U.S. patent application number 15/709258 was filed with the patent office on 2018-06-28 for novel uses.
This patent application is currently assigned to INTRA-CELLULAR THERAPIES, INC.. The applicant listed for this patent is INTRA-CELLULAR THERAPIES, INC.. Invention is credited to Robert Davis, Lawrence P. Wennogle.
Application Number | 20180177782 15/709258 |
Document ID | / |
Family ID | 51354608 |
Filed Date | 2018-06-28 |
United States Patent
Application |
20180177782 |
Kind Code |
A9 |
Wennogle; Lawrence P. ; et
al. |
June 28, 2018 |
NOVEL USES
Abstract
The invention relates to the administration of inhibitors of
phosphodiesterase 1 (PDE1) for the treatment of diseases or
disorders characterized by disruption of or damage to various
cGMP/PKG mediated pathways. In one embodiment the invention relates
to inhibitors of phosphodiesterase 1 (PDE1) for treatment of
cardiovascular disease and related disorders, e.g., congestive
heart disease, atherosclerosis, myocardial infarction, and
stroke.
Inventors: |
Wennogle; Lawrence P.;
(Hillsborough, NJ) ; Davis; Robert; (New York,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTRA-CELLULAR THERAPIES, INC. |
New York |
NY |
US |
|
|
Assignee: |
INTRA-CELLULAR THERAPIES,
INC.
New York
NY
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20180000825 A1 |
January 4, 2018 |
|
|
Family ID: |
51354608 |
Appl. No.: |
15/709258 |
Filed: |
September 19, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14767489 |
Aug 12, 2015 |
9801882 |
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PCT/US14/16741 |
Feb 17, 2014 |
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15709258 |
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61765804 |
Feb 17, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 9/00 20180101; A61P 9/12 20180101; A61K 31/519 20130101; A61P
9/10 20180101; A61P 21/04 20180101; A61P 11/00 20180101; A61K 45/06
20130101; A61P 13/12 20180101; A61P 43/00 20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method of treatment or prophylaxis of a condition which may be
ameliorated by modulating cGMP/PKG-dependent signaling pathways
comprising administration of a PDE1 inhibitor to a patient in need
thereof, wherein the disease or disorder is selected from the group
consisting of: cardiovascular disease, angina, stroke, renal
failure, essential hypertension, pulmonary hypertension, secondary
hypertension, isolated systolic hypertension, hypertension
associated with diabetes, hypertension associated with
atherosclerosis, renovascular hypertension, congestive heart
failure, myocardial infarction, an inflammatory disease or
disorder, Duchenne muscular dystrophy, Becker muscular dystrophy,
limb-girdle muscular dystrophy, myotonic dystrophy, Emery-Dreifuss
muscular dystrophy and a connective tissue disease or disorder
(e.g., Marfan Syndrome).
2. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula II: ##STR00026## wherein (i) Q is C(.dbd.O), C(.dbd.S),
C(.dbd.N(R.sub.20)) or CH.sub.2; (ii) L is a single bond, --N(H)--,
--CH.sub.2--, --S--, --S(O)-- or --S(O.sub.2)--; (iii) R.sub.1 is H
or C.sub.1-4 alkyl (e.g., methyl); (iv) R.sub.4 is H or C.sub.1-6
alkyl (e.g., methyl or isopropyl) and R.sub.2 and R.sub.3 are,
independently, H C.sub.1-6alkyl (e.g., methyl, isopropyl)
optionally substituted with halo or hydroxy (e.g., R.sub.2 and
R.sub.3 are both methyl, or R.sub.2 is H and R.sub.3 is methyl,
ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally
hetero)arylalkoxy, (optionally hetero)arylC.sub.1-6alkyl; or
R.sub.2 and R.sub.3 together form a 3- to 6-membered ring; or
R.sub.2 is H and R.sub.3 and R.sub.4 together form a di-, tri- or
tetramethylene bridge (pref. wherein the R.sub.3 and R.sub.4
together have the cis configuration, e.g., where the carbons
carrying R.sub.3 and R.sub.4 have the R and S configurations,
respectively); or (v) R.sub.5 is g) -D-E-F, wherein: D is
C.sub.1-4alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene);
E is a single bond, C.sub.2-4alkynylene (e.g., --C.ident.C--),
arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); F is
H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, diazolyl,
triazolyl, for example, pyrid-2-yl, imidazol-1-yl,
1,2,4-triazol-1-yl), halo (e.g., F, Br, Cl), haloC.sub.1-4alkyl
(e.g., trifluoromethyl), --C(O)--R.sub.15, --N(R.sub.16)(R.sub.17),
or C.sub.3-7cycloalkyl optionally containing at least one atom
selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl),
tetrahydro-2H-pyran-4-yl, or morpholinyl); wherein D, E and F are
independently and optionally substituted with one or more halo
(e.g., F, Cl or Br), C.sub.1-4alkyl (e.g., methyl),
haloC.sub.1-4alkyl (e.g., trifluoromethyl), C.sub.1-4alkoxy (e.g.,
methoxy), hydroxy, C.sub.1-4carboxy, or an additional aryl or
heteroaryl (e.g., biphenyl or pyridylphenyl), for example, F is
heteroaryl, e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC.sub.1-4alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or
C.sub.1-4alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g.,
phenyl, substituted with one or more halo (e.g., 4-fluorophenyl) or
F is a C.sub.3-7heterocycloalkyl (e.g., pyrrolidinyl) optionally
substituted with a C.sub.1-6alkyl (e.g., 1-methylpyrrolidin-3-yl);
or h) a substituted heteroarylalkyl, e.g., substituted with
haloC.sub.1-4alkyl; i) attached to the nitrogen on the pyrrolo
portion of Formula II-A or II-B and is a moiety of Formula A
##STR00027## wherein X, Y and Z are, independently, N or C, and
R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently H or
halogen (e.g., Cl or F), and R.sub.10 is halogen, C.sub.1-4alkyl,
haloC.sub.1-4alkyl (e.g., triflouromethyl) C.sub.1-4alkoxy (e.g.
methoxy), C.sub.3-7cycloalkyl, heteroC.sub.3-7cycloalkyl (e.g.,
pyrrolidinyl or piperidinyl), C.sub.1-4haloalkyl (e.g.,
trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl
(for example pyrid-2-yl or pyrid-4-yl), or thiadiazolyl (e.g.,
1,2,3-thiadiazol-4-yl)), diazolyl (e.g., imidazol-1-yl), triazolyl
(e.g., 1,2,4-triazol-1-yl), tetrazolyl, arylcarbonyl (e.g.,
benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl,
or alkoxycarbonyl; wherein the aryl, heteroaryl, cycloalkyl or
heterocycloalkyl is independently, optionally substituted with one
or more C.sub.1-4alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC.sub.1-4alkyl (e.g., trifluoromethyl), hydroxy,
C.sub.1-4carboxy, --SH or an additional aryl, heteroaryl (e.g.,
biphenyl or pyridylphenyl) or C.sub.3-8cycloalkyl, preferably
R.sub.10 is phenyl, pyridyl, piperidinyl or pyrrolidinyl optionally
substituted with the substituents previously defined, e.g.
optionally substituted with halo or alkyl provided that when X, Y,
or Z is nitrogen, R.sub.8, R.sub.9, or R.sub.10, respectively, is
not present; (vi) R.sub.6 is H, C.sub.1-4alkyl (e.g., methyl,
ethyl, n-propyl, isobutyl), C.sub.3-7cycloalkyl (e.g., cyclopentyl
or cyclohexyl), heteroC.sub.3-7cycloalkyl (e.g., pyrrolidinyl,
piperidinyl, morpholinyl), aryl (e.g., phenyl), heteroaryl (e.g.,
pyrid-4-yl), arylC.sub.1-4alkyl (e.g., benzyl), arylamino (e.g.,
phenylamino), heteroarylamino, N,N-diC.sub.1-4alkylamino,
N,N-diarylamino, N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or
--N(R.sub.18)(R.sub.19), wherein the aryl and heteroaryl are
optionally substituted with one or more C.sub.1-4 alkyl (e.g.,
methyl), halogen (e.g., chloro or fluoro), haloC.sub.1-4alkyl
(e.g., trifluoromethyl), hydroxy, C.sub.1-4carboxy, or an
additional aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or
C.sub.3-8cycloalkyl; (vii) R.sub.7 is H, C.sub.1-6alkyl (e.g.,
methyl or ethyl), halogen (e.g., Cl), --N(R.sub.18)(R.sub.19),
hydroxy or C.sub.1-6alkoxy; (viii) n=0 or 1; (ix) when n=1, A is
--C(R.sub.13R.sub.14)--, wherein R.sub.13 and R.sub.14, are,
independently, H or C.sub.1-4alkyl, aryl, heteroaryl, (optionally
hetero)arylC.sub.1-4alkoxy, (optionally hetero)arylC.sub.1-4alkyl
or R.sub.14 can form a bridge with R.sub.2 or R.sub.4; (x) R.sub.15
is C.sub.1-4alkyl, haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl
(e.g., --OCH.sub.3) (xi) R.sub.16 and R.sub.17 are independently H
or C.sub.1-4alkyl; (xii) R.sub.18 and R.sub.19 are independently H,
C.sub.1-4alky (e.g., methyl, ethyl, n-propyl, isobutyl),
C.sub.3-8cycloalky (e.g., cyclohexyl or cyclopenyl),
heteroC.sub.3-8cycloalky (e.g., pyrrolidinyl, piperidinyl,
morpholinyl), aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl),
wherein said aryl and heteroaryl are optionally substituted with
one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),
hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or
2-hydroxyphenyl), C.sub.1-4alkyl (e.g., methyl), haloC.sub.1-4alkyl
(e.g., trifluoromethyl), C.sub.1-4carboxy, or an additional aryl,
heteroaryl (e.g., biphenyl or pyridylphenyl) or
C.sub.3-8cycloalkyl, (xiii) R.sub.20 is H, C.sub.1-4alkyl or
C.sub.3-7cycloalkyl; in free or salt form.
3. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula I: ##STR00028## wherein (i) Q is C(.dbd.O), C(.dbd.S),
C(.dbd.N(R.sub.20)) or CH.sub.2; (ii) L is a single bond, --N(H)--,
--CH.sub.2--, --S--, --S(O)-- or --S(O.sub.2)--; (iii) R.sub.1 is H
or C.sub.1-4 alkyl (e.g., methyl); (iv) R.sub.4 is H or C.sub.1-6
alkyl (e.g., methyl or isopropyl) and R.sub.2 and R.sub.3 are,
independently, H or C.sub.1-6alkyl (e.g., methyl, isopropyl)
optionally substituted with halo or hydroxy (e.g., R.sub.2 and
R.sub.3 are both methyl, or R.sub.2 is H and R.sub.3 is methyl,
ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally
hetero)arylalkoxy, or (optionally hetero)arylC.sub.1-6alkyl; or
R.sub.2 is H and R.sub.3 and R.sub.4 together form a di-, tri- or
tetramethylene bridge (pref. wherein the R.sub.3 and R.sub.4
together have the cis configuration, e.g., where the carbons
carrying R.sub.3 and R.sub.4 have the R and S configurations,
respectively); (v) R.sub.5 is a) -D-E-F, wherein: D is
C.sub.1-4alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene);
E is a single bond, C.sub.2-4alkynylene (e.g., --C.ident.C--),
arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); F is
H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, diazolyl,
triazolyl, for example, pyrid-2-yl, imidazol-1-yl,
1,2,4-triazol-1-yl), halo (e.g., F, Br, Cl), haloC.sub.1-4alkyl
(e.g., trifluoromethyl), --C(O)--R.sub.15, --N(R.sub.16)(R.sub.17),
or C.sub.3-7cycloalkyl optionally containing at least one atom
selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl),
tetrahydro-2H-pyran-4-yl, or morpholinyl); wherein D, E and F are
independently and optionally substituted with one or more halo
(e.g., F, Cl or Br), C.sub.1-4alkyl (e.g., methyl),
haloC.sub.1-4alkyl (e.g., trifluoromethyl), for example, F is
heteroaryl, e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC.sub.1-4alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or
C.sub.1-4alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g.,
phenyl, substituted with one or more halo (e.g., 4-fluorophenyl) or
F is a C.sub.3-7heterocycloalkyl (e.g., pyrrolidinyl) optionally
substituted with a C.sub.1-6alkyl (e.g., 1-methylpyrrolidin-3-yl);
or b) a substituted heteroarylalkyl, e.g., substituted with
haloalkyl; c) attached to the nitrogen on the pyrrolo portion of
Formula I-A or I--B and is a moiety of Formula A ##STR00029##
wherein X, Y and Z are, independently, N or C, and R.sub.8,
R.sub.9, R.sub.11 and R.sub.12 are independently H or halogen
(e.g., Cl or F), and R.sub.10 is halogen, C.sub.1-4alkyl,
C.sub.3-7cycloalkyl, C.sub.1-4haloalkyl (e.g., trifluoromethyl),
aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example
pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),
diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl),
alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or
alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R.sub.8,
R.sub.9, or R.sub.10, respectively, is not present; (vi) R.sub.6 is
H, C.sub.1-4alkyl, C.sub.3-7cycloalkyl (e.g., cyclopentyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyrid-4-yl), arylC.sub.1-4alkyl
(e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino,
N,N-diC.sub.1-4alkylamino, N,N-diarylamino,
N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or
--N(R.sub.18)(R.sub.19); wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl), hydroxy
or C.sub.1-6alkoxy; (vii) R.sub.7 is H, C.sub.1-6alkyl, halogen
(e.g., Cl), --N(R.sub.18)(R.sub.19); (viii) n=0 or 1; (ix) when
n=1, A is --C(R.sub.13R.sub.14)--, wherein R.sub.13 and R.sub.14,
are, independently, H or C.sub.1-4alkyl, aryl, heteroaryl,
(optionally hetero)arylC.sub.1-4alkoxy or (optionally
hetero)arylC.sub.1-4alkyl; (x) R.sub.15 is C.sub.1-4alkyl,
haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl (e.g., --OCH.sub.3)
(xi) R.sub.16 and R.sub.17 are independently H or C.sub.1-4alkyl;
(xii) R.sub.18 and R.sub.19 are independently H, C.sub.1-4alky or
aryl (e.g., phenyl) wherein said aryl is optionally substituted
with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or
hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or
2-hydroxyphenyl) (xiii) R.sub.20 is H, C.sub.1-4alkyl or
C.sub.3-7cycloalkyl; in free or salt form.
4. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula III: ##STR00030## wherein (i) Q is C(.dbd.S),
C(.dbd.N(R.sub.20)) or CH.sub.2; (ii) L is a single bond, --N(H)--,
--CH.sub.2--; (iii) R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl
or ethyl); (iv) R.sub.4 is H or C.sub.1-6 alkyl (e.g., methyl,
isopropyl) and R.sub.2 and R.sub.3 are, independently: H or
C.sub.1-6alkyl (e.g., methyl or isopropyl) optionally substituted
with halo or hydroxy (e.g., R.sub.2 and R.sub.3 are both methyl, or
R.sub.2 is H and R.sub.3 is methyl, ethyl, isopropyl or
hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy,
(optionally hetero)arylC.sub.1-6alkyl, or R.sub.2 and R.sub.3
together form a 3- to 6-membered ring; or R.sub.2 is H and R.sub.3
and R.sub.4 together form a di-, tri- or tetramethylene bridge
(pref. wherein the R.sub.3 and R.sub.4 together have the cis
configuration, e.g., where the carbons carrying R.sub.3 and R.sub.4
have the R and S configurations, respectively); (v) R.sub.5 is j)
-D-E-F, wherein: D is C.sub.1-4alkylene (e.g., methylene, ethylene
or prop-2-yn-1-ylene); E is a single bond, C.sub.2-4alkynylene
(e.g., --C.ident.C--), arylene (e.g., phenylene) or heteroarylene
(e.g., pyridylene); F is H, aryl (e.g., phenyl), heteroaryl (e.g.,
pyridyl, diazolyl, triazolyl, for example, pyrid-2-yl,
imidazol-1-yl, 1,2,4-triazol-1-yl), halo (e.g., F, Br, Cl),
haloC.sub.1-4alkyl (e.g., trifluoromethyl), --C(O)--R.sub.15,
--N(R.sub.16)(R.sub.17), --S(O).sub.2R.sub.21 or
C.sub.3-7cycloalkyl optionally containing at least one atom
selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl),
tetrahydro-2H-pyran-4-yl, or morpholinyl); wherein D, E and F are
independently and optionally substituted with one or more: halo
(e.g., F, Cl or Br), C.sub.1-4alkyl (e.g., methyl),
haloC.sub.1-4alkyl (e.g., trifluoromethyl), C.sub.1-4alkoxy) or
C.sub.1-4alkyl (e.g., 5-methylpyrid-2-yl), for example, F is
heteroaryl, e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), or
F is aryl, e.g., phenyl, substituted with one or more halo (e.g.,
4-fluorophenyl) or F is a C.sub.3-7heterocycloalkyl (e.g.,
pyrrolidinyl) optionally substituted with a C.sub.1-6alkyl (e.g.,
1-methylpyrrolidin-3-yl); or k) a substituted heteroarylalkyl,
e.g., substituted with haloalkyl; l) attached to one of the
nitrogens on the pyrazolo portion of Formula III and is a moiety of
Formula A ##STR00031## wherein X, Y and Z are, independently, N or
C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently H
or halogen (e.g., Cl or F), and R.sub.10 is: halogen,
C.sub.1-4alkyl, C.sub.3-7cycloalkyl, hetC.sub.3-7cycloalkyl (e.g.,
pyrrolidinyl or piperidinyl), C.sub.1-4haloalkyl (e.g.,
trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl
(for example pyrid-2-yl), or thiadiazolyl (e.g.,
1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl,
arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl),
heteroarylcarbonyl, or alkoxycarbonyl; wherein the aryl,
heteroaryl, cycloalkyl or heterocycloalkyl is independently and
optionally substituted with one or more halo (e.g., F or Cl),
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl (e.g.,
trifluoromethyl), --SH; preferably R.sub.10 is phenyl, pyridyl,
piperidinyl or pyrrolidinyl optionally substituted with the
substituents previously defined, e.g. optionally substituted with
halo or alkyl provided that when X, Y, or Z is nitrogen, R.sub.8,
R.sub.9, or R.sub.10, respectively, is not present; (vi) R.sub.6 is
H, C.sub.1-4alkyl, C.sub.3-7cycloalkyl (e.g., cyclopentyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, for example,
pyrid-4-yl), arylC.sub.1-4alkyl (e.g., benzyl), arylamino (e.g.,
phenylamino), heterarylamino, N,N-diC.sub.1-4alkylamino,
N,N-diarylamino, N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or
--N(R.sub.18)(R.sub.19); wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl),
hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, for
example, R.sub.6 is 4-hydroxyphenyl or 4-fluorophenyl, (vii) n=0 or
1; (viii) when n=1, A is --C(R.sub.13R.sub.14)--, wherein R.sub.13
and R.sub.14, are, independently, H or C.sub.1-4alkyl, aryl,
heteroaryl, (optionally hetero)arylC.sub.1-4alkoxy(optionally
hetero)arylC.sub.1-4alkyl or R.sub.13 or R.sub.14 can form a bridge
with R.sub.2 or R.sub.4; (ix) R.sub.15 is C.sub.1-4alkyl,
haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl (e.g., --OCH.sub.3)
(x) R.sub.16 and R.sub.17 are independently H or C.sub.1-4alkyl;
(xi) R.sub.18 and R.sub.19 are independently H, C.sub.1-4alky,
C.sub.3-8cycloalkyl, heteroC.sub.3-8cycloalkyl, aryl (e.g.,
phenyl), or heteroaryl, wherein said aryl or heteroaryl is
optionally substituted with one or more halo (e.g., fluorophenyl,
e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g.,
4-hydroxyphenyl or 2-hydroxyphenyl), C.sub.1-6alkyl,
haloC.sub.1-6alkyl, C.sub.1-6alkoxy, aryl, heteroaryl, or
C.sub.3-8cycloalkyl; (xii) R.sub.20 is H, C.sub.1-4alkyl (e.g.,
methyl) or C.sub.3-7cycloalkyl, (xiii) R.sub.21 is C.sub.1-6alkyl;
in free or salt form.
5. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula IV: ##STR00032## wherein (i) Q is C(.dbd.S),
C(.dbd.N(R.sub.20)) or CH.sub.2; (ii) L is a single bond, --N(H)--,
--CH.sub.2--; (iii) R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl
or ethyl); (iv) R.sub.4 is H or C.sub.1-6 alkyl (e.g., methyl,
isopropyl) and R.sub.2 and R.sub.3 are, independently, H or
C.sub.1-6alkyl (e.g., methyl or isopropyl) optionally substituted
with halo or hydroxy (e.g., R.sub.2 and R.sub.3 are both methyl, or
R.sub.2 is H and R.sub.3 is methyl, ethyl, isopropyl or
hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, or
(optionally hetero)arylC.sub.1-6alkyl; or R.sub.2 is H and R.sub.3
and R.sub.4 together form a di-, tri- or tetramethylene bridge
(pref. wherein the R.sub.3 and R.sub.4 together have the cis
configuration, e.g., where the carbons carrying R.sub.3 and R.sub.4
have the R and S configurations, respectively); (v) R.sub.5 is d)
-D-E-F, wherein: D is C.sub.1-4alkylene (e.g., methylene, ethylene
or prop-2-yn-1-ylene); E is a single bond, C.sub.2-4alkynylene
(e.g., --C.ident.C--), arylene (e.g., phenylene) or heteroarylene
(e.g., pyridylene); F is H, aryl (e.g., phenyl), heteroaryl (e.g.,
pyridyl, diazolyl, triazolyl, for example, pyrid-2-yl,
imidazol-1-yl, 1,2,4-triazol-1-yl), halo (e.g., F, Br, Cl),
haloC.sub.1-4alkyl (e.g., trifluoromethyl), --C(O)--R.sub.15,
--N(R.sub.16)(R.sub.17), --S(O).sub.2R.sub.21 or
C.sub.3-7cycloalkyl optionally containing at least one atom
selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl),
tetrahydro-2H-pyran-4-yl, or morpholinyl); wherein D, E and F are
independently and optionally substituted with one or more: halo
(e.g., F, Cl or Br), C.sub.1-4alkyl (e.g., methyl),
haloC.sub.1-4alkyl (e.g., trifluoromethyl), for example, F is
heteroaryl, e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC.sub.1-4 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or
C.sub.1-4alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g.,
phenyl, substituted with one or more halo (e.g., 4-fluorophenyl) or
F is a C.sub.3-7heterocycloalkyl (e.g., pyrrolidinyl) optionally
substituted with a C.sub.1-6alkyl (e.g., 1-methylpyrrolidin-3-yl);
or e) a substituted heteroarylalkyl, e.g., substituted with
haloalkyl; f) attached to one of the nitrogens on the pyrazolo
portion of Formula IV and is a moiety of Formula A ##STR00033##
wherein X, Y and Z are, independently, N or C, and R.sub.8,
R.sub.9, R.sub.11 and R.sub.12 are independently H or halogen
(e.g., Cl or F), and R.sub.10 is: halogen, C.sub.1-4alkyl,
C.sub.3-7cycloalkyl, C.sub.1-4haloalkyl (e.g., trifluoromethyl),
aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example
pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),
diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl),
alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or
alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R.sub.8,
R.sub.9, or R.sub.10, respectively, is not present; (vi) R.sub.6 is
H, C.sub.1-4alkyl, C.sub.3-7cycloalkyl (e.g., cyclopentyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, for example,
pyrid-4-yl), arylC.sub.1-4alkyl (e.g., benzyl), arylamino (e.g.,
phenylamino), heterarylamino, N,N-diC.sub.1-4alkylamino,
N,N-diarylamino, N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or
--N(R.sub.18)(R.sub.19); wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl), hydroxy
or C.sub.1-6alkoxy, for example, R.sub.6 is 4-hydroxyphenyl or
4-fluorophenyl, (vii) n=0 or 1; (viii) when n=1, A is
--C(R.sub.13R.sub.14)--, wherein R.sub.13 and R.sub.14, are,
independently, H or C.sub.1-4alkyl, aryl, heteroaryl, (optionally
hetero)arylC.sub.1-4alkoxy or (optionally
hetero)arylC.sub.1-4alkyl; (ix) R.sub.15 is C.sub.1-4alkyl,
haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl (e.g., --OCH.sub.3)
(x) R.sub.16 and R.sub.17 are independently H or C.sub.1-4alkyl;
(xi) R.sub.18 and R.sub.19 are independently H, C.sub.1-4alky or
aryl (e.g., phenyl) wherein said aryl is optionally substituted
with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or
hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or
2-hydroxyphenyl) (xii) R.sub.20 is H, C.sub.1-4alkyl (e.g., methyl)
or C.sub.3-7cycloalkyl, (xiii) R.sub.21 is C.sub.1-6alkyl; in free
or salt form.
6. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula V: ##STR00034## wherein (i) R.sub.1 is H or C.sub.1-4 alkyl
(e.g., methyl); (ii) R.sub.4 is H or C.sub.1-4 alkyl and R.sub.2
and R.sub.3 are, independently, H or C.sub.1-4 alkyl (e.g., R.sub.2
and R.sub.3 are both methyl, or R.sub.2 is H and R.sub.3 is
isopropyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, or
(optionally hetero)arylalkyl; or R.sub.2 is H and R.sub.3 and
R.sub.4 together form a di-, tri- or tetramethylene bridge (pref.
wherein the R.sub.3 and R.sub.4 together have the cis
configuration, e.g., where the carbons carrying R.sub.3 and R.sub.4
have the R and S configurations, respectively); (iii) R.sub.5 is a
substituted heteroarylalkyl, e.g., substituted with haloalkyl or
R.sub.5 is attached to one of the nitrogens on the pyrazolo portion
of Formula V and is a moiety of Formula A ##STR00035## wherein X, Y
and Z are, independently, N or C, and R.sub.8, R.sub.9, R.sub.11
and R.sub.12 are independently H or halogen (e.g., Cl or F), and
R.sub.10 is halogen, alkyl, cycloalkyl, haloalkyl (e.g.,
trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl
(for example pyrid-2-yl), or thiadiazolyl (e.g.,
1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl,
arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl),
heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or
Z is nitrogen, R.sub.8, R.sub.9, or R.sub.10, respectively, is not
present; and (iv) R.sub.6 is H, alkyl, aryl, heteroaryl, arylalkyl
(e.g., benzyl), arylamino (e.g., phenylamino), heterarylamino,
N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylakyl)amino
(e.g., N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino); and (v) n=0 or 1;
(vi) when n=1, A is --C(R.sub.13R.sub.14)-- wherein R.sub.13 and
R.sub.14, are, independently, H or C.sub.1-4 alkyl, aryl,
heteroaryl, (optionally hetero)arylalkoxy or (optionally
hetero)arylalkyl; wherein aryl is optionally substituted with
C.sub.1-4 alkyl, halogen, haloC.sub.1-4alkyl, hydroxyl or
C.sub.1-4carboxy or an additional aryl or heteroaryl; or heteroaryl
or thiadiazolyl is optionally substituted with C.sub.1-4alkyl,
halogen, haloC.sub.1-4alkyl, hydroxyl or C.sub.1-4carboxy; in free
or pharmaceutically acceptable salt form.
7. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula VI: ##STR00036## wherein: (i) R.sub.1 is H or alkyl; (ii)
R.sub.2 is H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl,
hydroxyalkyl, arylalkyl, heteroarylalkyl, or alkoxyarylalkyl; (iii)
R.sub.3 is heteroarylmethyl or formula A ##STR00037## wherein X, Y
and Z are, independently, N or C, and R.sub.8, R.sub.9, R.sub.11
and R.sub.12 are independently H or halogen; and R.sub.10 is
halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, alkyl
sulfonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, or
aminocarbonyl; (iv) R.sub.4 is aryl or heteroaryl; and (v) R.sub.5
is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl; provided
that when X, Y or X is nitrogen, R.sub.8, R.sub.9 or R.sub.10,
respectively, is not present; wherein "alk" or "alkyl" refers to
C.sub.1-6 alkyl and "cycloalkyl" refers to C.sub.3-6 cycloalkyl, in
free, salt or physiologically hydrolysable and acceptable ester
prodrug form.
8. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula VII: ##STR00038## (i) X is C.sub.1-6alkylene (e.g.,
methylene, ethylene or prop-2-yn-1-ylene); (ii) Y is a single bond,
alkynylene (e.g., --C.ident.C--), arylene (e.g., phenylene) or
heteroarylene (e.g., pyridylene); (iii) Z is H, aryl (e.g.,
phenyl), heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl), halo (e.g.,
F, Br, Cl), haloC.sub.1-6alkyl (e.g., trifluoromethyl),
--C(O)--R.sup.1, --N(R.sup.2)(R.sup.3), or C.sub.3-7cycloalkyl
optionally containing at least one atom selected from a group
consisting of N or O (e.g., cyclopentyl, cyclohexyl,
tetrahydro-2H-pyran-4-yl, or morpholinyl); (iv) R.sup.1 is
C.sub.1-6alkyl, haloC.sub.1-6alkyl, --OH or --OC.sub.1-6alkyl
(e.g., --OCH.sub.3); (v) R.sup.2 and R.sup.3 are independently H or
C.sub.1-6alkyl; (vi) R.sup.4 and R.sup.5 are independently H,
C.sub.1-6alky or aryl (e.g., phenyl) optionally substituted with
one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),
hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or
2-hydroxyphenyl) or C.sub.1-6alkoxy; (vii) wherein X, Y and Z are
independently and optionally substituted with one or more halo
(e.g., F, Cl or Br), C.sub.1-6alkyl (e.g., methyl),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), for example, Z is
heteroaryl, e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC.sub.1-6alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or
C.sub.1-6-alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g.,
phenyl, substituted with one or more halo (e.g., 4-fluorophenyl),
in free, salt or prodrug form.
9. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula VIII: ##STR00039## wherein (i) R.sub.1 is H or
C.sub.1-6alkyl; (ii) R.sub.2 is H, C.sub.1-6alkyl,
C.sub.3-8cycloalkyl optionally substituted with one or more amino,
C.sub.3-8heterocycloalkyl optionally substituted with
C.sub.1-6alkyl, C.sub.3-8cycloalkyl-C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.0-6alkylaminoC.sub.0-6alkyl,
hydroxyC.sub.1-6alkyl, arylC.sub.0-6alkyl, heteroarylalkyl,
C.sub.1-6alkoxyarylC.sub.1-6alkyl, or -G-J wherein: G is a single
bond or, alkylene; J is cycloalkyl or heterocycloalkyl optionally
substituted with alkyl; (iii) R.sub.3 is a) -D-E-F wherein 1. D is
single bond, C.sub.1-6alkylene or arylC.sub.1-6alkylene; 2. E is a
C.sub.1-6alkylene, arylene, C.sub.1-6alkylarylene,
aminoC.sub.1-6alkylene- or amino; and 3. F is
heteroC.sub.3-8cycloalkyl optionally substituted with
C.sub.1-6alkyl; (iv) R.sub.4 is aryl optionally substituted with
one or more halo, hydroxy or C.sub.1-6alkoxy; heteroaryl; or
heteroC.sub.3-6cycloalkyl; and (v) R.sub.5 is H, C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, heteroaryl, aryl or p-benzylaryl; wherein
"alk", "alkyl", "haloalkyl" or "alkoxy" refers to C.sub.1-6 alkyl
and "cycloalkyl" refers to C.sub.3-8cycloalkyl; in free or salt
form.
10. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula IX: ##STR00040## wherein (i) Q is --C(.dbd.S)--,
--C(.dbd.N(R.sub.6))-- or --C(R.sub.14)(R.sub.15)--; (ii) R.sub.1
is H or C.sub.1-6alkyl (e.g., methyl or ethyl); (iii) R.sub.2 is H,
C.sub.1-6alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or
2,2-dimethylpropyl) wherein said alkyl group is optionally
substituted with one or more halo (e.g., fluoro) or hydroxy (e.g.,
hydroxyC.sub.1-6alkyl, for example 1-hydroxyprop-2-yl or
3-hydroxy-2-methylpropyl), haloC.sub.1-6alkyl (e.g.,
trifluoromethyl or 2,2,2-trifluoroethyl),
N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g., 2-(dimethylamino)ethyl
or 2-aminopropyl), arylC.sub.0-6alkyl (e.g., phenyl or benzyl),
wherein said aryl is optionally substituted with one or more
C.sub.1-6alkoxy, for example, C.sub.1-6alkoxyarylC.sub.0-6alkyl
(e.g., 4-methoxybenzyl), heteroarylC.sub.0-6alkyl (e.g.,
pyridinylmethyl), wherein said heteroaryl is optionally substituted
with one or more C.sub.1-6alkoxy (e.g.,
C.sub.1-6alkoxyheteroarylC.sub.1-6alkyl); -G-J wherein G is a
single bond or C.sub.1-6alkylene (e.g., methylene) and J is
C.sub.3-8cycloalkyl or heteroC.sub.3-8cycloalkyl (e.g.,
oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the
cycloalkyl and heterocycloalkyl group are optionally substituted
with one or more C.sub.1-6alkyl or amino, for example,
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g.,
--C.sub.0-4alkyl-cyclopentyl, --C.sub.0-4alkyl-cyclohexyl or
--C.sub.0-4alkyl-cyclopropyl), wherein said cycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl or amino
(for example, 2-aminocyclopentyl or 2-aminocyclohexyl),
--C.sub.0-4alkyl-C.sub.3-8heterocycloalkyl (e.g.,
--C.sub.0-4alkyl-pyrrolidinyl, for example,
--C.sub.0-4alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is
optionally substituted with C.sub.1-6alkyl (e.g., methyl), for
example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); (iv) R.sub.3 is 4) -D-E-F
wherein: D is a single bond, C.sub.1-6alkylene (e.g., methylene),
or arylC.sub.1-6alkylene (e.g., benzylene or
--CH.sub.2C.sub.6H.sub.4--); E is a single bond, C.sub.1-4alkylene
(e.g., methylene, ethynylene, prop-2-yn-1-ylene),
C.sub.0-4alkylarylene (e.g., phenylene or --C.sub.6H.sub.4--,
-benzylene- or --CH.sub.2C.sub.6H.sub.4--), wherein the arylene
group is optionally substituted with halo (e.g., Cl or F),
heteroarylene (e.g., pyridinylene or pyrimidinylene),
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), amino (e.g.,
--N(H)--); C.sub.3-8cycloalkylene optionally containing one or more
heteroatom selected from N or O (e.g., piperidinylene), F is H,
halo (e.g., F, Br, Cl), C.sub.1-6alkyl (e.g., isopropyl or
isobutyl), haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g.,
phenyl), C.sub.3-8cycloalkyl optionally containing one or more atom
selected from a group consisting of N, S or O (e.g., cyclopentyl,
cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or
morpholinyl), and optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl or isopropyl), for example,
1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,
piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,
heteroaryl (e.g., pyridyl (for example, pyrid-2-yl), pyrimidinyl
(for example, pyrimidin-2-yl), thiadiazolyl (for example,
1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example,
pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl)), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), wherein said
heteroaryl is optionally substituted with one or more
C.sub.1-6alkyl, halo (e.g., fluoro) or haloC.sub.1-6alkyl;
C.sub.1-6alkoxy, --O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3),
C.sub.1-6alkylsulfonyl (for example, methylsulfonyl or
--S(O).sub.2CH.sub.3), --C(O)--R.sub.13, wherein R.sub.13 is
--N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6 alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl;
--N(R.sub.14)(R.sub.15); or 5) a substituted
heteroarylC.sub.1-6alkyl, e.g., substituted with
haloC.sub.1-6alkyl; or 6) attached to one of the nitrogens on the
pyrazolo portion of Formula I and is a moiety of Formula A
##STR00041## wherein: X, Y and Z are, independently, N or C,
R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently H or
halogen (e.g., Cl or F); and R.sub.10 is halogen (e.g., fluoro or
chloro), C.sub.1-6alkyl, C.sub.3-8cycloalkyl,
heteroC.sub.3-8cycloalkyl (e.g., pyrrolidinyl or piperidinyl),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl) or
heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g.,
thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl,
triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,
tetrazol-5-yl), alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol),
pyrazolyl (e.g., pyrazol-1-yl), wherein said aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is optionally substituted with one
or more C.sub.1-6alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC.sub.1-6alkyl (e.g., trifluoromethyl), hydroxy,
carboxy, --SH, or an additional aryl or heteroaryl (e.g., biphenyl
or pyridylphenyl), C.sub.1-6alkyl sulfonyl (e.g., methyl sulfonyl),
arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl,
C.sub.1-6alkoxycarbonyl, (e.g., methoxycarbonyl), Aminocarbonyl,
--N(R.sub.14)(R.sub.15); preferably R.sub.10 is phenyl, pyridyl,
piperidinyl or pyrrolidinyl optionally substituted with the
substituents previously defined, e.g. optionally substituted with
halo or alkyl; provided that when X, Y or X is nitrogen, R.sub.8,
R.sub.9 or R.sub.10, respectively, is not present; (v) R.sub.4 and
R.sub.5 are independently: H, C.sub.1-6alkyl (e.g., methyl,
isopropyl, isobutyl, n-propyl), C.sub.3-8cycloalkyl (e.g.,
cyclopentyl or cyclohexyl), C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidinyl (for example pyrrolidin-3-yl or pyrrolidin-1-yl),
piperidinyl (for example, piperidin-1-yl), morpholinyl),
--C.sub.0-6alkylaryl (e.g., phenyl or benzyl) or
--C.sub.0-6alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or
pyrazol-3-yl) wherein said aryl or heteroaryl is optionally
substituted with one or more halo (e.g., 4-fluorophenyl), hydroxy
(e.g., 4-hydroxyphenyl), C.sub.1-6alkyl, C.sub.1-6alkoxy or another
aryl group (e.g., biphenyl-4-ylmethyl); (vi) R.sub.6 is H,
C.sub.1-6alkyl (e.g., methyl or ethyl) or C.sub.3-8cycloalkyl;
(vii) R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl,
in free or salt form.
11. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula X, e.g.: ##STR00042## Formula X-A Formula X-B wherein (i) Q
is --C(.dbd.S)--, --C(.dbd.O)--, --C(.dbd.N(R.sub.7))-- or
--C(R.sub.14)(R.sub.15)--; (ii) R.sub.1 is H or C.sub.1-6alkyl
(e.g., methyl or ethyl); (iii) R.sub.2 is H, C.sub.1-6alkyl (e.g.,
isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein
said alkyl group is optionally substituted with halo (e.g., fluoro)
or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl),
for example, R.sub.2 may be a trifluoromethyl or
2,2,2-trifluoroethyl, N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g.,
2-(dimethylamino)ethyl or 2-aminopropyl), arylC.sub.1-6alkyl (e.g.,
phenyl or benzyl), heteroaryl C.sub.1-6alkyl (e.g.,
pyridinylmethyl), C.sub.1-6alkoxyaryl-C.sub.1-6alkyl (e.g.,
4-methoxybenzyl); -G-J wherein: G is a single bond or, alkylene
(e.g., methylene); J is cycloalkyl or heterocycloalkyl (e.g.,
oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted
with one or more C.sub.1-6alkyl (e.g., (1-methylpyrolidin-2-yl)),
amino (e.g., --NH.sub.2), for example, -G-J may be
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g., cyclopentyl, cyclohexyl
or cyclopropylmethyl) optionally substituted with one or more
C.sub.1-6alkyl, amino (e.g., --NH.sub.2), for example,
2-aminocyclopentyl or 2-aminocyclohexyl, wherein said cycloalkyl
optionally contains one or more heteroatom selected from N and O
(e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or
pyrrolidin-2-yl, 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); (iv) R.sub.3 is 1) -D-E-F
wherein: D is a single bond, C.sub.1-6alkylene (e.g., methylene),
or arylalkylene (e.g., p-benzylene or --CH.sub.2C.sub.6H.sub.4--);
E is a single bond, C.sub.1-6alkylene (e.g., methylene)
C.sub.2-6alkynylene (e.g., ethynylene, prop-2-yn-1-ylene),
ethynylene, prop-2-yn-1-ylene), --C.sub.0-4alkylarylene (e.g.,
phenylene or --C.sub.6H.sub.4--, -benzyle{acute over (.eta.)} - or
--CH.sub.2C.sub.6H.sub.4--), wherein the arylene group is
optionally substituted with halo (e.g., Cl or F), heteroarylene
(e.g., pyridinylene or pyrimidinylene), aminoC.sub.1-6alkylene
(e.g., --CH.sub.2N(H)--), amino (e.g., --N(H)--);
C.sub.3-8cycloalkylene optionally containing one or more heteroatom
selected from N or O (e.g., piperidinylene), F is H, halo (e.g., F,
Br, Cl), C.sub.1-6alkyl (e.g., isopropyl or isobutyl),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
C.sub.3-8cycloalkyl optionally containing at least one atom
selected from a group consisting of N or O (e.g., cyclopentyl, N
cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or
morpholinyl), said cycloalkyl is optionally substituted with
C.sub.1-6alkyl (e.g., methyl or isopropyl), for example,
1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,
piperidin-2-yl, 1-methyrpiperidin-2-yl, 1-ethylpiperidin-2-yl,
heteroaryl optionally substituted with C.sub.1-6alkyl, (e.g.,
pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example,
pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl),
diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl
(for example, imidazol-1-yl, 4-methylimidazolyl,
1-methylimidazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl),
tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g.,
5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein
said heteroaryl is optionally substituted with halo (e.g., fluoro)
or haloC.sub.1-6alkyl, for example, 6-fluoropyrid-2-yl; amino
(e.g., --NH.sub.2), C.sub.1-6alkoxy, --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), C.sub.1-6alkylsulfonyl (for example, methylsulfonyl
or --S(O).sub.2CH.sub.3), --C(O)--R.sub.13,
--N(R.sub.14)(R.sub.15); or 2) a substituted heteroarylaklyl, e.g.,
substituted with haloalkyl; or 3) attached to the nitrogen on the
pyrrolo portion of Formula I and is a moiety of Formula A
##STR00043## wherein X, Y and Z are, independently, N or C, and
R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently H or
halogen (e.g., Cl or F); and R.sub.10 is halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy (e.g., methoxy), C.sub.3-8cycloalkyl,
heteroC.sub.3-8cycloalkyl (e.g., pyrrolidinyl) haloC.sub.1-6alkyl
(e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g.,
pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for
example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., imidazolyl or
pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,
tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol),
pyrazolyl (e.g., pyrazol-1-yl), C.sub.1-6alkyl sulfonyl (e.g.,
methyl sulfonyl), arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl,
alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; wherein the
aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally
substituted with one or more C.sub.1-6alkyl (e.g., methyl), halogen
(e.g., chloro or fluoro), haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), hydroxy, carboxy, --SH, or an additional aryl or
heteroaryl (e.g., biphenyl or pyridylphenyl) preferably R.sub.10 is
phenyl or pyridyl, e.g., 2-pyridyl optionally substituted with the
substituents previously defined; provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; (v) R.sub.4 and R.sub.5 are independently H,
C.sub.1-6alkyl (e.g., methyl, isopropyl), C.sub.3-8cycloalkyl
(e.g., cyclopentyl), C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g.,
pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or
heteroaryl is optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R.sub.6 is H, C.sub.1-6alkyl (e.g., methyl), hydroxy,
C.sub.1-6alkoxy, aryloxy, --N(R.sub.16)(R.sub.17), oxo (e.g.,
.dbd.O), or C.sub.3-8Cycloalkyl; (vii) R.sub.7 is H, C.sub.1-6alkyl
(e.g., methyl) or C.sub.3-8cycloalkyl wherein said cycloalkyl is
optionally substituted with one or more oxo (e.g.,
2,5-dioxopyrrolidin-1-yl); (viii) R.sub.13 is
--N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6 alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and (ix)
R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl; (x)
R.sub.16 and R.sub.17 are independently H, C.sub.1-6alkyl, aryl
(e.g., phenyl), heteroaryl, wherein said aryl or heteroaryl is
optionally substituted with halo (e.g., fluoro), C.sub.1-6alkoxy
(e.g., methoxy); in free or salt form.
12. A method of claim 1, wherein the PDE1 inhibitor is compound of
Formula XI: ##STR00044## wherein (i) L is S, SO or SO.sub.2; (ii)
R.sub.2 is H or C.sub.1-6alkyl (e.g., methyl or ethyl); (iii)
R.sub.2 is H, C.sub.1-6alkyl (e.g., isopropyl, isobutyl, neopentyl,
2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is
optionally substituted with halo (e.g., fluoro) or hydroxy (e.g.,
1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl),
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g., cyclopentyl,
cyclohexyl) optionally substituted with one or more amino (e.g.,
--NH.sub.2), for example, 2-aminocyclopentyl or 2-aminocyclohexyl),
wherein said cycloalkyl optionally contains one or more heteroatom
selected from N and O and is optionally substituted with
C.sub.1-6alkyl (e.g., 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl), C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidinyl, for example, pyrrolidin-3-yl) optionally substituted
with C.sub.1-6alkyl (e.g., methyl), for example,
1-methylpyrrolidin-3-yl, C.sub.3-8cycloalkyl-C.sub.1-6alkyl (e.g.,
cyclopropylmethyl), haloC.sub.1-6alkyl (e.g., trifluoromethyl,
2,2,2-trifluoroethyl), --N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl
(e.g., 2-(dimethylamino)ethyl, 2-aminopropyl),
hydroxyC.sub.1-6alkyl (e.g., (e.g., 3-hydroxy-2-methylpropyl,
1-hydroxyprop-2-yl), arylC.sub.0-6alkyl (e.g., benzyl),
heteroarylC.sub.1-6alkyl (e.g., pyridinylmethyl),
C.sub.1-6alkoxyarylC.sub.1-6alkyl (e.g., 4-methoxybenzyl); -G-J
wherein: G is a single bond or, alkylene (e.g., methylene); J is
cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl,
pyrolyin-2-yl) optionally substituted with C.sub.1-6alkyl (e.g.,
(1-methylpyrolidin-2-yl)); (iv) R.sub.3 is attached to one of the
nitrogens on the pyrazolo portion of Formula I and is a moiety of
Formula A ##STR00045## wherein X, Y and Z are, independently, N or
C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently H
or halogen (e.g., Cl or F); and R.sub.10 is halogen,
C.sub.1-6alkyl, C.sub.3-8 cycloalkyl, heteroC.sub.3-8cycloalkyl
(e.g., pyrrolidinyl or piperidinyl) haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl,
(for example, pyrid-2-yl) or e.g., thiadiazolyl (for example,
1,2,3-thiadiazol-4-15 yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl
(e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g.,
methoxycarbonyl), aminocarbonyl; preferably phenyl, pyridyl, e.g.,
2-pyridyl, piperidinyl, or pyrrolidinyl; wherein the aryl,
heteroaryl cycloalkyl or heterocycloalkyl is optionally substituted
with one or more halo (e.g., F or Cl), C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-4haloalkyl (e.g., trifluoromethyl), and/or
--SH, provided that when X, Y or X is nitrogen, R.sub.8, R.sub.9 or
R.sub.10, respectively, is not present; (v) R.sub.4 is H,
C.sub.1-6alkyl (e.g., methyl, isopropyl), C.sub.3-8cycloalkyl
(e.g., cyclopentyl), C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g.,
pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or
heteroaryl is optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl,
in free or salt form.
13. The method of claim 1, wherein the compound inhibits
phosphodiesterase mediated hydrolysis of cGMP/PKG (e.g., in cardiac
tissue) and wherein inhibition of phosphodiesterase prevents or
treats (e.g., reverses) cardiac hypertrophy.
14. The method of claim 1, wherein the PDE1 inhibitor is a PDE1A or
PDE1C inhibitor.
15. The method of claim 1, wherein the PDE1 inhibitor is a PDE1B
inhibitor.
16. The method claim 1, wherein the PDE1 inhibitor is administered
in order to treat or prevent a cardiovascular disease or
disorder.
17. (canceled)
18. The method of claim 1, wherein the disease is selected from the
group consisting of: Duchenne muscular dystrophy, Becker muscular
dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, and
Emery-Dreifuss muscular dystrophy.
19. The method of claim 1, wherein the disease or disorder is a
stroke.
20. The method of claim 19, wherein the stroke is characterized as
a transient ischemic attack.
21. The method of claim 1, wherein the PDE 1 inhibitor is
administered to prevent or treat cardiac hypertrophy.
22. The method of claim 1, wherein a PDE1 inhibitor is administered
in combination with a PDE5 inhibitor.
23. The method of claim 1, wherein the PDE1 inhibitor is selected
from the group of consisting of: selected from any of the
following: ##STR00046## ##STR00047## ##STR00048##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Application
Serial No. 14/767,489, filed on Aug. 12, 2015, which is a National
Phase Application filed under 35 U.S.C. 371 of International
Application No. PCT/US2014/016741, filed on Feb. 17, 2014, which
claims priority to U.S. Provisional Application No. 61/765,804,
filed on Feb. 17, 2013, the contents of each of which are herein
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The field relates to the administration of inhibitors of
phosphodiesterase 1 (PDE1) for the treatment of diseases or
disorders characterized by disruption of or damage to certain
cGMP/PKG mediated pathways (e.g., in cardiac tissue). The field
further relates to inhibitors of phosphodiesterase 1 (PDE1) for
treatment of cardiovascular disease and related disorders, e.g.,
congestive heart disease, atherosclerosis, myocardial infarction,
and stroke.
BACKGROUND OF THE INVENTION
[0003] Eleven families of phosphodiesterases (PDEs) have been
identified but only PDEs in Family I, the
Ca.sup.2+-calmodulin-dependent phosphodiesterases (CaM-PDEs), which
are activated by the Ca.sup.2+-calmodulin and have been shown to
mediate the calcium and cyclic nucleotide (e.g. cAMP and cGMP)
signaling pathways. The three known CaM-PDE genes, PDE1A, PDE1B,
and PDE1C, are all expressed in central nervous system tissue.
PDE1A is expressed throughout the brain with higher levels of
expression in the CA1 to CA3 layers of the hippocampus and
cerebellum and at a low level in the striatum. PDE1A is also
expressed in the lung and heart. PDE1B is predominately expressed
in the striatum, dentate gyrus, olfactory tract and cerebellum, and
its expression correlates with brain regions having high levels of
dopaminergic innervation.
[0004] Although PDE1B is primarily expressed in the central nervous
system, it may be detected in the heart. PDE1C is expressed in
olfactory epithelium, cerebellar granule cells, striatum, heart,
and vascular smooth muscle. Specifically, the major PDE activity in
the human cardiac ventricle is PDE1. And PDE1 has been shown to
promote human arterial smooth muscle cell proliferation. By virtue
of its modulation of cGMP in the monocyte, PDE1 has potential as a
hypertrophy regulator. (Circ Res. 2009 Nov. 6; 105(10): 931.)
Generally, there is a high abundance of PDE1 isoforms in: cardiac
myocytes, vascular endothelial smooth muscle, fibroblast and motor
neurons.
[0005] Cyclic nucleotide phosphodiesterases downregulate
intracellular cAMP and cGMP signaling by hydrolyzing these cyclic
nucleotides to their respective inactive 5'-monophosphates (5'AMP
and 5'GMP). cGMP is a central intracellular second-messenger
regulating numerous cellular functions. In the cardiac myocyte,
cGMP mediates effects of nitric oxide and atrial natriuretic
peptide, whereas its counterpart, cAMP, mediates catecholamine
signaling. Each cyclic nucleotide has a corresponding primary
targeted protein kinase, PKA for cAMP, and PKG for cGMP. PKA
stimulation is associated with enhanced contractility and can
stimulate growth, whereas PKG acts as a brake in the heart, capable
of countering cAMP-PKA-contractile stimulation and inhibiting
hypertrophy. Importantly, the duration and magnitude of these
signaling cascades are determined not only by generation of cyclic
nucleotides, but also by their hydrolysis catalyzed by
phosphodiesterases (PDEs). PDE regulation is quite potent--often
suppressing an acute rise in a given cyclic nucleotide back to
baseline within seconds to minutes. It is also compartmentalized
within the cell, so that specific targeted proteins can be
regulated by the same "generic" cyclic nucleotide.
[0006] Heart disease is typically a chronic and progressive illness
that kills more than 2.4 million Americans each year. There are
approximately 500,000 new cases of heart failure per year, with an
estimated 5 million patients in the United States alone having this
disease. Early intervention is likely to be most effective in
preserving cardiac function. It would be most desirable to prevent
as well to reverse the morphological, cellular, and molecular
remodeling that is associated with heart disease. Some of the most
important indicators of cardiac risk are age, hereditary factors,
weight, smoking, blood pressure, exercise history, and diabetes.
Other indicators of cardiac risk include the subject's lipid
profile, which is typically assayed using a blood test, or any
other biomarker associated with heart disease or hypertension.
Other methods for assaying cardiac risk include, but are not
limited to, an EKG stress test, thallium stress test, EKG, CT scan,
echocardiogram, magnetic resonance imaging study, non-invasive and
invasive arteriogram, and cardiac catheterization.
[0007] Pulmonary hypertension (PH or PHT) is an increase in blood
pressure in the pulmonary artery, pulmonary vein, and/or pulmonary
capillaries. It is a very serious condition, potentially leading to
shortness of breath, dizziness, fainting, decreased exercise
tolerance, heart failure, pulmonary edema, and death. It can be one
of five different groups, classified by the World Health
Organization as follows: WHO Group I Pulmonary arterial
hypertension (PAH)
a. Idiopathic (IPAH) b. Familial (FPAH) c. Associated with other
diseases (APAH): collagen vascular disease (e.g. scleroderma),
congenital shunts between the systemic and pulmonary circulation,
portal hypertension, HIV infection, drugs, toxins, or other
diseases or disorder. d. Associated with venous or capillary
disease
[0008] Pulmonary arterial hypertension involves the
vasoconstriction or tightening of blood vessels connected to and
within the lungs. This makes it harder for the heart to pump blood
through the lungs, much as it is harder to make water flow through
a narrow pipe as opposed to a wide one. Over time, the affected
blood vessels become both stiffer and thicker, in a process known
as fibrosis. This further increases the blood pressure within the
lungs and impairs their blood flow. In addition, the increased
workload of the heart causes thickening and enlargement of the
right ventricle, making the heart less able to pump blood through
the lungs, causing right heart failure. As the blood flowing
through the lungs decreases, the left side of the heart receives
less blood. This blood may also carry less oxygen than normal.
Therefore it becomes more and more difficult for the left side of
the heart to pump to supply sufficient oxygen to the rest of the
body, especially during physical activity.
