U.S. patent application number 14/020016 was filed with the patent office on 2014-01-02 for organic compounds.
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 Peng LI, Lawrence P. WENNOGLE, Jun ZHAO, Hailin ZHENG.
Application Number | 20140005155 14/020016 |
Document ID | / |
Family ID | 42233533 |
Filed Date | 2014-01-02 |
United States Patent
Application |
20140005155 |
Kind Code |
A1 |
LI; Peng ; et al. |
January 2, 2014 |
ORGANIC COMPOUNDS
Abstract
Optionally substituted 3-(thio, sulfinyl or
sulfonyl)-7,8-dihydro-(1H or
2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one or a
substituted 3-(thio, sulfinyl or sulfonyl)-7,8,9-trihydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one compounds or
Compounds of Formula (I), processes for their production, their use
as pharmaceuticals and pharmaceutical compositions comprising
them.
Inventors: |
LI; Peng; (New York, NY)
; ZHAO; Jun; (New York, NY) ; ZHENG; Hailin;
(New York, NY) ; WENNOGLE; Lawrence P.; (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
|
Family ID: |
42233533 |
Appl. No.: |
14/020016 |
Filed: |
September 6, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13133033 |
Jun 6, 2011 |
8536159 |
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PCT/US2009/006439 |
Dec 7, 2009 |
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14020016 |
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61120442 |
Dec 6, 2008 |
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Current U.S.
Class: |
514/171 ;
514/257; 544/247 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 35/00 20180101; A61P 11/02 20180101; A61P 37/08 20180101; A61K
31/529 20130101; A61P 9/00 20180101; A61P 25/20 20180101; A61K
45/06 20130101; A61P 25/18 20180101; A61P 27/02 20180101; C07D
487/04 20130101; A61K 31/5575 20130101; A61P 25/24 20180101; A61P
11/00 20180101; A61P 25/30 20180101; A61P 25/28 20180101; A61P
37/06 20180101; A61P 29/00 20180101; C07D 487/14 20130101; A61K
31/519 20130101; A61P 9/12 20180101; A61P 15/00 20180101; A61P
19/10 20180101; A61P 25/00 20180101; A61P 25/14 20180101; A61P
25/22 20180101; A61P 27/06 20180101; A61P 11/06 20180101; A61K
31/5025 20130101; A61P 13/08 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/171 ;
544/247; 514/257 |
International
Class: |
C07D 487/14 20060101
C07D487/14; A61K 45/06 20060101 A61K045/06; A61K 31/5025 20060101
A61K031/5025 |
Claims
1. An optionally substituted 3-(thio, sulfinyl or
sulfonyl)-7,8-dihydro-(1H or
2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones or or a
substituted 3-(thio, sulfinyl or sulfonyl)-7,8,9-trihydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one, in free or
salt form.
2. The compound according to claim 1, wherein said compound is a
Compound of Formula II ##STR00039## wherein (i) L is S, SO or
SO.sub.2; (ii) R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl or
ethyl); (iii) 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); (iv) 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.1-4
alkyl (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 e) a substituted heteroarylalkyl, e.g., substituted with
haloalkyl; f) attached to one of the nitrogens on the pyrazolo
portion of Formula I and is a moiety of Formula A ##STR00040##
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, 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 thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl,
triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl
(e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl,
wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is
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), and/or --SH, provided that when X, Y, or Z is
nitrogen, R.sub.8, R.sub.9, or R.sub.10, respectively, is not
present; (v) R.sub.6 is H, C.sub.1-4alkyl (e.g., methyl),
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 (e.g., methoxy), for example, R.sub.6 is
4-hydroxyphenyl or 4-fluorophenyl, (vi) n=0 or 1; (vii) 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
or R.sub.13 or R.sub.14 can form a bridge with R.sub.2 or R.sub.4;
(viii) R.sub.15 is C.sub.1-4alkyl, haloC.sub.1-4alkyl, --OH or
--OC.sub.1-4alkyl (e.g., --OCH.sub.3) (ix) R.sub.16 and R.sub.17
are independently H or C.sub.1-4alkyl; (x) 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, (xi) R.sub.20 is H,
C.sub.1-4alkyl (e.g., methyl) or C.sub.3-7cycloalkyl, (xii)
R.sub.21 is C.sub.1-6alkyl; in free, salt or prodrug form.
3. The compound according to claim 1, wherein said compound is a
Compound of Formula I ##STR00041## wherein (i) L is a single bond,
S, SO or SO.sub.2; (ii) R.sub.1 is H or C.sub.1-4 alkyl (e.g.,
methyl or ethyl); (iii) 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); (iv) 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), --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.1-4alkyl (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 one of the nitrogens on the pyrazolo
portion of Formula I and is a moiety of Formula A ##STR00042##
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; (v) 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 (e.g., methoxy), for example, R.sub.6 is
4-hydroxyphenyl or 4-fluorophenyl, (vi) n=0 or 1; (vii) 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; (viii) R.sub.15 is C.sub.1-4alkyl,
haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl (e.g., --OCH.sub.3)
(ix) R.sub.16 and R.sub.17 are independently H or C.sub.1-4alkyl;
(x) 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) (xi) R.sub.20 is H, C.sub.1-4alkyl (e.g., methyl)
or C.sub.3-7cycloalkyl, (xii) R.sub.21 is C.sub.1-6alkyl.
4. The compound according to claim 1, 2 or 3, selected from any of
the following: ##STR00043## ##STR00044## ##STR00045## ##STR00046##
in free or salt form.
5. The compound according to claim 1, 2 or 3, selected from any of
the following: ##STR00047## ##STR00048## in free or salt form.
6. A pharmaceutical composition comprising a compound according to
any of claims 1-5, in admixture with a pharmaceutically acceptable
diluent or carrier.
7. A method of treating any of the following conditions:
Parkinson's disease, restless leg, tremors, dyskinesias,
Huntington's disease, Alzheimer's disease, and drug-induced
movement disorders; depression, attention deficit disorder,
attention deficit hyperactivity disorder, bipolar illness, anxiety,
sleep disorder, narcolepsy, cognitive impairment, dementia,
Tourette's syndrome, autism, fragile X syndrome, psychostimulant
withdrawal, and/or drug addiction; cerebrovascular disease, stroke,
congestive heart disease, hypertension, pulmonary hypertension,
and/or sexual dysfunction; asthma, chronic obstructive pulmonary
disease, and/or allergic rhinitis, as well as autoimmune and
inflammatory diseases; and/or female sexual dysfunction, exercise
amenorrhoea, anovulation, menopause, menopausal symptoms,
hypothyroidism, pre-menstrual syndrome, premature labor,
infertility, irregular menstrual cycles, abnormal uterine bleeding,
osteoporosis, multiple sclerosis, prostate enlargement, prostate
cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or
carcinoma; and/or any disease or condition characterized by low
levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP
signaling pathways) in cells expressing PDE1, and/or by reduced
dopamine D1 receptor signaling activity; and/or any disease or
condition that may be ameliorated by the enhancement of
progesterone signaling; comprising administering an effective
amount of a compound according to any of claims 1-5, or a
pharmaceutical composition according to claim 6, to a patient in
need of such treatment.
8. The method of claim 7, wherein the condition is Parkinson's
disease.
9. The method of claim 7, wherein the condition is cognitive
impairment.
10. The method of claim 7, wherein the condition is narcolepsy.
11. The method of claim 10 further comprising administering a
compound or compounds selected from central nervous system
stimulants, modafinil, antidepressants, and gamma hydroxybutyrate,
to a patient in need thereof.
12. The method of claim 7, wherein said condition is female sexual
dysfunction.
13. The method of claim 12, further comprising administering a
compound or compounds selected from a group consisting of
estradiol, estriol, estradiol esters, progesterone and progestins
to a patient in need thereof.
14. A method for the treatment of treatment for glaucoma or
elevated intraocular pressure comprising topical administration of
a therapeutically effective amount of a compound according to any
of claims 1-5, in free or pharmaceutically acceptable salt form, in
an opthalmically compatible carrier to the eye of a patient in need
thereof.
15. A method for the treatment of psychosis, schizophrenia,
schizoaffective disorder, schizophreniform disorder, psychotic
disorder, delusional disorder, and mania, such as in acute manic
episodes and bipolar disorder, comprising administering a
therapeutically effective amount of a compound according to any of
claims 1-5, in free or pharmaceutically acceptable salt form, to a
patient in need thereof.
16. A method for the treatment of traumatic brain injury comprising
admistering to a patient in need thereof, a compound according to
any of claims 1-5, in free or pharmaceutically acceptable salt
form.
17. A method for lengthening or enhancing growth of the eyelashes
by administering an effective amount of a prostaglandin analogue,
e.g., bimatoprost, concomitantly, simultaneously or sequentially
with an effective amount of a compound according to any of claims
1-5, in free or salt form.
18. Use of the Compound according to any of claims 1-5, in free or
pharmaceutically acceptable salt form, or a pharmaceutical
composition according to claim 6 for the manufacture of a
medicament for the treatment or prophylactic treatment of the
following diseases: Parkinson's disease, restless leg, tremors,
dyskinesias, Huntington's disease, Alzheimer's disease, and
drug-induced movement disorders; depression, attention deficit
disorder, attention deficit hyperactivity disorder, bipolar
illness, anxiety, sleep disorder, narcolepsy, cognitive impairment,
dementia, Tourette's syndrome, autism, fragile X syndrome,
psychostimulant withdrawal, and/or drug addiction; cerebrovascular
disease, stroke, congestive heart disease, hypertension, pulmonary
hypertension, and/or sexual dysfunction; asthma, chronic
obstructive pulmonary disease, and/or allergic rhinitis, as well as
autoimmune and inflammatory diseases; and/or female sexual
dysfunction, exercise amenorrhoea, anovulation, menopause,
menopausal symptoms, hypothyroidism, pre-menstrual syndrome,
premature labor, infertility, irregular menstrual cycles, abnormal
uterine bleeding, osteoporosis, multiple sclerosis, prostate
enlargement, prostate cancer, hypothyroidism, estrogen-induced
endometrial hyperplasia or carcinoma; and/or any disease or
condition characterized by low levels of cAMP and/or cGMP (or
inhibition of cAMP and/or cGMP signaling pathways) in cells
expressing PDE1, and/or by reduced dopamine D1 receptor signaling
activity; and/or any disease or condition that may be ameliorated
by the enhancement of progesterone signaling.
