Organic compounds

Abstract

The present invention relates to PDEI inhibitory compounds of Formula I as described herein, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

1 . A Compound of Formula I 
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 1  is H or C 1-4  alkyl; 
 (ii) R 4  is H and R 2  and R 3  are independently H or C 1-6 alkyl; or
 R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge; 
 
 (iii) R 5  is 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 C; 
           R 8 , R 9 , R 11  and R 12  are H; and 
           R 10  is heteroaryl, optionally substituted with one or more halo; 
         
         (iv) R 6  is ethyl or isopropyl, 
       
       in free or form. 
     
     
         2 . The compound according to  claim 1 , selected from any of the following 
       
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         3 . The compound according to  claim 1 , wherein R 4  is H and R 2  and R 3  are independently H or C 1-6 alkyl, in free or salt form. 
     
     
         4 . The compound according to  claim 1 , wherein the compound is a compound of Formula I(i): 
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 1  is C 1-4  alkyl; 
 (ii) R 4  is H and R 2  and R 3  are independently C 1-6 alkyl; 
 (iii) R 5  is attached to one of the nitrogens on the pyrazolo portion of Formula I(i) and is a moiety of Formula A 
 
       
         
           
           
               
               
           
         
         
           wherein: 
           X, Y and Z are C; 
           R 8 , R 9 , R 11  and R 12  are H; and 
           R 10  is pyridyl, substituted with one or more halo; 
         
         (iv) R 6  is ethyl or isopropyl; 
       
       in free or form. 
     
     
         5 . The compound according to  claim 4 , selected from any of the following 
       
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         6 . The compound according to  claim 1 , wherein R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge, in free or salt form. 
     
     
         7 . The compound according to  claim 6 , wherein R 2  is H and R 3  and R 4  together form a tri-methylene bridge and the carbons carrying R 3  and R 4  have the R and S configurations, respectively, in free or salt form. 
     
     
         8 . The compound according to  claim 6 , selected from any of the following: 
       
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         9 . A pharmaceutical composition comprising the compound according to  claim 1 , in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. 
     
     
         10 . 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, 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, and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease, allergic rhinitis, autoimmune disease, 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 and elevated intraocular pressure, psychosis, e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, 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 the compound according to  claim 1 , in free or pharmaceutically acceptable salt form, to a patient in need of such treatment. 
     
     
         11 . The method of  claim 10 , wherein the condition is Parkinson's disease. 
     
     
         12 . The method of  claim 10 , wherein the condition is cognitive impairment. 
     
     
         13 . The method of  claim 10 , wherein the condition is cognitive impairment of schizophrenia. 
     
     
         14 . The method of  claim 10 , wherein the condition is narcolepsy. 
     
     
         15 . The method of  claim 14  further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof. 
     
     
         16 . The method of  claim 10 , wherein said condition is female sexual dysfunction. 
     
     
         17 . The method of  claim 16 , 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. 
     
     
         18 . 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. 
     
     
         19 . 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. 
     
     
         20 . A method for the treatment of traumatic brain injury comprising administering to a patient in need thereof, a therapeutically effective amount of the compound according to  claim 1 , in free or pharmaceutically acceptable salt form. 
     
     
         21 . 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 any  claim 1 , in free or salt form. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled)