Substituted anthranilic acids, their use as a medicament or...

Details Substituted anthranilic acids, their use as a medicament or... Substituted anthranilic acids, their use as a medicament or...

2001-12-06

2003-07-15

Davis, Brian (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S438000, C514S047000, C514S562000, C546S334000, C549S494000, C549S076000, C562S430000

Reexamination Certificate

active

06593352

ABSTRACT:

This application claims the benefit of foreign priority under 35 U.S.C. §119 of German patent application no. 10060809.4-43, filed on Dec. 7, 2000 the contents of which are incorporated by reference herein.
The present invention relates to substituted anthranilic acids. In one embodiment, the invention relates to the use of substituted anthranilic acids as a medicament or diagnostic, including a medicament comprising at least one substituted anthranilic acid, and a pharmaceutical combination preparation containing at least one sodium/hydrogen exchange (NHE) blocker and at least one substituted anthranilic acid.
The invention relates to anthranilic acids of the formula I
in which:
R(1) is H, Cl, Br, I, CN, (C
1
-C
8
)-alkyl, (C
3
-C
6
)-cycloalkyl, unsubstituted phenyl, or substituted phenyl
where the substituted phenyl is substituted by 1-3 substituents chosen from F, Cl, (C
1
-C
3
)-alkyl, methoxy and —(CF
2
)
a
—CF
3
; and
where a is zero, 1, 2 or 3;
R(2) is (C
1
-C
8
)-alkyl, —C
b
H
2b
—(C
3
-C
6
)-cycloalkyl, unsubstituted —C
b
H
2b
phenyl, substituted —C
b
H
2b
-phenyl, unsubstituted —C
b
H
2b
-pyridinyl, substituted —C
b
H
2b
-pyridinyl, unsubstituted —C
b
H
2b
-thiophenyl, substituted —C
b
H
2b
-thiophenyl, unsubstituted —C
b
H
2b
-furanyl, or substituted —C
b
H
2b
-furanyl
where the substituted —C
b
H
2b
-phenyl, the substituted —C
b
H
2b
-pyridinyl, the substituted —C
b
H
2b
-thiophenyl, and the substituted —C
b
H
2b
-furanyl are each independently substituted by 1-3 substituents chosen from F, Cl, CF
3
, (C
1
-C
3
)-alkyl, methoxy and —SO
2
NR(4)R(5);
where R(4) and R(5) independently of one another are H or (C
1
-C
4
)-alkyl, and
where b is zero, 1, 2, 3 or 4;
R(3) is unsubstituted —C
d
H
2d
-phenyl or substituted —C
d
H
2d
-phenyl,
where the substituted —C
d
H
2d
-phenyl is substituted by 1-3 substituents chosen from F, Cl, CF
3
, (C
1
-C
3
)-alkyl and methoxy; and
where d is 3 or 4;
and their pharmaceutically tolerable salts.
In one embodiment, the compounds of formula 1 are those in which:
R(1) is Cl, (C
1
-C
4
)-alkyl, unsubstituted phenyl, or substituted phenyl
where the substituted phenyl is substituted by 1-3 substituents chosen from F, Cl, CF
3
, (C
1
-C
3
)-alkyl and methoxy;
R(2) is (C
1
-C
4
)-alkyl, —C
b
H
2b
-cyclohexyl, unsubstituted —C
b
H
2b
-phenyl, substituted —C
b
H
2b
-phenyl, unsubstituted —C
b
H
2b
-pyridinyl, substituted —C
b
H
2b
-pyridinyl, unsubstituted —C
b
H
2b
-thiophenyl, substituted —C
b
H
2b
-thiophenyl, unsubstituted —C
b
H
2b
-furanyl, or substituted —C
b
H
2b
-furanyl
where the substituted —C
b
H
2b
-phenyl, the substituted —C
b
H
2b
-pyridinyl, the substituted —C
b
H
2b
-thiophenyl, and the substituted —C
b
H
2b
-furanyl are each independently substituted by 1-3 substituents chosen from F, Cl, CF
3
, (C
1
-C
3
)-alkyl, methoxy and —SO
2
NH
2
; and
where b is zero, 1 or 2;
R(3) is unsubstituted -n-C
4
H
8
-phenyl or substituted -n-C
4
H
8
-phenyl,
where the substituted -n-C
4
H
8
-phenyl is substituted by 1-3 substituents chosen from F, Cl, CF
3
, (C
1
-C
3
)-alkyl and methoxy;
and their pharmaceutically tolerable salts.
In another embodiment, the compounds of formula 1 are those in which:
R(1) is Cl, (C
1
-C
4
)-alkyl, unsubstituted phenyl or substituted phenyl,
where the substituted phenyl is substituted by 1-3 substituents chosen from F, Cl, CF
3
, (C
1
-C
3
)-alkyl and methoxy;
R(2) is (C
1
-C
4
)-alkyl, —C
b
H
2b
-cyclohexyl, unsubstituted —C
b
H
2b
-phenyl, substituted —C
b
H
2b
-phenyl, unsubstituted —C
b
H
2b
-pyridinyl, substituted —C
b
H
2b
-pyridinyl, unsubstituted —C
b
H
2b
-thiophenyl, substituted —C
b
H
2b
-thiophenyl, unsubstituted —C
b
H
2b
-furanyl, or substituted —C
b
H
2b
-furanyl
where the substituted —C
b
H
2b
-phenyl, the substituted —C
