Title:
PYRIMIDIN-2,4,6-TRION DERIVATIVES AND THEIR USE AS METALLOPROTEASE-INHIBITORS
Document Type and Number:
WIPO Patent Application WO1998058915
Kind Code:
A3
Abstract:
The invention relates to substances of general formula (I), where R1 and R2, independently of each other, can be H, alkenyl or alkyl, R3 is a W-V group, where W is a bond or a linear or branched alkyl group, which is optionally interrupted by oxygen, sulphur or nitrogen and can be substituted with hydroxy-, amino-, mercapto-, alkoxy-, oxo-, carboxy-, acyl-, alkyl-, aralkyl-, aryl- or heteroaryl groups, and in which V is H, a monocyclic or bicyclic, saturated or unsaturated ring, which can possibly contain between 1 and 4 nitrogen, oxygen or sulphur atoms and can be optionally substituted with hydroxy-, amino-, mercapto-, alkoxy-, oxo-, carboxy-, acyl-, acylamido-, alkyl-, aralkyl-, aryl- or heteroaryl groups; R4 is an -N(R13)-C(O)-R5, -N(R13)-C(O)-OR5, -N(R13)-SO2-R5, -N(R13)-C(S)-R5, -N(R13)-C(S)-OR5, -N(R13)-C(O)-CR14R15(-CR16R17)n -C(O)-R5, or -N(R13)-CR14R15(-CR16R17)n-C(O)-R18 rest, which in each case is linked by the nitrogen atom to the central pyrimidin ring; n is 0 or 1; R13 has the meaning given above for R3 or with R14 or R16 possibly forms a heterocycle having between 4 and 7 members; and R5 is an alkyl-, cycloalkyl-, aralkyl-, aryl- or heteroaryl rest, whereby these rests can be substituted with hydroxy-, amino groups or halogen. R14, R15, R16 and R17, independently of each other, are hydrogen, the C alpha radical of a proteinogenic amino acid, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, and R14 and R15 or alternatively R16 and R17 can together form a carbocycle having between 3 and 7 members; R18 is OH or N(R6R7), where R6 can be H, alkyl, cycloalkyl, aralkyl, aryl or heteroaryl and R7 is a group which, together with the N atom, represents a proteinogenic or non-proteinogenic alpha or beta amino acid or amino acid amide. In addition, R6 and R7 can together form a ring having between 4 and 7 members, which optionally contains heteroatoms such as oxygen, sulphur or nitrogen and is optionally substituted with alkyl, aralkyl, aryl or heteroaryl. The invention further relates to pharmacologically compatible salts and esters of general formula I and the use of these compounds for manufacturing medicinal products.
Inventors:
GRAMS FRANK (DE)
ZIMMERMANN GERD (DE)
ZIMMERMANN GERD (DE)
Application Number:
PCT/EP1998/003740
Publication Date:
May 14, 1999
Filing Date:
June 19, 1998
Export Citation:
Assignee:
ROCHE DIAGNOSTICS GMBH (DE)
GRAMS FRANK (DE)
ZIMMERMANN GERD (DE)
GRAMS FRANK (DE)
ZIMMERMANN GERD (DE)
International Classes:
A61K31/505; A61K31/506; A61P9/00; A61P9/12; A61P43/00; C07D239/60; C07D239/62; C07D403/04; C07D403/12; (IPC1-7): C07D239/60; C07D239/62; C07D403/04; C07D403/12
Domestic Patent References:
| WO1996017838A1 | 1996-06-13 | |||
| WO1997023465A1 | 1997-07-03 |
Foreign References:
| EP0058637A1 | 1982-08-25 | |||
| FR2222375A1 | 1974-10-18 | |||
| EP0640594A1 | 1995-03-01 |
Other References:
SKINNER G S ET AL: "Glycyl Derivatives of Aminobarbituric Acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 75, 1953, DC US, pages 5909 - 5911, XP002082825
