U.S. patent application number 15/266021 was filed with the patent office on 2017-03-09 for sgc stimulators.
This patent application is currently assigned to Ironwood Pharmaceuticals, Inc.. The applicant listed for this patent is Ironwood Pharmaceuticals, Inc.. Invention is credited to Joel MOORE, Takashi NAKAI, Nicholas Robert PERL.
Application Number | 20170065586 15/266021 |
Document ID | / |
Family ID | 49263499 |
Filed Date | 2017-03-09 |
United States Patent
Application |
20170065586 |
Kind Code |
A1 |
NAKAI; Takashi ; et
al. |
March 9, 2017 |
SGC STIMULATORS
Abstract
The present patent application discloses at least the compounds
according to Formula I or Formula Ib shown below, or
pharmaceutically acceptable salts thereof, ##STR00001## wherein
ring B, J.sup.B, n, J.sup.D, J, o, X, R.sup.C and R.sup.A are as
described herein.
Inventors: |
NAKAI; Takashi; (Newton,
MA) ; PERL; Nicholas Robert; (Somerville, MA)
; MOORE; Joel; (Lexington, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ironwood Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Ironwood Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
49263499 |
Appl. No.: |
15/266021 |
Filed: |
September 15, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14429028 |
Mar 18, 2015 |
9487508 |
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PCT/US2013/060680 |
Sep 19, 2013 |
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15266021 |
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61703114 |
Sep 19, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61P 7/00 20180101; A61K 31/506 20130101; A61K 31/519 20130101;
A61K 31/513 20130101; C07D 403/04 20130101; A61K 31/4155 20130101;
Y02A 50/30 20180101; C07D 487/04 20130101; Y02A 50/423 20180101;
A61P 15/00 20180101; A61P 9/00 20180101; A61K 45/06 20130101; C07D
413/14 20130101; A61K 31/506 20130101; A61K 2300/00 20130101; A61K
31/5377 20130101; A61K 2300/00 20130101; A61K 31/519 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61K 31/519 20060101 A61K031/519; A61K 31/5377
20060101 A61K031/5377; A61K 45/06 20060101 A61K045/06; A61K 31/506
20060101 A61K031/506 |
Claims
1-113. (canceled)
114. A method of treating a disease, health condition or disorder
in a subject, comprising administering a therapeutically effective
amount of the compound of Formula I, or a pharmaceutically
acceptable salt thereof, to the subject in need of the treatment,
wherein the disease, health condition or disorder is (a)
Peripheral, pulmonary, hepatic, liver, cardiac or cerebral
vascular/endothelial disorders/conditions: disorders related to
high blood pressure and decreased coronary blood flow such as
increased acute and chronic coronary blood pressure, arterial
hypertension and vascular disorder resulting from cardiac and renal
complications (e.g. heart disease, stroke, cerebral ischemia, renal
failure); resistant hypertension, diabetic hypertension, diabetic
nephropathy, congestive heart failure; diastolic or systolic
dysfunction; coronary insufficiency; arrhythmias; diastolic
dysfunction; thromboembolic disorders and ischemias such as
myocardial infarction, stroke, transient ischemic attacks (TIAs);
stable or unstable angina pectoris; peripheral arterial disease,
peripheral occlusive arterial disease, intermittent claudication,
critical limb ischemia, vasculitis pulmonary/respiratory conditions
such as pulmonary hypertension, pulmonary arterial hypertension,
portal hypertension, acute respiratory distress syndrome, and
associated pulmonary vascular remodeling (e.g. localized thrombosis
and right heart hypertrophy); pulmonary hypertonia; primary
pulmonary hypertension, secondary pulmonary hypertension, familial
pulmonary hypertension, sporadic pulmonary hypertension,
pre-capillary pulmonary hypertension, idiopathic pulmonary
hypertension, thrombotic pulmonary arteriopathy, plexogenic
pulmonary arteriopathy; pulmonary hypertension associated with or
related to: left ventricular dysfunction, hypoxemia, mitral valve
disease, constrictive pericarditis, aortic stenosis,
cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous
pulmonary venous drainage, pulmonary venooclusive disease,
pulmonary vasculitis, collagen vascular disease, congenital heart
disease, pulmonary venous hypertension, interstitial lung disease,
sleep-disordered breathing, sleep apnea, alveolar hypoventilation
disorders, chronic exposure to high altitude, neonatal lung
disease, alveolar-capillary dysplasia, sickle cell disease, other
coagulation disorders, chronic thromboembolism, pulmonary embolism
(due to tumor, parasites or foreign material), peripheral embolism,
connective tissue disease, lupus, schistosomiasis, sarcoidosis,
chronic obstructive pulmonary disease, bronchoconstriction,
pulmonary vasoconstriction, acute respiratory distress syndrome,
asthma, emphysema, chronic bronchitis, pulmonary capillary
hemangiomatosis; histiocytosis X, lymphangiomatosis and compressed
pulmonary vessels (such as due to adenopathy, tumor or fibrosing
mediastinitis); arterosclerotic diseases or conditions such as
atherosclerosis (e.g., associated with endothelial injury, platelet
and monocyte adhesion and aggregation, smooth muscle proliferation
and migration); restenosis (e.g. developed after thrombolysis
therapies, percutaneous transluminal angioplasties (PTAs),
percutaneous transluminal coronary angioplasties (PTCAs) and
bypass); inflammation; thrombogenic diseases; cardiovascular
disease associated with metabolic syndrome (e.g., obesity,
dyslipidemia, diabetes, high blood pressure); lipid related
disorders such as dyslipidemia, hypercholesterolemia,
hypertriglyceridemia, sitosterolemia, fatty liver disease, and
hepatitis; liver cirrhosis, associated with chronic liver disease,
hepatic fibrosis, hepatic stellate cell activation, hepatic fibrous
collagen and total collagen accumulation; liver disease of
necro-inflammatory and/or of immunological origin; and urogenital
system disorders, such as renal fibrosis and renal failure
resulting from chronic kidney diseases or insufficiency (e.g. due
to accumulation/ deposition and tissue injury, progressive
sclerosis, glomerunephritis); prostate hypertrophy; cardiac
interstitial fibrosis, cardiac remodeling and fibrosis, heart
failure, cardiorenal syndrome; cardiac hypertrophy; diabetic
nephropathy b) sexual disorders of conditions: erectile
dysfunction; female sexual dysfunction (e.g., female sexual arousal
dysfunction), vaginal atrophy and incontinence; or c) wound healing
(e.g., in diabetics), microvascular perfusion improvement (e.g.,
following injury, in perioperative care), microcirculation
abnormalities, control of vascular leakage and permeability, for
conserving blood substitutes in trauma patients, endothelial
dysfunction, inhibition of modulation of platelet aggregation, anal
fissures; shock, sepsis, cardiogenic shock, control of leukocyte
activation; diabetic ulcers; and wherein said compound of Formula
I, or a pharmaceutically acceptable salt thereof has the following
structure: ##STR00047## wherein ring B is a phenyl or a 5 or
6-membered heteroaryl ring, containing 1 or 2 ring heteroatoms
selected from N, O or S; n is an integer selected from 0 to 3; each
J.sup.B is independently selected from halogen, --CN, a C.sub.1-6
aliphatic, --OR.sup.B or a C.sub.3-8 cycloaliphatic group; wherein
each said C.sub.1-6 aliphatic and each said C.sub.3-8
cycloaliphatic group is optionally and independently substituted
with up to 3 instances of R.sup.3, each R.sup.B is independently
selected from hydrogen, a C.sub.1-6 aliphatic or a C.sub.3-8
cycloaliphatic; wherein each said C.sub.1-6 aliphatic and each said
C.sub.3-8 cycloaliphatic ring is optionally and independently
substituted with up to 3 instances of R.sup.3aa; each R.sup.3 is
independently selected from halogen, --CN, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); each R.sup.ia is independently selected from halogen,
--CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or
--O(C.sub.1-4 haloalkyl); o is an integer selected from 0 to 3;
each J.sup.D is independently selected from halogen, --NO.sub.2,
--OR.sup.D, --SR.sup.S, --C(O)R.sup.D, --C(O)OR.sup.D,
--C(O)N(R.sup.D).sub.2, --CN, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)R.sup.D, --N(R.sup.d)C(O)OR.sup.D,
--SO.sub.2R.sup.D, --SO.sub.2N(R.sup.D).sub.2,
--N(R.sup.d)SO.sub.2R.sup.D, a --(C.sub.1-6 aliphatic, (C.sub.1-6
aliphatic)-R.sup.D, a C.sub.3-8 cycloaliphatic ring, a 6 to
10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5
to 10-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocylic ring and each said 5 to 10-membered heteroaryl ring
contains between 1 and 3 heteroatoms independently selected from O,
N or S; and wherein each said C.sub.1-6 aliphatic, each said
C.sub.3-8 cycloaliphatic ring, each said 6 to 10-membered aryl
ring, each said 4 to 8-membered heterocyclic ring and each said 5
to 10-membered heteroaryl ring is optionally and independently
substituted with up to 3 instances of R.sup.5; each R.sup.D is
independently selected from hydrogen, a C.sub.1-6 aliphatic,
(C.sub.1-6 aliphatic)-R.sup.f, a C.sub.3-8 cycloaliphatic ring, a 4
to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered
heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring
and each said 5 to 6-membered heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted with up to 3 instances of
R.sup.5a; each R.sup.d is independently selected from hydrogen, a
C.sub.1-6 aliphatic, --(C.sub.1-6 aliphatic)-R.sup.f, a C.sub.3-8
cycloaliphatic ring, a 4 to 8-membered heterocyclic ring, phenyl or
a 5 to 6-membered heteroaryl ring; wherein each said heterocylic
ring and each said heteroaryl ring contains between 1 and 3
heteroatoms independently selected from O, N or S; and wherein each
said C.sub.1-6 aliphatic, each said C.sub.3-8 cycloaliphatic ring,
each said 4 to 8-membered heterocyclic ring, each said phenyl and
each said 5 to 6-membered heteroaryl ring is optionally and
independently substituted by up to 3 instances of R.sup.5b; each
R.sup.f is independently selected from a C.sub.3-8 cycloaliphatic
ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to
6-membered heteroaryl ring; wherein each said heterocylic ring and
each said heteroaryl ring contains between 1 and 3 heteroatoms
independently selected from O, N or S; and wherein each said
C.sub.3-8 cycloaliphatic ring, each said 4 to 8-membered
heterocyclic ring, each said phenyl and each said 5 to 6-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.5c; when J.sup.D is --C(O)N(R.sup.D).sub.2,
--N(R.sup.D).sub.2 or SO.sub.2N(R.sup.D).sub.2, the two R.sup.D
groups together with the nitrogen atom attached to the R.sup.D
groups alternatively form a 4 to 8-membered heterocyclic ring or a
5-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S, and wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.5; when J.sup.D is --N(R.sup.d)C(O)R.sup.D, the R.sup.D group
together with the carbon atom attached to the R.sup.D group, with
the nitrogen atom attached to the R.sup.d group, and with the
R.sup.d group alternatively form a 4 to 8-membered heterocyclic
ring or a 5-membered heteroaryl ring; wherein each said 4 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S, and wherein each said 4 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring is optionally and independently substituted by up to 3
instances of R.sup.5; when J.sup.D is --N(R.sup.d)C(O)OR.sup.D, the
R.sup.D group together with the oxygen atom attached to the R.sup.D
group, with the carbon atom of the --C(O)-- portion of the
--N(R.sup.d)C(O)OR.sup.D group, with the nitrogen atom attached to
the R.sup.d group, and with the R.sup.d group alternatively form a
4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S, and wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.5; when J.sup.D is
--N(R.sup.d)SO.sub.2R.sup.D, the R.sup.D group together with the
oxygen atom attached to the R.sup.D group, with the sulfur atom
attached to said oxygen atom in the --SO.sub.2R.sup.D portion of
the --N(R.sup.d)SO.sub.2R.sup.D group, with the nitrogen atom
attached to the R.sup.d group, and with the R.sup.d group
alternatively form a 4 to 8-membered heterocyclic ring or a
5-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S, and wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.5; each R.sup.5 is independently selected from halogen, --CN,
--NO.sub.2, C.sub.1-4 alkyl, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl,
--OR.sup.6, --SR.sup.6, --OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6--N(R.sup.6).sub.2,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); and wherein each said C.sub.7-12 aralkyl and each said
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; each R.sup.5a is independently
selected from halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, a
C.sub.7-12 aralkyl, C.sub.3-8 cycloalkyl ring, C.sub.1-4 haloalkyl,
C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6, --OCOR.sup.6,
--COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sub.6, --(R.sup.6).sup.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4alkyl) or --O(C.sub.1-4haloalkyl); and wherein each
said C.sub.7-12 aralkyl and each said cycloalkyl group is
optionally and independently substituted with up to 3 instances of
halogen; each R.sup.5b is independently selected from halogen,
--CN, --NO.sub.2, C.sub.1-4 alkyl, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 haloalkyl, C.sub.1-4 cyanoalkyl,
--OR.sup.6, --SR.sup.6, --OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4alkyl) or
--O(C.sub.1-4haloalkyl); and wherein each said C.sub.7-12 aralkyl
and each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; each R.sup.5c is
independently selected from halogen, --CN, --NO.sub.2, C.sub.1-4
alkyl, a C.sub.7-12 aralkyl, C.sub.3-8 cycloalkyl ring, C.sub.1-4
haloalkyl, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6--N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl and each said cycloalkyl group is
optionally and independently substituted with up to 3 instances of
halogen; each R.sup.6 is independently selected from hydrogen, a
C.sub.1-4 alkyl, a C
.sub.2-4 alkenyl, phenyl, a C.sub.7-12 aralkyl or a C.sub.3-8
cycloalkyl ring; wherein each said C.sub.1-4 alkyl, each said
C.sub.2-4 alkenyl, each said phenyl, each said C.sub.7-12 aralkyl
and each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; alternatively, two
instances of R.sup.6 linked to the same nitrogen atom of R.sup.5,
together with said nitrogen atom of R.sup.5, form a 5 to 8-membered
heterocyclic ring or a 5-membered heteroaryl ring; wherein each
said 5 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S; or alternatively, one
instance of R.sup.6 linked to a nitrogen atom of R.sup.5 and one
instance of R.sup.6 linked to a carbon or sulfur atom of the same
R.sup.5, together with said nitrogen and said carbon or sulfur atom
of the same R.sup.5, form a 5 to 8-membered heterocyclic ring or a
5-membered heteroaryl ring; wherein each said 5 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S. or, alternatively, two J.sup.D groups
attached to two vicinal ring D atoms, taken together with said two
vicinal ring D atoms, form a 5 to 7-membered heterocycle resulting
in a fused ring D wherein said 5 to 7-membered heterocycle contains
from 1 to 3 heteroatoms independently selected from N, O or S; and
wherein said 5 to 7-membered heterocycle is optionally and
independently substituted by up to 3 instances of halogen, --OH,
NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl),
--O(C.sub.1-4 haloalkyl), oxo or phenyl; wherein said phenyl is
optionally and independently substituted by up to three instances
of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); R.sup.C is a ring C; ring C is a phenyl ring, a
monocyclic 5 or 6-membered heteroaryl ring, a bicyclic 8 to
10-membered heteroaryl ring, a monocyclic 3 to 10-membered
cycloaliphatic ring, or a monocyclic 4 to 10-membered heterocycle;
wherein said monocyclic 5 or 6-membered heteroaryl ring, said
bicyclic 8 to 10-membered heteroaryl ring, or said monocyclic 4 to
10-membered heterocycle contain between 1 and 4 heteroatoms
selected from N, O or S; wherein said monocyclic 5 or 6-membered
heteroaryl ring is not a 1,3,5-triazinyl ring; and wherein said
phenyl, monocyclic 5 to 6-membered heteroaryl ring, bicyclic 8 to
10-membered heteroaryl ring, monocyclic 3 to 10-membered
cycloaliphatic ring, or monocyclic 4 to 10-membered heterocycle is
optionally and independently substituted with up to 3 instances of
J.sup.C; each J.sup.C is independently selected from halogen, --CN,
--NO.sub.2, a C.sub.1-6 aliphatic, --OR.sup.H, --SR.sup.H,
--N(R.sup.H).sub.2, a C.sub.3-8 cycloaliphatic ring or a 4 to
8-membered heterocyclic ring; wherein said 4 to 8-membered
heterocyclic ring contains 1 or 2 heteroatoms independently
selected from N, O or S; wherein each said C.sub.1-6 aliphatic,
each said C.sub.3-8 cycloaliphatic ring and each said 4 to
8-membered heterocyclic ring, is optionally and independently
substituted with up to 3 instances of R.sup.7; or alternatively,
two J.sup.C groups attached to two vicinal ring C atoms, taken
together with said two vicinal ring C atoms, form a 5 to 7-membered
heterocycle resulting in a fused ring C; wherein said 5 to
7-membered heterocycle contains from 1 to 2 heteroatoms
independently selected from N, O or S; each R.sup.H is
independently selected from hydrogen, a C.sub.1-6 aliphatic, a
C.sub.3-8 cycloaliphatic ring or a 4 to 8-membered heterocyclic
ring,; wherein each said 4 to 8-membered heterocylic ring contains
between 1 and 3 heteroatoms independently selected from O, N or S;
and wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
is optionally and independently substituted with up to 3 instances
of R.sup.7a; alternatively, two instances of R.sup.H linked to the
same nitrogen atom of J.sup.C, together with said nitrogen atom
off, form a 4 to 8-membered heterocyclic ring or a 5-membered
heteroaryl ring; wherein each said 4 to 8-membered heterocyclic
ring and each said 5-membered heteroaryl ring optionally contains
up to 2 additional heteroatoms independently selected from N, O or
S, and wherein each said 4 to 8-membered heterocyclic ring and each
said 5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.7b; each R.sup.7 is
independently selected from halogen, --CN, --NO.sub.2, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring, --OR.sup.8,
--SR.sup.8, --N(R.sup.8).sub.2, or an oxo group; wherein each said
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; each R.sup.7a is independently
selected from halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.3-8 cycloalkyl ring, --OR.sup.8,
--N(R.sup.8).sub.2, or an oxo group; wherein each said cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen; each R.sup.7b is independently selected from
halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.3-8 cycloalkyl ring, --OR.sup.8, --N(R.sup.8).sub.2, or an
oxo group; wherein each said cycloalkyl group is optionally and
independently substituted with up to 3 instances of halogen; each
R.sup.8 is independently selected from hydrogen, a C.sub.1-4 alkyl,
C.sub.1-4haloalkyl or a C.sub.3-8 cycloalkyl ring; wherein each
said cycloalkyl group is optionally and independently substituted
with up to 3 instances of halogen; alternatively, two instances of
R.sup.8 linked to the same nitrogen atom of R.sup.7, R.sup.7a or
R.sup.7b, together with said nitrogen atom of R.sup.7, R.sup.7aor
R.sup.7b, form a 5 to 8-membered heterocyclic ring or a 5-membered
heteroaryl ring; wherein each said 5 to 8-membered heterocyclic
ring and each said 5-membered heteroaryl ring optionally contains
up to 2 additional heteroatoms independently selected from N, O or
S; and R.sup.A is selected from hydrogen, halogen, C.sub.1-4 alkyl
or C.sub.1-4 haloalkyl.
115. The method of claim 114, wherein the disease, health condition
or disorder is (a) a peripheral or cardiac vascular disorder or
health condition selected from: pulmonary hypertension, pulmonary
arterial hypertension, and associated pulmonary vascular
remodeling, localized pulmonary thrombosis, obstructive
thromboanginosis, right heart hypertrophy, pulmonary hypertonia,
primary pulmonary hypertension, secondary pulmonary hypertension,
familial pulmonary hypertension, sporadic pulmonary hypertension,
pre-capillary pulmonary hypertension, idiopathic pulmonary
hypertension, thrombotic pulmonary artheriopathy, plexogenic
pulmonary artheriopathy; pulmonary hypertension associated with or
related to: left ventricular dysfunction, hypoxemia, mitral valve
disease, constrictive pericarditis, aortic stenosis,
cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalous
pulmonary venous drainage, pulmonary venooclusive disease,
pulmonary vasculitis, collagen vascular disease, congenital heart
disease, pulmonary venous hypertension, interstitial lung disease,
sleep-disordered breathing, apnea, alveolar hypoventilation
disorders, chronic exposure to high altitude, neonatal lung
disease, alveolar-capillary dysplasia, sickle cell disease, other
coagulation disorders, chronic thromboembolism, pulmonary embolism,
peripheral embolism, connective tissue disease, lupus,
schistosomiasis, sarcoidosis, chronic obstructive pulmonary
disease, bronchoconstriction, pulmonary vasoconstriction, acute
pulmonary distress syndrome, emphysema, chronic bronchitis,
pulmonary capillary hemangiomatosis; histiocytosis X,
lymphangiomatosis or compressed pulmonary vessels; (b) liver
cirrhosis, (c) a urogenital system disorder selected from renal
fibrosis, renal failure resulting from chronic kidney diseases or
insufficiency, erectile dysfunction or female sexual dysfunction.
(d) wound healing, microvascular perfusion improvement,
microcirculation abnormalities, control of vascular leakage and
permeability, for conserving blood substitutes in trauma patients,
endothelial dysfunction, inhibition of modulation of platelet
aggregation, anal fissures.
116. The method of claim 115, wherein the disease, health condition
or disorder is pulmonary hypertension, pulmonary arterial
hypertension, and associated pulmonary vascular remodeling,
localized pulmonary thrombosis, obstructive thromboanginosis, right
heart hypertrophy, pulmonary hypertonia, primary pulmonary
hypertension, secondary pulmonary hypertension, familial pulmonary
hypertension, sporadic pulmonary hypertension, pre-capillary
pulmonary hypertension, idiopathic pulmonary hypertension,
thrombotic pulmonary arteriopathy, plexogenic pulmonary
arteriopathy or chronic obstructive pulmonary disease,
bronchoconstriction, pulmonary vasoconstriction, acute pulmonary
distress syndrome, liver cirrhosis, renal fibrosis, renal failure
resulting from chronic kidney diseases or insufficiency, erectile
dysfunction, female sexual dysfunction or wound healing.
117. The method of claim 116, wherein the disease, health condition
or disorder is pulmonary hypertension, pulmonary arterial
hypertension, and associated pulmonary vascular remodeling,
pulmonary hypertonia, primary pulmonary hypertension, secondary
pulmonary hypertension, familial pulmonary hypertension, sporadic
pulmonary hypertension, pre-capillary pulmonary hypertension or
idiopathic pulmonary hypertension.
118. The method of claim 114, further comprising administering an
effective amount of one or more additional therapeutic agents to
the subject.
119. The method of claim 118, wherein the one or more additional
therapeutic agents are selected from endothelium-derived releasing
factor, NO donors, substances that enhance cGMP concentrations,
nitric oxide synthase substrates, compounds which enhance eNOS
transcription, NO-independent heme-independent sGC activators,
heme-dependent sGC stimulators; inhibitors of cGMP degradation,
calcium channel blockers, endothelin receptor antagonists,
prostacyclin derivatives, antihyperlipidemics, anticoagulants,
antiplatelet drugs, ACE inhibitors, supplemental oxygen, beta
blockers, antiarrhythmic agents, diuretics, exogenous vasodilators,
bronchodilators, corticosteroids, dietary supplements, PGD2
receptor antagonists, immunosuppressants, non-steroidal
antiasthmatics, non-steroidal anti-inflammatory agents,
cyclooxygenase-2 inhibitors or anti-diabetic agents.
120. (canceled)
121. The method of claim 114, wherein said compound of Formula I,
or a pharmaceutically acceptable salt thereof, is selected from:
##STR00048## ##STR00049##
122. The method of claim 114, wherein the disease is a health
disorder related to high blood pressure and decreased coronary
blood flow selected from: increased acute and chronic coronary
blood pressure, arterial hypertension, vascular disorder resulting
from heart disease, stroke, cerebral ischemia, or renal failure,
congestive heart failure, thromboembolic disorders, ischemias,
myocardial infarction, stroke, transient ischemic attacks, stable
or unstable angina pectoris, arrhythmias, diastolic dysfunction,
coronary insufficiency.
123. The method of claim 122, wherein the disease is a health
disorder related to high blood pressure and decreased coronary
blood flow selected from: stroke, cerebral ischemia, thromboembolic
disorders or transient ischemic attacks.
124. The method of claim 114, wherein the disease is selected from
liver cirrhosis, hepatic fibrosis, hepatic stellate cell
activation, hepatic fibrous collagen and total collagen
accumulation or liver disease of necro-inflammatory and/or of
immunological origin.
125. The method of claim 114, wherein the disease a urogenital
system disorder selected from renal fibrosis or renal failure
resulting from chronic kidney diseases or insufficiency.
126. The method of claim 121, wherein the disease is a health
disorder related to high blood pressure and decreased coronary
blood flow selected from: increased acute and chronic coronary
blood pressure, arterial hypertension, vascular disorder resulting
from heart disease, stroke, cerebral ischemia, or renal failure,
congestive heart failure, thromboembolic disorders, ischemias,
myocardial infarction, stroke, transient ischemic attacks, stable
or unstable angina pectoris, arrhythmias, diastolic dysfunction,
coronary insufficiency.
127. The method of claim 126, wherein the disease is a health
disorder related to high blood pressure and decreased coronary
blood flow selected from: stroke, cerebral ischemia, thromboembolic
disorders or transient ischemic attacks.
128. The method of claim 121, wherein the disease is selected from
liver cirrhosis, hepatic fibrosis, hepatic stellate cell
activation, hepatic fibrous collagen and total collagen
accumulation or liver disease of necro-inflammatory and/or of
immunological origin.
129. The method of claim 121, wherein the disease a urogenital
system disorder selected from renal fibrosis or renal failure
resulting from chronic kidney diseases or insufficiency.
Description
[0001] This application claims the priority of U.S. Provisional
Application, No. 61/703,114, filed Sep. 19, 2012, the disclosures
of which application are incorporated by reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates to stimulators of soluble
guanylate cyclase (sGC), pharmaceutical formulations comprising
thereof and their uses, alone or in combination with one or more
additional agents, for treating and/or preventing various diseases,
wherein an increase in the concentration of nitric oxide (NO) or an
increase in the concentration of cyclic Guanosine Monophosphate
(cGMP) might be desirable.
BACKGROUND OF THE INVENTION
[0003] Soluble guanylate cyclase (sGC) is the primary receptor for
nitric oxide (NO) in vivo. sGC can be activated via both
NO-dependent and NO-independent mechanisms. In response to this
activation, sGC converts GTP into the secondary messenger cyclic
GMP (cGMP). The increased level of cGMP, in turn, modulates the
activity of downstream effectors including protein kinases,
phosphodiesterases (PDEs) and ion channels.
[0004] In the body, NO is synthesized from arginine and oxygen by
various nitric oxide synthase (NOS) enzymes and by sequential
reduction of inorganic nitrate. Three distinct isoforms of NOS have
been identified: inducible NOS (iNOS or NOS II) found in activated
macrophage cells; constitutive neuronal NOS (nNOS or NOS I),
involved in neurotransmission and long term potentiation; and
constitutive endothelial NOS (eNOS or NOS III) which regulates
smooth muscle relaxation and blood pressure.
[0005] Experimental and clinical evidence indicates that reduced
bioavailability and/or responsiveness to endogenously produced NO
contributes to the development of cardiovascular, endothelial,
renal and hepatic disease, as well as erectile dysfunction and
other sexual disorders (e.g. female sexual disorder or vaginal
atrophy), wound healing. In particular, the NO signaling pathway is
altered in cardiovascular diseases, including, for instance,
systemic and pulmonary hypertension, portal hypertension, heart
failure, angina, stroke, thrombosis, obstructive thromboanginitis
and other thromboembolic diseases, peripheral vascular disease,
peripheral arterial disease, fibrosis of the liver, lung or kidney
and atherosclerosis.
[0006] sGC stimulators are also useful in the treatment of lipid
related disorders such as e.g., dyslipidemia, hypercholesterolemia,
hypertriglyceridemia, sitosterolemia, fatty liver disease, and
hepatitis.
[0007] Pulmonary hypertension (PH) is a disease characterized by
sustained elevation of blood pressure in the pulmonary vasculature
(pulmonary artery, pulmonary vein and pulmonary capillaries), which
results in right heart hypertrophy, eventually leading to right
heart failure and death. In PH, the bioactivity of NO and other
vasodilators such as prostacyclin is reduced, whereas the
production of endogenous vasoconstrictors such as endothelin is
increased, resulting in excessive pulmonary vasoconstriction. sGC
stimulators have been used to treat PH because they promote smooth
muscle relaxation, which leads to vasodilation.
[0008] Treatment with NO-independent sGC stimulators also promoted
smooth muscle relaxation in the corpus cavernosum of healthy
rabbits, rats and humans, causing penile erection, indicating that
sGC stimulators are useful for treating erectile dysfunction.
[0009] NO-independent, heme-dependent, sGC stimulators, such as
those disclosed herein, have several important differentiating
characteristics, including crucial dependency on the presence of
the reduced prosthetic heme moiety for their activity, strong
synergistic enzyme activation when combined with NO and stimulation
of the synthesis of cGMP by direct stimulation of sGC, independent
of NO. The benzylindazole compound YC-1 was the first sGC
stimulator to be identified. Additional sGC stimulators with
improved potency and specificity for sGC have since been developed.
These compounds have been shown to produce anti-aggregatory,
anti-proliferative and vasodilatory effects.
[0010] Since compounds that stimulate sGC in an NO-independent
manner offer considerable advantages over other current alternative
therapies, there is a need to develop novel stimulators of sGC.
They are potentially useful in the prevention, management and
treatment of disorders such as pulmonary hypertension, arterial
hypertension, portal hypertension, heart failure, atherosclerosis,
inflammation, thrombosis, thrombogenic disorders, obstructive
thromboanginitis, renal fibrosis and failure, liver cirrhosis, lung
fibrosis, erectile dysfunction, female sexual arousal disorder and
vaginal atrophy, wound healingand other cardiovascular disorders;
they are also potentially useful for the prevention, management and
treatment of lipid related disorders. Compounds that stimulate sGC
in an NO-independent manner are also useful for the treatment of
shock and related complications.
SUMMARY OF THE INVENTION
[0011] A compound according to Formula Ib, or a pharmaceutically
acceptable salt thereof,
##STR00002##
wherein X is either carbon or nitrogen; [0012] wherein either
[0013] i) ring B is absent with J.sup.B connected directly to the
carbon atom bearing two J groups, each J is independently selected
from hydrogen, methyl or fluorine, n is 1 and J.sup.B is a
C.sub.1-6 alkyl chain optionally substituted by up to 6 instances
of fluorine; or [0014] ii) ring B is a phenyl or a 5 or 6-membered
heteroaryl ring, containing 1 or 2 ring heteroatoms selected from
N, O or S; wherein with ring B being the phenyl or 5 or 6-membered
heteroaryl ring; each J is hydrogen; n is an integer selected from
0 to 3; and each J.sup.B is independently selected from halogen,
--CN, a C.sub.1-6 aliphatic, --OR.sup.B or a C.sub.3-8
cycloaliphatic group; wherein each said C.sub.1-6 aliphatic and
each said C.sub.3-8 cycloaliphatic group is optionally and
independently substituted with up to 3 instances of R.sup.3; each
R.sup.B is independently selected from hydrogen, a C.sub.1-6
aliphatic or a C.sub.3-8 cycloaliphatic; wherein each said
C.sub.1-6 aliphatic and each said C.sub.3-8 cycloaliphatic ring is
optionally and independently substituted with up to 3 instances of
R.sup.3a; [0015] each R.sup.3 is independently selected from
halogen, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4
alkyl) or --O(C.sub.1-4 haloalkyl); [0016] each R.sup.3a is
independently selected from halogen, --CN, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); [0017] o is an integer selected from 0 to 3; [0018]
each J.sup.D is independently selected from halogen, --CN,
--OR.sup.D, --SR.sup.D, --C(O)R.sup.D, --C(O)OR.sup.D,
--OC(O)R.sup.D, --C(O)N(R.sup.D).sub.2, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)R.sup.D, --N(R.sup.d)C(O)OR.sup.D,
--N(R.sup.d)C(O)N(R.sup.D).sub.2, --OC(O)N(R.sup.D).sub.2,
--SO.sub.2R.sup.D, --SO.sub.2N(R.sup.D).sub.2,
--N(R.sup.d)SO.sub.2R.sup.D, a C.sub.1-6 aliphatic, --(C.sub.1-6
aliphatic)-R.sup.D, a C.sub.3-8 cycloaliphatic ring, a 6 to
10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5
to 10-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocylic ring and [0019] each said 5 to 10-membered heteroaryl
ring contains between 1 and 3 heteroatoms independently selected
from O, N or S; and wherein each said C.sub.1-6 aliphatic, each
said C.sub.3-8 cycloaliphatic ring, each said 6 to 10-membered aryl
ring, each said 4 to 8-membered heterocyclic ring and each said 5
to 10-membered heteroaryl ring is optionally and independently
substituted with up to 3 instances of R.sup.5; [0020] each R.sup.D
is independently selected from hydrogen, a C.sub.1-6 aliphatic,
--(C.sub.1-6 aliphatic)-R.sup.f, a C.sub.3-8 cycloaliphatic ring, a
4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered
heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring
and each said 5 to 6-membered heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted with up to 3 instances of
R.sup.5a; [0021] each R.sup.d is independently selected from
hydrogen, a C.sub.1-6 aliphatic, (C.sub.1-6 aliphatic)-R.sup.f, a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.5b; [0022] each R.sup.f is independently selected from a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.3-8 cycloaliphatic ring, each said 4 to
8-membered heterocyclic ring, each said phenyl and each said 5 to
6-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5c; [0023] when J.sup.D
is --C(O)N(R.sup.D).sup.2, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)N(R.sup.D).sup.2, --OC(O)N(R.sup.D).sub.2 or
--SO.sub.2N(R.sup.D).sub.2, the two R.sup.D groups together with
the nitrogen atom attached to the two R.sup.D groups may form a 4
to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S; and wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.5d; [0024] when J.sup.D is
--N(R.sup.d)C(O)R.sup.D the R.sup.D group together with the carbon
atom attached to the R.sup.D group, with the nitrogen atom attached
to the R.sup.d group, and with the R.sup.d group may form a 4 to
8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S, and wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.5d; [0025] when J.sup.D is
--N(R.sup.d)C(O)OR.sup.D or --N(R.sup.d)C(O)N(R.sup.D).sub.2, the
R.sup.D group together with the oxygen atom attached to the R.sup.D
group, with the carbon atom of the --C(O)-- portion of the
--N(R.sup.d)C(O)OR.sup.D group, with the nitrogen atom attached to
the R.sup.d group, or, alternatively one of the R.sup.D groups
attached to the nitrogen atom, together with said nitrogen atom,
and with the N atom attached to the R.sup.d group and said R.sup.d
group may form a 4 to 8-membered heterocyclic ring; wherein said 4
to 8-membered heterocyclic ring optionally contains up to 2
additional heteroatoms independently selected from N, O or S, and
is optionally and independently substituted by up to 3 instances of
R.sup.5d; [0026] when J.sup.D is --N(R.sup.d)SO.sub.2R.sup.D, the
R.sup.D group together with the sulfur atom attached to the R.sup.D
group, with the nitrogen atom attached to the R.sup.d group, and
with the R.sup.d group may combine to form a 4 to 8-membered
heterocyclic ring; wherein said 4 to 8-membered heterocyclic ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S, and is optionally and independently
substituted by up to 3 instances of R.sup.5d; [0027] each R.sup.5
is independently selected from halogen, --CN, C.sub.1-4 alkyl,
--(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl, each said C.sub.1-4 alkyl chainand each
said C.sub.3-8 cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0028] each R.sup.5a
is independently selected from halogen, --CN, C.sub.1-4 alkyl,
--(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl, each said C.sub.1-4 alkyl chainand each
said C.sub.3-8 cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0029] each R.sup.5b
is independently selected from halogen, --CN, C.sub.1-4 alkyl,
--(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl, each said C.sub.1-4 alkyl chain and each
said C.sub.3-8 cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0030] each R.sup.5c
is independently selected from halogen, --CN, C.sub.1-4 alkyl,
--(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl, each said C.sub.1-4 alkyl chain and each
said C.sub.3-8 cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0031] each R.sup.5d
is independently selected from halogen, --CN, C.sub.1-4 alkyl,
--(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl, each said C.sub.1-4 alkyl chain and each
said C.sub.3-8 cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0032] each R.sup.6
is independently selected from hydrogen, a C.sub.1-4 alkyl, a
C.sub.2-4 alkenyl, phenyl, a C.sub.7-12 aralkyl or a C.sub.3-8
cycloalkyl ring; wherein each said C.sub.1-4 alkyl, each said
C.sub.2-4 alkenyl, each said phenyl, each said C.sub.7-12 aralkyl
and each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0033]
alternatively, two instances of R.sup.6 linked to the same nitrogen
atom of R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c or R.sup.5d, together
with said nitrogen atom of R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c or
R.sup.5d, respectively, may form a 5 to 8-membered heterocyclic
ring or a 5-membered heteroaryl ring; wherein each said 5 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S; or [0034] alternatively, one
instance of R.sup.6 linked to a nitrogen atom of R.sup.5, R.sup.5a,
R.sup.5b, R.sup.5c or R.sup.5d and one instance of R.sup.6 linked
to a carbon or sulfur atom of the same R.sup.5, R.sup.5a, R.sup.5b,
R.sup.5c or R.sup.5d, respectively, together with said nitrogen and
said carbon or sulfur atom of the same R.sup.5, R.sup.5a, R.sup.5b,
R.sup.5c or R.sup.5d, respectively, may form a 5 to 8-membered
heterocyclic ring or a 5-membered heteroaryl ring; wherein each
said 5 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S; [0035] alternatively, two
J.sup.D groups attached to two vicinal ring D atoms, taken together
with said two vicinal ring D atoms, form a 5 to 7-membered
heterocycle or a 5-membered heteroaryl ring that is fused to ring
D; wherein said 5 to 7-membered heterocycle or said 5-membered ring
heteroaryl contains from 1 to 3 heteroatoms independently selected
from N, O or S; and wherein said 5 to 7-membered heterocycle or
said 5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of oxo or -(Y)-R.sup.9; [0036]
wherein Y is either absent or is a linkage in the form of a
C.sub.1-6 alkyl chain, optionally substituted by up to 6 instances
of fluoro;
[0037] each R.sup.9 is independently selected from hydrogen, --CN,
--OR.sup.10, --COR.sup.10, --OC(O)R.sup.10, --C(O)OR.sup.10,
--C(O)N(R.sup.10).sup.2, --C(O)N(R.sup.10)SO.sub.2R.sup.10,
--N(R.sup.10)C(O)R.sup.10, --N(R.sup.10)C(O)OR.sup.10,
--N(R.sup.10)C(O)N(R.sup.10, --N(R.sup.10).sup.2,
--SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2,
--SO.sub.2N(R.sup.10)COOR.sup.10,
--SO.sub.2N(R.sup.10)C(O)R.sup.10, --N(R.sup.10)SO.sub.2R.sup.10, a
C3-6 cycloalkyl ring, a 4-8-membered heterocyclic ring, a phenyl
ring or a 5-6 membered heteroaroaryl ring; wherein each said 4 to
8-membered heterocyclic ring or 5 to 6-membered heteroaryl ring
contains up to 4 ring heteroatoms independently selected from N, O
or S; and wherein each of said C3-6 cycloalkyl rings, each of said
4 to 8-membered heterocyclic rings, each of said phenyl and each of
said 5 to 6-membered heteroaryl rings is optionally substituted
with up to 3 instances of R.sup.11a; [0038] wherein each R.sup.10
is independently selected from hydrogen, a C.sub.1-6 alkyl, phenyl,
benzyl, a C.sub.3-6 cycloalkyl ring, a 4 to 7-membered heterocyclic
ring or a 5 or 6-membered heteroaryl ring, wherein each 5 or
6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring
contains up to 4 ring heteroatoms independently selected from N, O
and S; and wherein each of said C.sub.1-6 alkyl, each said phenyl,
each said benzyl, each said C.sub.3-8 cycloalkyl group, each said 4
to 7-membered heterocyclic ring and each 5 or 6-membered heteroaryl
ring is optionally and independently substituted with up to 3
instances of R.sup.11b; [0039] each R.sup.11a is independently
selected from halogen, C.sub.1-6 alkyl, --CN, --OR.sup.12,
--COR.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--N(R.sup.12)C(O)R.sup.12, --N(R.sup.12)C(O)OR.sup.12,
--N(R.sup.12)C(O)N(R.sup.12).sub.2, --N(R.sup.12).sub.2,
--SO.sub.2R.sup.12, --SO.sub.2N(R.sup.12).sub.2 or
--N(R.sup.12)SO.sub.2R.sup.12; wherein each of said C.sub.1-6 alkyl
is optionally and independently substituted by up to 6 instances of
fluoro and/or 3 instances of R.sup.12; [0040] each R.sup.11b is
independently selected from halogen, C.sub.1-6 alkyl, --CN,
--OR.sup.12, --COR.sup.12, --C(O)OR.sup.12,
--C(O)N(R.sup.12).sub.2, --N(R.sup.12)C(O)R.sup.12,
--N(R.sup.12)C(O)OR.sup.12, --N(R.sup.12)C(O)N(R.sup.12).sub.2,
--N(R.sup.12).sub.2, --SO.sub.2R.sup.12,
--SO.sub.2N(R.sup.12).sub.2 or --N(R.sup.12)SO.sub.2R.sup.12;
wherein each of said C.sub.1-6 alkyl is optionally and
independently substituted by up to 6 instances of fluoro and/or 3
instances of R.sup.12; [0041] each R.sup.12 is selected from
C.sub.1-4 alkyl, C.sub.1-4 (fluoroalkyl), --OH, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN, --COOH,
--COO(C.sub.1-4 alkyl), --O(C.sub.1-4 alkyl), --O(C.sub.1-4
fluoroalkyl) or oxo; [0042] R.sup.C is either [0043] i) a ring C;
or [0044] ii) R.sup.c is selected from halogen, --CN, C.sub.1-6
alkyl, --(C.sub.1-6 alkyl)-R.sup.N, --OR.sup.K, --COR.sup.K,
--OC(O)R.sup.K, --C(O)OR.sup.K, --C(O)N(R.sup.K).sub.2,
--N(R.sup.k)C(O)R.sup.K, --N(R.sup.k)C(O)OR.sup.K,
--N(R.sup.k)C(O)N(R.sup.K).sub.2, --N(R.sup.K).sub.2,
--SO.sub.2R.sup.K, --SO.sub.2N(R.sup.K).sub.2 or
--N(R.sup.k)SO.sub.2R.sup.K; wherein said Rc that is a C.sub.1-6
alkyl is optionally and independently substituted with up to 6
instances of fluoro and/or up to 3 instances of R.sup.7c1; [0045]
each R.sup.k is independently selected from hydrogen or a C1-6
alkyl; [0046] each R.sup.K is independently selected from hydrogen,
a C.sub.1-6 alkyl, a phenyl ring, a monocyclic 5 or 6-membered
heteroaryl ring, a monocyclic C3-6 cycloaliphatic ring, or a
monocyclic 4 to 6-membered heterocycle; wherein said monocyclic 5
or 6-membered heteroaryl ring or said monocyclic 4 to 6-membered
heterocycle contain between 1 and 4 heteroatoms selected from N, O
or S; wherein said monocyclic 5 or 6-membered heteroaryl ring is
not a 1,3,5-triazinyl ring; and wherein said phenyl, said
monocyclic 5 to 6-membered heteroaryl ring, said monocyclic C3-6
cycloaliphatic ring, or said monocyclic 4 to 6-membered heterocycle
is optionally and independently substituted with up to 6 instances
of fluoro and/or up to 3 instances of J.sup.M; and wherein each
R.sup.K that is a C.sub.1-6 alkyl is optionally and independently
substituted by up to 3 instances of R.sup.7d; [0047] each R.sup.N
is independently selected from a phenyl ring, a monocyclic 5 or
6-membered heteroaryl ring, a monocyclic C3-6 cycloaliphatic ring,
or a monocyclic 4 to 6-membered heterocycle; wherein said
monocyclic 5 or 6-membered heteroaryl ring or said monocyclic 4 to
6-membered heterocycle contain between 1 and 4 heteroatoms selected
from N, O or S; wherein said monocyclic 5 or 6-membered heteroaryl
ring is not a 1,3,5-triazinyl ring; and wherein said phenyl, said
monocyclic 5 to 6-membered heteroaryl ring, said monocyclic
C.sub.3-6 cycloaliphatic ring, or said monocyclic 4 to 6-membered
heterocycle is optionally and independently substituted with up to
6 instances of fluoro and/or up to 3 instances of J.sup.M; [0048]
each J.sup.M is independently selected from --CN, a C.sub.1-6
aliphatic, --OR.sup.M, --SR.sup.M, --N(R.sup.M).sub.2, a C.sub.3-8
cycloaliphatic ring or a 4 to 8-membered heterocyclic ring; wherein
said 4 to 8-membered heterocyclic ring contains 1 or 2 heteroatoms
independently selected from N, O or S; wherein each said C.sub.1-6
aliphatic, each said C.sub.3-8 cycloaliphatic ring and each said 4
to 8-membered heterocyclic ring, is optionally and independently
substituted with up to 3 instances of R.sup.7c; [0049] each R.sup.M
is independently selected from hydrogen, a C.sub.1-6 aliphatic, a
C.sub.3-8 cycloaliphatic ring or a 4 to 8-membered heterocyclic
ring; wherein each said 4 to 8-membered heterocylic ring contains
between 1 and 3 heteroatoms independently selected from O, N or S;
and wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring and each said 4 to 8-membered heterocyclic
ring, is optionally and independently substituted with up to 3
instances of R.sup.7e; [0050] ring C is a phenyl ring, a monocyclic
5 or 6-membered heteroaryl ring, a bicyclic 8 to 10-membered
heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphatic ring,
or a monocyclic 4 to 10-membered heterocycle; wherein said
monocyclic 5 or 6-membered heteroaryl ring, said bicyclic 8 to
10-membered heteroaryl ring, or said monocyclic 4 to 10-membered
heterocycle contain between 1 and 4 heteroatoms selected from N, O
or S; wherein said monocyclic 5 or 6-membered heteroaryl ring is
not a 1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5
to 6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl
ring, monocyclic 3 to 10-membered cycloaliphatic ring, or
monocyclic 4 to 10-membered heterocycle is optionally and
independently substituted with up to 3 instances of J.sup.C; [0051]
each J.sup.C is independently selected from halogen, --CN,
NO.sub.2, a C.sub.1-6 aliphatic, --OR.sup.H, --SR.sup.H,
--N(R.sup.H).sub.2, a C.sub.3-8 cycloaliphatic ring or a 4 to
8-membered heterocyclic ring; wherein said 4 to 8-membered
heterocyclic ring contains 1 or 2 heteroatoms independently
selected from N, O or S; wherein each said C.sub.1-6 aliphatic,
each said C.sub.3-8 cycloaliphatic ring and each said 4 to
8-membered heterocyclic ring, is optionally and independently
substituted with up to 3 instances of R.sup.7; or [0052]
alternatively, two J.sup.C groups attached to two vicinal ring C
atoms, taken together with said two vicinal ring C atoms, form a 5
to 7-membered heterocycle that is a new ring fused to ring C;
wherein said 5 to 7-membered heterocycle contains from 1 to 2
heteroatoms independently selected from N, O or S; [0053] each
R.sup.H is independently selected from hydrogen, a C.sub.1-6
aliphatic, a C.sub.3-8 cycloaliphatic ring or a 4 to 8-membered
heterocyclic ring ; wherein each said 4 to 8-membered heterocylic
ring contains between 1 and 3 heteroatoms independently selected
from O, N or S; and wherein each said C.sub.1-6 aliphatic, each
said C.sub.3-8 cycloaliphatic ring and each said 4 to 8-membered
heterocyclic ring, is optionally and independently substituted with
up to 3 instances of R.sup.7a; [0054] alternatively, two instances
of R.sup.H linked to the same nitrogen atom of --N(R.sup.H).sub.2,
together with said nitrogen atom of --N(R.sup.H).sub.2, form a 4 to
8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S, and wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.7b; [0055] each R.sup.7 is independently
selected from halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.3-8 cycloalkyl ring, C.sub.3-8 (halocycloalkyl)
ring, --OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
[0056] each R.sup.7a is independently selected from halogen, --CN,
--NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8
cycloalkyl ring, C.sub.3-8 (halocycloalkyl) ring, --OR.sup.8,
--SR.sup.8, --N(R.sup.8).sub.2, or an oxo group; [0057] each
R.sup.7b is independently selected from halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
C.sub.3-8 (halocycloalkyl) ring, --OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, or an oxo group; [0058] each R.sup.7c is
independently selected from hydrogen, halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
wherein each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0059] each R.sup.7d
is independently selected from hydrogen, halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
wherein each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0060] each R.sup.7e
is independently selected from hydrogen, halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
wherein each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0061] each R.sup.8
is independently selected from hydrogen, a C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl or a C.sub.3-8 cycloalkyl ring, C.sub.3-8
(halocycloalkyl) ringalternatively, two instances of R.sup.8 linked
to the same nitrogen atom of R.sup.7, R.sup.7a, R.sup.7b, R.sup.7c,
R.sup.7d or R.sup.7e, together with said nitrogen atom of R.sup.7,
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d or R.sup.7e, form a 5 to
8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 5 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S; and [0062]
R.sup.A is selected from hydrogen, halogen, C.sub.1-4 alkyl or
C.sub.1-4 haloalkyl.
