U.S. patent application number 15/168937 was filed with the patent office on 2017-04-27 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 Charles KIM, Thomas Wai-Ho LEE, Joel MOORE, Takashi NAKAI, Nicholas Robert PERL, Jason ROHDE.
Application Number | 20170112845 15/168937 |
Document ID | / |
Family ID | 44993921 |
Filed Date | 2017-04-27 |
United States Patent
Application |
20170112845 |
Kind Code |
A1 |
KIM; Charles ; et
al. |
April 27, 2017 |
sGC STIMULATORS
Abstract
Compounds of Formula IA and Formula IB are described. They are
useful as stimulators of sGC, particularly NO-independent,
heme-dependent stimulators. These compounds may be useful for
treating, preventing or managing various disorders that are herein
disclosed. ##STR00001##
Inventors: |
KIM; Charles; (Ashburn,
VA) ; NAKAI; Takashi; (Newton, MA) ; LEE;
Thomas Wai-Ho; (Lexington, MA) ; MOORE; Joel;
(Lexington, MA) ; PERL; Nicholas Robert;
(Somerville, MA) ; ROHDE; Jason; (Andover,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ironwood Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Ironwood Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
44993921 |
Appl. No.: |
15/168937 |
Filed: |
May 31, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14698244 |
Apr 28, 2015 |
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15168937 |
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13883910 |
Dec 12, 2013 |
9061030 |
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PCT/US11/58902 |
Nov 2, 2011 |
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14698244 |
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61411730 |
Nov 9, 2010 |
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61546707 |
Oct 13, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y02A 50/423 20180101;
A61P 9/06 20180101; A61P 11/00 20180101; A61P 19/04 20180101; C07D
417/04 20130101; A61K 45/06 20130101; A61P 7/00 20180101; A61P 7/10
20180101; A61P 37/06 20180101; A61P 43/00 20180101; A61K 31/4439
20130101; C07D 401/04 20130101; Y02A 50/30 20180101; A61K 31/5377
20130101; A61P 1/16 20180101; A61K 31/506 20130101; A61K 31/444
20130101; A61P 13/08 20180101; A61P 15/10 20180101; A61P 35/00
20180101; A61P 13/10 20180101; A61P 33/12 20180101; A61K 31/497
20130101; A61P 15/00 20180101; A61P 9/04 20180101; C07D 417/14
20130101; A61P 9/10 20180101; A61K 31/427 20130101; A61P 7/06
20180101; A61P 17/02 20180101; A61P 13/00 20180101; A61P 13/12
20180101; A61P 7/02 20180101; C07D 405/14 20130101; C07D 403/04
20130101; C07D 413/14 20130101; A61P 9/12 20180101; C07D 401/14
20130101; A61P 9/00 20180101; A61P 9/08 20180101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 45/06 20060101 A61K045/06; A61K 31/497 20060101
A61K031/497; A61K 31/444 20060101 A61K031/444; A61K 31/427 20060101
A61K031/427; A61K 31/506 20060101 A61K031/506; A61K 31/4439
20060101 A61K031/4439 |
Claims
1-82. (canceled)
83. A method of treating a disease, health condition or disorder in
a subject, comprising administering a therapeutically effective
amount of a compound of Formula IA or Formula IB, or a
pharmaceutically acceptable salt thereof, to the subject in need of
the treatment, 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, 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, connective tissue disease,
lupus, schitosomiasis, sarcoidosis, chronic obstructive pulmonary
disease, emphysema, chronic bronchitis, pulmonary capillary
hemangiomatosis; histiocytosis X, lymphangiomatosis and compressed
pulmonary vessels; (b) 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; (c)
atherosclerosis, restenosis, percutaneous transluminal coronary
angioplasties or inflammation; (d) liver cirrhosis, hepatic
fibrosis, hepatic stellate cell activation, hepatic fibrous
collagen and total collagen accumulation, liver disease of
necro-inflammatory and/or of immunological origin; or (e) a
urogenital system disorder selected from renal fibrosis, renal
failure resulting from chronic kidney diseases or insufficiency,
prostate hypertrophy, erectile dysfunction, female sexual
dysfunction and incontinence; wherein the compound of Formula IA or
Formula IB is: ##STR00177## the symbol with the encircled letter B
represents ring B, and ring B is a phenyl or a 6-membered
heteroaryl ring, having 1 or 2 nitrogen ring atoms; n is an integer
selected from 0 to 3; each J.sup.B is independently selected from
halogen, --CN, --NO.sub.2, 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.3; 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); wherein ring D is the
5-membered ring heteroaryl of Formula IB or the 6-membered
heteroaryl ring of Formula IA that is substituted by m instances of
J.sup.D; X is selected from N or C; each Y is independently
selected from C, N, O or S; wherein a minimum of 0 and maximum of 3
instances of Y can be N, O or S simultaneously and the remaining
instance or instances of Y are C; m is an integer selected from 0
to 3; each J.sup.D that is a substituent on a carbon ring atom of
Formula IA or Formula IB 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; each J.sup.D that is
a substituent on a nitrogen ring atom of Formula IB is
independently selected from --C(O)R.sup.D, --C(O)OR.sup.D,
--C(O)N(R.sup.D).sub.2, --SO.sub.2R.sup.D,
--SO.sub.2N(R.sup.D).sub.2, 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 has
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 has 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; 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 has 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.5; 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 has 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.5;
alternatively, two instances of R.sup.D linked to the same nitrogen
atom of J.sup.D, together with said nitrogen atom of J.sup.D, 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 has 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; or alternatively, one instance of
R.sup.D linked to a carbon, oxygen or sulfur atom of J.sup.D and
one instance of R.sup.d linked to a nitrogen atom of the same
J.sup.D, together with said carbon, oxygen or sulfur and said
nitrogen atom of that same J.sup.D, 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 has 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, --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, phenyl, a C.sub.7-12
aralkyl or a C.sub.3-8 cycloalkyl ring; wherein each of said
C.sub.1-4 alkyl, 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 has 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 has 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 has 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) or oxo; R.sup.C is selected from halo,
--CN, C.sub.1-6 alkyl or 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 has between 1 and 4 heteroatoms selected
from N, O or S; and wherein said phenyl, monocyclic 5 to 6-membered
heteroaryl ring, bicyclic 8 to 10-membered heteroaryl 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 has 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 has 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 has
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; 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 has 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.7; or 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; 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;
and alternatively, two instances of R.sup.8 linked to the same
nitrogen atom of R
.sup.7, together with said nitrogen atom of R.sup.7, 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 has up to 2 additional
heteroatoms independently selected from N, O or S.
84. The method of claim 83, 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, 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,
connective tissue disease, lupus, schitosomiasis, sarcoidosis,
chronic obstructive pulmonary disease, emphysema, chronic
bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X,
lymphangiomatosis or compressed pulmonary vessels; (b) liver
cirrhosis, or (c) a urogenital system disorder selected from renal
fibrosis, renal failure resulting from chronic kidney diseases or
insufficiency, erectile dysfunction or female sexual
dysfunction.
85. The method of claim 84, wherein the disease, health condition
or disorder is pulmonary hypertension, pulmonary arterial
hypertension, and associated pulmonary vascular remodeling,
localized pulmonary thrombosis, 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, liver cirrhosis, renal fibrosis, renal failure resulting
from chronic kidney diseases or insufficiency, erectile dysfunction
or female sexual dysfunction.
86. The method of claim 85, 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.
87. The method of claim 83, further comprising administering an
effective amount of one or more additional therapeutic agents to
the subject.
88. The method of claim 87, wherein the one or more additional
therapeutic agents are selected from edothelium-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.
89. (canceled)
90. A method of treating a disease, health condition or disorder in
a subject, comprising administering a therapeutically effective
amount of a compound, or a pharmaceutically acceptable salt
thereof, selected from: ##STR00178## ##STR00179## ##STR00180##
##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185##
##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190##
##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## to
the subject in need of the treatment, 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, 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,
connective tissue disease, lupus, schitosomiasis, sarcoidosis,
chronic obstructive pulmonary disease, emphysema, chronic
bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X,
lymphangiomatosis and compressed pulmonary vessels; (b) 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; (c) atherosclerosis, restenosis,
percutaneous transluminal coronary angioplasties or inflammation;
(d) liver cirrhosis, hepatic fibrosis, hepatic stellate cell
activation, hepatic fibrous collagen and total collagen
accumulation, liver disease of necro-inflammatory and/or of
immunological origin; or (e) a urogenital system disorder selected
from renal fibrosis, renal failure resulting from chronic kidney
diseases or insufficiency, prostate hypertrophy, erectile
dysfunction, female sexual dysfunction and incontinence.
91. The method of claim 90, 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, 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,
connective tissue disease, lupus, schitosomiasis, sarcoidosis,
chronic obstructive pulmonary disease, emphysema, chronic
bronchitis, pulmonary capillary hemangiomatosis; histiocytosis X,
lymphangiomatosis or compressed pulmonary vessels; (b) liver
cirrhosis, or (c) a urogenital system disorder selected from renal
fibrosis, renal failure resulting from chronic kidney diseases or
insufficiency, erectile dysfunction or female sexual
dysfunction.
92. The method of claim 91, wherein the disease, health condition
or disorder is pulmonary hypertension, pulmonary arterial
hypertension, and associated pulmonary vascular remodeling,
localized pulmonary thrombosis, 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, liver cirrhosis, renal fibrosis, renal failure resulting
from chronic kidney diseases or insufficiency, erectile dysfunction
or female sexual dysfunction.
93. The method of claim 92, 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.
94. The method of claim 90, further comprising administering an
effective amount of one or more additional therapeutic agents to
the subject.
95. The method of claim 94, wherein the one or more additional
therapeutic agents are selected from edothelium-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.
96. The method of claim 83, 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.
97. The method of claim 83, 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.
98. The method of claim 83, 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.
99. The method of claim 83, wherein the disease a urogenital system
disorder selected from renal fibrosis or renal failure resulting
from chronic kidney diseases or insufficiency.
100. The method of claim 90, 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.
101. The method of claim 90, 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.
102. The method of claim 90, 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.
103. The method of claim 90, wherein the disease a urogenital
system disorder selected from renal fibrosis or renal failure
resulting from chronic kidney diseases or insufficiency.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation application of
U.S. patent application Ser. No. 13/833,910, filed Dec. 12, 2013,
now allowed. U.S. patent application Ser. No. 13/833,910 which is a
National Phase application of international application number
PCT/2011/058902, filed on Nov. 2, 2011, which claims the benefits
of priority of U.S. Provisional Application Nos. 61/411,730 filed
Nov. 9, 2010 and 61/546,707 filed Oct. 13, 2011. The disclosures of
all prior applications are hereby incorporated by reference herein
in their entirety.
FIELD OF THE INVENTION
[0002] The present disclosure relates to stimulators of soluble
guanylate cyclase (sGC), pharmaceutical formulations thereof and
methods of using the stimulators, 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) 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. In
particular, the NO signaling pathway is altered in cardiovascular
diseases, including, for instance, systemic and pulmonary
hypertension, heart failure, stroke, thrombosis and
atherosclerosis.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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 would be useful in the prevention, management and treatment of
disorders such as pulmonary hypertension, arterial hypertension,
heart failure, atherosclerosis, inflammation, thrombosis, renal
fibrosis and failure, liver cirrhosis, erectile dysfunction and
other cardiovascular disorders.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to compounds according to
Formula IA or IB, or a pharmaceutically acceptable salt
thereof,
##STR00002##
[0011] wherein: [0012] the symbol of the encircled letter B
represents ring B, and ring B is a phenyl or a 6-membered
heteroaryl ring, containing 1 or 2 nitrogen ring atoms; [0013] n is
an integer selected from 0 to 3; [0014] each J.sup.B is
independently selected from halogen, --CN, --NO.sub.2, 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; [0015] 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.3; [0016]
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); [0017] X is selected from N or C; [0018]
each Y is independently selected from C, N, O or S; [0019] m is an
integer selected from 0 to 3; [0020] each J.sup.D is a substituent
on a carbon or nitrogen ring atom and 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; [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 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; [0022] 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.5; [0023] 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.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.5; [0024] alternatively, two instances of R.sup.D linked to
the same nitrogen atom of J.sup.D, together with said nitrogen atom
of J.sup.D, 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; or [0025] alternatively, one instance of R.sup.D linked to
a carbon, oxygen or sulfur atom of J.sup.D and one instance of
R.sup.d linked to a nitrogen atom of the same J.sup.D, together
with said carbon, oxygen or sulfur and said nitrogen atom of that
same J.sup.D, 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; [0026] 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, --CORE, --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; [0027] each R.sup.6 is independently
selected from hydrogen, a C.sub.1-4 alkyl, phenyl, a C.sub.7-12
aralkyl or a C.sub.3-8 cycloalkyl ring; wherein each of said
C.sub.1-4 alkyl, 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; [0028]
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
[0029] 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; [0030] 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)
or oxo; [0031] R.sup.C is selected a halogen, --CN, C.sub.1-6 alkyl
or a ring C; [0032] 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; and
wherein said phenyl, monocyclic 5 to 6-membered heteroaryl ring,
bicyclic 8 to 10-membered heteroaryl ring, or monocyclic 4 to
10-membered heterocycle is optionally and independently substituted
with up to 3 instances of J.sup.C; [0033] 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; [0034] 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; [0035] 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.7; or [0036] 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', --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; [0037]
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; [0038]
alternatively, two instances of R.sup.8 linked to the same nitrogen
atom of R.sup.7, together with said nitrogen atom of R.sup.7, 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;
[0039] R.sup.A is selected from hydrogen, halogen, C.sub.1-4 alkyl
or C.sub.1-4 haloalkyl; provided that the compound is not one of
the compounds represented below:
##STR00003##
[0040] The invention also provides pharmaceutical compositions
comprising a compound of Formula IA or Formula IB or a
pharmaceutically acceptable salt thereof.
[0041] 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
the compound of Formula IA or Formula IB or a pharmaceutically
acceptable salt thereof to the subject; wherein the disease, health
condition or disorder is a peripheral or cardiac vascular
disorder/condition, or a urogenital system disorder that can
benefit from sGC stimulation.
DETAILED DESCRIPTION OF THE INVENTION
[0042] 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
[0043] 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.
[0044] As described herein, compounds of Formula IA or Formula IB
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.
If a substituent radical or structure is not identified or defined
as "optionally substituted", the substituent radical or structure
is not substituted. 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.
[0045] 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.
[0046] 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.
[0047] A compound, such as the compounds of Formula IA or Formula
IB or other compounds herein disclosed, may be present in its free
form or as part of a co-form. The compound may be present in a
solid form (e.g. an amorphous form, or a crystalline form or
polymorph). Under certain conditions, compounds may also form
salts. 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.
[0048] 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
within the scope of the disclosure.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] "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.
[0058] 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.
[0059] 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.
[0060] 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.
[0061] 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 IA 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.
[0062] 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.
[0063] 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).
[0064] 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.
[0065] "Fused" bicyclic ring systems comprise two rings which share
two adjoining ring atoms.
[0066] "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 of 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.
[0067] The term "ring atom" refers to an atom such as C, N, O or S
that is part of the ring of an aromatic group, a cycloaliphatic
group 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.
[0068] "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).