[0009] WHO Group II--Pulmonary hypertension associated with left
heart disease a. Atrial or ventricular disease
b. Valvular disease (e.g. mitral stenosis)
[0010] In pulmonary venous hypertension (WHO Group II) there may
not be any obstruction to blood flow in the lungs. Instead, the
left heart fails to pump blood efficiently out of the heart into
the body, leading to pooling of blood in veins leading from the
lungs to the left heart (congestive heart failure or CHF). This
causes pulmonary edema and pleural effusions. The fluid build-up
and damage to the lungs may also lead to hypoxia and consequent
vasoconstriction of the pulmonary arteries, so that the pathology
may come to resemble that of Group 1 or III.
[0011] WHO Group III--Pulmonary hypertension associated with lung
diseases and/or hypoxemia a. Chronic obstructive pulmonary disease
(COPD), interstitial lung disease (ILD)
b. Sleep-disordered breathing, alveolar hypoventilation c. Chronic
exposure to high altitude d. Developmental lung abnormalities In
hypoxic pulmonary hypertension (WHO Group II I), the low levels of
oxygen may cause vasoconstriction or tightening of pulmonary
arteries. This leads to a similar pathophysiology as pulmonary
arterial hypertension.
[0012] WHO Group IV--Pulmonary hypertension due to chronic
thrombotic and/or embolic disease a. Pulmonary embolism in the
proximal or distal pulmonary arteries b. Embolization of other
matter, such as tumor cells or parasites
[0013] In chronic thromboembolic pulmonary hypertension (WHO Group
IV), the blood vessels are blocked or narrowed with blood clots.
Again, this leads to a similar pathophysiology as pulmonary
arterial hypertension.
[0014] WHO Group V--Miscellaneous
[0015] Treatment of pulmonary hypertension has proven very
difficult.
[0016] Antihypertensive drugs that work by dilating the peripheral
arteries are frequently ineffective on the pulmonary vasculature.
For example, calcium channel blockers are effective in only about
5% of patients with IPAH. Left ventricular function can often be
improved by the use of diuretics, beta blockers, ACE inhibitors,
etc., or by repair/replacement of the mitral valve or aortic valve.
Where there is pulmonary arterial hypertension, treatment is more
challenging, and may include lifestyle changes, digoxin, diuretics,
oral anticoagulants, and oxygen therapy are conventional, but not
highly effective. Newer drugs targeting the pulmonary arteries,
include endothelin receptor antagonists (e.g., bosentan,
sitaxentan, ambrisentan), phosphodiesterase type 5 inhibitors
(e.g., sildenafil, tadalafil), prostacyclin derivatives (e.g.,
epoprostenol, treprostenil, iloprost, beroprost), and soluble
guanylate cyclase (sGC) activators (e.g., cinaciguat and
riociguat). Surgical approaches to PAH include atrial septostomy to
create a communication between the right and left atria, thereby
relieving pressure on the right side of the heart, but at the cost
of lower oxygen levels in blood (hypoxia); lung transplantation;
and pulmonary thromboendarterectomy (PTE) to remove large clots
along with the lining of the pulmonary artery. Heart failure and
acute myocardial infarction are common and serious conditions
frequently associated with thrombosis and/or plaque build-up in the
coronary arteries.
[0017] Cardiovascular disease or dysfunction may also be associated
with diseases or disorders typically thought of as affecting
skeletal muscle. One such disease is Duchenne muscular dystrophy
(DMD), which is a disorder that primarily affects skeletal muscle
development but can also result in cardiac dysfunction and
cardiomyopathy. DMD is a recessive X-linked form of muscular
dystrophy, affecting around 1 in 3,600 boys, which results in
muscle degeneration and eventual death. The disorder is caused by a
mutation in the dystrophin gene, located on the human X chromosome,
which codes for the protein dystrophin, an important structural
component within muscle tissue that provides structural stability
to the dystroglycan complex (DGC) of the cell membrane. While both
sexes can carry the mutation, females rarely exhibit signs of the
disease.
[0018] Patients with DMD lack expression of the protein dystrophin
as a result of mutations in the X-linked dystrophin gene.
Additionally, the loss of dystrophin leads to severe skeletal
muscle pathologies as well as cardiomyopathy, which manifests as
congestive heart failure and arrhythmias. The absence of a
functional dystrophin protein is believed to lead to reduced
expression and mis-localization of dystrophin-associated proteins
including neuronal nitric oxide (NO) synthase. Disruption of nNOS
signaling may result in muscle fatigue and unopposed sympathetic
vasoconstriction during exercise, thereby increasing
contraction-induced damage in dystrophin-deficient muscles. The
loss of normal nNOS signaling during exercise is central to the
vascular dysfunction proposed to be an important pathogenic
mechanism in DMD.
[0019] Currently, there is a largely unmet need for an effective
way of treating cardiovascular disease and disorders (e.g.
congestive heart disease), and diseases and disorders which may
result in cardiac dysfunction or cardiomyopathy (e.g., Duchenne
Muscular Dystrophy). Improved therapeutic compositions and methods
for the treatment of cardiac conditions and dysfunction are
urgently required.
SUMMARY OF THE INVENTION
[0020] PDE1A and PDE1C are believed to be abundantly expressed in
cardiac, vascular, and lung tissues. Moreover, PDE1 is also
believed to be up-regulated in chronic disease conditions such as
atherosclerosis, cardiac pressure-load stress and heart failure, as
well as in response to long-term exposure to nitrates. Without
being bound by theory, it is believed that the compounds of the
present invention are able to modulate cGMP/PKG mediated pathways.
Consequently, the PDE1 inhibitors disclosed herein are believed to
have significant modulatory activity (e.g., enhancement of cGMP) in
those areas of the body where PDE1 isoforms are predominately
located: e.g., cardiac, vascular, and lung tissue. PDE1 inhibitors
may have relatively little impact on resting function, but rather
maintain the ability to potently modulate acute contractile tone in
cells stimulated by vasoactive agonists.
[0021] For example, it is believed that PDE1 may modulate acute
contractile tone in cells that are activated by hypertrophic
stimuli. Consequently, without being bound by theory, it is
believed that in one embodiment that the application or
administration of the PDE1 inhibitors disclosed herein could work
to prevent hypertrophic responses and possibly reverse any existing
tissue hypertrophy.
[0022] Without being bound by theory, in one embodiment it is
believed that the selective PDE1 inhibitors, e.g., Compounds of
Formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI described
herein, may be involved in regulating cGMP/PKG involvement in
cardiac hypertrophy. Previous studies have demonstrated that
intracellular Ca2+/CaM-dependent signaling promotes maladaptive
hypertrophic gene expression in cardiomyocytes through various
effectors such as the protein phosphatase calcineurin,
Ca2+/CaM-dependent kinase II (CaMKII). Without being bound by any
theory, Endogenous cGMP/PKG-dependent signaling may be able to
negatively regulate cardiac hypertrophy, by suppressing Gq/11
activation and normalizing Ca2+ signaling. Ca2+/CaM, by activating
PDEIA, may decrease cGMP levels and PKG activity. In turn, this
process may lead to potentiated cardiomyocyte hypertrophy.
Additionally, upregulation of PDE1A expression upon neurohumoral or
biomechanical stress during cardiac hypertrophy may further enhance
PDE1A activity and attenuates cGMP/PKG signaling. Accordingly,
without being bound by any theory, it is believed that inhibition
of PDE1A, for example, could reverse or prevent the attenuation of
cGMP/PKG signaling. Therefore, administration of a preferred PDE1
inhibitor as described herein could provide a potential means to
regulate cardiac hypertrophy, and by extension provide a treatment
for various cardiovascular diseases and disorders.
[0023] Accordingly, in one embodiment, the invention provides a new
method of treatment or prophylaxis of cardiovascular disease and
disorders (e.g., atherosclerosis, pulmonary arterial hypertension,
myocardial infarction) that may be ameliorated by administration of
a specific inhibitor of phosphodiedsterase type I (e.g., PDE1
inhibitor, e.g., a PDE1A or PDE1C inhibitor) (e.g., a PDE1
inhibitor of Formula I, II, III, IV, V, VI, VII, VIII, IX, X,
and/or XI as herein described).
[0024] In one embodiment the cardiovascular disease or disorder may
selected from the group consisting of: hypertension, congestive
heart failure, angina, stroke, essential hypertension, pulmonary
hypertension, secondary pulmonary hypertension, isolated systolic
hypertension, hypertension associated with diabetes, hypertension
associated with atherosclerosis, renovascular hypertension,
congestive heart failure, angina, stroke. In certain embodiments,
the cardiovascular disease or disorder to be treated may also
relate to impaired cGMP/PKG-dependent signaling.
[0025] In another embodiment the PDE1 inhibitor (e.g., a PDE1
inhibitor of Formula I, II, III, IV, V, VI, VII, VIII, IX, X,
and/or XI as herein described) may be administered in combination
with an angiotensin II receptor antagonist. Examples of angiotensin
II receptor antagonists for use with the invention include
candesartan, eprosartan, irbesartan, losartan, olmesartan,
olmnesartan medoxomil, saralasin, telmisartan and valsartan.
[0026] The invention also provides a new method of treatment or
prophylaxis of cardiovascular disease or disorder that is
associated with a muscular dystrophy (e.g, Duchenne muscular
dystrophy). As previously noted, DMD is caused by the absence of a
functional dystrophin protein, which in turn leads to reduced
expression and mis-localization of dystrophin-associated proteins;
which can include neuronal nitric oxide (NO) synthase. Disruption
of nNOS signaling may result in muscle fatigue and unopposed
sympathetic vasoconstriction during exercise, thereby increasing
contraction-induced damage in dystrophin-deficient muscles. Without
being bound by theory, the loss of normal nNOS signaling during
exercise may be central to the vascular dysfunction proposed to be
an important pathogenic mechanism in DMD. Without being bound by
theory, it is contemplated that by inhibiting phosphodiesterases
(e.g. PDE1A, PDE1C), (e.g., administering or using a PDE1 inhibitor
of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, and/or XI as
herein described) that at least one mechanism of the compounds
described herein may be to circumvent defective nNOS signaling in
dystrophic skeletal and/or cardiac muscle; thereby potentially
improving cardiac outcomes in, at least, DMD patients.
[0027] In one particular embodiment, the invention provides a novel
method of treatment or prophylaxis for cardiac dysfunction
associated with Duchenne muscular dystrophy that may be ameliorated
by administration of a phosphodiesterase type I (PDE1 inhibitor,
e.g., a PDE1 inhibitor of Formula I, II, III, IV, V, VI, VII, VIII,
IX, X, and/or XI as herein described) as described herein.
[0028] In another embodiment, the PDE1 inhibitor is administered to
a patient with a type of muscular dystrophy which may be selected
from the group consisting of: Becker, limb-girdle, myotonic, and
Emery-Dreifuss muscular dystrophy.
[0029] In one embodiment, the invention provides for the treatment
of cardiovascular disease or disorder which may be associated with
impaired cGMP signaling (e.g., cGMP/PKG signaling), wherein the
disease or disorder may be selected from the group consisting of:
angina, stroke, essential hypertension, pulmonary hypertension,
secondary hypertension, isolated systolic hypertension,
hypertension associated with diabetes, hypertension associated with
atherosclerosis, renovascular hypertension, congestive heart
failure, angina, stroke, hypertension, fibrosis, an inflammatory
disease or disorder, cardiac hypertrophy, and an connective tissue
disease or disorder (e.g., Marfan Syndrome).
DETAILED DESCRIPTION OF THE INVENTION
Compounds for Use in the Methods of the Invention
[0030] In one embodiment, the PDE1 inhibitors for use in the
methods of treatment and prophylaxis described herein are
optionally substituted
4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or
4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine,
e.g., a Compound of Formula II, e.g., II-A or II-B:
##STR00001##
wherein [0031] (i) Q is C(.dbd.O), C(.dbd.S), C(.dbd.N(R.sub.20))
or CH.sub.2; [0032] (ii) L is a single bond, --N(H)--,
--CH.sub.2--, --S--, --S(O)-- or --S(O.sub.2)--; [0033] (iii)
R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl); [0034] (iv) R.sub.4
is H or C.sub.1-6 alkyl (e.g., methyl or isopropyl) and R.sub.2 and
R.sub.3 are, independently, [0035] H [0036] C.sub.1-6alkyl (e.g.,
methyl, isopropyl) optionally substituted with halo or hydroxy
(e.g., R.sub.2 and R.sub.3 are both methyl, or R.sub.2 is H and
R.sub.3 is methyl, ethyl, isopropyl or hydroxyethyl), [0037] aryl,
[0038] heteroaryl, [0039] (optionally hetero)arylalkoxy, [0040]
(optionally hetero)arylC.sub.1-6alkyl; or [0041] R.sub.2 and
R.sub.3 together form a 3- to 6-membered ring; or [0042] R.sub.2 is
H and R.sub.3 and R.sub.4 together form a di-, tri- or
tetramethylene bridge [0043] (pref. wherein the R.sub.3 and R.sub.4
together have the cis configuration, e.g., where the carbons
carrying R.sub.3 and R.sub.4 have the R and S configurations,
respectively); or [0044] (v) R.sub.5 is [0045] a) -D-E-F, wherein:
[0046] D is C.sub.1-4alkylene (e.g., methylene, ethylene or
prop-2-yn-1-ylene); [0047] E is a single bond, C.sub.2-4alkynylene
(e.g., --C.ident.C--), arylene (e.g., phenylene) or heteroarylene
(e.g., pyridylene); [0048] F is [0049] H, [0050] aryl (e.g.,
phenyl), [0051] heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for
example, pyrid-2-yl, imidazol-1-yl, 1,2,4-triazol-1-yl), halo
(e.g., F, Br, Cl), [0052] haloC.sub.1-4alkyl (e.g.,
trifluoromethyl), [0053] --C(O)--R.sub.15, [0054]
--N(R.sub.16)(R.sub.17), or [0055] C.sub.3-7cycloalkyl optionally
containing at least one atom selected from a group consisting of N
or O (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,
pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl); [0056]
wherein D, E and F are independently and optionally substituted
with one or more halo (e.g., F, Cl or Br), C.sub.1-4alkyl (e.g.,
methyl), haloC.sub.1-4alkyl (e.g., trifluoromethyl),
C.sub.1-4alkoxy (e.g., methoxy), hydroxy, C.sub.1-4carboxy, or an
additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl),
[0057] for example, F is heteroaryl, e.g., pyridyl substituted with
one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl,
6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,
4,6-dichloropyrid-2-yl), haloC.sub.1-4alkyl (e.g.,
5-trifluoromethylpyrid-2-yl) or C.sub.1-4alkyl (e.g.,
5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with
one or more halo (e.g., 4-fluorophenyl) or F is a
C.sub.3-7heterocycloalkyl (e.g., pyrrolidinyl) optionally
substituted with a C.sub.1-6alkyl (e.g., 1-methylpyrrolidin-3-yl);
or [0058] b) a substituted heteroarylalkyl, e.g., substituted with
haloC.sub.1-4alkyl; [0059] c) attached to the nitrogen on the
pyrrolo portion of Formula II-A or II-B and is a moiety of Formula
A
[0059] ##STR00002## [0060] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F), and R.sub.10 is [0061] halogen,
[0062] C.sub.1-4alkyl, [0063] haloC.sub.1-4alkyl (e.g.,
triflouromethyl) [0064] C.sub.1-4alkoxy (e.g. methoxy), [0065]
C.sub.3-7cycloalkyl, [0066] heteroC.sub.3-7cycloalkyl (e.g.,
pyrrolidinyl or piperidinyl), [0067] C.sub.1-4haloalkyl (e.g.,
trifluoromethyl), [0068] aryl (e.g., phenyl), [0069] heteroaryl
(e.g., pyridyl (for example pyrid-2-yl or pyrid-4-yl), or
thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,
imidazol-1-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl,
[0070] arylcarbonyl (e.g., benzoyl), [0071] alkylsulfonyl (e.g.,
methylsulfonyl), [0072] heteroarylcarbonyl, or [0073]
alkoxycarbonyl; [0074] wherein the aryl, heteroaryl, cycloalkyl or
heterocycloalkyl is independently, optionally substituted with one
or more C.sub.1-4 alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC.sub.1-4alkyl (e.g., trifluoromethyl), hydroxy,
C.sub.1-4carboxy, --SH or an additional aryl, heteroaryl (e.g.,
biphenyl or pyridylphenyl) or C.sub.3-8cycloalkyl, [0075]
preferably R.sub.10 is phenyl, pyridyl, piperidinyl or pyrrolidinyl
optionally substituted with the substituents previously defined,
e.g. optionally substituted with halo or alkyl [0076] provided that
when X, Y, or Z is nitrogen, R.sub.8, R.sub.9, or R.sub.10,
respectively, is not present; [0077] (vi) R.sub.6 is [0078] H,
[0079] C.sub.1-4alkyl (e.g., methyl, ethyl, n-propyl, isobutyl),
[0080] C.sub.3-7cycloalkyl (e.g., cyclopentyl or cyclohexyl),
[0081] heteroC.sub.3-7cycloalkyl (e.g., pyrrolidinyl, piperidinyl,
morpholinyl), [0082] aryl (e.g., phenyl), [0083] heteroaryl (e.g.,
pyrid-4-yl), [0084] arylC.sub.1-4alkyl (e.g., benzyl), [0085]
arylamino (e.g., phenylamino), [0086] heteroarylamino, [0087]
N,N-diC.sub.1-4alkylamino, [0088] N,N-diarylamino, [0089]
N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or [0090]
--N(R.sub.18)(R.sub.19), [0091] wherein the aryl and heteroaryl are
optionally substituted with one or more C.sub.1-4alkyl (e.g.,
methyl), halogen (e.g., chloro or fluoro), haloC.sub.1-4alkyl
(e.g., trifluoromethyl), hydroxy, C.sub.1-4carboxy, or an
additional aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or
C.sub.3-8 cycloalkyl; [0092] (vii) R.sub.7 is H, C.sub.1-6alkyl
(e.g., methyl or ethyl), halogen (e.g., Cl),
--N(R.sub.18)(R.sub.19), hydroxy or C.sub.1-6alkoxy; [0093] (viii)
n=0 or 1; [0094] (ix) when n=1, A is --C(R.sub.13R.sub.14)--,
wherein R.sub.13 and R.sub.14, are, independently, H or
C.sub.1-4alkyl, aryl, heteroaryl, (optionally
hetero)arylC.sub.1-4alkoxy, (optionally hetero)arylC.sub.1-4alkyl
or R.sub.14 can form a bridge with R.sub.2 or R.sub.4; [0095] (x)
R.sub.15 is C.sub.1-4alkyl, haloC.sub.1-4alkyl, --OH or
--OC.sub.1-4alkyl (e.g., --OCH.sub.3) [0096] (xi) R.sub.16 and
R.sub.17 are independently H or C.sub.1-4alkyl; [0097] (xii)
R.sub.18 and R.sub.19 are independently [0098] H, [0099]
C.sub.1-4alky (e.g., methyl, ethyl, n-propyl, isobutyl), [0100]
C.sub.3-8cycloalky (e.g., cyclohexyl or cyclopenyl), [0101]
heteroC.sub.3cycloalky (e.g., pyrrolidinyl, piperidinyl,
morpholinyl), [0102] aryl (e.g., phenyl) or [0103] heteroaryl
(e.g., pyridyl), [0104] wherein said aryl and heteroaryl are
optionally substituted with one or more [0105] halo (e.g.,
fluorophenyl, e.g., 4-fluorophenyl), [0106] hydroxy (e.g.,
hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl), [0107]
C.sub.1-4alkyl (e.g., methyl), [0108] haloC.sub.1-4alkyl (e.g.,
trifluoromethyl), [0109] C.sub.1-4carboxy, or [0110] an additional
aryl, heteroaryl (e.g., biphenyl or pyridylphenyl) or
C.sub.3-8cycloalkyl, [0111] (xiii) R.sub.20 is H, C.sub.1-4alkyl or
C.sub.3-7cycloalkyl; in free or salt form.
