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 polymitoyl-transferase, such as hyperglycemia, diabetes and pathologies related thereto, heart failure, ischemia.

1. A compound of formula (I) 
                 
 
       wherein: X +  is P + (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 phosphorus 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 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; and  
       with the proviso that when Z is —NHSO 2 R 4 , Y −  is —COO − , then R 4  is not tolyl;  
       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 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. 
     
     
       4. A compound according to  claim 1 , wherein 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. 
     
     
       5. A compound according to  claim 4 , wherein R 4  is a C 9 -C 18  saturated or unsaturated, straight or branched alkyl group. 
     
     
       6. A  The 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 -(octyloxycarbonyl)-aminobutyrate;  
 R,S- 4 -trimethylammonium- 3 -(nonyloxycarbonyl)-aminobutyrate;  
 R,S- 4 -trimethylammonium- 3 -octyloxybutyrate;  
 R,S- 4 -trimethylammonium- 3 -tetradecyloxybutyrate;  
 R- 4 -trimethylammonium- 3 -( 10 -phenoxydecylcarbamoyl)amino-butyrate; and  
 R- 4 -trimethylammonium- 3 -(trans-β-styrenesulfonyl)aminobutyrate .  
 
     
     
       7. 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. 
     
     
       8. A process for a preparation of a compound of  claim 1  wherein Z is aide  amide (—NHCOR 4 ), thiomide  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. 
     
     
       9. 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.  
 
     
     
       10. 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 carbaldehydes, wherein the alkyl moiety is a one-term lower homologue of the desired R 4 , and subsequent reduction, to produce the desired compound. 
     
     
       11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , in admixture with a pharmaceutically acceptable vehicle or and excipient. 
     
     
       12. The pharmaceutical composition according to  claim 11 , wherein an active ingredient suitable  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  comprising therapeutically effective amounts of R- 4 -trimethylphosphonium- 3 -(tetradecylcarbamoyl)-amino butyrate and metformin, in admixture with a pharmaceutically acceptable vehicle or an excipient. 
     
     
       13. A pharmaceutical composition according to  claim 11 , also including an active ingredient suitable for the treatment of obesity selected from the group consisting of fenfluramine, dexfenfluramine, phentriamine, and a β- 3 -adrenergic receptor agonist. 
     
     
       14. A pharmaceutical composition according to  claim 11 , 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 ihhibitors, anion exchange resins, nicotinyl alcohol, nicotinic acid or a salt thereof, vitamin E, thyromimetics and L-carnitine. 
     
     
       15. A method for treating a subject having hyperactive carnitine palmitoyl-transferase comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       16. A method for treating a subject having hyperglycaemia, diabetes, heart failure  or ischemia comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       17. A method for treating a subject having obesity comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       18. A method for treating a subject having high triglyceridemia comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       19. A method for treating a subject a subject having hypertension comprising administering to said subject an effective amount of a compound of  claim 1 . 
     
     
       20. A method of modulating high cholesterol levels or high density lipoprotein 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 .