[0069] 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 cycloalkyl 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,
carbocyclyl 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, carbocyclyl 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 R.sup.o as in Formula D1:
##STR00004##
[0070] these two occurrences of R.sup.o are taken together with the
oxygen atoms to which they are bound to form a fused 6-membered
oxygen containing ring as in Formula D2:
##STR00005##
[0071] 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.
[0072] 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 C.sub.3 aliphatic can be optionally
replaced by --N(R')--, --C(O)--, and --N(R')-- to form
--N(R')C(O)N(R')-- (a urea).
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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##
[0077] 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##
[0078] 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##
[0079] 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.
[0080] 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.
[0081] 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 C.sub.4 alkoxyalkyl could be,
for instance, --CH.sub.2CH.sub.2OCH.sub.2(Me)CH.sub.3 or
--CH.sub.2(OH)O CH.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.
[0082] 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.
[0083] As used herein, the terms "halogen" or "halo" mean F, Cl,
Br, or I.
[0084] 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.
[0085] As used herein, the term "cyano" refers to --CN or
--C.ident.N.
[0086] 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.
[0087] As used herein, an "amino" group refers to --NH.sub.2.
[0088] 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.
[0089] The term "hydroxyl" or "hydroxy" refers to --OH.
[0090] 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 C.sub.4 hydroxyalkoxy could be
--OCH.sub.2C(CH.sub.3)(OH)CH.sub.3.
[0091] 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).
[0092] As used herein, an "oxo" refers to .dbd.O, 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.
[0093] 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.
[0094] 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 C.sub.2 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 [0095]
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##
[0095] A linker can additionally be optionally substituted in any
portion or position.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] 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.
[0100] One of the aspects of the present invention is directed to a
compound according to Formula IA or IB, or a pharmaceutically
acceptable salt thereof,
##STR00010##
wherein:
[0101] the symbol with the encircled letter B represents ring B,
and ring B is a phenyl or a 6-membered heteroaryl ring, containing
1 or 2 nitrogen ring atoms;
[0102] n is an integer selected from 0 to 3;
[0103] each J.sup.B is independently selected from halogen, --CN,
--NO.sub.2, 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;
[0104] 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.3;
[0105] 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);
[0106] X is selected from N or C;
[0107] each Y is independently selected from C, N, O or S;
[0108] m is an integer selected from 0 to 3;
[0109] each J.sup.D is a substituent on a carbon or nitrogen ring
atom and 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;
[0110] 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;
[0111] 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.5;
[0112] 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.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.5;
[0113] alternatively, two instances of R.sup.D linked to the same
nitrogen atom of J.sup.D, together with said nitrogen atom of
J.sup.D, 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; or
[0114] alternatively, one instance of R.sup.D linked to a carbon,
oxygen or sulfur atom of J.sup.D and one instance of R.sup.d linked
to a nitrogen atom of the same J.sup.D, together with said carbon,
oxygen or sulfur and said nitrogen atom of that same J.sup.D, 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;
[0115] 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, --CORE, --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;
[0116] each R.sup.6 is independently selected from hydrogen, a
C.sub.1-4 alkyl, phenyl, a C.sub.7-12 aralkyl or a C.sub.3-8
cycloalkyl ring; wherein each of said C.sub.1-4 alkyl, 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;
[0117] 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
[0118] 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;
[0119] 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) or oxo;
[0120] R.sup.C is selected from halo, --CN, C.sub.1-6 alkyl or 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; and wherein said phenyl,
monocyclic 5 to 6-membered heteroaryl ring, bicyclic 8 to
10-membered heteroaryl ring, or monocyclic 4 to 10-membered
heterocycle is optionally and independently substituted with up to
3 instances of J.sup.C;
[0121] 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;
[0122] 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;
[0123] 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.7; or
[0124] 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', --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;
[0125] 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;
[0126] alternatively, two instances of R.sup.8 linked to the same
nitrogen atom of R.sup.7, together with said nitrogen atom of
R.sup.7, 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
[0127] R.sup.A is selected from hydrogen, halogen, C.sub.1-4 alkyl
or C.sub.1-4 haloalkyl; provided that the compound is not one of
the compounds represented below:
##STR00011##
[0128] In some of the embodiments of the compound of Formula IA or
IB, or a pharmaceutically acceptable salt thereof, ring B is
phenyl.
[0129] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, n is an integer selected
from 1 to 3, wherein each J.sup.B is independently selected from
halogen, a C.sub.1-6 aliphatic or --OR.sup.B. In further
embodiments, each J.sup.B is independently selected from halogen
atoms. In still further embodiments, each J.sup.B is independently
selected from fluoro or chloro. In yet further embodiments, each
J.sup.B is fluoro.
[0130] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, n is an integer selected
from 1 to 3, and each J.sup.B is a C.sub.1-6 aliphatic. In further
embodiments, each J.sup.B is methyl or ethyl.
[0131] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, n is 1. In further
embodiments, J.sup.B is selected from halogen atoms. In still
further embodiments, J.sup.B is fluoro or chloro. In yet further
embodiments, J.sup.B is fluoro.
[0132] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, n is an integer selected
from 1 to 3, and each J.sup.B is independently selected from
halogen, a C.sub.1-6 aliphatic or --OR.sup.B. In further
embodiments, at least one J.sup.B is ortho to the attachment of the
methylene linker between ring B and the triazolyl ring. In still
further embodiments, each J.sup.B is independently selected from
halogen atoms. In yet further embodiments, each J.sup.B is
independently selected from fluoro or chloro. In yet still further
embodiments, each J.sup.B is fluoro.
[0133] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, n is 1, and each J.sup.B
is independently selected from halogen, a C.sub.1-6 aliphatic or
--OR.sup.B, wherein at least one of the J.sup.B groups is ortho to
the attachment of the methylene linker between ring B and the
triazolyl ring is fluoro.
[0134] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, ring B is a 6-membered
heteroaryl ring.
[0135] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, ring B is a pyridyl or
pyrimidinyl ring.
[0136] In some of the embodiments of Formula IA, or a
pharmaceutically acceptable salt thereof, X in ring D of Formula AI
is a ring carbon atom and it is optionally substituted. In further
embodiments, ring B is a phenyl ring or 6-membered heteroaryl ring.
In still further embodiments, ring B is phenyl. Alternatively, in
some of the embodiments, ring B is pyridyl or pyrimidinyl ring.
[0137] In some of the embodiments of Formula IA, or a
pharmaceutically acceptable salt thereof, X in ring D of Formula AI
is a ring nitrogen atom.
[0138] In some of the embodiments of Formula IB, or a
pharmaceutically acceptable salt thereof, one of the 4 instances of
Y in ring D is selected from N, O or S and the other 3 instances of
Y in ring D are carbon atoms, wherein said carbon atoms are
optionally substituted.
[0139] In some of the embodiments of the compounds of Formula IB,
or a pharmaceutically acceptable salt thereof, ring D is a
thiazolyl or oxazolyl ring such as thiazol-2-yl, thiazol-4-yl,
oxazol-2-yl or oxazol-4-yl ring. In further embodiments of the
compounds of Formula IB, R.sup.C is ring C, and ring C is a
pyridyl, pyrimidinyl, oxazolyl or thiazol ring.
[0140] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, m is 0.
[0141] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, m is an integer selected
from 1, 2 or 3 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)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, --SR.sup.D, --OR.sup.D or an
optionally substituted C.sub.3-8 cycloaliphatic ring. In further
embodiments, each J.sup.D is independently selected from halogen
atoms. In still further embodiments, each J.sup.D is independently
selected from a chloro or fluoro.
[0142] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, m is an integer selected
from 1, 2 or 3 and each J.sup.D is independently selected from a
C.sub.1-6 aliphatic or a C.sub.3-8 cycloaliphatic ring. In further
embodiments, each J.sup.D is independently methyl, ethyl, propyl,
cyclobutyl, cyclopropyl or isopropyl. In still further embodiments,
each J.sup.D is independently methyl, ethyl or cyclopropyl.
[0143] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, m is an integer selected
from 1, 2 or 3 and each J.sup.D is independently selected from
--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 or
--OR.sup.D. In further embodiments, each R.sup.d is independently
selected from a C.sub.1-4 alkyl or hydrogen and each R.sup.D is
independently selected from hydrogen or C.sub.1-4 alkyl. In still
further embodiments, each R.sup.d is independently selected from
hydrogen or methyl, and each R.sup.D is independently selected from
hydrogen, methyl, ethyl, propyl or isopropyl. In yet further
embodiments, each R.sup.d and each R.sup.D is independently
selected from hydrogen or methyl.
[0144] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, m is an integer selected
from 1, 2 or 3 and each J.sup.D is independently selected from
methyl, fluoro, --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 or --N(R.sup.d)SO.sub.2R.sup.D; wherein
each R.sup.d and each R.sup.D is independently selected from
hydrogen or methyl. In further embodiments, R.sup.C is --CN or
halo. Alternatively, R.sup.C is a C.sub.1-6 alkyl. In other
alternative embodiments, R.sup.C is ring C. In some of the
alternative embodiments, R.sup.C is ring C, wherein ring C is a
phenyl ring, a monocyclic 5 or 6-membered heteroaryl ring, a
monocyclic 3 to 10-membered cycloaliphatic ring or a monocyclic 4
to 10-membered heterocycle; each of the phenyl ring, a monocyclic 5
or 6-membered heteroaryl ring, a monocyclic 3 to 10-membered
cycloaliphatic ring or a monocyclic 4 to 10-membered heterocycle is
optionally and independently substituted with up to 6 instances of
J.sup.C.
[0145] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is --CN or
halo.
[0146] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is a C.sub.1-6
alkyl. In further embodiments, R.sup.C is selected from methyl,
ethyl, propyl, isopropyl or butyl.
[0147] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is a ring C. In
further embodiments, ring C is a phenyl ring, a monocyclic 5 or
6-membered heteroaryl ring, a monocyclic 3 to 10-membered
cycloaliphatic ring or a monocyclic 4 to 10-membered heterocycle;
each of the phenyl ring, a monocyclic 5 or 6-membered heteroaryl
ring, a monocyclic 3 to 10-membered cycloaliphatic ring or a
monocyclic 4 to 10-membered heterocycle is optionally and
independently substituted with up to 6 instances of J.sup.C. In
still further embodiments, ring C is a phenyl, a monocyclic 5 or
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.
[0148] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is a ring C,
wherein ring C is a monocyclic 3 to 6-membered cycloaliphatic ring,
optionally substituted with up to 2 instances of J.sup.C. In
further embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl.
[0149] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is a ring C,
wherein ring C 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 J.sup.C or a 6-membered
cycloaliphatic ring substituted by 1 to 5 instances of J.sup.C, and
wherein each J.sup.C is independently selected from halogen or
C.sub.1-6 aliphatic.
[0150] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is a ring C,
wherein ring C is phenyl, optionally and independently substituted
by up to 5 instances of J.sup.C. In further embodiments, R.sup.C is
ring C and ring C is unsubstituted phenyl.
[0151] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is ring C and
ring C is substituted phenyl. In further embodiments, ring C is
substituted by 1 to 3 instances of J.sup.C and wherein each J.sup.C
is independently selected from halogen, C.sub.1-6 aliphatic,
--NH.sub.2, --CN or --O(C.sub.1-6 aliphatic). In still further
embodiments, each J.sup.C is independently selected from halogen,
C.sub.1-4 alkyl, --O(C.sub.1-4alkyl), --CN or --NH.sub.2. In yet
further embodiments, ring C is phenyl substituted by 1 to 2
instances of J.sup.C. In yet still further embodiments, each
J.sup.C is independently selected from fluoro, methyl, --CN or
--OCH.sub.3.
[0152] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is ring C,
wherein ring C is a 5 to 6-membered heteroaryl ring, optionally
substituted by up to 5 instances of J.sup.C.
[0153] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is ring C,
wherein ring C is an unsubstituted 5 to 6-membered heteroaryl ring.
In further embodiments, the 5 to 6-membered heteroaryl ring as ring
C is selected from thienyl, thiazolyl, oxadiazolyl, oxazolyl,
isooxazolyl, tetrazolyl, pyrrolyl, triazolyl, furanyl, pyridinyl,
pyrimidinyl, pyrazinyl or pyridazinyl. In still further
embodiments, the 5 to 6-membered heteroaryl ring as ring C is
selected from furanyl, thienyl, thiazolyl, oxazolyl,
1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl or pyrazin-3-yl. In yet
further embodiments, the 5 to 6-membered heteroaryl ring as ring C
is selected from thienyl, thiazolyl, oxazoly, 1,3,4-oxadiazolyl or
pyridinyl. In yet still further embodiments, the 5 to 6-membered
heteroaryl ring as ring C is selected from furan-2-yl, furan-3-yl,
thien-3-yl, thien-2-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl,
oxazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
pyrimidin-2-yl or pyrimidin-4-yl.
[0154] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is ring C,
wherein ring C is a 5 to 6-membered heteroaryl ring substituted by
up to 5 instances of J.sup.C. In further embodiments, the 5 to
6-membered heteroaryl ring as ring C is selected from thienyl,
thiazolyl, oxadiazolyl, oxazolyl, isooxazolyl, tetrazolyl,
pyrrolyl, triazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl or
pyridazinyl. In still further embodiments, the 5 to 6-membered
heteroaryl ring as ring C is selected from furanyl, thienyl,
thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl or
pyrazin-3-yl. In yet further embodiments, the 5 to 6-membered
heteroaryl ring as ring C is selected from thienyl, thiazolyl,
oxazolyl, 1,3,4-oxadiazolyl or pyridinyl. In yet still further
embodiments, the 5 to 6-membered heteroaryl ring as ring C is
selected from furan-2-yl, furan-3-yl, thien-3-yl, thien-2-yl,
thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, oxazol-4-yl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-4-yl; and
is independently substituted with up to 2 instances of J.sup.C. In
some of the embodiments, each J.sup.C is independently selected
from halogen, C.sub.1-6 aliphatic, --CN, --NH.sub.2 or
--O(C.sub.1-6 aliphatic).
[0155] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, R.sup.C is ring C,
wherein ring C is thienyl or pyridinyl substituted by 1 to 3
instances of J.sup.C and each J.sup.C is independently selected
from a halogen, C.sub.1-6 aliphatic, --NH.sub.2 or --O(C.sub.1-6
aliphatic). In further embodiments, each J.sup.C is independently
selected from C.sub.1-6 aliphatic. In still further embodiments,
each J.sup.C is independently selected from methyl, ethyl, propyl
or isopropyl. In yet further embodiments, each J.sup.C is
independently selected from a halogen atom, methyl, --NH.sub.2 or
--OCH.sub.3.
[0156] In some of the embodiments of Formula IA or IB, or a
pharmaceutically acceptable salt thereof, RC is ring C, wherein
ring C is a bicyclic 7 to 10-membered heteroaryl ring. In further
embodiments, ring C is benzofuran-2-yl, furo[3,2-b]pyridinyl,
furo[2,3-b]pyridinyl, benzothienyl or indolyl. In still further
embodiments, ring C is benzofuran-2-yl, furo[3,2-b]pyridinyl or
benzothienyl.
[0157] In some of the embodiments, the invention is directed to the
compound having Formula IA, or a pharmaceutically acceptable salt
thereof.
