U.S. patent application number 16/848746 was filed with the patent office on 2020-12-03 for modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto.
The applicant listed for this patent is Arena Pharmaceuticals, Inc.. Invention is credited to Weichao CHEN, Bryan A. KRAMER, Abu J.M. SADEQUE, Anna SHIFRINA, Young-Jun SHIN, Thuy-Anh TRAN, Pureza VALLAR, Ning ZOU.
Application Number | 20200375930 16/848746 |
Document ID | / |
Family ID | 1000005022808 |
Filed Date | 2020-12-03 |
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United States Patent
Application |
20200375930 |
Kind Code |
A1 |
TRAN; Thuy-Anh ; et
al. |
December 3, 2020 |
MODULATORS OF THE PROSTACYCLIN (PGI2) RECEPTOR USEFUL FOR THE
TREATMENT OF DISORDERS RELATED THERETO
Abstract
The present invention relates to amide derivatives of Formula
(XIIIa) and pharmaceutical compositions thereof that modulate the
activity of the PGI2 receptor. Compounds of the present invention
and pharmaceutical compositions thereof are directed to methods
useful in the treatment of: Pulmonary arterial hypertension (PAH);
idiopathic PAH; familial PAH; PAH associated with a collagen
vascular disease, a congenital heart disease, portal hypertension,
HIV infection, ingestion of a drug or toxin, hereditary hemorrhagic
telangiectasia, splenectomy, pulmonary veno-occlusive disease
(PVOD) or pulmonary capillary hemangiomatosis (PCH); PAH with
significant venous or capillary involvement; platelet aggregation;
coronary artery disease; myocardial infarction; transient ischemic
attack, angina; stroke; ischemia-reperfusion injury; restenosis;
atrial fibrillation; blood clot formation in an angioplasty or
coronary bypass surgery individual or in an individual suffering
from atrial fibrillation; atherosclerosis; atherothrombosis; asthma
or a symptom thereof; a diabetic-related disorder such as diabetic
peripheral neuropathy, diabetic nephropathy or diabetic
retinopathy; glaucoma or other disease of the eye with abnormal
intraocular pressure; hypertension; inflammation; psoriasis;
psoriatic arthritis; rheumatoid arthritis; Crohn's disease;
transplant rejection; multiple sclerosis; systemic lupus
erythematosus (SLE); ulcerative colitis; ischemia-reperfusion
injury; restenosis; atherosclerosis; acne; type 1 diabetes; type 2
diabetes; sepsis; and chronic obstructive pulmonary disorder
(COPD).
Inventors: |
TRAN; Thuy-Anh; (San Diego,
CA) ; CHEN; Weichao; (San Diego, CA) ; KRAMER;
Bryan A.; (San Diego, CA) ; SADEQUE; Abu J.M.;
(San Diego, CA) ; SHIFRINA; Anna; (San Diego,
CA) ; SHIN; Young-Jun; (San Diego, CA) ;
VALLAR; Pureza; (Chula Vista, CA) ; ZOU; Ning;
(San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Arena Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000005022808 |
Appl. No.: |
16/848746 |
Filed: |
April 14, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15447573 |
Mar 2, 2017 |
10668033 |
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16848746 |
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14510669 |
Oct 9, 2014 |
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15447573 |
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12933196 |
Oct 14, 2010 |
8895776 |
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PCT/US2009/001688 |
Mar 17, 2009 |
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14510669 |
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61209453 |
Mar 6, 2009 |
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61207220 |
Feb 9, 2009 |
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61123621 |
Apr 9, 2008 |
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61069857 |
Mar 18, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/426 20130101;
C07D 213/75 20130101; A61K 31/195 20130101; C07D 277/48 20130101;
A61K 31/381 20130101; C07D 333/36 20130101; C07C 309/15 20130101;
C07C 2601/14 20170501; A61K 31/4406 20130101; A61K 31/325 20130101;
C07C 271/28 20130101; C07B 2200/07 20130101; A61K 31/27 20130101;
C07D 241/20 20130101; A61K 31/4965 20130101; C07C 275/34 20130101;
C07C 275/28 20130101; A61K 31/4402 20130101; C07C 275/24 20130101;
C07C 271/12 20130101; C07B 2200/13 20130101; C07C 275/30 20130101;
A61K 31/44 20130101 |
International
Class: |
A61K 31/195 20060101
A61K031/195; C07C 271/12 20060101 C07C271/12; C07C 275/24 20060101
C07C275/24; C07C 275/28 20060101 C07C275/28; C07C 275/30 20060101
C07C275/30; C07C 275/34 20060101 C07C275/34; C07C 309/15 20060101
C07C309/15; C07D 213/75 20060101 C07D213/75; C07D 241/20 20060101
C07D241/20; C07D 277/48 20060101 C07D277/48; C07D 333/36 20060101
C07D333/36; A61K 31/27 20060101 A61K031/27; C07C 271/28 20060101
C07C271/28; A61K 31/325 20060101 A61K031/325; A61K 31/381 20060101
A61K031/381; A61K 31/426 20060101 A61K031/426; A61K 31/44 20060101
A61K031/44; A61K 31/4402 20060101 A61K031/4402; A61K 31/4406
20060101 A61K031/4406; A61K 31/4965 20060101 A61K031/4965 |
Claims
1.-72. (canceled)
73. A process for the preparation of a compound of Formula (III):
##STR00169## or a salt form thereof, wherein: R.sup.1 is selected
from C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; each optionally
substituted with one or two substituents selected from:
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, aryl,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl and halogen;
R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen; and
R.sup.5 is C.sub.1-C.sub.6 alkyl; comprising reacting a compound of
Formula (IV): ##STR00170## or a salt from thereof, with a compound
of Formula (V): ##STR00171## wherein: R.sup.6 is selected from:
C.sub.1-C.sub.6 alkylarylsulfonate, C.sub.1-C.sub.6 alkylsulfonate,
arylsulfonate, C.sub.1-C.sub.6 haloalkylsulfonate and halogen; in
the presence of a base to form a compound of Formula (III) or a
salt form thereof.
74. The process of claim 73, wherein the R.sup.1 is aryl,
optionally substituted with one or two substituents selected from:
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, aryl,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl and
halogen.
75. The process of claim 73, wherein the R.sup.2 is aryl optionally
substituted with one or two substituents selected from:
C.sub.1-C.sub.6 alkyl and halogen.
76. The process of claim 73, wherein the R.sup.5 is tert-butyl.
77. The process of claim 73, wherein the R.sup.6 is halogen.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to certain compounds of
Formula (Ia) and pharmaceutical compositions thereof that modulate
the activity of the PGI2 receptor. Compounds of the present
invention and pharmaceutical compositions thereof are directed to
methods useful in the treatment of: pulmonary arterial hypertension
(PAH); idiopathic PAH; familial PAH; PAH associated with: a
collagen vascular disease, a congenital heart disease, portal
hypertension, HIV infection, ingestion of a drug or toxin,
hereditary hemorrhagic telangiectasia, splenectomy, pulmonary
veno-occlusive disease (PVOD) or pulmonary capillary
hemangiomatosis (PCH); PAH with significant venous or capillary
involvement; platelet aggregation; coronary artery disease;
myocardial infarction; transient ischemic attack; angina; stroke;
ischemia-reperfusion injury; restenosis; atrial fibrillation; blood
clot formation in an angioplasty or coronary bypass surgery
individual or in an individual suffering from atrial fibrillation;
atherothrombosis; asthma or a symptom thereof; a diabetic-related
disorder such as diabetic peripheral neuropathy, diabetic
nephropathy or diabetic retinopathy; glaucoma or other disease of
the eye with abnormal intraocular pressure; hypertension;
inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis;
Crohn's disease; transplant rejection; multiple sclerosis; systemic
lupus erythematosus (SLE); ulcerative colitis; atherosclerosis;
acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic
obstructive pulmonary disorder (COPD).
BACKGROUND OF THE INVENTION
[0002] Prostacyclin (PGI2) is a lipid molecule derived from
arachidonic acid through the cyclooxygenase pathway. It is a potent
vasodilator, antiproliferative, anti-thrombotic and antiplatelet
agent that mediates its effects as an agonist of a G
protein-coupled receptor (PGI2 receptor; e.g., human PGI2 receptor,
GenBank.RTM. Accession No. NP_000951 and alleles thereof). It is
known that the binding of PGI2 (or other such agonist) to the PGI2
receptor leads to coupling with the Gs protein and increases
intracellular cAMP levels. (See, e.g., Zhang et al., Arch. Biochem.
Biophys., 2006, 454:80-88.)
[0003] Pulmonary arterial hypertension (PAH) is a life-threatening
disease characterized by a progressive pulmonary vasculopathy
leading to right ventricular hypertrophy. Right heart failure
occurs if left untreated. Prostacyclin, which has vasodilatory and
antiproliferative effects on the pulmonary vasculature has been
found to be low in patients with PAH compared with normal controls.
Exogenous administration of prostacyclin or an analog of
prostacyclin (i.e., an agonist of the PGI2 receptor) has become an
important strategy in the treatment of PAH. (See, e.g., Tuder et
al., Am. J. Respir. Crit. Care. Med., 1999, 159:1925-1932; Humbert
et al., J. Am. Coll. Cardiol., 2004, 43:13S-24S; Rosenzweig, Expert
Opin. Emerging Drugs, 2006, 11:609-619; McLaughlin et al.,
Circulation, 2006, 114:1417-1431; Rosenkranz, Clin. Res. Cardiol.,
2007, 96:527-541; Driscoll et al., Expert Opin. Pharmacother.,
2008, 9:65-81.)
[0004] Trepostinil and iloprost are FDA-approved analogs of
prostacyclin which, like prostacyclin, are not orally-active.
Beraprost is an orally-active analog of prostacyclin approved for
the treatment of PAH in Japan, but it has failed registration for
the treatment of PAH in Europe and in the US. Of the three
FDA-approved drugs, prostacyclin is the best studied in PAH
patients. The approximate annual cost of treating PAH with these
drugs is $25,000 to $200,000 depending on the dose. At present,
many experts consider intravenous prostacyclin to be the most
reliable agent for managing the sickest PAH patients. Due to the
short half-life of prostacyclin, intravenous treatment is
complicated by the need for a continuous infusion. Patients are at
risk for potentially fatal rebound pulmonary hypertension if the
infusion is abruptly disrupted, as well as significant risk of
catheter-related complications including sepsis. (See, e.g.,
Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619; Naeije
et al., Expert Opin. Pharmacother., 2007, 8:2247-2265; Strauss et
al., Clin. Chest. Med., 2007, 28:127-142; Driscoll et al., Expert
Opin. Pharmacother., 2008, 9:65-81.)
[0005] There is considerable interest in developing prostacyclin
analogs (i.e., agonists of the PGI2 receptor) for use in the
treatment of other diseases, such as atherothrombosis. Developing
stable, orally-active analogs of prostacyclin (i.e., stable,
orally-active agonists of the PGI2 receptor) is a rate-limiting
step in achieving this goal (see, e.g., Arehart et al., Curr. Med.
Chem., 2007, 14:2161-2169; Arehart et al., Circ. Res., 2008, Mar. 6
Epub ahead of print), as well as in the improved management of
PAH.
SUMMARY OF THE INVENTION
[0006] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula (Ia) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00001##
[0007] wherein:
[0008] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0009] X is O or NR.sup.3; and
[0010] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0011] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula (XIIIa)
and pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00002##
[0012] wherein:
[0013] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0014] X is O or NR.sup.3;
[0015] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl;
and
[0016] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0017] One aspect of the present invention pertains to methods of
modulating the activity of a PGI2 receptor by contacting the
receptor with a compound of the present invention or a
pharmaceutical composition thereof.
[0018] One aspect of the present invention pertains to methods of
agonizing a PGI2 receptor by contacting the receptor with a
compound of the present invention or a pharmaceutical composition
thereof.
[0019] One aspect of the present invention pertains to methods for
the treatment of PAH in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0020] One aspect of the present invention pertains to methods for
the treatment of idiopathic PAH in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0021] One aspect of the present invention pertains to methods for
the treatment of familial PAH in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0022] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a collagen vascular disease in
an individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0023] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a collagen vascular disease
selected from: scleroderma, CREST syndrome, systemic lupus
erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,
polymyositis, and dermatomyositis in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0024] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a congenital heart disease in
an individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0025] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a congenital heart disease
selected from: atrial septic defect (ASD), ventricular septic
defect (VSD) and patent ductus arteriosus in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0026] One aspect of the present invention pertains to methods for
the treatment of PAH associated with portal hypertension in an
individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0027] One aspect of the present invention pertains to methods for
the treatment of PAH associated with HIV infection in an
individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0028] One aspect of the present invention pertains to methods for
the treatment of PAH associated with ingestion of a drug or toxin
in an individual, comprising administering to said individual in
need thereof, a therapeutically effective amount of a compound of
the present invention or a pharmaceutical composition thereof.
[0029] One aspect of the present invention pertains to methods for
the treatment of PAH associated with hereditary hemorrhagic
telangiectasia in an individual, comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0030] One aspect of the present invention pertains to methods for
the treatment of PAH associated with splenectomy in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0031] One aspect of the present invention pertains to methods for
the treatment of PAH associated with significant venous or
capillary involvement in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0032] One aspect of the present invention pertains to methods for
the treatment of PAH associated with pulmonary veno-occlusive
disease (PVOD) in an individual, comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0033] One aspect of the present invention pertains to methods for
the treatment of PAH associated with pulmonary capillary
hemangiomatosis (PCH) in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0034] One aspect of the present invention pertains to methods for
the treatment of platelet aggregation in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0035] One aspect of the present invention pertains to methods for
the treatment of: coronary artery disease, myocardial infarction,
transient ischemic attack, angina, stroke, ischemia-reperfusion
injury, restenosis or atrial fibrillation in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0036] One aspect of the present invention pertains to methods for
reducing the risk of blood clot formation in an angioplasty or
coronary bypass surgery individual comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0037] One aspect of the present invention pertains to methods for
reducing the risk of blood clot formation in an individual
suffering from atrial fibrillation comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0038] One aspect of the present invention pertains to methods for
the treatment of atherosclerosis in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0039] One aspect of the present invention pertains to methods for
the treatment of atherothrombosis in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0040] One aspect of the present invention pertains to methods for
the treatment of asthma in an individual, comprising administering
to said individual in need thereof, a therapeutically effective
amount of a compound of the present invention or a pharmaceutical
composition thereof.
[0041] One aspect of the present invention pertains to methods for
the treatment of a symptom of asthma in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0042] One aspect of the present invention pertains to methods for
the treatment of a diabetic-related disorder in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0043] One aspect of the present invention pertains to methods for
the treatment of diabetic peripheral neuropathy in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0044] One aspect of the present invention pertains to methods for
the treatment of diabetic nephropathy in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0045] One aspect of the present invention pertains to methods for
the treatment of diabetic retinopathy in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0046] One aspect of the present invention pertains to methods for
the treatment of glaucoma or other disease of the eye with abnormal
intraocular pressure in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0047] One aspect of the present invention pertains to methods for
the treatment of hypertension in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0048] One aspect of the present invention pertains to methods for
the treatment of hypertension intended to confer protection against
cerebral ischemia in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound of the present invention or a pharmaceutical
composition thereof.
[0049] One aspect of the present invention pertains to methods for
the treatment of inflammation in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound of the present invention or a
pharmaceutical composition thereof.
[0050] One aspect of the present invention pertains to methods for
the treatment of an inflammatory disease in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound of the present
invention or a pharmaceutical composition thereof.
[0051] One aspect of the present invention pertains to methods for
the treatment of an inflammatory disease selected from: psoriasis,
psoriatic arthritis, rheumatoid arthritis, Crohn's disease,
transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) and
asthma in an individual, comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition
thereof.
[0052] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a PGI2 receptor mediated
disorder.
[0053] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH.
[0054] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of idiopathic PAH.
[0055] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of familial PAH.
[0056] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with vascular
collagen disease.
[0057] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with a collagen
vascular disease selected from: scleroderma, CREST syndrome,
systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis.
[0058] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with a congenital
heart disease.
[0059] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with a congenital
heart disease selected from: atrial septic defect (ASD),
ventricular septic defect (VSD) and patent ductus arteriosus.
[0060] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with portal
hypertension.
[0061] One aspect of the present invention pertains to the use of a
compound of the present, invention in the manufacture of a
medicament for the treatment of PAH associated with HIV
infection.
[0062] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with ingestion of a
drug or toxin.
[0063] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with hereditary
hemorrhagic telangiectasia.
[0064] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with
splenectomy.
[0065] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with significant
venous or capillary involvement.
[0066] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with pulmonary
veno-occlusive disease (PVOD).
[0067] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of PAH associated with pulmonary
capillary hemangiomatosis (PCH).
[0068] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of platelet aggregation.
[0069] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a PGI2 receptor mediated disorder
selected from: coronary artery disease, myocardial infarction,
transient ischemic attack, angina, stroke, ischemia-reperfusion
injury, restenosis and atrial fibrillation.
[0070] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of blood clot formation in an
angioplasty or coronary bypass surgery individual.
[0071] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of blood clot formation in an
individual suffering from atrial fibrillation.
[0072] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of atherosclerosis.
[0073] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of atherothrombosis.
[0074] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of asthma.
[0075] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a symptom of asthma.
[0076] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of a diabetic-related disorder.
[0077] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of diabetic peripheral neuropathy.
[0078] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of diabetic nephropathy.
[0079] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of diabetic retinopathy.
[0080] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of glaucoma or other disease of the
eye with abnormal intraocular pressure.
[0081] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of hypertension.
[0082] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of hypertension intended to confer
protection against cerebral ischemia.
[0083] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of inflammation.
[0084] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of an inflammatory disease.
[0085] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for the treatment of an inflammatory disease selected
from: psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) and
asthma.
[0086] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for modulating the activity of a PGI2 receptor.
[0087] One aspect of the present invention pertains to the use of a
compound of the present invention in the manufacture of a
medicament for agonizing a PGI2 receptor.
[0088] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of the human
or animal body by therapy.
[0089] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a PGI2
receptor mediated disorder.
[0090] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH.
[0091] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
idiopathic PAH.
[0092] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of familial
PAH.
[0093] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a collagen vascular disease.
[0094] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a collagen vascular disease selected from:
scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),
rheumatoid arthritis, Takayasu's arteritis, polymyositis, and
dermatomyositis.
[0095] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a congenital heart disease.
[0096] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus.
[0097] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with portal hypertension.
[0098] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with HIV infection.
[0099] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with ingestion of a drug or toxin.
[0100] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with hereditary hemorrhagic telangiectasia.
[0101] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with splenectomy.
[0102] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with significant venous or capillary involvement.
[0103] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAH
associated with pulmonary veno-occlusive disease (PVOD).
[0104] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of PAR
associated with pulmonary capillary hemangiomatosis (PCH).
[0105] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of platelet
aggregation.
[0106] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of: coronary
artery disease, myocardial infarction, transient ischemic attack,
angina, stroke, ischemia-reperfusion injury, restenosis or atrial
fibrillation.
[0107] One aspect of the present invention pertains to compounds of
the present invention for use in a method for the treatment of
blood clot formation in an angioplasty or coronary bypass surgery
individual.
[0108] One aspect of the present invention pertains to compounds of
the present invention for use in a method for the treatment of
blood clot formation in an individual suffering from atrial
fibrillation.
[0109] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
atherosclerosis.
[0110] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
atherothrombosis.
[0111] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
asthma.
[0112] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a symptom
of asthma.
[0113] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a
diabetic-related complication.
[0114] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of a
diabetic-related disorder.
[0115] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of diabetic
nephropathy.
[0116] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of diabetic
retinopathy.
[0117] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of glaucoma
or other disease of the eye with abnormal intraocular pressure.
[0118] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of glaucoma
or other disease of the eye with abnormal intraocular pressure.
[0119] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
hypertension.
[0120] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
hypertension intended to confer protection against cerebral
ischemia.
[0121] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of
inflammation.
[0122] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of an
inflammatory disease.
[0123] One aspect of the present invention pertains to compounds of
the present invention for use in a method of treatment of an
inflammatory disease selected from: psoriasis, psoriatic arthritis,
rheumatoid arthritis, Crohn's disease, transplant rejection,
multiple sclerosis, systemic lupus erythematosus (SLE), ulcerative
colitis, ischemia-reperfusion injury, restenosis, atherosclerosis,
acne, type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive
pulmonary disorder (COPD) and asthma.
[0124] One aspect of the present invention pertains to compounds of
the present invention for use in a method of modulating the
activity of a PGI2 receptor.
[0125] One aspect of the present invention pertains to compounds of
the present invention for use in a method of agonizing a PGI2
receptor.
[0126] One aspect of the present invention pertains to processes
for preparing a composition comprising admixing a compound of the
present invention and a pharmaceutically acceptable carrier.
[0127] One aspect of the present invention pertains to
pharmaceutical compositions comprising a compound, salt, hydrate,
solvate or crystalline form of the present invention and a
pharmaceutically acceptable carrier.
[0128] One aspect of the present invention pertains to methods of
modulating the activity of a PGI2 receptor by contacting the
receptor with a compound, salt, hydrate, solvate or crystalline
form of the present invention or a pharmaceutical composition
thereof.
[0129] One aspect of the present invention pertains to methods of
agonizing a PGI2 receptor by contacting the receptor with a
compound, salt, hydrate, solvate or crystalline form of the present
invention or a pharmaceutical composition thereof.
[0130] One aspect of the present invention pertains to methods for
the treatment of PAH in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound, salt, hydrate, solvate or crystalline form of the
present invention or a pharmaceutical composition thereof.
[0131] One aspect of the present invention pertains to methods for
the treatment of idiopathic PAH in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0132] One aspect of the present invention pertains to methods for
the treatment of familial PAH in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0133] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a collagen vascular disease in
an individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound, salt,
hydrate, solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0134] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a collagen vascular disease
selected from: scleroderma, CREST syndrome, systemic lupus
erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,
polymyositis, and dermatomyositis in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0135] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a congenital heart disease in
an individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound, salt,
hydrate, solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0136] One aspect of the present invention pertains to methods for
the treatment of PAH associated with a congenital heart disease
selected from: atrial septic defect (ASD), ventricular septic
defect (VSD) and patent ductus arteriosus in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound, salt, hydrate,
solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0137] One aspect of the present invention pertains to methods for
the treatment of PAH associated with portal hypertension in an
individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound, salt,
hydrate, solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0138] One aspect of the present invention pertains to methods for
the treatment of PAH associated with HIV infection in an
individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound, salt,
hydrate, solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0139] One aspect of the present invention pertains to methods for
the treatment of PAH associated with ingestion of a drug or toxin
in an individual, comprising administering to said individual in
need thereof, a therapeutically effective amount of a compound,
salt, hydrate, solvate or crystalline form of the present invention
or a pharmaceutical composition thereof.
[0140] One aspect of the present invention pertains to methods for
the treatment of PAH associated with hereditary hemorrhagic
telangiectasia in an individual, comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound, salt, hydrate, solvate or crystalline form of the present
invention or a pharmaceutical composition thereof.
[0141] One aspect of the present invention pertains to methods for
the treatment of PAH associated with splenectomy in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound, salt, hydrate,
solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0142] One aspect of the present invention pertains to methods for
the treatment of PAH associated with significant venous or
capillary involvement in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound, salt, hydrate, solvate or crystalline form of the
present invention or a pharmaceutical composition thereof.
[0143] One aspect of the present invention pertains to methods for
the treatment of PAH associated with pulmonary veno-occlusive
disease (PVOD) in an individual, comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound, salt, hydrate, solvate or crystalline form of the present
invention or a pharmaceutical composition thereof.
[0144] One aspect of the present invention pertains to methods for
the treatment of PAH associated with pulmonary capillary
hemangiomatosis (PCH) in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound, salt, hydrate, solvate or crystalline form of the
present invention or a pharmaceutical composition thereof.
[0145] One aspect of the present invention pertains to methods for
the treatment of platelet aggregation in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0146] One aspect of the present invention pertains to methods for
the treatment of: coronary artery disease, myocardial infarction,
transient ischemic attack, angina, stroke, ischemia-reperfusion
injury, restenosis or atrial fibrillation in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound, salt, hydrate,
solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0147] One aspect of the present invention pertains to methods for
reducing the risk of blood clot formation in an angioplasty or
coronary bypass surgery individual comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound, salt, hydrate, solvate or crystalline form of the present
invention or a pharmaceutical composition thereof.
[0148] One aspect of the present invention pertains to methods for
reducing the risk of blood clot formation in an individual
suffering from atrial fibrillation comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound, salt, hydrate, solvate or crystalline form of the present
invention or a pharmaceutical composition thereof.
[0149] One aspect of the present invention pertains to methods for
the treatment of atherosclerosis in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0150] One aspect of the present invention pertains to methods for
the treatment of atherothrombosis in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0151] One aspect of the present invention pertains to methods for
the treatment of asthma in an individual, comprising administering
to said individual in need thereof, a therapeutically effective
amount of a compound, salt, hydrate, solvate or crystalline form of
the present invention or a pharmaceutical composition thereof.
[0152] One aspect of the present invention pertains to methods for
the treatment of a symptom of asthma in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0153] One aspect of the present invention pertains to methods for
the treatment of a diabetic-related disorder in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound, salt, hydrate,
solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0154] One aspect of the present invention pertains to methods for
the treatment of diabetic peripheral neuropathy in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound, salt, hydrate,
solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0155] One aspect of the present invention pertains to methods for
the treatment of diabetic nephropathy in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0156] One aspect of the present invention pertains to methods for
the treatment of diabetic retinopathy in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0157] One aspect of the present invention pertains to methods for
the treatment of glaucoma or other disease of the eye with abnormal
intraocular pressure in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound, salt, hydrate, solvate or crystalline form of the
present invention or a pharmaceutical composition thereof.
[0158] One aspect of the present invention pertains to methods for
the treatment of hypertension in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0159] One aspect of the present invention pertains to methods for
the treatment of hypertension intended to confer protection against
cerebral ischemia in an individual, comprising administering to
said individual in need thereof, a therapeutically effective amount
of a compound, salt, hydrate, solvate or crystalline form of the
present invention or a pharmaceutical composition thereof.
[0160] One aspect of the present invention pertains to methods for
the treatment of inflammation in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0161] One aspect of the present invention pertains to methods for
the treatment of an inflammatory disease in an individual,
comprising administering to said individual in need thereof, a
therapeutically effective amount of a compound, salt, hydrate,
solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0162] One aspect of the present invention pertains to methods for
the treatment of an inflammatory disease selected from: psoriasis,
psoriatic arthritis, rheumatoid arthritis, Crohn's disease,
transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) and
asthma in an individual, comprising administering to said
individual in need thereof, a therapeutically effective amount of a
compound, salt, hydrate, solvate or crystalline form of the present
invention or a pharmaceutical composition thereof.
[0163] One aspect of the present invention pertains to methods for
the treatment of a PGI2 receptor mediated disorder in an
individual, comprising administering to said individual in need
thereof, a therapeutically effective amount of a compound, salt,
hydrate, solvate or crystalline form of the present invention or a
pharmaceutical composition thereof.
[0164] One aspect of the present invention pertains to methods for
the treatment of PAH selected from: idiopathic PAH; familial PAH;
PAH associated with a collagen vascular disease selected from:
scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),
rheumatoid arthritis, Takayasu's arteritis, polymyositis, and
dermatomyositis; PAH associated with a congenital heart disease
selected from: atrial septic defect (ASD), ventricular septic
defect (VSD) and patent ductus arteriosus in an individual; PAH
associated with portal hypertension; PAH associated with HIV
infection; PAH associated with ingestion of a drug or toxin; PAH
associated with hereditary hemorrhagic telangiectasia; PAH
associated with splenectomy; PAH associated with significant venous
or capillary involvement; PAH associated with pulmonary
veno-occlusive disease (PVOD); and PAH associated with pulmonary
capillary hemangiomatosis (PCH) in an individual, comprising
administering to said individual in need thereof, a therapeutically
effective amount of a compound, salt, hydrate, solvate or
crystalline form of the present invention or a pharmaceutical
composition thereof.
[0165] One aspect of the present invention pertains to methods for
the treatment of a disorder selected from: platelet aggregation,
coronary artery disease, myocardial infarction, transient ischemic
attack, angina, stroke, ischemia-reperfusion injury, restenosis,
atrial fibrillation, blood clot formation, atherosclerosis,
atherothrombosis, asthma, a symptom of asthma, a diabetic-related
disorder, diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy, glaucoma or other disease of the eye with
abnormal intraocular pressure, hypertension, inflammation,
psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis and chronic obstructive pulmonary disorder (COPD)
in an individual, comprising administering to said individual in
need thereof, a therapeutically effective amount of a compound,
salt, hydrate, solvate or crystalline form of the present invention
or a pharmaceutical composition thereof.
[0166] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
a PGI2 receptor mediated disorder.
[0167] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH.
[0168] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
idiopathic PAH.
[0169] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
familial PAH.
[0170] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with vascular collagen disease.
[0171] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with a collagen vascular disease selected from:
scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),
rheumatoid arthritis, Takayasu's arteritis, polymyositis, and
dermatomyositis.
[0172] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with a congenital heart disease.
[0173] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with a congenital heart disease selected from:
atrial septic defect (ASD), ventricular septic defect (VSD) and
patent ductus arteriosus.
[0174] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with portal hypertension.
[0175] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with HIV infection.
[0176] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with ingestion of a drug or toxin.
[0177] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with hereditary hemorrhagic telangiectasia.
[0178] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with splenectomy.
[0179] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with significant venous or capillary
involvement.
[0180] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with pulmonary veno-occlusive disease (PVOD).
[0181] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH associated with pulmonary capillary hemangiomatosis (PCH).
[0182] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
platelet aggregation.
[0183] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
a PGI2 receptor mediated disorder selected from: coronary artery
disease, myocardial infarction, transient ischemic attack, angina,
stroke, ischemia-reperfusion injury, restenosis and atrial
fibrillation.
[0184] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
blood clot formation in an angioplasty or coronary bypass surgery
individual.
[0185] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
blood clot formation in an individual suffering from atrial
fibrillation.
[0186] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
atherosclerosis.
[0187] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
atherothrombosis.
[0188] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
asthma.
[0189] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
a symptom of asthma.
[0190] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
a diabetic-related disorder.
[0191] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
diabetic peripheral neuropathy.
[0192] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
diabetic nephropathy.
[0193] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
diabetic retinopathy.
[0194] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
glaucoma or other disease of the eye with abnormal intraocular
pressure.
[0195] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
hypertension.
[0196] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
hypertension intended to confer protection against cerebral
ischemia.
[0197] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
inflammation.
[0198] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
an inflammatory disease.
[0199] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
an inflammatory disease selected from: psoriasis, psoriatic
arthritis, rheumatoid arthritis, Crohn's disease, transplant
rejection, multiple sclerosis, systemic lupus erythematosus (SLE),
ulcerative colitis, ischemia-reperfusion injury, restenosis,
atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis,
chronic obstructive pulmonary disorder (COPD) and asthma.
[0200] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for modulating the
activity of a PGI2 receptor.
[0201] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for agonizing a PGI2
receptor.
[0202] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
PAH selected from: idiopathic PAH; familial PAH; PAH associated
with a collagen vascular disease selected from: scleroderma, CREST
syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis; PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus in an individual; PAH associated with portal
hypertension; PAH associated with HIV infection; PAH associated
with ingestion of a drug or toxin; PAH associated with hereditary
hemorrhagic telangiectasia; PAH associated with splenectomy; PAH
associated with significant venous or capillary involvement; PAH
associated with pulmonary veno-occlusive disease (PVOD); and PAH
associated with pulmonary capillary hemangiomatosis (PCH).
[0203] One aspect of the present invention pertains to the use of a
compound, salt, hydrate, solvate or crystalline form of the present
invention, in the manufacture of a medicament for the treatment of
a disorder selected from: platelet aggregation, coronary artery
disease, myocardial infarction, transient ischemic attack, angina,
stroke, ischemia-reperfusion injury, restenosis, atrial
fibrillation, blood clot formation, atherosclerosis,
atherothrombosis, asthma, a symptom of asthma, a diabetic-related
disorder, diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy, glaucoma or other disease of the eye with
abnormal intraocular pressure, hypertension, inflammation,
psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis and chronic obstructive pulmonary disorder
(COPD).
[0204] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of the human or animal body by
therapy.
[0205] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of a PGI2 receptor mediated
disorder.
[0206] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH.
[0207] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of idiopathic PAH.
[0208] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of familial PAH.
[0209] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with a collagen
vascular disease.
[0210] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with a collagen
vascular disease selected from: scleroderma, CREST syndrome,
systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis.
[0211] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with a
congenital heart disease.
[0212] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with a
congenital heart disease selected from: atrial septic defect (ASD),
ventricular septic defect (VSD) and patent ductus arteriosus.
[0213] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with portal
hypertension.
[0214] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with HIV
infection.
[0215] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with ingestion
of a drug or toxin.
[0216] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with hereditary
hemorrhagic telangiectasia.
[0217] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with
splenectomy.
[0218] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with significant
venous or capillary involvement.
[0219] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with pulmonary
veno-occlusive disease (PVOD).
[0220] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of PAH associated with pulmonary
capillary hemangiomatosis (PCH).
[0221] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of platelet aggregation.
[0222] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of: coronary artery disease,
myocardial infarction, transient ischemic attack, angina, stroke,
ischemia-reperfusion injury, restenosis or atrial fibrillation.
[0223] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method for the treatment of blood clot formation in an
angioplasty or coronary bypass surgery individual.
[0224] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method for the treatment of blood clot formation in an
individual suffering from atrial fibrillation.
[0225] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of atherosclerosis.
[0226] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of atherothrombosis.
[0227] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of asthma.
[0228] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of a symptom of asthma.
[0229] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of a diabetic-related
complication.
[0230] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of a diabetic-related
disorder.
[0231] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of diabetic peripheral
neuropathy.
[0232] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of diabetic nephropathy.
[0233] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of glaucoma or other disease of
the eye with abnormal intraocular pressure.
[0234] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of hypertension.
[0235] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of hypertension intended to confer
protection against cerebral ischemia.
[0236] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of inflammation.
[0237] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of an inflammatory disease.
[0238] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of treatment of an inflammatory disease
selected from: psoriasis, psoriatic arthritis, rheumatoid
arthritis, Crohn's disease, transplant rejection, multiple
sclerosis, systemic lupus erythematosus (SLE), ulcerative colitis,
ischemia-reperfusion injury, restenosis, atherosclerosis, acne,
type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive
pulmonary disorder (COPD) and asthma.
[0239] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of modulating the activity of a PGI2
receptor.
[0240] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate or crystalline form of the present invention
for use in a method of agonizing a PGI2 receptor. One aspect of the
present invention pertains to a compound, salt, hydrate, solvate,
crystalline form or pharmaceutical composition of the present
invention for use in a method of treatment of PAH selected from:
idiopathic PAH; familial PAH; PAH associated with a collagen
vascular disease selected from: scleroderma, CREST syndrome,
systemic lupus erythematosus (SLE), rheumatoid arthritis,
Takayasu's arteritis, polymyositis, and dermatomyositis; PAH
associated with a congenital heart disease selected from: atrial
septic defect (ASD), ventricular septic defect (VSD) and patent
ductus arteriosus in an individual; PAH associated with portal
hypertension; PAH associated with HIV infection; PAH associated
with ingestion of a drug or toxin; PAH associated with hereditary
hemorrhagic telangiectasia; PAH associated with splenectomy; PAH
associated with significant venous or capillary involvement; PAH
associated with pulmonary veno-occlusive disease (PVOD); and PAH
associated with pulmonary capillary hemangiomatosis (PCH).
[0241] One aspect of the present invention pertains to a compound,
salt, hydrate, solvate, crystalline form or pharmaceutical
composition of the present invention for use in a method of
treatment of a disorder selected from: platelet aggregation,
coronary artery disease, myocardial infarction, transient ischemic
attack, angina, stroke, ischemia-reperfusion injury, restenosis,
atrial fibrillation, blood clot formation, atherosclerosis,
atherothrombosis, asthma, a symptom of asthma, a diabetic-related
disorder, diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy, glaucoma or other disease of the eye with
abnormal intraocular pressure, hypertension, inflammation,
psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's
disease, transplant rejection, multiple sclerosis, systemic lupus
erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2
diabetes, sepsis and chronic obstructive pulmonary disorder
(COPD).
[0242] One aspect of the present invention pertains to processes
for preparing a composition comprising admixing a compound, salt,
hydrate, solvate or crystalline form of the present invention, and
a pharmaceutically acceptable carrier.
[0243] The present invention further provides, inter alia,
processes for preparing compounds of Formula (H):
##STR00003##
or a salt, solvate or hydrate thereof; wherein:
[0244] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0245] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
[0246] comprising reacting a compound of Formula (I):
##STR00004##
or a salt form thereof; wherein:
[0247] R.sup.5 is C.sub.1-C.sub.6 alkyl;
with a hydrolyzing agent to form a compound of Formula (II) or a
salt, solvate or hydrate thereof.
[0248] The present invention further provides processes for
preparing compounds of Formula (III):
##STR00005##
or a salt form thereof; wherein:
[0249] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0250] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
and
[0251] R.sup.5 is C.sub.1-C.sub.6 alkyl;
comprising reacting a compound of Formula (IV):
##STR00006##
or a salt form thereof; with a compound of Formula (V):
##STR00007##
wherein:
[0252] R.sup.6 is selected from: C.sub.1-C.sub.6
alkylarylsulfonate, C.sub.1-C.sub.6 alkylsulfonate, arylsulfonate,
C.sub.1-C.sub.6 haloalkylsulfonate and halogen;
in the presence of a base to form a compound of Formula (III) or a
salt form thereof.
[0253] The present invention further provides processes for
preparing compounds of Formula (IV):
##STR00008##
or a salt form thereof; wherein:
[0254] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0255] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
[0256] comprising reacting a compound of Formula (VI):
##STR00009##
or a salt form thereof; wherein:
[0257] R.sup.7 is a first leaving group;
with a compound of formula (VII):
##STR00010##
to form a compound of Formula (IV) or a salt form thereof.
[0258] The present invention further provides processes for
preparing compounds of Formula (VI):
##STR00011##
or a salt form thereof; wherein:
[0259] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0260] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
and
[0261] R.sup.7 is a first leaving group;
comprising reacting a compound of Formula (VIII):
##STR00012##
or a salt form thereof; with a compound of formula (IX):
##STR00013##
wherein:
[0262] R.sup.8 is a second leaving group;
to form a compound of Formula (VI) or a salt form thereof.
[0263] The present invention further provides processes for
preparing salts of compounds of Formula (I):
##STR00014##
comprising reacting a compound of Formula (I) with a salt-forming
reagent to form a salt of a compound of formula (I).
[0264] The present invention further provides salts of compounds of
Formula (II) prepared by the processes described herein.
[0265] The present invention further provides pharmaceutical
compositions of compounds of Formula (I) prepared by the processes
described herein.
[0266] The present invention further provides compounds of Formula
(I) and Formula (IV) prepared by the processes described
herein.
[0267] These and other aspects of the invention disclosed herein
will be set forth in greater detail as the patent disclosure
proceeds.
BRIEF DESCRIPTION OF THE DRAWINGS
[0268] FIG. 1 shows two general methods for preparing an
intermediate useful in the synthesis of compounds of the present
invention. Cyclohexane-1,4-dicarboxylic acid may be converted to
the corresponding diol either directly, or via an ester, by
reduction with lithium aluminium hydride. Reaction of the diol,
with tert-butyldiazoacetate in the presence of a rhodium catalyst
affords a 2-tert-butoxy-2-oxoethoxy derivative which may be
converted to an amine via the azide.
[0269] FIG. 2 shows a general method of preparing compounds of the
present invention. An isocyanate is coupled to
cyclohexane-1,4-diyldimethanol in the presence of pyridine to form
a carbamate. This is converted to a 2-tert-butoxy-2-oxoethoxy
derivative with tert-butyldiazoacetate in the presence of a rhodium
catalyst and the carbamate is alkylated with a halide derivative.
Finally the ester is hydrolyzed to leave a compound of Formula
(Ia).
[0270] FIG. 3 shows general methods of preparing compounds of the
present invention. First, a halide derivative is reacted with an
amine in the presence of a palladium catalyst to form a secondary
amine. This is reacted with triphosgene to form a
chlorocarbonylamine which is reacted with a cyclohexane derivative
to form an alcohol. Next, the alcohol is converted in one pot via
the 2-tert-butoxy-2-oxoethoxy derivative to a compound of Formula
(Ia) by reaction with tert-butyldiazoacetate in the presence of a
rhodium catalyst, followed by acidic hydrolysis. Alternatively, a
compound of Formula (Ia) may be prepared by reaction of the
chlorocarbonylamine with a 2-tert-butoxy-2-oxoethoxycyclohexane
derivative in pyridine followed by acidic hydrolysis. A compound of
Formula (Ia) may be converted to the corresponding sodium salt by
treatment with sodium methoxide.
[0271] FIG. 4 shows general methods for preparing compounds of
Formula (Ia). In one method a chlorocarbonylamine is reacted with
tert-butyl 2-((4-(aminomethyl)cyclohexyl)methoxy)acetate in the
presence of a base and the product is hydrolyzed. In another method
a chlorocarbonylamine is reacted with
2-((4-(aminomethyl)cyclohexyl)methoxy)acetic acid in the presence
of a base. In another method a secondary amine is reacted with
2-((4-(aminomethyl)cyclohexyl)methoxy)acetate in the presence of
triphosgene.
[0272] FIG. 5 shows method for preparing intermediates useful in
the synthesis of compounds of the present invention. tert-Butyl
(4-(hydroxymethyl)cyclohexyl)methylcarbamate can be reacted with
bromoacetic acid to form tert-butyl
2-((4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate.
The resulting intermediate may be hydrolyzed with HCl at room
temperature to give tert-butyl
2-((4-(aminomethyl)cyclohexyl)methoxy)acetate, or hydrolyzed with
HCl at 60.degree. C. to give
2-((4-(aminomethyl)cyclohexyl)methoxy)acetic acid.
[0273] FIG. 6 shows a general method of preparing compounds of the
present invention. tert-Butyl
(4-(hydroxymethyl)cyclohexyl)methylcarbamate is alkylated with
ethyl 2-diazoacetate in the presence of a rhodium catalyst to give
ethyl
2-((4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate
which may be hydrolyzed to the free amine by treatment with HCl at
room temperature. This is reacted with disuccinimidyl carbonate and
then a secondary amine to give a urea. Finally the ester is
hydrolyzed with HCl at 60.degree. C. to afford a compound of
Formula (Ia).
[0274] FIG. 7 shows the results of an experiment which measured the
ability of Compound 23 to inhibit the right ventricle hypertrophic
response to MCT-induced pulmonary arterial hypertension in rat.
[0275] FIG. 8 shows the results of an experiment which measured the
ability of Compound 22 to inhibit the right ventricle hypertrophic
response to MCT-induced pulmonary arterial hypertension in rat.
[0276] FIG. 9 depicts a powder X-ray diffraction pattern (PXRD) for
a sample containing a crystalline form (Form 1) of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate (the sodium salt of Compound 22) (PANalytical X'Pert
Plus Powder X-Ray Diffractometer; 5.0 to 40.0.degree. 26).
