Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-19
2001-10-02
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...
C514S371000, C548S194000, C548S196000
Reexamination Certificate
active
06297266
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with novel thizzole derivatives. The derivatives inhibit the binding of adhesive proteins to the surface of different types of cell by influencing cell-cell and cell-matrix interactions.
SUMMARY OF THE INVENTION
The subject invention provides compounds of formula:
wherein
R
1
is
R
2
is
R
3
is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-O—CO— or aralkyl-O—CO—;
R
4
is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R
5
and R
6
, independent of one another, are hydrogen, alkyl, cycloalkyl or heteroaryl;
R
7
and R
8
, independent of one another, are hydrogen, alkyl, cycloalkyl or heteroaryl or R
7
and R
8
, together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring which can carry one or more alkyl substituents;
R
9
is hydrogen, alkyl or cycloalkyl;
R
10
is hydrogen, aryl, aralkyl, heteroaryl, heterocyclylalkyl, carboxyalkyl, alkyl, cycloalkyl, alkyl-O—CO—, aralkyl-O—CO—, alkyl-CO—, alkylsulphonyl, aryl-sulphonyl or heteroarylsulphonyl;
A is oxygen, sulphur, —CH═CH—
a to f are zero or whole positive integers, with a being zero to 2; b being zero to 4; c and d being zero or 1, with the proviso that c and d are not both simultaneously zero; e is zero to 5, with the proviso that e is other than zero when d is zero and e is zero to 3 when A is equal to —CH═CH—; and f is zero to 3, with the proviso that f is not zero when A is oxygen, sulphur or
and their pharmaceutically usable salts and esters.
A preferred group of compounds are those of the formula:
wherein,
R
a
is
R
b
is
R
c
is hydrogen or methyl.
A first series of preferred compounds have R
a
being
and R
b
being
When R
c
is methyl, the more preferred compounds of this first series are butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propoxy}-acetate, [3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propoxy]-acetic acid hydrochloride, ethyl {4-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate, [4-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy]-acetic acid hydrochloride, tert-butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate, and [3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy]-acetic acid.
When R
c
is hydrogen, the more preferred compounds of this first series are ethyl {4-[(2-guanidino-thiazole-4-carbonyl)-amino]-phenoxy}-acetate, [4-[(2-guanidino-thiazole-4-carbonyl)-amino]-phenoxy]-acetic acid hydrochloride, ethyl {4-[(2-guanidino-thiazole-5-carbonyl)-amino[-phenoxy}-acetate, and [4-[(2-guanidino-thiazole-5-carbonyl)-amino]-phenoxy]-acetic acid hydrochloride.
A second series of preferred compounds have R
a
being
R
c
being hydrogen, and R
b
being
In this second series, the preferred compounds are ethyl (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-phenoxy)-acetate, [4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenoxy]-acetic acid, ethyl (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-methoxy-phenoxy)-acetate, (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-methoxy-phenoxy)-acetic acid, ethoxycarbonylmethyl 5-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-ethoxycarbonylmethoxy-benzoate, 5-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-carboxymethoxy-benzoic acid, ethyl (E)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylate, and (E)-3-[4-[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-acrylic acid.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The present invention is concerned especially with thiazole derivatives of formula (I)
wherein
R
1
is
R
2
is
R
3
is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-O—CO— or aralkyl-O—CO—;
R
4
is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R
5
and R
6
independently of one another are hydrogen, alkyl, cycloalkyl or heteroaryl;
R
7
and R
8
independently of one another are hydrogen, alkyl, cycloalkyl or heteroaryl or R
7
and R
8
together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring which can carry one or more alkyl substituents;
R
9
is hydrogen, alkyl or cycloalkyl;
R
10
is hydrogen, aryl, aralkyl, heteroaryl, heterocyclylalkyl, carboxyalkyl, alkyl, cycloalkyl, alkyl-O—CO—, aralkyl-O—CO—, alkyl-CO—, alkylsulphonyl, aryl-sulphonyl or heteroarylsulphonyl;
A is oxygen, sulphur, —CH═CH—
a to f are zero or whole positive integers, with a being zero to 2; b being zero to 4; c and d being zero or 1, with the proviso that c and d are not both simultaneously zero; e is zero to 5, with the proviso that e is other than zero when d is zero and e is zero to 3 when A is equal to —CH═CH—; and f is zero to 3, with the proviso that f is not zero when A is oxygen, sulphur or
and their pharmaceutically usable salts and esters.
Further objects of the invention are the compounds of formula (I) described above for use as therapeutically active substances.
The compounds of formula (I) described above can be used for the production of medicaments for the prophylaxis and therapy of illnesses which are based on a malfunction of the binding of adhesive proteins to vitronectin receptors.
The subject invention provides pharmaceutical compositions containing a compound of formula (I) described above and a therapeutically inert carrier, such pharmaceutical compositions may additionally contain one or more compounds of formula (I) or additionally one or more compounds selected from the group comprising anticoagulants, fibrinolytics as well as medicaments for the prophylaxis and therapy of illnesses which are based on a malfunction of the binding of adhesive proteins to vitronectin receptors.
An object of the invention is to use the compounds of formula (I) described above for the production of medicaments for the treatment or prophylaxis of illnesses which are based on a malfunction of the binding of adhesive proteins to vitronectin receptors. Such medicaments may be used for the treatment or prophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi. Treatment and prophylasis of such illnesses typically comprise the administration of an effective amount of a compound of formula (I).
In the present description the term “alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight-chain or branched-chain alkyl group with 1-4 carbon atoms. Examples of straight-chain and branched C
1
-C
8
alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl, ethyl, isopropyl and tert-butyl.
The term “cycloalkyl”, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C
3
-C
8
cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopentyl and particularly cyclopentyl.
The term “alkoxy”, alone or in combination, signifies an alkyl ether group in which the term “alkyl”
Alig Leo
Hilpert Kurt
Weller Thomas
Epstein William H.
Gerstl Robert
Hoffmann-La Roche Inc.
Johnston George W.
Parise John P.
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