[0158] In some of the embodiments of the compound of Formula IA, or
a pharmaceutically acceptable salt thereof, the compound has
Formula IIA,
##STR00012##
[0159] In some of the embodiments of the compound of Formula IA, or
a pharmaceutically acceptable salt thereof, the compound has
Formula III or Formula IV:
##STR00013##
[0160] In further embodiments, the compound has one of Formulae VA,
VC, VD and VF:
##STR00014##
[0161] In some of the embodiments, the invention is directed to the
compound of Formula IB, or a pharmaceutically acceptable salt
thereof. In further embodiments, the compound has Formula IIB:
##STR00015##
[0162] In some of the embodiments of the compound of Formula IIB,
R.sup.C is halo, --CN or --C.sub.1-6 alkyl.
[0163] In some of the embodiments of the compound of Formula IIB,
R.sup.C is --CN and the compound is represented by Formula VI:
##STR00016##
[0164] In some of the embodiments of the compound of Formula IIB,
R.sup.C is ring C and the compound is represented by Formula
VII:
##STR00017##
wherein the symbol of the encircled letter C represents ring C. In
further embodiments, ring C is selected from a phenyl ring, a
monocyclic 5 or 6-membered heteroaryl ring, a monocyclic 3 to
10-membered cycloaliphatic ring, or a monocyclic 4, 5 or 6-membered
heterocycle; wherein each of said phenyl ring, monocyclic 5 or
6-membered heteroaryl ring, monocyclic 3 to 8-membered
cycloaliphatic ring, or monocyclic 4, 5 or 6-membered heterocycle
is optionally and independently substituted with up to 3 instances
of J.sup.C. In still further embodiments, ring C is selected from a
phenyl ring, cyclopropyl ring, cyclobutyl ring, azetidinyl ring,
thiazolyl ring or oxazolyl ring. In yet further embodiments, ring C
is a thiazolyl ring or oxazolyl ring, e.g., thiazol-2-yl ring,
thiazol-4-yl ring, oxazol-2-yl ring and oxazol-4-yl ring. In yet
still further embodiments, ring C is a thiazol-2-yl ring or
thiazol-4-yl ring.
[0165] In some embodiments, compounds of Formula IA and Formula IB
are selected from those listed in Tables 1a and 1b herein.
TABLE-US-00001 TABLE 1b ##STR00018## I-1 ##STR00019## I-2
##STR00020## I-3 ##STR00021## I-4 ##STR00022## I-5 ##STR00023## I-6
##STR00024## I-7 ##STR00025## I-8 ##STR00026## I-9 ##STR00027##
I-10 ##STR00028## I-11 ##STR00029## I-12 ##STR00030## I-13
##STR00031## I-14 ##STR00032## I-15 ##STR00033## I-16 ##STR00034##
I-17 ##STR00035## I-18 ##STR00036## I-19 ##STR00037## I-20
##STR00038## I-21 ##STR00039## I-22 ##STR00040## I-23 ##STR00041##
I-24 ##STR00042## I-25 ##STR00043## I-26 ##STR00044## I-27
##STR00045## I-28 ##STR00046## I-29 ##STR00047## I-30 ##STR00048##
I-31 ##STR00049## I-32 ##STR00050## I-33 ##STR00051## I-34
TABLE-US-00002 TABLE 1b ##STR00052## I-35 ##STR00053## I-36
##STR00054## I-37 ##STR00055## I-38 ##STR00056## I-39 ##STR00057##
I-40 ##STR00058## I-41 ##STR00059## I-42 ##STR00060## I-43
##STR00061## I-44 ##STR00062## I-45 ##STR00063## I-46 ##STR00064##
I-47 ##STR00065## I-48 ##STR00066## I-49 ##STR00067## I-50
##STR00068## I-51 ##STR00069## I-52 ##STR00070## I-53 ##STR00071##
I-54 ##STR00072## I-55 ##STR00073## I-56 ##STR00074## I-57
##STR00075## I-58 ##STR00076## I-59 ##STR00077## I-60 ##STR00078##
I-61 ##STR00079## I-62 ##STR00080## I-63 ##STR00081## I-64
##STR00082## I-65 ##STR00083## I-66 ##STR00084## I-67A ##STR00085##
I-67B ##STR00086## I-68
Methods of Preparing the Compounds
[0166] The compounds of Formula IA or 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 IA or Formula IB as
disclosed herein.
[0167] 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.
General Procedure A
##STR00087##
[0169] Step 1:
[0170] Triazole formation: A mixture of hydrazide A (1.0 eq) and
amidine B (1.0 eq) in EtOH (0.05 to 0.3 M depending on solubility)
in a sealed vial is heated, e.g., to about 100-110.degree. C. (bath
temperature) and monitored by LC/MS analysis. Once complete
(reaction time typically 24 h), the reaction mixture is
concentrated, azeotroped with toluene and dried in vacuo to afford
triazole C as the hydrochloride salt. It is carried on to
alkylation step without any further purification.
[0171] Step 2:
[0172] Alkylation: Triazole C is dissolved in DMF and treated with
sodium hydride (e.g., about 60% w/w in mineral oil, about 2.0 eq)
and the appropriate benzyl bromide (e.g., about 1.5 eq). The
reaction is stirred at room temperature and monitored by LC/MS
analysis. Once complete (reaction time typically 30 min), the
reaction solution is diluted with ethyl acetate and washed with
water (e.g., 4 times) and brine. The organic layer is dried, e.g.,
over MgSO.sub.4 or Na.sub.2SO4, filtered and concentrated. The
crude material is purified using SiO2 chromatography and an
appropriate solvent gradient (ethyl acetate/hexanes or
DCM/methanol) to afford products D and E. In all cases, the two
regioisomers are readily separable. Structural assignments are
based on 1H NMR analysis and confirmed by observed activities in
biological assays.
General Procedure B
##STR00088##
[0174] Amidine Formation:
[0175] Nitrile F is treated with sodium methoxide (e.g., about 0.5
M in methanol, about 0.5 eq) at room temperature and monitored by
LC/MS analysis. Once the starting nitrile is consumed (reaction
time was typically 2-7 h), ammonium chloride (e.g., about 1.1 eq)
is added and the reaction mixture is stirred for about 16-24 h. The
reaction mixture is concentrated and dried in vacuo. In some case,
the crude amidine is collected by filtration.
[0176] The crude amidine is then used as one of the starting
compounds in General Procedure A described above without any
further purification to yield Compounds D and E.
General Procedure C
##STR00089##
[0178] A solution of
2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine
(I-16), in DMA is treated with a large excess of azetidine (e.g.,
--30 eq). The resultant solution is warmed to about 100.degree. C.
and stirred at that temperature for about 18 h. The reaction
solution is cooled to room temperature, poured into 1N NaOH
solution and then extracted with EtOAc. The organic phases are
dried, e.g., over MgSO4 or Na2SO4, filtered and concentrated. The
crude product is purified using SiO2 chromatography and an
appropriate gradient (MeOH--CH3CN (1:7)/CH2Cl2) to yield
2-(5-(azetidin-1-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine
(I-23) as a solid.
General Procedure D
##STR00090##
[0180] A solution of pyrazole (1.1 eq) in DMF is treated with
sodium hydride (e.g., about 60% w/w in mineral oil, about 1.2 eq)
and stirred for about 10 min at room temperature.
2-(5-Bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16,
e.g., 1.0 eq) is then added. The resultant mixture is warmed to
about 50.degree. C. and stirred at that temperature for about 1 h.
The reaction solution is cooled to room temperature, poured into
water, and filtered to yield
2-(1-(2-fluorobenzyl)-5-(1H-pyrazol-1-yl)-1H-1,2,4-triazol-3-yl)-
pyridine (I-10) as a solid.
General Procedure E
##STR00091##
[0182] To a solution of
2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16,
e.g., about 0.95 g, 2.9 mmol) in N,N-dimethylformamide (e.g., 9.5
mL) is added potassium cyanide (e.g., about 0.928 g, 14.3 mmol).
After heating the solution at about 100.degree. C. for about 22 h,
the solution is diluted with ethyl acetate (e.g., about 125 mL) and
water (e.g., about 100 mL). The layers are separated, and the
aqueous layer is extracted with ethyl acetate (e.g., about
2.times.50 mL). The organics are combined, washed with water (e.g.,
about 50 mL) and brine (e.g., about 50 mL), dried, e.g., over
sodium sulfate or magnesium sulfate, filtered, and the solvent is
removed in vacuo to give the crude product, I-33. Purification by
silica gel chromatography (0-15% ethyl acetate in dichloromethane)
yields
1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile
1-33 (I-33) as a solid.
[0183] To a solution of
1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile
(I-33, e.g., about 100 mg, 0.358 mmol) and potassium carbonate
(e.g., about 198 mg, 1.43 mmol) in methanol (e.g., about 3.6 mL) is
added hydroxylamine hydrochloride (e.g., about 75 mg, 1.1 mmol).
The solution is heated to about 70.degree. C. for about 1.25 h, at
which point the solution is diluted with ethyl acetate (e.g., about
20 mL) and the solids are filtered off through a cotton plug. The
solvent is removed in vacuo and the crude residue is diluted with
water (e.g., about 50 mL) and a mixture of dichloromethane and
2-propanol, e.g., a 5:1 mixture of dichloromethane and 2-propanol
(e.g., about 50 mL). The layers are separated and the organic layer
is washed with water (e.g., about 50 mL), dried, e.g., over sodium
sulfate or magnesium sulfate, and the solvent is removed in vacuo.
To the resulting crude
1-(2-fluorobenzyl)-N'-hydroxy-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbox-
imidamide is added trimethyl orthorfomate (e.g., about 4.5 mL, 41
mmol) and a catalytic amount of p-toluensulfonic acid monohydrate
(e.g., about 3.4 mg, 0.018 mmol). The solution is heated to about
100.degree. C. for about 1.5 h, and the excess orthoformate is
removed in vacuo to give the crude product, I-34. Purification by
silica gel chromatography (e.g., 20-80% ethyl acetate in hexanes)
yields
3-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,2,4-oxadi-
azole, I-34, as a solid.
General Procedure F
[0184] In the compounds of Formula IA or IB, any bromo substituent
on ring D, i.e., when J.sup.D is Br, can be converted into an amino
substituent with the procedure as shown below to obtain the
corresponding compound having --NH.sub.2 as J.sup.D. Similarly, any
bromo substituent on ring C, i.e., when J.sup.C is Br, in a
compound of Formula IA or IB can be converted into an amino
substituent with the procedure as shown below to obtain the
corresponding compound having --NH.sub.2 as J.sup.C. In the
reaction scheme described below, compound I-19 is used as an
example to demonstrate the conversion of a bromo ring substituent,
e.g., Br as J.sup.D, to an amino ring substituent, e.g., --NH.sub.2
as J.sup.D, in a compound of Formula IA or IB.
##STR00092##
[0185] To a suspension of
2-(3-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiaz-
ole (I-19) and copper(I) oxide (e.g., about 0.2 eq) in ethylene
glycol-dioxane (e.g., about 4:1) in a sealed tube is added ammonium
hydroxide solution (e.g., --29% in water, .about.30 eq). The
resultant mixture is warmed to about 100.degree. C. and stirred at
that temperature for about 24 h. The reaction solution is cooled to
room temperature, poured into 1N NaOH solution and then extracted
with EtOAc. The organic phases are dried, e.g., over
Na.sub.2SO.sub.4 or MgSO.sub.4, filtered and concentrated. The
crude product is purified using SiO2 chromatography and an
appropriate gradient (EtOAc/hexanes) to give
6-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-am-
ine (I-14) as a solid.
Pharmaceutically Acceptable Salts
[0186] The phrase "pharmaceutically acceptable salt," as used
herein, refers to pharmaceutically acceptable organic or inorganic
salts of a compound of Formula IA or Formula IB. For use in
medicine, the salts of the compounds of Formula IA or Formula IB
will be pharmaceutically acceptable salts. Other salts may,
however, be useful in the preparation of the compounds of Formula
IA 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.
[0187] Pharmaceutically acceptable salts of the compounds described
herein include those derived from suitable inorganic and organic
acids and 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.
[0188] When the compound of Formula IA 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.
[0189] When the compound of Formula IA 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 palmoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
[0190] 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.
Pharmaceutical Compositions and Methods of Administration
[0191] The compounds herein disclosed, and their pharmaceutically
acceptable salts, may be formulated as pharmaceutical compositions
or "formulations".
[0192] A typical formulation is prepared by mixing a compound of
Formula IA 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 the compound of Formula IA 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 IA or Formula IB or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0193] The formulations may be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of Formula IA or Formula IB, a
pharmaceutically acceptable salt thereof, wherein the compound of
Formula IA or IB, or its pharmaceutically acceptable salt, can be
in a stabilized form, 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.
[0194] The compound of Formula IA 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 compounds of
Formula IA 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.
[0195] 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.
[0196] 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.
[0197] The pharmaceutical compositions of Formula IA 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.
[0198] 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).
[0199] 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-(methylmethacrylate) 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").
[0200] "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.
[0201] "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.
[0202] "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.
[0203] 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.
[0204] 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,
N.J.) and other acrylic acid derivatives such as homopolymers and
copolymers of butylmethacrylate, methylmethacrylate,
ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)
methacrylate, and (trimethylaminoethyl) methacrylate chloride.
[0205] 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).
[0206] 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
semipermeable 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.
[0207] 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.
[0208] 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.
[0209] 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.
[0210] 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., Avicel.TM.), 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.
[0211] 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.
[0212] 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.
[0213] 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. 6,419,952, 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.
[0214] 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.
[0215] 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.
[0216] 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.
[0217] 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.
[0218] 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.
[0219] 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.
[0220] 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.
[0221] 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.
[0222] 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, 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.
[0223] Formulations of a compound of Formula IA 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.
[0224] 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.
[0225] 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.
[0226] The active compounds can also be in microencapsulated form
with one or more excipients as noted above.
[0227] 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.
[0228] 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 di-glycerides. 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.
[0229] Oily suspensions may be formulated by suspending the
compound of Formula IA 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.
[0230] Aqueous suspensions of compounds of Formula IA 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
methylcellulose, 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.
[0231] 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.
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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.
[0236] 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.
[0237] 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.
[0238] 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.
[0239] 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.
[0240] The oily phase of emulsions prepared using compounds of
Formula IA 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
compounds of Formula IA or Formula IB include Tween.TM.-60,
Span.TM.-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol,
glyceryl mono-stearate and sodium lauryl sulfate.
[0241] 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.
[0242] 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.
[0243] 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.
[0244] In another aspect, a compound of Formula IA 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 acceptable in 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
[0245] 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 might be desirable, such as
pulmonary hypertension, arterial hypertension, heart failure,
atherosclerosis, inflammation, thrombosis, renal fibrosis and
failure, liver cirrhosis, erectile dysfunction and other related
cardiovascular disorders.
[0246] In one embodiment, the compounds herein disclosed are
NO-independent, heme-dependent sGC stimulators that can be used to
prevent and/or treat conditions, diseases or disorders in which it
is considered desirable to increase the concentration of cGMP.
Increased concentration of cGMP leads to vasodilatation, 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 cardiovascular,
endothelial, pulmonary, renal, hepatic and sexual diseases and
disorders.
[0247] 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.
