Benzoxazepine compounds, their production and use

Abstract

This invention provides new benzoxazepine compounds represented by the formula: [wherein R stands for a lower alkyl group optionally substituted with a hydroxyl group, X stands for an optionally substituted carbamoyl group or an optionally substituted heterocyclic group having a deprotonatable hydrogen atom, R 1 stands for a lower alkyl group and W stands for a halogen atom] having activities of lowering chlesterol-level and lowering trigluceride-level, and being useful for prophylaxis and therapy of hyperlipidemia.

1 . A compound represented by the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R stands for a lower alkyl group optionally substituted by hydroxyl group which may be substituted, X stands for an optionally substituted carbamoyl group or an optionally substituted heterocyclic group having a deprotonatable hydrogen atom, R 1  stands for a lower alkyl group and W stands for a halogen atom, or a salt thereof. 
     
     
         2 . The compound as claimed in  claim 1 , wherein R is C 1-6  alkyl which may have 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy. 
     
     
         3 . The compound as claimed in  claim 1 , wherein R is C 3-6  branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy. 
     
     
         4 . The compound as claimed in  claim 1 , wherein R is 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl or 3-acetoxy-2-acetoxymethyl-2-methylpropyl. 
     
     
         5 . The compound as claimed in  claim 1 , wherein R 1  is methyl. 
     
     
         6 . The compound as claimed in  claim 1 , wherein W is chlorine atom. 
     
     
         7 . The compound as claimed in  claim 1 , wherein X is a carbamoyl group represented by the formula 
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are independently
 (i) hydrogen, 
 (ii) optionally substituted hydrocarbon group, 
 (iii) optionally substituted heterocyclic group, or 
 (iv) acyl group 
 
       or R 2  and R 3  may form an optionally substituted 5 to 6 membered ring together with the adjacent nitrogen atom, said ring may contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to said nitrogen atom. 
     
     
         8 . The compound as claimed in  claim 7 , wherein R 2  is hydrogen or C 1-7  alkyl, R 3  is 
       (1) a hydrocarbon group selected from the group consisting of
 (a) C 1-4  alkyl, 
 (b) C 3-7  cycloalkyl, 
 (c) C 2-6  alkenyl, 
 (d) C 6-10  aryl and 
 (e) C 6-10  aryl-C 1-4  alkyl, 
 
       wherein each of said groups (a), (b) and (c) may have 1 to 4 substituents selected from the group consisting of
 (i) carboxyl which may be esterified with C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl, 
 (ii) phosphono group which may be mono- or di-substituted by C 1-6  alkyl or C 2-7  alkanoyloxy-C 1-6  alkyl, 
 (iii) sulfo group, 
 (iv) sulfonamido which may be substituted by C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl, 
 (v) hydroxyl group which may be alkylated with C 1-3  alkyl, 
 (vi) sulfhydryl group which may be alkylated with C 1-3  alkyl, 
 (vii) carbamoyl, 
 (viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, chlorine, fluorine, aminosulfonyl and amino which may be mono or di-substituted by C 1-3  alkyl, 
 (ix) amino which may be mono- or di-substituted by C 1-3  alkyl, 
 (x) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, 4-phenylpiperazinyl, 1,2,3,4-tetrahydroisoquinolinly and phthalimido, each of said group may be substituted by C 1-3  alkyl, benzyl or phenyl and 
 (xi) 5- to 6-membered heterocyclic group selected from the group consisting of pydinyl, imidazolyl, indolyl and tetrazolyl, 
 
       and each of said group (d) and (e) may have 1 to 4 substituents selected from the group consisting of
 (i) carboxyl which may be esterified by C 1-4  alkyl, 
 (ii) phosphono which may be mono- or di-substituted by C 1-6  alkyl or C 2-7  alkanoyloxy-C 1-6  alkyl, 
 (iii) sulfo, 
 (iv) C 1-4  alkylsulfonyl, C 6-10  arylsulfonyl or C 6-10  aryl-C 1-4  alkylsulfonyl, 
 (v) sulfonamido which may be substituted by C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl, 
 (vi) C 1-3  alkyl group which may be substituted by carboxyl group optionally esterified with C 1-4  alkyl, phosphono which may be mono- or di-substituted by C 1-6  alkyl, sulfo, sulfonamido which may be substituted by C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl and 
 (v) halogen, 
 
