Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity

Abstract

The use of a compound comprising formula (I), or a salt, ester, amide or prodrug thereof in the treatment of obesity and related disorders. The invention also relates to novel compounds within formula (I), to processes for preparing them and pharmaceutical compositions containing them. In formula (I): A is an optionally substituted thienyl moiety, Y is O, S, or NR 2 , R 1 is a branched or unbranched alkyl (optionally interrupted by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or a substituted derivative of any of the foregoing groups and R 2 is hydrogen or a group as defined for R 1 .

1 . A method for the treatment of obesity the method comprising administering to a patient a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, or ester thereof; 
         wherein A is an optionally substituted thienyl moiety; 
         Y is O, S, or NR 2 ; 
         and R 1  is a branched or unbranched alkyl (optionally interrupted by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or a substituted derivative of any of the foregoing groups, wherein the substituents are one or more independently of halogen, alkyl, halosubstituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy, cyano, nitro, —C(O)R 4 , —CO 2 R 4 , —SOR 4 , —SO 2 R 4 , —NR 6 R 7 , —OR 6 , —SR 6 , —C(O)CX 1 X 2 NR 6 R 7 , —C(O)N(OR 5 )R 6 , —C(O)NR 5 R 4 , —NR 6 C(O)R 4 , —CR 6 (NH 2 )CO 2 R 6 , —NHCX 1 X 2 CO 2 R 6 , —N(OH)C(O)NR 6 R 7 , —N(OH)C(O)R 4 , —NHC(O)NR 6 R 7 , —C(O)NHNR 6 R 7 , —C(O)N(OR 5 )R 6 , or a lipid or steroid (natural or synthetic) with the proviso that any hetero atom substituent in R 1  must be separated from the exocyclic hetero-atom by at least two carbon atoms; 
         and where: 
         R 2  is hydrogen or a group as defined for R 1 ; 
         R 4  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl, reduced heteroarylalkyl, —OR 6 , —NHCX 1 X 2 CO 2 R 6  or —NR 6 R 7  or a substituted derivative of any of the foregoing groups; 
         R 5  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; 
         R 6  and R 7  are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl or —(CH 2 ) n (OR 5 ) m  wherein n is 1 to 12, and m is 1-3, or a substituted derivative of any of the foregoing groups; and 
         X 1  and X 2  are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl. 
       
     
     
         2 . The method of  claim 1  wherein the thienyl moiety A is fused to the oxazinone ring in the 2,3- or 3,2-position and is optionally substituted with one or more of hydrogen, hydroxy, halogen, oxo, amino, nitro, cyano, alkyl, aryl, alkylaryl, haloalkyl, alkoxy, aryloxy, alkylthio, alkylamino, arylthio or arylamino wherein arylthio, arylamino and aryloxy can be substituted by one or more of halo, alkyl, haloalkyl, alkoxy, thioalkyl, or aminoalkyl; or by a group R 12 Q where Q is O, CO, CONH, NHCO, S, SO, SO 2 , or SO 2 NH 2  and R 12  is hydrogen or a group R 1  as defined above; or by a group R 1 R 2 N where R 1  is as defined above and R 2  is hydrogen or R 1 , with the proviso that any hetero atom substituent in R 1  and/or R 2  must be separated from the aromatic hetero atom substituent by at least two carbon atoms. 
     
     
         3 . The method of  claim 1  wherein the thienyl moiety A is optionally substituted with one or more of hydrogen, lower branched or unbranched alkyl having 1 to 20 carbon atoms, cyclic alkyl having 3 to 10 carbon atoms, aryl, haloalkyl, or a halogen;
 Y is O, S or NR 2 , wherein R 2  is hydrogen or alkyl;   and R 1  is alkyl, or aryl, optionally substituted with alkyl, haloalkyl, halo, cyano, nitro, OR 6 , SR 6 , COR 6 , CO 2 R 6 , NR 6 , R 7 , or aryl optionally substituted with aryloxy, arylthio, SO-aryl, SO 2 -aryl alkylaryl, CO-aryl, CO 2 -aryl, CONR 6 -aryl, NR 6 CO-aryl or NR 6 -aryl or a substituted derivative of any of the foregoing groups.   
     
     
         4 . The method of  claim 3  wherein R 1  is an alkyl group with from 4 to 30 carbon atoms. 
     
     
         5 . The method of  claim 1  wherein the compound is of formula II 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof, 
         wherein group A is as defined in  claim 1  for formula (I); 
         Y is as defined in  claim 1  for formula (I); and 
         R 20  is selected from OR 13 —COR 13 , CO 2 R 13 SR 13 , SOR 13 , SO 2 R 13 , CON 13 R 14 , NR 14 C(O)NR 13 ), C 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkyl, cyano, halo, aryl, aryl C 1-10 alkyl, heteroaryl or heteroaryl C 1-10 alkyl; wherein R 13  and R 14  each independently represents hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, reduced heteroaryl or reduced heteroarylC 1-10 alkyl or a substituted derivative of any of the foregoing groups. 
       
