxy-piperidine-1-
carboxylic acid {2-[5- (octahydro-quinoline-1-
carbonyl)-benzoimidazol-1-yl]- ethyl}-amide 454 17-12 ##STR00117##
441.53 Endo-4-hydroxy-piperidine-1- carboxylic acid {2-[5-(3-
hydroxy-8-aza- bicyclo[3.2.1]octane-8-
carbonyl)-benzoimidazol-1-yl]- ethyl}-amide 442 17-13 ##STR00118##
441.53 Exo-4-hydroxy-piperidine-1- carboxylic acid {2-[5-(3-
hydroxy-8-aza- bicyclo[3.2.1]octane-8-
carbonyl)-benzoimidazol-1-yl]- ethyl}-amide 442 17-14 ##STR00119##
515.64 1-{2-[(1,1-Dioxo- thiomorpholine-4-carbonyl)-
amino]-ethyl}-1H- benzoimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2- yl)-amide 516 17-15 ##STR00120## 475.57
1,1-Dioxo-thiomorpholine-4- carboxylic acid {2-[5-(3-
hydroxy-8-aza-bicyclo[3.2.1]- octane-8-carbonyl)-benzo-
imidazol-1-yl]-ethyl}-amide 476 17-16 ##STR00121## 481.60
1-{2-[(4-Hydroxy-piperidine-1- carbonyl)-amino]-ethyl}-1H-
benzoimidazole-5-carboxylic acid (5-hydroxy-adamantan-2- yl)-amide
482 17-17 ##STR00122## 467.57 1-{2-[(3-Hydroxy-pyrrolidine-1-
carbonyl)-amino]-ethyl}-1H- benzoimidazole-5-carboxylic acid
(5-hydroxy-adamantan-2- yl)-amide 468 17-18 ##STR00123## 427.51
Morpholine-4-carboxylic acid {2-[5-(3-hydroxy-8-aza-bicyclo-
[3.2.1]octane-8-carbonyl)- benzoimidazol-1-yl]-ethyl}- amide 428
17-19 ##STR00124## 509.61 Cis-1-{2-[5-(5-Hydroxy-
adamantan-2-ylcarbamoyl)- benzoimidazol-1-yl]-
ethylcarbamoyl}-piperidine-4- carboxylic acid 510 17-20
##STR00125## 509.61 Trans-1-{2-[5-(5-Hydroxy-
adamantan-2-ylcarbamoyl)- benzoimidazol-1-yl]-
ethylcarbamoyl}-piperidine-4- carboxylic acid 510 17-21
##STR00126## 469.55 1-{2-[5-(3-Hydroxy-8-aza-
bicyclo[3.2.1]octane-8- carbonyl)-benzoimidazol-1-yl]-
ethyl-carbamoyl}-piperidine-4- carboxylic acid 470
[0678] Pharmacological Methods
[0679] 11.beta.HSD1 Enzyme Assay
[0680] Materials
[0681] .sup.3H-cortisone and anti-rabbit Ig coated scintillation
proximity assay (SPA) beads were purchased from Amersham Pharmacia
Biotech, .beta.-NADPH was from Sigma and rabbit anti-cortisol
antibodies were from Fitzgerald. An extract of yeast transformed
with h-11.beta.HSD1 (Hutt et al., FEBS Lett., 441, 25 (1998)) was
used as the source of enzyme. The test compounds were dissolved in
DMSO (10 mM). All dilutions were performed in a buffer containing
50 mM TRIS-HCl (Sigma Chemical Co), 4 mM EDTA (Sigma Chemical Co),
0.1% BSA (Sigma Chemical Co), 0.01% Tween-20 (Sigma Chemical Co)
and 0.005% bacitracin (Novo Nordisk A/S), pH=7.4. Optiplate 96
wells plates were supplied by Packard. The amount of
.sup.3H-cortisol bound to the SPA beads was measured on TopCount
NXT, Packard.
[0682] Methods
[0683] h-11.beta.HSD1, 120 nM .sup.3H-cortisone, 4 mM .beta.-NADPH,
antibody (1:200), serial dilutions of test compound and SPA
particles (2 mg/well) were added to the wells. The reaction was
initiated by mixing the different components and was allowed to
proceed under shaking for 60 min at 30.degree. C. The reaction was
stopped be the addition of 10 fold excess of a stopping buffer
containing 500 .mu.M carbenoxolone and 1 .mu.M cortisone. Data was
analysed using GraphPad Prism software.
* * * * *