[0063] The present invention is also directed to compounds
according to Formula I, or pharmaceutically acceptable salts
thereof,
##STR00003## [0064] wherein, ring B is a phenyl or a 5 or
6-membered heteroaryl ring, containing 1 or 2 ring heteroatoms
selected from N, O or S; [0065] n is an integer selected from 0 to
3; [0066] each J.sup.B is independently selected from halogen,
--CN, a C.sub.1-6 aliphatic, --OR.sup.B or a C.sub.3-8
cycloaliphatic group; wherein each said C.sub.1-6 aliphatic and
each said C.sub.3-8 cycloaliphatic group is optionally and
independently substituted with up to 3 instances of R.sup.3; [0067]
each R.sup.B is independently selected from hydrogen, a C.sub.1-6
aliphatic or a C.sub.3-8 cycloaliphatic; wherein each said
C.sub.1-6 aliphatic and each said C.sub.3-8 cycloaliphatic ring is
optionally and independently substituted with up to 3 instances of
R.sup.3a; [0068] each R.sup.3 is independently selected from
halogen, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4
alkyl) or --O(C.sub.1-4 haloalkyl); [0069] each R.sup.3a is
independently selected from halogen, --CN, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); [0070] o is an integer selected from 0 to 3; [0071]
each J.sup.D is independently selected from halogen, --NO.sub.2,
--OR.sup.D, --SR.sup.S, --C(O)R.sup.D, --C(O)OR.sup.D,
--C(O)N(R.sup.D).sub.2, --CN, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)R.sup.D, --N(R.sup.d)C(O)OR.sup.D,
--SO.sub.2R.sup.D, --SO.sub.2N(R.sup.D).sub.2,
--N(R.sup.d)SO.sub.2R.sup.D, a C.sub.1-6 aliphatic, --(C.sub.1-6
aliphatic)-R.sup.D, a C.sub.3-8 cycloaliphatic ring, a 6 to
10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5
to 10-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocylic ring and each said 5 to 10-membered heteroaryl ring
contains between 1 and 3 heteroatoms independently selected from O,
N or S; and wherein each said C.sub.1-6 aliphatic, each said
C.sub.3-8 cycloaliphatic ring, each said 6 to 10-membered aryl
ring, each said 4 to 8-membered heterocyclic ring and each said 5
to 10-membered heteroaryl ring is optionally and independently
substituted with up to 3 instances of R.sup.5; [0072] each R.sup.D
is independently selected from hydrogen, a C.sub.1-6 aliphatic,
--(C.sub.1-6 aliphatic)-R.sup.f, a C.sub.3-8 cycloaliphatic ring, a
4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered
heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring
and each said 5 to 6-membered heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted with up to 3 instances of
R.sup.5a; [0073] each R.sup.d is independently selected from
hydrogen, a C.sub.1-6 aliphatic, (C.sub.1-6 aliphatic)-R.sup.f, a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.5b; [0074] each R.sup.f is independently selected from a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.3-8 cycloaliphatic ring, each said 4 to
8-membered heterocyclic ring, each said phenyl and each said 5 to
6-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5c; [0075] when J.sup.D
is --C(O)N(R.sup.D).sub.2, --N(R.sup.D).sub.2 or
--SO.sub.2N(R.sup.D).sub.2, the two R.sup.D groups together with
the nitrogen atom attached to the R.sup.D groups alternatively form
a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl
ring; wherein each said 4 to 8-membered heterocyclic ring and each
said 5-membered heteroaryl ring optionally contains up to 2
additional heteroatoms independently selected from N, O or S, and
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5; [0076] when J.sup.D is
--N(R.sup.d)C(O)R.sup.D, the R.sup.D group together with the carbon
atom attached to the R.sup.D group, with the nitrogen atom attached
to the R.sup.d group, and with the R.sup.d group alternatively form
a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl
ring; wherein each said 4 to 8-membered heterocyclic ring and each
said 5-membered heteroaryl ring optionally contains up to 2
additional heteroatoms independently selected from N, O or S, and
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5; [0077] when J.sup.D is
--N(R.sup.d)C(O)OR.sup.D, the R.sup.D group together with the
oxygen atom attached to the R.sup.D group, with the carbon atom of
the --C(O)-- portion of the --N(R.sup.d)C(O)OR.sup.D group, with
the nitrogen atom attached to the R.sup.d group, and with the
R.sup.d group alternatively form a 4 to 8-membered heterocyclic
ring or a 5-membered heteroaryl ring; wherein each said 4 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S, and wherein each said 4 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring is optionally and independently substituted by up to 3
instances of R.sup.5; [0078] when J.sup.D is
--N(R.sup.d)SO.sub.2R.sup.D, the R.sup.D group together with the
oxygen atom attached to the R.sup.D group, with the sulfur atom
attached to said oxygen atom in the SO.sub.2R.sup.D portion of the
--N(R.sup.d)SO.sub.2R.sup.D group, with the nitrogen atom attached
to the R.sup.d group, and with the R.sup.d group alternatively form
a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl
ring; [0079] wherein each said 4 to 8-membered heterocyclic ring
and each said 5-membered heteroaryl ring optionally contains up to
2 additional heteroatoms independently selected from N, O or S, and
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5; [0080] each R.sup.5 is
independently selected from halogen, --CN, --NO.sub.2, C.sub.1-4
alkyl, a C.sub.7-12 aralkyl, C.sub.3-8 cycloalkyl ring, C.sub.1-4
haloalkyl, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl and each said cycloalkyl group is
optionally and independently substituted with up to 3 instances of
halogen; [0081] each R.sup.5 is independently selected from
halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 haloalkyl, C.sub.1-4
cyanoalkyl, --OR.sup.6, --SR.sup.6, --OCOR.sup.6, --COR.sup.6,
--C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); and wherein each said C.sub.7-12 aralkyl and each said
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; [0082] each R.sup.5b is independently
selected from halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, a
C.sub.7-12 aralkyl, C.sub.3-8 cycloalkyl ring, C.sub.1-4 haloalkyl,
C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6, --OCOR.sup.6,
--COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl and each said cycloalkyl group is
optionally and independently substituted with up to 3 instances of
halogen; [0083] each R.sup.5c is independently selected from
halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 haloalkyl, C.sub.1-4
cyanoalkyl, --OR.sup.6, --SR.sup.6, --OCOR.sup.6, --COR.sup.6,
--C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, O(C.sub.1-4 alkyl) or O(C.sub.1-4
haloalkyl); and wherein each said C.sub.7-12 aralkyl and each said
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; [0084] each R.sup.6 is independently
selected from hydrogen, a C.sub.1-4 alkyl, a C.sub.2-4 alkenyl,
phenyl, a C.sub.7-12 aralkyl or a C.sub.3-8 cycloalkyl ring;
wherein each said C.sub.1-4 alkyl, each said C.sub.2-4 alkenyl,
each said phenyl, each said C.sub.7-12 aralkyl and each said
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; [0085] alternatively, two instances
of R.sup.6 linked to the same nitrogen atom of R.sup.5, together
with said nitrogen atom of R.sup.5, form a 5 to 8-membered
heterocyclic ring or a 5-membered heteroaryl ring; wherein each
said 5 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S; or [0086] alternatively, one
instance of R.sup.6 linked to a nitrogen atom of R.sup.5 and one
instance of R.sup.6 linked to a carbon or sulfur atom of the same
R.sup.5, together with said nitrogen and said carbon or sulfur atom
of the same R.sup.5, form a 5 to 8-membered heterocyclic ring or a
5-membered heteroaryl ring; wherein each said 5 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S; [0087] or, alternatively, two J.sup.D
groups attached to two vicinal ring D atoms, taken together with
said two vicinal ring D atoms, form a 5 to 7-membered heterocycle
resulting in a fused ring D wherein said 5 to 7-membered
heterocycle contains from 1 to 3 heteroatoms independently selected
from N, O or S; and wherein said 5 to 7-membered heterocycle is
optionally and independently substituted by up to 3 instances of
halogen, --OH, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl), --O(C.sub.1-4 haloalkyl), oxo or phenyl;
wherein said phenyl is optionally and independently substituted by
up to three instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl);
[0088] R.sup.C is a ring C; ring C is a phenyl ring, a monocyclic 5
or 6-membered heteroaryl ring, a bicyclic 8 to 10-membered
heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphatic ring,
or a monocyclic 4 to 10-membered heterocycle; wherein said
monocyclic 5 or 6-membered heteroaryl ring, said bicyclic 8 to
10-membered heteroaryl ring, or said monocyclic 4 to 10-membered
heterocycle contain between 1 and 4 heteroatoms selected from N, O
or S; wherein said monocyclic 5 or 6-membered heteroaryl ring is
not a 1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5
to 6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl
ring, monocyclic 3 to 10-membered cycloaliphatic ring, or
monocyclic 4 to 10-membered heterocycle is optionally and
independently substituted with up to 3 instances of J.sup.C; [0089]
each J.sup.C is independently selected from halogen, --CN,
--NO.sub.2, a C.sub.1-6 aliphatic, --OR.sup.H, --SR.sup.H,
--N(R.sup.H).sub.2, a C.sub.3-8 cycloaliphatic ring or a 4 to
8-membered heterocyclic ring; wherein said 4 to 8-membered
heterocyclic ring contains 1 or 2 heteroatoms independently
selected from N, O or S; wherein each said C.sub.1-6 aliphatic,
each said C.sub.3-8 cycloaliphatic ring and each said 4 to
8-membered heterocyclic ring, is optionally and independently
substituted with up to 3 instances of R.sup.7; or alternatively,
two J.sup.C groups attached to two vicinal ring C atoms, taken
together with said two vicinal ring C atoms, form a 5 to 7-membered
heterocycle resulting in a fused ring C; wherein said 5 to
7-membered heterocycle contains from 1 to 2 heteroatoms
independently selected from N, O or S; [0090] each R.sup.H is
independently selected from hydrogen, a C.sub.1-6 aliphatic, a
C.sub.3-8 cycloaliphatic ring or a 4 to 8-membered heterocyclic
ring,; wherein each said 4 to 8-membered heterocylic ring contains
between 1 and 3 heteroatoms independently selected from O, N or S;
and wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
is optionally and independently substituted with up to 3 instances
of R.sup.7 a; [0091] alternatively, two instances of R.sup.H linked
to the same nitrogen atom of J.sup.C, together with said nitrogen
atom of J.sup.C, form a 4 to 8-membered heterocyclic ring or a
5-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S, and wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.7b; [0092] each R.sup.7 is independently selected from
halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.3-8 cycloalkyl ring, --OR.sup.8, --N(R.sup.8).sub.2, or an
oxo group; wherein each said cycloalkyl group is optionally and
independently substituted with up to 3 instances of halogen; [0093]
each R.sup.7a is independently selected from halogen, --CN,
--NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8
cycloalkyl ring, --OR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
wherein each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0094] each R.sup.7b
is independently selected from halogen, --CN, --NO.sub.2, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring, --OR.sup.8,
--N(R.sup.8).sub.2, or an oxo group; wherein each said cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen; [0095] each R.sup.8 is independently selected
from hydrogen, a C.sub.1-4 alkyl, C.sub.1-4 haloalkyl or a
C.sub.3-8 cycloalkyl ring; wherein each said cycloalkyl group is
optionally and independently substituted with up to 3 instances of
halogen; [0096] alternatively, two instances of R.sup.8 linked to
the same nitrogen atom of R.sup.7, R.sup.7a or R.sup.7b, together
with said nitrogen atom of R.sup.7, R.sup.7a or 7.sup.b, form a 5
to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 5 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S; and [0097]
R.sup.A is selected from hydrogen, halogen, C.sub.1-4 alkyl or
C.sub.1-4 haloalkyl.
[0098] The invention also provides a method of treating or
preventing a disease, health condition or disorder in a subject in
need thereof, comprising administering, alone or in combination
therapy, a therapeutically or prophylactically effective amount of
a compound of Formula I or Formula Ib or a pharmaceutically
acceptable salt thereof to the subject; wherein the disease, health
condition or disorder is a peripheral, pulmonary, hepatic, liver,
cardiac or cerebral vascular/endothelial disorder or condition, a
urogenital-gynecological disorder or condition, a thromboembolic
disease, a fibrotic disorder, or other pulmonary or respiratory
disorder, renal or hepatic disorder, metabolic disorder,
atherosclerosis or a lipid related disorder that can benefit from
sGC stimulation or from an increase in the concentration of NO or
cGMP.
DETAILED DESCRIPTION
[0099] Reference will now be made in detail to certain embodiments
of the invention, examples of which are illustrated in the
accompanying structures and formulae. While the invention will be
described in conjunction with the enumerated embodiments, it will
be understood that they are not intended to limit the invention to
those embodiments. Rather, the invention is intended to cover all
alternatives, modifications and equivalents that may be included
within the scope of the present invention as defined by the claims.
The present invention is not limited to the methods and materials
described herein but include any methods and materials similar or
equivalent to those described herein that could be used in the
practice of the present invention. In the event that one or more of
the incorporated literature references, patents or similar
materials differ from or contradict this application, including but
not limited to defined terms, term usage, described techniques or
the like, this application controls.
Definitions and General Terminology
[0100] For purposes of this disclosure, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, and the Handbook of Chemistry and Physics, 75.sup.th
Ed. 1994. Additionally, general principles of organic chemistry are
described in "Organic Chemistry", Thomas Sorrell, University
Science Books, Sausalito: 1999, and "March's Advanced Organic
Chemistry", 5.sup.th Ed., Smith, M. B. and March, J., eds. John
Wiley & Sons, New York: 2001, which are herein incorporated by
reference in their entirety.
[0101] As described herein, compounds of Formula I or Formula b may
be optionally substituted with one or more substituents, such as
illustrated generally below, or as exemplified by particular
classes, subclasses and species of the invention. The phrase
"optionally substituted" is used interchangeably with the phrase
"substituted or unsubstituted." In general, the term "substituted"
refers to the replacement of one or more hydrogen radicals in a
given structure with the radical of a specified substituent. Unless
otherwise indicated, an optionally substituted group may have a
substituent at each substitutable position of the group. When more
than one position in a given structure can be substituted with more
than one substituent selected from a specified group, the
substituent may be either the same or different at each position
unless otherwise specified. As will be apparent to one of ordinary
skill in the art, groups such as --H, halogen, --NO.sub.2, --CN,
--OH, --NH.sub.2 or --OCF.sub.3 would not be substitutable
groups.
[0102] The phrase "up to", as used herein, refers to zero or any
integer number that is equal or less than the number following the
phrase. For example, "up to 3" means any one of 0, 1, 2, or 3. As
described herein, a specified number range of atoms includes any
integer therein. For example, a group having from 1-4 atoms could
have 1, 2, 3 or 4 atoms. When any variable occurs more than one
time at any position, its definition on each occurrence is
independent from every other occurrence.
[0103] Selection of substituents and combinations envisioned by
this disclosure are only those that result in the formation of
stable or chemically feasible compounds. Such choices and
combinations will be apparent to those of ordinary skill in the art
and may be determined without undue experimentation. The term
"stable", as used herein, refers to compounds that are not
substantially altered when subjected to conditions to allow for
their production, detection, and, in some embodiments, their
recovery, purification, and use for one or more of the purposes
disclosed herein. In some embodiments, a stable compound or
chemically feasible compound is one that is not substantially
altered when kept at a temperature of 25.degree. C. or less, in the
absence of moisture or other chemically reactive conditions, for at
least a week. A chemically feasible compound is a compound that can
be prepared by a person skilled in the art based on the disclosures
herein supplemented, if necessary, relevant knowledge of the
art.
[0104] A compound, such as the compounds of Formula I or Formula Ib
or other compounds herein disclosed, may be present in its free
form (e.g. an amorphous form, or a crystalline form or a
polymorph). Under certain conditions, compounds may also form
co-forms. As used herein, the term co-form is synonymous with the
term multi-component crystalline form. When one of the components
in the co-form has clearly transferred a proton to the other
component, the resulting co-form is referred to as a "salt". The
formation of a salt is determined by how large the difference is in
the pKas between the partners that form the mixture.
[0105] Unless only one of the isomers is drawn or named
specifically, structures depicted herein are also meant to include
all stereoisomeric (e.g., enantiomeric, diastereomeric,
atropoisomeric and cis-trans isomeric) forms of the structure; for
example, the R and S configurations for each asymmetric center, Ra
and Sa configurations for each asymmetric axis, (Z) and (E) double
bond configurations, and cis and trans conformational isomers.
Therefore, single stereochemical isomers as well as racemates, and
mixtures of enantiomers, diastereomers, and cis-trans isomers
(double bond or conformational) of the present compounds are within
the scope of the present disclosure. Unless otherwise stated, all
tautomeric forms of the compounds of the present disclosure are
also within the scope of the invention.
[0106] The present disclosure also embraces isotopically-labeled
compounds which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. All isotopes of any particular atom
or element as specified are contemplated within the scope of the
compounds of the invention, and their uses. Exemplary isotopes that
can be incorporated into compounds of the invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur,
fluorine, chlorine, and iodine, such as .sup.2H, .sup.3H, .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.32P, .sup.33P, .sup.35S, .sup.18F, .sup.36Cl,
.sup.123I, and .sup.125I , respectively. Certain
isotopically-labeled compounds of the present invention (e.g.,
those labeled with .sup.3H and .sup.14C) are useful in compound
and/or substrate tissue distribution assays. Tritiated (i.e.,
.sup.3H) and carbon-14 (i.e., .sup.14C) isotopes are useful for
their ease of preparation and detectability. 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.
Positron emitting isotopes such as .sup.15O, .sup.13N, .sup.11C,
and .sup.18F are useful for positron emission tomography (PET)
studies to examine substrate receptor occupancy. Isotopically
labeled compounds of the present invention can generally be
prepared by following procedures analogous to those disclosed in
the Schemes and/or in the Examples herein below, by substituting an
isotopically labeled reagent for a non-isotopically labeled
reagent.
[0107] The term "aliphatic" or "aliphatic group", as used herein,
means a straight-chain (i.e., unbranched) or branched, substituted
or unsubstituted hydrocarbon chain that is completely saturated or
that contains one or more units of unsaturation. Unless otherwise
specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In
some embodiments, aliphatic groups contain 1-10 aliphatic carbon
atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic
carbon atoms. In still other embodiments, aliphatic groups contain
1-6 aliphatic carbon atoms. In other embodiments, aliphatic groups
contain 1-4 aliphatic carbon atoms and in yet other embodiments,
aliphatic groups contain 1-3 aliphatic carbon atoms. Suitable
aliphatic groups include, but are not limited to, linear or
branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl
groups. Specific examples of aliphatic groups include, but are not
limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl,
vinyl, sec-butyl, tert-butyl, butenyl, propargyl, acetylene and the
like.
[0108] The term "alkyl", as used herein, refers to a saturated
linear or branched-chain monovalent hydrocarbon radical. Unless
otherwise specified, an alkyl group contains 1-20 carbon atoms
(e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6
carbon atoms, 1-4 carbon atoms or 1-3 carbon atoms). Examples of
alkyl groups include, but are not limited to, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl,
hexyl, heptyl, octyl and the like.
[0109] The term "alkenyl" refers to a linear or branched-chain
monovalent hydrocarbon radical with at least one site of
unsaturation, i.e., a carbon-carbon, sp.sup.2 double bond, wherein
the alkenyl radical includes radicals having "cis" and "trans"
orientations, or alternatively, "E" and "Z" orientations. Unless
otherwise specified, an alkenyl group contains 2-20 carbon atoms
(e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6
carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examples
include, but are not limited to, vinyl, allyl and the like.
[0110] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical with at least one site of unsaturation, i.e., a
carbon-carbon sp triple bond. Unless otherwise specified, an
alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms,
2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon
atoms or 2-3 carbon atoms). Examples include, but are not limited
to, ethynyl, propynyl, and the like.
[0111] The term "carbocyclic" refers to a ring system formed only
by carbon and hydrogen atoms. Unless otherwise specified,
throughout this disclosure, carbocycle is used as a synonym of
"non-aromatic carbocycle" or "cycloaliphatic". In some instances
the term can be used in the phrase "aromatic carbocycle", and in
this case it refers to an "aryl group" as defined below.
[0112] The term "cycloaliphatic" (or "non-aromatic carbocycle",
"non-aromatic carbocyclyl", "non-aromatic carbocyclic") refers to a
cyclic hydrocarbon that is completely saturated or that contains
one or more units of unsaturation but which is not aromatic, and
which has a single point of attachment to the rest of the molecule.
Unless otherwise specified, a cycloaliphatic group may be
monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In one
embodiment, the term "cycloaliphatic" refers to a monocyclic
C.sub.3-C.sub.12 hydrocarbon or a bicyclic C.sub.7-C.sub.12
hydrocarbon. In some embodiments, any individual ring in a bicyclic
or tricyclic ring system has 3-7 members. Suitable cycloaliphatic
groups include, but are not limited to, cycloalkyl, cycloalkenyl,
and cycloalkynyl. Examples of aliphatic groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl,
cyclodecyl, cycloundecyl, cyclododecyl, and the like.
[0113] The term "cycloaliphatic" also includes polycyclic ring
systems in which the non-aromatic carbocyclic ring can be "fused"
to one or more aromatic or non-aromatic carbocyclic or heterocyclic
rings or combinations thereof, as long as the radical or point of
attachment is on the non-aromatic carbocyclic ring.
[0114] "Heterocycle" (or "heterocyclyl" or "heterocyclic), as used
herein, refers to a ring system in which one or more ring members
are an independently selected heteroatom, which is completely
saturated or that contains one or more units of unsaturation but
which is not aromatic, and which has a single point of attachment
to the rest of the molecule. Unless otherwise specified, through
this disclosure, heterocycle is used as a synonym of "non-aromatic
heterocycle". In some instances the term can be used in the phrase
"aromatic heterocycle", and in this case it refers to a "heteroaryl
group" as defined below. The term heterocycle also includes fused,
spiro or bridged heterocyclic ring systems. Unless otherwise
specified, a heterocycle may be monocyclic, bicyclic or tricyclic.
In some embodiments, the heterocycle has 3-18 ring members in which
one or more ring members is a heteroatom independently selected
from oxygen, sulfur or nitrogen, and each ring in the system
contains 3 to 7 ring members. In other embodiments, a heterocycle
may be a monocycle having 3-7 ring members (2-6 carbon atoms and
1-4 heteroatoms) or a bicycle having 7-10 ring members (4-9 carbon
atoms and 1-6 heteroatoms). Examples of bicyclic heterocyclic ring
systems include, but are not limited to: adamantanyl,
2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl.
[0115] As used herein, the term "heterocycle" also includes
polycyclic ring systems wherein the heterocyclic ring is fused with
one or more aromatic or non-aromatic carbocyclic or heterocyclic
rings, or with combinations thereof, as long as the radical or
point of attachment is on the heterocyclic ring.
[0116] Examples of heterocyclic rings include, but are not limited
to, the following monocycles: 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,
2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,
3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl,
5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl,
1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
5-imidazolidinyl; and the following bicycles:
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, indolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,
benzodithiane, and 1,3-dihydro-imidazol-2-one.
[0117] As used herein, the term "aryl" (as in "aryl ring" or "aryl
group"), used alone or as part of a larger moiety, as in "aralkyl",
"aralkoxy", "aryloxyalkyl", refers to a carbocyclic ring system
wherein at least one ring in the system is aromatic and has a
single point of attachment to the rest of the molecule. Unless
otherwise specified, an aryl group may be monocyclic, bicyclic or
tricyclic and contain 6-18 ring members. The term also includes
polycyclic ring systems where the aryl ring is fused with one or
more aromatic or non-aromatic carbocyclic or heterocyclic rings, or
with combinations thereof, as long as the radical or point of
attachment is in the aryl ring. Examples of aryl rings include, but
are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin,
fluorenyl, and anthracenyl.
[0118] The term "aralkyl" refers to a radical having an aryl ring
substituted with an alkylene group, wherein the open end of the
alkylene group allows the aralkyl radical to bond to another part
of the compound of Formula I or Formula Ib. The alkylene group is a
bivalent, straight-chain or branched, saturated hydrocarbon group.
As used herein, the term "C.sub.7-12 aralkyl" means an aralkyl
radical wherein the total number of carbon atoms in the aryl ring
and the alkylene group combined is 7 to 12. Examples of "aralkyl"
include, but not limited to, a phenyl ring substituted by a
C.sub.1-6 alkylene group, e.g., benzyl and phenylethyl, and a
naphthyl group substituted by a C.sub.1-2 alkylene group.
[0119] The term "heteroaryl" (or "heteroaromatic" or "heteroaryl
group" or "aromatic heterocycle") used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy" refers to a ring
system wherein at least one ring in the system is aromatic and
contains one or more heteroatoms, wherein each ring in the system
contains 3 to 7 ring members and which has a single point of
attachment to the rest of the molecule. Unless otherwise specified,
a heteroaryl ring system may be monocyclic, bicyclic or tricyclic
and have a total of five to fourteen ring members. In one
embodiment, all rings in a heteroaryl system are aromatic. Also
included in this definition are heteroaryl radicals where the
heteroaryl ring is fused with one or more aromatic or non-aromatic
carbocyclic or heterocyclic rings, or combinations thereof, as long
as the radical or point of attachment is in the heteroaryl ring.
Bicyclic 6, 5 heteroaromatic system, as used herein, for example,
is a six membered heteroaromatic ring fused to a second five
membered ring wherein the radical or point of attachment is on the
six-membered ring.
[0120] Heteroaryl rings include, but are not limited to the
following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl,
4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,
N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl
(e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,
tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and
5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl),
isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl,
and the following bicycles: benzimidazolyl, benzofuryl,
benzothiophenyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g.,
2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,
4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,
3-isoquinolinyl, or 4-isoquinolinyl).
[0121] As used herein, "cyclo" (or "cyclic", or "cyclic moiety")
encompasses mono-, bi- and tri-cyclic ring systems including
cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which has
been previously defined.
[0122] "Fused" bicyclic ring systems comprise two rings which share
two adjoining ring atoms.
[0123] "Bridged" bicyclic ring systems comprise two rings which
share three or four adjacent ring atoms. As used herein, the term
"bridge" refers to an atom or a chain of atoms connecting two
different parts of a molecule. The two atoms that are connected
through the bridge (usually but not always, two tertiary carbon
atoms) are referred to as "bridgeheads". In addition to the bridge,
the two bridgeheads are connected by at least two individual atoms
or chains of atoms. Examples of bridged bicyclic ring systems
include, but are not limited to, adamantanyl, norbornanyl,
bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,
bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,
1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and
2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. "Spiro" bicyclic ring systems
share only one ring atom (usually a quaternary carbon atom) between
the two rings.
[0124] The term "ring atom" refers to an atom such as C, N, O or S
that is part of the ring of an aromatic ring, a cycloaliphatic
ring, a heterocyclic or a heteroaryl ring. A "substitutable ring
atom" is a ring carbon or nitrogen atom bonded to at least one
hydrogen atom. The hydrogen can be optionally replaced with a
suitable substituent group. Thus, the term "substitutable ring
atom" does not include ring nitrogen or carbon atoms which are
shared when two rings are fused. In addition, "substitutable ring
atom" does not include ring carbon or nitrogen atoms when the
structure depicts that they are already attached to one or more
moiety other than hydrogen and no hydrogens are available for
substitution.
[0125] "Heteroatom" refers to one or more of oxygen, sulfur,
nitrogen, phosphorus, or silicon, including any oxidized form of
nitrogen, sulfur, phosphorus, or silicon, the quaternized form of
any basic nitrogen, or a substitutable nitrogen of a heterocyclic
or heteroaryl ring, for example N (as in 3,4-dihydro-2H-pyrrolyl),
NH (as in pyrrolidinyl) or NR.sup.+ (as in N-substituted
pyrrolidinyl).
[0126] In some embodiments, two independent occurrences of a
variable may be taken together with the atom(s) to which each
variable is bound to form a 5-8-membered, heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloaliphatic ring. Exemplary
rings that are formed when two independent occurrences of a
substituent are taken together with the atom(s) to which each
variable is bound include, but are not limited to the following: a)
two independent occurrences of a substituent that are bound to the
same atom and are taken together with that atom to form a ring,
where both occurrences of the substituent are taken together with
the atom to which they are bound to form a heterocyclyl,
heteroaryl, cycloaliphatic or aryl ring, wherein the group is
attached to the rest of the molecule by a single point of
attachment; and b) two independent occurrences of a substituent
that are bound to different atoms and are taken together with both
of those atoms to form a heterocyclyl, heteroaryl, cycloaliphatic
or aryl ring, wherein the ring that is formed has two points of
attachment with the rest of the molecule. For example, where a
phenyl group is substituted with two occurrences of --OR.sup.o as
in Formula D1:
##STR00004##
[0127] these two occurrences of --OR.sup.o are taken together with
the carbon atoms to which they are bound to form a fused 6-membered
oxygen containing ring as in Formula D2:
##STR00005##
[0128] It will be appreciated that a variety of other rings can be
formed when two independent occurrences of a substituent are taken
together with the atom(s) to which each substituent is bound and
that the examples detailed above are not intended to be
limiting.
[0129] In some embodiments, an alkyl or aliphatic chain can be
optionally interrupted with another atom or group. This means that
a methylene unit of the alkyl or aliphatic chain can optionally be
replaced with said other atom or group. Unless otherwise specified,
the optional replacements form a chemically stable compound.
Optional interruptions can occur both within the chain and/or at
either end of the chain; i.e. both at the point of attachment(s) to
the rest of the molecule and/or at the terminal end. Two optional
replacements can also be adjacent to each other within a chain so
long as it results in a chemically stable compound. Unless
otherwise specified, if the replacement or interruption occurs at a
terminal end of the chain, the replacement atom is bound to an H on
the terminal end. For example, if --CH.sub.2CH.sub.2CH.sub.3 were
optionally interrupted with --O--, the resulting compound could be
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.3, or --CH.sub.2CH.sub.2OH.
In another example, if the divalent linker
--CH.sub.2CH.sub.2CH.sub.2-- were optionally interrupted with
--O--, the resulting compound could be --OCH.sub.2CH.sub.2--,
--CH.sub.2OCH.sub.2--, or --CH.sub.2CH.sub.2O--. The optional
replacements can also completely replace all of the carbon atoms in
a chain. For example, a C3 aliphatic can be optionally replaced by
--N(R')--, --C(O)--, and --N(R')-- to form --N(R')C(O)N(R')-- (a
urea).
[0130] In general, the term "vicinal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to adjacent carbon atoms.
[0131] In general, the term "geminal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to the same carbon atom.
[0132] The terms "terminally" and "internally" refer to the
location of a group within a substituent. A group is terminal when
the group is present at the end of the substituent not further
bonded to the rest of the chemical structure. Carboxyalkyl, i.e.,
R.sup.XO(O)C-alkyl is an example of a carboxy group used
terminally. A group is internal when the group is present in the
middle of a substituent at the end of the substituent bound to the
rest of the chemical structure. Alkylcarboxy (e.g., alkyl-C(O)O--
or alkyl-O(CO)--) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or
alkyl-O(CO)-aryl-) are examples of carboxy groups used
internally.
[0133] As described herein, a bond drawn from a substituent to the
center of one ring within a multiple-ring system (as shown below),
represents substitution of the substituent at any substitutable
position in any of the rings within the multiple ring system. For
example, formula D3 represents possible substitution in any of the
positions shown in formula D4:
##STR00006##
[0134] This also applies to multiple ring systems fused to optional
ring systems (which would be represented by dotted lines). For
example, in Formula D5, X is an optional substituent both for ring
A and ring B.
##STR00007##
[0135] If, however, two rings in a multiple ring system each have
different substituents drawn from the center of each ring, then,
unless otherwise specified, each substituent only represents
substitution on the ring to which it is attached. For example, in
Formula D6, Y is an optional substituent for ring A only, and X is
an optional substituent for ring B only.
##STR00008##
[0136] As used herein, the terms "alkoxy" or "alkylthio" refer to
an alkyl group, as previously defined, attached to the molecule, or
to another chain or ring, through an oxygen ("alkoxy" i.e.,
--O-alkyl) or a sulfur ("alkylthio" i.e., S-alkyl) atom.
[0137] The terms C.sub.n-m "alkoxyalkyl", C.sub.n-m
"alkoxyalkenyl", C.sub.n-m "alkoxyaliphatic", and C.sub.n-m
"alkoxyalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the
case may be, substituted with one or more alkoxy groups, wherein
the combined total number of carbons of the alkyl and alkoxy
groups, alkenyl and alkoxy groups, aliphatic and alkoxy groups or
alkoxy and alkoxy groups, combined, as the case may be, is between
the values of n and m. For example, a C.sub.4-6 alkoxyalkyl has a
total of 4-6 carbons divided between the alkyl and alkoxy portion;
e.g. it can be --CH.sub.2OCH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 or
--CH.sub.2CH.sub.2CH.sub.2OCH.sub.3.
[0138] When the moieties described in the preceding paragraph are
optionally substituted, they can be substituted in either or both
of the portions on either side of the oxygen or sulfur. For
example, an optionally substituted C4 alkoxyalkyl could be, for
instance, --CH.sub.2CH.sub.2OCH.sub.2(Me)CH.sub.3 or
--CH.sub.2(OH)OCH.sub.2CH.sub.2CH.sub.3; a C.sub.5 alkoxyalkenyl
could be, for instance, --CH.dbd.CHO CH.sub.2CH.sub.2CH.sub.3 or
--CH.dbd.CHCH.sub.2OCH.sub.2CH.sub.3.
