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MXPA00002656A - Cyclic amino acids and derivatives thereof useful as pharmaceutical agents - Google Patents

Cyclic amino acids and derivatives thereof useful as pharmaceutical agents

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Publication number
MXPA00002656A
MXPA00002656A MXPA/A/2000/002656A MXPA00002656A MXPA00002656A MX PA00002656 A MXPA00002656 A MX PA00002656A MX PA00002656 A MXPA00002656 A MX PA00002656A MX PA00002656 A MXPA00002656 A MX PA00002656A
Authority
MX
Mexico
Prior art keywords
acetic acid
cyclopentyl
methyl
aminomethyl
cyclobutyl
Prior art date
Application number
MXPA/A/2000/002656A
Other languages
Spanish (es)
Inventor
Justin Stephen Bryans
David Christopher Horwell
Andrew John Thorpe
David Juergen Wustrow
Powai Yuen
Original Assignee
Justin Stephen Bryans
David Christopher Horwell
Andrew John Thorpe
Warnerlambert Company
David Juergen Wustrow
Powai Yuen
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Justin Stephen Bryans, David Christopher Horwell, Andrew John Thorpe, Warnerlambert Company, David Juergen Wustrow, Powai Yuen filed Critical Justin Stephen Bryans
Publication of MXPA00002656A publication Critical patent/MXPA00002656A/en

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Abstract

The invention is a novel series of cyclic amino acids which are useful in the treatment of epilepsy, faintness attacks, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS), and inflammation, especially arthritis. A pharmaceutical composition containing a compound of the invention as well as methods of preparing the compounds and novel intermediates useful in the preparation of the final compounds are included.

Description

CYCLIC AMINO ACIDS AND DERIVATIVES OF THE SAME USERS AS PHARMACEUTICAL AGENTS BACKGROUND OF THE INVENTION Compounds of the formula wherein R-i is hydrogen or a lower alkyl radical and n is 4, 5 or 6 are described in U.S. Patent Number 4,024,175 and its divisional U.S. Patent Number 4,087,544. The described uses are: protective effect against numbness induced by thiosemicarbazide; protective action against numbness caused by cardiazol; brain diseases, epilepsy, mental lacunae, hypokinesia, and cranial traumas; and the improvement of brain functions. The compounds are useful in geriatric patients. The patents are incorporated herein by reference.
SUMMARY OF THE INVENTION The compounds of the invention are of the formula 1 and 1A 1 1A where R a R, 14 are as defined below.
The compounds of the invention and their pharmaceutically acceptable salts and the prodrugs of the compounds are useful in the treatment of epilepsy, mental lacunae, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS), and inflammation, especially arthritis. The invention is also a pharmaceutical composition of a compound of the formulas 1 and 1A ..
DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention and their pharmaceutically acceptable salts are as defined by formulas 1 and 1A 1A or a pharmaceutically acceptable salt thereof wherein: R is hydrogen or a lower alkyl; R1 to R14 are each independently selected from hydrogen, long or branched chain alkyl of 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, -CO2H, -CO2R15, - CH2CO2H, -CH2CO2R15, -OR15 wherein R15 is a long or branched chain alkyl of 1 to 6 carbons, phenyl or benzyl and R1 to R8 are not hydrogen simultaneously. Preferred compounds of the invention are those of Formula 1 wherein R 1 to R 14 are selected from hydrogen, methyl, ethyl, propyl, isopropyl, long or branched chain butyl, phenyl or benzyl. The most preferred compounds are those of Formula 1 wherein R 1 to R 14 are selected from hydrogen, methyl, ethyl or benzyl. The most preferred compounds are selected from: (1 a, 3o, 4 <) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid; (1 (X, 3ÍX, 4cx) - (1-Aminomethyl-3,4-diethyl-cyclopentyl) -acetic acid; (1 a, 3rx, 4 (x) - (1-Aminomethyl-3,4-diisopropyl-cyclopentyl) ) -acetic acid; 1S- (1 (x, 3? (, 4 (x)] - ((1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl) -acetic acid; 1R- [la, 3 (X , 4a)] - ((1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl) -acetic acid; M 1SS - ((1 1aa ,, 3 3 <? X (,, 4 4oa)] 1- - ((1-amino-methyl-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; 1R- [1 < x, 3o;, 4 < x)] - ((1-amino-methyl-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1cx, 3 < x, 4o)] - ((1-amino-methyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1R- (1o, 3 < x, 4a)] - ( (1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1S- (1 (x, 3a, 4 (x)] - ((1-amino-methyl-3-tert-butyl-4-methyl-cyclopentyl) -acetic acid; [1 1 RR - ([11 aa, , 3 3 < ax ,, 4 4aa)) l) - - ((1-amino-methyl-3-tert-butyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1 (X, 3a, 4a)] - ((1-amino-methyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1R- 1a, 3a, 4a)] - ((1- Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1S- (1a, 3 " x, 4 (x)] - ((1-Aminomethyl-3-tert-butyl-4-isopropyl- cyclopentyl) -acetic acid; [1 R- (1 a, 3 tx, 4 (x)] - (1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid; loe, 3o., 4 (x) - (1- Aminomethyl-3, 4-di-tert-butyl-cyclopentyl) -acetic acid; IS- (1 O, 3 (x, 4 (x)] - (1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl) - acetic acid; I R- (1OÍ, 3 (x, 4cx)] - (1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; IS- (1X, 3a, 4 (x) ] - (1-Amomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; IR- (1a, 3X, 4 (x)] - (1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl) )-acetic acid; S-cis (1-Aminomethyl-l-3-methyl-cyclopentyl) -acetic acid; S-cis (1-Aminomethyl-l-3-ethyl-cyclopentyl) -acetic acid; S-cis (1-Aminomethyl-l-3-isopropyl-cyclopentyl) -acetic acid; S-cis (1-Aminomethyl-l-3-tert-butyl-cyclopentyl) -acetic acid; S-cis (1-Aminomethyl-l-3-phenyl-cyclopentyl) -acetic acid; S-cis (1-Aminomethyl-l-3-benzyl-cyclopentyl) -acetic acid; R-cis (1-Aminomethyl-l-3-methyl-cyclopentyl) -acetic acid; R-cis (1-Aminomethyl-l-3-ethyl-cyclopentyl) -acetic acid; R-cis (1-Aminomethyl-l-3-isopropyl-cyclopentyl) -acetic acid; R-cis (1-Aminomethyl-l-3-isopropyl-cyclopentyl) -acetic acid; R-cis (1-Aminomethyl-l-3-tert-butyl-cyclopentyl) -acetic acid; R-cis (1-Aminomethyl-l-3-phenyl-cyclopentyl) -acetic acid; R-cis (1-Aminomethyl-3-benzyl-cyclopentyl) -acetic acid; S) - (1-Aminomethyl-3,3-dimethyl-cyclopentyl) -acetic acid; S) - (1-amino-methyl-3,3-diethyl-cyclopentyl) -acetic acid; 1-Aminomethyl-3,3,4,4-tetramethyl-cyclopentyl) -acetic acid; 1-Ammonomethyl-3,3,4,4-tetraethyl-cyclopentyl) -acetic acid; 1o., 3, 4) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid; 1cx, 3, 4) - (1-Aminomethyl-3,4-d.ethyl-cyclopentyl) -acetic acid; 1 < x, 3, 4 HI-Aminomethyl-S ^ -diisopropyl-cyclopentyl-acetic acid; 1 R- (1 (x, 3, 4)] - (1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1tx, 3, 4)] - (1-Aminomethyl-3) -ethyl-4-methyl-cyclopentyl) -acetic acid; 1 R- (1tx, 3, 4)] - (1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1o) (, 3, 4)] - (1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; 1R- (1 (x, 3, 4)] - (1-Aminomethyl-3-ethyl-4) -isopropyl-cyclopentyl) -acetic acid; 1S- (1a, 3, 4)] - (1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1R- (1 (X, 3, 4)] - (1-Aminomethyl-3-tert-butyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1 &x;, 3, 4)] - (1-Aminometl-3-) tert-butyl-4-methyl-cyclopentyl) -acetic acid; 1R- (1a, 3, 4)] - (1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1S- (1o, 3, 4)] - (1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1 R- (1a, 3, 4)] - (1-Aminomethyl-3) -tert-butyl-4-isopropyl-cyclopentyl) -acetic acid 1S- (1a, 3, 4)] - (1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid 1 < x, 3, 4 HI-Aminomethyl-S ^ -d i-tert-butyl-cyclopentyl-acetic acid; 1R- (1 (x, 3, 4)] - (1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; 1R- (1 (x, 3, 4)] - (1-Aminomethyl- 3-benzyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1? (, 3, 4)] - (1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; -trans) - (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-Aminomethyl-3-ethyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-Aminomethyl) -3-isopropyl-cyclopentyl) -acetic acid; (1 R-trans) - (1-amino-methyl-3-tert-butyl-cyclopentyl) -acetic acid; (1 R-trans) - (1-Aminomethyl-3-pheny-cyclopentyl) -acetic acid; (1 R-trans) - (1-Aminomethyl-3-benzyl-cyclopentyl) -acetic acid; (1S-trans) - (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid; (1 S-trans) - (1-Aminomethyl-3-etl-cyclopentyl) -acetic acid; (1S-trans) - (1-amino-methyl-3-isopropy-cyclopentyl) -acetic acid; (1S-trans) - (1-Aminomethyl-3-tert-butyl-cyclopentyl) -acetic acid; (1S-trans) - (1-Aminomethyl-3-phenyl-cyclopentyl) -acetic acid; (1 S-trans) - (1-Aminomethyl-3-benzyl-cyclopentyl) -acetic acid; (R) - (1-Aminomethyl-3,3-dimethyl-cyclopentyl) -acetic acid; (R) - (1-Aminomethyl-3,3-diethyl-cyclopentyl) -acetic acid; cis- (1-Aminomethyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-ethyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-benzyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-etl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-tert-butyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Ammonomethyl-3-benzyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-ethyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Am'nomethyl-3-isopropyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-benzyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-ethyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-isopropyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-benzyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-ethyl-3-phenyl-cyclobutyl) -acetic acid; Cis- (1-Aminomethyl-3-benzyl-3-ethyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-ethyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-benzyl-3-ethyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-Amomethyl-3-tert-butyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl) -acetic acid; 1-Ammonomethyl-3,3-dimethyl-cyclobutyl) -acetic acid; 1-Aminomethyl-3,3-diethylcyclobutyl) -acetic acid; 1-Aminomethyl-3,3-diisopropyl-cyclobutyl) -acetic acid; 1-amino-methyl-3,3-di-tert-butyl-cyclobutyl) -acetic acid; 1-Aminomethyl-3,3-diphenyl-cyclobutyl) -acetic acid; 1-Ammonomethyl-3,3-dibenzyl-cyclobutyl) -acetic acid; 1-Aminomethyl-2,2,4,4-tetramethyl-cyclobutyl) -acetic acid; 1-amino-methyl-2,2,3,3,4,4-hexamethyl-cyclobutyl) -acetic acid; R) - (1-amino-methyl-2,2-dimethyl-cyclobutyl) -acetic acid; S) - (1-Aminomethyl-2,2-dimethyl-cyclobutyl) -acetic acid; 1 R-cis) - (1-Aminomethyl-2-methyl-cyclobutyl) -acetic acid; 1 R- (1 (x, 2o (, 3o.)