US2010234397A1PendingUtilityA1

Enzyme inhibitors

42
Assignee: PROBIODRUG AGPriority: Apr 12, 2006Filed: Mar 31, 2010Published: Sep 16, 2010
Est. expiryApr 12, 2026(expired)· nominal 20-yr term from priority
Inventors:Michael ThormannMichael AlmstetterAndreas Treml
A61P 37/00A61P 35/00A61P 3/10A61P 37/06A61P 43/00A61P 25/04A61P 25/24A61P 3/00A61P 25/20A61P 25/00A61P 25/18A61P 25/08A61P 29/00A61P 3/02A61P 25/28A61P 25/22C07D 403/06A61P 19/02C07D 401/06C07D 233/64C07D 405/06C07D 409/06C07D 405/04C07D 403/04C07D 401/04
42
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Claims

Abstract

There is disclosed herein methods for using compounds of formula (I), wherein: R 1 , R 2 , R 3 , R 4 and R 5 are defined throughout the description and the claims. The compounds of formula (I) are useful for the treatment of neurological diseases and neurodegenerative diseases, e.g. anxiety, depression, Alzheimer's disease etc.

Claims

exact text as granted — not AI-modified
1 . A method for the treatment or prevention of a disease or disorder selected from the group consisting of neuronal disorders as well as psychosomatic, neuropsychiatric and depressive illnesses, anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm, chronic pain, cancer, dermal diseases, immune or autoimmune disorders, multiple sclerosis, inflammatory conditions, arthritis, allograft rejection, neurodegenerative disorders, cognitive disorders, metabolic disorders, and conditions characteristic of a pre-diabetic state; or for improving memory and learning ability, comprising:
 administering a therapeutically effective amount of (a) a compound according to formula (I) or (b) a pharmaceutical composition comprising a compound of formula (I), to a subject in need thereof;   
     
       
         
         
             
             
         
       
       wherein,
 R 1  represents a group selected from the list consisting of: C 1-12 alkyl; —C 1-6 alkylOC 1-6 alkyl; C 2-12 alkenyl; C 2-12 alkynyl; C 1-12 alkylamino; aryl, -aryl-aryl; —C 1-6 alkylaryl; —C 1-6 alkylarykaryl; —C 1-6 alkylaryl-heteroaryl; —C 1-6 alkylheteroaryl-aryl; —C 1-6 alkylheteroaryl-heteroaryl; —C 1-6 alkyl(aryl) 2 ; —C 1-6 alkyl(heteroaryl) 2 ; —C 1-6 alkyl(heteroaryl)(aryl); —C 1-6 alkylOaryl; —C 1-6 alkylNR 9 aryl; —C 2-6 alkenylaryl; —C 2-6 alkynylaryl; heteroaryl; —C 1-6 alkylheteroaryl; —C 1-6 alkyl(heteroaryl) 2 ; —C 1-6 alkylOheteroaryl; —C 1-6 alkylNR 9 heteroaryl; —C 2-6 alkenylheteroaryl; —C 2-6 alkynylheteroaryl; —C 3-12 carbocycle; —C 1-6 alkylC 3-12 carbocycle; —C 1-6 alkylOC 3-12 carbocycle; —C 1-6 alkylNR 9 C 3-12 carbocycle; —C 2-6 alkenylC 3-12 carbocycle; —C 2-6 alkynylC 3-12 carbocycle; —C 3-12 heterocycle; —C 1-6 alkylC 3-12 heterocycle; —C 2-6 alkenylC 3-12 heterocycle; and —C 2-6 alkynylC 3-12 heterocycle; any of which alkyl, alkenyl or alkynyl groups may optionally be substituted by one or more halogen and/or hydroxyl groups; any of which carbocycle and heterocycle may optionally be substituted by one or more methyl groups; 
 R 2  represents a group selected for the list consisting of —C 1-6 alkylNR 10 R 11  and —C 3-6 cycloalkylimine optionally N substituted by R 12 ; and R 9  , R 10 , R 11  and R 12  independently represents hydrogen or lower alkyl; 
 R 3  represents H; halogen; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy or C 1-4 haloalkoxy; 
 R 4  represents H; halogen; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy or C 1-4 haloalkoxy; 
 R 5 represents H; halogen; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy or C 1-4 haloalkoxy; and 
 wherein any of the aforesaid carbocycle and heterocycle groups may optionally be substituted by one or more groups selected from the list consisting of:
 (i) C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl; 
 (ii) C 1-6 haloalkyl; 
 (iii) halogen; 
 (iv) oxo; 
 (v) —S—C 1-6 alkyl (e.g. methylthio), —S(O)—C 1-6 alkyl and —S(O) 2 —C 1-6 alkyl; 
 (vi) cyano; 
 (vii) nitro; 
 (viii) amino; 
 (ix) —OR 13 ; wherein R 13  may represent hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl or C 1-6 haloalkyl; 
 (xii) —C(O)OR 13 ; wherein R 13  is as defined above; 
 (xiii) —S(O) 2 —C 3-12 cycloalkyl; 
 (xiv) —S(O) 2 —C 1-6 alkyl; 
 (xv) —S(O) 2 -amino; 
 (xvi) —C(O)-amino; 
 (xvii) C 1-6 alkanoyl; and 
 (xviii) C 1-6 alkoxyC 1-6 alkanoyl; and 
 
