U.S. patent application number 15/419902 was filed with the patent office on 2017-08-17 for organic compounds.
This patent application is currently assigned to INTRA-CELLULAR THERAPIES, INC.. The applicant listed for this patent is Peng LI, Lawrence P. WENNOGLE, Jun ZHAO, Hailin ZHENG. Invention is credited to Peng LI, Lawrence P. WENNOGLE, Jun ZHAO, Hailin ZHENG.
Application Number | 20170231994 15/419902 |
Document ID | / |
Family ID | 51529966 |
Filed Date | 2017-08-17 |
United States Patent
Application |
20170231994 |
Kind Code |
A1 |
LI; Peng ; et al. |
August 17, 2017 |
ORGANIC COMPOUNDS
Abstract
Provided are PDE1 inhibitors of Formula I, processes for their
production, their use as pharmaceuticals, and pharmaceutical
compositions comprising them.
Inventors: |
LI; Peng; (New Milford,
NJ) ; ZHENG; Hailin; (Teaneck, NJ) ; ZHAO;
Jun; (Highland Park, NJ) ; WENNOGLE; Lawrence P.;
(Hillsborough, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LI; Peng
ZHENG; Hailin
ZHAO; Jun
WENNOGLE; Lawrence P. |
New Milford
Teaneck
Highland Park
Hillsborough |
NJ
NJ
NJ
NJ |
US
US
US
US |
|
|
Assignee: |
INTRA-CELLULAR THERAPIES,
INC.
New York
NY
|
Family ID: |
51529966 |
Appl. No.: |
15/419902 |
Filed: |
January 30, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14731233 |
Jun 4, 2015 |
9556186 |
|
|
15419902 |
|
|
|
|
14209258 |
Mar 13, 2014 |
9073936 |
|
|
14731233 |
|
|
|
|
61788551 |
Mar 15, 2013 |
|
|
|
Current U.S.
Class: |
514/171 |
Current CPC
Class: |
A61P 5/00 20180101; A61P
27/06 20180101; A61P 11/00 20180101; A61P 25/18 20180101; A61P
43/00 20180101; A61P 25/30 20180101; A61K 45/06 20130101; A61P
25/16 20180101; A61K 31/57 20130101; A61K 31/519 20130101; A61P
15/00 20180101; C07D 487/14 20130101; A61K 31/5575 20130101; A61P
27/00 20180101; A61P 5/24 20180101; A61P 25/00 20180101; A61P 25/28
20180101; A61P 25/26 20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/57 20060101 A61K031/57; A61K 45/06 20060101
A61K045/06 |
Claims
1-6. (canceled)
7. A method of treating any of the following conditions:
Parkinson's disease, restless leg, tremors, dyskinesias,
Huntington's disease, Alzheimer's disease, drug-induced movement
disorders, depression, attention deficit disorder, attention
deficit hyperactivity disorder, bipolar illness, anxiety, sleep
disorder, narcolepsy, cognitive impairment, cognitive impairment of
schizophrenia, dementia, Tourette's syndrome, autism, fragile X
syndrome, psychostimulant withdrawal, drug addiction,
cerebrovascular disease, stroke, congestive heart disease,
hypertension, pulmonary hypertension, sexual dysfunction, asthma,
chronic obstructive pulmonary disease, allergic rhinitis,
autoimmune diseases, inflammatory diseases, 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, glaucoma, elevated
intraocular pressure, schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder,
and mania, and traumatic brain injury, 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 of Formula I:
##STR00032## wherein (i) R.sub.1 is H or C.sub.1-4 alkyl; (ii)
R.sub.2 and R.sub.3 are independently H or C.sub.1-6 alkyl; (iii)
R.sub.4 is H or C.sub.1-4 alkyl; (iv) R.sub.5 is aryl optionally
substituted with one or more groups independently selected from
--C(.dbd.O)--C.sub.1-6 alkyl and C.sub.1-6-hydroxyalkyl; (v)
R.sub.6 and R.sub.7 are independently H; aryl optionally
substituted with one or more groups independently selected from
C.sub.1-6 alkyl and halogen unsubstituted phenyl; phenyl
substituted with one or more halogen; phenyl substituted with one
or more C.sub.1-6 alkyl and one or more halogen; or phenyl
substituted with one C.sub.1-6 alkyl and one halogen; and (vi) n is
1, 2, 3, or 4, in free or pharmaceutically acceptable salt form, to
a patient in need thereof.
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 cognitive
impairment of schizophrenia.
11. The method of claim 7, wherein the condition is narcolepsy.
12. The method of claim 11 further comprising administering one or
more compounds selected from central nervous system stimulants,
modafinil, antidepressants, and gamma hydroxybutyrate, to a patient
in need thereof.
13. The method of claim 7, wherein the condition is female sexual
dysfunction.
14. The method of claim 13, further comprising administering one or
more compounds selected from estradiol, estriol, estradiol esters,
progesterone and progestins, to a patient in need thereof.
15. A method for the treatment of glaucoma or elevated intraocular
pressure comprising topical administration of an effective amount
of a compound of Formula I: ##STR00033## wherein (i) R.sub.1 is H
or C.sub.1-4 alkyl; (ii) R.sub.2 and R.sub.3 are independently H or
C.sub.1-6 alkyl; (iii) R.sub.4 is H or C.sub.1-4 alkyl; (iv)
R.sub.5 is aryl optionally substituted with one or more groups
independently selected from --C(.dbd.O)--C.sub.1-6 alkyl and
C.sub.1-6-hydroxyalkyl; (v) R.sub.6 and R.sub.7 are independently
H; aryl optionally substituted with one or more groups
independently selected from C.sub.1-6 alkyl and halogen
unsubstituted phenyl; phenyl substituted with one or more halogen;
phenyl substituted with one or more C.sub.1-6 alkyl and one or more
halogen; or phenyl substituted with one C.sub.1-6 alkyl and one
halogen; and (vi) n is 1, 2, 3, or 4, in free or pharmaceutically
acceptable salt form, in an ophthalmically compatible carrier to
the eye of a patient in need thereof.
16. A method for the treatment of traumatic brain injury comprising
administering an effective amount of a compound of Formula I:
##STR00034## wherein (i) R.sub.1 is H or C.sub.1-4 alkyl; (ii)
R.sub.2 and R.sub.3 are independently H or C.sub.1-6 alkyl; (iii)
R.sub.4 is H or C.sub.1-4 alkyl; (iv) R.sub.5 is aryl optionally
substituted with one or more groups independently selected from
--C(.dbd.O)--C.sub.1-6 alkyl and C.sub.1-6-hydroxyalkyl; (v)
R.sub.6 and R.sub.7 are independently H; aryl optionally
substituted with one or more groups independently selected from
C.sub.1-6 alkyl and halogen unsubstituted phenyl; phenyl
substituted with one or more halogen; phenyl substituted with one
or more C.sub.1-6 alkyl and one or more halogen; or phenyl
substituted with one C.sub.1-6 alkyl and one halogen; and (vi) n is
1, 2, 3, or 4, in free or pharmaceutically acceptable salt form, to
a patient in need thereof.
17-30. (canceled)
31. The method of claim 7, wherein the compound of Formula 1 is a
compound of Formula I(i): ##STR00035## wherein (i) R.sub.1 is H or
C.sub.1-4 alkyl; (ii) R.sub.2 and R.sub.3 are independently H or
C.sub.1-6 alkyl; (iii) R.sub.4 is H or C.sub.1-4 alkyl; (iv)
R.sub.5 is aryl optionally substituted with one or more groups
independently selected from --C(.dbd.O)--C.sub.1-6 alkyl and
C.sub.1-6-hydroxyalkyl; (v) R.sub.6 and R.sub.7 are independently
H; aryl optionally substituted with one or more groups
independently selected from C.sub.1-6 alkyl and halogen;
unsubstituted phenyl; phenyl substituted with one or more halogen;
phenyl substituted with one or more C.sub.1-6 alkyl and one or more
halogen; or phenyl substituted with one C.sub.1-6 alkyl and one
halogen; and (vi) n is 1, 2, 3, or 4, in free or salt form.
32. The method according to claim 7, wherein the compound is a
compound of Formula I(H): ##STR00036## wherein (i) R.sub.1 is H or
C.sub.1-4 alkyl; (ii) R.sub.2 and R.sub.3 are independently H or
C.sub.1-6 alkyl; (iii) R.sub.4 is H or C.sub.1-4 alkyl; (iv)
R.sub.5 is aryl optionally substituted with one or more groups
independently selected from --C(.dbd.O)--C.sub.1-6 alkyl and
C.sub.1-6-hydroxyalkyl; and (v) R.sub.6 and R.sub.7 are
independently H; aryl optionally substituted with one or more
groups independently selected from C.sub.1-6 alkyl and halogen;
unsubstituted phenyl; phenyl substituted with one or more halogen
phenyl substituted with one or more C.sub.1-6 alkyl and one or more
halogen; or phenyl substituted with one C.sub.1-6 alkyl and one
halogen, in free or salt form.
33. The method according to claim 32, wherein (i) R.sub.1 is
C.sub.1-4 alkyl; (ii) R.sub.2 and R.sub.3 are independently
C.sub.1-6 alkyl; (iii) R.sub.4 is H; (iv) R.sub.5 is aryl
substituted with one or more groups independently selected from
--C(.dbd.O)--C.sub.1-6 alkyl and C.sub.1-6-hydroxyalkyl; (v)
R.sub.6 is aryl substituted with one or more groups independently
selected from C.sub.1-6 alkyl; halogen; phenyl substituted with one
or more halogen; phenyl substituted with one or more C.sub.1-6
alkyl and one or more halogen; or phenyl substituted with one
C.sub.1-6 alkyl and one halogen; and (vi) R.sub.7 is H, in free or
salt form.
34. The method according to claim 32, wherein the compound is
selected from ##STR00037## in free or salt form.
35. The method according to claim 7, wherein the compound of
Formula I is ##STR00038## in free or salt form.
36. The method according to claim 7, wherein the compound of
Formula I is ##STR00039## in free or salt form.
37. The method according to claim 7, wherein the compound of
Formula I is ##STR00040## in free or salt form.
38. The method according to claim 7, wherein the compound of
Formula I is ##STR00041## in free or salt form.
