Substituted benzoylguanidines, process for their...

Details Substituted benzoylguanidines, process for their... Substituted benzoylguanidines, process for their...

2001-01-17

2004-03-09

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S267400, C548S336100

Reexamination Certificate

active

06703411

ABSTRACT:

The invention relates to benzoylguanidines of the formula (I)
in which:
R1 is hydrogen, F, Cl, Br, I, NO
2
, CN, —X
o
—(CH
2
)
p
—(CF
2
)
q
—CF
3
, R5—SO
m
—, R6—CO—, R6R7N—CO— or R6R7N—SO
2
—;
X is oxygen, —S— or NR14;
m is zero, 1 or 2;
o is zero or 1;
p is zero, 1 or 2;
q is zero, 1, 2, 3, 4, 5 or 6;
R5 and R6
independently of one another are (C
1
-C
8
)-alkyl, (C
3
-C
6
)-alkenyl, —C
n
H
2n
—R8 or CF
3
;
n is zero, 1, 2, 3 or 4;
R8 is (C
3
-C
7
)-cycloalkyl, or phenyl
which is not substituted or is substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF
3
, methyl, methoxy and NR9R10;
R9 and R10 are
 H or (C
1
-C
4
)-alkyl;
or
R6 is hydrogen;
R7 is hydrogen or (C
1
-C
4
)-alkyl;
or
R6 and R7
together can be 4 or 5 methylene groups, of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
or N-benzyl;
R2 is —Y-p-(C
6
H
4
—R11, —Y-m-(C
6
H
4
)—R11 or —Y-o-(C
6
H
4
)—R11;
R11 is (C
1
-C
9
)-heteroaryl which is linked via C or N and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino, dimethylamino and benzyl;
Y is oxygen, —S— or NR12;
R12 is H or (C
1
-C
4
)-alkyl;
R3 is defined as R1;
or
R3 is (C
1
-C
6
)-alkyl or —X—R13;
X is oxygen, —S— or NR14;
R14 is
H or (C
1
-C
3
)-alkyl;
R13 is
H, (C
1
-C
6
)-alkyl, (C
3
-C
8
)-cycloalkyl or —C
b
H
2b
—R15;
b is zero, 1, 2, 3 or 4;
R15 is
phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, methyl, methoxy and NR9R10;
R9 and R10 are
 H or (C
1
-C
4
)-alkyl;
or
R13 and R14
together are 4 or 5 methylene groups, of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
or N-benzyl;
R4 is F, Cl, Br, I or (C
1
-C
4
)-alkyl;
as well as pharmaceutically tolerated salts thereof.
Another embodiment of the invention comprises compounds of the formula (I) in which:
R1 is hydrogen, F, Cl, CN, CF
3
, R5—SO
m
—, R6—CO—, R6R7N—CO— or R6R7N—SO
2
—;
m is zero, 1 or 2;
R5 and R6
independently of one another are (C
1
-C
8
)-alkyl, (C
3
-C
4
)-alkenyl, —C
n
H
2n
—R8 or CF
3
;
n is zero or 1;
R8 is (C
3
-C
6
)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF
3
, methyl, methoxy and NR9R10;
R9 and R10 are
 H or methyl;
or
R6 is hydrogen;
R7 is hydrogen or methyl;
R2 is —Y-p-(C
6
H
4
)—R11, —Y-m-(C
6
H
4
)—R11 or —Y-o-(C
6
H
4
)—R11;
R11 is (C
1
-C
9
)-heteroaryl which is linked via C or N and which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino, dimethylamino and benzyl;
Y is oxygen, —S— or NR12;
R12 is H or (C
1
-C
4
)-alkyl;
R3 is hydrogen, methyl, CN, CF
3
, F or Cl;
R4 is F, Cl or (C
1
-C
4
)-alkyl;
as well as pharmaceutically tolerated salts thereof.
Yet another embodiment of the invention comprises compounds of formula (I) in which:
R1 is hydrogen, F, Cl, CN, CF
3
or R5—SO
m
—;
m is zero, 1 or 2;
R5 is
methyl or CF
3
;
R2 is —Y-p-(C
6
H
4
)—R11, —Y-m-(C
6
H
4
)—R11 or —Y-o-(C
6
H
4
)—R11;
R11 is (C
1
-C
9
)-heteroaryl which is linked via C or N and which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, dimethylamino and benzyl;
Y is oxygen;
R3 is hydrogen, methyl, CN, CF
3
, F or Cl;
R4 is (C
1
-C
4
)-alkyl;
as well as pharmaceutically tolerated salts thereof.
Other embodiments of the invention are compounds of the formula (I) in which:
R1 is hydrogen, F, Cl, CN, CF
3
or R5—SO2—;
R5 is methyl or CF
3
;
R2 is —Y-p-(C
6
H
4
)—R11, —Y-m-(C
6
H
4
)—R11 or —Y-o-(C
6
H
4
)—R11;
R11 is (C
1
-C
5
)-heteroaryl which is linked via C or N and which is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, dimethylamino and benzyl;