[0248] Specific diseases of disorders which may be treated and/or
prevented by administering an sGC stimulator, include but are not
limited to: arterial hypertension, pulmonary hypertension, heart
failure, stroke, septic shock, atherosclerosis, thrombosis, renal
fibrosis, ischemic renal disease and renal failure, liver
cirrhosis, erectile dysfunction, male and female sexual
dysfunction, sickle cell anemia, asthma, chronic obstructive
pulmonary disease, and neuro inflammatory diseases or
disorders.
[0249] Pulmonary hypertension (PH) is a disease characterized by
sustained elevations 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. 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 hypoxemia, 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.
[0250] The compounds according to Formula IA or Formula IB of the
present invention 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: [0251] (1)
Peripheral or cardiac vascular disorders/conditions: [0252]
pulmonary hypertension, pulmonary arterial hypertension, 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, 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), connective tissue
disease, lupus, schitosomiasis, sarcoidosis, chronic obstructive
pulmonary disease, emphysema, chronic bronchitis, pulmonary
capillary hemangiomatosis; histiocytosis X, lymphangiomatosis and
compressed pulmonary vessels (such as due to adenopathy, tumor or
fibrosing mediastinitis) [0253] 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);
congestive heart failure; thromboembolic disorders and ischemias
such as myocardial infarction, stroke, transient ischemic attacks;
stable or unstable angina pectoris; arrhythmias; diastolic
dysfunction; coronary insufficiency; [0254] 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; [0255] 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
[0256] (2) 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; erectile dysfunction; female sexual dysfunction and
incontinence.
[0257] In some embodiments of the invention, the compounds
according to Formula IA or Formula IB as well as pharmaceutically
acceptable salts thereof are also useful in the prevention and/or
treatment of the following types of diseases, conditions and
disorders which can benefit from sGC stimulation:
[0258] (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, 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, 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, connective tissue disease,
lupus, schitosomiasis, sarcoidosis, chronic obstructive pulmonary
disease, emphysema, chronic bronchitis, pulmonary capillary
hemangiomatosis; histiocytosis X, lymphangiomatosis or compressed
pulmonary vessels;
[0259] (b) Liver cirrhosis, or (c) a urogenital system disorder
selected from renal fibrosis, renal failure resulting from chronic
kidney diseases or insufficiency, erectile dysfunction or female
sexual dysfunction.
[0260] In other embodiments of the invention, the compounds
according to Formula IA or 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: [0261] pulmonary
hypertension, pulmonary arterial hypertension, and associated
pulmonary vascular remodeling, localized pulmonary thrombosis,
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, liver
cirrhosis, renal fibrosis, renal failure resulting from chronic
kidney diseases or insufficiency, erectile dysfunction or female
sexual dysfunction.
[0262] In still other embodiments, the compounds according to
Formula IA or 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: [0263] 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.
[0264] The terms, "disease", "disorder" and "condition" may be used
interchangeably here to refer to a sGC, cGMP and/or NO mediated
medical or pathological condition.
[0265] 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.
[0266] The invention also provides a method for treating one of
these diseases, conditions and disorders in a subject, comprising
administering a therapeutically effective amount of the compound of
Formula IA or Formula IB, or a pharmaceutically acceptable salt
thereof, in the subject in need of the treatment. Alternatively,
the invention provides the use of the compound of Formula IA or
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 a medicament useful for treating one of these
diseases, conditions and disorders comprising using the compound of
Formula IA or Formula IB, or a pharmaceutically acceptable salt
thereof.
[0267] 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.
[0268] "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 a 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 a sGC, cGMP and/or NO mediated
condition. In other embodiments the terms "treat", "treatment" and
"treating" refer to the inhibition of the progression of a 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.
[0269] 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.
[0270] 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 a sGC, cGMP and/or NO related disease, disorder or
symptom.
[0271] 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 a sGC, cGM or NO related disease,
disorder or symptom.
[0272] 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.
[0273] 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.
[0274] 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
[0275] 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.
[0276] 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.
[0277] When "combination therapy" is employed, an effective amount
can be achieved using a first amount of a compound of Formula IA or
Formula IB or a pharmaceutically acceptable salt thereof, and a
second amount of an additional suitable therapeutic agent.
[0278] In one embodiment of this invention, the compound of Formula
IA or 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 Structural Formula IA or
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 Structural Formula IA or 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 Structural Formula IA or
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.
[0279] 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.
[0280] 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 Structural Formulae I 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 IA or 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.
[0281] 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.
[0282] 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: [0283] (1) Endothelium-derived releasing factor (EDRF);
[0284] (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 trinitroglycerin), 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), 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; [0285] (3)
Other substances that enhance cGMP concentrations such as
protoporphyrin IX, arachidonic acid and phenyl hydrazine
derivatives; [0286] (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-hydroxyguanidine, 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; [0287] (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); [0288] (6) NO
independent heme-independent sGC activators, including, but not
limited to: [0289] BAY 58-2667 (see patent publication
DE19943635)
[0289] ##STR00093## [0290] HMR-1766 (ataciguat sodium, see patent
publication WO2000002851)
[0290] ##STR00094## [0291] S 3448
(2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-su-
lfonyl)-phenyl)-benzamide (see patent publications DE19830430 and
WO2000002851)
##STR00095##
[0291] and HMR-1069 (Sanofi-Aventis). [0292] (7) Heme-dependent sGC
stimulators including, but not limited to: [0293] YC-1 (see patent
publications EP667345 and DE19744026)
[0293] ##STR00096## [0294] BAY 41-2272 (see patent publications
DE19834047 and DE19942809)
[0294] ##STR00097## [0295] BAY 41-8543 (see patent publication
DE19834044)
[0295] ##STR00098## [0296] BAY 63-2521 (see patent publication
DE19834044) [0297] CFM-1571 (see patent publication
WO2000027394)
[0297] ##STR00099## [0298] and other compounds disclosed in
Tetrahedron Letters (2003), 44(48): 8661-8663. [0299] (8) Compounds
that inhibit the degradation of cGMP, such as: [0300] PDE5
inhibitors, such as, for example, Sildenafil (Viagra.RTM.) and
other related agents such as Avanafil, Lodenafil, Mirodenafil,
Sildenafil citrate, Tadalafil (Cialis.RTM.), Vardenafil
(Levitra.RTM.) and Udenafil; Alprostadil; and [0301] Dipyridamole;
[0302] (9) Calcium channel blockers such as: [0303] Dihydropyridine
calcium channel blockers: Amlodipine (Norvasc), Aranidipine
(Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa),
Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard),
Clevidipine (Cleviprex), 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); [0304]
Phenylalkylamine calcium channel blockers: Verapamil (Calan,
Isoptin)
[0304] ##STR00100## [0305] Gallopamil (Procorum, D600); [0306]
Benzothiazepines: Diltiazem (Cardizem);
[0306] ##STR00101## [0307] Nonselective calcium channel inhibitors
such as: mibefradil, bepridil and fluspirilene, fendiline [0308]
(10) Endothelin receptor antagonists (ERAs): for instance the dual
(ET.sub.A and ET.sub.B) 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; [0309] (11) Prostacyclin derivatives: 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; [0310] (12) Antihyperlipidemics such as:
cholestyramine, colestipol, and colesevelam; statins such as
Atorvastatin, Simvastatin, Lovastatin and Pravastatin;
Rosuvastatin; also combinations of statins, niacin, intestinal
cholesterol absorption-inhibiting supplements (ezetimibe and
others, and to a much lesser extent fibrates); [0311] (13)
Anticoagulants, such as the following types: [0312] 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.; [0313] Heparin and
derivative substances such as: Heparin; low molecular weight
heparin, Fondaparinux and Idraparinux; [0314] Direct thrombin
inhibitors such as: Argatroban, Lepirudin, Bivalirudin and
Dabigatran; Ximelagatran (Exanta.RTM.), not approved in the US;
[0315] Tissue plasminogen activators, used to dissolve clots and
unblock arteries, such as Alteplase; [0316] (14) Antiplatelet
drugs: for instance thienopyridines such as Lopidogrel and
Ticlopidine; Dipyridamole; Aspirin; [0317] (15) ACE inhibitors, for
example the following types: [0318] Sulfhydryl-containing agents
such as Captopril (trade name Capoten.RTM.), the first ACE
inhibitor and Zofenopril; [0319] 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.); [0320] Phosphonate-containing agents such as:
Fosinopril; [0321] 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; [0322] (16) Supplemental oxygen therapy; [0323] (17)
Beta blockers, such as the following types: [0324] Non-selective
agents: Alprenolol.RTM., Bucindolol.RTM., Carteolol.RTM.,
Carvedilol.RTM. (has additional .alpha.-blocking activity),
Labetalol.RTM. (has additional .alpha.-blocking activity),
Nadolol.RTM., Penbutolol.RTM. (has intrinsic sympathomimetic
activity), Pindolol.RTM. (has intrinsic sympathomimetic activity),
Propranolol.RTM. and Timolol.RTM.; [0325] .beta..sub.1-Selective
agents: Acebutolol.RTM. (has intrinsic sympathomimetic activity),
Atenolol.RTM., Betaxolol.RTM., Bisoprolol.RTM., Celiprolol.RTM.,
Esmolol.RTM., Metoprolol.RTM. and Nebivolol.RTM.; [0326]
.beta..sub.2-Selective agents: Butaxamine.RTM. (weak
.alpha.-adrenergic agonist activity); [0327] (18) Antiarrhythmic
agents such as the following types: [0328] Type I (sodium channel
blockers): Quinidine, Lidocaine, Phenytoin, Propafenone [0329] Type
III (potassium channel blockers): Amiodarone, Dofetilide, Sotalol
[0330] Type V: Adenosine, Digoxin [0331] (19) Diuretics such as:
Thiazide diuretics, e.g., chlorothiazide, chlorthalidone, and
hydrochlorothiazide; Loop diuretics, such as furosemide;
potassium-sparing diuretics such as amiloride, spironolactone, and
triamterene; combinations of these agents; [0332] (20) Exogenous
vasodilators such as: [0333] Adenocard.RTM., an adenosine agonist,
primarily used as an anti-arrhythmic; [0334] Alpha blockers (which
block the vasoconstricting effect of adrenaline); [0335] Atrial
natriuretic peptide (ANP); [0336] Ethanol; [0337]
Histamine-inducers, which complement proteins C3.sub.a, C4.sub.a
and C5.sub.a work by triggering histamine release from mast cells
and basophil granulocytes; [0338] Tetrahydrocannabinol (THC), major
active chemical in marijuana which has minor vasodilatory effects;
[0339] Papaverine, an alkaloid found in the opium poppy papaver
somniferum; [0340] (21) Bronchodilators: there are two major types
of bronchodilator, .beta..sub.2 agonists and anticholinergics,
exemplified below: [0341] .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.; [0342] 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; [0343]
Theophylline.RTM., a bronchodilator and phosphodiesterase
inhibitor; [0344] (22) Corticosteroids: such as beclomethasone,
methylprednisolone, betamethasone, prednisone, prenisolone,
triamcinolone, dexamethasone, fluticasone, flunisolide and
hydrocortisone, and corticosteroid analogs such as budesonide
[0345] (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,
Zoraxel, Naltrexone, Bremelanotide (formerly PT-141), Melanotan II,
hMaxi-K; Prelox: a Proprietary mix/combination of naturally
occurring ingredients, L-arginine aspartate and Pycnogenol; [0346]
(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;
[0347] (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.); [0348] (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); [0349] (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);
[0350] (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 [0351] (29)
Anti-diabetic agents such as insulin and insulin mimetics,
sulfonylureas (e.g., glyburide, meglinatide), biguanides, e.g.,
metformin (Glucophage.RTM.), .alpha.-glucosidase inhibitors
(acarbose), thiazolidinone compounds, e.g., rosiglitazone
(Avandia.RTM.), troglitazone (Rezulin.RTM.), ciglitazone,
pioglitazone (Actos.RTM.) and englitazone.
Kits
[0352] 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.
[0353] 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.
[0354] 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.
[0355] 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
[0356] All references provided in the Examples are herein
incorporated by reference in their entirety. 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.
[0357] The products of Examples 1-3 below were prepared using
General Procedure A described above, containing the following two
steps.
[0358] Step 1:
[0359] Triazole formation: A mixture of hydrazide A (1.0 eq) and
amidine B (1.0 eq) in EtOH (0.05 to 0.3 M depending on solubility)
in a sealed vial was heated at 100-110.degree. C. (bath
temperature) and monitored by LC/MS analysis. Once complete
(reaction time was typically 24 h), the reaction mixture was
concentrated, azeotroped with toluene and dried in vacuo to afford
triazole C as the hydrochloride salt. Triazole C was carried on to
the alkylation step without any further purification.
[0360] Step 2:
[0361] Alkylation: Triazole C was dissolved in DMF and treated with
sodium hydride (60% w/w in mineral oil, 2.0 eq) and the appropriate
benzyl bromide (1.5 eq). The reaction was stirred at room
temperature and monitored by LC/MS analysis. Once complete
(reaction time was typically 30 min), the reaction mixture was
diluted with ethyl acetate and washed with water (4 times) and
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude material was purified using SiO.sub.2
chromatography and an appropriate solvent gradient (ethyl
acetate/hexanes or DCM/methanol) to afford products D and E. In all
cases, the two regioisomers were readily separable. Structural
assignments were based on .sup.1H NMR analysis and confirmed by
observed activities in biological assays.
Example 1: Compounds I-8 and I-9
Step 1
##STR00102##
[0363] To a vial charged with pyrimidine-2-carboximidamide
hydrochloride (250 mg, 1.576 mmol) and oxazole-2-carbohydrazide
(200 mg, 1.576 mmol) was added EtOH (12 mL). The vial was sealed
and heated at 100.degree. C. for 23 h. The two starting materials
went into solution almost immediately. The yellow solution was
cooled (a ppt formed) and concentrated. The sample was azeotroped
two times with toluene. LCMS of the major peak: m/z 215.15 (M+1).
This crude product was used without further purification or
characterization. The product was a yellow solid.
Step 2
##STR00103##
[0365] To a vial charged with
2-(3-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole hydrochloride
(395 mg, 1.575 mmol) was added sodium hydride (157 mg, 3.94 mmol)
followed by DMF (8 mL). The reaction evolved gas, became yellow,
and was stirred at rt for .about.30 min. Then
1-(bromomethyl)-2-fluorobenzene (0.310 mL, 2.52 mmol) was added and
the reaction stirred at room temperature for 1 h. The reaction was
poured into water and extracted with EtOAc (twice). The organic
layers were washed with water and dried with MgSO.sub.4. The crude
product was added to an 80 g ISCO silica gel column and was
purified with a gradient of 0% to 20% (CH.sub.3CN/MeOH
[7:1])/DCM.
[0366] Examination of both products, I-8 and I-9, with mass
spectrometry resulted in the following peak: LCMS m/z 323.3
(M+1).
I-8: .sup.1H NMR (CDCl.sub.3/400 MHz) .delta. 8.88 (d, 2H), 7.76
(s, 1H), 7.35 (t, 1H), 7.29 (s, 1H), 7.22-7.15 (m, 1H), 7.10 (td,
1H), 7.00-6.94 (m, 2H), 6.21 (s, 2H); MS m/z: 323.3 (M+1). I-9:
.sup.1H NMR (CDCl.sub.3/400 MHz) .delta. 8.90 (d, 2H), 7.83 (d,
1H), 7.35-7.33 (m, 2H), 7.26-7.20 (m, 1H), 7.09 (td, 1H), 7.05-6.98
(m, 2H), 6.19 (s, 2H); MS m/z: 323.3 (M+1).