39. A method of treating any of the following conditions:
Parkinson's disease, restless leg, tremors, dyskinesias,
Huntington's disease, Alzheimer's disease, drug-induced movement
disorders, depression, attention deficit disorder, attention
deficit hyperactivity disorder, bipolar illness, anxiety, sleep
disorder, narcolepsy, cognitive impairment, cognitive impairment of
schizophrenia, dementia, Tourette's syndrome, autism, fragile X
syndrome, psychostimulant withdrawal, drug addiction,
cerebrovascular disease, stroke, congestive heart disease,
hypertension, pulmonary hypertension, sexual dysfunction, asthma,
chronic obstructive pulmonary disease, allergic rhinitis,
autoimmune diseases, inflammatory diseases, 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, glaucoma, elevated
intraocular pressure, schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder,
mania, traumatic brain injury, comprising administering a
pharmaceutical composition comprising an effective amount of a
compound of Formula I: ##STR00042## wherein (i) R.sub.1 is H or
C.sub.1-4 alkyl; (ii) R.sub.2 and R.sub.3 are independently H or
C.sub.1-6 alkyl; (iii) R.sub.4 is H or C.sub.1-4 alkyl; (iv)
R.sub.5 is aryl optionally substituted with one or more groups
independently selected from --C(.dbd.O)--C.sub.1-6 alkyl and
C.sub.1-6-hydroxyalkyl; (v) R.sub.6 and R.sub.7 are independently
H; aryl optionally substituted with one or more groups
independently selected from C.sub.1-6 alkyl and halogen
unsubstituted phenyl; phenyl substituted with one or more halogen;
phenyl substituted with one or more C.sub.1-6 alkyl and one or more
halogen; or phenyl substituted with one C.sub.1-6 alkyl and one
halogen; and (vi) n is 1, 2, 3, or 4, in free or pharmaceutically
acceptable salt form, in admixture with a pharmaceutically
acceptable diluent or carrier, to a patient in need thereof.
40. The method of claim 39, wherein the compound of Formula 1 is a
compound of Formula I(i): ##STR00043## wherein (i) R.sub.1 is H or
C.sub.1-4 alkyl; (ii) R.sub.2 and R.sub.3 are independently H or
C.sub.1-6 alkyl; (iii) R.sub.4 is H or C.sub.1-4 alkyl; (iv)
R.sub.5 is aryl optionally substituted with one or more groups
independently selected from --C(.dbd.O)--C.sub.1-6 alkyl and
C.sub.1-6-hydroxyalkyl; (v) R.sub.6 and R.sub.7 are independently
H; aryl optionally substituted with one or more groups
independently selected from C.sub.1-6 alkyl and halogen;
unsubstituted phenyl; phenyl substituted with one or more halogen;
phenyl substituted with one or more C.sub.1-6 alkyl and one or more
halogen; or phenyl substituted with one C.sub.1-6 alkyl and one
halogen; and (vi) n is 1, 2, 3, or 4, in free or salt form.
41. The method of claim 39, wherein the compound is a compound of
Formula I(ii): ##STR00044## wherein (i) R.sub.1 is H or C.sub.1-4
alkyl; (ii) R.sub.2 and R.sub.3 are independently H or C.sub.1-6
alkyl; (iii) R.sub.4 is H or C.sub.1-4 alkyl; (iv) R.sub.5 is aryl
optionally substituted with one or more groups independently
selected from --C(.dbd.O)--C.sub.1-6 alkyl and
C.sub.1-6-hydroxyalkyl; and (v) R.sub.6 and R.sub.7 are
independently H; aryl optionally substituted with one or more
groups independently selected from C.sub.1-6 alkyl and halogen;
unsubstituted phenyl; phenyl substituted with one or more halogen
phenyl substituted with one or more C.sub.1-6 alkyl and one or more
halogen; or phenyl substituted with one C.sub.1-6 alkyl and one
halogen, in free or salt form.
42. The method according to claim 41, wherein (i) R.sub.1 is
C.sub.1-4 alkyl; (ii) R.sub.2 and R.sub.3 are independently
C.sub.1-6 alkyl; (iii) R.sub.4 is H; (iv) R.sub.5 is aryl
substituted with one or more groups independently selected from
--C(.dbd.O)--C.sub.1-6 alkyl and C.sub.1-6-hydroxyalkyl; (v)
R.sub.6 is aryl substituted with one or more groups independently
selected from C.sub.1-6 alkyl; halogen; phenyl substituted with one
or more halogen; phenyl substituted with one or more C.sub.1-6
alkyl and one or more halogen; or phenyl substituted with one
C.sub.1-6 alkyl and one halogen; and (vi) R.sub.7 is H, in free or
salt form.
43. The method according to claim 39, wherein the compound is
selected from ##STR00045## in free or salt form.
44. The method according to claim 39, wherein the compound of
Formula I is ##STR00046## in free or salt form.
45. The method according to claim 39, wherein the compound of
Formula I is ##STR00047## in free or salt form.
46. The method according to claim 39, wherein the compound of
Formula I is ##STR00048## in free or salt form.
47. The method according to claim 39, wherein the compound of
Formula I is ##STR00049## in free or salt form.
Description
[0001] This application claims priority to U.S. Provisional
Application No. 61/788,551, filed on Mar. 15, 2013, the contents of
which are hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to PDE1 inhibitory compounds
of Formula I as described below, processes for their production,
their use as pharmaceuticals and pharmaceutical compositions
comprising them. These compounds are useful e.g., in the treatment
of diseases involving disorders of the dopamine D1 receptor
intracellular pathway, such as, among others, Parkinson's disease,
depression, narcolepsy, psychosis, 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 human central nervous
system tissue. PDE1A is expressed in the brain with high levels in
the CA1 to CA3 layers of the hippocampus and cerebellum and at a
low level in the striatum. PDE1B is predominately expressed in the
striatum, dentate gyrus, olfactory tract and in the prefrontal
cortex colocalized with the dopamine D1 receptor. Its expression
generally correlates with brain regions having high levels of
dopaminergic innervation. Although PDE1B is primarily expressed in
the central nervous system, it is present in neutrophils. PDE1C is
more ubiquitously expressed in the brain and is 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 adenylate cyclases, resulting in
increased cAMP. This cyclic nucleotide in turn activates protein
kinase A (PKA; cAMP-dependent protein kinase). Production of cGMP
is known to occur in tissues involved in cognitive function through
various stimulations such as nitric oxide production induced by
high intra-cellular calcium levels and to subsequently activate
protein kinase G (PKG; cGMP-dependent protein kinase). PKG and PKA
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. D1 receptor signaling is disrupted in
schizophrenia, contributing to cognitive impairment in the disease.
The role of cAMP and cGMP in cognitive function has been well
established in animal studies. Studies in rodents also 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, scrotonin, 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 that is a consequence of D2
receptor-mediated increases in intra-cellular calcium. Chronic
elevation in intracellular calcium levels is linked to cell death
in numerous disorders, particularly in neurodegenerative 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 such as
cognitive impairment associated with schizophrenia. 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.
SUMMARY OF THE INVENTION
[0008] The invention provides a compound of Formula I:
##STR00001##
[0009] wherein [0010] (i) R.sub.1 is H or C.sub.1-4 alkyl (e.g.,
methyl or ethyl); [0011] (ii) R.sub.2 and R.sub.3 are independently
H or C.sub.1-6 alkyl (e.g., methyl or ethyl); [0012] (iii) R.sub.4
is H or C.sub.1-4 alkyl (e.g., methyl or ethyl); [0013] (iv)
R.sub.5 is aryl (e.g., phenyl) optionally substituted with one or
more groups independently selected from --C(.dbd.O)--C.sub.1-6
alkyl (e.g., --C(.dbd.O)--CH.sub.3) and C.sub.1-6-hydroxyalkyl
(e.g., 1-hydroxyethyl); [0014] (v) R.sub.6 and R.sub.7 are
independently H or aryl (e.g., phenyl) optionally substituted with
one or more groups independently selected from C.sub.1-6 alkyl
(e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example
unsubstituted phenyl or phenyl substituted with one or more halogen
(e.g., F) or phenyl substituted with one or more C.sub.1-6 alkyl
and one or more halogen or phenyl substituted with one C.sub.1-6
alkyl and one halogen, for example 4-fluorophenyl or
3,4-difluorophenyl or 4-fluoro-3-methylphenyl; [0015] and [0016]
(vi) n is 1, 2, 3, or 4,
[0017] in free or salt form.
[0018] In one embodiment, the compound of Formula I as described
above, is a compound of Formula I(i):
##STR00002##
[0019] wherein [0020] (i) R.sub.1 is H or C.sub.1-4 alkyl (e.g.,
methyl or ethyl); [0021] (ii) R.sub.2 and R.sub.3 are independently
H or C.sub.1-6 alkyl (e.g., methyl or ethyl); [0022] (iii) R.sub.4
is H or C.sub.1-4 alkyl (e.g., methyl or ethyl); [0023] (iv)
R.sub.5 is aryl (e.g., phenyl) optionally substituted with one or
more groups independently selected from --C(.dbd.O)--C.sub.1-6
alkyl (e.g., --C(.dbd.O)--CH.sub.3) and C.sub.1-6-hydroxyalkyl
(e.g., 1-hydroxyethyl); [0024] (v) R.sub.6 and R.sub.7 are
independently H or aryl (e.g., phenyl) optionally substituted with
one or more groups independently selected from C.sub.1-6 alkyl
(e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example
unsubstituted phenyl or phenyl substituted with one or more halogen
(e.g., F) or phenyl substituted with one or more C.sub.1-6 alkyl
and one or more halogen or phenyl substituted with one C.sub.1-6
alkyl and one halogen, for example 4-fluorophenyl or
3,4-difluorophenyl or 4-fluoro-3-methylphenyl; [0025] and [0026]
(vi) n is 1, 2, 3, or 4,
[0027] in free or salt form.
[0028] In another embodiment, the compound of Formula I as
described above, is a compound of Formula
##STR00003##
[0029] wherein [0030] (i) R.sub.1 is H or C.sub.1-4 alkyl (e.g.,
methyl or ethyl); [0031] (ii) R.sub.2 and R.sub.3 are independently
H or C.sub.1-6 alkyl (e.g., methyl or ethyl); [0032] (iii) R.sub.4
is H or C.sub.1-4 alkyl (e.g., methyl or ethyl); [0033] (iv)
R.sub.5 is aryl (e.g., phenyl) optionally substituted with one or
more groups independently selected from --C(.dbd.O)--C.sub.1-6
alkyl (e.g., --C(.dbd.O)--CH.sub.3) and C.sub.1-6-hydroxyalkyl
(e.g., 1-hydroxyethyl); and [0034] (v) R.sub.6 and R.sub.7 are
independently H or aryl (e.g., phenyl) optionally substituted with
one or more groups independently selected from C.sub.1-6 alkyl
(e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example
unsubstituted phenyl or phenyl substituted with one or more halogen
(e.g., F) or phenyl substituted with one or more C.sub.1-6 alkyl
and one or more halogen or phenyl substituted with one C.sub.1-6
alkyl and one halogen, for example 4-fluorophenyl or
3,4-difluorophenyl or 4-fluoro-3-methylphenyl,
[0035] in free or salt form.
