# US 9,434,730 B2 · PDE1 inhibitor compounds

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- Number: US 9,434,730 B2
- Document ID: US9434730B2
- Status: Granted
- Kind: B2
- Application number: 13/701,284
- Filed: 2011-05-31
- Published: 2013-12-19
- Granted: 2016-09-06
- Earliest claimed: 2010-05-31
- Assignees: Intra-Cellular Therapies, Inc.
- Applicants: Peng Li; Jun Zhao
- Inventors: Peng Li; Jun Zhao
- Web page: https://patentgrep.com/patent/US9434730B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 15/10: for impotence
- A61P 15/12: for climacteric disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/36: Opioid-abuse
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to (1- or 2- and/or 5 and/or 7-substituted)-(3-oxy)-(4H,4-imino, 4-thioxo or 4-oxo)-pyrazolo[3,4-d]pyrimidin-6-ones, e.g., a compound of formula II as described below, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them. Of particular interest are novel compounds useful as inhibitors of phosphodiesterase 1 (PDE1), e.g., in the treatment of diseases involving disorders of the dopamine D1 receptor intracellular pathway, such as Parkinson's disease, depression, narcolepsy, damage to cognitive function, e.g., in schizophrenia, or disorders that may be ameliorated through enhanced progesterone-signaling pathway, e.g., female sexual dysfunction.

## Claims

### Claim 1

A compound of Formula II:
wherein
(i) Q is —C(═O)—, —C(═S)—,
(ii) R1 is C1-6alkyl;
(iii) R2 is
C1-6alkyl wherein said alkyl group is optionally substituted with one or more halo or hydroxy;
(iv) R3 is
1) attached to one of the nitrogens on the pyrazolo portion of Formula II and is a moiety of Formula A
wherein:
X, Y and Z are, independently, N or C,
R8, R9, R11 and R12 are independently H or halogen; and
R10 is
aryl or heteroaryl,
wherein said aryl, heteroaryl, is optionally substituted with one or more C1-6alkyl, halogen, haloC1-6alkyl, hydroxy, carboxy, —SH, or an additional aryl or heteroaryl;
provided that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present;
(v) R4 is:
C1-6alkyl,
C3-8cycloalkyl,
C3-8heterocycloalkyl,
—C0-6alkylaryl or
C0-6alkylheteroaryl
wherein said aryl or heteroaryl is optionally substituted with one or more halo, hydroxy, C1-6alkyl, C1-6alkoxy or another aryl group;
in free or salt form, provided that said compound is not:
(a) 7-[(2,4-dichlorophenyl)methyl]-3-ethoxy-2,5-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;
(b) 7-[(4-chlorophenyl)methyl]-3-ethoxy-2,5-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;
(c) 2-[(2,5-dichlorophenyl)methyl]-3-ethoxy-5,7-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;
(d) 2-[(4-bromophenyl)methyl]-3-ethoxy-5,7-dimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;
(e) 3-[(4-methoxyphenyl)methoxy]-2,5,7-trimethyl-2H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione;
(f) 1-[(3-bromophenyl)methyl]-5,7-dimethyl-3-(2-propen-1-yloxy)-1H-Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione.