       (2) a heterocyclic group selected from the group consisting of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-tetrazolyl and 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl, 
       (3) an acyl group selected from the group consisting of
 (i) C 2-7  alkanoyl which may be substituted by 1 to 2 halogen atoms, 
 (ii) C 6-10  arylsulfonyl, 
 (iii) C 1-4  alkylsulfonyl, and 
 (iv) C 6-10  aryl-C 1-4  alkylsulfonyl, 
 
       each of said group (ii), (iii) and (iv) may have 1 to 4 substituents selected from the group consisting of C 1-3  alkyl, C 1-3  alkoxy and halogen, 
       or R 2  and R 3  together with adjacent nitrogen form a 5- or 6-membered cyclic amino selected from the group consisting of piperazinyl, piperidyl, pyrrolidinyl, 2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl and thiomorpholinyl, each of said group may have 1 to 4 substituents selected from the group consisting of
 (A) hydroxyl which may be substituted with C 1-3  alkyl or C 2-7  alkanoyl, 
 (B) carboxyl which may be substituted with C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl, 
 (C) phosphono which may be mono- or di-substituted by C 1-6  alkyl or C 2-7  alkanoyloxy-C 1-6  alkyl, 
 (D) sulfo, 
 (E) sulfonamido which may be substituted with C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl, 
 (F) C 1-6  alkyl or C 2-5  alkenyl which may be substituted by
 (i) carboxyl group which may be esterified with C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl, 
 (ii) phosphono group which may be mono- or di-substituted by C 1-6  alkyl or C 2-7  alkanoyloxy-C 1-6  alkyl, 
 (iii) sulfo group, 
 (iv) sulfonamido which may be substituted by C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl, 
 (v) hydroxyl group which may be alkylated with C 1-3  alkyl or C 2-7  alkanoyl, 
 (vi) sulfhydryl group which may be alkylated with C 1-3  alkyl, 
 (vii) carbamoyl, 
 (viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, aminosulfonyl and amino which may be substituted with C 1-3  alkyl and 
 (ix) amino which may be mono- or di-substituted by C 1-3  alkyl, or 
 (x) tetrazolyl, 
 
 (G) amino which may be mono- or di-substituted with C 1-3  alkyl, 
 (H) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and 4-phenylpiperazinyl, 
 (I) cyano, 
 (J) carbamoyl, 
 (K) oxo, 
 (L) heterocyclic group selected from tetrazolyl and 2,5-dihydro-5-oxo-1,2,4-oxazolyl, 
 (M) carbamoyl substituted with C 1-4  alkylsulfonyl, C 6-10  arylsulfonyl or C 6-10  aryl-C 1-4  alkylsulfonyl, 
 (N) sulfhydryl which may be alkylated with C 1-3  alkyl and 
 (O) phenyl which may have 1 to 5 substituents selected from hydroxyl, halogen, aminosulfonyl and amino which may be substituted with C 1-3  alkyl. 
 
     
     
         9 . The compound as claimed in  claim 7 , wherein R 2  and R 3  together with the adjacent nitrogen of the carbamoyl form a 5 to 6-membered ring selected from the group consisting of 1-piperazinyl, piperidino, 1-pyrrolidinyl, 2-oxo-1-piperazinyl and 2,6-dioxo-1-piperazinyl, each of the said group may have 1 to 2 substituents of C 1-6  alkyl which may be substituted by
 (i) carboxyl which may be esterified with C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl,   (ii) phosphono group which may be mono- or di-substituted by C 1-6  alkyl or C 2-7  alkanoyl-C 1-6  alkyl,   (iii) sulfo group,   (iv) sulfonamido which may be substituted by C 1-6  alkyl or C 6-10  aryl-C 1-4  alkyl,   (v) hydroxyl group which may be alkylated by C 1-3  alkyl,   (vi) sulfhydryl which may be alkylated by C 1-3  alkyl,   (vii) carbamoyl,   (viii) phenyl which may have 1 to 5 substituents selected from the group consisting of hydroxy, halogen, aminosulfonyl and amino which may be substituted with C 1-3  alkyl,   (ix) amino which may be mono- or di-substituted by C 1-3  alkyl, or   (x) tetrazolyl.   
     