[0036] The invention further provides compounds of Formula I, I(i),
and I(ii) as follows: [0037] 1.1 Formula I or I(i), wherein n is 1,
2, or 3; [0038] 1.2 Formula I or I(i), wherein n is 1 or 2; [0039]
1.3 Formula I, wherein n is 1; [0040] 1.4 Any of Formulae I, I(i),
I(ii), or 1.1-1.3, wherein R.sub.1 is H or C.sub.1-3 alkyl (e.g.,
methyl); [0041] 1.5 Any of Formulae I, I(i), I(ii), or 1.1-1.3,
wherein R.sub.1 is H; [0042] 1.6 Any of Formulae I, I(i), I(ii), or
1.1-1.3, wherein R.sub.1 is C.sub.1-4 alkyl; [0043] 1.7 Any of
Formulae I, I(i), I(ii), or 1.1-1.3, wherein R.sub.1 is methyl;
[0044] 1.8 Any of Formulae I, I(i), I(ii), or 1.1-1.7, wherein
R.sub.2 and R.sub.3 are independently H or C.sub.1-5 alkyl (e.g.,
methyl or ethyl); [0045] 1.9 Any of Formulae I, I(i), or 1.1-1.7,
wherein R.sub.2 and R.sub.3 are independently H or C.sub.1-4 alkyl
(e.g., methyl); [0046] 1.10 Any of Formulae I, I(i), I(ii), or
1.1-1.7, wherein R.sub.2 and R.sub.3 are both C.sub.1-6 alkyl
(e.g., C.sub.1-4 alkyl, e.g., methyl); [0047] 1.11 Any of Formulae
I, I(i), I(ii), or 1.1-1.7, wherein R.sub.2 and R.sub.3 are both
C.sub.1-4 alkyl (e.g., methyl); [0048] 1.12 Any of Formulae I,
I(i), I(ii), or 1.1-1.7, wherein R.sub.2 and R.sub.1 are both
methyl; [0049] 1.13 Any of Formulae I, I(i), I(ii), or 1.1-1.12,
wherein R.sub.4 is H or C.sub.1-3 alkyl (e.g., methyl or ethyl);
[0050] 1.14 Any of Formulae I, I(i), I(ii), or 1.1-1.12, wherein
R.sub.4 is H; [0051] 1.15 Any of Formulae I, I(i), I(ii) or
1.1-1.14, wherein R.sub.5 is aryl (e.g., phenyl) substituted with
one or more groups independently selected from
--C(.dbd.O)--C.sub.1-6 alkyl (e.g., --C(.dbd.O)--C.sub.1-4 alkyl,
e.g., --C(.dbd.O)--CH.sub.3) and C.sub.1-6-hydroxyalkyl (e.g.,
C.sub.1-4-hydroxyalkyl, e.g., 1-hydroxyethyl), for example
substituted with one --C(.dbd.O)--C.sub.1-6 alkyl (e.g.,
--C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3) or one
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl); [0052] 1.16 Any of Formulae I, I(i), I(ii), or
1.1-1.14, wherein R.sub.5 is aryl (e.g., phenyl) substituted with
one or more groups independently selected from
--C(.dbd.O)--C.sub.1-4 alkyl (e.g., --C(.dbd.O)--CH.sub.3) and
C.sub.1-4-hydroxyalkyl (e.g., 1-hydroxyethyl), for example
substituted with one --C(.dbd.O)--C.sub.1-4 alkyl (e.g.,
--C(.dbd.O)--CH.sub.3) or one C.sub.1-4-hydroxyalkyl (e.g.,
1-hydroxyethyl); [0053] 1.17 Any of Formulae I, I(i), I(ii), or
1.1-1.14, wherein R.sub.5 is phenyl optionally substituted with one
or more groups independently selected from --C(.dbd.O)--C.sub.1-6
alkyl (e.g., --C(.dbd.O)--C.sub.1-4 alkyl, e.g.,
--C(.dbd.O)--CH.sub.3) and C.sub.1-6-hydroxyalkyl (e.g.,
C.sub.1-4-hydroxyalkyl, e.g., 1-hydroxyethyl); [0054] 1.18 Any of
Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is phenyl
substituted with one or more groups independently selected from
--C(.dbd.O)--C.sub.1-6 alkyl (e.g., --C(.dbd.O)--C.sub.1-4 alkyl,
e.g., --C(.dbd.O)--CH.sub.3) and C.sub.1-6-hydroxyalkyl (e.g.,
C.sub.1-4-hydroxyalkyl, e.g., 1-hydroxyethyl), for example
substituted with one --C(.dbd.O)--C.sub.1-6 alkyl (e.g.,
--C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3) or one
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl), for example wherein R.sub.5 is 4-acetylphenyl or
4-(1-hydroxyethyl)phenyl; [0055] 1.19 Any of Formulae I, I(i),
I(ii), or 1.1-1.14, wherein R.sub.5 is phenyl substituted with one
or more groups independently selected from --C(.dbd.O)--C.sub.1-4
alkyl (e.g., --C(.dbd.O)--CH.sub.3) and C.sub.1-4-hydroxyalkyl
(e.g., 1-hydroxyethyl), for example substituted with one
--C(.dbd.O)--C.sub.1-4 alkyl (e.g., --C(.dbd.O)--CH.sub.3) or one
C.sub.1-4-hydroxyalkyl (e.g., 1-hydroxyethyl), for example wherein
R.sub.5 is 4-acetylphenyl or 4-(1-hydroxyethyl)phenyl; [0056] 1.20
Any of Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is
aryl substituted with one or more --C(.dbd.O)--C.sub.1-6 alkyl
(e.g., --C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3);
[0057] 1.21 Any of Formulae I, I(i), I(ii), or 1.1-1.14, wherein
R.sub.5 is aryl substituted with one or more --C(.dbd.O)--C.sub.1-4
alkyl (e.g., --C(.dbd.O)--CH.sub.3); [0058] 1.22 Any of Formulae I,
I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is aryl substituted with
one --C(.dbd.O)--C.sub.1-6 alkyl (e.g., --C(.dbd.O)--C.sub.1-4
alkyl, e.g., --C(.dbd.O)--CH.sub.3); [0059] 1.23 Any of Formulae I,
I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is aryl substituted with
one --C(.dbd.O)--C.sub.1-4 alkyl (e.g., --C(.dbd.O)--CH.sub.3);
[0060] 1.24 Any of Formulae I, I(i), I(ii), or 1.1-1.14, wherein
R.sub.5 is aryl substituted with one --C(.dbd.O)--CH.sub.3; [0061]
1.25 Any of Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5
is aryl substituted with one or more C.sub.1-6-hydroxyalkyl (e.g.,
C.sub.1-4-hydroxyalkyl, e.g., 1-hydroxyethyl); [0062] 1.26 Any of
Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is aryl
substituted with one or more C.sub.1-4-hydroxyalkyl (e.g.,
1-hydroxyethyl); [0063] 1.27 Any of Formulae I, I(i), I(ii), or
1.1-1.14, wherein R.sub.5 is aryl substituted with one
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl); [0064] 1.28 Any of Formulae I, I(i), I(ii), or
1.1-1.14, wherein R.sub.5 is aryl substituted with one
C.sub.1-4-hydroxyalkyl (e.g., 1-hydroxyethyl); [0065] 1.29 Any of
Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is aryl
substituted with one 1-hydroxyethyl; [0066] 1.30 Any of Formulae I,
I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is phenyl substituted
with one or more --C(.dbd.O)--C.sub.1-6 alkyl (e.g.,
--C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3); [0067]
1.31 Any of Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5
is phenyl substituted with one or more --C(.dbd.O)--C.sub.1-4 alkyl
(e.g., --C(.dbd.O)--CH.sub.3); [0068] 1.32 Any of Formulae I, I(i),
I(ii), or 1.1-1.14, wherein R.sub.5 is phenyl substituted with one
--C(.dbd.O)--C.sub.1-6 alkyl (e.g., --C(.dbd.O)--C.sub.1-4 alkyl,
e.g., --C(.dbd.O)--CH.sub.3); [0069] 1.33 Any of Formulae I, I(i),
I(ii), or 1.1-1.14, wherein R.sub.5 is phenyl substituted with one
--C(.dbd.O)--C.sub.1-4 alkyl (e.g., --C(.dbd.O)--CH.sub.3); [0070]
1.34 Any of Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5
is phenyl substituted with one --C(.dbd.O)--CH.sub.3; [0071] 1.35
Any of Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is
4-acetylphenyl; [0072] 1.36 Any of Formulae I, I(i), I(ii), or
1.1-1.14, wherein R.sub.5 is phenyl substituted with one or more
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl); [0073] 1.37 Any of Formulae I, I(i), I(ii), or
1.1-1.14, wherein R.sub.5 is phenyl substituted with one or more
C.sub.1-4-hydroxyalkyl (e.g., 1-hydroxyethyl); [0074] 1.38 Any of
Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is phenyl
substituted with one C.sub.1-6-hydroxyalkyl (e.g.,
C.sub.1-4-hydroxyalkyl, e.g., 1-hydroxyethyl); [0075] 1.39 Any of
Formulae I, I(i), I(ii), or 1.1-1.14, wherein R.sub.5 is phenyl
substituted with one C.sub.1-4-hydroxyalkyl (e.g., 1-hydroxyethyl);
[0076] 1.40 Any of Formulae I, I(i), I(ii) or 1.1-1.14, wherein
R.sub.5 is phenyl substituted with one 1-hydroxyethyl; [0077] 1.41
Any of Formulae I, I(i), I(ii) or 1.1-1.14, wherein R.sub.5 is
4-(1-hydroxyethyl)phenyl; [0078] 1.42 Any of Formulae I, I(i),
I(ii) or 1.1-1.41, wherein R.sub.6 and R.sub.7 are independently H
or aryl (e.g., phenyl) substituted with one or more groups
independently selected from C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl,
e.g., methyl or ethyl) and halogen (e.g., F or Cl), for example
phenyl substituted with one or more (e.g., two) halogen (e.g., F)
or phenyl substituted with one or more C.sub.1-6 alkyl (e.g.,
C.sub.1-4 alkyl, e.g., methyl) and one or more halogen (e.g., F) or
phenyl substituted with one C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl,
e.g., methyl) and one halogen (e.g., F), for example 4-fluorophenyl
or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl; [0079] 1.43 Any
of Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and
R.sub.6 is aryl (e.g., phenyl) substituted with one or more groups
independently selected from C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl,
e.g., methyl) and halogen (e.g., F or Cl), for example R.sub.6 is
phenyl substituted with one or more (e.g., two) halogen (e.g., F)
or phenyl substituted with one C.sub.1-6 alkyl (e.g., C.sub.1-4
alkyl, e.g., methyl) and one halogen (e.g., F), for example wherein
R.sub.6 is 4-fluorophenyl or 3,4-difluorophenyl or
4-fluoro-3-methylphenyl; [0080] 1.44 Formulae I, I(i), I(ii), or
1.1-1.41, wherein R.sub.7 is H and R.sub.6 is aryl (e.g., phenyl)
substituted with one or more groups independently selected from