[0139] The terms aryloxy, arylthio, benzyloxy or benzylthio, refer
to an aryl or benzyl group attached to the molecule, or to another
chain or ring, through an oxygen ("aryloxy", benzyloxy e.g.,
--O-Ph, --OCH.sub.2Ph) or sulfur ("arylthio" e.g., --S-Ph,
S--CH.sub.2Ph) atom. Further, the terms "aryloxyalkyl",
"benzyloxyalkyl" "aryloxyalkenyl" and "aryloxyaliphatic" mean
alkyl, alkenyl or aliphatic, as the case may be, substituted with
one or more aryloxy or benzyloxy groups, as the case may be. In
this case, the number of atoms for each aryl, aryloxy, alkyl,
alkenyl or aliphatic will be indicated separately. Thus, a
5-6-membered aryloxy(C.sub.1-4alkyl) is a 5-6 membered aryl ring,
attached via an oxygen atom to a C.sub.1-4 alkyl chain which, in
turn, is attached to the rest of the molecule via the terminal
carbon of the C.sub.1-4 alkyl chain.
[0140] As used herein, the terms "halogen" or "halo" mean F, Cl,
Br, or I.
[0141] The terms "haloalkyl", "haloalkenyl", "haloaliphatic", and
"haloalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case
may be, substituted with one or more halogen atoms. For example a
C.sub.1-3 haloalkyl could be --CFHCH.sub.2CHF.sub.2 and a C.sub.1-2
haloalkoxy could be --OC(Br)HCHF.sub.2. This term includes
perfluorinated alkyl groups, such as --CF.sub.3 and
--CF.sub.2CF.sub.3.
[0142] As used herein, the term "cyano" refers to --CN or
--C.ident.N.
[0143] The terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic",
and "cyanoalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the
case may be, substituted with one or more cyano groups. For example
a C.sub.1-3 cyanoalkyl could be --C(CN).sub.2CH.sub.2CH.sub.3 and a
C.sub.1-2 cyanoalkenyl could be .dbd.CHC(CN)H.sub.2.
[0144] As used herein, an "amino" group refers to --NH.sub.2.
[0145] The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic",
and "aminoalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the
case may be, substituted with one or more amino groups. For example
a C.sub.1-3 aminoalkyl could be
--CH(NH.sub.2)CH.sub.2CH.sub.2NH.sub.2 and a C.sub.1-2 aminoalkoxy
could be --OCH.sub.2CH.sub.2NH.sub.2.
[0146] The term "hydroxyl" or "hydroxy" refers to --OH.
[0147] The terms "hydroxyalkyl", "hydroxyalkenyl",
"hydroxyaliphatic", and "hydroxyalkoxy" mean alkyl, alkenyl,
aliphatic or alkoxy, as the case may be, substituted with one or
more --OH groups. For example a C.sub.1-3 hydroxyalkyl could be
--CH.sub.2(CH.sub.2OH)CH.sub.3 and a C4 hydroxyalkoxy could be
--OCH.sub.2C(CH.sub.3)(OH)CH.sub.3.
[0148] As used herein, a "carbonyl", used alone or in connection
with another group refers to --C(O)-- or --C(O)H. For example, as
used herein, an "alkoxycarbonyl," refers to a group such as
--C(O)O(alkyl).
[0149] As used herein, an "oxo" refers to =0, wherein oxo is
usually, but not always, attached to a carbon atom (e.g., it can
also be attached to a sulfur atom). An aliphatic chain can be
optionally interrupted by a carbonyl group or can optionally be
substituted by an oxo group, and both expressions refer to the
same: e.g. --CH.sub.2--C(O)--CH.sub.3.
[0150] As used herein, in the context of resin chemistry (e.g.
using solid resins or soluble resins or beads), the term "linker"
refers to a bifunctional chemical moiety attaching a compound to a
solid support or soluble support.
[0151] In all other situations, a "linker", as used herein, refers
to a divalent group in which the two free valences are on different
atoms (e.g. carbon or heteroatom) or are on the same atom but can
be substituted by two different substituents. For example, a
methylene group can be C.sub.1 alkyl linker (--CH.sub.2--) which
can be substituted by two different groups, one for each of the
free valences (e.g. as in Ph-CH.sub.2-Ph, wherein methylene acts as
a linker between two phenyl rings). Ethylene can be C2 alkyl linker
(--CH.sub.2CH.sub.2--) wherein the two free valences are on
different atoms. The amide group, for example, can act as a linker
when placed in an internal position of a chain (e.g. --CONH--). A
linker can be the result of interrupting an aliphatic chain by
certain functional groups or of replacing methylene units on said
chain by said functional groups. E.g. a linker can be a C.sub.1-6
aliphatic chain in which up to two methylene units are substituted
by --C(O)-- or --NH-- (as in
--CH.sub.2--NH--CH.sub.2--C(O)--CH.sub.2-- or
--CH.sub.2--NH--C(O)--CH.sub.2--). An alternative way to define the
same --CH.sub.2--NH--CH.sub.2--C(O)--CH.sub.2-- and
--CH.sub.2--NH--C(O)--CH.sub.2-- groups is as a C.sub.3 alkyl chain
optionally interrupted by up to two --C(O)-- or --NH-- moieties.
Cyclic groups can also form linkers: e.g. a 1,6-cyclohexanediyl can
be a linker between two R groups, as in
##STR00009##
A linker can additionally be optionally substituted in any portion
or position.
[0152] Divalent groups of the type R--CH.dbd. or R.sub.2C.dbd.,
wherein both free valences are in the same atom and are attached to
the same substituent, are also possible. In this case, they will be
referred to by their IUPAC accepted names. For instance an
alkylidene (such as, for example, a methylidene (.dbd.CH.sub.2) or
an ethylidene (.dbd.CH--CH.sub.3)) would not be encompassed by the
definition of a linker in this disclosure.
[0153] The term "protecting group", as used herein, refers to an
agent used to temporarily block one or more desired reactive sites
in a multifunctional compound. In certain embodiments, a protecting
group has one or more, or preferably all, of the following
characteristics: a) reacts selectively in good yield to give a
protected substrate that is stable to the reactions occurring at
one or more of the other reactive sites; and b) is selectively
removable in good yield by reagents that do not attack the
regenerated functional group. Exemplary protecting groups are
detailed in Greene, T. W. et al., "Protective Groups in Organic
Synthesis", Third Edition, John Wiley & Sons, New York: 1999,
the entire contents of which is hereby incorporated by reference.
The term "nitrogen protecting group", as used herein, refers to an
agents used to temporarily block one or more desired nitrogen
reactive sites in a multifunctional compound. Preferred nitrogen
protecting groups also possess the characteristics exemplified
above, and certain exemplary nitrogen protecting groups are
detailed in Chapter 7 in Greene, T. W., Wuts, P. G in "Protective
Groups in Organic Synthesis", Third Edition, John Wiley & Sons,
New York: 1999, the entire contents of which are hereby
incorporated by reference.
[0154] As used herein, the term "displaceable moiety" or "leaving
group" refers to a group that is associated with an aliphatic or
aromatic group as defined herein and is subject to being displaced
by nucleophilic attack by a nucleophile.
[0155] As used herein, "amide coupling agent" or "amide coupling
reagent" means a compound that reacts with the hydroxyl moiety of a
carboxy moiety thereby rendering it susceptible to nucleophilic
attack. Exemplary amide coupling agents include DIC
(diisopropylcarbodiimide), EDCI
(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC
(dicyclohexylcarbodiimide), BOP
(benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium
hexafluorophosphate), pyBOP
((benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate), etc.
[0156] The compounds of the invention are defined herein by their
chemical structures and/or chemical names. Where a compound is
referred to by both a chemical structure and a chemical name, and
the chemical structure and chemical name conflict, the chemical
structure is determinative of the compound's identity.
Compound embodiments
[0157] The present invention includes compounds of Formula I or
Formula Ib, or pharmaceutically acceptable salts thereof,
##STR00010##
[0158] In the compounds of Formula Ib: [0159] X is either carbon or
nitrogen; [0160] wherein either [0161] i) ring B is absent with
J.sup.B connected directly to the carbon atom bearing two J groups,
each J is independently selected from hydrogen, methyl or fluorine,
n is 1 and J.sup.B is a C.sub.1-6 alkyl chain optionally
substituted by up to 6 instances of fluorine; or [0162] ii) ring B
is a phenyl or a 5 or 6-membered heteroaryl ring, containing 1 or 2
ring heteroatoms selected from N, O or S; wherein with ring B being
the phenyl or 5 or 6-membered heteroaryl ring; each J is hydrogen;
n is an integer selected from 0 to 3; and each J.sup.B is
independently selected from halogen, --CN, a C.sub.1-6 aliphatic,
--OR.sup.B or a C.sub.3-8 cycloaliphatic group; wherein each said
C.sub.1-6 aliphatic and each said C.sub.3-8 cycloaliphatic group is
optionally and independently substituted with up to 3 instances of
R.sup.3; each R.sup.B is independently selected from hydrogen, a
C.sub.1-6 aliphatic or a C.sub.3-8 cycloaliphatic; wherein each
said C.sub.1-6 aliphatic and each said C.sub.3-8 cycloaliphatic
ring is optionally and independently substituted with up to 3
instances of R.sup.3a; [0163] each R.sup.3 is independently
selected from halogen, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); [0164] each
R.sup.3a is independently selected from halogen, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); [0165] o is an integer selected from 0 to 3; [0166]
each J.sup.D is independently selected from halogen, --CN,
--OR.sup.D, --SR.sup.S, --C(O)R.sup.D, --C(O)OR.sup.D,
--OC(O)R.sup.D, --C(O)N(R.sup.D).sub.2, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)R.sup.D, --N(R.sup.d)C(O)OR.sup.D,
--N(R.sup.d)C(O)N(R.sup.D).sub.2, --OC(O)N(R.sup.D).sub.2,
--SO.sub.2R.sup.D, --SO.sub.2N(R.sup.D).sub.2,
--N(R.sup.d)SO.sub.2R.sup.D, a C.sub.1-6 aliphatic, --(C.sub.1-6
aliphatic)-R.sup.D, a C.sub.3-8 cycloaliphatic ring, a 6 to
10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5
to 10-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocylic ring and each said 5 to 10-membered heteroaryl ring
contains between 1 and 3 heteroatoms independently selected from O,
N or S; and wherein each said C.sub.1-6 aliphatic, each said
C.sub.3-8 cycloaliphatic ring, each said 6 to 10-membered aryl
ring, each said 4 to 8-membered heterocyclic ring and each said 5
to 10-membered heteroaryl ring is optionally and independently
substituted with up to 3 instances of R.sup.5; [0167] each R.sup.D
is independently selected from hydrogen, a C.sub.1-6 aliphatic,
--(C.sub.1-6 aliphatic)-R.sup.f, a C.sub.3-8 cycloaliphatic ring, a
4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered
heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring
and each said 5 to 6-membered heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted with up to 3 instances of
R.sup.5a; [0168] each R.sup.d is independently selected from
hydrogen, a C.sub.1-6 aliphatic, (C.sub.1-6 aliphatic)-R.sup.f, a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.5b; [0169] each R.sup.f is independently selected from a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.3-8 cycloaliphatic ring, each said 4 to
8-membered heterocyclic ring, each said phenyl and each said 5 to
6-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.SO; [0170] when J.sup.D
is --C(O)N(R.sup.D).sup.2, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)N(R.sup.D).sup.2, --OC(O)N(R.sup.D).sub.2 or
--SO.sub.2N(R.sup.D).sub.2, the two R.sup.D groups together with
the nitrogen atom attached to the two R.sup.D groups may form a 4
to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S; and wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.5d; [0171] when J.sup.D is
--N(R.sup.d)C(O)R.sup.D the R.sup.D group together with the carbon
atom attached to the R.sup.D group, with the nitrogen atom attached
to the R.sup.d group, and with the R.sup.d group may form a 4 to
8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S, and wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.5d; [0172] when J.sup.D is
--N(R.sup.d)C(O)OR.sup.D or --N(R.sup.d)C(O)N(R.sup.D).sub.2, the
R.sup.D group together with the oxygen atom attached to the R.sup.D
group, with the carbon atom of the --C(O)-- portion of the
--N(R.sup.d)C(O)OR.sup.D group, with the nitrogen atom attached to
the R.sup.d group, or, alternatively one of the R.sup.D groups
attached to the nitrogen atom, together with said nitrogen atom,
and with the N atom attached to the R.sup.d group and said R.sup.d
group may form a 4 to 8-membered heterocyclic ring; wherein said 4
to 8-membered heterocyclic ring optionally contains up to 2
additional heteroatoms independently selected from N, O or S, and
is optionally and independently substituted by up to 3 instances of
R5'; [0173] when J.sup.D is --N(R.sup.d)SO.sub.2R.sup.D, the
R.sup.D group together with the sulfur atom attached to the R.sup.D
group, with the nitrogen atom attached to the R.sup.d group, and
with the R.sup.d group may combine to form a 4 to 8-membered
heterocyclic ring; wherein said 4 to 8-membered heterocyclic ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S, and is optionally and independently
substituted by up to 3 instances of R.sup.5d; [0174] each R.sup.5
is independently selected from halogen, --CN, C.sub.1-4 alkyl,
--(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl, C.sub.3-8
cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4haloalkyl); and wherein each
said C.sub.7-12 aralkyl, each said C.sub.1-4 alkyl chainand each
said C.sub.3-8 cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen;
[0175] each R.sup.5a is independently selected from halogen, --CN,
C.sub.1-4 alkyl, --(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6,
--SR.sup.6, --OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4alkyl) or
--O(C.sub.1-4haloalkyl); and wherein each said C.sub.7-12 aralkyl,
each said C.sub.1-4 alkyl chainand each said C.sub.3-8 cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen;
[0176] each R.sup.5b is independently selected from halogen, --CN,
C.sub.1-4 alkyl, --(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6,
--SR.sup.6, --OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4alkyl) or
--O(C.sub.1-4haloalkyl); and wherein each said C.sub.7-12 aralkyl,
each said C.sub.1-4 alkyl chain and each said C.sub.3-8 cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen;
[0177] each R.sup.5c is independently selected from halogen, --CN,
C.sub.1-4 alkyl, --(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6,
--SR.sup.6, --OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4alkyl) or
--O(C.sub.1-4haloalkyl); and wherein each said C.sub.7-12 aralkyl,
each said C.sub.1-4 alkyl chain and each said C.sub.3-8 cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen;
[0178] each R.sup.5d is independently selected from halogen, --CN,
C.sub.1-4 alkyl, --(C.sub.1-4 alkyl)-R.sup.6, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 cyanoalkyl, --OR.sup.6,
--SR.sup.6, --OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4alkyl) or
--O(C.sub.1-4haloalkyl); and wherein each said C.sub.7-12 aralkyl,
[0179] each said C.sub.1-4 alkyl chain and each said C.sub.3-8
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; [0180] each R.sup.6 is independently
selected from hydrogen, a C.sub.1-4 alkyl, a C.sub.2-4 alkenyl,
phenyl, a C.sub.7-12 aralkyl or a C.sub.3-8 cycloalkyl ring;
wherein each said C.sub.1-4 alkyl, each said C.sub.2-4 alkenyl,
each said phenyl, each said C.sub.7-12 aralkyl and each said
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; [0181] alternatively, two instances
of R.sup.6 linked to the same nitrogen atom of R.sup.5, R.sup.5a,
R.sup.5b, R.sup.5c or R.sup.5d, together with said nitrogen atom of
R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c or R.sup.5d, respectively,
may form a 5 to 8-membered heterocyclic ring or a 5-membered
heteroaryl ring; wherein each said 5 to 8-membered heterocyclic
ring and each said 5-membered heteroaryl ring optionally contains
up to 2 additional heteroatoms independently selected from N, O or
S; or [0182] alternatively, one instance of R.sup.6 linked to a
nitrogen atom of R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c or R.sup.5d
and one instance of R.sup.6 linked to a carbon or sulfur atom of
the same R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c or R.sup.5d,
respectively, together with said nitrogen and said carbon or sulfur
atom of the same R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c or R.sup.5d,
respectively, may form a 5 to 8-membered heterocyclic ring or a
5-membered heteroaryl ring; wherein each said 5 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S; [0183] alternatively, two J.sup.D groups
attached to two vicinal ring D atoms, taken together with said two
vicinal ring D atoms, form a 5 to 7-membered heterocycle or a
5-membered heteroaryl ring that is fused to ring D; wherein said 5
to 7-membered heterocycle or said 5-membered ring heteroaryl
contains from 1 to 3 heteroatoms independently selected from N, O
or S; and wherein said 5 to 7-membered heterocycle or said
5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of oxo or --(Y)--R.sup.9; [0184]
wherein Y is either absent or is a linkage in the form of a
C.sub.1-6 alkyl chain, optionally substituted by up to 6 instances
of fluoro; [0185] each R.sup.9 is independently selected from
hydrogen, --CN, --OR.sup.10 , --COR.sup.10 , --OC(O)R.sup.10 ,
--C(O)OR.sup.10, --C(O)N(R.sup.10).sup.2,
--C(O)N(R.sup.10)SO.sub.2R.sup.10, --N(R.sup.10)C(O)R.sup.10,
N(R.sup.10)C(O)OR.sup.10, --N(R.sup.10C(O)N(R.sup.10).sub.2,
--N(R.sup.10).sub.2, --SO.sub.2R.sup.10,
--SO.sub.2N(R.sup.10).sub.2, --SO.sub.2N(R.sup.10)COOR.sup.10,
--SO.sub.2N(R.sup.10)C(O)R.sup.10, --N(R.sup.10)SO.sub.2R.sup.10, a
C3-6 cycloalkyl ring, a 4-8-membered heterocyclic ring, a phenyl
ring or a 5-6 membered heteroaroaryl ring; wherein each said 4 to
8-membered heterocyclic ring or 5 to 6-membered heteroaryl ring
contains up to 4 ring heteroatoms independently selected from N, O
or S; and wherein each of said C.sub.3-6 cycloalkyl rings, each of
said 4 to 8-membered heterocyclic rings, each of said phenyl and
each of said 5 to 6-membered heteroaryl rings is optionally
substituted with up to 3 instances of R.sup.11a; [0186] wherein
each R.sup.10 is independently selected from hydrogen, a C.sub.1-6
alkyl, phenyl, benzyl, a C.sub.3-6 cycloalkyl ring, a 4 to
7-membered heterocyclic ring or a 5 or 6-membered heteroaryl ring,
wherein each 5 or 6-membered heteroaryl ring or 4 to 7-membered
heterocyclic ring contains up to 4 ring heteroatoms independently
selected from N, O and S; and wherein each of said C.sub.1-6 alkyl,
each said phenyl, each said benzyl, each said C.sub.3-8 cycloalkyl
group, each said 4 to 7-membered heterocyclic ring and each 5 or
6-membered heteroaryl ring is optionally and independently
substituted with up to 3 instances of R.sup.11b; [0187] each
R.sup.11a is independently selected from halogen, C.sub.1-6 alkyl,
--CN, --OR.sup.12, --COR.sup.12, --C(O)OR.sup.12,
--C(O)N(R.sup.12).sub.2, --N(R.sup.12)C(O)R.sup.12,
--N(R.sup.12)C(OR.sup.12, --N(R.sup.12)C(O)N(R.sup.12).sub.2,
--N(R.sup.12).sub.2, --SO.sub.2R.sup.12,
--SO.sub.2N(R.sup.12).sub.2 or --N(R.sup.12)SO.sub.2R.sup.12;
wherein each of said C.sub.1-6 alkyl is optionally and
independently substituted by up to 6 instances of fluoro, and/or 3
instances of R.sup.12; [0188] each R.sup.11b is independently
selected from halogen, C.sub.1-6 alkyl, --CN, --OR.sup.12,
--COR.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--N(R.sup.12)C(O)R.sup.12, --N(R.sup.12)C(O)OR.sup.12,
--N(R.sup.12)C(O)N(R.sup.12).sub.2, --N(R.sup.12).sub.2,
--SO.sub.2R.sup.12, --SO.sub.2N(R.sup.12).sub.2 or
--N(R.sup.12)SO.sub.2R.sup.12; wherein each of said C.sub.1-6 alkyl
is optionally and independently substituted by up to 6 instances of
fluoro and/or 3 instances of R.sup.12; [0189] each R.sup.12 is
selected from C.sub.1-4 alkyl, C.sub.1-4 (fluoroalkyl), --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--CN, --COOH, --COO(C.sub.1-4 alkyl), --O(C.sub.1-4 alkyl),
--O(C.sub.1-4 fluoroalkyl) or oxo; [0190] R.sup.C is either [0191]
i) a ring C; or [0192] ii) R.sup.C is selected from halogen, --CN,
C.sub.1-6 alkyl, --(C.sub.1-6 alkyl)-R.sup.N, --OR.sup.K,
--COR.sup.K, --OC(O)R.sup.K, --C(O)OR.sup.K,
--C(O)N(R.sup.K).sub.2, --N(R.sup.k)C(O)R.sup.K,
--N(R.sup.k)C(O)OR.sup.K, --N(R.sup.1)C(O)N(R.sup.K).sub.2,
--N(R.sup.K).sub.2, --SO.sub.2R.sup.K, --SO.sub.2N(R.sup.K).sub.2
or --N(R.sup.k)SO.sub.2R.sup.K; wherein said R.sup.C that is a
C.sub.1-6 alkyl is optionally and independently substituted with up
to 6 instances of fluoro and/or up to 3 instances of R.sup.7c1;
[0193] each R.sup.k is independently selected from hydrogen or a
C.sub.1-6 alkyl; [0194] each R.sup.K is independently selected from
hydrogen, a C.sub.1-6 alkyl, a phenyl ring, a monocyclic 5 or
6-membered heteroaryl ring, a monocyclic C3-6 cycloaliphatic ring,
or a monocyclic 4 to 6-membered heterocycle; wherein said
monocyclic 5 or 6-membered heteroaryl ring or said monocyclic 4 to
6-membered heterocycle contain between 1 and 4 heteroatoms selected
from N, O or S; wherein said monocyclic 5 or 6-membered heteroaryl
ring is not a 1,3,5-triazinyl ring; and wherein said phenyl, said
monocyclic 5 to 6-membered heteroaryl ring, said monocyclic C3-6
cycloaliphatic ring, or said monocyclic 4 to 6-membered heterocycle
is optionally and independently substituted with up to 6 instances
of fluoro and/or up to 3 instances of J.sup.M; and wherein each
R.sup.K that is a C.sub.1-6 alkyl is optionally and independently
substituted by up to 3 instances of R.sup.7d; [0195] each R.sup.N
is independently selected from a phenyl ring, a monocyclic 5 or
6-membered heteroaryl ring, a monocyclic C3-6 cycloaliphatic ring,
or a monocyclic 4 to 6-membered heterocycle; wherein said
monocyclic 5 or 6-membered heteroaryl ring or said monocyclic 4 to
6-membered heterocycle contain between 1 and 4 heteroatoms selected
from N, O or S; wherein said monocyclic 5 or 6-membered heteroaryl
ring is not a 1,3,5-triazinyl ring; and wherein said phenyl, said
monocyclic 5 to 6-membered heteroaryl ring, said monocyclic C3-6
cycloaliphatic ring, or said monocyclic 4 to 6-membered heterocycle
is optionally and independently substituted with up to 6 instances
of fluoro and/or up to 3 instances of J.sup.M; [0196] each J.sup.M
is independently selected from --CN, a C.sub.1-6 aliphatic,
--OR.sup.M, --SR.sup.M, --N(R.sup.M).sub.2, a C.sub.3-8
cycloaliphatic ring or a 4 to 8-membered heterocyclic ring; wherein
said 4 to 8-membered heterocyclic ring contains 1 or 2 heteroatoms
independently selected from N, O or S; wherein each said C.sub.1-6
aliphatic, each said C.sub.3-8 cycloaliphatic ring and each said 4
to 8-membered heterocyclic ring, is optionally and independently
substituted with up to 3 instances of R.sup.7c; [0197] each R.sup.M
is independently selected from hydrogen, a C.sub.1-6 aliphatic, a
C.sub.3-8 cycloaliphatic ring or a 4 to 8-membered heterocyclic
ring; wherein each said 4 to 8-membered heterocylic ring contains
between 1 and 3 heteroatoms independently selected from O, N or S;
and wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring and each said 4 to 8-membered heterocyclic
ring, is optionally and independently substituted with up to 3
instances of R.sup.7e; [0198] ring C is a phenyl ring, a monocyclic
5 or 6-membered heteroaryl ring, a bicyclic 8 to 10-membered
heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphatic ring,
or a monocyclic 4 to 10-membered heterocycle; wherein said
monocyclic 5 or 6-membered heteroaryl ring, said bicyclic 8 to
10-membered heteroaryl ring, or said monocyclic 4 to 10-membered
heterocycle contain between 1 and 4 heteroatoms selected from N, O
or S; wherein said monocyclic 5 or 6-membered heteroaryl ring is
not a 1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5
to 6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl
ring, monocyclic 3 to 10-membered cycloaliphatic ring, or
monocyclic 4 to 10-membered heterocycle is optionally and
independently substituted with up to 3 instances of J.sup.C; [0199]
each J.sup.C is independently selected from halogen, --CN,
--NO.sub.2, a C.sub.1-6 aliphatic, --OR.sup.H, --SR.sup.H,
--N(R.sup.H).sub.2, a C.sub.3-8 cycloaliphatic ring or a 4 to
8-membered heterocyclic ring; wherein said 4 to 8-membered
heterocyclic ring contains 1 or 2 heteroatoms independently
selected from N, O or S; wherein each said C.sub.1-6 aliphatic,
each said C.sub.3-8 cycloaliphatic ring and each said 4 to
8-membered heterocyclic ring, is optionally and independently
substituted with up to 3 instances of R.sup.7; or [0200]
alternatively, two J.sup.C groups attached to two vicinal ring C
atoms, taken together with said two vicinal ring C atoms, form a 5
to 7-membered heterocycle that is a new ring fused to ring C;
[0201] wherein said 5 to 7-membered heterocycle contains from 1 to
2 heteroatoms independently selected from N, O or S; [0202] each
R.sup.H is independently selected from hydrogen, a C.sub.1-6
aliphatic, a C.sub.3-8 cycloaliphatic ring or a 4 to 8-membered
heterocyclic ring ; wherein each said 4 to 8-membered heterocylic
ring contains between 1 and 3 heteroatoms independently selected
from O, N or S; and wherein each said C.sub.1-6 aliphatic, each
said C.sub.3-8 cycloaliphatic ring and each said 4 to 8-membered
heterocyclic ring, is optionally and independently substituted with
up to 3 instances of R.sup.7a; [0203] alternatively, two instances
of R.sup.H linked to the same nitrogen atom of --N(R.sup.H).sub.2,
together with said nitrogen atom of --N(R.sup.H).sub.2, form a 4 to
8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S, and wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring is optionally and independently substituted by up
to 3 instances of R.sup.7b; [0204] each R.sup.7 is independently
selected from halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.3-8 cycloalkyl ring, C.sub.3-8 (halocycloalkyl)
ring, --OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
[0205] each R.sup.7a is independently selected from halogen, --CN,
--NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8
cycloalkyl ring, C.sub.3-8 (halocycloalkyl) ring, --OR.sup.8,
--SR.sup.8, --N(R.sup.8).sub.2, or an oxo group; [0206] each
R.sup.7b is independently selected from halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
C.sub.3-8 (halocycloalkyl) ring, --OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, or an oxo group; [0207] each R.sup.7c is
independently selected from hydrogen, halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
wherein each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0208] each R.sup.7d
is independently selected from hydrogen, halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
wherein each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0209] each R.sup.7e
is independently selected from hydrogen, halogen, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-8 cycloalkyl ring,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, or an oxo group;
wherein each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0210] each R.sup.8
is independently selected from hydrogen, a C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl or a C.sub.3-8 cycloalkyl ring, C.sub.3-8
(halocycloalkyl) ringalternatively, two instances of R.sup.8 linked
to the same nitrogen atom of R.sup.7, R.sup.7a, R.sup.7b, R.sup.7c,
R.sup.7d or R.sup.7e, together with said nitrogen atom of R.sup.7,
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d or R.sup.7e form a 5 to
8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 5 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S; and [0211]
R.sup.A is selected from hydrogen, halogen, C.sub.1-4 alkyl or
C.sub.1-4 haloalkyl. [0212] In the compounds of Formula I: [0213]
ring B is a phenyl or a 5 or 6-membered heteroaryl ring, containing
1 or 2 ring heteroatoms selected from N, O or S; [0214] n is an
integer selected from 0 to 3; [0215] each J.sup.B is independently
selected from halogen, --CN, a C.sub.1-6 aliphatic, --OR.sup.B or a
C.sub.3-8 cycloaliphatic group; wherein each said C.sub.1-6
aliphatic and each said C.sub.3-8 cycloaliphatic group is
optionally and independently substituted with up to 3 instances of
R.sup.3; [0216] each R.sup.B is independently selected from
hydrogen, a C
.sub.1-6 aliphatic or a C.sub.3-8 cycloaliphatic; wherein each said
C.sub.1-6 aliphatic and each said C.sub.3-8 cycloaliphatic ring is
optionally and independently substituted with up to 3 instances of
R.sup.3a; [0217] each R.sup.3 is independently selected from
halogen, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4
alkyl) or --O(C.sub.1-4 haloalkyl); [0218] each R.sup.3a is
independently selected from halogen, --CN, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); [0219] o is an integer selected from 0 to 3; [0220]
each J.sup.D is independently selected from halogen, --NO.sub.2,
--OR.sup.D, --SR.sup.D, --C(O)R.sup.D, --C(O)OR.sup.D,
--C(O)N(R.sup.D).sub.2, --CN, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)R.sup.D, --N(R.sup.d)C(O)OR.sup.D,
--SO.sub.2R.sup.D, --SO.sub.2N(R.sup.D).sub.2,
--N(R.sup.d)SO.sub.2R.sup.D, a C.sub.1-6 aliphatic, (C.sub.1-6
aliphatic)-R.sup.D, a C.sub.3-8 cycloaliphatic ring, a 6 to
10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5
to 10-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocylic ring and each said 5 to 10-membered heteroaryl ring
contains between 1 and 3 heteroatoms independently selected from O,
N or S; and wherein each said C.sub.1-6 aliphatic, each said
C.sub.3-8 cycloaliphatic ring, each said 6 to 10-membered aryl
ring, each said 4 to 8-membered heterocyclic ring and each said 5
to 10-membered heteroaryl ring is optionally and independently
substituted with up to 3 instances of R.sup.5; [0221] each R.sup.D
is independently selected from hydrogen, a C.sub.1-6 aliphatic,
(C.sub.1-6 aliphatic)-R.sup.f, a C.sub.3-8 cycloaliphatic ring, a 4
to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered
heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring
and each said 5 to 6-membered heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted with up to 3 instances of
R.sup.5'; [0222] each R.sup.d is independently selected from
hydrogen, a C.sub.1-6 aliphatic, (C.sub.1-6 aliphatic)-R.sup.f, a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.1-6 aliphatic, each said C.sub.3-8
cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,
each said phenyl and each said 5 to 6-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.5b; [0223] each R.sup.f is independently selected from a
C.sub.3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring,
phenyl or a 5 to 6-membered heteroaryl ring; wherein each said
heterocylic ring and each said heteroaryl ring contains between 1
and 3 heteroatoms independently selected from O, N or S; and
wherein each said C.sub.3-8 cycloaliphatic ring, each said 4 to
8-membered heterocyclic ring, each said phenyl and each said 5 to
6-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5c; [0224] when J.sup.D
is --C(O)N(R.sup.D).sub.2, --N(R.sup.D).sub.2 or
--SO.sub.2N(R.sup.D).sub.2, the two R.sup.D groups together with
the nitrogen atom attached to the R.sup.D groups alternatively form
a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl
ring; wherein each said 4 to 8-membered heterocyclic ring and each
said 5-membered heteroaryl ring optionally contains up to 2
additional heteroatoms independently selected from N, O or S, and
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5; [0225] when J.sup.D is
--N(R.sup.d)C(O)R.sup.D, the R.sup.D group together with the carbon
atom attached to the R.sup.D group, with the nitrogen atom attached
to the R.sup.d group, and with the R.sup.d group alternatively form
a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl
ring; wherein each said 4 to 8-membered heterocyclic ring and each
said 5-membered heteroaryl ring optionally contains up to 2
additional heteroatoms independently selected from N, O or S, and
wherein each said 4 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of R.sup.5; [0226] when J.sup.D is
--N(R.sup.d)C(O)OR.sup.D, the R.sup.D group together with the
oxygen atom attached to the R.sup.D group, with the carbon atom of
the --C(O)-- portion of the --N(R.sup.d)C(O)OR.sup.D group, with
the nitrogen atom attached to the R.sup.d group, and with the
R.sup.d group alternatively form a 4 to 8-membered heterocyclic
ring or a 5-membered heteroaryl ring; wherein each said 4 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S, and wherein each said 4 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring is optionally and independently substituted by up to 3
instances of R.sup.5; [0227] when J.sup.D is
--N(R.sup.d)SO.sub.2R.sup.D, the R.sup.D group together with the
oxygen atom attached to the R.sup.D group, with the sulfur atom
attached to said oxygen atom in the --SO.sub.2R.sup.D portion of
the --N(R.sup.d)SO.sub.2R.sup.D group, with the nitrogen atom
attached to the R.sup.d group, and with the R.sup.d group
alternatively form a 4 to 8-membered heterocyclic ring or a
5-membered heteroaryl ring; wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring
optionally contains up to 2 additional heteroatoms independently
selected from N, O or S, and wherein each said 4 to 8-membered
heterocyclic ring and each said 5-membered heteroaryl ring is
optionally and independently substituted by up to 3 instances of
R.sup.5; [0228] each R.sup.5 is independently selected from
halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 haloalkyl, C.sub.1-4
cyanoalkyl, --OR.sup.6, --SR.sup.6, --OCOR.sup.6, --COR.sup.6,
--C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4
haloalkyl); and wherein each said C.sub.7-12 aralkyl and each said
cycloalkyl group is optionally and independently substituted with
up to 3 instances of halogen; [0229] each R.sup.5a is independently
selected from halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, a
C.sub.7-12 aralkyl, C.sub.3-8 cycloalkyl ring, C.sub.1-4 haloalkyl,
C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6, --OCOR.sup.6,
--COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
--O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); and wherein each
said C.sub.7-12 aralkyl and each said cycloalkyl group is
optionally and independently substituted with up to 3 instances of
halogen; [0230] each R.sup.5b is independently selected from
halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, a C.sub.7-12 aralkyl,
C.sub.3-8 cycloalkyl ring, C.sub.1-4 haloalkyl, C.sub.1-4
cyanoalkyl, --OR.sup.6, --SR.sup.6, --OCOR.sup.6, --COR.sup.6,
--C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2, --N(R.sup.6)C(O)R.sup.6,
--N(R.sup.6).sub.2, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--N(R.sup.6)SO.sub.2R.sup.6, phenyl or an oxo group; wherein each
said phenyl group is optionally and independently substituted with
up to 3 instances of halogen, --OH, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, O(C.sub.1-4 alkyl) or
O(C.sub.1-4haloalkyl); and wherein each said C.sub.7-12 aralkyl and
each said cycloalkyl group is optionally and independently
substituted with up to 3 instances of halogen; [0231] each R.sup.5c
is independently selected from halogen, --CN, --NO.sub.2, C.sub.1-4
alkyl, a C.sub.7-12 aralkyl, C.sub.3-8 cycloalkyl ring, C.sub.1-4
haloalkyl, C.sub.1-4 cyanoalkyl, --OR.sup.6, --SR.sup.6,
--OCOR.sup.6, --COR.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6).sub.2,
--N(R.sup.6)C(O)R.sup.6, --N(R.sup.6).sub.2, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --N(R.sup.6)SO.sub.2R.sup.6, phenyl or
an oxo group; wherein each said phenyl group is optionally and
independently substituted with up to 3 instances of halogen, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4
alkyl) or --O(C.sub.1-4haloalkyl); and wherein each said C.sub.7-12
aralkyl and each said cycloalkyl group is optionally and
independently substituted with up to 3 instances of halogen; [0232]
each R.sup.6 is independently selected from hydrogen, a C.sub.1-4
alkyl, a C.sub.2-4 alkenyl, phenyl, a C.sub.7-12 aralkyl or a
C.sub.3-8 cycloalkyl ring; wherein each said C.sub.1-4 alkyl, each
said C.sub.2-4 alkenyl, each said phenyl, each said C.sub.7-12
aralkyl and each said cycloalkyl group is optionally and
independently substituted with up to 3 instances of halogen; [0233]
alternatively, two instances of R.sup.6 linked to the same nitrogen
atom of R.sup.5, together with said nitrogen atom of R.sup.5, form
a 5 to 8-membered heterocyclic ring or a 5-membered heteroaryl
ring; wherein each said 5 to 8-membered heterocyclic ring and each
said 5-membered heteroaryl ring optionally contains up to 2
additional heteroatoms independently selected from N, O or S; or
[0234] alternatively, one instance of R.sup.6 linked to a nitrogen
atom of R.sup.5 and one instance of R.sup.6 linked to a carbon or
sulfur atom of the same R.sup.5, together with said nitrogen and
said carbon or sulfur atom of the same R.sup.5, form a 5 to
8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 5 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S;
[0235] or, alternatively, two J.sup.D groups attached to two
vicinal ring D atoms, taken together with said two vicinal ring D
atoms, form a 5 to 7-membered heterocycle resulting in a fused ring
D wherein said 5 to 7-membered heterocycle contains from 1 to 3
heteroatoms independently selected from N, O or S; and wherein said
5 to 7-membered heterocycle is optionally and independently
substituted by up to 3 instances of halogen, --OH, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, --O(C.sub.1-4 alkyl), --O(C.sub.1-4
haloalkyl), oxo or phenyl; wherein said phenyl is optionally and
independently substituted by up to three instances of halogen,
--OH, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, --NO.sub.2, --CN, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, --O(C.sub.1-4 alkyl) or --O(C.sub.1-4 haloalkyl); [0236]
R.sup.C is a ring C; ring C is a phenyl ring, a monocyclic 5 or
6-membered heteroaryl ring, a bicyclic 8 to 10-membered heteroaryl
ring, a monocyclic 3 to 10-membered cycloaliphatic ring, or a
monocyclic 4 to 10-membered heterocycle; wherein said monocyclic 5
or 6-membered heteroaryl ring, said bicyclic 8 to 10-membered
heteroaryl ring, or said monocyclic 4 to 10-membered heterocycle
contain between 1 and 4 heteroatoms selected from N, O or S;
wherein said monocyclic 5 or 6-membered heteroaryl ring is not a
1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5 to
6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl
ring, monocyclic 3 to 10-membered cycloaliphatic ring, or
monocyclic 4 to 10-membered heterocycle is optionally and
independently substituted with up to 3 instances of J.sup.C; [0237]
each J.sup.C is independently selected from halogen, --CN,
--NO.sub.2, a C.sub.1-6 aliphatic, --OR.sup.H, --SR.sup.H,
--N(R.sup.H).sub.2, a C.sub.3-8 cycloaliphatic ring or a 4 to
8-membered heterocyclic ring; wherein said 4 to 8-membered
heterocyclic ring contains 1 or 2 heteroatoms independently
selected from N, O or S; wherein each said C.sub.1-6 aliphatic,
each said C.sub.3-8 cycloaliphatic ring and each said 4 to
8-membered heterocyclic ring, is optionally and independently
substituted with up to 3 instances of R.sup.7; or alternatively,
two J.sup.C groups attached to two vicinal ring C atoms, taken
together with said two vicinal ring C atoms, form a 5 to 7-membered
heterocycle resulting in a fused ring C; wherein said 5 to
7-membered heterocycle contains from 1 to 2 heteroatoms
independently selected from N, O or S; [0238] each R.sup.H is
independently selected from hydrogen, a C.sub.1-6 aliphatic, a
C.sub.3-8 cycloaliphatic ring or a 4 to 8-membered heterocyclic
ring,; wherein each said 4 to 8-membered heterocylic ring contains
between 1 and 3 heteroatoms independently selected from O, N or S;
and wherein [0239] each said C.sub.1-6 aliphatic, each said
C.sub.3-8 cycloaliphatic ring, each said 4 to 8-membered
heterocyclic ring, is optionally and independently substituted with
up to 3 instances of R.sup.7a; [0240] alternatively, two instances
of R.sup.H linked to the same nitrogen atom of J.sup.C, together
with said nitrogen atom of J.sup.C, form a 4 to 8-membered
heterocyclic ring or a 5-membered heteroaryl ring; wherein each
said 4 to 8-membered heterocyclic ring and each said 5-membered
heteroaryl ring optionally contains up to 2 additional heteroatoms
independently selected from N, O or S, and wherein each said 4 to
8-membered heterocyclic ring and each said 5-membered heteroaryl
ring is optionally and independently substituted by up to 3
instances of R.sup.7b; [0241] each R.sup.7 is independently
selected from halogen, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.3-8 cycloalkyl ring, --OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, or an oxo group; wherein each said cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen; [0242] each R.sup.7a is independently
selected from halogen, CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.3-8 cycloalkyl ring, OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, or an oxo group; wherein each said cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen; [0243] each R.sup.7b is independently
selected from halogen, CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.3-8 cycloalkyl ring, OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, or an oxo group; wherein each said cycloalkyl
group is optionally and independently substituted with up to 3
instances of halogen; [0244] each R.sup.8 is independently selected
from hydrogen, a C.sub.1-4 alkyl, C.sub.1-4 haloalkyl or a
C.sub.3-8 cycloalkyl ring; wherein each said cycloalkyl group is
optionally and independently substituted with up to 3 instances of
halogen; [0245] alternatively, two instances of R.sup.8 linked to
the same nitrogen atom of R.sup.7, R.sup.7a or R.sup.7b, together
with said nitrogen atom of R.sup.7, R.sup.7a or R.sup.7b, form a 5
to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;
wherein each said 5 to 8-membered heterocyclic ring and each said
5-membered heteroaryl ring optionally contains up to 2 additional
heteroatoms independently selected from N, O or S; and [0246]
R.sup.A is selected from hydrogen, halogen, C.sub.1-4 alkyl or
C.sub.1-4 haloalkyl.
