Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1998-05-13
1999-12-14
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544399, 544400, 546192, 564297, 564299, 564301, C07D21108, C07D24104, C07D26530, C07C23904
Patent
active
060020024
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to novel hydroxylamine derivatives represented by the general formula (I), ##STR1## the pharmaceutically acceptable acid addition salts thereof as well as the pharmaceutical compositions containing the same as active ingredient. Another object of the invention is the preparation of the hydroxylamine derivatives and salts thereof.
The compounds according to the invention possess anti-ischaemic effect.
BACKGROUND ART
Compounds of similar structure have been described in C.A. 67 (p. 6886) 73271 g and C.A. 113 (p. 674) 171694k.
DISCLOSURE OF INVENTION
One object of the present invention is the group of hydroxylamine derivatives represented by the general formula (I) and the pharmaceutically acceptable acid addition salts thereof. In the above formula phenylalkyl; a phenyl group optionally substituted with halo, haloalkyl, alkyl, alkoxy or nitro; or an N-containing hetero ring, group of the formula --C(O)--NH--R wherein R is as defined above, or, R.sup.4 and R.sup.5, when taken together with the adjacent nitrogen attached thereto, form a 5 to 7-membered hetero ring which may contain one additional hetero atom selected from nitrogen, oxygen and sulfur and which is optionally substituted with alkyl of phenylalkyl.
Another object of the invention is a pharmaceutical composition which contains at least one of the compounds of the general formula (I) or the pharmaceutically active acid addition salt thereof as active ingredient.
Still another object of the invention is a plurality of processes for preparing the compounds of the general formula (I) and the pharmaceutically acceptable acid addition salts thereof. Though these compounds may be prepared by any process known in the art for preparing compounds of similar structure, the most favorable methods to obtain the same include the followings: ##STR2## wherein R.sup.2 and R.sup.3 are as defined above, is reacted with a compound of the general formula (III) ##STR3## wherein R is as defined above and Y is halo or azido, or ii) a compound of the general formula (VI) ##STR4## is reacted with a compound of the general formula (VII) ##STR5## or iii) a compound of the general formula (VI) is reacted with a compound of the general formula (VIII) ##STR6## or iv) a compound of the general formula (VI) is reacted with a compound of the general formula (IX) ##STR7## and subsequently with a compound of the formula R.sup.3 H, wherein in the formulae (VI), (VII), (VIII) and (IX) R, R.sup.2 and R.sup.3 are as defined above and Y is halo, a compound of the general formula (II) wherein R.sup.2 and R.sup.3 are as defined above, is reacted with a compound of the formula (IV) or (IVa) ##STR8## wherein R is as defined above and Y is halo, or c) for preparing compounds of the general formula (I) wherein X is --NH-- or --NR'--, a compound of the general formula (X) ##STR9## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above and Z is alkyl, aralkyl or optionally substituted aryl, is reacted with a compound of the general formula RNH.sub.2 or RR'NH, wherein R and R' are as defined above, or R.sup.3 is --N(R.sup.4)R.sup.5, R.sup.4 is alkyl and R.sup.5 is --C(O)--NH--R, R.sup.4 is alkyl R.sup.5 is H, and R .sup.2 is as defined above, is reacted with an excess of a compound of the formula (IV) or (IVa) wherein R is as defined above and Y is halo, or --N(R.sup.4)R.sup.5, R.sup.4 is alkyl, R.sup.5 is H and R.sup.1, R.sup.2 and R.sup.3 are as defined above, is reacted with a compound of the general formula (IV) or (Iva) wherein R is as defined above and Y is halo, or a compound of the general formula (II) is reacted with a compound of the general formula (V) ##STR10## wherein R, R', R.sup.2 and R.sup.3 are as specified above and Y is halo, and, if desired, a compound of the general formula (I) is transformed in its acid addition salt, or R.sup.2 is hydroxy, is transformed into a compound of the general formula (I) wherein R.sup.2 is acyloxy or R.sup.1 is acyl and R.sup.2 is acyloxy, optionally followed by salt forming.
Best Mode for Carrying o
REFERENCES:
patent: 4404384 (1983-09-01), Gebert et al.
2-Substituted 3-(Aminooxy) propanamines as inhibitors of Ornithine Decarboxylose: Synthesis and Biological Activity, J. Med. Chem, 1992, 35, 1339-1344.
Lipid metabolism of the Heart and Arteries in Relation to Ischemic Heart Disease, (L.H. Opie), The Lancet, Jan. 27, 1973, p. 192-195.
The Synthesis of Hydroxylamine Derivatives Possessing Hypocholesteremic Activity, (B.J. Ludwig et al), Ludwig, Dursch, Auerbach, Tomeczek and Berger, Jul., 1967.
Chemical Abstracts, vol. 67, 1967 P. 6887, Abstract No. 73271g.
International Search Report, International Application PCT/HU 96/00033, Nov. 8, 1996, 3 pages.
Alfred Burger, A guide to the Chemical Basis of Drug Design. p. 15, 1.3.1 Pro-Drugs, Jan. 13, 1983.
Barabas Mihaly
Biro Katalin
Jaszlits Laszlo
Jednakovits Andrea
Kurthy Maria
Biorex Research & Development Co.
Desai Rita
Rotman Alan L.
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