C.sub.1-4 alkyl (e.g., methyl) and halogen (e.g., F), for example
R.sub.6 is phenyl substituted with one or more (e.g., two) halogen
(e.g., F) or phenyl substituted with one C.sub.1-4 alkyl (e.g.,
methyl) and one halogen (e.g., F), for example wherein R.sub.6 is
4-fluorophenyl or 3,4-difluorophenyl or 4-fluoro-3-methylphenyl;
[0081] 1.45 Any of Formulae I, I(i), I(ii), or 1.1-1.41, wherein
R.sub.7 is H and R.sub.6 is aryl (e.g., phenyl) substituted with
one or more halogen (e.g., F); [0082] 1.46 Any of Formulae I, I(i),
I(ii), or 1.1-1.41, wherein R.sub.7 is H and R.sub.6 is aryl (e.g.,
phenyl) substituted with two halogens (e.g., F); [0083] 1.47 Any of
Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and
R.sub.6 is aryl (e.g., phenyl) substituted with one halogen (e.g.,
F); [0084] 1.48 Any of Formulae I, I(i), I(ii), or 1.1-1.41,
wherein R.sub.7 is H and R.sub.6 is aryl (e.g., phenyl) substituted
with two F; [0085] 1.49 Any of Formulae I, I(i), I(ii), or
1.1-1.41, wherein R.sub.7 is H and R.sub.6 is aryl (e.g., phenyl)
substituted with one F; [0086] 1.50 Any of Formulae I, I(i), I(ii),
or 1.1-1.41, wherein R.sub.7 is H and R.sub.6 is aryl (e.g.,
phenyl) substituted with one or more C.sub.1-6 alkyl (e.g.,
C.sub.1-4 alkyl, e.g., methyl) and one or more halogen (e.g., F);
[0087] 1.51 Any of Formulae I, I(i), I(ii), or 1.1-1.41, wherein
R.sub.7 is H and R.sub.6 is aryl (e.g., phenyl) substituted with
one or more C.sub.1-4 alkyl (e.g., methyl) and one or more halogen
(e.g., F); [0088] 1.52 Any of Formulae I, I(i), I(ii), or 1.1-1.41,
wherein R.sub.7 is H and R.sub.6 is aryl (e.g., phenyl) substituted
with one C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl) and
one halogen (e.g., F); [0089] 1.53 Any of Formulae I, I(i), I(ii),
or 1.1-1.41, wherein R.sub.7 is H and R.sub.6 is aryl (e.g.,
phenyl) substituted with one C.sub.1-4 alkyl (e.g., methyl) and one
halogen (e.g., F); [0090] 1.54 Any of Formulae I, I(i), I(ii), or
1.1-1.41, wherein R.sub.7 is H and R.sub.6 is aryl (e.g., phenyl)
substituted with one methyl and one F; [0091] 1.55 Any of Formulae
I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and R.sub.6 is
phenyl substituted with one or more halogen (e.g., F); [0092] 1.56
Any of Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H
and R.sub.6 is phenyl substituted with two halogens (e.g., F);
[0093] 1.57 Any of Formulae I, I(i), I(ii), or 1.1-1.41, wherein
R.sub.7 is H and R.sub.6 is phenyl substituted with one halogen
(e.g., F); [0094] 1.58 Any of Formulae I, I(i), I(ii), or 1.1-1.41,
wherein R.sub.6 is phenyl substituted with two F; [0095] 1.59 Any
of Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and
R.sub.6 is phenyl substituted with one F; [0096] 1.60 Any of
Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and
R.sub.6 is 3,4-difluorophenyl; [0097] 1.61 Any of Formulae I, I(i),
I(ii), or 1.1-1.41, wherein R.sub.7 is H and R.sub.6 is
4-fluorophenyl; [0098] 1.62 Any of Formulae I, I(i), I(ii), or
1.1-1.41, wherein R.sub.7 is H and R.sub.6 is phenyl substituted
with one or more C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl, e.g.,
methyl) and one or more halogen (e.g., F); [0099] 1.63 Any of
Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and
R.sub.6 is phenyl substituted with one or more C.sub.1-4 alkyl
(e.g., methyl) and one or more halogen (e.g., F); [0100] 1.64 Any
of Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and
R.sub.6 is phenyl substituted with one C.sub.1-6 alkyl (e.g.,
C.sub.1-4 alkyl, e.g., methyl) and one halogen (e.g., F); [0101]
1.65 Any of Formula I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is
H and R.sub.6 is phenyl substituted with one C.sub.1-4 alkyl (e.g.,
methyl) and one halogen (e.g., F); [0102] 1.66 Any of Formulae I,
I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and R.sub.6 is
phenyl substituted with one methyl and one F; [0103] 1.67 Any of
Formulae I, I(i), I(ii), or 1.1-1.41, wherein R.sub.7 is H and
R.sub.6 is 4-fluoro-3-methylphenyl; [0104] 1.68 Any of Formulae I,
I(i), or I(ii), wherein R.sub.1 is C.sub.1-4 alkyl (e.g., methyl);
R.sub.2 and R.sub.3 are independently C.sub.1-6 alkyl (e.g.,
C.sub.1-4 alkyl, e.g., methyl); R.sub.4 is H; R.sub.5 is aryl
(e.g., phenyl) substituted with one or more groups independently
selected from --C(.dbd.O)--C.sub.1-6 alkyl (e.g.,
--C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3) and
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl), for example R.sub.5 is aryl (e.g., phenyl)
substituted with one --C(.dbd.O)--C.sub.1-6 alkyl (e.g.,
--C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3) or one
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl), for example wherein R.sub.5 is 4-acetylphenyl or
4-(1-hydroxyethyl)phenyl; R.sub.6 is aryl (e.g., phenyl)
substituted with one or more groups independently selected from
C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl) and halogen
(e.g., F), for example phenyl substituted with one or more (e.g.,
two) halogen (e.g., F) or phenyl substituted with one or more
C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl) and one or
more halogen (e.g., F) or phenyl substituted with one C.sub.1-6
alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl) and one halogen (e.g.,
F), for example wherein R.sub.6 is 4-fluorophenyl or
3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and R.sup.7 is H;
[0105] 1.69 Formula I(ii), wherein R.sub.1 is C.sub.1-4 alkyl
(e.g., methyl); R.sub.2 and R.sub.3 are independently C.sub.1-6
alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl); R.sub.4 is H; R.sub.5
is aryl (e.g., phenyl) substituted with one or more groups
independently selected from --C(.dbd.O)--C.sub.1-6 alkyl (e.g.,
--C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3) and
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl), for example R.sub.5 is aryl (e.g., phenyl)
substituted with one --C(.dbd.O)--C.sub.1-6 alkyl (e.g.,
--C(.dbd.O)--C.sub.1-4 alkyl, e.g., --C(.dbd.O)--CH.sub.3) or one
C.sub.1-6-hydroxyalkyl (e.g., C.sub.1-4-hydroxyalkyl, e.g.,
1-hydroxyethyl), for example wherein R.sub.5 is 4-acetylphenyl or
4-(1-hydroxyethyl)phenyl; R.sub.6 is aryl (e.g., phenyl)
substituted with one or more groups independently selected from
C
.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl) and halogen
(e.g., F), for example phenyl substituted with one or more (e.g.,
two) halogen (e.g., F) or phenyl substituted with one or more
C.sub.1-6 alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl) and one or
more halogen (e.g., F) or phenyl substituted with one C.sub.1-6
alkyl (e.g., C.sub.1-4 alkyl, e.g., methyl) and one halogen (e.g.,
F), for example wherein R.sub.6 is 4-fluorophenyl or
3,4-difluorophenyl or 4-fluoro-3-methylphenyl; and R.sup.7 is H;
[0106] 1.70 Formula 1.69, wherein R.sub.2 and R.sub.3 are
independently C.sub.1-4 alkyl (e.g., methyl); R.sub.5 is aryl
(e.g., phenyl) substituted with one or more groups independently
selected from --C(.dbd.O)--C.sub.1-4 alkyl (e.g.,
--C(.dbd.O)--CH.sub.3) and C.sub.1-4-hydroxyalkyl (e.g.,
1-hydroxyethyl), for example R.sub.5 is aryl (e.g., phenyl)
substituted with one --C(.dbd.O)--C.sub.1-4 alkyl (e.g.,
--C(.dbd.O)--CH.sub.3) or one C.sub.1-4-hydroxyalkyl (e.g.,
1-hydroxyethyl), for example wherein R.sub.5 is 4-acetylphenyl or
4-(1-hydroxyethyl)phenyl; R.sub.6 is aryl (e.g., phenyl)
substituted with one or more groups independently selected from
C.sub.1-4 alkyl (e.g., methyl) and halogen (e.g., F), for example
phenyl substituted with one or more (e.g., two) halogen (e.g., F)
or phenyl substituted with one or more C.sub.1-4 alkyl (e.g.,
methyl) and one or more halogen (e.g., F) or phenyl substituted
with one C.sub.1-4 alkyl (e.g., methyl) and one halogen (e.g., F),
for example wherein R.sub.6 is 4-fluorophenyl or 3,4-difluorophenyl
or 4-fluoro-3-methylphenyl; and R.sup.7 is H; [0107] 1.71 Any of
the preceding Formulae, wherein R.sub.5 is aryl (e.g., phenyl)
substituted only in the 4-position with --C(.dbd.O)--C.sub.1-6
alkyl (e.g., --C(.dbd.O)--C.sub.1-4 alkyl, e.g.,
--C(.dbd.O)--CH.sub.3) or C.sub.1-6-hydroxyalkyl (e.g.,
C.sub.1-4-hydroxyalkyl, e.g., 1-hydroxyethyl), for example wherein
R.sub.5 is 4-acetylphenyl or 4-(1-hydroxyethyl)phenyl); [0108] 1.72
Any of the preceding Formulae, wherein the compound is selected
from:
[0108] ##STR00004## [0109] 1.73 Any of the preceding Formulae
wherein the compounds inhibit phosphodiesterase-mediated (e.g.,
PDE1-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, still more preferably less than 10 nM, most preferably
less than or equal to 5 nM in an immobilized-metal affinity
particle reagent PDE assay, for example, as described in Example
5,
[0110] in free or salt form.