19. Use of the Compound according to any of claims 1-5, in free or
pharmaceutically acceptable salt form, or a pharmaceutical
composition according to claim 6 for the manufacture of a
medicament for the treatment or prophylactic treatment of a disease
or condition selected from: glaucoma or elevated intraocular
pressure; psychosis, schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder,
and mania, such as in acute manic episodes and bipolar disorder;
traumatic brain injury.
20. A pharmaceutical comprising a Compound according to any of
claims 1-5, in free or pharmaceutically acceptable salt form, in
combination or association with a pharmaceutically acceptable
diluent or carrier for use in the treatment of any disease or
condition selected from: Parkinson's disease, restless leg,
tremors, dyskinesias, Huntington's disease, Alzheimer's disease,
and drug-induced movement disorders; depression, attention deficit
disorder, attention deficit hyperactivity disorder, bipolar
illness, anxiety, sleep disorder, narcolepsy, cognitive impairment,
dementia, Tourette's syndrome, autism, fragile X syndrome,
psychostimulant withdrawal, and/or drug addiction; cerebrovascular
disease, stroke, congestive heart disease, hypertension, pulmonary
hypertension, and/or sexual dysfunction; asthma, chronic
obstructive pulmonary disease, and/or allergic rhinitis, as well as
autoimmune and inflammatory diseases; and/or female sexual
dysfunction, exercise amenorrhoea, anovulation, menopause,
menopausal symptoms, hypothyroidism, pre-menstrual syndrome,
premature labor, infertility, irregular menstrual cycles, abnormal
uterine bleeding, osteoporosis, multiple sclerosis, prostate
enlargement, prostate cancer, hypothyroidism, estrogen-induced
endometrial hyperplasia or carcinoma; and/or any disease or
condition characterized by low levels of cAMP and/or cGMP (or
inhibition of cAMP and/or cGMP signaling pathways) in cells
expressing PDE1, and/or by reduced dopamine D1 receptor signaling
activity; and/or any disease or condition that may be ameliorated
by the enhancement of progesterone signaling; glaucoma or elevated
intraocular pressure; psychosis, schizophrenia, schizoaffective
disorder, schizophreniform disorder, psychotic disorder, delusional
disorder, and mania, such as in acute manic episodes and bipolar
disorder; and traumatic brain injury.
Description
[0001] This application claims priority from U.S. Provisional
Application No. 61/120,442, filed Dec. 6, 2008, the contents of
which are hereby incorporated by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to optionally substituted
3-(thio, sulfinyl or sulfonyl)-7,8-dihydro-(1H or
2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one or a
substituted 3-(thio, sulfinyl or sulfonyl)-7,8,9-trihydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one compounds,
e.g., compounds of Formula I as described below, processes for
their production, their use as pharmaceuticals and pharmaceutical
compositions comprising them. Of particular interest are novel
compounds useful as inhibitors of phosphodiesterase 1 (PDE1), e.g.,
in the treatment of diseases involving disorders of the dopamine D1
receptor intracellular pathway, such as Parkinson's disease,
depression, narcolepsy, damage to cognitive function, e.g., in
schizophrenia, or disorders that may be ameliorated through
enhanced progesterone-signaling pathway, e.g., female sexual
dysfunction.
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), have
been shown to mediate both 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 gyms, olfactory tract and cerebellum, and
its expression correlates with brain regions having high levels of
dopaminergic innervation. Although PDE1B is primarily expressed in
the central nervous system, it may be detected in the heart. PDE1C
is primarily expressed in olfactory epithelium, cerebellar granule
cells, and striatum. PDE1C is also expressed in the heart and
vascular smooth muscle.
[0004] Cyclic nucleotide phosphodiesterases decrease intracellular
cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to
their respective inactive 5'-monophosphates (5'AMP and 5'GMP).
CaM-PDEs play a critical role in mediating signal transduction in
brain cells, particularly within an area of the brain known as the
basal ganglia or striatum. For example, NMDA-type glutamate
receptor activation and/or dopamine D2 receptor activation result
in increased intracellular calcium concentrations, leading to
activation of effectors such as calmodulin-dependent kinase II
(CaMKII) and calcineurin and to activation of CaM-PDEs, resulting
in reduced cAMP and cGMP. Dopamine D1 receptor activation, on the
other hand, leads to activation of nucleotide cyclases, resulting
in increased cAMP and cGMP. These cyclic nucleotides in turn
activate protein kinase A (PKA; cAMP-dependent protein kinase)
and/or protein kinase G (PKG; cGMP-dependent protein kinase) that
phosphorylate downstream signal transduction pathway elements such
as DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP
responsive element binding protein (CREB). Phosphorylated DARPP-32
in turn inhibits the activity of protein phosphates-1 (PP-1),
thereby increasing the state of phosphorylation of substrate
proteins such as progesterone receptor (PR), leading to induction
of physiologic responses. Studies in rodents have suggested that
inducing cAMP and cGMP synthesis through activation of dopamine D1
or progesterone receptor enhances progesterone signaling associated
with various physiological responses, including the lordosis
response associated with receptivity to mating in some rodents. See
Mani, et al., Science (2000) 287: 1053, the contents of which are
incorporated herein by reference.
[0005] CaM-PDEs can therefore affect dopamine-regulated and other
intracellular signaling pathways in the basal ganglia (striatum),
including but not limited to nitric oxide, noradrenergic,
neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor,
AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A
receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP,
BNP, CNP), DARPP-32, and endorphin intracellular signaling
pathways.
[0006] Phosphodiesterase (PDE) activity, in particular,
phosphodiesterase 1 (PDE1) activity, functions in brain tissue as a
regulator of locomotor activity and learning and memory. PDE1 is a
therapeutic target for regulation of intracellular signaling
pathways, preferably in the nervous system, including but not
limited to a dopamine D1 receptor, dopamine D2 receptor, nitric
oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate
(e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine,
adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic
peptide (e.g., ANP, BNP, CNP), endorphin intracellular signaling
pathway and progesterone signaling pathway. For example, inhibition
of PDE1B should act to potentiate the effect of a dopamine D1
agonist by protecting cGMP and cAMP from degradation, and should
similarly inhibit dopamine D2 receptor signaling pathways, by
inhibiting PDE1 activity. Chronic elevation in intracellular
calcium levels is linked to cell death in numerous disorders,
particularly in neurodegerative diseases such as Alzheimer's,
Parkinson's and Huntington's Diseases and in disorders of the
circulatory system leading to stroke and myocardial infarction.
PDE1 inhibitors are therefore potentially useful in diseases
characterized by reduced dopamine D1 receptor signaling activity,
such as Parkinson's disease, restless leg syndrome, depression,
narcolepsy and cognitive impairment. PDE1 inhibitors are also
useful in diseases that may be alleviated by the enhancement of
progesterone-signaling such as female sexual dysfunction.
[0007] There is thus a need for compounds that selectively inhibit
PDE1 activity, especially PDE1A or PDE1B activity.
SUMMARY OF THE INVENTION
[0008] The invention provides optionally substituted 3-(thio,
sulfinyl or sulfonyl)-7,8-dihydro-(1H or
2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones or a
substituted 3-(thio, sulfinyl or sulfonyl)-7,8,9-trihydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one, e.g., (1 or
2 and/or 5)-substituted, e.g., a Compound of Formula II:
##STR00001##
wherein [0009] (i) L is S, SO or SO.sub.2; [0010] (ii) R.sub.1 is H
or C.sub.1-4 alkyl (e.g., methyl or ethyl); [0011] (iii) 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; [0012] or [0013] 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); [0014] (iv) R.sub.5
is [0015] a) -D-E-F, wherein: [0016] D is C.sub.1-4alkylene (e.g.,
methylene, ethylene or prop-2-yn-1-ylene); [0017] E is a single
bond, C.sub.2-4alkynylene (e.g., --C.ident.C--), arylene (e.g.,
phenylene) or heteroarylene (e.g., pyridylene); [0018] F is [0019]
H, [0020] aryl (e.g., phenyl), [0021] heteroaryl (e.g., pyridyl,
diazolyl, triazolyl, for example, pyrid-2-yl, imidazol-1-yl,
1,2,4-triazol-1-yl), [0022] halo (e.g., F, Br, Cl), [0023]
haloC.sub.1-4alkyl (e.g., trifluoromethyl), [0024]
--C(O)--R.sub.15, [0025] --N(R.sub.16)(R.sub.17), [0026]
--S(O).sub.2R.sub.21 or [0027] 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); [0028]
wherein D, E and F are independently and optionally substituted
with one or more [0029] halo (e.g., F, Cl or Br), [0030]
C.sub.1-4alkyl (e.g., methyl), [0031] haloC.sub.1-4alkyl (e.g.,
trifluoromethyl), [0032] 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 [0033] b) a substituted heteroarylalkyl, e.g., substituted with
haloalkyl; [0034] c) attached to one of the nitrogens on the
pyrazolo portion of Formula I and is a moiety of Formula A
[0034] ##STR00002## [0035] 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 [0036] halogen,
[0037] C.sub.3-7cycloalkyl, [0038] heteroC.sub.3-7cycloalkyl (e.g.
