Pharmaceutically active compounds and methods of use

Details Pharmaceutically active compounds and methods of use Pharmaceutically active compounds and methods of use

1996-08-09

2004-06-29

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S231000, C546S215000

Reexamination Certificate

active

06756389

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to certain imine-substituted heterocyclic compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.
2. Background
Nerve cell death (degeneration) can cause potentially devastating and irreversible effects for an individual and may occur e.g. as a result of stroke, heart attack or other brain or spinal chord ischemia or trauma. Additionally, neurodegenerative disorders involve nerve cell death (degeneration) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoff's disease.
Therapies have been investigated to treat nerve cell degeneration and related disorders, e.g., by limiting the extent of nerve cell death that may otherwise occur to an individual. See, e.g., N. L. Reddy et al.,
J. Med. Chem.,
37:260-267 (1994); and WO 95/20950.
The compound MK-801 has exhibited good results in a variety of in vivo models of stroke. See B. Meldrum,
Cerbrovascular Brain Metab. Rev.,
2:27-57 (1990); D. Choi,
Cerbrovascular Brain Metab. Rev.,
2:105-147 (1990). See also Merck Index, monograph 3392, 11th ed., 1989. For example, MK-801 exhibits good activity in mouse audiogenic tests, a recognized model for evaluation of neuroprotective drugs. See, e.g., M. Tricklebank et al.,
European Journal of Pharmacology,
167:127-135 (1989); T. Seyfried,
Federation Proceedings,
38(10):2399-2404 (1979).
However, MK-801 also has shown toxicity and further clinical development of the compound is currently uncertain. See J. W. Olney et al.,
Science,
244:1360-1362 (1989); W. Koek et al.,
J. Pharmacol. Exp. Ther.,
252:349-357 (1990); F. R. Sharp et al.,
Society for Neuroscience Abstr
., abstr. no. 482.3 (1992).
It thus would be highly desirable to have new neuroprotective agents, particularly agents to limit the extent or otherwise treat nerve cell death (degeneration) such as may occur with stroke, heart attack or brain or spinal cord trauma, or to treat neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoff's disease.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides imine-substituted compounds of the following Formula I:
wherein Z is sulfur, oxygen, carbon or nitrogen;
m and n are each independently an integer from 0 to 4, and the sum of m and n is at least 2, preferably is 3, 4, 5 or 6, more preferably 3, 4 or 5;
each X is independently substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsilyl preferably having 1 to about 20 carbon atoms and 1 or more Si atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms, including haloalkoxy; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylamino preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl preferably having at least about 6 ring carbon atoms; substituted or unsubstituted aralkyl preferably having from 7 to about 18 carbons; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
p is an integer equal to 0 (where the ring is substituted only by the depicted —C(═NH)NH
2
substituent) to 14, more typically from 0 to about 4; and pharmaceutically acceptable salts thereof.
Substituted or unsubstituted methylene (—CH
2
—) is a generally preferred Z ring member. Generally preferred X groups include substituted and unsubstituted alkyl, substituted and unsubstituted alkylsilyl, substituted and unsubstituted alkenyl, substituted and unsubstited alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylsulfinyl, substituted and unsubstituted alkylsulfonyl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaromatic or heteroalicyclic groups.
Particularly preferred X groups included substituted and unsubstituted alkyl and substituted and unsubstituted carbocyclic aryl, particularly substituted and unsubstituted naphthyl or phenyl such as naphthyl or phenyl substituted by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio and ethylthio, and alkylsilyl preferably having 1 to about 15 carbon atoms.
It is understood that the imine-substituted ring nitrogen shown in the above formula generally would not be substituted by an X group. It is further understood that the ring methylene (CH
2
) groups (which include Z where Z is carbon) of the above Formula I will include only a single hydrogen if the methylene unit is mono-substituted by an X group, i.e. the methylene unit will be (CHX), or the methylene unit will contain no hydrogens if di-substituted by X groups, i.e. the methylene unit will be (CXX). It is also understood the range of p values will depend in part on the sum of m and n as well as the valence of the Z ring substituent. Thus, for example, if the sum of m and n is 4 and without limitation on the Z ring member, p will be an integer of from 0 to 10, but if Z is specified to be oxygen, then p will be an integer of from 0 to 8, or if Z is nitrogen then p will be an integer of from 0 to 10.
Generally preferred compounds of Formula I include six-member ring compounds (i.e. where the sum of m and n above is four), particularly compounds of the following Formula Ia:
wherein Z and X are each the same as defined above for Formula I; p′ is an integer of from 0 (where the ring is substituted only by the —C(═NH)NH
2
substituent) to 10, more typically from 0 to about 4; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula I are substituted piperidines of the following Formula Ib:
wherein X is the same as defined above for Formula I; p″ is an integer of from 0 (where the ring is substituted only by the depicted imine) to 10, more typically from 0 to about 4; and pharmaceutically acceptable salts thereof.
Preferred compounds of the invention have at least two ring substituents (p≧2 in Formula I), particularly 2,6-substituted compounds of Formula Ia, such as the following substituted piperidine compounds of Formula Ic:
wherein W and Y are each independently substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsilyl preferably having 1 to about 20 carbon atoms and 1 or more Si atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms, including haloalkoxy; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl preferably having at least about 6 ring

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