Conformationally constrained amino acid compounds having...

Details Conformationally constrained amino acid compounds having... Conformationally constrained amino acid compounds having...

2000-08-16

2001-11-13

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S953000, C514S210170, C514S409000

Reexamination Certificate

active

06316638

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 compounds, 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
or a pharmaceutically acceptable salt thereof or a prodrug thereof wherein
R
1
to R
10
are each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl;
m is an integer of from 0 to 3;
n is an integer of from 1 to 2;
o is an integer of from 0 to 3;
p is an integer of from 1 to 2;
q is an integer of from 0 to 2;
r is an integer of from 1 to 2;
s is an integer of from 1 to 3;
t is an integer of from 0 to 2; and
u is an integer of from 0 to 1.
Novel intermediates useful in the preparation of the final compounds are, for example:
2-Benzyl-2-aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethyl ester hydrochloride;
2-Aza-spiro[4.5]decane-4,4-dicarboxylic acid dimethyl ester hydrochloride;
1-Benzyloxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester;
1-Hydroxymethyl-2-aza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester;
2-Aza-spiro[3.5]nonane-1,2-dicarboxylic acid 2-tert-butyl ester;
[3aS-(3&agr;7a&agr;)]-7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindole-2-carboxylic acid tert-butyl ester; and
[3aS-(&agr;7a&agr;)]-3a-tert-Butoxycarbonylmethyl-octahydro-isoindole-2-carboxylic acid tert-butyl ester.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the instant invention and their pharmaceutically acceptable salts and prodrugs are as defined by Formula I to VIII above.
Preferred compounds are those of Formula I above.
Especially preferred are those of Formula I wherein
R
1
to R
10
is hydrogen;
m is of from 0 to 3; and
n is 1 or 2.
More especially preferred are those compounds selected from:
(±)-2-Aza-spiro[3.5]nonane-1-carboxylic acid hydrochloride;
(±)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride;
(R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride;
(S)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride; and
(R)-2-Aza-spiro[4.5]decane-4-carboxylic acid.
Other preferred compounds are those of Formula II above.
Especially preferred are those of Formula II wherein
R
1
to R
10
is hydrogen,
o is from 0 to 3; and
p is 1 to 2.
Other preferred compounds are those of Formula III above wherein
R
1
to R
10
is hydrogen,
q is from 0 to 2; and
r is 1 to 2.
Especially preferred is (±)-[3aS-(3&agr;,7a&agr;)]-(Octahydro-isoindol-3a-yl)-acetic acid trifluoroacetate.
Also especially preferred are compounds selected from:
7-Methyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;
[4&agr;,5&bgr;(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;
[4&agr;,5&agr;(S*)]7-Methyl-2-aza-spiro[4.5]decanc-4-carboxylic acid;
[4&agr;,5&agr;(R*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;
[4&agr;,5&bgr;(S*)]7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;
7,8-Dimethyl-2-aza-spiro[4.4]nonane-4-carboxylic acid;
7-Methyl-2-aza-spiro[4.5]decane-4-carboxylic acid;
7,9-Dimethyl-2-aza-spiro[4.5]decane-4-carboxylic acid;
Spiro[bicyclo[3.3.1]nonane-9,3′-pyrrolidine]-4′-carboxylic acid;
Spiro[pyrrolidine-3,2′-tricyclo[3.3.1.1
3,7
]decane]-4-carboxylic acid;
3-Amino-6-methyl-spiro[3.5]nonane-1-carboxylic acid;
3-Amino-6,8-dimethyl-spiro[3.5]nonane-1-carboxylic acid;
4-Amino-7-methyl-spiro[4.5]decane-1-carboxylic acid;
4-Amino-7,9-dimethyl-spiro[4.5]decane-1-carboxylic acid;
3-Amino-6-methyl-spiro[3.4]octane-1-carboxylic acid;
3-Amino-6,7-dimethyl-spiro[3.4]octane-1-carboxylic acid;
4-Amino-7-methyl-spiro[4.4]nonane-1-carboxylic acid; and
4-Amino-7,8-dimethyl-spiro[4.4]nonane-1-carboxylic acid.
Pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulas I-VIII 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, and neuropathological disorders are part of the invention.
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 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 efficient transport across the mucosal epithelium and its stability in entero-hepatic circulation. Drugs that are effective after parenteral administration but less effective orally, or whose plasma half-life is considered too short, may be chemically modified into a prodrug form.
A prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form.
This chemically modified drug, or prodrug, should have a different pharmacokinetic profile to the parent, enabling easier absorption across the mucosal epithelium, better salt formulation and/or solubility, improved systemic stability (for an increase in plasma half-life, for example). These chemical modifications may be
1) ester or amide derivatives which may be cleaved by, for example, esterases or lipases. For ester derivatives, the ester is derived from the carboxylic acid moiety of the drug molecule by known means. For amide derivatives, the amide may be derived from the carboxylic acid moiety or the amine moiety of the drug molecule by known means.
2) peptides which may be recognized by specific or nonspecific proteinases. A peptide may be coupled to the drug molecule via amide bond formation with the amine or carboxylic acid moiety of the drug molecule by known means.
3) deri

Affiliated with

Also associated with

Rating

Conformationally constrained amino acid compounds having... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Conformationally constrained amino acid compounds having..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Conformationally constrained amino acid compounds having... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2606831