pyrrolidinyl or piperidinyl), [0039] C.sub.1-4haloalkyl (e.g.,
trifluoromethyl), [0040] aryl (e.g., phenyl), [0041] heteroaryl
(e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g.,
1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, [0042]
arylcarbonyl (e.g., benzoyl), [0043] alkylsulfonyl (e.g.,
methylsulfonyl), [0044] heteroarylcarbonyl, or [0045]
alkoxycarbonyl, [0046] wherein said aryl, heteroaryl, cycloalkyl or
heterocycloalkyl is 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), and/or --SH, [0047]
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; [0048] provided
that when X, Y, or Z is nitrogen, R.sub.8, R.sub.9, or R.sub.10,
respectively, is not present; [0049] (v) R.sub.6 is [0050] H,
[0051] C.sub.1-4alkyl (e.g., methyl), [0052] C.sub.3-7cycloalkyl
(e.g., cyclopentyl), [0053] aryl (e.g., phenyl), [0054] heteroaryl
(e.g., pyridyl, for example, pyrid-4-yl), [0055] arylC.sub.1-4alkyl
(e.g., benzyl), [0056] arylamino (e.g., phenylamino), [0057]
heterarylamino, [0058] N,N-diC.sub.1-4alkylamino, [0059]
N,N-diarylamino, [0060] N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or [0061]
--N(R.sub.18)(R.sub.19); [0062] wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl), hydroxy
or C.sub.1-6alkoxy (e.g., methoxy), for example, R.sub.6 is
4-hydroxyphenyl or 4-fluorophenyl, [0063] (vi) n=0 or 1; [0064]
(vii) 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 or R.sub.13 or R.sub.14 can form a bridge
with R.sub.2 or R.sub.4; [0065] (viii) R.sub.15 is C.sub.1-4alkyl,
haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl (e.g., --OCH.sub.3)
[0066] (ix) R.sub.16 and R.sub.17 are independently H or
C.sub.1-4alkyl; [0067] (x) 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, [0068] (xi) R.sub.20 is H, C.sub.1-4alkyl
(e.g., methyl) or C.sub.3-7cycloalkyl, [0069] (xii) R.sub.21 is
C.sub.1-6alkyl; in free or form.
[0070] In another embodiment, the invention provides a Compound of
Formula I:
##STR00003##
wherein [0071] (i) L is S, SO or SO.sub.2; [0072] (ii) R.sub.1 is H
or C.sub.1-4 alkyl (e.g., methyl or ethyl); [0073] (iii) 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; [0074] or [0075] 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); [0076] (iv) R.sub.5
is [0077] a) -D-E-F, wherein: [0078] D is C.sub.1-4alkylene (e.g.,
methylene, ethylene or prop-2-yn-1-ylene); [0079] E is a single
bond, C.sub.2-4alkynylene (e.g., --C.ident.C--), arylene (e.g.,
phenylene) or heteroarylene (e.g., pyridylene); [0080] F is [0081]
H, [0082] aryl (e.g., phenyl), [0083] heteroaryl (e.g., pyridyl,
diazolyl, triazolyl, for example, pyrid-2-yl, imidazol-1-yl,
1,2,4-triazol-1-yl), [0084] halo (e.g., F, Br, Cl), [0085]
haloC.sub.1-4alkyl (e.g., trifluoromethyl), [0086]
--C(O)--R.sub.15, [0087] --N(R.sub.16)(R.sub.17), [0088]
--S(O).sub.2R.sub.21 or [0089] 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); [0090]
wherein D, E and F are independently and optionally substituted
with one or more [0091] halo (e.g., F, Cl or Br), [0092]
C.sub.1-4alkyl (e.g., methyl), [0093] haloC.sub.1-4alkyl (e.g.,
trifluoromethyl), [0094] 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 [0095] b) a substituted heteroarylalkyl, e.g., substituted with
haloalkyl; [0096] c) attached to one of the nitrogens on the
pyrazolo portion of Formula I and is a moiety of Formula A
[0096] ##STR00004## [0097] 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; [0098] (v) R.sub.6 is [0099] H, [0100] C.sub.1-4alkyl
(e.g., methyl), [0101] C.sub.3-7cycloalkyl (e.g., cyclopentyl),
[0102] aryl (e.g., phenyl), [0103] heteroaryl (e.g., pyridyl, for
example, pyrid-4-yl), [0104] arylC.sub.1-4alkyl (e.g., benzyl),
[0105] arylamino (e.g., phenylamino), [0106] heterarylamino, [0107]
N,N-diC.sub.1-4alkylamino, [0108] N,N-diarylamino, [0109]
N-aryl-N-(arylC.sub.1-4alkyl)amino (e.g.,
N-phenyl-N-(1,1'-biphen-4-ylmethyl)amino), or [0110]
--N(R.sub.18)(R.sub.19); [0111] wherein the aryl or heteroaryl is
optionally substituted with one or more halo (e.g., F, Cl), hydroxy
or C.sub.1-6alkoxy (e.g., methoxy), for example, R.sub.6 is
4-hydroxyphenyl or 4-fluorophenyl, [0112] (vi) n=0 or 1; [0113]
(vii) 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; [0114] (viii) R.sub.15 is
C.sub.1-4alkyl, haloC.sub.1-4alkyl, --OH or --OC.sub.1-4alkyl
(e.g., --OCH.sub.3) [0115] (ix) R.sub.16 and R.sub.17 are
independently H or C.sub.1-4alkyl; [0116] (x) 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) [0117]
(xi) R.sub.20 is H, C.sub.1-4alkyl (e.g., methyl) or
C.sub.3-7cycloalkyl, [0118] (xii) R.sub.21 is C.sub.1-6alkyl; in
free or salt form.
[0119] The invention further provides compounds of Formula I as
follows: [0120] 1.1 Formula I, wherein L is a S, SO or SO.sub.2;
[0121] 1.2 Formula I or 1.1, wherein Lisa S; [0122] 1.3 Formula I
or 1.1, wherein L is --SO--; [0123] 1.4 Formula I or 1.1, wherein L
is --SO.sub.2--; [0124] 1.5 Formula I, or any of 1.1-1.4, wherein
R.sub.1 is H or C.sub.1-4 alkyl (e.g., methyl); [0125] 1.6 Formula
1.5, wherein R.sub.1 is H, [0126] 1.7 Formula 1.5, wherein R.sub.1
is C.sub.1-4 alkyl (e.g., methyl or ethyl); [0127] 1.8 Formula I,
or any of 1.1-1.7, wherein R.sub.4 is H or C.sub.1-6alkyl (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; [0128] 1.9 Formula 1.8,
wherein R.sub.2 or R.sub.3 is H or C.sub.1-6alkyl (e.g., methyl or
isopropyl); [0129] 1.10 Formula 1.8, wherein R.sub.2 or R.sub.3 is
H, [0130] 1.11 Formula 1.8, wherein R.sub.2 or R.sub.3 is
C.sub.1-6alkyl (e.g., methyl or isopropyl); [0131] 1.12 Formula
1.8, wherein R.sub.2 or R.sub.3 is methyl; [0132] 1.13 Formula 1.8,
wherein R.sub.2 or R.sub.3 is isopropyl; [0133] 1.14 Formula I, or
any of 1.1-1.7, wherein 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); [0134] 1.15 Formula I or any of
1.1-1.14, wherein R.sub.5 is -D-E-F; [0135] 1.16 Formula 1.15,
wherein D is C.sub.1-4alkylene (e.g., methylene, ethylene or
prop-2-yn-1-ylene); [0136] 1.17 Formula 1.16, wherein D is
methylene; [0137] 1.18 Any of formulae 1.15-1.17, wherein E is a
single bond, C.sub.2-4alkynylene (e.g., --C.ident.C--), arylene
(e.g., phenylene) or heteroarylene (e.g., pyridylene); [0138] 1.19
Any of formulae 1.15-1.17, wherein E is arylene (e.g., phenylene);
[0139] 1.20 Any of formulae 1.15-1.17, wherein E is phenylene;
[0140] 1.21 Any of formulae 1.15-1.17, wherein E is heteroarylene
(e.g., pyridylene); [0141] 1.22 Any of formulae 1.15-1.17, wherein
E is phenylene wherein F is para-substituted; [0142] 1.23 Any of
formulae 1.15-1.17, wherein E is heteroarylene (e.g., pyridylene);
[0143] 1.24 Any of formulae 1.15-1.17, wherein E is a single bond;
[0144] 1.25 Any of formulae 1.15-1.24, wherein 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); [0145] 1.26 Formula
1.25, wherein F is haloC.sub.1-4alkyl (e.g., trifluoromethyl);
[0146] 1.27 Formula 1.25, wherein F is trifluoromethyl; [0147] 1.28
Formula 1.25, wherein F is halo (e.g., F, Br, Cl); [0148] 1.29
Formula 1.25, wherein F is Cl; [0149] 1.30 Formula 1.25, wherein F
is heteroaryl (e.g., pyridyl, e.g., pyrid-2-yl); [0150] 1.31
Formula 1.25, wherein F is pyridyl; [0151] 1.32 Formula 1.25,
wherein F is pyrid-2-yl; [0152] 1.33 Formula 1.25, wherein F is
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, morpholinyl); [0153] 1.34 Formula 1.25,
wherein F is cyclohexyl; [0154] 1.35 Formula 1.25, wherein F is
pyrrolidinyl (e.g., pyrrolidin-3-yl); [0155] 1.36 Formula 1.25,
wherein F is cyclopentyl; [0156] 1.37 Formula 1.25, wherein F is
tetrahydro-2H-pyran-4-yl; [0157] 1.38 Formula 1.25, wherein F is
aryl (e.g., phenyl); [0158] 1.39 Formula 1.25, wherein F is phenyl;
[0159] 1.40 Formula 1.25, wherein F is 4-chlorophenyl; [0160] 1.41
Formula 1.25, wherein F is --S(O).sub.2R.sub.21 wherein R.sub.21 is
C.sub.1-4alkyl (e.g., methyl); [0161] 1.42 Formula 1.25, wherein F
is --C(O)--R.sub.15 and R.sub.15 is C.sub.1-4alky (e.g., methyl),
haloC.sub.1-4alkyl (e.g., trifluoromethyl), --OH or
--OC.sub.1-4alkyl (e.g., --OCH.sub.3); [0162] 1.43 Any of formulae
1.15-1.42, 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 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);
[0163] 1.44 Formula 1.43, wherein F is 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); [0164] 1.45 Formula
1.43, wherein F is 6-fluoropyrid-2-yl; [0165] 1.46 Formula 1.43,
wherein F is 3-fluoropyrid-2-yl; [0166] 1.47 Formula 1.43, wherein
F is 4-fluoropyrid-2-yl; [0167] 1.48 Formula 1.43, wherein F is
5-fluoropyrid-2-yl; [0168] 1.49 Formula 1.43, wherein F is
heteroaryl, e.g., pyridyl, optionally substituted with one or more
haloC.sub.1-4alkyl (e.g., 5-trifluoromethylpyrid-2-yl; [0169] 1.50
Formula 1.43, wherein F is 5-trifluoromethylpyrid-2-yl; [0170] 1.51
Formula 1.43, wherein F is heteroaryl, e.g., pyridyl, optionally
substituted with one or more C.sub.1-4alkyl (e.g.,
5-methylpyrid-2-yl); [0171] 1.52 Formula 1.43, wherein F is
5-methylpyrid-2-yl; [0172] 1.53 Formula 1.25, wherein F is
--C(O)--R.sub.15 and R.sub.15 is methyl; [0173] 1.54 Formula 1.25,
wherein F is --C(O)--R.sub.15 and R.sub.15 is trifluoromethyl;
[0174] 1.55 Formula 1.25, wherein F is --C(O)--R.sub.15 and
R.sub.15 is --OH; [0175] 1.56 Formula 1.25, wherein F is
--C(O)--R.sub.15 and R.sub.15 is --OC.sub.1-4alkyl (e.g.,
--OCH.sub.3); [0176] 1.57 Formula 1.25, wherein F is
--C(O)--R.sub.15 and R.sub.15 is --OCH.sub.3; [0177] 1.58 Formula
1.25, wherein F is --N(R.sub.16)(R.sub.17); [0178] 1.59 Formula I
or any of 1.1-1.14, wherein R.sub.5 is a substituted
heteroarylalkyl, e.g., substituted with haloalkyl; [0179] 1.60
Formula I or any of 1.1-1.14, wherein R.sub.5 is attached to one of
the nitrogens on the pyrazolo portion of Formula I and is a moiety
of Formula A
[0179] ##STR00005## [0180] 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 [0181] 1.61 Formula 1.60, wherein R.sub.5 is a substituted
heteroarylmethyl, e.g., para-substituted with haloalkyl; [0182]
1.62 Formula 1.60, wherein R.sub.5 is a moiety of Formula A wherein
R.sub.8, R.sub.9, R.sub.11, and R.sub.12 are H and R.sub.10 is
phenyl; [0183] 1.63 Formula 1.60, wherein R.sub.5 is a moiety of
Formula A wherein R.sub.8, R.sub.9, R.sub.11, and R.sub.12 are H
and R.sub.10 is pyridyl or thiadiazolyl; [0184] 1.64 Formula 1.60,
wherein R.sub.5 is a moiety of Formula A wherein R.sub.8, R.sub.9,
R.sub.11, and R.sub.12 are, independently, H or halogen, and
R.sub.10 is haloalkyl; [0185] 1.65 Formula 1.60, wherein R.sub.5 is
a moiety of Formula A wherein R.sub.8, R.sub.9, R.sub.11, and
R.sub.12 are, independently, H, and R.sub.10 is alkyl sulfonyl;
[0186] 1.66 Formula I or any of 1.1-1.65, wherein R.sub.6 is H,
C.sub.1-4alkyl (e.g., methyl), C.sub.3-7cycloalkyl (e.g.,
cyclopentyl), aryl, heteroaryl, 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 (e.g., methoxy); [0187] 1.67 Formula 1.66,
wherein R.sub.6 is H, [0188] 1.68 Formula 1.66, wherein R.sub.6 is
C.sub.1-4alkyl (e.g., methyl); [0189] 1.69 Formula 1.66, wherein
R.sub.6 is C.sub.3-7cycloalkyl (e.g., cyclopentyl); [0190] 1.70
Formula 1.66, wherein R.sub.6 is aryl (e.g., phenyl) optionally
substituted with one or more halo (e.g., F, Cl), hydroxy or
C.sub.1-6alkoxy (e.g., methoxy); [0191] 1.71 Formula 1.66, wherein
R.sub.6 is fluorophenyl (e.g., 4-fluorophenyl) or hydroxyphenyl
(e.g., 4-hydroxyphenyl); [0192] 1.72 Formula I or any of 1.1-1.71,
wherein n=0; [0193] 1.73 Formula I or any of 1.1-1.71, wherein n=1;
[0194] 1.74 Formula 1.73, wherein 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; [0195] 1.75 any of the preceding
formulae wherein the compound is selected from a group consisting
of:
[0195] ##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010## [0196] 1.76 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 500 nM, more
preferably less than 50 nM in an immobilized-metal affinity
particle reagent PDE assay, for example, as described in Example 9,
in free or salt form.
[0197] In another embodiment, the invention provides a Compound of
Formula I or II, wherein R.sub.6 is: [0198] H, [0199]
C.sub.1-4alkyl (e.g., methyl), [0200] C.sub.3-7cycloalkyl (e.g.,
cyclopentyl), [0201] aryl (e.g., phenyl), [0202] heteroaryl (e.g.,
pyridyl, for example, pyrid-4-yl), [0203] arylC.sub.1-4alkyl (e.g.,
benzyl), [0204] wherein the aryl or heteroaryl is optionally
substituted with one or more halo (e.g., F, Cl), hydroxy or
C.sub.1-6alkoxy (e.g., methoxy), for example, R.sub.6 is
4-hydroxyphenyl or 4-fluorophenyl, and the remaining substituents
are as previously defined in Formula I or II or any of 1.1-1.76, in
free or salt form.
[0205] In another embodiment, the invention provides a Compound of
Formula I or II, wherein [0206] R.sub.5 is attached to one of the
nitrogens on the pyrazolo portion of Formula I or II and is a
moiety of Formula A
[0206] ##STR00011## [0207] 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 [0208] halogen,
[0209] C.sub.1-4alkyl, [0210] C.sub.3-7cycloalkyl, [0211]
heterocycloalkyl (e.g., pyrrolidinyl or piperidinyl), [0212]
C.sub.1-4haloalkyl (e.g., trifluoromethyl), [0213] aryl (e.g.,
phenyl), [0214] heteroaryl (e.g., pyridyl (for example pyrid-2-yl),
or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl,
triazolyl, tetrazolyl, [0215] arylcarbonyl (e.g., benzoyl), [0216]
alkylsulfonyl (e.g., methylsulfonyl), [0217] heteroarylcarbonyl, or
[0218] alkoxycarbonyl, [0219] wherein said aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is 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), and/or --SH, [0220]
provided that when X, Y, or Z is nitrogen, R.sub.8, R.sub.9, or
R.sub.10, respectively, is not present; [0221] R.sub.6 is: [0222]
H, [0223] C.sub.1-4alkyl (e.g., methyl), [0224] C.sub.3-7cycloalkyl
(e.g., cyclopentyl), [0225] aryl (e.g., phenyl), [0226] heteroaryl
(e.g., pyridyl, for example, pyrid-4-yl), [0227] arylC.sub.1-4alkyl
(e.g., benzyl), [0228] wherein the aryl or heteroaryl is optionally
substituted with one or more halo (e.g., F, Cl), hydroxy or
C.sub.1-6alkoxy (e.g., methoxy), for example, R.sub.6 is
4-hydroxyphenyl or 4-fluorophenyl, and the remaining substituents
are as previously defined in Formula I or II or any of 1.1-1.76, in
free or salt form.
[0229] In still another embodiment, the invention provides a
Compound of Formula I or II, wherein [0230] R.sub.5 is attached to
one of the nitrogens on the pyrazolo portion of Formula I or II and
is a moiety of Formula A
[0230] ##STR00012## [0231] 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 [0232] halogen,
[0233] C.sub.1-4alkyl, [0234] C.sub.3-7cycloalkyl, [0235]
heterocycloalkyl (e.g., pyrrolidinyl or piperidinyl), [0236]
C.sub.1-4haloalkyl (e.g., trifluoromethyl), [0237] aryl (e.g.,
phenyl), [0238] heteroaryl (e.g., pyridyl (for example pyrid-2-yl),
or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl,
triazolyl, tetrazolyl, [0239] arylcarbonyl (e.g., benzoyl), [0240]
alkylsulfonyl (e.g., methylsulfonyl), [0241] heteroarylcarbonyl, or
[0242] alkoxycarbonyl, [0243] wherein said aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is 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), and/or --SH, [0244]
provided that when X, Y, or Z is nitrogen, R.sub.8, R.sub.9, or
R.sub.10, respectively, is not present; [0245] R.sub.6 is: [0246]
H, [0247] C.sub.1-4alkyl (e.g., methyl), [0248] aryl (e.g.,
phenyl), [0249] heteroaryl (e.g., pyridyl, for example,
pyrid-4-yl), [0250] wherein the aryl or heteroaryl is optionally
substituted with one or more halo (e.g., F, Cl), hydroxy or
C.sub.1-6alkoxy (e.g., methoxy), for example, R.sub.6 is
4-hydroxyphenyl or 4-fluorophenyl, and the remaining substituents
are as previously defined in Formula I or II or any of 1.1-1.76, in
free or salt form.