Example 2: Compounds I-12 and I-13
[0367] To a solution of oxazole-4-carbohydrazide (228 mg, 1.794
mmol) in ethanol (8.9 mL) was added picolinimidamide hydrochloride
(283 mg, 1.79 mmol). After heating the orange solution at
100.degree. C. for 50 h, the solvent was removed in vacuo and the
residue was azeotroped with toluene (2.times.4 mL) to give 514 mg
of crude material. 187 mg of the crude material (0.75 mmol) was
dissolved in N,N-dimethylformamide (3.7 mL) and treated with sodium
hydride (60% dispersion in mineral oil, 75 mg, 1.9 mmol) in a
single portion at ambient temperature. After stirring for 20 min,
1-(bromomethyl)-2-fluorobenzene (0.136 mL, 1.12 mmol) was added.
The solution was stirred for an additional 45 min, at which point
the solution was poured into water (75 mL) and extracted with ethyl
acetate (3.times.50 mL). The organics were combined, washed with
water (2.times.50 mL) and brine (1.times.50 mL), dried over
magnesium sulfate, filtered, and the solvent was removed in vacuo
to give the crude product as an orange oil. Purification by silica
gel chromatography (10-100% ethyl acetate in hexanes) provided
4-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole,
I-12 (58 mg, 0.18 mmol, 24% yield over two steps) as a tan solid
and
4-(1-(2-fluorobenzyl)-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)oxazole,
I-13 (21 mg, 0.06 mmol, 8.7% yield over two steps) as a brown
solid.
##STR00104##
I-12: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.75-8.53 (m, 1H),
8.50 (s, 1H), 8.17-8.15 (m, 1H), 7.97 (s, 1H), 7.77 (dt, 1H),
7.32-7.29 (m, 1H), 7.26-7.21 (m, 1H), 7.07-6.99 (m, 3H), 6.10 (s,
2H).
##STR00105##
I-13: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.63-8.61 (m, 1H),
8.32-8.30 (m, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.84-7.80 (m, 1H),
7.34-7.31 (m, 1H), 7.23-7.17 (m, 1H), 7.10-6.97 (m, 3H), 6.23 (s,
2H).
Example 3: Compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-11, I-16,
I-20, I-21, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32,
I-58, I-59, I-51, I-52, I-45, I-46 and I-54, and Intermediate-1
[0368] Compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-11, I-16,
I-20, I-21, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32,
I-58, I-59, I-51, I-52, I-45, I-46 and I-54, and Intermediate-1
were prepared, analogously, using the conditions summarized in
General Scheme A and exemplified by Example 1 and Example 2.
Compound I-1
[0369] Compound I-1 was synthesized as a white solid (9.4% yield
over 2 steps) following the General Procedure A using
picolinohydrazide and picolinimidamide in step 1 and 2-fluorobenzyl
bromide in step 2.
##STR00106##
I-1: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (d, 1H), 8.62
(d, 1H), 8.41 (d, 1H), 8.22 (d, 1H), 7.82 (ddd, 1H), 7.79 (ddd,
1H), 7.33-7.30 (m, 2H), 7.22-7.16 (m, 1H), 7.09-7.00 (m, 2H), 6.97
(t, 1H), 6.29 (s, 2H) ppm.
Compound I-2
[0370] Compound I-2 was synthesized as a clear oil (20%) over 2
steps, following General Procedure A and using benzoic hydrazide
and 2-amidinopyridine hydrochloride in step 1 and 2-fluorobenzyl
bromide in step 2.
##STR00107##
I-2: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (m, 1H), 8.22
(d, 1H), 7.80 (app. td, 1H), 7.65 (m, 2H), 7.52-7.42 (m, 3H),
7.32-7.26 (m, 2H), 7.16 (app. t, 1H), 7.12-7.04 (m, 2H), 5.59 (s,
2H) ppm. MS: [M+H]=331.
Compounds I-3 and I-20
##STR00108##
[0371] I-3: .sup.1H NMR (CDCl.sub.3/400 MHz) .delta. 8.92 (d, 2H),
8.85 (dd, 1H), 8.48 (dd, 1H), 7.33 (td, 1H), 7.22-7.16 (m, 1H),
7.03-6.94 (m, 3H), 6.26 (s, 2H); MS m/z: 339.3 (M+1).
##STR00109##
I-20: .sup.1H NMR (CDCl.sub.3/400 MHz) .delta. 8.91 (dd, 2H), 8.72
(br d, 1H), 8.27 (d, 1H), 7.36 (t, 1H), 7.23-7.17 (m, 1H), 7.11
(td, 1H), 7.04-6.95 (m, 2H), 6.24 (s, 2H); MS m/z: 339.3 (M+1).
##STR00110##
Compounds I-4 and I-5
[0372] I-4: .sup.1H NMR (CDCl.sub.3/400 MHz) 8.86 (dd, 1H),
8.77-8.75 (m, 1H), 8.39 (dd, 1H), 8.21-8.18 (m, 1H), 7.81-7.76 (m,
1H), 7.33-7.30 (m, 1H), 7.25-7.18 (m, 1H), 7.06-6.97 (m, 3H), 6.20
(s, 2H); MS m/z: 338.3 (M+1).
##STR00111##
I-5: .sup.1H NMR (CDCl.sub.3/400 MHz) 8.92 (d, 1H), 8.64-8.62 (m,
1H), 8.36 (dt, 1H), 8.05 (d, 1H), 7.83 (td, 1H), 7.35-7.31 (m, 1H),
7.23-7.17 (m, 1H), 7.09 (td, 1H), 7.05-6.96 (m, 2H), 6.26 (s, 2H);
MS m/z: 338.3 (M+1).
Compounds I-6 and I-7
##STR00112##
[0373] I-6: First eluting product: (Rf 0.51 in 15% (CH.sub.3CN/MeOH
[7/1])/DCM) (I-6) was obtained as a white solid (124.3 mg, 24%).
.sup.1H NMR (CDCl.sub.3/400 MHz) .delta. 8.74-8.73 (m, 1H), 8.23
(d, 1H), 7.84 (d, 1H), 7.78 (td, 1H), 7.33-7.30 (m, 2H), 7.25-7.20
(m, 1H), 7.11 (td, 1H), 7.06-7.00 (m, 2H), 6.15 (s, 2H); MS m/z:
322.3 (M+1).
##STR00113##
I-7: Second eluting product: (Rf 0.40 in 15% (CH.sub.3CN/MeOH
[7/1])/DCM) (I-7) was obtained as a white solid (132.7 mg, 26%).
.sup.1H NMR (CDCl.sub.3/400 MHz) .delta. 8.64-8.62 (m, 1H),
8.40-8.37 (m, 1H), 7.85-7.80 (m, 1H), 7.78 (t, 1H), 7.36-7.32 (m,
1H), 7.32 (t, 1H), 7.23-7.17 (m 1H), 7.12-7.08 (m, 1H), 7.05-6.97
(m, 2H), 6.29 (s, 2H); MS m/z: 322.3 (M+1).
Compound I-11
##STR00114##
[0374] I-11: .sup.1H NMR (CDCl.sub.3/400 MHz) .delta. 8.90 (d, 2H),
7.53 (dd, 1H), 7.35 (t, 1H), 7.24-7.18 (m, 2H), 7.08-6.98 (m, 3H),
6.52 (dd, 1H), 6.21 (s, 2H); MS m/z: 322.3 (M+1).
Compound I-16 and Intermediate-1
[0375] I-16 and Intermediate-1 were synthesized as a white solid
(49%) and an off-white solid (39%), respectively, following General
Procedure A (step 2 only) and using commercially available
2-(5-bromo-1H-1,2,4-triazol-3-yl)pyridine and 2-fluorobenzyl
bromide.
##STR00115##
I-16: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.73 (m, 1H), 8.11
(d, 1H), 7.79 (m, 1H), 7.35-7.29 (m, 2H), 7.22 (app. t, 1H),
7.13-7.08 (m, 2H), 5.54 (s, 2H) ppm. MS: [M+H]=333, 335 (bromine
isotopes).
##STR00116##
Intermediate 1: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.64 (m,
1H), 8.21 (d, 1H), 7.84 (app. td, 1H), 7.36 (m, 1H), 7.25 (m, 1H),
7.14 (m, 1H), 7.06-7.01 (m, 2H), 6.18 (s, 2H) ppm. MS: [M+H]=333,
335 (bromine isotopes).
Compound I-21
[0376] Compound I-21 was synthesized as a white solid (16%) over 2
steps, following General Procedure A and using
cyclopropanecarbohydrazide and 2-amidinopyridine hydrochloride in
step 1 and 2-fluorobenzyl bromide in step 2.
##STR00117##
I-21: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.60 (br. d, 1H),
8.07 (d, 1H), 7.73 (app. td, 1H), 7.32-7.24 (m, 2H), 7.18 (app. t,
1H), 7.11-7.05 (m, 2H), 5.55 (s, 2H), 1.89 (m, 1H), 1.20 (m, 2H),
1.04 (m, 2H) ppm. MS: [M+H]=295.
Compound I-24
[0377] Compound I-24 was synthesized as a clear oil (17%, over 2
steps) following General Procedure A and using
cyclobutanecarbohydrazide and 2-amidinopyridine hydrochloride in
step 1 and 2-fluorobenzyl bromide in step 2. The other isomer was
not isolated in this experiment.
##STR00118##
I-24: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.72 (m, 1H), 8.14
(d, 1H), 7.75 (app. td, 1H), 7.29-7.23 (m, 2H), 7.10-7.02 (m, 3H),
5.38 (s, 2H), 3.59 (app. pent., 1H), 2.54 (m, 2H), 2.27 (m, 2H),
2.07-1.93 (m, 2H) ppm. MS: [M+H]=309.
Compounds I-25 and I-26
[0378] Compounds I-25 and I-26 were synthesized as white solids
(26% and 16%, respectively, over 2 steps) following General
Procedure A and using thiazole-2-carboxylic acid hydrazide and
2-amidinopyridine hydrochloride in step 1 and 2-fluorobenzyl
bromide in step 2.
##STR00119##
I-25: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.64 (m, 1H), 8.39
(d, 1H), 7.96 (m, 1H), 7.84 (m, 1H), 7.43 (m, 1H), 7.35 (m, 1H),
7.22 (m, 1H), 7.12 (app. t, 1H), 7.05-6.98 (m, 2H), 6.28 (s, 2H)
ppm. MS: [M+H]=338.
##STR00120##
I-26: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.77 (m, 1H), 8.21
(d, 1H), 7.95 (d, 1H), 7.80 (app. td, 1H), 7.54 (d, 1H), 7.33 (m,
1H), 7.24 (m, 1H), 7.14-7.00 (m, 3H), 6.24 (s, 2H) ppm. MS:
[M+H]=338.
Compound I-27
[0379] Compound I-27 was synthesized as a white solid (48% over 2
steps) following General Procedure A using benzoic hydrazide and
2-amidinopyrimidine hydrochloride in step 1 and 2-fluorobenzyl
bromide in step 2.
##STR00121##
I-27: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.93 (d, 2H), 7.69
(m, 2H), 7.52-7.43 (m, 3H), 7.34 (app. t, 1H), 7.30 (m, 1H),
7.15-7.04 (m, 3H), 5.65 (s, 2H) ppm. MS: [M+H]=332.
Compound I-28
[0380] Compound I-28 was synthesized as a clear oil (48% over 2
steps) following General Procedure A and using acetic acid
hydrazide and 2-amidinopyrimidine hydrochloride in step 1 and
2-fluorobenzyl bromide in step 2.
##STR00122##
I-28: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.88 (d, 2H),
7.32-7.29 (m, 1H), 7.31 (app. t, 1H), 7.23-7.19 (m, 1H), 7.10-7.07
(m, 2H), 5.48 (s, 2H), 2.54 (s, 3H) ppm. MS: [M+H]=270.
Compounds I-29 and I-30
[0381] These two regioisomers, I-29 and I-30, were synthesized as a
white solid (20%, I-30) and light yellow solid (26%, I-29) over 2
steps, following General Procedure A and using
thiazole-2-carboxylic acid hydrazide and 2-amidinopyrimidine
hydrochloride in step 1 and 2-fluorobenzyl bromide in step 2.
##STR00123##
I-29: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.92 (d, 2H), 7.96
(d, 1H), 7.45 (d, 1H), 7.37 (app. t, 1H), 7.22-7.13 (m, 2H),
7.03-6.98 (m, 2H), 6.23 (s, 2H) ppm. MS: [M+H]=339.
##STR00124##
I-30: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.94 (d, 2H), 7.95
(d, 1H), 7.55 (d, 1H), 7.36 (app. t, 1H), 7.22 (m, 1H), 7.09-6.98
(m, 3H), 6.29 (s, 2H) ppm. MS: [M+H]=339.
Compounds I-31 and I-32
[0382] These regioisomers, I-31 and I-32, were synthesized as white
solids (29% and 23% for I-31 and I-32, respectively, over 2 steps)
following General Procedure A using picolinohydrazide and
2-amidinopyrimidine hydrochloride in step 1 and 2-fluorobenzyl
bromide in step 2.
##STR00125##
I-31: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.90 (d, 2H), 8.74
(m, 1H), 8.40 (d, 1H), 7.81 (app. td, 1H), 7.34 (app. t, 1H), 7.33
(m, 1H), 7.18 (m, 1H), 7.08 (app. br t, 1H), 7.03-6.95 (m, 2H),
6.27 (s, 2H) ppm. MS: [M+H]=333.
##STR00126##
I-32: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.94 (d, 2H), 8.62
(m, 1H), 8.48 (d, 1H), 7.82 (app. td, 1H), 7.35 (app. t, 1H), 7.33
(m, 1H), 7.18 (m, 1H), 7.06-6.94 (m, 3H), 6.35 (s, 2H) ppm. MS:
[M+H]=333.
Compounds I-58 and I-59
Step 2:
[0383] To a stirring solution of
3-(3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)isoxazole hydrochloride
(1 eq) in DMF was added sodium hydride (2.1 eq). After 10 minutes,
1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction
was stirred overnight at room temperature. Brine was used to quench
the reaction. Methylene chloride was used to extract the aqueous
layer. The combined organic layers were washed with brine, dried
over sodium sulfate and concentrated. SiO.sub.2 chromatography
yielded
3-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)isoxazole
in 13.5% yield as a solid and
3-(1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl)isoxazole
in 15.7% yield as a solid.
##STR00127##
I-58: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.72-8.74 (m, 1H), 8.51 (d,
1H), 8.14 (td, 1H), 7.75 (dt, 1H), 7.28-7.31 (m, 1H), 7.19-7.24 (m,
1H), 7.13 (d, 1H), 6.97-7.09 (m, 3H), 6.02 (s, 2H).
##STR00128##
I-59: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.90-8.92 (m, 2H),
8.49-8.50 (m, 1H), 7.36 (t, 1H), 7.17-7.24 (m, 1H), 7.08-7.12 (m,
1H), 7.06-7.07 (m, 1H), 6.97-7.04 (m, 2H), 6.23 (s, 2H).
