Organic compounds

Abstract

Optionally substituted 3-(thio, sulfinyl or sulfonyl)-7,8-dihydro-(1H or 2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one or a substituted 3-(thio, sulfinyl or sulfonyl)-7,8,9-trihydro-(1H or 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one compounds or Compounds of Formula (I), processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

1 . An optionally substituted 3-(thio, sulfinyl or sulfonyl)-7,8-dihydro-(1H or 2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones or a substituted 3-(thio, sulfinyl or sulfonyl)-7,8,9-trihydro-(1H or 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one, in free or salt form. 
     
     
         2 . The compound according to  claim 1 , wherein said compound is a Compound of Formula II 
       
         
           
           
               
               
           
         
       
       wherein
 (i) L is S, SO or SO 2 ; 
 (ii) R 1  is H or C 1-4  alkyl (e.g., methyl or ethyl); 
 (iii) R 4  is H or C 1-6  alkyl (e.g., methyl, isopropyl) and R 2  and R 3  are, independently, H or C 1-6  alkyl (e.g., methyl or isopropyl) optionally substituted with halo or hydroxy (e.g., R 2  and R 3  are both methyl, or R 2  is H and R 3  is methyl, ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, (optionally hetero)arylC 1-6  alkyl or R 2  and R 3  together form a 3- to 6-membered ring; or
 R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively); 
 
 (iv) R 5  is
 a) -D-E-F, wherein:
 D is C 1-4 alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene); 
 E is a single bond, C 2-4  alkynylene (e.g., —C≡C—), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); 
 F is
 H, 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for example, pyrid-2-yl, imidazol-1-yl, 1,2,4-triazol-1-yl), 
 halo (e.g., F, Br, Cl), 
 haloC 1-4 alkyl (e.g., trifluoromethyl), 
 —C(O)—R 15 , 
 —N(R 16 )(R 17 ), 
 —S(O) 2 R 21  or 
 C 3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl); 
 
 wherein D, E and F are independently and optionally substituted with one or more
 halo (e.g., F, Cl or Br), 
 C 1-4 alkyl (e.g., methyl), 
 haloC 1-4 alkyl (e.g., trifluoromethyl), 
 
 for example, F is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC 1-4 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C 1-4 alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl) or F is a C 3-7  heterocycloalkyl (e.g., pyrrolidinyl) optionally substituted with a C 1-6  alkyl (e.g., 1-methylpyrrolidin-3-yl); or 
 
 b) a substituted heteroarylalkyl, e.g., substituted with haloalkyl; 
 c) 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 (e.g., Cl or F), and R 10  is
 halogen, 
 C 1-4 alkyl, 
 C 3-7  cycloalkyl, 
 heteroC 3-7  cycloalkyl (e.g., pyrrolidinyl or piperidinyl), 
 C 1-4 haloalkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, 
 arylcarbonyl (e.g., benzoyl), 
 alkylsulfonyl (e.g., methylsulfonyl), 
 heteroarylcarbonyl, or 
 alkoxycarbonyl, 
 
             wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more halo (e.g., F or Cl), C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl (e.g., trifluoromethyl), and/or —SH, 
             provided that when X, Y, or Z is nitrogen, R 8 , R 9 , or R 10 , respectively, is not present; 
           
         
         (v) R 6  is
 H, 
 C 1-4 alkyl (e.g., methyl), 
 C 3-7  cycloalkyl (e.g., cyclopentyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), 
 arylC 1-4 alkyl (e.g., benzyl), 
 arylamino (e.g., phenylamino), 
 heterarylamino, 
 N,N-diC 1-4 alkylamino, 
 N,N-diarylamino, 
 N-aryl-N-(arylC 1-4 alkyl)amino (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or 
 —N(R 18 )(R 19 ); 
 wherein the aryl or heteroaryl is optionally substituted with one or more halo (e.g., F, Cl), hydroxy or C 1-6  alkoxy (e.g., methoxy), for example, R 6  is 4-hydroxyphenyl or 4-fluorophenyl, 
 
         (vi) n=0 or 1; 
         (vii) when n=1, A is —C(R 13 R 14 )—, wherein R 13  and R 14 , are, independently, H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylC 1-4 alkoxy or (optionally hetero)arylC 1-4 alkyl or R 13  or R 14  can form a bridge with R 2  or R 4 ; 
         (viii) R 15  is C 1-4 alkyl, haloC 1-4 alkyl, —OH or —OC 1-4  alkyl (e.g., —OCH 3 ) 
         (ix) R 16  and R 17  are independently H or C 1-4 alkyl; 
         (x) R 18  and R 19  are independently H, C 1-4 alky, C 3-8 cycloalkyl, heteroC 3-8 cycloalkyl, aryl (e.g., phenyl) or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl), C 1-6 alkyl, haloC 1-6  alkyl, C 1-6  alkoxy, aryl, heteroaryl, or C 3-8 cycloalkyl, 
         (xi) R 20  is H, C 1-4  alkyl (e.g., methyl) or C 3-7  cycloalkyl, 
         (xii) R 21  is C 1-6  alkyl; 
       
       in free, salt or prodrug form. 
     