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; 1 (x, 2o., 4o.) - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; 1 R- (1a, 2a, 3)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; 1 < x, 2oc, 4ß) - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; 1 S-trans) - (1-amino-methyl-2-methyl-cyclobutyl) -acetic acid; 1S- (1 (x, 2, 3)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; 1a, 2, 4) - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; 1S- (1o, 2, 3a)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; 1X, 2, 4 < x)] - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; 1 R-trans) - (1-Aminomethyl-2-methyl-cyclobutyl) -acetic acid; [1R- (1 (x, 2, 3)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; [1 R- (1? (, 2, 4)] - (1-Aminomethyl) -2-ethyl-4-methyl-cyclobutyl) -acetic acid; [1R- (1a, 2, 3 «)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; (1 (X, 2, 4 (x) - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; (1S-cis) - (1-Aminomethyl-2-methyl-cyclobutyl) -acetic acid; (1a, 2 (x, 3o.)] - (1-Amomethyl-2,3-dimethylcyclobutyl) -acetic acid; [1S- (1 (x, 2 (X, 3 (x )] - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; [1S- (1 (x, 2ß, 3 (x)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) - acetic acid; (1tx, 2 (x, 4ß) - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) - acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-diethyl-cyclopentyl) -acetic acid; 3R, 4R) - (1-Aminomethyl-3,4-diethyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-diisopropyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-diisopropyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-amino-methyl-3,4-di-tert-butyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-diphenyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-diphenyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3) 4-dibenzyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-dibenzyl-cyclopentyl) -acetic acid; [1 S- (1 oe, 3a, 4ß)] - (1-amino-methyl-3-methyl-4-eti-cyclopentyl) -acetic acid; [1 R- (1 o., 3β, 4 (x)] - (1-Aminomethyl-3-methyl-4-ethyl-cyclopentyl) -acetic acid; [1 R- (1 (x, 3 (X , 4ß)] - (1-Aminomethyl-3-methyl-4-etl-cyclopentyl) -acetic acid; -Aminometi -3-methyl-4-ethyl-cyclopentyl) -acetic acid; -Amethyl-3-methyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomet: • 3-methyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminometi • 3-methyl-4-isopropyl-cyclopentyl) -acetic acid; -Amethyl 3-methyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminometi -3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminometi 3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminomet 3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminometi -3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminometi -3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomet -3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomet -3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomet -3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomet -3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminometi -3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminomet -3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminomet -3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminometi -3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomet -3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomet -3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomet -3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; -Aminomethyl -3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; -Aminometi -3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1 - . 1-amino-methyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1-Aminomethyl-3-ethyl-4-phenyl-cyclopentyl) -acetic acid; 1-Aminomethyl-3-etl-4-phenyl-cyclopentyl) -acetic acid; 1-amino-methyl-3-ethyl-4-phenyl-cyclopentyl) -acetic acid; 1-amino-methyl-3-ethyl-4-phenyl-cyclopentyl) -acetic acid; 1-amino-methyl-3-benzyl-4-ethyl-cyclopentyl) -acetic acid; 1-amino-methyl-3-benzyl-4-ethyl-cyclopentyl) -acetic acid; 1-amino-methyl-3-benzyl-4-ethyl-cyclopentyl) -acetic acid; 1-amino-methyl-3-benzyl-4-ethyl-cyclopentyl) -acetic acid; 1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid 1 R- 1a, 3ß, 4? () - 1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acid acetic acid 1R-1a, 3 (X, 4ß)] - 1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid IS1o., 3β, 4 < x)] - 1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid IS-1 < x, 3 < x, 4ß)] - 1-amino-methyl-3-isopropyl-4-phenyl-cyclopentyl) -acetic acid; 1R- 1 (x, 3ß, 4 < x)} 1-Methyl-methyl-3-isopropyl-4-phenyl-cyclopentyl) -acetic acid; 1 R-l a.S ß)] - 1 -Aminomethyl-3-isopropyl-4-phenyl-cyclopentyl) -acetic acid; IS1 (X, 3β, 4? ()] - 1 -Aminomethyl-3-isopropyl-4-phenyl-cyclopentyl) -acetic acid; IS- 1 o., 3 < x, 4ß)] - 1-amino-methyl-3-benzyl-4-isopropyl-cyclopentyl) -acetic acid; 1R- 1o., 3ß, 4 < x)] - 1-amino-methyl-3-benzyl-4-isopropyl-cyclopentyl) -acetic acid; 1 R- 1o., 3oc, 4ß)} 1-amino-methyl-3-benzyl-4-isopropy-cyclopentyl) -acetic acid; 1 S- (1a, 3ß, 4a)} (1-Aminometi I-3-benzyl-4-isopropyl-cyclopentyl) -acetic acid; 1S- (1 a, 3a, 4ß)] H (1-amino-methyl-l-3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1R- (1 <x, 3β, 4 <x)] - (1-amino-methyl-3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1 R- (1o, 3a, 4ß) J (1-Aminomet 3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1S- (1a, 3β, 4a)] - (1 -Aminomet l-3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1 R- (1 a, 3 a, 4 b)] (1-amino-methyl-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1S- (1 (x, 3β, 4 (x).}. (1-amino-methyl-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1S- (1a, 3a, 4ß)} (1-Aminomet l-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1 R- (1 (X, 3β, 4 (x)] - (1-amino-methyl-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1S- (1 <x, 3o, 4ß)] - (1-amino-methyl-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1 R- (1a, 3ß, 4a)] -? (1-amino-methyl-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1 R- (1a, 3a, 4ß)} (1-Aminomet l-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1S- (1al3ß, 4a)} (1-Aminomet l-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1 R-cis) - (1-amino-methyl-2-methyl-cyclopentyl) -acetic acid; 1S-cis) - (1-Aminomethyl-2-met-cyclopentyl) -acetic acid; (1 R-trans) - (1-Aminomethyl-2-methyl-cyclopentyl) -acetic acid; (1 S-trans) - (1-Aminomethyl-2-methyl-cyclopentyl) -acetic acid; (R) - (1-amino-methyl-2,2-dimethyl-cyclopentyl) -acetic acid; (S) - (1-Methyl-methyl-2,2-dimethyl-cyclopentyl) -acetic acid; (1-Aminomethyl-2,2,5,5-tetramethyl-cyclopentyl) -acetic acid; (1a, 2, 5) - (1-Aminomethyl-2,5-dimethyl-cyclopentyl) -acetic acid; (2R, 5R) - (1-Aminomethyl-2,5-dimethyl-cyclopentyl) -acetic acid; (2S, 5S) - (1-amino-methyl-2,5-dimethyl-cyclopentyl) -acetic acid; (1 < x, 2 < x, 5 < x) - (1-amino-methyl-2,5-dimethyl-cyclopentyl) -acetic acid; [1R (1st, 2nd, 3rd.)} (1-Aminometi • 2,3-dimethyl-cyclopentyl) -acetic acid; [1R (1 (X, 2β, 3o ()] - (1-Aminomethyl-2,3-dimethyl-cyclopentyl) -acetic acid; [1 R (1 (x, 2c., 3β)] - (1 -Aminometi -2,3-dimeti l-cyclopentyl) -acetic acid; [1 R (Kx, 2β, 3β)] - (1-amino-2-dimethyl-1-cyclopentyl) -acetic acid; - (1 (X, 2oc, 3o <)) - (1 -Aminometi • 2,3-dimeti-l-cyclopentyl) -acetic acid; [1S- (1 a, 2ß, 3? ()] - (1 -Aminometi-2,3-dimethyl-cyclopentyl) -acetic acid; [1S- (1 a, 2o., 3ß)] - (1-amino-methyl-2,3-dimethyl-cyclopentyl) -acetic acid; [1S- (1 <x, 2ß, 3ß)] - (1-amino-methyl-2,3-dimethyl-cyclopentyl) -acetic acid; [1 R (1 (x, 2a, 4a)] - (1 -Aminometi-2,4-dimethyl-cyclopentyl-1-acetic acid; [1S- (1a, 2o, 4 (x)] - (1-Aminomethyl-2,4-dimethyl-cyclopentyl) -acetic acid; [IR (1", 2ü, 4ß). (1-Aminomethyl-2,4-dimethyl-cyclopentyl) -acetic acid; EIS (1 &x;, 2o., 4ß)] - (1-Aminomethyl) 2,4-dimethyl-cyclopentyl) -acetic acid; [1 R- (1 (X, 2β, 4 (x).}. (1-Aminomethyl-2,4-dimethyl-cyclopentyl) -acid acetic; [1S - (1 <x, 2ß, 4 (x)] - (1-Aminomethyl) 2,4-dimethyl-cyclopentyl) -acetic acid; [1R (1 <x, 2ß, 4ß)] - (1-amino-methyl-2,4-dimethyl-cyclopentyl) -acetic acid; [1 S - (1o, 2β, 4β)] - (1-amino-methyl-2,4-dimethyl-cyclopentyl) -acetic acid; Certain intermediates are useful in the preparation of the compounds of the invention: (trans) - (3,4-Dimethyl-cyclopentyl-ene) -ester ethyl-acetic acid; (trans) - (3,4-Dimethyl-1-nitromethyl-cyclopentyl) -acetic acid; (±) - (trans) -7,8-Dimethyl-spiro [4,4] nonane-2-one; (l-Nitromethyl-cyclobutyl) -ester ethyl acetic acid; (cis / trans) - (3R) - (3-Methyl-nitromethyl-cyclopentyl) -ester ethyl acetic acid; (cis / trans) - (7R) -Methyl-spiro [4,4] nonane-2-one; (cis) - (3,4-Dimethyl-cyclopentyl-ene) -ester ethyl acetic acid; (trans) -3,4-Dimethyl-1-nitromethyl-cyclopentyl) -ester ethyl acetic acid; (trans) -7,8-Dimethyl-spiro [4,4] nonane-2-one; (3-Benzyl-cyclobutyl-diene) -ester ethyl acetic acid; and (cis / trans) - (3-Benzyl-1-nitromethyl-cyclopentyl) -ester ethyl acetic acid. The term "lower alkyl" is a long or branched chain group of 1 to 4 carbons. The term "alkyl" is a long or branched chain group of 1 to 6 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, except when it is established otherwise. The benzyl and phenyl groups can be substituted or unsubstituted by 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy, halogen, CF3, nitro, alkyl and alkoxy. Halogens are preferred. Since the amino acids are pharmacologically compatible amphoteric salts when R is hydrogen, they can be salts of organic and inorganic acids, for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, acid salicylic acid, malonic acid, maleic acid, succinic acid, methanesulfonic acid and ascorbic acid. They are formed starting from the corresponding hydroxides or carbonates, the salts with alkali metals or other alkaline earth metals, for example, sodium, potassium, magnesium or calcium. 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 in solvated forms, including hydrated forms. In general, solvated forms including hydrated forms are equivalent to unsolvated forms and are included 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 epimeric and enantiomeric forms as well as appropriate mixtures thereof.
METHODS AND MATERIALS Animals Male Sprague-Dawley rats (180-250 g) were obtained from Bantin and Kingman, (Hull, G.B.). The animals were housed in groups of 6 to 10 in a light / dark cycle of 12 hours (lights on for 7 hours, 0 minutes) with food and water ad libitum.
Induced Thermal Hyperalgesia-Carrageenan in the Rat Thermal hyperalgesia was determined using the plantar test for rats (Ugo Basile, Italy) following a modified method of Hargreaves, et al., 1988. The rats were habituated to the apparatus which consisted of three boxes of individual perspex on a raised glass table. A radial heat source movable under the table was fixed in the desired leg and leg withdrawal dormant states (PWL) were recorded. The PWL was taken 3 times on both hind legs of each animal, the average of which represented the normal conditions for the right and left hind legs. At least 5 minutes were left between each PWL for an animal. The apparatus was calibrated to provide a PWL of approximately 10 s. There was an automatic closing point of 20 s to prevent tissue damage. After the normal PWLs were determined, the animals received an intraplantar injection of carrageenan (100 μL of 20 mg / ml) in the right hind paw. The PWL were re-determined following the same protocol as the previous one, 2-hours after carrageenan (this time represented the beginning of maximum hyperalgesia) to find out that hyperalgesia has developed. The test compounds were administered orally (in a volume of 1 ml / kg) in 2.5 hours after the carrageenan. The PWL were redetermined several times after the administration of the drug.
An Anticonvulsant Efficiency Model and the Protocol for the DBA2 Test: Prevention of Audiogenic Access in DBA / 2 Mice Methods All procedures were carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals under a protocol approved by the Parke-Davis Committee for the Use of Animals. Male DBA / 2 mice, 3 to 4 weeks old, were obtained from Jackson Laboratories, Bar Harbor, ME. Immediately before the anticonvulsive test, the mice were placed inside a wire mesh, a 10.16 cm2 square suspended from a steel bar. The picture was slowly inverted by 180 degrees and the mice were observed for 30 seconds. Any mouse that fell from the wire mesh was marked as ataxic. The mice were placed inside an enclosed plastic acrylic chamber (21 cm in height, approximately 30 cm in diameter) with a high frequency microphone (4 cm in diameter) in the center of the top cover. An audio signal generator (Protek model B-810) was used to produce a continuous sinusoidal tone that was linearly swept at a frequency between 8 kHz and 16 kHz once every 10 msec. The average sound pressure level (SPL) during the stimulation was approximately 100 dB on the floor of the chamber. The mice were placed inside the chamber and allowed to acclimate for 1 minute. The DBA / 2 mice in the sample group responded to the sound stimulus (applied until the tonic extension occurred, or for a maximum of 60 seconds) with a characteristic access sequence consisting of a wild stroke followed by clonal accesses and later by tonic extension and finally by respiratory arrest and death in more than 80% of the mice. In the mice shown, the total sequence of respiratory arrest accessions lasted approximately 15 to 20 seconds. The incidence of all access phases in the mice sample treated with drugs was recorded and the occurrence of tonic accesses was used to calculate ED50 anticonvulsant values by probity analysis. The mice were used only once per test at each dose point. Groups of DBA / 2 mice (n = 5-10 per dose) were tested for the measurement of sound-induced access responses in 2 hours (previously determined maximum effect time) then given orally. All the drugs of the present study were dissolved in distilled water and provided by forced oral feeding in a volume of 10 ml / kg of body weight, the compounds that were insoluble were suspended in 1% carboxymethocellulose. The doses are expressed as half the weight of the active drug.