Compounds I-51 and 52
[0384] Step 2:
[0385] To a stirring solution of
4-(3-(4-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)thiazole (1 eq) in
DMF was added sodium hydride (2.1 eq). After 10 minutes,
1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction
was stirred overnight at room temperature. Brine was used to quench
the reaction. Methylene chloride was used to extract the aqueous
layer. The combined organic layers were washed with brine, dried
over sodium sulfate and concentrated. SiO.sub.2 chromatography
yielded
4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiaz-
ole in 1% yield as a solid and
4-(5-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)thiaz-
ole in 1% yield as a solid.
##STR00129##
I-51: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.88 (d, 1H), 8.56 (d, 1H),
8.39-8.40 (m, 2H), 7.48-7.50 (m, 1H), 7.21-7.25 (m, 1H), 6.99-7.07
(m, 3H), 6.21 (s, 2H).
##STR00130##
I-52: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.92 (d, 1H), 8.43 (d, 1H),
8.27 (d, 1H), 8.24 (s, 1H), 7.97 (dd, 1H), 7.27-7.28 (m, 1H),
7.03-7.11 (m, 3H), 6.15 (s, 2H).
##STR00131##
Compound I-54
Step 2:
[0386] To a stirring solution of
4-(3-(4-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole (1 eq) in
DMF was added sodium hydride (2.1 eq). After 10 minutes,
1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction
was stirred overnight at room temperature. Brine was used to quench
the reaction. Methylene chloride was used to extract the aqueous
layer. The combined organic layers were washed with brine, dried
over sodium sulfate and concentrated. SiO.sub.2 chromatography
yielded
4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazo-
le as a solid in 1% yield.
I-54: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.55 (dd, 1H), 8.50 (d,
1H), 8.36 (dd, 1H), 7.98 (d, 1H), 7.48 (dd, 1H), 7.22-7.28 (m, 1H),
7.00-7.14 (m, 3H), 6.10 (s, 2H).
Compounds I-45 and I-46
[0387] These were synthesized (white solids, 1.5% and 2.7%
respectively over 2 steps) following General Procedure A using
pyrimidine-2-carboximidamide hydrochloride and
oxazole-4-carbohydrazide in step 1.
##STR00132##
I-45: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..quadrature.8.90 (d,
2H), 8.42 (s, 1H), 7.98 (s, 1H), 7.34 (t, 1H), 7.22-7.17 (m, 1H),
7.11-7.07 (m, 1H), 7.02-6.95 (m, 2H), 6.21 (s, 2H).
##STR00133##
I-46: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..quadrature.8.89 (d,
2H), 8.57 (s, 1H), 7.95 (s, 1H), 7.32 (t, 1H), 7.23-7.17 (m, 1H),
7.03-6.95 (m, 3H), 6.16 (s, 2H).
Example 4: I-15, I-18, I-19, I-36, I-37, I-38, I-39, I-40, I-41,
I-55, I-56, I-62 and I-63
[0388] Compounds I-15, I-18, I-19, I-36, I-37, I-38, I-39, I-40,
I-41, I-55, I-56, I-62 and I-63 were synthesized following General
Procedure B described above according to the following
conditions.
[0389] Step 1:
[0390] Amidine formation: Nitrile F was treated with sodium
methoxide (0.5 M in methanol, 0.5 eq) at room temperature and the
reaction monitored by LC/MS analysis. Once the starting nitrile was
consumed (reaction time was typically 2-7 h), ammonium chloride
(1.1 eq) was added and the reaction mixture was stirred for 16-24
h. The reaction mixture was concentrated and dried in vacuo
resulting in the amidine B. In some case, the crude amidine was
collected by filtration. The crude amidine was carried on as
described in General Procedure A without any further purification
to yield products D and E.
Compound I-15
[0391] Compound I-15 was synthesized as a light yellow solid (33%
over 3 steps) following General Procedure B and using
2-cyanothiazole in step 1. The subsequent steps were performed as
described following General Procedure A, using
thiazole-2-carboxylic acid hydrazide and 2-fluorobenzyl bromide in
the respective steps.
##STR00134##
I-15: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.97 (d, 2H), 7.56
(d, 1H), 7.44 (d, 1H), 7.26 (m, 1H), 7.16 (app. t, 1H), 7.09-7.02
(m, 2H), 6.22 (s, 2H) ppm. MS: [M+H]=344.
Compounds I-18 and I-19
[0392] Compounds I-19 and I-18 were synthesized as white solids
(13% and 8%, respectively, over 3 steps) following General
Procedure B and using 6-bromopicolinonitrile in step 1. The
subsequent steps were performed as described following General
Procedure A using thiazole-2-carboxylic acid hydrazide and
2-fluorobenzyl bromide in the respective steps.
##STR00135##
I-18: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.35 (d, 1H), 7.97
(d, 1H), 7.70 (app. t, 1H), 7.53 (d, 1H), 7.44 (d, 1H), 7.24 (m,
1H), 7.16 (app. t, 1H), 7.08-7.00 (m, 2H), 6.20 (s, 2H) ppm. MS:
[M+H]=416, 418 (bromine isotopes).
##STR00136##
I-19: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.16 (d, 1H), 7.95
(m, 1H), 7.65 (app. t, 1H), 7.54 (m, 2H), 7.25 (m, 1H), 7.11-7.00
(m, 3H), 6.24 (s, 2H) ppm. MS: [M+H]=416, 418 (bromine
isotopes).
Compounds I-36 and I-37
[0393] These compounds were synthesized (white solids, 33% and 24%
yields, respectively, over 3 steps) following General Procedure B
and using 4-bromopicolinonitrile in step 1. The subsequent steps
were performed as described following General Procedure A using
thiazole-2-carboxylic acid hydrazide and 2-fluorobenzyl bromide in
the respective steps.
##STR00137##
I-36: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.57 (d, 1H), 8.40
(d, 1H), 7.96 (d, 1H), 7.55 (d, 1H), 7.51 (dd, 1H), 7.26 (m, 1H),
7.14-7.01 (m, 3H), 6.24 (s, 2H) ppm. MS: [M+H]=416, 418 (bromine
isotopes).
##STR00138##
I-37: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.64 (d, 1H), 8.45
(d, 1H), 7.98 (d, 1H), 7.52 (dd, 1H), 7.45 (d, 1H), 7.23 (m, 1H),
7.12-6.99 (m, 3H), 6.25 (s, 2H) ppm. MS: [M+H]=416, 418 (bromine
isotopes).
Compounds I-38 and I-39
[0394] These compounds were synthesized (white solids, 22% and 20%
respectively over 3 steps) following General Procedure B using
5-fluoropicolinonitrile in step 1. The subsequent steps were
performed as described following General Procedure A using
thiazole-2-carboxylic acid hydrazide and 2-fluorobenzyl bromide in
the respective steps.
##STR00139##
I-38: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.61 (d, 1H), 8.23
(dd, 1H), 7.96 (d, 1H), 7.54 (d, 1H), 7.51 (app. td, 1H), 7.25 (m,
1H), 7.14-7.00 (m, 3H), 6.23 (s, 2H) ppm. MS: [M+H]=356.
##STR00140##
I-39: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.49 (d, 1H), 8.45
(dd, 1H), 7.97 (d, 1H), 7.55 (app. td, 1H), 7.44 (d, 1H), 7.23 (m,
1H), 7.12-6.98 (m, 3H), 6.21 (s, 2H) ppm. MS: [M+H]=356.
Compounds I-40 and I-41
[0395] These compounds were synthesized (off-white solids, 11% and
30% respectively over 3 steps) following General Procedure B using
2-cyanothiazole in step 1. The subsequent steps were performed as
described following General Procedure A using thiazole-4-carboxylic
acid hydrazide and 2-fluorobenzyl bromide in the respective
steps.
##STR00141##
I-40: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.92 (d, 1H), 8.07
(d, 1H), 7.95 (d, 1H), 7.54 (d, 1H), 7.24 (m, 1H), 7.13 (app. t,
1H), 7.08-7.00 (m, 2H), 6.21 (s, 2H) ppm. MS: [M+H]=344.
##STR00142##
I-41: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.89 (d, 1H), 8.39
(d, 1H), 7.96 (d, 1H), 7.43 (d, 1H), 7.24 (m, 1H), 7.12-6.89 (m,
3H), 6.19 (s, 2H) ppm. MS: [M+H]=344.
Compounds I-55 and I-56
[0396] These compounds were synthesized (off-white solids, 14% and
38% respectively over 3 steps) following General Procedure B using
pyrazine-2-carbonitrile in step 1. The subsequent steps were
performed as described following General Procedure A using
thiazole-4-carboxylic acid hydrazide and 2-fluorobenzyl bromide in
the respective steps.
##STR00143##
I-55: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.61 (d, 1H), 8.95
(d, 1H), 8.64 (d, 1H), 8.60 (dd, 1H), 8.10 (d, 1H), 7.23 (m, 1H),
7.12-6.98 (m, 3H), 6.19 (s, 2H) ppm. MS: [M+H]=339.
##STR00144##
I-56: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.44 (d, 1H), 8.90
(d, 1H), 8.70 (dd, 1H), 8.61 (d, 1H), 8.41 (d, 1H), 7.25 (m, 1H),
7.11-7.00 (m, 3H), 6.23 (s, 2H) ppm. MS: [M+H]=339.
Compounds I-62 and I-63
[0397] These compounds were synthesized (tan solid, 3% and white
solid, 5% respectively over 3 steps) following General Procedure B
using oxazole-4-carbonitrile in step 1. The subsequent steps were
performed as described following General Procedure A using
thiazole-2-carboxylic acid hydrazide and 2-fluorobenzyl bromide in
the respective steps.
##STR00145##
I-62: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.28 (s, 1H), 7.99
(s, 1H), 7.95 (d, 1H), 7.53 (d, 1H), 7.25 (m, 1H), 7.12 (app. t,
1H), 7.08-7.00 (m, 2H), 6.19 (s, 2H) ppm. MS: [M+H]=328.
##STR00146##
I-63: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.49 (s, 1H), 7.99
(s, 1H), 7.95 (d, 1H), 7.42 (d, 1H), 7.26 (m, 1H), 7.13-7.02 (m,
3H), 6.09 (s, 2H) ppm. MS: [M+H]=328.
Example 5: Compound I-23
[0398] This compound was prepared according to General Procedure
C.
##STR00147##
[0399] A solution of
2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine
(I-16), in DMA was treated with a large excess of azetidine
(.about.30 eq). The resultant solution was warmed to 100.degree. C.
and stirred at that temperature for 18 h. The reaction solution was
cooled to rt, poured into 1N NaOH solution and then extracted with
EtOAc. The organic phases were dried over Na.sub.2SO.sub.4,
filtered and conc. The crude product was purified using SiO.sub.2
chromatography and an appropriate gradient (MeOH--CH.sub.3CN
(1:7)/CH.sub.2Cl.sub.2) to give
2-(5-(azetidin-1-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine,
1-23, as a white solid (88% yield).
I-23: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.70 (m, 1H), 8.06
(m, 1H), 7.73 (m, 1H), 7.29-7.23 (m, 2H), 7.16-7.03 (m, 3H), 5.26
(s, 2H), 4.13 (t, 4H), 2.34 (pent., 2H) ppm. MS: [M+H]=310.
Example 6: Compounds I-10, I-17, I-67, I-49 and I-50
[0400] Compounds I-10, I-17, I-67, I-49 and I-50 were prepared with
General Procedure D.
Compound I-10
##STR00148##
[0402] A solution of pyrazole (1.1 eq) in DMF was treated with
sodium hydride (60% w/w in mineral oil, 1.2 eq) and stirred for 10
min at room temperature.
2-(5-Bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16,
1.0 eq) was then added. The resultant mixture was warmed to
50.degree. C. and stirred at that temperature for 1 h. The reaction
solution was cooled to rt, poured into water, and filtered to give
2-(1-(2-fluorobenzyl)-5-(1H-pyrazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine,
I-10, as a white solid (84% yield).
I-10: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (br. d, 1H),
8.43 (d, 1H), 8.15 (d, 1H), 7.79 (app. td, 1H), 7.77 (br. s, 1H),
7.33 (m, 1H), 7.24 (m, 1H), 7.14 (app. t, 1H), 7.06-7.01 (m, 2H),
6.50 (m, 1H), 6.07 (s, 2H) ppm. MS: [M+H]=321.
Compound I-17
[0403] Compound I-17 was synthesized as an off-white solid (12%
yield) from
2-(3-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)pyridine
(Intermediate 1). In this experiment, the temperature was raised to
140.degree. C. and additional equivalents of pyrazole and sodium
hydride were added during the reaction.
##STR00149##
I-17: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.65 (br. d, 1H),
8.34 (d, 1H), 8.28 (d, 1H), 7.85 (app. td, 1H), 7.78 (m, 1H), 7.36
(m, 1H), 7.23 (m, 1H), 7.17 (app. t, 1H), 7.06-7.00 (m, 2H), 6.46
(m, 1H), 6.23 (s, 2H) ppm. MS: [M+H]=321.
Compound I-67 (A+B Mixture)
##STR00150##
[0405] 1,2,3-triazole (1.8 eq) was stirred in a vial in DMF. Sodium
hydride (2.5 eq) was added and this mixture was stirred for 20
minutes.
2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16)
was added and the reaction mixture was stirred at 100.degree. C.
for 12 hr. Brine was poured into the reaction mixture. The aqueous
layer was extracted with ethyl acetate, dried over sodium sulfate
and concentrated. Two isomers were generated, which were purified
together by SiO.sub.2 chromatography. Both isomers were
characterized as
2-(1-(2-fluorobenzyl)-5-(1H-1,2,3-triazol-1-yl)-1H-1,2,4-triazol-3-yl)pyr-
idine and
2-(1-(2-fluorobenzyl)-5-(2H-1,2,3-triazol-2-yl)-1H-1,2,4-triazol-
-3-yl)pyridine in 47.1% yield. They seem to be present in a 3:1
mixture although it is difficult to tell which compound is in the
majority.
I-67 (A+B): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.75-8.78 (m, 1H),
8.5 (d, 0.3H), 8.26-8.28 (m, 1H), 8.14-8.16 (m, 0.3H), 7.88 (d,
0.3H), 7.8-7.84 (m, 1.3H), 7.34-7.39 (m, 1.3H), 7.15-7.24 (m, 2H),
6.99-7.08 (m, 2.5H), 6.02 (s, 1H), 5.97 (s, 2H).
Compound I-49
##STR00151##
[0407] To a stirring suspension of imidazole (1.2 eq) in DMF was
added sodium hydride (2 eq). The reaction generated gas and was
stirred for 10 minutes. Then
2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16)
was added. The reaction was stirred at 100.degree. C. for 12 hr.
The reaction was quenched with brine, extracted with methylene
chloride, dried over sodium sulfate and concentrated. The mixture
was purified by SiO.sub.2 chromatography to afford
2-(1-(2-fluorobenzyl)-5-(1H-imidazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine
as a solid in 26.7% yield.