[0112] In another embodiment, the PDE1 inhibitors for use in the
methods of treatment and prophylaxis described herein are Compound
of Formula I, e.g. Formula I-A and I-B:
##STR00003##
wherein [0113] (i) Q is C(.dbd.O), C(.dbd.S), C(.dbd.N(R.sub.20))
or CH.sub.2; [0114] (ii) L is a single bond, --N(H)--,
--CH.sub.2--, --S--, --S(O)-- or S(O.sub.2)--; [0115] (iii) R.sub.1
is H or C.sub.1-4 alkyl (e.g., methyl); [0116] (iv) R.sub.4 is H or
C.sub.1-6 alkyl (e.g., methyl or isopropyl) and R.sub.2 and R.sub.3
are, independently, [0117] H or C.sub.1-6alkyl (e.g., methyl,
isopropyl) optionally substituted with halo or hydroxy (e.g.,
R.sub.2 and R.sub.3 are both methyl, or R.sub.2 is H and R.sub.3 is
methyl, ethyl, isopropyl or hydroxyethyl), [0118] aryl, [0119]
heteroaryl, [0120] (optionally hetero)arylalkoxy, or [0121]
(optionally hetero)arylC.sub.1-6alkyl; [0122] or [0123] R.sub.2 is
H and R.sub.3 and R.sub.4 together form a di-, tri- or
tetramethylene bridge (pref. wherein the R.sub.3 and R.sub.4
together have the cis configuration, e.g., where the carbons
carrying R.sub.3 and R.sub.4 have the R and S configurations,
respectively); [0124] (v) R.sub.5 is [0125] a) -D-E-F, wherein:
[0126] D is C.sub.1-4alkylene (e.g., methylene, ethylene or
prop-2-yn-1-ylene); [0127] E is a single bond, C.sub.2-4alkynylene
(e.g., --C.ident.C--), arylene (e.g., phenylene) or heteroarylene
(e.g., pyridylene); [0128] F is [0129] H, [0130] aryl (e.g.,
phenyl), [0131] heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for
example, pyrid-2-yl, imidazol-1-yl, 1,2,4-triazol-1-yl), [0132]
halo (e.g., F, Br, Cl), [0133] haloC.sub.1-4alkyl (e.g.,
trifluoromethyl), [0134] --C(O)--R.sub.15, [0135]
--N(R.sub.16)(R.sub.17), or [0136] C.sub.3-7cycloalkyl optionally
containing at least one atom selected from a group consisting of N
or O (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,
pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl); [0137]
wherein D, E and F are independently and optionally substituted
with one or more halo (e.g., F, Cl or Br), C.sub.1-4alkyl (e.g.,
methyl), haloC.sub.1-4alkyl (e.g., trifluoromethyl), for example, F
is heteroaryl, e.g., pyridyl substituted with one or more halo
(e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC.sub.1-4alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or
C.sub.1-4alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g.,
phenyl, substituted with one or more halo (e.g., 4-fluorophenyl) or
F is a C.sub.3-7 heterocycloalkyl (e.g., pyrrolidinyl) optionally
substituted with a C.sub.1-6alkyl (e.g., 1-methylpyrrolidin-3-yl);
or [0138] b) a substituted heteroarylalkyl, e.g., substituted with
haloalkyl; [0139] c) attached to the nitrogen on the pyrrolo
portion of Formula I-A or I-B and is a moiety of Formula A
[0139] ##STR00004## [0140] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F), and R.sub.10 is [0141] halogen,
[0142] C.sub.1-4alkyl, [0143] C.sub.3-7cycloalkyl, [0144]
C.sub.1-4haloalkyl (e.g., trifluoromethyl), [0145] aryl (e.g.,
phenyl), [0146] heteroaryl (e.g., pyridyl (for example pyrid-2-yl),
or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl,
triazolyl, tetrazolyl, [0147] arylcarbonyl (e.g., benzoyl), [0148]
alkylsulfonyl (e.g., methylsulfonyl), [0149] heteroarylcarbonyl, or
[0150] alkoxycarbonyl; [0151] provided that when X, Y, or Z is
nitrogen, R.sub.8, R.sub.9, or R.sub.10, respectively, is not
present; [0152] (vi) R.sub.6 is [0153] H, [0154] C.sub.1-4alkyl,
[0155] C.sub.3-7cycloalkyl (e.g., cyclopentyl), [0156] aryl (e.g.,
phenyl), [0157] heteroaryl (e.g., pyrid-4-yl), [0158]
arylC.sub.1-4alkyl (e.g., benzyl), [0159] arylamino (e.g.,
phenylamino), [0160] heteroarylamino, [0161]
N,N-diC.sub.1-4alkylamino, [0162] N,N-diarylamino, [0163]
N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or [0164]
--N(R.sub.18)(R.sub.19); [0165] wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl), hydroxy
or C.sub.1-6alkoxy; [0166] (vii) R.sub.7 is H, C.sub.1-6alkyl,
halogen (e.g., Cl), --N(R.sub.18)(R.sub.19); [0167] (viii) n=0 or
1; [0168] (ix) when n=1, A is --C(R.sub.13R.sub.14)--, wherein
R.sub.13 and R.sub.14, are, independently, H or C.sub.1-4alkyl,
aryl, heteroaryl, (optionally hetero)arylC.sub.1-4alkoxy or
(optionally hetero)arylC.sub.1-4alkyl; [0169] (x) R.sub.15 is
C.sub.1-4alkyl, haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl
(e.g., --OCH.sub.3) [0170] (xi) R.sub.16 and R.sub.17 are
independently H or C.sub.1-4alkyl; [0171] (xii) R.sub.18 and
R.sub.19 are independently H, C.sub.1-4alky or aryl (e.g., phenyl)
wherein said aryl is optionally substituted with one or more halo
(e.g., fluorophenyl, e.g., 4-fluorophenyl) or hydroxy (e.g.,
hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) [0172]
(xiii) R.sub.20 is H, C.sub.1-4alkyl or C.sub.3-7cycloalkyl; in
free or salt form. [0173] 1.1 any of the preceding formulae wherein
the compounds inhibit phosphodiesterase-mediated (e.g.,
PDE1-mediated, especially PDE1B-mediated) hydrolysis of cGMP, e.g.,
with an IC.sub.50 of less than 1 .mu.M, preferably less than 750
nM, more preferably less than 500 nM, more preferably less than 50
nM in an immobilized-metal affinity particle reagent PDE assay,
[0174] in free or salt form.
[0175] The invention further provides optionally substituted
4,5,7,8-tetrahydro-(optionally 4-thioxo or 4-imino)-(1H or
2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or
4,5,7,8,9-pentahydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, in free or
salt form, e.g., (1 or 2 and/or 3 and/or 5)-substituted
4,5,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,
4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrazol o[4,3-e]pyrimidine,
4,5,7,8-tetrahydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,
7,8-dihydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione
or
7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione
compounds, e.g., a Compound of Formula III:
##STR00005##
wherein [0176] (xiv) Q is C(.dbd.S), C(.dbd.N(R.sub.20)) or
CH.sub.2; [0177] (xv) L is a single bond, --N(H)--, --CH.sub.2--;
[0178] (xvi) R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl or
ethyl); [0179] (xvii) R.sub.4 is H or C.sub.1-6 alkyl (e.g.,
methyl, isopropyl) and R.sub.2 and R.sub.3 are, independently:
[0180] H or C.sub.1-6alkyl (e.g., methyl or isopropyl) optionally
substituted with halo or hydroxy (e.g., R.sub.2 and R.sub.3 are
both methyl, or R.sub.2 is H and R.sub.3 is methyl, ethyl,
isopropyl or hydroxyethyl), [0181] aryl, [0182] heteroaryl, [0183]
(optionally hetero)arylalkoxy, [0184] (optionally
hetero)arylC.sub.1-6alkyl, or [0185] R.sub.2 and R.sub.3 together
form a 3- to 6-membered ring; [0186] or [0187] R.sub.2 is H and
R.sub.3 and R.sub.4 together form a di-, tri- or tetramethylene
bridge (pref. wherein the R.sub.3 and R.sub.4 together have the cis
configuration, e.g., where the carbons carrying R.sub.3 and R.sub.4
have the R and S configurations, respectively); [0188] (xviii)
R.sub.5 is [0189] d) -D-E-F, wherein: [0190] D is C.sub.1-4alkylene
(e.g., methylene, ethylene or prop-2-yn-1-ylene); [0191] E is a
single bond, C.sub.2-4alkynylene (e.g., --C.ident.C--), arylene
(e.g., phenylene) or heteroarylene (e.g., pyridylene); [0192] F is
[0193] H, [0194] aryl (e.g., phenyl), [0195] heteroaryl (e.g.,
pyridyl, diazolyl, triazolyl, for example, pyrid-2-yl,
imidazol-1-yl, 1,2,4-triazol-1-yl), [0196] halo (e.g., F, Br, Cl),
[0197] haloC.sub.1-4alkyl (e.g., trifluoromethyl), [0198]
--C(O)--R.sub.15, [0199] --N(R.sub.16)(R.sub.17), [0200]
--S(O).sub.2R.sub.21 or [0201] C.sub.3-7cycloalkyl optionally
containing at least one atom selected from a group consisting of N
or O (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,
pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl); [0202]
wherein D, E and F are independently and optionally substituted
with one or more: [0203] halo (e.g., F, Cl or Br), [0204]
C.sub.1-4alkyl (e.g., methyl), [0205] haloC.sub.1-4alkyl (e.g.,
trifluoromethyl), [0206] C.sub.1-4alkoxy) or [0207] C.sub.1-4alkyl
(e.g., 5-methylpyrid-2-yl), [0208] for example, F is heteroaryl,
e.g., pyridyl substituted with one or more halo (e.g.,
6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
[0209] or F is aryl, e.g., phenyl, substituted with one or more
halo (e.g., 4-fluorophenyl) [0210] or F is a
C.sub.3-7heterocycloalkyl (e.g., pyrrolidinyl) optionally
substituted with a C.sub.1 6alkyl (e.g., 1-methylpyrrolidin-3-yl);
[0211] or [0212] e) a substituted heteroarylalkyl, e.g.,
substituted with haloalkyl; [0213] f) attached to one of the
nitrogens on the pyrazolo portion of Formula III and is a moiety of
Formula A
[0213] ##STR00006## [0214] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F), and R.sub.10 is: [0215] halogen,
[0216] C.sub.1-4alkyl, [0217] C.sub.3-7cycloalkyl, [0218]
hetC.sub.3-7cycloalkyl (e.g., pyrrolidinyl or piperidinyl), [0219]
C.sub.1-4haloalkyl (e.g., trifluoromethyl), [0220] aryl (e.g.,
phenyl), [0221] heteroaryl (e.g., pyridyl (for example pyrid-2-yl),
or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl,
triazolyl, tetrazolyl, [0222] arylcarbonyl (e.g., benzoyl), [0223]
alkylsulfonyl (e.g., methylsulfonyl), [0224] heteroarylcarbonyl, or
[0225] alkoxycarbonyl; [0226] wherein the aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is independently and optionally
substituted with one or more halo (e.g., F or Cl), C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4haloalkyl (e.g., trifluoromethyl), --SH;
[0227] preferably R.sub.10 is phenyl, pyridyl, piperidinyl or
pyrrolidinyl optionally substituted with the substituents
previously defined, e.g. optionally substituted with halo or alkyl
[0228] provided that when X, Y, or Z is nitrogen, R.sub.8, R.sub.9,
or R.sub.10, respectively, is not present; [0229] (xix) R.sub.6 is
[0230] H, [0231] C.sub.1-4alkyl, [0232] C.sub.3-7cycloalkyl (e.g.,
cyclopentyl), [0233] aryl (e.g., phenyl), [0234] heteroaryl (e.g.,
pyridyl, for example, pyrid-4-yl), [0235] arylC.sub.1-4alkyl (e.g.,
benzyl), [0236] arylamino (e.g., phenylamino), [0237]
heterarylamino, [0238] N,N-diC.sub.1-4alkylamino, [0239]
N,N-diarylamino, [0240] N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or [0241]
--N(R.sub.18)(R.sub.19); [0242] wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl),
hydroxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3 scycloalkyl, for
example, R.sub.6 is 4-hydroxyphenyl or 4-fluorophenyl, [0243] (xx)
n=0 or 1; [0244] (xxi) when n=1, A is --C(R.sub.13R.sub.14)--,
wherein R.sub.13 and R.sub.14, are, independently, H or
C.sub.1-4alkyl, aryl, heteroaryl, (optionally
hetero)arylC.sub.1-4alkoxy, (optionally hetero)arylC.sub.1-4alkyl
or R.sub.13 or R.sub.14 can form a bridge with R.sub.2 or R.sub.4;
[0245] (xxii) R.sub.15 is C.sub.1-4alkyl, haloC.sub.1-4alkyl, --OH
or --OC.sub.1-4alkyl (e.g., --OCH.sub.3) [0246] (xxiii) R.sub.16
and R.sub.17 are independently H or C.sub.1-4alkyl; [0247] (xxiv)
R.sub.18 and R.sub.19 are independently [0248] H, [0249]
C.sub.1-4alky, [0250] C.sub.3-8cycloalkyl, [0251]
heteroC.sub.3-8cycloalkyl, [0252] aryl (e.g., phenyl), or [0253]
heteroaryl, [0254] wherein said aryl or heteroaryl is optionally
substituted with one or more [0255] halo (e.g., fluorophenyl, e.g.,
4-fluorophenyl), [0256] hydroxy (e.g., hydroxyphenyl, e.g.,
4-hydroxyphenyl or 2-hydroxyphenyl), [0257] C.sub.1-6alkyl, [0258]
haloC.sub.1-6alkyl, [0259] C.sub.1-6alkoxy, [0260] aryl, [0261]
heteroaryl, or [0262] C.sub.3-8cycloalkyl; [0263] (xxv) R.sub.20 is
H, C.sub.1-4alkyl (e.g., methyl) or C.sub.3-7cycloalkyl, [0264]
(xxvi) R.sub.21 is C.sub.1-6alkyl; in free or salt form.
[0265] In yet another embodiment, the invention also provides a
Compound of Formula IV:
##STR00007##
wherein [0266] (i) Q is C(.dbd.S), C(.dbd.N(R.sub.20)) or CH.sub.2;
[0267] (ii) L is a single bond, --N(H)--, --CH.sub.2--; [0268]
(iii) R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl or ethyl);
[0269] (iv) R.sub.4 is H or C.sub.1-6 alkyl (e.g., methyl,
isopropyl) and R.sub.2 and R.sub.3 are, independently, H or
C.sub.1-6alkyl (e.g., methyl or isopropyl) optionally substituted
with halo or hydroxy (e.g., R.sub.2 and R.sub.3 are both methyl, or
R.sub.2 is H and R.sub.3 is methyl, ethyl, isopropyl or
hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, or
(optionally hetero)arylC.sub.1-6alkyl; or [0270] R.sub.2 is H and
R.sub.3 and R.sub.4 together form a di-, tri- or tetramethylene
bridge (pref. wherein the R.sub.3 and R.sub.4 together have the cis
configuration, e.g., where the carbons carrying R.sub.3 and R.sub.4
have the R and S configurations, respectively); [0271] (v) R.sub.5
is [0272] a) -D-E-F, wherein: [0273] D is C.sub.1-4alkylene (e.g.,
methylene, ethylene or prop-2-yn-1-ylene); [0274] E is a single
bond, C.sub.2-4alkynylene (e.g., --C.ident.C--), arylene (e.g.,
phenylene) or heteroarylene (e.g., pyridylene); [0275] F is H, aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for
example, pyrid-2-yl, imidazol-1-yl, 1,2,4-triazol-1-yl), halo
(e.g., F, Br, Cl), haloC.sub.1-4alkyl (e.g., trifluoromethyl),
--C(O)--R.sub.15, --N(R.sub.16)(R.sub.17), --S(O).sub.2R.sub.21 or
C.sub.3-7cycloalkyl optionally containing at least one atom
selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl),
tetrahydro-2H-pyran-4-yl, or morpholinyl); [0276] wherein D, E and
F are independently and optionally substituted with one or more:
[0277] halo (e.g., F, Cl or Br), [0278] C.sub.1-4alkyl (e.g.,
methyl), [0279] haloC.sub.1-4alkyl (e.g., trifluoromethyl), [0280]
for example, F is heteroaryl, e.g., pyridyl substituted with one or
more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl,
6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,
4,6-dichloropyrid-2-yl), haloC.sub.1-4alkyl (e.g.,
5-trifluoromethylpyrid-2-yl) or C.sub.1-4alkyl (e.g.,
5-methylpyrid-2-yl), [0281] or F is aryl, e.g., phenyl, substituted
with one or more halo (e.g., 4-fluorophenyl) [0282] or F is a
C.sub.3-7heterocycloalkyl (e.g., pyrrolidinyl) optionally
substituted with a C.sub.1-6alkyl (e.g., 1-methylpyrrolidin-3-yl);
or [0283] b) a substituted heteroarylalkyl, e.g., substituted with
haloalkyl; [0284] c) attached to one of the nitrogens on the
pyrazolo portion of Formula IV and is a moiety of Formula A
[0284] ##STR00008## [0285] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F), and R.sub.10 is: [0286] halogen,
[0287] C.sub.1-4alkyl, [0288] C.sub.3-7cycloalkyl, [0289]
C.sub.1-4haloalkyl (e.g., trifluoromethyl), [0290] aryl (e.g.,
phenyl), [0291] heteroaryl (e.g., pyridyl (for example pyrid-2-yl),
or [0292] thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl,
triazolyl, tetrazolyl, [0293] arylcarbonyl (e.g., benzoyl), [0294]
alkylsulfonyl (e.g., methylsulfonyl), [0295] heteroarylcarbonyl, or
[0296] alkoxycarbonyl; [0297] provided that when X, Y, or Z is
nitrogen, R.sub.8, R.sub.9, or R.sub.10, respectively, is not
present; [0298] (vi) R.sub.6 is [0299] H, [0300] C.sub.1-4alkyl,
[0301] C.sub.3-7cycloalkyl (e.g., cyclopentyl), [0302] aryl (e.g.,
phenyl), [0303] heteroaryl (e.g., pyridyl, for example,
pyrid-4-yl), [0304] arylC.sub.1-4alkyl (e.g., benzyl), [0305]
arylamino (e.g., phenylamino), [0306] heterarylamino, [0307]
N,N-diC.sub.1-4alkylamino, [0308] N,N-diarylamino, [0309]
N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or [0310]
--N(R.sub.18)(R.sub.19); [0311] wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl), hydroxy
or C.sub.1-6alkoxy, for example, R.sub.6 is 4-hydroxyphenyl or
4-fluorophenyl, [0312] (vii) n=0 or 1; [0313] (viii) when n=l, A is
--C(R.sub.13R.sub.14)--, wherein R.sub.13 and R.sub.14, are,
independently, H or C.sub.1-4alkyl, aryl, heteroaryl, (optionally
hetero)arylC.sub.1-4alkoxy or (optionally
hetero)arylC.sub.1-4alkyl; [0314] (ix) R.sub.15 is C.sub.1-4alkyl,
haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl (e.g., --OCH.sub.3)
[0315] (x) R.sub.16 and R.sub.17 are independently H or
C.sub.1-4alkyl; [0316] (xi) R.sub.18 and R.sub.19 are independently
H, C.sub.1-4alky or aryl (e.g., phenyl) wherein said aryl is
optionally substituted with one or more halo (e.g., fluorophenyl,
e.g., 4-fluorophenyl) or hydroxy (e.g., hydroxyphenyl, e.g.,
4-hydroxyphenyl or 2-hydroxyphenyl) [0317] (xii) R.sub.20 is H,
C.sub.1-4alkyl (e.g., methyl) or C.sub.3-7cycloalkyl, [0318] (xiii)
R.sub.21 is C.sub.1-6alkyl; in free or salt form.
