ORGANIC COMPOUNDS

• US 20110281832A1
• Filed: 12/07/2009
• Published: 11/17/2011
• Est. Priority Date: 12/06/2008
• Status: Active Grant

• Current Assignee: Intra-Cellular Therapies, Inc.
• Original Assignee: Intra-Cellular Therapies, Inc.
• Inventors: Zheng, Hailin, Zhao, Jun, Li, Peng, Wennogle, Lawrence P.
• Granted Patent: US 8,859,564 B2
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/164 of a carboxylic acid with an aminoalcohol, e.g. ceramides
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/26 : Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: 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
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

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.

Claims

16. (canceled)

17. (canceled)

18. (canceled)

19. a compound of formula I:

1. The compound according to claim 19, wherein said compound is a compound of Formula II:

2. The compound according to claim 1 selected from:

3. The compound according to claim 1, selected from any of the following:

4. A pharmaceutical composition comprising a compound according to claim 1, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

5. A method of treating any of the following conditions:

Parkinson'"'"'s disease, restless leg, tremors, dyskinesias, Huntington'"'"'s disease, Alzheimer'"'"'s disease, and drug-induced movement disorders;

depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorder, narcolepsy, cognitive impairment, dementia, Tourette'"'"'s syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction;

cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and/or sexual dysfunction;

asthma, chronic obstructive pulmonary disease, and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and

/or female sexual dysfunction, exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma; and

/or any disease or condition characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE1, and/or by reduced dopamine D1 receptor signaling activity; and

/or any disease or condition that may be ameliorated by the enhancement of progesterone signaling;

comprising administering an effective amount of a compound according to claim 1, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 4, to a patient in need of such treatment.

6. The method of claim 5, wherein the condition is Parkinson'"'"'s disease.

7. The method of claim 5, wherein the condition is cognitive impairment.

8. The method of claim 5, wherein the condition is narcolepsy.

9. The method of claim 8 further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof.

10. The method of claim 5, wherein said condition is female sexual dysfunction.

11. The method of claim 10, 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.

12. A method for the treatment of treatment for glaucoma or elevated intraocular pressure comprising topical administration of a therapeutically effective amount of a compound according to claim 1, in free or pharmaceutically acceptable salt form, in an opthalmically compatible carrier to the eye of a patient in need thereof.

13. A method for the treatment of psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, comprising administering a therapeutically effective amount of a compound according to claim 1, in free or pharmaceutically acceptable salt form, to a patient in need thereof.

14. A method for the treatment of traumatic brain injury comprising administering to a patient in need thereof, a compound according to claim 1, in free or pharmaceutically acceptable salt form.

15. A method for lengthening or enhancing growth of the eyelashes by administering an effective amount of a prostaglandin analogue, e.g., bimatoprost, concomitantly, simultaneously or sequentially with an effective amount of a compound according to claim 1, in free or salt form.

20. The compound according to claim 19, wherein R₂ is 2,2-dimethylpropyl, in free or salt form.

21. The compound according to claim 20, wherein R₄ is C_1-6alkyl, in free or salt form.

22. The compound according to claim 20, wherein R₄ is aryl (e.g., phenyl) optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C_1-6alkyl, C_1-6alkoxy or another aryl group, in free or salt form.

23. The compound according to claim 20, wherein R₄ is phenyl, in free or salt form.

24. The compound according to claim 23, wherein R₃ is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A

25. The compound according to claim 23, wherein R₃ is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A

26. The compound according to claim 23, wherein R₃ is attached to one of the nitrogens on the pyrazolo portion of Formula I and is a moiety of Formula A

27. The compound according to claim 19, wherein said compound is:

28. The compound according to claim 1, wherein:

(i) R₁ is H or alkyl (e.g., methyl);

(ii) R₂ is selected from a group consisting of isobutyl, 2-methylbutyl, 2,2-dimethyl propyl, cycloalkyl (e.g., cyclopentyl, cyclohexyl), haloalkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), alkylaminoalkyl (e.g., 2-(dimethylamino)ethyl), hydroxyalkyl (e.g., 3-hydroxy-2-methyl propyl), arylalkyl (e.g., benzyl), heteroarylalkyl (e.g., pyridylmethyl), or alkoxyarylalkyl (e.g., 4-methoxybenzyl);

(iii) R₃ is a substituted heteroarylaklyl, e.g., substituted with haloalkyl

or

R₃ is attached to one of the nitrogens on the pyrazolo portion of Formula I(i) and is a moiety of Formula A