Heterocyclic substituted acylaminothiazoles, their...

Details Heterocyclic substituted acylaminothiazoles, their... Heterocyclic substituted acylaminothiazoles, their...

1995-09-11

2001-03-13

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S301000, C514S307000, C514S314000, C546S114000, C546S146000, C546S169000, C548S150000, C548S181000, C548S195000

Reissue Patent

active

RE037094

ABSTRACT:

The present invention relates to heterocyclic compounds which are cholecystokinin and gastrin antagonists.
Cholecystokinin (CCK) is a polypeptide hormone present in vivo in various forms comprising from 8 t 39 amino acids. It has numerous physiological activities on the bile ducts, the gastrointestinal tract and on the central and peripheral nervous systems and reference can be made to the article by J. E. Morley in Life Sciences vol. 30, p. 479-493 (1982), which gives a detailed review of its properties. Two different types of CCK receptors have been demonstrated with the use of specific antagonists; those of type A present in particular in the
pancrease

pancreas
, the
glass

gall
bladder and some
area

areas
of the central nervous system, while those of type B are found above all in the central nervous system.
Gastrin is a polypeptide hormone which acts in particular on the acid secretion of the stomach; its 5 C-terminal amino acids are identical to those of CCK.
Gastrin and/or CCK antagonist compounds have already been described, in particular proglumide and p-chlorobenzoyl-L-tryptophane, or, more recently, benzodiazepin derivatives which are specific antagonists either of CCK A receptors, such as 3S(−)-N-[1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-indole-2-carboxamide (cf. Eur. J. Pharmacology 162, 273-280, (1989)) or of CCK B receptors, such as 3R(+)-N-[1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-[3-methylphenyl]urea.
The compounds according to the invention are heterocyclic
unsubstituted

substituted
2-acylaminothiazoles of formula I:
in which
R
1
represents a hydrogen atom, a (C
1
to C
4
) alkyl group or a phenylalkyl group containing (C
1
to C
3
) alkyl; an amino alkyl group of formula —Z
1
—NR
4
R
5
, in which Z
1
represents a (C
2
to C
4
) alkylene and R
4
and R
5
independently represent H or a (C
1
to C
4
) alkyl or form, with the nitrogen atom to which they are bonded, a saturated heterocycle such as morpholino, pyrrolidinyl, piperidino, piperazinyl or 4-(C
1
-C
3
)alkylpiperazinyl; an optionally esterified carboxyalkyl group of formula —Z
2
—COOR
6
, in which Z
2
represents a (C
1
to C
4
) alkylene and R
6
represents H or a (C
1
to C
6
) alkyl; a (C
2
to C
5
) cyanoalkyl group; a carbamoylalkyl group of formula —Z
3
—CONR
7
R
8
, in which Z
3
represents a (C
1
to C
4
) alkylene and R
7
and
R
6

R
8
independently represent H or a (C
1
to C
4
) alkyl or, with N, represent a heterocycle such as NR
4
R
5
; a (C
2
to C
6
) hydroxyalkyl group or a (C
2
to C
10
) alkoxyalkyl group, R
2
represents a hydrogen atom or a (C
1
to C
4
) alkyl group; R
3
represents a (C
5
to C
8
) cycloalkyl group which is optionally substituted by one or more (C
1
to C
4
) alkyl groups; an aromatic group, such as a phenyl, optionally carrying one
of