[0247] In some of the embodiments of the compounds of Formula Ib,
or pharmaceutically acceptable salts thereof, ring B is absent. In
some of the embodiments, R.sup.A is hydrogen.
[0248] In some of the embodiments of the compounds of Formula Ib,
or pharmaceutically acceptable salts thereof, the compounds are
represented by Formula IIb:
##STR00011##
wherein each instance of Z is independently selected from fluorine
or hydrogen; the (CZ.sub.2).sub.1-5 group is linked to the
3-positon of the pyrazolyl group via a terminal carbon atom with a
single bond; each of the CZ.sub.2 in the (CZ.sub.2).sub.1-5 group
is linked to the adjacent CZ.sub.2 or CZ.sub.3 groups via a single
bond attached to the adjacent carbon atoms; and the CZ.sub.3 group
is linked to the adjacent CZ.sub.2 group via a single bond attached
to the adjacent carbon atoms.
[0249] In some of the embodiments of the compounds of Formula IIb,
or pharmaceuticaly acceptable salts thereof, up to 5 instances of Z
are fluorine and the remaining instances of Z are hydrogen. In some
of these embodiments, R.sup.A is hydrogen.
[0250] In some of the embodiments of the compounds of Formula Ib or
IIb, or pharmaceutically acceptable salts thereof, R.sup.C is not a
ring. In some of these embodiments, or pharmaceutically acceptable
salts thereof, R.sup.C can be selected from halogen, --CN,
C.sub.1-6 alkyl, --(C.sub.1-6 alkyl)-R.sup.N, --OR.sup.K,
--COR.sup.K, --C(O)OR.sup.K, --C(O)N(R.sup.K).sub.2,
--N(R.sup.k)C(O)R.sup.K, --N(R.sup.k)C(O)OR.sup.K,
--N(R.sup.k)C(O)N(R.sup.K).sub.2, --N(R.sup.K).sub.2,
--SO.sub.2R.sup.K, --SO.sub.2N(R.sup.K).sub.2, or
--N(R.sup.k)SO.sub.2R.sup.K; wherein when said R.sup.C is a
C.sub.1-6 alkyl, the C.sub.1-6 alkyl is optionally and
independently substituted with up to 6 instances of fluoro and/or
up to 2 instances of R.sup.7c. In some of these embodiments, or
pharmaceutically acceptable salts thereof, R.sup.C can be --CN,
C.sub.1-6 alkyl, --COR.sup.K, --C(O)OR.sup.K,
--C(O)N(R.sup.K).sub.2, --N(R.sup.K).sub.2, --SO.sub.2R.sup.7K, or
--SO.sub.2N(R.sup.K).sub.2; wherein when said R.sup.C is a
C.sub.1-6 alkyl, the C.sub.1-6 alkyl is optionally and
independently substituted with up to 6 instances of fluoro and/or
up to 2 instances of R.sup.7c. In some of these embodiments, or
pharmaceutically acceptable salts thereof, R.sup.C can be
--COR.sup.K, --C(O)OR.sup.K, --C(O)N(R.sup.K).sub.2,
--N(R.sup.K).sub.2, --SO.sub.2R.sup.K or
--SO.sub.2N(R.sup.K).sub.2.
[0251] In some of the embodiments of the compounds of Formula Ib or
IIb, or pharmaceutically acceptable salts thereof, R.sup.c is ring
C. In some of these compounds, or the pharmaceutically acceptable
salts thereof, ring C is a phenyl, a monocyclic 5 or 6-membered
heteroaryl ring, a monocyclic C3-6 cycloaliphatic ring or a
monocyclic 4 to 6-membered heterocycle; each of the phenyl,
monocyclic 5 or 6-membered heteroaryl ring, monocyclic C.sub.3-6
cycloaliphatic ring or monocyclic 4 to 6-membered heterocycle is
optionally and independently substituted with up to 3 instances of
f. Ring C can also be a 5 or 6-membered heteroaryl ring, optionally
substituted with up to 2 instances of f, or ring C can be
unsubstituted. For instance, Ring C can be thienyl, thiazolyl,
oxadiazolyl, oxazolyl, isoxazolyl, tetrazolyl, pyrrolyl, triazolyl,
furanyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, which
can be unsubstituted or substituted. Ring C can also be
unsubstituted or substituted oxazolyl or unsubstituted
isoxazolyl.
[0252] In some of the embodiments of the compounds of Formula Ib or
IIb, or pharmaceutically acceptable salts thereof, the compounds
are represented by Formula IIIb:
##STR00012##
wherein each instance of Z is independently selected from fluorine
or hydrogen; the (CZ.sub.2).sub.1-5 group is linked to the
3-positon of the pyrazolyl group via a terminal carbon atom with a
single bond; each of the CZ.sub.2 in the (CZ.sub.2).sub.1-5 group
is linked to the adjacent CZ.sub.2 or CZ.sub.3 groups via a single
bond attached to the carbon atom; and the CZ.sub.3 group is linked
to the adjacent CZ.sub.2 via a single bond attached to the carbon
atom; [0253] the circle with a letter C in the middle represents
ring C; [0254] when X is N, the moiety --N(R.sup.1)(R.sup.2) is
absent, [0255] when X is C, the moiety --N(R.sup.1)(R.sup.2) is
present, [0256] J.sup.A is selected from hydrogen, halogen, methyl,
methoxy, trifluoromethyl, trifluoromethoxy or --NR.sup.aR.sup.b,
wherein R.sup.a and R.sup.b are each independently selected from
hydrogen, C.sub.1-6 alkyl or a 3-6 cycloalkyl ring; or wherein
R.sup.a and R.sup.b together with the N atom to which they are
attached form a 4 to 6-membered heterocyclic ring; [0257] J.sup.D
is selected from hydrogen, halogen, --CN, --CF.sub.3, methoxy,
trifluoromethoxy or methyl; [0258] R.sup.1 and R.sup.2, together
with the nitrogen atom to which they are attached, form a 4 to
8-membered heterocyclic ring or 5 or 6-membered heteroaryl ring;
wherein said 4 to 8-membered heterocyclic ring or 5 or 6-membered
heteroaryl ring optionally contains in addition to the nitrogen
atom up to 3 ring heteroatoms independently selected from N, O or
S, and is optionally substituted by up to 5 instances of R.sup.5e;
or [0259] alternatively, R.sup.1 and R.sup.2 are each independently
selected from hydrogen, C.sub.1-6 alkyl, a C.sub.3-8 cycloalkyl
ring, a 4 to 8-membered heterocyclic ring, a 5 or 6-membered
heteroaryl or a C.sub.1-6 alkyl-R.sup.Y; wherein each of said 4 to
8-membered heterocyclic ring and each of said 5 or 6-membered
heteroaryl ring contains up to 3 ring heteroatoms independently
selected from N, O and S; and wherein each of said C.sub.1-6 alkyl,
C.sub.3-8 cycloalkyl ring, 4 to 8-membered heterocyclic ring group,
5 or 6-membered heteroaryl and C.sub.1-6 alkyl-R.sup.Y is
optionally and independently substituted with up to 5 instances of
R.sup.5f; provided that R.sup.1 and R.sup.2 are never
simultaneously hydrogen; or [0260] alternatively, when R.sup.1 and
R.sup.2 attached to the nitrogen atom form the 4 to 8-membered
heterocyclic ring or 5 or 6-membered heteroaryl ring substituted
with up to 5 instances of R.sup.5e, two of the instances of
R.sup.5e attached to the same or different atoms of said ring,
together with said atom or atoms, optionally form a C.sub.3-8
cycloalkyl ring, a 4 to 6-membered heterocyclic ring; a phenyl or a
5 or 6-membered heteroaryl ring, resulting in a bicyclic system
wherein the two rings of the bicyclic system are in a spiro, fused
or bridged relationship, wherein said 4 to 6-membered heterocycle
or said 5 or 6-membered heteroaryl ring contains up to three ring
heteroatoms independently selected from N, O or S; and wherein said
C.sub.3-8 cycloalkyl ring, 4 to 6-membered heterocyclic ring,
phenyl or 5 or 6-membered heteroaryl ring is optionally and
independently substituted by up to 3 instances of C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, oxo,
--C(O)O(C.sub.1-4alkyl), --C(O)OH, --NR(CO)CO(C.sub.1-4 alkyl),
--OH or halogen; wherein R is hydrogen or a C.sub.1-2 alkyl; [0261]
R.sup.Y is selected from a C.sub.3-8 cycloalkyl ring, a 4 to
8-membered heterocyclic ring, phenyl, or a 5 to 6-membered
heteroaromatic ring; wherein each of said 4 to 8-membered
heterocyclic ring or 5 to 6-membered heteroaromatic ring contains
up to 4 ring heteroatoms independently selected from N, O or S; and
wherein each of said C.sub.3-8 cycloalkyl ring, each of said 4 to
8-membered heterocyclic ring, each of said phenyl, and each of said
5 to 6-membered heteroaromatic ring is optionally substituted with
up to 5 instances of R.sup.5g; or [0262] alternatively, when one of
R.sup.1 or R.sup.2 is the C.sub.3-8 cycloalkyl ring, 4 to
8-membered heterocyclic ring or 5 or 6-membered heteroaryl
substituted with up to 5 instances of R.sup.5f, two of the
instances of R.sup.5f attached to the same or different ring atoms
of said R.sup.1 or R.sup.2, together with said atom or atoms, form
a C.sub.3-8 cycloalkyl ring, a 4 to 6-membered heterocyclic ring, a
phenyl or a 5 or 6-membered heterocyclic ring, resulting in a
bicyclic system wherein the two rings are in a spiro, fused or
bridged relationship, wherein said 4 to 6-membered heterocycle or
said 5 or 6-membered heterocyclic ring contains up to two ring
heteroatoms independently selected from N, O or S; and wherein said
C.sub.3-8 cycloalkyl ring, 4 to 6-membered heterocyclic ring,
phenyl or 5 or 6-membered heterocyclic ring is optionally
substituted by up to 2 instances of C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, oxo, --(CO)CO(C.sub.1-4 alkyl), --NR'(CO)CO(C.sub.1-4
alkyl) or halogen; wherein R' is hydrogen or a C.sub.1-2 alkyl;
[0263] each R.sup.5e is independently selected from halogen, --CN,
C.sub.1-6 alkyl, --OR.sup.6a, --SR.sup.6a, --COR.sup.6a,
--OC(O)R.sup.6a, --C(O)OR.sup.6a, --C(O)N(R.sup.6a).sub.2,
--C(O)N(R.sup.6a)SO.sub.2R.sup.6a, --N(R.sup.6a)C(O)R.sup.6a,
--N(R.sup.6a)C(O)OR.sup.6a, --N(R.sup.6a)C(O)N(R.sup.6a).sub.2,
--N(R.sup.6a).sup.2, --SO.sub.2R.sup.6a,
--SO.sub.2N(R.sup.6a).sub.2, --SO.sub.2N(R.sup.6a)COOR.sup.6a,
--SO.sub.2N(R.sup.6a)C(O)R.sup.6a, --N(R.sup.6a)SO.sub.2R.sup.6a, a
C.sub.3-8 cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5
or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group or a
bicyclic group; wherein each 5 or 6-membered heteroaryl ring or 4
to 7-membered heterocyclic ring contains up to 4 ring heteroatoms
independently selected from N, O and S, wherein each of said
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl ring, 4 to 7-membered
heterocyclic ring, 5 or 6-membered heteroaryl ring, benzyl or
phenyl group is optionally and independently substituted with up to
3 instances of halogen, C.sub.1-4 alkyl, --OH, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN, --COOH,
--COO(C.sub.1-4 alkyl), --O(C.sub.1-4 alkyl), --O(C.sub.1-4
haloalkyl) or oxo; wherein said bicyclic group contains ring one
and ring two in a fused or bridged relationship, said ring one is a
4 to 7-membered heterocyclic ring, a 5 or 6-membered heteroaryl
ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5
or 6-membered heteroaryl ring containing up to 3 ring heteroatoms
selected from N, O or S; and wherein said bicyclic group is
optionally and independently substituted by up to six instances of
halogen, C.sub.1-4 alkyl, --OH, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, --CN, --COOH, --COO(C.sub.1-4 alkyl),
--O(C.sub.1-4 alkyl), --O(C.sub.1-4 haloalkyl) or oxo; [0264] each
R.sup.5f is independently selected from halogen, --CN, C.sub.1-6
alkyl, --OR', --SR.sup.6a, --COR.sup.6a, --OC(O)R.sup.6a,
--C(O)OR.sup.6a, --C(O)N(R.sup.6a).sub.2,
--C(O)N(R.sup.6a)SO.sub.2R.sup.6a, --N(R.sup.6a)C(O)R.sup.6a,
--N(R.sup.6a)C(O)OR.sup.6a, --N(R.sup.6a)C(O)N(R.sup.6a).sub.2,
--N(R.sup.6a).sub.2, --SO.sub.2R.sup.6a,
--SO.sub.2N(R.sup.6a).sub.2, --SO.sub.2N(R.sup.6a)COOR.sup.6a,
--SO.sub.2N(R.sup.6a)C(O)R.sup.6a, --N(R.sup.6a)SO.sub.2R.sup.6a, a
C.sub.3-8 cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5
or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group or a
bicyclic group; wherein each 5 or 6-membered heteroaryl ring or 4
to 7-membered heterocyclic ring contains up to 4 ring heteroatoms
independently selected from N, O and S, wherein each of said
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl ring, 4 to 7-membered
heterocyclic ring, 5 or 6-membered heteroaryl ring, benzyl or
phenyl group is optionally and independently substituted with up to
3 instances of halogen, C.sub.1-4 alkyl, --OH, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN, --COOH,
--COO(C.sub.1-4 alkyl), --O(C.sub.1-4 alkyl), --O(C.sub.1-4
haloalkyl) or oxo; wherein said bicyclic group contains ring one
and ring two in a fused or bridged relationship, said ring one is a
4 to 7-membered heterocyclic ring, a 5 or 6-membered heteroaryl
ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5
or 6-membered heteroaryl ring containing up to 3 ring heteroatoms
selected from N, O or S; and wherein said bicyclic group is
optionally and independently substituted by up to six instances of
halogen, C.sub.1-4 alkyl, OH, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, --CN, --COOH, --COO(C.sub.1-4 alkyl),
--O(C.sub.1-4 alkyl), --O(C.sub.1-4 haloalkyl) or oxo; [0265] each
R.sup.6a is independently selected from hydrogen, a C.sub.1-6
alkyl, phenyl, benzyl, a C.sub.3-8 cycloalkyl ring, a 4 to
7-membered heterocyclic ring or a 5 or 6-membered heteroaryl ring,
wherein each of said C.sub.1-6 alkyl, each of said phenyl, each of
said benzyl, each of said C.sub.3-8 cycloalkyl group, each of said
4 to 7-membered heterocyclic ring and each of said 5 or 6-membered
heteroaryl ring is optionally and independently substituted with up
to 3 instances of halogen, C.sub.1-4 alkyl, --OH, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN, --COOH,
--COO(C.sub.1-4alkyl), --O(C.sub.1-4 alkyl), --O(C.sub.1-4
haloalkyl) or oxo, wherein each of said 5 or 6-membered heteroaryl
ring or 4 to 7-membered heterocyclic ring contains up to 4 ring
heteroatoms independently selected from N, O and S; or [0266] each
R.sup.5g is independently selected from halogen, --CN, C.sub.1-6
alkyl, --OR.sup.6b, --SR.sup.6b, --COR.sup.6b, --OC(O)R.sup.6b,
--C(O)OR.sup.6b, --C(O)N(R.sup.6b).sub.2,
--C(O)N(R.sup.6b)SO.sub.2R.sup.6b, --N(R.sup.6b)C(O)R.sup.6b,
--N(R.sup.6b)C(O)OR.sup.6b, --N(R.sup.6b)C(O)N(R.sup.6b).sub.2,
--N(R.sup.6b).sub.2, --SO.sub.2R.sup.6b,
--SO.sub.2N(R.sup.6b).sub.2, --SO.sub.2N(R.sup.6b)COOR.sup.6b,
--SO.sub.2N(R.sup.6b)C(O)R.sup.6b, --N(R.sup.6a)SO.sub.2R.sup.6b, a
C.sub.3-8 cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5
or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group or a
bicyclic group; wherein each of said 5 or 6-membered heteroaryl
ring or 4 to 7-membered heterocyclic ring contains up to 4 ring
heteroatoms independently selected from N, O and S; and wherein
each of said C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl ring, 4 to
7-membered heterocyclic ring, 5 or 6-membered heteroaryl ring,
benzyl or phenyl group is optionally and independently substituted
with up to 3 instances of halogen, C.sub.1-4 alkyl, --OH,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--CN, --COOH, --COO(C.sub.1-4 alkyl), --O(C.sub.1-4 alkyl),
--O(C.sub.1-4 haloalkyl) or oxo; wherein said bicyclic group
contains ring one and ring two in a fused or bridged relationship,
said ring one is a 4 to 7-membered heterocyclic ring, a 5 or
6-membered heteroaryl ring, phenyl or benzyl, and said ring two is
a phenyl ring or a 5 or 6-membered heteroaryl ring containing up to
3 ring heteroatoms selected from N, O or S; and wherein said
bicyclic group is optionally and independently substituted by up to
six instances of halogen, C.sub.1-4 alkyl, --OH, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN, --COOH,
--COO(C.sub.1-4 alkyl), --O(C.sub.1-4 alkyl), --O(C.sub.1-4
haloalkyl) or oxo; [0267] each R.sup.6b is independently selected
from hydrogen, a C.sub.1-6 alkyl, phenyl, benzyl, a C.sub.3-8
cycloalkyl ring or a 4 to 7-membered heterocyclic ring, a 5 or
6-membered heteroaryl ring; wherein each of said 5 or 6-membered
heteroaryl ring or 4 to 7-membered heterocyclic ring contains up to
4 ring heteroatoms independently selected from N, O and S; and
wherein each of said C.sub.1-6 alkyl, each of said phenyl, each of
said benzyl, each of said C.sub.3-8 cycloalkyl group, each of said
4 to 7-membered heterocyclic ring and each of said 5 or 6-membered
heteroaryl ring is optionally and independently substituted with up
to 3 instances of halogen, C.sub.1-4 alkyl, --OH, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, --CN, --COOH,
--COO(C.sub.1-4alkyl), --O(C.sub.1-4 alkyl), --O(C.sub.1-4
haloalkyl) or oxo; or [0268] alternatively, two instances of
R.sup.5g attached to the same or different ring atoms of R.sup.Y,
together with said ring atom or atoms, form a C.sub.3-8 cycloalkyl
ring, a 4 to 6-membered heterocyclic ring; a phenyl or a 5 or
6-membered heteroaryl ring, resulting in a bicyclic system wherein
the two rings are in a spiro, fused or bridged relationship,
wherein said 4 to 6-membered heterocycle or said 5 or 6-membered
heteroaryl ring contains up to three heteroatoms independently
selected from N, O or S; and wherein said C.sub.3-8 cycloalkyl
ring, 4 to 6-membered heterocyclic ring, phenyl or a 5 or
6-membered heteroaryl ring is optionally and independently
substituted by up to 3 instances of C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, oxo,
--C(O)O(C.sub.1-4alkyl), --C(O)OH, --NR''(CO)CO(C.sub.1-4 alkyl),
--OH or halogen; and [0269] R'' is hydrogen or a C.sub.1-2
alkyl.
[0270] In some of the compounds of Formula IIIb, or
pharmaceutically acceptable salts thereof, J.sup.A and J.sup.D,
together with the two vicinal ring D atoms to which they are
attached, form a 5 to 7-membered heterocycle fused to ring D,
wherein said 5 to 7-membered heterocycle contains from 1 to 3
heteroatoms independently selected from N, O or S; and wherein said
5 to 7-membered heterocycle is optionally and independently
substituted by up to 3 instances of oxo or --(Y)--R.sup.9.
[0271] In some of the embodiments of the compounds of Formula IIIb,
or pharmaceutically acceptable salts thereof, the compounds are
represented by Formula IVb
##STR00013##
In some of these compounds, or pharmaceutically acceptable salts
thereof, J.sup.A is hydrogen and J.sup.D is fluoro. In some of
these compounds, or pharmaceutically acceptable salts thereof, ring
C is unsubstituted oxazole or unsubstituted isoxazole. In some of
these compounds, or pharmaceutically acceptable salts thereof,
J.sup.A and J.sup.D, together with the two vicinal ring D atoms to
which they are attached, form a 5 to 7-membered heterocycle fused
to ring D, wherein said 5 to 7-membered heterocycle contains from 1
to 3 heteroatoms independently selected from N, O or S; and wherein
said 5 to 7-membered heterocycle is optionally and independently
substituted by up to 3 instances of oxo or (Y)R.sup.9.
[0272] In some of the compounds of Formula IVb, or pharmaceutically
acceptable salts thereof, the compounds can be compounds
represented by Formula Vb:
##STR00014##
In some of these compounds, or pharmaceutically acceptable salts
thereof, J.sup.A is hydrogen and J.sup.D is fluoro. In some of
these compounds, or pharmaceutically acceptable salts thereof, ring
C is unsubstituted oxazole or unsubstituted isoxazole. In some of
these compounds, or pharmaceutically acceptable salts thereof,
J.sup.A and J.sup.D, together with the two vicinal ring D atoms to
which they are attached, form a 5 to 7-membered heterocycle fused
to ring D, wherein said 5 to 7-membered heterocycle contains from 1
to 3 heteroatoms independently selected from N, O or S; and wherein
said 5 to 7-membered heterocycle is optionally and independently
substituted by up to 3 instances of oxo or --(Y)--R.sup.9.
[0273] In some of the compounds of Formula IIIb, or
pharmaceutically acceptable salts thereof, X is carbon, J.sup.A is
hydrogen and J.sup.D is fluoro. In some of these compounds, or
pharmaceutically acceptable salts thereof, ring C is unsubstituted
oxazole or unsubstituted isoxazole. In some of these compounds, or
pharmaceutically acceptable salts thereof, J.sup.A and J.sup.D,
together with the two vicinal ring D atoms to which they are
attached, form a 5 to 7-membered heterocycle fused to ring D,
wherein said 5 to 7-membered heterocycle contains from 1 to 3
heteroatoms independently selected from N, O or S; and wherein said
5 to 7-membered heterocycle is optionally and independently
substituted by up to 3 instances of oxo or --(Y)--R.sup.9.
In some of the embodiments of the compounds of Formula Ib or IIb,
or pharmaceutically acceptable salts thereof, R.sup.C is not a ring
and X is carbon.
[0274] In some of the embodiments of the compounds of Formula IIIb,
or pharmaceutically acceptable salts thereof, the compounds are
represented by one of Formulae VIb, VIIb, VIc or VIId:
##STR00015##
wherein, ring E is a 5 or 6-membered heterocyclic ring, containing
up to 3 heteroatoms selected from N, O and S; and wherein each
J.sup.6 is independently selected from oxo or --(Y)--R.sup.9. In
some of these compounds, or pharmaceutically acceptable salts
thereof, J.sup.A is --NH.sub.2, --OH, or hydrogen. In some of these
compounds, or pharmaceutically acceptable salts thereof, ring E is
a heterocyclic ring containing one nitrogen ring atom and wherein
at least one instance of J.sup.6 is oxo. In some of the
embodiments, one J.sup.6 is oxo and the other two instances of
J.sup.6 are independently selected from --(Y)--R.sup.9.
[0275] In some embodiments of the compounds of Formula I or Formula
Ib, ring B is phenyl or a 6-membered heteroaryl ring. In some
embodiments, said phenyl or 6-membered heteroaryl ring is
unsubstituted and n=0. In other embodiments, ring B is substituted
phenyl, pyridine or pyrimidine, and n is an integer selected
between 1 and 3.
[0276] In some embodiments of the compounds of Formula I or Formula
Ib wherein ring B is substituted phenyl, pyridine or pyrimidine,
each J.sup.B is independently selected from halogen, a C.sub.1-6
aliphatic or --OR.sup.B. In some embodiments, each J.sup.B is
independently selected from a halogen atom. In some embodiments,
when J.sup.B is independently selected from a halogen atom, each
J.sup.B can be independently selected from fluoro or chloro, or
each J.sup.B is fluoro. In other embodiments, each J.sup.B is
independently selected from a C.sub.1-6 aliphatic. In some
embodiments, each J.sup.B is methyl or ethyl. In other embodiments,
each J.sup.B is methyl. In still other embodiments of the compounds
of Formula I or Formula Ib, wherein ring B is substituted phenyl,
pyridine or pyrimidine, each J.sup.B is independently selected from
--OR.sup.B; wherein each R.sup.B is hydrogen or a C.sub.1-6 alkyl.
In some embodiments, each R.sup.B is methyl, ethyl, propyl or
isopropyl.
[0277] In some of the above embodiments, wherein ring B is
substituted phenyl, pyridine or pyrimidine, n is 1 or 2 and each
J.sup.B is independently selected from fluoro, chloro, methyl or
methoxy. In other embodiments of Formula I and Formula Ib, ring B
is a 6-membered heteroaryl ring. In some embodiments, n=0 and the
6-membered heteroaryl ring in unsubstituted. In other embodiments,
ring B is a substituted pyridyl ring and n is an integer selected
between 1 and 3. In other embodiments, ring B is a substituted
pyrimidinyl ring and n is selected between 1 and 3. In some of the
above embodiments, wherein ring B is substituted pyridine or
pyrimidine, n is 1 or 2 and each J.sup.B is independently selected
from fluoro, chloro, methyl or methoxy.
[0278] In some embodiments of the compounds of Formula I or Formula
Ib, at least one J.sup.B is ortho to the attachment of the
methylene linker between ring B and the pyrazolyl ring. In some
embodiments, said ortho J.sup.B is independently selected from a
halogen atom. In other embodiments, said ortho J.sup.B is selected
from fluoro or chloro. In further embodiments, said ortho J.sup.B
is fluoro.
[0279] In other embodiments of the compounds of Formula I or
Formula Ib, ring B is thiophene. In some embodiments, said
thiophene ring is a 3-thiophenyl ring. In other embodiments it is a
2-thiophenyl ring. In some embodiments, said thiophene ring is
unsubstituted and n=0. In other embodiments, said thiophene is
substituted and n is an integer selected from 1, 2 or 3.
[0280] In some embodiments of the compounds of Formula I or Formula
Ib wherein ring B is substituted thiophene, each J.sup.B is
independently selected from halogen, a C.sub.1-6 aliphatic or
OR.sup.B. In other embodiments, each J.sup.B is independently
selected from a halogen atom. In some embodiments, when J.sup.B is
independently selected from a halogen atom, each J.sup.B can be
independently selected from fluoro or chloro, or each J.sup.B is
fluoro. In other embodiments, each J.sup.B is independently
selected from a C.sub.1-6 aliphatic. In some embodiments, each
J.sup.B is methyl or ethyl. In other embodiments, each J.sup.B is
methyl. In still other embodiments of Formula I and Formula Ib,
wherein ring B is substituted thiophene, each J.sup.B is
independently selected from OR.sup.B; wherein each R.sup.B is
hydrogen or a C.sub.1-6 alkyl. In some embodiments, each R.sup.B is
methyl, ethyl, propyl or isopropyl.
[0281] In some of the above embodiments, wherein ring B is
substituted thiophene, n is 1 or 2 and each J.sup.B is
independently selected from fluoro, chloro, methyl or methoxy. In
other embodiments, ring B is a mono substituted thiophene and
J.sup.B is fluoro.
[0282] In other embodiments of the compounds of Formula I or
Formula Ib, ring B is a furan ring. In some embodiments, n=0 and
the furan ring in unsubstituted. In other embodiments, ring B is a
substituted furan ring and n is an integer selected from 1 and 2.
In some of the above embodiments, wherein ring B is substituted
furan, n is 1 or 2 and each J.sup.B is independently selected from
fluoro, chloro, methyl or methoxy. In other embodiments, ring B is
a mono substituted furan and J.sup.B is fluoro.
[0283] In some embodiments of the compounds of Formula I or Formula
Ib, ring D is substituted and o is an integer selected from 1 to 3.
In other embodiments, o is 2. In some embodiments o is 2 and the
two instances of J.sup.D are attached to two vicinal atoms of ring
D.
[0284] In those embodiments of the compounds of Formula I or
Formula Ib wherein ring D is substituted, each J.sup.D is
independently selected from halogen, a C.sub.1-6 aliphatic,
--N(R.sup.D).sub.2, --N(R.sup.d)C(O)R.sup.D,
--N(R.sup.d)C(O)OR.sup.D, N(R.sup.d)C(O)N(R.sup.D).sub.2,
--SO.sub.2R.sup.D, --SO.sub.2N(R.sup.D).sub.2,
--N(R.sup.d)SO.sub.2R.sup.D, --SR.sup.D, --OR.sup.D or an
optionally substituted C.sub.3-8 cycloaliphatic ring. In some
embodiments of Formula I and Formula Ib, wherein ring D is
substituted, o is 1, 2 or 3 and each J.sup.D is independently
selected from methyl, chloro, fluoro, --N(R.sup.D).sub.2,
--N(R.sup.d)C(O)R.sup.D, oxo or --OR.sup.D; wherein each R.sup.d is
independently selected from hydrogen or methyl. In other
embodiments, o is 2 and at least one instance of J.sup.D is
independently selected from fluoro, chloro, oxo, hydroxyl or
amino.
[0285] In some embodiments of the compounds of Formula I or Formula
Ib, R.sup.C is a phenyl ring, a monocyclic 5 to or 6-membered
heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphatic ring
or a monocyclic 4 to 10-membered heterocycle; each of them
optionally and independently substituted by up to 6 instances of
J.sup.C. In other embodiments of Formula I and Formula Ib, ring C
is a phenyl ring, a monocyclic 5 to 6-membered heteroaryl ring, a
monocyclic 3 to 6-membered cycloaliphatic ring or a monocyclic 4 to
6-membered heterocycle; each of them optionally and independently
substituted with up to 3 instances of J.sup.C.
[0286] In some embodiments of the compounds of Formula Ior Formula
Ib, R.sup.C is a monocyclic 3 to 6-membered cycloaliphatic ring,
optionally and independently substituted with up to 2 instances of
f. In other embodiments, ring C is cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl. In other embodiments of the compounds of
Formula Ior Formula Ib, R.sup.C is a ring C which is a 4-membered
cycloaliphatic ring substituted by 1 to 3 instances of J.sup.C, a
5-membered cycloaliphatic ring substituted by 1 to 4 instances of f
or a 6-membered cycloaliphatic ring substituted by 1 to 5 instances
of J.sup.C; wherein each f is independently selected from halogen
or a C.sub.1-6 aliphatic.
[0287] In other embodiments of the compounds of Formula I or
Formula Ib, R.sup.C is phenyl, optionally and independently
substituted by up to 5 instances of J.sup.C. In some embodiments,
ring C is phenyl and it is unsubstituted. In other embodiments, it
is substituted by 1 to 3 instances of f; wherein each f is
independently selected from halogen, a C.sub.1-6 aliphatic,
--NH.sub.2, --CN or --O(C.sub.1-6 aliphatic). In other embodiments,
each J.sup.C is independently selected from halogen, --NH.sub.2,
--CN, C.sub.1-6 alkyl or --O(C.sub.1-4 alkyl). In still other
embodiments, ring C is phenyl substituted by 1 to 2 instances of
J.sup.C and each J.sup.C is selected from fluoro, chloro, methyl,
--CN or --OCH.sub.3.
[0288] In still other embodiments of Formula I and Formula Ib,
R.sup.C is a 5 to 6-membered heteroaryl ring and is optionally and
independently substituted by up to 5 instances of J.sup.C. In some
embodiments, said 5 to 6-membered heteroaryl ring is unsubstituted.
In other embodiments, it is substituted with 1 to 3 instances of f.
In some of these embodiments, the 5 to 6-membered heteroaryl ring
can be selected from thienyl, thiazolyl, oxadiazolyl, oxazolyl,
isooxazolyl, tetrazolyl, pyrrolyl, triazolyl, furanyl, pyridinyl,
pyrimidinyl, pyrazinyl or pyridazinyl. In yet other embodiments,
ring C is an isoxazolyl or oxazolyl ring and it is
unsubstituted.
[0289] In some embodiments of Formula I and Formula Ib, ring C is a
5 to 6-membered heteroaryl ring and it is substituted by 1 to 5
instances of J.sup.C; wherein each J.sup.C is independently
selected from halogen, a C.sub.1-6 aliphatic, --CN, --NH.sub.2 or
--O(C.sub.1-6 aliphatic). In other embodiments, ring C is
unsubstituted.
[0290] In some embodiments, the compounds of the invention are
represented by structural Formula I or Formula Ib shown above, or
Formula IIA, Formula IIB or Formula IIC shown below:
##STR00016##
[0291] wherein ring B is selected from a phenyl or 6-membered
heteroaryl ring; wherein J.sup.B is independently selected from
hydrogen or a halogen atom; and wherein n is an integer selected
from 1 or 2.
[0292] In some embodiments of the compounds of Formulae IIA, IIB or
IIC, each J.sup.B is a halogen and the halogen is independently
selected from chloro or fluoro. In other embodiments n is 1 and
J.sup.B is fluoro. In other embodiments, n is 2 and J.sup.B is
either chloro or fluoro. In still other embodiments, n is 2 and all
instances of J.sup.B are fluoro.
[0293] In some embodiments of the compounds of Formulae IIA, IIB or
IIC, o is an integer selected from 1 or 2. In some embodiments of
Formulae IIA, IIB and IIC o is 1 or 2 and each J.sup.D is
independently selected from halogen, a C.sub.1-6 aliphatic,
--N(R.sup.D).sub.2, --N(R.sup.d)COR.sup.D, --OR.sup.D, oxo or an
optionally substituted C.sub.3-8 cycloaliphatic ring. In other
embodiments, o is 2 and each J.sup.D is independently selected from
a halogen atom or --N(R.sup.D).sub.2, --N(R.sup.d)COR.sup.D, --OH
or oxo. In still other embodiments, o is 2 and one instance of
J.sup.D is fluoro or chloro and the other instance of J.sup.D is
--OH or oxo. In other embodiments, o is 2 and one J.sup.D is
--NH.sub.2 and the other one is independently selected from
--N(R.sup.D).sub.2, wherein at least one instance of R.sup.D is not
hydrogen, or is --NHCOR.sup.D. In still other embodiments, o is 2
and one instance of J.sup.D is independently selected from
--N(R.sup.D).sub.2 or --NHCOR.sup.D and the other instance of
J.sup.D is selected from fluoro or chloro. In still other
embodiments, o is 1 and J.sup.D is amino.
[0294] In some embodiments of the compounds of Formulae IIA, IIB or
IIC, R.sup.C is phenyl, optionally and independently substituted by
up to 5 instances of J.sup.C. In some embodiments, ring C is phenyl
and it is unsubstituted. In other embodiments, it is substituted by
1 to 3 instances of J.sup.C; wherein each J.sup.C is independently
selected from halogen, a C.sub.1-6 aliphatic, --NH.sub.2, --CN or
--O(C.sub.1-6 aliphatic). In other embodiments, each J.sup.C is
independently selected from halogen, --NH.sub.2, --CN, C.sub.1-6
alkyl or --O(C.sub.1-4 alkyl). In still other embodiments, ring C
is phenyl substituted by 1 to 2 instances of J.sup.C and each
J.sup.C is selected from fluoro, chloro, methyl, --CN or
--OCH.sub.3.
[0295] In still other embodiments of the compounds of Formulae IIA,
IIB or IIC, R.sup.C is a 5 to 6-membered heteroaryl ring and is
optionally and independently substituted by up to 5 instances of f.
In some embodiments, said 5 to 6-membered heteroaryl ring is
unsubstituted. In other embodiments, it is substituted with 1 to 3
instances of J.sup.C. In some of these embodiments, the 5 to
6-membered heteroaryl ring can be selected from thienyl, thiazolyl,
oxadiazolyl, oxazolyl, isoxazolyl, tetrazolyl, pyrrolyl, triazolyl,
furanyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. In other
embodiments, the heteroaryl ring C is selected from isoxazolyl,
oxazolyl, furanyl, thienyl, thiazolyl, 1,3,4-oxadiazolyl,
pyridinyl, pyrimidinyl or pyrazin-3-yl. In still other embodiments,
the heteroaryl ring C is selected from isoxazolyl or oxazolyl. In
other embodiments, ring C is a oxazolyl or isoxazolyl ring and it
is substituted by up to 2 instances of J.sup.C; wherein each
J.sup.C is selected from fluoro, chloro, bromo, methyl, --CN,
--NH.sub.2 or --OCH.sub.3. In yet other embodiments of the
compounds of Formula I, Formula Ib, Formula IA, Formula IIB or
Formula IIC, ring C is an unsubstituted isoxazolyl or oxazolyl
ring.
[0296] The compounds of the invention are defined herein by their
chemical structures and/or chemical names. Where a compound is
referred to by both a chemical structure and a chemical name, and
the chemical structure and chemical name conflict, the chemical
structure is determinative of the compound's identity.
[0297] In some embodiments, the compound of Formula I or Formula Ib
is one of the compounds depicted below:
TABLE-US-00001 TABLE 1 ##STR00017## I-1 ##STR00018## I-2
##STR00019## I-3 ##STR00020## I-4 ##STR00021## I-5 ##STR00022## I-6
##STR00023## I-7 ##STR00024## I-8 ##STR00025## I-9 ##STR00026##
I-10
Methods of Preparing the Compounds
[0298] The compounds of Formula I and Formula Ib may be prepared
according to the schemes and examples depicted and described below.
Unless otherwise specified, the starting materials and various
intermediates may be obtained from commercial sources, prepared
from commercially available compounds or prepared using well-known
synthetic methods. Another aspect of the present invention is a
process for preparing the compounds of Formula I and Formula Ib as
disclosed herein.
[0299] General synthetic procedures for the compounds of this
invention are described below. The synthetic schemes are presented
as examples and do not limit the scope of the invention in any
way.
Pharmaceutically Acceptable Salts of the Invention
[0300] The phrase "pharmaceutically acceptable salt," as used
herein, refers to pharmaceutically acceptable organic or inorganic
salts of a compound of Formula I or Formula Ib. For use in
medicine, the salts of a compound of Formula I or Formula Ib will
be pharmaceutically acceptable salts. Other salts may, however, may
be useful in the preparation of a compound of Formula I or Formula
Ib or of their pharmaceutically acceptable salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound. Furthermore, a
pharmaceutically acceptable salt may have more than one charged
atom in its structure. Instances where multiple charged atoms are
part of the pharmaceutically acceptable salt can have multiple
counter ions. Hence, a pharmaceutically acceptable salt can have
one or more charged atoms and/or one or more counter ion.
[0301] Pharmaceutically acceptable salts of the compounds of
Formula I or Formula IB described herein include those derived from
suitable inorganic or organic acids or bases. In some embodiments,
the salts can be prepared in situ during the final isolation and
purification of the compounds. In other embodiments the salts can
be prepared from the free form of the compound in a separate
synthetic step.
[0302] When a compound of Formula I or Formula Ib is acidic or
contains a sufficiently acidic bioisostere, suitable
"pharmaceutically acceptable salts" refers to salts prepared form
pharmaceutically acceptable non-toxic bases including inorganic
bases and organic bases. Salts derived from inorganic bases include
aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic salts, manganous, potassium, sodium, zinc and
the like. Particular embodiments include ammonium, calcium,
magnesium, potassium and sodium salts. Salts derived from
pharmaceutically acceptable organic non-toxic bases include salts
of primary, secondary and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines and
basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,N.sup.1-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine tripropylamine, tromethamine and the like.
[0303] When a compound of Formula I or Formula Ib is basic or
contains a sufficiently basic bioisostere, salts may be prepared
from pharmaceutically acceptable non-toxic acids, including
inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like. Particular embodiments include
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and
tartaric acids. Other exemplary salts include, but are not limited,
to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,
nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,
lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
[0304] The preparation of the pharmaceutically acceptable salts
described above and other typical pharmaceutically acceptable salts
is more fully described by Berg et al., "Pharmaceutical Salts," J.
Pharm. Sci., 1977:66:1-19, incorporated here by reference in its
entirety.
[0305] In addition to the compounds described herein, their
pharmaceutically acceptable salts may also be employed in
compositions to treat or prevent the herein identified
disorders.
Pharmaceutical Compositions and Methods of Administration.
[0306] The compounds herein disclosed, and their pharmaceutically
acceptable salts thereof may be formulated as pharmaceutical
compositions or "formulations".