     
     
         6 . The method of  claim 5  wherein R 20  is phenyloxy, phenylthio, SO-phenyl, SO 2 -phenyl, alkylphenyl, CO-phenyl, CO 2 -phenyl, CONR 13 -phenyl, NR 13 CO-phenyl or NR 13 -phenyl optionally substituted with one or more of halo, alkyl, alkylhalo, alkoxy, aryl, alkylaryl, aryloxy, amino, cyano, hydroxy or heteroaryl. 
     
     
         7 . A method for the treatment of an obesity related disorder selected from one or more of hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), or hypertension, the method comprising administering to a patient a compound formula (I) or (II) as defined in  claim 1  or  5 . 
     
     
         8 . A food product comprising a compound of formula (Ia) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof; 
         wherein A is a thiophenyl moiety that is 
         optionally substituted with one or more of alkyl, aryl, halo, alkoxy, haloalkyl, aryloxy, amino, heteroaryl, or arylalkyl; 
         Y is O, S or NR 2 , wherein R 2  is hydrogen or an alkyl group having 1 to 6 carbon atoms; 
         and R 1  is 
         an unbranched alkyl group having from 6 to 25 carbon atoms, a branched alkyl group having from 6 to 25 carbon atoms, an arylalkyl group wherein the alkyl moiety has from 4 to 12 carbon atoms; or 
         a phenyl group substituted with one or more optionally substituted phenyloxy, phenylthio, SO-phenyl, SO 2 -phenyl, alkylphenyl, CO-phenyl, CO 2 -phenyl, CONR 16 -phenyl, NR 16 CO-phenyl or NR 16 -phenyl groups; wherein R 16  is hydrogen or an alkyl group having from 1 to 4 carbon atoms and wherein the phenyloxy, phenylthio, SO-phenyl, SO 2 -phenyl, alkylphenyl, CO-phenyl, CO 2 -phenyl, CONR 16 -phenyl, NR 16 CO-phenyl or NR 16 -phenyl groups are optionally substituted with one or more of halo, cyano, nitro, alkyl, alkylhalo, alkoxy, aryl, alkylaryl, aryloxy, amino, hydroxy or heteroaryl; or 
         a phenyl group substituted with one or more of halo, NR 6 R 7 , OR 6 , SR 6 , COR 6 , CO 2 R 6 , nitro, cyano, aryl, hetereoaryl, alkyl aryl, alkyl, haloalkyl or alkoxy with the proviso that said compound is not 5-methyl-2-(4-methoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one, 6-pentyl-2-(4-chlorophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one or 6-pentyl-2-(4-methoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one. 
       
     
     
         9 . The food product of  claim 8  wherein the compound is of formula IIa 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof; 
         wherein group A is as defined in  claim 8  for formula (Ia); 
         Y is as defined in  claim 8  for formula (Ia); 
         and R 20  is phenyloxy, phenylthio, SO-phenyl, SO 2 -phenyl, alkylphenyl, CO-phenyl, CO 2 -phenyl, CONR 6 -phenyl, NR 6 CO-phenyl or NR 6 -phenyl, optionally substituted with one or more of halo, cyano, alkyl, alkylhalo, alkoxy, aryl, alkylaryl, aryloxy, amino, hydroxy or heteroaryl. 
       
     
     