Results The dose-dependent suppression of sound-induced tonic accesses in DBA / 2 mice was tested and the corresponding ED50 values are shown in Table 1. The present results show that compounds of the invention administered orally cause dose-related anticonvulsant effects in an exhaustion susceptible to the sound of the mice (DBA / 2), according to the previous data showing the anticonvulsive activity in other models of experimental epilepsy. The effective doses of the drugs in this model are lower than those in the maximum electroshock test, confirming that the DBA / 2 mice are a sensitive model for the detection of anticonvulsant actions.
TABLE 1 Mice Thermal Hyperalgesia Induced by Audiogenic Carrageenan in Rat DBA / 2 Compound Structure ICso (μM)% MPEa 1 hr% MPEa 2 hr% Protected 1 In the postdose site @ postdose @ hr postdose link o ^ d 30 mg / kg PO 30 mg / kg PO 30 mg / kg PO (±) - (trans) - (1- 0.034 23 72 100 Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid hydrochloride (+) - (trans) - (1- 0.022 109 118 100 Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid hydrochloride (-) - (transMI- HCl-HjN 1.0 Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid hydrochloride (cis / trans) - (3R) - HCI-H2N C02H 0.088 67 53 100 (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid hydrochloride TABLE 1 (continued) Mice Thermal Hyperalgesia Induced by Audiogenic Carrageenan in Rat DBA / 2 Compound Structure IC50 (μM)% MPEa 1 hr% MPEa 2 hr% Protected 1 On the site of postdose @ postdose @ hr postdose link to? D 30 mg / kg PO 30 mg / kg PO 30 mg / kg PO (trans) - (1- HCl H2N 82H 0.154 -7 -2 100 Aminomethyl-3,4-dimethyl-cyclopentyl) - acetic acid hydrochloride (1-Aminomethyl-HC 1 H 2 N CO H 0.598 4 4 20 (2 hours cyclobutyl) - postdose) acetic acid hydrochloride (cis / trans) - (1 - HCl H2 2H > 10 0 0 not tested Aminomethyl-3-benzyl-cyclobutyl) - acetic acid hydrochloride MPE: maximum possible effect - established as a normal value before treatment with carrageenan.
The radioligand binding test was used using gabapentin [3H] and the subunit (x2d derived from porcine brain tissue ("The Novel Anti-convulsant Drug, Gabapentin to the (x2d Subunit of a Calcium Channel", Gee N. et al. J. Biological Chemistry, in press.) Compounds of the invention show good binding affinity to the subunit (x2d) Gabapentin (Neurontin®) is approximately 0.10 to 0.12 μM in this test. the present invention also binds to the subunit, it is expected that they exhibit pharmacological properties comparable to gabapentin, for example, as agents for seizures, anxiety and pain.
The compounds of the invention are related to Neurontin®, an effective drug marketed for the treatment of epilepsy. Neurontin® is 1- (aminomethyl) -cyclohexane acetic acid of the structural formula It is also expected that the compounds of the invention are useful in the treatment of epilepsy. The present invention also relates to the therapeutic use of the mimetic compounds as agents for neurodegenerative disorders. Such neurodegenerative disorders are, for example, the disease of Alzheimer's, Huntington's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. The present invention also covers the treatment of acute brain injuries called neurodegenerative disorders. These include but are not limited to: stroke, brain trauma and asphyxia. Stroke refers to a cerebrovascular disease and can also be referred to as a cerebrovascular incident (CVA) and includes acute thromboembolic stroke. Stroke includes global and focal ischemia. Also included are cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia for example in a patient undergoing carotid endoarterectomy specifically or other vascular or cerebrovascular surgical procedures in general or vascular diagnostic procedures including cerebral angiography and the like. Other incidents are trauma to the head, dorsal spinal trauma or general damage of anoxia, hypoxia, hypoglycaemia, hypotension as well as similar damages observed during the events of embolism, hyperfusion and hypoxia. The present invention would be useful in a wide range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest and epileptic status. An empowered physician will be able to determine the administration of the methods of the present invention in the appropriate situation in which the subjects are susceptible to or at risk of, for example, stroke, as well as those suffering from the apoplexy. The compounds of the invention are also expected to be useful in the treatment of depression. Depression can be the result of an organic disease, secondary to stress associated with personal or idiopathic loss by nature. There is a strong tendency for the familiar occurrence of some forms of depression that suggest a mechanical cause in at least some forms of depression. The diagnosis of depression is first made by quantifying the alterations of the patients' moods. These mood assessments are usually performed by a physician or quantified by a neuropsychologist using valid classification scales, such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Other scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty concentrating, lack of energy, feelings of low self-esteem and guilt. The standards for the diagnosis of depression as well as all psychiatric diagnoses are gathered in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) referred to as the DSM-IV-R manual published by the American Psychiatric Association, 1994. GABA is a neurotransmitter inhibitor of the central nervous system. Within the general context of inhibition, it appears that GABA-mimetics will decrease or inhibit brain function and therefore retard function and decrease the mood that leads to depression. The compounds of the present invention can produce an anticonvulsant effect by increasing the GABA created again in the synaptic junction. If gabapentin truly increases GABA levels or the effectiveness of GABA in the synaptic junction, then it could be classified as a GABA-mimetic and could decrease or inhibit brain function and could therefore slow down the function and decrease the mood that leads to the Depression. The fact that a GABA agonist or a mimetic GABA can work just in the opposite way by increasing mood and thus being an antidepressant, is a new concept, different from the prevailing opinion so far of GABA activity.
It is also expected that the compounds of the present invention are useful in the treatment of anxiety and panic as demonstrated by standard pharmacological procedures.
MATERIAL AND METHODS Induced hyperalgesia-Carrageenan Nociceptive pressure onset was measured in the rat paw pressure test using an analgesimeter (Randall-Sellito method: Randall LO, Sellito JJ, A method for mesurement of analgesic activity on inflamed tissue. Int. Pharmacodyn., 1957; 4: 409-419). Male Sprague-Dawley rats (70-90 g) were trained in this apparatus before the day of the test. The pressure was applied gradually to the hind paw of each rat and the nociceptive starts were determined as the pressure (g) required to achieve leg withdrawal. A closing point of 250 g was used to prevent any damage to the leg tissue. On the day of the test, two to three normal measurements were taken before the animals were given 100 μL of 2% carrageenan by intraplantar injection into the right hind paw. Again the nociceptive beginnings were taken for 3 hours after carrageenan to establish which animals exhibited hyperalgesia. The animals were dosed with gabapentin (3-300 mg / kg, sc), or morphine (3 mg / kg, sc) or saline in 3.5 hours after carrageenan and the nociceptive onset at 4, 4.5 and 5 was examined. post-carrageenan hours.
Induced Tonic Accesses - Semicarbazide Tonic accesses were induced in mice by subcutaneous administration of semicarbazide (750 mg / kg). The latent state was recorded to the tonic extension of the front legs. Any of the mice that were not convulsed in the 2.0 hours after semicarbazide were considered protected and provided a maximum latent marking of 120 minutes.
Animals Male Hooded Lister rats (200-250 g) from Interfauna were obtained (Huntingdon, GB) and male TO mice (20-25 g) were obtained from Bantin and Kingman (Hull, GB). Both species of rodents were housed in groups of six. Ten Common Tities (Callithrix Jacchus) were housed in pairs weighing between 280 and 360 g, bred at the Medical School of the University of Manchester (Manchester, GB). All the animals were housed in a cycle of 12 light / dark hours (lights lit by 07:00 hours) and with food and water ad libitum.
Drug Administration The drugs were administered either intraperitoneally (IP) or subcutaneously (SC) 40 minutes before the test in a volume of 1 ml / kg for rats and marmosets and 10 ml / kg for mice.
Light / Dark Box for Mice The device is a covered open box, 45 cm long, 27 cm wide and 27 cm high, divided into a small area (2/5) and a large area (3/5) by a division that extends 20 cm above the walls (Costall B., et al., Exploration of mice in a black and white box: validation as a model of anxiety, Pharmacol., Biochem. Behav., 1989; 32: 777- 785). There is an opening of 7.5 x 7.5 cm in the center of the division at ground level. The small compartment is painted black and the large compartment is white. The small compartment was illuminated by a 60-W tungsten bulb. The lab lit up with a red light. Each mouse was studied by placing it in the center of the white area and allowing it to explore the new environment for 5 minutes. The time consumed on the illuminated side was measured. (Kilfoil T., et al., Effects of anxiolytic and anxiogenic drugs on exploratory activity in a simple model of anxiety in mice, Neuropharmacol., 1989; 28: 901-905).
Raised X Maze for Rats A standardized high X-labyrinth was automated (Handley SL, et al., Effects of alpha-adrenoceptor agonist and antagonists, naze-exploration model of 'fear' - motivated behavior, Naunyn-Schiederberg's Arch. Pharmacol., 1984; 327: 1-5) as previously described (Field, et al., Automation of the rat elevated X-maze test of anxiety, Br. J. Pharmacol., 1991; 102 (Suppl): 304P). The animals were placed in the center of labyrinth X facing one of the open areas.
To determine the anxiolytic effects, the time at the entrances and exits of the intermediate sections of the open areas during the 5-minute test period was measured. (Costall, et al., Use of the elevated plus maze to asses anxiolytic potential in the rat, Br. J. Pharmacol., 1989; 96 (Suppl): 312P).
Human Threat Test for Titi The total number of bodily postures shown by the animal towards the threat stimulus (a human staying 0.5 m away from the marmoset cage and staring at the marmoset) was recorded during a test period of two minutes. Registered body postures are hair ruffling intervals, tail postures, cage marking / hooks by smell, erect positions, withdrawals, and bowing of the back. Each animal was exposed to the threat stimulus twice on the test day before and after treatment with the drug. The difference between the two marks was analyzed using the analysis of a variance path followed by the Dunnett test. All treatments were performed in the SC in at least 2 hours after the first threat (control). The pretreatment time for each compound is 40 minutes.
Rat Conflict Test The rats were trained to press levers for food rewards in operating chambers. The program consists of alterations of four 4-minutes of periods without punishment in variable intervals of 30 seconds indicated by the lights on in the camera and three 3-minutes of periods of punishment in a fixed radius 5 (by concomitant shock in the legs to delivery of food) indicated by the lights off of the camera. The degree of shock in the legs was adjusted for each rat to obtain approximately 80% to 90% suppression of the response compared to the response without punishment. The rats received saline vehicles on training days.
The compounds of the present invention are also expected to be useful in the treatment of pain and phobic disorders. { Am. J. Pain Manag., 1995; 5: 7-9). It is also expected that the compounds of the present invention are useful in the treatment of symptoms of acute or chronic mania, simple, or recurrent disorders. They are also expected to be useful in the treatment and / or prevention of bipolar disorders (U.S. Patent Number ,510,381).
Models of Irritable Bowel Syndrome Induced Chronic Visceral Allodynia-TNBS in Rats Trinitrobenzene sulphonic injections (TNBS) in the colon have been found to induce chronic colitis. In humans, digestive disorders are frequently associated with visceral pains. In these pathologies, the onset of visceral pain decreases indicating a visceral hypersensitivity. Consequently, this study was designed to evaluate the effect of TNBS injection on the colon at the onset of visceral pain in an experimental model of colon distension.
Materials and Methods Animals and surgery Male Sprague-Dawley rats (Janvier, Le Genest-St-llse, France) weighing 340-400 g were used. The animals were housed 3 per cage in a regulated environment (20 ± 1 ° C, 50 ± 5% humidity, with light from 8:00 am to 8:00 pm). Under anesthesia (ketamine 80mg / kg ip, acepromazine 12 mg / kg p), the injection of TNBS (50 mg / kg) or saline (1.5 ml / kg) was performed in the proximal colon (1 cm from the cecum) . After the surgery, the animals were housed individually in polypropylene cages and kept in a regulated environment (20 ± 1 ° C, 50 ± 5% humidity, with light from 8:00 am to 8:00 pm) during 7 days.
