Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1990-04-18
1993-06-08
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514621, 514622, 564165, 564169, 564170, A61K 31165, C07C23305, C07C23365
Patent
active
052180000
DESCRIPTION:
BRIEF SUMMARY
This invention relates to polyamine amides of interest for the treatment of cerebral disorders and in particular psychoses, senile dementia, ischaemia, stroke, hypoxia, aneurysm, epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's chorea, and related syndromes and neurological disorders.
Accordingly, the present invention comprises a compound of formula I optionally in the form of an acid addition salt ##STR2## in which formula: A represents a substituent which is: hydroxyl, O-alkyl, O-cycloalkyl, O-alkenyl, O-aryl, O-aralkyl, O-carbamate, O-carbonate, O-acyl or halogen carrying one or more of the substituents: hydroxyl, amino, halogen, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, aryloxy or carboalkoxy and optionally comprising one or more sites of unsaturation and/or one or more carbonyl groups or ketal derivatives thereof; and C.sub.1 -C.sub.4 alkyl or cycloalkyl, and cycloalkyl or G and J together with the nitrogen atom to which they are attached represent a saturated heterocyclic ring system.
Typically: when A represents O-alkyl, the alkyl group is C.sub.1 -C.sub.4 alkyl; when A represents O-cycloalkyl the group is cyclohexyl; when A represents O-alkenyl the alkenyl group is a C.sub.1 -C.sub.4 alkenyl group such as ethenyl, propenyl or butenyl; when A represents O-aryl, the aryl group is a phenyl group; when A represents O-aralkyl, the aralkyl group is a C.sub.7 -C.sub.10 phenalkyl group; when A represents O-carbamate, the O-carbamate group is of formula --O--CO--NR.sup.I R.sup.II wherein R.sup.1 and R.sup.11, which may be identical or different, represent C.sub.1 -C.sub.4 alkyl groups; when A represents O-carbonate, the O-carbonate is of formula --O--CO--OR.sup.III wherein R.sup.III represents a C.sub.1 -C.sub.4 alkyl group; when A represents O-acyl, the O-acyl group is of formula --O--CO--R.sup.IV wherein R.sup.IV represents a C.sub.1 -C.sub.4 alkyl group e.g. methyl and when A represents halogen, the halogen is typically Cl, Br or F.
It will be appreciated that the compounds in which A represents a substituent other than hydroxyl or halogen may act through conversion in vivo to the corresponding compound in which the group or groups A are hydroxy groups. Indeed, the present invention extends in general to compounds of formula (I) as defined above in which A is hydroxyl when in pro-drug form.
Although a may be 0-5, it is typically at least 1 and normally no more than 3, mono or di substitution of the aromatic ring being preferred and disposition of a mono substituent e.g. a hydroxyl group, at the 2, 3 or 4 position in the ring being especially so.
The aliphatic hydrocarbon group B is typically unbranched and generally contains no more than two carbon atoms intermediate between the aromatic ring and the carbonyl group of the CONH(CH.sub.2).sub.c -- function. It will be appreciated that, when present, substituents may be identical or different. Sites of unsaturation may be present as double bonds (typically configurationally trans) or triple bonds or both. Groups of the following formula are of particular interest, R.sub.1 R.sub.2 and R.sub.3 representing hydrogen or one or more of the substituents hereinbefore described as carried on the C.sub.1 -C.sub.6 aliphatic hydrocarbon group: --CHR.sub.1 --, --CHR.sub.1 CHR.sub.2 --, --CR.sub.1 .dbd.CR.sub.2 --, --CHR.sub.1 CHR.sub.2 CHR.sub.3 --, --CR.sub.1 .dbd.CR.sub.2 CHR.sub.3 -- and --CHR.sub.1 --CR.sub.2 .dbd.CR.sub.3 --.
Although R.sub.1, R.sub.2 and R.sub.3 may represent one or more of the hereinbefore identified substituents it is most usual for all to be hydrogen.
Usually no more than one carbonyl group or ketal derivative thereof is present in the group B (i.e. one carbon atom of the C.sub.1-6 aliphatic hydrocarbon group is substituted by an oxo group or such a group in ketal form) and there is generally at least one other carbon atom present in the carbon chain between the aromatic ring and the CONH(CH.sub.2).sub.c -- function as in the phenylpyruvic and hydroxyphenylpyruvic moieties wherein B represents --CH.sub.2 CO--, which are
REFERENCES:
patent: 3272861 (1966-09-01), Riggs
patent: 3390124 (1968-06-01), Kittridge et al.
patent: 4058624 (1977-11-01), Jacobus et al.
patent: 4172094 (1979-10-01), Dybas et al.
patent: 4990511 (1991-02-01), Nakajima et al.
Asami et al., Biomedical Research, 10(3), pp. 185-189 (1989).
Martin-Janguy et al., Chem. Abstracts, Abstract 183157, vol. 90 No. 23, Jun. 4, 1979.
B. Meldrum and J. Garthwaite, "Excitatory amino acid neurotoxicity and neurodegenerative disease", Trends in Pharmacological Sciences (TIPS), Special Report 1991 The Pharmacology of Excitatory Amino Acids, pp. 54-62.
J. C. Watkins et al., "Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists", Trends in Pharmacological Sciences (TIPS), Special Report 1991, The Pharmacology of Excitatory Amino Acids, p. 4.
Quicke et al., Pesticides Science, 20(4):315-317 (1987).
Oediger, Chem. Abst. 72-21525b (1970).
Blagbrough Ian S.
Bycroft Barrie W.
Mather Alan J.
Usherwood Peter N. R.
Kumar Shailendra
National Research Development Corporation
Raymond Richard L.
LandOfFree
Therapeutic polyamine-amides does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Therapeutic polyamine-amides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic polyamine-amides will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1934383