[0307] A typical formulation is prepared by mixing a compound of
Formula I or Formula Ib, or a pharmaceutically acceptable salt
thereof, and a carrier, diluent or excipient. Suitable carriers,
diluents and excipients are well known to those skilled in the art
and include materials such as carbohydrates, waxes, water soluble
and/or swellable polymers, hydrophilic or hydrophobic materials,
gelatin, oils, solvents, water, and the like. The particular
carrier, diluent or excipient used will depend upon the means and
purpose for which a compound of Formula I or Formula Ib is being
formulated. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS-Generally
Regarded as Safe) to be administered to a mammal. In general, safe
solvents are non-toxic aqueous solvents such as water and other
non-toxic solvents that are soluble or miscible in water. Suitable
aqueous solvents include water, ethanol, propylene glycol,
polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures
thereof. The formulations may also include other types of
excipients such as one or more buffers, stabilizing agents,
antiadherents, surfactants, wetting agents, lubricating agents,
emulsifiers, binders, suspending agents, disintegrants, fillers,
sorbents, coatings (e.g. enteric or slow release) preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents and other
known additives to provide an elegant presentation of the drug
(i.e., a compound of Formula I or Formula Ib or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0308] The formulations may be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., a compound of Formula I or Formula Ib, a
pharmaceutically acceptable salt thereof, or a stabilized form of
the compound, such as a complex with a cyclodextrin derivative or
other known complexation agent) is dissolved in a suitable solvent
in the presence of one or more of the excipients described above. A
compound having the desired degree of purity is optionally mixed
with pharmaceutically acceptable diluents, carriers, excipients or
stabilizers, in the form of a lyophilized formulation, milled
powder, or an aqueous solution. Formulation may be conducted by
mixing at ambient temperature at the appropriate pH, and at the
desired degree of purity, with physiologically acceptable carriers.
The pH of the formulation depends mainly on the particular use and
the concentration of compound, but may range from about 3 to about
8. When the agent described herein is a solid amorphous dispersion
formed by a solvent process, additives may be added directly to the
spray-drying solution when forming the mixture such as the additive
is dissolved or suspended in the solution as a slurry which can
then be spray dried. Alternatively, the additives may be added
following spray-drying process to aid in the forming of the final
formulated product.
[0309] The compound of Formula I or Formula Ib or a
pharmaceutically acceptable salt thereof is typically formulated
into pharmaceutical dosage forms to provide an easily controllable
dosage of the drug and to enable patient compliance with the
prescribed regimen. Pharmaceutical formulations of a compound of
Formula I or Formula Ib, or a pharmaceutically acceptable salt
thereof, may be prepared for various routes and types of
administration. Various dosage forms may exist for the same
compound, since different medical conditions may warrant different
routes of administration.
[0310] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the subject treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight: weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur. As a general proposition, the initial
pharmaceutically effective amount of the inhibitor administered
will be in the range of about 0.01-100 mg/kg per dose, namely about
0.1 to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day.
[0311] The term "therapeutically effective amount" as used herein
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician. The therapeutically or
pharmaceutically effective amount of the compound to be
administered will be governed by such considerations, and is the
minimum amount necessary to ameliorate, cure or treat the disease
or disorder or one or more of its symptoms.
[0312] The pharmaceutical compositions of a compound of Formula I
or Formula Ib will be formulated, dosed, and administered in a
fashion, i.e., amounts, concentrations, schedules, course,
vehicles, and route of administration, consistent with good medical
practice. Factors for consideration in this context include the
particular disorder being treated, the particular mammal being
treated, the clinical condition of the individual patient, the
cause of the disorder, the site of delivery of the agent, the
method of administration, the scheduling of administration, and
other factors known to medical practitioners, such as the age,
weight, and response of the individual patient.
[0313] The term "prophylactically effective amount" refers to an
amount effective in preventing or substantially lessening the
chances of acquiring a disease or disorder or in reducing the
severity of the disease or disorder before it is acquired or
reducing the severity of one or more of its symptoms before the
symptoms develop. Roughly, prophylactic measures are divided
between primary prophylaxis (to prevent the development of a
disease) and secondary prophylaxis (whereby the disease has already
developed and the patient is protected against worsening of this
process).
[0314] Acceptable diluents, carriers, excipients, and stabilizers
are those that are nontoxic to recipients at the dosages and
concentrations employed, and include buffers such as phosphate,
citrate, and other organic acids; antioxidants including ascorbic
acid and methionine; preservatives (such as octadecyldimethylbenzyl
ammonium chloride; hexamethonium chloride; benzalkonium chloride,
benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl
parabens such as methyl or propyl paraben; catechol; resorcinol;
cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum
albumin, gelatin, or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparagine, histidine, arginine, or lysine; monosaccharides,
disaccharides, and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, tretralose or sorbitol; salt-forming counter-ions such as
sodium; metal complexes (e.g. Zn-protein complexes); and/or
non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or
polyethylene glycol (PEG). The active pharmaceutical ingredients
may also be entrapped in microcapsules prepared, for example, by
coacervation techniques or by interfacial polymerization, e.g.,
hydroxymethylcellulose or gelatin-microcapsules and
poly-(methylmethacylate) microcapsules, respectively; in colloidal
drug delivery systems (for example, liposomes, albumin
microspheres, microemulsions, nano-particles and nanocapsules) or
in macroemulsions. Such techniques are disclosed in Remington's:
The Science and Practice of Pharmacy, 21.sup.st Edition, University
of the Sciences in Philadelphia, Eds., 2005 (hereafter
"Remington's").
[0315] "Controlled drug delivery systems" supply the drug to the
body in a manner precisely controlled to suit the drug and the
conditions being treated. The primary aim is to achieve a
therapeutic drug concentration at the site of action for the
desired duration of time. The term "controlled release" is often
used to refer to a variety of methods that modify release of drug
from a dosage form. This term includes preparations labeled as
"extended release", "delayed release", "modified release" or
"sustained release". In general, one can provide for controlled
release of the agents described herein through the use of a wide
variety of polymeric carriers and controlled release systems
including erodible and non-erodible matrices, osmotic control
devices, various reservoir devices, enteric coatings and
multiparticulate control devices.
[0316] "Sustained-release preparations" are the most common
applications of controlled release. Suitable examples of
sustained-release preparations include semipermeable matrices of
solid hydrophobic polymers containing the compound, which matrices
are in the form of shaped articles, e.g. films, or microcapsules.
Examples of sustained-release matrices include polyesters,
hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or
poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),
copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,
non-degradable ethylene-vinyl acetate, degradable lactic
acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric
acid.
[0317] "Immediate-release preparations" may also be prepared. The
objective of these formulations is to get the drug into the
bloodstream and to the site of action as rapidly as possible. For
instance, for rapid dissolution, most tablets are designed to
undergo rapid disintegration to granules and subsequent
deaggregation to fine particles. This provides a larger surface
area exposed to the dissolution medium, resulting in a faster
dissolution rate.
[0318] Agents described herein can be incorporated into an erodible
or non-erodible polymeric matrix controlled release device. By an
erodible matrix is meant aqueous-erodible or water-swellable or
aqueous-soluble in the sense of being either erodible or swellable
or dissolvable in pure water or requiring the presence of an acid
or base to ionize the polymeric matrix sufficiently to cause
erosion or dissolution. When contacted with the aqueous environment
of use, the erodible polymeric matrix imbibes water and forms an
aqueous-swollen gel or matrix that entraps the agent described
herein. The aqueous-swollen matrix gradually erodes, swells,
disintegrates or dissolves in the environment of use, thereby
controlling the release of a compound described herein to the
environment of use. One ingredient of this water-swollen matrix is
the water-swellable, erodible, or soluble polymer, which may
generally be described as an osmopolymer, hydrogel or
water-swellable polymer. Such polymers may be linear, branched, or
cross linked. The polymers may be homopolymers or copolymers. In
certain embodiments, they may be synthetic polymers derived from
vinyl, acrylate, methacrylate, urethane, ester and oxide monomers.
In other embodiments, they can be derivatives of naturally
occurring polymers such as polysaccharides (e.g. chitin, chitosan,
dextran and pullulan; gum agar, gum arabic, gum karaya, locust bean
gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan
gum and scleroglucan), starches (e.g. dextrin and maltodextrin),
hydrophilic colloids (e.g. pectin), phosphatides (e.g. lecithin),
alginates (e.g. ammonium alginate, sodium, potassium or calcium
alginate, propylene glycol alginate), gelatin, collagen, and
cellulosics. Cellulosics are cellulose polymer that has been
modified by reaction of at least a portion of the hydroxyl groups
on the saccharide repeat units with a compound to form an
ester-linked or an ether-linked substituent. For example, the
cellulosic ethyl cellulose has an ether linked ethyl substituent
attached to the saccharide repeat unit, while the cellulosic
cellulose acetate has an ester linked acetate substituent. In
certain embodiments, the cellulosics for the erodible matrix
comprises aqueous-soluble and aqueous-erodible cellulosics can
include, for example, ethyl cellulose (EC), methylethyl cellulose
(MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose
(HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA),
cellulose propionate (CP), cellulose butyrate (CB), cellulose
acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose
(HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate
trimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC). In
certain embodiments, the cellulosics comprises various grades of
low viscosity (MW less than or equal to 50,000 daltons, for
example, the Dow Methocel.TM. series E5, E15LV, E50LV and K100LY)
and high viscosity (MW greater than 50,000 daltons, for example,
E4MCR, E10MCR, K4M, K15M and K100M and the Methocel.TM. K series)
HPMC. Other commercially available types of HPMC include the Shin
Etsu Metolose 90SH series.
[0319] Other materials useful as the erodible matrix material
include, but are not limited to, pullulan, polyvinyl pyrrolidone,
polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters,
polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or
methacrylic acid (EUDRAGIT.RTM., Rohm America, Inc., Piscataway,
New Jersey) and other acrylic acid derivatives such as homopolymers
and copolymers of butylmethacrylate, methylmethacrylate,
ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)
methacrylate, and (trimethylaminoethyl) methacrylate chloride.
[0320] Alternatively, the agents of the present invention may be
administered by or incorporated into a non-erodible matrix device.
In such devices, an agent described herein is distributed in an
inert matrix. The agent is released by diffusion through the inert
matrix. Examples of materials suitable for the inert matrix include
insoluble plastics (e.g methyl acrylate-methyl methacrylate
copolymers, polyvinyl chloride, polyethylene), hydrophilic polymers
(e.g. ethyl cellulose, cellulose acetate, cross linked
polyvinylpyrrolidone (also known as crospovidone)), and fatty
compounds (e.g. carnauba wax, microcrystalline wax, and
triglycerides). Such devices are described further in Remington:
The Science and Practice of Pharmacy, 20th edition (2000).
[0321] As noted above, the agents described herein may also be
incorporated into an osmotic control device. Such devices generally
include a core containing one or more agents as described herein
and a water permeable, non-dissolving and non-eroding coating
surrounding the core which controls the influx of water into the
core from an aqueous environment of use so as to cause drug release
by extrusion of some or all of the core to the environment of use.
In certain embodiments, the coating is polymeric,
aqueous-permeable, and has at least one delivery port. The core of
the osmotic device optionally includes an osmotic agent which acts
to imbibe water from the surrounding environment via such a
semi-permeable membrane. The osmotic agent contained in the core of
this device may be an aqueous-swellable hydrophilic polymer or it
may be an osmogen, also known as an osmagent. Pressure is generated
within the device which forces the agent(s) out of the device via
an orifice (of a size designed to minimize solute diffusion while
preventing the build-up of a hydrostatic pressure head). Non
limiting examples of osmotic control devices are disclosed in U.S.
patent application Ser. No. 09/495,061.
[0322] The amount of water-swellable hydrophilic polymers present
in the core may range from about 5 to about 80 wt % (including for
example, 10 to 50 wt %). Non limiting examples of core materials
include hydrophilic vinyl and acrylic polymers, polysaccharides
such as calcium alginate, polyethylene oxide (PEO), polyethylene
glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl
methacrylate), poly (acrylic) acid, poly (methacrylic) acid,
polyvinylpyrrolidone (PVP) and cross linked PVP, polyvinyl alcohol
(PVA), PVA/PVP copolymers and PVA/PVP copolymers with hydrophobic
monomers such as methyl methacrylate, vinyl acetate, and the like,
hydrophilic polyurethanes containing large PEO blocks, sodium
croscarmellose, carrageenan, hydroxyethyl cellulose (HEC),
hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose
(HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose
(CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and
sodium starch glycolat. Other materials include hydrogels
comprising interpenetrating networks of polymers that may be formed
by addition or by condensation polymerization, the components of
which may comprise hydrophilic and hydrophobic monomers such as
those just mentioned. Water-swellable hydrophilic polymers include
but are not limited to PEO, PEG, PVP, sodium croscarmellose, HPMC,
sodium starch glycolate, polyacrylic acid and cross linked versions
or mixtures thereof
[0323] The core may also include an osmogen (or osmagent). The
amount of osmogen present in the core may range from about 2 to
about 70 wt % (including, for example, from 10 to 50 wt %). Typical
classes of suitable osmogens are water-soluble organic acids, salts
and sugars that are capable of imbibing water to thereby effect an
osmotic pressure gradient across the barrier of the surrounding
coating. Typical useful osmogens include but are not limited to
magnesium sulfate, magnesium chloride, calcium chloride, sodium
chloride, lithium chloride, potassium sulfate, sodium carbonate,
sodium sulfite, lithium sulfate, potassium chloride, sodium
sulfate, mannitol, xylitol, urea, sorbitol, inositol, raffinose,
sucrose, glucose, fructose, lactose, citric acid, succinic acid,
tartaric acid, and mixtures thereof In certain embodiments, the
osmogen is glucose, lactose, sucrose, mannitol, xylitol, sodium
chloride, including combinations thereof.
[0324] The rate of drug delivery is controlled by such factors as
the permeability and thickness of the coating, the osmotic pressure
of the drug-containing layer, the degree of hydrophilicity of the
hydrogel layer, and the surface area of the device. Those skilled
in the art will appreciate that increasing the thickness of the
coating will reduce the release rate, while any of the following
will increase the release rate: increasing the permeability of the
coating; increasing the hydrophilicity of the hydrogel layer;
increasing the osmotic pressure of the drug-containing layer; or
increasing the device's surface area.
[0325] In certain embodiments, entrainment of particles of agents
described herein in the extruding fluid during operation of such
osmotic device is desirable. For the particles to be well
entrained, the agent drug form is dispersed in the fluid before the
particles have an opportunity to settle in the tablet core. One
means of accomplishing this is by adding a disintegrant that serves
to break up the compressed core into its particulate components.
Non limiting examples of standard disintegrants include materials
such as sodium starch glycolate (e. g., Explotab.TM. CLV),
microcrystalline cellulose (e. g., Avicer), microcrystalline
silicified cellulose (e. g., ProSoIv.TM.) and croscarmellose sodium
(e. g., Ac-Di-Sol.TM.), and other disintegrants known to those
skilled in the art. Depending upon the particular formulation, some
disintegrants work better than others. Several disintegrants tend
to form gels as they swell with water, thus hindering drug delivery
from the device. Non-gelling, non-swelling disintegrants provide a
more rapid dispersion of the drug particles within the core as
water enters the core. In certain embodiments, non-gelling,
non-swelling disintegrants are resins, for example, ion-exchange
resins. In one embodiment, the resin is Amberlite.TM. IRP 88
(available from Rohm and Haas, Philadelphia, Pa.). When used, the
disintegrant is present in amounts ranging from about 1-25% of the
core agent.
[0326] Another example of an osmotic device is an osmotic capsule.
The capsule shell or portion of the capsule shell can be
semipermeable. The capsule can be filled either by a powder or
liquid consisting of an agent described herein, excipients that
imbibe water to provide osmotic potential, and/or a water-swellable
polymer, or optionally solubilizing excipients. The capsule core
can also be made such that it has a bilayer or multilayer agent
analogous to the bilayer, trilayer or concentric geometries
described above.
[0327] Another class of osmotic device useful in this invention
comprises coated swellable tablets, for example, as described in
EP378404. Coated swellable tablets comprise a tablet core
comprising an agent described herein and a swelling material,
preferably a hydrophilic polymer, coated with a membrane, which
contains holes, or pores through which, in the aqueous use
environment, the hydrophilic polymer can extrude and carry out the
agent. Alternatively, the membrane may contain polymeric or low
molecular weight water-soluble porosigens. Porosigens dissolve in
the aqueous use environment, providing pores through which the
hydrophilic polymer and agent may extrude. Examples of porosigens
are water-soluble polymers such as HPMC, PEG, and low molecular
weight compounds such as glycerol, sucrose, glucose, and sodium
chloride. In addition, pores may be formed in the coating by
drilling holes in the coating using a laser or other mechanical
means. In this class of osmotic devices, the membrane material may
comprise any film-forming polymer, including polymers which are
water permeable or impermeable, providing that the membrane
deposited on the tablet core is porous or contains water-soluble
porosigens or possesses a macroscopic hole for water ingress and
drug release. Embodiments of this class of sustained release
devices may also be multilayered, as described, for example, in
EP378404.
[0328] When an agent described herein is a liquid or oil, such as a
lipid vehicle formulation, for example as described in WO05/011634,
the osmotic controlled-release device may comprise a soft-gel or
gelatin capsule formed with a composite wall and comprising the
liquid formulation where the wall comprises a barrier layer formed
over the external surface of the capsule, an expandable layer
formed over the barrier layer, and a semipermeable layer formed
over the expandable layer. A delivery port connects the liquid
formulation with the aqueous use environment. Such devices are
described, for example, in U.S. Pat. No. 6,4199,52, U.S. Pat. No.
6,342,249, U.S. Pat. No. 5,324,280, U.S. Pat. No. 4,672,850, U.S.
Pat. No. 4,627,850, U.S. Pat. No. 4,203,440, and U.S. Pat. No.
3,995,631.
[0329] As further noted above, the agents described herein may be
provided in the form of microparticulates, generally ranging in
size from about 10 .mu.m to about 2 mm (including, for example,
from about 100 .mu.m to 1 mm in diameter). Such multiparticulates
may be packaged, for example, in a capsule such as a gelatin
capsule or a capsule formed from an aqueous-soluble polymer such as
HPMCAS, HPMC or starch; dosed as a suspension or slurry in a liquid
; or they may be formed into a tablet, caplet, or pill by
compression or other processes known in the art. Such
multiparticulates may be made by any known process, such as wet-
and dry-granulation processes, extrusion/spheronization,
roller-compaction, melt-congealing, or by spray-coating seed cores.
For example, in wet-and dry- granulation processes, the agent
described herein and optional excipients may be granulated to form
multiparticulates of the desired size.
[0330] The agents can be incorporated into microemulsions, which
generally are thermodynamically stable, isotropically clear
dispersions of two immiscible liquids, such as oil and water,
stabilized by an interfacial film of surfactant molecules
(Encyclopedia of Pharmaceutical Technology, New York: Marcel
Dekker, 1992, volume 9). For the preparation of microemulsions,
surfactant (emulsifier), co-surfactant (co-emulsifier), an oil
phase and a water phase are necessary. Suitable surfactants include
any surfactants that are useful in the preparation of emulsions,
e.g., emulsifiers that are typically used in the preparation of
creams. The co-surfactant (or "co-emulsifier") is generally
selected from the group of polyglycerol derivatives, glycerol
derivatives and fatty alcohols. Preferred emulsifier/co-emulsifier
combinations are generally although not necessarily selected from
the group consisting of: glyceryl monostearate and polyoxyethylene
stearate; polyethylene glycol and ethylene glycol palmitostearate;
and caprilic and capric triglycerides and oleoyl
macrogolglycerides. The water phase includes not only water but
also, typically, buffers, glucose, propylene glycol, polyethylene
glycols, preferably lower molecular weight polyethylene glycols
(e.g., PEG 300 and PEG 400), and/or glycerol, and the like, while
the oil phase will generally comprise, for example, fatty acid
esters, modified vegetable oils, silicone oils, mixtures of mono-
di- and triglycerides, mono- and di-esters of PEG (e.g., oleoyl
macrogol glycerides), etc.
[0331] The compounds described herein can be incorporated into
pharmaceutically-acceptable nanoparticle, nanosphere, and
nanocapsule formulations (Delie and Blanco-Prieto, 2005, Molecule
10:65-80). Nanocapsules can generally entrap compounds in a stable
and reproducible way. To avoid side effects due to intracellular
polymeric overloading, ultrafine particles (sized around 0.1 .mu.m)
can be designed using polymers able to be degraded in vivo (e.g.
biodegradable polyalkyl-cyanoacrylate nanoparticles). Such
particles are described in the prior art.
[0332] Implantable devices coated with a compound of this invention
are another embodiment of the present invention. The compounds may
also be coated on implantable medical devices, such as beads, or
co-formulated with a polymer or other molecule, to provide a "drug
depot", thus permitting the drug to be released over a longer time
period than administration of an aqueous solution of the drug.
Suitable coatings and the general preparation of coated implantable
devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and
5,304,121. The coatings are typically biocompatible polymeric
materials such as a hydrogel polymer, polymethyldisiloxane,
polycaprolactone, polyethylene glycol, polylactic acid, ethylene
vinyl acetate, and mixtures thereof. The coatings may optionally be
further covered by a suitable topcoat of fluorosilicone,
polysaccharides, polyethylene glycol, phospholipids or combinations
thereof to impart controlled release characteristics in the
composition.
[0333] The formulations include those suitable for the
administration routes detailed herein. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any of the methods well known in the art of pharmacy. Techniques
and formulations generally are found in Remington's. Such methods
include the step of bringing into association the active ingredient
with the carrier which constitutes one or more accessory
ingredients. In general the formulations are prepared by uniformly
and intimately bringing into association the active ingredient with
liquid carriers or finely divided solid carriers or both, and then,
if necessary, shaping the product.
[0334] The terms "administer", "administering" or "administration"
in reference to a compound, composition or formulation of the
invention means introducing the compound into the system of the
animal in need of treatment. When a compound of the invention is
provided in combination with one or more other active agents,
"administration" and its variants are each understood to include
concurrent and/or sequential introduction of the compound and the
other active agents.
[0335] The compositions described herein may be administered
systemically or locally, e.g.: orally (e.g. using capsules,
powders, solutions, suspensions, tablets, sublingual tablets and
the like), by inhalation (e.g. with an aerosol, gas, inhaler,
nebulizer or the like), to the ear (e.g. using ear drops),
topically (e.g. using creams, gels, liniments, lotions, ointments,
pastes, transdermal patches, etc), ophthalmically (e.g. with eye
drops, ophthalmic gels, ophthalmic ointments), rectally (e.g. using
enemas or suppositories), nasally, buccally, vaginally (e.g. using
douches, intrauterine devices, vaginal suppositories, vaginal rings
or tablets, etc), via an implanted reservoir or the like, or
parenterally depending on the severity and type of the disease
being treated. The term "parenteral" as used herein includes, but
is not limited to, subcutaneous, intravenous, intramuscular,
intra-articular, intra-synovial, intrasternal, intrathecal,
intrahepatic, intralesional and intracranial injection or infusion
techniques. Preferably, the compositions are administered orally,
intraperitoneally or intravenously.
[0336] The pharmaceutical compositions described herein may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. Liquid dosage forms for oral administration include, but
are not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0337] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. Tablets may be uncoated or may be
coated by known techniques including microencapsulation to mask an
unpleasant taste or to delay disintegration and adsorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate alone or with a wax
may be employed. A water soluble taste masking material such as
hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be
employed.
[0338] Formulations of a compound of Formula I or Formula Ib that
are suitable for oral administration may be prepared as discrete
units such as tablets, pills, troches, lozenges, aqueous or oil
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, e.g. gelatin capsules, syrups or elixirs.
Formulations of a compound intended for oral use may be prepared
according to any method known to the art for the manufacture of
pharmaceutical compositions.
[0339] Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as a powder or granules, optionally mixed with a binder, lubricant,
inert diluent, preservative, surface active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent.
[0340] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water soluble carrier such as
polyethyleneglycol or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0341] The active compounds can also be in microencapsulated form
with one or more excipients as noted above.
[0342] When aqueous suspensions are required for oral use, the
active ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening and/or flavoring agents may
be added. Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, flavoring and coloring agents and antioxidant.
[0343] Sterile injectable forms of the compositions described
herein (e.g. for parenteral administration) may be aqueous or
oleaginous suspension. These suspensions may be formulated
according to techniques known in the 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 non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed including synthetic mono- or diglycerides. Fatty acids,
such as oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of injectable formulations.
[0344] Oily suspensions may be formulated by suspending a compound
of Formula I or Formula Ib in a vegetable oil, for example arachis
oil, olive oil, sesame oil or coconut oil, or in mineral oil such
as liquid paraffin. The oily suspensions may contain a thickening
agent, for example beeswax, hard paraffin or cetyl alcohol.
Sweetening agents such as those set forth above, and flavoring
agents may be added to provide a palatable oral preparation. These
compositions may be preserved by the addition of an anti-oxidant
such as butylated hydroxyanisol or alpha-tocopherol.
[0345] Aqueous suspensions of a compound of Formula I or Formula Ib
contain the active materials in admixture with excipients suitable
for the manufacture of aqueous suspensions. Such excipients include
a suspending agent, such as sodium carboxymethylcellulose,
croscarmellose, povidone, methylcellulose, hydroxypropyl
methylcelluose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, and dispersing or wetting agents such as
a naturally occurring phosphatide (e.g., lecithin), a condensation
product of an alkylene oxide with a fatty acid (e.g.,
polyoxyethylene stearate), a condensation product of ethylene oxide
with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0346] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0347] In order to prolong the effect of a compound described
herein, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsulated matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0348] The injectable solutions or microemulsions may be introduced
into a patient's bloodstream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.TM. model 5400 intravenous pump.
[0349] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds described herein with suitable non-irritating excipients
or carriers such as cocoa butter, beeswax, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound. Other formulations suitable
for vaginal administration may be presented as pessaries, tampons,
creams, gels, pastes, foams or sprays.
[0350] The pharmaceutical compositions described herein may also be
administered topically, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the ear, the skin, or the lower
intestinal tract. Suitable topical formulations are readily
prepared for each of these areas or organs.
[0351] Dosage forms for topical or transdermal administration of a
compound described herein include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, eardrops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel. Topical application for the
lower intestinal tract can be effected in a rectal suppository
formulation (see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used.
[0352] For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions can be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and
water.
[0353] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with or without a preservative such
as benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutical compositions may be formulated in an ointment such
as petrolatum. For treatment of the eye or other external tissues,
e.g., mouth and skin, the formulations may be applied as a topical
ointment or cream containing the active ingredient(s) in an amount
of, for example, 0.075 to 20% w/w. When formulated in an ointment,
the active ingredients may be employed with either an oil-based,
paraffinic or a water-miscible ointment base.
[0354] Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG 400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethyl sulfoxide and related
analogs.
[0355] The oily phase of emulsions prepared using a compound of
Formula I or Formula Ib may be constituted from known ingredients
in a known manner. While the phase may comprise merely an
emulsifier (otherwise known as an emulgent), it desirably comprises
a mixture of at least one emulsifier with a fat or an oil or with
both a fat and an oil. A hydrophilic emulsifier may be included
together with a lipophilic emulsifier which acts as a stabilizer.
In some embodiments, the emulsifier includes both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make up
the so-called emulsifying wax, and the wax together with the oil
and fat make up the so-called emulsifying ointment base which forms
the oily dispersed phase of the cream formulations. Emulgents and
emulsion stabilizers suitable for use in the formulation of a
compound of Formula I or Formula Ib include Tween.TM.-60,
Span.TM.-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol,
glyceryl mono-stearate and sodium lauryl sulfate.
[0356] The pharmaceutical compositions may also be administered by
nasal aerosol or by inhalation. Such compositions are prepared
according to techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline, employing
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, fluorocarbons, and/or other
conventional solubilizing or dispersing agents. Formulations
suitable for intrapulmonary or nasal administration have a particle
size for example in the range of 0.1 to 500 micros (including
particles in a range between 0.1 and 500 microns in increments
microns such as 0.5, 1, 30, 35 microns, etc) which is administered
by rapid inhalation through the nasal passage or by inhalation
through the mouth so as to reach the alveolar sacs.
[0357] The pharmaceutical composition (or formulation) for use may
be packaged in a variety of ways depending upon the method used for
administering the drug. Generally, an article for distribution
includes a container having deposited therein the pharmaceutical
formulation in an appropriate form. Suitable containers are
well-known to those skilled in the art and include materials such
as bottles (plastic and glass), sachets, ampoules, plastic bags,
metal cylinders, and the like. The container may also include a
tamper-proof assemblage to prevent indiscreet access to the
contents of the package. In addition, the container has deposited
thereon a label that describes the contents of the container. The
label may also include appropriate warnings.
[0358] The formulations may be packaged in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water, for
injection immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0359] In another aspect, a compound of Formula I or Formula Ib or
a pharmaceutically acceptable salt thereof may be formulated in a
veterinary composition comprising a veterinary carrier. Veterinary
carriers are materials useful for the purpose of administering the
composition and may be solid, liquid or gaseous materials which are
otherwise inert or accepFormula I or Formula Ibn the veterinary art
and are compatible with the active ingredient. These veterinary
compositions may be administered parenterally, orally or by any
other desired route.
Therapeutic Methods
[0360] The present disclosure relates to stimulators of soluble
guanylate cyclase (sGC), pharmaceutical formulations thereof and
their use, alone or in combination with one or more additional
agents, for treating and/or preventing various diseases, wherein an
increase in the concentration of NO or an increase in the
concentration of cGMP might be desirable. The diseases that can be
treated include but are not limited topulmonary hypertension,
arterial hypertension, portal hypertension, heart failure,
atherosclerosis, inflammation, thrombosis, obstructive
thromboanginitis, renal fibrosis and failure, liver cirrhosis,
cancer metastasis, female sexual disorders, erectile dysfunction,
vaginal atrophy, wound healingand other related cardiovascular
disorders.
[0361] Increased concentration of cGMP leads to vasodilation,
inhibition of platelet aggregation and adhesion, anti-hypertensive
effects, anti-remodeling effects, anti-apoptotic effects,
anti-inflammatory effects and neuronal signal transmission effects.
Thus, sGC stimulators may be used to treat and/or prevent a range
of diseases and disorders, including but not limited to a
peripheral, pulmonary, hepatic, liver, cardiac or
cerebralvascular/endothelial disorders or conditions, a
urogenital-gynecological disorder or condition, a thromboembolic
disease, a fibrotic disorder, a pulmonary or respiratory disorder,
a renal or hepatic disorder, a metabolic disorder, atherosclerosis,
or a lipid related disorder.
[0362] In other embodiments, the compounds here disclosed are sGC
stimulators that may be useful in the prevention and/or treatment
of diseases and disorders characterized by undesirable reduced
bioavailability of and/or sensitivity to NO, such as those
associated with conditions of oxidative stress or nitrosative
stress.
[0363] Throughout this disclosure, the terms "hypertension",
"arterial hypertension" or "high blood pressure (HBP)" are used
interchangeable and refer to an extremely common and highly
preventable chronic condition in which blood pressure (BP) in the
arteries is higher than normal. If not properly controlled, it
represents a significant risk factor for several serious
cardiovascular and renal conditions. Hypertension may be a primary
disease, called "essential hypertension" or "idiopathic
hypertension", or it may be caused by other diseases, in which case
it is classified as "secondary hypertension". Essential
hypertension accounts for 90-95% of all cases.
[0364] As used herein, the term "resistant hypertension" refers to
hypertension that remains above goal blood pressure (usually less
than 140/90 mmHg, although a lower goal of less than 130/80 mmHg is
recommended for patients with comorbid diabetes or kidney disease),
in spite of concurrent use of three antihypertensive agents
belonging to different antihypertensive drug classes. People who
require four or more drugs to control their blood pressure are also
considered to have resistant hypertension.
[0365] Hypertension is an extremely common comorbid condition in
diabetes, affecting .about.20-60% of patients with diabetes,
depending on obesity, ethnicity, and age. This type of hypertension
is herein refered to as "diabetic hypertension". In type 2
diabetes, hypertension is often present as part of the metabolic
syndrome of insulin resistance also including central obesity and
dyslipidemia. In type 1 diabetes, hypertension may affect the onset
of diabetic nephropathy.
[0366] "Pulmonary hypertension (PH)", as used herein, is a disease
characterized by sustained elevations of blood pressure in the
pulmonary vasculature (pulmonary artery, pulmonary vein and
pulmonary capillaries), which results in cardiac hypertrophy, right
heart hypertrophy, eventually leading to right heart failure and
death. Common symptoms of PH include shortness of breath, dizziness
and fainting, all of which are exacerbated by exertion. Without
treatment, median life expectancy following diagnosis is 2.8 years.
PH exists in many different forms, which are categorized according
to their etiology. Categories include pulmonary arterial
hypertension (PAH), PH with left heart disease, PH associated with
lung diseases and/or hypoxaemia, PH due to chronic thrombotic
and/or embolic disease and miscellaneous PH. PAH is rare in the
general population, but the prevalence increases in association
with certain common conditions such as HIV infection, scleroderma
and sickle cell disease. Other forms of PH are generally more
common than PAH, and, for instance, the association of PH with
chronic obstructive pulmonary disease (COPD) is of particular
concern. Current treatment for pulmonary hypertension depends on
the stage and the mechanism of the disease.
[0367] As used herein "heart failure" is a progressive disorder of
left ventricular (LV) myocardial remodeling that culminates in a
complex clinical syndrome in which impaired cardiac function and
circulatory congestion are the defining features, and results in
insufficient delivery of blood and nutrients to body tissues. The
condition occurs when the heart is damaged or overworked and unable
to pump out all the blood that returns to it from the systemic
circulation. As less blood is pumped out, blood returning to the
heart backs up and fluid builds up in other parts of the body.
Heart failure also impairs the kidneys' ability to dispose of
sodium and water, complicating fluid retention further. Heart
failure is characterized by autonomic dysfunction, neurohormonal
activation and overproduction of cytokines, which contribute to
progressive circulatory failure. Symptoms of heart failure include:
dyspnea (shortness of breath) while exercising or resting and
waking at night due to sudden breathlessness, both indicative of
pulmonary edema; general fatigue or weakness, edema of the feet,
ankles and legs, rapid weight gain, chronic cough, including that
producing mucus or blood. Depending on its clinical presentation,
heart failure is classified as de novo, transient or chronic. Acute
heart failure, i.e. the rapid or gradual onset of symptoms
requiring urgent therapy, may develop de novo or as a result of
chronic heart failure becoming decompensated. Diabetes is a common
comorbidity in patients with heart failure and is associated with
poorer outcomes as well as potentially compromising the efficacy of
treatments. Other important comorbidities include systemic
hypertension, chronic airflow obstruction, sleep apnea, cognitive
dysfunction, anemia, chronic kidney disease and arthritis. Chronic
left heart failure is frequently associated with the development of
pulmonary hypertension. The frequency of certain comorbidities
varies by gender: among women, hypertension and thyroid disease are
more common, while men more commonly suffer from chronic
obstructive pulmonary disease, bronchoconstriction, pulmonary
vasoconstriction, acute pulmonary distress syndrome, peripheral
vascular disease, coronary artery disease and renal insufficiency.
Depression is a frequent comorbidity of heart failure and the two
conditions can and often do complicate one another. Cachexia has
long been recognized as a serious and frequent complication of
heart failure, affecting up to 15% of all heart failure patients
and being associated with poor prognosis. Cardiac cachexia is
defined as the nonedematous, nonvoluntary loss of at least 6% of
body weight over a period of six months.
[0368] The term "sleep apnea" refers to the most common of the
sleep-disordered breathing disorders. It is a condition
characterized by intermittent, cyclical reductions or total
cessations of airflow, which may or may not involve obstruction of
the upper airway. There are three types of sleep apnea: obstructive
sleep apnea, the most common form, central sleep apnea and mixed
sleep apnea.
[0369] "Central sleep apnea (CSA)", is caused by a malfunction in
the brain's normal signal to breathe, rather than physical blockage
of the airway. The lack of respiratory effort leads to an increase
in carbon dioxide in the blood, which may rouse the patient. CSA is
rare in the general population, but is a relatively common
occurrence in patients with systolic heart failure.
[0370] As used herein, the term "metabolic syndrome", "insulin
resistance syndrome" or "syndrome X", refers to a group or
clustering of metabolic conditions (abdominal obesity, elevated
fasting glucose, "dyslipidemia" (i.e,. elevated lipid levels) and
elevated blood pressure (HBP)) which occur together more often than
by chance alone and that together promote the development of type 2
diabetes and cardiovascular disease. Metabolic syndrome is
characterized by a specific lipid profile of increased
triglycerides, decreased high-density lipoprotein cholesterol
(HDL-cholesterol) and in some cases moderately elevated low-density
lipoprotein cholesterol (LDL-cholesterol) levels, as well as
accelerated progression of "atherosclerotic disease" due to the
pressure of the component risk factors. There are several types of
dyslipidemias: "hypercholesterolemia" refers to elevated levels of
cholesterol. Familial hypercholesterolemia is a specific form of
hypercholesterolemia due to a defect on chromosome 19
(19p13.1-13.3). "Hyperglyceridemia" refers to elevated levels of
glycerides (e.g., "hypertrigliceridemia" involves elevated levels
of triglycerides). "Hyperlipoproteinemia" refers to elevated levels
of lipoproteins (usually LDL unless otherwise specified).
[0371] As used herein, the term "peripheral vascular disease
(PVD)", also commonly referred to as "peripheral arterial disease
(PAD)" or "peripheral artery occlusive disease (PAOD)", refers to
the obstruction of large arteries not within the coronary, aortic
arch vasculature, or brain. PVD can result from atherosclerosis,
inflammatory processes leading to stenosis, an embolism, peripheral
embolism, or thrombus formation. It causes either acute or chronic
"ischemia (lack of blood supply)". Often PVD is a term used to
refer to atherosclerotic blockages found in the lower extremity.
PVD also includes a subset of diseases classified as microvascular
diseases resulting from episodal narrowing of the arteries (e.g.,
"Raynaud's phenomenon"), or widening thereof (erythromelalgia),
i.e. vascular spasms.
[0372] The term "thrombosis" refers to the formation of a blood
clot ("thrombus") inside a blood vessel, obstructing the flow of
blood through the circulatory system. When a blood vessel is
injured, the body uses platelets (thrombocytes) and fibrin to form
a blood clot to prevent blood loss. Alternatively, even when a
blood vessel is not injured, blood clots may form in the body if
the proper conditions present themselves. If the clotting is too
severe and the clot breaks free, the traveling clot is now known as
an "embolus". The term "thromboembolism" refers to the combination
of thrombosis and its main complication, "embolism". When a
thrombus occupies more than 75% of surface area of the lumen of an
artery, blood flow to the tissue supplied is reduced enough to
cause symptoms because of decreased oxygen (hypoxia) and
accumulation of metabolic products like lactic acid ("gout"). More
than 90% obstruction can result in anoxia, the complete deprivation
of oxygen, and "infarction", a mode of cell death.
[0373] An "embolism" (plural embolisms) is the event of lodging of
an embolus (a detached intravascular mass capable of clogging
arterial capillary beds at a site far from its origin) into a
narrow capillary vessel of an arterial bed which causes a blockage
(vascular occlusion) in a distant part of the body. This is not to
be confused with a thrombus which blocks at the site of origin.
[0374] A "stroke", or cerebrovascular accident (CVA), is the rapid
loss of brain function(s) due to disturbance in the blood supply to
the brain. This can be due to "ischemia" (lack of blood flow)
caused by blockage (thrombosis, arterial embolism, peripheral
embolism), or a hemorrhage (leakage of blood). As a result, the
affected area of the brain cannot function, which might result in
an inability to move one or more limbs on one side of the body,
inability to understand or formulate speech, or an inability to see
one side of the visual field. Risk factors for stroke include old
age, hypertension, previous stroke or transient ischemic attack
(TIA), diabetes, high cholesterol, cigarette smoking and atrial
fibrillation. High blood pressure is the most important modifiable
risk factor of stroke. An "ischemic stroke" is occasionally treated
in a hospital with thrombolysis (also known as a "clot buster"),
and some hemorrhagic strokes benefit from neurosurgery. Prevention
of recurrence may involve the administration of antiplatelet drugs
such as aspirin and dipyridamole, control and reduction of
hypertension, and the use of statins. Selected patients may benefit
from carotid endarterectomy and the use of anticoagulants.
[0375] "Ischemia", is a restriction in blood supply to tissues,
causing a shortage of oxygen and glucose needed for cellular
metabolism (to keep tissue alive). Ischemia is generally caused by
problems with blood vessels, with resultant damage to or
dysfunction of tissue. It also means local anemia in a given part
of a body sometimes resulting from congestion (such as
vasoconstriction, thrombosis or embolism).
[0376] According to the American Psychiatric Association's
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV), the term "sexual dysfunction" encompasses a
series of conditions "characterized by disturbances in sexual
desire and in the psychophysiological changes associated with the
sexual response cycle"; while problems of this type are common,
sexual dysfunction is only considered to exist when the problems
cause distress for the patient. Sexual dysfunction can be either
physical or psychological in origin. It can exist as a primary
condition, generally hormonal in nature, although most often it is
secondary to other medical conditions or to drug therapy for said
conditions. All types of sexual dysfunction can be further
classified as life-long, acquired, situational or generalized (or
combinations thereof).
[0377] The DSM-IV-TR specifies five major categories of "female
sexual dysfunction": sexual desire/interest disorders; "sexual
arousal disorders (including genital, subjective and combined)";
orgasmic disorder; dyspareunia and vaginismus; and persistent
sexual arousal disorder.