Experimental procedure On the 7th day after administration of TNBS, a balloon (5-6 cm in length) was inserted through the anus and held in place (the tip of the balloon, 5 cm from the anus) attaching the catheter to the base of the tail. The balloon was inflated progressively by the passage of 5 mm Hg, from 0 to 75 mm Hg, each stage of inflation lasted 30 seconds. Each cycle of colon distension was controlled by a standard barostat (ABS, St-Dié-France). The onset corresponds to the pressure produced by the first abdominal contraction and then the distension cycle was discontinued. The colonic onset (pressure expressed in mm Hg) was determined after performing the four cycles of distension in the same animal.
Determination of compound activity The data were analyzed by comparing the group treated with test compounds with the group treated with TNBS and the control group. The mean and the proportional mean were calculated for each group. The antialodynamic activity of the compound was calculated as follows: Activity (%) = (group C - group T) / (group A - group T) Group C: mean of the colonic onset in the control group Group T: mean of the colonic onset in the group treated with TNBS Group A: mean of the colonic onset in the group treated with test compounds Statistical analysis The statistical significance between each group was determined by using ANOVA of a path followed by the Student's odd t-test. The differences were considered statistically significant in p < 0.05.
Compounds The TNBS was dissolved in 30% EtOH and injected under a volume of 0.5 ml / rat. The TNBS was purchased in Fluka. Oral administration of the test compound or its excipient was performed 1 hour before the colon distention cycle. The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention may be administered by injection, which may be intravenous, intramuscular, intracutaneous, subcutaneous, intraduodenal or intraperitoneal. Also, the compounds of the present invention can be administered by inhalation, for example intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be apparent to those skilled in the art that the following dosage forms may comprise as the active compound either a compound of Formula 1 or 1A or a pharmaceutically acceptable salt of a corresponding compound of Formula 1 or 1A. For the preparation of the pharmaceutical compositions of the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, caches, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In the powders, the carrier is a finely divided solid that is mixed with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and is compacted in the desired shape and size. The powders and tablets preferably contain from five to ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low-grade wax. melting point, cocoa butter, and the like. The term "preparation" includes the formulation of the active compound with the encapsulating material as a carrier that provides a capsule in which the active compound with or without other carriers is surrounded by a carrier, which is thus in association with the carrier. Similarly, cachets and pills are included. It includes tablets, powders, capsules, pills, cachets and pills. Tablets, powders, capsules, pills, cachets and pills can be used as solid dosage forms suitable for oral administration. For the preparation of suppositories, a low-melting wax is first melted, such as a mixture of fatty acids and glycerides or cocoa butter and the active compound is dispersed homogeneously therein by stirring. Subsequently, the homogeneous mixture dissolved in molds of suitable size is added, to cool down and thereby solidify. Liquid form preparations include solutions, suspensions and emulsions, for example water or propylene glycol water solutions. Liquid preparations for parenteral injection can be formulated in aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with a viscous material, such as synthetic or natural gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Also included are solid form preparations which are intended to be converted to liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active compound, colorants, flavors, stabilizers, buffers, natural and artificial sweeteners, dispersants, thickeners, solubility agents and the like. It is preferred that the pharmaceutical preparation be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dose form can be a packaged preparation, the package contains discrete quantities of the preparation, such as packed tablets, capsules and powders in small vials or ampoules. Also, the unit dosage form can be a capsule, a tablet, cachet or a tablet by itself, or it can be the appropriate number of any of these in packaged form. The amount of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 1 g according to the particular application and potency of the active component. In medical use the drug can be administered three times a day, as for example, capsules of 100 or 300 mg. The composition may, if desired, also contain other compatible therapeutic agents. In therapeutic use, the compounds used in the pharmaceutical method of this invention were administered in an initial dose of about 0.01 mg to about 100 mg / kg daily. A range of about 0.01 mg to about 100 mg / kg was preferred. The doses, however, can vary depending on the requirements of the patient, the severity of the condition to be treated and the component used. The determination of the appropriate dose for a particular situation is within the reach of the person skilled in the art. Generally, treatment starts with smaller doses that are less than the optimal dose of the compound. After this, the dose was increased in small increments until the optimum effect was reached under the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day, if desired.
Composite General Synthetic Models 1A wherein R1-R14 can be independently selected from: hydrogen, long or branched chain alkyl of 1 to 6 carbon atoms, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, -OR15, in where R15 can be long or branched chain alkyl of 1 to 6 carbon atoms, phenyl or benzyl, -C02H, C02R15, -CH2C02H, -CH2C02R15. R1-R8 may not be hydrogen in its entirety and may be made by the following methods. Both 4 and 5-membered ring compounds can be synthesized by means subsequently established for the 5-membered ring system. The claimed compounds can be synthesized, for example, by the use of the general strategy (General Scheme 1) indicated by G. Griffiths et al., Helv. Chim. Acta, 1991; 74: 309. Alternatively, they can also be processed as shown (General Scheme 2), analogous to the procedure published by the synthesis of 3-oxo-2,8-diazaspiro [4,5] decane-8-carboxylic ester-tert-butyl ester (PW Smith et al. al., J. Med. Chem., 1995; 38: 3772). The compounds can also be synthesized by the methods set forth by G. Satzinger et al., (Ger Offen 2,460,891, E.U.A. 4,024,172 and Ger Offen 2,311, 690, E.U.A. 4,152,326) (General Schemes 3 and 4). The compounds can also be synthesized by the route indicated by G. Griffiths et al., Helv. Chim. Acta, 1991; 74: 309 (General Scheme 5).
General Scheme 1 (i) Ethyl cyanoacetate, piperidine (COPE et al., J. Am. Chem. Soc, 1941; 63: 3452); (ii) NaCN, EtOH / H20; (iii) EtOH, HCl; (iv) H20 / H +; (v) H2, Rh / C, MeOH; (vi) HCl.
General Scheme 2 (i) Ph3P = CHC02Me; (ii) MeN02, 1, 1, 3,3-tetramethylguanidine; (Ii) Raney nickel, EtOH / H20; (V) HCl.
General Scheme 3 (i) Ethylcyanoacetate, ammonia subsequently H30 +; (¡I) H2S0; (iii) AC20; (iv) MeOH; (v) The Curtius reaction; (vi) HCl, H20 after anion exchange.
General Scheme 4 (i) Ethylcyanoacetate, ammonia subsequently H30 +; (¡I) H2S04; (iii) AC20; (V) H2NOH; (v) PhS02CI; (vi) Et 3 N, MeOH; (vii) HCl, H20 subsequently anion exchange.
General Scheme 5 (i) Ethyl cyanoacetate, piperidine (Cope et al., J. Am. Chem. Soc, 1941; 63: 3452); (ii) NaCN, EtOH / H20; (iii) BnOH, HCl; (iv) H20 / H +; (v) H2, Rh / C, MeOH. The following examples are illustrative of the present invention; but they do not intend to limit its scope. In Examples 1 to 8, the first step involves the conversion of a cyclic ketone to an unsaturated ester α, β via a trialkylphosphonoacetate or a (alkoxycarbonylmethyl) triphenylphosphonium halide and a base, such as sodium hydride, potassium hydride, potassium or sodium or lithium hexamethyldisilazide, potassium t-butoxide or butyl lithium in a solvent such as tetrahydrofuran, dimethylfomamide, diethylether or dimethylsulfoxide at an appropriate temperature in a range from -78 ° C at 100 ° C. The second stage involves the reaction of unsaturated ester 2, β with nitromethane and an appropriate base such as tetrabutylammonium fluoride, tetramethylguanidine, 1,5-diazabicyclo [4.3.0] non- 5-ene, 1, 8-diazabicyclo [5.4.0] undec-7-ene, a potassium or sodium alkoxide, sodium hydride or potassium fluoride in a solvent such as tetrahydrofuran, diethylether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, dichlorome the chloroform or the tetrachloromethane at an appropriate temperature in the range from -20 ° C to 100 ° C.
The third stage involves the catalytic hydrogenation of half of the present amount of nitro of 3 using a catalyst such as Raney nickel, palladium on carbon or a rhodium catalyst or another catalyst containing palladium or nickel in a solvent such as methanol, ethanol , Sopropanol, ethyl acetate, acetic acid, 1,4-dioxane, chloroform or diethyl ether at an appropriate temperature in the range from 20 ° C to 80 ° C. The fourth stage involves the hydrolysis of lactam 4 using hydrochloric acid and can also use a co-solvent such as tetrahydrofuran or 1,4-dioxane or another inert solvent miscible in water at an appropriate temperature in the range from 20 ° C to reflux.
EXAMPLE 1 Reagents: (i) Triethylphosphonoacetate, NaH; (ii) MeN02, Bu4N + F "; (iii) H2, Ni; (iv) HCl Synthesis of (trans) - (3,4-Dimethyl-cyclopentyl-ene) -ester ethyl-acetic acid (2) NaH (60% dispersion) in oil, 737mg, 18.42 mmol) was suspended in dry tetrahydrofuran (50 mL) and cooled to 0 ° C. Triethylphosphonoacetate (3.83 mL, 19.30 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. Ketone (1) (1965 g, 17.54 mmol) in THF (10 mL) was subsequently added and the mixture was warmed to room temperature.After 2 hours, the mixture was partitioned between diethyl ether (200 mL) and water (150 mL). The organic phase was separated, washed with brine, dried (MgSO) and the solvent was removed in vacuo The residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 9) to give 3.01 g. (94%) of (2) as a colorless oil.1H NMR 400 MHz (CDCL3): d 1.01 (3H, d, J = 6 Hz), 1.03 (3H, d, J = 6 Hz), 1.26 (3H, t, J = 7 Hz), 1.49 (2H, m), 2.07 (1H, m), 2.24 (1H, m), 2.61 (1H, m), 4.13 (2H, q, J = 7 Hz), 5.72 (1 H, s) MS (CI + m / e: 183 ([MH +], 18%).
Synthesis of (trans) - (3,4-Dimethyl-1-nitromethyl-cyclopentyl) -ester ethyl acetic acid (3) The unsaturated ester (2) (2.95 g, 16.2 mmol) was dissolved in tetrahydrofuran (10 ml) and it was stirred at 70 ° C with nitromethane (1.9 ml, 35.2 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 22 ml, 22.0 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and washed with 2N HCl (30 ml) followed by brine (50 ml). The organic phase was collected, dried (MgSO) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 9) to give 1152 g (29%) of a clear oil. 1 H NMR 400 MHz (CDCl 3): d 0.98 (6H, d, J = 6 Hz), 1.10-1.39 (5H, m), 1.47 (2H, m), 1.87 (1H, m), 2.03 (1H, m) , 2.57 (2H, ABq, J = 16, 38 Hz), 4.14 (2H, q, J = 7 Hz), 4.61 (2H, ABq, J = 12, 60 Hz). MS (ES +) m / e: 244 ([MH +], 8%). IR (film) v cm-1: 1186, 1376, 1549, 1732, 2956.
Synthesis of (±) - (trans) -7,8-Dimethyl-spiro [4,4] nonane-2-one (4) Nitroster (3) (1.14 g, 4.7 mmol) was dissolved in methanol (50 ml) and stirred on a Raney nickel catalyst under a hydrogen atmosphere (40 psi) at 30 ° C. After 5 hours, the catalyst was removed by filtration through celite. The solvent was removed under vacuum to give 746 mg (95%) of a pale yellow oil which solidified. 1 H NMR 400 MHz (CDCl 3): d 0.98 (6H, d, J = 6 Hz), 1.32 (2H, m), 1.46 (2H, m), 1.97 (2H, m), 2.27 (2H, ABq, J = 16, 27 Hz), 3.23 (2H, s), 5.62 (1 H, br s). MS (ES +) m / e: 168 ([MH +], 100%). IR (film) v cm "1: 1451, 1681, 1715, 2948, 3196.
Synthesis of (±) - (trans) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid hydrochloride (5) The lactam (4) (734 mg, 4.40 mmol) was heated to reflux in a mixture of 1,4-dioxane (5 ml) and 6N HCl (15 ml). After 4 hours, the mixture was cooled to room temperature, diluted with water (20 ml) and washed with dichloromethane (3 x 30 ml). The aqueous phase was collected and the solvent removed in vacuo. The residue was triturated with ethyl acetate to give 675 mg (69%) of a white solid after collection and drying. 1 H NMR 400 MHz (d6-DMSO): d 0.91 (6H, d, J = 6 Hz), 1.18 (2H, m), 1.42 (2H, m), 1. 72 (1H, m) 1.87 (1H, m), 2.42 (2H, ABq, J = 16, 24Hz), 2.90 (2H, ABq, J = 12, 34 Hz), 8.00 (3H, br s), 12.34 (1H, br s). MS (ES +) m / e: 186 ([MH-H 100%).