[0319] In still yet another embodiment, the invention provides that
the PDE1 inhibitors for use in the methods of treatment and
prophylaxis which are described herein are selected from any of the
Applicant's own publications: US 2008-0188492 A1, US 2010-0173878
A1, US 2010-0273754 A1, US 2010-0273753 A1, WO 2010/065153, WO
2010/065151, WO 2010/065151, WO 2010/065149, WO 2010/065147, WO
2010/065152, WO 2011/153129, WO 2011/133224, WO 2011/153135, WO
2011/153136, and WO 2011/153138, the entire contents of each of
which are incorporated herein by reference in their entireties.
[0320] In yet another embodiment the invention provides that the
PDE1 inhibitors for use in the methods of treatment and prophylaxis
described herein are compounds of Formula V:
##STR00009##
wherein [0321] (i) R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl);
[0322] (ii) R.sub.4 is H or C.sub.1-4 alkyl and R.sub.2 and R.sub.3
are, independently, H or C.sub.1-4 alkyl (e.g., R.sub.2 and R.sub.3
are both methyl, or R.sub.2 is H and R.sub.3 is isopropyl), aryl,
heteroaryl, (optionally hetero)arylalkoxy, or (optionally
hetero)arylalkyl; or [0323] R.sub.2 is H and R.sub.3 and R.sub.4
together form a di-, tri- or tetramethylene bridge (pref. wherein
the R.sub.3 and R.sub.4 together have the cis configuration, e.g.,
where the carbons carrying R.sub.3 and R.sub.4 have the R and S
configurations, respectively); [0324] (iii) R.sub.5 is a
substituted heteroarylalkyl, e.g., substituted with haloalkyl or
[0325] R.sub.5 is attached to one of the nitrogens on the pyrazolo
portion of Formula V and is a moiety of Formula A
##STR00010##
[0325] wherein X, Y and Z are, independently, N or C, and R.sub.8,
R.sub.9, R.sub.11 and R.sub.12 are independently H or halogen
(e.g., Cl or F), and R.sub.10 is halogen, alkyl, cycloalkyl,
haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl
(e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g.,
1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl,
arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl),
heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or
Z is nitrogen, R.sub.8, R.sub.9, or R.sub.10, respectively, is not
present; and (iv) R.sub.6 is H, alkyl, aryl, heteroaryl, arylalkyl
(e.g., benzyl), arylamino (e.g., phenylamino), heterarylamino,
N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylakyl)amino
(e.g., N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino); and (v) n=0 or 1;
(vi) when n=1, A is --C(R.sub.13R.sub.14)--
[0326] wherein R.sub.13 and R.sub.14, are, independently, H or
C.sub.1-4 alkyl, aryl, heteroaryl,
[0327] (optionally hetero)arylalkoxy or (optionally
hetero)arylalkyl;
in free, salt or prodrug form, including its enantiomers,
diastereoisomers and racemates.
[0328] In one embodiment the invention provides that the PDE1
inhibitors for use in the methods of treatment and prophylaxis
described herein are compounds of Formula VI:
##STR00011##
wherein: [0329] (i) R.sub.1 is H or alkyl; [0330] (ii) R.sub.2 is
H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl, hydroxyalkyl,
arylalkyl, heteroarylalkyl, or alkoxyarylalkyl; [0331] (iii)
R.sub.3 is heteroarylmethyl or formula A
##STR00012##
[0331] wherein X, Y and Z are, independently, N or C, and R.sub.8,
R.sub.9, R.sub.11 and R.sub.12 are independently H or halogen; and
R.sub.10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl,
heteroaryl, alkyl sulfonyl, arylcarbonyl, heteroarylcarbonyl,
alkoxycarbonyl, or aminocarbonyl; [0332] (iv) R.sub.4 is aryl or
heteroaryl; and [0333] (v) R.sub.5 is H, alkyl, cycloalkyl,
heteroaryl, aryl, p-benzylaryl; provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; wherein "alk" or "alkyl" refers to C.sub.1-6 alkyl and
"cycloalkyl" refers to C.sub.3-6 cycloalkyl, in free, salt or
physiologically hydrolysable and acceptable ester prodrug form.
[0334] In one embodiment the invention provides that the PDE1
inhibitors for use in the methods of treatment and prophylaxis
described herein are compounds of Formula VII:
##STR00013##
(i) X is C.sub.1-6alkylene (e.g., methylene, ethylene or
prop-2-yn-1-ylene); (ii) Y is a single bond, alkynylene (e.g.,
--C.ident.C--), arylene (e.g., phenylene) or heteroarylene (e.g.,
pyridylene); (iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g.,
pyridyl, e.g., pyrid-2-yl), halo (e.g., F, Br, Cl),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), --C(O)--R.sup.1,
N(R.sup.2)(R.sup.3), or C.sub.3-7cycloalkyl optionally containing
at least one atom selected from a group consisting of N or O (e.g.,
cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);
(iv) R.sup.1 is C.sub.1-6alkyl, haloC.sub.1-6alkyl, --OH or
--OC.sub.1-6alkyl (e.g., --OCH.sub.3); (v) R.sup.2 and R.sup.3 are
independently H or C.sub.1-6alkyl; (vi) R.sup.4 and R.sup.5 are
independently H, C.sub.1-6alky or aryl (e.g., phenyl) optionally
substituted with one or more halo (e.g., fluorophenyl, e.g.,
4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g.,
4-hydroxyphenyl or 2-hydroxyphenyl) or C.sub.1-6alkoxy; (vii)
wherein X, Y and Z are independently and optionally substituted
with one or more halo (e.g., F, Cl or Br), C.sub.1-6alkyl (e.g.,
methyl), haloC.sub.1-6alkyl (e.g., trifluoromethyl), for example, Z
is heteroaryl, e.g., pyridyl substituted with one or more halo
(e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,
3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),
haloC.sub.1-6alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or
C.sub.1-6-alkyl (e.g., 5-methylpyrid-2-yl), or Z is aryl, e.g.,
phenyl, substituted with one or more halo (e.g., 4-fluorophenyl),
in free, salt or prodrug form.
[0335] In one embodiment the invention provides that the PDE1
inhibitors for use in the methods of treatment and prophylaxis
described herein are compounds of Formula VIII:
##STR00014##
wherein [0336] (i) R.sub.1 is H or C.sub.1-6alkyl; [0337] (ii)
R.sub.2 is [0338] H, [0339] C.sub.1-6alkyl, [0340]
C.sub.3-8cycloalkyl optionally substituted with one or more amino,
[0341] C.sub.3-8heterocycloalkyl optionally substituted with
C.sub.1-6alkyl, [0342] C.sub.3-8cycloalkyl-C.sub.1-6alkyl, [0343]
C.sub.1-6haloalkyl, [0344] C.sub.1-6alkylaminoC.sub.1-6alkyl,
[0345] hydroxyC.sub.1-6alkyl, [0346] arylC.sub.1-6alkyl, [0347]
heteroarylalkyl, [0348] C.sub.1-6alkoxyarylC.sub.1-6alkyl, or
[0349] -G-J wherein: [0350] G is a single bond or, alkylene; [0351]
J is cycloalkyl or heterocycloalkyl optionally substituted with
alkyl; [0352] (iii) R.sub.3 is [0353] a) -D-E-F wherein [0354] 1. D
is single bond, C.sub.1-6alkylene or arylC.sub.1-6alkylene; [0355]
2. E is a C.sub.1-6alkylene, arylene, C.sub.1-6alkylarylene,
aminoC.sub.1-6alkylene- or amino; and [0356] 3. F is
heteroC.sub.3-8cycloalkyl optionally substituted with
C.sub.1-6alkyl; [0357] (iv) R.sub.4 is aryl optionally substituted
with one or more halo, hydroxyl or C.sub.1-6 alkoxy; heteroaryl; or
heteroC.sub.3-6cycloalkyl; and [0358] (v) R.sub.5 is H,
C.sub.1-6alkyl, C.sub.3-8cycloalkyl, heteroaryl, aryl or
p-benzylaryl; wherein "alk", "alkyl", "haloalkyl" or "alkoxy"
refers to C.sub.1-6 alkyl and "cycloalkyl" refers to
C.sub.3-8cycloalkyl; in free or salt form.
[0359] In one embodiment the invention provides that the PDE1
inhibitors for use in the methods of treatment and prophylaxis
described herein are compounds of Formula IX:
##STR00015##
wherein [0360] (i) Q is --C(.dbd.S)--, --C(.dbd.N(R.sub.6))-- or
--C(R.sub.14)(R.sub.15)--; [0361] (ii) R.sub.1 is H or
C.sub.1-6alkyl (e.g., methyl or ethyl); [0362] (iii) R.sub.2 is
[0363] H, [0364] C.sub.1-6alkyl (e.g., isopropyl, isobutyl,
2-methylbutyl or 2,2-dimethylpropyl) wherein said alkyl group is
optionally substituted with one or more halo (e.g., fluoro) or
hydroxy (e.g., hydroxyC.sub.1-6alkyl, for example
1-hydroxyprop-2-yl or 3-hydroxy-2-methylpropyl), [0365]
haloC.sub.1-6alkyl (e.g., trifluoromethyl or 2,2,2-trifluoroethyl),
[0366] N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g.,
2-(dimethylamino)ethyl or 2-aminopropyl), [0367] arylC.sub.0-6alkyl
(e.g., phenyl or benzyl), wherein said aryl is optionally
substituted with one or more C.sub.1-6alkoxy, for example,
C.sub.1-6alkoxyarylC.sub.0-6alkyl (e.g., 4-methoxybenzyl), [0368]
heteroarylC.sub.0-6alkyl (e.g., pyridinylmethyl), wherein said
heteroaryl is optionally substituted with one or more
C.sub.1-6alkoxy (e.g., C.sub.1-6alkoxyheteroarylC.sub.1-6alkyl);
[0369] -G-J wherein G is a single bond or C.sub.1-6alkylene (e.g.,
methylene) and J is C.sub.3scycloalkyl or heteroC.sub.3scycloalkyl
(e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl) wherein the
cycloalkyl and heterocycloalkyl group are optionally substituted
with one or more C.sub.1-6alkyl or amino, for example, [0370]
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g.,
--C.sub.1-4alkyl-cyclopentyl, --C.sub.0-4 alkyl-cyclohexyl or
--C.sub.0-4alkyl-cyclopropyl), wherein said cycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl or amino
(for example, 2-aminocyclopentyl or 2-aminocyclohexyl), [0371]
--C.sub.0-4alkyl-C.sub.3-8heterocycloalkyl (e.g.,
--C.sub.1-4alkyl-pyrrolidinyl, for example,
--C.sub.0-4alkylpyrrolidin-3-yl) wherein said heterocycloalkyl is
optionally substituted with C.sub.1-6alkyl (e.g., methyl), for
example, 1-methylpyrrolidin-3-yl, 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); [0372] (iv) R.sub.3 is [0373] 1)
-D-E-F wherein: [0374] D is a single bond, C.sub.1-6alkylene (e.g.,
methylene), or arylC.sub.1-6 alkylene (e.g., benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0375] E is [0376] a single bond,
[0377] C.sub.1-4alkylene (e.g., methylene, ethynylene,
prop-2-yn-1-ylene), [0378] C.sub.0-4alkylarylene (e.g., phenylene
or --C.sub.6H.sub.4--, -benzylene- or --CH.sub.2C.sub.6H.sub.4--),
wherein the arylene group is optionally substituted with halo
(e.g., Cl or F), [0379] heteroarylene (e.g., pyridinylene or
pyrimidinylene), [0380] aminoC.sub.1-6alkylene (e.g.,
--CH.sub.2N(H)--), [0381] amino (e.g., --N(H)--); [0382]
C.sub.3-8cycloalkylene optionally containing one or more heteroatom
selected from N or O (e.g., piperidinylene), [0383] F is [0384] H,
[0385] halo (e.g., F, Br, Cl), [0386] C.sub.1-6alkyl (e.g.,
isopropyl or isobutyl), [0387] haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), [0388] aryl (e.g., phenyl), [0389]
C.sub.3-8cycloalkyl optionally containing one or more atom selected
from a group consisting of N, S or O (e.g., cyclopentyl,
cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or
morpholinyl), and optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl or isopropyl), for example,
1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,
piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,
[0390] heteroaryl (e.g., pyridyl (for example, pyrid-2-yl),
pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for
example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for
example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl)), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), wherein said
heteroaryl is optionally substituted with one or more
C.sub.1-6alkyl, halo (e.g., fluoro) or haloC.sub.1-6alkyl; [0391]
C.sub.1-6alkoxy, [0392] --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), [0393] C.sub.1-6alkylsulfonyl (for example,
methylsulfonyl or --S(O).sub.2CH.sub.3), [0394] --C(O)--R.sub.13,
wherein R.sub.13 is --N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g.,
methyl), --OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; [0395]
--N(R.sub.14)(R.sub.15); or [0396] 2) a substituted
heteroarylC.sub.1-6aklyl, e.g., substituted with
haloC.sub.1-6alkyl; or [0397] 3) attached to one of the nitrogens
on the pyrazolo portion of Formula I and is a moiety of Formula
A
[0397] ##STR00016## [0398] wherein: [0399] X, Y and Z are,
independently, N or C, [0400] R.sub.8, R.sub.9, R.sub.11 and
R.sub.12 are independently H or halogen (e.g., C; or F); and [0401]
R.sub.10 is [0402] halogen (e.g., fluoro or chloro), [0403]
C.sub.1-6alkyl, [0404] C.sub.3-8cycloalkyl, [0405]
heteroC.sub.3-8cycloalkyl (e.g., pyrrolidinyl or piperidinyl),
[0406] haloC.sub.1-6alkyl (e.g., trifluoromethyl), [0407] aryl
(e.g., phenyl) or heteroaryl (e.g., pyridyl, (for example,
pyrid-2-yl) or e.g., thiadiazolyl (for example,
1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkyloxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), [0408] wherein said aryl, heteroaryl, cycloalkyl or
heterocycloalkyl is optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), hydroxy, carboxy, --SH,
or an additional aryl or heteroaryl (e.g., biphenyl or
pyridylphenyl), [0409] C.sub.1-6alkyl sulfonyl (e.g., methyl
sulfonyl), [0410] arylcarbonyl (e.g., benzoyl), [0411]
heteroarylcarbonyl, [0412] C.sub.1-6alkoxycarbonyl, (e.g.,
methoxycarbonyl), [0413] Aminocarbonyl, [0414]
--N(R.sub.14)(R.sub.15); [0415] preferably R.sub.10 is phenyl,
pyridyl, piperidinyl or pyrrolidinyl optionally substituted with
the substituents previously defined, e.g. optionally substituted
with halo or alkyl; [0416] provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; [0417] (v) R.sub.4 and R.sub.5 are independently: [0418]
H, [0419] C.sub.1-6alkyl (e.g., methyl, isopropyl, isobutyl,
n-propyl), [0420] C.sub.3-8cycloalkyl (e.g., cyclopentyl or
cyclohexyl), [0421] C.sub.3-8heterocycloalkyl (e.g., pyrrolidinyl
(for example pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for
example, piperidin-1-yl), morpholinyl), [0422] --C.sub.1-6alkylaryl
(e.g., phenyl or benzyl) or [0423] --C.sub.0-6alkylheteroaryl
(e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) [0424] wherein said
aryl or heteroaryl is optionally substituted with one or more halo
(e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl),
C.sub.1-6alkyl, C.sub.1-6alkoxy or another aryl group (e.g.,
biphenyl-4-ylmethyl); [0425] (vi) R.sub.6 is H, C.sub.1-6alkyl
(e.g., methyl or ethyl) or C.sub.3-8cycloalkyl; [0426] (vii)
R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl, in
free or salt form.