[0251] In yet another embodiment, the invention provides a Compound
of Formula I or II, wherein [0252] R.sub.5 is attached to one of
the nitrogens on the pyrazolo portion of Formula I or II and is a
moiety of Formula A
[0252] ##STR00013## [0253] 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 [0254]
heterocycloalkyl (e.g., pyrrolidinyl or piperidinyl), [0255] aryl
(e.g., phenyl), [0256] heteroaryl (e.g., pyridyl (for example
pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),
diazolyl, triazolyl, tetrazolyl, [0257] wherein said aryl,
heteroaryl or heterocycloalkyl is 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), and/or --SH, provided
that when X, Y, or Z is nitrogen, R.sub.8, R.sub.9, or R.sub.10,
respectively, is not present; [0258] R.sub.6 is: [0259] H, [0260]
C.sub.1-4alkyl (e.g., methyl), [0261] aryl (e.g., phenyl), [0262]
heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), [0263] wherein
the aryl or heteroaryl is optionally substituted with one or more
halo (e.g., F, Cl), hydroxy or C.sub.1-6alkoxy (e.g., methoxy), for
example, R.sub.6 is 4-hydroxyphenyl or 4-fluorophenyl, and the
remaining substituents are as previously defined in Formula I or II
or any of 1.1-1.76, in free or salt form.
[0264] If not otherwise specified or clear from context, the
following terms herein have the following meanings [0265] (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. [0266] (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. [0267] (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. [0268] (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). [0269] (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. [0270] (f) Wherein E is phenylene, the
numbering is as follows:
[0270] ##STR00014## [0271] (g) 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--.
[0272] Compounds of the Invention, e.g., substituted
4,5,7,8-tetrahydro-(1H or
2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or a substituted
3-(thio, sulfinyl or sulfonyl)-7,8,9-trihydro-(1H or
2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one compounds,
e.g., Compounds of Formula I, e.g., any of formulae 1.1-1.76, 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.
[0273] 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.
[0274] The invention also provides methods of making the Compounds
of the Invention and methods of using the Compounds of the
Invention for treatment of diseases and disorders as set forth
below (especially treatment of diseases characterized by reduced
dopamine D1 receptor signaling activity, such as Parkinson's
disease, Tourette's Syndrome, Autism, fragile X syndrome, ADHD,
restless leg syndrome, depression, cognitive impairment of
schizophrenia, narcolepsy and diseases that may be alleviated by
the enhancement of progesterone-signaling such as female sexual
dysfunction), or a disease or disorder such as psychosis or
glaucoma). This list is not intended to be exhaustive and may
include other diseases and disorders as set forth below.
[0275] 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.
DETAILED DESCRIPTION OF THE INVENTION
Methods of Making Compounds of the Invention
[0276] 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. Various starting
materials and/or Compounds of the Invention may be prepared using
methods described in WO 2006/133261 and PCT/US2007/070551. All
references cited herein are hereby incorporated by reference in
their entirety.
[0277] 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.
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.
[0278] 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.
[0279] 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.
TERMS AND ABBREVIATIONS
[0280] BuLi=n-butyllithium [0281] Bu.sup.tOH=tert-butyl alcohol,
[0282] CAN=ammonium cerium (IV) nitrate, [0283]
DIPEA=diisopropylethylamine, [0284] DMF=N,N-dimethylforamide,
[0285] DMSO=dimethyl sulfoxide, [0286] Et.sub.2O=diethyl ether,
[0287] EtOAc=ethyl acetate, [0288] equiv.=equivalent(s), [0289]
h=hour(s), [0290] HPLC=high performance liquid chromatography,
[0291] LDA=lithium diisopropylamide [0292] MeOH=methanol, [0293]
NBS=N-bromosuccinimide [0294] NCS=N-chlorosuccinimide [0295]
NaHCO.sub.3=sodium bicarbonate, [0296] NH.sub.4OH=ammonium
hydroxide, [0297]
Pd.sub.2(dba).sub.3=tris[dibenzylideneacetone]dipalladium(0) [0298]
PMB=p-methoxybenzyl, [0299] POCl.sub.3=phosphorous oxychloride,
[0300] SOCl.sub.2=thionyl chloride, [0301] TFA=trifluoroacetic
acid, [0302] TFMSA=trifluoromethanesulfonic acid [0303]
THF=tetrahedrofuran.
[0304] The synthetic methods in this invention are illustrated
below. The significances for the R groups are as set forth above
for formula I or II unless otherwise indicated.
[0305] In an aspect of the invention, intermediate compounds of
formula IIb can be synthesized by reacting a compound of formula
IIa with a dicarboxylic acid, acetic anhydride and acetic acid
mixing with heat for about 3 hours and then cooled:
##STR00015##
[0306] wherein R' is methyl.
[0307] Intermediate IIc can be prepared by for example reacting a
compound of IIb with for example a chlorinating compound such as
POCl.sub.3, sometimes with small amounts of water and heated for
about 4 hours and then cooled
##STR00016##
[0308] Intermediate IId may be formed by reacting a compound of IIc
with for example a P'--X in a solvent such as DMF and a base such
as K.sub.2CO.sub.3 at room temperature or with heating:
##STR00017##
wherein P' is a protective group [e.g., p-methoxybenzyl group
(PMB)]; X is a leaving group such as a halogen, mesylate, or
tosylate.
[0309] Intermediate IIe may be prepared by reacting a compound of
IId with hydrazine or hydrazine hydrate in a solvent such as
methanol and refluxed for about 4 hours and then cooled:
##STR00018##
[0310] Intermediate IVa may be formed by for example reacting a
compound of IIe with POCl.sub.3 and DMF:
##STR00019##
[0311] wherein R.sup.1 is as defined previously in Formula I or II,
e.g., such as a methyl group.
[0312] Intermediate IVb may be formed by reacting a compound of IVa
with for example a R.sub.5--X in a solvent such as DMF and a base
such as K.sub.2CO.sub.3 at room temperature or with heating:
##STR00020##
[0313] Intermediate IVc may be synthesized from a compound of IVb
by removing the protective group P.sup.1 with an appropriate
method. For example, if P.sup.1 is a PMB group, then it can be
removed with CAN or TFA/TFMSA at room temperature:
##STR00021##
[0314] Intermediate IVd can be prepared by reacting a compound of
IVc with for example a chlorinating compound such as POCl.sub.3 and
refluxed for about 2 days, or heated at 150-200.degree. C. for
about 10 min in a sealed vial with a microwave instrument and then
cooled:
##STR00022##
[0315] Intermediate IVe can be formed by reacting a compound of IVd
with an amino alcohol under basic condition in a solvent such as
DMF and heated overnight then cooled:
##STR00023##
[0316] Alternatively, intermediate IVe can be synthesized directly
from a compound of IVc by reacting with an amino alcohol and a
coupling reagent such as BOP in the presence of a base such as
DBU:
##STR00024##
[0317] wherein all the substituents are as defined previously.
[0318] Compound IVf may be formed by reacting a compound of IVe
with for example a dehydrating/halogenating agent such as
SOCl.sub.2 in a solvent such as CH.sub.2Cl.sub.2 at room
temperature overnight or heated at 35.degree. C. for several hours,
and then cooled.
##STR00025##
[0319] Compound IVg may be formed by reacting a compound of IVf
with for example a halogenating agent such as NCS and a base such
as LDA in a solvent such as THF at low temperature for several
hours.
##STR00026##
[0320] Alternatively, Compound IVg may be formed by reacting a
compound of IVf with for example a halogenating agent such as
hexachloroethane and a base such as LiHMDS in a solvent such as THF
at low temperature for several hours:
##STR00027##
[0321] Compound I may be formed by reacting a compound of IVg with
R.sub.6-LH for example a thiol upon heating.
##STR00028##
[0322] Alternatively, compound I may be formed by reacting a
compound of IVf with a thiol R.sub.6-LH or a disulfide
R.sub.6-L-L-R.sub.6 in the presence of a strong base, such as a
lithium reagent (e.g. LiHMDS) in a solvent such as THF.
[0323] The corresponding sulfinyl or sulfonyl derivative may be
formed by reacting the 3-thio compound (e.g., wherein L is --S--)
with an oxidizer such as a peroxide (e.g. oxone or hydrogen
peroxide) at room temperature in a solvent such as
acetonitrile.
[0324] In another aspect of the invention, The invention thus
provides methods of making Compounds of Formula I or II, for
example, comprising reacting Compounds I-A with, for example,
R.sub.5--X, in a solvent such as DMF and a base such as
K.sub.2CO.sub.3 at room temperature or with heating:
##STR00029##
wherein all the substitutents are as defined previously; X is a
leaving group such as a halogen, mesylate, or tosylate.
[0325] The thio Compounds of the Invention, e.g., Formula I or II
wherein L is S or Compound (I)-B may be prepared by reacting
compound (IVf), e.g., with a disulfide and lithium
bis(trimethylsilyl)azanide (LiHMDS).
##STR00030##
[0326] The sulfinyl or sulfonyl derivatives of the Invention, e.g.,
Formula I or II, wherein L is SO or SO.sub.2 may be prepared by
(I)-B oxidation using, e.g. oxone, in a solvent such as
acetonitrile and methanol.
[0327] Methods of Using Compounds of the Invention
[0328] The Compounds of the Invention are useful in the treatment
of diseases characterized by disruption of or damage to cAMP and
cGMP mediated pathways, e.g., as a result of increased expression
of PDE1 or decreased expression of cAMP and cGMP due to inhibition
or reduced levels of inducers of cyclic nucleotide synthesis, such
as dopamine and nitric oxide (NO). By preventing the degradation of
cAMP and cGMP by PDE1B, thereby increasing intracellular levels of
cAMP and cGMP, the Compounds of the Invention potentiate the
activity of cyclic nucleotide synthesis inducers.
[0329] The invention provides methods of treatment of any one or
more of the following conditions: [0330] (i) Neurodegenerative
diseases, including Parkinson's disease, restless leg, tremors,
dyskinesias, Huntington's disease, Alzheimer's disease, and
drug-induced movement disorders; [0331] (ii) Mental disorders,
including depression, attention deficit disorder, attention deficit
hyperactivity disorder, bipolar illness, anxiety, sleep disorders,
e.g., narcolepsy, cognitive impairment, dementia, Tourette's
syndrome, autism, fragile X syndrome, psychostimulant withdrawal,
and drug addiction; [0332] (iii) Circulatory and cardiovascular
disorders, including cerebrovascular disease, stroke, congestive
heart disease, hypertension, pulmonary hypertension, and sexual
dysfunction; [0333] (iv) Respiratory and inflammatory disorders,
including asthma, chronic obstructive pulmonary disease, and
allergic rhinitis, as well as autoimmune and inflammatory diseases;
[0334] (v) Any disease or condition characterized by low levels of
cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling
pathways) in cells expressing PDE1; and/or [0335] (vi) Any disease
or condition characterized by reduced dopamine D1 receptor
signaling activity, comprising administering an effective amount of
a Compound of the Invention, e.g., a compound according to any of
Formula I or any of 1.1-1.76, in free, pharmaceutically acceptable
salt or prodrug form, to a human or animal patient in need thereof.