[0378] "Female sexual arousal disorder (FSAD)" is defined as a
persistent or recurring inability to attain or maintain sufficient
levels of sexual excitement, causing personal distress. FSAD
encompasses both the lack of subjective feelings of excitement
(i.e., subjective sexual arousal disorder) and the lack of somatic
responses such as lubrication and swelling (i.e., genital/physical
sexual arousal disorder). FSAD may be strictly psychological in
origin, although it generally is caused or complicated by medical
or physiological factors. Hypoestrogenism is the most common
physiologic condition associated with FSAD, which leads to
urogenital atrophy and a decrease in vaginal lubrication.
[0379] As used herein, "erectile dysfunction (ED)" is a male sexual
dysfunction characterized by the inability to develop or maintain
an erection of the penis during sexual performance. A penile
erection is the hydraulic effect of blood entering and being
retained in sponge-like bodies within the penis. The process is
often initiated as a result of sexual arousal, when signals are
transmitted from the brain to nerves in the penis. Erectile
dysfunction is indicated when an erection is difficult to produce.
The most important organic causes are cardiovascular disease and
diabetes, neurological problems (for example, trauma from
prostatectomy surgery), hormonal insufficiencies (hypogonadism) and
drug side effects. [0380] (1) Specific diseases of disorders which
may be treated and/or prevented by administering an sGC stimulator
of the invention, include but are not limited to: hypertension
(e.g., diabetic hypertension, arterial hypertension, portal
hypertension, pulmonary hypertension, resistant hypertension,
peripheral vascular disease, peripheral artery disease, etc), heart
failure (e.g., diastolic dysfunction, left ventricular diastolic
dysfunction (LVDD) and left ventricular systolic dysfunction
(LVSD), sleep apnea associated with heart failure),
arteriosclerotic disease (e.g., atherosclerosis), thromboembolic
disorders (e.g., chronic thromboembolic pulmonary hypertension,
thrombosis, obstructive thromboanginosis, stroke, embolism,
pulmonary embolism, peripheral embolism), renal diseases (e.g.,
renal fibrosis, ischemic renal disease,renal failure, renal
insufficiency, chronic kidney disease), hepatic disease (e.g.,liver
fibrosis or cirrhosis), respiratory disease (e.g., pulmonary
fibrosis, asthma, chronic obstructive pulmonary disease,
bronchoconstriction, pulmonary vasoconstriction, acute respiratory
distress syndrome, interstitial lung disease), sexual disorders
(e.g., erectile dysfunction, male and female sexual dysfunction,
vaginal atrophy), sickle cell anemia, neuro inflammatory diseases
or disorders and metabolic disorders (e.g., lipid related
disorders), wound healing (e.g., in diabetics), microvascular or
microcirculation abnormalities, control of vascular leakage and
permeability, endothelial dysfunction, inhibition of modulation of
platelet aggregation, anal fissures.
[0381] The compounds of Formula I and Formula Ib as well as
pharmaceutically acceptable salts thereof, as stimulators of sGC,
are useful in the prevention and/or treatment of the following
types of diseases, conditions and disorders which can benefit from
sGC stimulation: [0382] a. Peripheral, pulmonary, hepatic, liver,
cardiac or cerebral vascular/endothelial disorders/conditions:
[0383] disorders related to high blood pressure and decreased
coronary blood flow such as increased acute and chronic coronary
blood pressure, arterial hypertension and vascular disorder
resulting from cardiac and renal complications (e.g. heart disease,
stroke, cerebral ischemia, renal failure); resistant hypertension,
diabetic hypertension, diabetic nephropathy, congestive heart
failure; diastolic or sistolic dysfunction; coronary insufficiency;
arrhythmias; diastolic dysfunction; [0384] thromboembolic disorders
and ischemias such as myocardial infarction, stroke, transient
ischemic attacks (TIAs); stable or unstable angina pectoris; [0385]
peripheral arterial disease, peripheral occlusive arterial disease,
intermittent claudication, critical limb ischemia, vasculitis
[0386] pulmonary/respiratory conditions such as pulmonary
hypertension, pulmonary arterial hypertension, portal hypertension,
acute respiratory distress syndrome, and associated pulmonary
vascular remodeling (e.g. localized thrombosis and right heart
hypertrophy); pulmonary hypertonia; primary pulmonary hypertension,
secondary pulmonary hypertension, familial pulmonary hypertension,
sporadic pulmonary hypertension, pre-capillary pulmonary
hypertension, idiopathic pulmonary hypertension, thrombotic
pulmonary arteriopathy, plexogenic pulmonary arteriopathy; [0387]
pulmonary hypertension associated with or related to: left
ventricular dysfunction, hypoxemia, mitral valve disease,
constrictive pericarditis, aortic stenosis, cardiomyopathy,
mediastinal fibrosis, pulmonary fibrosis, anomalous pulmonary
venous drainage, pulmonary venooclusive disease, pulmonary
vasculitis, collagen vascular disease, congenital heart disease,
pulmonary venous hypertension, interstitial lung disease,
sleep-disordered breathing, sleep apnea, alveolar hypoventilation
disorders, chronic exposure to high altitude, neonatal lung
disease, alveolar-capillary dysplasia, sickle cell disease, other
coagulation disorders, chronic thromboembolism, pulmonary embolism
(due to tumor, parasites or foreign material), peripheral embolism,
connective tissue disease, lupus, schitosomiasis, sarcoidosis,
chronic obstructive pulmonary disease, bronchoconstriction,
pulmonary vasoconstriction, acute respiratory distress syndrome,
asthma, emphysema, chronic bronchitis, pulmonary capillary
hemangiomatosis; histiocytosis X, lymphangiomatosis and compressed
pulmonary vessels (such as due to adenopathy, tumor or fibrosing
mediastinitis); [0388] arterosclerotic diseases or conditions such
as atherosclerosis (e.g., associated with endothelial injury,
platelet and monocyte adhesion and aggregation, smooth muscle
proliferation and migration); restenosis (e.g. developed after
thrombolysis therapies, percutaneous transluminal angioplasties
(PTAs), percutaneous transluminal coronary angioplasties (PTCAs)
and bypass); inflammation; thrombogenic diseases; [0389]
cardiovascular disease associated with metabolic syndrome (e.g.,
obesity, dyslipidemia, diabetis, high blood pressure); lipid
related disorders such as dyslipidemia, hypercholesterolemia,
hypertriglyceridemia, sitosterolemia, fatty liver disease, and
hepatitis; [0390] liver cirrhosis, associated with chronic liver
disease, hepatic fibrosis, hepatic stellate cell activation,
hepatic fibrous collagen and total collagen accumulation; liver
disease of necro-inflammatory and/or of immunological origin;
andurogenital system disorders, such as renal fibrosis and renal
failure resulting from chronic kidney diseases or insufficiency
(e.g. due to accumulation/ deposition and tissue injury,
progressive sclerosis, glomerunephritis); prostate hypertrophy;
cardiac interstitial fibrosis, cardiac remodeling and fibrosis,
heart failure, cardiorenal syndrome; cardiac hypertrophy; diabetic
nephropathy [0391] b. sexual disorders of conditions: erectile
dysfunction; female sexual dysfunction (e.g., female sexual arousal
dysfunction), vaginal atrophy and incontinence. [0392] c. wound
healing (e.g., in diabetics), microvascular persufion improvement
(e.g., following injury, in perioperative care), microcirculation
abnormalities, control of vascular leakage and permeability, for
conserving blood substitutes in trauma patients, endothelial
dysfunction, inhibition of modulation of platelet aggregation, anal
fissures; shock, sepsis, cardiogenic shock, control of leukocite
activation; diabetic ulcers
[0393] In other embodiments of the invention, the compounds of
Formula I and Formula Ib as well as pharmaceutically acceptable
salts thereof are useful in the prevention and/or treatment of the
following types of diseases, conditions and disorders which can
benefit from sGC stimulation: [0394] hypertension, resistant
hypertension, diabetic hypertension, pulmonary hypertension (PH),
pulmonary arterial hypertension, PH associated with COPD, acute
respiratory distress syndrome, chronic airflow obstruction, asthma
or pulmonary fibrosis, thrombosis, obstructive thromboanginosis,
embolism, peripheral embolism, thromboembolic disorders,
atherosclerosis, right heart hypertrophy, heart failure, diastolic
dysfunction, systolic dysfunction, sleep apnea associated with
heart failure, liver cirrhosis, renal fibrosis, renal failure
resulting from chronic kidney diseases or insufficiency, metabolic
disorder, dyslipidemia, hypercholesterolemia, hypertriglyceridemia,
sitosterolemia, fatty liver disease, hepatitis, erectile
dysfunction, female sexual dysfunction, female sexual arousal
dysfunction, vaginal atrophy and wound healing.
[0395] The terms, "disease", "disorder" and "condition" may be used
interchangeably here to refer to an sGC, cGMP and/or NO mediated
medical or pathological condition.
[0396] As used herein, the terms "subject" and "patient" are used
interchangeably. The terms "subject" and "patient" refer to an
animal (e.g., a bird such as a chicken, quail or turkey, or a
mammal), specifically a "mammal" including a non-primate (e.g., a
cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and
mouse) and a primate (e.g., a monkey, chimpanzee and a human), and
more specifically a human. In some embodiments, the subject is a
non-human animal such as a farm animal (e.g., a horse, cow, pig or
sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In some
embodiments, the subject is a human.
[0397] The invention also provides a method for treating one of the
above diseases, conditions and disorders in a subject, comprising
administering a therapeutically effective amount of a compound of
Formula I and Formula Ib, or a pharmaceutically acceptable salt
thereof, to the subject in need of the treatment. Alternatively,
the invention provides the use of a compound of Formula I and
Formula Ib, or a pharmaceutically acceptable salt thereof, in the
treatment of one of these diseases, conditions and disorders in a
subject in need of the treatment. The invention further provides a
method of making or manufacturing a medicament useful for treating
one of these diseases, conditions and disorders comprising using a
compound of Formula I and Formula Ib, or a pharmaceutically
acceptable salt thereof.
[0398] The term "biological sample", as used herein, refers to an
in vitro or ex vivo sample, and includes, without limitation, cell
cultures or extracts thereof; biopsied material obtained from a
mammal or extracts thereof; blood, saliva, urine, faeces, semen,
tears, lymphatic fluid, ocular fluid, vitreous humour, or other
body fluids or extracts thereof.
[0399] "Treat", "treating" or "treatment" with regard to a disorder
or disease refers to alleviating or abrogating the cause and/or the
effects of the disorder or disease. As used herein, the terms
"treat", "treatment" and "treating" refer to the reduction or
amelioration of the progression, severity and/or duration of an
sGC, cGMP and/or NO mediated condition, or the amelioration of one
or more symptoms (preferably, one or more discernable symptoms) of
said condition (i.e. "managing" without "curing" the condition),
resulting from the administration of one or more therapies (e.g.,
one or more therapeutic agents such as a compound or composition of
the invention). In specific embodiments, the terms "treat";
"treatment" and "treating" refer to the amelioration of at least
one measurable physical parameter of an sGC, cGMP and/or NO
mediated condition. In other embodiments the terms "treat",
"treatment" and "treating" refer to the inhibition of the
progression of an sGC, cGMP and/or NO mediated condition, either
physically by, e.g., stabilization of a discernable symptom or
physiologically by, e.g., stabilization of a physical parameter, or
both.
[0400] The term "preventing" as used herein refers to administering
a medicament beforehand to avert or forestall the appearance of one
or more symptoms of a disease or disorder. The person of ordinary
skill in the medical art recognizes that the term "prevent" is not
an absolute term. In the medical art it is understood to refer to
the prophylactic administration of a drug to substantially diminish
the likelihood or seriousness of a condition, or symptom of the
condition and this is the sense intended in this disclosure. The
Physician's Desk Reference, a standard text in the field, uses the
term "prevent" hundreds of times. As used therein, the terms
"prevent", "preventing" and "prevention" with regard to a disorder
or disease, refer to averting the cause, effects, symptoms or
progression of a disease or disorder prior to the disease or
disorder fully manifesting itself
[0401] In one embodiment, the methods of the invention are a
preventative or "pre-emptive" measure to a patient, specifically a
human, having a predisposition (e.g. a genetic predisposition) to
developing an sGC, cGMP and/or NO related disease, disorder or
symptom.
[0402] In other embodiments, the methods of the invention are a
preventative or "pre-emptive" measure to a patient, specifically a
human, suffering from a disease, disorder or condition that makes
him at risk of developing an sGC, cGMP or NO related disease,
disorder or symptom.
[0403] The compounds and pharmaceutical compositions described
herein can be used alone or in combination therapy for the
treatment or prevention of a disease or disorder mediated,
regulated or influenced by sGC, cGMP and/or NO.
[0404] Compounds and compositions here disclosed are also useful
for veterinary treatment of companion animals, exotic animals and
farm animals, including, without limitation, dogs, cats, mice,
rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and
cattle.
[0405] In other embodiments, the invention provides a method of
stimulating sGC activity in a biological sample, comprising
contacting said biological sample with a compound or composition of
the invention. Use of a sGC stimulator in a biological sample is
useful for a variety of purposes known to one of skill in the art.
Examples of such purposes include, without limitation, biological
assays and biological specimen storage.
Combination Therapies
[0406] The compounds and pharmaceutical compositions described
herein can be used in combination therapy with one or more
additional therapeutic agents. For combination treatment with more
than one active agent, where the active agents are in separate
dosage formulations, the active agents may be administered
separately or in conjunction. In addition, the administration of
one element may be prior to, concurrent to, or subsequent to the
administration of the other agent.
[0407] When co-administered with other agents, e.g., when
co-administered with another pain medication, an "effective amount"
of the second agent will depend on the type of drug used. Suitable
dosages are known for approved agents and can be adjusted by the
skilled artisan according to the condition of the subject, the type
of condition(s) being treated and the amount of a compound
described herein being used. In cases where no amount is expressly
noted, an effective amount should be assumed. For example,
compounds described herein can be administered to a subject in a
dosage range from between about 0.01 to about 10,000 mg/kg body
weight/day, about 0.01 to about 5000 mg/kg body weight/day, about
0.01 to about 3000 mg/kg body weight/day, about 0.01 to about 1000
mg/kg body weight/day, about 0.01 to about 500 mg/kg body
weight/day, about 0.01 to about 300 mg/kg body weight/day, about
0.01 to about 100 mg/kg body weight/day.
[0408] When "combination therapy" is employed, an effective amount
can be achieved using a first amount of a compound of Formula I and
Formula Ib or a pharmaceutically acceptable salt thereof and a
second amount of an additional suitable therapeutic agent.
[0409] In one embodiment of this invention, a compound of Formula I
and Formula Ib and the additional therapeutic agent are each
administered in an effective amount (i.e., each in an amount which
would be therapeutically effective if administered alone). In
another embodiment, the compound of Formula I and Formula Ib and
the additional therapeutic agent are each administered in an amount
which alone does not provide a therapeutic effect (a
sub-therapeutic dose). In yet another embodiment, the compound of
Formula I and Formula Ib can be administered in an effective
amount, while the additional therapeutic agent is administered in a
sub-therapeutic dose. In still another embodiment, the compound of
Formula I and Formula Ib can be administered in a sub-therapeutic
dose, while the additional therapeutic agent, for example, a
suitable cancer-therapeutic agent is administered in an effective
amount.
[0410] As used herein, the terms "in combination" or
"co-administration" can be used interchangeably to refer to the use
of more than one therapy (e.g., one or more prophylactic and/or
therapeutic agents). The use of the terms does not restrict the
order in which therapies (e.g., prophylactic and/or therapeutic
agents) are administered to a subject.
[0411] Co-administration encompasses administration of the first
and second amounts of the compounds in an essentially simultaneous
manner, such as in a single pharmaceutical composition, for
example, capsule or tablet having a fixed ratio of first and second
amounts, or in multiple, separate capsules or tablets for each. In
addition, such co administration also encompasses use of each
compound in a sequential manner in either order. When
co-administration involves the separate administration of the first
amount of a compound of Formula I and Formula Ib and a second
amount of an additional therapeutic agent, the compounds are
administered sufficiently close in time to have the desired
therapeutic effect. For example, the period of time between each
administration which can result in the desired therapeutic effect,
can range from minutes to hours and can be determined taking into
account the properties of each compound such as potency,
solubility, bioavailability, plasma half-life and kinetic profile.
For example, a compound of Formula I and Formula Ib and the second
therapeutic agent can be administered in any order within about 24
hours of each other, within about 16 hours of each other, within
about 8 hours of each other, within about 4 hours of each other,
within about 1 hour of each other or within about 30 minutes of
each other.
[0412] More, specifically, a first therapy (e.g., a prophylactic or
therapeutic agent such as a compound described herein) can be
administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with,
or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a
second therapy (e.g., a prophylactic or therapeutic agent such as
an anti-cancer agent) to a subject.
[0413] Examples of other therapeutic agents that may be combined
with a compound of this disclosure, either administered separately
or in the same pharmaceutical composition, include, but are not
limited to: [0414] (1) Endothelium-derived releasing factor (EDRF);
[0415] (2) NO donors such as a nitrosothiol, a nitrite, a
sydnonimine, a NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine,
a nitrosimine, nitrotyrosine, a diazetine dioxide, an oxatriazole
5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a
hydroxyurea or a furoxan. Some examples of these types of compounds
include: glyceryl trinitrate (also known as GTN, nitroglycerin,
nitroglycerine, and trinitrogylcerin), the nitrate ester of
glycerol; sodium nitroprusside (SNP), wherein a molecule of nitric
oxide is coordinated to iron metal forming a square bipyramidal
complex; 3-morpholinosydnonimine (SIN-1), a zwitterionic compound
formed by combination of a morpholine and a sydnonimine;
S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acid
derivative with a nitrosothiol functional group;
diethylenetriamine/NO (DETA/NO), a compound of nitric oxide
covalently linked to diethylenetriamine; and NCX 4016, an
m-nitroxymethyl phenyl ester of acetyl salicylic acid. More
specific examples of some of these classes of NO donors include:
the classic nitrovasodilators, such as organic nitrate and nitrite
esters, including nitroglycerin, amyl nitrite, isosorbide
dinitrate, isosorbide 5-mononitrate, and nicorandil; Isosorbide
(Dilatrate.RTM.-SR, Imdur.RTM., Ismo.RTM., Isordil.RTM.,
Isordil.RTM., Titradose.RTM., Monoket.RTM.), FK 409 (NOR-3); FR
144420 (NOR-4); 3-morpholinosydnonimine; Linsidomine chlorohydrate
("SIN-1"); S-nitroso-N-acetylpenicillamine ("SNAP"); AZD3582 (CINOD
lead compound), NCX 4016, NCX 701, NCX 1022, HCT 1026, NCX 1015,
NCX 950, NCX 1000, NCX 1020, AZD 4717, NCX 1510/NCX 1512, NCX 2216,
and NCX 4040 (all available from NicOx S.A.), S-nitrosoglutathione
(GSNO), Sodium Nitroprusside, S-nitrosoglutathione mono-ethyl-ester
(GSNO-ester),
6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexanamine
(NOC-9) or diethylamine NONOate. Nitric oxide donors are also as
disclosed in U.S. Pat. Nos. 5,155,137, 5,366,997, 5,405,919,
5,650,442, 5,700,830, 5,632,981, 6,290,981, 5,691,423 5,721,365,
5,714,511, 6,511,911, and 5,814,666, Chrysselis et al. (2002) J Med
Chem. 45:5406-9 (such as NO donors 14 and 17), and Nitric Oxide
Donors for Pharmaceutical and Biological Research, Eds: Peng George
Wang, Tingwei Bill Cai, Naoyuki Taniguchi, Wiley, 2005; [0416] (3)
Other substances that enhance cGMP concentrations such as
protoporphyrin IX, arachidonic acid and phenyl hydrazine
derivatives; [0417] (4) Nitric Oxide Synthase substrates: for
example, n-hydroxyguanidine based analogs, such as
N[G]-hydroxy-L-arginine (NOHA),
1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguani dine, and
PR5
(1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine);
L-arginine derivatives (such as homo-Arg, homo-NOHA,
N-tert-butyloxy- and N-(3-methyl-2-butenyl)oxy-L-arginine,
canavanine, epsilon guanidine-carpoic acid, agmatine,
hydroxyl-agmatine, and L-tyrosyl-L-arginine);
N-alkyl-N'-hydroxyguanidines (such as
N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hydroxyguanidine),
N-aryl-N'-hydroxyguanidines (such as N-phenyl-N'-hydroxyguanidine
and its para-substituted derivatives which bear F, --Cl, -methyl,
--OH substituents, respectively); guanidine derivatives such as
3-(trifluormethyl) propylguanidine; and others reviewed in Cali et
al. (2005, Current Topics in Medicinal Chemistry 5:721-736) and
disclosed in the references cited therein; [0418] (5) Compounds
which enhance eNOS transcription: for example those described in WO
02/064146, WO 02/064545, WO 02/064546 and WO 02/064565, and
corresponding patent documents such as US2003/0008915,
US2003/0022935, US2003/0022939 and US2003/0055093. Other eNOS
transcriptional enhancers including those described in
US20050101599 (e.g. 2,2-difluorobenzo[1,3]dioxol-5-carboxylic acid
indan-2-ylamide, and 4-fluoro-N-(indan-2-yl)-benzamide), and
Sanofi-Aventis compounds AVE3085 and AVE9488 (CA Registry NO.
916514-70-0; Schafer et al., Journal of Thrombosis and Homeostasis
2005; Volume 3, Supplement 1: abstract number P1487); [0419] (6) NO
independent heme-independent sGC activators, including, but not
limited to:BAY 58-2667 (see patent publication DE19943635)
##STR00027##
[0419] HMR-1766 (ataciguat sodium, see patent publication
WO2000002851)
##STR00028##
S 3448
(2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholi-
ne-4-sulfonyl)-phenyl)-benzamide (see patent publications
DE19830430 and WO2000002851)
##STR00029##
and HMR-1069 (Sanofi-Aventis).
[0420] (7) Heme-dependent sGC stimulators including, but not
limited to:
[0421] YC-1 (see patent publications EP667345 and DE19744026)
##STR00030##
[0422] BAY 41-2272 (see patent publications DE19834047 and
DE19942809)
##STR00031##
[0423] BAY 41-8543 (see patent publication DE19834044)
##STR00032##
[0424] BAY 63-2521 (see patent publication DE19834044)
[0425] CFM-1571 (see patent publication WO2000027394)
##STR00033##
and other compounds disclosed in Tetrahedron Letters (2003),
44(48): 8661-8663. [0426] (8) Compounds that inhibit the
degradation of cGMP, such as: [0427] PDE5 inhibitors, such as, for
example, Sildenafil (Viagra.RTM.) and other related agents such as
Avanafil, Lodenafil, Mirodenafil, Sildenafil citrate
(Revatio.RTM.), Tadalafil (Cialis.RTM. or Adcirca.RTM.), Vardenafil
(Levitra.RTM.) and Udenafil; Alprostadil; and Dipyridamole; [0428]
(9) Calcium channel blockers such as: [0429] Dihydropyridine
calcium channel blockers: Amlodipine (Norvasc), Aranidipine
(Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa),
Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard),
Clevidipine (Cleviprex), Diltiazem, Efonidipine (Landel),
Felodipine (Plendil), Lacidipine (Motens, Lacipil), Lercanidipine
(Zanidip), Manidipine (Calslot, Madipine), Nicardipine (Cardene,
Carden SR), Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil),
Nimodipine (Nimotop), Nisoldipine (Baymycard, Sular, Syscor),
Nitrendipine (Cardif, Nitrepin, Baylotensin), Pranidipine (Acalas),
Isradipine (Lomir); [0430] Phenylalkylamine calcium channel
blockers: Verapamil (Calan, Isoptin)
##STR00034##
[0430] Gallopamil (Procorum, D600);
[0431] Benzothiazepines: Diltiazem (Cardizem);
##STR00035##
[0431] Nonselective calcium channel inhibitors such as: mibefradil,
bepridil and fluspirilene, fendiline [0432] (10) Endothelin
receptor antagonists (ERAs): for instance the dual (ETA and ETB)
endothelin receptor antagonist Bosentan (marketed as
Tracleer.RTM.); Sitaxentan, marketed under the name Thelin.RTM.;
Ambrisentan is marketed as Letairis.RTM. in U. S; dual/nonselective
endothelin antagonist Actelion-1, that entered clinical trials in
2008; [0433] (11) Prostacyclin derivatives or analogues: for
instance prostacyclin (prostaglandin 12), Epoprostenol (synthetic
prostacyclin, marketed as Flolan.RTM.); Treprostinil
(Remodulin.RTM.), Iloprost (Ilomedin.RTM.), Iloprost (marketed as
Ventavis.RTM.); oral and inhaled forms of Remodulin.RTM. that are
under development; Beraprost, an oral prostanoid available in Japan
and South Korea; [0434] (12) Antihyperlipidemics such as: bile acid
sequestrants (e.g., Cholestyramine, Colestipol, Colestilan and
Colesevelam); statins such as Atorvastatin, Simvastatin,
Lovastatin, Fluvastatin, Pitavastatin, Rosuvastatin and
Pravastatin; cholesterol absorption inhibitors such as Ezetimibe;
other lipid lowering agents such as Icosapent ethyl ester,
Omega-3-acid ethyl esters, Reducol;; fibric acid derivatives such
as Clofibrate, Bezafibrate, Clinofibrate, Gemfibrozil, Ronifibrate,
Binifibrate, Fenofirate, Ciprofibrate, Choline fenofibrate;
nicotinic acid derivatives such as Acipimox and Niacin; also
combinations of statins, niacin, intestinal cholesterol
absorption-inhibiting supplements (ezetimibe and others) and
fibrates; antiplatelet therapies such as Clopidogrel bisulfate;
[0435] (13) Anticoagulants, such as the following types: [0436]
Coumarines (Vitamin K antagonists): Warfarin.RTM. (Coumadin) mostly
used in the US and UK; Acenocoumarol.RTM. and Phenprocoumon.RTM.,
mainly used in other countries; Phenindione.RTM.; [0437] Heparin
and derivative substances such as: Heparin; low molecular weight
heparin, Fondaparinux and Idraparinux; [0438] Direct thrombin
inhibitors such as: Argatroban, Lepirudin, Bivalirudin and
Dabigatran; Ximelagatran (Exanta.RTM.), not approved in the US;
[0439] Tissue plasminogen activators, used to dissolve clots and
unblock arteries, such as Alteplase; [0440] (14) Antiplatelet
drugs: for instance thienopyridines such as Lopidogrel and
Ticlopidine; Dipyridamole; Aspirin; [0441] (15) ACE inhibitors, for
example the following types: [0442] Sulfhydryl-containing agents
such as Captopril (trade name Capoten.RTM.), the first ACE
inhibitor and Zofenopril; [0443] Dicarboxylate-containing agents
such as Enalapril (Vasotec/Renitec.RTM.); Ramipril
(Altace/Tritace/Ramace/Ramiwin.RTM.); Quinapril (Accupril.RTM.),
Perindopril (Coversyl/Aceon.RTM.); Lisinopril
(Lisodur/Lopril/Novatec/Prinivil/Zestril.RTM.) and Benazepril
(Lotensin.RTM.); [0444] Phosphonate-containing agents such as:
Fosinopril; [0445] Naturally occurring ACE inhibitors such as:
Casokinins and lactokinins, which are breakdown products of casein
and whey that occur naturally after ingestion of milk products,
especially cultured milk; The Lactotripeptides Val-Pro-Pro and
Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or
derived from casein also have ACE-inhibiting and antihypertensive
functions; [0446] Other ACE inhibitors such as Alacepril, Delapril,
Cilazapril, Imidapril, Trandolapril, Temocapril, Moexipril,
Spirapril, [0447] (16) Supplemental oxygen therapy; [0448] (17)
Beta blockers, such as the following types: [0449] Non-selective
agents: Alprenolol.RTM., Bucindolol.RTM., Carteolol.RTM.,
Carvedilol.RTM. (has additional .alpha.-blocking activity),
Labetalol.RTM. (has additional a-blocking activity), Nadolol.RTM.,
Penbutolol.RTM. (has intrinsic sympathomimetic activity),
Pindolol.RTM. (has intrinsic sympathomimetic activity), Oxprenonol,
Acebutolol, Sotalol, Mepindolol, Celiprolol, Arotinolol,
Tertatolol, Amosulalol, Nipradilol, Propranolol.RTM. and
Timolol.RTM.; [0450] .beta..sub.1-Selective agents: Acebutolol.RTM.
(has intrinsic sympathomimetic activity), Atenolol.RTM.,
Betaxolol.RTM., Bisoprolol.RTM., Celiprolol.RTM., Dobutamine
hydrochloride, Irsogladine maleate, Carvedilol, Talinolol,
Esmolol.RTM., Metoprolol.RTM. and Nebivolol.RTM.; [0451]
.beta..sub.2-Selective agents: Butaxamine.RTM. (weak
.alpha.-adrenergic agonist activity); [0452] (18) Antiarrhythmic
agents such as the following types: [0453] Type I (sodium channel
blockers): Quinidine, Lidocaine, Phenytoin, Propafenone [0454] Type
III (potassium channel blockers): Amiodarone, Dofetilide, Sotalol
[0455] Type V: Adenosine, Digoxin [0456] (19) Diuretics such as:
Thiazide diuretics, e.g., Chlorothiazide, Chlorthalidone, and
Hydrochlorothiazide, Bendroflumethiazide, Cyclopenthiazide,
Methyclothiazide, Polythiazide , Quinethazone, Xipamide,
Metolazone, Indapamide, Cicletanine; Loop diuretics, such as
Furosemide and Toresamide; potassium-sparing diuretics such as
Amiloride, Spironolactone, Canrenoate potassium, Eplerenone and
Triamterene; combinations of these agents; other diuretics such as
Acetazolamid and Carperitide [0457] (20a) Direct acting
vasodilators such as Hydralazine hydrochloride, Diazoxide, Sodium
nitroprusside, Cadralazine; other vasodilators such as Isosorbide
dinitrate and Isosorbide 5-mononitrate; [0458] (20b) Exogenous
vasodilators such as: [0459] Adenocard.RTM., an adenosine agonist,
primarily used as an anti-arrhythmic; [0460] Alpha blockers (which
block the vasoconstricting effect of adrenaline): [0461]
Alpha-1-adrenoceptor antagonists such as Prazosin, Indoramin,
Urapidil, Bunazosin, Terazosin, Doxazosin [0462] Atrial natriuretic
peptide (ANP); [0463] Ethanol; [0464] Histamine-inducers, which
complement proteins C3a, C4a and C5a work by triggering histamine
release from mast cells and basophil granulocytes; [0465]
Tetrahydrocannabinol (THC), major active chemical in marijuana
which has minor vasodilatory effects; [0466] Papaverine, an
alkaloid found in the opium poppy papaver somniferum;b [0467] (21)
Bronchodilators: there are two major types of bronchodilator,
.beta..sub.2 agonists and anticholinergics, exemplified below:
[0468] .beta..sub.2 agonists: Salbutamol.RTM. or albuterol (common
brand name: Ventolin) and Terbutaline.RTM. are short acting
.beta..sub.2 agonists for rapid relief of COPD symptoms. Long
acting .beta..sub.2 agonists (LABAs) such as Salmeterol.RTM. and
Formoterol.RTM.; [0469] anticholinergics: Ipratropium.RTM. is the
most widely prescribed short acting anticholinergic drug.
Tiotropium.RTM. is the most commonly prescribed long-acting
anticholinergic drug in COPD; [0470] Theophylline.RTM., a
bronchodilator and phosphodiesterase inhibitor; [0471] (22)
Corticosteroids: such as beclomethasone, methylprednisolone,
betamethasone, prednisone, prenisolone, triamcinolone,
dexamethasone, fluticasone, flunisolide and hydrocortisone, and
corticosteroid analogs such as budesonide [0472] (23) Dietary
supplements such as, for example: omega-3 oils; folid acid, niacin,
zinc, copper, Korean red ginseng root, ginkgo, pine bark, Tribulus
terrestris, arginine, Avena sativa, horny goat weed, maca root,
muira puama, saw palmetto, and Swedish flower pollen; Vitamin C,
Vitamin E, Vitamin K2; Testosterone supplements, Testosterone
transdermal patch; Zoraxel, Naltrexone, Bremelanotide (formerly
PT-141), Melanotan II, hMaxi-K; Prelox: a Proprietary
mix/combination of naturally occurring ingredients, L-arginine
aspartate and Pycnogenol; [0473] (24) PGD2 receptor antagonists
including, but not limited to, compounds described as having PGD2
antagonizing activity in United States Published Applications
US20020022218, US20010051624, and US20030055077, PCT Published
Applications WO9700853, WO9825919, WO03066046, WO03066047,
WO03101961, WO03101981, WO04007451, WO0178697, WO04032848,
WO03097042, WO03097598, WO03022814, WO03022813, and WO04058164,
European Patent Applications EP945450 and EP944614, and those
listed in: Torisu et al. 2004 Bioorg Med Chem Lett 14:4557, Torisu
et al. 2004 Bioorg Med Chem Lett 2004 14:4891, and Torisu et al.
2004 Bioorg & Med Chem 2004 12:4685; [0474] (25)
Immunosuppressants such as cyclosporine (cyclosporine A,
Sandimmune.RTM. Neoral.RTM.), tacrolimus (FK-506, Prograf.RTM.),
rapamycin (sirolimus, Rapamune.RTM.) and other FK-506 type
immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil
(CellCept.RTM.); [0475] (26) Non-steroidal anti-asthmatics such as
.beta.2-agonists (e.g., terbutaline, metaproterenol, fenoterol,
isoetharine, albuterol, salmeterol, bitolterol and pirbuterol) and
.beta.2-agonist-corticosteroid combinations (e.g.,
salmeterol-fluticasone (Advair.RTM.), formoterol-budesonid
(Symbicort.RTM.)), theophylline, cromolyn, cromolyn sodium,
nedocromil, atropine, ipratropium, ipratropium bromide, leukotriene
biosynthesis inhibitors (zileuton, BAY1005); [0476] (27)
Non-steroidal anti-inflammatory agents (NSAIDs) such as propionic
acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,
carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,
ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,
pirprofen, pranoprofen, suprofen, tiaprofenic acid and
tioxaprofen), acetic acid derivatives (e.g., indomethacin,
acemetacin, alclofenac, clidanac, diclofenac, fenclofenac,
fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac,
sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic
acid derivatives (e.g., flufenamic acid, meclofenamic acid,
mefenamic acid, niflumic acid and tolfenamic acid),
biphenylcarboxylic acid derivatives (e.g., diflunisal and
flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam and
tenoxican), salicylates (e.g., acetyl salicylic acid and
sulfasalazine) and the pyrazolones (e.g., apazone, bezpiperylon,
feprazone, mofebutazone, oxyphenbutazone and phenylbutazone);
[0477] (28) Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib
(Celebrex.RTM.), rofecoxib (Vioxx.RTM.), valdecoxib, etoricoxib,
parecoxib and lumiracoxib; (opioid analgesics such as codeine,
fentanyl, hydromorphone, levorphanol, meperidine, methadone,
morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine,
butorphanol, dezocine, nalbuphine and pentazocine; and [0478] (29)
Anti-diabetic agents such as insulin and insulin mimetics,
sulfonylureas (e.g., Glyburide, Glybenclamide, Glipizide,
Gliclazide, Gliquidone, Glimepiride, Meglinatide, Tolbutamide,
Chlorpropamide, Acetohexamide, Tolazamide), biguanides, e.g.,
metformin (Glucophage.RTM.), a-glucosidase inhibitors (such as
Acarbose, Epalrestat, Voglibose, Miglitol), thiazolidinone
compounds, e.g., rosiglitazone (Avandia.RTM.), troglitazone
(Rezulin.RTM.), ciglitazone, pioglitazone (Actos.RTM.) and
englitazone; insulin sensitizers such as Pioglitazone and
Rosiglitazone; Insulin secretagogues such as Repaglinide,
Nateglinide and Mitiglinide; Incretin mimetics such as Exanatide
and Liraglutide; Amylin analogues such as Pramlintide; glucose
lowering agents such as Chromiumm picolinate (optinally combined
with biotin); dipeptidyl peptidase IV inhibitors such as
Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin and Linagliptin;
vaccines currently being developed for the treatment of diabetes;
AVE-0277, Alum-GAD, BHT-3021, IBC-VS01; cytokine targeted therapies
in development for the treatment of diabetes such as Anakinra,
Canakinumab, Diacerein,Gevokizumab, LY-2189102, MABP-1, GIT-027;
drugs in development for the treatment of diabetes:
TABLE-US-00002 [0478] Drugs in development for the treatment of
diabetes Drug Name Organization Mechanism of Action Status
Dapagliflozin AstraZeneca/Bristol- SGLT-2 Inhibitors Recommended
Myers Squibb Approval Alogliptin Takeda Insulin Sensitizers/
Pre-Registered benzoate/metformin Dipeptidyl Peptidase
hydrochloride IV (CD26; DPP-IV; DP-IV) Inhibitors Anagliptin
Kowa/Sanwa Dipeptidyl Peptidase Pre-Registered IV (CD26; DPP-IV;
DP-IV) Inhibitors Insulin degludec Novo Nordisk Pre-Registered
Insulin degludec/insulin Novo Nordisk Pre-Registered aspart Insulin
human (rDNA MannKind Pre-Registered origin) inhalation powder
Lixisenatide Sanofi Insulin Pre-Registered Secretagogues/GLP- 1
Receptor Agonists Recombinant human Biodel Pre-Registered insulin
Teneligliptin Mitsubishi Tanabe Dipeptidyl Peptidase Pre-Registered
Pharma IV (CD26; DPP-IV; DP-IV) Inhibitors AVE-0277 Andromeda
Biotech/ Phase III Teva Albiglutide GlaxoSmithKline GLP-1 Receptor
Phase III Agonists Aleglitazar Roche PPARalpha Agonists/ Phase III
PPARgamma Agonists Atorvastatin GlaxoSmithKline K(ATP) Channel
Phase III calcium/glimepiride Blockers/Dipeptidyl Peptidase IV
(CD26; DPP-IV; DP-IV) Inhibitors/HMG-CoA Reductase Inhibitors/
TNFSF6 Expression Inhibitors BYK-324677 Nycomed Phase III
Balaglitazone Dr. Reddy's Insulin Sensitizers/ Phase III
Laboratories PPARgamma Partial Agonists CSG-452 Chugai SGLT-2
Inhibitors Phase III Pharmaceutical Canagliflozin Johnson &
Johnson/ SGLT-2 Inhibitors Phase III Mitsubishi Tanabe Pharma
Canagliflozin/metformin Johnson & Johnson SGLT-2 Inhibitors/
Phase III hydrochloride Insulin Sensitizers Dapagliflozin/Metformin
AstraZeneca/Bristol- SGLT-2 Inhibitors/ Phase III hydrochloride
Myers Squibb Insulin Sensitizers Dulaglutide Lilly Insulin Phase
III Secretagogues/GLP-1 Receptor Agonists Empagliflozin Boehringer
Ingelheim/ SGLT-2 Inhibitors Phase III Lilly
Empagliflozin/linagliptin Boehringer Ingelheim/ SGLT-2 Inhibitors/
Phase III Lilly Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV)
Inhibitors Gemigliptin LG Life Sciences Dipeptidyl Peptidase Phase
III IV (CD26; DPP-IV; DP-IV) Inhibitors Hepatic-directed vesicle
Diasome Phase III insulin Pharmaceuticals Human isophane insulin
Wockhardt Phase III IN-105 Biocon Phase III Insulin Novo Nordisk
Insulin Phase III degludec/liraglutide Secretagogues/GLP-1 Receptor
Agonists Insulin glargine Sanofi Phase III Ipragliflozin L-proline
Astellas Pharma/ SGLT-2 Inhibitors Phase III Kotobuki LY-2605541
Lilly Phase III LY-2963016 Lilly Phase III Lixisenatide/Insulin
Sanofi Insulin Phase III glargine Secretagogues/GLP-1 Receptor
Agonists Lobeglitazone sulfate Chong Kun Dang PPARalpha Agonists/
Phase III Pharm (CKD Pharm) PPARgamma Agonists/Insulin Sensitizers
Luseogliflozin Taisho SGLT-2 Inhibitors Phase III Otelixizumab
Tolerx Anti-CD3 Phase III Ranolazine Gilead Sodium Channel Phase
III Blockers Recombinant human National Institute of Phase III
insulin Health Sciences Sitagliptin phosphate Merck & Co.
PPARgamma Phase III monohydrate/pioglitazone Agonists/Insulin
hydrochloride Sensitizers/ Dipeptidyl Peptidase IV (CD26; DPP-IV;
DP-IV) Inhibitors Sitagliptin/atorvastatin Merck & Co.
