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Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase |
| RE40861 |
Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase
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| Patent Drawings: | |
| Inventor: |
Giannessi, et al. |
| Date Issued: |
July 21, 2009 |
| Application: |
11/606,322 |
| Filed: |
November 30, 2006 |
| Inventors: |
Giannessi; Fabio (Rome, IT)
Marzi; Mauro (Rome, IT)
Minetti; Patrizia (Rome, IT)
De Angelis; Francesco (Rome, IT)
Tinti; Maria O. (Rome, IT)
Chiodi; Piero (Rome, IT)
Arduini; Arduino (Rome, IT)
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| Assignee: |
Sigma-Tau Industrie Farmaceutiche Reunite S.p.A. (Rome, IT) |
| Primary Examiner: |
Aulakh; Charanjit S |
| Assistant Examiner: |
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| Attorney Or Agent: |
Nixon & Vanderhye P.C. |
| U.S. Class: |
514/305; 514/357; 514/381; 514/476; 514/588; 514/600; 546/133; 546/22; 548/252; 564/17; 564/32; 564/47; 564/63; 564/79 |
| Field Of Search: |
514/305; 514/357; 514/381; 514/476; 514/588; 514/600; 546/133; 546/22; 548/252; 564/17; 564/32; 564/47; 560/155; 560/179 |
| International Class: |
A61K 31/46; C07D 453/02 |
| U.S Patent Documents: |
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| Foreign Patent Documents: |
0 127 098; 0 574 355; 0 591 857; 1 484 313; WO 85 04396; WO 93 25197; WO 98 00389 |
| Other References: |
Zhi-Heng Huang et al, "Analysis of Acylcarnitines as Their N-Demethylated Ester . . . ", Analytical Biochemistry, vol. 199, No. 1, Nov. 15,1991, pp. 98-105; XP002115164. cited by other.
Anderson Current Pharmaceutical Design, 1998, 4, 1-15 "Carnitine Palmitoyltransferase: A Viable Target for the Treatment of NIDDM?". cited by other.
Shinagawa et al J. Med. Chem., 1987, 30, 1458-1463 "Chemistry and Inhibitory Activity of Long Chain Fatty Acid Oxidation of Emeriamine and Its Analogues". cited by other.
Nutrition Reviews, vol. 48, No. 6, Jun. 1990 "Aminocarnitine and related compounds as inhibitors of carnitine transferases: Physiologic Implications". cited by other.
Kanamaru et al Novel Microbial Products for Medicine and Agriculture, 135-144 "Emeriamine: a new inhbitor of long chain fatty acid oxidation and its antidiabetic activity". cited by other.
Anderson et al J. Med. Chem., 1995, 38, 3448-3450 Antidiabetic Agents: A New Class of Reversible Carnitine Palmitoyltranserase I Inhibitors. cited by other.
Nagen et al ACS 212 mtg. Aug. 25-29, 1996, Abst Medi 133 "Synthesis and Biological Activity of A chiral and Reversible Inhibitors of Carnitine Palitoyl transferase I". cited by other.
Fraser et al ACS, 214 mtg. Sep. 7-11, 1997 Abst. Medi 207 "A series of monothiophosphate carnitine analogs, potent carnitine, palmitoyltrnsferase I inhibitors". cited by other.
Deems et al Am. J. Physiol. vol. 274, Issue 2, R524-528, Feb. 1998 "Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys". cited by other.
Gandour et al Archives of Biochemistry and Biophysics, vol. 267, No. 2, Dec, 515-520 Hemipalmitoylcarnitinium, a Strong Competitive Inhibitor of Purified Hepatic Carnitine Palmitoyltransferase. cited by other.
Gandour et al J. Org. Chem., 1992, 57, 3426-3431 "Synthesis, Structures and Enzymatic Evaluations of Hemiacrylcarnitiniums, a New Class of Carnitine Acyltransferase Inhibitors". cited by other.
Gandour et al J. Med. Chem., 1993, 36, 237-242 "Hemipalmitoylcarnitium Strongly Inhibits Carnitine Palmitoyltransferase-I in Intact Mitochondria". cited by other.
Selby et al TIPS, Dec. 1989, vol. 10, 495-500 "Substituted 2-oxiranecaboxylic acids: a new group of candidate hypoglycaemic drugs". cited by other.