Y is oxygen;
R3 is hydrogen;
R4 is (C
1
-C
4
)-alkyl;
as well as pharmaceutically tolerated salts thereof.
Still other embodiments of the invention encompass compounds of the formula (I) in which:
R1 is CF
3
;
R2 is —Y-p-(C
6
H
4
)—R11, —Y-m-(C
6
H
4
)—R11 or —Y-o-(C
6
H
4
)—R11;
R11 is imidazolyl or triazolyl which in each case is unsubstituted or substituted by 1 to 2 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, dimethylamino and benzyl;
Y is oxygen;
R3 is hydrogen;
R4 is methyl;
as well as pharmaceutically tolerated salts thereof.
All alkyl radicals can be either straight-chain or branched.
(C
1
-C
9
)-heteroaryl is understood to mean radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N, and/or in which at least two neighboring CH groups are replaced by S, NH, or O (with the formation of a five-membered aromatic ring). In addition, one or both atoms of the fusion site of bicyclic radicals (as in indolizinyl) can also be N atoms.
Heteroaryl may be furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl; particularly furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, indolyl, quinolyl, and isoquinolyl.
The invention furthermore relates to processes for preparing the compound I, which comprises reacting a compound of the formula (II)
where R1 to R4 have the meanings given above, and L is a leaving group which can readily be substituted nucleophilically, with guanidine.
The activated acid derivatives of the formula (II), in which L is an alkoxy group, such as a methoxy group, a phenoxy group, a phenylthio, methylthio or 2-pyridylthio group, or a nitrogen heterocycle, e.g., 1-imidazolyl, are advantageously obtained, in a manner known in the art, from the underlying carbonyl chlorides (formula (II), L=Cl), which, for their part, can in turn be prepared, in a manner known in the art, from the underlying carboxylic acids (formula (II), L=OH), for example, using thionyl chloride.
In addition to the carbonyl chlorides of the formula (II) (L=Cl), further activated acid derivatives of the formula (II) can also be prepared, in a manner known in the art, directly from the underlying benzoic acid derivatives (formula (II), L=OH). Such activated acid derivatives include the methyl esters of the formula (II) where L=OCH
3
, prepared by treating with gaseous HCl in methanol; the imidazolides of the formula (II), prepared by treating with carbonyldiimidazole (L=1-imidazolyl, Staab,
Angew. Chem. Int. Ed. Engl
. 1, 351-367 (1962)); the mixed anhydrides II, prepared with Cl—COOC
2
H
5
or tosyl chloride in the presence of triethylamine in an inert solvent; as well as the activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) (Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991). A series of suitable methods for preparing activated carboxylic acid derivatives of the formula (II) are given, with citation of the source literature, in J. March,
Advanced Organic Chemistry
, Third Edition (John Wiley & Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the formula (II) with guanidine is effected, in a manner known per se, in a protic or aprotic organic solvent which is polar but inert. In this context, methanol, isopropanol or THF have proven to be suitable, at temperatures of from 20° C. up to the boiling temperature of these solvents, for use in the reaction of the methyl benzoates (formula (II), L=OMe) with guanidine. Aprotic, inert solvents, such as THF, dimethoxyethane and dioxane, were advantageously employed in most of the reactions of compounds of formula (II) with salt-free guanidine. However, while employing a

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