Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase

Abstract

Compounds of formula (I) wherein the groups are as defined in the description are disclosed. The compounds of formula (I) are endowed with reversible inhibiting activity of carnitine palmitoyl-transferase and are useful in the preparation of medicaments useful in the pathologies related to a hyperactivity of carnitine palmitoyl-transferase, such as hyperglycemia, diabetes and pathologies related thereto, heart failure, ischemia.

1. A compound of formula (I) 
                 
 
       wherein: X +  is
 N + (R 1 ,R 2 ,R 3 ), wherein  
 R 1 ,R 2 ,R 3 , being the same or different, are selected in the group consisting of hydrogen, a C 1 -C 9  straight or branched alkyl group, —CH═NH(NH 2 ), —NH 2 , and —OH; or one or more R 1 , R 2  and R 3 , together with the nitrogen atom which they are linked to, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic system; with the proviso that at least one of the R 1 , R 2  and R 3  is different from hydrogen;  
 Z is selected from 
 —OR 4 , 
 —OCOOR 4 ,  
 —OCONHR 4 ,  
 —OCSNHR 4 ,  
 —OCSOR 4 ,  
 —NHR 4 , 
 —NHCOR 4 , 
 —NHCSR 4 ,  
 —NHCOOR 4 ,  
 —NHCSOR 4 ,  
 —NHCONHR 4 ,  
 —NHCSNHR 4 ,  
 —NHSOR 4 ,  
 —NHSONHR 4 ,  
 —NHSO 2 R 4 ,  
 —NHSO 2 NHR 4 , and  
 —SR 4 ,  
 wherein —R 4  is a C 1 -C 20  saturated or unsaturated,  straight or branched alkyl group, optionally  selected from the group consisting of ethyl, propyl, butyl, pentyl, hexyl, heptyl, octal, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl and their possible isomers or a linear or branched alkenyl group selected from the group consisting of ethylidene, vinyl, allyl, propenyl, butenyl, pentenyl, and their possible isomers, wherein said alkyl or alkenyl group is substituted with an A 1  group, wherein A 1  is selected from the group consisting of a halogen atom, or an aryl, heteroaryl, aryloxy or heteroaryloxy group, said aryl, heteroaryl, aryloxy or heteroaryloxy groups being optionally substituted with one or more C 1 -C 20  saturated or unsaturated, straight or branched alkyl or alkoxy group and/or halogen atom;  
 
 Y −  is selected from the group consisting of —COO − , PO 3 H − , —OPO 3 H − , tetrazolate-5-yl;  
 with the proviso that when Z is —NHCOR 4 , Y is —COO − , then R 4  is C 20  alkyl; 
 with the proviso that when Z is —NHSO 2 R 4 , Y −  is —COO − , then R 4  is not tolyl;  
 with the proviso that when Z is —NHR 4 , X +  is trimethylammonium and Y −  is —COO − , then R 4  is not C 1 -C 6  alkyl, 
 
       their (R,S) racemic mixtures, their single R or S enantiomers, or their pharmaceutically acceptable salts. 
     
     
       2. A compounds according to  claim 1 , wherein R 1 , R 2  and R 3  are methyl. 
     
     
       3. A compounds according to  claim 1 , wherein the heterocyclic system formed by R 1 , R 2  and R 3  together with nitrogen is selected from the group consisting of morpholinium, quinuclidinium, pyridinium, quinolinium and pyrrolidinium. 
     
     
       4. A compound according to  claim 1 , wherein R 1  and R 2  are H, R 3  is selected from the group consisting of —CH═NH(NH 2 ), —NH 2  and —OH. 
     
     
       5. A compound according to  claim 1 , wherein  of formula  1 
                 
 wherein: X+  is N   + ( R   1   ,R   2   ,R   3 ) , wherein R   1   , R   2   , R   3   , being the same or different, are selected in the group consisting of hydrogen, a C   1   -C   9    straight or branched alkyl group, —CH═NH ( NH   2 ) , —NH   2    and —OH; or one or more R   1   , R   2    and R   3   , together with the nitrogen atom which they are linked to, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic system; with the proviso that at least one of the R   1   , R   2    and R   3   , is different from hydrogen; and   
 Z is selected from the group consisting of ureido (—NHCONHR 4 ) or carbamate (—OCONHR 4 ), and R 4  is a C 7 -C 20  saturated or unsaturated, straight or branched alkyl group.  
 