[0111] If not otherwise specified or clear from context, the
following terms herein have the following meanings: [0112] (a)
"Alkyl" as used herein is a saturated or unsaturated hydrocarbon
moiety, preferably saturated, preferably having one to six carbon
atoms, preferably having one to four carbon atoms, which may be
linear or branched, and may be optionally mono-, di- or
tri-substituted, e.g., with halogen (e.g., Cl or F) or carboxy.
[0113] (b) "Hydroxyalkyl" as used herein is a saturated hydrocarbon
moiety, preferably having one to six carbon atoms, preferably
having one to four carbon atoms, which may be linear or branched,
and is mono-, di- or tri-substituted with hydroxy. [0114] (c)
"Haloalkyl" as used herein is a saturated hydrocarbon moiety,
preferably having one to six carbon atoms, preferably having one to
four carbon atoms, which may be linear or branched, and is mono-,
di- or tri-substituted with halogen. For di- or tri-substituted
haloalkyl, the halogens may be the same (e.g., dichloromethyl) or
different (e.g., chlorofluoromethyl). [0115] (d) "Aryl" as used
herein is a mono or bicyclic aromatic hydrocarbon, preferably
phenyl, which may be optionally substituted, e.g., optionally
substituted with one or more groups independently selected from
C.sub.1-6 alkyl (e.g., methyl), halogen (e.g., Cl or F),
C.sub.1-6-haloalkyl (e.g., trifluoromethyl), hydroxy, and carboxy.
In some embodiments, aryl, in addition to being substituted with
the groups disclosed herein, is further substituted with an aryl or
a heteroaryl to form, e.g., biphenyl or pyridylphenyl. [0116] (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., optionally substituted with one or
more groups independently selected from C.sub.1-6 alkyl (e.g.,
methyl), halogen (e.g., Cl or F), C.sub.1-6-haloalkyl (e.g.,
trifluoromethyl), hydroxy, and carboxy. [0117] (f) "Hydroxy" as
used herein is --OH. [0118] (g) "Carboxy" as used herein is --COOH.
[0119] (h) "Halogen" as used herein is F, Cl, Br, or I.
[0120] Compounds of the Invention, e.g., compounds of Formulae I,
I(i), or I(ii), e.g., any of Formulae 1.1-1.73, 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.
[0121] 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, i.e., 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.
[0122] 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, e.g.,
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.
[0123] 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 diluent or
carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0124] Methods of Making Compounds of the Invention
[0125] 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 are 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, intermediates and/or Compounds of the Invention
may be prepared using methods described or similarly described in
WO 2006/133261, WO 2009/075784, WO 2010/065148, WO 2010/065149,
and/or WO 2010/065151. All references cited herein are hereby
incorporated by reference in their entirety.
[0126] 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.
[0127] 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.121I, .sup.111I, .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. Methods
of making isotopes of PDE1 inhibitors disclosed in WO 2011/043816,
the contents of which are incorporated by reference in their
entirety, may be used for making the isotopes of the compounds of
the current invention.
[0128] Melting points are uncorrected and (dec) indicates
decomposition. Temperatures 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
[0129] BOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate [0130] BOC=tert-butyloxycarbonyl, [0131]
CAN=ammonium cerium (IV) nitrate, [0132]
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene [0133]
DIPEA=diisopropylethylamine, [0134] DMF=N,N-dimethylformamide,
[0135] DMSO=dimethyl sulfoxide, [0136] Et.sub.2O=diethyl ether,
[0137] EtOAc=ethyl acetate, [0138] equiv.=equivalent(s), [0139]
h=hour(s), [0140] HPLC=high performance liquid chromatography,
[0141] LDA=lithium diisopropylamide, [0142] LiHMDS=lithium
bis(trimethylsilyl)amide, [0143] MeOH=methanol, [0144]
NBS=N-bromosuccinimide, [0145] NCS=N-chlorosuccinimide, [0146]
NMP=N-methyl-2-pyrrolidone, [0147] NaHCO.sub.3=sodium bicarbonate,
[0148] NH.sub.4OH=ammonium hydroxide, [0149]
Pd.sub.2(dba).sub.3=tris[dibenzylideneacetone]dipalladium(0) [0150]
PMB=p-methoxybenzyl, [0151] POCl.sub.3=phosphorous oxychloride,
[0152] SOCl.sub.2=thionyl chloride, [0153] TFA=trifluoroacetic
acid, [0154] TFMSA=trifluoromethanesulfonic acid, and [0155]
THF=tetrahydrofuran.
[0156] The synthetic methods in this invention are illustrated
below. The significances for the R groups are as set forth above
for any of Formulae I, I(i), I(ii), or 1.1-1.73 unless otherwise
indicated.
[0157] In an aspect of the invention, intermediate compounds of
formula IIb can be synthesized by reacting a compound of formula
IIa with malonic acid and acetic anhydride in acetic acid with
heating, e.g., to about 90.degree. C. for about 3 hours, and then
cooled:
##STR00005##
wherein R.sub.1 is H or C.sub.1-4 alkyl, e.g., methyl.
[0158] Intermediate IIc can be prepared by for example reacting
intermediate IIb with for example a chlorinating compound such as
POCl.sub.3, sometimes with small amounts of water and heat, e.g.,
heating to about 80.degree. C. for about 4 hours, and then
cooled:
##STR00006##
[0159] Intermediate IId may be formed by reacting intermediate IIc
with for example P.sup.1-L in a solvent such as DMF and a base such
as K.sub.2CO.sub.3, sodium bicarbonate, cesium carbonate, sodium
hydroxide, triethylamine, diisopropylethylamine or the like at room
temperature or with heating:
##STR00007##
wherein P.sup.1 is a protective group [e.g., p-methoxybenzyl group
(PMB) or BOC]; L is a leaving group such as a halogen, mesylate, or
tosylate. Preferably, P.sup.1 is PMB and the base is potassium
carbonate.
[0160] Intermediate IIe may be prepared by reacting intermediate
IId with hydrazine or hydrazine hydrate in a solvent such as
methanol and with heating, e.g. refluxed for about 4 hours, and
then cooled:
##STR00008##
[0161] Intermediate IVa may be formed by for example reacting
intermediate IIe with POCl.sub.3 and DMF:
##STR00009##
wherein R.sub.1 is as defined previously for any of Formulae I,
I(i), I(ii), or 1.1-1.73, e.g., such as a methyl group.
[0162] Intermediate IVb may be formed by reacting intermediate IVa
with for example F.sup.1--X in a solvent such as DMF with a base
such as K.sub.2CO.sub.3 at room temperature (Reaction 1):
##STR00010##
wherein F.sup.1 is for example benzyl substituted with a halogen
such as 4-bromobenzyl and X is a halogen (e.g., Br).
[0163] Intermediate IVc may be synthesized from intermediate 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 (Reaction 2):
##STR00011##
wherein if P.sup.1 is BOC, the compound may be deprotected by using
acid such as hydrochloric acid or TFA.
[0164] Intermediate IVd can be prepared by reacting intermediate
IVc with for example a chlorinating compound such as POCl.sub.3 and
optionally with heating, e.g., reflux for about 2 days or more, or
heated at 150.about.200.degree. C. for about 5-10 minutes in a
sealed vial with a microwave instrument and then cooled (Reaction
3):
##STR00012##
[0165] Intermediate IVe can be formed by reacting intermediate IVd
with an amino alcohol under basic condition in a solvent such as
DMF or NMP and heated then cooled (Reaction 4A):
##STR00013##
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as defined
previously for any of Formulae I, I(i), I(ii), or 1.1-1.73.
[0166] Alternatively, intermediate IVe can be synthesized directly
from intermediate IVc by reacting with an amino alcohol and a
coupling reagent such as BOP in the presence of a base such as DBU
(Reaction 4B):
##STR00014##
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as defined
previously for any of Formulae I, I(i), I(ii), or 1.1-1.73.
[0167] Intermediate 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 or heated at 35.degree. C. for several hours, and then
cooled (Reaction 5):
##STR00015##
[0168] Intermediate IVg may be formed by reacting intermediate IVf
with, for example, catalysts such as a copper salt and
2,2,6,6-tetramethylheptane-3,5-dione and a base such as cesium
carbonate in a solvent such as NMP with heat for several hours
(Reaction 6):
##STR00016##
wherein, F.sup.2 is a diaryl ether.
[0169] Intermediate IVh may be formed by reacting intermediate IVg
with, for example, TFA and TFMSA in a solvent such as
CH.sub.2Cl.sub.2 at room temperature (Reaction 7):
##STR00017##
[0170] Intermediate IVi may be formed by reacting intermediate IVh
with R.sub.5--(CH.sub.2).sub.n-L in the presence of a base, for
example K.sub.2CO.sub.3, in a solvent such as DMF at room
temperature (Reaction 8):
##STR00018##
wherein R.sub.5 and n are as defined previously for any of Formulae
I, I(i), I(ii), or 1.1-1.73 and L is a leaving group such as a
halogen (e.g., Br).
[0171] Intermediate IVj wherein X is halogen (e.g., Cl) may be
formed by reacting intermediate IVi with, for example, a
halogenating agent such as hexachloroethane, NCS, NBS, I.sub.2 and
a base such as LiHMDS in a solvent such as THF at low temperature
(Reaction 9):
##STR00019##
[0172] Compounds of the Invention may be formed by reacting
intermediate IVj wherein X is halogen (e.g., Cl) with
NHR.sub.6R.sub.7 and a catalyst with heating (Reaction 10):
##STR00020##
wherein R.sub.6 and R.sub.7 are as defined previously for any of
Formulae I, I(i), I(ii), or 1.1-1.73.
[0173] In another aspect of the invention, intermediate IIf may be
prepared by reacting intermediate IIc with hydrazine or hydrazine
hydrate in a solvent such as methoxyethanol and refluxed for about
30 minutes and then cooled:
##STR00021##
[0174] Intermediate Va can be synthesized by reacting a compound of
formula IIe with for example an aryl isothiocyanate or isocyanate
in a solvent such as DMF and heated at 110.degree. C. for about 2
days and then cooled:
##STR00022##
wherein R.sub.6 is as defined previously for any of Formulae I,
I(i), I(ii), or 1.1-1.73.
[0175] Intermediate Vb may be formed 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 AlCl.sub.3 or TFA/TFMSA
at room temperature. Intermediate Vb may also be prepared directly
from a compound of IIf using the similar methods, but the yields
are relatively low.