Ratheiser et al Metabolism, vol. 40 No. 11 (Nov. 1991), 1185-1190 Inhibition of Etomoxir of Carnitine Palmitoyl-transferase I Reduces Hepatic Glucose Production and Plasma Lipids in Non-Insulsin-Dependent Diabetes Mellitus. cited by other. |
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| Abstract: |
Compounds of formula (I) ##STR00001## 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. |
| Claim: |
What is claimed is:
1. A compound of formula (I) ##STR00003## wherein: X.sup.+ is N.sup.+(R.sub.1,R.sub.2,R.sub.3), wherein R.sub.1,R.sub.2,R.sub.3, being the same or different, are selected inthe group consisting of hydrogen, a C.sub.1-C.sub.9 straight or branched alkyl group, --CH.dbd.NH(NH.sub.2), --NH.sub.2, and --OH; or one or more R.sub.1, R.sub.2 and R.sub.3, together with the nitrogen atom which they are linked to, form a saturated orunsaturated, monocyclic or bicyclic heterocyclic system; with the proviso that at least one of the R.sub.1, R.sub.2 and R.sub.3 is different from hydrogen; Z is selected from .[.--OR.sub.4,.]. --OCOOR.sub.4, --OCONHR.sub.4, --OCSNHR.sub.4,--OCSOR.sub.4, .[.--NHR.sub.4,.]. .[.--NHCOR.sub.4,.]. --NHCSR.sub.4, --NHCOOR.sub.4, --NHCSOR.sub.4, --NHCONHR.sub.4, --NHCSNHR.sub.4, --NHSOR.sub.4, --NHSONHR.sub.4, --NHSO.sub.2R.sub.4, --NHSO.sub.2NHR.sub.4, and --SR.sub.4, wherein --R.sub.4 is a.[.C.sub.1-C.sub.20 saturated or unsaturated,.]. straight or branched alkyl group, .[.optionally.]. .Iadd.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 .Iaddend.substituted with an A.sub.1 group, wherein A.sub.1 is selected from the group consisting of a halogen atom, or an aryl, heteroaryl, aryloxy or heteroaryloxy group, said aryl, heteroaryl, aryloxy orheteroaryloxy groups being optionally substituted with one or more C.sub.1-C.sub.20 saturated or unsaturated, straight or branched alkyl or alkoxy group and/or halogen atom; Y.sup.- is selected from the group consisting of --COO.sup.-, PO.sub.3H.sup.-,--OPO.sub.3H.sup.-, tetrazolate-5-yl; .[.with the proviso that when Z is --NHCOR.sub.4, Y is --COO.sup.-, then R.sub.4 is C.sub.20 alkyl;.]. with the proviso that when Z is --NHSO.sub.2R.sub.4, Y.sup.- is --COO.sup.-, then R.sub.4 is not tolyl; .[.withthe proviso that when Z is --NHR.sub.4, X.sup.+ is trimethylammonium and Y.sup.- is --COO.sup.-, then R.sub.4 is not C.sub.1-C.sub.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.sub.1, R.sub.2 and R.sub.3 are methyl.
3. A compounds according to claim 1, wherein the heterocyclic system formed by R.sub.1, R.sub.2 and R.sub.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.sub.1 and R.sub.2 are H, R.sub.3 is selected from the group consisting of --CH.dbd.NH(NH.sub.2), --NH.sub.2 and --OH.
5. A compound .[.according to claim 1, wherein.]. .Iadd.of formula 1.Iaddend. ##STR00004## .Iadd.wherein: X+ is N.sup.+(R.sub.1,R.sub.2,R.sub.3), wherein R.sub.1, R.sub.2, R.sub.3, being the same or different, are selected in the groupconsisting of hydrogen, a C.sub.1-C.sub.9 straight or branched alkyl group, --CH.dbd.NH(NH.sub.2), --NH.sub.2 and --OH; or one or more R.sub.1, R.sub.2 and R.sub.3, together with the nitrogen atom which they are linked to, form a saturated orunsaturated, monocyclic or bicyclic heterocyclic system; with the proviso that at least one of the R.sub.1, R.sub.2 and R.sub.3, is different from hydrogen; and.Iaddend. Z is selected from the group consisting of ureido (--NHCONHR.sub.4) or carbamate(--OCONHR.sub.4), and R.sub.4 is a C.sub.7-C.sub.20 saturated or unsaturated, straight or branched alkyl group.
