Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-03-10
2001-07-24
Huang, Evelyn Mei (Department: 1609)
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
06265415
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).
An imidazo pyridine derivative being substituted in 8-position with 2,4,6-(CH
3
)
3
—C
6
H
2
CH
2
O is disclosed in EP-B-0033094 and as “Compound No. 49” in Kaminski et al., J. Med. Chem. vol. 28, 876-892, 1985. However, according to the latter publication, the said compound did not show favorable characteristics when tested as an inhibitor of gastric acid secretion.
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 imidazo pyridine 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 CH
3
or CH
2
OH;
R
2
is lower alkyl;
R
3
is lower alkyl;
R
4
is H or halogen;
R
5
is H, halogen, or lower alkyl;
X is NH or O.
As used herein, the term “lower alkyl” denotes a straight or branched alkyl group having from 1 to 6, preferably 1 to 4, carbon atoms. Examples of “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. Preferably, “lower alkyl” means methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
The term “halogen” includes fluoro, chloro, bromo and iodo.
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 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
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; and R
5
is H, CH
3
, Br, Cl or F, more preferably H, CH
3
, or F.
Particularly preferred compounds according to the invention are:
8-(2,6-dimethylbenzylamino)-2,3,6-trimethylimidazo[1,2-a]pyridine;
8-(2,6-dimethylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;
2,3-dimethyl-8-(2,6-dimethyl-4-fluorobenzylamino)imidazo[1,2-a]pyridine;
2,6-dimethyl-8-(2,6-dimethylbenzylamino)-3-hydroxymethyl imidazo[1,2-a]pyridine;
2,6-dimethyl-8-(2,6-dimethyl-4-fluorobenzylamino)-3-hydroxymethylimidazo[1,2-a]pyridine;
8-(2,6-dimethyl-4-fluorobenzylamino)-2,3,6-trimethyl imidazo[1,2-a]pyridine;
2,3-dimethyl-8-(2,6-dimethyl-4-chlorobenzylamino)imidazo[1,2-a]pyridine;
2,6-dimethyl-8-(2-ethyl-6-methylbenzylamino)-3-hydroxymethylimidazo[1,2-a]pyridine;
8-(2,6-diethylbenzylamino)-2,6-dimethyl-3-hydroxymethylimidazo[1,2-a]pyridine;
8-(2-ethyl-6-methylbenzylamino)-2,3,6-trimethylimidazo[1,2-a]pyridine;
8-(2,6-dimethyl-4-fluorobenzyloxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;
2,6-dimethyl-8-(2,6-dimethylbenzyloxy)-3-hydroxymethylimidazo[1,2-a]pyridine;
2,6-dimethyl-8-(2-ethyl-4-fluoro-6-methylbenzylamino)-3-hydroxymethylimidazo[1,2-a]pyridine;
8-(2-ethyl-4-fluoro-6-methylbenzylamino)-2,3,6-trimethylimidazo[1,2-a]pyridine.
Preparation
The present invention also provides the following processes A, B, C, D, and E 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:
Compounds of the general Formula II
wherein X
1
is NH
2
or OH, and R
1
and R
5
are as defined for Formula I, can be reacted with compounds of the general Formula III
wherein R
2
, R
3
and R
4
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; 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, wherein X is NH, comprises the following steps:
Compounds of the general Formula IV
wherein R
1
and R
5
are as defined for Formula I, can be reacted with compounds of the general Formula V
wherein R
2
, R
3
and R
4
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
1
, R
2
, R
3
, R
4
and R
5
are as defined for Formula I, whereupon the compounds of the general Formula VI are reduced e.g. by using sodiumborohydride or sodiumcyano borohydride to compounds of the general Formula I wherein X is NH. The reactions can be carried out under standard conditions in an inert solvent e.g. methanol or ethanol.
Process C
Process C for manufacture of compounds with the general Formula I, wherein R
1
is CH
2
OH, comprises the following steps:
Compounds of the general Formula VII
wherein X
1
is NH
2
or OH and R
5
are as defined for Formula I, can be reacted with compounds of the general Formula III
wherein R
2
, R
3
and R
4
are as defined for Formula I and Y is a leaving group, such as a halide, tosyloxy or mesy
Amin Kosrat
Dahlström Mikael
Nordberg Peter
Starke Ingemar
Astrazeneca AB
Huang Evelyn Mei
White & Case LLP
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