 wherein any of the aforesaid aryl and heteroaryl groups may optionally be substituted by one or more groups selected from the list consisting of:
 (i) C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl; 
 (ii) C 1-6 haloalkyl; 
 (iii) halogen; 
 (iv) oxo; 
 (v) —S—C 1-6 alkyl (e.g. methylthio), —S(O)—C 1-6 alkyl and —S(O) 2 —C 1-6 alkyl; 
 (vi) cyano; 
 (vii) nitro; 
 (viii) amino; 
 (ix) —OR 13 ; wherein R 13  may represent hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl or C 1-6 haloalkyl; 
 (xii) —C(O)OR 13 ; wherein R 13  is as defined above; 
 (xiii) —S(O) 2 —C 3-12 cycloalkyl; 
 (xiv) —S(O) 2 —C 1-6 alkyl; 
 (xv) —S(O) 2 -amino; 
 (xvi) —C(O)-amino; 
 (xvii) C 1-6 alkanoyl; 
 (xviii) C 1-6 alkoxyC 1-6 alkanoyl; 
 (xix) —C 2-6 alkenyloxy-; 
 (xx) C 2-6 alkynyloxy-; 
 (xxi) C 1-6 alkoxyC 1-6 alkyl-; 
 (xxii) —C(O)N(C 1-6 alkyl) 2 , —C(O)NH 2  and —C(O)NH(C 1-6 alkyl); and 
 (xxiii) C 3-12 cycloalkyl; 
 
 
       or a pharmaceutically acceptable salt, polymorph or solvate thereof, including all tautomers and stereoisomers thereof. 
     
   
   
       2 . A method of  claim 1  comprising administering a therapeutically effective amount of a compound according to formula (I). 
   
   
       3 . A method of  claim 1  comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I). 
   
   
       4 . A method of  claim 1  for the treatment of a disease selected from the group consisting of neuronal disorders as well as psychosomatic, neuropsychiatric and depressive illnesses, such as anxiety, depression, sleep disorders, chronic fatigue, schizophrenia, epilepsy, nutritional disorders, spasm, chronic pain, cancer, dermal diseases, immune and autoimmune disorders, multiple sclerosis, and inflammatory conditions, arthritis, allograft rejection, neurodegenerative disorders, cognitive disorders and/or for improving memory and learning ability. 
   
   
       5 . A method of  claim 4  for the treatment of a disease selected from the group consisting of anxiety, depression, and schizophrenia. 
   
   
       6 . A method of  claim 1  for the treatment of a disease selected from the group consisting of metabolic disorders and conditions characteristic of a pre-diabetic state. 
   