Dipeptidyl Peptidase Phase III calcium IV (CD26; DPP-IV; DP-IV)
Inhibitors/ HMG-CoA Reductase Inhibitors/TNFSF6 Expression
Inhibitors TAK-875 Takeda Free Fatty Acid Phase III Receptor 1
(FFAR1; GPR40) Agonists/ Insulin Secretagogues TT-401 7TM Pharma
Cannabinoid CB1 Phase I Antagonists TT-401 Transition Phase I
Therapeutics ZYH-2 Cadila Healthcare PPARalpha Ligands/ Phase I
(d/b/a Zydus Cadila) PPARgamma Ligands ZYO-1 Cadila Healthcare
Cannabinoid CB1 Phase I (d/b/a Zydus Cadila) Antagonists 701645
Cellonis Phase I Biotechnologies 701499 Cellonis Phase I
Biotechnologies 743300 University of Phase I California, San
Francisco 448661 University of Phase I Pittsburgh AD-1 National
Institute Clinical Pharma Res Dev Colesevelam Daiichi Sankyo Bile
Acid Clinical hydrochloride Sequestrants DBPR-108 National Health
IND Filed Research Institutes/ ScinoPharm Nodlin Biolaxy IND Filed
PSN-491 Prosidion Glucose-Dependent IND Filed Insulinotropic
Receptor (GDIR, GPR119) Agonists/ Dipeptidyl Peptidase IV (CD26;
DPP-IV; DP-IV) Inhibitors Tolimidone Melior Discovery Lyn Kinase
Activators IND Filed ZYD-1 Cadila Healthcare GLP-1 Receptor IND
Filed (d/b/a Zydus Cadila) Agonists ZYOG-1 Cadila Healthcare GLP-1
Receptor IND Filed (d/b/a Zydus Cadila) Agonists
[0479] (30) HDL cholesterol-increasing agents such as Anacetrapib,
MK-524A, CER-001, DRL-17822, Dalcetrapib, JTT-302, RVX-000222,
TA-8995; [0480] (31) Antiobesity drugs such as Methamphetamine
hydrochloride, Amfepramone hydrochloride (Tenuate.RTM.),
Phentermine (Ionamin.RTM.), Benzfetamine hydrochloride
(Didrex.RTM.), Phendimetrazine tartrate (Bontril.RTM.,
Prelu-2.RTM., Plegine.RTM.), Mazindol (Sanorex.RTM.), Orlistat
(Xenical.RTM.), Sibutramine hydrochloride monohydrate
(Meridia.RTM., Reductil.RTM.), Rimonabant (Acomplia.RTM.),
Amfepramone, Chromium picolinate, RM-493, TZP-301; combination such
as Phentermine/Topiramate, Bupropion/Naltrexone,
Sibutramine/Metformin, Bupropion SR/Zonisamide SR, Salmeterol,
xinafoate/fluticasone propionate; Lorcaserin hydrochloride,
Phentermine/topiramate, Bupropion/naltrexone, Cetilistat,
Exenatide, KI-0803, Liraglutide, Metformin hydrochloride,
Sibutramine/Metformin, 876167, ALS-L-1023, Bupropion SR/Zonisamide
SR, CORT-108297, Canagliflozin, Chromium picolinate, GSK-1521498,
LY-377604, Metreleptin, Obinepitide, P-57AS3, PSN-821, Salmeterol
xinafoate/fluticasone propionate, Sodium tungstate, Somatropin
(recombinant), TM-30339, TTP-435, Tesamorelin, Tesofensine,
Velneperit, Zonisamide, BMS-830216, ALB-127158, AP-1030, ATHX-105,
AZD-2820, AZD-8329, Beloranib hemioxalate, CP-404, HPP-404,
ISIS-FGFR4Rx, Insulinotropin, KD-3010PF, 05212389, PP-1420,
PSN-842, Peptide YY3-36, Resveratrol, S-234462; S-234462,
Sobetirome, TM-38837, Tetrahydrocannabivarin, ZYO-1,
beta-Lapachone; [0481] 32) Angiotensin receptor blockers such as
Losartan, Valsartan, Candesartan cilexetil, Eprosaran, Irbesartan,
Telmisartan, Olmesartran medoxomil, Azilsartan medoxomil; [0482]
(33) Renin inhibitors such as Aliskiren hemifumirate; [0483] (34)
Centrally acting alpha-2-adrenoceptor agonists such as Methyldopa,
Clonidine, Guanfacine; [0484] (35) Adrenergic neuron blockers such
as Guanethidine, Guanadrel; [0485] (36) Imidazoline I-1 receptor
agonists such as Rimenidine dihydrogen phosphate and Moxonidine
hydrochloride hydrate; [0486] (37) Aldosterone antagonists such as
Spironolactone and Eplerenone [0487] (38) Potassium channel
activators such as Pinacidil [0488] (39) Dopamine D1 agonists such
as Fenoldopam mesilate; Other dopamine agonists such as Ibopamine,
Dopexamine and Docarpamine; [0489] (40) 5-HT2 antagonists such as
Ketanserin; [0490] (41) Drugs that are currently being developed
for the treatment of arterial hypertension:
TABLE-US-00003 [0490] Drug Name Organization Mechanism of Action
Status Azilsartan Takeda Angiotensin AT1 Registered Antagonists/
Angiotensin AT2 Antagonists/ Insulin Sensitizers Amlodipine
besylate/irbesartan Dainippon Sumitomo Angiotensin AT1
Pre-Registered Pharma Antagonists/ Calcium Channel Blockers
Azilsartan/amlodipine besilate Takeda Angiotensin AT1 Phase III
Antagonists/ Insulin Sensitizers/ Calcium Channel Blockers
Cilnidipine/valsartan Ajinomoto/Mochida Angiotensin AT1 Phase III
Antagonists/ Calcium Channel Blockers Fimasartan Boryung
Angiotensin AT1 Phase III Antagonists Irbesartan/atorvastatin Hanmi
Angiotensin AT1 Phase III Antagonists/ Dipeptidyl Peptidase IV
(CD26; DPP-IV; DP-IV) Inhibitors/HMG- CoA Reductase Inhibitors/
TNFSF6 Expression Inhibitors Irbesartan/trichlormethiazide Shionogi
Angiotensin AT1 Phase III Antagonists Losartan Merck & Co.
Angiotensin AT1 Phase III potassium/hydrochlorothiazide/
Antagonists/ amlodipine besylate Calcium Channel Blockers
Pratosartan Boryung Angiotensin AT1 Phase III Antagonists
ACT-280778 Actelion Phase II Amiloride Hemodynamic
Mineralocorticoid Phase II hydrochloride/spironolactone
Therapeutics Receptor (MR) Antagonists/ Na+/H+ Exchanger (NHE)
Inhibitors/ Epithelial Sodium Channels (ENaC) Blockers/ K(V)1.5
Channel Blockers/ K(V)4.3 Channel Blockers Angiotensin
vaccine/CoVaccine HT BTG Phase II CYT006-AngQb Cytos Biotechnology
Anti-Angiotensin Phase II II Cholecalciferol Emory University Phase
II Cobiprostone Sucampo CIC-2 Channel Phase II Pharmaceuticals
Activators INT-001 IntelGenx Phase II LCZ-696 Novartis Angiotensin
AT1 Phase II Antagonists/ Neprilysin (Enkephalinase, Neutral
Endopeptidase, NEP) Inhibitors LFF-269 Novartis Phase II Octreotide
acetate Chiasma Growth Hormone Phase II Release Inhibitors/
Somatostatin Agonists PL-3994 Palatin Technologies Atrial
Natriuretic Phase II Peptide A (NPR1; Guanylate Cyclase A) Receptor
Agonists Rostafuroxine Sigma-Tau Phase II SLx-2101 NT Life Sciences
Phosphodiesterase Phase II V (PDE5A) Inhibitors TBC-3711 Encysive
Endothelin ETA Phase II Pharmaceuticals Receptor Antagonists
Udenafil Dong-A/Falk Pharma Phosphodiesterase Phase II V (PDE5A)
Inhibitors Atorvastatin calcium/losartan HanAll BioPharma
Angiotensin AT1 Phase I potassium Antagonists/ Dipeptidyl Peptidase
IV (CD26; DPP-IV; DP-IV) Inhibitors/HMG- CoA Reductase Inhibitors/
TNFSF6 Expression Inhibitors BIA-5-1058 BIAL Dopamine beta- Phase I
monooxygenase Inhibitors CS-3150 Daiichi Sankyo Phase I DSP-9599
Dainippon Sumitomo Renin Inhibitors Phase I Pharma MK-1597
Actelion/Merck & Co. Renin Inhibitors Phase I MK-4618 Merck
& Co. Phase I MK-5478 Merck & Co. Phase I MK-7145 Merck
& Co. Phase I MK-8266 Merck & Co. Phase I MK-8457 Merck
& Co. Phase I MP-157 Mitsubishi Tanabe Angiotensin AT2 Phase I
Pharma Agonists MT-3995 Mitsubishi Tanabe Mineralocorticoid Phase I
Pharma Receptor (MR) Antagonists Mirodenafil hydrochloride SK
Chemicals Phosphodiesterase Phase I V (PDE5A) Inhibitors NV-04
Novogen Antioxidants Phase I Nifedipine/Candesartan cilexetil Bayer
Angiotensin AT1 Phase I Antagonists/ Calcium Channel Blockers/
Antioxidants QGC-001 Quantum Genomics Glutamyl Phase I
Aminopeptidase (Aminopeptidase A) Inhibitors RDX-5791 Ardelyx
Na+/H+ Phase I Exchanger type 3 (NHE-3) Inhibitors TAK-272 Takeda
Renin Inhibitors Phase I TAK-591 Takeda Angiotensin AT2 Phase I
Antagonists VTP-27999 Vitae Pharmaceuticals Renin Inhibitors Phase
I Vasomera PhaseBio VPAC2 (VIP2) Phase I Agonists Tylerdipine
hydrochloride Sihuan Calicum Channel IND Filed Pharmaceutical
Blockers
[0491] (42) Vasopressin antagonists such as Tolvaptan; [0492] (43)
Calcium channel sensitizers such as Levosimendan or activators such
as Nicorandil; [0493] (44) PDE-3 inhibitors such as Amrinone,
Milrinone, Enoximone, Vesnarinone, Pimobendan, Olprinone; [0494]
(45) Adenylate cyclase activators such as Colforsin dapropate
hydrochloride; [0495] (46) Positive inotropic agents such as
Digoxin and Metildigoxin; metabolic cardiotonic agents such as
Ubidecarenone; brain naturetic peptides such as Nesiritide; [0496]
(47) Drugs that are currently in development for the treatment of
heart failure:
TABLE-US-00004 [0496] Drugs in development for the treatment of
heart failure Drug Name Organization Mechanism of Action Status
Bucindolol ARCA beta-Adrenoceptor Pre-Registered hydrochloride
Antagonists Aliskiren Novartis Renin Inhibitors Phase III
hemifumarate Ferric Vifor Phase III carboxymaltose LCZ-696 Novartis
Angiotensin AT1 Phase III Antagonists/Neprilysin (Enkephalinase,
Neutral Endopeptidase, NEP) Inhibitors Neuregulin-1 Zensun Phase
III Olmesartan Tohoku University Angiotensin AT1 Phase III
medoxomil Antagonists C3BS-CQR-1 Cardio3 BioSciences Phase II/III
MyoCell Bioheart Phase II/III Serelaxin Novartis Phase II/III
AAV1/SERCA2a AmpliPhi Biosciences/ Phase II Celladon/Mount Sinai
School of Medicine Albiglutide GlaxoSmithKline GLP-1 Receptor Phase
II Agonists Allogeneic Mesoblast Phase II mesenchymal precursor
cells AlsterMACS Miltenyi Biotec Phase II BAY-94-8862 Bayer
Mineralocorticoid Phase II Receptor (MR) Antagonists COR-1 Corimmun
Phase II CXL-1020 Cardioxyl Nitric Oxide Donors Phase II
Pharmaceuticals Cenderitide Nile Therapeutics Guanylate Cyclase
Phase II Activators Endometrial ERCell/Medistem Phase II
regenerative cells JNJ-39588146 Johnson & Johnson Phase II
Omecamtiv Amgen/Cytokinetics Cardiac Myosin Phase II mecarbil
Activators PL-3994 Palatin Technologies Atrial Natriuretic Phase II
Peptide A (NPR1; Guanylate Cyclase A) Receptor Agonists
Remestemcel-L Osiris Phase II TRV-120027 Trevena Angiotensin AT1
Phase II Receptor Ligands Urocortin 2 Neurocrine CRF2 Agonists
Phase II Biosciences AAV6-CMV- Imperial College Phase I/II SERCA2a
Anakinra National Institutes of IL-1 Receptor Phase I/II Health
(NIH) Antagonists LipiCell Bioheart/Instituto de Phase I/II
Medicina Regenerativa ALD-201 Cytomedix/Texas Phase I Heart
Institute BAY-1021189 Bayer Phase I BAY-1067197 Bayer Adenine
Receptor Phase I Agonists BAY-86-8050 Bayer Drugs Acting on Phase I
Vasopressin (AVP) Receptors BIA-5-1058 BIAL Dopamine beta- Phase I
monooxygenase Inhibitors CSCs University of Phase I Louisville
Calcitonin gene VasoGenix Phase I related peptide JVS-100 Juventas
Phase I Therapeutics MyoCell SDF-1 Bioheart Phase I Myoblast
Advanced Cell Phase I Technology (ACT) RO-1160367 Serodus 5-HT4
Antagonists Phase I Recombinant Acorda/Vanderbilt Phase I human
glial University growth factor 2 [18F]LMI-1195 Lantheus Medical
Phase I Imaging 677950 Kyoto Prefectural Phase I University of
Medicine
[0497] (48) Drugs currently in develonment for the treatment of
nulmonary hvnertension:
TABLE-US-00005 [0497] Drugs in development for the treatment of
pulmonary hypertension Drug Name Organization Mechanism of Action
Status Imatinib Novartis Breast Cancer-Resistant Protein (BCRP;
Pre-Registered mesylate ABCG2) Inhibitors/Abl Kinase Inhibitors/
Angiogenesis Inhibitors/Bcr-Abl Kinase Inhibitors/CSF1R (c-FMS)
Inhibitors/KIT (C-KIT) Inhibitors/Apoptosis Inducers/ PDGFRalpha
Inhibitors/PDGFRbeta Inhibitors/Inhibitors of Signal Transduction
Pathways Treprostinil United Prostacyclin Analogs Pre-Registered
diethanolamine Therapeutics GSK-1325760A GlaxoSmithKline Phase III
Macitentan Actelion Endothelin ETA Receptor Antagonists/ Phase III
Endothelin ETB Receptor Antagonists Riociguat Bayer Guanylate
Cyclase Activators Phase III Selexipag Actelion/Nippon Prostanoid
IP Agonists Phase III Shinyaku Udenafil Dong-A Phosphodiesterase V
(PDE5A) Inhibitors Phase III L-Citrulline Nat Heart, Lung, Phase
II/III and Blood Institute/ Vanderbilt University BQ-123 Brigham
& Endothelin ETA Receptor Antagonists Phase II Women's Hospital
Cicletanine Gilead Phase II Fasudil Asahi Kasei Rho Kinase
Inhibitors/Calcium Phase II hydrochloride Sensitizers Nilotinib
Novartis Bcr-Abl Kinase Inhibitors/Apoptosis Phase II hydrochloride
Inducers/Inhibitors of Signal monohydrate Transduction Pathways
PRX-08066 Clinical Data 5-HT2B Antagonists Phase II Terguride
ErgoNex 5-HT2A Antagonists/5-HT2B Phase II Pharma
Antagonists/Dopamine Autoreceptor Agonists/Dopamine D2 Receptor
Partial Agonists/Prolactin Secretion Inhibitors Tezosentan Actelion
Endothelin ETA Receptor Antagonists/ Phase II disodium Endothelin
ETB Receptor Antagonists Anakinra Virginia IL-1 Receptor
Antagonists Phase I/II Commonwealth University (VCU) Simvastatin
Imperial College HDL-Cholesterol Increasing Agents/ Phase I/II
HMG-CoA Reductase Inhibitors 99mTC- Montreal Heart Phase I
PulmoBind Institute (MHI) APD-811 Arena Prostanoid IP Agonists
Phase I Sorafenib Bayer Raf kinase B Inhibitors/Raf kinase C Phase
I Inhibitors/Angiogenesis Inhibitors/Flt3 (FLK2/STK1)
Inhibitors/VEGFR-1 (Flt-1) Inhibitors/KIT (C-KIT) Inhibitors/
VEGFR-2 (FLK-1/KDR) Inhibitors/VEGFR- 3 (FLT4) Inhibitors/PDGFRbeta
Inhibitors/RET Inhibitors/Inhibitors of Signal Transduction
Pathways Triplelastat Proteo Biotech Elastase Inhibitors Phase I
2586881 Apeiron Preclinical Biologics C-122 Corridor Caspase 3
Activators/Dopamine D1 Preclinical Pharmaceuticals
Antagonists/5-HT2B Antagonists/5-HT7 Antagonists/Caspase 8
Activators/ Dopamine D2 Antagonists/Dopamine D3
Antagonists/Histamine H1 Receptor Antagonists/Caspase 9 Activators/
Apoptosis Inducers PLX-I United Angiogenesis Inducers Preclinical
Therapeutics
[0498] (49) Drugs in current development for the treatment of
female sexual dysfunction:
TABLE-US-00006 [0498] Drugs in active development for the treatment
of female sexual dysfunction Mechanism Drug Name Organization of
Action Status Alprostadil Apricus Phase III Biosciences/ VIVUS
Prasterone EndoCeutics/ HSD11B1 Phase III Monash Expression
University Inhibitors Testosterone BioSante Androgen Phase III
transdermal gel Receptor Agonists Bremelanotide Palatin
Melanocortin Phase II Technologies MC3 Receptor Agonists/
Melanocortin MC4 Receptor Agonists Pill-Plus Pantarhei Phase II
Bioscience Testosterone MDTS Acrux Androgen Phase II Receptor
Agonists Estradiol/testosterone BioSante Estrogen Phase I Receptor
(ER) Agonists/ Androgen Receptor Agonists LGD-2941 Ligand Selective
Phase I Androgen Receptor Modulators (SARM) Lidocaine/heparin
Urigen Phase I OnabotulinumtoxinA Allergan Phase I S1P-104 S1
Biopharma IND Filed PL-6983 Palatin Preclinical Technologies
S1P-401 S1 Biopharma Preclinical
[0499] (50) Drugs used for the treatment of erectile dysfunction
such as Alprostadil, Aviptadil, Phentolamine mesilate, Weige,
Alprostadil; [0500] (51) Drugs currently in development for the
treatment of male sexual dysfunction:
TABLE-US-00007 [0500] Drugs in active development for the treatment
of erectile dysfunction Mechanism of Drug Name Organization Action
Status Fluvastatin Novartis Apoptosis Phase III sodium
Inducers/HMG- CoA Reductase Inhibitors Lodenafil Cristalia
Phosphodiesterase Phase III carbonate V (PDE5A) Inhibitors EFLA-400
Chonbuk Phase II/III National University Hospital Apomorphine
Vectura Dopamine D2 Phase II hydrochloride Agonists LY-900010 Lilly
Phosphodiesterase Phase II V (PDE5A) Inhibitors/ Selective Androgen
Receptor Modulators (SARM) Nitroglycerin Futura Medical Phase II
RX-10100 Rexahn Drugs Acting on Phase II Dopaminergic Transmission/
Drugs Acting on Serotonergic Transmission YHD-1023 Yuhan Phase II
INT-007 IntelGenx Phase I LY-2452473 Lilly Selective Phase I
Androgen Receptor Modulators (SARM) hMaxi-K Albert Einstein Phase I
College of Medicine/Ion Channel Innovations/ Mount Sinai School of
Medicine KH-204 KMSI Clinical CKD-533 Chong Kun Dang
Phosphodiesterase Preclinical Pharm (CKD V (PDE5A) Pharm)
Inhibitors MP-52 Biopharm Preclinical TGHW01AP Fabre-Kramer
Dopamine D1 Preclinical Agonists/ Dopamine D2 Agonists
[0501] (51) Drugs in development for the treatment of sleep
apnea:
TABLE-US-00008 [0501] Drugs in development for the treatment of
sleep apnea Mechanism of Drug Name Organization Action Status
CX-1739 Cortex AMPA Receptor Phase II Modulators
Phentermine/topiramate VIVUS AMPA Phase II Antagonists/ Kainate
Antagonists/ Sodium Channel Blockers/ Carbonic Anhydrase Type II
Inhibitors AVE-0118 Sanofi Potassium Phase I Channel Blockers
Suvorexant Merck & Co. Orexin Receptor Phase I Antagonists
COL-132 Collegium Clinical Pharmaceutical
[0502] (52) Drugs currently in development for the treatment of
metabolic syndrome:
TABLE-US-00009 [0502] Drug Name Organization Mechanism of Action
Status Antiobesity drugs under active development for the treatment
of patients with metabolic syndrome Chromium University of Phase II
picolinate Pennsylvania RM-493 Ipsen Melanocortin MC4 XPreclinical
Receptor Agonists TZP-301 Tranzyme GHS Receptor Preclinical
Antagonists Antihyperlipidemic drugs under active development for
the treatment of patients with metabolic syndrome GFT-505 Genfit
PPARalpha Phase II Agonists/ PPARdelta Agonists MBX-8025 Metabolex
PPARdelta Phase II Agonists Pitavastatin Kowa APOA1 Phase I calcium
Expression Enhancers/ HMG-CoA Reductase Inhibitors/ SPP1
(Osteopontin) Expression Inhibitors CDX-085 Cardax Antioxidants
Preclinical Pharmaceuticals
[0503] (53) Antiobesity drugs:
TABLE-US-00010 [0503] Drugs marketed for the treatment of obesity
Mechanism of Year and country Drug Name Organization Action of
first launch Methamphetamine Abbott Noradrenergic, alpha- 1943
(U.S.) hydrochloride and beta- (Desoxyn) adrenoceptor agonist
Amfepramone Sanofi Noradrenergic release 1959 (U.S.) hydrochloride
stimulant (Tenuate) Phentermine UCB Celltech Noradrenergic release
1959 (U.S.) (Ionamin) stimulant Benzfetamine Pfizer Noradrenergic
release 1960 (U.S.) hydrochloride stimulant (Didrex)
Phendimetrazine Pfizer Noradrenergic release 1961 (U.S.) tartrate
(Bontril, stimulant Prelu-2, Plegine) Mazindol (Sanorex) Novartis
Noradrenergic 1973 (U.S.) reuptake inhibitor Orlistat (Xenical)
Roche Pancreatic lipase 1998 (New Zealand) inhibitor Sibutramine
Abbott Norepinephrine and 5- 1998 (U.S.) (withdrawn hydrochloride
HT reuptake inhibitor 2010) monohydrate (Meridia, Reductil)
Rimonabant Sanofi Cannabinoid CB1 2006 (U.K.) (withdrawn (Acomplia)
antagonist 2008)
Kits
[0504] The compounds and pharmaceutical formulations described
herein may be contained in a kit. The kit may include single or
multiple doses of two or more agents, each packaged or formulated
individually, or single or multiple doses of two or more agents
packaged or formulated in combination. Thus, one or more agents can
be present in first container, and the kit can optionally include
one or more agents in a second container. The container or
containers are placed within a package, and the package can
optionally include administration or dosage instructions. A kit can
include additional components such as syringes or other means for
administering the agents as well as diluents or other means for
formulation. Thus, the kits can comprise: a) a pharmaceutical
composition comprising a compound described herein and a
pharmaceutically acceptable carrier, vehicle or diluent; and b) a
container or packaging. The kits may optionally comprise
instructions describing a method of using the pharmaceutical
compositions in one or more of the methods described herein (e.g.
preventing or treating one or more of the diseases and disorders
described herein). The kit may optionally comprise a second
pharmaceutical composition comprising one or more additional agents
described herein for co therapy use, a pharmaceutically acceptable
carrier, vehicle or diluent. The pharmaceutical composition
comprising the compound described herein and the second
pharmaceutical composition contained in the kit may be optionally
combined in the same pharmaceutical composition.
[0505] A kit includes a container or packaging for containing the
pharmaceutical compositions and may also include divided containers
such as a divided bottle or a divided foil packet. The container
can be, for example a paper or cardboard box, a glass or plastic
bottle or jar, a re-sealable bag (for example, to hold a "refill"
of tablets for placement into a different container), or a blister
pack with individual doses for pressing out of the pack according
to a therapeutic schedule. It is feasible that more than one
container can be used together in a single package to market a
single dosage form. For example, tablets may be contained in a
bottle which is in turn contained within a box.
[0506] An example of a kit is a so-called blister pack. Blister
packs are well known in the packaging industry and are being widely
used for the packaging of pharmaceutical unit dosage forms
(tablets, capsules, and the like). Blister packs generally consist
of a sheet of relatively stiff material covered with a foil of a
preferably transparent plastic material. During the packaging
process, recesses are formed in the plastic foil. The recesses have
the size and shape of individual tablets or capsules to be packed
or may have the size and shape to accommodate multiple tablets
and/or capsules to be packed. Next, the tablets or capsules are
placed in the recesses accordingly and the sheet of relatively
stiff material is sealed against the plastic foil at the face of
the foil which is opposite from the direction in which the recesses
were formed. As a result, the tablets or capsules are individually
sealed or collectively sealed, as desired, in the recesses between
the plastic foil and the sheet. Preferably the strength of the
sheet is such that the tablets or capsules can be removed from the
blister pack by manually applying pressure on the recesses whereby
an opening is formed in the sheet at the place of the recess. The
tablet or capsule can then be removed via said opening.
[0507] It may be desirable to provide written memory aid containing
information and/or instructions for the physician, pharmacist or
subject regarding when the medication is to be taken. A "daily
dose" can be a single tablet or capsule or several tablets or
capsules to be taken on a given day. When the kit contains separate
compositions, a daily dose of one or more compositions of the kit
can consist of one tablet or capsule while a daily dose of another
or more compositions of the kit can consist of several tablets or
capsules. A kit can take the form of a dispenser designed to
dispense the daily doses one at a time in the order of their
intended use. The dispenser can be equipped with a memory-aid, so
as to further facilitate compliance with the regimen. An example of
such a memory-aid is a mechanical counter which indicates the
number of daily doses that have been dispensed. Another example of
such a memory-aid is a battery-powered micro-chip memory coupled
with a liquid crystal readout, or audible reminder signal which,
for example, reads out the date that the last daily dose has been
taken and/or reminds one when the next dose is to be taken.
EXAMPLES
[0508] All references provided in the Examples are herein
incorporated by reference. As used herein, all abbreviations,
symbols and conventions are consistent with those used in the
contemporary scientific literature. See, e.g. Janet S. Dodd, ed.,
The ACS Style Guide: A Manual for Authors and Editors, 2.sup.nd
Ed., Washington, D.C.: American Chemical Society, 1997, herein
incorporated in its entirety by reference.
Example 1
Syntheses of Compounds
Intermediate 1 (Scheme 1)
##STR00036##
[0509] Step 1. Preparation of A
[0510] To a solution of 1,3-dicyclohexylcarbodiimide (DCC, 23.0 g,
1.0 equiv.) in dichloromethane (200 ml), were added
4-dimethylaminopyridine (DMAP, 13.6 g, 1.0 equiv.),
o-fluorophenylacetic acid (17.2 g, 1.0 equiv.) and Meldrums acid
(16.1 g, 1.0 equiv.). The mixture and the resulting precipitate was
removed by filtration. The filtrate was diluted with
dichloromethane and washed with 1N HCl (100 ml). The organic layer
was dried, filtered and evaporated to give a solid. This was
suspended in ethanol and heated at reflux for 24 h. The mixture was
concentrated under vacuum. The resulting residue was purified by
column chromatography (0 to 30% ethyl acetate in hexanes) to give
ethyl 4-(2-fluorophenyl)-3-oxobutanoate (A, 19.1 g, 76% yield) as
an orange oil.
[0511] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.26-7.33
(m, 1H), 7.22 (td, 1H), 7.12-7.17 (m, 1H), 7.09 (t, 1H), 4.18-4.24
(m, 2H), 3.90 (s, 2H), 3.53 (s, 2H), 1.27-1.32 (m, 3H).
Step 2. Preparation of B
[0512] A mixture of ethyl 4-(2-fluorophenyl)-3-oxobutanoate (A,
19.0 g, 1.0 equiv.), ethyl orthoformate (42.3 ml, 3.0 equiv.) and
acetic anhydride (12.8 ml, 1.6 equiv.) was heated at 100.degree. C.
for 24 h and then concentrated under vacuum to give a thick oil.
The resulting residue was diluted in ethanol (85 ml) and cooled to
0.degree. C. in an ice bath. To this mixture, was added, very
slowly, hydrazine monohydrate (2.7 ml, 1.0 equiv.). The mixture was
stirred at rt for 2 h and thenconcentrated. The resulting residue
was purified by column chromatography (0 to 30% ethyl acetate in
hexanes) to give ethyl 3-(2-fluorobenzyl)-1H-pyrazole-4-carboxylate
(B, 14.0 g, 66% yield) as a dark red oil.
[0513] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.93 (s,
1H), 7.18-7.26 (m, 3H), 7.01-7.09 (m, 2H), 4.34 (s, 2H), 4.28 (q,
2H), 1.33 (t, 3H).
Step 3. Preparation of C and D
[0514] A mixture of ethyl
3-(2-fluorobenzyl)-1H-pyrazole-4-carboxylate (12.6 g, 1.0 equiv.),
potassium carbonate (10.5 g, 1.5 equiv.) and 4-methoxybenzyl
chloride (7.2 ml, 1.1 mmol) in acetonitrile (60 ml) was heated at
reflux for 24 h. The mixture was cooled and filtered. The filtrate
was concentrated to give a thick oil. Purification of the oil by
column chromatography (0 to 5% ethyl acetate in hexanes) gave ethyl
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate
(C, 8.4 g, 45% yield) as a clear oil. In addition, ethyl
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate
(D, 4.2 g, 23% yield) was also obtained as a side product as a
clear oil. Side product D was also used for the preparation of the
final product (Intermediate-1) by an alternative route described
below.
[0515] Ethyl
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate
(C): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.74 (s, 1H),
7.16-7.22 (m, 2H), 7.06-7.16 (m, 2H), 6.94-7.04 (m, 2H), 6.88 (d,
2H), 5.17 (s, 2H), 4.27 (s, 2H), 4.17 (q, 2H), 3.80 (s, 3H), 1.19
(t, 3H).
[0516] Ethyl
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate
(D): .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.96 (s, 1H),
7.13-7.20 (m, 1H), 7.02 (d, 1H), 6.94-6.99 (m, 3H), 6.84-6.91 (m,
1H), 6.75 (d, 2H), 5.11 (s, 2H), 4.37 (s, 2H), 4.25 (q, 2H), 3.74
(s, 3H), 1.27 (q, 3H).
Step 4. Preparation of E
4.1: Synthesis of
(3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol
[0517] To a cold solution of ethyl
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate
(C, 8.4 g, 1.0 equiv.) in THF (114 ml) at 0.degree. C., was added
2.0 M solution of lithium aluminum hydride in THF (11.4 ml, 1.0
equiv.). The mixture was stirred at rt for 30 min. and cooled to
0.degree. C. The mixture was sequentially quenched with
870.sub.1--11 of water, 870 .mu.l of 15% NaOH and 2.5 ml of water.
The precipitate formed was removed by filtration. The filtrate was
concentrated under vacuum to give
(3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol
(8.4 g, 100% yield) as a clear oil. This compound was used in step
5.2 without further purification.
[0518] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (s,
1H), 7.13-7.20 (m, 4H), 6.97-7.06 (m, 2H), 6.83-6.89 (m, 2H), 5.16
(s, 2H), 4.37 (s, 2H), 4.04 (s, 2H), 3.78 (s, 3H).
4.2. Synthesis of E
[0519] A mixture of the crude
(3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol
(8.4 g, 1.0 equiv.), magnesium sulfate (4.3 g, 1.4 equiv.) and
manganese dioxide (15.4 g, 6.9 equiv.) in dichloromethane (129 ml)
was stirred at rt for 24 h. The mixture was filtered through a
funnel to remove insoluble materials. The filtrate was concentrated
under vacuum to give
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
(E, 6.9 g, 82% yield) as a light yellow oil.
[0520] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 9.77 (s,
1H), 7.69 (s, 1H), 7.13-7.25 (m, 4H), 6.98-7.06 (m, 2H), 6.89 (d,
2H), 5.19 (s, 2H), 4.26 (s, 2H), 3.80 (s, 3H).
Step 5. Preparation of F
5.1. Synthesis of
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
oxime
[0521] A mixture containing
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
(E, 6.9 g, 1 equiv.), hydroxylamine hydrochloride (1.6 g, 1.1
equiv.) and sodium acetate (1.8 g, 1.0 equiv.) in a mixture of
methanol (95 ml) and water (11 ml) was heated at 50.degree. C. for
3 h. The mixture was cooled to rt and concentrated under vacuum.
The resulting residue was diluted in ethyl acetate (100 ml) and
washed with brine (50 ml). The organic layer was dried, filtered
and evaporated to give
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
oxime (4.3 g, 60% yield) as a white solid. This material was used
directly in the following step (5.2) without additional
purification.
[0522] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.27 (s,
1H), 7.39 (s, 1H), 7.15-7.23 (m, 3H), 7.10 (t, 1H), 6.97-7.06 (m,
2H), 6.87 (d, 2H), 5.16-5.25 (m, 2H), 3.79 (s, 3H), 3.47 (s,
2H).
5.2. Synthesis of F
[0523] A mixture of
3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
oxime (4.3 g, 1.0 equiv.) and N-chlorosuccinimide (NCS, 1.8 g, 1.1
equiv.) in DMF (13 ml) was heated at 40.degree. C. for 3 h. The
mixture was cooled to rt. Then, it was diluted in ethyl acetate
(200 ml) and washed with water (50 ml.times.3). The organic layer
was dried, filtered and evaporated to give an oil. Purification of
the oil by column chromatography (0 to 20% ethyl acetate in
hexanes) gave
3-(2-fluorobenzyl)-N-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbimidoy-
l chloride (F, 4.0 g, 85% yield) as a yellow solid.
[0524] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.58 (s,
1H), 7.19 (d, 2H), 7.10-7.17 (m, 1H), 6.93-7.04 (m, 3H), 6.86-6.91
(m, 2H), 5.17 (s, 2H), 4.19 (s, 2H), 3.79 (s, 3H).
Step 6. Preparation of G
[0525] A mixture of
3-(2-fluorobenzyl)-N-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbimidoy-
l chloride (F, 4.0 g, 1.0 equiv.), ethyl vinyl ether (2.3 ml, 2.2
equiv.) and sodium bicarbonate (1.3 g, 1.5 equiv) in 2-propanol (15
ml) was heated at 50.degree. C. for 24 h. The precipitate was
removed by filtration. The filtrate was concentrated under vacuum
to give an oil. Purification of the oil by column chromatography (0
to 100% ethyl acetate in hexanes) gave
5-ethoxy-3-(3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5-d-
ihydroisoxaz ol e (G, 1.0 g, 23% yield) as a clear oil.
[0526] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.42 (s, 1H)
7.14-7.24 (m, 4H) 6.98-7.06 (m, 2H) 6.87-6.93 (m, 2H) 5.50-5.55 (m,
1H) 5.21 (s, 2H) 4.23-4.37 (m, 2H) 3.84-3.91 (m, 1H) 3.83 (s, 3H)
3.49-3.59 (m, 1H) 3.20 (dd, 1H) 2.93-2.99 (m, 1H) 1.27 (t, 3H).
Step 7. Synthesis of Intermediate 1
[0527] A mixture of
5-ethoxy-3-(3-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5-d-
ihydroisoxazole (G, 1.0 g, 1.0 equiv.) and 1.0 M solution of sodium
hydroxide in water (2.4 ml, 1.0 equiv.) in ethanol (12 ml) was
stirred at rt for 24 h. The mixture was concentrated under vacuum
and thenit was diluted in ethyl acetate (100 ml) and washed with 1N
HCl (50 ml). The organic layer was dried, filtered and evaporated
to give an oil. Purification of the oil by column chromatography (0
to 80% ethyl acetate in hexanes) gave Intermediate-1 (797 mg, 90%
yield) as a clear oil.
[0528] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.34 (br.
s., 1H), 7.70 (br. s., 1H), 7.25-7.32 (m, 2H), 7.12-7.24 (m, 2H),
7.00-7.10 (m, 2H), 6.88-6.97 (m, 2H), 6.31 (br. s., 1H), 5.24-5.34
(m, 2H), 4.32 (br. s., 2H), 3.84 (br.s., 3H).
Alternative Synthesis of Intermediate-1 from Side Product D
Step 8
8.1. Synthesis of
(5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol
[0529] To a cold solution of ethyl
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate
(D, 4.2 g, 1.0 equiv.) in THF (57 ml) at 0.degree. C., was added
2.0 M solution of lithium aluminum hydride in THF (5.7 ml, 1.0
equiv.). The mixture was stirred at rt and cooled to 0.degree. C.
The mixture was sequentially quenched with 435 .mu.L of water, 435
.sub.1--11 of 15% NaOH and 1.3 ml of water. The precipitate that
formed was removed by filtration. The filtrate was concentrated
under vacuum to give
(5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol
(3.2 g, 85% yield) as a clear oil. This was used in the following
step without additional purification.
[0530] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.58 (s, 1H)
7.15-7.22 (m, 2H), 6.96-7.01 (m, 3H), 6.81-6.89 (m, 2H) 6.74-6.78
(m, 1H), 5.10-5.14 (m, 2H) 4.51 (s, 2H) 4.00 (s, 2H) 3.72-3.76 (m,
3H).
8.2. Synthesis of
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
[0531] A mixture of
(5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol
(3.2 g, 1.0 equiv.), magnesium sulfate (1.6 g, 1.4 equiv.) and
manganese dioxide (5.9 g, 6.9 equiv.) in dichloromethane (49 ml)
was stirred at rt for 24 h. The solid precipitate was removed by
filtration. The filtrate was concentrated under vacuum to give
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
(3.1 g, 98% yield) as a light yellow oil.
[0532] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 9.87-9.96
(m, 1H), 7.98 (s, 1H), 7.15-7.23 (m, 2H), 6.96-7.07 (m, 2H),
6.87-6.96 (m, 2H), 6.77 (d, 2H), 5.15 (s, 2H), 4.34 (s, 2H), 3.75
(s, 3H).
Step 9
9.1. Synthesis of
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
oxime
[0533] A mixture containing
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
(3.1 g, 1.0 equiv.), hydroxylamine hydrochloride (0.72 g, 1.1
equiv.) and sodium acetate (0.83 g, 1.1 equiv.) in a 9:1 mixture of
MeOH (43 ml) and water (5 ml) was heated at 50.degree. C. for 3 h.
The mixture was cooled to rt and concentrated under vacuum. The
resulting residue was diluted in ethyl acetate (100 ml) and washed
with brine (50 ml). The organic layer was dried, filtered and
evaporated to give
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
oxime (3.0 g, 91% yield) as a white solid. This was used in the
following step without additional purification.
[0534] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.47 (s,
1H), 7.49 (br. s., 1H), 7.21 (d, 3H), 6.94-7.01 (m, 3H), 6.70-6.82
(m, 2H), 5.19 (s, 2H), 4.09 (s, 2H), 3.75 (s, 3H).
9.2. Synthesis of
5-(2-fluorobenzyl)-N-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbimidoy-
l chloride
[0535] A mixture of
5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde
oxime (3.0 g, 1.0 equiv.) and N-chlorosuccinimide (1.2 g, 1.1
equiv.) in DMF (9.0 ml) was heated at 40.degree. C. for 3 h. The
mixture was cooled to rt and diluted ethyl acetate (500 ml). The
organic layer was washed with water (50 ml.times.3), dried,
filtered and evaporated to give an oil. The oil was purified by
column chromatography (0 to 20% ethyl acetate in hexanes) to give
5-(2-fluorobenzyl)-N-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbimidoy-
l chloride (2.4 g, 73% yield) as a yellow solid.
[0536] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.86 (s,
1H), 7.57 (s, 1H), 7.55-7.55 (m, 1H), 7.12-7.22 (m, 2H), 6.92-7.00
(m, 2H), 6.72-6.80 (m, 3H), 5.07 (s, 2H), 4.26 (s, 2H), 3.74 (s,
3H).
Step 10. Alternative Synthesis of Intermediate-1
10.1. Preparation of G
[0537] A mixture of
5-(2-fluorobenzyl)-N-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbimidoy-
l chloride (2.4 g, 1.0 equiv.), ethyl vinyl ether (1.3 ml, 2.2
equiv.) and sodium bicarbonate (0.80 g, 1.5 equiv.) in 2-propanol
(7.1 ml) was heated at 50.degree. C. for 3 h. The precipitate was
removed by flitration. The filtrate was concentrated under vacuum
to give an oil. Purification of the oil by column chromatography (0
to 100% ethyl acetate in hexanes) gave compound G (2.0 g, 75%
yield) as a yellow oil.
[0538] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.63 (s,
1H), 7.11-7.20 (m, 2H), 6.85-7.04 (m, 4H), 6.75 (d, 2H), 5.55-5.58
(m, 1H), 5.11 (s, 2H), 4.28-4.47 (m, 2H), 3.81-3.94 (m, 1H), 3.74
(s, 3H) 3.50-3.61 (m, 1H) 3.36 (dd, 1H) 3.10-3.19 (m, 1H) 1.21-1.27
(m, 3H).
10.2. Preparation of Intermediate 1
[0539] A mixture of
5-ethoxy-3-(5-(2-fluorobenzyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-4,5-d-
ihydroisoxazole (G, 2.0 g, 1.0 equiv.) and 1.0 M solution of sodium
hydroxide in water (4.8 ml, 1.0 equiv.) was stirred at rt for 24 h.
The mixture was concentrated under vacuum. The mixture was diluted
in ethyl acetate (100 ml) and washed with 1N HCl (50 ml). The
organic layer was dried, filtered and evaporated to give an oil.
Purification of the oil by column chromatography (0 to 80% ethyl
acetate in hexanes) gave Intermediate 1 (1.3 g, 77% yield) as a
yellow oil.
[0540] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.42 (br.
s., 1H), 7.88 (br. s., 1H), 7.20 (br. s., 2H), 7.01-7.10 (m, 2H),
6.89-7.01 (m, 2H), 6.80 (d, 2H), 6.50 (br. s., 1H), 5.18 (br. s.,
2H), 4.42 (br. s., 2H), 3.79 (br. s., 3H).
