Bicyclic amino acids as pharmaceutical agents

Details Bicyclic amino acids as pharmaceutical agents Bicyclic amino acids as pharmaceutical agents

2002-04-19

2004-02-10

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acids and salts thereof

C514S530000, C514S572000, C514S573000

Reexamination Certificate

active

06689906

ABSTRACT:

BACKGROUND OF THE INVENTION
Compounds of formula
wherein R
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 instant invention is a series of novel bicyclic amino acids, their pharmaceutically acceptable salts, and the prodrugs of the amino acids.
The compounds are those of formula:
wherein n is an integer of from 1 to 4, where there are stereocenters, each center may be independently R or S.
Preferred compounds of the invention are those of Formulae I-IV above wherein n is an integer of from 2 to 4.
Other preferred compounds are those of Formula I above.
Especially preferred compounds are:
(1&agr;,6&agr;,8&bgr;)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid;
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid;
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid;
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid;
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid;
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid; and
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid.
Other preferred compounds are those selected from
(1&agr;,5&bgr;)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1&agr;,5&bgr;)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1&agr;,5&bgr;)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1&agr;,6&bgr;)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1&agr;,7&bgr;)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1&agr;,5&bgr;)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1&agr;,5&bgr;)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1&agr;,5&bgr;)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1&agr;,6&bgr;)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1&agr;,7&bgr;)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1&agr;,3&agr;,5&agr;)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1&agr;,3&agr;,5&agr;)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1&agr;,3&agr;,5&agr;)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1&agr;,6&agr;,8&agr;)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1&agr;,7&agr;,9&agr;)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1&agr;,3&bgr;,5&agr;)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1&agr;,3&bgr;,5&agr;)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1&agr;,3&bgr;,5&agr;)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1&agr;,6&agr;,8&bgr;)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1&agr;,7&agr;,9&bgr;)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1R,3S,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3R,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((3&agr;R,5R,7&agr;S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3&agr;R,5S,7&agr;S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3&agr;S,5S,7&agr;R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3&agr;S,5R,7&agr;R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((2R,4&agr;S,8&agr;R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4&agr;S,8&agr;R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4&agr;S,8&agr;S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4&agr;R,8&agr;S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4&agr;S,9&agr;R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4&agr;S,9&agr;R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4&agr;R,9&agr;S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2R,4&agr;R,9&agr;S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1R,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3S,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((3&agr;R,5R,7&agr;R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3&agr;R,5S,7&agr;R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3&agr;S,5S,7&agr;S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3&agr;S,5R,7&agr;S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((2R,4&agr;R,8&agr;R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4&agr;S,8&agr;R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4&agr;R,8&agr;S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4&agr;S,8&agr;S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4&agr;R,9&agr;R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4&agr;R,9&agr;R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4&agr;S,9&agr;S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, and
((2R,4&agr;S,9&agr;S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid.
The compounds of the invention are useful in treating a variety of disorders. The disorders include: epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, and sleep disorders.
Intermediates useful in the preparation of the final products are also included in the scope of the invention.
DETAILED DESCRIPTION
The compounds of the instant invention, their prodrugs, and their pharmaceutically acceptable salts are as defined above in Formulae I-IV.
Pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulas I-VII above are included in the instant invention.
Methods of using the compounds of the invention as agents for treating epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, sleep disorders, and premenstrual syndrome are part of the invention.
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 earth 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.
Prodrugs of compounds I-VIII are included in the scope of the instant invention. Aminoacyl-glycolic and -lactic esters are known as prodrugs of amino acids (Wermuth C. G.,
Chemistry and Industry
, 1980:433-435). The carbonyl group of the amino acids can be esterified by known means. Prodrugs and soft drugs are known in the art (Palomino E.,
Drugs of the Future
, 1990;15(4):361-368). The last two citations are hereby incorporated by reference.
The effectiveness of an orally administered drug is dependent upon the drug's efficien

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