b
H
2b
-pyridinyl, the substituted —C
b
H
2b
-thiophenyl, and the substituted —C
b
H
2b
-furanyl are each independently substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, (C
1
-C
3
)-alkyl, methoxy or —SO
2
NH
2
; and
where b is 1;
R(3) is unsubstituted -n-C
4
H
8
-phenyl or substituted -n-C
4
H
8
-phenyl,
where the substituted -n-C
4
H
8
-phenyl is substituted by 1-3 substituents chosen from F, Cl, CF
3
, (C
1
-C
3
)-alkyl and methoxy;
and their pharmaceutically tolerable salts.
In one embodiment, the compound of formula 1 may be chosen from 4-chloro-5-(3-chloro-4-fluorobenzylsulfamoyl)-2-phenylbutylaminobenzoic acid, and its pharmaceutically tolerable salts.
In another embodiment, if one of the substituents R(1) to R(5) comprises one or more asymmetric centers, each asymmetric center may independently have either the S or R configuration. Thus, for example, compounds of the invention may be present as optical isomers, as diastereomers, as racemates and as mixtures thereof. Alkyl, as used herein, may be either a straight-chain alkyl group or branched alkyl group.
In one embodiment, compounds of the formula I may be synthesized by the person skilled in the art according to processes known from the literature, including but not limited to:
Possible leaving groups, X2 (formula VI), which can be taken into consideration in the nucleophilic aromatic substitution reaction with amines III include, but are not limited to, fluorine and chlorine.
The introduction of some substituents in the 4 position of intermediate II (X1, for example, may be bromine, iodine or —O—SO
2
CF
3
) may, in one embodiment, be carried out by methods of palladium-mediated cross-coupling, which are likewise known from the literature, of aryl halides or aryl triflates with, for example, organostannanes, organoboronic acids or organoboranes or organocopper or zinc compounds.
In general, anthranilic acids are weak acids which bind bases with formation of salts. Possible base addition products are all pharmacologically tolerable salts, for example, alkali metal salts, lysinates and tris(hydroxymethyl)methylamine salts.
In one embodiment, the compounds of formula I are substituted anthranilic acids.
A prominent representative of the anthranilic acid class is the furfuryl derivative furosemide, which is used as a diuretic in therapy. Furosemide inhibits the sodium/potassium/2chlorine cotransporter in the ascending branch of Henle's loop in the kidney.
DE 18 02 208 describes anthranilic acids which differ from the compounds of the present invention in that they carry an exclusively benzyl, furfuryl or thienyl substituents on R3 and have diuretic action. U.S. Pat. No. 3,565,920 also discloses anthranilic acids that differ from the compounds of the formula I in that they demonstrate a strong salidiuretic activity.
It was therefore surprising that the compounds according to the invention have no undesired and disadvantageous salidiuretic properties, but very good cardioprotective properties, for example in the case of oxygen deficiency symptoms. As a result of their pharmacological properties, the compounds, in one embodiment, are outstandingly suitable as cardioprotective pharmaceuticals for infarct prophylaxis and infarct treatment, and for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention may, for example, be used, as a result of inhibition of the cellular Na
+
/HCO
3−
cotransporter (NBC), as pharmaceuticals for the treatment of all acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby. In one embodiment, this relates to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantation, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and during the transfer to the recipient's body.
The compounds may also be useful pharmaceuticals having a protective ac

Affiliated with

Also associated with

Rating

Substituted anthranilic acids, their use as a medicament or... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted anthranilic acids, their use as a medicament or..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted anthranilic acids, their use as a medicament or... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3092087