Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-11-20
2000-05-23
Clardy, S. Mark
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142312, 5142355, 514357, 514422, 514424, 514425, 514396, 514359, 514383, 514384, 514361, 5483001, 5483111, 5483147, 5483235, 5483157, 548517, 548518, 548541, 548543, 548530, 548546, 5482628, 5482632, 5482634, 5482636, 5483164, 5483171, 5483185, 548397, 548398, 544106, 544111, 546184, 546192, 546207, 546208, C07D23374, C07C25906, C07C23918
Patent
active
060666625
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with hydroxylamine derivatives.
The hydroxylamine derivatives provided by the present invention are compounds of the general formula ##STR2## wherein A represents a group of the formula ##STR3## R.sup.1 represents cyclopropyl, cyclobutyl or cyclopentyl; R.sup.2 represents hydrogen, hydroxy, lower alkyl or a group of the formula --(CH.sub.2).sub.n -aryl or --(CH.sub.2).sub.n -Het in which n stands for 1-4 and Het represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S as additional hetero atom(s) in a position or positions other than adjacent to the linking N atom, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other carbon atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; and amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl, protected carboxyl, carbamoyl, pyrrolidino, piperidino or morpholino;
The compounds of formula I possess valuable pharmacological properties. In particular, they are matrix metalloproteinase inhibitors and can also prevent TNF release. They can be used in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.
Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts per se and for use as therapeutically active substances; a process for the manufacture of said compounds and salts; intermediates useful in said process; medicaments containing said compounds and salts and the manufacture of these medicaments; the use of said compounds and salts in the control or prevention of illnesses or in the improvement of health, especially in the control or prevention of degenerative joint diseases or in the treatment of invasive tumours or atherosclerosis, or for the manufacture of a medicament for the control or prevention of degenerative joint diseases or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis.
As used in this Specification, the term "lower" means that the group qualified thereby is a straight-chain or branched-chain group containing a maximum of 7, preferably a maximum of 4, carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl and n-hexyl. The term "aryl" means an optionally substituted phenyl or naphthyl group, with the substituent(s) being selected from halogen (i.e. fluorine, chlorine, bromine or iodine), trifluoromethyl, lower alkyl, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.butoxy etc.), phenyl and the like.
The terms "protected amino" and "protected carboxy" mean amino and carboxy groups, respectively, which are protected in a manner known per se, e.g. as in peptide chemistry. Thus, an amino group can be protected by a benzyloxycarbonyl, tert. butoxycarbonyl, trifluoroacetyl or like group. A carboxy group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or like ester.
The compounds of formula I form pharmaceutically acceptable salts with bases such as alkali metal hydroxides (e.g. sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium hydroxide and magnesium hydroxide), ammonium hydroxide and the like. The compounds of formula I which are basic form pharmaceutically acceptable salts with acids. As such salts there come into consideration not only salts with inorganic acids such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), sulphuric acid, nitric acid, phosphoric acid etc, but also salts with organic acids such as acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulphonic acid, p-toluenesulphonic acid etc.
The compounds of formula I contain at
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English Abstract for Document B5.
Broadhurst Michael John
Brown Paul Anthony
Johnson William Henry
Clardy S. Mark
Epstein William H.
Hoffmann-La Roche Inc.
Johnston George W.
Kreisler Lewis J.
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