SINGH P ET AL: "Synthesis of 5-Acetamido Substituted Barbiturates", CANADIAN JOURNAL OF CHEMISTRY., vol. 42, no. 3, 1964, OTTAWA CA, pages 605 - 609, XP002082826
STEIN A ET AL: "Preparation of 1-Alkyluramil-7,7-diacetic Acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 78, 1956, DC US, pages 6185 - 6188, XP002082827
FALCO E A ET AL: "Studies on Condensed Pyrimidine Systems. IV. Some Thiazolo[5,4-d]pyrimidines", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 72, 1950, DC US, pages 3203 - 3205, XP002082828
MATJEKA E R ET AL: "Synthesis of stable isotope-enriched metabolites of theophylline", J. LABELLED COMPD. RADIOPHARM., vol. 23, no. 9, 1986, pages 969 - 980, XP002082829
PEICHL E ET AL: "Ylides of heterocycles, 6. Ylides of barbituric acids with nicotinic acid derivatives as cationic moieties", ARCH. PHARM., vol. 317, no. 11, 1984, pages 946 - 951, XP002082830
ICHIBA M ET AL: "Synthesis of fervenulin 4-oxide and its conversion to the antibiotics fervenulin and 2-methylfervenulone", J. ORG. CHEM., vol. 43, no. 3, 1978, pages 469 - 472, XP002082831
TAYLOR E C ET AL: "Synthesis of the pyrimido[5,4-e]-as-triazine antibiotics fervenulin and 2-methylfervenulone", J. ORG. CHEM. (JOCEAH);75; VOL.40 (16); PP.2321-9, vol. 40, no. 16, 1975, Princeton Univ.;Dep. Chem.; Princeton; N. J., pages 2321 - 2329, XP002082832
CHEMICAL ABSTRACTS, vol. 128, no. 18, 4 May 1998, Columbus, Ohio, US; abstract no. 217352n, PAN S ET AL: "Synthesis and biological activity of tyrosine protein kinase inhibitors" page 585; column 2; XP002082833
SINGH P ET AL: "Synthesis of 5-Acetamido Substituted Barbiturates", CANADIAN JOURNAL OF CHEMISTRY., vol. 42, no. 3, 1964, OTTAWA CA, pages 605 - 609, XP002082826
STEIN A ET AL: "Preparation of 1-Alkyluramil-7,7-diacetic Acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 78, 1956, DC US, pages 6185 - 6188, XP002082827
FALCO E A ET AL: "Studies on Condensed Pyrimidine Systems. IV. Some Thiazolo[5,4-d]pyrimidines", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 72, 1950, DC US, pages 3203 - 3205, XP002082828
MATJEKA E R ET AL: "Synthesis of stable isotope-enriched metabolites of theophylline", J. LABELLED COMPD. RADIOPHARM., vol. 23, no. 9, 1986, pages 969 - 980, XP002082829
PEICHL E ET AL: "Ylides of heterocycles, 6. Ylides of barbituric acids with nicotinic acid derivatives as cationic moieties", ARCH. PHARM., vol. 317, no. 11, 1984, pages 946 - 951, XP002082830
ICHIBA M ET AL: "Synthesis of fervenulin 4-oxide and its conversion to the antibiotics fervenulin and 2-methylfervenulone", J. ORG. CHEM., vol. 43, no. 3, 1978, pages 469 - 472, XP002082831
TAYLOR E C ET AL: "Synthesis of the pyrimido[5,4-e]-as-triazine antibiotics fervenulin and 2-methylfervenulone", J. ORG. CHEM. (JOCEAH);75; VOL.40 (16); PP.2321-9, vol. 40, no. 16, 1975, Princeton Univ.;Dep. Chem.; Princeton; N. J., pages 2321 - 2329, XP002082832
CHEMICAL ABSTRACTS, vol. 128, no. 18, 4 May 1998, Columbus, Ohio, US; abstract no. 217352n, PAN S ET AL: "Synthesis and biological activity of tyrosine protein kinase inhibitors" page 585; column 2; XP002082833
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