Pharmaceutical compounds

Details Pharmaceutical compounds Pharmaceutical compounds

1996-09-25

1997-10-21

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

558154, A61K 3166, C07F 932

Patent

active

056796633

DESCRIPTION:

BRIEF SUMMARY
This application was filed under 35 U.S.C. 371 and was based upon International Application No. PCT/IB94/00009, filed Jan. 10, 1994.
The invention relates to hydrazides of phosphorylated carboxylic acids having therapeutic activity, particularly in treating depression and for effecting memory enhancement.
Razumov et al., Zhurnal obshchei khimii, 1967, vol. 37, 421-424 describe hydrazides of phosphorylated carboxylic acids of structure R.sub.1 R.sub.2 P(O)CH.sub.2 C(O)NHNH.sub.2 in which R.sub.1 and R.sub.2 are selected from phenyl, p-tolyl, ethyl, ethoxy and butoxy groups and N-substituted derivatives thereof. These hydrazides were reported as showing a low level of antimicrobial activity. U.S. Pat. Nos. 4,162,264 and 4,162,311 describe a hydrazide of diphenylphosphinylacetic acid H.sub.5).sub.2 P(O)CH.sub.2 C(O)NHNH.sub.2 ! which has vegetropic, anti-epileptic and anti-serotonin properties. Hydrazides of phosphorylated acetic acids, which display a low level of neurotropic activity, are also described by Ismagilov et al., Khim.-Farm. Zhurnal, 1982, 16, 296-300 and Zhuravleva et al., Khim.-Farm. Zhurnal, 1978, vol. 12, 79-93 (both also published in English translation).
It is well known that patients who suffer from neurodegenerative diseases, for example Alzheimer's disease and Parkinson's disease, or, as a result of a stroke or head injury or merely as the result of advancing age, suffer from memory-loss, often also have symptoms ranging from mild anxiety to severe depression. Such patients respond to treatment with neuroprotective agents and in particular memory-enhancing drugs (so-called "cognitive enhancers") and anti-depressants.
It is an object of the present invention to expand the arsenal of remedies available for use in these areas and it has now been found, for example, that the novel compound (2-chloroethoxy)-(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide =R.sup.2 .dbd.H and R.sup.3 .dbd.R.sup.4 .dbd.H! is a potent neuroprotective agent and in particular displays anti-depressant and memory enhancing activity.
Accordingly the present invention comprises a compound having the following general formula (I): ##STR2## wherein each X separately is halogeno, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro or an unsubstituted or substituted amino group NRR' in which R and R' are each separately selected from hydrogen, C.sub.1-4 alkyl groups and C.sub.2-4 halogenated alkyl groups; substituted amino group NRR' in which R and R' are as defined above; phenyl or a C.sub.1-4 alkyl group, or together represent a group .dbd.NOR" in which R" is hydrogen or is a group ZC(O)-- or (ZO).sub.2 P(O)-- where Z is a C.sub.1-4 alkyl group; and phenyl, 2,2,2-trichloro-1-hydroxyethyl or a C.sub.1-4 alkyl group, or together represent a group .dbd.CHR"' in which R"' is a C.sub.1-4 alkyl, C.sub.1-4 halogenated alkyl or phenyl group or represent a group .dbd.CH--CH.dbd.CHR"' in which R"' is as defined above, with any phenyl group present in R.sup.3, R.sup.4 or R.sup.3 +R.sup.4 optionally being substituted by 1 to 3 groups selected from halogeno, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, nitro and unsubstituted or substituted amino groups NRR' in which R and R' are as defined above; the compound optionally being in the form of a physiologically acceptable salt.
In the compounds (I) halogeno groups are preferably iodo, bromo, or especially chloro and the C.sub.1-4 alkyl and alkoxy groups may comprise alkyl groups which are branched or preferably straight chain such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl, with the smaller groups such as methyl being of particular interest. Halogenated alkyl groups are constituted of such halogeno and alkyl groups, such groups preferably containing one halogeno group and with the C.sub.2-4 halogenated alkyl groups preferably being substituted on a carbon atom other than the .alpha. carbon atom of the alkyl group, as for example in 2-chloroethyl.
As regards the group (X).sub.n, n is preferably either 0, in which case the phenyl group in the compound (I) is unsubstituted o

REFERENCES:
patent: 4162311 (1979-07-01), Razumov et al.
Ismagilov, R.K. et al "Synthesis and biological activity . . . " Khim-Farm ZH. (Khfzan, 00231134); 1982 vol. 16 (3); pp.296-300.
Razumov A.I. et al "Derivatives of phosphinic and phosphinous acids . . . " ZH. Obshich. Khim. (Zokha4); 1967; vol. 37 (2); pp. 421-424.
Zhuravleva, G.G. et al "Synthesis and biological activity of phosphorylated carboxylic acid . . . " Khim-Farm ZH. (Khfzan, 00231134); 1978 vol. 12 (4); pp.79-83.
Semina, I.I et al "Synthesis and neurotropic activity of diarylphosphorylacetyl . . . " Khim-Farm ZH. (Khfzan, 00231134); 1991 vol. 25 (5); pp.45-46.

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