Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-07-17
2002-10-15
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S309700, C548S310100
Reexamination Certificate
active
06465505
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
Benzimidazole derivatives of the following formula, active as anti-ulcer agents, are disclosed in EP-B-0 266 326 and in U.S. Pat. No. 5,106,862:
wherein R
1
is i.a. an aryl group of the formula:
in which each of R
7
, R
8
and R
9
independently represents i.a. H or C
1
-C
6
alkyl, or halogen;
R
2
is i.a. H;
R
3
is i.a. H or C
1
-C
6
alkyl;
n is an integer 0-6;
R
4
, R
5
and R
6
are H or C
1
-C
6
alkyl;
A is alkylene up to 6 carbon atoms optionally interrupted by a hetero atom such as O or N.
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, which are substituted benzimidazole derivatives in which the phenyl moiety is substituted with lower alkyl in 2- and 6-position, 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 lower alkyl;
R
2
is lower alkyl;
R
3
, which is in position 3, 4, or 5 of the phenyl ring, is
(a) H,
(b) halogen, or
(c) lower alkyl;
R
4
is
(a) H, or
(b) lower alkyl;
X, which is connected to the heterocycle in the position 4 or 7, is
(a) NH, or
(b) O.
As used herein, the term “lower alkyl” denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower 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.
Both 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 suitably therapeutically acceptable salts. Examples of such acids are hydrohalogen acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic 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-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
Preferred compounds according to the invention are those of the formula I wherein R
1
is CH
3
or CH
2
CH
3
; R
2
is CH
3
or CH
2
CH
3
; R
3
is H, 4-F or 4-Cl; R
4
is H or CH
3
and X is NH or O connected to the heterocycle in the 4-position.
Particularly preferred compounds according to the invention are:
4-(2,6-dimethylbenzylamino)-2-methylbenzimidazole;
4-(2,6-dimethylbenzyloxy)-2-methylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzylamino)-2-methylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzyloxy)-2-methylbenzimidazole;
4-(2,6-dimethylbenzylamino)-1,2-dimethylbenzimidazole;
4-(2-ethyl-6-methylbenzylamino)-2-methylbenzimidazole;
4-(2,6-diethylbenzylamino)-2-methylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzylamino)-1,2-dimethylbenzimidazole;
4-(2,6-dimethyl-4-fluorobenzyloxy)-1,2-dimethylbenzimidazole.
Preparation
The present invention also provides the following processes A to C for the manufacture of compounds with the general Formula I:
Process A
Process A for manufacture of compounds with the general Formula I comprises the following steps:
a) Compounds of the general Formula II
wherein X
1
is NH
2
or OH connected to the heterocycle in the position 4 or 7 and R
4
is as defined for Formula I, can be reacted with compounds of the general Formula III:
wherein R
1
, R
2
and R
3
are as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesyloxy, to the compounds of the Formula I.
It is convenient to conduct this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide with or without a base. The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; a sodium alcoholate, such as sodium methoxide and sodium ethoxide; an alkali metal hydride such as sodium hydride and potassium hydride; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamin.
Process B
Process B for manufacture of compounds with the general Formula I comprises the following step:
A compound of the Formula IV:
wherein R
4
is as defined for Formula I and the NH
2
group is connected to the heterocycle in the position 4 or 7, can be reacted with compounds of the general Formula V:
wherein R
1
, R
2
and R
3
are as defined for Formula I, in the presence of a Lewis acid e.g. zinc chloride to the compounds of the Formula VI:
wherein R
4
is as defined for Formula I and the imine nitrogen is connected to the heterocycle in the position 4 or 7, whereby the compounds of the general Formula VI are reduced e.g. by using sodium borhydride or sodiumcyano borhydride to compounds of the general Formula I. The reactions can be carried out under standard conditions in an inert solvent e.g. methanol orethanol.
Process C
Compounds of the general Formula I wherein R
4
is “lower alkyl” can be made by alkylation of compounds of the general Formula I wherein R
4
is H in an inert solvent, e.g. acetonitrile or acetone, with or without base with compounds of the general Formula VII:
R
4
X
2
VII
wherein R
4
is as defined for Formula I and X
2
is a leaving group e.g. a halide, mesylate or tosylate. The base is e.g. an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide; a sodium alcoholate, such as sodium methoxide and sodium ethoxide; an alkali metal hydride such as sodium hydride and potassium hydride; an alkali metal carbonate, such as potassium carbonate and sodium carbonate; or an organic amine, such as triethylamine.
Medical Use
In a further aspect, the invention relates to compounds of the formula I for use in therapy, in particular for use against gastrointestinal inflammatory diseases. The invention also provides the use of a compound of the formula I in the manufacture of a medicament for the inhibition of gastric acid secretion, or for the treatment of gastrointestinal inflammatory diseases.
The compounds according to the invention may thus be used for prevention and treatment of gastrointestinal inflammatory dis
Amin Kosrat
Dahlström Mikael
Nordberg Peter
Starke Ingemar
AstraZeneca AB
Morris Patricia L.
White & Case LLP
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