Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1994-12-12
1996-05-14
Burn, Brian M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564300, 514895, A61K 3113, C07C23910
Patent
active
055168060
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/01035, filed Apr. 2, 1994.
The present invention relates to novel pharmaceutically active cyclic aminooxy compounds, processes for the preparation of these compounds, pharmaceutical compositions comprising these compounds, these compounds for use in a prophylactic, therapeutic or diagnostic method for the treatment of the human or animal body, and the use of these compounds for the prophylactic or therapeutic treatment of the human or animal body and for the preparation of pharmaceutical compositions.
According to the current state of knowledge, participation of the polyamines spermidine and spermine and the diamine putrescine in regulation of growth processes is to be assumed.
A number of cell functions can be favourably influenced by inhibition of polyamine biosynthesis.
The enzyme ornithine decarboxylase (ODC) is one of the key enzymes of polyamine biosynthesis. A reduction in the activity of ODC leads to a reduced polyamine biosynthesis and therefore to reduced polyamine levels in the cell. If inhibition of the activity of this enzyme by ODC inhibitors is achieved, the polyamine concentration in mammalian cells (including human cells) can be influenced, i.e. lowered, with the aid of such ODC inhibitors.
In mammalian cells, ODC catalyses the synthesis of putrescine, a diamine which at the same time is also an intermediate in polyamine biosynthesis.
It has now been found, surprisingly, that the compounds of the present invention which have a cyclic central constituent have advantageous pharmacological properties.
The compounds according to the invention are those of the formula I N--O-- and the amino group --NH.sub.2 is at least 3 and not more than 4 carbon atoms and that b) the two radicals H.sub.2 N--(CH.sub.2).sub.n -- and --(CH.sub.2).sub.m --O--NH.sub.2 are not bonded to the same ring carbon atom of A, and salts thereof.
The compounds of the present invention can exist as mixtures of cis and trans isomers or, preferably, as pure cis or pure trans isomers; if asymmetric carbon atoms are present (i.e. if A is other than 1,4-cyclohexylene or 1,3-cyclobutylene), these carbon atoms can be in the (R), (S) or (R,S) configuration, independently of one another. In mixtures of cis and trans isomers, in each case both or only one of the optical antipodes of the cis and of the trans isomer can be present. Pure cis or trans isomers, which can exist as pure enantiomers or enantiomer mixtures, for example as racemic mixtures, in particular as pure enantiomers, are preferred.
The terms and general expressions used in the description of the present invention are preferably defined as follows:
C.sub.3 -C.sub.6 Cycloalkylene A, in which the two radicals H.sub.2 N--(CH.sub.2).sub.n -- and --(CH.sub.2).sub.m --O--NH.sub.2 are not bonded to the same ring carbon atom, is the bivalent radical of a cyclic hydrocarbon and is chosen from 1,2-cyclopropylene; 1,2- or 1,3-cyclobutylene; 1,2- or 1,3-cyclopentylene; and 1,2-, 1,3-or 1,4-cyclohexylene; 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene or 1,3- or 1,4-cyclohexylene is preferred.
The distance between the aminooxy radical H.sub.2 N--O-- and the amino group --NH.sub.2 of at least 3 and not more than 4 carbon atoms is defined such that the shortest connection between the radical H.sub.2 N--(CH.sub.2).sub.n -- and the radical --(CH.sub.2).sub.m --O--NH.sub.2 is to be included when counting the carbon atoms in ring A. The numerical values; of n and m are to be chosen accordingly within the context of proviso a); preferably, n is 0 and m is 0 or 1.
Salts of compounds according to the invention are acid addition salts, in particular pharmaceutically acceptable acid addition salts, i.e. those acid addition salts which do not have a troublesome toxicity in the particular dosage to be used, for example salts with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example acetic acid, octanoic acid, succinic acid, adipic acid, fumaric acid, maleic a
REFERENCES:
patent: 3192110 (1965-06-01), Biel et al.
patent: 4425340 (1984-01-01), Teraji et al.
patent: 4472194 (1984-09-01), Van Assche et al.
patent: 5254717 (1993-10-01), Grammenos et al.
AU 44711/89 (text) english equivelant of 0-369-944 (1989).
AU 10177/92 (text) english equivelant of 0-495-750 (1992).
92-286002/27 Derwent Abstract EP 499823 (see U.S. 5,254,717) (1992).
92-218598/35 Derwent Abstract EP 492366 (1992).
Stanek et al "2-Substituted 3-(Aminooxy) Propanamines as Inhibitors of Ornithine Decaeboxylase: Synthesis and Biological Activity" J. Med. Chem. vol. 35 (1992) pp. 1339-1344.
Moyano et al "Inhibition of Ornithine Decarboxylase by the Isomers of 1,4 Dimethylputrescine" J. Med. Chem. vol. 33, (1990) 1969-1974.
Frei Jorg
Stanek Jaroslav
Burn Brian M.
Ciba-Geigy Corporation
Fishman Irving M.
Kaiser Karen G.
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