[0277] FIG. 10 depicts a dynamic vapor sorption (DVS) profile for
Form 1 of the sodium salt of Compound 22 (VTI dynamic vapor
sorption analyzer).
[0278] FIG. 11 depicts a differential scanning calorimetry (DSC)
thermogram for Form 1 of the sodium salt of Compound 22 (TA
Instruments DSC Q1000; 10.degree. C./min). FIG. 11 also depicts a
thermogravimetric analysis (TGA) thermogram for Form 1 of the
sodium salt of Compound 22 (TA Instruments TGA Q500 in open cell;
10.degree. C./min).
[0279] FIG. 12 depicts a thermogravimetric analysis (TGA)
thermogram for a hydrate of the sodium salt of Compound 22.
[0280] FIG. 13 depicts a powder X-ray diffraction pattern (PXRD)
for a sample containing a hydrate of the sodium salt of Compound
22.
[0281] FIG. 14 depicts a thermogravimetric analysis (TGA)
thermogram for a hydrate of the sodium salt of Compound 23.
[0282] FIG. 15 depicts a powder X-ray diffraction pattern (PXRD)
for a sample containing a hydrate of the sodium salt of Compound
23.
[0283] FIG. 16 depicts a thermogravimetric analysis (TGA)
thermogram for a solvate of the magnesium salt of Compound 23.
[0284] FIG. 17 depicts a powder X-ray diffraction pattern (PXRD)
for a sample containing a solvate of the magnesium salt of Compound
23.
[0285] FIG. 18 depicts a thermogravimetric analysis (TGA)
thermogram for a solvate of the potassium salt of Compound 23.
[0286] FIG. 19 depicts a powder X-ray diffraction pattern (PXRD)
for a sample containing a solvate of the potassium salt of Compound
23.
[0287] FIG. 20 depicts a thermogravimetric analysis (TGA)
thermogram for a solvate of the calcium salt of Compound 23.
[0288] FIG. 21 depicts a powder X-ray diffraction pattern (PXRD)
for a sample containing a solvate of the calcium salt of Compound
23.
[0289] FIG. 22 depicts the MS (top) and MS/MS (bottom) spectra of
the taurine conjugate of Compound 22 (Compound 99).
[0290] FIG. 23 depicts the MS (top) and MS/MS (bottom) spectra of
the glycine conjugate of Compound 22 (Compound 100).
[0291] FIG. 24 shows the mean plasma concentration-time profiles of
Compound 22 and Compound 22 taurine conjugate (Compound 99) after a
1.25 mg/kg oral dose of Compound 22 taurine conjugate to male
rats.
[0292] FIG. 25 shows the mean plasma concentration-time profile of
Compound 22 after a 10 mg/kg oral dose of Compound 22 sodium salt
to male rats.
[0293] FIG. 26 depicts a differential scanning calorimetry (DSC)
thermogram for the crystalline form of Compound 22 of the present
invention (TA Instruments DSC Q1000; 10.degree. C./min). FIG. 26
also depicts a thermogravimetric analysis (TGA) thermogram for the
crystalline form of Compound 22 of the present invention (TA
Instruments TGA Q500 in open cell; 10.degree. C./min).
[0294] FIG. 27 depicts a powder X-ray diffraction pattern (PXRD)
for a sample containing the crystalline form of Compound 22 of the
present invention (PANalytical X'Pert Plus Powder X-Ray
Diffractometer; 5.0 to 40.0.degree. 26).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0295] For clarity and consistency, the following definitions will
be used throughout this patent document.
[0296] The term "agonists" is intended to mean moieties that
interact and activate the receptor, such as, the PGI2 receptor and
initiate a physiological or pharmacological response characteristic
of that receptor. For example, when moieties activate the
intracellular response upon binding to the receptor, or enhance GTP
binding to membranes.
[0297] The term "contact or contacting" is intended to mean
bringing the indicated moieties together, whether in an in vitro
system or an in vivo system. Thus, "contacting" a PGI2 receptor
with a compound of the invention includes the administration of a
compound of the present invention to an individual, preferably a
human, having a PGI2 receptor, as well as, for example, introducing
a compound of the invention into a sample containing a cellular or
more purified preparation containing a PGI2 receptor.
[0298] The term "hydrate" as used herein means a compound of the
invention or a salt thereof, that further includes a stoichiometric
or non-stoichiometric amount of water bound by non-covalent
intermolecular forces.
[0299] The term "in need of treatment" and the term "in need
thereof," when referring to treatment are used interchangeably to
mean a judgment made by a caregiver (e.g. physician, nurse, nurse
practitioner, etc. in the case of humans; veterinarian in the case
of animals, including non-human mammals) that an individual or
animal requires or will benefit from treatment. This judgment is
made based on a variety of factors that are in the realm of a
caregiver's expertise, but that includes the knowledge that the
individual or animal is ill, or will become ill, as the result of a
disease, condition or disorder that is treatable by the compounds
of the invention. Accordingly, the compounds of the invention can
be used in a protective or preventive manner; or compounds of the
invention can be used to alleviate, inhibit or ameliorate the
disease, condition or disorder.
[0300] The term "individual" is intended to mean any animal,
including mammals, preferably mice, rats, other rodents, rabbits,
dogs, cats, swine, cattle, sheep, horses, or primates and most
preferably humans.
[0301] The term "modulate or modulating" is intended to mean an
increase or decrease in the amount, quality, response or effect of
a particular activity, function or molecule.
[0302] The term "pharmaceutical composition" is intended to mean a
composition comprising at least one active ingredient; including
but not limited to, salts, solvates and hydrates of compounds of
the present invention; whereby the composition is amenable to
investigation for a specified, efficacious outcome in a mammal (for
example, without limitation, a human). Those of ordinary skill in
the art will understand and appreciate the techniques appropriate
for determining whether an active ingredient has a desired
efficacious outcome based upon the needs of the artisan. The term
"solvate" as used herein means a compound of the invention or a
salt, thereof, that further includes a stoichiometric or
non-stoichiometric amount of a solvent bound by non-covalent
intermolecular forces. Preferred solvents are volatile, non-toxic,
and/or acceptable for administration to humans in trace
amounts.
[0303] The term "therapeutically effective amount" is intended to
mean the amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
animal, individual or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician or caregiver; or in
an individual, which includes one or more of the following:
[0304] (1) Preventing the disease; for example, preventing a
disease, condition or disorder in an individual that may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease,
[0305] (2) Inhibiting the disease; for example, inhibiting a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology) and
[0306] (3) Ameliorating the disease; for example, ameliorating a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., reversing the pathology
and/or symptomatology).
[0307] The term "reacting" is used herein as known in the art and
generally refers to the bringing together of chemical reagents in
such a manner so as to allow their interaction at the molecular
level to achieve a chemical or physical transformation of at least
one chemical reagent.
Chemical Group, Moiety or Radical
[0308] The term "C.sub.1-C.sub.6 acyl" is intended to mean a
C.sub.1-C.sub.6 alkyl radical attached to the carbon of a carbonyl
group wherein the definition of alkyl has the same definition as
described herein; some examples include, but are not limited to,
acetyl, propionyl, n-butanoyl, sec-butanoyl, pivaloyl, pentanoyl
and the like.
[0309] The term "C.sub.1-C.sub.6 alkoxy" is intended to mean a
C.sub.1-C.sub.6 alkyl radical, as defined herein, attached directly
to an oxygen atom. The embodiments are 1 to 5 carbons; some
embodiments are 1 to 4 carbons; some embodiments are 1 to 3
carbons; and some embodiments are 1 or 2 carbons. Examples include
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
isobutoxy, sec-butoxy and the like.
[0310] The term "C.sub.1-C.sub.6 alkyl" is intended to mean a
straight or branched carbon radical containing 1 to 6 carbons. The
embodiments are 1 to 5 carbons. The embodiments are 1 to 4 carbons.
The embodiments are 1 to 3 carbons. The embodiments are 1 or 2
carbons. The embodiments are 1 carbon. Examples of an alkyl
include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl,
isopentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3], 2-methylbutyl [i.e.,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3], n-hexyl and the like.
[0311] The term "C.sub.1-C.sub.6 alkylamino" is intended to mean
one alkyl radical attached to a NH radical wherein the alkyl
radical has the same meaning as described herein. The examples
include, but not limited to, methylamino, ethylamino,
n-propylamino, isopropylamino, n-butylamino, sec-butylamino,
isobutylamino, t-butylamino, and the like. The embodiments are
"C.sub.1-C.sub.2 alkylamino."
[0312] The term "C.sub.1-C.sub.6 alkylcarboxamido" or
"C.sub.1-C.sub.6 alkylcarboxamide" is intended to mean one
C.sub.1-C.sub.6 alkyl group attached to either the carbon or the
nitrogen of an amide group, wherein alkyl has the same definition
as found herein. The C.sub.1-C.sub.6 alkylcarboxamido may be
represented by the following:
##STR00015##
[0313] Examples include, but are not limited to,
N-methylcarboxamide, N-ethylcarboxamide, N-n-propylcarboxamide,
N-isopropylcarboxamide, N-n-butylcarboxamide,
N-sec-butylcarboxamide, N-isobutylcarboxamide, N-t-butylcarboxamide
and the like.
[0314] The term "C.sub.1-C.sub.6 alkylsulfanyl" is intended to mean
a C.sub.1-C.sub.6 alkyl radical attached to a sulfur atom (i.e., S)
wherein the alkyl radical has the same definition as described
herein. Examples include, but are not limited to, methylsulfanyl
(i.e., CH.sub.3S--), ethylsulfanyl, n-propylsulfanyl,
isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,
isobutylsulfanyl, t-butylsulfanyl, and the like.
[0315] The term "C.sub.1-C.sub.6 alkylsulfinyl" is intended to mean
a C.sub.1-C.sub.6 alkyl radical attached to the sulfur of a
sulfoxide radical having the formula: --S(O)-- wherein the alkyl
radical has the same definition as described herein. Examples
include, but are not limited to, methylsulfinyl, ethylsulfinyl,
n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl,
sec-butylsulfinyl, isobutylsulfinyl, t-butylsulfinyl, and the
like.
[0316] The term "C.sub.1-C.sub.6 alkylsulfonamide" is intended to
mean the groups shown below:
##STR00016##
wherein C.sub.1-C.sub.6 alkyl has the same definition as described
herein.
[0317] The term "C.sub.1-C.sub.6 alkylsulfonyl" is intended to mean
a C.sub.1-C.sub.6 alkyl radical attached to the sulfur of a sulfone
radical having the formula: --S(O).sub.2-- wherein the alkyl
radical has the same definition as described herein. Examples
include, but are not limited to, methylsulfonyl, ethylsulfonyl,
n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl,
sec-butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl, and the
like.
[0318] The term "amino" is intended to mean the group
--NH.sub.2.
[0319] The term "aryl" is intended to mean an aromatic ring radical
containing 6 to 10 ring carbons. Examples include phenyl and
naphthyl.
[0320] The term "carbo-C.sub.1-C.sub.6-alkoxy" is intended to mean
a C.sub.1-C.sub.6 alkyl ester of a carboxylic acid, wherein the
alkyl group is as defined herein. Examples include, but are not
limited to, carbomethoxy [--C(.dbd.O)OCH.sub.3], carbo-ethoxy,
carbo-propoxy, carbo-isopropoxy, carbo-butoxy, carbo-sec-butoxy,
carbo-isobutoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-isopentoxy,
carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy, and the
like.
[0321] The term "carboxamide" is intended to mean the group
--CONH.sub.2.
[0322] The term "carboxy" or "carboxyl" is intended to mean the
group --CO.sub.2H, also referred to as a carboxylic acid group.
[0323] The term "cyano" is intended to mean the group --CN.
[0324] The term "C.sub.2-C.sub.8 dialkylamino" is intended to mean
an amino substituted with two of the same or different
C.sub.1-C.sub.4 alkyl radicals wherein alkyl radical has the same
definition as described herein. The examples include, but are not
limited to, dimethylamino, methylethylamino, diethylamino,
methylpropylamino, methylisopropylamino, ethylpropylamino,
ethylisopropylamino, dipropylamino, propylisopropylamino and the
like. The embodiments are "C.sub.2-C.sub.4 dialkylamino."
[0325] The term "C.sub.2-C.sub.8 dialkylcarboxamido" or
"C.sub.2-C.sub.8 dialkylcarboxamide" is intended to mean two alkyl
radicals, that are the same or different, attached to an amide
group, wherein alkyl has the same definition as described herein. A
C.sub.2-C.sub.8 dialkylcarboxamido may be represented by the
following groups:
##STR00017##
[0326] wherein C.sub.1-C.sub.4 has the same definition as described
herein. Examples of a dialkylcarboxamide include, but are not
limited to, N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,
N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the
like.
[0327] The term "C.sub.2-C.sub.8 dialkylsulfonamide" is intended to
mean one of the following groups shown below:
##STR00018##
[0328] wherein C.sub.1-C.sub.4 has the same definition as described
herein, for example but not limited to, methyl, ethyl, n-propyl,
isopropyl, and the like.
[0329] The term "guanidino" is intended to mean
--NHC(.dbd.NH)NH.sub.2.
[0330] The term "halogen" or "halo" is intended to mean to a
fluoro, chloro, bromo or iodo group.
[0331] The term "C.sub.1-C.sub.6 haloalkoxy" is intended to mean a
C.sub.1-C.sub.6 haloalkyl, as defined herein, which is directly
attached to an oxygen atom. Examples include, but are not limited
to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,
pentafluoroethoxy and the like.
[0332] The term "C.sub.1-C.sub.6 haloalkyl" is intended to mean a
C.sub.1-C.sub.6 alkyl group, defined herein, wherein the alkyl is
substituted with one halogen up to fully substituted and a fully
substituted C.sub.1-C.sub.6 haloalkyl can be represented by the
formula C.sub.nL.sub.2+1 wherein L is a halogen and "n" is 1, 2, 3,
4, 5 or 6; when more than one halogen is present then they may be
the same or different and selected from the group consisting of F,
Cl, Br and I, preferably F, some embodiments are 1 to 5 carbons,
some embodiments are 1 to 4 carbons, some embodiments are 1 to 3
carbons, and some embodiments are 1 or 2 carbons. Examples of
haloalkyl groups include, but are not limited to, fluoromethyl,
difluoromethyl, trifluoromethyl, chlorodifluoromethyl,
2,2,2-trifluoroethyl, pentafluoroethyl and the like.
[0333] The term "heteroaryl" is intended to mean an aromatic ring
system containing 5 to 14 aromatic ring atoms that may be a single
ring, two fused rings or three fused rings wherein at least one
aromatic ring atom is a heteroatom selected from, but not limited
to, the group consisting of O, S and N wherein the N can be
optionally substituted with H, C.sub.1-C.sub.4 acyl or
C.sub.1-C.sub.4 alkyl. The embodiments contain 5 to 6 ring atoms
for example furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl,
thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, triazinyl and the like. The embodiments contain 8 to
14 ring atoms for example carbazolyl, quinolizinyl, quinolinyl,
isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl,
indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl,
acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl,
benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl,
benzofuranyl, isobenzofuran and the like.
[0334] The term "heterocyclic" or "heterocyclyl" is intended to
mean a ring system containing 3 to 15 ring atoms that may be a
single ring, two fused rings or three fused rings, wherein at least
one ring atom is a heteroatom or substituted heteroatom selected
from, but not limited to, the group consisting of O, S, S(.dbd.O),
S(.dbd.O).sub.2 and NH, wherein the N is optionally substituted
with C.sub.1-C.sub.4 acyl or C.sub.1-C.sub.4 alkyl. In some
embodiments, the ring carbon atoms are optionally substituted with
oxo thus forming a carbonyl group. In some embodiments the
heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered ring. In some
embodiments the heterocyclic group is a bicyclic group in which any
of the above-defined heterocyclic rings is fused to a benzene ring.
In some embodiments the heterocyclic group is a tricyclic group in
which any of the above-defined heterocyclic rings is fused to two
benzene rings. Examples of a heterocyclic group include, but are
not limited to, [1,3]-dioxolanyl, [1,4]-dioxanyl, [1,4]-oxazepanyl,
10,11-dihydro-5H-dibenzo [b,f]azepinyl, azepanyl, azetidinyl,
aziridinyl, chromanyl, dithianyl, imidazolidinyl, imidazolinyl,
indolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, succinimidyl,
tetrahydrofuranyl, tetrahydropyranyl, thiochromanyl,
thiomorpholinyl, trithianyl, xanthenyl and the like. It is
understood that a heterocyclic group can be bonded only at any
available ring carbon or ring nitrogen as allowed by the respective
formulae unless otherwise specified.
[0335] The term "hydroxyl" is intended to mean the group --OH.
[0336] The term "nitro" is intended to mean the group
--NO.sub.2.
[0337] The term "sulfo" is intended to mean the group
--SO.sub.3H.
[0338] The term "thiol" is intended to mean the group --SH.
Compounds of the Invention:
[0339] One aspect of the present invention pertains to certain
compounds as shown in Formula (XIIa):
##STR00019##
[0340] and pharmaceutically acceptable salts, solvates and hydrates
thereof, wherein:
[0341] R.sup.1, R.sup.2, X and Q have the same definitions as
described herein, supra and infra.
[0342] One aspect of the present invention pertains to certain
compounds as shown in Formula (Ia):
##STR00020##
[0343] and pharmaceutically acceptable salts, solvates and hydrates
thereof;
wherein:
[0344] R.sup.1, R.sup.2 and X have the same definitions as
described herein, supra and infra.
[0345] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination.
All combinations of the embodiments pertaining to the chemical
groups represented by the variables (e.g., R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, X and Q) contained within the generic chemical
formulae described herein, for example, (Ia), (Ic), (Ie), (Ig),
(Ii), (Ik), (Im), (II), (XIIa), (XIIIc), (XIIIe), (XIg), (XIIIi),
(XIIk), (XIm) are specifically embraced by the present invention
just as if each and every combination was individually explicitly
recited, to the extent that such combinations embrace compounds
that result in stable compounds (i.e., compounds that can be
isolated, characterized and tested for biological activity). In
addition, all subcombinations of the chemical groups listed in the
embodiments describing such variables, as well as all
subcombinations of uses and medical indications described herein,
are also specifically embraced by the present invention just as if
each and every subcombination of chemical groups and subcombination
of uses and medical indications was individually and explicitly
recited herein. In addition, all subcombinations of the salts,
solvates, hydrates and crystalline forms specifically exemplified
herein, as well as all subcombinations of uses thereof and medical
indications related thereto described herein, are also specifically
embraced by the present invention just as if each and every
subcombination of salts, solvates, hydrates and crystalline forms
specifically exemplified herein and subcombination of uses thereof
and medical indications related thereto was individually and
explicitly recited herein.
[0346] As used herein, "substituted" indicates that at least one
hydrogen atom of the chemical group is replaced by a non-hydrogen
substituent or group, the non-hydrogen substituent or group can be
monovalent or divalent. When the substituent or group is divalent,
then it is understood that this group is further substituted with
another substituent or group. When a chemical group herein is
"substituted" it may have up to the full valance of substitution;
for example, a methyl group can be substituted by 1, 2, or 3
substituents, a methylene group can be substituted by 1 or 2
substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5
substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5,
6, or 7 substituents and the like. Likewise, "substituted with one
or more substituents" refers to the substitution of a group with
one substituent up to the total number of substituents physically
allowed by the group. Further, when a group is substituted with
more than one group they can be identical or they can be
different.
[0347] Compounds of the invention can also include tautomeric
forms, such as keto-enol tautomers and the like. Tautomeric forms
can be in equilibrium or sterically locked into one form by
appropriate substitution. It is understood that the various
tautomeric forms are within the scope of the compounds of the
present invention.
[0348] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates and/or final compounds.
Isotopes include those atoms having the same atomic number but
different mass numbers. For example, isotopes of hydrogen include
deuterium and tritium.
[0349] It is understood and appreciated that compounds of Formula
(Ia) and formulae related thereto may have one or more chiral
centers and therefore can exist as enantiomers and/or
diastereoisomers. The invention is understood to extend to and
embrace all such enantiomers, diastereoisomers and mixtures
thereof, including but not limited to racemates. It is understood
that compounds of Formula (Ia) and formulae used throughout this
disclosure are intended to represent all individual enantiomers and
mixtures thereof, unless stated or shown otherwise.
[0350] It is understood and appreciated that compounds of Formula
(Ia) and formulae related thereto exist as meso isomers. Such meso
isomers may be referred to as cis and trans. The cis meso isomers
of compounds of Formula (Ia) are named herein using the prefix
(1s,4s) and the trans meso isomers of compounds of Formula (Ia) are
named herein using the prefix (1r,4r) as shown below:
##STR00021##
[0351] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula (XIIIa)
and pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00022##
[0352] wherein:
[0353] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0354] X is O or NR.sup.3;
[0355] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl;
and
[0356] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0357] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula (Ia) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00023##
[0358] wherein:
[0359] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl, hydroxyl and halogen;
[0360] X is O or NR.sup.3; and
[0361] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0362] One aspect of the present invention encompasses certain
cyclohexane derivatives selected from compounds of Formula (Ia) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00024##
[0363] wherein:
[0364] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0365] X is O or NR.sup.3; and
[0366] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0367] The Group R.sup.1:
[0368] In some embodiments, R.sup.1 is selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0369] In some embodiments, R.sup.1 is selected from:
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0370] In some embodiments, R.sup.1 is selected from:
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; each optionally
substituted with one or two substituents selected from: methoxy,
ethoxy, methyl, phenyl, trifluoromethyl, trifluoromethoxy, fluoro
and chloro.
[0371] In some embodiments, R.sup.1 is selected from:
diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,
2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,
3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl.
[0372] In some embodiments, R.sup.1 is selected from:
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with
one, two or three substituents selected from: C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylamino, C.sub.1-C.sub.6 alkylcarboxamide, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6
alkylsulfonamide, C.sub.1-C.sub.6 alkylsulfonyl, amino, aryl,
carbo-C.sub.1-C.sub.6-alkoxy, carboxamide, carboxy, cyano,
C.sub.2-C.sub.8 dialkylamino, C.sub.2-C.sub.8 dialkylcarboxamide,
C.sub.2-C.sub.8 dialkylsulfonamide, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl, halogen, hydroxyl and nitro.
[0373] In some embodiments, R.sup.1 is diphenylmethyl.
[0374] In some embodiments, R.sup.1 is 2,3-difluorophenyl.
[0375] In some embodiments, R.sup.1 is
2-fluoro-3-methoxyphenyl.
[0376] In some embodiments, R.sup.1 is 2-fluorophenyl.
[0377] In some embodiments, R.sup.1 is 2-fluoropyridin-4-yl.
[0378] In some embodiments, R.sup.1 is 2-methoxyphenyl.
[0379] In some embodiments, R.sup.1 is
3-(trifluoromethoxy)phenyl.
[0380] In some embodiments, R.sup.1 is 3,4-difluorophenyl.
[0381] In some embodiments, R.sup.1 is 3,5-difluorophenyl.
[0382] In some embodiments, R.sup.1 is 3,5-dimethylphenyl.
[0383] In some embodiments, R.sup.1 is 3-chloro-2-fluorophenyl.
[0384] In some embodiments, R.sup.1 is 3-chloro-4-fluorophenyl.
[0385] In some embodiments, R.sup.1 is 3-chloro-5-fluorophenyl.
[0386] In some embodiments, R.sup.1 is 3-chlorophenyl.
[0387] In some embodiments, R.sup.1 is 3-fluoro-4-methylphenyl.
[0388] In some embodiments, R.sup.1 is 3-fluorophenyl.
[0389] In some embodiments, R.sup.1 is 3-methoxyphenyl.
[0390] In some embodiments, R.sup.1 is 3-tolyl.
[0391] In some embodiments, R.sup.1 is
3-(trifluoromethyl)phenyl.
[0392] In some embodiments, R.sup.1 is
4-(trifluoromethoxy)phenyl.
[0393] In some embodiments, R.sup.1 is 4-chloro-3-fluorophenyl.
[0394] In some embodiments, R.sup.1 is 4-chlorophenyl.
[0395] In some embodiments, R.sup.1 is 4-ethoxyphenyl.
[0396] In some embodiments, R.sup.1 is 4-fluorophenyl.
[0397] In some embodiments, R.sup.1 is
4-methoxy-2-methylphenyl.
[0398] In some embodiments, R.sup.1 is 4-methoxyphenyl.
[0399] In some embodiments, R.sup.1 is 4-tolyl.
[0400] In some embodiments, R.sup.1 is
5-(trifluoromethyl)pyridin-2-yl.
[0401] In some embodiments, R.sup.1 is 5-chloropyridin-2-yl.
[0402] In some embodiments, R.sup.1 is 5-fluoropyridin-2-yl.
[0403] In some embodiments, R.sup.1 is 5-fluoropyridin-3-yl.
[0404] In some embodiments, R.sup.1 is 5-methoxypyridin-3-yl.
[0405] In some embodiments, R.sup.1 is 5-methylpyridin-3-yl.
[0406] In some embodiments, R.sup.1 is 5-methylthiazol-2-yl.
[0407] In some embodiments, R.sup.1 is 5-methylthiophen-2-yl.
[0408] In some embodiments, R.sup.1 is 6-fluoropyridin-3-yl.
[0409] In some embodiments, R.sup.1 is phenyl.
[0410] In some embodiments, R.sup.1 is pyrazin-2-yl.
[0411] In some embodiments, R.sup.1 is pyridin-2-yl.
[0412] In some embodiments, R.sup.1 is pyridin-3-yl.
[0413] The Group R.sup.2:
[0414] In some embodiments, R.sup.2 is selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0415] In some embodiments, R.sup.2 is selected from: H,
C.sub.1-C.sub.6 alkyl and aryl; wherein said aryl is optionally
substituted with one or two substituents selected from:
C.sub.1-C.sub.6 alkyl and halogen.
[0416] In some embodiments, R.sup.2 is selected from: H,
C.sub.1-C.sub.6 alkyl and aryl; wherein said aryl is optionally
substituted with one or two substituents selected from: methyl and
fluoro.
[0417] In some embodiments, R.sup.2 is selected from: H, methyl,
n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and
4-fluorophenyl.
[0418] In some embodiments, R.sup.2 is selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl, halogen and hydroxy.
[0419] In some embodiments, R.sup.2 is selected from: H,
C.sub.1-C.sub.6 alkyl and aryl; wherein said aryl is optionally
substituted with one or two substituents selected from:
C.sub.1-C.sub.6 alkyl, halogen and hydroxy.
[0420] In some embodiments, R.sup.2 is selected from: H,
C.sub.1-C.sub.6 alkyl and aryl; wherein said aryl is optionally
substituted with one or two substituents selected from: methyl,
fluoro and hydroxy.
[0421] In some embodiments, R.sup.2 is selected from: H, methyl,
n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl, 4-fluorophenyl
and 4-hydroxyphenyl.
[0422] In some embodiments, R.sup.2 is H.
[0423] In some embodiments, R.sup.2 is methyl.
[0424] In some embodiments, R.sup.2 is phenyl.
[0425] In some embodiments, R.sup.2 is 3-tolyl.
[0426] In some embodiments, R.sup.2 is 4-tolyl.
[0427] In some embodiments, R.sup.2 is 3-fluorophenyl.
[0428] In some embodiments, R.sup.2 is 4-fluorophenyl.
[0429] In some embodiments, R.sup.2 is 4-hydroxyphenyl.
[0430] The Group R.sup.3:
[0431] In some embodiments, R.sup.3 is H.
[0432] In some embodiments, R.sup.3 is C.sub.1-C.sub.6 alkyl.
[0433] In some embodiments, R.sup.3 is methyl.
[0434] The Group X:
[0435] In some embodiments, X is O.
[0436] In some embodiments, X is NR.sup.3.
[0437] The Group O:
[0438] In some embodiments, Q is OH.
[0439] In some embodiments, Q is --NHCH.sub.2CH.sub.2SO.sub.3H.
[0440] In some embodiments, Q is selected from:
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0441] In some embodiments, Q is selected from:
(S)-1-carboxyethylamino, (S)-1-carboxy-4-guanidinobutylamino,
(S)-3-amino-1-carboxy-3-oxopropylamino,
(S)-1,2-dicarboxyethylamino, (S)-1-carboxy-2-mercaptoethylamino,
(S)-4-amino-1-carboxy-4-oxobutylamino,
(S)-3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
(S)-1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
(1S,2S)-1-carboxy-2-methylbutylamino,
(S)-1-carboxy-3-methylbutylamino, (S)-5-amino-1-carboxypentylamino,
(S)-1-carboxy-3-(methylthio)propylamino,
(S)-1-carboxy-2-phenylethylamino, (S)-2-carboxypyrrolidin-1-yl,
(S)-1-carboxy-2-hydroxyethylamino,
(1S,2R)-1-carboxy-2-hydroxypropylamino,
(S)-1-carboxy-2-(1H-indol-3-yl)ethylamino,
(S)-1-carboxy-2-(4-hydroxyphenyl)ethylamino and
(S)-1-carboxy-2-methylpropylamino.
[0442] In some embodiments, Q is 1-carboxyethylamino.
[0443] In some embodiments, Q is
1-carboxy-4-guanidinobutylamino.
[0444] In some embodiments, Q is
3-amino-1-carboxy-3-oxopropylamino.
[0445] In some embodiments, Q is 1,2-dicarboxyethylamino.
[0446] In some embodiments, Q is
1-carboxy-2-mercaptoethylamino.
[0447] In some embodiments, Q is
4-amino-1-carboxy-4-oxobutylamino.
[0448] In some embodiments, Q is
3-carboxy-1-carboxylatopropylamino.
[0449] In some embodiments, Q is carboxymethylamino.
[0450] In some embodiments, Q is
1-carboxy-2-(1H-imidazol-4-yl)ethylamino.
[0451] In some embodiments, Q is 1-carboxy-2-methylbutylamino.
[0452] In some embodiments, Q is 1-carboxy-3-methylbutylamino.
[0453] In some embodiments, Q is 5-amino-1-carboxypentylamino.
[0454] In some embodiments, Q is
1-carboxy-3-(methylthio)propylamino.
[0455] In some embodiments, Q is 1-carboxy-2-phenylethylamino.
[0456] In some embodiments, Q is 2-carboxypyrrolidin-1-yl.
[0457] In some embodiments, Q is 1-carboxy-2-hydroxyethylamino.
[0458] In some embodiments, Q is
1-carboxy-2-hydroxypropylamino.
[0459] In some embodiments, Q is
1-carboxy-2-(1H-indol-3-yl)ethylamino.
[0460] In some embodiments, Q is
1-carboxy-2-(4-hydroxyphenyl)ethylamino.
[0461] In some embodiments, Q is 1-carboxy-2-methylpropylamino.
[0462] In some embodiments, Q is (S)-1-carboxyethylamino.
[0463] In some embodiments, Q is
(S)-1-carboxy-4-guanidinobutylamino.
[0464] In some embodiments, Q is
(S)-3-amino-1-carboxy-3-oxopropylamino.
[0465] In some embodiments, Q is (S)-1,2-dicarboxyethylamino.
[0466] In some embodiments, Q is
(S)-1-carboxy-2-mercaptoethylamino.
[0467] In some embodiments, Q is
(S)-4-amino-1-carboxy-4-oxobutylamino.
[0468] In some embodiments, Q is
(S)-3-carboxy-1-carboxylatopropylamino.
[0469] In some embodiments, Q is carboxymethylamino.
[0470] In some embodiments, Q is
(S)-1-carboxy-2-(H-imidazol-4-yl)ethylamino.
[0471] In some embodiments, Q is
(1S,2S)-1-carboxy-2-methylbutylamino.
[0472] In some embodiments, Q is
(S)-1-carboxy-3-methylbutylamino.
[0473] In some embodiments, Q is
(S)-5-amino-1-carboxypentylamino.
[0474] In some embodiments, Q is
(S)-1-carboxy-3-(methylthio)propylamino.
[0475] In some embodiments, Q is
(S)-1-carboxy-2-phenylethylamino.
[0476] In some embodiments, Q is (S)-2-carboxypyrrolidin-1-yl.
[0477] In some embodiments, Q is
(S)-1-carboxy-2-hydroxyethylamino.
[0478] In some embodiments, Q is
(1S,2R)-1-carboxy-2-hydroxypropylamino.
[0479] In some embodiments, Q is
(S)-1-carboxy-2-(1H-indol-3-yl)ethylamino.
[0480] In some embodiments, Q is
(S)-1-carboxy-2-(4-hydroxyphenyl)ethylamino.
[0481] In some embodiments, Q is
(S)-1-carboxy-2-methylpropylamino.
[0482] Certain Combinations of the Present Invention:
[0483] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIc) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00025##
[0484] wherein:
[0485] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0486] X is O or NR.sup.3;
[0487] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl;
and
[0488] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0489] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIIc) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00026##
[0490] wherein:
[0491] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0492] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl;
[0493] X is O or NR.sup.3;
[0494] R.sup.3 is selected from H and methyl; and
[0495] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H and
carboxymethylamino.
[0496] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIIe) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00027##
[0497] wherein:
[0498] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0499] X is O or NR.sup.3;
[0500] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl;
and
[0501] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0502] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIe) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00028##
[0503] wherein:
[0504] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0505] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl;
[0506] X is O or NR.sup.3;
[0507] R.sup.3 is selected from H and methyl; and
[0508] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H and
carboxymethylamino.
[0509] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIIg) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00029##
[0510] wherein:
[0511] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen; and
[0512] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl;
and
[0513] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0514] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIIg) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00030##
wherein:
[0515] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0516] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl;
[0517] R.sup.3 is selected from H and methyl; and
[0518] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H and
carboxymethylamino.
[0519] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIIi) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00031##
[0520] wherein:
[0521] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0522] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl;
and
[0523] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0524] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIi) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00032##
[0525] wherein:
[0526] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0527] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl;
[0528] R.sup.3 is selected from H and methyl; and
[0529] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H and
carboxymethylamino.
[0530] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIk) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00033##
[0531] wherein:
[0532] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen; and
[0533] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(lH-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0534] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIk) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00034##
[0535] wherein:
[0536] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-choropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0537] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl; and
[0538] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H and
carboxymethylamino.
[0539] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (XIIIm) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00035##
[0540] wherein:
[0541] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen; and
[0542] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H,
1-carboxyethylamino, 1-carboxy-4-guanidinobutylamino,
3-amino-1-carboxy-3-oxopropylamino, 1,2-dicarboxyethylamino,
1-carboxy-2-mercaptoethylamino, 4-amino-1-carboxy-4-oxobutylamino,
3-carboxy-1-carboxylatopropylamino, carboxymethylamino,
1-carboxy-2-(1H-imidazol-4-yl)ethylamino,
1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,
5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,
1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,
1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,
1-carboxy-2-(1H-indol-3-yl)ethylamino,
1-carboxy-2-(4-hydroxyphenyl)ethylamino and
1-carboxy-2-methylpropylamino.
[0543] The compound according to claim 1, selected from compounds
of Formula (XIIm) and pharmaceutically acceptable salts, solvates
and hydrates thereof:
##STR00036##
[0544] wherein:
[0545] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0546] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl; and
[0547] Q is selected from: OH, --NHCH.sub.2CH.sub.2SO.sub.3H and
carboxymethylamino.
[0548] One aspect of the present invention encompasses certain
amide derivatives selected from compounds of Formula (Ia) and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00037##
[0549] wherein:
[0550] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with
one, two or three substituents selected from: C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylamino, C.sub.1-C.sub.6 alkylcarboxamide, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6
alkylsulfonamide, C.sub.1-C.sub.6 alkylsulfonyl, amino, aryl,
carbo-C.sub.1-C.sub.6-alkoxy, carboxamide, carboxy, cyano,
C.sub.2-C.sub.8 dialkylamino, C.sub.2-C.sub.8 dialkylcarboxamide,
C.sub.2-C.sub.8 dialkylsulfonamide, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl, halogen, hydroxyl and nitro;
[0551] X is O or NR.sup.3; and
[0552] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0553] In some embodiments, R.sup.1 and R.sup.2 are each
independently selected from: H, C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; wherein C.sub.1-C.sub.6 alkyl, aryl and heteroaryl are
each optionally substituted with one, two or three substituents
selected from: C.sub.1-C.sub.6 acyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6
alkylcarboxamide, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonamide, C.sub.1-C.sub.6
alkylsulfonyl, amino, aryl, carbo-C.sub.1-C.sub.6-alkoxy,
carboxamide, carboxy, cyano, C.sub.2-C.sub.5 dialkylamino,
C.sub.2--C dialkylcarboxamide, C.sub.2-C.sub.8 dialkylsulfonamide,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl, halogen,
hydroxyl and nitro.
[0554] In some embodiments, R.sup.1 is selected from:
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with
one, two or three substituents selected from: C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylamino, C.sub.1-C.sub.6 alkylcarboxamide, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6
alkylsulfonamide, C.sub.1-C.sub.6 alkylsulfonyl, amino, aryl,
carbo-C.sub.1-C.sub.6-alkoxy, carboxamide, carboxy, cyano,
C.sub.2--C dialkylamino, C.sub.2-C.sub.8 dialkylcarboxamide,
C.sub.2-C.sub.8 dialkylsulfonamide, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl, halogen, hydroxyl and nitro; and R.sup.2
is selected from: H, C.sub.1-C.sub.6 alkyl and aryl; wherein said
aryl is optionally substituted with one or two substituents
selected from: C.sub.1-C.sub.6 alkyl and halogen.
[0555] In some embodiments, R.sup.1 is selected from:
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with
one, two or three substituents selected from: C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylamino, C.sub.1-C.sub.6 alkylcarboxamide, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6
alkylsulfonamide, C.sub.1-C.sub.6 alkylsulfonyl, amino, aryl,
carbo-C.sub.1-C.sub.6-alkoxy, carboxamide, carboxy, cyano,
C.sub.2-C.sub.8 dialkylamino, C.sub.2-C.sub.8 dialkylcarboxamide,
C.sub.2-C.sub.8 dialkylsulfonamide, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl, halogen, hydroxyl and nitro; and R.sup.2
is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,
3-fluorophenyl and 4-fluorophenyl.
[0556] In some embodiments, R.sup.1 and R.sup.2 are each
independently selected from: H, C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; wherein C.sub.1-C.sub.6 alkyl, aryl and heteroaryl are
each optionally substituted with one or two substituents selected
from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, aryl,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl and
halogen.
[0557] In some embodiments, R.sup.1 and R.sup.2 are each
independently selected from: H, C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; wherein C.sub.1-C.sub.6 alkyl, aryl and heteroaryl are
each optionally substituted with one or two substituents selected
from: methoxy, ethoxy, methyl, phenyl, trifluoromethyl,
trifluoromethoxy, fluoro and chloro.
[0558] In some embodiments, R.sup.1 and R.sup.2 are each
independently selected from: H, diphenylmethyl, 2,3-difluorophenyl,
2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,
2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,
3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, methyl, phenyl, n-propyl, pyrazin-2-yl,
pyridin-2-yl and pyridin-3-yl.
[0559] In some embodiments, R.sup.1 is selected from:
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; each optionally
substituted with one or two substituents selected from:
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, aryl,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl and halogen;
and R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen.
[0560] In some embodiments, R.sup.1 is selected from:
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; each optionally
substituted with one or two substituents selected from: methoxy,
ethoxy, methyl, phenyl, trifluoromethyl, trifluoromethoxy, fluoro
and chloro; and R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl
and aryl; wherein said aryl is optionally substituted with one or
two substituents selected from: methyl and fluoro.
[0561] In some embodiments, R.sup.1 is selected from:
diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,
2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,
3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,
3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,
3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,
3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl; and R.sup.2 is selected from: H, methyl, n-propyl,
phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl.
[0562] The embodiments of the present invention pertain to
compounds of Formula (Ic) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00038##
[0563] wherein:
[0564] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0565] X is O or NR.sup.3; and
[0566] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0567] The embodiments of the present invention pertain to
compounds of Formula (Ic) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00039##
[0568] wherein:
[0569] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0570] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl;
[0571] X is O or NR.sup.3; and
[0572] R.sup.3 is selected from H and methyl.
[0573] The embodiments of the present invention pertain to
compounds of Formula (Ie) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00040##
[0574] wherein:
[0575] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[0576] X is O or NR.sup.3; and
[0577] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0578] The embodiments of the present invention pertain to
compounds of Formula (Ie) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00041##
[0579] wherein:
[0580] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl; R is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl;
[0581] X is O or NR.sup.3; and
[0582] R.sup.3 is selected from H and methyl.
[0583] The embodiments of the present invention pertain to
compounds of Formula (Ig) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00042##
[0584] wherein:
[0585] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen; and
[0586] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0587] The embodiments of the present invention pertain to
compounds of Formula (Ig) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00043##
[0588] wherein:
[0589] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0590] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl; and
[0591] R.sup.3 is selected from H and methyl.
[0592] The embodiments of the present invention pertain to
compounds of Formula (Ii) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00044##
[0593] wherein:
[0594] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen; and
[0595] R.sup.3 is selected from H and C.sub.1-C.sub.6 alkyl.
[0596] The embodiments of the present invention pertain to
compounds of Formula (Ii) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00045##
[0597] wherein:
[0598] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl;
[0599] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl; and
[0600] R.sup.3 is selected from H and methyl.
[0601] The embodiments of the present invention pertain to
compounds of Formula (Ik) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00046##
[0602] wherein:
[0603] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0604] The embodiments of the present invention pertain to
compounds of Formula (Ik) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00047##
[0605] wherein:
[0606] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl; and
[0607] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl.
[0608] The embodiments of the present invention pertain to
compounds of Formula (Im) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00048##
[0609] wherein:
[0610] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0611] The embodiments of the present invention pertain to
compounds of Formula (m) and pharmaceutically acceptable salts,
solvates and hydrates thereof:
##STR00049##
[0612] wherein:
[0613] R.sup.1 is selected from: diphenylmethyl,
2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,
2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,
3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,
3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,
3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,
4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl,
4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,
5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,
5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,
5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,
6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl and
pyridin-3-yl; and
[0614] R.sup.2 is selected from: H, methyl, n-propyl, phenyl,
3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl.