     
         10 . The compound as claimed in  claim 7 , wherein R 2  is hydrogen or C 1-7  alkyl and R 3  is C 1-4  alkylsulfonyl. 
     
     
         11 . The compound as claimed in  claim 1 , wherein the heterocyclic group represented by X is tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-tetrazolyl, or 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl. 
     
     
         12 . The compound as claimed in  claim 1 , wherein
 R 1  is methyl, W is chlorine atom,   R is C 3-6  branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is a carbamoyl group represented by the formula   
       
         
           
           
               
               
           
         
         wherein R 2 ′ is hydrogen or C 1-7  alkyl and R 3 ′ is C 1-4  alkyl. 
       
     
     
         13 . The compound as claimed in  claim 1 , wherein
 R 1  is methyl, W is chlorine atom,   R is C 3-6  branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is a carbamoyl group represented by the formula   
       
         
           
           
               
               
           
         
         wherein R′ is hydrogen or C 1-7  alkyl and n is an integer from 1 to 5. 
       
     
     
         14 . The compound as claimed in  claim 1 , wherein
 R 1  is methyl, W is chlorine atom,   R is C 3-6  branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is a carbamoyl group represented by the formula   
       
         
           
           
               
               
           
         
         wherein R″ is hydrogen or C 1-4  alkyl. 
       
     
     
         15 . The compound as claimed in  claim 1 , wherein
 R 1  is methyl, W is chlorine atom,   R is C 3-6  branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is tetrazolyl.   
     
     
         16 . The compound as claimed in  claim 1 , which is 
       (3R,5S)—N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, 
       (3R,5S)—N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, 
       (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, 
       (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-acetamide, 
       or a salt thereof. 
     
     
         17 . The compound as claimed in  claim 1 , which is 
       (3R,5S)—N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, 
       (3R,5S)—N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, 
       N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,-3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid, 
       N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid, 
       N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester, 
       N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester or a salt thereof. 
     
     
         18 . The compound as claimed in  claim 1 , which is 
       (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, 
       (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, 
       (3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one, 
       (3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-]1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-3-one 
       or a salt thereof. 
     
     
         19 . The compound as claimed in  claim 1 , which is 
       (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof. 
     
     
         20 . The compound as claimed in  claim 1 , wherein
 R is a lower alkyl group which may be substituted with one or two hydroxyl groups,   X is carbamoyl group, which may have substituent(s) on the nitrogen atom of the carbamoyl group,
 said substituent being 
   (1) hydrocarbon selected from the group consisting of
 (a) C 1-7  alkyl, 
 (b) C 3-7  cycloaklyl, 
 (c) C 2-6  alkenyl, 
 (d) C 6-10  aryl and 
 (e) C 7-14  arylalkyl, 
   wherein each of said groups (a), (b) and (c) may have 1 to 4 substituents selected from the group consisting of
 (i) carboxyl which may be esterified with C 1-6  alkyl or C 7-10  arylalkyl, 
 (ii) phosphono group, 
 (iii) sulfo group, 
 (iv) sulfonamido which may be substituted by C 1-6  alkyl or C 7-10  arylalkyl, 
 (v) hydroxyl group which may be alkylated with C 1-3  alkyl, 
 (vi) sulfhydryl group which may be alkylated with C 1-3  alkyl, 
 (vii) carbamoyl, 
 (viii) phenyl which may have substituent(s) selected from the group consisting of hydroxyl, chlorine, fluorine, aminosulfonyl and amino which may be mono or di-substituted by C 1-3  alkyl, 
 (ix) amino which may be mono- or di-substituted by C 1-3  alkyl, 
 (x) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and 4-phenylpiperazinyl, each of said group may be substituted by C 1-3  alkyl, benzyl or phenyl and 
 (xi) 5- to 6-membered heterocyclic group selected from the group consisting of pyridinyl, imidazolyl, indolyl and tetrazolyl, 
   and each of said group (d) and (e) may have 1 to 4 substituents selected from the group consisting of
 (i) carboxyl which may be esterified by C 1-4  alkyl, 
 (ii) phosphono, 
 (iii) sulfo, 
 (iv) sulfonamido which may be substituted by C 1-6  alkyl or C 7-10  arylalkyl, 
 (v) C 1-3  alkyl group which may be substituted by carboxyl group optionally esterified with C 1-4  alkyl, phosphono, sulfo, or sulfonamido optionally substituted with C 1-6  alkyl or C 7-10  arylalkyl, and 
 (vi) halogen. 
   (2) a heterocyclic group selected from the group consisting of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-tetrazolyl and 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl,   (3) an acyl group selected from the group consisting of
 (i) C 2-7  alkanoyl which may be substituted by 1 to 2 halogen atoms, 
 (ii) C 6-10  arylsulfonyl, 
 (iii) C 1-4  alkylsulfonyl, and 
 (iv) C 7-14  arylalkylsulfonyl, 
   each of said group (ii), (iii) and (iv) may have 1 to 4 substituents selected from the group consisting of C 1-3  alkyl, C 1-3  alkoxy and halogen or   (4) cyclic amino carbonyl group, the cyclic amino group being selected from the group consisting of piperazinyl, piperidyl, pyrrolidinyl, 2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl and thionorpholinyl, each of said group may have 1 to 4 substituents selected from the group consisting of
 (i) hydroxyl, 
 (ii) carboxyl optionally esterified with C 1-4 , alkyl, 
 (iii) phosphono, 
 (iv) sulfo, 
 (v) sulfonamido optionally substituted with C 1-6  alkyl or C 7-10  arylalkyl, 
 (vi) C 1-3  alkyl or C 2-5  alkenyl optionally substituted with (i), (ii), (iii), (iv) or (v) defined above, 
 (vii) amino optionally mono- or di-substituted with C 1-3  alkyl, 
 (viii) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl and 4-phenylpiperazinyl, 
 (ix) cyano, 
 (x) carbamoyl, 
 (xi) oxo, 
 (xii) C 1-3  alkoxy, 
 (xiii) heterocyclic group selected from tetrazolyl and 2,5-dihydro-5-oxo-1,2,4-oxazolyl, and 
 (xiv) carbamoyl substituted with C 6-10  arylsulfonyl, C 1-4  alkylsulfonyl or C 7-14  arylalkylsulfonyl. 
   