or
more substituents chosen from halogen atoms, in particular chlorine or fluorine, (C
1
-C
6
) alkyl and (C
1
to C
3
) alkoxy and thioalkoxy groups and nitro and trifluoromethyl groups, or such as a heterocycle comprising at least one hetero-atom chosen from O, S, and N, in particular furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl and thiazolyl, which are optionally substituted by a (C
1
to C
3
) alkyl group or a halogen atom, or R
2
and R
3
considered together represent the group
fixed by the carbon of the phenyl in position 4 of the thiazolyl ring and in which q is 1 to 4, optionally carrying one or more (np) substituents Xp, which may be identical or different and are chosen from halogen atoms, (C
1
to C
3
) alkyl and alkoxy groups and
the
nitro and trifluoromethyl groups, np being from 0 to 3, and Z represents a heterocycle comprising one or more heteroatoms chosen from O, S and N, fused with an aromatic ring which may also comprise a hetero-atom chosen from O, S and N and which may be substituted by one or more groups chosen from halogen atoms, (C
1
to C
3
) alkyl and alkoxy, benzyloxy, nitro, amino and trifluoromethyl groups, as well as the addition salts of these compounds with inorganic or organic acids and bases; the pharmaceutically acceptable non-toxic salts are preferred, but other salts which can be used to isolate or purify the compounds of formula I are also within the invention.
The alkyl, alkylene, alkoxy and thioalkoxy groups can be straight-chain or branched.
Z represents in particular benzothienyl, benzofuranyl, benzoxazolyl, benzimidazoly, benzothiazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl and [2,3-c] or [3,2-c]thienopyridyl groups.
When Z represents an indolyl or indolinyl group of formula
in which (X
i
)
ni
represents the optional substituents on the aromatic ring, R
9
may represent H; a (C
1
to C
4
) alkyl group; a (C
1
to C
6
) hydroxyalkyl group; an optionally cyclised (C
2
to C
10
) alkoxyalkyl group, such as a tetrahydropyranyl; an amino alkyl group of formula —Z
4
—NR
10
R
11
, in which Z
4
represents a (C
2
to C
4
) alkylene and R
10
and R
11
independently represent H or a (C
1
to C
4
) alkyl or form, with the nitrogen atom to which they are bonded, a saturated heterocyclic group such as morpholino, pyrrolidinyl, piperidino, piperazinyl or 4-(C
1
-C
3
)alkylpiperazinyl; an optionally esterified carboxyalkyl group of formula —Z
5
—COOR
12
in which Z
5
represents a (C
1
to C
4
) alkylene and R
12
represents H, benzyl or a (C
1
to C
6
) alkyl; a cyanoalkyl group containing (C
1
to C
4
) alkyl; a carbamoylalkyl group of formula —Z
6
—CONR
13
R
14
in which R
13
and R
14
independently represent H or a (C
1
to C
6
) alkyl or form, with N, a saturated heterocycle such as NR
10
R
11
, and Z
6
is a (C
1
to C
4
) alkylene; an acyl group of formula COR
15
, in which R
15
represents a (C
1
to C
4
) alkyl or phenyl; or an alkoxycarbonyl group of formula COOR
16
, in which R
16
represents t-butyl or benzyl.
Amongst the compounds of formula I, those in which R
1
represents H, an alkyl or an amino alkyl are preferred, and amongst these, those in which Z represents an indolyl group which is unsubstituted or substituted on the nitrogen are more particularly preferred; amongst the groups R
3
, the preferred groups are phenyl which are at least ortho-substituted, when R
2
represents H.
The compounds of formula I may be prepared by a coupling reaction of an aminothiazole of formula II
under the usual conditions for acylation of an amine, with an acid of formula Z′COOH, in which Z′ represents Z or a derivative of Z in which the reactive groups of Z have been protected, and R
1
, R
2
, R
3
and Z have the same meaning as in the formula I, or with an activated form of the acid Z′COOH, such as an acid halide, an acid anhydride, and preferably a mixed anhydride such as a carbonic anhydride, or an activated ester, obtained using the reagents commonly used in peptide synthesis.
The compounds of formula I in which Z is replaced by Z′ are also within the invention as synthetic intermediates; furthermore, some have, in vivo, the same therapeutic activity, in particular owing to their metabolisation to compounds of formula I.
When groups have been protected, the appropriate deprotection reaction is carried out, if necessary, after the condensation reaction.
Numerous aminothiazoles of formula II are known.
The new aminothiazoles may be prepared in accordance with one of the processes described previously, in particular in Bull. Soc. Chim. (C) p. 2498-2503 (1963).
In general, a thiourea will be reacted with an alpha-halogenated, and preferably alpha-brominated, ketone, in accordance with the reaction scheme:
R
1
, R
2
and R
3
having the same meaning as in the formula II.
The preparation of various compounds II in which R
1
represents an aminoalkyl group is described in EP-A-0,283,390.
The alpha-halogenated ketones and the thioureas can be prepared by processes for which the principles are described in the literature; thus, the alpha-

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