[0615] The embodiments of the present invention include every
combination of one or more compounds selected from the following
group: [0616]
2-((-4-((3-benzhydrylureido)methyl)cyclohexyl)methoxy)acetic acid;
[0617] 2-((-4-((3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic
acid; [0618]
2-((-4-((3-(3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acet-
ic acid; [0619]
2-((-4-((1-methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic
acid; [0620]
2-((-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic
acid; [0621]
2-((-4-((3-(3-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)metho-
xy)acetic acid; [0622]
2-((-4-((3-(4-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acet-
ic acid; [0623]
2-((-4-((3-(2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acet-
ic acid; [0624]
2-((-4-((3-(4-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acet-
ic acid; [0625]
2-((-4-((3-phenyl-3-m-tolylureido)methyl)cyclohexyl)methoxy)acetic
acid; [0626]
2-((-4-((3-phenyl-3-p-tolylureido)methyl)cyclohexyl)methoxy)acetic
acid; [0627]
2-((-4-(((3-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic acid; [0628] 2-((-4-((3,3-di
p-tolylureido)methyl)cyclohexyl)methoxy)acetic acid; [0629]
2-((-4-((3,3-di m-tolylureido)methyl)cyclohexyl)methoxy)acetic
acid; [0630]
2-((-4-((3-(3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)meth-
oxy)acetic acid; [0631]
2-((-4-((3-(4-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)ace-
tic acid; [0632]
2-((-4-((3-(4-methoxy-2-methylphenyl)-3-phenylureido)methyl)cyclohexyl)me-
thoxy)acetic acid; [0633]
2-((-4-((3-phenyl-3-(3-(trifluoromethyl)phenyl)ureido)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0634]
2-((-4-(((4-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic acid; [0635]
2-((-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)a-
cetic acid; [0636]
2-((-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)a-
cetic acid; [0637]
2-((-4-((phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic
acid; [0638]
2-((-4-(((3-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)a-
cetic acid; [0639]
2-((-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;
[0640]
2-((-4-(((2-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic acid; [0641]
2-((-4-((phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic
acid; [0642]
2-((-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)a-
cetic acid; [0643]
2-((-4-(((4-chloro-3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetic acid; [0644]
2-((-4-(((3-chloro-4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetic acid; [0645]
2-((-4-(((3-fluoro-4-methylphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetic acid; [0646]
2-((-4-(((3,5-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)metho-
xy)acetic acid; [0647]
2-((-4-(((3,4-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)metho-
xy)acetic acid; [0648]
2-((-4-((3-(2,3-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)-
acetic acid; [0649]
2-((-4-((3-(3,5-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)-
acetic acid; [0650]
2-((-4-((3-(3-chloro-2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)met-
hoxy)acetic acid; [0651]
2-((-4-(((3-chloro-5-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetic acid; [0652]
2-((-4-((3-(3-chloro-5-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)met-
hoxy)acetic acid; [0653]
2-((-4-((3-benzhydryl-3-methylureido)methyl)cyclohexyl)methoxy)acetic
acid; [0654]
2-((-4-((phenyl(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceti-
c acid; [0655]
2-((-4-(((5-methylthiophen-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid; [0656]
2-((-4-(((2,3-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)metho-
xy)acetic acid; [0657]
2-((-4-((3-(4-chloro-3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)met-
hoxy)acetic acid; [0658]
2-((-4-((3-(2-fluoro-3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)me-
thoxy)acetic acid; [0659]
2-((-4-((3-(3,4-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)-
acetic acid; [0660]
2-((-4-(((3-fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetic acid; [0661]
2-((-4-(((4-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0662]
2-((-4-(((3-fluorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0663]
2-((-4-(((3-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0664]
2-((-4-(((3-fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic acid; [0665]
2-((-4-(((4-chloro-3-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyc-
lohexyl)methoxy)acetic acid; [0666]
2-((-4-(((3-chloro-4-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyc-
lohexyl)methoxy)acetic acid; [0667]
2-((-4-(((3-fluoro-4-methylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyc-
lohexyl)methoxy)acetic acid; [0668]
2-((-4-((phenyl(pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceti-
c acid; [0669]
2-((-4-(((3,5-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic acid; [0670]
2-((-4-(((3,4-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic acid; [0671]
2-((-4-((bis(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic
acid; [0672]
2-((-4-(((3-fluorophenyl)(3-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetic acid; [0673]
2-((-4-(((3,5-dimethylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic acid; [0674]
2-((-4-(((3-fluorophenyl)(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic acid; [0675]
2-((-4-(((3-fluorophenyl)(6-fluoropyridin-3-yl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic acid; [0676]
2-((-4-(((3-fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic acid; [0677]
2-((-4-(((4-ethoxyphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0678]
2-((-4-(((3-fluorophenyl)(3-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)-
cyclohexyl)methoxy)acetic acid; [0679]
2-((-4-(((3-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0680]
2-((-4-(((3-fluorophenyl)(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0681]
2-((-4-(((4-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0682]
2-((-4-(((4-fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic acid; [0683]
2-((-4-(((3-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0684]
2-((-4-(((4-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0685]
2-((-4-(((4-ethoxyphenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic acid; [0686]
2-((-4-(((4-fluorophenyl)(4-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)-
cyclohexyl)methoxy)acetic acid; [0687]
2-((-4-(((4-fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic acid; [0688]
2-((-4-((bis(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic
acid; [0689]
2-((-4-(((6-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0690]
2-((-4-((phenyl(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceti-
c acid; [0691]
2-((-4-((benzhydryl(methyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic
acid; [0692]
2-((-4-((3-benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy)acetic
acid; [0693]
2-((-4-(((4-ethoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)a-
cetic acid; [0694]
2-((-4-(((2-fluoropyridin-4-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0695]
2-((-4-(((5-methoxypyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid; [0696]
2-((-4-(((5-fluoropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0697]
2-((-4-((phenyl(5-(trifluoromethyl)pyridin-2-yl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic acid; [0698]
2-((-4-(((5-methylpyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0699]
2-((-4-(((5-chloropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0700]
2-((-4-(((5-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid; [0701]
2-((-4-((benzhydryl(propyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic
acid; and [0702]
2-((-4-(((5-methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid.
[0703] The embodiments of the present invention include every
combination of one or more compounds selected from the following
group shown in TABLE A.
TABLE-US-00001 TABLE A Cmpd No. Chemical Structure Chemical Name 1
##STR00050## 2-(((1r,4r)-4-((3- benzhydrylureido)methyl)
cyclohexyl)methoxy)acetic acid 2 ##STR00051## 2-(((1r,4r)-4-((3,3-
diphenylureido)methyl) cyclohexyl)methoxy)acetic acid 3
##STR00052## 2-(((1r,4r)-4-((3-(3- fluorophenyl)-3-
phenylureido)methyl) cyclohexyl)methoxy)acetic acid 4 ##STR00053##
2-(((1r,4r)-4-((1-methyl-3,3- diphenylureido)methyl)
cyclohexyl)methoxy)acetic acid 5 ##STR00054## 2-(((1r,4r)-4-
((diphenylcarbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 6
##STR00055## 2-(((1r,4r)-4-((3-(3- chlorophenyl)-3-
phenylureido)methyl) cyclohexyl)methoxy)acetic acid 7 ##STR00056##
2-(((1s,4s)-4- ((diphenylcarbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 8 ##STR00057## 2-(((1r,4r)-4-((3-(4-
fluorophenyl)-3- phenylureido)methyl) cyclohexyl)methoxy)acetic
acid 9 ##STR00058## 2-(((1s,4s)-4-((3,3- diphenylureido)methyl)
cyclohexyl)methoxy)acetic acid 10 ##STR00059##
2-(((1r,4r)-4-((3-(2- fluorophenyl)-3- phenylureido)methyl)
cyclohexyl)methoxy)acetic acid 11 ##STR00060##
2-(((1r,4r)-4-((3-(4- chlorophenyl)-3- phenylureido)methyl)
cyclohexyl)methoxy)acetic acid 12 ##STR00061##
2-(((1r,4r)-4-((3-phenyl-3-m- tolylureido)methyl)
cyclohexyl)methoxy)acetic acid 13 ##STR00062##
2-(((1r,4r)-4-((3-phenyl-3-p- tolylureido)methyl)
cyclohexyl)methoxy)acetic acid 14 ##STR00063## 2-(((1r,4r)-4-(((3-
methoxyphenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 15 ##STR00064##
2-(((1r,4r)-4-((3,3-di p- tolylureido)methyl)
cyclohexyl)methoxy)acetic acid 16 ##STR00065##
2-(((1r,4r)-4-((3,3-di m- tolylureido)methyl)
cyclohexyl)methoxy)acetic acid 17 ##STR00066##
2-(((1r,4r)-4-((3-(3- methoxyphenyl)-3- phenylureido)methyl)
cyclohexyl)methoxy)acetic acid 18 ##STR00067##
2-(((1r,4r)-4-((3-(4- methoxyphenyl)-3- phenylureido)methyl)
cyclohexyl)methoxy)acetic acid 19 ##STR00068##
2-(((1r,4r)-4-((3-(4-methoxy-2- methylphenyl)-3-
phenylureido)methyl) cyclohexyl)methoxy)acetic acid 20 ##STR00069##
2-(((1r,4r)-4-((3-phenyl-3-(3- (trifluoromethyl)phenyl)
ureido)methyl) cyclohexyl)methoxy)acetic acid 21 ##STR00070##
2-(((1r,4r)-4-(((4- methoxyphenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 22 ##STR00071## 2-(((1r,4r)-4-(((4-
chlorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 23 ##STR00072## 2-(((1r,4r)-4-(((3-
fluorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 24 ##STR00073## 2-(((1s,4s)-4-(((4-
methoxyphenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 25 ##STR00074## 2-(((1s,4s)-4-(((4-
chlorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 26 ##STR00075## 2-(((1s,4s)-4-(((3-
fluorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 27 ##STR00076##
2-(((1r,4r)-4-((phenyl(m- tolyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 28 ##STR00077## 2-(((1r,4r)-4-(((3-
chlorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 29 ##STR00078## 2-(((1r,4r)-4-
((phenylcarbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 30
##STR00079## 2-(((1s,4s)-4-(((3- chlorophenyl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 31 ##STR00080##
2-(((1s,4s)-4-((phenyl(m- tolyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 32 ##STR00081## 2-(((1s,4s)-4-(((2-
methoxyphenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 33 ##STR00082## 2-(((1s,4s)-4-(((3-
methoxyphenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 34 ##STR00083##
2-(((1s,4s)-4-((phenyl(p- tolyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 35 ##STR00084## 2-(((1s,4s)-4-(((4-
fluorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 36 ##STR00085##
2-(((1r,4r)-4-(((4-chloro-3- fluorophenyl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 37 ##STR00086##
2-(((1r,4r)-4-(((3-chloro-4- fluorophenyl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 38 ##STR00087##
2-(((1r,4r)-4-(((3-fluoro-4- methylphenyl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 39 ##STR00088##
2-(((1r,4r)-4-(((3,5- difluorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 40 ##STR00089##
2-(((1r,4r)-4-(((3,4- difluorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 41 ##STR00090## 2-(((1r,4r)-4-(((4-
fluorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 42 ##STR00091##
2-(((1r,4r)-4-((phenyl(p- tolyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 43 ##STR00092##
2-(((1r,4r)-4-((3-(2,3- difluorophenyl)-3- phenylureido)methyl)
cyclohexyl)methoxy)acetic acid 44 ##STR00093##
2-(((1r,4r)-4-((3-(3,5- difluorophenyl)-3- phenylureido)methyl)
cyclohexyl)methoxy)acetic acid 45 ##STR00094##
2-(((1r,4r)-4-((3-(3-chloro-2- fluorophenyl)-3-
phenylureido)methyl) cyclohexyl)methoxy)acetic acid 46 ##STR00095##
2-(((1r,4r)-4-(((3-chloro-5- fluorophenyl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 47 ##STR00096##
2-(((1r,4r)-4-((3-(3-chloro-5- fluorophenyl)-3-
phenylureido)methyl) cyclohexyl)methoxy)acetic acid 48 ##STR00097##
2-(((1r,4r)-4-((3-benzhydryl-3- methylureido)methyl)
cyclohexyl)methoxy)acetic acid 49 ##STR00098##
2-(((1r,4r)-4-((phenyl(pyridin-3- yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 50 ##STR00099##
2-(((1r,4r)-4-(((5-methylthiophen- 2-yl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 51 ##STR00100##
2-(((1r,4r)-4-(((2,3- difluorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 52 ##STR00101##
2-(((1r,4r)-4-((3-(4-chloro-3- fluorophenyl)-3-
phenylureido)methyl) cyclohexyl)methoxy)acetic acid 53 ##STR00102##
2-(((1r,4r)-4-((3-(2-fluoro-3- methoxyphenyl)-3-
phenylureido)methyl) cyclohexyl)methoxy)acetic acid 54 ##STR00103##
2-(((1r,4r)-4-((3-(3,4- difluorophenyl)-3- phenylureido)methyl)
cyclohexyl)methoxy)acetic acid 55 ##STR00104## 2-(((1r,4r)-4-(((3-
fluorophenyl)(4- methoxyphenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 56 ##STR00105## 2-(((1r,4r)-4-(((4-
chlorophenyl)(3- fluorophenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 57 ##STR00106## 2-(((1r,4r)-4-(((3-
fluorophenyl)(4- fluorophenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 58 ##STR00107## 2-(((1r,4r)-4-(((3-
chlorophenyl)(3- fluorophenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 59 ##STR00108## 2-(((1r,4r)-4-(((3-
fluorophenyl)(m- tolyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 60 ##STR00109##
2-(((1r,4r)-4-(((4-chloro-3- fluorophenyl)(3-
fluorophenyl)carbamoyloxy) methyl)cyclohexyl) methoxy)acetic acid
61 ##STR00110## 2-(((1r,4r)-4-(((3-chloro-4- fluorophenyl)(3-
fluorophenyl)carbamoyloxy) methyl)cyclohexyl) methoxy)acetic acid
62 ##STR00111## 2-(((1r,4r)-4-(((3-fluoro-4- methylphenyl)(3-
fluorophenyl)carbamoyloxy) methyl)cyclohexyl) methoxy)acetic acid
63 ##STR00112## 2-(((1r,4r)-4-((phenyl(pyridin-2-
yl)carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 64
##STR00113## 2-(((1r,4r)-4-(((3,5- difluorophenyl)(3-
fluorophenyl)carbamoyloxy) methyl)cyclohexyl) methoxy)acetic acid
65 ##STR00114## 2-(((1r,4r)-4-(((3,4- difluorophenyl)(3-
fluorophenyl)carbamoyloxy) methyl)cyclohexyl) methoxy)acetic acid
66 ##STR00115## 2-(((1r,4r)-4-((bis(3- fluorophenyl)carbamoyloxy)
methyl)cyclohexyl) methoxy)acetic acid 67 ##STR00116##
2-(((1r,4r)-4-(((3- fluorophenyl)(3- methoxyphenyl)carbamoyloxy)
methyl)cyclohexyl) methoxy)acetic acid 68 ##STR00117##
2-(((1r,4r)-4-(((3,5- dimethylphenyl)(3- fluorophenyl)carbamoyloxy)
methyl)cyclohexyl) methoxy)acetic acid 69 ##STR00118##
2-(((1r,4r)-4-(((3- fluorophenyl)(p- tolyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 70 ##STR00119## 2-(((1r,4r)-4-(((3-
fluorophenyl)(6-fluoropyridin-3- yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 71 ##STR00120## 2-(((1r,4r)-4-(((3-
fluorophenyl)(5-methylthiophen- 2-yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 72 ##STR00121## 2-(((1r,4r)-4-(((4-
ethoxyphenyl)(3- fluorophenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 73 ##STR00122## 2-(((1r,4r)-4-(((3-
fluorophenyl)(3- (trifluoromethoxy)phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 74 ##STR00123## 2-(((1r,4r)-4-(((3-
fluorophenyl)(pyridin-3- yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 75 ##STR00124## 2-(((1r,4r)-4-(((3-
fluorophenyl)(pyrazin-2- yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 76 ##STR00125## 2-(((1r,4r)-4-(((4-
chlorophenyl)(4- fluorophenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 77 ##STR00126## 2-(((1r,4r)-4-(((4-
fluorophenyl)(5-methylthiophen- 2-yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 78 ##STR00127## 2-(((1r,4r)-4-(((3-
chlorophenyl)(4- fluorophenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 79 ##STR00128## 2-(((1r,4r)-4-(((4-
fluorophenyl)(pyridin-3- yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 80 ##STR00129## 2-(((1r,4r)-4-(((4-
ethoxyphenyl)(4- fluorophenyl)carbamoyloxy) methyl)cyclohexyl)
methoxy)acetic acid 81 ##STR00130## 2-(((1r,4r)-4-(((4-
fluorophenyl)(4- (trifluoromethoxy)phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid
82 ##STR00131## 2-(((1r,4r)-4-(((4- fluorophenyl)(m-
tolyl)carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 83
##STR00132## 2-(((1r,4r)-4-((bis(4- fluorophenyl)carbamoyloxy)
methyl)cyclohexyl) methoxy)acetic acid 84 ##STR00133##
2-(((1r,4r)-4-(((6-fluoropyridin-3- yl)(phenyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 85 ##STR00134##
2-(((1r,4r)-4-((phenyl(pyrazin-2- yl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 86 ##STR00135## 2-(((1r,4r)-4-
((benzhydryl(methyl) carbamoyloxy)methyl) cyclohexyl)methoxy)acetic
acid 87 ##STR00136## 2-(((1r,4r)-4-((3-benzhydryl-1,3-
dimethylureido)methyl) cyclohexyl)methoxy)acetic acid 88
##STR00137## 2-(((1r,4r)-4-(((4- ethoxyphenyl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 89 ##STR00138##
2-(((1r,4r)-4-(((2-fluoropyridin-4- yl)(phenyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 90 ##STR00139## 2-(((1r,4r)-4-(((5-
methoxypyridin-3- yl)(phenyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 91 ##STR00140##
2-(((1r,4r)-4-(((5-fluoropyridin-2- yl)(phenyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 92 ##STR00141##
2-(((1r,4r)-4-((phenyl(5- (trifluoromethyl)pyridin-2-
yl)carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 93
##STR00142## 2-(((1r,4r)-4-(((5-methylpyridin- 3-yl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 94 ##STR00143##
2-(((1r,4r)-4-(((5-chloropyridin-2- yl)(phenyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 95 ##STR00144##
2-(((1r,4r)-4-(((5-fluoropyridin-3- yl)(phenyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 96 ##STR00145##
2-(((1r,4r)-4-((benzhydryl(propyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetic acid 97 ##STR00146##
2-(((1r,4r)-4-(((5-methylthiazol- 2-yl)(phenyl)
carbamoyloxy)methyl) cyclohexyl)methoxy)acetic acid 98 ##STR00147##
2-(((1r,4r)-4-(((4- chlorophenyl)(4- hydroxyphenyl)carbamoyloxy)
methyl)cyclohexyl)methoxy) acetic acid 99 ##STR00148##
2-(2-(((1r,4r)-4-(((4- chlorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetamido) ethanesulfonic acid 100 ##STR00149##
2-(2-(((1r,4r)-4-(((4- chlorophenyl)(phenyl) carbamoyloxy)methyl)
cyclohexyl)methoxy)acetamido) acetic acid
[0704] Additionally, individual compounds and chemical genera of
the present invention, for example those compounds found in TABLE A
including diastereoisomers and enantiomers thereof, encompass all
pharmaceutically acceptable salts, solvates and particularly
hydrates, thereof. Further, mesoisomers of individual compounds and
chemical genera of the present invention, for example those
compounds found in TABLE A, encompass all pharmaceutically
acceptable salts, solvates and particularly hydrates, thereof. The
compounds of the Formula (Ia) of the present invention may be
prepared according to relevant published literature procedures that
are used by one skilled in the art. Exemplary reagents and
procedures for these reactions appear hereinafter in the working
Examples.
[0705] The embodiments of the present invention include every
combination of one or more salts selected from the following group
and pharmaceutically acceptable solvates and hydrates thereof:
[0706] sodium
2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate;
[0707] sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0708] sodium
2-(((1r,4r)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0709] sodium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0710] magnesium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0711] potassium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; and [0712] calcium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate.
[0713] It is understood that the present invention embraces each
diastereoisomer, each enantiomer and mixtures thereof of each
compound and generic formulae disclosed herein just as if they were
each individually disclosed with the specific stereochemical
designation for each chiral carbon. Separation of the individual
isomers (such as, by chiral HPLC, recrystallization of
diastereoisomeric mixtures and the like) or selective synthesis
(such as, by enantiomeric selective syntheses and the like) of the
individual isomers is accomplished by application of various
methods which are well known to practitioners in the art.
Indications and Methods of Prophylaxis and/or Treatment
[0714] In addition to the foregoing beneficial uses for the
modulators of PGI2 receptor activity disclosed herein, the
compounds disclosed herein are useful in the treatment of several
additional diseases and disorders, and in the amelioration of
symptoms thereof. Without limitation, these include the
following:
[0715] 1. Pulmonary Arterial Hypertension (PAR)
[0716] Pulmonary arterial hypertension (PAH) has a multifactorial
pathobiology. Vasoconstriction, remodeling of the pulmonary vessel
wall, and thrombosis contribute to increased pulmonary vascular
resistance in PAH (Humbert et al., J. Am. Coll. Cardiol., 2004,
43:13S-24S.)
[0717] The compounds of the present invention disclosed herein are
useful in the treatment of pulmonary arterial hypertension (PAH)
and symptoms thereof. PAH shall be understood to encompass the
following forms of pulmonary arterial hypertension described in the
2003 World Health Organization (WHO) clinical classification of
pulmonary arterial hypertension: idiopathic PAH (IPAH); familial
PAH (FPAH); PAH associated with other conditions (APAH), such as
PAH associated with collagen vascular disease, PAH associated with
congenital systemic-to-pulmonary shunts, PAH associated with portal
hypertension, PAH associated with HIV infection, PAR associated
with drugs or toxins, or PAH associated with Other; and PAH
associated with significant venous or capillary involvement.
[0718] Idiopathic PAH refers to PAH of undetermined cause.
[0719] Familial PAH refers to PAH for which hereditary transmission
is suspected or documented.
[0720] PAH associated with collagen vascular disease shall be
understood to encompass PAH associated with scleroderma, PAH
associated with CREST (calcinosis cutis, Raynaud's phenomenon,
esophageal dysfunction, sclerodactyly, and telangiectasias)
syndrome, PAH associated with systemic lupus erythematosus (SLE),
PAH associated with rheumatoid arthritis, PAH associated with
Takayasu's arteritis, PAH associated with polymyositis, and PAH
associated with dermatomyositis.
[0721] PAH associated with congenital systemic-to-pulmonary shunts
shall be understood to encompass PAH associated with atrial septic
defect (ASD), PAH associated with ventricular septic defect (VSD)
and PAH associated with patent ductus arteriosus.
[0722] PAH associated with drugs or toxins shall be understood to
encompass PAH associated with ingestion of aminorex, PAH associated
with ingestion of a fenfluramine compound (e.g., PAH associated
with ingestion of fenfluramine or PAH associated with ingestion of
dexfenfluramine), PAH associated with ingestion of certain toxic
oils (e.g., PAH associated with ingestion of rapeseed oil), PAH
associated with ingestion of pyrrolizidine alkaloids (e.g., PAH
associated with ingestion of bush tea) and PAH associated with
ingestion of monocrotaline.
[0723] PAH associated with Other shall be understood to encompass
PAH associated with a thyroid disorder, PAH associated with
glycogen storage disease, PAH associated with Gaucher disease, PAH
associated with hereditary hemorrhagic telangiectasia, PAH
associated with a hemoglobinopathy, PAH associated with a
myeloproliferative disorder, and PAH associated with
splenectomy.
[0724] PAH associated with significant venous or capillary
involvement shall be understood to encompass PAH associated with
pulmonary veno-occlusive disease (PVOD) and PAR associated with
pulmonary capillary hemangiomatosis (PCH).
[0725] (See, e.g., Simonneau et al., J. Am. Coll. Cardiol., 2004,
43:5S-12S; McGoon et al., Chest, 2004, 126:14S-34S; Rabinovitch,
Annu. Rev. Pathol. Mech. Dis., 2007, 2:369-399; McLaughlin et al.,
Circulation, 2006, 114:1417-1431; Strauss et al., Clin. Chest.
Med., 2007, 28:127-142; Taichman et al., Clin. Chest. Med., 2007,
28:1-22.)
[0726] Evidence for the association of PAH with scleroderma and the
beneficial effect of an agonist of the PGI2 receptor on PAH is
given by Badesch et al. (Badesch et al., Ann. Intern. Med., 2000,
132:425-434). Evidence for the association of PAH with the collagen
vascular diseases mixed connective tissue disease (MCTD), systemic
lupus erythematosus (SLE), Sjogren's syndrome and CREST syndrome
and the beneficial effect of an agonist of the PGI2 receptor on PAH
is given by Humbert et al. (Eur. Respir. J., 1999, 13:1351-1356).
Evidence for the association of PAH with CREST syndrome and the
beneficial effect of an agonist of the PGI2 receptor on PAH is
given by Miwa et al. (Int. Heart J., 2007, 48:417-422). Evidence
for the association of PAH with SLE and the beneficial effect of an
agonist of the PGI2 receptor on PAH is given by Robbins et al.
(Chest, 2000, 117:14-18). Evidence for the association of PAH with
HIV infection and the beneficial of an agonist of the PGI2 receptor
on PAH is given by Aguilar et al. (Am. J. Respir. Crit. Care Med.,
2000, 162:1846-1850). Evidence for the association of PAH with
congenital heart defects (including ASD, VSD and patent ductus
arteriosus) and the beneficial effect of an agonist of the PGI2
receptor on PAH is given by Rosenzweig et al. (Circulation, 1999,
99:1858-1865). Evidence for the association of PAH with
fenfluramine and with dexfenfluramine, anorexigens, is given by
Archer et al. (Am. J. Respir. Crit. Care Med., 1998,
158:1061-1067). Evidence for the association of PAH with hereditary
hemorrhagic telangiectasia is given by McGoon et al. (Chest, 2004,
126:14-34). Evidence for the association of PAH with splenectomy is
given by Hoeper et al. (Ann. Intern. Med., 1999, 130:506-509).
Evidence for the association of PAH with portal hypertension and
the beneficial effect of an agonist of the PGI2 receptor on PAH is
given by Hoeper et a. (Eur. Respir. J., 2005, 25:502-508).
[0727] Symptoms of PAH include dyspnea, angina, syncope and edema
(McLaughlin et al., Circulation, 2006, 114:1417-1431). The
compounds of the present invention disclosed herein are useful in
the treatment of symptoms of PAH.
[0728] 2. Antiplatelet Therapies (Conditions Related to Platelet
Aggregation)
[0729] Antiplatelet agents (antiplatelets) are prescribed for a
variety of conditions. For example, in coronary artery disease they
are used to help prevent myocardial infarction or stroke in
patients who are at risk of developing obstructive blood clots
(e.g., coronary thrombosis).
[0730] In a myocardial infarction ("MI" or "heart attack"), the
heart muscle does not receive enough oxygen-rich blood as a result
of a blockage in the coronary blood vessels. If taken while an
attack is in progress or immediately afterward (preferably within
30 min), antiplatelets can reduce the damage to the heart.
[0731] A transient ischemic attack ("TIA" or "mini-stroke") is a
brief interruption of oxygen flow to the brain due to decreased
blood flow through arteries, usually due to an obstructing blood
clot. Antiplatelet drugs have been found to be effective in
preventing TIAs.
[0732] Angina is a temporary and often recurring chest pain,
pressure or discomfort caused by inadequate oxygen-rich blood flow
(ischemia) to some parts of the heart. In patients with angina,
antiplatelet therapy can reduce the effects of angina and the risk
of myocardial infarction.
[0733] Stroke is an event in which the brain does not receive
enough oxygen-rich blood, usually due to blockage of a cerebral
blood vessel by a blood clot. In high-risk patients, taking
antiplatelets regularly has been found to prevent the formation of
blood clots that cause first or second strokes.
[0734] Angioplasty is a catheter based technique used to open
arteries obstructed by a blood clot. Whether or not stenting is
performed immediately after this procedure to keep the artery open,
antiplatelets can reduce the risk of forming additional blood clots
following the procedure(s).
[0735] Coronary bypass surgery is a surgical procedure in which an
artery or vein is taken from elsewhere in the body and grafted to a
blocked coronary artery, rerouting blood around the blockage and
through the newly attached vessel. After the procedure,
antiplatelets can reduce the risk of secondary blood clots.
[0736] Atrial fibrillation is the most common type of sustained
irregular heart rhythm (arrhythmia). Atrial fibrillation affects
about two million Americans every year. In atrial fibrillation, the
atria (the heart's upper chambers) rapidly fire electrical signals
that cause them to quiver rather than contract normally. The result
is an abnormally fast and highly irregular heartbeat. When given
after an episode of atrial fibrillation, antiplatelets can reduce
the risk of blood clots forming in the heart and traveling to the
brain (embolism).
[0737] There is evidence that a PGI2 receptor agonist will inhibit
platelet aggregation and thus be a potential treatment as an
antiplatelet therapy (see, e.g., Moncada et al., Lancet, 1977,
1:18-20). It has been shown that genetic deficiency of the PGI2
receptor in mice leads to an increased propensity towards
thrombosis (Murata et al., Nature, 1997, 388:678-682).
[0738] PGI2 receptor agonists can be used to treat, for example,
claudication or peripheral artery disease as well as cardiovascular
complications, arterial thrombosis, atherosclerosis,
vasoconstriction caused by serotonin, ischemia-reperfusion injury,
and restenosis of arteries following angioplasty or stent
placement. (See, e.g., Fetalvero et al., Prostaglandins Other Lipid
Mediat., 2007, 82:109-118; Arehart et al., Curr. Med. Chem., 2007,
14:2161-2169; Davi et al., N. Engl. J. Med., 2007, 357:2482-2494;
Fetalvero et al., Am. J. Physiol. Heart. Circ. Physiol., 2006,
290:H1337-H1346; Murata et al., Nature, 1997, 388:678-682; Wang et
al., Proc. Natl. Acad. Sci. USA, 2006, 103:14507-14512; Xiao et
al., Circulation, 2001, 104:2210-2215; McCormick et al., Biochem.
Soc. Trans., 2007, 35:910-911; Arehart et al., Circ. Res., 2008,
Mar. 6 Epub ahead of print.)
[0739] PGI2 receptor agonists can also be used alone or in
combination with thrombolytic therapy, for example, tissue-type
plasminogen activator (t-PA), to provide cardioprotection following
MI or postischemic myocardial dysfunction or protection from
ischemic injury during percutaneous coronary intervention, and the
like, including complications resulting therefrom. PGI2 receptor
agonists can also be used in antiplatelet therapies in combination
with, for example, alpha-tocopherol (vitamin E), echistatin (a
disintegrin) or, in states of hypercoagulability, heparin. (See,
e.g., Chan., J. Nutr., 1998, 128:1593-1596; Mardla et al.,
Platelets, 2004, 15:319-324; Bernabei et al., Ann. Thorac. Surg.,
1995, 59:149-153; Gainza et al., J. Nephrol., 2006,
19:648-655.)
[0740] The PGI2 receptor agonists disclosed herein provide
beneficial improvement in microcirculation to patients in need of
antiplatelet therapy by antagonizing the vasoconstrictive products
of the aggregating platelets in, for example and not limited to the
indications described above. Accordingly, in some embodiments, the
present invention provides methods for reducing platelet
aggregation in a patient in need thereof, comprising administering
to the patient a composition comprising a PGI2 receptor agonist
disclosed herein. In further embodiments, the present invention
provides methods for treating coronary artery disease, myocardial
infarction, transient ischemic attack, angina, stroke, atrial
fibrillation, or a symptom of any of the foregoing in a patient in
need of the treatment, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed
herein.
[0741] In further embodiments, the present invention provides
methods for reducing risk of blood clot formation in an angioplasty
or coronary bypass surgery patient, or a patient suffering from
atrial fibrillation, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein at
a time where such risk exists.
[0742] 3. Atherosclerosis
[0743] Atherosclerosis is a complex disease characterized by
inflammation, lipid accumulation, cell death and fibrosis. It is
the leading cause of mortality in many countries, including the
United States. Atherosclerosis, as the term is used herein, shall
be understood to encompass disorders of large and medium-sized
arteries that result in the progressive accumulation within the
intima of smooth muscle cells and lipids.
[0744] It has been shown that an agonist of the PGI2 receptor can
confer protection from atherosclerosis, such as from
atherothrombosis (Arehart et al., Curr. Med. Chem., 2007,
14:2161-2169; Stitham et al., Prostaglandins Other Lipid Mediat.,
2007, 82:95-108; Fries et al., Hematology Am. Soc. Hematol. Educ.
Program, 2005:445-451; Egan et al., Science, 2004, 306:1954-1957;
Kobayashi et al., J. Clin. Invest., 2004, 114:784-794; Arehart et
al., Circ. Res., 2008, Mar. 6 Epub ahead of print).
[0745] It has been shown that defective PGI2 receptor signaling
appears to accelerate atherothrombosis in humans, i.e. that an
agonist of the PGI2 receptor can confer protection from
atherothrombosis in humans (Arehart et al., Circ. Res., 2008, Mar.
6 Epub ahead of print).
[0746] The compounds of the present invention disclosed herein are
useful in the treatment of atherosclerosis, and the treatment of
the symptoms thereof. Accordingly, in some embodiments, the present
invention provides methods for treating atherosclerosis in a
patient in need of the treatment, comprising administering to the
patient a composition comprising a PGI2 receptor agonist disclosed
herein. In further embodiments, methods are provided for treating a
symptom of atherosclerosis in a patient in need of the treatment,
comprising administering to the patient a composition comprising a
PGI2 receptor agonist disclosed herein.
[0747] 4. Asthma
[0748] Asthma is a lymphocyte-mediated inflammatory airway disorder
characterized by airway eosinophilia, increased mucus production by
goblet cells, and structural remodeling of the airway wall. The
prevalence of asthma has dramatically increased worldwide in recent
decades. It has been shown that genetic deficiency of the PGI2
receptor in mice augments allergic airway inflammation (Takahashi
et al., Br J Pharmacol, 2002, 137:315-322). It has been shown that
an agonist of the PGI2 receptor can suppress not only the
development of asthma when given during the sensitization phase,
but also the cardinal features of experimental asthma when given
during the challenge phase (Idzko et al., J. Clin. Invest., 2007,
117:464-472; Nagao et al., Am. J. Respir. Cell Mol. Biol., 2003,
29:314-320), at least in part through markedly interfering with the
function of antigen-presenting dendritic cells within the airways
(Idzko et al., J. Clin. Invest., 2007, 117:464-472; Zhou et al., J.
Immunol., 2007, 178:702-710; Jaffar et al., J. Immunol., 2007,
179:6193-6203; Jozefowski et al., Int. Immunopharmacol., 2003,
3:865-878). These cells are crucial for both the initiation and the
maintenance phases of allergic asthma, as depletion of airway
dendritic cells during secondary challenge in sensitized mice
abolished all characteristic features of asthma, an effect that
could be completely restored by adoptive transfer of wild-type
dendritic cells (van Rijt et al., J. Exp. Med., 2005, 201:981-991).
It has also been shown that an agonist of the PGI2 receptor can
inhibit proinflammatory cytokine secretion by human alveolar
macrophages (Raychaudhuri et al., J. Biol. Chem., 2002,
277:33344-33348). The compounds of the present invention disclosed
herein are useful in the treatment of asthma, and the treatment of
the symptoms thereof. Accordingly, in some embodiments, the present
invention provides methods for treating asthma in a patient in need
of the treatment, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
further embodiments, methods are provided for treating a symptom of
asthma in a patient in need of the treatment, comprising
administering to the patient a composition comprising a PGL2
receptor agonist disclosed herein.
[0749] 5. Diabetic-Related Pathologies
[0750] Although hyperglycemia is the major cause for the
pathogenesis of diabetic complications such as diabetic peripheral
neuropathy (DPN), diabetic nephropathy (DN) and diabetic
retinopathy (DR), enhanced vasoconstriction and platelet
aggregation in diabetic patients has also been implicated to play a
role in disease progression (Cameron et al., Naunyn Schmiedebergs
Arch. Pharmacol., 2003, 367:607-614). Agonists of the PGI2 receptor
promote vasodilation and inhibit platelet aggregation. Improving
microvascular blood flow is able to benefit diabetic complications
(Cameron, Diabetologia, 2001, 44:1973-1988).
[0751] It has been shown that an agonist of the PGI2 receptor can
prevent and reverse motor and sensory peripheral nerve conduction
abnormalities in streptozotocin-diabetic rats (Cotter et al.,
Naunyn Schmiedebergs Arch. Pharmacol., 1993, 347:534-540). Further
evidence for the beneficial effect of an agonist of the PGI2
receptor in the treatment of diabetic peripheral neuropathy is
given by Hotta et al. (Diabetes, 1996, 45:361-366), Ueno et al.
(Jpn. J. Pharmacol., 1996, 70:177-182), Ueno et al. (Life Sci.,
1996, 59:PL105-PL1I10), Hotta et al. (Prostaglandins, 1995,
49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okuda
et al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB
J., 2003, 17:779-781). Evidence for the beneficial effect of an
agonist of the PGI2 receptor in the treatment of diabetic
nephropathy is given by Owada et al. (Nephron, 2002, 92:788-796)
and Yamashita et al. (Diabetes Res. Clin. Pract., 2002,
57:149-161). Evidence for the beneficial effect of an agonist of
the PGI2 receptor in the treatment of diabetic retinopathy is given
by Yamagishi et al. (Mol. Med., 2002, 8:546-550), Burnette et al.
(Exp. Eye Res., 2006, 83:1359-1365), and Hotta et al. (Diabetes,
1996, 45:361-366). It has been shown that an agonist of the PGI2
receptor can reduce increased tumor necrosis factor-.alpha.
(TNF-.alpha.) levels in diabetic patients, implying that an agonist
of the PGI2 receptor may contribute to the prevention of
progression in diabetic complications (Fujiwara et al., Exp. Clin.
Endocrinol. Diabetes, 2004, 112:390-394).
[0752] 6. Glaucoma
[0753] Evidence that topical administration of an agonist of the
PGI2 receptor can result in a decrease in intraocular pressure
(IOP) in rabbits and dogs and thereby have beneficial effect in the
treatment of glaucoma is given by Hoyng et al. (Hoyng et al.,
Invest. Ophthalmol. Vis. Sci., 1987, 28:470-476).
[0754] 7. Hypertension
[0755] Agonists of the PGI2 receptor have been shown to have
activity for regulation of vascular tone, for vasodilation, and for
amelioration of pulmonary hypertension (see, e.g., Strauss et al.,
Clin Chest Med, 2007, 28:127-142; Driscoll et al., Expert Opin.
Pharmacother., 2008, 9:65-81). Evidence for a beneficial effect of
an agonist of the PGI2 receptor in the treatment of hypertension is
given by Yamada et al. (Peptides, 2008, 29:412-418). Evidence that
an agonist of the PGI2 receptor can protect against cerebral
ischemia is given by Dogan et al. (Gen. Pharmacol., 1996,
27:1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab., 2006,
26:491-501).
[0756] 8. Anti-Inflammation Therapies
[0757] Anti-inflammation agents are prescribed for a variety of
conditions. For example, in an inflammatory disease they are used
to interfere with and thereby reduce an underlying deleterious
There is evidence that a PGI2 receptor agonist can inhibit
inflammation and thus be a potential treatment as an
anti-inflammation therapy. It has been shown that an agonist of the
PGI2 receptor can inhibit pro-inflammatory cytokine and chemokine
(interleukin-12 (IL-12), tumor necrosis factor-.alpha.
(TNF-.alpha.), IL-la, 11-6, macrophage inflammatory protein-lalpha
(MIP-la), monocyte chemoattractant protein-1 (MCP-1)) production
and T cell stimulatory function of dendritic cells (Jozefowski et
al., Int. Immunopharmacol., 2003, 865-878; Zhou et al., J.
Immunol., 2007, 178:702-710; Nagao et al., Am. J. Respir. Cell Mol.
Biol., 2003, 29:314-320; Idzko et al., J. Clin. Invest., 2007,
117:464-472). It has been shown that an agonist of the PGI2
receptor can inhibit pro-inflammatory cytokine (TNF-.alpha., IL-13,
IL-6, granulocyte macrophage stimulating factor (GM-CSF))
production by macrophages (Raychaudhuri et al., J. Biol. Chem.,
2002, 277:33344-33348; Czeslick et al., Eur. J. Clin. Invest.,
2003, 33:1013-1017; Di Renzo et al., Prostaglandin Leukot. Essent.
Fatty Acids, 2005, 73:405-410; Shinomiya et al., Biochem.
Pharmacol., 2001, 61:1153-1160). It has been shown that an agonist
of the PGI2 receptor can stimulate anti-inflammatory cytokine
(IL-10) production by dendritic cells (Jozefowski et al., Int.
Immunopharmacol., 2003, 865-878; Zhou et al., J. Immunol., 2007,
178:702-710). It has been shown that an agonist of the PGI2
receptor can stimulate anti-inflammatory cytokine (IL-10)
production by macrophages (Shinomiya et al., Biochem. Pharmacol.,
2001, 61:1153-1160). It has been shown that an agonist of the PGI2
receptor can inhibit a chemokine (CCL17)-induced chemotaxis of
leukocytes (CD4.sup.+ Th2 T cells) (Jaffar et al., J. Immunol.,
2007, 179:6193-6203). It has been shown that an agonist of the PGI2
receptor can confer protection from atherosclerosis, such as from
atherothrombosis (Arehart et al., Curr. Med. Chem., 2007,
14:2161-2169; Stitham et al., Prostaglandins Other Lipid Mediat.,
2007, 82:95-108; Fries et al., Hematology Am. Soc. Hematol. Educ.
Program, 2005:445-451; Egan et al., Science, 2004, 306:1954-1957;
Kobayashi et al., J. Clin. Invest., 2004, 114:784-794; Arehart et
al., Circ. Res., 2008, Mar. 6 Epub ahead of print). It has been
shown that an agonist of the PGI2 receptor can attenuate asthma
(Idzko et al., J. Clin. Invest., 2007, 117:464-472; Jaffar et al.,
J. Immunol., 2007, 179:6193-6203; Nagao et al., Am. J. Respir.
Cell. Mol. Biol., 2003, 29:314-320). It has been shown that an
agonist of the PGI2 receptor can decrease TNF-.alpha. production in
type 2 diabetes patients (Fujiwara et al., Exp. Clin. Endocrinol.
Diabetes, 2004, 112:390-394; Goya et al., Metabolism, 2003,
52:192-198). It has been shown that an agonist of the PGI2 receptor
can inhibit ischemia-reperfusion injury (Xiao et al., Circulation,
2001, 104:2210-2215). It has been shown that an agonist of the PGI2
receptor can inhibit restenosis (Cheng et al., Science, 2002,
296:539-541). It has been shown that an agonist of the PGI2
receptor can attenuate pulmonary vascular injury and shock in a rat
model of septic shock (Harada et al., Shock, 2008, Feb. 21 Epub
ahead of print). It has been shown that an agonist of the PGI2
receptor can reduce the serum levels of TNF-.alpha. in vivo in
patients with rheumatoid arthritis, and this is associated with
improvement in the clinical course of the disease (Gao et al.,
Rheumatol. Int., 2002, 22:45-51; Boehme et al., Rheumatol. Int.,
2006, 26:340-347).
[0758] The compounds of the present invention disclosed herein
provide beneficial reduction of inflammation. The compounds of the
present invention disclosed herein provide beneficial reduction of
a deleterious inflammatory response associated with an inflammatory
disease. Accordingly, in some embodiments, the present invention
provides methods for reducing inflammation in a patient in need
thereof, comprising administering to the patient a composition
comprising a PGI2 receptor agonist disclosed herein. In some
embodiments, the present invention provides methods for decreasing
IL-12, TNF-.alpha., IL-1.alpha., IL-1.beta., IL-6, MIP-la or MCP-1
production in a patient in need thereof, comprising administering
to the patient a composition comprising a PGI2 receptor agonist
disclosed herein. In some embodiments, the present invention
provides methods for decreasing TNF-.alpha. production in a patient
in need thereof, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
some embodiments, the present invention provides methods for
increasing IL-10 production in a patient in need thereof,
comprising administering to the patient a composition comprising a
PGI2 receptor agonist disclosed herein. In some embodiments, the
present invention provides methods for reducing a deleterious
inflammatory response associated with an inflammatory disease in a
patient in need thereof, comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
some embodiments, the present invention provides methods for
treating an inflammatory disease or a symptom thereof in a patient
in need of the treatment comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
some embodiments, the present invention provides methods for
treating an inflammatory disease or a symptom thereof in a patient
in need of the treatment comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein. In
some embodiments, the present invention provides methods for
treating an inflammatory disease or a symptom thereof in a patient
in need of the treatment comprising administering to the patient a
composition comprising a PGI2 receptor agonist disclosed herein,
wherein the inflammatory disease is selected from the group
consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis,
Crohn's disease, transplant rejection, multiple sclerosis, systemic
lupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusion
injury, restenosis, atherosclerosis, acne, diabetes (including type
1 diabetes and type 2 diabetes), sepsis, chronic obstructive
pulmonary disease (COPD), and asthma.
