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
1997-03-11
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...
564301, A61K 3113
Patent
active
056101953
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/01036, filed Apr. 4, 1994.
The present invention relates to novel pharmaceutically active 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, there are a number of states of the human or animal body which can be influenced favourably 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 can be 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, an intermediate in polyamine biosynthesis. The breakdown of putrescine in the cell is effected in particular by diamine oxidase (DAO). If the DAO is active, excess putrescine can be broken down, which further promotes the action of an ODC inhibitor. The less an inhibitor of ODC inhibits DAO, i.e. the higher its specificity, the more advantageous its properties.
The compound of the formula ##STR2## with the name 1-aminooxy-3-aminopropane (APA) is known. This compound is a potent inhibitor of ODC, but is not selective with respect to diamine oxidase. Furthermore, according to Eloranta et at., Life Chemistry Reports Volume 9, 163-169 (1991), it has practically no action in whole animal tests.
It has now been found, surprisingly, that the compounds according to the invention described in this invention which carry, on the central carbon chain, substituents which are bonded directly to the central carbon chain merely by a non-polar carbon atom belonging to the substituent, and the terminal polar groups of which are partly sterically hindered and protected from metabolic breakdown by the substituents mentioned, have advantageous pharmacological properties.
The compounds are potent inhibitors of ornithine decarboxylase.
Compared with APA, the compounds of the present invention tested show, for example, an increased selectivity in the inhibition of ODC with respect to inhibition of DAO.
The compounds of the formula I investigated furthermore are active in vivo and are also tolerated well at high doses.
The compounds according to the invention are those of the formula I ##STR3## in which a) four of the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are hydrogen and the others independently of one another am in each case C.sub.1 -C.sub.2 alkyl, these groups being bonded to the same carbon atom or to two different carbon atoms, or R.sub.6 are hydrogen and the other radical is C.sub.1 -C.sub.2 alkyl or hydroxymethyl,
The compounds of the present invention can in some cases exist as pure enantiomers or enantiomer mixtures, for example racemates. A condition for this is that only one or two of the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 (bonded to two different carbon atoms) is or are as defined, except for hydrogen (i.e. one of these radicals is C.sub.1 -C.sub.2 alkyl or hydroxymethyl, or two of these radicals, which are bonded to two different carbon atoms, are C.sub.1 -C.sub.2 alkyl), while the others are hydrogen; or that, if two of these radicals are C.sub.1 -C.sub.2 alkyl and are bonded to one carbon atom, these two radicals are not identical. If the two C.sub.1 -C.sub.2 alkyl radicals are bonded to two different carbon atoms, the compounds of the formula I can also exist as diastereomer mixtures (with or without optical activity). In all these cases, compounds of t
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Frei J org
Stanek Jaroslav
Burn Brian M.
Ciba-Geigy Corporation
Ferraro Gregory D.
Kaiser Karen G.
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