Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-08
2003-02-11
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S249000, C514S558000, C514S300000, C544S236000, C544S281000, C544S349000, C544S350000, C546S113000
Reexamination Certificate
active
06518270
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]pyrazines are disclosed in EP-A-0068378, U.S. Pat. No. 4,507,294 and EP-A-0204285. Pyrrolo[2,3-d]pyridazines are disclosed in WO 91/17164, WO 92/06979, WO 93/08190 and WO 95/19980. Pyrrolo[1,2-a]pyrazines are disclosed in U.S. Pat. No. 5,041,442.
Benzimidazole and imidazo pyridine derivatives, in which the phenyl moiety is substituted with lower alkyl in 2- and 6-position, and which are effective as inhibitors of the gastrointestinal H
+
, K
+
-ATPase, are disclosed in the International Patent Application PCT/SE97/00991 (filing date: Jun. 5, 1997) and in the Swedish Patent Application No. 9700661-3 (filing date: Feb. 25, 1997), respectively.
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 heterocyclic compounds in which the phenyl moiety is substituted with lower (C
1
-C
6
) 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:
wherein
R
1
is C
1
-C
6
alkyl;
R
2
is C
1
-C
6
alkyl;
R
3
is H or halogen; and
is a substituted heterocycle selected from
wherein
R
4
is H, CH
3
, CH
2
OH or CH
2
CN;
R
5
is H or C
1
-C
6
alkyl;
R
6
is H , C
1
-C
6
alkyl, aryl, arylalkyl containing 1-2 carbon atoms in the alkyl part, C
2
-C
6
alkenyl, halo(C
2
-C
6
alkenyl), C
2
-C
6
alkynyl, C
3
-C
7
cycloalkyl or halo(C
1
-C
6
alkyl);
R
7
is H, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkylthio or thiocyano;
n is 0 or 1; and
X is NH or O.
Preferred compounds according to the invention are those wherein:
R
1
is CH
3
or CH
2
CH
3
;
R
2
is CH
3
or CH
2
CH
3
; and
R
3
is H, Br, Cl or F.
Other preferred compounds according to the invention are:
wherein
R
4
is CH
3
or CH
2
OH; and
X, n, R
1
, R
2
, R
3
, R
5
, R
6
and R
7
are as defined for Formula I. Particularly preferred are those compounds wherein R
1
, R
2
and R
3
are the preferred substituents defined above.
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 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 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, 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-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
Preparation
The present invention also provides the following processes A and B 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 OH or NH
2
, can be reacted with compounds of the general Formula III
wherein R
1
, R
3
and R
4
are as defined for Formula I and Y
1
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, xylene 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 triethylamine.
Process B
Process B for manufacture of compounds with the general Formula I comprises the following steps:
Compounds of the general Formula IV
wherein X
2
is a leaving group e.g. halide, can be reacted with compounds of the general Formula V
wherein R
1
, R
3
and R
4
are as defined for Formula I and Y
2
is NH
2
or OH to compounds of the general Formula I.
It is convenient to conduct this reaction in an inert solvent, e.g. acetone, acetonitrile, dimethoxyethane, methanol, ethanol, xylene 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 triethylamine.
Pharmaceutical Formulations
In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the invention, or a therapeutically acceptable salt thereof, as active ingredient.
The compounds of the invention can also be used in formulations together with other active ingredients, e.g. antibiotics such as amoxicillin.
For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.1-20% by weight in preparations for parenteral use and preferably between 0.1 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration
Amin Kosrat
Dahlström Mikael
Nordberg Peter
Starke Ingemar
AstraZeneca AB
Raymond Richard L.
White & Case LLP
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