### Claim 2 (depends on 1)

The compound according to claim 1, which compound is selected from any one of the following:
A) a Compound of Formula II(a):
wherein
(i) Q is —C(═O)—, —C(═S)—,
(ii) R1 is C1-6alkyl;
(iii) R2 is C1-6alkyl wherein said alkyl group is optionally substituted with one or more halo or hydroxy,
(iv) R3 is attached to one of the nitrogens on the pyrazolo portion of Formula II(a) and is a moiety of Formula A
wherein:
X, Y and Z are, independently, N or C,
R8, R9, R11 and R12 are independently H or halogen; and
R10 is
aryl or heteroaryl,
wherein said aryl, heteroaryl, is optionally substituted with one or more C1-6alkyl, halogen, haloC1-6alkyl, hydroxy, carboxy, —SH or an additional aryl or heteroaryl, C1-6alkyl sulfonyl;
provided that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present;
(v) R4 is:
C1-6alkyl,
C3-8cycloalkyl,
C3-8heterocycloalkyl,
—C0-6alkylaryl or —C0-6alkylheteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halo, hydroxy, C1-6alkyl, C1-6alkoxy or another aryl group;
in free or salt form;
B) a Compound of formula II(b):
wherein:
(i) Q is —C(═O)—, —C(═S)—;
(ii) R1 is C1-6alkyl;
(iii) R2 is C1-6alkyl wherein said alkyl group is optionally substituted with one or more halo or hydroxy,
(iv) R3 is attached to one of the nitrogens on the pyrazolo portion of Formula II(b) and is a moiety of Formula A
wherein:
X, Y and Z are, independently, N or C,
R8, R9, R11 and R12 are independently H or halogen; and
R10 is phenyl, or pyridyl optionally substituted with one or more C1-6alkyl, halogen, haloC1-6alkyl, hydroxy, carboxy, —SH or an additional aryl or;
provided that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present;
(v) R4 is:
C1-6alkyl,
C3-8cycloalkyl,
C3-8heterocycloalkyl,
—C0-6alkylaryl or —C0-6alkylheteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halo, hydroxy, C1-6alkyl, C1-6alkoxy or another aryl group;
in free or salt form;
C) a Compound of Formula II(c):
wherein:
(i) Q is —C(═O)—, —C(═S)—;
(ii) R1 is C1-6alkyl;
(iii) R2 is C1-6alkyl wherein said alkyl group is optionally substituted with one or more halo or hydroxy,
(iv) R3 is attached to one of the nitrogens on the pyrazolo portion of Formula II(c) and is a moiety of Formula A
wherein:
X, Y and Z are, independently, N or C,
R8, R9, R11 and R12 are independently H or halogen; and
R10 is phenyl, or pyridyl optionally substituted with one or more C1-6alkyl, halogen, haloC1-6alkyl, hydroxy, carboxy, —SH or an additional aryl or heteroaryl;
provided that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present;
(v) R4 is:
—C0-6alkylaryl or —C0-6alkylheteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halo, hydroxy, C1-6alkyl C1-6alkoxy or another aryl group;
in free or salt form;
D) a Compound of Formula II(d):
wherein:
(i) Q is —C(═O)—, —C(═S)—;
(ii) R1 is C1-6alkyl;
(iii) R2 is C1-6alkyl wherein said alkyl group is optionally substituted with one or more halo or hydroxy,
(iv) R3 is attached to one of the nitrogens on the pyrazolo portion of Formula II(d) and is a moiety of Formula A
wherein:
X, Y and Z are independently, N or C,
R8, R9, R11 and R12 are independently H or halogen; and
R10 is phenyl, or pyridyl optionally substituted with one or more C1-6alkyl, halogen, haloC1-6alkyl, hydroxy, carboxy, —SH or an additional aryl or heteroaryl;
provided that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present;
(v) R4 is:
C3-8cycloalkyl,
C3-8heterocycloalkyl,
—C0-6alkylaryl or —C0-6alkylheteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halo, hydroxy, C1-6alkyl, C1-6alkoxy or another aryl group;
in free or salt form,
E) a Compound of Formula II(e):
wherein:
(i) Q is —C(═O)—, —C(═S)—;
(ii) R1 is C1-6alkyl;
(iii) R2 is C1-6alkyl wherein said alkyl group is optionally substituted with one or more halo or hydroxy,
(iv) R3 is attached to one of the nitrogens on the pyrazolo portion of Formula II(e) and is a moiety of Formula A
wherein:
X, Y and Z are, independently, N or C,
R8, R9, R11 and R12 are independently H or halogen; and
R10 is phenyl, or pyridyl optionally substituted with one or more C1-6alkyl or halogen;
provided that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present;
(v) R4 is phenyl optionally substituted with one or more halo, hydroxy, C1-6alkyl, C1-6alkoxy or another aryl group;
in free or salt form;
F) a Compound of Formula II(f):
wherein:
(i) Q is —C(═O)—;
(ii) R1 is C1-6alkyl;
(iii) R2 is C1-6alkyl;
(iv) R3 is attached to one of the nitrogens on the pyrazolo portion of Formula II(f) and is a moiety of Formula A
wherein:
X, Y and Z are C;
R8, R9, R11 and R12 are H; and
R10 is pyridyl, optionally substituted with one or more halogen;
(v) R4 is
phenyl optionally substituted with one or more halo, hydroxy, C1-6alkyl, C1-6alkoxy or another aryl group;
C1-6alkyl,
C3-8 cycloalkyl,
in free or salt form.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein Q is —C(═O) in free or salt form.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R2 is C1-6alkyl, and wherein the C1-6alkyl is not substituted, in free or salt form.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein R4 is phenyl or cyclopentyl in free or salt form.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein said compound is selected from any of the following:
in free or salt form.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein said compound is:
in free or salt form.

### Claim 8

A pharmaceutical composition comprising a compound of Formula II:
wherein
(i) Q is —C(═O)—, —C(═S)—;
(ii) R1 is C1-6alkyl;
(iii) R2 is
C1-6alkyl wherein said alkyl group is optionally substituted with one or more halo or hydroxy,
(iv) R3 is
1) attached to one of the nitrogens on the pyrazolo portion of Formula II and is a moiety of Formula A
wherein:
X, Y and Z are independently, N or C,
R8, R9, R11 and R12 are independently H or halogen; and
R10 is
aryl or heteroaryl,
wherein said aryl, heteroaryl, is optionally substituted with one or more C1-6alkyl, halogen, haloC1-6alkyl, hydroxy, carboxy, —SH, or an additional aryl or heteroaryl,
provided that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present;
(v) R4 is:
C1-6alkyl,
C3-8 cycloalkyl,
C3-8 heterocycloalkyl,
—C0-6alkylaryl or
—C0-6alkylheteroaryl,
wherein said aryl or heteroaryl is optionally substituted with one or more halo, hydroxy, C1-6alkyl, C1-6alkoxy or another aryl group;
in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

### Claim 9 (depends on 8)

A pharmaceutical composition for topical ophthalmic use comprising a composition according to claim 8 in combination or association with an ophthamologically acceptable diluents or carrier.

### Claim 10 (depends on 7)

A method for the treatment of 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, estrogen-induced endometrial hyperplasia or carcinoma comprising administering a therapeutically effective amount of a composition according to claim 7, to a patient in need of such treatment.

### Claim 11 (depends on 10)

The method of claim 10, wherein the condition is Parkinson's disease.

### Claim 12 (depends on 10)

The method of claim 10, wherein the condition is cognitive impairment.

### Claim 13 (depends on 10)

The method of claim 10, wherein the condition is narcolepsy.

### Claim 14 (depends on 13)

The method of claim 13 further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof.

### Claim 15 (depends on 10)

The method of claim 10, wherein said condition is female sexual dysfunction.

### Claim 16 (depends on 15)

The method of claim 15, further comprising administering a compound or compounds selected from a group consisting of estradiol, estriol, estradiol esters, progesterone and progestins to a patient in need thereof.

### Claim 17 (depends on 8)

A method for the treatment for glaucoma or elevated intraocular pressure comprising topical administration of a therapeutically effective amount of a composition according to claim 8 to a patient in need of such treatment.

### Claim 18 (depends on 8)

A method for the treatment of psychosis including schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, comprising administering an effective amount of a composition according to claim 8.