EXAMPLE 2 Reagents: (i) Triethylphosphonoacetate, NaH; (ii) MeN02, Bu4N + F; (iii) H2, Ni; (iv) HCl Synthesis of the ethyl ester acetic acid - Cyclobutyldiene (2) NaH (60% dispersion in oil, 1.80 g, 44.94 mmol) was suspended in dry tetrahydrofuran (80 ml) and cooled to 0 ° C. Triethylphosphonoacetate (9.33 ml, 47.08 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. Subsequently, cyclobutanone (1) (3.0 g, 42.8 mmol) in THF (20 mL) was added and the mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 ml) and water (150 ml). The organic phase was separated, washed with brine and dried (MgSO), and the solvent was removed under vacuum at 600 mm Hg. The residue was purified by flash chromatography (silica, ethyl acetate: pentane 1:19) to give 5.81 g (96%) of (2) as a colorless oil. 1H NMR, 400 MHz (CDCL3): d 1.27 (3H, t, J = 6Hz), 2.09 (2H, m), 2.82 (2H, m), 3. 15 (2H, m), 4.14 (2H, q, J = 6 Hz), 5.58 (1H, s). MS (ES +) m / e: 141 ([MH "], 100%). IR (film) v crt? 1: 1088, 1189, 1336, 1673, 1716, 2926.
Synthesis of (l-Nitromethyl-cyclobutyl) ethyl ester acetic acid (3) The unsaturated ester (2) (5.79 g, 41.4 mmol) was dissolved in tetrahydrofuran (20 mL) and stirred at 70 ° C with nitromethane (4.67). mi, 86.4 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 55 mL, 55.0 mmol). After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (150 ml), and washed with 2N HCl (60 ml) followed by brine (100 ml). The organic phase was collected, dried (MgSO) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 1) to give 4.34 g (52%) of a clear oil. 1 H NMR 400 MHz (CDCl 3): d 1.27 (3 H, t, J = 6 Hz), 1.96-2.20 (6 H, m), 2.71 (2 H, s), 4.15 (2 H, q, J = 6 Hz), 4.71 (2H, s). MS (ES +) m / e: 202 ([MH +], 100%). IR (film) v cm "1: 1189, 1378, 1549, 1732, 2984.
Synthesis of (l-Aminomethyl-cyclobutyl) -acetic acid hydrochloride (4) Nitroster (3) (2095 g, 10.4 mmol) was dissolved in methanol (50 ml) and stirred on a Raney nickel catalyst under an atmosphere of hydrogen (45 psi) at 30 ° C. After 6 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 1.53 g of a pale yellow oil which was used without purification. The oil was dissolved in 1,4-dioxane (5 mL) and 6N HCl (15 mL) and heated to reflux. After 5 hours, the mixture was cooled to room temperature, diluted with water (20 ml) and washed with dichloromethane (3 x 30 ml). The aqueous phase was collected and the solvent removed in vacuo. The residue was triturated with ethyl acetate to give 1.35 g (72%) of a white solid after collection and drying. 1 H NMR 400 MHz (d6-DMSO): d 1.80-2.03 (6H, m), 2.59 (2H, s), 3.02 (2H, s), 8.04 (3H, br s), 12.28 (1 H, br s) . MS (ES +) m / e: 144 ([MH-HCl] "", 100%). The microanalysis calculated for C H? N02CI: C, 46.80%; H, 7.86%; N, 7.80%. Found: C, 46.45%, H, 7.98%; N, 7.71%.
EXAMPLE 3 otf? o2Et Reagents: (i) Triethylphosphonoacetate, NaH; (ii) MeNo2, Bu N + F; (iii) H2, Ni; (iv) HCl Synthesis of (R) - (3-Methyl-cyclopentyldiene) -acetic acid ethyl ester (2) NaH (60% dispersion in oil, 1.86 g, 46.5 mmol) was suspended in dry tetrahydrofuran (40 ml) and cooled to 0 ° C. Triethylphosphonoacetate (9.69 ml, 48.8 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. Then the ketone (1) (5 mL, 46.5 mmol) in THF (10 mL) was added and the mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 ml) and water (150 ml). The organic phase was separated, washed with brine, dried (MgSO) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 9) to give 5.45 g (70%) of (2) as a colorless oil. 1 H NMR 400 MHz (CDCl 3): d 1.04 (3H, m), 1.27 (3H, t, J = 7 Hz), 1.80-2.74 (7H, m), 2.90-3.15 (1H, m), 4.13 (2H, q, J = 7 Hz), 5.76 (1H, s). MS (CI +) m / e: 169 ([MH +], 20%). IR (film) v cm "1: 1205, 1371, 1653, 1716, 2955.
Synthesis of (cis / trans) - (3R) - (3-Methyl-1-nitromethyl-cyclopentyl) -ester ethyl-acetic acid (3) Unsaturated ester (2) (3.0 g, 17.8 mmol) was dissolved in tetrahydrofuran (20 ml) and stirred at 70 ° C with nitromethane (1.92 ml, 35.6 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 25 ml, 25.0 mmol). After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and washed with 2N HCl (30 ml) followed by brine (50 ml). The organic phase was collected, dried (MgSO) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 9) to give 2.00 g (49%) of a clear oil. 1 H NMR 400 MHz (CDCl 3): d 1.02 (3H, d, J = 6 Hz), 1.08-1.37 (5H, m), 1.59-2.17 (5H, m), 2.64 (2H, m), 4.15 (2H, q, J = 7 Hz), 4.64 (2H, m). MS (ES +) m / e: 230 ([MH +], 4%). IR (film) v cm "1: 1183, 1377, 1548, 1732, 2956.
Synthesis of (cis / trans) - (7R) -7-Methyl-spiro [4,4] nonane-2-one (4) Nitroster (3) (1.98 g, 8.66 mmol) was dissolved in methanol (50 ml) and was stirred over a Raney nickel catalyst under a hydrogen atmosphere (40 psi) at 30 ° C. After 18 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 1) to give 1.05 g (79%) of a white solid. 1 H NMR 400 MHz (CDCl 3): d 1.03 (3H, m), 1.22 (2H, m), 1.60-2.15 (5H, m), 2.22 (2H, m), 3.20 and 3.27 (2H total, 2 xs, cis and trans), 6.18 (1 H, br s). MS (ES +) m / e: 154 ([MH +], 100%). IR (film) v cm "1: 1695, 2949, 3231.
Synthesis of (cis / trans) - (3R) - (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid hydrochloride (5) Lactam (4) (746 mg, 4.88 mmol) was heated to reflux in a mixture of 1,4-dioxane (5 ml) and 6N HCl (15 ml). After 4 hours, the mixture was cooled to room temperature, diluted in water (20 ml) and washed with dichloromethane (3 x 30 ml). The aqueous phase was collected and the solvent removed in vacuo. The residue was triturated with ethyl acetate to give a white solid which was collected and dried. This was recrystallized from ethyl acetate / methanol to give 656 mg (65%) of (5) after collection and drying. 1 H NMR 400 MHz (d6-DMSO): d 0.96 (3H, m), 1.01-1.24 (2H, m), 1.42-2.10 (5H, m), 2.41 and 2.44 (2H total, 2 xs, cis / trans) , 2.94 (2H, m), 7.96 (3H, br s), 12.35 (1H, br s). MS (ES +) m / e: 172 ([MH-HCl) +, 100%).
EXAMPLE 4 Reagents: (i) Triethylphosphonoacetate, NaH; (ii) MeNO2, Bu N + F "; (iii) H2, Ni; (iv) HCl Synthesis of (cis) - (3,4-dimethyl-cyclopentyl-ene) -ester ethyl-acetic acid (2) NaH (60% dispersion in oil, 519 mg, 12.96 mmol) was suspended in dry tetrahydrofuran (30 ml) and cooled at 0 ° C. Triethylphosphonoacetate (2.68 ml, 13.5 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. Then the ketone (1) (1.21 g, 10.80 mmol) in THF (10 mL) was added and the mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 ml) and water (150 ml). The organic phase was separated, washed with brine, dried (MgSO 4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, 5:95 ethyl acetate: heptane) to give 1.40 g (71%) of (2) as a colorless oil. 1 H NMR 400 MHz (CDCl 13): d 0.84 (3 H, d, J = 6 Hz), 0.91 (3 H, d, J = 6 Hz), 1. 26 (3H, t, J = 7 Hz), 2.01-2.95 (6H, m), 4.13 (2H, q, J = 7 Hz), 5.76 (1H, s). MS (CI +) m / e: 183 ([MH +], 18%). IR (film) v cm "1: 1043, 1125, 1200, 1658, 1715, 2959.
Synthesis of (trans) - (3,4-D-methyl-1-nitromethyl-cyclopentyl) -ester ethyl acetic acid (3) Unsaturated ester (2) (1384 g, 7.60 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 70 ° C with nitromethane (0.82 mL, 15.2 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 11.4 mL, 11.4 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and washed with 2N HCl (30 ml) followed by brine (50 ml). The organic phase was collected, dried (MgSO 4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, 5:95 ethyl acetate: heptane) to give 0.837 g (45%) of a clear oil. 1H NMR 400 MHz (CDCL3): d 0.91 (6H, d, J = 6 Hz), 1.21-1.39 (5H, m), 1.98 (2H, m), 2.18 (2H, m), 2.64 (2H, s) , 4.15 (2H, q, J = 7 Hz), 4.61 (2H, s). MS (ES +) m / e: 244 ([MH +], 8%). IR (film) v cm'1: 1184, 1377, 1548, 1732, 2961.
Synthesis of (trans) -7,8-Dimethyl-spiro [4.4] nonane-2-one (4) Nitroster (3) (0.83 g, 3.4 mmol) was dissolved in methanol (30 ml) and stirred on a catalyst of Raney nickel under a hydrogen atmosphere (40 psi) at 30 ° C. After 4 hours, the catalyst was removed by filtration through celite. The solvent was removed under vacuum to give 567 mg (99%) of a pale yellow oil which solidified. 1 H NMR 400 MHz (CDCl 3): d 0.89 (6H, d, J = 6 Hz), 1.38 (2H, m), 1.91 (2H, m), 2.10 (2H, m), 2.32 (2H, s), 3.18 (2H, s), 5.61 (1 H, br s). MS (ES +) m / e: 168 ([MH +], 100%). IR (film) * v cm "1: 1304, 1450, 1699, 2871, 3186.
Synthesis of (1 <x, 3β, 4β) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) - acetic acid hydrochloride (5) Lactam (4) (563 mg, 4.40 mmol) was heated to reflux in a mixture of 1,4-dioxane (5 ml) and 6N HCl (15 ml). After 4 hours, the mixture was cooled to room temperature, diluted with water (20 ml), and washed with dichloromethane (3 x 30 ml). The aqueous phase was collected and the solvent removed in vacuo. The residue was triturated with ethyl acetate to give a white solid which was collected and dried. This was recrystallized from ethyl acetate / methanol to give 440 mg (59%) of (5) after collection and drying. 1 H NMR 400 MHz (d6-DMSO): d 0.84 (6H, d, J = 6 Hz), 1.21 (2H, m), 1.81 (2H, m), 2.06 (2H, m), 2.47 (2H, s) , 2.89 (2H, s), 7.94 (3H, br s), 12.30 (1H, br s). MS (ES +) m / e: 186 ([MH-HCl] "", 100%).
EXAMPLE 5 Reagents: (i) Triethylphosphonoacetate, NaH; (ii) MeN02, Bu N + F "; (iii) H2, Ni; (iv) HCl Synthesis of (3-Benzyl-cyclobutyldiene) -acetic acid ethyl ester (2) NaH (60% dispersion in oil, 0.496 g, 12.4 mmol), was suspended in dry tetrahydrofuran (40 ml) and cooled to 0 ° C. Triethylphosphonoacetate (2.58 ml, 13.0 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. Cyclobutanone (1) (1.89 g, 11.8 mmol) in THF (15 ml) was then added and the mixture was warmed to room temperature. After 4 hours, the mixture was partitioned between diethyl ether (200 ml) and water (150 ml). The organic phase was separated, washed with brine and dried (MgSO 4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 4) to give 2.19 g (81%) of (2) as a colorless oil. 1 H NMR 400 MHz (CDCl 3): d 1.26 (3 H, t, J = 6 Hz), 2.55 (1 H, m), 2.64-2.95 (5 H, m), 3.28 (2 H, m), 4.14 (2 H, q , J = 6 Hz), 5.63 (1 H, s), 7.10-7.32 (5H, m). MS (ES +) m / e: 231 ([MH +], 8%). IR (film) v cm "1: 1190, 1335, 1675, 1715, 2980.
