Branched alkyl pyrrolidine-3-carboxylic acids

Details Branched alkyl pyrrolidine-3-carboxylic acids Branched alkyl pyrrolidine-3-carboxylic acids

2000-10-13

2001-06-12

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S572000

Reexamination Certificate

active

06245801

ABSTRACT:

BACKGROUND OF THE INVENTION
Compounds of formula
wherein R
1
is hydrogen or a lower alkyl radical and n is 4, 5, or 6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. The uses disclosed are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The patents are hereby incorporated by reference.
SUMMARY OF THE INVENTION
The compounds, prodrugs, and pharmaceutically acceptable salts are useful in a variety of disorders. The disorders include: convulsions such as in epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, inflammatory disorders such as arthritis, irritable bowel syndrome, and neuropathological disorders.
The compounds are those of formula
or a pharmaceutically acceptable salt thereof or a prodrug thereof wherein
R
1
is hydrogen or a straight or branched alkyl of from 1 to 5 carbons;
R
2
is a straight or branched alkyl of from 1 to 5 carbons; and
R
1
and R
2
when taken together form a carbocyclic ring of from 3 to 7 atoms.
Preferred compounds are those wherein
R
1
is H, methyl, or ethyl; and
R
2
is methyl or ethyl.
The most preferred compounds are those wherein (cis)-4-isobutyl-pyrrolidine-3-carboxylic acid and (trans)-4-isobutyl-pyrrolidine-3-carboxylic acid.
Other preferred compounds are those wherein R
1
and R
2
are taken to form a carbocylic ring of from 3 to 7 atoms.
More preferred compounds are those wherein R
1
and R
2
form a five or six membered ring.
Novel intermediates useful in the preparation of the final compounds are also encompassed by the invention.
Other compounds of the invention are those of Formula IA
or a pharmaceutically acceptable salt thereof wherein R
4
is alkyl of 3 or 4 carbons. Such compounds are selected from:
trans-4-isopropylpyrrolidine-3-carboxylic acid;
trans-4-propyl-pyrrolidine-3-carboxylic acid; and
trans-4-butyl-pyrrolidine-3-carboxylic acid.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the instant invention and their pharmaceutically acceptable salts and prodrugs are as defined by Formula I above.
The term “alkyl” is a straight or branched group of from 1 to 5 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, and pentyl.
Preferred groups are methyl and tert-butyl.
The stereocenters in Formula I can have independently be of either an R or S configuration.
Compounds of Formula I wherein the two substituents have a cis relative orientation about the pyrrolidine ring can be prepared in the following manner outlined in Scheme 1.
Compounds of Formula I wherein the two substituents have a trans relative orientation about the pyrrolidine ring, can be prepared in the following manner outlined in Scheme 2.
Scheme 5


Compound
R
1
R
2
2 (%)
3 (%)
a
CH
3
H
100
90
b
CH
3
CH
3
28
84
c
C
2
H
5
H
95
78
d
i-Pr
H
79
88
e
n-Pr
H
72
88
f
i-Bu
H
99
86
g
H
i-Bu
41
85
h
n-Bu
H
82
85
TABLE I
[3H]GAP
NA Release
CITH
DBA 2
Vogel
Binding
% Inhibition
Sys L
% MPE
% Protect
% of
Structure
IC
50
(&mgr;M)
@ 100 &mgr;M
IC
50
(&mgr;M)
1 h
2 h
(time)
C1-1008
0.140
 25
48.9
19.9
100
63.7
0.087
193
52.5
50.1
100
100
100

0.120
>10,000
53
4.6
20
20

0.051
3
−15
0
0

0.700
23
3.3
0
0

0.015
16
20
40
0.63

1.166
8
−0.63

3.101

1.192


0.543

0.030

0.064
Since amino acids are amphoteric, pharmacologically compatible salts when R is hydrogen can be salts of appropriate inorganic or organic acids, for example, hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic, citric, malic, salicylic, malonic, maleic, succinic, and ascorbic. Starting from corresponding hydroxides or carbonates, salts with alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium, or calcium are formed. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion.
Prodrugs of compounds I-VIII are included in the scope of the instant invention. Aminoacyl-glycolic and -lactic esters are known as prodrugs of amino acids (Wermuth C. G.,
Chemistry and Industry
, 1980:433-435). The carbonyl group of the amino acids can be esterified by known means. Prodrugs and soft drugs are known in the art (Palomino E.,
Drugs of the Future
, 1990;15(4):361-368). The last two citations are hereby incorporated by reference.
The effectiveness of an orally administered drug is dependent upon the drug's efficient transport across the mucosal epithelium and its stability in entero-hepatic circulation. Drugs that are effective after parenteral administration but less effective orally, or whose plasma half-life is considered too short, may be chemically modified into a prodrug form.
A prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form.
This chemically modified drug, or prodrug, should have a different pharmacokinetic profile to the parent, enabling easier absorption across the mucosal epithelium, better salt formulation and/or solubility, improved systemic stability (for an increase in plasma half-life, for example). These chemical modifications may be
1) ester or amide derivatives which may be cleaved by, for example, esterases or lipases. For ester derivatives, the ester is derived from the carboxylic acid moiety of the drug molecule by known means. For amide derivatives, the amide may be derived from the carboxylic acid moiety or the amine moiety of the drug molecule by known means.
2) peptides which may be recognized by specific or nonspecific proteinases. A peptide may be coupled to the drug molecule via amide bond formation with the amine or carboxylic acid moiety of the drug molecule by known means.
3) derivatives that accumulate at a site of action through membrane selection of a prodrug form or modified prodrug form,
4) any combination of 1 to 3.
Current research in animal experiments has shown that the oral absorption of certain drugs may be increased by the preparation of “soft” quaternary salts. The quaternary salt is termed a “soft” quaternary salt since, unlike normal quaternary salts, e.g., R—N
+
(CH
3
)
3
, it can release the active drug on hydrolysis.
“Soft” quaternary salts have useful physical properties compared with the basic drug or its salts. Water solubility may be increased compared with other salts, such as the hydrochloride, but more important there may be an increased absorption of the drug from the intestine. Increased absorption is probably due to the fact that the “soft” quaternary salt has surfactant properties and is capable of forming micelles and unionized ion pairs with bile acids, etc., which are able to penetrate the intestinal epithelium more effectively. The prodrug, after absorption, is rapidly hydrolyzed with release of the active parent drug.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof. For example, the compound of Example 1 is a mixture of all four possible stereoisomers. The compound of Example 6 is one of the isomers. The configuration of the cyclohexane ring carbon centers may be R or S in these compounds where a configuration can be defined.
The radioligand binding assay using [
3
H]gabapentin and the &agr;
2
&dgr; subunit derived from porcine

Affiliated with

Also associated with

Rating

Branched alkyl pyrrolidine-3-carboxylic acids does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Branched alkyl pyrrolidine-3-carboxylic acids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Branched alkyl pyrrolidine-3-carboxylic acids will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2486754