   
       7 . A method of  claim 1 , wherein
 R 1  represents C 1-12 alkyl; C 2-12 alkenyl, wherein the double bond is not at the C-1 position; C 2-12 alkynyl, wherein the triple bond is not at the C-1 position; C 3-12 carbocycle; - which may optionally be substituted by one or more methyl groups; C 1-6 -alkyl-C 3-12 carbocycle, in which the carbocycle ring may optionally be substituted by one or more methyl groups; C 1-6 haloalkyl; —C 1-6 alkyl-aryl; —C 1-6 alkyl-C 3-12 heterocycle in which the heterocycle ring may optionally be substituted by one or more methyl groups; or —C 1-6 alkyl-heteroaryl;   R 2  represents —C 1-4 alkyl-NH 2 ; azetidin-2-yl; azetidin-3-yl; pyrrolidin-2-yl or pyrrolidin-3-yl;   R 3  represents H; halogen; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy or C 1-4 haloalkoxy;   R 4  represents H; halogen; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy or C 1-4 haloalkoxy;   R 5  represents H; halogen; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy or C 1-4 haloalkoxy;   wherein any of the forementioned aryl and heteroaryl groups may optionally be substituted by one or more substituent groups selected from C 1-12  alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-6 haloalkyl, -thioC 1-6 alkyl, —SO 2 C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, —SO 2 C 3-12 cycloalkyl, C 2-6 alkenyloxy-, C 2-6 alkynyloxy-, —C(O)—C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl-, nitro, halogen, cyano, hydroxyl, oxo, —C(O)OH, —C(O)OC 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)N(C 1-6 alkyl) 2 , —C(O)NH 2  and —C(O)NH(C 1-6 alkyl);   or a pharmaceutically acceptable salt, polymorph or solvate thereof, including all tautomers and stereoisomers thereof.   
   
   
       8 . A method according to  claim 1  wherein R 1  represents —C 1-6 alkyl-aryl, which aryl may optionally be substituted. 
   
   
       9 . A method according to  claim 8  wherein R 1  represents —CH 2 -ary which aryl may optionally be substituted. 
   
   
       10 . A method according to  claim 1  wherein R 1  represents —C 1-6 alkyl-heteroaryl which heteroaryl may optionally be substituted. 
   
   
       11 . A method according to  claim 10  wherein R 1  represents —CH 2 -heteroaryl which heteroaryl may optionally be substituted. 
   
   
       12 . A method according to  claim 1  wherein R 1  represents —C 1-6 alkyl. 
   
   
       13 . A method according to  claim 1  wherein R 2  represents -azetidin-3-yl. 
   
   
       14 . A method according to  claim 1  wherein R 2  represents —C 1-4 alkyl-NH 2 . 
   
   
       15 . A method according to  claim 14  wherein R 2  represents -methyl-amino. 
   
   
       16 . A method according to  claim 1  wherein R 3  represents F. 
   
   
       17 . A method according to  claim 1  wherein R 3  represents Cl. 
   
   
       18 . A method according to  claim 1  wherein R 3  represents methyl. 
   
   
       19 . A method according to  claim 1  wherein R 4  represents Cl. 
   
   
       20 . A method according to  claim 1  wherein R 4  represents F. 
   
   
       21 . A method according to  claim 1  wherein R 4  represents methyl. 
   
   
       22 . A method according to  claim 1  wherein R 4  represents methoxy. 
   
   
       23 . A method according to  claim 1  wherein R 5  represents H. 
   
