Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-22
2003-09-02
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S121000
Reexamination Certificate
active
06613775
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases. In further aspects, the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.
BACKGROUND ART
Substituted imidazo[1,2-a]pyridines, useful in the treatment of peptic ulcer diseases, are known in the art, e.g. from EP-B-0033094 and U.S. Pat. No. 4,450,164 (Schering Corporation); from EP-B-0204285 and U.S. Pat. No. 4,725,601 (Fujisawa Pharmaceutical Co.); and from publications by J. J. Kaminski et al. in the Journal of Medical Chemistry (vol. 28, 876-892, 1985; vol. 30, 2031-2046, 1987; vol. 30, 2047-2051, 1987; vol. 32, 1686-1700, 1989; and vol. 34, 533-541, 1991).
For a review of the pharmacology of the gastric acid pump (the H
+
, K
+
-ATPase), see Sachs et al. (1995) Annu. Rev. Pharmacol. Toxicol. 35: 277-305.
DISCLOSURE OF THE INVENTION
It has surprisingly been found that compounds of the Formula I
or a pharmaceutically acceptable salt thereof, are particularly effective as inhibitors of the gastrointestinal H
+
, K
+
-ATPase and thereby as inhibitors of gastric acid secretion.
In one aspect, the invention thus relates to compounds of the general Formula I
or a pharmaceutically acceptable salt thereof, wherein
R
1
is
(a) H,
(b) CH
3
, or
(c) CH
2
OH;
R
2
is C
1
-C
6
alkyl;
R
3
is C
1
-C
6
alkyl;
R
4
is
(a) H, or
(b) halogen;
R
5
is
(a) H, or
(b) C
1
-C
6
alkyl;
R
6
is
(a) H,
(b) C
1
-C
6
alkyl carbonyl
(c) C
3
-C
7
cycloalkyl carbonyl, in which the cycloalkyl group is optionally substituted by one or more substituents selected from, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —COOH or —COO—(C
1
-C
6
)alkyl
(d) Aryl C
1
-C
6
alkyl carbonyl, in which aryl represents phenyl, pyridyl, thienyl or furanyl, optionally substituted by one or more substituents selected from, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —COOH or —COO—(C
1
-C
6
)alkyl
(e) C
1
-C
6
alkoxy C
1
-C
6
alkyl carbonyl
(f) C
1
-C
6
alkoxy carbonyl
(g) aryl carbonyl, in which aryl represents phenyl, pyridyl, thienyl or furanyl, optionally substituted by one or more substituents selected from, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —COOH or —COO—(C
1
-C
6
)alkyl
(h) C
3
-C
7
cycloalkyl C
1
-C
6
alkylcarbonyl, in which the cycloalkyl group is optionally substituted by one or more substituents selected from, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —COOH or —COO—(C
1
-C
6
)alkyl
(i) C
1
-C
6
alkoxy C
1
-C
6
alkoxycarbonyl
(j) C
1
-C
6
alkoxy C
1
-C
6
alkoxy C
1
-C
6
alkylcarbonyl
(k) acarbamoylgroup with the formula
wherein R
7
and R
8
are the same or different and are H, or C
1
-C
6
alkyl
(l) R
9
—(C
1
-C
6
)alkylcarbonyl
wherein R
9
is
HOC═O—, C
1
-C
6
alkyl-O—C═O—, or
an amino group with the formula
wherein R
7
and R
8
are the same or different and are H,or C
1
-C
6
alkyl
(m) R
9
-hydroxylated-(C
1
-C
6
)alkylcarbonyl
(n) R
9
—(C
1
-C
6
)alkenylcarbonyl
X is
(a) NH, or
(b) O.
As used herein, the term “C
1
-C
6
alkyl” denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said C
1
-C
6
alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
The term “halogen” includes fluoro, chloro, bromo and iodo.
The term “pyridyl” includes the 2-, 3-, and 4-isomers and the terms thienyl and furanyl include the 2-, and 3-isomers.
Both the pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It should be understood that all the diastereomeric forms possible (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Also included in the invention are derivatives of the compounds of the Formula I which have the biological function of the compounds of the Formula I.
Depending on the process conditions the end products of the Formula I are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.
Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
In the preparation of acid addition salts, preferably such acids are used which form suitable therapeutically acceptable salts. Examples of such acids are hydrohalogen acids such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbenzenesulphonic acid, toluenesulphonic acid or naphthalenesulphonic acid.
Preferred compounds according to the invention are those of Formula I wherein R
1
is CH
3
or CH
2
OH; R
2
is CH
3
or CH
2
CH
3
; R
3
is CH
3
or CH
2
CH
3
; R
4
is H, Br, Cl or F; R
5
is H or CH
3
.
Particularly preferred compounds according to the invention are:
8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine
8-(2-ethyl-6-methylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine
8-(2,6-dimethylbenzylamino)-3,6-dimethyl-2-hydroxymethylimidazo[1,2-a]pyridine
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl acetate
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl ethyl carbonate
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl N,N-dimethylcarbamate
1-[[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl]3-ethyl malonate
4-[[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methoxy]-4-oxobutanoic acid
4-[[8-(2-ethyl-6-methylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methoxy]-4-oxobutanoic acid
5-[[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methoxy]-5-oxopentanoic acid
[8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridin-2-yl]methyl 2-(dimethylamino)acetate
8-(2,6-dimethylbenzylamino)-2,3-dihydroxymethyl-imidazo[1,2-a]pyridine
Preparation
The present invention also provides the following processes A and B for the manufacture of compounds with the general Formula I.
The process A for manufacture of compounds with the general Formula I comprises the following steps:
a) The imidazo[1,2-a]pyridine compounds of the Formula II
wherein Y is a lower alkyl group, R represents H, CH
3
or an ester group such as COOCH
3
, COOC
2
H
5
etc, X
1
is NH
2
or OH and R
5
is as defined for Formula I, can be prepared by reacting compounds of the general Formula III
with compounds of the general Formula IV
wherein Z is a leaving group such as halogen, mesyl, or tosyl.
The reaction is carried out under standard conditions in an inert solvent such as acetone acetonitrile, alcohol, N,N-dimethylformamide etc., with or without a base.
b) Compounds of the Formula II can be reacted with compounds of the Formula V
wherein R
2
, R
3
and R
4
are as defined for Formula I and Z
1
is a leaving group, such as halogen, tosyl or mesyl, under standard conditions in an i
Amin Kosrat
Dahlström Mikael
Nordberg Peter
Starke Ingemar
AstraZeneca AB
Huang Evelyn Mei
White & Case LLP
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