Bridged cyclic amino acids as pharmaceutical agents

Details Bridged cyclic amino acids as pharmaceutical agents Bridged cyclic amino acids as pharmaceutical agents

1998-05-19

2000-02-01

Keys, Rasalynd

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514561, 560117, 560118, 560120, 560122, 560125, 562499, 562500, 562502, 562504, 562507, A61K 31215, C07C 6974, C07C 6112

Patent

active

060203706

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Compounds of formula ##STR2## wherein R.sub.1 is hydrogen or a lower alkyl radical and n is 4, 5, or 6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. The uses disclosed are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The patents are hereby incorporated by reference.


SUMMARY OF THE INVENTION

The novel bridged cyclic amino acids, their derivatives, pharmaceutically acceptable salts, and prodrugs are useful in a variety of disorders. The disorders include: epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders.
The compounds are those of formula ##STR3## a pharmaceutically acceptable salt thereof or a prodrug thereof wherein A is a bridged ring selected from ##STR4## wherein R.sub.1 and R.sub.2 are each independently selected from hydrogen and methyl; methyl;
Preferred compounds are those of Formula I wherein ##STR5## or a pharmaceutically acceptable salt thereof wherein A is a bridged ring selected from ##STR6## wherein n is an integer of from 1 to 4; and
Other preferred compounds are, for example, (2-Aminomethyl-bicyclo[2.2.1]hept-2-yl)-acetic acid methyl ester monohydrochloride, [2-(Acetylamino-methyl)-bicyclo[2.2.1]hept-2-yl]-acetic acid, and [2-(2-Aminomethyl-bicyclo[2.2.1]hept-2-yl)-acetylamino ]-acetic acid monohydrochloride.
Novel intermediates useful in the preparation of the final products are disclosed as well as a novel process for the preparation of the compounds.


DETAILED DESCRIPTION

The compounds of the instant invention and their pharmaceutically acceptable salts are as defined by Formula I.
The term "alkyl" is a straight or branched group of from 1 to 6 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl.
The benzyl and phenyl groups may be unsubstituted or substituted by from 1 to 3 substituents selected from halogen, CF.sub.3, nitro, alkyl, alkoxy.
Since amino acids are amphoteric, pharmacologically compatible salts when R is hydrogen can be salts of appropriate inorganic or organic acids, for example, hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic, citric, malic, salicylic, malonic, maleic, succinic, and ascorbic. Starting from corresponding hydroxides or carbonates, salts with alkali metals or alkaline earit metals, for example, sodium, potassium, magnesium, or calcium are formed. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion. The carboxyl group of the amino acids can be esterified by known means.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof. In all cases where there is a chiral center at the point where the amino methyl and acetic acid moieties are joined to the ring, the center may have either the R or S configuration.
The compounds of the invention may be synthesized, for example, by utilizing the general strategy (Scheme 1 below) outlined by Griffiths G., et al., Helv. Chim. Acta, 74:309 (1991). Alternatively, they may also be made as shown (in Scheme 2 below), analogously to the published procedure for the synthesis of 3-oxo-2,8-diazaspiro[4,5]decane-8-carboxylic acid tert-butyl ester (1) (Smith P. W., et al., J. Med. Che

REFERENCES:
patent: 3641129 (1972-02-01), Loeffler et al.
patent: 3743742 (1973-07-01), Loeffler et al.
patent: 4024175 (1977-05-01), Satzinger et al.
patent: 4087544 (1978-05-01), Satzinger et al.
Loeffler et al., Bridged . . . Process, J. of Medicinal Chemistry, vol. 13, No. 5, pp. 926-935, Sep. 1970.
PCT International Search Report, PCT/US97/02401.
Mann et al., Chemical Abstracts, vol. 114, No. 19, 1991, abstract No. 184942k.

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