In another aspect, the invention provides a method of treatment of
the conditions disclosed above comprising administering a
therapeutically effective amount of a Compound of Formula II, in
free or pharmaceutically acceptable salt form.
[0336] In an especially preferred embodiment, the invention
provides methods of treatment or prophylaxis for narcolepsy. In
this embodiment, PDE1 Inhibitors may be used as a sole therapeutic
agent, but may also be used in combination or for co-administration
with other active agents. Thus, the invention further comprises a
method of treating narcolepsy comprising administering
simultaneously, sequentially, or contemporaneously administering
therapeutically effective amounts of [0337] (i) a PDE1 Inhibitor,
e.g., a compound according to any of Formula I or any of 1.1-1.76,
and [0338] (ii) a compound to promote wakefulness or regulate
sleep, e.g., selected from (a) central nervous system
stimulants-amphetamines and amphetamine like compounds, e.g.,
methylphenidate, dextroamphetamine, methamphetamine, and pemoline;
(b) modafinil, (c) antidepressants, e.g., tricyclics (including
imipramine, desipramine, clomipramine, and protriptyline) and
selective serotonin reuptake inhibitors (including fluoxetine and
sertraline); and/or (d) gamma hydroxybutyrate (GHB). in free,
pharmaceutically acceptable salt or prodrug form, to a human or
animal patient in need thereof. In still another embodiment, the
methods of treatment or prophylaxis for narcolepsy as hereinbefore
described, comprises administering a therapeutically effective
amount of a Compound of Formula II as hereinbefore described, in
free or pharmaceutically acceptable salt form, as a sole
therapeutic agent or use in combination for co-administered with
another active agent.
[0339] In another embodiment, the invention further provides
methods of treatment or prophylaxis of a condition which may be
alleviated by the enhancement of the progesterone signaling
comprising administering an effective amount of a Compound of the
Invention, e.g., a compound according to any of Formula I or any of
any of 1.1-1.76, in free, pharmaceutically acceptable salt or
prodrug form, to a human or animal patient in need thereof. The
invention also provides methods of treatment as disclosed here,
comprising administering a therapeutically effective amount of a
Compound of Formula II, in free or pharmaceutically acceptable salt
form. Disease or condition that may be ameliorated by enhancement
of progesterone signaling include, but are not limited to, female
sexual dysfunction, secondary amenorrhea (e.g., exercise
amenorrhoea, anovulation, menopause, menopausal symptoms,
hypothyroidism), pre-menstrual syndrome, premature labor,
infertility, for example infertility due to repeated miscarriage,
irregular menstrual cycles, abnormal uterine bleeding,
osteoporosis, autoimmmune disease, multiple sclerosis, prostate
enlargement, prostate cancer, and hypothyroidism. For example, by
enhancing progesterone signaling, the PDE1 inhibitors may be used
to encourage egg implantation through effects on the lining of
uterus, and to help maintain pregnancy in women who are prone to
miscarriage due to immune response to pregnancy or low progesterone
function. The novel PDE1 inhibitors, e.g., as described herein, may
also be useful to enhance the effectiveness of hormone replacement
therapy, e.g., administered in combination with
estrogen/estradiol/estriol and/or progesterone/progestins in
postmenopausal women, and estrogen-induced endometrial hyperplasia
and carcinoma. The methods of the invention are also useful for
animal breeding, for example to induce sexual receptivity and/or
estrus in a nonhuman female mammal to be bred.
[0340] In this embodiment, PDE1 Inhibitors may be used in the
foregoing methods of treatment or prophylaxis as a sole therapeutic
agent, but may also be used in combination or for co-administration
with other active agents, for example in conjunction with hormone
replacement therapy. Thus, the invention further comprises a method
of treating disorders that may be ameliorated by enhancement of
progesterone signaling comprising administering simultaneously,
sequentially, or contemporaneously administering therapeutically
effective amounts of [0341] (i) a PDE1 Inhibitor, e.g., a compound
according to any of Formula I or any of any of 1.1-1.76, and [0342]
(ii) a hormone, e.g., selected from estrogen and estrogen analogues
(e.g., estradiol, estriol, estradiol esters) and progesterone and
progesterone analogues (e.g., progestins) in free, pharmaceutically
acceptable salt or prodrug form, to a human or animal patient in
need thereof. In another embodiment, the invention provides the
method described above wherein the PDE 1 inhibitor is a Compound of
Formula II, in free or pharmaceutically acceptable salt form.
[0343] The invention also provides a method for enhancing or
potentiating dopamine D1 intracellular signaling activity in a cell
or tissue comprising contacting said cell or tissue with an amount
of a Compound of the Invention, e.g., Formula I or any of any of
1.1-1.76, sufficient to inhibit PDE activity. The invention further
provides a method for enhancing or potentiating dopamine D1
intracellular signaling activity in a cell or tissue comprising
contacting said cell or tissue with an amount of a Compound of
Formula II, in free or salt form, sufficient to inhibit PDE1
activity, e.g., PDE1A or PDE activity.
[0344] The invention also provides a method for treating a
PDE1-related, especially PDE1B-related disorder, a dopamine D1
receptor intracellular signaling pathway disorder, or disorders
that may be alleviated by the enhancement of the progesterone
signaling pathway in a patient in need thereof comprising
administering to the patient an effective amount of a Compound of
the Invention, e.g., Formula I or any of any of 1.1-1.76, in that
inhibits PDE1B, wherein PDE activity modulates phosphorylation of
DARPP-32 and/or the GluR1 AMPA receptor. Similarly, the invention
provides a method for treating a PDE1-related, especially
PDE1B-related disorder, a dopamine D1 receptor intracellular
signaling pathway disorder, or disorders that may be alleviated by
the enhancement of the progesterone signaling pathway in a patient
in need thereof comprising administering to the patient an
effective amount of a Compound of Formula II as hereinbefore
described, in free or pharmaceutically acceptable salt form.
[0345] In another aspect, the invention also provides a method for
the treatment for glaucoma or elevated intraocular pressure
comprising topical administration of a therapeutically effective
amount of a phosphodiesterase type I (PDE1) Inhibitor of the
Invention, in free or pharmaceutically acceptable salt form, in an
opthalmically compatible carrier to the eye of a patient in need
thereof. However, treatment may alternatively include a systemic
therapy. Systemic therapy includes treatment that can directly
reach the bloodstream, or oral methods of administration, for
example.
[0346] The invention further provides a pharmaceutical composition
for topical ophthalmic use comprising a PDE1 inhibitor; for example
an ophthalmic solution, suspension, cream or ointment comprising a
PDE1 Inhibitor of the Invention, in free or ophthamalogically
acceptable salt form, in combination or association with an
ophthamologically acceptable diluent or carrier.
[0347] Optionally, the PDE1 inhibitor may be administered
sequentially or simultaneously with a second drug useful for
treatment of glaucoma or elevated intraocular pressure. Where two
active agents are administered, the therapeutically effective
amount of each agent may be below the amount needed for activity as
monotherapy. Accordingly, a subthreshold amount (i.e., an amount
below the level necessary for efficacy as monotherapy) may be
considered therapeutically effective and also may also be referred
alternatively as an effective amount. Indeed, an advantage of
administering different agents with different mechanisms of action
and different side effect profiles may be to reduce the dosage and
side effects of either or both agents, as well as to enhance or
potentiate their activity as monotherapy.
[0348] The invention thus provides the method of treatment of a
condition selected from glaucoma and elevated intraocular pressure
comprising administering to a patient in need thereof an effective
amount, e.g., a subthreshold amount, of an agent known to lower
intraocular pressure concomitantly, simultaneously or sequentially
with an effective amount, e.g., a subthreshold amount, of a PDE1
Inhibitor of the Invention, in free or pharmaceutically acceptable
salt form, such that amount of the agent known to lower intraocular
pressure and the amount of the PDE1 inhibitor in combination are
effective to treat the condition.
[0349] In one embodiment, one or both of the agents are
administered topically to the eye. Thus the invention provides a
method of reducing the side effects of treatment of glaucoma or
elevated intraocular pressure by administering a reduced dose of an
agent known to lower intraocular pressure concomitantly,
simultaneously or sequentially with an effective amount of a PDE1
inhibitor. However, methods other than topical administration, such
as systemic therapeutic administration, may also be utilized.
[0350] The optional additional agent or agents for use in
combination with a PDE1 inhibitor may, for example, be selected
from the existing drugs comprise typically of instillation of a
prostaglandin, pilocarpine, epinephrine, or topical beta-blocker
treatment, e.g. with timolol, as well as systemically administered
inhibitors of carbonic anhydrase, e.g. acetazolamide.
Cholinesterase inhibitors such as physostigmine and echothiopate
may also be employed and have an effect similar to that of
pilocarpine. Drugs currently used to treat glaucoma thus include,
e.g., [0351] 1. Prostaglandin analogs such as latanoprost
(Xalatan), bimatoprost (Lumigan) and travoprost (Travatan), which
increase uveoscleral outflow of aqueous humor. Bimatoprost also
increases trabecular outflow. [0352] 2. Topical beta-adrenergic
receptor antagonists such as timolol, levobunolol (Betagan), and
betaxolol, which decrease aqueous humor production by the ciliary
body. [0353] 3. Alpha.sub.2-adrenergic agonists such as brimonidine
(Alphagan), which work by a dual mechanism, decreasing aqueous
production and increasing uveo-scleral outflow. [0354] 4.