   
       24 . A method of  claim 1 , wherein
 R 1  represents a group selected from the list consisting of: C 1-12 alkyl; —C 1-6 alkylOC 1-6 —C 2-12 alkenyl; —C 2-12 alkynyl; —C 1-12 alkylamino; aryl; -aryl-aryl; —C 1-6 alkylaryl; —C 1-6 alkylaryl-aryl; —C 1-6 alkylaryl-heteroaryl; —C 1-6 alkylheteroarykaryl; —C 1-6 alkylheteroaryl-heteroaryl; —C 1-6 alkyl(aryl) 2 ; —C 1-6 alkyl(heteroaryl) 2 ; —C 1-6 alkyl(heteroaryl)(aryl); —C 1-6 alkylOaryl; —C 1-6 alkylNR 9 aryl; —C 2-6 alkenylaryl; —C 2-6 alkynylaryl; heteroaryl; —C 1-6 alkylheteroaryl; —C 1-6 alkyl(heteroaryl) 2 ; —C 1-6 alkylOheteroaryl; —C 1-6 alkylNR 9 heteroaryl; —C 2-6 alkenylheteroaryl; —C 2-6 alkynylheteroaryl; C 3-12 carbocycle; —C 1-6 alkylC 3-12 carbocycle; —C 1-6 alkylOC 3-12 carbocycle; —C 1-6 alkylNR 9 C 3-12 carbocycle; —C 2-6 alkenylC 3-12 carbocycle; —C 2-6 alkynylC 3-12 carbocycle; —C 3-12 heterocycle; —C 1-6 alkylC 3-12 heterocycle; —C 2-6 alkenylC 3-12 heterocycle; and —C 2-6 alkynylC 3-12 heterocycle; any of which alkyl, alkenyl or alkynyl groups may optionally be substituted by one or more halogen and/or hydroxyl groups;   R 2  represents a group selected from the list consisting of: C 1-6 alkylNR 10 R 11 and C 3-6 cycloalkylimine optionally N substituted by R 12 ;   R 3  represents Cl;   R 4  represents Cl;   R 5  represents H; and   R 9 , R 10 , R 11  and R 12  independently represents hydrogen or C 1-4 alkyl;   wherein any of the aforementioned aryl, heteroaryl, carbocycle and heterocycle groups may optionally be substituted by one or more groups selected from the list consisting of:
 (i) C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl; 
 (ii) C 1-6 haloalkyl; 
 (iii) halogen; 
 (iv) oxo 
 (v) —S—C 1-6 alkyl, —S(O)—C 1-6 alkyl and —S(O) 2 —C 1-6 alkyl; 
 (vi) cyano; 
 (vii) nitro; 
 (viii) amino; 
 (ix) —OR 13 ; wherein R 13  may represent hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl or C 1-6 haloalkyl; 
 (xii) —C(O)OR 13 ; wherein R 13  is as defined above; 
 (xiii) —S(O) 2 —C 3-12 cycloalkyl 
 (xiv) —S(O) 2 —C 1-6 alkyl 
 (xv) —S(O) 2 -amino; 
 (xvi) —C(O)-amino; 
 (xvii) C 1-6 alkanoyl; and 
 (xviii) C 1-6 alkoxyC 1-6 alkanoyl; or 
   a pharmaceutically acceptable salt, polymorph or solvate thereof, including all tautomers and stereoisomers thereof.   
   
   
       25 . A method according to  claim 1 , wherein R 2  represents C 1-6 alkylNR 10 R 11 . 
   
   
       26 . A method according to  claim 25 , where in R 2  represents methylamine. 
   
   
       27 . A method according to  claim 25 , wherein R 2  represents 1-ethylamine. 
   
   
       28 . A method according to  claim 25 , wherein R 2  represents 2-ethylamine. 
   
   
       29 . A method according to  claim 25 , wherein R 2  represents 3-propylamine. 
   
   
       30 . A method according to  claim 1 , wherein R 2  represents C 3-6 cycloalkylimine optionally N substituted by R 12 . 
   
   
       31 . A method according to  claim 30 , wherein R 2  represents 3-azetidine. 
   
   
       32 . A method according to  claim 1 , wherein R 1  represents C 1-12 alkyl, which may be optionally substituted. 
   
   
       33 . A method according to  claim 1 , wherein R 1  represents C 2-12 alkenyl, which may be optionally substituted. 
   
   
       34 . A method according to  claim 1 , wherein R 1  represents C 2-12 alkynyl, which may be optionally substituted. 
   
   
       35 . A method according to  claim 1 , wherein R 1  represents aryl, which may optionally be substituted. 
   
   
       36 . A method according to  claim 1 , wherein R 1  represents heteroaryl, which may optionally be substituted. 
   
   
       37 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylOC 1-6 alkyl, which alkyl groups may be optionally substituted. 
   
   
       38 . A method according to  claim 1 , wherein R 1  represents C 1-12 alkylamino, which alkyl group may be optionally substituted. 
   
   
       39 . A method according to  claim 1 , wherein R 1  represents -aryl-aryl, which aryl groups may optionally be substituted. 
   
   
       40 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylaryl, which alkyl and aryl groups may be optionally substituted. 
   
