Compounds

Details Compounds Compounds

1999-10-13

2003-06-17

Aulakh, Charanjit S. (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

06579884

ABSTRACT:

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.); from WO 9418199 and WO 9510518 (Byk Gulden Lomberg Chem.) 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, which are substituted imidazopyridine derivatives, are 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) C
1
-C
6
alkyl,
(c) C
1
-C
6
alkenyl,
(d) CH
2
OH,
(e) halogen, or
(f) thiocyano
R
2
is
(a) C
1
-C
6
alkyl,
(b) hydroxyalkyl,
(c) C
1
-C
6
alkoxy C
1
-C
6
alkyl,
(d) hydroxy C
1
-C
6
alkoxy C
1
-C
6
alkyl,
(e) C
1
-C
6
alkylthio C
1
-C
6
alkyl,
(f) cyano C
1
-C
6
alkyl,
(g) halogenated C
1
-C
6
alkyl, or
(h) aminocarbonyl C
1
-C
6
alkyl
R
3
is
(a) H,
(b) C
1
-C
6
alkoxy,
(c) C
1
-C
6
alkyl,
(d) halogen,
(e) hydroxy C
1
-C
6
alkyl.
(f) hydroxy C
1
-C
6
alkoxy,
(g) C
1
-C
6
alkoxy C
1
-C
6
alkyl,
(h) C
1
-C
6
alkoxy C
1
-C
6
alkoxy,
(i) C
1
-C
6
alkoxycarbonyl,
(j) C
1
-C
6
alkanoyl,
(k) halogenated C
1
-C
6
alkyl,
(l) NO
2
,
(m) CN,
(n) C
1
-C
6
sulfonyl,
(o) C
1
-C
6
sulfinyl,
(p) C
1
-C
6
alkylthio,
(q) C
1
-C
6
alkylaminosulfonyl,
(r) C
1
-C
6
(alkyl)
2
aminosulfonyl,
(s) aminosulfonyl,
(t) C
1
-C
6
alkylsulfonylamino,
(u) C
1
-C
6
(alkylsulfonyl)
2
amino,
(v) trifluoromethylsulfonylamino,
(x) C
1
-C
6
alkylcarbonylamino,
(y) C
1
-C
6
alkoxycarbonylamino, or
(Z) C
1
-C
6
aminocarbonylamino, optionally substituted by one or two C
1
-C
6
alkyl groups,
R
4
is
(a) H,
(b) C
1
-C
6
alkyl,
(c) halogenated C
1
-C
6
alkyl,
(d) C
1
-C
6
alkoxy, or
(e) halogen.
Ar is a phenyl, thienyl, furanyl, naphthyl, or pyridyl group substituted with one or more substituents selected from the group consisting of R
5
, R
6
, and R
7
.
X is
R
5
is
(a) H,
(b) C
1
-C
6
alkyl,
(c) C
1
-C
6
alkoxy,
(d) hydroxy,
(e) hydroxy C
1
-C
6
alkyl,
(f) hydroxy C
1
-C
6
alkoxy,
(g) halogenated C
1
-C
6
alkyl,
(h) halogenated C
1
-C
6
alkoxy,
(i) C
1
-C
6
alkoxy C
1
-C
6
alkyl,
() halogen,
(k) hydroxy C
1
-C
6
alkoxy C
1
-C
6
alkyl,
(l) CN,
(m) C
1
-C
6
alkoxycarbonyl,
(n) C
1
-C
6
alkoxycarbonyloxy,
(O) C
1
-C
6
alkylsulfonyloxy,
(p) trifluoromethylsulfonyloxy,
(q) C
1
-C
6
acyloxy C
1
-C
6
alkyl,
(r) C
1
-C
6
alkylsulfonyl C
1
-C
6
alkyl.
(s) C
1
-C
6
alkylsulfinyl C
1
-C
6
alkyl,
(t) C
1
-C
6
alkylthio C
1
-C
6
alkyl,
(u) C
1
-C
6
alkoxycarbonylamino C
1
-C
6
alkyl,
(v) aryl,
(x) amino C
1
-C
6
alkyl,
(y) NHC═OR
12
(z) H or C
1
-C
4
alkyl substituted
 -group
(aa) H or C
1
-C
4
alkyl substituted
 -group, or
(ab) C
1
-C
6
alkyl sulfonyl amino
R
6
is
(a) H,
(b) C
1
-C
6
alkyl,
(c) halogen,
(d) hydroxy C
1
-C
6
alkyl,
(e) halogenated C
1
-C
6
alkyl,
(f) halogenated C
1
-C
6
alkoxy,
(e) C
1
-C
6
alkoxy C
1
-C
6
alkyl, or
(f) CN
R
7
is
(a) H,
(b) C
1
-C
6
alkyl,
(c) C
1
-C
6
alkoxy,
(d) halogen,
(e) NO
2
,
(f) halogenated C
1
-C
6
alkyl,
(g) halogenated C
1
-C
6
alkoxy,
(h) aryloxy, or
(i) CN
R
8
is
(a) H or
(b) C
1
-C
6
alkyl R
12
is
(a) C
1
-C
6
alkoxy,
(b) C
1
-C
6
alkoxy C
1
-C
4
alkoxy,
(c) NH
2
,
(d) hydroxy C
2
-C
4
alkoxy,
(e) C
1
-C
6
alkyl carbonyloxy C
2
-C
4
alkoxy,
(f) halogenated C
2
-C
4
alkoxy,
(g) halogenated C
1
-C
4
alkyl,
(h) hydroxy C
1
-C
4
alkyl,
(i) C
1
-C
6
alkyl carbonyloxy C
1
-C
4
alkyl,
(j) aryl,
(k) aryl C
1
-C
4
alkyl,
(l) C
1
-C
4
sulfanyl C
2
-C
4
alkoxy,
(m) C
1
-C
4
sulfinyl C
2
-C
4
alkoxy, or
(n) C
1
-C
4
sulfonyl C
2
-C
4
alkoxy,
R
5
and R
6
are in the ortho positions relative to X
R
7
is in the meta or para position relative to X
R
5
and R
8
may together form a hydroxy- or alkoxy-substituted 5- or 6-membered ring,
provided that one of R
3
and R
4
≠H or halogen
provided also that at least one of R
5
, R
6
and R
7
≠H
provided also that when R
5
=(y),(z),(aa) or (ab), at least one of R
3
and R
4
≠H
provided also that when R
1
=H or Cl, XAr≠OCH
2
Ar
provided also that when R
1
=H, halogen or CH
2
OH, at least one of R
5
and R
6
is C
1
-C
6
alkyl
provided also that when R
2
is CH
2
OH or CH
2
CN, at least one of R
5
and R
6
is C
1
-C
6
alkyl
The term “aryl” includes phenyl, naphthyl, thienyl, furyl, pyridyl or imidazolyl, optionally substituents by 1-3 substituents selected from H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen or CF
3
.
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 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 the two enantiomers are within the scope of the invention. It should be understood that all the possible diastereomeric forms (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the present 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 present 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, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic 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 H, CH
3
, CH
2
OH;
R
2
is CH
3
, CH
2
CH
3
, CH
2
CH
2
OH, CH
2
CH
2
SCH
3
, CH
2
CH
2
OCH
3
or CH
2
CH
2
CN;
R
3
is H, CH
3
, CH
2
CH
3
, F, Cl, Br, OCH
3
,OCH
2
C

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