Substituted cyclic amino acids as pharmaceutical agents

Details Substituted cyclic amino acids as pharmaceutical agents Substituted cyclic amino acids as pharmaceutical agents

1998-05-20

2000-08-15

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

562508, 514561, C07C 6108, A61K 31195

Patent

active

061039322

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 substituted cyclic amino acids, their derivatives, prodrugs, and pharmaceutically acceptable salts 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 R.sub.1 to R.sub.10 are each independently selected from straight or branched alkyl of from 1 to 6 carbon atoms, unsubstituted or substituted benzyl or phenyl which substituents are selected from halogen, alkoxy, alkyl, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro, and
Especially preferred compounds of the invention are: monohydrochloride; 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.
Preferred groups are methyl and tert-butyl.
The benzyl and phenyl groups may be unsubstituted or substituted by from 1 to 3 substituents selected from halogen, alkyl, alkoxy, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro.
Halogen includes fluorine, bromine, chlorine, and iodine.
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. For example, the compound of Example 1 is a mixture of all four possible stereoisomers. The compound of Example 6 is one of the isomers. The configuration of the cyclohexane ring carbon centers may be R or S in these compounds where a configuration can be defined.
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. Chem., 38:3772 (19

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