     
         3 . The compound according to  claim 1 , wherein said compound is a Compound of Formula I 
       
         
           
           
               
               
           
         
       
       wherein
 (i) L is S, SO or SO 2 ; 
 (ii) R 1  is H or C 1-4  alkyl (e.g., methyl or ethyl); 
 (iii) R 4  is H or C 1-6  alkyl (e.g., methyl, isopropyl) and R 2  and R 3  are, independently, H or C 1-6  alkyl (e.g., methyl or isopropyl) optionally substituted with halo or hydroxy (e.g., R 2  and R 3  are both methyl, or R 2  is H and R 3  is methyl, ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally hetero)arylalkoxy, or (optionally hetero)arylC 1-6 alkyl;
 or 
 R 2  is H and R 3  and R 4  together form a di-, tri- or tetramethylene bridge (pref. wherein the R 3  and R 4  together have the cis configuration, e.g., where the carbons carrying R 3  and R 4  have the R and S configurations, respectively); 
 
 (iv) R 5  is
 a) -D-E-F, wherein:
 D is C 1-4  alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene); 
 E is a single bond, C 2-4 alkynylene (e.g., —C≡C—), arylene (e.g., phenylene) or heteroarylene (e.g., pyridylene); 
 F is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for example, pyrid-2-yl, imidazol-1-yl, 1,2,4-triazol-1-yl), halo (e.g., F, Br, Cl), haloC 1-4  alkyl (e.g., trifluoromethyl), —C(O)—R 15 , —N(R 16 )(R 17 ), —S(O) 2 R 21  or C 3-7  cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g., pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or morpholinyl); 
 wherein D, E and F are independently and optionally substituted with one or more halo (e.g., F, Cl or Br), C 1-4 alkyl (e.g., methyl), haloC 1-4 alkyl (e.g., trifluoromethyl), for example, F is heteroaryl, e.g., pyridyl substituted with one or more halo (e.g., 6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl), haloC 1-4 alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C 1-4 alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl, e.g., phenyl, substituted with one or more halo (e.g., 4-fluorophenyl) or F is a C 3-7  heterocycloalkyl (e.g., pyrrolidinyl) optionally substituted with a C 1-6  alkyl (e.g., 1-methylpyrrolidin-3-yl); or 
 
 b) a substituted heteroarylalkyl, e.g., substituted with haloalkyl; 
 c) 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 (e.g., Cl or F), and R 10  is halogen, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4  haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R 8 , R 9 , or R 10 , respectively, is not present; 
           
         
         (v) R 6  is
 H, 
 C 3-7  cycloalkyl (e.g., cyclopentyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl, for example, pyrid-4-yl), 
 arylC 1-4 alkyl (e.g., benzyl), 
 arylamino (e.g., phenylamino), 
 heterarylamino, 
 N,N-diC 1-4  alkylamino, 
 N,N-diarylamino, 
 N-aryl-N-(arylC 1-4 alkyl)amino (e.g., N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or 
 —N(R 18 )(R 19 ); 
 wherein the aryl or heteroaryl is optionally substituted with one or more halo (e.g., F, Cl), hydroxy or C 1-6  alkoxy (e.g., methoxy), for example, R 6  is 4-hydroxyphenyl or 4-fluorophenyl, 
 
         (vi) n=0 or 1; 
         (vii) when n=1, A is —C(R 13 R 14 )—, wherein R 13  and R 14 , are, independently, H or C 1-4 alkyl, aryl, heteroaryl, (optionally hetero)arylC 1-4 alkoxy or (optionally hetero)arylC 1-4 alkyl; 
         (viii) R 15  is C 1-4 alkyl, haloC 1-4 alkyl, —OH or —OC 1-4  alkyl (e.g., —OCH 3 ) 
         (ix) R 16  and R 17  are independently H or C 1-4 alkyl; 
         (x) R 18  and R 19  are independently H, C 1-4 alky or aryl (e.g., phenyl) wherein said aryl is optionally substituted with one or more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl) 
         (xi) R 20  is H, C 1-4 alkyl (e.g., methyl) or C 3-7  cycloalkyl, 
         (xii) R 21  is C 1-6  alkyl, 
       
       in free or salt form. 
     
     
         4 . The compound according to  claim 2 , selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         5 . The compound according to  claim 2 , selected from any of the following: 
       
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 2 , in admixture with a pharmaceutically acceptable diluent or carrier. 
     
     
         7 . 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 2 , to a patient in need of such treatment. 
     
     
         8 . The method of  claim 7 , wherein the condition is Parkinson's disease. 
     
     
         9 . The method of  claim 7 , wherein the condition is cognitive impairment. 
     
     
         10 . The method of  claim 7 , wherein the condition is narcolepsy. 
     
     
         11 . The method of  claim 10  further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof. 
     
     
         12 . The method of  claim 7 , wherein said condition is female sexual dysfunction. 
     
     
         13 . The method of  claim 12 , 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. 
     
     
         14 . 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 2 , in free or pharmaceutically acceptable salt form, in an opthalmically compatible carrier to the eye of a patient in need thereof. 
     
     
         15 . 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 2 , in free or pharmaceutically acceptable salt form, to a patient in need thereof. 
     
     
         16 . A method for the treatment of traumatic brain injury comprising administering to a patient in need thereof, a compound according to  claim 2 , in free or pharmaceutically acceptable salt form. 
     
     
         17 . 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 2  in free or salt form. 
     
     
         18 - 20 . (canceled)