Organic compounds

Abstract

1- or 2- or 7-(substituted)-3-(optionally hetero)arylamino-[1H,2H]-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives, in free, salt or prodrug form, are useful as pharmaceuticals, particularly as phosphodiesterase 1 inhibitors, useful for the treatment of diseases involving disorders of the dopamine D1 receptor intracellular pathway, such as Parkinson's disease, depression, narcolepsy and damage to cognitive function, e.g., in schizophrenia or disorders that may be ameliorated through enhanced progesterone—signaling pathway, e.g., female sexual dysfunction.

What is claimed is: 
     
         1 . A compound of formula Q: 
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 1  is H or C 1-6 alkyl; 
 (ii) R 2  is
 H, 
 C 1-6  alkyl, 
 C 3-8  cycloalkyl optionally substituted with one or more amino, 
 C 3-8 heterocycloalkyl optionally substituted with C 1-6 alkyl, 
 C 3-8 cycloalkyl-C 1-6 alkyl, 
 C 1-6 haloalkyl, 
 C 0-6 alkylaminoC 0-6 alkyl, 
 hydroxyC 1-6 alkyl, 
 arylC 0-6 alkyl, 
 heteroarylalkyl, 
 C 1-6 alkoxyarylC 1-6 alkyl, or 
 -G-J wherein:
 G is a single bond or, alkylene; 
 J is cycloalkyl or heterocycloalkyl optionally substituted with alkyl; 
 
 
 (iii) R 3  is
 a) D-E-F wherein
 1. D is single bond, C 1-6 alkylene, or arylC 1-6 alkylene; 
 2. E is a C 1-6 alkylene, arylene, C 1-6 alkylarylene, aminoC 1-6 alkylene or amino; and 
 3. F is
 C 1-6 alkyl, 
 aryl, 
 heteroaryl optionally substituted with C 1-6 alkyl, 
 heteroC 3-8 cycloalkyl optionally substituted with C 1-6 alkyl, 
 amino 
 C 1-6 alkoxy, or 
 —O-haloC 1-6 alkyl 
 
 
 b) R 3  is a substituted heteroarylalkyl, 
 c) R 3  is attached to one of the nitrogen atoms 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 halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, aryl, heteroaryl, 
         
         (iv) R 4  is aryl (e.g., phenyl) optionally substituted with one or more halo, hydroxyl or C 1-6 alkoxy, heteroaryl or heteroC 3-6  cycloalkyl; and 
         (v) R 5  is H, C 1-6 alkyl, C 3-8  cycloalkyl, heteroaryl, aryl, or p-benzylaryl; 
       
       wherein “alk”, “alkyl”, “haloalkyl” or “alkoxy” refers to C 1-6  alkyl and “cycloalkyl” refers to C 3-8 cycloalkyl; 
       in free or salt form. 
     
     
         2 . The compound according to  claim 1 , wherein said compound is a compound of formula Q-I 
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 1  is H or C 1-6 alkyl; 
 (ii) R 2  is H, alkyl, cycloalkyl, alkylaminoalkyl, hydroxyalkyl arylalkyl, heteroarylalkyl, or alkoxyarylalkyl; 
 (iii) R 3  is D-E-F wherein
 1. D is single bond, C 1-6 alkylene, or arylC 1-6 alkylene; 
 2. E is a C 1-6 alkylene, arylene, C 1 -6alkylarylene, aminoC 1-6 alkylene or amino; and 
 3. F is
 C 1-6 alkyl, 
 aryl, 
 heteroaryl, optionally substituted with C 1-6 alkyl, 
 heteroC 3-8 cycloalkyliperidinyl, optionally substituted with C 1-6 alkyl 
 amino 
 C 1-6 alkoxy, or 
 —O-haloC 1-6 alkyl 
 
 provided that when -D-E- is an heteroarylalkyl or arylalkyl, F is not aryl or heteroaryl; 
 
 (iv) R 4  is aryl, heteroaryl or heterocycloalkyl; and 
 (v) R 5  is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl; 
 
       wherein “alk”, “alkyl”, “haloalkyl” or “alkoxy” refers to C 1-6  alkyl and “cycloalkyl” refers to C 3-8  cycloalkyl. 
     
     
         3 . The compound according to  claim 1 , wherein said compound is a compound of formula Q-II: 
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 1  is H or alkyl; 
 (ii) G is a single bond or, alkylene; 
 (iii) J is cycloalkyl or heterocycloalkyl optionally substituted with alkyl; or
 -G-J is
 C 3-8 cycloalkyl substituted with one or more amino, 
 C 3-8 heterocycloalkyl optionally substituted with C 1-6 alkyl, for example, 1-methylpyrrolidin-3-yl, 
 C 3-8 cycloalkyl-C 1-6 alkyl, 
 aminoC 1-6 alkyl, 
 
 provided that when G is a single bond, J is not an unsubstituted cycloalkyl; 
 
 (iv) R 3  is
 a) D-E-F wherein
 1. D is single bond, C 1-6 alkylene, or arylC 1-6 alkylene; 
 2. E is a C 1-6 alkylene, arylene, C 1-6 alkylarylene, aminoC 1-6 alkylene or amino; and 
 3. F is
 C 1-6 alkyl, 
 aryl, 
 heteroaryl optionally substituted with C 1-6 alkyl, 
 heteroC 3-8 cycloalkyl optionally substituted with C 1-6 alkyl 
 amino 
 C 1-6 alkoxy, or 
 —O-haloC 1-6 alkyl 
 
 
 b) R 3  is a substituted heteroarylaklyl, or 
 c) R 3  is attached to one of the nitrogen atoms on the pyrazolo portion of Formula II 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 halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl; 
           
         
         (v) R 4  is aryl optionally substituted with one or more halo or hydroxyl, heteroaryl or heteroC 3-6 cycloalkyl; and 
         (vi) R 5  is H, C 1-6 alkyl, C 3-8 cycloalkyl, heteroaryl, aryl, p-benzylaryl, 
       
       wherein “alk”, “alkyl”, “haloalkyl” or “alkoxy” refers to C 1-6  alkyl and “cycloalkyl” refers to C 3-6  cycloalkyl. 
     
     
         4 . The compound according to  claim 1 , wherein said compound is a compound of formula Q-III: 
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 1  is H or alkyl; 
 (ii) R 2  is alkyl; 
 (iii) R 3  is
 a) D-E-F wherein
 1. D is single bond, C 1-6 alkylene, or arylC 1-6 alkylene; 
 2. E is a C 1-6 alkylene, arylene, C 1-6 alkylarylene, aminoC 1-6 alkylene or amino; and 
 3. F is
 C 1-6 alkyl, 
 aryl 
 heteroaryl optionally substituted with C 1-6 alkyl, 
 heteroC 3-8 cycloalkyl optionally substituted with C 1-6 alkyl 
 amino 
 C 1-6 alkoxy, or 
 —O-haloC 1-6 alkyl 
 
 
 b) R 3  is a substituted heteroarylaklyl 
 C) R 3  is attached to one of the nitrogen atoms 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 halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl 
         
         (iv) R 4  is aryl optionally substituted with one or more halo, hydroxy or C 1-6 alkoxy, heteroaryl or heteroC 3-6 cycloalkyl; 
       
       wherein “alk”, “alkyl”, “haloalkyl” or “alkoxy” refers to Ci-6 alkyl and “cycloalkyl” refers to C 3-6  cycloalkyl. 
     
     
         5 . The compound according to  claim 1  selected from the following: 
       
         
           
           
               
               
           
         
         in free, salt or prodrug form. 
       
     
     
         6 . The compound according to  claim 1  selected from the following; 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1  selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 1  selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 1  selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in free, salt or prodrug form. 
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 1 , in free or pharmaceutically acceptable salt or prodrug form, in admixture with a pharmaceutically acceptable diluent or carrier. 
     
     
         11 . A method for the treatment of diseases involving disorders of the dopamine D1 receptor intracellular pathway comprising administering a therapeutically effective amounts of a PDE 1 Inhibitor according to  claim 1 - 9 , in free or pharmaceutically acceptable salt or prodrug form, to a person in need thereof. 
     
     
         12 . The method according to  claim 11 , wherein said disease is any of the following: 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. 
     
     
         13 . The method of  claim 11 , wherein the condition is Parkinson's disease. 
     
     
         14 . The method of  claim 11 , wherein the condition is cognitive impairment. 
     
     
         15 . The method of  claim 11 , wherein the condition is narcolepsy. 
     
     
         16 . The method of  claim 15  further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof. 
     
     
         17 . The method of  claim 11 , wherein said condition is female sexual dysfunction. 
     
     
         18 . The method of  claim 17  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. 
     
     
         19 . A method of making a compound according to  claim 1  comprising reacting a pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione with a compound of formula X—R 3  wherein X is a leaving group and isolating the compound thus obtained. 
     
     
         20 . The method of  claim 19 , wherein the pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is a compound of Formula IIIC: 
       
         
           
           
               
               
           
         
       
     
     
         21 . A method of making a compound according to  claim 1  comprising reacting a pyrazolo[3,4-d]pyrimidine-4,6(5H or 7H)-dione with a compound of formula X—R 2  wherein X is a leaving group, and isolating the compound thus obtained. 
     
     
         22 . The method of  claim 21  wherein the pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is a compound of Formula IIh: 
       
         
           
           
               
               
           
         
       
     
     
         23 . (canceled)