Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives useful as inhibitors of phosphodiesterase I

Patent metadata

Field	Value
Publication number	US-9487527-B2
Application number	US-201414473701-A
Country	US
Kind code	B2
Filing date	Aug 29, 2014
Priority date	Dec 6, 2008
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

Optionally substituted (5- or 7- amino)-3,4-dihydro-(optionally 4-oxo, 4-thioxo or 4-imino)- 1H-pyrrolo [3,4-d]pyrimidin-2(6H)-ones, Compounds of Formula I, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

First claim

What is claimed is:

1. A method of treating any of the following conditions: Parkinson's disease, restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorder, narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease, and/or allergic rhinitis, and/or female sexual dysfunction, exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma; comprising administering an effective amount of a compound according to Formula I:

wherein
(i) L is S or SO 2 ;
(ii) R 1 is H or C 1-6 alkyl;
(iii) R 2 is
H,
C 1-6 alkyl wherein said alkyl group is optionally substituted with halo or hydroxy,
—C 0-4 alkyl-C 3-8 cycloalkyl optionally substituted with one or more amino,wherein said cycloalkyl optionally contains one or more heteroatom selected from N and O and is optionally substituted with C 1-6 alkyl,
haloC 1-6 alkyl,
N(R 14 )(R 15 )—C 1-6 alkyl,
hydroxyC 1-6 alkyl,
arylC 0-6 alkyl,
heteroarylC 1-6 alkyl,
C 1-6 alkoxyarylC 1-6 alkyl;

(iv) R 3 is
1) -D-E-F wherein:
D is a single bond, C 1-6 alkylene or arylalkylene,
E is
a single bond,
C 1 - 4 alkylene,
—C 0-4 alkylarylene, wherein the arylene group is optionally substituted with halo,
heteroarylene,
aminoC 1 - 6 alkylene,
amino,
C 3-8 cycloalkylene optionally containing one or more heteroatom selected from N or O,

F is
haloC 1-6 alkyl,
aryl,
C 3-8 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O, and optionally substituted with C 1-6 alkyl,
heteroaryl optionally substituted with C 1-6 alkyl, halo or haloC 1-6 alkyl,
alkoxadiazoly,
amino,
—O-haloC 1-6 alkyl,
C 1-6 alkylsulfonyl,
—C(O)—R 13 ,
—N(R 14 )(R 15 );

2) a haloalkyl substituted heteroarylaklyl; or
3) attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11 and R 12 are independently H or halogen; and R 10 is C 3-8 cycloalkyl, haloC 1-6 alkyl, aryl, heteroaryl, C 1-6 alkyl sulfonyl, arylcarbonyl alkoxadiazolyl, heteroarylcarbonyl, alkoxycarbonyl, or aminocarbonyl; provided that when X, Y or Z is nitrogen, R 8 , R 9 or R 10 , respectively, is not present;

(v) R 4 is selected from:
H,
C 1-6 alkyl,
C 3-8 cycloalkyl,
C 3-8 heterocycloalkyl,
aryl or heteroaryl wherein said aryl or heteroaryl is optionally substituted with halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or another aryl group;

(vi) R 13 is —N(R 14 )(R 15 ), C 1-6 alkyl, —OC 1-6 alkyl, haloC 1-6 alkyl, aryl, or heteroaryl; and
(vii) R 14 and R 15 are independently H or C 1-6 alkyl,

in free or salt form to a patient in need of such treatment.

2. The method of claim 1 , wherein the condition is Parkinson's disease.

3. The method of claim 1 , wherein the condition is cognitive impairment.

4. The method of claim 1 , wherein the condition is narcolepsy.

5. The method of claim 4 , further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof.

6. The method of claim 1 , wherein said condition is female sexual dysfunction.

Assignees

• Li Peng
• Zhao Jun
• Zheng Hailin
• Wennogle Lawrence P
• Intra Cellular Therapies Inc

Inventors

• Li Peng
• Zhao Jun
• Zheng Hailin
• Wennogle Lawrence P

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title