Synthesis of (cis / trans) - (3-Benzyl-1-nitromethyl-cyclobutyl) -ester ethyl acetic acid (3) The unsaturated ester (2) (2.17 g, 9.42 mmol) was dissolved in tetrahydrofuran (15 ml) and it was stirred at 70 ° C with nitromethane (1.02 ml, 18.8 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 14 ml, 14.0 mmol). After 24 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (150 ml) and washed with 2N HCl (60 ml) followed by brine (100 ml). The organic phase was collected, dried (MgSO 4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate: heptane 1: 1) to give 1.55 g (57%) of a clear oil. 1 H NMR 400 MHz (CDCl 3): d 1.25 (3H, m), 1.86 (2H, m), 2.09-2.33 (2H, m), 2.53-2.78 (3H, m), 4.15 (2H, q, J = 6 Hz), 4.62 and 4.71 (2H total, 2 xs, cis / trans), 7.08-7.34 (5H, m). MS (ES +) m / e: 292 ([MH +], 100%). IR (film) v cm "1: 1185, 1378, 1549, 1732, 2933.
Synthesis of (cis / trans) - (1-Aminomethyl-3-benzyl-cyclobutyl) -acetic acid hydrochloride (4) Nitroster (3) (1.53 g, 5.25 mmol) was dissolved in methanol (50 ml) and stirred on a Raney nickel catalyst under a hydrogen atmosphere (45 psi) at 30 ° C. After 5 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 1.32 g of a pale yellow oil which was used without purification. The oil was dissolved in 1,4-dioxane (5 ml) and 6N HCl (15 ml) and heated to reflux. After 4 hours, the mixture was cooled to room temperature, diluted with water (20 ml) and washed with dichloromethane (3 x 30 ml). The aqueous phase was collected and the solvent removed in vacuo. The residue was triturated with ethyl acetate to give 0.88 g (62%) of a white solid after collection and drying. 1 H NMR 400 MHz (d6-DMSO): d 1.64 (1 H, m), 1.84 (2 H, m), 2.07 (1 H, m), 2.20-2.74 (5 H, m), 2.98 and 3.04 (2 H total, 2 xs, cis / trans), 7.10-7.31 (5H, m), 8.00 (3H, br s), 12.28 (1 H, br s). MS (ES +) m / e: 234 ([MH-HClf, 100%).
EXAMPLE 6 Reactive: (i) Triethylphosphonoacetate, NaH; (ii) MeN02, Bu N + F "; (iii) H2, Ni; (iv) Hcl.
The ketone (1) is known in the literature and can be synthesized by the methods explained in the following documents: Y. Kato, Chem. Pharm. Bull., 1966; 14: 1438-1439 and related references: W.C.M.C. Kokke, F. A. Varkevisser, J. Org. Chem., 1974; 39: 1535; R. Baker, D.C. Billington, N. Eranayake, JCS Chem. Comm., 1981: 1234; K. Furuta, K. Iwanaga, H. Yamamoto, Tet. Lett., 1986; 27: 4507; G. Solladie, O. Lohse, Tet. Asymm., 1993; 4: 1547; A. Rosenquist, I. Kvarnstrom, S.C.T. Svensson, B. Classon, B. Samueisson, Acta Chem. Scand., 1992; 46: 1127; E.J. Corey, W. Su, Tet. Lett., 1988; 29: 3423; D.W. Knight, B. Ojhara, Tet. Lett., 1981; 22: 5101.
Synthesis of (trans) - (3,4-Dimethyl-cyclopentyl-ene) -ester ethyl-acetic acid (2) To a suspension of sodium hydride (1.3 g, 32.5 mmol) in THF (60 ml) under nitrogen at 0 ° C. added triethylphosphonoacetate (6.5 ml, 32.7 mmol) for 5 minutes. After stirring for more than 10 minutes, a solution of (1) about 2.68 g, about 30 mmol) in THF (2 x 10 ml) was added to the now clear solution and the ice bath was removed. After 4 hours the reaction was warmed by pouring it into water (100 ml) and the mixture was extracted with ether (400 ml). The organic phase was washed with saturated brine (100 ml), dried and concentrated in vacuo. Column chromatography (10: 1 heptane / ethyl acetate) gave the product as an oil, 4.53 g, approximately 100%; 91% 1 H NMR 400 MHz (CDCl 3): d 1.01 (3 H, d, J = 6 Hz), 1.03 (3 H, d, J = 6 Hz), 1.26 (3 H, t, J = 7 Hz), 1.49 (2 H, m ), 2.07 (1 H, m), 2.24 (1 H, m), 2.61 (1 H, m), 4.13 (2 H, q, J = 7 Hz), 5.72 (1 H, s). MS (CI +) m / e: 183 ([MH +], 21%).
Synthesis of (trans) - (3,4 Dimethyl-1-nitromethyl-cyclopentyl) -ester ethyl acetic acid (3) It was added to a solution of (2) (4.24 g, 23.3 mmol) in THF (15 ml) TBAF ( 32 ml of a 1M solution in THF, 32 mmol) followed by nitromethane (3 ml) and the reaction was heated at 60 ° C for 8 hours. After cooling, the reaction mixture was diluted with ethyl acetate (150 ml) and washed with 2N HCl (40 ml) then with saturated brine (50 ml). Column chromatography (10: 1 heptane / ethyl acetate) gave the product as an oil, 2.24 g, 40%. 1 H NMR 400 MHz (CDCl 3): d 0.98 (6H, d, J = 6 Hz), 1.10-1.39 (5H, m) 1.47 (2H, m), 1.87 (1H, m), 2.03 (1H, m), 2.57 (2H, ABq, J = 16, 38 Hz), 4.14 (2H, q, J = 7 Hz), 4.61 (2H, Abq, J = 12, 60 Hz). MS (ES +) m / e: 244 ([MH +], 5%). IR (film) v cm, - "11: 1186, 1376, 1549, 1732, 2956.
Synthesis of (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) acetic acid hydrochloride (6) A solution of (3) (3.5 g, 14.4 mmol) in methanol (100 ml) in the presence of a Ni sponge was hydrogenated at 30 ° C and 50 psi for 4 hours. Filtration discarded the catalyst and concentration in vacuo gave a 2: 1 mixture of lactam and amino ester, 2.53 g, calculated as 96%, which was used without purification. This mixture (2.53 g, 13.8 mmol) in dioxane (15 ml) and 6N HCl (45 ml) was heated under reflux (oil bath = 110 ° C) for 4 hours. After cooling and dilution with water (60 ml), the mixture was washed with dichloromethane (3 x 50 ml) and then concentrated in vacuo. The resulting oil was washed with ethyl acetate, then with dichloromethane to give a viscous foam which was dried to give the product as a white powder, 2.32 g, 76%. aD (23 ° C) (H20) (c = 1.002) = + 28.2 °. 1 H NMR 400 MHz (d6-DMSO): d 0.91 (6 H, d, J = 6 Hz), 1.18 (2 H, m), 1.42 (2 H, m), 1.72 (1 H, m), 1.87 (1 H, m), 2.42 (2H, ABq, J = 16, 24 Hz), 2.90 (2H, ABq, J = 12, 34 Hz), 8.00 (3H, br s), 12.34 (1 H, br s). MS (ES +) m / e: 186 ([MH-HCl] "", 100%).
EXAMPLE 7 The ketone (1) is known in the literature and can be synthesized by the methods set forth in the documents: W. C. M. Kokke, F. A. Varkevisser, J. Org. Chem., 1974; 39: 1535; Cammalm, Ark. Kemi, 1960; 15: 215, 219; Cammalm, Chem. Ind., 1956: 1093; Linder et al., J. Am. Chem. Soc, 1977; 99: 727, 733; A. E. Greene, F. Charbonnier, 7ef. Lett., 1985; 26: 5525 and related references: R. Baker, D.C. Billington, N. Eranayake, JCS Chem. Comm., 1981: 1234; K. Furuta, K. Iwanaga, H. Yamamoto, Tet. Lett., 1986; 27: 4507; G. Solladie, O. Lohse, Tet. Asymm., 1993; 4: 1547; A. Rosenquist, I. Kvarnstrom, S. C. T. Svensson, B. Classon, B. Samueisson, Acta Chem. Scand., 1992; 46: 1127; E. J. Corey, W. Su, Tet. Lett., 1988; 29: 3423; D. W. Knight, B. Ojhara. Tet. Lett., 1981; 22: 5101.
Synthesis of (trans) - (3,4-Dimethyl-cyclopentyl-ene) -ester ethyl-acetic acid (2) It was added to a suspension of sodium hydride (0.824 g, 20.6 mmol) in THF (40 ml) under nitrogen at 0 °. C, triethylphosphonoacetate (4.1 ml, 20.7 mmol) for 5 minutes. After stirring for a further 10 minutes, a solution of (1) (approximately 2.10 g, approximately 15.8 mmol) in THF (2 x 10 mL) was added to the now clear solution and the ice bath was removed. After 4 hours, the reaction was warmed by pouring it into water (100 ml) and the mixture was extracted with ether (4 x 100 ml). The organic phase was washed with saturated brine (50 ml), dried and concentrated in vacuo. Column chromatography (10: 1 heptane / ethyl acetate) gave the product as an oil, 2643 g, approximately 100%; 91% 1 H NMR 400 MHz (CDCl 3): d 1.01 (3 H, d, J = 6 Hz), 1.03 (3 H, d, J = 6 Hz), 1.26 (3 H, t, J = 7 Hz), 1.49 (2 H, m ), 2.07 (1H, m), 2.24 (1 H, m), 2.61 (1 H, m), 4.13 (2H, q, J = 7 Hz), 5.72 (1H, s). MS (CI +) m / e: ([MH +], 19%).
Synthesis of (trans) - (3,4-Dimethyl-1-nitromethyl-cyclopentyl) -ester ethyl acetic acid (3) To a solution of (2) (2.44 g, 13.4 mmol) in THF (12 ml) was added TBAF (18 ml of a 1M solution in THF, 18 mmol) followed by nitromethane (2 ml) and the reaction was heated at 60 ° C for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate (250 ml) and washed with 2N HCl (50 ml), then with saturated brine (50 ml). Column chromatography (10: 1 heptane / ethyl acetate) gave the product as an oil, 1351 g, 41%. 1 H NMR 400 MHz (CDCl 3): d 0.98 (6H, d, J = 6 Hz), 1.10-1.39 (5H, m), 1.47 (2H, m), 1.87 (1H, m), 2.03 (1H, m) , 2.57 (2H, ABq, J = 16, 38 Hz), 4.14 (2H, q, J = 7 Hz), 4.61 (2H, ABq, J = 12, 60 Hz). MS (ES +) m / e: 244 ([MH +], 12%). IR (film) v cm "1: 1186, 1376, 1549, 1732, 2956.
Synthesis of (3R, 4R) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid hydrochloride (6) A solution of (3) (1.217 g, 5.0 mmol) in methanol (100 ml) in the The presence of a Ni sponge was hydrogenated at 30 ° C and 50 psi for 4 hours. Filtration removed the catalyst and concentration in vacuo gave a 3: 5 mixture of lactam and aminoster, 1.00 g, calculated as 100%, which was used without purification. This mixture (1.00 g, 5.0 mmol) in dioxane (10 ml) and 6N HCl (30 ml) was heated under reflux (oil bath = 110 ° C) for 4 hours. After cooling and dilution with water (100 ml), the mixture was washed with dichloromethane (2 x 50 ml) and then concentrated in vacuo. The resulting oil was washed with ethyl acetate, then with dichloromethane to give a viscous foam which was dried to give the product as a white powder, 0.532 g, 48%. aD (23 ° C) (H20) (c = 1.01) = -27.0 °. 1 H NMR 400 MHz (d6-DMSO): d 0.91 (6H, d, J = 6 Hz), 1.18 (2H, m), 1.42 (2H, m), 1.72 (1H, m), 1.87 (1H, m ), 2.42 (2H, ABq, J = 16, 24 Hz), 2.90 (2H, ABq, J = 12, 34 Hz), 8.00 (3H, br s), 12.34 (1 H, br s). MS (ES +) m / e: 186 ([MH-HCIJ \ 100%).
EXAMPLE 8 III Reagents and conditions: (i) (EtO) 2POCH2C02Et, NaH, THF; (ii) CH3N02, pBu4NF, THF; (iii) RaNi, H2 (MeOH; (iv) 6H HCl.
Synthesis of dimethylcyclopentanone 1 3,3-Dimethylcyclopentanone was prepared according to the procedure of Hiegel and Burk, J. Org. Chem., 1973; 38: 3637.