     
     
       6. A compound according to  claim 5 , wherein R 4  is a C 9 -C 18  saturated or unsaturated, straight or branched alkyl group. 
     
     
       7. A compound selected from the group consisting of
 R,S-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate;  
 R,S-4-quinuclidinium-3-(tetradecyloxycarbonyl)-oxybutyrate;  
 R,S-4-trimethylammonium-3-(nonylcarbamoyl)-oxybutyrate;  
 R,S-4-trimethylammonium-3-(nonyloxycarbonyl)-oxybutyric acid chloride;  
 R,S-4-trimethylphosphonium-3-(nonylcarbamoyl)-oxybutyrate; 
 R,S-4-trimethylammonium-3-(nonyloxycarbonyl)-aminobutyrate;  
 R,S-4-trimethylammonium-3-(octyloxycarbonyl)-aminobutyrate;  
 R,S-4-trimethylammonium-3-(nonyloxycarbonyl)-aminobutyrate; 
 R,S-4-trimethylammonium-3-octyloxybutyrate;  
 R,S-4-trimethylammonium-3-tetradecyloxybutyrate;  
 R,S-1-guanidinium-2-tetradecyloxy-3-(tetrazolate-5-yl)-propane;  
 R,S-4-trimethylammonium-2-tetradecyloxy-3-(tetrazolate-5-yl)-propane;  
 R,S-3-quinuclidinium-2-(tetradecyloxycarbonyl)-oxy-1-propanephosphonate monobasic;  
 R,S-3-trimethylammonium-2-(nonylaminocarbonyl)-oxy-1-propanephosphonate monobasic;  
 R,S-3-pyridinium-2-(nonylaminocarbonyl)-oxy-1-propanephosphonic acid chloride;  
 R-4-trimethylammonium-3-(tetradecylcarbamoyl)-aminobutyrate;  
 R-4-trimethylammonium-3-(undecylcarbamoyl)-aminobutyrate;  
 R-4-trimethylammonium-3-(heptylcarbamoyl)-aminobutyrate;  
 R,S-4-trimethylammonium-3-(nonylthiocarbamoyl)-aminobutyrate;  
 R-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate;  
 S-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate;  
 S-4-trimethylammonium-3-(tetradecylcarbamoyl)-aminobutyrate;  
 R,S-4-trimethylammonium-3-tetradecylaminobutyrate; 
 R,S-4-trimethylammonium-3-octylaminobutyrate; 
 R,S-4-trimethylammonium-3-(decansulfonyl)aminobutyrate;  
 R,S-4-trimethylammonium-3-(nonylsulfamoyl)aminobutyrate;  
 S-4-trimethylammonium-3-(dodecansulfonyl)aminobutyrate;  
 R-4-trimethylammonium-3-(dodecansulfonyl)aminobutyrate;  
 S-4-trimethylammonium-3-(undecylsulfamoyl)aminobutyrate;  
 R-4-trimethylammonium-3-(undecylsulfamoyl)aminobutyrate;  
 R-4-trimethylammonium-3-(dodecylcarbamoyl)aminobutyrate;  
 R-4-trimethylammonium-3-(10-phenoxydecylcarbamoyl)aminobutyrate; and  
 R-4-trimethylammonium-3-(trans-β-styrenesulfonyl)aminobutyrate.  
 
     
     
       8. A process for the preparation of a compound of  claim 1 , wherein Z is carbonate (—OCOOR 4 ), carbamate (—NHCOOR 4 ), thiocarbamate (—OCSNHR 4 ) or thiocarbonate (—OCSOR 4 ), said process comprising reacting X+—CH 2 —CH(OH)—CH 2 —Y—, of the desired structure, optionally protected on the acid Y— group, respectively with an alkyl chloroformate, alkyl isocyanate, alkyl isothiocyanate or alkyl thiochloroformate, wherein the alkyl moiety is the desired R 4  alkyl group, to produce the desired compound. 
     