[0427] In one embodiment the invention provides that the PDE1
inhibitors for use in the methods of treatment and prophylaxis
described herein are Formula X, e.g.:
##STR00017##
[0428] Formula X-A Formula X-B wherein [0429] (i) Q is
--C(.dbd.S)--, --C(.dbd.O)--, --C(.dbd.N(R.sub.7))-- or
--C(R.sub.14)(R.sub.15)--; [0430] (ii) R.sub.1 is H or
C.sub.1-6alkyl (e.g., methyl or ethyl); [0431] (iii) R.sub.2 is H,
C.sub.1-6alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl,
2,2-dimethylpropyl) wherein said alkyl group is optionally
substituted with halo (e.g., fluoro) or hydroxy (e.g.,
1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), for example,
R.sub.2 may be a trifluoromethyl or 2,2,2-trifluoroethyl,
N(R.sub.14)(R.sub.15)-- C.sub.1-6alkyl (e.g.,
2-(dimethylamino)ethyl or 2-aminopropyl), arylC.sub.1-6alkyl (e.g.,
phenyl or benzyl), heteroaryl C.sub.1-6alkyl (e.g.,
pyridinylmethyl), C.sub.1-6alkoxyaryl-C.sub.1-6alkyl (e.g.,
4-methoxybenzyl); -G-J wherein: [0432] G is a single bond or,
alkylene (e.g., methylene); J is cycloalkyl or heterocycloalkyl
(e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally
substituted with one or more C.sub.1-6alkyl (e.g.,
(1-methylpyrolidin-2-yl)), amino (e.g., --NH.sub.2), for example,
-G-J may be --C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g.,
cyclopentyl, cyclohexyl or cyclopropylmethyl) optionally
substituted with one or more C.sub.1-6 alkyl, amino (e.g.,
--NH.sub.2), for example, 2-aminocyclopentyl or 2-aminocyclohexyl,
wherein said cycloalkyl optionally contains one or more heteroatom
selected from N and O (e.g., pyrrolidinyl, for example,
pyrrolidin-3-yl or pyrrolidin-2-yl, 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); [0433] (iv) R.sub.3 is [0434] 1)
-D-E-F wherein: [0435] D is a single bond, C.sub.1-6alkylene (e.g.,
methylene), or arylalkylene [0436] (e.g., p-benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0437] E is a single bond, [0438]
C.sub.1-6alkylene (e.g., methylene) C.sub.2-6alkynylene (e.g.,
ethynylene, prop-2-yn-1-ylene), ethynylene, prop-2-yn-1-ylene),
--C.sub.0-4alkylarylene (e.g., phenylene or --C.sub.6H.sub.4--,
-benzyle{acute over (.eta.)} - or --CH.sub.2C.sub.6H.sub.4--),
wherein the arylene group is optionally substituted with halo
(e.g., Cl or F), heteroarylene (e.g., pyridinylene or
pyrimidinylene), aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--),
amino (e.g., --N(H)--); [0439] C.sub.3-8cycloalkylene optionally
containing one or more heteroatom selected from N or O (e.g.,
piperidinylene), [0440] F is [0441] H, [0442] halo (e.g., F, Br,
Cl), C.sub.1-6alkyl (e.g., isopropyl or isobutyl),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), [0443] aryl (e.g.,
phenyl), [0444] C.sub.3-8cycloalkyl optionally containing at least
one atom selected from a group consisting of N or O (e.g.,
cyclopentyl, N cyclohexyl, piperidinyl, pyrrolidinyl,
tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl is
optionally substituted with C.sub.1-6alkyl (e.g., methyl or
isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, piperidin-2-yl, 1-methyrpiperidin-2-yl,
1-ethylpiperidin-2-yl, heteroaryl optionally substituted with
C.sub.1-6alkyl, (e.g., pyridyl, (for example, pyrid-2-yl),
pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for
example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for
example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), wherein said [0445] heteroaryl is optionally
substituted with halo (e.g., fluoro) or haloC.sub.1-6alkyl, for
example, 6-fluoropyrid-2-yl; amino (e.g., --NH.sub.2),
C.sub.1-6alkoxy, --O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3),
C.sub.1-6alkylsulfonyl (for example, methylsulfonyl or
--S(O).sub.2CH.sub.3), [0446] --C(O)--R.sub.13, [0447]
--N(R.sub.14)(R.sub.15); or [0448] 2) a substituted
heteroarylaklyl, e.g., substituted with haloalkyl; or [0449] 3)
attached to the nitrogen on the pyrrolo portion of Formula I and is
a moiety of Formula A
[0449] ##STR00018## [0450] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and R.sub.10 is halogen,
C.sub.1-6alkyl, [0451] C.sub.1-6alkoxy (e.g., methoxy),
C.sub.3-8cycloalkyl, heteroC.sub.3-8cycloalkyl (e.g., pyrrolidinyl)
haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g.,
thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g.,
imidazolyl or pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl),
tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g.,
5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl),
C.sub.1-6alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl
(e.g., benzoyl), heteroarylcarbonyl, [0452] alkoxycarbonyl, (e.g.,
methoxycarbonyl), aminocarbonyl; wherein the aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is optionally substituted with one
or more C.sub.1-6alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC.sub.1-6alkyl (e.g., trifluoromethyl), hydroxy,
carboxy, --SH, or an additional aryl or heteroaryl (e.g., biphenyl
or pyridylphenyl) preferably R.sub.10 is phenyl or pyridyl, e.g.,
2-pyridyl optionally substituted with the substituents previously
defined; [0453] provided that when X, Y or X is nitrogen, R.sub.8,
R.sub.9 or R.sub.10, respectively, is not present; (v) R.sub.4 and
R.sub.5 are independently H, C.sub.1-6alkyl (e.g., methyl,
isopropyl), [0454] C.sub.3-8cycloalkyl (e.g., cyclopentyl),
C.sub.3-8heterocycloalkyl (e.g., pyrrolidin-3-yl), aryl (e.g.,
phenyl) or heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or
pyrazol-3-yl) wherein said aryl or heteroaryl is optionally
substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g.,
4-hydroxyphenyl), C.sub.1-6alkyl, C.sub.1-6alkoxy or another aryl
group (e.g., biphenyl-4-ylmethyl); [0455] (vi) R.sub.6 is H,
C.sub.1-6alkyl (e.g., methyl), hydroxy, C.sub.1-6alkoxy, aryloxy,
--N(R.sub.16)(R.sub.17), oxo (e.g., .dbd.O), or
C.sub.3-8Cycloalkyl; [0456] (vii) R.sub.7 is H, C.sub.1-6alkyl
(e.g., methyl) or C.sub.3-8cycloalkyl wherein said cycloalkyl is
optionally substituted with one or more oxo (e.g.,
2,5-dioxopyrrolidin-1-yl); [0457] (viii) R.sub.13 is
--N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and [0458]
(ix) R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl;
[0459] (x) R.sub.16 and R.sub.17 are independently H,
C.sub.1-6alkyl, aryl (e.g., phenyl), heteroaryl, wherein said aryl
or heteroaryl is optionally substituted with halo (e.g., fluoro),
C.sub.1-6alkoxy (e.g., methoxy); in free or salt form.
[0460] In one embodiment the invention provides that the PDE1
inhibitors for use in the methods of treatment and prophylaxis
described herein are Formula XI:
##STR00019##
wherein [0461] (i) L is S, SO or SO.sub.2; [0462] (ii) R.sub.2 is H
or C.sub.1-6alkyl (e.g., methyl or ethyl); [0463] (iii) R.sub.2 is
[0464] H, [0465] C.sub.1-6alkyl (e.g., isopropyl, isobutyl,
neopentyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl
group is optionally substituted with halo (e.g., fluoro) or hydroxy
(e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl),
--C.sub.0-4alkyl-C.sub.3-8 cycloalkyl (e.g., cyclopentyl,
cyclohexyl) optionally substituted with one or more amino (e.g.,
--NH.sub.2), for example, 2-aminocyclopentyl or 2-aminocyclohexyl),
wherein said cycloalkyl optionally contains one or more heteroatom
selected from N and O and is optionally substituted with
C.sub.1-6alkyl (e.g., 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl), C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidinyl, for example, pyrrolidin-3-yl) optionally substituted
with C.sub.1-6alkyl (e.g., methyl), for example,
1-methylpyrrolidin-3-yl, C.sub.3-8cycloalkyl-C.sub.1-6alkyl (e.g.,
cyclopropylmethyl), haloC.sub.1-6alkyl (e.g., trifluoromethyl,
2,2,2-trifluoroethyl), --N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl
(e.g., 2-(dimethylamino)ethyl, 2-aminopropyl),
hydroxyC.sub.1-6alkyl (e.g., (e.g., 3-hydroxy-2-methylpropyl,
1-hydroxyprop-2-yl), arylC.sub.0-6alkyl (e.g., benzyl),
heteroarylC.sub.1-6 alkyl (e.g., pyridinylmethyl),
C.sub.1-6alkoxyarylC.sub.1-6alkyl (e.g., 4-methoxybenzyl); -G-J
wherein: G is a single bond or, alkylene (e.g., methylene); [0466]
J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl,
pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with
C.sub.1-6alkyl (e.g., (1-methylpyrolidin-2-yl)); [0467] (iv)
R.sub.3 is attached to one of the nitrogens on the pyrazolo portion
of Formula I and is a moiety of Formula A
##STR00020##
[0467] wherein X, Y and Z are, independently, N or C, and R.sub.8,
R.sub.9, R.sub.11 and R.sub.12 are independently H or halogen
(e.g., Cl or F); and R.sub.10 is halogen, C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, heteroC.sub.3-8cycloalkyl (e.g., pyrrolidinyl
or piperidinyl) haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl
(e.g., phenyl), heteroaryl (e.g., pyridyl, (for example,
pyrid-2-yl) or e.g., thiadiazolyl (for example,
1,2,3-thiadiazol-4-15 yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl
(e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g.,
methoxycarbonyl), aminocarbonyl; preferably phenyl, pyridyl, e.g.,
2-pyridyl, piperidinyl, or pyrrolidinyl; wherein the aryl,
heteroaryl cycloalkyl or heterocycloalkyl is optionally substituted
with one or more halo (e.g., F or Cl), C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-4 haloalkyl (e.g., trifluoromethyl),
and/or --SH, provided that when X, Y or X is nitrogen, R.sub.8,
R.sub.9 or R.sub.10, respectively, is not present; (v) R.sub.4 is
H, C.sub.1-6alkyl (e.g., methyl, isopropyl), C.sub.3-8cycloalkyl
(e.g., cyclopentyl), C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g.,
pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or
heteroaryl is optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl,
in free or salt form.
[0468] The invention further provides the use of PDE1 inhibitors of
any of the preceding formulae (e.g., Formula I, II, III, IV, V, VI,
VII, VIII, IX, X, XI), wherein the compound is selected from any of
the following:
##STR00021## ##STR00022## ##STR00023##
[0469] In one embodiment, selective PDE1 inhibitors of the any of
the preceding formulae (e.g., Formula I, II, III, IV, V, VI, VII,
VIII, IX, X, XI) are compounds that inhibit
phosphodiesterase-mediated (e.g., PDE1-mediated, especially PDE1A
or PDE1C-mediated) hydrolysis of cGMP, e.g., the preferred
compounds have an IC.sub.50 of less than 1 .mu.M, preferably less
than 500 nM, preferably less than 50 nM, and preferably less than 5
nM in an immobilized-metal affinity particle reagent PDE assay, in
free or salt form.
[0470] If not otherwise specified or clear from context, the
following terms herein have the following meanings: [0471] (a)
"Alkyl" as used herein is a saturated or unsaturated hydrocarbon
moiety, preferably saturated, preferably having one to six carbon
atoms, which may be linear or branched, and may be optionally
mono-, di- or tri-substituted, e.g., with halogen (e.g., chloro or
fluoro), hydroxy, or carboxy. [0472] (b) "Cycloalkyl" as used
herein is a saturated or unsaturated nonaromatic hydrocarbon
moiety, preferably saturated, preferably comprising three to nine
carbon atoms, at least some of which form a nonaromatic mono- or
bicyclic, or bridged cyclic structure, and which may be optionally
substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy,
or carboxy. Wherein the cycloalkyl optionally contains one or more
atoms selected from N and O and/or S, said cycloalkyl may also be a
heterocycloalkyl. [0473] (c) "Heterocycloalkyl" is, unless
otherwise indicated, saturated or unsaturated nonaromatic
hydrocarbon moiety, preferably saturated, preferably comprising
three to nine carbon atoms, at least some of which form a
nonaromatic mono- or bicyclic, or bridged cyclic structure, wherein
at least one carbon atom is replaced with N, O or S, which
heterocycloalkyl may be optionally substituted, e.g., with halogen
(e.g., chloro or fluoro), hydroxy, or carboxy. [0474] (d) "Aryl" as
used herein is a mono or bicyclic aromatic hydrocarbon, preferably
phenyl, optionally substituted, e.g., with alkyl (e.g., methyl),
halogen (e.g., chloro or fluoro), haloalkyl (e.g.,
trifluoromethyl), hydroxy, carboxy, or an additional aryl or
heteroaryl (e.g., biphenyl or pyridylphenyl). [0475] (e)
"Heteroaryl" as used herein is an aromatic moiety wherein one or
more of the atoms making up the aromatic ring is sulfur or nitrogen
rather than carbon, e.g., pyridyl or thiadiazolyl, which may be
optionally substituted, e.g., with alkyl, halogen, haloalkyl,
hydroxy or carboxy. [0476] (f) For ease of reference, the atoms on
the pyrazolo-pyrimidine core of the Compounds of the Invention are
numbered in accordance with the numbering depicted in Formula I,
unless otherwise noted. [0477] (g) Wherein E is phenylene, the
numbering is as follows:
[0477] ##STR00024## [0478] (h) It is intended that wherein the
substituents end in "ene", for example, alkylene, phenylene or
arylalkylene, said substitutents are intended to bridge or be
connected to two other substituents. Therefore, methylene is
intended to be --CH.sub.2-- and phenylene intended to be
--C.sub.6H.sub.4-- and arylalkylene is intended to be
--C.sub.6H.sub.4--CH.sub.2-- or --CH.sub.2--C.sub.6H.sub.4--.
[0479] (i) The Compounds of the Invention are intended to be
numbered as follows:
##STR00025##
[0480] Compounds of the Invention, e.g., substituted
4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or
4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine,
e.g., Compounds of Formula I (Formula I-A and I-B), or a Compound
of Formula II (e.g., II-A or II-B), may exist in free or salt form,
e.g., as acid addition salts. In this specification unless
otherwise indicated, language such as "Compounds of the Invention"
is to be understood as embracing the compounds in any form, for
example free or acid addition salt form, or where the compounds
contain acidic substituents, in base addition salt form. The
Compounds of the Invention are intended for use as pharmaceuticals,
therefore pharmaceutically acceptable salts are preferred. Salts
which are unsuitable for pharmaceutical uses may be useful, for
example, for the isolation or purification of free Compounds of the
Invention or their pharmaceutically acceptable salts, are therefore
also included.
[0481] Compounds of the Invention, encompassing any of the
compounds disclosed herein, e.g., optionally substituted
4,5,7,8-tetrahydro-(optionally 4-thioxo or 4-imino)-(1H or
2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or
4,5,7,8,9-pentahydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, e.g., (1 or
2 and/or 3 and/or 5)-substituted
4,5,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,
4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,
4,5,7,8-tetrahydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,
7,8-dihydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione
or
7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione
compounds, e.g., Compounds of Formula III, or Compound of Formula
IV as described herein, may exist in free or salt form, e.g., as
acid addition salts.
[0482] Compounds of the Invention may in some cases also exist in
prodrug form. A prodrug form is compound which converts in the body
to a Compound of the Invention. For example when the Compounds of
the Invention contain hydroxy or carboxy substituents, these
substituents may form physiologically hydrolysable and acceptable
esters. As used herein, "physiologically hydrolysable and
acceptable ester" means esters of Compounds of the Invention which
are hydrolysable under physiological conditions to yield acids (in
the case of Compounds of the Invention which have hydroxy
substituents) or alcohols (in the case of Compounds of the
Invention which have carboxy substituents) which are themselves
physiologically tolerable at doses to be administered. Therefore,
wherein the Compound of the Invention contains a hydroxy group, for
example, Compound-OH, the acyl ester prodrug of such compound,
i.e., Compound-O--C(O)--C.sub.1-4alkyl, can hydrolyze in the body
to form physiologically hydrolysable alcohol (Compound-OH) on the
one hand and acid on the other (e.g., HOC(O)--C.sub.1-4alkyl).
Alternatively, wherein the Compound of the Invention contains a
carboxylic acid, for example, Compound-C(O)OH, the acid ester
prodrug of such compound, Compound-C(O)O--C.sub.1-4alkyl can
hydrolyze to form Compound-C(O)OH and HO--C.sub.1-4alkyl. As will
be appreciated the term thus embraces conventional pharmaceutical
prodrug forms.
[0483] In another embodiment, the invention further provides a
pharmaceutical composition comprising a Compound of the Invention,
in free or pharmaceutically acceptable salt form, in admixture with
a pharmaceutically acceptable carrier.
[0484] Compounds of the Invention may in some cases also exist in
prodrug form. A prodrug form is compound which converts in the body
to a Compound of the Invention. For example when the Compounds of
the Invention contain hydroxy or carboxy substituents, these
substituents may form physiologically hydrolysable and acceptable
esters. As used herein, "physiologically hydrolysable and
acceptable ester" means esters of Compounds of the Invention which
are hydrolysable under physiological conditions to yield acids (in
the case of Compounds of the Invention which have hydroxy
substituents) or alcohols (in the case of Compounds of the
Invention which have carboxy substituents) which are themselves
physiologically tolerable at doses to be administered. Therefore,
wherein the Compound of the Invention contains a hydroxy group, for
example, Compound-OH, the acyl ester prodrug of such compound,
i.e., Compound-O--C(O)--C.sub.1-4 alkyl, can hydrolyze in the body
to form physiologically hydrolysable alcohol (Compound-OH) on the
one hand and acid on the other (e.g., HOC(O)--C.sub.1-4alkyl).
Alternatively, wherein the Compound of the Invention contains a
carboxylic acid, for example, Compound-C(O)OH, the acid ester
prodrug of such compound, Compound-C(O)O--C.sub.1-4alkyl can
hydrolyze to form Compound-C(O)OH and HO--C.sub.1-4alkyl. As will
be appreciated the term thus embraces conventional pharmaceutical
prodrug forms.
