Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1997-11-21
2000-11-21
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514381, 514557, 514570, 514646, 514741, 548250, 558411, 558412, 562458, 562409, 562473, 562474, 562475, A61K 31192, A61P 912, A61P 2516, C07C22942
Patent
active
061504122
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new trisubstituted catechol derivatives, to their preparation and use, to pharmaceutically acceptable esters and salts thereof and to pharmaceutical compositions containing them.
The compounds of the present invention are very potent peripheral, long acting COMT (catechol-O-methyl transferase) inhibitors. The main use of COMT-inhibitors lies presently in the potentiation of levodopa therapy which is used to treat Parkinson's disease. However, many other uses have been suggested including use as natriuretic and antihypertensive agents (Eklof A. C., et al. Natriuretic and vasodilating effects of dopamine are mimicked by oral administration of a catechol-O-methyltransferase (COMT) inhibitor, J. Am. Soc. Nephrology Vol. 5, No. 3, p. 657).
GB-A-2200109 discloses disubstituted catechols of formula: ##STR2## wherein R.sub.1 and R.sub.2 represent different substituents including hydrogen, X comprises an electronegative substituent such as halogen, nitro, cyano, lower alkyl sulfonyl, sulfonamido, trifluoromethyl, aldehyde or carboxyl and R.sub.3 can be, inter alia, carboxyalkyl or substituted vinyl (comparison compounds 1 and 2 fall within this formula). These compounds are COMT inhibitors. Disubstituted catechols having 2-(3,4-dihydroxy-2-nitrophenyl)vinyl structure disclosed by Perez et al in Biochemical Pharmacology, Vol. 45 (1993) No. 10 pp. 1973-1981 are also reported to be COMT-inhibitors.
The compound of the present invention are of formula I: ##STR3## wherein R.sub.1 is an electronegative substituent, preferably nitro, cyanoa formyl or carboxy one carboxy or 5-tetrazolyl; halogen, formyl, carboxy, C.sub.1-5 alkyl carbonyl, aryl carbonyl or SO.sub.2 R.sub.6 wherein NR.sub.7 R.sub.8, wherein chain C.sub.1-5 alkyl or together form a C.sub.3-6 ring or a pharmaceutically acceptable ester or salt thereof.
The term "aryl" as employed herein means phenyl or naphthyl.
Preferably R.sub.1 and R.sub.3 are both nitro or cyano and A has at least 2 carbon atoms.
Preferred salts are metal or amine salts. More preferred are alkaline metal salts such as the sodium salt.
The compounds of the invention may be prepared by dealkylating a compound of formula II ##STR4## wherein R.sup.1 is a lower alkyl or benzyl and R.sub.1 to R.sub.3 are as defined above to form a compound of formula I. The dealkylation may be carried out by usual dealkylation procedures described in the literature (See, Cleavage of Ethers, Bhatt, M. V., Synthesis 1983, page 249), for example, using boron tribromide at a temperature ranging from -20.degree. C. to 40.degree. C. under an inert atmosphere or using pyridine hydrochloride at a temperature between 180.degree. C. and 225.degree. C.
The starting materials may be prepared by any method known for the preparation of analogous compounds.
Compounds of formula I wherein R.sub.1 and R.sub.3 are both nitro or formyl are typically prepared by first disubstituting a compound of formula III ##STR5## wherein R' and R.sub.2 are the same as above to obtain the intermediate of formula II wherein R.sub.1 and R.sub.3 are both nitro or formyl which intermediate is then demethylated to form the desired compound.
The dinitro intermediates of formula II may be prepared by any procedure known in the art, for instance, by using nitric acid in acetic acid at temperatures ranging from 20.degree. C. to 80.degree. C., by using nitric acid in dichloromethane between 0.degree. C. to 40.degree. C. or by using potassium nitrate in sulfuric acid at temperatures from -15.degree. C. to 20.degree. C. The corresponding diformyl compounds may be prepared by common electrophilic formylation procedures, preferably by the Duff reaction using hexamethylenetetramine in acetic or trifluoroacetic acid.
The intermediates of formula II wherein R.sub.1 and R.sub.3 are both cyano may be prepared from the compounds of formula III wherein R.sub.1 and R.sub.3 are both formyl in a known manner, for example, by refluxing them in a mixture of hydroxylamine hydrochloride, (sodium formate) and formic acid. The corresponding c
REFERENCES:
patent: 4707488 (1987-11-01), Kaiser et al.
patent: 5191108 (1993-03-01), Carson et al.
patent: 5389653 (1995-02-01), Bernauer et al.
Bhatt M. V. and Kulkarni S. U., "Cleavage of Ethers", Synthesis, 1983, 249-282, Georg Thieme Verlag.
Backstrom R. et al., "Synthesis of Some Novel Potent and Selective Catechol O-Methyltransferase Inhibitors", J. Med. Chem., 1989, 32, 841-846.
Perez R. A. et al., "Inhibition of Catechol-O-methyltransferase by 1-Vinyl Derivatives of Nitrocatechols and Nitroguaiacols", Biochemical Pharmacology, 1993, 45(10), 1973-1981.
Eklof A.-C. et al., "Natriuretic and Vasodilating Effects of Dopamine Are Mimicked by Oral Administration of a Catechol-O-methyltransferase (COMT) Inhibitor", J. Am. Soc. Nephrology, 1994, 5(3), 657.
Lotta Timo
Luiro Anne
Ovaska Martti
Pystynen Jarmo
Vidgren Jukka
McKane Joseph
Orion-yhtyma Oy
Oswecki Jane C.
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