         10 . The food product of  claim 8 , wherein the compound is selected from the group consisting of: 
       2-Phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Butyloxy-4H-thieno-[2,3-d][1,3]oxazin-4-one 
       5-Methyl-2-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       5,6-Dimethyl-2-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       5-Phenyl-2-phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one 
       2-(4-(3-Trifluoromethyl-phenoxy)phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 
       5-(1,1-Dimethylethyl)-2-phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenoxy)phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one 
       2-(4-Phenylmethyl)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Benzoyl)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-phenoxy)phenoxy-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-(4-Trifluoromethyl-phenoxy)phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-(3-Trifluoromethyl-phenoxy)phenoxy)-4H-thieno[3,2-d][1,3]oxazin-4-one 
       2-(4-Phenylthio) phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       5,6-Dimethyl-2-(4-phenoxy)phenoxy-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Dodecylamino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-N-Dodecyl-N-methylamino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Dodecylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Dodecylthio-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-N-(1-Methylethyl)-N-phenylamino)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenylsulfonyl)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenylcarbamoyl)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-(4-Chlorophenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-(4-Methylphenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Cyanophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Cyanophenyl)amino-6-propyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Cyanophenyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Phenylmethyl-2-(4-cyanophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Cyanophenyl)amino-6-dodecyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-phenylbutyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(2-Chloroethyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(Hept-6-enyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(5-Methoxycarbonylpentyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Phenylamino-5,6,7,8-tetrahydro-4H-benzothieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenoxy)phenylamino-4H-thieno-[3,4-d][1,3]oxazin-4-one 
       2-(4-(4-Trifluoromethylphenoxy)phenylamino)-4H-thieno[3,2-d][1,3]oxazin-4-one 
       2-(4-Cyanophenyl)amino-4H-thieno[3,2-d][1,3]oxazin-4-one 
       2-Dodecylamino-4H-thieno[3,2-d][1,3]oxazin-4-one 
       2-(5-Methylhexyl)amino-4H-thieno[3,2-d][1,3]oxazin-4-one 
       5-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one 
       6-Propyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Hexadecylamino-6-methyl-4H-thieno-[2,3-d][1,3]oxazin-4-one 
       6-Chloro-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Dodecyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Phenylmethyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-(4-Phenoxyphenylamino)-7-oxa-9-thia-1,5-diazafluoren-8-one 
       2(5,5,5-Trifluoropentyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Eicosylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Octadecylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Hexadecyloxy-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(12-Nitrododecyl)-amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(12-Phenyldodecyl)-amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(12-(Pyrid-2-yl)dodecyl)-amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-Octylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(8-Phenyloctyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenylsulfinyl)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenoxycarbonyl)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2(4-(4-Methoxyphenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2(4-(4-Dimethylaminophenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2(4-(4-Hydroxyphenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2(3-Phenoxy)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2(2-Phenoxy)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(3-Cyanophenyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Chlorophenyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Aminophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Hydroxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Methoxycarbonylphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Trifluoromethylphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-N-(4-Phenoxy)phenyl-N-ethylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-N-(4-Phenoxy)phenyl-N-1-methylethylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Cyclopropyl-2-(4-phenoxy)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenoxy)phenyl-thio-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenoxy)phenylamino-6-trifluoromethyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methoxy-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Phenoxy-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-methoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       2-(4-Phenoxy)phenylamino-6-propyl-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Cyano-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Chloro-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-phenoxy)phenylthio-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-phenoxy)phenoxy-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-phenoxy)phenoxy-4H-thieno[3,2-d][1,3]oxazin-4-one 
       7-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[3,4-d][1,3]oxazin-4-one 
       5-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[3,4-d][1,3]oxazin-4-one 
       6-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       6-Methyl-2-(3-methylisoxazol-5-yl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one 
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         11 . The food product of  claim 8  wherein the compound is 6-methyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one. 
     
     
         12 - 22 . (canceled) 
     
     
         23 . A method for the prevention or treatment of obesity or an obesity-related disorder selected from one or more of hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes) or hypertension, the method comprising administering to a patient a compound of formula (I) or (II) as defined in  claim 1  or  5 , a pharmaceutical composition comprising a compound of formula (I) or (II) in combination with a pharmaceutically acceptable carrier or diluent, as claimed in claim  21  or a food product comprising a compound of formula (I) or (II). 
     
     
         24 . A method for inhibiting an enzyme in vitro, comprising contacting the enzyme with a compound of formula (I) or (II) as defined in  claim 1  or  5 , wherein the enzyme is a lipase. 
     
     
         25 . (canceled) 
     
     
         26 . A method for reducing fat content of animals, the method comprising administering to an animal a compound of formula (I) or (II) as defined in  claim 1  or  5 . 
     
     
         27 . A cosmetic method for maintaining a given weight, or for weight loss, the method comprising administering to a patient a compound of formula (I) or (II) as defined in  claim 1  or  5 . 
     
     
         28 . The method of  claim 24  wherein the step of contacting the compound with the enzyme controls and inhibits unwanted enzymes in a process or product. 
     
     
         29 . The method of  claim 24  wherein the step of contacting the compound with the enzyme controls and inhibits enzymes in the process of manufacturing healthcare goods comprising surfactants, soap or detergents. 
     
     
         30 . The method of  claim 24  wherein the step of contacting the compound with the enzyme prevents the degradation of foodstuff which comprises a fat. 
     
     
         31 - 37 . (canceled) 
     
     
         38 . The method of  claim 1  with the proviso that any hetero atom substituent in R 1  must be separated from the exocyclic hetero-atom by at least two saturated carbon atoms. 
     
     
         39 . The method of  claim 1  wherein n is 2 to 10. 
     
     
         40 . The method of  claim 2  with the proviso that any hetero atom substituent in R 1  and/or R 2  must be separated from the aromatic hetero atom substituent by at least two saturated carbon atoms.