Pharmaceutical Compositions
[0759] A further aspect of the present invention pertains to
pharmaceutical compositions comprising one or more compounds as
described herein and one or more pharmaceutically acceptable
carriers. The embodiments pertain to pharmaceutical compositions
comprising a compound of the present invention and a
pharmaceutically acceptable carrier.
[0760] The embodiments of the present invention include a method of
producing a pharmaceutical composition comprising admixing at least
one compound according to any of the compound embodiments disclosed
herein and a pharmaceutically acceptable carrier.
[0761] Formulations may be prepared by any suitable method,
typically by uniformly mixing the active compound(s) with liquids
or finely divided solid carriers, or both, in the required
proportions and then, if necessary, forming the resulting mixture
into a desired shape.
[0762] Conventional excipients, such as binding agents, fillers,
acceptable wetting agents, tabletting lubricants and disintegrants
may be used in tablets and capsules for oral administration. Liquid
preparations for oral administration may be in the form of
solutions, emulsions, aqueous or oily suspensions and syrups.
Alternatively, the oral preparations may be in the form of dry
powder that can be reconstituted with water or another suitable
liquid vehicle before use. Additional additives such as suspending
or emulsifying agents, non-aqueous vehicles (including edible
oils), preservatives and flavorings and colorants may be added to
the liquid preparations. Parenteral dosage forms may be prepared by
dissolving the compound of the invention in a suitable liquid
vehicle and filter sterilizing the solution before filling and
sealing an appropriate vial or ampule. These are just a few
examples of the many appropriate methods well known in the art for
preparing dosage forms.
[0763] A compound of the present invention can be formulated into
pharmaceutical compositions using techniques well known to those in
the art. Suitable pharmaceutically-acceptable carriers, outside
those mentioned herein, are known in the art; for example, see
Remington, The Science and Practice of Pharmacy, 20.sup.th Edition,
2000, Lippincott Williams & Wilkins, (Editors: Gennaro et
al.)
[0764] While it is possible that, for use in the prophylaxis or
treatment, a compound of the invention may, in an alternative use,
be administered as a raw or pure chemical, it is preferable however
to present the compound or active ingredient as a pharmaceutical
formulation or composition further comprising a pharmaceutically
acceptable carrier.
[0765] The invention thus further provides pharmaceutical
formulations comprising a compound of the invention or a
pharmaceutically acceptable salt, solvate, hydrate or derivative
thereof together with one or more pharmaceutically acceptable
carriers thereof and/or prophylactic ingredients. The carrier(s)
must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not overly deleterious to
the recipient thereof. Typical procedures for making and
identifying suitable hydrates and solvates, outside those mentioned
herein, are well known to those in the art; see for example, pages
202-209 of K. J. Guillory, "Generation of Polymorphs, Hydrates,
Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical
Solids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc.; New
York, 1999, incorporated herein by reference in its entirety.
[0766] Pharmaceutical formulations include those suitable for oral,
rectal, nasal, topical (including buccal and sub-lingual), vaginal
or parenteral (including intramuscular, subcutaneous and
intravenous) administration or in a form suitable for
administration by inhalation, insufflation or by a transdermal
patch. Transdermal patches dispense a drug at a controlled rate by
presenting the drug for absorption in an efficient manner with a
minimum of degradation of the drug. Typically, transdermal patches
comprise an impermeable backing layer, a single pressure sensitive
adhesive and a removable protective layer with a release liner. One
of ordinary skill in the art will understand and appreciate the
techniques appropriate for manufacturing a desired efficacious
transdermal patch based upon the needs of the artisan.
[0767] The compounds of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical formulations and unit dosages thereof and in such
form may be employed as solids, such as tablets or filled capsules,
or liquids such as solutions, suspensions, emulsions, elixirs, gels
or capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous) use.
Such pharmaceutical compositions and unit dosage forms thereof may
comprise conventional ingredients in conventional proportions, with
or without additional active compounds or principles and such unit
dosage forms may contain any suitable effective amount of the
active ingredient commensurate with the intended daily dosage range
to be employed.
[0768] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are capsules, tablets,
powders, granules or a suspension, with conventional additives such
as lactose, mannitol, corn starch or potato starch; with binders
such as crystalline cellulose, cellulose derivatives, acacia, corn
starch or gelatins; with disintegrators such as corn starch, potato
starch or sodium carboxymethyl-cellulose; and with lubricants such
as talc or magnesium stearate. The active ingredient may also be
administered by injection as a composition wherein, for example,
saline, dextrose or water may be used as a suitable
pharmaceutically acceptable carrier.
[0769] Compounds of the present invention or a solvate, hydrate or
physiologically functional derivative thereof can be used as active
ingredients in pharmaceutical compositions, specifically as PGI2
receptor modulators. By the term "active ingredient" is defined in
the context of a "pharmaceutical composition" and is intended to
mean a component of a pharmaceutical composition that provides the
primary pharmacological effect, as opposed to an "inactive
ingredient" which would generally be recognized as providing no
pharmaceutical benefit.
[0770] The dose when using the compounds of the present invention
can vary within wide limits and as is customary and is known to the
physician, it is to be tailored to the individual conditions in
each individual case. It depends, for example, on the nature and
severity of the illness to be treated, on the condition of the
patient, on the compound employed or on whether an acute or chronic
disease state is treated or prophylaxis is conducted or on whether
further active compounds are administered in addition to the
compounds of the present invention. Representative doses of the
present invention include, but not limited to, about 0.001 mg to
about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to
about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg,
about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about
0.001 mg to about 25 mg. Multiple doses may be administered during
the day, especially when relatively large amounts are deemed to be
needed, for example 2, 3 or 4 doses. Depending on the individual
and as deemed appropriate from the patient's physician or caregiver
it may be necessary to deviate upward or downward from the doses
described herein.
[0771] The amount of active ingredient, or an active salt or
derivative thereof, required for use in treatment will vary not
only with the particular salt selected but also with the route of
administration, the nature of the condition being treated and the
age and condition of the patient and will ultimately be at the
discretion of the attendant physician or clinician. In general, one
skilled in the art understands how to extrapolate in vivo data
obtained in a model system, typically an animal model, to another,
such as a human. In some circumstances, these extrapolations may
merely be based on the weight of the animal model in comparison to
another, such as a mammal, preferably a human, however, more often,
these extrapolations are not simply based on weights, but rather
incorporate a variety of factors. Representative factors include
the type, age, weight, sex, diet and medical condition of the
patient, the severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy,
pharmacokinetic and toxicology profiles of the particular compound
employed, whether a drug delivery system is utilized, on whether an
acute or chronic disease state is being treated or prophylaxis is
conducted or on whether further active compounds are administered
in addition to the compounds of the present invention and as part
of a drug combination. The dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
is selected in accordance with a variety factors as cited above.
Thus, the actual dosage regimen employed may vary widely and
therefore may deviate from a preferred dosage regimen and one
skilled in the art will recognize that dosage and dosage regimen
outside these typical ranges can be tested and, where appropriate,
may be used in the methods of this invention.
[0772] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations. The daily dose can be
divided, especially when relatively large amounts are administered
as deemed appropriate, into several, for example 2, 3 or 4 part
administrations. If appropriate, depending on individual behavior,
it may be necessary to deviate upward or downward from the daily
dose indicated.
[0773] The compounds of the present invention can be administrated
in a wide variety of oral and parenteral dosage forms. It will be
obvious to those skilled in the art that the following dosage forms
may comprise, as the active component, either a compound of the
invention or a pharmaceutically acceptable salt, solvate or hydrate
of a compound of the invention.
[0774] For preparing pharmaceutical compositions from the compounds
of the present invention, the selection of a suitable
pharmaceutically acceptable carrier can be either solid, liquid or
a mixture of both. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0775] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0776] In tablets, the active component is mixed with the carrier
having the necessary binding capacity in suitable proportions and
compacted to the desire shape and size.
The powders and tablets may contain varying percentage amounts of
the active compound. A representative amount in a powder or tablet
may contain from 0.5 to about 90 percent of the active compound;
however, an artisan would know when amounts outside of this range
are necessary. Suitable carriers for powders and tablets are
magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as
carrier providing a capsule in which the active component, with or
without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets and lozenges can be used
as solid forms suitable for oral administration.
[0777] For preparing suppositories, a low melting wax, such as an
admixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool and thereby to
solidify.
[0778] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0779] Liquid form preparations include solutions, suspensions and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol solution.
Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions may be formulated according to the known art
using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable
solution or suspension in a nontoxic 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 conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0780] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for
example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added
preservative. The pharmaceutical compositions may take such forms
as suspensions, solutions, or emulsions in oily or aqueous vehicles
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form, obtained by aseptic isolation of sterile solid
or by lyophilization from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.
[0781] Aqueous formulations suitable for oral use can be prepared
by dissolving or suspending the active component in water and
adding suitable colorants, flavors, stabilizing and thickening
agents, as desired.
[0782] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well-known
suspending agents.
[0783] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents and the like.
[0784] For topical administration to the epidermis the compounds
according to the invention may be formulated as ointments, creams
or lotions, or as a transdermal patch.
[0785] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions may be formulated with an aqueous or
oily base and will in general also contain one or more emulsifying
agents, stabilizing agents, dispersing agents, suspending agents,
thickening agents, or coloring agents.
[0786] Formulations suitable for topical administration in the
mouth include lozenges comprising active agent in a flavored base,
usually sucrose and acacia or tragacanth; pastilles comprising the
active ingredient in an inert base such as gelatin and glycerin or
sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.
[0787] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The formulations may be provided in single or multi-dose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension. In the case of a spray, this
may be achieved for example by means of a metering atomizing spray
pump.
[0788] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurized pack with a suitable propellant. If
the compounds of the present invention or pharmaceutical
compositions comprising them are administered as aerosols, for
example as nasal aerosols or by inhalation, this can be carried
out, for example, using a spray, a nebulizer, a pump nebulizer, an
inhalation apparatus, a metered inhaler or a dry powder inhaler.
Pharmaceutical forms for administration of the compounds of the
present invention as an aerosol can be prepared by processes well
known to the person skilled in the art. For their preparation, for
example, solutions or dispersions of the compounds of the present
invention in water, water/alcohol mixtures or suitable saline
solutions can be employed using customary additives, for example
benzyl alcohol or other suitable preservatives, absorption
enhancers for increasing the bioavailability, solubilizers,
dispersants and others and, if appropriate, customary propellants,
for example include carbon dioxide, CFCs, such as,
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane; and the like. The aerosol may
conveniently also contain a surfactant such as lecithin. The dose
of drug may be controlled by provision of a metered valve.
[0789] In formulations intended for administration to the
respiratory tract, including intranasal formulations, the compound
will generally have a small particle size for example of the order
of 10 microns or less. Such a particle size may be obtained by
means known in the art, for example by micronization. When desired,
formulations adapted to give sustained release of the active
ingredient may be employed.
[0790] Alternatively the active ingredients may be provided in the
form of a dry powder, for example, a powder mix of the compound in
a suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0791] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0792] Tablets or capsules for oral administration and liquids for
intravenous administration are preferred compositions.
[0793] The compounds according to the invention may optionally
exist as pharmaceutically acceptable salts including
pharmaceutically acceptable acid addition salts prepared from
pharmaceutically acceptable non-toxic acids including inorganic and
organic acids. Representative acids include, but are not limited
to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, dichloroacetic, formic, fumaric, gluconic,
glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic,
pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric,
oxalic, p-toluenesulfonic and the like. Certain compounds of the
present invention which contain a carboxylic acid functional group
may optionally exist as pharmaceutically acceptable salts
containing non-toxic, pharmaceutically acceptable metal cations and
cations derived from organic bases. Representative metals include,
but are not limited to, aluminium, calcium, lithium, magnesium,
potassium, sodium, zinc and the like. In some embodiments the
pharmaceutically acceptable metal is sodium. Representative organic
bases include, but are not limited to, benzathine
(N.sup.1,N.sup.2-dibenzylethane-1,2-diamine), chloroprocaine
(2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,
diethanolamine, ethylenediamine, meglumine
((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine
(2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certain
pharmaceutically acceptable salts are listed in Berge, et al.,
Journal of Pharmaceutical Sciences, 66:1-19 (1977), incorporated
herein by reference in its entirety.
[0794] The embodiments of the present invention include every
combination of one or more compounds selected from the following
group and pharmaceutically acceptable solvates and hydrates
thereof: [0795] sodium
2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate;
[0796] sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0797] sodium
2-(((1r,4r)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0798] sodium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0799] magnesium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; [0800] potassium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate; and [0801] calcium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate.
[0802] The acid addition salts may be obtained as the direct
products of compound synthesis. In the alternative, the free base
may be dissolved in a suitable solvent containing the appropriate
acid and the salt isolated by evaporating the solvent or otherwise
separating the salt and solvent. The compounds of this invention
may form solvates with standard low molecular weight solvents using
methods known to the skilled artisan.
[0803] Compounds of the present invention can be converted to
"pro-drugs." The term "pro-drugs" refers to compounds that have
been modified with specific chemical groups known in the art and
when administered into an individual these groups undergo
biotransformation to give the parent compound. Pro-drugs can thus
be viewed as compounds of the invention containing one or more
specialized non-toxic protective groups used in a transient manner
to alter or to eliminate a property of the compound. In one general
aspect, the "pro-drug" approach is utilized to facilitate oral
absorption. A thorough discussion is provided in T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.
Symposium Series; and in Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon
Press, 1987, both of which are hereby incorporated by reference in
their entirety.
[0804] The embodiments of the present invention include a method of
producing a pharmaceutical composition for "combination-therapy"
comprising admixing at least one compound according to any of the
compound embodiments disclosed herein, together with at least one
known pharmaceutical agent as described herein and a
pharmaceutically acceptable carrier.
[0805] It is noted that when the PGI2 receptor modulators are
utilized as active ingredients in a pharmaceutical composition,
these are not intended for use only in humans, but in other
non-human mammals as well. Indeed, recent advances in the area of
animal health-care mandate that consideration be given for the use
of active agents, such as PGI2 receptor modulators, for the
treatment of an PGI2-associated disease or disorder in
companionship animals (e.g., cats, dogs, etc.) and in livestock
animals (e.g., cows, chickens, fish, etc.) Those of ordinary skill
in the art are readily credited with understanding the utility of
such compounds in such settings.
Hydrates and Solvates
[0806] It is understood that when the phrase "pharmaceutically
acceptable salts, solvates and hydrates" is used in reference to a
particular formula herein, it is intended to embrace solvates
and/or hydrates of compounds of the particular formula,
pharmaceutically acceptable salts of compounds of the particular
formula as well as solvates and/or hydrates of pharmaceutically
acceptable salts of compounds of the particular formula. It is also
understood by a person of ordinary skill in the art that hydrates
are a subgenus of solvates.
[0807] The compounds of the present invention can be administrated
in a wide variety of oral and parenteral dosage forms. It will be
apparent to those skilled in the art that the following dosage
forms may comprise, as the active component, either a compound of
the invention or a pharmaceutically acceptable salt or as a solvate
or hydrate thereof. Moreover, various hydrates and solvates of the
compounds of the invention and their salts will find use as
intermediates in the manufacture of pharmaceutical compositions.
Typical procedures for making and identifying suitable hydrates and
solvates, outside those mentioned herein, are well known to those
in the art; see for example, pages 202-209 of K. J. Guillory,
"Generation of Polymorphs, Hydrates, Solvates, and Amorphous
Solids," in: Polymorphism in Pharmaceutical Solids, ed. Harry G.
Brittan, Vol. 95, Marcel Dekker, Inc., New York, 1999, incorporated
herein by reference in its entirety. Accordingly, one aspect of the
present invention pertains to hydrates and solvates of compounds of
the present invention and/or their pharmaceutical acceptable salts,
as described herein, that can be isolated and characterized by
methods known in the art, such as, thermogravimetric analysis
(TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder
X-ray diffraction (PXRD), Karl Fisher titration, high resolution
X-ray diffraction, and the like. There are several commercial
entities that provide quick and efficient services for identifying
solvates and hydrates on a routine basis. Example companies
offering these services include Wilmington PharmaTech (Wilmington,
Del.), Avantium Technologies (Amsterdam) and Aptuit (Greenwich,
Conn.).
[0808] The embodiments of the present invention include every
combination of one or more solvate or hydrate selected from the
following group: [0809] sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate hydrate; [0810] sodium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate hydrate; [0811] magnesium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate isopropanol solvate; [0812] potassium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate isopropanol solvate; and [0813] calcium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate isopropanol solvate.
[0814] Certain solvates and hydrates of compounds of the present
invention are described in Examples 1.107 to 1.111.
Crystalline Forms
[0815] A further aspect of the present invention pertains to a
crystalline form (Form 1) of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate (the sodium salt of Compound 22). Form 1 of the
sodium salt of Compound 22 can be identified by its unique solid
state signature with respect to, for example, differential scanning
calorimetry (DSC), X-ray powder diffraction (PXRD), and other solid
state methods. Further characterization with respect to water or
solvent content of the crystalline form can be gauged by any of the
following methods for example, thermogravimetric analysis (TGA),
DSC and the like. For DSC, it is known that the temperatures
observed will depend upon sample purity, the rate of temperature
change, as well as sample preparation technique and the particular
instrument employed. Thus, the values reported herein relating to
DSC thermograms can vary by plus or minus about 6.degree. C. The
values reported herein relating to DSC thermograms can also vary by
plus or minus about 20 joules per gram. For PXRD, the relative
intensities of the peaks can vary, depending upon the sample
preparation technique, the sample mounting procedure and the
particular instrument employed. Moreover, instrument variation and
other factors can often affect the 2.theta. values. Therefore, the
peak assignments of diffraction patterns can vary by plus or minus
about 0.2.degree. 2.theta.. For TGA, the features reported herein
can vary by plus or minus about 5.degree. C. The TGA features
reported herein can also vary by plus or minus about 2% weight
change due to, for example, sample variation. Further
characterization with respect to hygroscopicity of the crystalline
form can be gauged by, for example, dynamic vapor sorption (DVS).
The DVS features reported herein can vary by plus or minus about 5%
relative humidity. The DVS features reported herein can also vary
by plus or minus about 5% weight change. The physical properties of
Form 1 of the sodium salt of Compound 22 are summarized in Table 1
below.
TABLE-US-00002 TABLE 1 Sodium Salt of Compound 22 (Form 1) TGA FIG.
11: <0.1% weight loss below about 200.degree. C. DSC FIG. 11:
extrapolated onset temperature: 243.degree. C.; endotherm peak
temperature: 245.degree. C. (maximum); associated heat flow 105 J/g
PXRD FIG. 9: Peaks of .gtoreq.10% relative intensity at 6.1, 7.5,
9.6, 12.3, 14.5, 19.4, 20.0, 22.1, 23.1 and 23.9 .degree.2.theta.
DVS Figure 10: absorption of <0.25% at 90% relative humidity
[0816] The small weight loss observed in the TGA data suggests that
Form 1 of the sodium salt of Compound 22 is an anhydrous,
non-solvated crystalline form. The DSC thermogram further reveals a
melting endotherm with an onset at about 243.degree. C.
[0817] DVS data for the crystalline form of the Form 1 of the
sodium salt of Compound 22 reveals low hygroscopicity, with
absorption of less than 0.25% at 90% relative humidity. Certain
X-ray powder diffraction peaks for Form 1 of the sodium salt of
Compound 22 are shown in Table 2 below.
TABLE-US-00003 TABLE 2 Sodium Salt of Compound 22 (Form 1) PXRD
Peaks with Relative Intensity of 10% or Higher (.degree.2.theta.)
Peak Position (.degree.2.theta.) Relative Intensity (%) 6.1 65 7.5
32 9.6 11 12.3 14 14.5 15 19.4 27 20.0 100 22.1 29 23.1 16 23.9
31
[0818] One aspect of the present invention is directed to a
crystalline form (Form 1) of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate having an X-ray powder diffraction pattern comprising
a peak, in terms of 20, at about 20.0. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
a peak, in terms of 20, at about 6.1.degree.. In some embodiments,
the crystalline form has an X-ray powder diffraction pattern
comprising a peak, in terms of 20, at about 20.0.degree. and about
6.1.degree.. In some embodiments, the crystalline form has an X-ray
powder diffraction pattern comprising a peak, in terms of 20, at
about 20.0.degree. and about 7.5.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
a peak, in terms of 20, at about 20.0.degree., about 6.1.degree.,
and about 7.5.degree.. In some embodiments, the crystalline form
has an X-ray powder diffraction pattern comprising a peak, in terms
of 2, at about 20.0.degree., about 6.1.degree., about 7.5.degree.
about 23.9.degree., about 22.1.degree., about 19.4.degree., about
23.1.degree. and about 14.5. In some embodiments, the crystalline
form has an X-ray powder diffraction pattern comprising a peak, in
terms of 20, at about 20.00 about 6.1.degree., about 7.5.degree.,
about 23.9.degree., about 22.1.degree., about 19.4.degree., about
23.1.degree., about 14.50 about 12.3.degree. and about 9.6.degree..
In yet further embodiments, the crystalline form has an X-ray
powder diffraction pattern substantially as shown in FIG. 9,
wherein by "substantially" is meant that the reported peaks can
vary by about 0.2.degree. 20.
[0819] In some embodiments, the crystalline form (Form 1) of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate has a differential scanning calorimetry thermogram
comprising an endotherm with an extrapolated onset temperature
between about 235.degree. C. and about 250.degree. C. In some
embodiments, the crystalline form has a differential scanning
calorimetry thermogram comprising an endotherm with an extrapolated
onset temperature at about 243.degree. C. In some embodiments, the
crystalline form has a differential scanning calorimetry thermogram
comprising an endotherm with a peak temperature between about
237.degree. C. and about 252.degree. C. In some embodiments, the
crystalline form has a differential scanning calorimetry thermogram
comprising an endotherm with a peak temperature at about
245.degree. C. In some embodiments, the crystalline form has a
differential scanning calorimetry thermogram comprising an
endotherm with an associated heat flow of about 105 joules per
gram. In further embodiments, the crystalline form has a
differential scanning calorimetry thermogram substantially as shown
in FIG. 11, wherein by "substantially" is meant that the reported
DSC features can vary by about .+-.4.degree. C.
[0820] In some embodiments, the crystalline form (Form 1) of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate has a dynamic vapor sorption profile substantially as
shown in FIG. 10, wherein by "substantially" is meant that the
reported DVS features can vary by about 5% relative humidity.
[0821] In some embodiments, the crystalline form (Form 1) of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate has a thermogravimetric analysis profile
substantially as shown in FIG. 11, wherein by "substantially" is
meant that the reported TGA features can vary by about +5.degree.
C.
[0822] The crystalline form (Form 1) of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate, the sodium salt of Compound 22 described herein, can
be prepared by any of the suitable procedures known in the art for
preparing crystalline polymorphs. In some embodiments Form 1 of the
sodium salt of Compound 22 can be prepared as described in Example
1.106. In some embodiments, Form 1 of the sodium salt of Compound
22 can be prepared by heating crystalline sodium salt of Compound
22, containing one or more crystalline forms other than Form 1. In
some embodiments, Form 1 of the sodium salt of Compound 22 can be
prepared by recrystallizing crystalline sodium salt of Compound 22,
containing one or more crystalline forms other than Form 1 of the
sodium salt of Compound 22.
[0823] A further aspect of the present invention pertains to a
crystalline form of
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic acid (Compound 22). The crystalline form of
Compound 22 of the present invention can be identified by its
unique solid state signature with respect to, for example,
differential scanning calorimetry (DSC), X-ray powder diffraction
(PXRD), and other solid state methods. Further characterization
with respect to water or solvent content of the crystalline form
can be gauged by any of the following methods for example,
thermogravimetric analysis (TGA), DSC and the like. For DSC, it is
known that the temperatures observed will depend upon sample
purity, the rate of temperature change, as well as sample
preparation technique and the particular instrument employed. Thus,
the values reported herein relating to DSC thermograms can vary by
plus or minus about 6.degree. C. The values reported herein
relating to DSC thermograms can also vary by plus or minus about 20
joules per gram. For PXRD, the relative intensities of the peaks
can vary, depending upon the sample preparation technique, the
sample mounting procedure and the particular instrument employed.
Moreover, instrument variation and other factors can often affect
the 2.theta. values. Therefore, the peak assignments of diffraction
patterns can vary by plus or minus about 0.2.degree. 20. For TGA,
the features reported herein can vary by plus or minus about
5.degree. C. The TGA features reported herein can also vary by plus
or minus about 2% weight change due to, for example, sample
variation. Further characterization with respect to hygroscopicity
of the crystalline form can be gauged by, for example, dynamic
vapor sorption (DVS). The physical properties of the crystalline
form of Compound 22 of the present invention are summarized in
Table 3 below.
TABLE-US-00004 TABLE 3 Crystalline form of Compound 22 TGA FIG. 26:
Insignificant weight loss below about 128.degree. C. DSC FIG. 26:
extrapolated onset temperature: 128.degree. C.; endotherm peak
temperature: 129.degree. C. (maximum); associated heat flow 109 J/g
PXRD FIG. 27: Peaks of .gtoreq.8% relative intensity at 8.9, 10.8,
11.9, 15.2, 16.4, 16.9, 18.9, 20.3, 20.7 and 21.5
.degree.2.theta.
[0824] The insignificant weight loss observed in the TGA data
suggests that the crystalline form of Compound 22 of the present
invention is an anhydrous, non-solvated crystalline form. The DSC
thermogram further reveals a melting endotherm with an onset at
about 128.degree. C.
[0825] Certain X-ray powder diffraction peaks for the crystalline
form of Compound 22 of the present invention are shown in Table 4
below.
TABLE-US-00005 TABLE 4 Compound 22 Crystalline Form PXRD Peaks with
Relative Intensity of 8% or Higher (.degree.2.theta.) Peak Position
(.degree.2.theta.) Relative Intensity (%) 8.9 8 10.8 19 11.9 29
15.2 9 16.4 49 16.8 63 18.9 84 20.3 34 20.7 62 21.5 100
[0826] One aspect of the present invention is directed to a
crystalline form of
2-(((r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic acid having an X-ray powder diffraction pattern
comprising a peak, in terms of 2, at about 21.5. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising a peak, in terms of 20, at about 18.9.degree..
In some embodiments, the crystalline form has an X-ray powder
diffraction pattern comprising a peak, in terms of 20, at about
21.5.degree. and about 18.9.degree.. In some embodiments, the
crystalline form has an X-ray powder diffraction pattern comprising
a peak, in terms of 20, at about 21.5.degree. and about
20.7.degree.. In some embodiments, the crystalline form has an
X-ray powder diffraction pattern comprising a peak, in terms of 2,
at about 21.5.degree., about 18.90 and about 20.7.degree.. In some
embodiments, the crystalline form has an X-ray powder diffraction
pattern comprising a peak, in terms of 26, at about 21.5.degree.,
about 18.9.degree., about 20.7.degree., about 16.9.degree., about
16.4.degree., about 20.3.degree., about 11.9.degree. and about
10.8. In some embodiments, the crystalline form has an X-ray powder
diffraction pattern comprising a peak, in terms of 2, at about
18.90, about 20.7.degree., about 16.9.degree., about 16.4.degree.,
about 20.3.degree., about 11.9.degree., about 10.8.degree., about
15.2.degree. and about 8.9.degree.. In yet further embodiments, the
crystalline form has an X-ray powder diffraction pattern
substantially as shown in FIG. 27, wherein by "substantially" is
meant that the reported peaks can vary by about 0.2.degree. 20.
[0827] In some embodiments, the crystalline form of
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid has a differential scanning calorimetry
thermogram comprising an endotherm with an extrapolated onset
temperature between about 120.degree. C. and about 135.degree. C.
In some embodiments, the crystalline form has a differential
scanning calorimetry thermogram comprising an endotherm with an
extrapolated onset temperature at about 128.degree. C. In some
embodiments, the crystalline form has a differential scanning
calorimetry thermogram comprising an endotherm with a peak
temperature between about 121.degree. C. and about 136.degree. C.
In some embodiments, the crystalline form has a differential
scanning calorimetry thermogram comprising an endotherm with a peak
temperature at about 129.degree. C. In some embodiments, the
crystalline form has a differential scanning calorimetry thermogram
comprising an endotherm with an associated heat flow of about 109
joules per gram. In further embodiments, the crystalline form has a
differential scanning calorimetry thermogram substantially as shown
in FIG. 26, wherein by "substantially" is meant that the reported
DSC features can vary by about 4.degree. C.
[0828] In some embodiments, the crystalline form of
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid has a thermogravimetric analysis profile
substantially as shown in FIG. 28, wherein by "substantially" is
meant that the reported TGA features can vary by about 5.degree.
C.
[0829] The crystalline form of
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid, Compound 22, described herein, can be prepared
by any of the suitable procedures known in the art for preparing
crystalline polymorphs. In some embodiments the crystalline form of
Compound 22 of the present invention can be prepared as described
in Example 1.115. In some embodiments, the crystalline form of
Compound 22 of the present invention can be prepared by heating
crystalline Compound 22, containing one or more crystalline forms
other than the crystalline form of Compound 22 of the present
invention. In some embodiments, the crystalline form of Compound 22
of the present invention can be prepared by recrystallizing
crystalline Compound 22, containing one or more crystalline forms
other than the crystalline form of Compound 22 of the present
invention.
Compositions Containing Crystalline Forms of the Present
Invention
[0830] The present invention further provides compositions
containing the crystalline form (Form 1) of sodium
2-((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate, the sodium salt of Compound 22 described herein.
[0831] In some embodiments, the compositions of the invention
include at least about 1, about 5, about 10, about 20, about 30, or
about 40% by weight of Form 1 of the sodium salt of Compound
22.
[0832] In some embodiments, the compositions of the invention
include at least about 50, about 60, about 70, about 80, about 90,
about 95, about 96, about 97, about 98, or about 99% by weight of
Form 1 of the sodium salt of Compound 22.
[0833] In some embodiments, compositions of the invention include
Form 1 of the sodium salt of Compound 22 and a pharmaceutically
acceptable carrier.
[0834] The present invention further provides compositions
containing the crystalline form of
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid, Compound 22, described herein.
[0835] In some embodiments, the compositions of the invention
include at least about 1, about 5, about 10, about 20, about 30, or
about 40% by weight of the crystalline form of Compound 22 of the
present invention.
[0836] In some embodiments, the compositions of the invention
include at least about 50, about 60, about 70, about 80, about 90,
about 95, about 96, about 97, about 98, or about 99% by weight of
the crystalline form of Compound 22 of the present invention.
[0837] In some embodiments, compositions of the invention include
the crystalline form of Compound 22 of the present invention and a
pharmaceutically acceptable carrier.
Processes of the Present Invention
[0838] The present invention is directed, inter alia, to processes
and intermediates for the preparation of cyclohexane derivatives
that are useful in the treatment of: pulmonary arterial
hypertension (PAH); idiopathic PAH; familial PAH; PAH associated
with: a collagen vascular disease, a congenital heart disease,
portal hypertension, HIV infection, ingestion of a drug or toxin,
hereditary hemorrhagic telangiectasia, splenectomy, pulmonary
veno-occlusive disease (PVOD) or pulmonary capillary
hemangiomatosis (PCH); PAH with significant venous or capillary
involvement; platelet aggregation; coronary artery disease;
myocardial infarction; transient ischemic attack; angina; stroke;
ischemia-reperfusion injury; restenosis; atrial fibrillation; blood
clot formation in an angioplasty or coronary bypass surgery
individual or in an individual suffering from atrial fibrillation;
atherothrombosis; asthma or a symptom thereof, a diabetic-related
disorder such as diabetic peripheral neuropathy, diabetic
nephropathy or diabetic retinopathy; glaucoma or other disease of
the eye with abnormal intraocular pressure; hypertension;
inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis;
Crohn's disease; transplant rejection; multiple sclerosis; systemic
lupus erythematosus (SLE); ulcerative colitis; atherosclerosis;
acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic
obstructive pulmonary disorder (COPD).
[0839] The processes described herein can be monitored according to
any suitable method known in the art. For example, product
formation can be monitored by spectroscopic means, such as nuclear
magnetic resonance spectroscopy (e.g., .sup.1H or .sup.13C),
infrared spectroscopy, spectrophotometry (e.g., UV-visible), or
mass spectrometry, or by chromatography such as high performance
liquid chromatography (HPLC) or thin layer chromatography.
[0840] In some embodiments, preparation of compounds can involve
the protection and deprotection of various chemical groups. The
need for protection and deprotection, and the selection of
appropriate protecting groups can be readily determined by one
skilled in the art. The chemistry of protecting groups can be
found, for example, in Greene and Wuts, Protective Groups in
Organic Synthesis, 3rd Ed., Wiley & Sons, 1999, which is
incorporated herein by reference in its entirety.
[0841] The reactions of the processes described herein can be
carried out in suitable solvents which can be readily selected by
one of skill in the art of organic synthesis. Suitable solvents can
be substantially nonreactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected. In some embodiments, reactions can
be carried out in the absence of solvent, such as when at least one
of the reagents is a liquid or gas.
[0842] Suitable solvents can include halogenated solvents such as
carbon tetrachloride, bromodichloromethane, dibromochloromethane,
bromoform, chloroform, bromochloromethane, dibromomethane, butyl
chloride, dichloromethane, tetrachloroethylene, trichloroethylene,
1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,
2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene,
o-dichlorobenzene, chlorobenzene, fluorobenzene,
fluorotrichloromethane, chlorotrifluoromethane,
bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane,
chlorodifluoromethane, trifluoromethane,
1,2-dichlorotetrafluorethane and hexafluoroethane.
[0843] Suitable ether solvents include: dimethoxymethane,
tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether,
ethylene glycol dimethyl ether, ethylene glycol diethyl ether,
diethylene glycol dimethyl ether, diethylene glycol diethyl ether,
triethylene glycol dimethyl ether, anisole, or t-butyl methyl
ether.
[0844] Suitable protic solvents can include, by way of example and
without limitation, water, methanol, ethanol, 2-nitroethanol,
2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol,
i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene
glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl
alcohol, diethylene glycol monomethyl ether, diethylene glycol
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or
glycerol.
[0845] Suitable aprotic solvents can include, by way of example and
without limitation, tetrahydrofuran, N,N-dimethylformamide,
N,N-dimethylacetamide,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,
1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, formamide,
N-methylacetamide, N-methylformamide, acetonitrile, dimethyl
sulfoxide, propionitrile, ethyl formate, methyl acetate,
hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,
sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,
nitrobenzene, or hexamethylphosphoramide.
[0846] Suitable hydrocarbon solvents include benzene, cyclohexane,
pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane,
ethylbenzene, o, m-, orp-xylene, octane, indane, nonane, or
naphthalene.
[0847] Supercritical carbon dioxide can also be used as a
solvent.
[0848] The reactions of the processes described herein can be
carried out at appropriate temperatures which can be readily
determined by one skilled in the art. Reaction temperatures will
depend on, for example, the melting and boiling points of the
reagents and solvent, if present; the thermodynamics of the
reaction (e.g., vigorously exothermic reactions may need to be
carried out at reduced temperatures); and the kinetics of the
reaction (e.g., a high activation energy barrier may need elevated
temperatures).
[0849] The reactions of the processes described herein can be
carried out in air or under an inert atmosphere. Typically,
reactions containing reagents or products that are substantially
reactive with air can be carried out using air-sensitive synthetic
techniques that are well known to one skilled in the art.
[0850] In some embodiments, preparation of compounds can involve
the addition of acids or bases to effect, for example, catalysis of
a desired reaction or formation of salt forms such as acid addition
salts.
[0851] Example acids can be inorganic or organic acids. Inorganic
acids include hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, and nitric acid. Organic acids include formic
acid, acetic acid, propionic acid, butanoic acid, methanesulfonic
acid, p-toluene sulfonic acid, benzenesulfonic acid, propiolic
acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic
acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid
and decanoic acid.
[0852] Example bases include lithium hydroxide, sodium hydroxide,
potassium hydroxide, lithium carbonate, sodium carbonate, and
potassium carbonate. Some example strong bases include, but are not
limited to, hydroxide, alkoxides, metal amides, metal hydrides,
metal dialkylamides and arylamines, wherein; alkoxides include
lithium, sodium and potassium salts of methyl, ethyl and t-butyl
oxides; metal amides include sodium amide, potassium amide and
lithium amide; metal hydrides include sodium hydride, potassium
hydride and lithium hydride; and metal dialkylamides include sodium
and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl,
t-butyl, trimethylsilyl and cyclohexyl substituted amides.
[0853] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present invention that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically active starting materials are
known in the art, such as by resolution of racemic mixtures or by
stereoselective synthesis.
[0854] The processes described herein can be stereoselective such
that any given reaction starting with one or more chiral reagents
enriched in one stereoisomer forms a product that is also enriched
in one stereoisomer. The reaction can be conducted such that the
product of the reaction substantially retains one or more chiral
centers present in the starting materials. The reaction can also be
conducted such that the product of the reaction contains a chiral
center that is substantially inverted relative to a corresponding
chiral center present in the starting materials.
[0855] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. An example method
includes fractional recrystallization (for example, diastereomeric
salt resolution) using a "chiral resolving acid" which is an
optically active, salt-forming organic acid. Suitable resolving
agents for fractional recrystallization methods are, for example,
optically active acids, such as the D and L forms of tartaric acid,
diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic
acid, lactic acid or the various optically active camphorsulfonic
acids such as p-camphorsulfonic acid. Other resolving agents
suitable for fractional crystallization methods include
stereoisomerically pure forms of O-methylbenzylamine (e.g., S and R
forms, or diastereomerically pure forms), 2-phenylglycinol,
norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,
1,2-diaminocyclohexane, and the like.
[0856] Resolution of racemic mixtures can also be carried out by
elution on a column packed with an optically active resolving agent
(e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
[0857] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates or final compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. For example, isotopes of hydrogen include tritium and
deuterium.
[0858] Compounds of the invention can also include tautomeric
forms, such as keto-enol tautomers. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate
substitution.
[0859] Upon carrying out preparation of compounds according to the
processes described herein, the usual isolation and purification
operations such as concentration, filtration, extraction,
solid-phase extraction, recrystallization, chromatography, and the
like may be used, to isolate the desired products.
[0860] Example processes and certain intermediates of the present
invention, are shown in Scheme I below, wherein each substituent of
the compounds depicted are defined herein.
##STR00150##
[0861] One aspect of the present invention pertains to processes,
such as that exemplified by Scheme I (supra), that involve
compounds of Formulae (II), (III), (IV), (V), (VI), (VII), (VIII)
and (IX) or salt forms thereof, wherein:
[0862] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0863] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
[0864] R.sup.5 is C.sub.1-C.sub.6 alkyl;
[0865] R.sup.6 is selected from: C.sub.1-C.sub.6
alkylarylsulfonate, C.sub.1-C.sub.6 alkylsulfonate, arylsulfonate,
C.sub.1-C.sub.6 haloalkylsulfonate and halogen;
[0866] R.sup.7 is a first leaving group;
[0867] R.sup.8 is a second leaving group; and
[0868] M.sym. is a metal cation or a cation derived from an organic
base.
[0869] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination.
All combinations of the embodiments pertaining to the chemical
groups represented by the variables (e.g., R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and M)
contained within the generic chemical formulae described herein,
for example, (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX)
are specifically embraced by the present invention just as if each
and every combination was individually explicitly recited, to the
extent that such combinations embrace compounds that result in
stable compounds (i.e., compounds that can be isolated,
characterized and tested for biological activity).
Hydrolysis Step
[0870] The present invention provides, inter alia, processes for
preparing compounds of Formula (I):
##STR00151##
or a salt, solvate or hydrate thereof; comprising reacting a
compound of Formula (III):
##STR00152##
or a salt form thereof, with a hydrolyzing agent to form a compound
of Formula (II) or a salt form thereof.
[0871] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0872] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[0873] In some embodiments, R.sup.1 is 4-chlorophenyl.
[0874] In some embodiments, R.sup.1 is 3-fluorophenyl.
[0875] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[0876] In some embodiments, R.sup.2 is phenyl.
[0877] In some embodiments, R.sup.5 is tert-butyl.
[0878] In some embodiments, R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; and R.sup.5 is tert-butyl.
[0879] In some embodiments, R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; and R.sup.5 is tert-butyl.
[0880] The hydrolyzing agent can be any suitable reagent, readily
selected by one skilled in the art. Examples of hydrolyzing agents
include bases such as lithium hydroxide and sodium hydroxide; acids
such as hydrochloric acid, trifluoroacetic acid and formic acid;
lithium salts such as LiBr, LiCl, LiBF.sub.4, LiCF.sub.3CO.sub.2,
LiSO.sub.4, LiNO.sub.3, LiCF.sub.3SO.sub.3 and lithium
propanethiolate; and electrophiles such as TMSI.
[0881] In some embodiments, the hydrolyzing agent is a base.
[0882] In some embodiments, the hydrolyzing agent is an alkali
metal hydroxide.
[0883] In some embodiments, the hydrolyzing agent is sodium
hydroxide.
[0884] The reacting of a compound of Formula (III) with a
hydrolyzing agent can be optionally carried out in the presence of
any suitable solvent, readily selected by one skilled in the
art.
[0885] Example solvents include polar to moderately polar solvents
or high boiling solvents such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide, toluene, acetonitrile, propionitrile,
tetrahydrofuran and N-methylpyrrolidinone.
[0886] In some embodiments, the solvent comprises toluene.
[0887] In some embodiments, the solvent comprises a mixture of
toluene and water.
[0888] In some embodiments, the solvent comprises a mixture of
approximately equal parts by weight of toluene and water.
[0889] The reacting of a compound of Formula (III) with a
hydrolyzing agent can be carried out at any suitable temperature,
readily selected by one skilled in the art.
[0890] In some embodiments, the reacting is carried out at a
temperature of about 20.degree. C. to about 90.degree. C.
[0891] In some embodiments, the reacting is carried out at a
temperature of about 30.degree. C. to about 80.degree. C.
[0892] In some embodiments, the reacting is carried out at a
temperature of about 40.degree. C. to about 70.degree. C.
[0893] In some embodiments, the reacting is carried out at a
temperature of about 50.degree. C. to about 60.degree. C.
[0894] The reacting of a compound of Formula (III) with a
hydrolyzing agent can be optionally carried out in situ following
the reacting of a compound of Formula (IV) with a compound of
Formula (V) in the presence of a base to form a compound of Formula
(III), without substantial purification of the compound of Formula
(III).