     
       9. A process for a preparation of a compound of  claim 1 , wherein Z is amide (—NHCOR 4 ),  thioamide (—NHCSR 4 ), carbamate (—NHCOOR 4 ), thiocarbamate (—NHCSOR 4 ), ureido (—NHCONHR 4 ), thioureido (—NHCSNHR 4 ), sulfinamide (—NHSOR 4 ), sulfonamide (—NHSO 2 R 4 ), sulfinamoylamino (—NHSONHR 4 ), and sulfamide (—NHSO 2 NHR 4 ), said process comprising reacting X + —CH 2 —CH(OH)—CH 2 —Y − , of the desired structure, optionally protected on the acid Y −  group, respectively with an acyl chloride, thioacyl chloride, alkyl chloroformate, alkyl thiochloroformate, alkyl isocyanate, alkyl thioisocyanate, alkyl sulfinyl chlorides, alkyl sulfonyl chlorides, SOCl 2  and alkyl amines, alkyl sulfamoyl chloride or SOCl 2  and alkyl amine, wherein the alkyl moiety is the desired R 4  alkyl group, to produce the desired compound. 
     
     
       10. A process for the preparation of a compound of  claim 1 , wherein Z is —OR 4  or  —SR 4 , said process comprising the steps of:
 (a) reacting a carbonyl compound of formula Hal-CH 2 —CO—CH 2 —COOR′, wherein Hal is a halogen atom and R′ is the residue of a suitable ester, with respectively alcohols and  thiols R 4 OH or  R 4 SH, to give the respective ketal or  thioketal;  
 (b) transforming the respective ketal or  thioketal into the respective ether or  thioether;  
 (c) substituting the Hal atom with an azido group, and  
 (d) transforming the azido group into the X+ group to produce the desired compound.  
 
     
     
       11. A process for the preparation of a compound of  claim 1 , wherein Z is —NHR 4 , said process comprising reacting of X + —CH 2 —CH(NH 2 )—CH 2 —Y −  of the desired structure, optionally protected on the acid Y −  group, with alkane carbaldheydes, wherein the alkyl moiety is a one-term lower homologue of the desired R 4 , and subsequent reduction, to produce the desired compound. 
     
     
       12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , in admixture with a pharmaceutically acceptable vehicle or and excipient. 
     
     
       13. The pharmaceutical composition according to  claim 12 , wherein an active ingredient suitable  a biguanide for the treatment of diabetes is also present and is selected from the group consisting of sulfonylurea, L-carnitine, fibrate and other agonists of peroxisomal proliferator activated receptor (PPAR-α), HMG-CoA reductase inhibitor, β-sitosterol inhibitor, cholesterol acyltransferase inhibitor, biguanides, cholestyramine, angiotensin II antagonist, melinamide, nicotinic acid, fibrinogen receptor antagonists, aspirin, α-glucosidase inhibitors, insulin secretogogue, insulin and glucagon-like peptides and agonists of PPAR-γ . 
     
     
       14. A pharmaceutical composition according to  claim 12 , also including an active ingredient suitable for the treatment of obesity selected from the group consisting of fenfluramine, dexfenfluramine, phentiramine, and a β-3-adrenergic receptor agonist. 
     
     
       15. A pharmaceutical composition according to  claim 12 , also including an active ingredient suitable for the treatment of high cholesterol levels and in modulating HDL plasma levels, which is selected from the group consisting of fibrates, and other PPAR-α agonists; inhibitors of cholesterol biosynthesis, HMG-CoA reductase inhibitors, statins, inhibitors of cholesterol absorption, acyl CoA:cholesterol acyltransferase inhibitors, anion exchange resins, nicotinyl alcohol, nicotinic acid or a salt thereof, vitamin E, thyromimetics and L-carnitine. 
     
     
       16. A method for treating obesity in a subject having hyperactive  and inhibiting carnitine palmitoyl-transferase in the subject comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       17. A method for treating a subject having  hyperglycaemia, diabetes, heart failure  or ischemia in a subject comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       18. A method for treating a subject having obesity comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       19. A method for treating a subject having high triglyceridemia comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       20. A method for treating a subject having hypertension comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       21. A method of modulating high cholesterol levels or MDL plasma levels in a subject in need of same, said method comprising administering to said subject an effective amount of a compound of  claim 1 .