Synthesis of (3,3-Dimethyl-cyclopentyldiene) -ethyl ethyl acetic acid ester (2) To a stirred solution of triethylphosphonoacetate (1.84 g, 7.52 mmol) in THF (20 ml) at 0 C was added sodium hydride (300 mg of a 60% dispersion in oil). After 30 minutes, ketone 1 (766 mg, 6.84 mmol) in THF (5 ml) was added. After 24 hours, the solution was diluted with a saturated solution of ammonium chloride and the two phases were separated. The aqueous phase was extracted with diethyl ether (3 x 50 ml) and dried (MgSO 4). The combined organic phases were concentrated and subjected to flash chromatography (25: 1 hexane / ethyl acetate) to give ester 2 as an oil, (697 mg, 56%). 1 H NMR (400 MHz, CDCl 3): d 5.7 (1 H, s), 4.1 (2 H, q), 2.8 (1 H, t), 2.5 (1 H, t), 2.2 (1 H s), 1.55 ( 1 H, m), 1.45 (1 H, m), 1.2 (3 H, t), 1.0 (3 H, s), 0.98 (3 H, s). MS (m / z): 183 (MH +, 100%), 224 (50%).
Synthesis of (±) - (3,3-D-methyl-1-nitromethyl-cyclopentyl) -ester ethyl acetic acid (3) Tetrabutylammonium fluoride (5.75 ml of a 1 M solution in THF, 5.75 mmol) was added to a solution of ester 2 (697 mg, 3.83 mmol) and nitromethane (467 mg, 7.66 mmol) in THF (20 ml) and the mix at 70 ° C. After 19 hours, nitromethane (2.33 mg, 1.9 mmol and tetrabutylammonium fluoride (1.9 ml of a 1 M solution in THF, 1.9 mmol) were added and the reflux continued for 7 hours, after which the solution was cooled at room temperature, it was diluted with ethyl acetate (40 ml) and washed with 2N HCl (20 ml), then with brine (20 ml), the organic base was dried (MgSO 4) and concentrated. by flash chromatography (9: 1 hexane / ethyl acetate) to give nitro ester 3 (380 mg, 41%) as an oil.1H NMR (400 MHz, CDCl3): d 4.62 (1 H, d), 4.6 (1 H, d), 4.1 (2 H, q), 2.6 (1 H, d), 2.58 (1 H, d), 1.8 (1 H, m), 1.7 (1 H, m), 1.6-1.4 (4 H, m ), 1.2 (3H, t), 0.98 (6H, s) MS (m / z): 244 (MH +, 40%, 198 (100%).
Synthesis of (±) -7,7-Dimethyl-spiro [4.4] nonane-2-one (4) Ester 3 (380 mg, 1.6 mmol) and Raney Nickel (1 g) were suspended in methanol (75 ml) and stirred under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration, the concentrate was filtered to give lactam 4 (246 mg, 94%) as a white solid. 1H NMR (400 MHz, CD3OD): d 3.21 (1H, d), 3.08 (1H, d), 2.24 (1H, d), 2.18 (1H, d), 1.7 (2H, m), 1.5-1.4 (4H , m), 0.98 (6H, s). MS (m / z): 168 (MH \ 40%).
Synthesis of (±) - (1-Aminomethyl-3,3-dimethyl-cyclopentyl) -acetic acid hydrochloride (5) The lactam (240 mg, 1.44 mmol) in 6N HCl was heated to reflux for 24 hours. The residue was concentrated under reduced pressure and triturated with ether to give amino acid 5 as a white solid. 1 H NMR (400 MHz, CD30D): d 2.98 (2H, s), 2.4 (2H, s), 1.5 (2H, m), 1.4-1.2 (4H, m), 0.84 (3H, s), 0.84 (3H , s), 0.84 (3H, s). MS (m / z): 186 (MH +, 100%), 168 (M-NH 3, 20%).
EXAMPLE 9 Synthesis of (cis) - (3R) - (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid hydrochloride Reagents and conditions: (i) H2, Pd / C, MeOH; (ii) 12, Ph3P, imidazole CH3CN; (iii) LAH, THF; (iv) TsNHN = CHCOCI, PhNMe2, Et3N; (v) Rh2 (cap) 4, CH2Cl2, reflux; (vi) a) BBr3, EtOH; b) NH3; (vii) 6N HCl, reflux. Monoester 1 was prepared according to the procedure described in Tetrahedron: Asymmetry 3, 1992: 431. In the first step, the ester 1 is hydrogenated using a catalyst such as Raney nickel, palladium on carbon or rhodium catalyst or another catalyst containing nickel or palladium in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, acetic acid, 1-4-dioxane, chloroform or diethyl ether at an appropriate temperature in the range from 20 ° C to 80 ° C.
In the second step, the alcohol 2 was treated with triphenylphosphine, imidazole and iodine in a solvent such as ether, tetrahydrofuran or acetonitrile at 0 ° C at room temperature to give the iodide 3. In the third step, the iodide 3 treated with an appropriate reducing agent such as lithium aluminum hydride or lithium borohydride in a solvent such as ether or tetrahydrofuran at a temperature of approximately 0 ° C and reflux to give alcohol 4. In the fourth step, the alcohol 4 is treated with glyoxylic acid chloride (p-toluenesulfonyl) hydrazone and N, N-dimethylaniline followed by triethylamine in a solvent such as methylene chloride, chloroform, benzene or toluene to give diazoacetate 5. In the fifth step, diazoacetate 5 is added to a reflux or suspension solution of an appropriate rhodium (II) catalyst such as Rh2 (cap) 4, Rh2 (5S-MEOX) 4, Rh2 (5S-MEPY) 4) Rh2 (5R-MEPY) 4 , or Rh2 (Oac) 4 in a solvent such as methylene chloride, benzene, toluene or 1, 2-dichloroethane as described in Doyle and Dyatkin in J. Org. Chem., 1995; 60: 3035 to give the spirolactone 6. In the sixth step, the spirolactone 6 is treated with hydrogen bromide or boron tribromide in methanol or ethanol to give an intermediate bromoester which then reacts with ammonium to give the spirolactam 7. In the seventh step, the spirolactam 7 is treated with a solution of hydrochloric acid (6N to 12N) at reflux, to which a water-miscible co-solvent such as 1,4-dioxane or tetrahydrofuran can be added to give the amino acid 8.

Claims (18)

  1. A compound of formula 1A or a pharmaceutically acceptable salt thereof wherein: R is hydrogen or a lower alkyl; R1 to R14 are each independently selected from hydrogen, from long chain or branched alkyl from 1 to 6 carbons, from phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl , of trifluoromethyl, -C02H, -C02R15, -CH2C02H, -CH2C02R15, -OR15 wherein R15 is a long or branched chain alkyl of 1 to 6 carbons, phenyl or benzyl and R1 to R8 are not simultaneously hydrogen.
  2. 2. A compound according to claim 1, wherein R1 to R14 are selected from hydrogen, methyl, ethyl, propyl, isopropyl, long or branched chain butyl, phenyl or benzyl.
  3. 3. A compound according to claim 1, wherein R. 1 a., D R 14 are selected from hydrogen, methyl, ethyl or benzyl.
  4. 4. A compound according to claim 1 and selected from: (±) - (trans) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -hydrochloride of acetic acid; (l-Aminomethyl-cyclobutyl) -acetic acid hydrochloride; (cis / trans) - (3R) - (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid hydrochloride; (cis / trans) - (1-Ammonomethyl-3-benzyl-cyclobutyl) -acetic acid hydrochloride; (±) - (1-Aminomethyl-3,3-dimethyl-cyclopentyl) -acetic acid hydrochloride and (cis) - (3R) - (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid hydrochloride.
  5. A compound according to claim 1 and selected from: (1 a, 3 a, 4 a) - (1-amino-methyl-3,4-dimethyl-cyclopentyl) -acetic acid; (1 a, 3 a, 4 a) - (1-amino-methyl-3,4-diethyl-cyclopentyl) -acetic acid; (1a, 3a, 4a) - (1-Aminomethyl-3,4-d¡¡sopropyl-cyclopentyl) -acetic acid; [1 S- (1 a, 3 a, 4 a)] - (1-Methyl-methyl-3-ethyl-4-methyl-cyclopentyl) -acetic acid; [1 R- (1a, 3a, 4a)] - (1-Aminomethyl-3-ethyl-4-methyl-cyclopentyl) -acetic acid; [1S- (1a, 3a, 4a)] - (1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; [1 R- (1a, 3a, 4a)] - (1-Aminomethyl-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; [1S- (1a, 3a, 4a)] - (1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; [1 R- (1 a, 3 a, 4 a) j- (1-Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; [1 S- (1 a, 3 a, 4 a)] - (1-amino-methyl-3-tert-butyl-4-methyl-cyclopentyl) -acetic acid; [1 R- (1 a, 3 a, 4 a)] - (1-Aminomethyl-3-tert-butyl-4-methyl-cyclopentyl) -acetic acid; [1S- (1, 3a, 4a)] - (1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; [1 R- (1, 3a, 4a)] - (1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; [1S- (1a, 3o., 4a)] - (1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid; [1 R- (1, 3a, 4a)] - (1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid; (1a, 3a, 4a) - (1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl) -acetic acid; [1S- (1, 3a, 4a)] - (1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; [1 R- (1 a, 3 a, 4 a)] - (1-amino-methyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; [1S- (1a, 3a, 4a)] - (1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; [1 R- (1, 3a, 4a)] - (1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; L-3-methyl-cyclopentyl) -acetic acid; L-3-ethyl-cyclopentyl) -acetic acid; l-3-isopropyl-cyclopentyl) -acetic acid; l-3-tert-butyl-cyclopentyl) -acetic acid; l-3-phenyl-cyclopentyl) -acetic acid; l-3-benzyl-cyclopentyl) -acetic acid; L-3-methyl-cyclopentyl) -acetic acid; l-3-ethyl-cyclopentyl) -acetic acid; l-3-isopropyl-cyclopentyl) -acetic acid; l-3-tert-butyl-cyclopentyl) -acetic acid; l-3-phenyl-cyclopentyl) -acetic acid; l-3-benzyl-cyclopentyl) -acetic acid; S) - (1-Ammonitrile-3,3-dimethyl-cyclopentyl) -acetic acid; S) - (1-amino-methyl-3,3-diethyl-cyclopentyl) -acetic acid; 1-Aminomethyl-3,3,4,4-tetramethyl-cyclopentyl) -acetic acid; 1-Aminomethyl-3,3,4,4-tetraethyl-cyclopentyl) -acetic acid; 1a, 3, 4) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid; 1a, 3, 4) - (1-Aminomethyl-3,4-diethyl-cyclopentyl) -acetic acid; 1a, 3, 4) - (1-Aminomethyl-3,4-diisopropyl-cyclopentyl) -acetic acid; 1R- (1a, 3 A)] - ((1-Aminomet-l-3-ethyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1a, 3 A)] - ((1-Aminomethyl) -3- ethyl-4-methyl-cyclopentyl) -acetic acid; 1 R- (1a, 3 A)] - ((1-amino-methyl-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1a, 3 A)] - ((1-amino-methyl-l-3-isopropyl-4-methyl-cyclopentyl) -acetic acid; 1R- (1a, 3 A)] - ((1-amino-methyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1S- (1a, 3 A)] - ((1-amino-methyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1R- (1a, 3A)] - ((1-amino-methyl-3-tert-butyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1a, 3 A)] - ((1-amino-methyl-3-tert-butyl-4-methyl-cyclopentyl) -acetic acid; 1 R- (1a, 3 A)] - ((1-Aminomethyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1S- (1a, 3 > 4)] - (( 1 -Aminomet l-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1R- (1a, 3 > 4)] - ((1-amino-methyl-3-tert-butyl-4-isopropyl) cyclopentyl) -acetic acid 1S- (1a, 3, 4)] - (1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid 1a, 3, 4) - (1- Aminomethyl-3,4-di-tert-butyl-cyclopentyl) -acetic acid; 1R- (1a, 3, 4)] - (1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; (1a, 3, 4)] - (1-Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; 1R- (1a, 3, 4)] - (1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; 1S- (1, 3, 4)] - (1-Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-Aminomethyl-3-methyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-Aminomethyl-3-ethyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-amino-methyl-3-isopropyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-amino-methyl-3-tert-butyl-cyclopentyl) -acetic acid; 1R-trans) - (1-Aminomethyl-3-phenyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-Aminomethyl-3-benzyl-cyclopentyl) -acetic acid; 1 S-trans) - (1-amino-methyl-3-methyl-cyclopentyl) -acetic acid; 1S-trans) - (1-Aminomethyl-3-ethyl-cyclopentyl) -acetic acid; 1 S-trans) - (1-amino-methyl-3-isopropyl-cyclopentyl) -acetic acid; 1 S-trans) - (1-amino-methyl-3-tert-butyl-cyclopentyl) -acetic acid; 1 S-trans) - (1-amino-methyl-3-phenyl-cyclopentyl) -acetic acid; 1 S-trans) - (1-Aminomethyl-3-benzyl-cyclopentyl) -acetic acid; R) - (1-amino-methyl-3,3-dimethyl-cyclopentyl) -acetic acid; R) - (1-Aminomethyl-3,3-diethyl-cyclopentyl) -acetic