[0485] In another embodiment, the invention further provides a
pharmaceutical composition comprising a Compound of the Invention,
in free, pharmaceutically acceptable salt or prodrug form, in
admixture with a pharmaceutically acceptable carrier.
Methods of Making Compounds of the Invention
[0486] The compounds of the Invention and their pharmaceutically
acceptable salts may be made using the methods as described and
exemplified herein and by methods similar thereto and by methods
known in the chemical art. Such methods include, but not limited
to, those described below. If not commercially available, starting
materials for these processes may be made by procedures, which are
selected from the chemical art using techniques which are similar
or analogous to the synthesis of known compounds.
[0487] Various starting materials and/or Compounds of the Invention
may be prepared using methods described in US 2008-0188492 A1, US
2010-0173878 A1, US 2010-0273754 A1, US 2010-0273753 A1, WO
2010/065153, WO 2010/065151, WO 2010/065151, WO 2010/065149, WO
2010/065147, WO 2010/065152, WO 2011/153129, WO 2011/133224, WO
2011/153135, WO 2011/153136, WO 2011/153138. All references cited
herein are hereby incorporated by reference in their entirety.
[0488] The Compounds of the Invention include their enantiomers,
diastereoisomers and racemates, as well as their polymorphs,
hydrates, solvates and complexes. Some individual compounds within
the scope of this invention may contain double bonds.
[0489] Representations of double bonds in this invention are meant
to include both the E and the Z isomer of the double bond. In
addition, some compounds within the scope of this invention may
contain one or more asymmetric centers. This invention includes the
use of any of the optically pure stereoisomers as well as any
combination of stereoisomers.
[0490] It is also intended that the Compounds of the Invention
encompass their stable and unstable isotopes. Stable isotopes are
nonradioactive isotopes which contain one additional neutron
compared to the abundant nuclides of the same species (i.e.,
element). It is expected that the activity of compounds comprising
such isotopes would be retained, and such compound would also have
utility for measuring pharmacokinetics of the non-isotopic analogs.
For example, the hydrogen atom at a certain position on the
Compounds of the Invention may be replaced with deuterium (a stable
isotope which is non-radioactive). Examples of known stable
isotopes include, but not limited to, deuterium, .sup.13C,
.sup.15N, .sup.18O. Alternatively, unstable isotopes, which are
radioactive isotopes which contain additional neutrons compared to
the abundant nuclides of the same species (i.e., element), e.g.,
.sup.123I, .sup.131I, .sup.125I, .sup.11C, .sup.18F, may replace
the corresponding abundant species of I, C and F. Another example
of useful isotope of the compound of the invention is the .sup.11C
isotope. These radio isotopes are useful for radio-imaging and/or
pharmacokinetic studies of the compounds of the invention.
[0491] Melting points are uncorrected and (dec) indicates
decomposition. Temperature are given in degrees Celsius (.degree.
C.); unless otherwise stated, operations are carried out at room or
ambient temperature, that is, at a temperature in the range of
18-25.degree. C. Chromatography means flash chromatography on
silica gel; thin layer chromatography (TLC) is carried out on
silica gel plates. NMR data is in the delta values of major
diagnostic protons, given in parts per million (ppm) relative to
tetramethylsilane (TMS) as an internal standard. Conventional
abbreviations for signal shape are used. Coupling constants (J) are
given in Hz. For mass spectra (MS), the lowest mass major ion is
reported for molecules where isotope splitting results in multiple
mass spectral peaks Solvent mixture compositions are given as
volume percentages or volume ratios. In cases where the NMR spectra
are complex, only diagnostic signals are reported.
[0492] Terms and Abbreviations: [0493] BuLi=n-butyllithium [0494]
Bu.sup.tOH=tert-butyl alcohol, [0495] CAN=ammonium cerium (IV)
nitrate, [0496] DIPEA=diisopropylethylamine, [0497]
DMF=N,N-dimethylforamide, [0498] DMSO=dimethyl sulfoxide, [0499]
Et.sub.2O=diethyl ether, [0500] EtOAc=ethyl acetate, [0501]
equiv.=equivalent(s), [0502] h=hour(s), [0503] HPLC=high
performance liquid chromatography, [0504] LDA=lithium
diisopropylamide [0505] MeOH=methanol, [0506]
NBS=N-bromosuccinimide [0507] NCS=N-chlorosuccinimide [0508]
NaHCO.sub.3=sodium bicarbonate, [0509] NH.sub.4OH=ammonium
hydroxide, [0510]
Pd.sub.2(dba).sub.3=tris[dibenzylideneacetone]dipalladium(0) [0511]
PMB=p-methoxybenzyl, [0512] POCl.sub.3=phosphorous oxychloride,
[0513] SOCl.sub.2=thionyl chloride, [0514] TFA=trifluoroacetic
acid, [0515] TFMSA=trifluoromethanesulfonic acid [0516]
THF=tetrahedrofuran.
[0517] Methods of Using Compounds of the Invention
[0518] The Compounds of the Invention are useful in the treatment
of diseases characterized by disruption of or damage to cGMP/PKG
mediated pathways, e.g., as a result of increased expression of
PDE1 or decreased expression of cGMP/PKG activity due to inhibition
or reduced levels of inducers of cyclic nucleotide synthesis, such
as dopamine and nitric oxide (NO). It is believed that by
inhibiting PDE1A, for example, that this action could reverse or
prevent the attenuation of cGMP/PKG signaling (e.g., enhance cGMP)
and that this action could modulate cardiac hypertrophy. Therefore,
administration or use of a preferred PDE1 inhibitor as described
herein, e.g., a PDE1 inhibitor as hereinbefore described, e.g., a
Compound of Formula Ia, Ib, IIa, IIb, III, IV, V, VI, VII, VIII,
IX, X, XI, could provide a potential means to regulate cardiac
hypertrophy (e.g., prevent and/or reverse cardiac hypertrophy), and
in certain embodiments provide a treatment for various
cardiovascular diseases and disorders.
[0519] A selective PDE1 inhibitor of the present invention, (e.g.,
of Formula Ia, Ib, IIa, IIb, III, IV, V, VI, VII, VIII, IX, X, XI),
exhibit good oral availability in plasma with very minimal brain
penetration in mice. Preferably, the half-life of the compounds is
less than 2 hours. Preferably the Tmax is less than 1 hour. The
blood/plasma ratio in mice administered the selective PDE1
inhibitor of the present invention is preferably less than
0.20.
[0520] Diseases and disorders that may be prevented or ameliorated
by the enhancement of cGMP/PKG signaling (e.g., cardiovascular
disease), e.g., using a Compound of Formula Ia, Ib, IIa, IIb, III,
IV, V, VI, VII, VIII, IX, X, XI, include, but are not limited to:
angina, stroke, renal failure, essential hypertension, pulmonary
hypertension, secondary hypertension, isolated systolic
hypertension, hypertension associated with diabetes, hypertension
associated with atherosclerosis, renovascular hypertension,
congestive heart failure, myocardial, angina, stroke and renal
failure, hypertension, an inflammatory disease or disorder,
fibrosis, cardiac hypertrophy, vascular remodeling, and an
connective tissue disease or disorder (e.g., Marfan Syndrome).
[0521] In one embodiment the compounds of the invention as
described herein (e.g., a Compound of Formula Ia, Ib, IIa, IIb,
III, IV, V, VI, VII, VIII, IX, X, XI) are useful in the treatment
or prevention of stroke by treating or preventing transient
ischemic attacks (TIA). Without being bound by any theory, it is
believed that the compounds may prevent or treat the risk of
transient ischemic attacks by actually increasing the amount and/or
concentration of blood flow to the brain. It is contemplated that
the compounds as described herein could increase the blood flow to
the brain without significant passage across the blood brain
barrier.
[0522] In another embodiment, the invention further provides using
the compounds of the invention (e.g., a Compound of Formula Ia, Ib,
IIa, IIb, III, IV, V, VI, VII, VIII, IX, X, XI) for treatment of
disease and disorders as follows: Duchenne muscular dystrophy,
Becker muscular dystrophy, limb-girdle muscular dystrophy, myotonic
dystrophy, and Emery-Dreifuss muscular dystrophy. In one
embodiment, the compounds of the present invention are useful in
treating cardiac dysfunction associated with aforementioned types
of muscular dystrophy. In one embodiment the compounds as described
herein may potentially reduce or reverse the cardiac hypertrophy
that may be associated with these aforementioned types of muscular
dystrophy.
[0523] "PDE1 inhibitor" as used herein describes a compound(s)
which selectively inhibit phosphodiesterase-mediated (e.g.,
PDE1-mediated, especially PDE1B-mediated) hydrolysis of cGMP, e.g.,
with an IC.sub.50 of less than 1 .mu.M, preferably less than 750
nM, more preferably less than 500 nM, more preferably less than 50
nM in an immobilized-metal affinity particle reagent PDE assay.
[0524] The phrase "Compounds of the Invention" or "PDE 1 inhibitors
of the Invention", or like terms, encompasses any and all of the
compounds disclosed herewith, e.g., a Compound of Formula I,
Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula
VII, Formula VIII, Formula IX, Formula X, or Formula XI.
[0525] The words "treatment" and "treating" are to be understood
accordingly as embracing prophylaxis and treatment or amelioration
of symptoms of disease as well as treatment of the cause of the
disease.
[0526] For methods of treatment, the word "effective amount" is
intended to encompass a therapeutically effective amount to treat a
specific disease or disorder.
[0527] The term "pulmonary hypertension" is intended to encompass
pulmonary arterial hypertension.
[0528] The term "patient" include human or non-human (i.e., animal)
patient. In particular embodiment, the invention encompasses both
human and nonhuman. In another embodiment, the invention
encompasses nonhuman. In other embodiment, the term encompasses
human.
[0529] The term "comprising" as used in this disclosure is intended
to be open-ended and does not exclude additional, unrecited
elements or method steps.
[0530] Compounds of the Invention, e.g., Formula I, II, III, IV, V,
VI, VII, VIII, IX, X, and XI as hereinbefore described, in free or
pharmaceutically acceptable salt form, may be used as a sole
therapeutic agent, but may also be used in combination or for
co-administration with other active agents.
[0531] Dosages employed in practicing the present invention will of
course vary depending, e.g. on the particular disease or condition
to be treated, the particular Compound of the Invention used, the
mode of administration, and the therapy desired. Compounds of the
Invention may be administered by any suitable route, including
orally, parenterally, transdermally, or by inhalation, but are
preferably administered orally. In general, satisfactory results,
e.g. for the treatment of diseases as hereinbefore set forth are
indicated to be obtained on oral administration at dosages of the
order from about 0.01 to 2.0 mg/kg. In larger mammals, for example
humans, an indicated daily dosage for oral administration will
accordingly be in the range of from about 0.75 to 150 mg,
conveniently administered once, or in divided doses 2 to 4 times,
daily or in sustained release form. Unit dosage forms for oral
administration thus for example may comprise from about 0.2 to 75
or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a
Compound of the Invention, together with a pharmaceutically
acceptable diluent or carrier therefor.
[0532] Pharmaceutical compositions comprising Compounds of the
Invention may be prepared using conventional diluents or excipients
and techniques known in the galenic art. Thus oral dosage forms may
include tablets, capsules, solutions, suspensions and the like.
EXAMPLES
Example 1
Measurement of PDEIB Inhibition In Vitro Using IMAP
Phosphodiesterase Assay Kit
[0533] Phosphodiesterase I B (PDEIB) is a calcium/calmodulin
dependent phosphodiesterase enzyme that converts cyclic guanosine
monophosphate (cGMP) to 5'-guanosine monophosphate (5'-GMP). PDEIB
can also convert a modified cGMP substrate, such as the fluorescent
molecule cGMP-fluorescein, to the corresponding GMP-fluorescein.
The generation of GMP-fluorescein from cGMP-fluorescein can be
quantitated, using, for example, the IMAP (Molecular Devices,
Sunnyvale, Calif.) immobilized-metal affinity particle reagent.
[0534] Briefly, the IMAP reagent binds with high affinity to the
free 5'-phosphate that is found in GMP-fluorescein and not in
cGMP-fluorescein. The resulting GMP-fluorescein--IMAP complex is
large relative to cGMP-fluorescein. Small fluorophores that are
bound up in a large, slowly tumbling, complex can be distinguished
from unbound fluorophores, because the photons emitted as they
fluoresce retain the same polarity as the photons used to excite
the fluorescence.
[0535] In the phosphodiesterase assay, cGMP-fluorescein, which
cannot be bound to IMAP, and therefore retains little fluorescence
polarization, is converted to GMP-fluorescein, which, when bound to
IMAP, yields a large increase in fluorescence polarization (Amp).
Inhibition of phosphodiesterase, therefore, is detected as a
decrease in Amp.
Enzyme Assay
[0536] Materials: All chemicals are available from Sigma-Aldrich
(St. Louis, Mo.) except for IMAP reagents (reaction buffer, binding
buffer, FL-GMP and IMAP beads), which are available from Molecular
Devices (Sunnyvale, Calif.).
Assay: The following phosphodiesterase enzymes may be used:
3',5'-cyclic-nucleotide-specific bovine brain phosphodiesterase
(Sigma, St. Louis, Mo.) (predominantly PDEIB) and recombinant full
length human PDE1 A and PDE1B (r-hPDE1 A and r-hPDE1B respectively)
which may be produced e.g., in HEK or SF9 cells by one skilled in
the art. The PDE1 enzyme is reconstituted with 50% glycerol to 2.5
U/ml. One unit of enzyme will hydrolyze 1.0 m of 3',5'-cAMP to
5'-AMP per min at pH 7.5 at 30.degree. C. One part enzyme is added
to 1999 parts reaction buffer (30 .mu.M CaCl.sub.2, 10 U/ml of
calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM MgCl.sub.2,
0.1% BSA, 0.05% NaN.sub.3) to yield a final concentration of 1.25
mU/ml. 99 i of diluted enzyme solution is added into each well in a
flat bottom 96-well polystyrene plate to which 1 .mu.l of test
compound dissolved in 100% DMSO is added. The compounds are mixed
and pre-incubated with the enzyme for 10 min at room temperature.
[0084] The FL-GMP conversion reaction is initiated by combining 4
parts enzyme and inhibitor mix with 1 part substrate solution
(0.225 .mu.M) in a 384-well microtiter plate. The reaction is
incubated in dark at room temperature for 15 min. The reaction is
halted by addition of 60 .mu.l of binding reagent (1:400 dilution
of IMAP beads in binding buffer supplemented with 1:1800 dilution
of antifoam) to each well of the 384-well plate. The plate is
incubated at room temperature for 1 hour to allow IMAP binding to
proceed to completion, and then placed in an Envision multimode
microplate reader (PerkinElmer, Shelton, Conn.) to measure the
fluorescence polarization (Amp).
[0537] A decrease in GMP concentration, measured as decreased Amp,
is indicative of inhibition of PDE activity. IC50 values are
determined by measuring enzyme activity in the presence of 8 to 16
concentrations of compound ranging from 0.0037 nM to 80,000 nM and
then plotting drug concentration versus AmP, which allows IC50
values to be estimated using nonlinear regression software (XLFit;
IDBS, Cambridge, Mass.).
[0538] The Compounds of the Invention are tested in an assay as
described or similarly described herein for PDE1 inhibitory
activity.
Example 2
Inhibition of Cardiac Hypertrophy
[0539] A selective PDE1 inhibitor of the present invention is
tested in a mouse model where the mice are treated with
isoproterenol. Such a model can be useful for extrapolating to
diseases or disorders involving an enlargement of the heart or
cardiac tissue, e.g., congestive heart disease.
[0540] Isoproterenol treatment in mice increases cardiac size in
mice untreated with a selective PDE1 inhibitor of the present
invention. Size is indicated by heart weight (g)/tibia length (mm).
At 3 mg/kg, administration of the selective PDE1 inhibitor of the
present invention significantly decreases cardiac hypertrophy in
mice which are treated with isoproterenol. A selective PDE1
inhibitor of the present Invention also significantly prevent
cardiac hypertrophy at administration of 10 mg/kg.
Example 3
Cellular Screening Systems
Primary Human Cardiomyocytes
[0541] Primary human cardiomyocytes have a unique signaling system
involving a synergy of calcium and cAMP to achieve proper force of
contraction. cGMP is an important moderator of cell function that
prevents hypertrophic responses that are the mark of Heart Disease,
and PDE1C is abundant in these cells.
[0542] A selective PDE1 inhibitor of the present invention elevates
cGMP in Human Cardiomyocytes in Culture. When measured in
conjunction with Sildenafil, the selective PDE1 inhibitor is about
100-fold more potent than Sildenafil in enhancing cGMP. Such
potency would have various application in various cardiovascular
applications.
Primary Human Smooth Muscle Cells
[0543] Primary human smooth muscle cells contain PDE1C as well as
PDE3, 4 and. Consequently, primary human smooth muscle cell may be
important mediators of the pathology in Heart Disease.
[0544] Atrial natriuretic peptide (ANP) is a peptide which binds
the natriuretic peptide receptor-A (NPRA) and which may trigger
activation of its guanylyl cyclase domain increasing cGMP
production. Following a 30-minute pretreatment with a selective
PDE1 inhibitor of the present invention there is an increase in ANP
response in vascular aortic smooth muscle (VASM) Cells.
Neutrophils
[0545] During heart disease progression, part of the inflammatory
component of Heart Disease PDE1B may be up-regulated during the
process of differentiation from Neutrophils to Macrophages.
[0546] Immortalized Human Neutrophil Line (HL60 Cells) are used to
study the Macrophage differentiation (inflammatory) process. In
HL60 macrophages, at about 100 nM, a selective PDE1 inhibitor of
the present invention amplifies the effect of Atrial Natriuretic
Peptide (ANF), wherein cGMP production increases as compared to
cells where a selective PDE1 inhibitor is not used in combination
with ANF.
Example 4
Mdx Mouse Model
[0547] The mdx mouse model is used to understand muscle
degeneration and regeneration in Duchenne Muscular Dystrophy.
[0548] The dystrophic mdx mouse has a point mutation within its
dystrophin gene. This mutation has changed a codon representing
glutamine amino acid to one representing thymine amino acid. This
single amino acid change causes the cell's machinery to stop; when
this happens, the synthesis of dystrophin stops prematurely (known
as premature stop codon). As a result, the mouse has no functional
dystrophin in its muscles.
[0549] In conjunction with chronic dosing, a selective PDE1
inhibitor of the present invention demonstrates a cardio-protective
effect in an mdx Mouse Model of diastolic heart failure.
* * * * *