##STR00023##
[0176] Intermediate Vc can be prepared by for example reacting
intermediate Vb with for example a chlorinating compound such as
POCl.sub.3. The reaction may be carried out at atmospheric pressure
and refluxed for about 2 days or heated at 150.about.200.degree. C.
for about 10 minutes in a sealed vial with a microwave instrument
and then cooled (Reaction 11):
##STR00024##
[0177] Intermediate Vd can be prepared by reacting intermediate Vc
with an amino alcohol under basic condition in a solvent such as
DMF. The reaction may be heated overnight and then cooled (Reaction
12):
##STR00025##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.6 are as
defined previously for any of Formulae I, I(i), I(ii), or
1.1-1.73.
[0178] Intermediate Ve can be formed by reacting intermediate Vd
with for example a dehydrating 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 about 4 hours, and then cooled
(Reaction 13):
##STR00026##
[0179] Compounds of the Invention may be formed by reacting
intermediate Ve with for example R.sub.5--(CH.sub.2).sub.n-L in a
solvent such as DMF and a base such as K.sub.2CO.sub.3 at room
temperature or with heating (Reaction 14):
##STR00027##
wherein R.sub.5 is as defined previously for any of Formulae I,
I(i), I(ii), or 1.1-1.73 and L is a leaving group such as a
halogen, mesylate, or tosylate.
[0180] Methods of Using Compounds of the Invention
[0181] 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 PDE1, thereby increasing intracellular levels of
cAMP and cGMP, the Compounds of the Invention potentiate the
activity of cyclic nucleotide synthesis inducers.
[0182] The invention provides methods of treatment of any one or
more of the following conditions: [0183] (i) Neurodegenerative
diseases, including Parkinson's disease, restless leg, tremors,
dyskinesias, Huntington's disease, Alzheimer's disease, and
drug-induced movement disorders; [0184] (ii) Mental disorders,
including depression, attention deficit disorder, attention deficit
hyperactivity disorder, bipolar illness, anxiety, sleep disorders,
e.g., narcolepsy, cognitive impairment, e.g., cognitive impairment
of schizophrenia, dementia, Tourette's syndrome, autism, fragile X
syndrome, psychostimulant withdrawal, and drug addiction; [0185]
(iii) Circulatory and cardiovascular disorders, including
cerebrovascular disease, stroke, congestive heart disease,
hypertension, pulmonary hypertension, e.g., pulmonary arterial
hypertension, and sexual dysfunction, including cardiovascular
diseases and related disorders as described in International
Application No. PCT/US2014/16741, the contents of which are
incorporated herein by reference; [0186] (iv) Respiratory and
inflammatory disorders, including asthma, chronic obstructive
pulmonary disease, and allergic rhinitis, as well as autoimmune and
inflammatory diseases; [0187] (v) Diseases that may be alleviated
by the enhancement of progesterone-signaling such as female sexual
dysfunction; [0188] (vi) A disease or disorder such as psychosis,
glaucoma, or elevated intraocular pressure; [0189] (vii) Traumatic
brain injury; [0190] (viii) 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 [0191]
(ix) 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 Formulae I, I(i), I(ii), or 1.1-1.73, in free or
pharmaceutically acceptable salt or prodrug form, to a human or
animal patient in need thereof.
[0192] 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 therapeutically
effective amounts of [0193] (i) a PDE1 Inhibitor, e.g., a compound
according to any of Formulae I, I(i), I(ii) or 1.1-1.73, and [0194]
(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 or
pharmaceutically acceptable salt or prodrug form, to a human or
animal patient in need thereof.
[0195] 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 Formulae I, I(i),
I(ii), or 1.1-1.73, in free or pharmaceutically acceptable salt or
prodrug form, to a human or animal patient in need thereof.
Diseases or conditions 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.
[0196] 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 therapeutically effective
amounts of [0197] (i) a PDE1 Inhibitor, e.g., a compound according
to any of Formulae I, I(i), I(ii), or 1.1-1.73, and [0198] (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 or
pharmaceutically acceptable salt or prodrug form, to a human or
animal patient in need thereof.
[0199] 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., a compound according to any
of Formulae I, I(i), I(ii), or 1.1-1.73, in free or
pharmaceutically acceptable salt or prodrug form, sufficient to
inhibit PDE1 activity.
[0200] The invention also provides a method for treating a
PDE1-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., a compound
according to any of Formulae I, I(i), I(ii), or 1.1-1.73, in free
or pharmaceutically acceptable salt or prodrug form, that inhibits
PDE1, wherein PDE1 activity modulates phosphorylation of DARPP-32
and/or the GluR1 AMPA receptor.
[0201] 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 PDE1 Inhibitor of the Invention, e.g., a compound
according to any of Formulae I, I(i), I(ii), or 1.1-1.73, in free
or pharmaceutically acceptable salt form, in an ophthalmically
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.
[0202] 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, e.g., a compound according to any
of Formulae I, I(i), I(ii) or 1.1-1.73, in free or
ophthalmologically acceptable salt form, in combination or
association with an ophthalmologically acceptable diluent or
carrier.
[0203] 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 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.
[0204] 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, e.g., a compound according to any of
Formulae I, I(i), I(ii) or 1.1-1.73, 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.
[0205] 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.
[0206] 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., [0207] 1. Prostaglandin analogs such as latanoprost
(Xalatan), bimatoprost (Lumigan) and travoprost (Travatan), which
increase uveoscleral outflow of aqueous humor. Bimatoprost also
increases trabecular outflow. [0208] 2. Topical beta-adrenergic
receptor antagonists such as timolol, levobunolol (Betagan), and
betaxolol, which decrease aqueous humor production by the ciliary
body. [0209] 3. Alpha.sub.2-adrenergic agonists such as brimonidine
(Alphagan), which work by a dual mechanism, decreasing aqueous
production and increasing uveo-scleral outflow. [0210] 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. [0211] 5. Miotic agents
(para-sympathomimetics) like pilocarpine work by contraction of the
ciliary muscle, tightening the trabecular meshwork and allowing
increased outflow of the aqueous humour. [0212] 6. Carbonic
anhydrase inhibitors like dorzolamide (Trusopt), brinzolamide
(Azopt), acetazolamide (Diamox) lower secretion of aqueous humor by
inhibiting carbonic anhydrase in the ciliary body. [0213] 7.
Physostigmine is also used to treat glaucoma and delayed gastric
emptying.
[0214] For example, the invention provides pharmaceutical
compositions comprising a PDE1 Inhibitor of the Invention, e.g., a
compound according to any of Formulae I, I(i), I(ii), or 1.1-1.73,
in free or pharmaceutically acceptable salt form, 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, in combination or association with a
pharmaceutically acceptable diluent or carrier. For example, the
invention provides ophthalmic formulations comprising a PDE-1
Inhibitor of the Invention, e.g., a compound according to any of
Formulae I, I(i), I(ii), or 1.1-1.73, 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..sub.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.
[0215] 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.
[0216] In yet another example, the PDE1 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.
[0217] 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.
[0218] 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,
e.g., a compound according to any of Formulae I, I(i), I(ii), or
1.1-1.73, in free or pharmaceutically acceptable salt form, to a
patient in need thereof.
[0219] PDE 1 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 therapeutically effective amounts of: [0220] (i)
a PDE1 Inhibitor of the invention, in free or pharmaceutically
acceptable salt form; and [0221] (ii) an antipsychotic, e.g.,
[0222] Typical antipsychotics, e.g., [0223] Butyrophenones, e.g.
Haloperidol (Haldol, Serenace), Droperidol (Droleptan); [0224]
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); [0225] Thioxanthenes, e.g., Chlorprothixene,
Flupenthixol (Depixol, Fluanxol), Thiothixene (Navane),
Zuclopenthixol (Clopixol, Acuphase); [0226] Atypical
antipsychotics, e.g., [0227] Clozapine (Clozaril), Olanzapine
(Zyprexa), Risperidone (Risperdal), Quetiapine (Seroquel),
Ziprasidone (Geodon), Amisulpride (Solian), Paliperidone (Invega),
Aripiprazole (Abilify), Bifeprunox; norclozapine,
[0228] in free or pharmaceutically acceptable salt form, to a
patient in need thereof.
[0229] In a particular embodiment, the Compounds of the Invention
are particularly useful for the treatment or prophylaxis of
schizophrenia.
[0230] 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.
[0231] 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.
[0232] 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, e.g., a compound according to any of
Formulae I, I(i), I(ii), or 1.1-1.73, 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.
[0233] The present invention also provides [0234] (i) a Compound of
the Invention, e.g., a compound according to any of Formulae I,
I(i), I(ii), or 1.1-1.73, as hereinbefore described, in free or
pharmaceutically acceptable salt form for example for use in any
method or in the treatment of any disease or condition as
hereinbefore set forth, [0235] (ii) the use of a Compound of the
Invention, e.g., a compound according to any of Formulae I, I(i),
I(ii) or 1.1-1.73, as hereinbefore described, in free or
pharmaceutically acceptable salt form, (in the manufacture of a
medicament) for treating any disease or condition as hereinbefore
set forth, [0236] (iii) a pharmaceutical composition comprising a
Compound of the Invention, e.g., a compound according to any of
Formulae I, I(i), I(ii), or 1.1-1.73, as hereinbefore described, in
free or pharmaceutically acceptable salt form, in combination or
association with a pharmaceutically acceptable diluent or carrier,
and [0237] (iv) a pharmaceutical composition comprising a Compound
of the Invention, e.g., a compound according to any of Formulae I,
I(i), I(ii), or 1.1-1.73, as hereinbefore described, 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 as
hereinbefore set forth.
[0238] Therefore, the invention provides use of a Compound of the
Invention, e.g., a compound according to any of Formulae I, I(i),
I(ii), or 1.1-1.73, as hereinbefore described, in free or
pharmaceutically acceptable salt form, or a Compound of the
Invention in a pharmaceutical composition form (in the manufacture
of a medicament) for the treatment or prophylactic treatment of any
one or more of the following diseases: Parkinson's disease,
restless leg, tremors, dyskinesias, Huntington's disease,
Alzheimer's disease, and/or drug-induced movement disorders;
depression, attention deficit disorder, attention deficit
hyperactivity disorder, bipolar illness, anxiety, sleep disorder,
narcolepsy, cognitive impairment, e.g., cognitive impairment of
schizophrenia, dementia, Tourette's syndrome, autism, fragile X
syndrome, psychostimulant withdrawal, and/or drug addiction;
cerebrovascular disease, stroke, congestive heart disease,
hypertension, pulmonary hypertension, e.g., pulmonary arterial
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, and/or
estrogen-induced endometrial hyperplasia and/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.
[0239] The invention also provides use of a Compound of the
Invention, in free or pharmaceutically acceptable salt form, (the
manufacture of a medicament) for the treatment or prophylactic
treatment of any one or more of: [0240] a) glaucoma, elevated
intraocular pressure, [0241] 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,
[0242] c) traumatic brain injury, and/or [0243] d) central and
peripheral degenerative disorders particularly those with
inflammatory components.