     
     
         21 . A composition which comprises the compound as claimed in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . A pharmaceutical composition for inhibiting squalene synthetase, which comprises the compound as claimed in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         23 . A pharmaceutical-composition for lowering the level of triglyceride, which comprises the compound as claimed in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         24 . A pharmaceutical composition for lowering the lipid-level, which comprises the compound as claimed in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         25 . A pharmaceutical composition for prophylaxis or therapy of hyperlipidaemia, which comprises the compound as claimed in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         26 . Use of the compound as claimed in  claim 1  for manufacturing a pharmaceutical composition. 
     
     
         27 . Use of the compound as claimed in  claim 1  for manufacturing a squalene synthetase inhibitor. 
     
     
         28 . Use of the compound as claimed in  claim 1  for manufacturing a pharmaceutical composition for lowering the level of triglyceride. 
     
     
         29 . Use of the compound as claimed in  claim 1  for manufacturing a pharmaceutical composition for lowering the lipid-level. 
     
     
         30 . Use of the compound as claimed in  claim 1  for manufacturing a pharmaceutical composition for prophylaxis or therapy of hyperlipidaemia or coronary sclerosis. 
     
     
         31 . A method for inhibiting squalene synthetase in a mammal comprising administering an effective amount of the compound as claimed in  claim 1  to said mammal. 
     
     
         32 . A method for lowering the level of triglyceride in a mammal comprising administering an effective amount of the compound as claimed in  claim 1  to said mammal. 
     
     
         33 . A method for lowering the lipid-level in a mammal comprising administering an effective amount of the compound as claimed in  claim 1  to said mammal. 
     
     
         34 . A method for prophylaxis or therapy of hyperlipidaemia or coronary sclerosis in a mammal comprising administering an effective amount of the compound as claimed in  claim 1  to said mammal. 
     
     
         35 . A process for producing the compound as claimed in  claim 1 , wherein X is an optionally substituted carbamoyl group, which comprises reacting a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein the symbols are as defined in  claim 1 , or a salt thereof with a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein the symbols are as defined in  claim 7 , or a salt thereof. 
     
     
         36 . The compound as claimed in  claim 1 , wherein R is 2,2-dimethyl-3-hydroxypropyl.