6. A compound according to claim 5, wherein R.sub.4 is a C.sub.9-C.sub.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; andR-4-trimethylammonium-3-(trans-.beta.-styrenesulfonyl)aminobutyrate.
8. A process for the preparation of a compound of claim 1, wherein Z is carbonate (--OCOOR.sub.4), carbamate (--NHCOOR.sub.4), thiocarbamate (--OCSNHR.sub.4) or thiocarbonate (--OCSOR.sub.4), said process comprising reactingX+--CH.sub.2--CH(OH)--CH.sub.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 thedesired R.sub.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.sub.4),.]. thioamide (--NHCSR.sub.4), carbamate (--NHCOOR.sub.4), thiocarbamate (--NHCSOR.sub.4), ureido (--NHCONHR.sub.4), thioureido (--NHCSNHR.sub.4),sulfinamide (--NHSOR.sub.4), sulfonamide (--NHSO.sub.2R.sub.4), sulfinamoylamino (--NHSONHR.sub.4), and sulfamide (--NHSO.sub.2NHR.sub.4), said process comprising reacting X.sup.+--CH.sub.2--CH(OH)--CH.sub.2--Y.sup.-, of the desired structure, optionallyprotected on the acid Y.sup.- group, respectively with an acyl chloride, thioacyl chloride, alkyl chloroformate, alkyl thiochloroformate, alkyl isocyanate, alkyl thioisocyanate, alkyl sulfinyl chlorides, alkyl sulfonyl chlorides, SOCl.sub.2 and alkylamines, alkyl sulfamoyl chloride or SOCl.sub.2 and alkyl amine, wherein the alkyl moiety is the desired R.sub.4 alkyl group, to produce the desired compound.
10. A process for the preparation of a compound of claim 1, wherein Z is .[.--OR.sub.4 or.]. --SR.sub.4, said process comprising the steps of: (a) reacting a carbonyl compound of formula Hal-CH.sub.2--CO--CH.sub.2--COOR', wherein Hal is ahalogen atom and R' is the residue of a suitable ester, with .[.respectively alcohols and.]. thiols .[.R.sub.4OH or.]. R.sub.4SH, to give the respective .[.ketal or.]. thioketal; (b) transforming the respective .[.ketal or.]. thioketal into therespective .[.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.sub.4, said process comprising reacting of X.sup.+--CH.sub.2--CH(NH.sub.2)--CH.sub.2--Y.sup.- of the desired structure, optionally protected on the acid Y.sup.-group, with alkane carbaldheydes, wherein the alkyl moiety is a one-term lower homologue of the desired R.sub.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.]. .Iadd.a biguanide .Iaddend.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-.alpha.), HMG-CoA reductase inhibitor, .beta.-sitosterol inhibitor, cholesterol acyltransferase inhibitor, biguanides, cholestyramine, angiotensin II antagonist,melinamide, nicotinic acid, fibrinogen receptor antagonists, aspirin, .alpha.-glucosidase inhibitors, insulin secretogogue, insulin and glucagon-like peptides and agonists of PPAR-.gamma..]. .
.[.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 .beta.-3-adrenergicreceptor 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-.alpha. agonists; inhibitors of cholesterol biosynthesis, HMG-CoA reductase inhibitors, statins, inhibitors of cholesterol absorption, acyl CoA:cholesterol acyltransferase inhibitors, anion exchange resins, nicotinyl alcohol, nicotinicacid or a salt thereof, vitamin E, thyromimetics and L-carnitine..].
16. A method for treating .Iadd.obesity in .Iaddend.a subject .[.having hyperactive.]. .Iadd.and inhibiting .Iaddend.carnitine palmitoyl-transferase .Iadd.in the subject .Iaddend.comprising administering to said subject an effective amount ofa compound of claim 1.
17. A method for treating .[.a subject having.]. hyperglycaemia, diabetes.[., heart failure.]. or ischemia .Iadd.in a subject .Iaddend.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..]. |
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