[0244] The phrase "Compounds of the Invention" or "PDE1 Inhibitor
of the Invention" encompasses any and all of the compounds
disclosed herewith, e.g., compounds according to any of Formulae I,
I(i), I(ii) or 1.1-1.73, as hereinbefore described, in free or salt
form.
[0245] 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. In one embodiment, the invention provides a method for the
treatment of the disease or disorder disclosed herein. In another
embodiment, the invention provides a method for the prophylaxis of
a disease or disorder as disclosed herein.
[0246] For methods of treatment, the word "effective amount" is
intended to encompass a therapeutically effective amount to treat a
specific disease or disorder.
[0247] The term "pulmonary hypertension" is intended to encompass
pulmonary arterial hypertension.
[0248] The term "patient" includes human or non-human (i.e.,
animal) patient. In one embodiment, the invention encompasses both
human and nonhuman. In another embodiment, the invention
encompasses nonhuman. In other embodiment, the term encompasses
human.
[0249] The term "comprising" as used in this disclosure is intended
to be open-ended and does not exclude additional, unrecited
elements or method steps.
[0250] Compounds of the Invention are in particular useful for the
treatment of Parkinson's disease, narcolepsy and female sexual
dysfunction.
[0251] Compounds of the Invention, 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 PDE1
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.
[0252] 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.
[0253] 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
[0254] The synthetic methods for various Compounds of the Invention
are illustrated below. The intermediates of Compounds of the
Invention as well as other Compounds of the Invention (e.g.,
compounds of Formula 1.73) 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
7,8-Dihydro-2-(4-acetylbenzyl)-3-(4-fluorophenylamino)-5,7,7-trimethyl-[2H-
]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one
##STR00028##
[0255] (a)
2-(4-Bromobenzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4--
d]pyrimidine-4,6(5H,7H)-dione
[0256] A suspension of
7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dion-
e (161 g, 562 mmol), 1-bromo-4-(bromomethyl)benzene (157 g, 628
mmol) and K.sub.2CO.sub.3 (93.2 g, 674 mmol) in DMF (800 mL) is
stirred at room temperature until the reaction is complete. The
reaction mixture is poured into water (5 L). After filtration, the
filter cake is washed with water and ethanol successively, and then
dried under vacuum to give 226 g of product (yield: 88%). MS (ESI)
m/z 455.1 [M+H].sup.+.
(b)
2-(4-Bromobenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dio-
ne
[0257] TFA (500 mL) is slowly added into a suspension of
2-(4-bromobenzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidi-
ne-4,6(5H,7H)-dione (226 g, 496 mmol) in methylene chloride (320
mL), and then TFMSA (160 mL) is added slowly. The reaction mixture
is stirred at room temperature overnight. Solvents are removed
under reduced pressure. The obtained residue is treated with water
(4 L) and ethyl acetate (2 L), stirred at room temperature for 30
min, and then filtered. The filter cake is thoroughly washed with
water to remove residual acids, followed by washing with ethyl
acetate. The obtained white solids are dried in a heated oven to
give 159 g of product (yield: 96%). MS (ESI) m/z 335.0
[M+H].sup.+.
(c)
6-Chloro-5-methyl-2-(4-bromobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)--
one
[0258]
2-(4-Bromobenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)--
dione (159 g, 475 mmol) is suspended in POCl.sub.3 (300 mL), and
then slowly heated to reflux. After the mixture is refluxed for 60
h, POCl.sub.3 is removed under reduced pressure. The obtained
residue is dissolved in methylene chloride (5 L), cooled to
0.degree. C., and then adjusted to pH 8-9 with saturated sodium
bicarbonate. After filtration, the obtained solids are washed with
water twice, and then dried under vacuum to give 157 g of product
(yield: 94%). MS (ESI) m/z 353.0 [M+H].sup.+.
(d)
6-(1-Hydroxy-2-methylpropan-2-ylamino)-5-methyl-2-(4-bromobenzyl)-2H-p-
yrazolo[3,4-d]pyrimidin-4(5H)-one
[0259] A mixture of
6-chloro-5-methyl-2-(4-bromobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one
(157 g, 444 mmol) and 2-amino-2-methylpropan-1-ol (236 g, 2.65 mol)
in NMP (1.3 L) is heated at 120-125.degree. C. for 2 h, and then
poured into cold water. After filtration, the filter cake is washed
with water twice, and then dried under vacuum to give 134 g of
product (yield: 74%). MS (ESI) m/z 406.1 [M+H].sup.+.
(e)
2-(4-Bromobenzyl)-7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyra-
zolo[4,3-e]pyrimidin-4(5H)-one
[0260] Thionyl chloride (67 mL, 922 mmol) is added dropwise to a
solution of
6-(1-hydroxy-2-methylpropan-2-ylamino)-5-methyl-2-(4-bromobenzyl)-2H-p-
yrazolo[3,4-d]pyrimidin-4(5H)-one (134 g, 330 mmol) in DMF (800
mL). The reaction mixture is stirred at room temperature until the
reaction is complete. The mixture is poured into cold water, and
then adjusted to pH 8-9 with ammonium hydroxide aqueous solution.
After filtration, the obtained solids are washed with water, and
then dried under vacuum to give 118 g of product (yield: 92%). MS
(ESI) 388.1 [M+H].sup.+.
(f)
2-(4-Phenoxybenzyl)-7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]py-
razolo[4,3-e]pyrimidin-4(5H)-one
[0261]
2-(4-Bromobenzyl)-7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]p-
yrazolo[4,3-e]pyrimidin-4(5H)-one (118 g, 304 mmol) is added into a
suspension of phenol (57 g, 606 mmol) and cesium carbonate (200 g,
614 mmol) in NMP (900 mL), followed by
2,2,6,6-tetramethylheptane-3,5-dione (7 mL, 33.5 mmol) and CuCl (15
g, 152 mmol). The reaction mixture is heated at 120.degree. C.
under argon atmosphere for 10 h. After the completion of the
reaction, the mixture is diluted with water (4 L), and then
extracted with ethyl acetate. The combined organic phase is
evaporated to dryness. The obtained crude product is purified by
silica gel column chromatography to give 103 g of product (yield:
84%). MS (ESI) m/z 402.2 [M+H].sup.+.
(g)
7,8-Dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimid-
in-4(5H)-one
[0262] TFA (600 mL) is added into a suspension of
2-(4-phenoxybenzyl)-7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyraz-
olo[4,3-e]pyrimidin-4(5H)-one (103 g, 257 mmol) in methylene
chloride (210 mL) to give a tan solution, and then TFMSA (168 mL)
is added. The reaction mixture is stirred at room temperature until
the starting material disappears. The mixture is poured into cold
water (3 L). After filtration, the filter cake is washed with water
twice, and then basified with ammonium hydroxide aqueous solution,
followed by adding ethyl acetate with stirring. The precipitated
solids are filtered, washed successively with water three times,
ethyl acetate twice and methanol once, and then dried under vacuum
to give 45 g of product (yield: 80%). MS (ESI) m/z 220.2
[M+H].sup.+.
(h)
7,8-Dihydro-2-(4-acetylbenzyl)-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyr-
azolo[4,3-e]pyrimidin-4(5H)-one
[0263] A suspension of
7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin--
4(5H)-one (438 mg, 2.0 mmol), 1-(4-(bromomethyl)phenyl)ethanone
(520 mg, 2.4 mmol) and K.sub.2CO.sub.3 (828 mg, 6.0 mmol) in DMF
(18 mL) is stirred at room temperature over a weekend. Solvent is
removed under reduced pressure. The obtained residue is purified on
a basic alumina oxide column to give 634 mg of product (yield:
90%). MS (ESI) m/z 352.2 [M+H].sup.+.
(i)
7,8-Dihydro-2-(4-acetylbenzyl)-3-chloro-5,7,7-trimethyl-[2H]-imidazo-[-
1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one
[0264] 1.0M LiHMDS (2.5 mL, 2.5 mmol) in THF is added dropwise into
a solution of
7,8-dihydro-2-(4-acetylbenzyl)-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazo-
lo[4,3-e]pyrimidin-4(5H)-one (580 mg, 1.65 mmol) and
hexachloroethane (782 mg, 3.32 mmol) in methylene chloride (8 mL)
at -20.degree. C. The reaction mixture is stirred at -20.degree. C.
for 30 min, and then quenched with acetic acid (60 .mu.L). Solvents
are removed under reduced pressure and the obtained residue is
purified on a basic alumina oxide column to give 273 mg of product
(yield: 43%). MS (ESI) m/z 386.2 [M+H].sup.+.
(j)
7,8-Dihydro-2-(4-acetylbenzyl)-3-(4-fluorophenylamino)-5,7,7-trimethyl-
-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one
[0265]
7,8-Dihydro-2-(4-acetylbenzyl)-3-chloro-5,7,7-trimethyl-[2H]-imidaz-
o-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (150 mg, 0.389 mmol),
4-fluorobenzenamine (41 .mu.L, 0.428 mmol) and potassium carbonate
(107 mg, 0.775 mmol) in tert-amyl alcohol (1.3 mL) are degassed
with argon and then Xantphos (9.0 mg, 0.016 mmol) and
Pd.sub.2(dba).sub.3 (7.13 mg, 0.0078 mmol) are added. The
suspension is degassed again, and then heated to 110.degree. C. The
reaction mixture is stirred at 110.degree. C. under argon for 24 h.
After routine workup, the crude mixture is purified with a
semi-preparative HPLC to give 107 mg of the final product as a
formate salt (HPLC purity: 96%; yield: 54%). .sup.1H NMR (500 MHz,
Chloroform-d) .delta. 8.20 (s, 1H), 7.84 (d, J=8.3 Hz, 2H),
7.06-7.00 (m, 3H), 6.99-6.92 (m, 2H), 6.92-6.86 (m, 2H), 4.91 (s,
2H), 3.77 (s, 2H), 3.37 (s, 3H), 2.57 (s, 3H), 1.48 (s, 6H). MS
(ESI) m/z 461.2 [M+H].sup.+.