acid; cis- (1-amino-methyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-ethyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-tert-butyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-benzyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-ethyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-benzyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-ethyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-isopropyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-amino-methyl-3-benzyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-ethyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-isopropyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-3-methyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-methyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-benzyl-3-methyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-etl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-benzyl-3-ethyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-ethyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-3-ethyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-ethyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-amino-methyl-3-benzyl-3-ethyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-tert-butyl-3-phenyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-isopropyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-benzyl-3-isopropyl-cyclobutyl) -acetic acid; trans- (1-Aminomethyl-3-tert-butyl-3-phenyl-cyclobutyl) -acetic acid; cis- (1-Aminomethyl-3-benzyl-3-tert-butyl-cyclobutyl) -acetic acid; (1-amino-methyl-3,3-dimethyl-cyclobutyl) -acetic acid; (1-amino-methyl-3,3-diethyl-cyclobutyl) -acetic acid; (1-Aminomethyl-3,3-diisopropyl-cyclobutyl) -acetic acid; (1-amino-methyl-3,3-di-tert-butyl-cyclobutyl) -acetic acid; (1-Aminomethyl-3,3-diphenyl-cyclobutyl) -acetic acid; (1-amino-methyl-3,3-dibenzyl-cyclobutyl) -acetic acid; (1-Aminomethyl-2,2,4,4-tetramethyl-cyclobutyl) -acetic acid; (1-amino-methyl-2,2,3,3,4,4-hexamethyl-cyclobutyl) -acetic acid; (R) - (1-Aminomethyl-2,2-dimethyl-cyclobutyl) -acetic acid; (S) - (1-Aminomethyl-2,2-dimethyl-cyclobutyl) -acetic acid; (1 R-cis) - (1-amino-methyl-2-methyl-cyclobutyl) -acetic acid; [1 R- (1a, 2a, 3a)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; (1a, 2a, 4a) - (1-Aminomethyl-2,4-d-methyl-cyclobutyl) -acetic acid; [1R- (1a, 2a, 3)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; (1, 2a, 4ß) - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; (1 S-trans) - (1-Aminomethyl-2-methyl-cyclobutyl) -acetic acid; [1S- (1o., 2, 3)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; (1a, 2, 4) - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; [1 S- (1 a, 2, 3 a)] - (1-amino-methyl-2,3-d-methyl-cyclobutyl) -acetic acid; (1a, 2, 4a)] - (1-Aminomethyl-2,4-dimethyl-cyclobutyl) -acetic acid; (1 R-trans) - (1-Aminomethyl-2-methyl-cyclobutyl) -acetic acid; [1R- (1a, 2, 3)] - (1-Aminomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; [1R- (1, 2, 4)] - (1-Aminomethyl-2-ethyl-4-methyl-cyclobutyl) -acetic acid; [1R- (1a, 2, 3a)] - (1-Aminomethyl-2,3-d-methyl-cyclobutyl) -acetic acid; (1a, 2, 4a) - (1-Aminomethyl-2,4-d-methyl-cyclobutyl) -acetic acid; (1 S-cis) - (1-Aminomethyl-2-methyl-cyclobutyl) -acetic acid; [1 S- (1 a, 2a, 3a)] - (1-Ammonomethyl-2,3-dimethyl-cyclobutyl) -acetic acid; [1 S- (1 a, 2 a, 3 a)] - (1-amino-methyl-2,4-dimethyl-cyclobutyl) -acetic acid; [1 S- (1 a, 2 b, 3 a)] - (1-amino-methyl-2,3-dimethyl-cyclobutyl) -acetic acid; (1 a, 2a, 4ß) - (1-amino-methyl-2,4-dimethyl-cyclobutyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-diethylcyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-diethyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-diisopropyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-diisopropyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-amino-methyl-3,4-di-tert-butyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-di-tert-butyl-cyclopentyl) -acetic acid; (3S, 4S) - (1-Aminomethyl-3,4-diphenyl-cyclopentyl) -acetic acid; (3R, 4R) - (1-Aminomethyl-3,4-diphenyl-cyclopentyl) -acetic acid; methyl-3,4-dibenzyl-cyclopentyl) -acetic acid; methyl-3,4-dibenzyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-ethyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-ethyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-ethyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-ethyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyI-4-isopropyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-tert-butyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomethyl-3-methyl-4-phenyl-cyclopentyl) -acetic acid; -Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminomethyl-3-benzyl-4-methyl-cyclopentyl) -acetic acid; -Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; -Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1R-1a, 3a, 4ß)] - 1 -Aminomethyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1S-1a, 3β, 4a)] - 1-amino-methyl-3-ethyl-4-isopropyl-cyclopentyl) -acetic acid; 1S-1a, 3a, 4ß)] - 1-amino-methyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1R-1a, 3β, 4a)] - 1-amino-methyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1R-1a, 3a, 4ß)] - 1-amino-methyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1S-1a, 3β, 4a)] - 1-amino-methyl-3-tert-butyl-4-ethyl-cyclopentyl) -acetic acid; 1S-1a, 3a, 4ß)] - 1-amino-methyl-3-ethyl-4-phenyl-cyclopentyl) -acetic acid; 1 R-1a, 3β, 4a)] - 1-amino-methyl-3-ethyl-4-phenyl-cyclopentyl) -acetic acid; 1R-1a, 3a, 4ß)] - 1-amino-methyl-3-ethyl-4-phenyl-cyclopentyl) -acetic acid; 1S-1a, 3β, 4a)] - 1-amino-methyl-3-ethyl-4-phenyl-cyclopentyl) -acetic acid; 1S-1a, 3a, 4ß)] - 1-amino-methyl-3-benzyl-4-eti-cyclopentyl) -acetic acid; 1R-1a, 3β, 4a)] - 1-amino-methyl-3-benzyl-4-ethyl-cyclopentyl) -acetic acid; 1R-1a, 3a, 4ß)] - 1-amino-methyl-3-benzyl-4-ethyl-cyclopentyl) -acetic acid; IS1a, 3ß, 4a)] - 1-Aminomethyl-3-benzyl-4-ethyl-cyclopentyl) -acetic acid; IS-1a, 3a, 4ß)] - 1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid 1R-1a, 3β, 4a)] - 1-Aminomethyl-3-tert-butyl- 4-isopropyl-cyclopentyl) -acetic acid 1R-1a, 3a, 4ß)] - 1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid 1S-1a, 3ß, 4a)] - 1-Aminomethyl-3-tert-butyl-4-isopropyl-cyclopentyl) -acetic acid 1S-1a, 3a, 4ß)] - 1-Aminomethyl-3-isopropyl-4-phenyl-cyclopentyl) -acid acetic; 1R-1a, 3β, 4a)] - 1-amino-methyl-3-isopropyl-4-phenyl-cyclopentyl) -acetic acid; 1R-; a, 3a, 4ß)] - [1-Aminomet-l-3-isopropyl-4-phenyl-cyclopentyl) -acetic acid; 1S- (1a, 3β, 4a)] - (1-amino-methyl-3-isopropyl-4-phenyl-cyclopentyl) -acetic acid; 1S- (1a, 3a, 4ß)] - < 1 -Aminometi l-3-benzyl-4-isopropyl-cyclopentyl) -acetic acid; 1R-; a, 3ß, 4a)] - [1-amino-methyl-3-benzyl-4-isopropyl-cyclopentyl) -acetic acid; 1R-: ia, 3a, 4ß)] - (1-Aminomet l-3-benzyl-4-isopropyl-cyclopentyl) -acetic acid; 1S- (1a, 3β, 4a)] - (1-amino-methyl-3-benzyl-4-isopropyl-cyclopentyl) -acetic acid; 1S- (1a, 3a, 4ß)] - (1-amino-methyl-3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1R- (1a, 3ß, 4a)] -? -Aminomet l-3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1R- (1a, 3a, 4ß)] - (1 -Aminomet I-3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1S- (1a, 3β, 4a)] - ('1 -Aminomet l-3-tert-butyl-4-phenyl-cyclopentyl) -acetic acid; 1R- [1a, 3a, 4ß)] - (1-Aminomet l-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1S- (1a, 3β, 4a)] - ([1-amino-methyl-I-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1S- (1a, 3a, 4ß)] - | '1-Aminomet l-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1R- (1a, 3β, 4 (x)] - (1 -Aminomet l-3-benzyl-4-tert-butyl-cyclopentyl) -acetic acid; 1S- (r1a, 3a, 4ß)] - [1-amino-methyl-l-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1R- (1a, 3β, 4a) j- (1-Aminomet l-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1 R- (1a, 3a, 4ß)] - (1 -Aminomet l-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1S- (1a, 3β, 4a)] - (1-amino-methyl-3-benzyl-4-phenyl-cyclopentyl) -acetic acid; 1R- cis) - (1-Amin-omethyl-2-methyl-cyclopentyl) -acetic acid; 1S- cis) - (1-Amin omethyl-2-methyl-cyclopentyl) -acetic acid; 1 R-trans) - (1-Aminomethyl-2-methyl-cyclopentyl) -acetic acid; 1S-trans) - (1-Aminomethyl-2-methyl-cyclopentyl) -acetic acid; R) - (1-amino-methyl-2,2-dimethyl-cyclopentyl) -acetic acid; S) - (1-Aminomethyl-2,2-dimethyl-cyclopentyl) -acetic acid; 1 - . 1-amino-methyl-2,2,5,5-tetramethyl-cyclopentyl) -acetic acid; 1a, 2, 5) - (1-Aminomethyl-2,5-dimethyl-cyclopentyl) -acetic acid; 2R, 5R) - (1-amino-methyl-2,5-dimethyl-cyclopentyl) -acetic acid; 2S, 5S) - (1-amino-methyl-2,5-dimethyl-cyclopentyl) -acetic acid; 1 a, 2a, 5a) - (1-amino-methyl-2,5-dimethyl-cyclopentyl) -acetic acid; 1S- (1a, 2ß, 4ß)] - (1-Amomethyl-2,4-dimethyl-cyclopentyl) -acetic acid;
  6. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
  7. 7. A method for the treatment of epilepsy comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  8. 8. A method for treating attacks of memory loss, hypokinesia and cranial disorders, comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  9. 9. A method for the treatment of neurodegenerative disorders comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  10. 10. A method for the treatment of depression, comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  11. 11. A method for the treatment of anxiety comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  12. 12. A method for treating panic comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  13. 13. A method for pain treatment comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  14. 14. A method for the treatment of neuropathological disorders comprising the administration of a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment.
  15. 15. A method for the treatment of inflammation comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  16. 16. A method for the treatment of gastrointestinal disorders comprising the administration of a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment.
  17. 17. A method for the treatment of irritable bowel syndrome comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of such treatment.
  18. 18. A compound selected from: (trans) - (3,4-dimethyl-cyclopentyldiene) -acetic acid ethyl ester; (trans) ~ (3,4-Dimethyl-1-nitromethyl-cyclopentyl) -acetic acid; (±) - (trans) -7,8-Dimethyl-spiro [4,4] nonane-2-one; (l-Nitromethyl-cyclobutyl) -acetic acid ethyl ester; (cis / trans) - (3R) - (3-Methyl-1-nitromethyl-cyclopentyl) -acetic acid ethyl ester; (cis / trans) - (7R) -7-Methyl-spiro [4,4] nonane-2-ano; (cis) - (3,4-dimethyl-cyclopentylldiene) -acetic acid ethyl ester; (trans) -3,4-Dimethyl-1-nitromethyl-cyclopentyl) ethyl ester of acetic acid; (trans) -7,8-DimetiI-spiro [4,4] nonane-2-one; (3-Benzyl-cyclopentyl-ene) -acetic acid ethyl ester and (cis / trans) - (3-benzyl-1-nitromethyl-cyclopentyl) -acetic acid ethyl ester.
MXPA/A/2000/002656A 1997-10-27 2000-03-16 Cyclic amino acids and derivatives thereof useful as pharmaceutical agents MXPA00002656A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60/063,644 1997-10-27
US60/097,685 1998-08-24

Publications (1)

Publication Number Publication Date
MXPA00002656A true MXPA00002656A (en) 2001-06-26

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