Alkylation Step
[0895] The present invention further provides processes for
preparing compounds of Formula (III):
##STR00153##
or a salt form thereof; wherein:
[0896] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0897] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
and
[0898] R.sup.5 is C.sub.1-C.sub.6 alkyl;
comprising reacting a compound of Formula (IV):
##STR00154##
or a salt form thereof; with a compound of Formula (V):
##STR00155##
wherein:
[0899] R.sup.6 is selected from: C.sub.1-C.sub.6
alkylarylsulfonate, C.sub.1-C.sub.6 alkylsulfonate, arylsulfonate,
C.sub.1-C.sub.6 haloalkylsulfonate and halogen;
in the presence of a base to form a compound of Formula (III) or a
salt form thereof.
[0900] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0901] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[0902] In some embodiments, R.sup.1 is 4-chlorophenyl.
[0903] In some embodiments, R.sup.1 is 3-fluorophenyl.
[0904] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[0905] In some embodiments, R.sup.2 is phenyl.
[0906] In some embodiments, R.sup.5 is tert-butyl.
[0907] In some embodiments, R.sup.6 is halogen.
[0908] In some embodiments, R.sup.6 is bromo.
[0909] In some embodiments, R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; R.sup.5 is tert-butyl; and R.sup.6 is bromo.
[0910] In some embodiments, R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; R.sup.5 is tert-butyl; and R.sup.6 is bromo.
[0911] The base can be any suitable base, readily selected by one
skilled in the art. Examples of suitable bases include inorganic
bases such as ammonia and carbonates, hydroxides and hydrogen
carbonates of metals such as sodium, potassium, magnesium, calcium,
cesium and the like; and organic bases such as methylamine,
triethylamine, N-ethyldiisopropylamine, benzylamine, dibenzylamine,
morpholine and pyridine.
[0912] In some embodiments, the base is an alkali metal
hydroxide.
[0913] In some embodiments, the base is sodium hydroxide.
[0914] The reacting of a compound of Formula (IV) with a compound
of Formula (V) can be optionally carried out in the presence of a
catalyst.
[0915] In some embodiments, the catalyst is a phase-transfer
catalyst.
[0916] In some embodiments, the catalyst is a tetraalkylammonium
salt.
[0917] In some embodiments, the catalyst is a tetra-n-butylammonium
bromide.
[0918] In some embodiments the molar ratio of the compound of
Formula (IV) to the catalyst is about 20:1 to about 0.5:1.
[0919] In some embodiments the molar ratio of the compound of
Formula (IV) to the catalyst is about 10:1 to about 1:1.
[0920] In some embodiments the molar ratio of the compound of
Formula (IV) to the catalyst is about 5:1 to about 2:1.
[0921] In some embodiments the molar ratio of the compound of
Formula (IV) to the catalyst is about 4:1 to about 3:1.
[0922] The reacting of a compound of Formula (IV) with a compound
of Formula (V) can be optionally carried out in the presence of any
suitable solvent, readily selected by one skilled in the art.
Example solvents include polar to moderately polar solvents or high
boiling solvents such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide, toluene, acetonitrile, propionitrile,
tetrahydrofuran and N-methylpyrrolidinone.
[0923] In some embodiments, the solvent comprises toluene.
[0924] In some embodiments, the solvent comprises a mixture of
toluene and water.
[0925] In some embodiments, the solvent comprises a mixture of
approximately equal parts by weight of toluene and water.
[0926] The reacting of a compound of Formula (IV) with a compound
of Formula (V) can be carried out at any suitable temperature,
readily selected by one skilled in the art.
[0927] In some embodiments, the reacting is carried out at a
temperature of about -10.degree. C. to about 20.degree. C.
[0928] In some embodiments, the reacting is carried out at a
temperature of about -5.degree. C. to about 15.degree. C.
[0929] In some embodiments, the reacting is carried out at a
temperature of about 0.degree. C. to about 15.degree. C.
[0930] In some embodiments, the reacting is carried out at a
temperature of about 5.degree. C. to about 15.degree. C.
Carbamate Formation Step
[0931] The present invention further provides processes for
preparing compounds of Formula (IV):
##STR00156##
or a salt form thereof; wherein:
[0932] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0933] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
comprising reacting a compound of Formula (VI):
##STR00157##
or a salt form thereof; wherein:
[0934] R.sup.7 is a first leaving group;
with a compound of formula (VII):
##STR00158##
to form a compound of Formula (IV) or a salt form thereof.
[0935] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0936] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[0937] In some embodiments, R.sup.1 is 4-chlorophenyl.
[0938] In some embodiments, R.sup.1 is 3-fluorophenyl.
[0939] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[0940] In some embodiments, R.sup.2 is phenyl.
[0941] In some embodiments, R.sup.7 is halogen.
[0942] In some embodiments, R.sup.7 is chlorine.
[0943] In some embodiments, R.sup.7 is heteroaryl.
[0944] In some embodiments, R.sup.7 is benzotriazol-1-yl
[0945] In some embodiments, R.sup.7 is imidazol-1-yl.
[0946] In some embodiments, R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; and R.sup.7 is imidazol-1-yl.
[0947] In some embodiments, R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; and R.sup.7 is imidazol-1-yl.
[0948] The reacting of a compound of Formula (VI) with a compound
of Formula (VII) can be optionally carried out in the presence of
any suitable solvent, readily selected by one skilled in the art.
Example solvents include polar to moderately polar solvents or high
boiling solvents. such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide, toluene, acetonitrile, propionitrile,
tetrahydrofuran and N-methylpyrrolidinone.
[0949] In some embodiments, the solvent comprises acetonitrile.
[0950] The reacting of a compound of Formula (VI) with a compound
of Formula (VII) can be carried out at any suitable temperature,
readily selected by one skilled in the art.
[0951] In some embodiments, the reacting is carried out at a
temperature of about 35.degree. C. to about 105.degree. C.
[0952] In some embodiments, the reacting is carried out at a
temperature of about 45.degree. C. to about 95.degree. C.
[0953] In some embodiments, the reacting is carried out at a
temperature of about 55.degree. C. to about 85.degree. C.
[0954] In some embodiments, the reacting is carried out at a
temperature of about 65.degree. C. to about 70.degree. C.
[0955] The reacting of a compound of Formula (VI) with a compound
of Formula (VII) can be optionally carried out in situ following
the reacting of a compound of Formula (VIII) with a compound of
Formula (IX) in the presence of a base to form a compound of
Formula (VI), without substantial purification of the compound of
Formula (VI).
Acylation Step
[0956] The present invention further provides processes for
preparing compounds of Formula (VI):
##STR00159##
or a salt form thereof; wherein:
[0957] R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, aryl and
heteroaryl; each optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkyl
and halogen; and
[0958] R.sup.2 is selected from: H, C.sub.1-C.sub.6 alkyl and aryl;
wherein said aryl is optionally substituted with one or two
substituents selected from: C.sub.1-C.sub.6 alkyl and halogen;
and
[0959] R.sup.7 is a first leaving group;
comprising reacting a compound of Formula (VIII):
##STR00160##
or a salt form thereof; with a compound of formula (IX):
##STR00161##
wherein:
[0960] R.sup.8 is a second leaving group;
to form a compound of Formula (VI) or a salt form thereof.
[0961] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0962] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[0963] In some embodiments, R.sup.1 is 4-chlorophenyl.
[0964] In some embodiments, R.sup.1 is 3-fluorophenyl.
[0965] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[0966] In some embodiments, R.sup.2 is phenyl.
[0967] In some embodiments, R.sup.7 and R.sup.8 are both
halogen.
[0968] In some embodiments, R.sup.7 and R.sup.8 are both
chlorine.
[0969] In some embodiments, R.sup.7 and R.sup.8 are both
heteroaryl.
[0970] In some embodiments, R.sup.7 and R.sup.8 are both
benzotriazol-1-yl
[0971] In some embodiments, R.sup.7 and R.sup.8 are both
imidazol-1-yl.
[0972] In some embodiments, R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; and R.sup.7 and R$ are both imidazol-1-yl.
[0973] In some embodiments, R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; and R.sup.7 and R.sup.8 are both imidazol-1-yl.
[0974] The reacting of a compound of Formula (VI) with a compound
of Formula (VI) can be optionally carried out in the presence of
any suitable solvent, readily selected by one skilled in the art.
Example solvents include polar to moderately polar solvents or high
boiling solvents such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide, toluene, acetonitrile, propionitrile,
tetrahydrofuran and N-methylpyrrolidinone.
[0975] In some embodiments, the solvent comprises acetonitrile.
[0976] The reacting of a compound of Formula (VI) with a compound
of Formula (VII) can be carried out at any suitable temperature,
readily selected by one skilled in the art.
[0977] In some embodiments, the reacting is carried out at a
temperature of about 35.degree. C. to about 105.degree. C.
[0978] In some embodiments, the reacting is carried out at a
temperature of about 45.degree. C. to about 95.degree. C.
[0979] In some embodiments, the reacting is carried out at a
temperature of about 55.degree. C. to about 85.degree. C.
[0980] In some embodiments, the reacting is carried out at a
temperature of about 65.degree. C. to about 70.degree. C.
Salt Formation
[0981] The present invention further provides processes for
preparing salts of compounds of Formula (II):
##STR00162##
and solvates and hydrates thereof; comprising reacting a compound
of Formula (I) with a salt-forming reagent to form a salt of a
compound of formula (II).
[0982] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[0983] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[0984] In some embodiments, R.sup.1 is 4-chlorophenyl.
[0985] In some embodiments, R.sup.1 is 3-fluorophenyl.
[0986] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[0987] In some embodiments, R.sup.2 is phenyl.
[0988] In some embodiments, R.sup.1 is 4-chlorophenyl and R.sup.2
is phenyl.
[0989] In some embodiments, R.sup.1 is 3-fluorophenyl and R.sup.2
is phenyl.
[0990] In some embodiments, the salt forming reagent is an alkali
metal hydroxide.
[0991] In some embodiments, the salt forming reagent is sodium
hydroxide.
[0992] The reacting a compound of Formula (H) with a salt-forming
reagent to form a salt of a compound of formula (I) can be
optionally carried out in the presence of any suitable solvent,
readily selected by one skilled in the art.
[0993] In some embodiments, the solvent comprises an alcohol such
as ethanol, n-propanol, isopropanol, n-butanol and the like.
[0994] In some embodiments, the solvent comprises isopropanol.
[0995] In some embodiments, the solvent comprises a mixture of
isopropanol and water.
[0996] The reacting a compound of Formula (II) with a salt-forming
reagent to form a salt of a compound of formula (H) can be carried
out at any suitable temperature, readily selected by-one skilled in
the art.
[0997] In some embodiments, the reacting is carried out at a
temperature of about 10.degree. C. to about 70.degree. C.
[0998] In some embodiments, the reacting is carried out at a
temperature of about 20.degree. C. to about 60.degree. C.
[0999] In some embodiments, the reacting is carried out at a
temperature of about 30.degree. C. to about 50.degree. C.
[1000] In some embodiments, the reacting is carried out at a
temperature of about 40.degree. C.
Pharmaceutically Acceptable Salts
[1001] Some embodiments of the present invention pertain to
pharmaceutically acceptable salts of compounds of Formula (II):
##STR00163##
[1002] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[1003] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[1004] In some embodiments, R.sup.1 is 4-chlorophenyl.
[1005] In some embodiments, R.sup.1 is 3-fluorophenyl.
[1006] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[1007] In some embodiments, R.sup.2 is phenyl.
[1008] In some embodiments, R.sup.1 is 4-chlorophenyl and R.sup.2
is phenyl.
[1009] In some embodiments, R.sup.1 is 3-fluorophenyl and R.sup.2
is phenyl.
[1010] In some embodiments, the pharmaceutically acceptable salt
has a purity of 80% or greater.
[1011] In some embodiments, the pharmaceutically acceptable salt
has a purity of 90% or greater.
[1012] In some embodiments, the pharmaceutically acceptable salt
has a purity of 95% or greater.
[1013] In some embodiments, the pharmaceutically acceptable salt
has a purity of 99% or greater.
[1014] In some embodiments, the pharmaceutically acceptable salt
has a purity of 99.5% or greater.
[1015] In some embodiments, the pharmaceutically acceptable salt
comprises a pharmaceutically acceptable salt of a compound of
Formula (II) and a compound of Formula (II) in a ratio of about 4:1
or greater.
[1016] In some embodiments, the pharmaceutically acceptable salt
comprises a pharmaceutically acceptable salt of a compound of
Formula (II) and a compound of Formula (II) in a ratio of about 9:1
or greater.
[1017] In some embodiments, the pharmaceutically acceptable salt
comprises a pharmaceutically acceptable salt of a compound of
Formula (II) and a compound of Formula (II) in a ratio of about
19:1 or greater.
[1018] In some embodiments, the pharmaceutically acceptable salt
comprises a pharmaceutically acceptable salt of a compound of
Formula (II) and a compound of Formula (II) in a ratio of about
99:1 or greater.
[1019] In some embodiments, the pharmaceutically acceptable salt is
a sodium salt.
Intermediates
[1020] The present invention further provides intermediates that
are useful in the preparation of compounds of Formula (I) and salts
thereof.
[1021] Some embodiments pertain to compounds of Formula (I) or a
salt form thereof:
##STR00164##
[1022] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[1023] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[1024] In some embodiments, R.sup.1 is 4-chlorophenyl.
[1025] In some embodiments, R.sup.1 is 3-fluorophenyl.
[1026] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[1027] In some embodiments, R.sup.2 is phenyl.
[1028] In some embodiments, R.sup.5 is tert-butyl.
[1029] In some embodiments, R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; and R.sup.5 is tert-butyl.
[1030] In some embodiments, R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; and R.sup.5 is tert-butyl.
[1031] Some embodiments pertain to compounds of Formula (IV) or a
salt form thereof:
##STR00165##
[1032] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[1033] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[1034] In some embodiments, R.sup.1 is 4-chlorophenyl.
[1035] In some embodiments, R.sup.1 is 3-fluorophenyl.
[1036] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[1037] In some embodiments, R.sup.2 is phenyl.
[1038] In some embodiments, R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl.
[1039] In some embodiments, R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl.
[1040] Some embodiments pertain to compounds of Formula (VI) or a
salt form thereof:
##STR00166##
[1041] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[1042] In some embodiments, R.sup.1 is aryl, optionally substituted
with F or Cl.
[1043] In some embodiments, R.sup.1 is 4-chlorophenyl.
[1044] In some embodiments, R.sup.1 is 3-fluorophenyl.
[1045] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[1046] In some embodiments, R.sup.2 is phenyl.
[1047] In some embodiments, R.sup.7 is halogen.
[1048] In some embodiments, R.sup.7 is chlorine.
[1049] In some embodiments, R.sup.7 is heteroaryl.
[1050] In some embodiments, R.sup.7 is benzotriazol-1-yl
[1051] In some embodiments, R.sup.7 is imidazol-1-yl.
[1052] In some embodiments, R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; and R.sup.7 is imidazol-1-yl.
[1053] In some embodiments, R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; and R.sup.7 is imidazol-1-yl.
Pro-Drugs of the Present Invention
[1054] The compounds of the Formula (Ia) may be administered in the
form of a pro-drug which is broken down in the human or animal body
to give a compound of the Formula (Ia). Pro-drugs of the present
invention may employ any pro-drug strategy known in the art. A
pro-drug may be used to alter or improve the physical and/or
pharmacokinetic profile of the parent compound and can be formed
when the parent compound contains a suitable group or substituent
which can be derivatized to form apro-drug. Examples of pro-drugs
include in-vivo hydrolyzable amides of a compound of the Formula
(Ia) or pharmaceutically-acceptable salts thereof.
[1055] One aspect of the present invention pertains to compounds of
Formula (X) useful as pro-drugs for the delivery of compounds of
Formula (Ia):
##STR00167##
[1056] wherein:
[1057] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[1058] X is O or NR.sup.3;
[1059] R.sup.3 is selected from: H and C.sub.1-C.sub.6 alkyl;
and
[1060] R.sup.9 is a radical derived from any natural or unnatural
amino acid, upon the loss of a hydrogen atom from the .alpha.-amino
group of said natural or unnatural amino acid; or
[1061] R.sup.9 is --NHCH.sub.2CH.sub.2SO.sub.3H.
[1062] One aspect of the present invention pertains to compounds of
Formula (Xa) useful as pro-drugs for the delivery of compounds of
Formula (Ia):
##STR00168##
[1063] R.sup.1 and R.sup.2 are each independently selected from: H,
C.sub.1-C.sub.6 alkyl, aryl and heteroaryl; wherein C.sub.1-C.sub.6
alkyl, aryl and heteroaryl are each optionally substituted with one
or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen;
[1064] R.sup.10 is selected from: H and carboxyl; and
[1065] R.sup.11 is selected from: H and C.sub.1-C.sub.6 alkyl;
wherein C.sub.1-C.sub.6 alkyl is optionally substituted with
4-hydroxyphenyl, amino, carboxamide, carboxyl, guanidino, hydroxyl,
imidazolyl, indolyl, methylthio, phenyl, pyrrolidinyl, sulfo and
thiol.
[1066] In some embodiments, R.sup.1 is aryl, optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, aryl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkyl and halogen.
[1067] In some embodiments, R.sup.1 is aryl; optionally substituted
with F or Cl.
[1068] In some embodiments, R.sup.1 is 4-chlorophenyl.
[1069] In some embodiments, R.sup.1 is 3-fluorophenyl.
[1070] In some embodiments, R.sup.2 is aryl optionally substituted
with one or two substituents selected from: C.sub.1-C.sub.6 alkyl
and halogen.
[1071] In some embodiments, R.sup.2 is phenyl.
[1072] In some embodiments, R.sup.10 is H and R.sup.11 is
--CH.sub.2SO.sub.3H.
[1073] In some embodiments, R.sup.10 is carboxyl and R.sup.11 is
H.
[1074] In some embodiments: R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; R.sup.10 is H and R.sup.11 is --CH.sub.2SO.sub.3H.
[1075] In some embodiments: R.sup.1 is 4-chlorophenyl; R.sup.2 is
phenyl; R.sup.10 is carboxyl and R.sup.11 is H.
[1076] In some embodiments: R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; R.sup.10 is H and R.sup.11 is --CH.sub.2SO.sub.3H.
[1077] In some embodiments: R.sup.1 is 3-fluorophenyl; R.sup.2 is
phenyl; R.sup.10 is carboxyl and R.sup.11 is H.
[1078] Certain pro-drugs of compounds of the present invention are
described in Examples 1.112, 1.113 and 9-11.
Other Utilities
[1079] Another object of the present invention relates to
radio-labeled compounds of the present invention that would be
useful not only in radio-imaging but also in assays, both in vitro
and in vivo, for localizing and quantitating the PGI2 receptor in
tissue samples, including human and for identifying PGI2 receptor
ligands by inhibition binding of a radio-labeled compound. It is a
further object of this invention to develop novel PGI2 receptor
assays of which comprise such radio-labeled compounds.
[1080] The present invention embraces isotopically-labeled
compounds of the present invention. Isotopically or radio-labeled
compounds are those which are identical to compounds disclosed
herein, but for the fact that one or more atoms are replaced or
substituted by an atom having an atomic mass or mass number
different from the atomic mass or mass number most commonly found
in nature. Suitable radionuclides that may be incorporated in
compounds of the present invention include but are not limited to
.sup.2H (also written as D for deuterium), .sup.3H (also written as
T for tritium), .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.17O, .sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.75Br,
.sup.76Br, .sup.77Br, .sup.82Br, .sup.123I, .sup.124I, .sup.125I
and .sup.131I. The radionuclide that is incorporated in the instant
radio-labeled compounds will depend on the specific application of
that radio-labeled compound. For example, for in vitro PGI2
receptor labeling and competition assays, compounds that
incorporate .sup.3H, .sup.14C, .sup.82Br, .sup.15I, .sup.13I or
.sup.35S will generally be most useful. For radio-imaging
applications .sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I,
.sup.131I, .sup.75Br, .sup.76Br or .sup.77Br will generally be most
useful.
[1081] It is understood that a "radio-labeled" or "labeled
compound" is a compound of Formula (Ia), (Ic), (Ie), (Ig), (Ii),
(Ik), (Im) or (II) that has incorporated at least one radionuclide;
in some embodiments the radionuclide is selected from the group
consisting of .sup.3H, .sup.14C, .sup.125I, .sup.35S and
.sup.82Br.
[1082] Certain isotopically-labeled compounds of the present
invention are useful in compound and/or substrate tissue
distribution assays. In some embodiments the radionuclide .sup.3H
and/or .sup.14C isotopes are useful in these studies. Further,
substitution with heavier isotopes such as deuterium (i.e.,
.sup.2H) may afford certain therapeutic advantages resulting from
greater metabolic stability (e.g., increased in vivo half-life or
reduced dosage requirements) and hence may be preferred in some
circumstances. Isotopically labeled compounds of the present
invention can generally be prepared by following procedures
analogous to those disclosed in the Drawings and Examples infra, by
substituting an isotopically labeled reagent for a non-isotopically
labeled reagent.
[1083] Other synthetic methods that are useful are discussed infra.
Moreover, it should be understood that all of the atoms represented
in the compounds of the invention can be either the most commonly
occurring isotope of such atoms or the scarcer radio-isotope or
nonradioactive isotope.
[1084] Synthetic methods for incorporating radio-isotopes into
organic compounds are applicable to compounds of the invention and
are well known in the art. These synthetic methods, for example,
incorporating activity levels of tritium into target molecules, are
as follows:
[1085] A. Catalytic Reduction with Tritium Gas: This procedure
normally yields high specific activity products and requires
halogenated or unsaturated precursors.
[1086] B. Reduction with Sodium Borohydride [.sup.3H]: This
procedure is rather inexpensive and requires precursors containing
reducible functional groups such as aldehydes, ketones, lactones,
esters and the like.
[1087] C. Reduction with Lithium Aluminum Hydride [.sup.3H]: This
procedure offers products at almost theoretical specific
activities. It also requires precursors containing reducible
functional groups such as aldehydes, ketones, lactones, esters and
the like.
[1088] D. Tritium Gas Exposure Labeling: This procedure involves
exposing precursors containing exchangeable protons to tritium gas
in the presence of a suitable catalyst.
[1089] E. N-Methylation using Methyl Iodide [.sup.3H]: This
procedure is usually employed to prepare O-methyl or N-methyl (3H)
products by treating appropriate precursors with high specific
activity methyl iodide (3H). This method in general allows for
higher specific activity, such as for example, about 70-90
Ci/mmol.
[1090] Synthetic methods for incorporating activity levels of
.sup.125I into target molecules include:
[1091] A. Sandmeyer and like reactions: This procedure transforms
an aryl amine or a heteroaryl amine into a diazonium salt, such as
a diazonium tetrafluoroborate salt and subsequently to .sup.125I
labeled compound using Na.sup.125I. A represented procedure was
reported by Zhu, G-D. and co-workers in J. Org. Chem., 2002, 67,
943-948.
[1092] B. Ortho .sup.125Iodination of phenols: This procedure
allows for the incorporation of .sup.125I at the ortho position of
a phenol as reported by Collier, T. L. and co-workers in J.
Labelled Compd. Radiopharm., 1999, 42, S264-S266.
[1093] C. Aryl and heteroaryl bromide exchange with .sup.125I: This
method is generally a two step process. The first step is the
conversion of the aryl or heteroaryl bromide to the corresponding
tri-alkyltin intermediate using for example, a Pd catalyzed
reaction [i.e. Pd(Ph.sub.3P).sub.4] or through an aryl or
heteroaryl lithium, in the presence of a tri-alkyltinhalide or
hexaalkylditin [e.g., (CH.sub.3).sub.3SnSn(CH.sub.3).sub.3]. A
representative procedure was reported by Le Bas, M.-D. and
co-workers in J. Labelled Compd. Radiopharm. 2001, 44,
S280-S282.
[1094] A radiolabeled PGI2 receptor compound of Formula (Ia) can be
used in a screening assay to identify/evaluate compounds. In
general terms, a newly synthesized or identified compound (i.e.,
test compound) can be evaluated for its ability to reduce binding
of the "radio-labeled compound of Formula (Ia)" to the PGI2
receptor. Accordingly, the ability of a test compound to compete
with the "radio-labeled compound of Formula (Ia)" for the binding
to the PGI2 receptor directly correlates to its binding
affinity.
[1095] The labeled compounds of the present invention bind to the
PGI2 receptor. In one embodiment the labeled compound has an
IC.sub.50 less than about 500 .mu.M, in another embodiment the
labeled compound has an IC.sub.50 less than about 100 .mu.M, in yet
another embodiment the labeled compound has an IC.sub.50 less than
about 10 .mu.M, in yet another embodiment the labeled compound has
an IC.sub.50 less than about 1 .mu.M and in still yet another
embodiment the labeled inhibitor has an IC.sub.50 less than about
0.1 .mu.M.
[1096] Other uses of the disclosed receptors and methods will
become apparent to those skilled in the art based upon, inter alia,
a review of this disclosure.
[1097] As will be recognized, the steps of the methods of the
present invention need not be performed any particular number of
times or in any particular sequence. Additional objects, advantages
and novel features of this invention will become apparent to those
skilled in the art upon examination of the following examples
thereof, which are intended to be illustrative and not intended to
be limiting.
EXAMPLES
Example 1: Syntheses of Compounds of the Present Invention
[1098] Illustrated syntheses for compounds of the present invention
are shown in FIGS. 1 through 6 where the symbols have the same
definitions as used throughout this disclosure.
[1099] The compounds of the invention and their syntheses are
further illustrated by the following examples. The following
examples are provided to further define the invention without,
however, limiting the invention to the particulars of these
examples. The compounds described herein, supra and infra, are
named according to the CS ChemDraw Ultra Version 7.0.1, AutoNom
version 2.2, or CS ChemDraw Ultra Version 9.0.7. In certain
instances common names are used and it is understood that these
common names would be recognized by those skilled in the art.
[1100] Chemistry:
[1101] Proton nuclear magnetic resonance (.sup.1H NMR) spectra were
recorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus
Probe) or a BBI (Broad Band Inverse) and z-gradient. Chemical
shifts are given in parts per million (ppm) with the residual
solvent signal used as reference. NMR abbreviations are used as
follows: s=singlet, d=doublet, dd=doublet of doublets, ddd=doublet
of doublet of doublets, dt=doublet of triplets, t=triplet,
td=triplet of doublets, tt=triplet of triplets, q=quartet,
m=multiplet, bs=broad singlet, bt=broad triplet. Microwave
irradiations were carried out using a Smith Synthesizer.TM. or an
Emrys Optimizer.TM. (Biotage). Thin-layer chromatography (TLC) was
performed on silica gel 60 F.sub.254 (Merck), preparatory
thin-layer chromatography (prep TLC) was preformed on PK6F silica
gel 60 A 1 mm plates (Whatman) and column chromatography was
carried out on a silica gel column using Kieselgel 60, 0.063-0.200
mm (Merck). Evaporation was done under reduced pressure on a Buchi
rotary evaporator.
[1102] LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC
system controller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A
VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass
spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex;
Software: Analyst 1.2.
Example 1.1: Preparation of tert-Butyl
2-(((1s,4s)-4-((Phenylcarbamoyloxy)methyl)cyclo-hexyl)methoxy)acetate
Step A: Preparation of (1s,4s)-Diethyl
Cyclohexane-1,4-dicarboxylate
[1103] To a solution of (1s,4s)-cyclohexane-1,4-dicarboxylic acid
(25 g, 145 mmol) in ethanol (150 mL) was added concentrated
H.sub.2SO.sub.4 (98%, 1 mL). The reaction was heated to reflux for
16 h, cooled to room temperature and concentrated. The residue was
extracted with EtOAc and saturated NaHCO.sub.3, washed with brine,
dried over MgSO.sub.4, and filtered. The filtrate was concentrated
to provide the title compound as colorless oil (30.5 g). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.25 (t, J=7.14 Hz, 6H),
1.62-1.75 (m, 4H), 1.84-1.97 (m, 4H), 2.40-2.50 (m, 2H), 4.13 (q,
J=7.12 Hz, 4H).
Step B: Preparation of (1s,4s)-Cyclohexane-1,4-diyldimethanol
[1104] To a solution of (s,4s)-diethyl
cyclohexane-1,4-dicarboxylate (13.0 g, 56.9 mmol) in THE (500 mL)
was added lithium aluminum hydride (4.54 g, 120 mmol) in portions
at 0.degree. C. The mixture was stirred at that temperature for 2 h
and quenched with cold water, filtered and concentrated to give the
title compound as colorless oil (8.2 g). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.25-1.44 (m, 8H), 1.45-1.56 (m, 2H),
3.24-3.33 (m, 4H), 4.29 (t, J=5.31 Hz, 2H).
Step C: Preparation of ((s,4s)-4-(Hydroxymethyl)cyclohexyl)methyl
Phenylcarbamate
[1105] To a solution of (s,4s)-cyclohexane-1,4-diyldimethanol (3.0
g, 20.80 mmol) in pyridine (100 mL) were added phenyl isocyanate
(2.478 g, 20.80 mmol). The reaction was stirred overnight at room
temperature. The mixture was concentrated and purified via silica
gel column chromatography to provide the title compound as
colorless oil (2.55 g). LCMS m/z=264.1 [M+H].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 1.37-1.61 (m, 8H), 1.63-1.76 (m,
1H), 1.85-1.97 (m, 1H), 3.54 (d, J=6.95 Hz, 2H), 4.10 (d, J=7.20
Hz, 2H), 6.72 (s, 1H), 7.02-7.08 (m, 1H), 7.25-7.33 (m, 2H),
7.34-7.41 (m, 2H).
Step D: Preparation of tert-Butyl
2-(((1s,4s)-4-((Phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
[1106] To a solution of ((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl
phenylcarbamate (1.55 g, 5.89 mmol) in CH.sub.2Cl.sub.2 (100 mL)
was added diacetoxyrhodium (0.15 g, 0.339 mmol) and tert-butyl
2-diazoacetate (0.837 g, 5.89 mmol) and the mixture was stirred for
2 h at 0.degree. C. The mixture was concentrated and purified via
silica gel column chromatography to provide the title compound as
colorless oil (1.85 g). LCMS m/z=378.2 [M+H].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 1.40-1.64 (m, 811), 1.48 (s, 9H),
1.79-1.95 (m, 2H), 3.42 (d, J=6.95 Hz, 2H), 3.94 (s, 2H), 4.09 (d,
J=7.20 Hz, 2H), 6.63 (s, 111), 7.02-7.08 (m, 111), 7.25-7.33 (m,
2H), 7.35-7.41 (m, 2H).
Example 1.2: Preparation of
2-(((s,4s)-4-(((4-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 24)
[1107] To a solution of tert-butyl
2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
(0.1 g, 0.265 mmol) in dioxane (2 mL) were added
1-iodo-4-methoxybenzene (0.062 g, 0.265 mmol),
(1R,2R)-cyclohexane-1,2-diamine (0.030 g, 0.265 mmol), CuI (0.02 g,
0.158 mmol), and K.sub.3PO.sub.4 (0.1 g, 0.471 mmol) at room
temperature. The reaction mixture was sealed in a reaction vial and
heated to 150.degree. C. under microwave irradiation for 4 h. The
mixture was filtered and the filtrate was concentrated. The residue
was treated with HCl (4.0 N in dioxane, 5 mL) for 16 h. The
resulting mixture was concentrated and purified by preparative
HPLC. LCMS m/z=428.2 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.34-1.56 (m, 8H), 1.70-1.88 (m, 2H),
3.31 (s, 311), 3.39 (d, J=7.07 Hz, 2H), 4.00 (d, J=7.20 Hz, 2H),
4.11 (s, 21), 6.94-7.01 (m, 2H), 7.23-7.31 (m, 4H), 7.42-7.49 (m,
3H).
Example 1.3: Preparation of
2-(((s,4s)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic Acid (Compound 25)
[1108] From tert-butyl
2-(((s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-chloro-4-iodobenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=432.1 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.28-1.53 (m, 8H), 1.60-1.81 (m, 211), 3.29 (d, J=7.07 Hz, 2H),
3.96 (s, 2H), 3.98 (d, J=6.69 Hz, 2H), 7.24-7.33 (m, 5H), 7.36-7.48
(m, 4H).
Example 1.4: Preparation of
2-(((s,4s)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic Acid (Compound 26)
[1109] From tert-butyl
2-(((s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-fluoro-3-iodobenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=416.4 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.28-1.42 (m, 8H), 1.71 (s, 21), 3.28 (d, J=7.07 Hz, 2H), 3.96
(s, 2H), 3.99 (d, J=6.44 Hz, 2H), 7.03-7.11 (m, 2H), 7.20-7.33 (m,
4H), 7.37-7.43 (m, 3H).
Example 1.5: Preparation of
2-(((s,4s)-4-(((3-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic Acid (Compound 30)
[1110] From tert-butyl
2-(((s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-chloro-3-iodobenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=432.1 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.27-1.55 (m, 8H), 1.60-1.87 (m, 2H), 3.29 (d, J=7.07 Hz, 2H),
3.96 (s, 2H), 3.99 (d, J=6.57 Hz, 2H), 7.18-7.34 (m, 5H), 7.35-7.48
(m, 4H).
Example 1.6: Preparation of
2-(((1s,4s)-4-((Phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)ace-
tic Acid (Compound 31)
[1111] From tert-butyl
2-(((s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-iodo-3-methylbenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=412.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.28-1.53 (m, 8H), 1.60-1.76 (m, 2H), 2.27 (s, 3H), 3.28 (d,
J=6.95 Hz, 2H), 3.95 (s, 2H), 4.00 (d, J=7.20 Hz, 2H), 7.02-7.11
(m, 3H), 7.19-7.29 (m, 4H), 7.33-7.39 (m, 2H).
Example 1.7: Preparation of
2-(((s,4s)-4-(((2-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 32)
[1112] From tert-butyl
2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-iodo-2-methoxybenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=428.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.34-1.56 (m, 8H), 1.70-1.88 (m, 2H), 3.32 (s, 3H), 3.40 (d,
J=7.07 Hz, 2H), 4.00 (d, J=7.33 Hz, 2H), 4.11 (s, 2H), 6.93-7.02
(m, 2H), 7.23-7.31 (m, 4H), 7.42-7.49 (m, 3H).
Example 1.8: Preparation of
2-(((s,4s)-4-(((3-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 33)
[1113] From tert-butyl
2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-iodo-3-methoxybenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=428.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.34-1.56 (m, 8H), 1.71-1.88 (m, 2H), 3.32 (s, 3H), 3.40 (d,
J=7.07 Hz, 2H), 4.00 (d, J=7.33 Hz, 2H), 4.11 (s, 2H), 6.94-7.01
(m, 2H), 7.23-7.30 (m, 4H), 7.43-7.48 (m, 3H).
Example 1.9: Preparation of
2-(((s,4s)-4-((Phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ic Acid (Compound 34)
[1114] From tert-butyl
2-(((s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-iodo-4-methylbenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=412.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.28-1.53 (m, 811), 1.59-1.80 (m, 2H), 2.29 (s, 3H), 3.38 (d,
J=7.07 Iz, 2), 3.96 (s, 21), 4.00 (d, J=7.20 Hz, 2H), 7.13-7.21 (m,
2H), 7.21-7.30 (m, 411), 7.32-7.39 (m, 3H).
Example 1.10: Preparation of
2-(((s,4s)-4-(((4-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic Acid(Compound 35)
[1115] From tert-butyl
2-(((s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-fluoro-4-iodobenzene, using a similar method to the one
described in Example 1.2, the title compound was obtained. LCMS
m/z=416.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.28-1.54 (m, 8H), 1.60-1.75 (m, 2H), 3.29 (d, J=7.07 Hz, 211),
3.96 (s, 2H), 3.97 (d, J=6.69 Hz, 2H), 7.17-7.31 (m, 5H), 7.31-7.41
(m, 4H).
Example 1.11: Preparation of
2-(((1s,4s)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 7)
Step A: Preparation of ((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methyl
diphenylcarbamate
[1116] To a solution of (s,4s)-cyclohexane-1,4-diyldimethanol
(0.560 g, 3.88 mmol) in pyridine (5 mL) was added diphenylcarbamic
chloride (0.9 g, 3.88 mmol) at room temperature. The reaction was
refluxed for 5 h, cooled to room temperature, and concentrated
under reduced pressure. The residue was poured into water. The
organic material was extracted with ethyl acetate and washed with
1.0 M HCl. The extract was dried over MgSO.sub.4 and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography to provide the title compound (0.870 g). LCMS
m/z=340.23 [M+H].sup.+.
Step B: Preparation of
2-(((1s,4s)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic
Acid
[1117] To a solution of ((s,4s)-4-(hydroxymethyl)cyclohexyl)methyl
diphenylcarbamate (300 mg, 0.884 mmol) and diacetoxyrhodium (19.53
mg, 0.044 mmol) in CH.sub.2Cl2 (3 mL), was added dropwise a
solution of tert-butyl 2-diazoacetate (188 mg, 1.326 mmol) in
CH.sub.2C.sub.2 (1 mL) at 0.degree. C. After stirring for 1 h at
room temperature, the reaction was filtered and concentrated under
reduced pressure. The residue was treated with HCl (4.0 M in
dioxane, 2 mL). After stirring for 8 h, the reaction was
concentrated under reduced pressure and the residue was purified by
HPLC to provide the title compound (198 mg). LCMS m/z=398.45
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.15-1.40
(m, 8H), 1.50-1.62 (m, 2H), 1.75-1.81 (m, 2H), 3.90-3.92 (d, J=4.3
Hz, 2H), 3.96 (s, 2H), 7.21-7.32 (m, 6H), 7.35-7.39 (m, 4H).
Example 1.12: Preparation of Sodium
2-(((1r,4r)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
[1118] To a solution of
2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)
acetic acid (25 mg, 0.063 mmol) in MeOH (1 mL), was added sodium
methanolate (0.126 mL, 0.063 mmol) at -10.degree. C. After stirring
for 30 min, the reaction was concentrated under reduced pressure to
provide the title compound as a white solid (26.1 mg). LCMS
m/z=398.41 [M+H].sup.+.
Example 1.13: Preparation of
2-(((r,4r)-4-(((3-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 14)
Step A: Preparation of ((r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl
Phenylcarbamate
[1119] To a solution of (r,4r)-cyclohexane-1,4-diyldimethanol (5 g,
34.7 mmol) in pyridine, was added phenyl isocyanate (4.13 g, 34.7
mmol) at room temperature. The reaction was stirred for 5 h,
concentrated and extracted with ethyl acetate. The extract was
dried over MgSO.sub.4 and concentrated. The residue was purified by
silica gel column chromatography to give the title compound (4.69
g). LCMS m/z=264.43 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.81-1.09 (m, 4H), 1.30-1.39 (m, 1H),
1.51-1.62 (m, 1H), 1.75-1.88 (m, 4H), 3.15-3.25 (d, J=5.8 Hz, 2H),
3.82-3.95 (d, J=6.56 Hz, 2H), 4.52 (t, J=5.31 Hz, 1H), 6.29 (m,
1H), 7.30 (m, 2H), 7.48 (m, 2H), 9.62 (s, 1H).
Step B: Preparation of tert-Butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl) cyclohexyl)methoxy)
Acetate
[1120] To a solution of ((r,4r)-4-(hydroxymethyl)cyclohexyl)methyl
phenylcarbamate (2.5 g, 9.49 mmol) and diacetoxyrhodium (0.210 g,
0.475 mmol) in dichloromethane (50 mL) was added dropwise a
solution of tert-butyl 2-diazoacetate (1.350 g, 9.49 mmol) in
dichloromethane (5 mL) at 0.degree. C. for 20 min. After stirring
for 30 min at room temperature, the solid was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to give the title
compound (3.32 g). LCMS m/z=378.43 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.85-1.08 (m, 4H), 1.42 (s, 9H),
1.41-1.62 (m, 2H), 1.78-1.81 (m, 4H), 3.25 (d, J=6.3 Hz, 2H), 3.92
(d, J=4.6 Hz, 2H), 6.29 (m, 1H), 7.31 (m, 2H), 7.48 (m, 2H), 9.62
(s, 1H).
Step C: Preparation of
2-(((1r,4r)-4-(((3-Methoxyphenyl)(phenyl)carbamoyloxy)
methyl)cyclohexyl)methoxy)acetic Acid
[1121] To a solution of tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)
acetate (0.2 g, 0.530 mmol) in dioxane (95 mL) were added
1-bromo-3-methoxybenzene (0.099 g, 0.530 mmol),
(1R,2R)-cyclohexane-1,2-diamine (0.012 g, 0.106 mmol), copper(I)
iodide (10.09 mg, 0.053 mmol), and K.sub.3PO.sub.4 (0.225 g, 1.060
mmol) at room temperature. The reaction was irradiated under
microwave for 4 h at 150.degree. C. The reaction mixture was
filtered and concentrated under reduced pressure. The residue was
treated with HCl (4.0 M in dioxane, 5 mL). After stirring for 10 h,
the reaction was concentrated under reduced pressure and the
residue was purified by preparative HPLC to provide the title
compound (0.123 g). LCMS m/z=428.52 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.85-1.90 (m, 4H), 1.35-1.50 (s,
2H), 1.51-1.72 (m, 4H), 3.25 (d, J=6.4 Hz, 2H), 3.72 (s, 3H), 3.92
(d, J=6.1 Hz, 2H), 6.81-6.89 (m, 3H), 7.21-7.45 (m, 6H).
Example 1.14: Preparation of
2-(((1r,4r)-4-((1-Methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)ace-
tic Acid (Compound 4)
Step A: Preparation of
1-(((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl)-1-methyl-3,3-diphenylurea
[1122] To a solution of
((r,4r)-4-((methylamino)methyl)cyclohexyl)methanol (0.339 g, 2.158
mmol) in pyridine (3 mL) was added diphenylcarbamic chloride (0.5
g, 2.158 mmol) at room temperature. The reaction was refluxed for 5
h. The mixture was cooled to room temperature and poured into
water. The organic material was extracted and washed with 10 M HCl.
The extract was dried over MgSO.sub.4 and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography to provide the title compound (0.685 g). LCMS
m/z=353.16 [M+H].sup.+.
Step B: Preparation of
2-(((1r,4r)-4-((1-Methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)ace-
tic Acid
[1123] To a solution of
1-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)-1-methyl-3,3-diphenylurea
(0.1 g, 0.284 mmol) in CH.sub.2Cl.sub.2 (5 mL), was added rhodium
(I) acetate dimer (6.27 mg, 0.014 mmol) followed by tert-butyl
2-diazoacetate (0.040 g, 0.284 mmol) at 0.degree. C. The reaction
was stirred for 1 h and concentrated under reduced pressure. The
residue was treated with 4.0 M HCl in dioxane and stirred
overnight. The mixture was concentrated under reduced pressure and
the residue was purified by preparative HPLC to provide the title
compound (58 mg). LCMS m/z=411.32 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.35-1.41 (m, 2H), 1.81-1.92 (m,
1H), 2.21-2.51 (m, 4H), 2.62-2.86 (m, 2H), 3.21 (m, 2H), 4.62 (s,
3H), 7.15-7.38 (m, 1 OH).
Example 1.15: Preparation of
2-(((1r,4r)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 5)
[1124] From (1r,4r)-cyclohexane-1,4-diyldimethanol, the title
compound was obtained using a similar method to the one described
in Example 1.11. LCMS m/z=398.10 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.10-1.42 (m, 8H), 1.53-1.60 (m, 2H),
1.70-1.87 (m, 2H), 3.91-3.93 (d, J=4.2 Hz, 2H), 3.98 (s, 2H),
7.20-7.31 (m, 6H), 7.30-7.50 (m, 4H).