Example 2
7,8-Dihydro-2-(4-(1-hydroxyethyl)benzyl)-3-(4-fluorophenylamino)-5,7,7-tri-
methyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one
##STR00029##
[0267] NaBH.sub.4 (18 mg, 0.48 mmol) is slowly added to a solution
of
7,8-dihydro-2-(4-acetylbenzyl)-3-(4-fluorophenylamino)-5,7,7-trimethyl-[2-
H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (22 mg, 0.048
mmol) in methanol (1 mL) at -20.degree. C. The reaction mixture is
stirred at -10.degree. C. for 3 h, and then quenched with water
(0.5 mL). After filtration, the obtained crude product is purified
by a semi-preparative HPLC to give 20 mg of pure product as a
formate salt (HPLC purity: 98%; yield: 82%). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.64 (s, 1H), 8.15 (s, 1H), 7.24 (d, J=8.1 Hz,
2H), 7.05 (d, J=8.2 Hz, 2H), 7.03-6.94 (m, 2H), 6.82-6.73 (m, 2H),
5.13 (s, 2H), 4.66 (q, J=6.5 Hz, 1H), 3.58 (s, 2H), 3.17 (s, 1H),
3.08 (s, 3H), 1.34-1.19 (m, 9H). MS (ESI) m/z 463.2 [M+H].sup.+
Example 3
7,8-Dihydro-2-(4-acetylbenzyl)-3-(3,4-difluorophenylamino)-5,7,7-trimethyl-
-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one
##STR00030##
[0269] The synthesis method is analogous to example 1 wherein
3,4-difluorobenzenamine is added in step (j) instead of
4-fluorobenzenamine. Final product is obtained as a formate salt
(HPLC purity: 99%). .sup.1H NMR (500 MHz, DMSO-d6) 8.86 (s, 1H),
8.15 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.32 -7.12 (m, 3H), 6.72
(ddd, J=12.8, 6.9, 2.7 Hz, 1H), 6.57 (m, 1H), 5.28 (s, 2H), 3.58
(s, 2H), 3.10 (s, 3H), 2.53 (s, 3H), 1.26 (s, 6H). MS (ESI) m/z
479.2 [M+H].sup.+
Example 4
7,8-Dihydro-2-(4-acetylbenzyl)-3-(4-fluoro-3-methylphenylamino)-5,7,7-trim-
ethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one
##STR00031##
[0271] The synthesis method is analogous to example 1 wherein
4-fluoro-3-methylbenzenamine is added in step (j) instead of
4-fluorobenzenamine. Final product is obtained as a formate salt
(HPLC purity: 98%). .sup.1H NMR (500 MHz, Chloroform-d) .delta.
8.15 (s, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H),
6.96-6.85 (m, 2H), 6.79-6.66 (m, 2H), 4.89 (s, 2H), 3.75 (s, 2H),
3.40 (s, 3H), 2.57 (s, 3H), 2.11 (d, J=1.8 Hz, 3H), 1.47 (s, 6H).
MS (ESI) m/z 475.2 [M+H].sup.+
Example 5
Measurement of PDE1 Inhibition In Vitro Using IMAP
Phosphodiesterase Assay Kit
[0272] Phosphodiesterase 1 (PDE1) is a calcium/calmodulin dependent
phosphodiesterase enzyme that converts cyclic guanosine
monophosphate (cGMP) to 5'-guanosine monophosphate (5'-GMP). PDE1
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.
[0273] 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.
[0274] 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.
[0275] Enzyme Assay
Materials: All chemicals are available from Sigma-Aldrich (St.
Louis, Mo.) except for IMAP reagents (reaction buffer, binding
buffer, FL-GMP and IMAP beads), which are available from Molecular
Devices (Sunnyvale, Calif.). Assay: The following phosphodiesterase
enzymes may be used: 3',5'-cyclic-nucleotide-specific bovine brain
phosphodiesterase (Sigma, St. Louis, Mo.) and recombinant full
length human PDE1A and PDE1B (r-hPDE1A and r-hPDE1B, respectively)
which may be produced e.g., in HEK or SF9 cells by one skilled in
the art. The PDE1 enzyme is reconstituted with 50% glycerol to 2.5
U/ml. One unit of enzyme will hydrolyze 1.0 .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 1.25 mU/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
test compounds are mixed and pre-incubated with the enzyme for 10
min at room temperature.
[0276] 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).
[0277] 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.).
[0278] The Compounds of the Invention may be selected and tested in
an assay as described or similarly described herein for PDE1
inhibitory activity. Exemplified Compounds of the Invention (e.g.,
compounds of Examples 1, 2, 3, and 4) have IC.sub.50 values of less
than or equal to 5 nm. K.sub.i values for Exemplified Compounds of
the Invention are as shown in Table 1 below.
TABLE-US-00001 TABLE 1 Example r-hPDE1A - K.sub.i (.mu.m) r-hPDE1B
- K.sub.i (.mu.m) 1 0.0002 0.001 2 0.0005 0.004 3 0.0003 0.004 4
0.0001 0.0004
Example 6
Novel Object Recognition Assay
[0279] To measure the cognition-enhancing effects of the compounds
of the invention, the candidate compounds may be evaluated in a
Novel Object Recognition (NOR) assay. This assay protocol is
described in detail in Ennaceur et al., Behav. Brain Res. (1988)
31:47-59 and Prickaerts et al., Eur. J. Pharmacol. (1997)
337:125-136, the contents of each of which are incorporated by
reference in their entirety. In this protocol, the rats are
introduced to a chamber at time T1 and allowed to interrogate two
identical "familiar objects" for six minutes. Twenty-four hours
later, they are re-introduced to this chamber, where one of the
familiar objects has been replaced with a novel object. The
"discrimination index", a measure of the time spent in close
proximity to the novel over the familiar object, may then be
measured. Since rodents will forget the original experiment at T1
within 4 hours, this test with a 24 h interval is a measure of
strong cognitive enhancement.
[0280] This assay protocol can be modified in order to evaluate
different phases of memory. There are three general phases of
memory, namely, acquisition, consolidation and retrieval. In this
modified protocol, the rats may be dosed with the candidate
compound two hours before T1 and tested 24 h later without
additional dosing. This is a test of the acquisition process. In
addition, administration at various other times after the T1 test
may be done to understand the compound's effectiveness in memory
consolidation and recall. Specifically, these dosing times
represent acquisition (T1-2 h), early consolidation (T1+0.1 h),
late consolidation (T1+3 h), and retrieval (T2-2 h).
[0281] Using the protocol described above or similarly described
above, the compound of Example 1 is shown to have a minimal
effective dose of 0.1 mg/kg PO when administering to a rat 2 hours
before T1.
Example 7
PDE1 Inhibitor Effect on Sexual Response in Female Rats
[0282] The effect of PDE1 inhibitors on Lordosis Response in female
rats may be measured as described in Mani, et al., Science (2000)
287: 1053, the contents of which are incorporated herein by
reference. Ovariectomized and cannulated wild-type rats are primed
with 2 .mu.g estrogen followed 24 hours later by
intracerebroventricular (icv) injection of progesterone (2 .mu.g),
PDE1 Inhibitors of the Invention (0.1 mg, 1.0 mg or 2.5 mg) or
sesame oil vehicle (control). The rats may be 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).
Example 8
Haloperidol Induced Catalepsy Model
[0283] To evaluate the potential beneficial effects to motor
defects present in schizophrenics treated with typical and atypical
antipsychotic agents and in Parkinson's disease patients, the
compounds of the invention may be tested in a reversal of catalepsy
model in which motor freezing, or catalepsy, is induced by potent
dopamine D2 receptor antagonists such as haloperidol or
risperidone. The method uses the "bar grip test", in which the
front paws of the mouse are placed so as to grip a 3 mm-diameter,
suspended wooden bar. A "step down latency" is measured by
recording the time until the mouse removes its paws from the wooden
bar to the floor surface. Catalepsy is a freezing of the
musculature that prevents the mouse from moving off the bar.
Reduction in the catalepsy induced in this model will indicate that
the compound will have a beneficial effect both in schizophrenia
where extrapyramidal side effects are frequent and in Parkinson's
disease.
[0284] A total of seventeen (17) eight week-old, male C57BL/6 mice
(Jackson Laboratories) are used in a typical experiment testing the
effect of the compound of Example 1. Mice are divided into six (6)
groups (N=2 for vehicle group; N=3 mice/drug-treated group),
receiving the following treatments: Vehicle alone, haloperidol
alone (3 mg/Kg PO), Compound of Example 1 alone (0.3 mg/Kg PO),
haloperidol (3 mg/Kg PO)+Compound of Example 1 (0.1 mg/Kg PO),
haloperidol (3 mg/Kg PO)+Compound of Example 1 (0.3 mg/Kg PO), or
haloperidol (3 mg/Kg PO)+Compound of Example 1 (1 mg/Kg PO). A
catalepsy score is recorded for each mouse at 2, 3, 4, and 6 hours
after administration of drugs. The chamber used for measuring
catalepsy is comprised of a Plexiglas cage outfitted with a 3
mm-diameter wooden bar fixed horizontally 4 cm above the floor of
cage. For each test session, both forepaws of the mouse are placed
on the bar while the hind paws are on the Plexiglas floor. The
latency until the mouse steps both paws down from the bar to the
floor surface (i.e., step down latency) is recorded up to 120 sec.
If the mouse steps off immediately (less than 10 sec after
placement), another attempt is made up to a maximum of 10 attempts.
If none of the 10 attempts are beyond 10 sec, the longest duration
recorded is used as the catalepsy score. Otherwise, the initial
cataleptic duration (>10 sec) is recorded during the 120 sec
testing time. Mean step down latency is calculated for each
treatment group. The effect of the compound of Example 1 on step
down latency after haloperidol treatment is statistically evaluated
by comparing group differences by analysis of variance (ANOVA,
F.sub.5,16) followed by application of Newman-Keuls post-hoc
multiple comparison tests at each time point across all doses
tested.
[0285] By using the protocol described or similarly described in
this example, the compound of Example 1 is shown to be active in a
catalepsy model with a minimal effective dose of 0.1 mg/Kg.
Example 9
Measurement of Metabolism Rates in Human Liver Microsomes
Stability Protocol
[0286] Pooled human liver microsomes (final protein concentration
0.5 mg/ml) are incubated with test compound (final concentration 1
.mu.M) in the presence of a NADPH regenerating system. The final
buffer composition is: 1 mM EDTA, 100 mM potassium phosphate pH
7.5. The reactions are initiated by addition of the cofactor NADPH,
and terminated after a 0, 15, 30, 45 and 60 minute incubation at
37.degree. C. by addition of cold acetonitrile containing the
internal analysis standard. After centrifuging at 4000 rpm for 20
minutes at 4.degree. C., the supernatant are transferred for
analysis using HPLC/MS/MS to measure the disappearance of the test
compound. The percentage of the test compound remaining over time
is calculated relative to the zero time point. The intrinsic
clearance rates were calculated based on percentage of compound
remaining at the 15-60 min. time points.
[0287] By using the protocol described or similarly described in
this example, the compound of Example 1 is shown to have a
T.sub.1/2 of 171 minutes, the compound of Example 3 is shown to
have a T.sub.1/2 of 78 minutes, and the compound of Example 4 is
shown to have a T.sub.1/2 of 67 minutes.
* * * * *