   
       41 . A method according to  claim 1 , wherein R 1  represents —C 1-6 alkylaryl aryl, which alkyl and aryl groups may be optionally substituted. 
   
   
       42 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkyl(aryl) 2 , which alkyl and aryl groups may be optionally substituted. 
   
   
       43 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkyl(heteroaryl) 2 , which alkyl and heteroaryl groups may be optionally substituted. 
   
   
       44 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkenylaryl, which alkenyl and aryl groups may be optionally substituted. 
   
   
       45 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkynylaryl, which alkynyl and aryl groups may be optionally substituted. 
   
   
       46 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylaryl-heteroaryl, which alkyl, aryl and heteroaryl groups may be optionally substituted. 
   
   
       47 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylheteroaryl-aryl, which alkyl, aryl and heteroaryl groups may be optionally substituted. 
   
   
       48 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylheteroaryl-heteroaryl, which alkyl and heteroaryl groups may be optionally substituted. 
   
   
       49 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkyl(heteroaryl)(aryl), which alkyl, aryl and heteroaryl groups may be optionally substituted. 
   
   
       50 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylheteroaryl, which alkyl and heteroaryl groups may be optionally substituted. 
   
   
       51 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkenylheteroaryl, which alkenyl and heteroaryl groups may be optionally substituted. 
   
   
       52 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkynylheteroaryl, which alkynyl and heteroaryl groups may be optionally substituted. 
   
   
       53 . A method according to  claim 1 , wherein R 1  represents C 3-12 carbocycle, which carbocycle may optionally be substituted. 
   
   
       54 . A method according to  claim 1 , wherein R 1  represents C 3-12 heterocycle, which heterocycle may optionally be substituted. 
   
   
       55 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylC 3-12 carbocycle, which alkyl and carbocycle groups may be optionally substituted. 
   
   
       56 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkenylC 3-12 carbocycle, which alkenyl and carbocycle groups may be optionally substituted. 
   
   
       57 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkynylC 3-12 carbocycle, which alkynyl and carbocycle groups may be optionally substituted. 
   
   
       58 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylNR 9 aryl, which alkyl and aryl groups may be optionally substituted. 
   
   
       59 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylNR 9 heteroaryl, which alkyl and heteroaryl groups may be optionally substituted. 
   
   
       60 . A method according to  claims 1 , wherein R 1  represents C 1-6 alkylOC 3-12 carbocycle, which alkyl and carbocycle groups may be optionally substituted. 
   
   
       61 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylNR 9 C 3-12 carbocycle, which alkyl and carbocycle groups may be optionally substituted. 
   
   
       62 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylOaryl, which alkyl and aryl groups may be optionally substituted. 
   
   
       63 . A method according to  claim 1 , wherein R 1  represents C 1-6 alkylOheteroaryl, which alkyl and heteroaryl groups may be optionally substituted. 
   
   
       64 . A method according to  claim 1 , wherein R 1  represents C 16 alkylC 3-12 heterocycle, which alkyl and heterocycle groups may be optionally substituted. 
   
   
       65 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkenylC 3-12 heterocycle, which alkenyl group and heterocycle groups may be optionally substituted. 
   
   
       66 . A method according to  claim 1 , wherein R 1  represents C 2-6 alkynylC 3-12 heterocycle, which alkynyl and heterocycle groups may be optionally substituted. 
   
   
       67 . A method according to  claim 1 , wherein the compound is as defined in any one of examples 1a to 89a or a pharmaceutically acceptable salt or solvate of any one thereof. 
   
   
       68 . A method according to  claim 1 , wherein the compound is as defined in example 34a, 36a, 38a, 39a, 41a, 42a, 46a, 47a, 49a, 50a, 55a or 62a or a pharmaceutically acceptable salt or solvate of any one thereof. 
   
   
       69 . A method according to  claim 1 , wherein the compound is as defined in examples 37a, 45a, 51a, 52a, 54a, 56a, 58a, 60a, 61a or 63a or a pharmaceutically acceptable salt or solvate of any one thereof. 
   
   
       70 . A method according to  claim 1 , wherein the compound is as defined in any one of examples 1b to 131b or a pharmaceutically acceptable salt or solvate of any one thereof.

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