Example 1.16: Preparation of
2-(((s,4s)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 9)
Step A: Preparation of (1s,4s)-Cyclohexane-1, 4-diyldimethanol
[1125] To a mixture of (s,4s)-cyclohexane-1,4-dicarboxylic acid (4
g, 23.23 mmol) in THF (30 mL) was added lithium aluminum hydride (1
M, 93 mL, 93 mmol) dropwise at 0.degree. C. The mixture was stirred
at room temperature overnight. The reaction was quenched with
water, extracted with EtOAc (3.times.40 mL), and dried over
anhydrous MgSO.sub.4. The mixture was filtered and the filtrate was
concentrated under reduced pressure to provide the title compound
as colorless oil (3.3 g). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.6-1.38 (m, 8H), 1.70 (m, 2H), 3.56 (d, J=4 Hz, 4H).
Step B: Preparation of tert-Butyl
2-(((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methoxy)acetate
[1126] To a mixture of (1s,4s)-cyclohexane-1,4-diyldimethanol (1.0
g, 6.93 mmol) and rhodium(II) acetate dimer (0.184 g, 0.416 mmol)
in DCM (10 mL) was added tert-butyl 2-diazoacetate (1.281 g, 9.01
mmol) dropwise at room temperature over 1 h period. The mixture was
stirred overnight. The mixture was purified via column
chromatography to provide the title compound as pale yellow oil
(0.89 g). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.42 (m,
4H), 1.48 (s, 9H), 1.54 (m, 4H), 1.68 (m, 1H), 1.86 (m, 1H), 3.43
(d, 2H, J=8 Hz), 3.55 (d, 2H, J=8 Hz), 3.94 (s, 2H).
Step C: Preparation of tert-Butyl
2-(((s,4s)-4-((Methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate
[1127] To a mixture of tert-butyl
2-(((s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (0.87 g,
3.37 mmol) and triethylamine (1.408 mL, 10.10 mmol) in DCM (10 mL)
was added methanesulfonyl chloride (0.579 g, 5.05 mmol) at
0.degree. C. The mixture was stirred at 0.degree. C. for 5 h. The
reaction was quenched with water and extracted with DCM (3.times.20
mL) and dried over anhydrous MgSO.sub.4. The mixture was filtered
and concentrated under reduced pressure to provide the title
compound as pale yellow oil (1.1 g).
Step D: Preparation of tert-Butyl
2-(((1s,4s)-4-(Aminomethyl)cyclohexyl)methoxy) acetate
[1128] A mixture of tert-butyl
2-(((1s,4s)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate
(0.25 g, 0.743 mmol) and sodium azide (0.097 g, 1.486 mmol) in DMF
(5 mL) was stirred for 48 h. The reaction was diluted with EtOAc
(20 mL) and washed with water. The organic layer was dried over
anhydrous MgSO.sub.4 and concentrated under reduced pressure. The
residue was dissolved into MeOH (5.00 mL) and added Pd/C (3.95 mg,
0.037 mmol). The mixture was stirred under H.sub.2 atmosphere
overnight. The mixture was filtered through a celite column and
concentrated under reduced pressure to provide the title compound
as yellow oil (0.164 g) without further purification. LCMS
m/z=258.2 [M+H].sup.+.
Step E: Preparation of
2-(((s,4s)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic
Acid
[1129] To a mixture of tert-butyl
2-(((s,4s)-4-(aminomethyl)cyclohexyl)methoxy)acetate (50 mg, 0.194
mmol) in THE (5 ml) was added potassium tert-butoxide (65.4 mg,
0.583 mmol) at room temperature. After stirring for 10 min,
diphenylcarbamic chloride (45.0 mg, 0.194 mmol) was added. The
reaction mixture was stirred at room temperature overnight. The
reaction was quenched with water and the mixture was purified by
preparative HPLC to provide the title compound as a white solid (6
mg). LCMS m/z=397.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 0.93 (m, 4H), 1.44 (m, 1H), 1.58 (m, 1H), 1.74 (d, J=11
Hz, 2H), 1.83 (d, J=11 Hz, 2H), 3.10 (t, J=6.3 Hz, 2H), 3.38 (d,
J=6.3 Hz, 2H), 4.06 (s, 2H), 4.59 (t, J=5.8 Hz, 1H), 7.21 (dd,
J.sub.1=J.sub.2=7.2 Hz, 2H), 7.26 (m, 4H), 7.35 (m, 4H).
Example 1.17: Preparation of
2-(((r,4r)-4-((3-Benzhydryl-3-methylureido)methyl)cyclohexyl)methoxy)acet-
ic Acid (Compound 48)
[1130] A solution of N-methyl-1, 1-diphenylmethanamine (25 mg,
0.127 mmol), triphosgene (41.4 mg, 0.139 mmol), triethylamine
(0.088 mL, 0.634 mmol) in DCM (5 mL) was refluxed at 40.degree. C.
for 3 h. tert-Butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate (48.9 mg,
0.190 mmol) was added. The reaction mixture was refluxed overnight,
quenched with H.sub.2O, and extracted with DCM. The organic layer
was washed with brine, dried over MgSO.sub.4 and concentrated. The
residue was purified by preparative LCMS to provide the title
compound as a white solid (7.6 mg). LCMS m/z=425.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.82-1.02 (m, 4H),
1.41 (m, 1H), 1.57 (m, 1H), 1.70 (d, J=10.36 Hz, 2H), 1.80 (d,
J=10.36 Hz, 2H), 2.72 (s, 3H), 3.11 (t, J=5.68 Hz, 2H), 3.36 (d,
J=6.32 Hz, 2H), 4.06 (s, 2H), 4.53 (m, 111), 6.64 (s, 1H), 7.19 (d,
J=7.07 Hz, 4H), 7.27-7.38 (m, 6H).
Example 1.18: Preparation of
2-(((1r,4r)-4-(((2,3-Difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexy-
l)methoxy)acetic Acid (Compound 51)
Step A: Preparation of 2,3-Difluoro-N-phenylaniline
[1131] A mixture of 1-bromo-2,3-difluorobenzene (0.232 mL, 2.073
mmol), aniline (0.208 mL, 2.280 mmol), Pd.sub.2(dba).sub.3 (95 mg,
0.104 mmol), BINAP (194 mg, 0.311 mmol), sodium tert-butoxide (299
mg, 3.11 mmol), and toluene (3 mL) in a sealed vessel under argon
was heated in an oil bath at 110.degree. C. overnight. The reaction
mixture was filtered through a plug of celite. The filtrate was
concentrated and the residue was purified by silica gel column
chromatography to give the title compound as a light brown oil (411
mg). LCMS m/z=206.1 [M+H].sup.+; .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. ppm 6.53-6.64 (m, 1H), 6.80-6.88 (m, 2H),
6.88-6.95 (m, 1H), 6.95-7.03 (m, 2H), 7.11-7.19 (m, 2H).
Step B: Preparation of 2,3-Difluorophenyl(phenyl)carbamic
Chloride
[1132] 2,3-Difluoro-N-phenylaniline (100 mg, 0.487 mmol) and
triphosgene (159 mg, 0.536 mmol) were dissolved in CH.sub.2Cl.sub.2
(1 mL). The solution was cooled in an ice bath, and pyridine (79
.mu.L, 0.975 mmol) was added slowly. Upon complete addition, the
reaction was warmed to room temperature and stirred for 1 h. Then,
it was cooled in an ice bath and quenched by the slow addition of
H.sub.2O (1 mL). The reaction mixture was extracted with H.sub.2O
(5 mL) and CH.sub.2Cl.sub.2 (5 mL). The aqueous layer was extracted
again with CH.sub.2Cl.sub.2 (5 mL). The organic layers were
combined and washed once with H.sub.2O (10 mL), dried over
MgSO.sub.4, and concentrated. The residue was purified by silica
gel column chromatography to yield the title compound as a light
brown oil (114.7 mg).
Step C: Preparation of
2-(((r,4r)-4-(((2,3-Difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl-
)methoxy)acetic Acid
[1133] 2,3-Difluorophenyl(phenyl)carbamic chloride (50 mg, 0.187
mmol) and tert-butyl 2-(((1r,4r)-4-(hydroxymethyl)
cyclohexyl)methoxy)acetate (48.3 mg, 0.187 mmol) were dissolved in
pyridine (1 mL). The reaction mixture was heated to 100.degree. C.
and stirred overnight. The solvent was removed from the mixture and
the residue was purified by silica gel column chromatography to
provide an oil, which was redissolved in HCl (4 M in dioxane) (500
.mu.L, 1.999 mmol). The reaction mixture was stirred at room
temperature for 5 h. After removal of the solvent, the residue was
purified by preparative LCMS to provide the title compound as a
white solid (12.3 mg). LCMS m/z=434.2 [M+H].sup.+; .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. ppm 0.78-0.94 (m, 4H), 1.32-1.49 (m,
2H), 1.51-1.62 (m, 2H), 1.63-1.77 (m, J=7.33 Hz, 2H), 3.20-3.22 (m,
2H), 3.89 (d, J=6.06 Hz, 2H), 3.92 (s, 2H), 6.99-7.10 (m, 2H),
7.11-7.22 (m, 4H), 7.22-7.31 (m, 2H).
Example 1.19: Preparation of Sodium
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate
Step A: Preparation of 4-Chlorophenyl(phenyl)carbamic Chloride
[1134] From 4-chloro-N-phenylaniline, using a similar method to the
one described in Example 1.18, Step B, the title compound was
obtained as a light yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.31-7.81 (m, 9H).
Step B: Preparation of ((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate
[1135] 4-Chlorophenyl(phenyl)carbamic chloride (12.34 g, 46.4 mmol)
and (1r,4r)-cyclohexane-1,4-diyldimethanol (6.69 g, 46.4 mmol) were
dissolved in pyridine (50 mL, 618 mmol). The reaction mixture was
heated to reflux overnight, cooled and concentrated under reduced
pressure. The residue was resuspended in Et.sub.2O/EtOAc (50:50),
filtered and washed with EtOAc and Et.sub.2O. The filtrate was
extracted with 1 M HCl (200 mL) and EtOAc (200 mL). The aqueous
layer was extracted again with EtOAc (100 mL). The organic layers
were combined and washed with H.sub.2O (200 mL), dried, and
concentrated. The residue was purified by silica gel column
chromatography to provide the title compound as a light pink
colored solid (10.4 g). LCMS m/z=374.1 [M+H].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.73-0.92 (m, 4H), 1.13-1.27
(m, 1H), 1.36-1.50 (m, 1H), 1.53-1.62 (m, 2H), 1.62-1.73 (m, 2H),
3.17 (d, J=6.19 Hz, 2H), 3.89 (d, J=6.06 Hz, 2H), 4.29 (bs, 1H),
7.23-7.32 (m, 5H), 7.34-7.45 (m, 4H).
Step C: Preparation of tert-Butyl
2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate
[1136] ((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate (8.9 g, 23.80 mmol) was dissolved
in CH.sub.2Cl.sub.2 (30 mL). Diacetoxyrhodium (0.526 g, 1.190 mmol)
was added and the reaction was cooled on an ice bath. tert-Butyl
2-diazoacetate (3.63 mL, 26.2 mmol) pre-dissolved in
CH.sub.2Cl.sub.2 (10 mL) was added slowly to the reaction via an
addition funnel. The reaction was stirred in an ice bath for 1 h,
warmed to room temperature and stirred for an additional 1 h. After
removal of the solvent, the residue was purified by silica gel
column chromatography to provide the title compound as a colorless
oil (8.8 g). LCMS m/z=432.6 [M-tert-butyl group+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.77-0.95 (m, 4H),
1.33-1.50 (m, 2H), 1.42 (s, 9H), 1.52-1.62 (m, 2H), 1.63-1.75 (m,
2H), 3.22 (d, J=6.32 Hz, 2H), 3.83-3.93 (m, 4H), 7.23-7.32 (m, 5H),
7.35-7.44 (m, 4H).
Step D: Preparation of Sodium
2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate
[1137] tert-Butyl
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)
cyclohexyl)methoxy)acetate (8.8 g, 18.03 mmol) was dissolved in HCl
(4 M in dioxane, 100 mL, 400 mmol). The reaction was stirred at
room temperature overnight and concentrated under reduced pressure
to provide an oil. The oil was extracted with H.sub.2O (100 mL) and
EtOAc (100 mL). The aqueous layer was extracted again with EtOAc
(100 mL). The combined organic layer was washed with H.sub.2O (150
mL), dried, and concentrated to yield a light yellow oil. The oil
was dissolved in a minimal amount of MeOH (10-20 mL) and cooled in
an ice bath. NaOH (1 M, 27.0 mL, 27.0 mmol) was added with
stirring. A white solid precipitate was formed. The mixture was
diluted with H.sub.2O (20 mL). The solid was filtered and washed
with cold H.sub.2O (20 mL). The solid was dried in a vacuum oven
(60.degree. C. overnight) to provide the title compound as a white
solid (7.7 g). LCMS m/z=432.5 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.73-0.93 (m, 4H), 1.28-1.40 (bs, 1H),
1.40-1.50 (bs, 1H), 1.50-1.61 (m, 2H), 1.63-1.77 (m, 2H), 3.16 (d,
J=6.57 Hz, 2H), 3.47 (s, 2H), 3.89 (d, J=6.06 Hz, 2H), 7.23-7.32
(m, 5H), 7.35-7.44 (m, 4H).
Example 1.20: Preparation of Sodium
2-(((1r,4r)-4-(((4-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate
[1138] From 4-fluoro-N-phenylaniline, using a similar method to the
one described in Example 1.19, the title compound was obtained as a
white solid. LCMS m/z=416.4 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.72-0.94 (m, 4H), 1.28-1.39 (m, 1H),
1.39-1.49 (m, 1H), 1.50-1.61 (m, 2H), 1.62-1.76 (m, 2H), 3.15 (d,
J=6.44 Hz, 2H), 3.45 (s, 2H), 3.88 (d, J=6.06 Hz, 2H), 7.16-7.41
(m, 9H).
Example 1.21: Preparation of
2-(((1r,4r)-4-(((4-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic Acid (Compound 21)
[1139] tert-Butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
(50.0 mg, 0.132 mmol), copper(I) iodide (12.61 mg, 0.066 mmol),
K.sub.3PO.sub.4 (56.2 mg, 0.265 mmol), 4-methoxyphenyl iodide (31.0
mg, 0.132 mmol) and dioxane (1.6 mL) were added to a vial. The
reaction was heated under microwave irradiation at 150.degree. C.
for 4-5 h. The reaction mixture was filtered through a plug of
MgSO.sub.4. The solvent was evaporated and the resulting oil was
redissolved in HCl (4 M in dioxane, 497 .mu.L, 1.987 mmol). The
mixture was stirred overnight. After removal of the solvent, the
residue was purified by preparative LCMS to provide the title
compound as a white solid (12.2 mg). LCMS m/z=428.4
[M+H].sup.+.
Example 1.22: Preparation of
2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic Acid (Compound 22)
[1140] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-chloro-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=432.5 [M+H].sup.+.
Example 1.23: Preparation of
2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 23)
[1141] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-fluoro-3-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a 15
white solid. LCMS m/z=416.5 [M+H].sup.+.
Example 1.24: Preparation of
2-(((r,4r)-4-((Phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ic Acid (Compound 27)
[1142] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-iodo-3-methylbenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=412.2 [M+H].sup.+.
Example 1.25: Preparation of
2-(((1r,4r)-4-(((3-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 28)
[1143] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-chloro-3-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=432.6 [M+H].sup.+.
Example 1.26: Preparation of
2-(((r,4r)-4-(((4-Chloro-3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid (Compound 36)
[1144] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-chloro-2-fluoro-4-iodobenzene, using a similar method to the
one described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=450.1 [M+H].sup.+; .sup.1H NMR (400 MHz,
Methanol-d.sub.6) .delta. ppm 0.69-0.91 (m, 4H), 1.08-1.31 (m, 1H),
1.32-1.48 (m, 1H), 1.48-1.64 (m, 2H), 1.64-1.81 (m, 2H), 3.17 (d,
J=6.57 Hz, 2H), 3.71 (s, 2f), 3.87 (d, J=6.06 Hz, 2H), 6.94 (ddd,
J=8.75, 2.43, 1.20 Hz, 1H), 7.14-7.24 (m, 4H), 7.27-7.34 (m,
3H).
Example 1.27: Preparation of
2-(((1r,4r)-4-(((3-Chloro-4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cycl-
ohexyl)methoxy)acetic Acid (Compound 37)
[1145] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 2-chloro-1-fluoro-4-iodobenzene, using a similar method to the
one described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=450.2 [M+H].sup.+.
Example 1.28: Preparation of
2-(((1r,4r)-4-(((3-Fluoro-4-methylphenyl)(phenyl)carbamoyloxy)methyl)cycl-
ohexyl)methoxy)acetic Acid (Compound 38)
[1146] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 2-fluoro-4-iodo-1-methylbenzene, using a similar method to the
one described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=430.2 [M+H].sup.+.
Example 1.29: Preparation of
2-(((r,4r)-4-(((3,5-Difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl-
)methoxy)acetic Acid (Compound 39)
[1147] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1,3-difluoro-5-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=434.3 [M+H].sup.+; .sup.1H NMR (400 MHz,
Methanol-d.sub.6) .delta. ppm 0.85-1.02 (m, 4H), 1.46-1.58 (m, 2H),
1.59-1.70 (m, 2H), 1.79-1.87 (m, 2H), 3.28 (d, J=6.44 Hz, 2H), 3.82
(s, 211), 3.99 (d, J=6.19 Hz, 211), 6.79 (tt, J=9.02, 2.23 Hz, 1H),
6.88-6.95 (m, 2H), 7.25-7.32 (m, 2H), 7.33-7.41 (m, 1H), 7.41-7.50
(m, 2H).
Example 1.30: Preparation of
2-(((r,4r)-4-(((3,4-Difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl-
)methoxy)acetic Acid (Compound 40)
[1148] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1,2-difluoro-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=434.5 [M+H].sup.+; .sup.1H NMR (400 MHz,
Methanol-d.sub.6) .delta. ppm 0.93-1.11 (m, 4H), 1.52-1.68 (m, 2H),
1.67-1.81 (m, 2H), 1.84-1.98 (m, 2H), 3.36 (d, J=6.44 Hz, 2H), 3.90
(s, 2H), 4.05 (d, J=6.06 Hz, 2H), 7.10-7.18 (m, 1H), 7.27-7.42 (m,
5H), 7.45-7.53 (m, 2H).
Example 1.31: Preparation of
2-(((r,4r)-4-(((4-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic Acid (Compound 41)
[1149] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-fluoro-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=416.5 [M+H].sup.+; .sup.1H NMR (400 MHz,
Methanol-d.sub.6) .delta. ppm 0.79-1.08 (m, 4H), 1.45-1.60 (m, 2H),
1.61-1.73 (m, 2H), 1.77-1.89 (m, 2H), 3.29 (d, J=6.57 Hz, 2H), 3.83
(s, 2H), 3.97 (d, J=6.06 Hz, 2H), 7.07-7.14 (m, 2H), 7.21-7.34 (m,
5H), 7.35-7.41 (m, 2H).
Example 1.32: Preparation of
2-(((r,4r)-4-((Phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ic Acid (Compound 42)
[1150] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-iodo-4-methylbenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=412.2 [M+H].sup.+.
Example 1.33: Preparation of
2-(((r,4r)-4-((Phenyl(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy-
)acetic Acid (Compound 49)
[1151] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 3-iodopyridine, using a similar method to the one described in
Example 1.21, the title compound was obtained as a white solid.
LCMS m/z=399.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 0.67-0.91 (m, 4H), 1.31-1.47 (m, 2H), 1.47-1.58 (m,
2H), 1.62-1.76 (m, 2H), 3.21-3.27 (m, 2H), 3.93 (d, J=6.06 Hz, 2H),
3.96 (s, 2H), 7.12 (d, J=7.58 Hz, 2H), 7.26-7.45 (m, 3H), 7.56 (dd,
J=7.96, 5.43 Hz, 1H), 8.13 (d, J=8.08 Hz, 1H), 8.36 (d, J=4.29 Hz,
1H), 8.56 (s, 1H).
Example 1.34: Preparation of
2-(((r,4r)-4-(((5-Methylthiophen-2-yl)(phenyl)carbamoyloxy)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 50)
[1152] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 2-iodo-5-methylthiophene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=418.4 [M+H].sup.+.
Example 1.35: Preparation of
2-(((r,4r)-4-(((6-Fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 84)
[1153] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 2-fluoro-5-iodopyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=417.6 [M+H].sup.+.
Example 1.36: Preparation of
2-(((r,4r)-4-((Phenyl(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy-
)acetic Acid (Compound 85)
[1154] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and the 2-iodopyrazine, using a similar method to the one described
in Example 1.21, the title compound was obtained as a white solid.
LCMS m/z=400.2 [M+H].sup.+.
Example 1.37: Preparation of
2-(((r,4r)-4-(((4-Ethoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic Acid (Compound 88)
[1155] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 1-ethoxy-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=442.1 [M+H].sup.+.
Example 1.38: Preparation of
2-(((r,4r)-4-(((2-Fluoropyridin-4-yl)(phenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 89)
[1156] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 2-fluoro-4-iodopyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=417.6 [M+H].sup.+.
Example 1.39: Preparation of
2-(((r,4r)-4-(((5-Methoxypyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 90)
[1157] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 3-iodo-5-methoxypyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=429.4 [M+H].sup.+.
Example 1.40: Preparation of
2-(((r,4r)-4-(((5-Fluoropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 91)
[1158] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 5-fluoro-2-iodopyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=417.6 [M+H].sup.+.
Example 1.41: Preparation of
2-(((r,4r)-4-((Phenyl(5-(trifluoromethyl)pyridin-2-yl)carbamoyloxy)methyl-
)cyclohexyl)methoxy)acetic Acid (Compound 92)
[1159] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 2-iodo-5-(trifluoromethyl)pyridine, using a similar method to
the one described in Example 1.21, the title compound was obtained
as a white solid. LCMS m/z=467.5 [M+H].sup.+.
Example 1.42: Preparation of
2-(((r,4r)-4-(((5-Methylpyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 93)
[1160] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 3-iodo-5-methylpyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=413.2 [M+H].sup.+.
Example 1.43: Preparation of
2-(((r,4r)-4-(((5-Chloropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 94)
[1161] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 5-chloro-2-iodopyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=433.3 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.77-0.95 (m, 4H), 1.32-1.41 (m, 1H),
1.41-1.50 (m, 1H), 1.51-1.61 (m, 2H), 1.63-1.75 (m, 2H), 3.22 (d,
J=6.44 Hz, 2H), 3.93 (d, J=6.06 Hz, 211), 3.94 (s, 211), 7.21-7.32
(m, 3H), 7.36-7.44 (m, 2H), 7.70-775 (m, 1H), 7.97-8.02 (m, 1H),
8.33-8.41 (m, 1H), 12.52 (bs, 1H).
Example 1.44: Preparation of
2-(((r,4r)-4-(((5-Fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 95)
[1162] From tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
and 5-fluoro-3-iodopyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=417.5 [M+H].sup.+.
Example 1.45: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid (Compound 55)
Step A: Preparation of tert-Butyl
2-(((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methoxy)acetate
[1163] To a solution of (r,4r)-cyclohexane-1,4-diyldimethanol (5.0
g, 34.7 mmol) in benzene (20 mL) was added tetrabutylammonium
iodide (6.40 g, 17.34 mmol) and 50% aqueous NaOH (10 mL, 34.7 mmol)
at room temperature. The reaction was stirred vigorously for 5 min
and then tert-butyl 2-bromoacetate (5.63 mL, 38.1 mmol) was added.
The reaction was stirred vigorously for 2 h. The mixture was
extracted with H.sub.2O/NaOH (100 mL) and EtOAc/benzene (100 mL).
The aqueous layer was extracted again with EtOAc (100 mL). The
combined organic layer was dried and concentrated. The residue was
purified by silica gel column chromatography to provide the title
compound as a colorless oil (3.96 g). LCMS m/z=259.3 [M+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.89-1.06 (m, 4H),
1.47 (s, 9H), 1.55-1.68 (m, 2H), 1.76-1.98 (m, 4H), 3.32 (d, J=6.57
Hz, 2H), 3.45 (d, J=6.32 Hz, 2H), 3.93 (s, 2H).
Step B: Preparation of tert-Butyl
2-(((1r,4r)-4-((3-Fluorophenylcarbamoyloxy)
methyl)cyclohexyl)methoxy)acetate
[1164] To a solution of tert-butyl 2-(((1r,4r)-4-(hydroxymethyl)
cyclohexyl)methoxy)acetate (1.0 g, 3.87 mmol) and pyridine (0.438
mL, 5.42 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added 3-fluorophenyl
isocyanate (0.480 mL, 4.26 mmol) and the reaction was stirred at
room temperature overnight. The reaction was then heated to reflux
for 5 h. After removal of the solvent, the residue was purified by
silica gel column chromatography to yield the title compound as a
white solid (1.12 g). LCMS m/z=340.4 [M-tert-butyl+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.85-1.04 (m, 4H),
1.41 (s, 9H), 1.51-1.64 (m, 2H), 1.69-1.87 (m, 4H), 3.26 (d, J=6.32
Hz, 2H), 3.87 (s, 2H), 3.92 (d, J=6.57 Hz, 2H), 6.57 (s, 1H), 6.68
(dt, J=8.34, 2.53 Hz, 1H), 6.94 (d, J=8.59 Hz, 1H), 7.13-7.18 (m,
1H), 7.20-7.28 (m, 1H).
Step C: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid
[1165] From 1-iodo-4-methoxybenzene and tert-butyl
2-(((1r,4r)-4-((3-fluorophenyl-carbamoyloxy)methyl)cyclohexyl)methoxy)ace-
tate, using a similar method to the one described in Example 1.21,
the title compound was obtained as a white solid. LCMS m/z=446.5
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.86
(t, J=10.11 Hz, 4H), 1.39 (s, 2H), 1.54-1.62 (m, 2H), 1.64-1.74 (m,
2H), 3.23 (d, J=6.32 Hz, 2H), 3.76 (s, 3H), 3.89 (d, J=6.19 Hz,
2H), 3.94 (s, 2H), 6.91-6.98 (m, 2H), 6.99-7.07 (m, 2H), 7.17-7.26
(m, 3H), 7.36 (dt, J=8.18, 6.88 Hz, 1H), 12.52 (bs, 1H).
Example 1.46: Preparation of
2-(((r,4r)-4-(((4-Chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic Acid (Compound 56)
[1166] From 1-chloro-4-iodobenzene and tert-butyl
2-(((1r,4r)-4-((3-fluorophenyl-carbamoyloxy)methyl)cyclohexyl)methoxy)ace-
tate, using a similar method to the one described in Example 1.21,
the title compound was obtained as a white solid. LCMS m/z=450.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.77-0.98 (m, 4H), 1.34-1.42 (m, 1H), 1.42-1.52 (m, 1H), 1.53-1.63
(m, 2H), 1.63-1.75 (m, 2H), 3.23 (d, J=6.44 Hz, 2H), 3.91 (d,
J=6.06 Hz, 2H), 3.94 (s, 2H), 7.04-7.14 (m, 2H), 7.23-7.28 (m,
111), 7.29-7.36 (m, 2H), 7.36-7.42 (m, 1H), 7.42-7.49 (m, 2H),
12.52 (bs, 1H).
Example 1.47: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic Acid (Compound 57)
[1167] From 1-fluoro-4-iodobenzene and tert-butyl
2-(((1r,4r)-4-((3-fluorophenyl-carbamoyloxy)methyl)cyclohexyl)methoxy)ace-
tate, using a similar method to the one described in Example 1.21,
the title compound was obtained as a white solid. LCMS m/z=434.4
[M+H].sup.+.
Example 1.48: Preparation of
2-(((r,4r)-4-(((3-Chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic Acid (Compound 58)
[1168] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-chloro-3-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=450.2 [M+H].sup.+.
Example 1.49: Preparation of
2-(((1r,4r)-4-(((3-Fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic Acid (Compound 59)
[1169] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-iodo-3-methylbenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=430.5 [M+H].sup.+.
Example 1.50: Preparation of
2-(((r,4r)-4-(((4-Chloro-3-fluorophenyl)(3-fluorophenyl)carbamoyloxy)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 60)
[1170] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-chloro-2-fluoro-4-iodobenzene, using a similar method to
the one described in Example 1.21, the title compound was obtained
as a white solid. LCMS m/z=468.5 [M+H].sup.+.
Example 1.51: Preparation of
2-(((r,4r)-4-(((3-Chloro-4-fluorophenyl)(3-fluorophenyl)carbamoyloxy)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 61)
[1171] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 2-chloro-1-fluoro-4-iodobenzene, using a similar method to
the one described in Example 1.21, the title compound was obtained
as a white solid. LCMS r/z=468.4 [M+H].sup.+.
Example 1.52: Preparation of
2-(((r,4r)-4-(((3-Fluoro-4-methylphenyl)(3-fluorophenyl)carbamoyloxy)meth-
yl)cyclohexyl)methoxy)acetic Acid (Compound 62)
[1172] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 2-fluoro-4-iodo-1-methylbenzene, using a similar method to
the one described in Example 1.21, the title compound was obtained
as a white solid (17.4 mg). LCMS m/z=448.2 [M+H].sup.+.
Example 1.53: Preparation of
2-(((r,4r)-4-(((3,5-Difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cy-
clohexyl)methoxy)acetic Acid (Compound 64)
[1173] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1,3-difluoro-5-iodobenzene, using a similar method to the
one described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=452.3 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.77-0.94 (m, 4H), 1.32-1.42 (m, J=3.41
Hz, 1H), 1.42-1.52 (m, IH), 1.52-1.60 (m, 2H), 1.64-1.76 (m, 2H),
3.23 (d, J=6.32 Hz, 2H), 3.92 (d, J=5.94 Hz, 2H), 3.94 (s, 2H),
7.07-7.21 (m, 5H), 7.32 (dt, J=10.36, 2.27 Hz, 1H), 7.45 (td,
J=8.18, 6.76 Hz, 1H), 12.53 (bs, 1H).
Example 1.54: Preparation of
2-(((r,4r)-4-(((3,4-Difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cy-
clohexyl)methoxy)acetic Acid (Compound 65)
[1174] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1,2-difluoro-4-iodobenzene, using a similar method to the
one described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=452.1 [M+H].sup.+.
Example 1.55: Preparation of
2-(((r,4r)-4-((Bis(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic Acid (Compound 66)
[1175] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-fluoro-3-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=434.4 [M+H].sup.+.
Example 1.56: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(3-methoxyphenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid (Compound 67)
[1176] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-iodo-3-methoxybenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=446.4 [M+H].sup.+.
Example 1.57: Preparation of
2-(((r,4r)-4-(((3,5-Dimethylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cy-
clohexyl)methoxy)acetic Acid (Compound 68)
[1177] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-iodo-3,5-dimethylbenzene, using a similar method to the
one described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=444.7 [M+H].sup.+.
Example 1.58: Preparation of
2-(((1r,4r)-4-(((3-Fluorophenyl)(p-tolyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic Acid (Compound 69)
[1178] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-iodo-4-methylbenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=430.3 [M+H].sup.+.
Example 1.59: Preparation of
2-(((1r,4r)-4-(((3-Fluorophenyl)(6-fluoropyridin-3-yl)carbamoyloxy)methyl-
)cyclohexyl)methoxy)acetic Acid (Compound 70)
[1179] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 5-fluoro-2-iodopyridine, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=435.3 [M+H].sup.+.
Example 1.60: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl-
)cyclohexyl)methoxy)acetic Acid (Compound 71)
[1180] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 2-iodo-5-methylthiophene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=436.3 [M+H].sup.+.
Example 1.61: Preparation of
2-(((r,4r)-4-(((4-Ethoxyphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic Acid (Compound 72)
[1181] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-ethoxy-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=460.5 [M+H].sup.+.
Example 1.62: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(3-(trifluoromethoxy)phenyl)carbamoyloxy)m-
ethyl)cyclohexyl)methoxy)acetic Acid (Compound 73)
[1182] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-iodo-3-(trifluoromethoxy)benzene, using a similar method
to the one described in Example 1.21, the title compound was
obtained as a white solid. LCMS m/z=500.5 [M+H].sup.+.
Experiment 1.63: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 74)
[1183] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 3-iodopyridine, using a similar method to the one described
in Example 1.21, the title compound was obtained as a white solid.
LCMS m/z=417.4 [M+H].sup.+.
Experiment 1.64: Preparation of
2-(((r,4r)-4-(((3-Fluorophenyl)(pyrazin-2-yl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 75)
[1184] From tert-butyl
2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexy)methoxy)aceta-
te and 2-iodopyrazine, using a similar method to the one described
in Example 1.21, the title compound was obtained as a white solid.
LCMS m/z=418.5 [M+H].sup.+.
Example 1.65: Preparation of
2-(((r,4r)-4-(((4-Chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic Acid (Compound 76)
Step A: Preparation of Methyl
4-Fluoro-2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)phenylcarbamate
[1185] 4-Fluorophenyl isocyanate (4.75 g, 34.7 mmol),
(1r,4r)-cyclohexane-1,4-diyldimethanol (5.0 g, 34.7 mmol), and
pyridine (3.93 mL, 48.5 mmol) were dissolved in CH.sub.2Cl.sub.2
(30 mL). The reaction mixture was stirred at room temperature
overnight. After removal of the solvent, the residue was purified
by silica gel column chromatography to yield the title compound as
a white solid (4.92 g). LCMS m/z=282.4 [M+H].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.81-1.07 (m, 4H), 1.25-1.38
(m, 1H), 1.49-1.64 (m, 1H), 1.72-1.82 (m, 4H), 3.19-3.24 (m, 2H),
3.89 (d, J=6.57 Hz, 2H), 4.34 (t, J=5.31 Hz, 1H), 7.06-7.15 (m,
2H), 7.46 (dd, J=8.97, 4.93 Hz, 2H), 9.61 (s, 1H).
Step B: Preparation of tert-Butyl
2-(((1r,4r)-4-((4-Fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate
[1186] To a solution of methyl
4-fluoro-2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)phenylcarbamate
(2.0 g, 7.11 mmol) and rhodium(II) acetate dimer (0.157 g, 0.355
mmol) in CH.sub.2Cl.sub.2 (10 mL) was added slowly tert-butyl
2-diazoacetate (1.084 mL, 7.82 mmol) pre-dissolved in
CH.sub.2Cl.sub.2 (5 mL) via an addition funnel at 0.degree. C. The
reaction was stirred at 0.degree. C. for 1 h and stirred at room
temperature for another 1 h. After removal of the solvent, the
residue was purified by silica gel column chromatography to yield
the title compound as a tan solid (1.9 g). LCMS m/z=340.4
[M-tert-butyl+H].sup.+, 396.2 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.97 (d, J=10.36 Hz, 4H), 1.42 (s, 9H),
1.44-1.53 (m, 1H), 1.54-1.64 (m, 1H), 1.72-1.82 (m, 41), 3.26 (d,
J=6.32 Hz, 2H), 3.90 (d, J=6.57 Hz, 2H), 3.92 (s, 2H), 7.06-7.15
(m, 2H), 7.46 (dd, J=8.84, 4.93 Hz, 2H), 9.61 (s, 1H).
Step C: Preparation of
2-(((r,4r)-4-(((4-Chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetic Acid
[1187] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-chloro-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=450.1 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.78-0.94 (m, 4H), 1.33-1.52 (m, J=29.68
Hz, 2H), 1.53-1.62 (m, 2H), 1.64-1.74 (m, 2H), 3.23 (d, J=6.32 Hz,
2H), 3.89 (d, J=6.06 Hz, 2H), 3.93 (s, 2H), 7.17-7.27 (m, 2H),
7.27-7.39 (m, 4H), 7.39-7.50 (m, 2H), 12.51 (bs, 1H).
Example 1.66: Preparation of
2-(((r,4r)-4-(((4-Fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl-
)cyclohexyl)methoxy)acetic Acid (Compound 77)
[1188] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 2-iodo-5-methylthiophene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=436.4 [M+H].sup.+.
Example 1.67: Preparation of
2-(((1r,4r)-4-(((3-Chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid (Compound 78)
[1189] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-chloro-3-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=450.0 [M+H].sup.+.
Example 1.68: Preparation of
2-(((1r,4r)-4-(((4-Fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 79)
[1190] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 3-iodopyridine, using a similar method to the one described
in Example 1.21, the title compound was obtained as a white solid.
LCMS m/z=417.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.79-0.94 (m, J=10.57, 10.57, 10.57 Hz, 4H), 1.31-1.43
(m, 1H), 1.42-1.52 (m, 1H), 1.52-1.63 (m, 2H), 1.64-1.78 (m, 2H),
3.23 (d, J=6.44 Hz, 2H), 3.92 (d, J=5.94 Hz, 2H), 3.95 (s, 2H),
7.20-7.30 (m, 2H), 7.39-7.46 (m, 2H), 7.49 (dd, J=8.27, 4.86 Hz,
1H), 7.77-7.84 (m, 1H), 8.46 (dd, J=4.86, 1.45 Hz, 1H), 8.62 (d,
J=2.15 Hz, 1H).
Example 1.69: Preparation of
2-(((1r,4r)-4-(((4-Ethoxyphenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid (Compound 80)
[1191] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-ethoxy-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=460.3 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.79-0.94 (m, 4H), 1.31 (t, J=6.95 Hz,
3H), 1.34-1.50 (m, 2H), 1.51-1.64 (m, 2H), 1.64-1.76 (m, 2H), 3.23
(d, J=6.44 Hz, 2H), 3.86 (d, J=6.19 Hz, 2H), 3.94 (s, 2H), 4.00 (q,
J=6.95 Hz, 2H), 6.85-6.95 (m, 2H), 7.11-7.25 (m, 4H), 7.28-7.36 (m,
2H), 12.53 (s, 1H).
Example 1.70: Preparation of
2-(((r,4r)-4-(((4-Fluorophenyl)(4-(trifluoromethoxy)phenyl)carbamoyloxy)m-
ethyl)cyclohexyl)methoxy)acetic Acid (Compound 81)
[1192] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and I-iodo-4-(trifluoromethoxy)benzene, using a similar method
to the one described in Example 1.21, the title compound was
obtained as a white solid. LCMS m/z=500.5 [M+H].
Example 1.71: Preparation of
2-(((1r,4r)-4-(((4-Fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)m-
ethoxy)acetic Acid (Compound 82)
[1193] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-iodo-3-methylbenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=430.5 [M+H].sup.+.
Example 1.72: Preparation of
2-(((r,4r)-4-((Bis(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic Acid (Compound 83)
[1194] From tert-butyl
2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate and 1-fluoro-4-iodobenzene, using a similar method to the one
described in Example 1.21, the title compound was obtained as a
white solid. LCMS m/z=434.5 [M+H].sup.+.
Example 1.73: Preparation of
2-(((1r,4r)-4-((Phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 29)
[1195] tert-Butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate
(20.0 mg, 0.053 mmol) was dissolved in HCl (4 M in dioxane) (397
.mu.L, 1.590 mmol). The reaction was stirred at room temperature
overnight. The solvent was removed and the residue was purified by
preparative LCMS to yield the title compound as a white solid (9.2
mg). LCMS m/z=322.4 [M+H].sup.+.
Example 1.74: Preparation of
2-(((r,4r)-4-(((3-Chloro-5-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid (Compound 46)
[1196] From 1-bromo-3-chloro-5-fluorobenzene, using a similar
method to the one described in Example 1.18, the title compound was
obtained as a light brown oil. LCMS m/z=450.2 [M+H].sup.+.
Example 1.75: Preparation of
2-(((r,4r)-4-((Phenyl(pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy-
)acetic Acid (Compound 63)
[1197] From N-phenylpyridin-2-amine, using a similar method to the
one described in Example 1.18 (Steps B and C), the title compound
was obtained as a colorless oil. LCMS m/z=399.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.77-0.93 (m, 4H),
1.32-1.41 (m, 1H), 1.41-1.49 (m, J=3.28 Hz, 1H), 1.50-1.63 (m,
J=7.20 Hz, 2H), 1.62-1.77 (m, J=7.33 Hz, 2H), 3.22 (d, J=6.32 Hz,
2H), 3.92 (d, J=6.06 Hz, 2H), 3.94 (s, 2H), 7.19-7.29 (m, 4H),
7.33-7.41 (m, 2H), 7.60 (d, J=8.21 Hz, 1H), 7.83-7.91 (m, 1H),
8.31-8.38 (m, 1H).
Example 1.76: Preparation of
2-(((1r,4r)-4-(((5-Methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 97)
Step A: Preparation of 2-Iodo-5-methylthiazole
[1198] 5-Methylthiazole (179 .mu.L, 2.017 mmol) was dissolved in
THE (5 mL). The solution was cooled in a dry ice/acetone bath
(-70.degree. C.) and LDA (1.8 M in heptane/THF/ethylbenzene, 1233
.mu.L, 2.219 mmol) was added slowly via syringe. The reaction was
stirred at -70.degree. C. for 30 min. Iodine (614 mg, 2.420 mmol)
pre-dissolved in THE (2 mL) was added slowly via syringe. The
reaction was warmed to room temperature, stirred for 1 h, and
quenched with H.sub.2O (5 mL). The mixture was extracted with
H.sub.2O (20 mL) and EtOAc (20 mL). The aqueous layer was extracted
again with EtOAc (20 mL). The combined organic layers were dried,
concentrated, and the residue was purified by silica gel column
chromatography to provide the title compound as a light brown oil
(61 mg). LCMS m/z=226.1 [M+H].sup.+.
Step B: Preparation of
2-(((r,4r)-4-(((5-Methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl)cyclohex-
yl)methoxy)acetic Acid
[1199] From 2-iodo-5-methylthiazole and tert-butyl
2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate,
using a similar method to the one described in Example 1.21, the
title compound was obtained as a light brown oil. LCMS m/z=419.5
[M+H].sup.+.
Example 1.77: Preparation of Sodium
2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate
[1200] From 3-fluoro-N-phenylaniline, using a similar method to the
one described in Example 1.19, the sodium salt of the title
compound was obtained as a white solid. LCMS m/z=416.5 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.71-0.93 (m, 4H),
1.34 (bs, 1H), 1.44 (bs, 1H), 1.54-1.57 (m, 2H), 1.65-1.69 (m, 2H),
3.15 (d, J=6.57 Hz, 2H), 3.44 (s, 2H), 3.90 (d, J=5.94 Hz, 2H),
7.02-7.11 (m, 2H), 7.22 (dt, J=10.67, 2.24 Hz, 1H), 7.25-7.33 (m,
3H), 7.34-7.44 (m, 3H).
Example 1.78: Preparation of
2-(((r,4r)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 2)
Step A: Preparation of tert-Butyl
2-(((r,4r)-4-((tert-Butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate
[1201] A cooled solution of tert-butyl
((1r,4r)-4-(hydroxymethyl)cyclohexyl)methylcarbamate (2.0 g, 8.22
mmol) in THF (30 mL) was treated with NaH (60% dispersion in
mineral oil, 1.315 g, 32.9 mmol). The resulting suspension was
stirred at room temperature for 1 h then tert-butyl 2-bromoacetate
(1.822 mL, 12.33 mmol) was added. The reaction was heated in the
microwave to 60.degree. C. for 1 h and then left stirring overnight
at room temperature. Additional tert-butyl 2-bromoacetate (975
.mu.L) was added and the reaction was heated to 60.degree. C. and
stirred for 2 h. The reaction was quenched with water and extracted
with DCM. The combined DCM extract was washed with water; dried
over MgSO.sub.4 and concentrated. The resulting residue was
purified by preparative LCMS to provide the title compound as a
white solid (0.250 g). LCMS m/z=380.4 [M+Na].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.78-0.96 (m, 4H), 1.29 (bs,
1H), 1.39 (s, 9H), 1.44 (s, 9H), 1.66-1.79 (m, 4H), 2.78 (t, J=6.32
Hz, 2H), 3.26 (d, J=6.32 Hz, 2H), 3.94 (s, 2H), 6.80 (t, J=5.68 Hz,
1H).
