# US 5,703,050 A · Urea derivatives, their preparation and use

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- Number: US 5,703,050 A
- Document ID: US5703050A
- Status: Granted
- Kind: A
- Application number: 08/513,815
- Filed: 1996-01-17
- Granted: 1997-12-30
- Earliest claimed: 1993-03-26
- Assignees: Hoechst Aktiengesellschaft
- Inventors: Otmar Klingler; Gerhard Zoller; Bernd Jablonka; Melitta Just; Gerhard Breipohl; Jochen Knolle; Wolfgang Konig; Hans Ulrich Stilz
- Web page: https://patentgrep.com/patent/US5703050A

## CPC

- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 275/40: being further substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07K 5/06113: {Asp- or Asn-amino acid}
- C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 5/0821: {with the first amino acid being heterocyclic, e.g. His, Pro, Trp}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Urea derivates are disclosed having the formula (I). ##STR1## in which A, B, W, Z, R, R.sup.1, R.sup.2, R.sup.3 and r have the meaning given in the description, as well as a process for preparing the same and their use as inhibitors of thrombocyte aggregation, carcinom cell metastasis and osteoclast binding to bone surface.

## Claims

### Claim 1

Urea derivatives of the formula I ##STR21## in which r denotes an integer from 0 to 1;
Z denotes oxygen or sulphur;
W denotes --COW.sup.1 or tetrazolyl;
W.sup.1 denotes hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, benzyloxy, amino or mono- or di-((C.sub.1 -C.sub.8)-alkyl)amino;
A denotes ##STR22## in which n stands for an integer from 0 to 1; B denotes --NR.sup.b --(CH.sub.2).sub.m --CO--, in which m stands for an integer from 1 to 2; R.sup.a and R.sup.b independently of one another denote hydrogen, hydroxyl, (C.sub.1 -C.sub.18)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.8)-alkyl, (C.sub.1 -C.sub.28)-alkoxy, (C.sub.6 -C.sub.14)-aryloxy, or (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.8)-alkoxy;
R denotes hydrogen or (C.sub.1 -C.sub.6)-alkyl;
R.sup.1 denotes --NHX or --C(.dbd.NX)--NH.sub.2 ;
X denotes hydrogen, (C.sub.1 -C.sub.6)-alkylcarbonyl, (C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.1 -C.sub.18)-alkylcarbonyloxy(C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl, hydroxyl, or a radical of the formula II
R'--NH--C(.dbd.N--R")-- (II)
where R' and R" independently of one another stand for hydrogen, (C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.1 -C.sub.6)-alkylcarbonyl, (C.sub.1 -C.sub.18)-alkylcarbonyloxy-(C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl or hydroxyl;
R.sup.2 denotes hydrogen or phenyl;
R.sup.3 denotes --CO--NH--R.sup.4, where --NH--R.sup.4 stands for the radical of an .alpha.-amino acid, its .omega.-amino-(C.sub.2 -C.sub.8)-alkylamide or its (C.sub.1 -C.sub.8)-alkyl or benzyl ester, or where R.sub.4 denotes methyl which is substituted by an amino acid side chain and also by a radical from the series --SO.sub.2 --OH, --SO.sub.2 -- NHR.sup.9 and tetrazolyl;
R.sup.9 denotes hydrogen, aminocarbonyl, (C.sub.1 -C.sub.18)-alkylaminocarbonyl, (C.sub.3 -C.sub.8)-cycloalkylaminocarbonyl, (C.sub.1 -C.sub.18)-alkyl or (C.sub.3 -C.sub.8)-cycloalkyl;
and their physiologically tolerable salts.

### Claim 2 (depends on 1)

Urea derivatives according to claim 1, wherein, in the formula I,
r denotes the number 1;
W denotes --COW.sup.1 ;
W.sup.1 denotes hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, or benzyloxy;
A denotes ##STR23## in which n stands for the numbers 0 or 1; B denotes --NR.sup.b --(CH.sub.2).sub.m --CO-- in which m stands for the numbers 1 or 2;
R denotes hydrogen,
X denotes hydrogen, (C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.1 -C.sub.6)-alkylcarbonyl, (C.sub.1 -C.sub.18)-alkylcarbonyloxy-(C.sub.1 -C.sub.6)-alkoxycarbonyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl or a radical of the formula ##STR24## in which R' and R" independently of one another stand for hydrogen, (C.sub.1 -C.sub.6)-alkylcarbonyl, (C.sub.1 -C.sub.6)-alkoxy-carbonyl, (C.sub.1 -C.sub.18)-alkylcarbonyloxy-(C.sub.1-C.sub.6)-alkoxycarbonyl or (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkoxycarbonyl;
R.sup.2 denotes hydrogen;
R.sup.3 denotes --CO--NH--R.sup.4, where --NH--R.sup.4 stands for the radical of an .alpha.-amino acid, its .omega.-amino-(C.sub.2 -C.sub.8)-alkylamide or its (C.sub.1 -C.sub.8)-alkyl or benzyl ester, or where R.sub.4 denotes methyl which is substituted by an amino acid side chain and also by a radical from the series --SO.sub.2 --OH, --SO.sub.2 -- NHR.sup.9 and tetrazolyl.

### Claim 3 (depends on 2)

Urea derivatives according to claim 2 in which W' denotes methoxy, ethoxy, 2-propyloxy, isobutyloxy or tert-butyloxy.

### Claim 4 (depends on 2)

Urea derivates according to claim 2, in which R.sup.3 denotes --CO--NH--R.sup.4, where --NH--R.sup.4 stands for the radical of the .alpha.-amino acids valine, lysine, phenylalanine, phenylglycine or 4-chlorophenylglycine, their .omega.-amino-(C.sub.2 -C.sub.8)-alkylamides or their (C.sub.1 -C.sub.8)-alkyl or benzyl esters.

### Claim 5 (depends on 4)

Urea derivatives according to claim 4, wherein the (C.sub.1 -C.sub.8)-alkyl ester of the .alpha.-amino acids is the methyl, ethyl, isopropyl, isobutyl or tert-butyl ester.

### Claim 6 (depends on 1)

Process for the preparation of compounds of the general formula I according to claim 1, comprising a fragment condensation of a compound of the general formula III ##STR25## with a compound of the general formula IV ##STR26## where the radicals A, B, W, Z, R, R.sup.1, R.sup.2 and R.sup.3 and also r are defined as indicated in claim 1.

### Claim 7 (depends on 1)

Pharmaceutical preparation, containing one or more compounds of the general formula I according to claim 1 and/or one or more physiologically tolerable salts thereof as active compound together with pharmaceutically acceptable excipients and additives.

### Claim 8 (depends on 1)

Process for the production of a pharmaceutical preparation, containing one or more compounds of the general formula I according to claim 1, and/or one or more physiologically tolerable salts thereof, comprising mixing such compounds into a suitable administration form together with pharmaceutically acceptable excipients and additives.

### Claim 9 (depends on 1)

Method for inhibiting platelet aggregation, the metastasis of carcinoma cells and osteoclast binding to a bone surface, which comprises administering to a host in need thereof an effective dose of a urea derivative or physiologically tolerable salt thereof according to claim 1.