I-49: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.75-8.77 (m, 1H),
8.13-8.16 (m, 1H), 7.90 (s, 1H), 7.82 (dt, 1H), 7.31-7.38 (m, 2H),
7.28-7.29 (m, 1H), 7.23-7.24 (m, 1H), 7.18-7.20 (m, 1H), 7.07-7.15
(m, 2H), 5.50 (s, 2H).
Compound I-50
##STR00152##
[0409] To a stirring suspension of 1,2,3-triazole (1.8 eq) in DMF
was added sodium hydride (2.5 eq). The reaction generated gas and
was stirred for 10 minutes. Then
2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16)
was added. The reaction was stirred at 100.degree. C. for 12 hr.
The reaction was quenched with brine, extracted with methylene
chloride, dried over sodium sulfate and concentrated. The mixture
was purified by SiO.sub.2 chromatography to afford
2'-(2-fluorobenzyl)-5'-(pyridin-2-yl)-2'H-1,3'-bi(1',2',4-triazole)
in 17.3% yield.
I-50: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.05 (s, 1H), 8.76 (d, 1H),
8.17 (s, 1H), 8.14 (d, 1H), 7.81 (dt, 1H), 7.34-7.37 (m, 1H),
7.24-7.30 (m, 1H), 7.16-7.20 (m, 1H), 7.02-7.07 (m, 2H), 5.98 (s,
2H).
Example 7: Compounds I-33 and I-34
[0410] Compounds I-33 and I-34 were prepared in accordance with
General Procedure E.
##STR00153##
Compound I-33
[0411] To a solution of
2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16,
0.95 g, 2.9 mmol) in N,N-dimethylformamide (9.5 mL) was added
potassium cyanide (0.928 g, 14.3 mmol). After heating the solution
at 100.degree. C. for 22 h, the solution was diluted with ethyl
acetate (125 mL) and water (100 mL). The layers were separated, and
the aqueous layer was extracted with ethyl acetate (2.times.50 mL).
The organics were combined, washed with water (50 mL) and brine (50
mL), dried over magnesium sulfate, filtered, and the solvent was
removed in vacuo to give the crude product as an orange oil.
Purification by silica gel chromatography (0-15% ethyl acetate in
dichloromethane) gave
1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile,
I-33 (250 mg, 0.90 mmol, 31% yield) as a white solid.
##STR00154##
I-33: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.67-8.65 (m, 1H),
8.06-8.03 (m, 1H), 7.73 (dt, 1H), 7.37-7.27 (m, 3H), 7.12-7.02 (m,
2H), 5.60 (s, 2H).
Compound I-34
[0412] To a solution of
1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile
(I-33, 100 mg, 0.358 mmol) and potassium carbonate (198 mg, 1.43
mmol) in methanol (3.6 mL) was added hydroxylamine hydrochloride
(75 mg, 1.1 mmol). The solution was heated at 70.degree. C. for
1.25 h, at which point the solution was diluted with ethyl acetate
(20 mL) and the solids were filtered off through a cotton plug. The
solvent was removed in vacuo and the crude residue was diluted with
water (50 mL) and a 5:1 mixture of dichloromethane and 2-propanol
(50 mL). The layers were separated and the organic layer was washed
with water (50 mL), dried over magnesium sulfate, and the solvent
was removed in vacuo. To the resulting crude
1-(2-fluorobenzyl)-N'-hydroxy-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbox-
imidamide was added trimethyl orthorfomate (4.5 mL, 41 mmol) and a
catalytic amount of p-toluensulfonic acid monohydrate (3.4 mg,
0.018 mmol). The solution was heated at 100.degree. C. for 1.5 h,
and the excess orthoformate was removed in vacuo to give the crude
product as a dull yellow solid. Purification by silica gel
chromatography (20-80% ethyl acetate in hexanes) gave
3-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,2,4-oxadi-
azole, I-34 (52 mg, 0.16 mmol, 46% yield over 2 steps) as a white
solid.
##STR00155##
I-34: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.98 (s, 1H),
8.73-8.72 (m, 1H), 8.29-8.27 (m, 1H), 7.79 (dt, 1H), 7.34-7.31 (m,
1H), 7.26-7.20 (m, 1H), 7.12-7.08 (m, 1H), 7.03-6.99 (m, 2H), 6.05
(s, 2H).
Example 8: I-14, I-22, I-44, I-47, I-64, I-65, I-66, I-53, I-68
[0413] Compounds I-14, I-22, I-44, I-47, I-64, I-65, I-66, I-53,
I-68 were prepared with General Procedure F.
Compound I-14
##STR00156##
[0415] To a suspension of
2-(3-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiaz-
ole (I-19) and copper(I) oxide (0.2 eq) in ethylene glycol-dioxane
(4:1) in a sealed tube was added ammonium hydroxide solution
(.about.29% in water, --30 eq). The resultant mixture was warmed to
100.degree. C. and stirred at that temperature for 24 h. The
reaction solution was cooled to rt, poured into 1N NaOH solution
and then extracted with EtOAc. The organic phases were dried over
Na.sub.2SO.sub.4, filtered and conc. The crude product was purified
using SiO.sub.2 chromatography and an appropriate gradient
(EtOAc/hexanes) to give
6-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-am-
ine as a white solid (I-14, 69% yield).
I-14: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (d, 1H), 7.59
(d, 1H), 7.55 (app. t, 1H), 7.14 (d, 1H), 7.22 (m, 1H), 7.07-6.98
(m, 3H), 6.56 (d, 1H), 6.22 (s, 2H), 4.74 (br. s, 2H) ppm. MS:
[M+H]=353.
Compound I-22
[0416] Compound I-22 was synthesized following General Procedure F
as a white solid (81% yield) from
2-(5-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)thiaz-
ole (I-18).
##STR00157##
I-22: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (d, 1H), 7.73
(d, 1H), 7.54 (app. t, 1H), 7.43 (d, 1H), 7.22 (m, 1H), 7.14 (m,
1H), 7.09-6.99 (m, 2H), 6.52 (d, 1H), 6.19 (s, 2H), 4.50 (br. s,
2H) ppm. MS: [M+H]=353.
Compound I-44
##STR00158##
[0418] This compound was synthesized as a pale green solid (73%
yield) from
2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-
thiazole (I-36).
[0419] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.37 (m, 1H), 7.93
(d, 1H), 7.52 (d, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 7.13-6.98 (m,
3H), 6.56 (m, 1H), 6.22 (s, 2H), 4.24 (br. s, 2H) ppm. MS:
[M+H]=353.
Compound I-47
##STR00159##
[0421] This was synthesized as a white solid (81% yield) from
2-(5-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)thiaz-
ole (I-37).
I-47: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.24 (d, 1H), 7.95
(d, 1H), 7.65 (d, 1H), 7.41 (d, 1H), 7.21 (m, 1H), 7.11 (app. t,
1H), 7.06-6.98 (m, 2H), 6.56 (dd, 1H), 6.29 (s, 2H), 4.28 (br. s,
2H) ppm. MS: [M+H]=353.
Compound I-64
##STR00160##
[0423] To a stirring suspension of
2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiaz-
ole (I-36, 1 equiv) in ethylene glycol-dioxane (approx. 4:1) in a
sealed tube was added copper(I) cyanide (3 equiv). The resultant
reaction mixture was heated at 100.degree. C. for 24 hr and then
cooled to room temperature, treated with brine and extracted with
ethyl acetate. The combined organic layers were dried over sodium
sulfate, concentrated and purified using SiO.sub.2 chromatography
(ethyl acetate/hexanes) to afford
2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)isonicotinam-
ide as a solid in 11% yield.
I-64: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.91 (d, 1H), 8.44 (s, 1H),
7.96 (d, 1H), 7.56 (d, 1H), 7.53-7.55 (m, 1H), 7.03-7.13 (m, 3H),
6.23 (s, 2H).
Compound I-65
##STR00161##
[0425] To a stirring suspension of
2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiaz-
ole (I-36, 1 eq) and copper(I) oxide (1 eq) in ethylene
glycol-dioxane (approx. 4:1) in a sealed tube is added morpholine
(30 eq). The resultant reaction mixture was heated at 100.degree.
C. for 12 hr. The reaction was cooled to room temperature and
treated with brine and then extracted with ethyl acetate. The
combined organic layers were dried over sodium sulfate,
concentrated and purified using SiO.sub.2 chromatography (methylene
chloride/acetonitrile/methanol) to afford
4-(2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-
-yl)morpholine as a solid in 79% yield.
I-65: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.42 (d, 1H), 7.90 (d, 1H),
7.59 (d, 1H), 7.49 (d, 1H), 7.17-7.23 (m, 1H), 6.95-7.05 (m, 3H),
6.66-6.69 (m, 1H), 6.19 (s, 2H), 3.82-3.85 (m, 4H), 3.36-3.39 (m,
4H).
Compound I-66
##STR00162##
[0427] To a stirring suspension of
4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazo-
le (I-54, 1 eq) and copper(I) oxide (0.2 eq) in ethylene
glycol-dioxane (approx. 4:1) in a sealed tube was added ammonium
hydroxide (30 eq). The resultant reaction mixture was heated at
100.degree. C. for 12 hr. The reaction was cooled to room
temperature and treated with brine and extracted with ethyl
acetate. The combined organic layers were dried over sodium
sulfate, concentrated and purified using SiO.sub.2 chromatography
(DCM/CAN/MeOH) to afford
2-(1-(2-fluorobenzyl)-5-(oxazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-ami-
ne in 41.2% yield.
I-66: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.47 (d, 1H), 8.34 (d, 1H),
7.96 (d, 1H), 7.42 (d, 1H), 7.20-7.24 (m, 1H), 6.98-7.10 (m, 3H),
6.55 (dd, 1H), 6.06 (s, 2H).
Compound I-68
##STR00163##
[0429] To a stirring suspension of
4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazo-
le (I-54, 1 eq) and copper(I) oxide (1 eq) in ethylene
glycol-dioxane (approx. 4:1) in a sealed tube was added morpholine
(30 eq). The resultant reaction mixture was heated at 100.degree.
C. for 12 hr and then cooled to room temperature, treated with
brine and extracted with ethyl acetate. The combined organic layers
were dried over sodium sulfate, concentrated and purified using
SiO.sub.2 chromatography (methylene chloride/acetonitrile/methanol)
to afford
4-(2-(1-(2-fluorobenzyl)-5-(oxazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4--
yl)morpholine in 10.3% yield.
I-68: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.51 (d, 1H), 8.47 (d, 1H),
7.96 (d, 1H), 7.58 (d, 1H), 7.21-7.25 (m, 1H), 7.00-7.07 (m, 3H),
6.71-6.74 (m, 1H), 6.08 (s, 2H), 3.85-3.87 (m, 4H), 3.42-3.45 (m,
4H).
Compound I-53
##STR00164##
[0431] To a stirring suspension of
4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiaz-
ole (I-51, 1 eq) and copper(I) oxide (1 eq) in ethylene
glycol-dioxane (approx. 4:1) in a sealed tube was added ammonium
hydroxide. The resultant reaction mixture was heated at 100.degree.
C. for 12 h and then cooled to room temperature, treated with brine
and extracted with ethyl acetate. The combined organic layers were
dried over sodium sulfate, concentrated and purified using
SiO.sub.2 chromatography (methylene chloride/acetonitrile/methanol)
to afford
2-(1-(2-fluorobenzyl)-5-(thiazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-am-
ine as a solid in 59.6% yield.
I-53: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.87 (s, 1H), 8.38 (s, 1H),
8.34 (d, 1H), 7.46 (s, 1H), 7.23-7.25 (m, 1H), 7.01-7.06 (m, 3H),
6.63 (d, 1H), 6.18 (s, 2H), 4.69 (br. s, 2H).
Example 9: The Following Compounds were Prepared as Described in
Each Case
Compounds I-43 and I-48 and Intermediates 2, 3, 4, 5 and 6
Step 1:
##STR00165##
[0433] A suspension of thiazole-2-carbohydrazide (4.2 mmol), ethyl
2-amino-2-thioxoacetate (1 equiv) and ammonium chloride (6 equiv)
in ethanol (150 mL) was placed in a sealed tube and this was warmed
to 110.degree. C. and stirred at that temperature for 11 days. The
reaction solution was cooled to rt and conc. Brine was added and
the mixture was adjusted to pH-6 and extracted with EtOAc. The
organic phases were dried over Na.sub.2SO.sub.4, filtered and conc.
The crude product was purified using SiO.sub.2 chromatography and
an appropriate solvent gradient (CH.sub.3CN/MeOH/CH.sub.2Cl.sub.2)
to give ethyl 3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate as
an off-white solid (Intermediate-2, 37% yield).
Step 2:
##STR00166##
[0435] To a solution of ethyl
3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate (Intermediate-2,
1.7 mmol) in DMF (8 mL) was added sodium hydride (1.2 equiv). After
10 min, 1-(bromomethyl)-2-fluorobenzene (1.2 equiv) was added. The
reaction was stirred at ambient temperature for 35 min. The
reaction mixture was poured into water and extracted with EtOAc.
The organic phases were washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and conc. The crude product was purified
using SiO.sub.2 chromatography and an appropriate solvent gradient
(EtOAc/hexanes) to give ethyl
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate
(48%) and ethyl
1-(2-fluorobenzyl)-3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxy-
late as white solids (44% yield).
Intermediate-3: Ethyl
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (d, 1H), 7.57 (d,
1H), 7.25 (m, 1H), 7.10-7.00 (m, 3H), 6.22 (s, 2H), 4.51 (q, 2H),
1.45 (t, 3H) ppm. MS: [M+H]=333. I-43: Ethyl
1-(2-fluorobenzyl)-3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (d, 1H), 7.46 (d,
1H), 7.29 (m, 1H), 7.19 (app. t, 1H), 7.11-7.05 (m, 2H), 5.97 (s,
2H), 4.49 (q, 2H), 1.43 (t, 3H) ppm. MS: [M+H]=333.
Step 3:
##STR00167##
[0437] A solution of ethyl
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate
(Intermediate-3, 0.78 mmol) and sodium cyanide (0.1 equiv) in
ammonia/MeOH (7N, 30 equiv, 3.4 mL) in a seal tube was heated at
90.degree. C. for 24 h. The reaction mixture was cooled to room
temperature, conc. and dried in vacuo to afford
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxamide
as a tan solid (>99% yield).
Step 4:
##STR00168##
[0439] A solution of
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxamide
(Intermediate-4, 0.86 mmol) in pyridine (3.0 mL) at 0.degree. C.
was treated with trifluoroacetic anhydride (2 equiv) dropwise over
the course of 5 min. The reaction was then warmed to ambient
temperature and stirred for 2 h. The reaction mixture was poured
into saturated NaHCO.sub.3 solution and extracted with
CH.sub.2Cl.sub.2. The organic phases were dried over MgSO.sub.4,
filtered and conc. The crude product was purified using SiO.sub.2
chromatography and an appropriate solvent gradient (EtOAc/hexanes)
to give
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carbonitrile
as white solid (88% yield).
Step 5:
##STR00169##
[0441] To
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carbonit-
rile (Intermediate-5, 0.74 mmol) was added sodium methoxide/MeOH
(0.5M, 4 equiv, 5.9 mL). After stirring at ambient temperature for
3 h, additional portion of sodium methoxide/MeOH (1 equiv) was
added. After 2 h, ammonium chloride (10 equiv) was added and the
resultant mixture was stirred at ambient for 17 h. The reaction
mixture was conc. Half-saturated NaHCO.sub.3/1N NaOH solution
(10:1) was added and the aqueous mixture was extracted with EtOAc.