Step B: Preparation of
2-(((1r,4r)-4-(Aminomethyl)cyclohexyl)methoxy)acetic Acid
[1202] tert-Butyl
2-(((1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetat-
e (61 mg, 0.171 mmol) was treated with 4.0 M HCl in dioxane (5.00
mL, 165 mmol) at room temperature for 1 h, followed by heating at
60.degree. C. for 45 min. The solvent was evaporated and the
resulting residue was washed 3.times. with DCM and concentrated to
yield the title compound as an off white solid (40 mg) without
further purification. LCMS m/z=202.4 [M+H].sup.+.
Step C: Preparation of
2-(((r,4r)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 2)
[1203] A solution of
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid (39.1 mg,
0.194 mmol) in THE (2 mL) was treated with potassium tert-butoxide
(0.583 mL, 0.583 mmol). Diphenylcarbamic chloride (45 mg, 0.194
mmol) was added and the resulting solution was stirred at room
temperature for 45 min. The reaction was quenched with water. The
water layer was concentrated under reduced pressure. The residue
was purified by preparative LCMS. The appropriate fractions were
collected. After removal of the solvent, the residue was dissolved
in MeOH (2.0 mL) and to this mixture was added 0.5 M sodium
methoxide in MeOH (0.388 mL, 0.194 mmol). The solution was stirred
at room temperature for 1 h. After removal of the solvent, the
residue was dissolved in minimal amount of 1:1 H.sub.2O/The
solution, frozen and lyophilized to provide the title compound (32
mg). LCMS m/z=397.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d)
.delta. ppm 0.69-0.87 (m, 4H), 125-1.43 (m, 2H), 1.53-1.70 (m, 4H),
2.83 (t, J=6.19 Hz, 2H), 3.18 (d, J=6.32 Hz, 2H), 3.89 (s, 2H),
5.88 (t, J=5.68 Hz, 1H), 7.05-7.14 (m, 6H), 7.28 (t, J=7.83 Hz,
4H).
Example 1.79: Preparation of
2-(((r,4r)-4-((3-Benzhydrylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 1)
[1204] A solution of
2-(((r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid (20.0 mg,
0.099 mmol) in DMF was treated with TEA (0.021 mL, 0.149 mmol)
followed by (isocyanatomethylene)dibenzene (0.019 mL, 0.099 mmol);
the resulting solution was stirred at room temperature for 1.0 h.
The reaction was stopped and the reaction mixture was purified by
preparative LCMS to provide the title compound as a white solid
(9.0 mg). LCMS m/z=411.4 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.80-0.97 (m, 4H), 1.27 (bs, 1H), 1.47
(bs, 1H), 1.66-1.79 (m, 4H), 2.89 (t, J=6.06 Hz, 2H), 3.27 (d,
J=6.32 Hz, 2H), 3.98 (s, 2H), 5.89 (d, J=8.34 Hz, 1H), 5.96 (t,
J=5.68 Hz, 1H), 6.80 (d, J=8.59 Hz, 1H), 7.21-7.29 (m, 6H),
7.31-7.37 (m, 4H), 12.57 (bs, 1H).
Example 1.80: Preparation of
2-(((r,4r)-4-((3-(3-Methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)metho-
xy)acetic acid (Compound 17)
Step A: Preparation of 3-Methoxyphenyl(phenyl)carbamic Chloride
[1205] To a cooled solution of 3-methoxy-N-phenylaniline (100.0 mg,
0.502 mmol) and pyridine (0.102 mL, 1.267 mmol) in DCM (500 mL) was
added triphosgene (120.0 mg, 0.406 mmol). The solution was allowed
to warm up to room temperature and stirred overnight. The organic
solvent was evaporated. The residue was dissolved in ethyl acetate,
washed with water, brine, dried over MgSO.sub.4 and concentrated to
provide the title compound (105.0 mg). LCMS m/z=261.9 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) 4 ppm 3.79 (s, 3H), 6.90-7.31
(m, 3H), 7.32-7.52 (m, 4H), 7.52-7.70 (m, 2H).
Step B: Preparation of tert-Butyl
2-(((r,4r)-4-((tert-Butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate
[1206] To a solution of tert-butyl
((1r,4r)-4-(hydroxymethyl)cyclohexyl)methylcarbamate (1.0 g, 4.11
mmol) and rhodium(I) acetate (0.091 g, 0.205 mmol) in
dichloromethane (10 mL) was added dropwise a solution of tert-butyl
2-diazoacetate (0.584 g, 4.11 mmol) in dichloromethane (10 mL). The
resulting solution was stirred at room temperature overnight. The
reaction was quenched with water; the organic layer was
subsequently washed with water (twice) and brine; dried over
MgSO.sub.4 and concentrated. The residue was purified by
preparative LCMS to provide the title compound as a white solid
(571 mg). LCMS m/z=380.4 [M+Na].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.78-0.97 (m, 4H), 1.29 (bs, 1H), 1.39
(s, 9H), 1.44 (s, 9H), 1.66-1.79 (m, 4H), 2.78 (t, J=6.32 Hz, 2H),
3.26 (d, J=6.32 Hz, 2H), 3.94 (s, 2H), 6.80 (t, J=5.68 Hz, 1H).
Step C: Preparation of tert-Butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate
[1207] tert-Butyl
2-(((1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetat-
e (61.0 mg; 0.171 mmol) was treated with HCl (4.0 M in dioxane, 3.0
mL) and stirred at room temperature for 1 h. The mixture was
concentrated to provide the title compound without further
purification. LCMS m/z=258.4 [M+H].sup.+.
Step D: Preparation of
2-(((r,4r)-4-((3-(3-Methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)metho-
xy)acetic Acid (Compound 17)
[1208] To tert-butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate (25.3 mg,
0.098 mmol) in a 5 mL microwave reaction vial were added DCM (1.0
mL) and TEA (0.036 mL, 0.262 mmol). The solution was stirred
briefly then 3-methoxyphenyl(phenyl)carbamic chloride (17.0 mg,
0.065 mmol) was added in three portions. The resulting solution was
heated under microwave irradiation at 80.degree. C. 2 h. The
reaction mixture was concentrated and the residue was treated with
HCl (4.0 M in dioxane, 3 mL) at 60.degree. C. for 1 h. The mixture
was concentrated and the residue was purified by preparative LCMS
to provide the title compound as a white solid (8.0 mg). LCMS
m/z=427.4 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.68-0.88 (m, 4H), 1.25-1.43 (m, 2H), 1.54-1.70 (m, 4H), 2.83
(t, J=6.19 Hz, 2H), 3.17 (d, J=6.57 Hz, 2H), 3.65 (s, 3H), 3.89 (s,
2H), 5.96 (t, J=5.81 Hz, 1H), 6.63 (dd, J=7.83, 1.52 Hz, 1H), 6.68
(t, J=2.15 Hz, 1H), 6.72 (dd, J=8.21, 2.40 Hz, 1H), 7.06-7.13 (m,
3H), 7.19 (t, J=8.08 Hz, 1H), 7.27 (t, J=7.71 Hz, 2H), 12.50 (bs,
1H).
Example 1.81: Preparation of
2-(((r,4r)-4-((3,3-di-p-Tolylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 15)
[1209] From di-p-tolyl carbamic chloride and tert-butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a
similar method to the one described in Example 1.80, Step D, the
title compound was obtained as a white solid. LCMS m/z=425.3
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.66-0.88 (m, 4H), 1.23-1.43 (m, 2H), 1.52-1.72 (m, 4H), 2.20 (s,
6H), 2.81 (t, J=6.32 Hz, 2H), 3.17 (d, J=6.32 Hz, 2H), 3.89 (s,
2H), 5.76 (t, J=5.81 Hz, 1H), 6.96 (d, J=8.34 Hz, 4H), 7.07 (d,
J=8.08 Hz, 4H), 12.50 (bs, 1H).
Example 1.82: Preparation of
2-(((r,4r)-4-((3,3-di-m-Tolylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 16)
[1210] From di-m-tolyl carbamic chloride and tert-butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a
similar method to the one described in Example 1.80, Step D, the
title compound was obtained as a white solid. LCMS m/z=425.3
[M+H].sup.+.
Example 1.83: Preparation of
2-(((r,4r)-4-((3-(4-Methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)metho-
xy)acetic Acid (Compound 18)
[1211] From 4-methoxyphenyl(phenyl)carbamic chloride and tert-butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a
similar method to the one described in Example 1.80, Step D, the
title compound was obtained as a white solid. LCMS m/z=427.4
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.66-0.87 (m, 4H), 1.23-1.43 (m, 2H), 1.51-1.70 (m, 4H), 2.81 (t,
J=6.19 Hz, 2H), 3.17 (d, J=6.32 Hz, 2H), 3.68 (s, 3H), 3.89 (s,
2H), 5.77 (t, J=5.68 Hz, 1H), 6.88 (d, J=8.84 Hz, 2H), 7.00-7.10
(m, 5H), 7.22 (t, J=7.83 Hz, 2H), 12.50 (bs, 1H).
Example 1.84: Preparation of
2-(((r,4r)-4-((3-(4-Methoxy-2-methylphenyl)-3-phenylureido)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 19)
[1212] From 4-methoxy-2-methylphenyl(phenyl)carbamic chloride and
tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate,
using a similar method to the one described in 10 Example 1.80,
Step D, the title compound was obtained as a white solid. LCMS
m/z=441.3 [M+H].sup.+.
Example 1.85: Preparation of
2-(((1r,4r)-4-((3-Phenyl-3-(3-(trifluoromethyl)phenyl)ureido)methyl)cyclo-
hexyl)methoxy)acetic Acid (Compound 20)
[1213] From phenyl(3-(trifluoromethyl)phenyl)carbamic chloride and
tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate,
using a similar method to the one described in Example 1.80, Step
D, the title compound was obtained as a white solid. LCMS m/z=465.3
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.68-0.87 (m, 4H), 1.26-1.43 (m, 2H), 1.54-1.71 (m, 4H), 2.84 (t,
J=6.19 Hz, 2H), 3.18 (d, J=6.32 Hz, 2H), 3.89 (s, 2H), 6.23 (t,
J=5.68 Hz, 1H), 7.16 (d, J=7.58 Hz, 2H), 7.21-7.27 (m, 2H),
7.33-7.49 (m, 5H), 12.50 (bs, 1H).
Example 1.86: Preparation of
2-(((r,4r)-4-((3-(3-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methox-
y)acetic Acid (Compound 3)
Step A: Preparation of 3-Fluoro-N-phenylaniline
[1214] In a round bottom flask equipped with a condenser was placed
N-phenylacetamide (1.0 g, 7.40 mmol), copper (I) chloride (0.146 g,
1.480 mmol), potassium carbonate (1.329 g, 9.62 mmol),
1-bromo-3-fluorobenzene (1.942 g, 11.10 mmol) and xylene (5 mL).
The suspension was heated to 180.degree. C. and refluxed for 66 h.
The suspension was filtered; and the filtrate was concentrated. The
dark brown residue was dissolved in ether; filtered; and the
filtrate was 30 concentrated. The dark brown residue was dissolved
in ethanol (10.00 mL), treated with potassium hydroxide (1.909 g,
34.0 mmol) and refluxed for 2 h. The solution was poured into of
water (80 mL) and extracted with DCM. The combined DCM extract was
washed with water (6 X), dried over MgSO.sub.4 and concentrated to
afford the title compound as a dark brown solid (0.669 g). LCMS
m/z=188.2 [M+H].sup.+.
Step B: Preparation of 3-Fluorophenyl(phenyl)carbamic Chloride
[1215] From 3-fluoro-N-phenylaniline, using a similar method to the
one described in Example 1.80, Step A, the title compound was
obtained as a brown oil. LCMS m/z=250.2 [M+H].sup.+.
Step C: Preparation of
2-(((r,4r)-4-((3-(3-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methox-
y)acetic Acid (Compound 3)
[1216] From 3-fluorophenyl(phenyl)carbamic chloride and tert-butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a
similar method to the one described in Example 1.80, Step D, the
title compound was obtained as a white solid. LCMS m/z=415.5
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.78-0.97 (m, 4H), 0.89-0.96 (m, 2H), 1.34-1.54 (m, 2H), 1.64-1.80
(m, 4H), 2.93 (t, J=6.25 Hz, 2H), 3.27 (d, J=6.44 Hz, 2H), 3.98 (s,
2H), 6.12 (t, J=5.81 Hz, 1H), 6.91 (ddd, J=8.08, 1.96, 0.82 Hz,
1H), 6.96-7.05 (m, 2H), 7.22 (dd, J=8.46, 1.14 Hz, 2H), 7.26-7.39
(m, 2H), 7.43 (t, J=7.83 Hz, 2H), 12.55 (bs, 1H).
Example 1.87: Preparation of
2-(((r,4r)-4-((3-(3-Chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methox-
y)acetic Acid (Compound 6)
[1217] To a solution of
2-(((r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid (24.96 mg,
0.124 mmol) in THF (1.5 mL) was added potassium tert-butoxide (50.6
mg, 0.451 mmol). The solution was stirred briefly then
3-chlorophenyl(phenyl)carbamic chloride (30 mg, 0.113 mmol) was
added. The resulting solution was stirred at room temperature for 1
h. The reaction was quenched with water. The aqueous layer was
concentrated under vacuum. The residue was purified by preparative
LCMS to provide the title compound as a white solid (5.0 mg). LCMS
m/z=431.3 [M+H].sup.+.
Example 1.88: Preparation of
2-(((r,4r)-4-((3-(4-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methox-
y)acetic Acid (Compound 8)
[1218] From 4-fluorophenyl(phenyl)carbamic chloride and
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using a
similar method to the one described in Example 1.87, the title
compound was obtained as a white solid. LCMS m/z=415.5 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.66-0.88 (m, 4H),
1.24-1.43 (m, 2H), 1.54-1.71 (m, 4H), 2.83 (t, J=6.25 Hz, 2H), 3.18
(d, J=6.44 Hz, 2H), 3.88 (s, 2H), 5.88 (t, J=5.75 Hz, 1H),
7.06-7.17 (m, 7H), 7.28 (t, J=7.77 Hz, 2H), 12.41 (bs, 1H).
Example 1.89: Preparation of
2-(((r,4r)-4-((3-(2-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methox-
y)acetic Acid (Compound 10)
[1219] From 2-fluorophenyl(phenyl)carbamic chloride and
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using a
similar method to the one described in Example 1.87, the title
compound was obtained as a white solid. LCMS m/z=415.5
[M+H].sup.+.
Example 1.90: Preparation of
2-(((r,4r)-4-((3-(4-Chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methox-
y)acetic Acid (Compound 11)
[1220] From 4-chlorophenyl(phenyl)carbamic chloride and
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using a
similar method to the one described in Example 1.87, the title
compound was obtained as a white solid. LCMS m/z=431.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.77-1.01 (m, 4H),
1.34-1.55 (m, 2H), 1.63-1.85 (m, 4H), 2.92 (t, J=5.87 Hz, 2H), 3.28
(d, J=6.44 Hz, 2H).3.98 (s, 2H), 5.88 (t, J=5.75 Hz, 1H), 7.13-7.29
(m, 5H), 7.36-7.45 (m, 4H).
Example 1.91: Preparation of
2-(((r,4r)-4-((3-Phenyl-3-m-tolylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 12)
[1221] From phenyl(m-tolyl)carbamic chloride and
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using a
similar method to the one described in Example 1.87, the title
compound was obtained as a white solid. LCMS m/z=411.5 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.77-0.98 (m, 4H),
1.34-1.54 (m, 2H), 1.63-1.81 (m, 4H), 2.29 (s, 3H), 2.93 (t, J=6.32
Hz, 2H), 3.28 (d, J=6.44 Hz, 2H), 3.98 (s, 2H), 5.89 (t, J=5.81 Hz,
1H), 6.98 (d, J=7.96 Hz, 1H), 7.05 (d, J=8.21 Hz, 2H), 7.13-7.22
(m, 3H), 7.27 (t, J=7.71 Hz, 1H), 7.33-7.39 (m, 2H), 12.51 (bs,
1H).
Example 1.92: Preparation of
2-(((r,4r)-4-((3-Phenyl-3-p-tolylureido)methyl)cyclohexyl)methoxy)acetic
Acid (Compound 13)
[1222] From phenyl(p-tolyl)carbamic chloride and
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using a
similar method to the one described in Example 1.87, the title
compound was obtained as a white solid. LCMS m/z=411.5
[M+H].sup.+.
Example 1.93: Preparation of
2-(((r,4r)-4-((3-(3,5-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 44)
Step A: Preparation of 3,5-Difluoro-N-phenylaniline
[1223] In a 5 mL microwave reaction vial was placed aniline (0.298
g, 3.20 mmol) and 1,3-difluoro-5-iodobenzene (0.768 g, 3.20 mmol)
in toluene (3 mL). KOH (0.323 g, 5.76 mmol) in water (650 .mu.L)
and N,N,N-trimethylhexadecan-1-aminium bromide (6.30 mg, 0.017
mmol) were added to the vial with stirring. After the reaction was
warmed to 90.degree. C., bis[tri(t-butylphosphine]palladium[0]
(0.016 g, 0.032 mmol) was added and the reaction was stirred at
150.degree. C. for 4 h and then 160.degree. C. for 2 h. The mixture
was diluted with water and brine, and extracted with toluene. The
toluene extract was subsequently washed with water, dried over
MgSO.sub.4 and concentrated. The residue was purified by flash
column chromatography to provide the title compound as a brown oil
(0.132 g). LCMS m/z=206.2 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 6.54 (tt, J=9.35, 2.27 Hz, 1H), 6.63 (dd,
J=10.48, 2.15 Hz, 2H), 7.01 (dt, J=14.65, 1.14 Hz, 1H), 7.17 (dd,
J=8.59, 1.01 Hz, 2H), 7.34 (t, J=7.83 Hz, 2H), 8.69 (s, 1H).
Step B: Preparation of 3,5-Difluorophenyl(phenyl)carbamic
Chloride
[1224] From 3,5-difluoro-N-phenylaniline, using a similar method to
the one described in Example 1.80, Step A, the title compound was
obtained as a brown oil. LCMS m/z=268.7 [M+H].sup.+.
Step C: Preparation of
2-(((r,4r)-4-((3-(3,5-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)me-
thoxy)acetic acid (Compound 44)
[1225] From 3,5-difluorophenyl(phenyl)carbamic chloride and
tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate,
using a similar method to the one described in Example 1.80, Step
D, the title compound was obtained as a white solid. LCMS m/z=433.4
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.77-0.97 (m, 4H), 1.35-1.53 (m, 2H), 1.62-1.79 (m, 4H), 2.92 (t,
J=6.19 Hz, 2H), 3.27 (d, J=6.32 Hz, 2H), 3.98 (s, 2H), 6.32 (t,
J=5.56 Hz, 1H), 6.76-6.84 (m, 2H), 6.96-7.04 (m, 1H), 7.26 (d,
J=7.33 Hz, 2H), 7.33-7.40 (m, 1H), 7.48 (t, J=7.71 Hz, 2H).
Example 1.94: Preparation of
2-(((r,4r)-4-((3-(2,3-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)me-
thoxy)acetic acid (Compound 43)
[1226] From 2,3-difluorophenyl(phenyl)carbamic chloride and
tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate,
using a similar method to the one described in Example 1.80, Step
D, the title compound was obtained as a white solid. LCMS m/z=433.4
[M+H].sup.+.
Example 1.95: Preparation of
2-(((r,4r)-4-((3-(3-Chloro-2-fluorophenyl)-3-phenylureido)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 45)
[1227] From 3-chloro-2-fluorophenyl(phenyl)carbamic chloride and
tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate,
using a similar method to the one described in Example 1.80, Step
D, the title compound was obtained as a white solid. LCMS m/z=449.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.78-0.97 (m, 4H), 1.34-1.53 (m, 2H), 1.64-1.80 (m, 4H), 2.92 (t,
J=5.94 Hz, 2H), 3.27 (d, J=6.32 Hz, 2H), 3.98 (s, 2H), 6.51 (t,
J=5.56 Hz, 1H), 7.16-7.30 (m, 5H), 7.38 (t, J=7.20 Hz, 2H),
7.50-7.56 (m, 1H).
Example 1.96: Preparation of
2-(((r,4r)-4-((3-(3-Chloro-5-fluorophenyl)-3-phenylureido)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 47)
[1228] From 3-chloro-5-fluorophenyl(phenyl)carbamic chloride and
tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate,
using a similar method to the one described in Example 1.80, Step
D, the title compound was obtained as a white solid. LCMS m/z=449.2
[M+H].
Example 1.97: Preparation of
2-(((r,4r)-4-((3-(2-Fluoro-3-methoxyphenyl)-3-phenylureido)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 53)
Step A: Preparation of 2-Fluoro-3-methoxy-N-phenylaniline
[1229] In a reaction vial were placed aniline (0.200 g, 2.182
mmol); 2-fluoro-1-iodo-3-methoxybenzene (0.500 g., 1.984 mmol),
Pd.sub.2(dba).sub.3 (0.091 g, 0.099 mmol), BINAP (0.185 g, 0.298
mmol), NaOtBu (0.286 g, 2.98 mmol), and toluene (3 mL). The
reaction was stirred at 80.degree. C. overnight and quenched with
water. The organic layer was separated and concentrated. The
residue was purified by flash column chromatography to provide the
title compound as a brown oil (0.313 g). LCMS m/z=218.4
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.82
(s, 3H), 6.73 (ddd, J=10.93, 8.15, 1.64 Hz, 1H), 6.88-7.05 (m, 3H),
7.15 (d, J=7.33 Hz, 2H), 7.25-7.31 (m, 2H), 7.80 (s, 1H).
Step B: Preparation of 2-Fluoro-3-methoxyphenyl(phenyl)carbamic
Chloride
[1230] From 2-fluoro-3-methoxy-N-phenylaniline, using a similar
method to the one described in Example 1.80, Step A, the title
compound was obtained as a brown oil. LCMS m/z=280.5 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.98 (s, 3H),
7.12-7.24 (m, 1H), 7.33-7.53 (m, 6H), 7.59 (d, J=7.33 Hz, 1H).
Step C: Preparation of Ethyl
2-(((r,4r)-4-((tert-Butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate
[1231] To a solution of tert-butyl
((1r,4r)-4-(hydroxymethyl)cyclohexyl)methylcarbamate (500 mg, 2.055
mmol) and rhodium(II) acetate (45.4 mg, 0.103 mmol) in DCM (5.0 mL)
was added dropwise a solution of ethyl 2-diazoacetate (0.213 mL,
2.055 mmol) in DCM (10 mL). The resulting solution was stirred at
room temperature overnight. The reaction was quenched with water;
the organic layer was washed with water (twice) and brine, dried
over MgSO.sub.4 and concentrated. The residue was purified by
preparative LCMS to provide the title compound as a white solid.
(244 mg). LCMS m/z=330.2 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.78-0.97 (m, 4H), 1.22 (t, J=7.07 Hz,
3H), 1.29 (bs, 1H), 1.39 (s, 9H), 1.48 (bs, 1H), 1.66-1.79 (m, 4H),
2.78 (t, J=6.32 Hz, 2H), 3.28 (d, J=6.57 Hz, 2H), 4.07 (s, 2H),
4.13 (q, J=7.07 Hz, 2H), 6.81 (t, J=5.81 Hz, 1H).
Step D: Preparation of Ethyl
2-(((1r,4r)-4-(Aminomethyl)cyclohexyl)methoxy)acetate
[1232] In a round-bottomed flask ethyl
2-(((1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetat-
e (244 mg, 0.741 mmol) was treated with HCl (4.0 M in dioxane, 4.0
mL) and the mixture was stirred for 30 min at room temperature. The
mixture was concentrated under reduced pressure and the residue was
dried in a vacuum oven overnight to afford the title compound (110
mg) without further purification. LCMS m/z=230.4 [M+H].sup.+.
Step E: Preparation of
2-(((r,4r)-4-((3-(2-Fluoro-3-methoxyphenyl)-3-phenylureido)methyl)cyclohe-
xyl)methoxy)acetic Acid (Compound 53)
[1233] To ter-butyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate (36.9 mg,
0.161 mmol) in a 5 mL microwave reaction vial were added DCM (1.0
mL) and TEA (0.045 mL, 0.322 mmol). The solution was stirred
briefly and 2-fluoro-3-methoxyphenyl(phenyl)carbamic chloride (30.0
mg, 0.107 mmol) was added. The reaction mixture was heated under
microwave irradiation at 80.degree. C. and stirred for 2 h. After
removal of the solvent the residue was treated with 1.0 M LiOH
(2.145 mL, 2.145 mmol) and the solution was stirred overnight at
room temperature. The reaction mixture was acidified to pH 4 by
dropwise addition of 1 M HCl and extracted with ethyl acetate.
After evaporation of the ethyl acetate, the residue was purified by
preparative LCMS to provide the title compound as a white solid
(22.8 mg). LCMS m/z=445.3 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.79-1.02 (m, 4H), 1.35-1.54 (m, 2H),
1.66-1.81 (m, 4H), 2.93 (t, J=6.00 Hz, 2H), 3.28 (d, J=6.32 Hz,
2H), 3.75 (s, 3H), 3.98 (s, 2H), 6.18 (t, J=5.75 Hz, 1H), 7.02-7.07
(m, lH), 7.08-7.18 (m, 4H), 7.21-7.27 (m, 1H), 7.33 (t, J=7.83 Hz,
2H).
Example 1.98: Preparation of
2-(((r,4r)-4-((3-(4-Chloro-3-fluorophenyl)-3-phenylureido)methyl)cyclohex-
yl)methoxy)acetic Acid (Compound 52)
[1234] From ethyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate and
4-chloro-3-fluorophenyl(phenyl)carbamic chloride, using a similar
method to the one described in Example 1.97, Step E, the title
compound was obtained as a white solid. LCMS m/z=449.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.76-0.99 (m, 4H),
1.35-1.54 (m, 2H), 1.66-1.81 (m, 4H), 2.93 (t, J=6.25 Hz, 2H), 3.27
(d, J=6.32 Hz, 2H), 3.98 (s, 2H), 6.24 (t, J=5.68 Hz, 1H), 6.91
(dd, J=9.98, 1.26 Hz, 1H), 7.21-7.35 (m, 4H), 7.40-7.56 (m,
3H).
Example 1.99: Preparation of
2-(((r,4r)-4-((3-(3,4-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 54)
[1235] From ethyl
2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate and
3,4-difluorophenyl(phenyl)carbamic chloride, using a similar method
to the one described in Example 1.97, Step E, the title compound
was obtained as a white solid. LCMS m/z=433.4 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.76-0.98 (m, 4H),
1.35-1.53 (m, 2H), 1.64-1.80 (m, 4H), 2.92 (t, J=6.13 Hz, 2H), 3.28
(d, J=6.44 Hz, 2H), 3.98 (s, 2H), 6.12 (t, J=5.68 Hz, 1H), 6.96 (d,
J=4.17 Hz, 1H), 7.20-7.37 (m, 4H), 7.38-7.45 (m, 3H).
Example 1.100: Preparation of
2-(((1r,4r)-4-((Benzhydryl(methyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic Acid (Compound 86)
[1236] To tert-butyl
2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (15 mg,
0.058 mmol) in DCM (0.5 mL) was added bis(2,5-dioxopyrrolidin-1-yl)
carbonate (15.62 mg, 0.061 mmol) followed by TEA (0.016 mL, 0.116
mmol). The suspension was heated until the solution turned clear.
The reaction was then stirred for 2 h at room temperature, followed
by 2 h at 80.degree. C. N-methyl-1,1-diphenylmethanamine (17.18 mg,
0.087 mmol) and TEA (0.016 mL, 0.116 mmol) were added to the
reaction mixture and the resulting solution was heated under
microwave irradiation at 60.degree. C. for 2 h. The organic solvent
was evaporated and the residue was purified by preparative LCMS to
provide an intermediate which was treated with 4.0 M HCl in dioxane
for 1 h at 60.degree. C. The acid solution was evaporated and the
residue was purified by preparative LCMS to provide the title
compound as an oil (1.0 mg). LCMS m/z=426.3 [M+H].sup.+.
Example 1.101: Preparation of
2-(((1r,4r)-4-((3-Benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy-
)acetic Acid (Compound 87)
Step A: Preparation of
1-Benzhydryl-3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)-1,3-dimethyl-
urea
[1237] A solution of
((1r,4r)-4-((methylamino)methyl)cyclohexyl)methanol (40.7 mg, 0.259
mmol) in DCM (0.5 mL) was treated with TEA (0.090 mL, 0.647 mmol)
and benzhydryl(methyl)carbamic chloride (56 mg, 0.216 mmol). The
reaction was heated under microwave irradiation at 80.degree. C.
for 2 h. The reaction mixture was concentrated and the residue was
purified by preparative LCMS to provide the title compound as an
oil (26 mg). LCMS m/z=381.2 [M+H].sup.+.
Step B: Preparation of
2-(((r,4r)-4-((3-Benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy)-
acetic Acid (Compound 87)
[1238] To
1-benzhydryl-3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)-1,3-
-dimethylurea (26 mg, 0.068 mmol) and rhodium(H) acetate (6.04 mg,
0.014 mmol) in dichloromethane (2.0 mL) was added dropwise a
solution of ethyl 2-diazoacetate (9.36 mg, 0.082 mmol) in DCM (2
mL). The reaction was stirred at room temperature for 4 days. The
mixture was diluted with DCM, washed with water (five times), 1 M
HCl (twice), saturated NaHCO.sub.3 (twice); and brine (twice). The
combined organic layers were dried over MgSO.sub.4 and
concentrated. To the residue was added 1.0 M LiOH (2 mL), and the
mixture was stirred at 65.degree. C. for 2 h and acidified to pH 4
with 1.0 M HCl. The mixture was extracted into ethyl acetate which
was subsequently evaporated and the residue was purified by
preparative LCMS to provide the title compound as an oil (1.0 mg).
LCMS m/z=439.6 [M+H].sup.+.
Example 1.102: Preparation of
2-(((1r,4r)-4-((Benzhydryl(propyl)carbamoyloxy)methyl)cyclohexyl)methoxy)-
acetic Acid (Compound 96)
[1239] To tert-butyl
2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (200 mg,
0.774 mmol) in DCM (2.0 mL) were added
bis(2,5-dioxopyrrolidin-1-yl) carbonate (397 mg, 1.548 mmol) and
TEA (0.324 mL, 2.322 mmol). The reaction was heated under microwave
irradiation at 80.degree. C. for 2 h. N-Benzhydrylpropan-1-amine
(174 mg, 0.774 mmol) was added and the resulting solution was again
heated under microwave irradiation at 60.degree. C. for 1 h. The
reaction mixture was concentrated and the residue was purified by
flash column chromatography to provide 210 mg of the t-butyl ester
intermediate, 102 mg of which was treated with HCl (4.0 M in
dioxane, 1.161 mL, 4.64 mmol) for 3 h at room temperature. The
reaction mixture was concentrated and the resulting residue was
purified by preparative LCMS to provide the title compound as an
oil (17.8 mg). LCMS m/z=454.4 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.54 (t, J=7.39 Hz, 3H), 0.82-1.05 (m,
6H), 1.44 (bs, 2H), 1.56-1.78 (m, 4H), 3.17 (t, J=7.96 Hz, 2H),
3.26 (d, J=6.32 Hz, 2H), 3.87 (d, J=5.81 Hz, 2H), 3.97 (s, 2H),
6.43 (bs, 1H), 7.18 (d, J=7.20 Hz, 4H), 7.29-7.43 (m, 6H).
Example 1.103: Preparation of Sodium
2-(((r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate
Step A: Preparation of 3-Fluoro-N-phenylaniline
[1240] In a 3 liter, three-neck flask equipped with mechanical
stirring, a solution of 3-fluoroaniline (75 g, 675 mol),
bromobenzene (73 mL, 690 mol), and
dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II)
dichloromethane adduct (15 g, 18 mmol) in anhydrous toluene (1.3 L)
containing sodium tert-butoxide (130 g, 1.35 mol) was heated at
105.degree. C. for 3 h. The reaction mixture was then cooled to
80.degree. C., and then quenched by gradually pouring the reaction
mixture into ice water (1 L). The aqueous layer was removed, and
was then extracted with an additional volume of toluene (300 mL).
The organic extracts were combined, rinsed with brine, dried over
MgSO.sub.4, and passed through a silica plug (1.3 kg), eluting with
toluene. The solvent was removed to give a dark amber oil (86 g).
LCMS m/z (%)=188.0 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.45 (t, J=8.5 Hz, 1H), 6.62-6.66 (m, 2H), 6.87 (t, J=7.2
Hz, 1H), 6.98 (d, J=7.6 Hz, 2H), 7.05 (q, J=7.5 Hz, 1H), 7.17 (t,
J=8.6 Hz, 2H).
Step B: Preparation of 3-Fluorophenyl(phenyl)carbamic Chloride
[1241] A 3 liter three-neck mechanically stirred flask under
N.sub.2 containing a solution of 3-fluoro-N-phenylaniline (86 g,
460 mmol) in 1.2 L dichloromethane was cooled in an ice bath to
0.degree. C., and then triphosgene (150 g, 505 mmol) was added. A
solution of pyridine (52 mL, 640 mmol) in dichloromethane (200 mL)
was added in a dropwise fashion. Initial addition resulted in a
temperature spike to 25.degree. C. after the first 10 mL had been
added over 10 min. The addition was paused, and the reaction
mixture was stirred for 1 h while cooling to 5.degree. C. Addition
of the pyridine solution was again commenced at a rate of 5 mL/min,
at which a reaction temperature of 5-10.degree. C. was maintained.
After addition was complete (about 1 h), the reaction had proceeded
to completion, and was quenched by the slow addition of ice water
(500 g). Gas formation from the quench was controlled by adjusting
the stirring speed, as decomposition was largely a function of the
mixing of the two immiscible layers. Gas effluent was passed
through a 20% sodium hydroxide trap, until all gas evolution had
ceased (about 3 h). The aqueous layer was removed, and was then
extracted with an additional 300 mL of dichloromethane. The organic
extracts were combined, dried over MgSO.sub.4, and the solvent was
removed. Clean product was readily isolated as a viscous, pink oil,
which gradually formed a pale pink solid upon seeding with
crystals. LCMS m/z (%)=250.0 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 7.00-7.07 (m, 1H), 7.10 (d, J=9.6 Hz, 1H), 7.15
(d, J=8.1 Hz, 1H), 7.35 (d, J=7.7 Hz, 2H), 7.35-7.41 (m, 2H),
7.42-7.48 (m, 2H).
Step C: Preparation of
4-(Dimethylamino)-1-((3-fluorophenyl)(phenyl)carbamoyl)pyridinium
Chloride
[1242] To a solution of 3-fluorophenyl(phenyl)carbamic chloride
(62.4 g, 250 mmol) in acetonitrile (500 mL) in a 2 liter
mechanically stirred three-neck flask was added a solution of
4-dimethylaminopyridine (30.5 g, 250 mmol) in 500 mL acetonitrile.
The flask warmed slightly as crystallization began to occur, and
then cooled again to ambient temperature. The resulting suspension
was stirred overnight, cooled to 10.degree. C. in an ice bath and
filtered, rinsing with cold acetonitrile (100 mL) to provide the
title compound as a fine, white solid (88.27 g). LCMS m/z=336.4
[M+H].sup.+; .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 3.29
(s, 6H), 6.92 (d, J=8.1 Hz, 2H), 7.11 (t, J=8.6 Hz, 1H), 7.16 (d,
J=8.8 Hz, 1H), 7.21 (d, J=9.5 Hz, H), 7.33-7.38 (m, 3H), 7.41-7.47
(m, 3H), 8.37 (d, J=8.1 Hz, 2H).
Step D: Preparation of
((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl-3-fluorophenyl(phenyl)carbama-
te
[1243] A suspension of
4-(dimethylamino)-1-((3-fluorophenyl)(phenyl)carbamoyl)-pyridinium
chloride (88.25 g, 237 mmol),
(1r,4r)-cyclohexane-1,4-diyldimethanol (137 g, 950 mmol) and
4-dimethylaminopyridine (29.0 g, 237 mmol) in acetonitrile (1 L)
was heated at 53.degree. C. for 18 h. Upon cooling, the solvent was
removed, and the residue was taken up in isopropyl acetate (500 mL)
and 1 N HCl (500 mL), heated to suspend all solids, and then
filtered through glass fiber filter paper to remove the insoluble
bis-carbamate impurity. The aqueous filtrate was discarded, and the
organic filtrate was washed with an additional 500 mL of 1 N HCl,
followed by water (5.times.500 mL). Heptane (100 mL) was added to
the organic phase, which was further washed with water (2.times.500
mL) and brine (100 mL), dried over MgSO.sub.4, and concentrated to
dryness. The residue was taken up in isopropyl acetate (100 mL) and
heptane (300 mL) was added. Crystals gradually formed over 1 h,
forming a white precipitate, which was collected by filtration,
rinsing with 25% isopropyl acetate/heptane (100 mL). The filtrate
was concentrated to dryness, and the hot residue was taken up in
25% isopropyl acetate/heptane (100 mL) and filtered hot. As the
filtrate cooled, more solids precipitated, which were collected by
filtration and combined with the first crop. This material still
contained about 5% bis-carbamate by-product, which could not be
readily removed by filtration. The solid was then taken up in
dichloromethane (200 mL) and subjected to plug filtration over 1.6
kg of silica gel, eluting the remaining bis-carbamate with
dichloromethane and the product with 20% ethyl
acetate/dichloromethane to provide the title compound as a white
solid (71 g). LCMS m/z=358.2 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 0.91-0.98 (m, 4H), 1.35-1.44 (m, 1H), 1.54-1.60
(m, 1H), 1.68-1.73 (m, 2H), 1.79-1.83 (m, 2H), 3.45 (d, J=6.4 Hz,
2H), 4.01 (d, J=6.4 Hz, 2H), 6.91 (t, J=7.6 Hz, 1H), 7.04 (d, J=8.6
Hz, 2H), 7.22-7.30 (m, 411), 7.38 (t, J=7.8 Hz, 2H).
Step E: Preparation of Ethyl-2-(((1r,4r)-4-(((3-fluorophenyl)
(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate
[1244] In a 250 mL three-neck reactor equipped with a stirrer, a
thermocouple, a cooling bath, an addition funnel and a nitrogen
inlet was placed
((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl-3-fluorophenyl(phenyl)-
carbamate (8 g, 22.38 mmol). This was dissolved in
dichloromethane(150 mL). The mixture was cooled and stirred well at
4.degree. C. in an isopropanol/ice bath. Diacetoxyrhodium (0.5 g,
1.12 mmol) was added. After the addition was complete, ethyl
diazoacetate (3.69 g, 32.34 mmol) was dissolved in dichloromethane
(30 mL) and added to the reaction mixture keeping the temperature
below 10.degree. C. After addition, the reaction mixture was warmed
to 30.degree. C. and the progress of the reaction was followed by
LCMS. Based on the LCMS ethyl diazoacetate (0.63 g, 5.52 mmol) was
added, followed by more ethyl diazoacetate (0.710 g, 6.22 mmol)
dissolved in dichloromethane (15 mL) separately at 25.degree. C.
The reaction mixture was stirred at 30.degree. C. until LCMS showed
complete consumption of the starting material. The reaction mixture
was diluted with water (100 mL) and the mixture was filtered
through a bed of celite (35 g) to remove the catalyst. The organic
layer was then separated and dried over magnesium sulfate (15 g)
and filtered. The solvent was removed to provide the title compound
as an oil (9.9 g), which still contained a small amount of ethyl
diazoacetate and was used without further purification. LCMS
m/z=444.5 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.82-0.96 (m, 411), 1.22 (t, J=7.07 Hz, 311), 1.27 (t, J=7.14
Hz, 1H), 1.37-1.53 (m, 2H), 1.57-1.78 (m, 4H), 3.26 (d, J=6.32 Hz,
2H), 3.94 (d, J=6.06 Hz, 2H), 4.06 (s, 2H), 4.14 (q, J=7.07 Hz,
3H), 4.23 (q, J=7.07 Hz, 1H), 7.05-7.11 (m, 2H), 7.24 (dt, J=10.64,
2.26 Hz, 1H), 7.28-7.35 (m, 311), 7.36-7.45 (m, 3H).
Step F: Preparation of 2-(((r,4r)-4-(((3-Fluorophenyl)
(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic Acid
[1245] In a 500 mL, three-neck reactor equipped with a stirrer, a
thermocouple, a heating oil bath, an addition funnel and a nitrogen
inlet was placed ethyl-2-(((r,4r)-4-(((3-fluorophenyl)
(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate (9.9 g,
22.32 mmol), which was dissolved in acetonitrile (150 mL). To this
mixture lithium bromide (19.58 g, 225.00 mmol) was added. After the
addition was complete, triethylamine (6.84 g, 67.6 mmol) was added
and the reaction mixture was heated at 70.degree. C. The progress
of the reaction was followed by LCMS. Based on the LCMS the
starting material was consumed in 2 h. Solvent was removed and the
reaction mixture was diluted with water (200 mL) and made acidic
with hydrochloric acid (3 M, 7.8 mL). The precipitated solids were
filtered and the wet solid was dissolved in isopropyl acetate (200
mL). Isopropyl acetate layer was dried over magnesium sulfate (15
g), filtered and the solvent was removed. The residue was dried in
a vacuum oven to provide the title compound (9.2 g). LCMS m/z=416.4
[M+H].sup.+; NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.81-0.96 (m,
4H), 1.36-1.53 (m, 2H), 1.55-1.77 (m, 4H), 3.25 (d, J=6.44 Hz, 2H),
3.93 (d, J=5.94 Hz, 2H), 3.97 (s, 2H), 7.05-7.13 (m, 2H), 7.24 (dt,
J=10.64, 2.26 Hz, 1H), 7.28-7.36 (m, 3H), 7.37-7.46 (m, 3H), 12.53
(bs, 1H)
Step G: Preparation of 2-(((1r,4r)-4-(((3-Fluorophenyl)
(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic Acid Sodium
Salt
[1246] In a 500 mL, three-neck reactor equipped with a stirrer, a
thermocouple, a heating oil bath, an addition funnel and a nitrogen
inlet was placed 2-(((r,4r)-4-(((3-fluorophenyl)
(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (9.2 g,
22.83 mmol) and 2-propanol (100 mL). The reaction mixture was
heated at 30.degree. C. (bath temperature), until all of the acid
was dissolved completely. To the orange solution, sodium hydroxide
(1 M, 22 mL, 22 mmol) was added slowly keeping the temperature
around 25.degree. C. The sodium salt separated out as crystals. The
thick slurry was stirred at 25.degree. C. for 2 h and then cooled
in an ice water bath for 40 min. The solids were filtered and dried
in a vacuum oven at 40.degree. C. overnight until most of the
residual 2-propanol was removed to provide the title compound (7.4
g). LCMS m/z=416.5 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.77-0.95 (m, 4H), 1.34-1.53 (m, 2H), 1.55-1.75 (m,
4H), 3.19 (d, J=6.44 Hz, 2H), 3.52 (s, 2H), 3.93 (d, J=5.94 Hz,
2H), 7.05-7.13 (m, 2H), 7.24 (dt, J=10.64, 2.26 Hz, 1H), 7.28-7.35
(m, 3H), 7.37-7.46 (m, 3H).