Less-selective sympathomimetics like epinephrine and dipivefrin
(Propine) increase outflow of aqueous humor through trabecular
meshwork and possibly through uveoscleral outflow pathway, probably
by a beta.sub.2-agonist action. [0355] 5. Miotic agents
(parasympathomimetics) like pilocarpine work by contraction of the
ciliary muscle, tightening the trabecular meshwork and allowing
increased outflow of the aqueous humour. [0356] 6. Carbonic
anhydrase inhibitors like dorzolamide (Trusopt), brinzolamide
(Azopt), acetazolamide (Diamox) lower secretion of aqueous humor by
inhibiting carbonic anhydrase in the ciliary body. [0357] 7.
Physostigmine is also used to treat glaucoma and delayed gastric
emptying.
[0358] For example, the invention provides pharmaceutical
compositions comprising a PDE1 Inhibitor of the Invention and an
agent selected from (i) the prostanoids, unoprostone, latanoprost,
travoprost, or bimatoprost; (ii) an alpha adrenergic agonist such
as brimonidine, apraclonidine, or dipivefrin and (iii) a muscarinic
agonist, such as pilocarpine. For example, the invention provides
ophthalmic formulations comprising a PDE-1 Inhibitor of the
Invention together with bimatoprost, abrimonidine, brimonidine,
timolol, or combinations thereof, in free or ophthamalogically
acceptable salt form, in combination or association with an
ophthamologically acceptable diluent or carrier. In addition to
selecting a combination, however, a person of ordinary skill in the
art can select an appropriate selective receptor subtype agonist or
antagonist. For example, for alpha adrenergic agonist, one can
select an agonist selective for an alpha 1 adrenergic receptor, or
an agonist selective for an alpha.sub.2 adrenergic receptor such as
brimonidine, for example. For a beta-adrenergic receptor
antagonist, one can select an antagonist selective for either
.beta..sub.1, or .beta.2, or .beta..sub.3, depending on the
appropriate therapeutic application. One can also select a
muscarinic agonist selective for a particular receptor subtype such
as M.sub.1-M.sub.5.
[0359] The PDE1 inhibitor may be administered in the form of an
ophthalmic composition, which includes an ophthalmic solution,
cream or ointment. The ophthalmic composition may additionally
include an intraocular-pressure lowering agent.
[0360] In yet another example, the PDE-1 Inhibitors disclosed may
be combined with a subthreshold amount of an intraocular
pressure-lowering agent which may be a bimatoprost ophthalmic
solution, a brimonidine tartrate ophthalmic solution, or
brimonidine tartrate/timolol maleate ophthalmic solution.
[0361] In addition to the above-mentioned methods, it has also been
surprisingly discovered that PDE1 inhibitors are useful to treat
psychosis, for example, any conditions characterized by psychotic
symptoms such as hallucinations, paranoid or bizarre delusions, or
disorganized speech and thinking, e.g., schizophrenia,
schizoaffective disorder, schizophreniform disorder, psychotic
disorder, delusional disorder, and mania, such as in acute manic
episodes and bipolar disorder. Without intending to be bound by any
theory, it is believed that typical and atypical antipsychotic
drugs such as clozapine primarily have their antagonistic activity
at the dopamine D2 receptor. PDE1 inhibitors, however, primarily
act to enhance signaling at the dopamine D1 receptor. By enhancing
D1 receptor signaling, PDE1 inhibitors can increase NMDA receptor
function in various brain regions, for example in nucleus accumbens
neurons and in the prefrontal cortex. This enhancement of function
may be seen for example in NMDA receptors containing the NR2B
subunit, and may occur e.g., via activation of the Src and protein
kinase A family of kinases.
[0362] Therefore, the invention provides a new method for the
treatment of psychosis, e.g., schizophrenia, schizoaffective
disorder, schizophreniform disorder, psychotic disorder, delusional
disorder, and mania, such as in acute manic episodes and bipolar
disorder, comprising administering a therapeutically effective
amount of a phosphodiesterase-1 (PDE1) Inhibitor of the Invention,
in free or pharmaceutically acceptable salt form, to a patient in
need thereof.
[0363] PDE1 Inhibitors may be used in the foregoing methods of
treatment prophylaxis as a sole therapeutic agent, but may also be
used in combination or for co-administration with other active
agents. Thus, the invention further comprises a method of treating
psychosis, e.g., schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder,
or mania, comprising administering simultaneously, sequentially, or
contemporaneously administering therapeutically effective amounts
of: [0364] (i) a PDE1 Inhibitor of the invention, in free or
pharmaceutically acceptable salt form; and [0365] (ii) an
antipsychotic, e.g., [0366] Typical antipsychotics, e.g., [0367]
Butyrophenones, e.g. Haloperidol (Haldol, Serenace), Droperidol
(Droleptan); [0368] Phenothiazines, e.g., Chlorpromazine
(Thorazine, Largactil), Fluphenazine (Prolixin), Perphenazine
(Trilafon), Prochlorperazine (Compazine), Thioridazine (Mellaril,
Melleril), Trifluoperazine (Stelazine), Mesoridazine, Periciazine,
Promazine, Triflupromazine (Vesprin), Levomepromazine (Nozinan),
Promethazine (Phenergan), Pimozide (Orap); [0369] Thioxanthenes,
e.g., Chlorprothixene, Flupenthixol (Depixol, Fluanxol),
Thiothixene (Navane), Zuclopenthixol (Clopixol, Acuphase); [0370]
Atypical antipsychotics, e.g., [0371] Clozapine (Clozaril),
Olanzapine (Zyprexa), Risperidone (Risperdal), Quetiapine
(Seroquel), Ziprasidone (Geodon), Amisulpride (Solian),
Paliperidone (Invega), Aripiprazole (Abilify), Bifeprunox;
norclozapine,
[0372] in free or pharmaceutically acceptable salt form, to a
patient in need thereof.
[0373] In a particular embodiment, the Compounds of the Invention
are particularly useful for the treatment or prophylaxis of
schizophrenia.
[0374] Compounds of the Invention, in free or pharmaceutically
acceptable salt form, are particularly useful for the treatment of
Parkinson's disease, schizophrenia, narcolepsy, glaucoma and female
sexual dysfunction.
[0375] In still another aspect, the invention provides a method of
lengthening or enhancing growth of the eyelashes by administering
an effective amount of a prostaglandin analogue, e.g., bimatoprost,
concomitantly, simultaneously or sequentially with an effective
amount of a PDE1 inhibitor of the Invention, in free or
pharmaceutically acceptable salt form, to the eye of a patient in
need thereof.
[0376] In yet another aspect, the invention provides a method for
the treatment or prophylaxis of traumatic brain injury comprising
administering a therapeutically effective amount of a PDE1
inhibitor of the invention, in free or pharmaceutically acceptable
salt form, to a patient in need thereof. Traumatic brain injury
(TBI) encompasses primary injury as well as secondary injury,
including both focal and diffuse brain injuries. Secondary injuries
are multiple, parallel, interacting and interdependent cascades of
biological reactions arising from discrete subcellular processes
(e.g., toxicity due to reactive oxygen species, overstimulation of
glutamate receptors, excessive influx of calcium and inflammatory
upregulation) which are caused or exacerbated by the inflammatory
response and progress after the initial (primary) injury. Abnormal
calcium homeostasis is believed to be a critical component of the
progression of secondary injury in both grey and white matter. For
a review of TBI, see Park et al., CMAJ (2008) 178(9):1163-1170, the
contents of which are incorporated herein in their entirety.
Studies have shown that the cAMP-PKA signaling cascade is
downregulated after TBI and treatment of PDE IV inhibitors such as
rolipram to raise or restore cAMP level improves histopathological
outcome and decreases inflammation after TBI. As Compounds of the
present invention is a PDE1 inhibitor, it is believed that these
compounds are also useful for the treatment of TBI, e.g., by
restoring cAMP level and/or calcium homeostasis after traumatic
brain injury.
[0377] The present invention also provides [0378] (i) a Compound of
the Invention, e.g., Formula I or any of any of 1.1-1.76, or
Formula II as hereinbefore described in free, pharmaceutically
acceptable salt or prodrug form for example for use in any method
or in the treatment of any disease or condition as hereinbefore set
forth, [0379] (ii) the use of a Compound of the Invention, e.g.,
Formula I or any of 1.1-1.76, or Formula II as hereinbefore
described, in free, pharmaceutically acceptable salt or prodrug
form, in the manufacture of a medicament for treating any disease
or condition as hereinbefore set forth, [0380] (iii) a
pharmaceutical composition comprising a Compound of the Invention,
e.g., Formula I or any of 1.1-1.76, or Formula II as hereinbefore
described, in free, pharmaceutically acceptable salt or prodrug
form, in combination or association with a pharmaceutically
acceptable diluent or carrier, and [0381] (iv) a pharmaceutical
composition comprising a Compound of the Invention, e.g., Formula I
or any of 1.1-1.76, or Formula II as hereinbefore described, in
free, pharmaceutically acceptable salt or prodrug form, in
combination or association with a pharmaceutically acceptable
diluent or carrier for use in the treatment of any disease or
condition as hereinbefore set forth.
[0382] Therefore, the invention provides use of a Compound of the
Invention, e.g., Formula I or any of 1.1-1.76, or Formula II as
hereinbefore described, in free, pharmaceutically acceptable salt
or prodrug form, or a Compound of the Invention in a pharmaceutical
composition form, for the manufacture of a medicament for the
treatment or prophylactic treatment of the following diseases:
Parkinson's disease, restless leg, tremors, dyskinesias,
Huntington's disease, Alzheimer's disease, and drug-induced
movement disorders; depression, attention deficit disorder,
attention deficit hyperactivity disorder, bipolar illness, anxiety,
sleep disorder, narcolepsy, cognitive impairment, dementia,
Tourette's syndrome, autism, fragile X syndrome, psychostimulant
withdrawal, and/or drug addiction; cerebrovascular disease, stroke,
congestive heart disease, hypertension, pulmonary hypertension,
and/or sexual dysfunction; asthma, chronic obstructive pulmonary
disease, and/or allergic rhinitis, as well as autoimmune and
inflammatory diseases; and/or female sexual dysfunction, exercise
amenorrhoea, anovulation, menopause, menopausal symptoms,
hypothyroidism, pre-menstrual syndrome, premature labor,
infertility, irregular menstrual cycles, abnormal uterine bleeding,
osteoporosis, multiple sclerosis, prostate enlargement, prostate
cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or
carcinoma; and/or any disease or condition characterized by low
levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP
signaling pathways) in cells expressing PDE1, and/or by reduced
dopamine D1 receptor signaling activity; and/or any disease or
condition that may be ameliorated by the enhancement of
progesterone signaling.