Intermediate 2
##STR00037##
[0542] A solution containing Intermediate 1 (182 mg, 1.0 equiv.) in
trifluoroacetic acid (1.7 ml) was heated at 70.degree. C. for 24 h.
The mixture was cooled to rt and diluted in dichloromethane. The
organic layer was washed with a saturated solution of sodium
bicarbonate (100 ml), dried, filtered and evaporated to give an
oil. The oil was purified by column chromatography (0 to 80% ethyl
acetate in hexanes) to give Intermediate 2 (93 mg, 76% yield) as an
off-white solid.
[0543] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 10.14 (br.
s., 1H) 8.42-8.53 (m, 1H) 7.91 (d, 1H) 7.18-7.23 (m, 1H) 6.97-7.04
(m, 2H) 6.51-6.63 (m, 1H) 6.28-6.39 (m, 1H) 5.74-5.93 (m, 2H).
Compound I-1
##STR00038##
[0545] A mixture of Intermediate 2 (295 mg, 1.0 equiv.) and
2-chloro-5-fluoropyrimidin-4-one (360 mg, 2.0 equiv.) in NMP (6.0
ml) was heated at 130.degree. C. for 24 h. To this mixture, was
added DBU (0.4 ml, 2.0 equiv.). The mixture was stirred at
80.degree. C. for 4 h. The mixture was cooled to rt and diluted
with ethyl acetate (100 ml). The organic layer was washed with 1N
HCl (50 ml), dried, filtered and evaporated to give an oil. The oil
was purified by column chromatography (0 to 5% 7:1 ACN:MeOH in
DCM). Recrystalliztion of the purified material gave Compound I-1
(58 mg, 13% yield) as a white solid.
[0546] .sup.1H NMR (500 MHz, METHANOL-d4) .delta. ppm 9.00 (s, 1H),
8.69 (s, 1H), 8.03 (br. s., 1H), 7.22-7.29 (m, 1H), 7.18 (t, 1H),
7.02-7.12 (m, 2H), 6.78 (s, 1H), 4.42-4.48 (m, 2H).
Intermediate-3 and Compound I-2 (Scheme 2)
##STR00039##
[0547] Step 1. Synthesis of H
[0548] A mixture of ethyl
3-(2-fluorobenzyl)-1H-pyrazole-4-carboxylate (B, 5.0 g, 1.0 equiv.)
and lithium hydroxide (2.4 g, 5.0 equiv.) in a 1:1 mixture of THF
(51 ml) and water (51 ml) was heated at 100.degree. C. for 4 h. The
organic solvent of the mixture was evaporated. The resulting
aqueous mixture was acidified to pH=3 by the addition of 3N HC1.
The resulting white precipitate was collected and dried under
vacuum to give 3-(2-fluorobenzyl)-1H-pyrazole-4-carboxylic acid (H,
4.1 g, 92% yield) as an off-white solid which was used directly in
the next step without additional purification.
[0549] .sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 7.94 (br. s.,
1H), 7.12-7.20 (m, 2H), 7.02-7.08 (m, 1H), 6.95-7.02 (m, 2H), 4.26
(s, 2H). Step 2. Synthesis of I
[0550] To a mixture of 3-(2-fluorobenzyl)-1H-pyrazole-4-carboxylic
acid (H, 4.1 g, 1.0 equiv.), EDC (3.9 g, 1.1 equiv.), HOBT (3.1 g,
1.1 equiv.) and triethylamine (5.2 ml, 2.0 equiv.) in
N,N-dimethylformamide (93 ml), was added 2,2-dimethoxyethanamine
(2.2 ml, 1.1 equiv.). The mixture was stirred at 25.degree. C. for
24 h. It was diluted in ethyl acetate (100 ml) and washed with
brine (50 ml.times.3). The organic layer was dried, filtered, and
concentrated to give
N-(2,2-dimethoxyethyl)-3-(2-fluorobenzyl)-1H-pyrazole-4-carboxamide
(I, 3.2 g, 57% yield) as a light yellow oil.
[0551] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.74 (s,
1H), 7.23 (t, 1H), 7.13-7.20 (m, 1H), 6.94-7.04 (m, 2H), 4.39 (t,
1H), 4.34 (s, 2H), 3.46 (t, 2H), 3.33 (s, 6H).
Step 3. Synthesis of Intermediate-3
[0552] A mixture of
N-(2,2-dimethoxyethyl)-3-(2-fluorobenzyl)-1H-pyrazole-4-carboxamide
(3.2 g, 1.0 equiv.) and phosphorous pentoxide (10 g, 6.8 equiv.) in
methanesulfonic acid (70 ml) was heated at 120.degree. C. for 24 h.
The mixture turned dark brown. The mixture was cooled to rt and
poured over ice. It was basified with a 3N NaOH solution to pH=7.
The mixture was extracted with ethyl acetate (200 ml.times.3). The
combined organic layer were dried, filtered, and evaporated to give
an oil. Purification of the oil by column chromgatography (0 to 50%
acetone in hexanes) gave Intermediate-3 (1.3 g, 51% yield) as a
yellow oil.
[0553] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.01 (s,
1H), 7.62 (d, 1H), 7.30 (td, 1H), 7.19-7.26 (m, 1H), 7.17 (d, 1H),
7.03-7.09 (m, 2H), 4.46 (s, 2H).
Step 4. Preparation of Compound I-2
[0554] A mixture of Intermediate-3 (160 mg, 1.0 equiv.),
2-chloropyrimidin-4-amine (170 mg, 2.0 equiv.) and cesium carbonate
(429 mg, 2.0 equiv.) in NMP (7.0 ml) was heated at 165.degree. C.
in a sealed vial for 2 days. The reaction was cooled to rt and
diluted in ethyl acetate (200 ml). The mixture was washed with
water (30 ml.times.3) and brine. The organic layer was dried,
filtered, and evaporated to give a crude oil. The oil was purified
by column chromatography (0 to 80% ethyl acetate in hexanes), and
the resulting crude product was tritrated with acetone to Compound
I-2 (52 mg, 23% yield) as an off-white solid.
[0555] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.94 (s,
1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.41 (br. s., 2H), 7.32-7.35 (m,
1H), 7.22-7.30 (m, 1H), 7.13-7.22 (m, 2H), 7.03-7.13 (m, 1H), 6.39
(d, 1H), 4.41 (s, 2H).
Compounds I-3 and I-4 (Scheme 3)
##STR00040##
[0556] Step 1. Compound I-3
[0557] A mixture of Compound I-1 (365 mg, 1 equiv.) and phosphorous
oxytrichloride (2.0 ml, 20 equiv.) was heated at 80.degree. C. for
24 h. The mixture was concentrated under vacuum. The resulting
residue was diluted with ethyl acetate (100 ml) and washed with
water (50 ml). The organic layer was dried, filtered and evaporated
to give an oil. The oil was purified by column chromatography (0 to
30% ethyl acetate in hexanes) to give Compound I-3 (164 mg, 43%
yield) as a white solid.
[0558] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.89-8.94
(m, 1H) 8.63 (s, 1H) 8.40-8.44 (m, 1H) 7.13-7.22 (m, 2H) 6.95-7.08
(m, 2H) 6.40-6.46 (m, 1H) 4.44-4.50 (m, 2H).
Step 2. Compound I-4
[0559] A mixture of Compound I-3 (159 mg, 1 equiv.),
(S)-3-methyl-2-(methylamino)butyric acid (112 mg, 2 equiv.) and
triethylamine (119 2 equiv.) in 1,4-dioxane (5.7 ml) and water (2.8
ml) was heated at 80.degree. C. for 24 h. The mixture was diluted
in ethyl acetate (100 ml) and washed with 1N HCl (50 ml). The
organic layer was dried, filtered and evaporated to give a solid.
The solid was purified by column chromatography (0 to 10% methanol
in dichloromethane) to give Compound I-4 (50 mg, 25% yield) as a
solid.
[0560] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.02 (s, 1H)
8.97 (d, 1H) 8.33 (d, 1H) 7.22-7.28 (m, 1H) 7.20 (t, 1H) 7.13-7.18
(m, 1H) 7.07 (td, 1H) 7.00 (s, 1H) 4.62 (br. s., 1H) 4.33 (s, 2H)
3.32 (s, 2H) 3.22 (d, 3H) 2.34-2.43 (m, 1H) 1.07 (d, 3H) 0.88 (d,
3H).
Compound I-5
##STR00041##
[0562] A mixture of
3-(1-(4-chloro-5-fluoropyrimidin-2-yl)-3-(2-fluorobenzyl)-1H-pyrazol-4-yl-
)isoxazole (Compound I-3, 100 mg, 1 equiv.), triethylamine (149
.mu.l equiv.) and 2-amino-1,3-propanediol (98 mg, 4 equiv.) in
1,4-dioxane (2.0 ml) and water (0.5 ml) was heated at 80.degree. C.
for 4 h. The mixture was diluted in ethyl acetate (100 ml) and
washed with 1N HCl (50 ml). The organic layer was dried, filtered
and evaporated to give Compound I-5 (53 mg, 46% yield) as a white
solid.
[0563] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. ppm 8.99 (s,
1H) 8.62 (d, 1H) 8.03 (d, 1H) 7.17 (d, 1H) 7.00-7.07 (m, 2H)
6.95-6.99 (m, 1H) 6.71 (d, 1H) 4.54 (t, 1H) 4.39 (s, 2H) 3.73-3.82
(m, 4H).
Compound I-6
##STR00042##
[0565] A mixture of
3-(1-(4-chloro-5-fluoropyrimidin-2-yl)-3-(2-fluorobenzyl)-1H-pyrazol-4-yl-
)isoxazole (Compound I-3,45 mg, 1 equiv.), triethylamine (67 .mu.l
equiv.) and morpholine (42 .mu.l, 4 equiv.) in 1,4-dioxane (0.9 ml)
and water (0.2 ml) was heated at 80.degree. C. for 4 h. The mixture
was diluted in ethyl acetate (100 ml) and washed with 1N HCl (50
ml). The organic layer was dried, filtered and evaporated to give a
white solid. The solid was rinsed with a minimal amount of methanol
to give Compound I-6 (38 mg, 74% yield) as a white solid.
[0566] .sup.1H NMR (500 MHz, DMSO-d6) .delta. ppm 9.13 (s, 1H) 8.95
(d, 1H) 8.31 (d, 1H) 7.21-7.28 (m, 1H) 7.09-7.19 (m, 3H) 7.04-7.09
(m, 1H) 4.33 (s, 2H) 3.79-3.88 (m, 4H) 3.69-3.79 (m, 4H) 3.57 (s,
1H).
Compound I-7
##STR00043##
[0567] Step 1. Preparation of K
[0568] A mixture of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.94 g, 1
equiv.), potassium carbonate (1.1 g, 1.3 equiv.) and
(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate
(1.7 g, 1 equiv.) was heated at 80.degree. C. in DMF (31 ml) for 24
h. The mixture was diluted in ethyl acetate (100 ml) and washed
with water (50 ml). The organic layer was dried, filtered and
evaporated to give an oil. The oil was purified by column
chromatography (0 to 50% ethyl acetate in hexanes) to give
2-chloro-7-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-7H-pyrrolo[2,-
3-d]pyrimidine (K, 1.2 g, 74% yield) as a white solid.
[0569] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.73 (s, 1H)
7.30 (d, 1H) 6.50 (d, 1H) 4.35-4.46 (m, 2H) 4.14-4.30 (m, 1H) 4.05
(dd, 1H) 3.62 (dd, 1H) 1.51 (s, 2H) 1.34 (s, 3H) 1.27 (s, 3H).
Step 2. Reaction of K with Intermediate-2
[0570] A mixture containing 3-(3-(2-fluorobenzyl)-1H-pyrazol-4-yl)i
sox azol e (Intermediate-2 162 mg, 1 equiv.),
2-chloro-7-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-7H-pyrrolo[2,3-d]pyri-
midine (K, 267 mg, 1.5 equiv.) and potassium carbonate (184 mg, 2
equiv.) in DMF (3.3 ml) was heated at 120.degree. C. for 2 days.
The mixture was diluted in ethyl acetate (100 ml) and washed with
water (50 ml). The organic layer was dried, filtered and evaporated
to give an oil. The oil was purified by column chromatography (0 to
80% ethyl acetate in hexanes) to give a residue containing the
starting pyrrazole and the desired product.
Step 3. Preparation of Compound I-7
[0571] Then, this residue was treated with HCl [4.0 M in
1,4-dioxane] (1.7 ml). The mixture was stirred at rt for 30 min.
The mixture was diluted in ethyl acetate (100 ml) and washed with
1IN NaOH (50 ml). The organic layer was dried, filtered and
evaporated to give a solid. The solid was purified by column
chromatography (0 to 100% ethyl acetate in hexanes) to give
Compound I-7 (50 mg, 17% yield over two steps) as a light yellow
solid.
[0572] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.31 (s, 1H)
9.02 (s, 1H) 8.95 (d, 1H) 7.65 (d, 1H) 7.23-7.29 (m, 1H) 7.11-7.20
(m, 3H) 7.04-7.10 (m, 1H) 6.69 (d, 1H) 5.07 (d, 1H) 4.82 (t, 1H)
4.39 (s, 3H) 4.17-4.24 (m, 1H) 3.89-3.96 (m, 1H) 3.34-3.44 (m,
2H).
Compound I-8
##STR00044##
[0574] A mixture of 2-(3-(2-fluorobenzyl)-1H-pyrazol-4-yl)oxazole
(Intermediate-3, 171 mg, 1 equiv.), cesium carbonate (275 mg, 1.2
equiv.) and 2-chloro-5-fluoropyrimidin-4-amine (104 mg, 1 equiv.)
in NMP (3.5 ml) was heated at 165.degree. C. for 18 h. The reaction
was cooled to room temp and diluted in ethyl acetate (50 ml). The
organic layer was washed with water (10 ml.times.2). The organic
layer was dried, filtered and evaporated to give an oil. This oil
was purified by column chromatography (0 to 80% ethyl acetate in
hexanes) to give Compound I-8 (48 mg, 17% yield) as light yellow
solid.
[0575] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.88 (s,
1H), 8.21 (d, 1H), 8.15 (d, 1H), 7.86 (br. s., 2H), 7.35-7.38 (m,
1H), 7.23-7.28 (m, 1H), 7.16-7.20 (m, 2H), 7.06-7.10 (m, 1H), 4.34
(s, 2H).
Compound I-9
##STR00045##
[0577] To a solution of
3-(3-(2-fluorobenzyl)-1H-pyrazol-4-yl)isoxazole (Intermediate-2,
354 mg, 1 equiv.) in THF (7.3 ml) at 25.degree. C., was added
sodium hydride (40 mg, 2 equiv.). To this mixture, was added
2-chloropyrimidin-4-amine (192 mg, 3 equiv). The resulting mixture
was stirred at 80.degree. C. for 24 h and then quenched with a
saturated solution of ammonium chloride (50 ml) and extracted with
ethyl acetate (100 ml). The organic layer was dried, filtered and
evaporated to give a solid. This solid was purified by column
chromatography (0 to 80% ethyl acetate in hexanes) and
recrystallized from methanol. The solid was further purified by
HPLC (5 to 95% acetonitrile in water) to give Compound I-9 (8 mg,
5% yield) as a white solid.
[0578] .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta. ppm 9.04 (s,
1H) 8.70 (d, 1H) 8.02 (d, 1H) 7.19-7.26 (m, 1H) 7.13-7.19 (m, 1H)
6.99-7.09 (m, 2H) 6.75 (d, 1H) 6.59 (d, 1H) 4.45 (s, 2H).
Compound I-10
##STR00046##
[0580] To a solution of
3-(3-(2-fluorobenzyl)-1H-pyrazol-4-yl)isoxazole (Intermediate-2,
354 mg, 1 equiv.) in THF (7 ml) at 25.degree. C., was added sodium
hydride [60 wt % dispersion on mineral oil] (137 mg, 2.4 equiv.).
The mixture was stirred until the bubbling ceased. To this mixture,
was added 2-chloro-5-fluoro-4-methoxypyrimidine (473 mg, 2 equiv).
The mixture was stirred at room temp for 24 h and then it was
diluted wtih ethyl aceate (100 ml) and washed with 1N HCl (50
ml.times.3). The organic layer was dried, filtered and evaporated
to give an oil. The oil was purified by column chromatography (0 to
100% ethyl acetate in hexanes) to give Compound I-10 (383 mg, 71%
yield) as a white solid.
[0581] .sup.1H NMR (500 MHz, METHANOL-d4) .delta. ppm 9.06 (s, 1H)
8.63-8.69 (m, 1H) 8.45 (d, 1H) 7.16-7.26 (m, 1H) 6.97-7.14 (m, 3H)
6.76 (s, 1H) 4.44 (s, 2H) 4.25 (s, 3H).
Example 2
Biological Activity Measurement by the sGC-HEK-cGMP Assay
[0582] (Assay Run with SNP Incubation)
[0583] Human embryonic kidney cells (HEK293), endogenously
expressing soluble guanylate cyclase (sGC), were used to evaluate
the activity of test compounds. Compounds stimulating the sGC
receptor should cause an increase in the intracellular
concentration of cGMP. HEK 293 cells were seeded in Dulbecco's
Modification of Eagle's Medium supplemented with fetal bovine serum
(10% final) and L-glutamine (2 mM final) in a 200 .mu.L volume at a
density of 1.times.10.sup.5 cells/well in a poly-D-lysine coated 96
well flat bottom plate and grown overnight at 37.degree. C. Medium
was aspirated and cells were washed with 1.times. Hank's Buffered
Saline Salt Solution (200 .mu.L). Cells were then incubated for 15
minutes at 37.degree. C. with 200 .mu.L of a 0.5 mM
3-isobutyl-1-methylxanthine (IBMX) solution. Test article and
sodium nitroprusside solutions (x .mu.M concentration for test
article solution and 10 .mu.M concentration for SNP solution;
wherein x is one of the following concentrations); [0584] 30 .mu.M
[0585] 10 .mu.M [0586] 3 .mu.M [0587] 1 .mu.M [0588] 0.3 .mu.M
[0589] 0.1 .mu.M [0590] 0.03 .mu.M [0591] 0.01 .mu.M [0592] 0.003
.mu.M [0593] 0.001 .mu.M [0594] 0.0003 .mu.M [0595] 0.0001 .mu.M
were then added to the assay mixture (2 .mu.L each) and the
resulting mixture incubated at 37.degree. C. for 10 minutes. After
the 10 minute incubation, the assay mixture was aspirated and 0.1M
HCl (200 .mu.L) was added to the cells. The plate was incubated at
4.degree. C. for 30 minutes in the 0.1M HCl to stop the reaction
and lyse the cells. The plates were then centrifuged at 1,200 g for
5 minutes at room temperature. Supernatants were collected and
transferred to a new flat bottom 96 well plate for analysis by
HPLC-MS. Vehicle controls were carried out using DMSO (1%)
solutions. A known sGC stimulator, BAY 41-2272, was used as the
positive control. Samples were diluted with an equal volume of 1 M
Ammonium Acetate (pH 7) to neutralize samples for better
chromatography. A 2.times. cGMP standard solution was prepared in
0.1 M HCl and then diluted with an equal volume of 1 M Ammonium
Acetate, with the following final concentrations in nM: 1024, 512,
256, 128, 64, 32, 16, 8, 4, 2, 1. cGMP concentrations in the test
plates were determined from each sample using the LC/MS conditions
shown in Table 2 below and the calculated cGMP standard curve.
EC.sub.50 values were calculated from concentration-response curves
generated with GraphPad Prism Software.
[0596] The biological activities of some of the compounds of
Formula I or Formula Ib determined with the sGC-HEK assay with SNP
incubation are summarized in Tables 3A and 3B.
TABLE-US-00011 TABLE 2 (HPLC LC/MS experimental conditions) MS:
Thermo Quantum or Waters LCMS Ion Mode: ESI.sup.+ Scan Type: MRM
Dwell Collision Retention Time Energy Tube Time Compound:
Transition (msec) (V) Lens (min) cGMP 346 > 152 100 28 139 1.0
HPLC: Agilent Technologies 1200 Series with CTC Analytics HTS PAL
Column: Thermo Hypersil Gold 2.1 .times. 50 mm 5 micron particle
size Flow Rate: 400 uL/min Column RT Temperature: Autosampler
6.degree. C. Temperature: Injection Volume: 20 uL Mobile Phases: A
= 98:2 Water:Acetonitrile + 0.1% Formic Acid B = 2:98
Water:Acetonitrile + 0.1% Formic Acid Time (min) % A % B Gradient:
0 100 0 0.3 30 70 2.00 30 70 2.01 100 0 4 100 0
TABLE-US-00012 TABLE 3A Whole cell activity in the HEK assay. HEK
assay HEK assay HEK assay HEK assay (Percent (Percent (Percent
Emax- Compound Emax Emax at Emax at unconstrained No. at 1 .mu.M)*
10 .mu.M)* 30 .mu.M)* (Percent)+ I-1 E F F F I-2 -- F F -- I-3 --
-- -- -- I-4 F G G G I-8 -- E E -- I-9 E F F F I-10 C C C C
*Percent Emax was obtained at twelve concentrations of the test
compound as explained above; the results for three of them (1, 10
and 30 .mu.M) are shown in Table 3A. The code definitions for the
sGC enzyme activity values, expressed as % E.sub.max in the
presence of 10 .mu.M of SNP (wherein E.sub.max = 100% was the
activity in the HEK assay obtained with the positive control BAY
41-2272 at 10 .mu.M in the presence of 100 .mu.M SNP) are: A = 0 to
<10% B = 10 to <20% C = 20 to <40% D = 40 to <60 E = 60
or <80% F = 80 to <100% G = 100 to <120% H = 120% or
higher -- = not determined +The same code definitions apply for
Emax unconstrained, wherein this value is defined as the maximum
activity value obtained from the full concentration-response curve
for the compound, relative to the positive control value of 100%
obtained as above. Here, the term "unconstrained" means that,
during analysis of the sGC enzyme activity data, the top portion of
the concentration-response curve was not fitted to 100%.
TABLE-US-00013 TABLE 3B More whole cell activity in the HEK assay.
HEK assay EC50- HEK assay EC50- Compound No. constrained (.mu.M)#
unconstrained (.mu.M)# I-1 -- A I-2 D -- I-3 -- -- I-4 -- A I-8 --
-- I-9 -- B I-10 -- C #EC.sub.50 values were obtained from the full
concentration response curve following two methods: EC50
constrained refers to the value obtained when the top of the curve
was fitted to 100% (wherein E.sub.max = 100% was the activity in
the HEK assay obtained with the positive control BAY 41-2272 at 10
.mu.M in the presence of 100 .mu.M SNP); EC.sub.50 unconstrained
here repored refer to the value obtained from a full
concentration-response curve when the top of the curve is not
fitted to 100%. The EC50 code definitions in micromolar (.mu.M)
are: 0.01 .ltoreq. EC50 < 0.1 = A 0.1 .ltoreq. EC50 < 0.5 = B
0.5 .ltoreq. EC50 < 1.0 = C 1.0 .ltoreq. EC50 < 5.0 = D 5.0
.ltoreq. EC50 < 10.0 = E EC50 .gtoreq. 10.0 = F
(Assay Run with SNP Incubation)
[0597] Human embryonic kidney cells (HEK293), endogenously
expressing soluble guanylate cyclase (sGC), were used to evaluate
the activity of test compounds. Compounds stimulating the sGC
enzyme should cause an increase in the intracellular concentration
of cGMP. HEK 293 cells were seeded in Dulbecco's Modification of
Eagle's Medium supplemented with fetal bovine serum (10% final) and
L-glutamine (2 mM final) in a 200 .mu.L volume at a density of
1.times.10.sup.5 cells/well in a poly-D-lysine coated 96 well flat
bottom plate and grown overnight at 37.degree. C. Medium was
aspirated and cells were washed with 1.times. Hank's Buffered
Saline Salt Solution (200 .mu.L). Cells were then incubated for 15
minutes at 37.degree. C. with 200 .mu.L of a 0.5 mM
3-isobutyl-1-methylxanthine (IBMX) solution. Test article and
sodium nitroprusside solutions (x .mu.M concentration for test
article solution and 10 .mu.M concentration for SNP solution;
wherein x is one of the following concentrations); [0598] 30 .mu.M
[0599] 10 .mu.M [0600] 3 .mu.M [0601] 1 .mu.M [0602] 0.3 .mu.M
[0603] 0.1 .mu.M [0604] 0.03 .mu.M [0605] 0.01 .mu.M [0606] 0.003
.mu.M [0607] 0.001 .mu.M [0608] 0.0003 .mu.M [0609] 0.01 .mu.M
[0610] were then added to the assay mixture (2 .mu.L each) and the
resulting mixture incubated at 37.degree. C. for 10 minutes. After
the 10 minute incubation, the assay mixture was aspirated and 0.1M
HCl (200 .mu.L) was added to the cells. The plate was incubated at
4.degree. C. for 30 minutes in the 0.1M HCl to stop the reaction
and lyse the cells. The plates were then centrifuged at 1,200 g for
5 minutes at room temperature. [0611] cGMP levels were determined
using a cGMP HTRF assay (Cisbio Product #62GM2PEC). For each
sample, 5 uL of HEK assay supernatant was diluted 1:5 in HTRF kit
assay diluent and transferred to a well of the assay plate, and the
HTRF assay was performed according to the HTRF kit manufacturer's
instructions. Sample calculations were performed using high and low
controls, where high control was supernatant from HEK assay
performed in the presence of 10 uM Bay 41-2272+100 uM SNP, and the
low control was the supernatant from the HEK assay performed in the
presence of vehicle. A cGMP standard solution was prepared in 0.1 M
HCl and diluted in order to perform a cGMP standard curve using the
HTRF assay. Using Mean Ratio data from the HTRF assay, sample date
were normalized according to the equation: 100*(Sample-Low
Control)/(High Control-Low Control). Data were fit to a 3-parameter
log agonist dose response (Top (%EMax), Bottom, log EC50) using
Graphpad (Prism Software). Data in Table 3C was obtained using this
modified assay procedure.
TABLE-US-00014 [0611] TABLE 3C HEK assay Emax- HEK assay EC50-
unconstrained Compound No. unconstrained (.mu.M)# (Percent)+ I-5 B
F I-6 B F I-7 B F #EC.sub.50 values were obtained from the full
concentration response curve following two methods: EC50
constrained refers to the value obtained when the top of the curve
was fitted to 100% (wherein E.sub.max = 100% was the activity in
the HEK assay obtained with the positive control BAY 41-2272 at 10
.mu.M in the presence of 100 .mu.M SNP); EC.sub.50 unconstrained
here repored refer to the value obtained from a full
concentration-response curve when the top of the curve is not
fitted to 100%. The EC50 code definitions in micromolar (.mu.M)
are: 0.01 .ltoreq. EC50 < 0.1 = A 0.1 .ltoreq. EC50 < 0.5 = B
0.5 .ltoreq. EC50 < 1.0 = C 1.0 .ltoreq. EC50 < 5.0 = D 5.0
.ltoreq. EC50 < 10.0 = E EC50 .gtoreq. 10.0 = F +% E.sub.max in
the presence of 10 .mu.M of SNP (wherein E.sub.max = 100% was the
activity in the HEK assay obtained with the positive control BAY
41-2272 at 10 .mu.M in the presence of 100 .mu.M SNP) are: A = 0 to
<10% B = 10 to <20% C = 20 to <40% D = 40 to <60 E = 60
or <80% F = 80 to <100% G = 100 to <120% H = 120% or
higher -- = not determined wherein Emax unconstrained is defined as
the maximum activity value obtained from the full
concentration-response curve for the compound, relative to the
positive control value of 100% obtained as above. Here, the term
"unconstrained" means that, during analysis of the sGC enzyme
activity data, the top portion of the concentration-response curve
was not fitted to 100%.
Example 3A
Biological Activity Measurements by the Purified Human sGC Enzyme
Activity Assay
[0612] Human soluble guanylate cyclase enzyme (hsGC) obtained from
Enzo Inc. (P/N: ALX-201-177) was used to evaluate the activity of
test compounds. The assay reactions contained 0.1 M Tris (pH 8.0),
0.5 mg/mL BSA (pH 8.0), 2 mM DTT, 2 mM MgCl.sub.12, 300 .mu.M GTP,
1 mM 3-isobutyl-1-methylxanthine (IBMX) and 5 ng human soluble
guanylate cyclase enzyme. Test compounds in DMSO were then added (2
.mu.L, 10 or 30 .mu.M final concentration) and incubated (water,
200 .mu.L, 96-well plate format) at 37.degree. C. for 30 minutes.
The controls were carried out using 2 .mu.L DMSO. After the 30
minute incubation, the reaction was stopped with the addition of
200 .mu.L of cold methanol. The plate was then centrifuged at 3,200
rpm for 10 minutes at room temperature. Supernatants (200 .mu.L)
were collected and transferred to a new 96 well plate for analysis
by HPLC LC/MS/MS.
[0613] An 8 point cGMP (Sigma-Aldrich P/N: G6129) standard curve
was prepared in assay buffer ranging from 0.156-20 .mu.M. Samples
for the cGMP standard curve were then diluted with an equal volume
of methanol resulting in final cGMP concentrations of 0.078-10
.mu.M.
[0614] cGMP concentrations in all samples were determined using
LC/MS/MS analysis, using the conditions listed in Table 4 below.
The cGMP standard curve was generated using GraphPad Prism
Software.
[0615] Calculations: Specific Activity was determined by the amount
of cGMP formed (nmoles) per mg of sGC per min. Enzyme "fold-change"
was calculated by dividing Specific Activity for test compounds by
Specific Activity of DMSO controls.
TABLE-US-00015 TABLE 4 LC/MS/MS method for detection of cGMP Inlet
Method: HPLC: Waters Acquity Column: Thermo Hypersile Gold PFP, 2.1
.times. 30 mm, 3 .mu.m Guard Column: Thermo Hypersile Gold, 2.1
.times. 10 mm Column Temp: 25.degree. C. Flow Rate: 0.4 mL/min Auto
sampler: Acquity; 6.degree. C. Injection Volume: 10 uL Mobile
Phases: A = 0.1% Acetic Acid (v/v) in 100% water B = 0.1% Acetic
Acid (v/v) in 100 methanol Time (min) % A % B Curve Gradient: 0 95
5 6 0.5 95 5 6 0.6 10 90 6 2.0 10 90 6 2.1 95 5 6 4 (end) MS File:
cGMP.exp Mass Spectrum: Waters Quattro micro Ionization: ES.sup.+
Source, Desolvation: 150.degree. C., 450.degree. C. MS Function:
MRM Dwell Cone Collision Energy Compound Transition (sec) (V) (eV)
cGMP 346 > 152 0.1 35 20
Example 3B
Biological Measurement by the Purified Human sGC Enzyme Synergy
Performed in the Presence of Sodium Nitroprusside (SNP), a Nitric
Oxide Donor
[0616] Enzyme assays were performed as described above, but the
assay was done in the presence of 1 .mu.M sodium nitroprusside
(SNP). Data for compounds of Table 1 is summarized in Table 5
below.
TABLE-US-00016 TABLE 5 Enzyme Data With and without SNP.* Enzyme
Activity Enzyme Activity (increase (increase at 30 .mu.M with
Compound No. at 30 .mu.M without SNP)* SNP)* I-2 C D I-8 C E *The
compounds were tested at a concentration of 30 .mu.M in the
presence of 1 .mu.M SNP. The code for the fold increase in enzyme
activity is: A = no increase to <2 fold increase B = 2 to <5
fold increase C = 5 to <10 fold increase D = 10 or <20 fold
increase E = 20 to 30 fold increase F = >30 fold increase
Example 4
Biological Activity Measurement by the Thoracic Aortic Rings
Assay
[0617] Thoracic aortic rings were dissected from anesthetized
(isoflurane) male Sprague-Dawley rats weighing 275-299 g. Tissues
were immediately transferred to ice-cold Krebs-Henseleit solution,
which had been aerated with 95% O.sub.2 and 5% CO.sub.2 for 30
minutes. Following removal of connective tissue, aortic sections
were cut into 4 rings (.about.2 mm each) and suspended on 2
L-shaped hooks, with one hook fixed at the bottom of the tissue
bath (Schuler Organ Bath, Harvard Apparatus) and the other
connected to a force transducer (F30 Force Transducer, Harvard
Apparatus). Baths contained Krebs Henseleit solution (10 mL) heated
to 37.degree. C. and aerated with 95% O.sub.2 and 5% CO.sub.2.
Rings were brought to an initial tension of 0.3-0.5 g and gradually
raised to a resting tension of 1.0 g over 60 minutes. Rings were
rinsed with Krebs Henseleit solution (heated to 37.degree. C. and
aerated with 95% O.sub.2 and 5% CO.sub.2) at 15 minute intervals
until a stable baseline was obtained. Rings were considered to be
stable after a resting tension of 1.0 g was maintained (for
approximately 10 minutes) without need for adjustment. Rings were
then contracted with 100 ng/mL phenylephrine by adding 100 .mu.L of
a 10 .mu.g/mL phenylephrine stock solution. Tissues achieving a
stable contraction were then treated in a cumulative, dose
dependent manner with test compounds prepared in dimethylsulfoxide
(DMSO). In some cases, tissues were rinsed three times over a 5
minute period with Krebs-Heinseleit's solution (heated to
37.degree. C. and aerated with 95% O.sub.2 and 5% CO2), allowed to
stabilize at baseline, and then used for characterization of other
test articles or DMSO effects. All data were collected using the
HSE-ACAD software provided by Harvard Apparatus. Percent relaxation
effects were calculated in Microsoft Excel using the recorded
tension value of 100 ng/mL phenylephrine treatment as 0% inhibition
and treatment with 100 .mu.M 3-isobutyl-1-methylxanthine as 100%
inhibition. EC.sub.50 values were calculated from
concentration-response curves generated with GraphPad Prism
Software.
Example 5
Biological Activity Measurement by the Thoracic Aortic Rings
Assay
[0618] As an alternative thoracic aortic rings assay, the procedure
of Example 5 was used except that percent relaxation effects were
calculated in Microsoft Excel using the recorded tension value of
100 ng/mL phenylephrine treatment as 0% inhibition and, after
washing the tissue with buffer, the original resting tesnsion of
the tissue was used as 100% inhibition.
[0619] The biological data for some of the compounds of Formula I
or Formula Ib, in comparison with the known compound, BAY 41-2272,
as the reference compound, determined by the thoracic aorta ring
assay of Example 5 are presented in Table 6 below.
TABLE-US-00017 TABLE 6 Thoracic Aortic Ring Assay Results. Aortic
Ring Aortic Ring Aortic Ring Percent Percent Percent Aortic Ring
Compound Relaxation Relaxation Relaxation EC50 No. at 1 .mu.M* at 3
.mu.M* at 10 .mu.M* (.mu.M)** I-1 -- -- -- -- I-2 E F G A *The
compounds were tested at a concentration of 1, 3 or 10 .mu.M to
obtain data using the method described in Example 5. The code for
the percent relaxation of the aotic ring is: A = 0 to <10% B =
10 to <20% C = 20 to <40% D = 40 to <60% E = 60 or <80%
F = 80 to <100% G = 100 to <120% H = higher than 120% **The
code for the EC.sub.50 value obtained is: A = 0 to <2 .mu.M B =
2 to <4 .mu.M C = 4 to <8 .mu.M D = 8 to <12 .mu.M
[0620] A number of embodiments have been described. Nevertheless,
it will be understood that various modifications may be made
without departing from the spirit and scope of the invention.
Example 6
Animal Models Descriptions
[0621] Lamb Model of Pulmonary Hemodynamics using Inhaled sGC
Stimulator
[0622] ("Inhaled Agonists of Soluble Guanylate Cyclase Induce
Selective Pulmonary Vasodilation", Oleg V. et al, American J of
Resp and Critical Care Medicine, Vol 176, 2007, p 1138)
[0623] It is possible to test whether inhalation of novel
dry-powder microparticle formulations containing sGC stimulators
would produce selective pulmonary vasodilation in lambs with acute
pulmonary hypertension by following a published procedure. It is
also possible to evaluate the combined administration of the
microparticles of sGC stimulator and inhaled nitric oxide (iNO) in
this system. Finally, it is possible to examine whether inhaling
microparticles of an sGC stimulator would produce pulmonary
vasodilation when the response to iNO (inducible nitric oxide
synthase) is impaired.
[0624] Protocol: In awake, spontaneously breathing lambs
instrumented with vascular catheters and a tracheostomy tube,
U-46619 is infused intravenously to increase mean pulmonary
arterial pressure to 35 mm Hg. Inhalation of microparticles
composed of either BAY 41-2272, BAY 41-8543, or BAY 58-2667 and
excipients (dipalmitoylphosphatidylcholine, albumin, lactose)
produced dose dependent pulmonary vasodilation and increased
transpulmonary cGMP release without significant effect on mean
arterial pressure. Inhalation of microparticles containing BAY
41-8543 or BAY 58-2667 increased systemic arterial oxygenation. The
magnitude and duration of pulmonary vasodilation induced by iNO
were augmented after inhaling BAY 41-8543 microparticles.
Intravenous administration of
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes
the prosthetic heme group of sGC, markedly reduced the pulmonary
vasodilator effect of iNO. In contrast, pulmonary vasodilation and
transpulmonary cGMP release induced by inhaling BAY 58-2667
microparticles were greatly enhanced after treatment with ODQ.
Thus, inhalation of microparticles containing agonists of sGC may
provide an effective novel treatment for patients with pulmonary
hypertension, particularly when responsiveness to iNO is impaired
by oxidation of sGC. Note: BAY 41-2272, BAY 41-8543 are sGC
stimulators whereas BAY 58-2667 is an sGC activator.
Electrical Field Stimulated Guinea Pig Tracheal Smooth Muscle In
Vitro (Ex Vivo) Model for the Assessment of Bronchodilation.
[0625] It is possible to assess the bronchodilating effects of sGC
stimulators by using the system described below. This system
allowed us to determine potency, efficacy and duration of action of
several sGC stimulators, as well as to assess potential side
effects such as blood pressure, or heart rate changes.
[0626] Animals: Guinea pig, Dunkin Hartley, male, Full barrier-bred
and certified free of specific micro-organisms on receipt 525-609 g
on the experimental day, Harlan UK Ltd. Guinea pigs were housed in
a group of 4 in solid-bottomed cages with Gold Flake bedding in a
controlled environment (airflow, temperature and humidity). Food
(FD1, Special Diet Services) and water were provided ad
libitum.
Guinea Pig Tracheal Smooth Muscle Contraction in Response to EFS.
Assessment of Compound Potency and Efficacy:
[0627] On each experimental day, a guinea pig was killed by
exposure to a rising concentration of CO2 and the trachea removed.
The trachea was cleaned of extraneous tissue and cut open
longitudinally in a line opposite the muscle, opened out and cut
into strips 2-3 cartilage rings wide. A cotton loop was attached to
one end of each tracheal strip and a length of cotton to the other
end. Tracheal strips were then suspended between two platinum
electrodes, using tissue holders, in a Myobath system (World
Precision Instruments Stevenage, UK). The loop was attached over
the hook at the bottom of the tissue holder and the other end
attached to the arm of a FORT10 force transducer (World Precision
Instruments Stevenage, UK) ensuring that the tissue was positioned
between the two platinum electrodes. The whole assembly was then
lowered into a 10 ml tissue bath containing modified
Kreb's-Henseleit buffer, at 37.degree. C., bubbled with Carbogen. A
1 g tension was applied to each piece of tissue and the tissue
washed, followed by a 1 hour stabilization period. Once the tissues
had been allowed to stabilize, the apparatus for electrical field
stimulation was set to deliver a stimulation of frequency 80Hz
pulse width 0.1 ms, with a gated, uni-polar pulse, every 2 minutes
using a DS8000 8 channel digital stimulator (World Precision
Instruments Stevenage, UK). A voltage response curve was carried
out on each tracheal strip at 2, 4, 6, 7, 8, 10, 12 V and a
sub-maximal voltage then selected to apply to each tissue during
the remainder of the experiment. Guinea pig tracheal smooth muscle
(GPTSM) contraction was induced using sub-maximal Electrical Field
Stimulation (EFS) (It is also possible to induce contraction by
using a spasmogen substance, such as methacholine or histamine as
described in Coleman et al.*). Compounds were dissolved in 100%
DMSO at 3.times.10-2M and aliquots stored at -200 C. A separate
aliquot was used for each experiment. Tissues were washed with
Kreb's buffer and stimulated using the previously determined
sub-maximal voltage for 1 hour to establish a stable baseline
contraction prior to assessment of compound activity.
[0628] A cumulative dose response curve (DRC) to each test
substance was then performed and changes in smooth muscle
contraction measured. The effect of each test substance in each
experiment was expressed as a percentage inhibition of the baseline
contraction, normalized to the relevant vehicle controls. The
experiment was performed three times, using tissue from three
different animals. The data from all three experiments was pooled,
the DRC plotted, and the test substance potency and efficacy
determined. The potency of Ipratropium bromide was assessed
alongside the test compounds and the IC50 determined to be 0.86 nM
(95% Cl, 0.78-0.94), in agreement with data previously produced in
the system. *"Novel and Versatile Superfusion System. Its use in
the Evaluation of Some Spasmogenic and Spasmolytic Agents Using
Guinea pig isolated Tracheal Smooth Muscle.", R. A. Coleman et al.,
J. Pharmacol. Methods, 21, 71-86, 1989.
* * * * *