Example 1.104: Preparation of Sodium
2-(((r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate
[1247] To 5.0 g of ((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl
3-fluorophenyl(phenyl)carbamate was added toluene (30 mL), 50% NaOH
(28 mL), tetrabutylammonium bromide (2.3 g) and tert-butyl
bromoacetate (10.3 mL). The reaction mixture was stirred at room
temperature for about 7 h and monitored by LC-MS to give tert-butyl
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate. The mixture was then heated at 50-60.degree. C. for
about 4 hours and monitored by LC-MS to give
2-(((r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid (Compound 23). The mixture was then acidified with
12 N HCl and the phases separated. The organic layer was
concentrated and the residue suspended in isopropyl alcohol (20
mL). Thereafter, 50% sodium hydroxide (.about.1 mL) and water (4
mL) were added at 50-60.degree. C. The mixture was stirred at
40-50.degree. C. for 1 h and then cooled to room temperature. The
mixture was filtered and washed with isopropyl alcohol (10 mL). The
solid was dried under reduced pressure at 50.degree. C. to leave
the title compound (4.0 g, 66%). LCMS m/z=416.5 [M-Na+H].sup.+.
Example 1.105: Preparation of 4-Chloro-N-phenylaniline
[1248] Method 1.
[1249] A solution of 4-chloroaniline (25.5 g, 200 mmol),
bromobenzene (31.4 g, 200 mmol), and
dichloro[1,1'bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (4.9 g, 6.0 mmol) in anhydrous toluene (500
mL) containing sodium tert-butoxide (38.4 g, 400 mmol) was refluxed
under N.sub.2 for 90 min. The reaction mixture was cooled until it
began to solidify, and then water (400 mL) was added, and the
aqueous layer was removed. The organic layer was rinsed with brine,
dried over MgSO.sub.4, and passed through a silica plug, eluting
with toluene. The solvent was removed to give a pale reddish amber
solid (35.3 g). LCMS m/z=204.4 [M+H].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.00 (t, J=7.6 Hz, 1H), 7.04 (d, J=8.8 Hz,
2H), 7.10 (d, J=7.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 7.31 (t, J=7.7
Hz, 2H).
[1250] Method 2.
[1251] A solution of 4-bromochlorobenzene (38.3 g, 200 mmol),
aniline (18.6 g, 200 mmol), and
dichloro[1,1'bis(diphenylphosphino)ferrocene]palladium(H)
dichloromethane adduct (4.9 g, 6.0 mmol) in anhydrous toluene (500
mL) containing sodium tert-butoxide (38.4 g, 400 mmol) was refluxed
under N.sub.2 for 90 min. The reaction mixture was cooled until it
began to solidify, and then water (400 mL) was added, and the
aqueous layer was removed. The organic layer was rinsed with brine,
dried over MgSO.sub.4, and passed through a silica plug, eluting
with toluene. The solvent was removed to give a reddish amber solid
(37.2 g). LCMS m/z=204.4 [M+H].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.00 (t, J=7.6 Hz, 1H), 7.04 (d, J=8.8 Hz,
2H), 7.10 (d, J=7.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 7.31 (t, J=7.7
Hz, 2H).
Example 1.106: Preparation of Sodium
2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate
[1252] Method 1.
Step A: Preparation of ((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate
[1253] 4-Chloro-N-phenylaniline (15.0 g, 73.6 mmol), tribasic
potassium phosphate, (fine powder, 4.69 g, 22.1 mmol),
N,N-carbonyldiimidazole (13.14 g, 81 mmol) and acetonitrile (75 mL)
were charged to a 500-mL, jacketed, four-necked cylindrical
reaction flask equipped with a mechanical stirrer and a condenser.
The reaction mixture was heated at 65.degree. C. under nitrogen and
monitored by HPLC. After about 2.5 h HPLC showed >98% conversion
to the intermediate
N-(4-chlorophenyl)-N-phenyl-1H-imidazole-1-carboxamide. After about
5.5 h a solution of (1r,4r)-cyclohexane-1,4-diyldimethanol (37.2 g,
258 mmol) in acetonitrile (150 mL) at 65.degree. C. was added to
the reaction mixture over 20 min. The resulting mixture was heated
at 65.degree. C. overnight. HPLC showed about 98% conversion to the
required product. The mixture was filtered, and the cake was rinsed
with acetonitrile (2.times.25 mL). The filtrate was concentrated
under reduced pressure (40.degree. C., 32 torr) 124.125 g of
distillate was collected. The residue was diluted with water (50
mL) and this mixture was concentrated under reduced pressure
(40.degree. C., 32 torr) and 35.184 g of distillate was collected.
The residue was diluted with water (50 mL) and the resulting
mixture was allowed to stir overnight to give a white paste. The
mixture was filtered, and the cake was rinsed with 25%
acetonitrile/water (2.times.75 mL). The solid was dried in a vacuum
oven to leave a white solid (22.271 g); 94.8% purity by HPLC peak
area. LCMS m/z=374.3 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.77-0.93 (m, 4H) 1.23 (dd, J=6.22, 3.51
Hz, 1H) 1.47 (dd, J=6.32, 2.91 Hz, 1H) 1.56-1.76 (m, 4H) 3.20 (t,
J=5.78 Hz, 2H) 3.92 (d, J=6.13 Hz, 2H) 4.33 (t, J=5.31 Hz, 1H)
7.28-7.35 (m, 5H) 7.38-7.47 (m, 4H).
Step B: Preparation of Sodium
2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate
[1254] In a 1 L 3-neck flask fitted with an overhead stirrer was
placed ((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate (30 g), TBAB (7.8 g) and toluene
(180 mL) and the mixture stirred at room temperature. To this
mixture was added 50% NaOH (180 mL) followed by addition of
tert-butyl bromoacetate (17.8 mL). The mixture was stirred at room
temperature for 7 h. The mixture was then heated at 50-60.degree.
C. for 4 h. The mixture was then neutralized with concentrated HCl
(300 mL). The mixture was filtered and the resulting filtrate was
separated into two phases. The aqueous layer was extracted with
toluene (80 mL). The combined organic layers were washed with water
and the solvent was evaporated. The residue was azeotroped with
isopropyl alcohol (150 mL) to remove the remaining toluene.
Isopropyl alcohol (150 mL) was added to dissolve the residue and to
this solution was added 12.5% NaOH solution (17 mL) to give a pH of
7-8. The resulting precipitate was collected by filtration and the
filter cake was dissolved in water/acetone (280 mL; 1:1) at
55-60.degree. C. The solution was filtered and the filtrate was
diluted with acetone (320 mL) and stirred at room temperature
overnight. The resulting slurry was cooled to 0-5.degree. C. and
then filtered. The filter cake was suspended in acetonitrile (400
mL), stirred at room temperature for 16 h and then filtered. The
filter cake was dried at 60-70.degree. C. under reduce pressure to
leave the desired product (21.1 g); >99% purity by HPLC peak
area. LCMS m/z=432.3 [M-Na+H].sup.+.
[1255] Method 2.
Step A: Preparation of ((r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate
[1256] A 50-liter glass-lined reactor equipped with overhead
agitation, jacket temperature control, and a nitrogen atmosphere
was charged with (1r,4r)-cyclohexane-1,4-diyldimethanol (3.97 kg)
and acetonitrile (12.71 kg). The reactor contents were stirred at
130 rpm and heated to 63.degree. C. for 1.2 h to achieve
dissolution. The mixture was cooled to <40.degree. C. and then
filtered. The filtrate was stored in a carboy.
4-Chloro-N-phenylaniline (1.60 kg), K.sub.3PO.sub.4 (0.50 kg), CDI
(1.41 kg) and acetonitrile (6.29 kg) were charged to a 50-liter
glass-lined reactor equipped with overhead agitation, jacket
temperature control, and a nitrogen atmosphere. The reactor
contents were stirred at 130 rpm and heated to 65.degree. C. to
70.degree. C. for 3 h, after which conversion of
4-chloro-N-phenylaniline to
N-(4-chlorophenyl)-N-phenyl-1H-imidazole-1-carboxamide was 98.0% by
HPLC peak area. The reaction mixture was cooled to less than
40.degree. C. and the solution of
(1r,4r)-cyclohexane-1,4-diyldimethanol in acetonitrile prepared
earlier was added to the mixture. The reactor contents were stirred
at 130 rpm and heated at 65 to 70.degree. C. for 19 h, after which
conversion of
N-(4-chlorophenyl)-N-phenyl-1H-imidazole-1-carboxamide to
((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate was verified to be 98.0% by HPLC
peak area. The reactor contents were filtered and the filter cake
was rinsed with acetonitrile (2.00 kg). The filtrate was
transferred back to the reactor and most of the acetonitrile (18.48
kg) was then removed at 22.degree. C. by vacuum distillation at 80
mm Hg. Water (5.34 kg) was added to the reactor and 1.55 kg of
water/acetonitrile mixture was then removed by vacuum distillation
at 29.degree. C. and 70 mm Hg. Water (5.34 kg) was added to the
reactor and the product precipitated during the addition. The
resulting mixture was stirred at 20.degree. C. to 25.degree. C. for
13 h. The precipitated product was filtered and washed with aqueous
acetonitrile in two portions (1.59 kg acetonitrile dissolved in
6.00 kg water). The product was dried under reduced pressure at
.ltoreq.60.degree. C. (until loss-on-drying was 2 wt %) to give the
title compound as an off-while solid (2.29 kg, 78% yield; 97%
purity by HPLC peak area.)
Step B: Preparation of Sodium
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate
[1257] ((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate (1.70 kg), tetrabutylammonium
bromide (0.44 kg) and toluene (7.36 kg) were charged to a 50-liter
glass-lined reactor equipped with overhead agitation, jacket
temperature control, and a nitrogen atmosphere. The mixture was
stirred for 1 h at 20.degree. C. To the resulting solution was
added 50 wt % aqueous sodium hydroxide (15.34 kg) and the jacket
temperature was set to 10.degree. C. Then tert-butyl bromoacetate
(1.33 kg) was added sufficiently slowly to maintain the stirred
reaction mixture at 5-15.degree. C. with reactor jacket cooling.
The mixture was stirred at 5-15.degree. C. for 8.1 h. Conversion of
((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate to tert-butyl
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate was >90.0% by HPLC peak area. The reactor contents
were heated at 50-60.degree. C. for 7.2 h. Conversion of tert-butyl
(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)meth-
oxy)acetate to
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid was >90.0% by HPLC peak area. The reactor
contents were then cooled to 15.degree. C. and concentrated
hydrochloric acid (18.87 kg) was added to the mixture at a rate
sufficiently slow to maintain an internal temperature
<50.degree. C. The mixture was filtered to remove the solid
sodium chloride from the reactor. The filtrate separated into two
phases and the organic phase was removed. The aqueous layer was
extracted with toluene (4.55 kg). The organic phases were combined
and the mixture was distilled at 30.degree. C. and 40 mm Hg to
remove most of the toluene. Then, IPA (6.75 kg) was charged to the
reactor and the resulting solution was distilled at 28.degree. C.
and 40 mm Hg to remove solvent (5.05 Kg). IPA (6.68 kg) was charged
a second time to the reactor and the resulting mixture was vacuum
distilled at 37.degree. C. and 40 mm Hg to remove solvent (4.98
kg). Then, IPA (6.77 kg) was charged to the reactor for the third
time and the reactor contents were heated to 40.degree. C. Sodium
hydroxide (12.5%, 0.87 kg) was added to the reactor. The resulting
mixture had a pH of 7. The mixture was agitated at 155 rpm for 2 h
at 40.degree. C. The product precipitated, and the solid was
filtered. The filter cake was washed with IPA (3.01 kg). The filter
cake was transferred to a reactor using acetone (6.27 kg) and water
(7.95 kg) and the mixture was heated at 59.degree. C. for 3 h. The
resulting mixture was filtered through a sintered glass filter and
the filtrate was transferred to a reactor. Acetone (15.82 kg) was
added and the mixture stirred for 66 h at 20.degree. C. The reactor
contents were further stirred at 0.degree. C. for 2 hours, filtered
and the filter cake was washed with acetone (3.2 kg). The filter
cake was then transferred back to the reactor with the aid of
acetonitrile (17.79 kg). The reactor contents were stirred at 100
rpm and 20.degree. C. for 18.5 h. The slurry was filtered and the
cake was washed with two portions of acetonitrile (10.26 kg total).
The solid was dried at 65.degree. C. to 70.degree. C. under reduced
pressure for 27 h, and then sieved through a 1.18 mm mesh screen.
The product was further dried under reduced pressure at 70.degree.
C. to an acetonitrile level of 2000 ppm, to leave the title
compound as a white to off-white solid (0.65 kg, 32% yield; 98.8%
purity by HPLC peak area.)
Example 1.107: Preparation of Sodium
2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate Hydrate
[1258] Sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate was slurried in water for 3 days at 40.degree. C.,
and then filtered to give the title compound as a solid. The TGA
thermogram of the title compound (FIG. 12) shows a weight loss of
about 13%, indicating that the compound is a hydrate. The PXRD
pattern for the hydrate is shown in FIG. 13.
Example 1.108: Preparation of Sodium
2-(((r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetate Hydrate
[1259] Crude sodium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate (0.422 g) was suspended in water (10 volumes) and
heated to 85.degree. C. (bath). The sodium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate did not dissolve. Ethanol (8.5 volume) was added and
a solution formed. The solution was hot-filtered, the solvate
crystallized, and the suspension was stirred at room temperature
for 1 h and filtered. The solids were dried in vacuum oven at
45.degree. C. overnight. The TGA thermogram of the title compound
(FIG. 14) shows a weight loss of about 4.3%, indicating that the
compound is a mono-hydrate. The PXRD pattern is shown in FIG.
15.
Example 1.109: Preparation of Magnesium
2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate Solvate
[1260] Mg(OAc).sub.2 (aqueous solution, 2.13 M) was added to a
solution of
2-(((r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid in IPA (64.456 mg/mL) at room temperature to
achieve a 1:2 ratio of magnesium to
2-(((r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid. No precipitation occurred so the solution was
allowed to evaporate to dryness to produce a crystalline solid. The
TGA thermogram of the title compound (FIG. 16) shows a weight loss
of about 18.9%, indicating that the compound is a solvate. The PXRD
pattern for the solvate is shown in FIG. 17.
Example 1.110: Preparation of Potassium
2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate Solvate
[1261] Potassium carbonate (aqueous solution, 2.19M) was added to a
solution of
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid in IPA (64.456 mg/mL) at room temperature to
achieve a 1:1 ratio of potassium to
2-(((r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid. A precipitate formed after .about.15 min and the
solid was isolated by filtration. The TGA thermogram of the title
compound (FIG. 18) shows weight losses of about 2.0% below about
93.degree. C. and about a further 3.8% below about 177.degree. C.,
indicating that the compound is a solvate. The PXRD pattern for the
solvate is shown in FIG. 19.
Example 1.111: Preparation of Calcium
2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate Solvate
[1262] Ca(OA).sub.2 (aqueous solution, 2.13M) was added to a
solution of
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid in IPA (64.456 mg/mL) at room temperature to
achieve a 1:2 ratio of calcium to
2-(((r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)met-
hoxy)acetic acid. A white precipitate formed immediately. The solid
was isolated by filtration. The TGA thermogram of the title
compound (FIG. 20) shows a weight loss of about 8.2%, indicating
that the compound is a solvate. The PXRD pattern for the solvate is
shown in FIG. 21.
Example 1.112: Preparation of
2-(2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl-
)methoxy)acetamido)ethanesulfonic Acid (Compound 99)
[1263] Method 1.
[1264]
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohe-
xyl) methoxy)acetic acid (0.30 g, 0.695 mmol) was dissolved in
SOCl.sub.2 (5.0 mL, 68.5 mmol) (bubbling was observed). The
reaction was heated to reflux and stirred for 2 h, and then
concentrated and dried overnight under reduced pressure. The
resulting
((1r,4r)-4-((2-chloro-2-oxoethoxy)methyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate was dissolved in THE (2 mL) with
gentle heating. To this was added a solution of
2-aminoethanesulfonic acid (0.113 g, 0.903 mmol) and sodium
hydroxide (0.038 g, 0.938 mmol) in water (0.6 mL). The reaction was
vigorously stirred at room temperature for 1 h. The solvent was
removed under reduced pressure and the residue was dissolved in
DMSO (3 mL) and filtered. The filtrate was purified by HPLC to
yield the title compound as a white solid (70.1 mg, 18.35%). Exact
mass calculated for C.sub.25H.sub.31CN.sub.2O.sub.7S: 538.2, found:
LCMS m/z=539.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.78-0.97 (m, 4H) 1.37-1.52 (m, 2H) 1.52-1.62 (m,
J=7.83 Hz, 2H) 1.67-1.77 (m, 2H) 2.54 (t, J=6.44 Hz, 2H) 3.21 (d,
J=6.32 Hz, 2H) 3.37 (q, J=5.81 Hz, 2H) 3.76 (s, 2H) 3.90 (d, J=6.06
Hz, 2H) 7.22-7.34 (m, 5H) 7.35-7.48 (m, 4H) 7.91 (bs, 1H).
[1265] Method 2.
[1266] To a solution of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate (50 mg, 0.11 mmol) in DMF (5 ml) and H.sub.2O (2.5
ml), was added 1H-benzo[d][1,2,3]triazol-1-ol hydrate (16.87 mg,
0.11 mmol) followed by 2-aminoethanesulfonic acid (13.79 mg, 0.11
mmol) at ambient temperature. The reaction was heated to
120.degree. C. for 10 h. After cooling to room temperature, the
reaction was poured into water, extracted with ethyl acetate, and
then dried with MgSO.sub.4. The organic layer was concentrated
under reduced pressure and the resulting residue was purified by
HPLC to afford the title compound as a white solid (12 mg). Exact
mass calculated for C.sub.25H.sub.31C.sub.1N.sub.2O.sub.7S: 538.2,
found: LCMS m/z=539.3 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.73-1.85 (m, 4H), 1.35-1.41 (m, 2H),
1.50-1.52 (m, 2H), 1.65-1.69 (m, 2H), 2.50 (m, 2H), 3.15 (d, J=6.4
Hz, 2H), 3.36 (m, 2H), 3.72 (s, 2H), 3.89 (d, J=6.2 Hz, 2H),
7.12-7.25 (m, 5H), 7.27-7.49 (m, 4H), 7.85 (br, 1H).
Example 1.113: Preparation of
2-(2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetamido)acetic Acid (Compound 100)
[1267]
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohe-
xyl) methoxy)acetic acid (0.30 g, 0.695 mmol) was dissolved in
SOCl.sub.2 (5.0 mL, 68.5 mmol) (bubbling was observed). The
reaction was heated to reflux and stirred for 2 h, and then
concentrated and dried overnight under reduced pressure. The
resulting
((1r,4r)-4-((2-chloro-2-oxoethoxy)methyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate was dissolved in THE (2 mL) with
gentle heating. To the resulting solution was added a solution of
glycine (0.052 g, 0.688 mmol) and sodium hydroxide (0.030 g, 0.757
mmol) in water (0.6 mL). The reaction was vigorously stirred at
room temperature for 1 h. The solvent was removed under reduced
pressure and the residue was dissolved in DMSO (3 mL) and filtered.
The filtrate was purified by HPLC to yield the title compound as a
white solid (20.0 mg, 5.88%). Exact mass calculated for
C.sub.25H.sub.29CN.sub.2O.sub.6: 488.2, found: LCMS m/z=489.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.80-0.97 (m, 4H) 1.40-1.53 (m, 2H) 1.55-1.63 (m, 2H) 1.69-1.80 (m,
2H) 3.25 (d, J=6.57 Hz, 2H) 3.78 (d, J=6.06 Hz, 2H) 3.84 (s, 2H)
3.90 (d, J=6.06 Hz, 2H) 7.22-7.33 (m, 5H) 7.34-7.46 (m, 4H) 7.80
(bs, J=5.81, 5.81 Hz, 1H).
Example 1.114: Preparation of
2-(((1r,4r)-4-(((4-Chlorophenyl)(4-hydroxyphenyl)carbamoyloxy)methyl)cycl-
ohexyl)methoxy)acetic Acid (Compound 98)
Step A: Preparation of tert-Butyl(4-iodophenoxy)dimethylsilane
[1268] 4-Iodophenol (1.0 g, 4.55 mmol) was dissolved in
dichloromethane (5 mL). tert-Butyldimethylsilyl chloride (0.685 g,
4.55 mmol) and imidazole (0.309 g, 4.55 mmol) were added. The
reaction was stirred overnight at room temperature. The reaction
mixture was partitioned between water (30 mL) and dichloromethane
(30 mL). The organic layer was removed and the aqueous layer was
extracted with dichloromethane (30 mL). The organic layers were
combined, dried and concentrated, and the residue was purified by
chromatography (0-10% EtOAc/hexanes) to give the title compound as
a light yellow oil (1.45 g, 94%).
Step B: Preparation of tert-Butyl
2-(((1r,4r)-4-((4-chlorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acet-
ate
[1269] tert-Butyl
2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (2.4 g,
9.29 mmol) and 4-chlorophenylisocyanate (1.712 g, 11.15 mmol) were
dissolved in dichloromethane (20 mL). Then, pyridine (1.503 ml,
18.58 mmol) was added. The reaction was heated to reflux and
stirred overnight. The solvents were removed under reduced pressure
and the residue was purified by column chromatography (0-10%
EtOAc/hexanes) to yield the title compound as a light yellow solid
(1.45 g, 36.4%).
Step C: Preparation of
2-(((r,4r)-4-(((4-Chlorophenyl)(4-hydroxyphenyl)carbamoyloxy)methyl)cyclo-
hexyl)methoxy)acetic Acid
[1270] tert-Butyl 2-(((1r,4r)-4-((4
chlorophenycarbamoyloxy)methyl)cyclohexyl)methoxy)acetate (100 mg,
0.243 mmol), tert-butyl(4-iodophenoxy)dimethylsilane (81 mg, 0.243
mmol), potassium phosphate (103 mg, 0.486 mmol), copper(I) iodide
(23.12 mg, 0.121 mmol), and trans-1,2-diaminocyclohexane (29.2
.mu.L, 0.243 mmol) in dioxane (1.6 mL) were heated at 150.degree.
C. for 5 h under microwave irradiation. The reaction mixture was
filtered though a plug of MgSO.sub.4, the solvent was removed under
reduced pressure, and the residue was purified by column
chromatography (0-10% EtOAc/hexanes). The purified material was
dissolved in HC (4 M in Dioxane; 0.5 mL) and the mixture was
stirred at room temperature overnight. The solvent was removed
under reduced pressure and the title compound was isolated by
preparative HPLC (30-85% MeOH/H.sub.2, 30 min).
Example 1.115:
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic Acid (Compound 22)
[1271] In a 1 L 3-neck flask fitted with an overhead stirrer was
added ((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl
4-chlorophenyl(phenyl)carbamate (30 g), TBAB (7.8 g) and toluene
(150 mL). To the resulting solution was added tert-butyl
bromoacetate (17.8 mL). The mixture was cooled to 5-10.degree. C.
before slowly adding 50% sodium hydroxide (180 mL). The mixture was
stirred at 3-10.degree. C. for 7 h, allowed to sit at 18-24.degree.
C. overnight, and then heated at 45-50.degree. C. for 4 h. The
mixture was then acidified with conc. HCl (.about.260 mL) to pH 2.
The mixture was filtered and the filtrate was transferred to a
seperatory funnel. The phases were separated and the aqueous layer
extracted once again with toluene (30 mL). The combined toluene
layer was evaporated to an oil. To the oil was added 25% aqueous
acetone (90 mL) and 12.5% sodium hydroxide solution (14 mL). The
resulting solid was filtered and the filter cake was recrystallized
from water (60 mL) and acetone (300 m). The recrystallized material
was suspended in water (100 mL) and 2 N HCl (30 mL) was added to pH
3. The mixture was allowed to stir overnight. The suspension was
filtered and the filter cake was resuspended in water (150 m). The
mixture was stirred and filtered and the filter cake was dried at
65.degree. C. in a vacuum oven to give the title compound as a
white solid (19.33 g, HPLC purity: 97.4% by weight). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.82-0.99 (m, 4H), 1.38-1.52
(m, 2H), 1.52-1.80 (m, 411), 3.26 (d, J=3.0 Hz, 2H), 3.93 (d, J=3.0
Hz, 2H), 3.97 (s, 1H), 7.25-7.38 (m, 5H), 7.39-7.50 (m, 4H), 12.51
(bs, 1H).
Example 2: Homogeneous Time-Resolved Fluorescence (HTRF.RTM.) Assay
For Direct cAMP Measurement
[1272] Compounds were screened for agonists of the human
prostacyclin (PGI2) receptor using the HTRF.RTM. assay for direct
cAMP measurement (Gabriel et al., ASSAY and Drug Development
Technologies, 1:291-303, 2003) and recombinant CHO-K1 cells stably
transfected with human prostacyclin receptor. CHO-K1 cells were
obtained from ATCC.RTM. (Manassas, Va.; Catalog #CCL-61). An
agonist of the prostacyclin receptor was detected in HTRF.RTM.
assay for direct cAMP measurement as a compound which increased
cAMP concentration. HTRFV assay also was used to determine ECso
values for prostacyclin receptor agonists.
[1273] Principle of the Assay:
[1274] The HTRF.RTM. assay kit was purchased from Cisbio-US, Inc.
(Bedford, Mass.; Catalog #62AM4PEC). The HTRF.RTM. assay supported
by the kit is a competitive immunoassay between endogenous cAMP
produced by the CHO-K1 cells and tracer cAMP labeled with the dye
d2. The tracer binding is visualized by a monoclonal anti-cAMP
antibody labeled with Cryptate. The specific signal (i.e.,
fluorescence resonance energy transfer, FRET) is inversely
proportional to the concentration of unlabeled cAMP in the standard
or sample.
[1275] Standard Curve:
[1276] The fluorescence ratio (665 nm/620 nm) of the standards
(0.17 to 712 nM cAMP) included in the assay was calculated and used
to generate a cAMP standard curve according to the kit
manufacturer's instructions. The fluorescence ratio of the samples
(test compound or compound buffer) was calculated and used to
deduce respective cAMP concentrations by reference to the cAMP
standard curve.
[1277] Setup of the Assay:
[1278] The HTRF.RTM. assay was carried out using a two-step
protocol essentially according to the kit manufacturer's
instructions, in 20 .mu.L total volume per well in 384-well plate
format (ProxiPlates; PerkinElmer, Fremont, Calif.; catalog
#6008280). To each of the experimental wells was transferred 3000
recombinant CHO-K1 cells in 5 .mu.L assay buffer (phosphate
buffered saline containing calcium chloride and magnesium chloride
(Invitrogen, Carlsbad, Calif.; catalog #14040) supplemented with
IBMX (100 .mu.M) and rolipram (10 .mu.M) (phosphodiesterase
inhibitors; Sigma-Aldrich, St. Louis, Mo.; catalog #15879 and
catalog #R6520, respectively) and 0.1% bovine serum albumin (BSA)
fraction V (Sigma-Aldrich; catalog #A3059)), followed by test
compound in 5 .mu.L assay buffer or 5 .mu.L assay buffer. The plate
was then incubated at room temperature for 1 h. To each well was
then added 5 .mu.L cAMP-d2 conjugate in lysis buffer and 5 .mu.L
Cryptate conjugate in lysis buffer according to the kit
manufacturer's instructions. The plate was then further incubated
at room temperature for 1 h, after which the assay plate was
read.
[1279] Assay Readout:
[1280] The HTRF.RTM. readout was accomplished using a PHERAstar
(BMG LABTECH Inc., Durham, N.C.) or EnVision.TM. (PerkinElmer,
Fremont Calif.) microplate reader.
[1281] Certain compounds of the present invention and their
corresponding activity values are shown in TABLE B.
TABLE-US-00006 TABLE B human PGI2 receptor Compound No. EC.sub.50
(nM) (HTRF .RTM.) 6 61.09 35 56.89 55 5.14 71 19.10
[1282] Certain other compounds of the invention had activity values
ranging from about 2.7 nM to about 2.65 .mu.M in this assay.
Example 3: Human Platelet Aggregation Inhibition Test
[1283] Blood collected from healthy human volunteers in aqueous
trisodium citrate solution was centrifuged at 150 g for 15 min and
the upper layer was recovered to obtain platelet-rich plasma (PRP).
The residual blood was centrifuged at 3000 g for 10 min and the
supernatant was collected as platelet-poor plasma (PPP). Platelet
concentration in the PRP was determined using the Z series Beckman
Coulter particle counter (Beckman, Fullerton, Calif.) and adjusted
to 250,000 platelets/.mu.L using PPP. 480 .mu.L of PRP was
pre-incubated at 37.degree. C. and stirred at 1200 rpm with 10
.mu.L aqueous test compound solution for 1 min prior to induction
of aggregation by the addition of 10 .mu.L of aqueous adenosine
diphosphate (ADP) solution to adjust the final ADP concentration in
the PRP to 1.times.10.sup.-5 M. The maximal amplitude of
aggregation response within 3 min was determined and measured in
triplicate using the Chronolog model 490 aggregometer (Chrono-log
Corp., Havertown, Pa.). Percent inhibition of aggregation was
calculated from the maximum decrease in optical density of the
control (addition of water in place of the test compound solution)
sample and of the samples containing test compound. The test
compound was added to adjust the final concentration to the range
10.sup.-9 to 10.sup.-4 M, and IC.sub.50 values were determined by
inhibition percentage of aggregation at each concentration. The
results are shown in Table C.
TABLE-US-00007 TABLE C Compound No. human PRP IC.sub.50 (nM) 2 73
30 210 50 12.6 88 70
[1284] Certain other compounds of the invention had activity values
ranging from about 10.5 nM to about 1.59 .mu.M in this assay.
[1285] It is apparent that the compounds of the present invention
markedly inhibit platelet aggregation in human PRP.
Example 4: Rat Model of Pulmonary Arterial Hypertension
[1286] Animals:
[1287] Male Wistar rats (100-150 g at start of study) (Charles
River Laboratories, Wilmington, Mass.) were housed two per cage and
maintained in a humidity- (40-60%) and temperature- (68-72.degree.
F.) controlled facility on a 12 hr:12 hr light/dark cycle (lights
on at 6:30 am) with free access to food (Harlan Teklad, Orange
Calif., Rodent Diet 8604) and water. Rats were allowed one week of
habituation to the animal facility before testing.
[1288] Rat Monocrotaline Model:
[1289] The rat monocrotaline (MCT) model is a standard and
well-accepted model of pulmonary arterial hypertension. MCT induces
acute pulmonary endothelial damage associated with pulmonary
vascular inflammation. Subsequently, pulmonary artery smooth muscle
cells proliferate, occluding small pulmonary vessels and leading to
severe pulmonary arterial hypertension including right ventricular
hypertrophy. (See, e.g., Schermuly et al., Circ. Res., 2004,
94:1101-1108.)
[1290] Rats were randomly given a single subcutaneous injection of
either 60 mg/kg MCT (Sigma, St. Louis, Mo.) or 0.9% saline (sham)
and assigned to receive oral administration of 20% hydroxypropyl
beta-cyclodextrin (vehicle) or test compound (30 mg/kg; FIGS. 7 and
8). 10-11 rats were used per treatment group. 24 h following MCT
administration, test compound or vehicle was administered by oral
gavage twice a day for 21 consecutive days. Heart chamber weights
were measured on Day 22. Rats were anesthetized with
intraperitoneal pentobarbital (50 mg/kg), the chest cavity was
opened and the heart was excised. The right ventricle was dissected
free from the septum and left ventricle and both parts were
weighed. The ratio of right ventricular (RV) weight to left
ventricle plus septum (LV+S) weight (this ratio is indicated as
"RV/(LV+S)" in FIGS. 7 and 8) was calculated as an index of the
hypertrophic response to the induced pulmonary arterial
hypertension and, as such, as an index of a test compound's
therapeutic efficacy for pulmonary arterial hypertension.
[1291] It is apparent from inspection of FIGS. 7 and 8 that oral
administration of Compounds 23 and 22 inhibited the hypertrophic
response to the induced pulmonary arterial hypertension and, as
such, evidenced therapeutic efficacy for pulmonary arterial
hypertension.
Example 5: Powder X-Ray Diffraction
[1292] Powder X-ray Diffraction (PXRD) data were collected on an
X'Pert PRO MPD powder diffractometer (PANalytical, Inc.) with a Cu
source set at 45 kV and 40 mA, a Ni-filter to remove Cu K1
radiation, and an X'Celerator detector. The instrument was
calibrated by the vendor using a silicon powder standard NIST
#640c. The calibration was found to be correct when it was tested
with NIST #675 low-angle diffraction standard. Samples were
prepared for PXRD scanning by placing several milligrams of as-is
compound onto a sample holder and smoothing as flat as possible by
pressing weigh paper down on the sample with a flat object. The
samples were analyzed using a spinning-sample stage. Scans covered
the range of 5 to 40.degree. 2.theta.. A continuous scan mode was
used with a step size of 0.0170.degree. 2.theta.. Diffraction data
were viewed and analyzed with the X'Pert Data Viewer Software,
version 1.0a and X'Pert HighScore Software, version 1.0b. The PXRD
pattern for the crystalline form of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetate is shown in FIG. 9. The PXRD pattern for a
sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexy)met-
hoxy)acetate hydrate is shown in FIG. 13. The PXRD pattern for a
sodium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate hydrate is shown in FIG. 15. The PXRD pattern for a
magnesium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyc-
lohexyl)methoxy)acetate solvate is shown in FIG. 17. The PXRD
pattern for a potassium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate solvate is shown in FIG. 19. The PXRD pattern for a
calcium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate solvate is shown in FIG. 21.
Example 6: Differential Scanning Calorimetry
[1293] Differential Scanning Calorimetry (DSC) was performed on a
TA instruments, Inc. DSC Q1000 or Q2000 at 10.degree. C./min. The
instrument was calibrated at this scan rate by the vendor for
temperature and energy using the melting point and enthalpy of
fusion of an indium standard. Samples were prepared by taring a
sample-pan lid along with a sample-pan bottom on a Mettler Toldeo
MX5 balance. Sample was placed in the bottom of the tared sample
pan. The sample-pan lid fitted snuggly in the sample-pan bottom.
The sample and pan were reweighed to get the sample weight. Thermal
events (for example, onset temperature, enthalpy of fusion) are
calculated using the Universal Analysis 2000 software, version
4.1D, Build 4.1.0.16. The DSC thermogram for the crystalline form
of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyc-
lohexyl)methoxy)acetate is shown in FIG. 11 overlaid with the TGA
trace.
Example 7: Thermal Gravimetric Analysis
[1294] Thermal Gravimetric Analysis (TGA) was performed on the TA
Instruments, Inc. TGA Q500 or Q5000. The instrument is calibrated
by the vendor at 10.degree. C./min. for temperature using the curie
point of a ferromagnetic standard. The balance is calibrated with a
standard weight. Sample is placed into an open sample pan,
previously tared on the TGA balance. Thermal events such as
weight-loss are calculated using the Universal Analysis 2000
software, version 4.1D, Build 4.1.0.16. The TGA thermogram for the
crystalline form of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate is shown in FIG. 11 overlaid with the DSC trace. The
TGA thermogram for a sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate hydrate is shown in FIG. 12. The TGA thermogram for a
sodium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate hydrate is shown in FIG. 14. The TGA thermogram for a
magnesium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyc-
lohexyl)methoxy)acetate solvate is shown in FIG. 16. The TGA
thermogram for potassium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate solvate is shown in FIG. 18. The TGA thermogram for
calcium
2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate solvate is shown in FIG. 20.
Example 8: Dynamic Vapor Sorption (DVS)
[1295] Hygroscopicity was measured using a dynamic
moisture-sorption analyzer, VTI Corporation, SGA-100. The sample
was placed as-is in a tared sample holder on the VTI balance. A
drying step was run at 40.degree. C. and .about.1% RH for 60 to 120
min. The isotherm conditions are 25.degree. C. with steps of 20% RH
from 10% RH up to 90% RH and back to 10% RH. The weight was checked
every 2 min. Percent weight change of <0.01% in 20 min or 2 h,
whichever occurs first, is required before continuing to the next
step. The DVS profile for the crystalline form of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cycloh-
exyl)methoxy)acetate is shown in FIG. 10.
Example 9: Interspecies Comparison of Hepatocyte Metabolism of
Sodium
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate
[1296] All cryopreserved hepatocytes were thawed and diluted to a
desired cell density (1.times.10.sup.6 cells/mL) according to the
supplier's (Xenotech) guidelines using hepatocytes isolation kit.
Cell viability was determined by trypan blue exclusion using a
hemacytometer. A typical incubation mixture contained human,
cynomolgus monkey, beagle dog or Sprague-Dawley rat hepatocytes
(200,000 cells/199 .mu.L) in designated wells of a 48-well plate
containing incubation medium (Phenol red-free Waymouth's medium).
The incubation mixture plate was incubated at 37.degree. C., 5%
CO.sub.2, for 5 min before starting the reaction with 1 .mu.L of
sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate (Compound 22 sodium salt)(100 .mu.M final
concentration). One incubation plate was prepared for each time
point (i.e., 0, 60, 120, and 240 min) with samples being prepared
in duplicate. Incubations were conducted at 37.degree. C., 5%
CO.sub.2 and 100% relative humidity in an incubator. At each time
point, one incubation plate was removed form the incubator, and
reaction was terminated by adding 400 .mu.L of acetonitrile
containing an internal standard. For the 0 min time point, the
reactions were kept on ice before adding Compound 22 sodium salt.
After 5 min on ice, the reaction mixture was terminated by adding
400 .mu.L of acetonitrile containing an internal standard.
Supernatants were transferred to labeled strip tubes with caps,
which were vortexed for 3 min, and then sonicated for an additional
3 min. The samples were centrifuged for 10 min at 4000 rpm and the
supernatants were used for metabolite identification.
[1297] Two major metabolites of sodium Compound 22 sodium salt were
identified in hepatocytes. The taurine conjugate (Compound 99), was
detected in human, monkey, dog and rat. The glycine conjugate
(Compound 100), was only detected in human and monkey.
[1298] MS/MS fragmentation was used to identify the metabolites.
The identity of the taurine conjugate of Compound 22 was confirmed
by the characteristic m/z=202 peak, corresponding to the
(4-chlorophenyl)(phenyl)amino group and the m/z=290 peak,
corresponding to the
(4-((2-oxo-2-(2-sulfonatoethylamino)ethoxy)methyl)cyclohexyl)methy-
l group. See FIG. 22. The identity of the glycine conjugate of
Compound 22 was confirmed by the characteristic, m/z=487 consistent
with an addition of glycine moiety. Furthermore, the fragmentation
pattern also showed the characteristic m/z=202 peak, indicating the
(4-chlorophenyl)(phenyl)amino group moiety was intact. See FIG.
23.
Example 10: In Vivo Metabolism Of Sodium
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate in Rats
[1299] Three bile-duct cannulated male Sprague-Dawley rats were
dosed intravenously (IV) at 2.00 mg/kg. In addition to plasma
samples, bile and urine were collected from 0 to 48 hours
post-dose.
[1300]
2-(2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cycl-
ohexyl)methoxy)acetamido)ethanesulfonic acid (the taurine conjugate
of Compound 22) (Compound 99) is a major metabolite of sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate in rats. The taurine conjugate of Compound 22 was
observed in bile but not observed in urine.
Example 11: Pharmacokinetics in Rats after an Oral Administration
of
2-(2-(((r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)-
methoxy)acetamido)ethanesulfonic Acid (Compound 99)
[1301] Male Sprague-Dawley rats (N=3) were given a 1.25 mg/kg oral
(PO) administration of
2-(2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl-
)methoxy)acetamido)ethanesulfonic acid (the taurine conjugate of
Compound 22) (Compound 99) formulated in 20% hydroxypropyl
cyclodextrin (HPCD) and dosed at 1.00 mL/kg. Blood samples were
obtained from 0.100 to 21.0 h post-dose for plasma drug
concentration measurements. Plasma levels of the taurine conjugate
of Compound 22 and
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid (Compound 22) were determined using a selective
LC/MS/MS method. Pharmacokinetic parameters were estimated using
non-compartmental pharmacokinetic-analysis.
[1302] The taurine conjugate of Compound 22 showed minimal exposure
and was converted to Compound 22 after a 1.25 mg/kg oral dose in
rats. The terminal phase half-lives (T.sub.y) of Compound 22 and
the taurine conjugate of Compound 22 were 3.51 and 3.24 hr,
respectively. The C.sub.max of Compound 22 and the taurine
conjugate of Compound 22 were 0.214 .mu.g/mL at 2.67 hr and 0.00193
.mu.g/mL at 3.33 hr, respectively. The AUC.sub.last values of
Compound 22 and the taurine conjugate of Compound 22 were 0.935 and
0.0119 hr.mu.g/mL, respectively. See FIG. 24.
[1303] The time to T.sub.max (3 h) for the taurine conjugate of
Compound 22 was extended compared to the T.sub.max (1.5 h) after a
10 mg/kg oral dose of Compound 22. See FIG. 25
[1304] It is apparent from these data that the taurine conjugate of
Compound 22 can act as a pro-drug for Compound 22.
Example 12: Excipient Solubility and Compatibility Study of
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid (Compound 22) and Sodium
2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate (Compound 22 Sodium Salt)
[1305] The solubility of
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetic acid (Compound 22) and sodium
2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)me-
thoxy)acetate (Compound 22 sodium salt) in various excipients was
measured. The results of the solubility study are presented in the
following table.
TABLE-US-00008 Solubility (mg/mL) Sodium Salt of Solvents Compound
22 Compound 22 Corn Oil <0.10 0.93 Safflower oil <0.10 0.82
Labrasol 12.98 54.1 Cremophor RH 40 7.82 44.8 Imwitor 742 16.20
37.4 TPGS 1000 2.55 35.0 Gelucire 44/14 1.61 43.4 PEG400 4.85 44.6
Lauroglycol 90 0.26 46.6 PEG6000 <10 >20 Gelucire 50/13
<10 >20
[1306] As can be seen from the preceding table, Compound 22 was
observed to be generally more soluble than Compound 22 sodium salt
in the excipients tested.
[1307] Compound 22 was tested for stability in three of the
excipients. Solutions of Compound 22 in Cremophor RH 40, Imwitor
742 and TPGS 1000 showed no observable degradation or API assay
loss after four weeks in a glass vial at 50.degree. C.
[1308] Based in part on the foregoing solubility and stability
data, it is apparent that Compound 22 is suitable for formulation
in liquid media.
[1309] Those skilled in the art will recognize that various
modifications, additions, substitutions and variations to the
illustrative examples set forth herein can be made without
departing from the spirit of the invention and are, therefore,
considered within the scope of the invention. All documents
referenced above, including, but not limited to, printed
publications and provisional and regular patent applications, are
incorporated herein by reference in their entirety.
* * * * *