The organic phases were dried over Na.sub.2SO.sub.4, filtered and
conc. to afford
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide
as a white solid (>99% yield).
Step 6:
##STR00170##
[0443] To
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-carboximid-
amide (Intermediate-6, 0.33 mmol) was added a stock solution of
3-ethoxyacrylonitrile (3 equiv) and DBU (1 equiv) in pyridine (3
mL). The reaction was warmed to 110.degree. C. and stirred for 46
h. The reaction mixture was conc. and purified using SiO.sub.2
chromatography and an appropriate gradient
(CH.sub.3CN/MeOH/CH.sub.2Cl.sub.2) to afford
2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4--
amine (I-48) as a light tan solid (78% yield).
I-48: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.15 (d, 1H),
8.13 (d, 1H), 8.08 (d, 1H), 7.38 (m, 1H), 7.27-7.14 (m, 3H), 7.13
(br. s, 2H), 6.44 (d, 1H), 6.16 (s, 2H) ppm. MS: [M+H]=354.
Compound I-57 and Intermediate-7
Step 1:
##STR00171##
[0445] A suspension of
1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide
(Intermediate-6, 0.38 mmol) and 2-(phenyldiazenyl)malononitrile (1
equiv) in ethanol (6 mL) in a sealed tube was heated at 110.degree.
C. for 2 h. The reaction was conc. to afford
2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-5-(phenyldi-
azenyl)pyrimidine-4,6-diamine as an orange solid (>99%
yield).
Step 2:
##STR00172##
[0447] To a solution of
2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-5-(phenyldi-
azenyl)pyrimidine-4,6-diamine (Intermediate-7, 0.38 mmol) in DMF
(2.5 mL) was added sodium hydroxide solution (2N, 3 equiv) and
sodium dithionite (5.5 equiv). The reaction was heated to
150.degree. C. and stirred for 2 h. The reaction mixture was
diluted with CH.sub.2Cl.sub.2 and filtered. The filtrate was conc.
and purified using SiO.sub.2 chromatography and an appropriate
gradient (CH.sub.3CN/MeOH/CH.sub.2Cl.sub.2) to afford
2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4,-
5,6-triamine as a tan solid (89% yield).
I-57: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.10 (d, 1H),
8.04 (d, 1H), 7.36 (m, 1H), 7.23 (m, 1H), 7.16 (m, 2H), 6.11 (s,
2H), 5.83 (br. s, 4H), 4.10 (br. s, 2H) ppm. MS: [M+H]=384.
Compound I-60
##STR00173##
[0449] To a suspension of
2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4,-
5,6-triamine (I-57, 0.31 mmol) in pyridine (2.0 mL) at 0.degree. C.
was treated with methyl chloroformate (1 equiv). After 30 min,
additional portions of methyl chloroformate (3 equiv) were added
and the reaction was stirred for 3 h. The reaction mixture was
poured into water and the resultant tan solid was collected by
filtration to afford methyl
4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-
pyrimidin-5-ylcarbamate (74% yield).
I-60: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.11 (d, 1H),
8.06 (d, 1H), 7.98 (br. s, 1H), 7.37 (m, 1H), 7.23 (m, 1H), 7.16
(m, 2H), 6.22 (br. s, 4H), 6.14 (s, 2H), 3.60 (s, 3H) ppm. MS:
[M+H]=442.
Compound I-61
##STR00174##
[0451] A suspension of methyl 4,6-di
amino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimi-
din-5-ylcarbamate (I-60, 0.16 mmol) in DMF (3.0 mL) at 0.degree. C.
was treated with sodium hydride (1.1 equiv). After 15 min, the
reaction mixture was warmed to ambient temperature and stirred for
15 min. The reaction was cooled to 0.degree. C. and iodomethane
(1.1 equiv) was added. The resultant mixture was brought to ambient
temperature and stirred for 20 min. Water was added and the aqueous
mixture was extracted with EtOAc and iPrOH/CH.sub.2Cl.sub.2 (1:4).
The organic phases were dried over Na.sub.2SO.sub.4, filtered,
conc. and purified using SiO.sub.2 chromatography and an
appropriate gradient (CH.sub.3CN/MeOH/CH.sub.2Cl.sub.2) to afford
methyl 4,6-di
amino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimi-
din-5-yl(methyl)carbamate as an off-white solid (81% yield).
I-61: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.11 (d, 1H),
8.05 (d, 1H), 7.37 (m, 1H), 7.23 (m, 1H), 7.15 (m, 2H), 6.43 (br.
s, 4H), 6.14 (s, 2H), 3.64 (s, 0.3 of 3H, rotamer), 3.52 (s, 0.7 of
3H, rotamer), 2.97 (s, 3H) ppm. MS: [M+H]=456.
Compound I-35
##STR00175##
[0453] To a solution of
1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile
(I-33, 120 mg, 0.430 mmol) in methanol (2.0 mL) was added cesium
carbonate (280 mg, 0.859 mmol). After stirring at room temperature
for 3.75 h, aqueous 0.1 N hydrochloric acid (10 mL) was added,
followed by aqueous 1 N hydrochloric acid (.about.1 mL) until
pH.about.3. After stirring for 45 min, the methanol was removed in
vacuo, and the crude residue was brought up in ethyl acetate (75
mL) and saturated aqueous sodium bicarbonate (50 mL). The layers
were separated, and the aqueous layer was extracted with ethyl
acetate (2.times.50 mL). The organics were washed with brine (50
mL), dried over magnesium sulfate, filtered, and the solvent was
removed in vacuo to give the crude product as white solid.
Purification by silica gel chromatography (20-80% ethyl acetate in
hexanes) gave methyl
1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate
(99% yield) as a white solid.
[0454] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76-8.74 (m, 1H),
8.22 (d, 1H), 7.80 (dt, 1H), 7.36-7.33 (m, 1H), 7.31-7.25 (m, 1H),
7.16-7.05 (m, 3H), 6.00 (s, 2H), 4.02 (s, 3H).
Compound I-42
##STR00176##
[0456] To a solution of methyl 1-(2-fluorobenzyl)-3-(pyri
din-2-yl)-1H-1,2,4-triazole-5-carboxylate I-35 (115 mg, 0.368 mmol)
in methanol (2 mL) was added hydrazine hydrate (72 .mu.L, 1.5
mmol). The solution was heated to 70.degree. C. for 3.5 h, at which
point the solvent was removed in vacuo to give
1-(2-fluorobenzyl)-3-(pyri
din-2-yl)-1H-1,2,4-triazole-5-carbohydrazide C as a white solid. To
the crude solid (17 mg, 0.054 mmol) suspended in ethyl acetate (600
.mu.L) was added acetic formic anhydride (0.03 mL, taken from a 2:1
(molar ratio) of formic acid to acetic anhydride, allowed to age 2
h prior to addition). After stirring for 1.25 h, the solution was
diluted with ethyl acetate (50 mL) and water (50 mL). The layers
were separated and the aqueous layer was extracted with ethyl
acetate (2.times.50 mL). The organics were dried over MgSO4,
filtered, and the solvent was removed in vacuo to give the crude
intermediate D that was carried on without further purification. To
the crude solid was added phosphoryl chloride (237 .mu.l, 2.54
mmol) and the solution was heated to 60.degree. C. for 6.5 h. The
solution was diluted with ethyl acetate (75 mL) and saturated
aqueous sodium bicarbonate (75 mL).
[0457] The layers were separated, and the aqueous layer was
extracted with ethyl acetate (2.times.50 mL). The organics were
washed with brine (50 mL), dried over magnesium sulfate, filtered,
and the solvent was removed in vacuo. Purification by silica gel
chromatography (20-95% ethyl acetate in hexanes) gave
2-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,3,4-oxadi-
azole I-42 (7.5 mg, 0.023 mmol, 42% yield for three steps) as a
white solid.
I-42: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.78-8.76 (m, 1H),
8.64 (s, 1H), 8.21 (d, 1H), 7.82 (dt, 1H), 7.38-7.35 (m, 1H),
7.32-7.21 (m, 2H), 7.09-7.04 (m, 2H), 6.17 (s, 2H).
Example 10: Biological Activity Measurement by the sGC-HEK-cGMP
Assay
[0458] Human embryonic kidney cells (HEK293), endogenously
expressing soluble guanylate cyclase (sGC), were used to evaluate
the activity of the 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 0.5 mM 3-isobutyl-1-methylxanthine
(200 .mu.L). Test article was then added to the assay mixture (2
.mu.L) and incubated in the presence of 10 .mu.M Sodium
Nitroprusside (SNP) 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 lysed 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.
Vehicle controls were carried out using DMSO (1%). A known sGC
stimulator, BAY 41-2272, was used as the positive control.
[0459] 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 curve 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 were determined from each sample
using the LC/MS conditions (Table 2 below) and calculated standard
curve. EC50 values were calculated from concentration-response
curves generated with GraphPad Prism Software.
TABLE-US-00003 TABLE 2 (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
[0460] The biological activities of some of the compounds according
to Formula IA or Formula IB determined with the sGC-HEK assay are
summarized in Table 3 below.
TABLE-US-00004 TABLE 3 Test HEK Assay HEK Assay Compound (%
E.sub.max at 10 .mu.m)* (% E.sub.max at 30 .mu.m)* I-1 B D I-2 B B
I-3 A D I-4 D E I-5 B C I-6 D D I-7 A B I-8 A A I-9 A B I-11 C C
I-12 D E I-13 A A I-14 B C I-16 A B I-18 A A I-19 C A I-20 A A I-21
A A I-24 B C I-25 D E I-26 C C I-27 A A I-28 A A I-29 A A I-30 C D
I-31 A A I-32 A C I-35 A A I-36 A A I-37 C D I-38 E D I-39 B B I-40
D C I-41 E F I-42 A B I-43 A A I-44 E F I-45 A A I-46 D D I-47 A A
I-48 E F I-49 A B I-50 D D I-51 D D I-52 A A I-53 E F I-54 D E I-55
A B I-56 C E I-57 A A I-58 E F I-59 A A I-60 C D I-61 D E I-62 C B
I-63 F D I-64 C B I-65 G G I-66 E E I-67 C C I-68 D E *The
compounds were tested at a concentration of 10 or 30 .mu.M. The
code for the sGC activity expressed as % E.sub.max (i.e.,
percentage of the sGC activity obtained with the positive control,
BAY 41-2272, of Bayer; wherein E.sub.max = 100% was the sGC
activity in the HEK assay obtained with the positive control)
obtained is: A = 0 to <5% B = 5 to <10% C = 10 to <20% D =
20 to <40% E = 40 to <60%
Example 11: Biological Activity Measurements by the Purified Human
sGC Enzyme Activity Assay
[0461] 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.2, 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 (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.
[0462] 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.
[0463] 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.
[0464] Calculations: Specific Activity was determined by the amount
of cGMP formed (nmoles) per mg of sGC per min. Enzyme activity
"fold-change" was calculated by dividing the Specific Activity for
a test compound by the Specific Activity of DMSO control.
TABLE-US-00005 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
[0465] The enzymatic activity fold-change of the purified human sGC
enzyme determined in the presence of each of the test compounds
individually at 10 or 30 .mu.m without the addition of sodium
nitroprusside (SNP), a nitric oxide donor, is presented in Table
5.
[0466] Enzyme assays were also performed as described above, but in
the presence of 1 .mu.M sodium nitroprusside (SNP). The results of
the enzyme activity assay performed in the presence of SNP are also
presented in Table 5. Enzymatic activity fold-changes are reported
for selected test compounds in the presence of both SNP and the
test compound. These were calculated by dividing the specific
activity (activity increase) for the test compound dissolved in
DMSO and SNP over the specific activity for the mixture of DMSO and
SNP.
TABLE-US-00006 TABLE 5 (Enzyme Data With or without SNP) sGC Enzyme
sGC Enzyme Activity Activity sGC Enzyme sGC Enzyme Increase
Increase Activity Activity at 10 .mu.M at 30 .mu.M Increase
Increase without without at 10 .mu.M at 30 .mu.M Compound SNP* SNP*
with SNP* with SNP* I-1 B C B C I-2 N D N C I-3 N B N D I-4 N C N E
I-5 N B N C I-6 N D N D I-7 N B N B I-8 N C N B I-9 N C N B I-11 N
C N C I-12 N C N E I-13 N C N B I-14 N B N C I-16 N B N C I-18 N B
N C I-19 N B N C I-20 N B N B I-21 N B N B I-24 N C N C I-25 N D N
E I-26 N C N D I-27 N B N B I-28 N B N B I-29 N B N C I-30 N B N C
I-31 N B N C I-32 N C N C I-35 N B N C I-36 N B N B I-37 N C N D
I-38 N C N E I-39 N B N C I-40 N B N D I-41 N C N E I-42 N B N C
I-43 N B N B I-44 N D N F I-45 N B N B I-46 N B N C I-47 N B N B
I-48 N C N D I-49 N B N B I-50 N B N C I-51 N C N E I-52 N B N B
I-53 N D N F I-54 N C N D I-55 N B N C I-56 N B N D I-57 N B N C
I-58 N C N D I-59 N A N A I-60 N B N D I-61 N C N D I-62 N A N C
I-63 N B N D I-65 N D N E I-68 N C N E *Code for the increase in
the activity of the sGC enzyme in the presence of the test compound
with or without SNP: A = no increase to <1 fold increase B = 1
to <2 fold increase C = 2 to <5 fold increase D = 5 to <10
fold increase E = 10 to <20 fold increase F = 20 to <50 fold
increase N = not determined
Example 12: Biological Activity Measurement by the Thoracic Aortic
Rings Assay
[0467] 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% 02 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% 02 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% 02
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% 02 and 5% CO.sub.2), 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, after
washing the tissue with buffer, the original resting tension of
tissue is used as 100% inhibition. EC50 values were calculated from
concentration-response curves generated with GraphPad Prism
Software.
[0468] The biological data for some of the compounds of Formula IA
and Formula IB, in comparison with the prior art compound, BAY
41-2272, as the reference compound, determined by the thoracic
aorta ring assay are presented in Table 6 below.
TABLE-US-00007 TABLE 6 Thoracic Ring Assay Results* Percent Percent
Percent Compound Relaxation Relaxation Relaxation at Aortic Ring
Tested at 1 .mu.M* at 3 .mu.M* 10 .mu.M* EC.sub.50 (.mu.M)**
BAY-41-2272 N N N A I-1 C E G B I-3 D F G B I-4 E G N A I-6 C E G B
I-12 D F G A I-25 D F G A I-30 C E G C I-38 D F G B I-40 C E G B
I-41 F G G A I-44 F G G A I-46 C E F C I-48 D F G B I-50 B C E N
I-53 C F G B I-61 E F N A *Each of the compound was tested at a
concentration of 1, 3 or 10 .mu.M to obtain data using the method
described in Example 11. 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 to <80% F = 80 to <100% G = 100 to
<120% N = not determined **The code for the EC.sub.50 value
obtained is: A = 0 to <1 .mu.M B = 1 to <2 .mu.M C = 2 to
<3 .mu.M N = not determined
[0469] 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.
* * * * *