[0383] The invention also provides use of a Compound of the
Invention, in free or pharmaceutically acceptable salt form, for
the manufacture of a medicament for the treatment or prophylactic
treatment of: [0384] a) glaucoma or elevated intraocular pressure,
[0385] b) psychosis, for example, any conditions characterized by
psychotic symptoms such as hallucinations, paranoid or bizarre
delusions, or disorganized speech and thinking, e.g.,
schizophrenia, schizoaffective disorder, schizophreniform disorder,
psychotic disorder, delusional disorder, and mania, such as in
acute manic episodes and bipolar disorder, [0386] c) traumatic
brain injury.
[0387] The phrase "Compounds of the Invention" or "PDE1 inhibitors
of the Invention" encompasses any and all of the compounds
disclosed herewith, e.g., a Compound of Formula I or any of
1.1-1.76, or Formula II as hereinbefore described, in free or salt
form.
[0388] 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.
[0389] For methods of treatment, the word "effective amount" is
intended to encompass a therapeutically effective amount to treat a
specific disease or disorder.
[0390] The term "pulmonary hypertension" is intended to encompass
pulmonary arterial hypertension.
[0391] 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.
[0392] The term "comprising" as used in this disclosure is intended
to be open-ended and does not exclude additional, unrecited
elements or method steps.
[0393] Compounds of the Invention are in particular useful for the
treatment of Parkinson's disease, narcolepsy and female sexual
dysfunction.
[0394] Compounds of the Invention, e.g., Formula I or any of
1.1-1.76, or Formula II 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. For example, as
Compounds of the Invention potentiate the activity of D1 agonists,
such as dopamine, they may be simultaneously, sequentially, or
contemporaneously administered with conventional dopaminergic
medications, such as levodopa and levodopa adjuncts (carbidopa,
COMT inhibitors, MAO-B inhibitors), dopamine agonists, and
anticholinergics, e.g., in the treatment of a patient having
Parkinson's disease. In addition, the novel PDE 1 inhibitors, e.g.,
as described herein, may also be administered in combination with
estrogen/estradiol/estriol and/or progesterone/progestins to
enhance the effectiveness of hormone replacement therapy or
treatment of estrogen-induced endometrial hyperplasia or
carcinoma.
[0395] 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.
[0396] 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
[0397] The synthetic methods for various Compounds of the Present
Invention are illustrated below. Other compounds of the Invention
and their salts may be made using the methods as similarly
described below and/or by methods similar to those generally
described in the detailed description and by methods known in the
chemical art.
Example 1
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylthio)-2-(4-(6-fluoropy-
ridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(-
2H)-one
##STR00031##
[0399]
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(6-fluoropyridin-2--
yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one
(56.8 mg, 0.136 mmol) and phenyl disulfide (59.6 mg, 0.273 mmol)
are dissolved in 1 mL of anhydrous THF, and then 273 uL of 1.0 M
LiHMDS in THF is added dropwise. The reaction mixture is stirred at
room temperature for an hour, and then quenched with saline. The
mixture is separated with a semi-preparative HPLC to give 27 mg of
pure product as yellow solids. MS (ESI) m/z 525.2 [M+H].sup.+.
Example 2
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylsulfinyl)-2-(4-(6-fluo-
ropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidi-
n-4(2H)-one
##STR00032##
[0401]
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylthio)-2-(4-(6-f-
luoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrim-
idin-4(2H)-one (12 mg, 0.023 mmol) is dissolved in CH.sub.3CN (2
mL) and CH.sub.3OH (2 mL), and then an aqueous solution of oxone is
added. The reaction mixture is stirred at room temperature for a
week, and then purified by a semi-preparative HPLC to give pure
product as white solids. MS (ESI) m/z 541.2 [M+H].sup.+.
Example 3
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-fluoropy-
ridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(-
2H)-one
##STR00033##
[0403]
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(6-fluoropyridin-2--
yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one
(50 mg, 0.12 mmol) and methyl disulfide (21.3 .mu.L, 0.24 mmol) are
dissolved in 1 mL of anhydrous THF, and then 360 uL of 1.0 M LDA in
THF is added dropwise. The reaction mixture is stirred at room
temperature for an hour, and then quenched with saline. The mixture
is separated with a semi-preparative HPLC to give 6.8 mg of pure
product as pale yellow solids. MS (ESI) m/z 463.2 [M+H].sup.+.
Example 4
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-(methylthio)-2-(4-(6-fluoropyridin-2-y-
l)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one
##STR00034##
[0405]
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-f-
luoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrim-
idin-4(2H)-one (25 mg, 0.054 mmol) and P.sub.4S.sub.10 (48.1 mg,
0.108 mmol) are placed in a Biotage microwave vial, and then 1.0 mL
of 7N ammonia in MeOH is added. The sealed vial is heated in a
Biotage microwave at 150.degree. C. for 6 h. After solvent is
removed, the residue is suspended in DMF, and then filtered. The
obtained filtrate is purified by a semi-preparative HPLC to give
10.6 mg of pure product as pale yellow solids (yield: 44%). MS
(ESI) m/z 449.2 [M+H].sup.+.
Example 5
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-(pyridin-2-ylthio)-2-(4-(6-fluoropyrid-
in-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-
-one
##STR00035##
[0407] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein 2-pyridyl disulfide is used instead of phenyl
disulfide. MS (ESI) m/z 526.2 [M+H].sup.+.
Example 6
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-((R)-methylsulfinyl)-2-(4-(6--
fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyri-
midin-4(2H)-one
##STR00036##
[0409]
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-f-
luoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrim-
idin-4(2H)-one (35.2 mg, 0.076 mmol) is dissolved in CH.sub.3CN
(0.5 mL) and CH.sub.3OH (2 mL), and then an aqueous solution of
oxone (93.7 mg, 0.152 mmol) is added. The reaction mixture is
stirred at room temperature for 20 h, and then purified by a
semi-preparative HPLC to give pure product as white solids. MS
(ESI) m/z 479.2 [M+H].sup.+.
Example 7
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-((S)-methylsulfinyl)-2-(4-(6--
fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyri-
midin-4(2H)-one
##STR00037##
[0411] The synthetic procedure of this compound is the same as
EXAMPLE 6. A pair of diastereoisomers is obtained during the
synthesis. Both diastereoisomers can be separated using an achiral
reversed-phase HPLC column. Product is obtained as white solids. MS
(ESI) m/z 479.2 [M+H].sup.+.
Example 8
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylsulfonyl)-2-(4-(6-fluo-
ropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidi-
n-4(2H)-one
##STR00038##
[0413]
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-f-
luoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrim-
idin-4(2H)-one (35.2 mg, 0.076 mmol) is dissolved in CH.sub.3CN
(0.5 mL) and CH.sub.3OH (2 mL), and then an aqueous solution of
oxone (139 mg, 0.226 mmol) is added. The reaction mixture is
stirred at room temperature for 2 days, and then purified by a
semi-preparative HPLC to give pure product as white solids. MS
(ESI) m/z 495.2 [M+H].sup.+.
Example 9
Measurement of PDE1B Inhibition In Vitro Using IMAP
Phosphodiesterase Assay Kit
[0414] Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin
dependent phosphodiesterase enzyme that converts cyclic guanosine
monophosphate (cGMP) to 5'-guanosine monophosphate (5'-GMP). PDE1B
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.
[0415] 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.
[0416] 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
(.DELTA.mp). Inhibition of phosphodiesterase, therefore, is
detected as a decrease in .DELTA.mp.
Enzyme Assay
[0417] 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:
3',5'-cyclic-nucleotide-specific bovine brain phosphodiesterase
(Sigma, St. Louis, Mo.) is reconstituted with 50% glycerol to 2.5
U/ml. One unit of enzyme will hydrolyze 1.0 .mu.mole 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 1.25mU/ml. 99 .mu.l 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.
[0418] 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 (.DELTA.mp).
[0419] A decrease in GMP concentration, measured as decreased
.DELTA.mp, is indicative of inhibition of PDE activity. IC.sub.50
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 .DELTA.mP,
which allows IC.sub.50 values to be estimated using nonlinear
regression software (XLFit; IDBS, Cambridge, Mass.).
[0420] The Compounds of the Invention may be selected and tested in
an assay as described or similarly described herein for PDE1
inhibitory activity. The exemplified compounds of the invention
generally have IC.sub.50 values of less than 1 .mu.M, e.g., some
less than 250 nM, some less than 10 nM, some less than 5 nM, e.g.,
the Compounds of Examples 1, 2 and 3 generally have IC.sub.50
values of less than 250 nM.
Example 10
PDE1 Inhibitor Effect on Sexual Response in Female Rats
[0421] The effect of PDE1 inhibitors on Lordosis Response in female
rats may be measured as described in Mani, et al., Science (2000)
287: 1053. Ovariectomized and cannulated wild-type rats are primed
with 2 .mu.g estrogen followed 24 hours later by
intracerebroventricular (icy) injection of progesterone (2 .mu.g),
PDE1 inhibitors of the present invention (0.1 mg, 1.0 mg or 2.5 mg)
or sesame oil vehicle (control). The rats are tested for lordosis
response in the presence of male rats. Lordosis response is
quantified by the lordosis quotient (LQ=number of lordosis/10
mounts.times.100).
* * * * *