Claims
- 1. Compounds of the formula I in whichR1 is OR4, NHR4 or NA″2, R2 is H, Hal, NO2, NHR4, NA″2, OR4, SO3R4, SO2R4 or SR4, R3 is NH2, H2N—C(═NH) or H2N—(C═NH)—NH, where the primary amino groups are optionally protected with an amino protective group or R5—NH—, R4 is H, A, Ar, or Aralk, R5 is a mono- or binuclear heterocycle having 1 to 4 N, O and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A″, —CO—A, OA′, CN, COOA′, CONH2, NO2, ═NH or ═O, A is alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or mono-, di- or trisubstituted by R6, and in which one, two or three methylene groups can be replaced by N, O and/or S, R6 is Hal, NO2, NHA′, NA″2, OA′, phenoxy, CO—A′, SO3A′, CN, NHCOA′, COOA′, CONA′2, or SO2A′, A′ is H or alkyl having 1-6 C atoms, A″ is alkyl having 1-6 C atoms, Ar is a mono- or binuclear aromatic ring system, which is unsubstituted or mono-, di- or trisubstituted by alkyl having 1-6 C atoms and/or an R6-substituted mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms, Aralk is a aralkylene having 7-14 C atoms, which is unsubstituted or mono-, di- or trisubstituted by R6 and in which one, two or three methylene groups can be replaced by N, O and/or S, Hal is F, Cl, Br, or I, m, n in each case independently of one another are 0, 1, 2, 3, or 4, and their physiologically acceptable salts and solvates.
- 2. Enantiomers or diastereomers of the compounds of the formula I according to claim 1.
- 3. Compounds of the formula I according to claim 1a) 8-[3-(pyridin-2-ylamino)propoxy]-6,11-dihydro-2H-dibenzo[cd, g]azulene-1-carboxylic acid; b) 8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-2,6,11,11a-tetrahydro-1H-dibenzo[cd,g]azulene-1-carboxylic acid; c) {8-[3-(1,4,5,6-tetrahydropyrimidin-2-ylamino)propoxy]-2,6,11,11a-tetrahydro-1H-dibenzo[cd,g]azulene-2-yl}acetic acid; and their physiologically acceptable salts and solvates.
- 4. Process for the preparation of compounds of the formula I according to claim 1, and of their salts and solvates, characterized in thata) a compound of the formula I is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) a radical R1, R2, and/or R3 is converted into another radical, R1, R2, and/or R3 by, i) converting an amino group into a guanidino group by reaction with an amidinating agent, ii) hydrolysing an ester, iii) reducing a carboxylic acid to an alcohol, or iv) converting a hydroxyamidine into an amidine by hydrogenation or c) a base or acid of the formula I is converted into one of its salts.
- 5. Compounds of the formula I according to claim 1 and their physiologically acceptable salts and solvates as GPIIb/IIIa antagonists for the control of thromboses, cardiac infarct, coronary heart disorders and arteriosclerosis.
- 6. Compounds of the formula I according to claim 1 and their physiologically acceptable salts and solvates as αv integrin inhibitors for the control of pathologically angiogenic disorders, thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis, tumours, osteoporosis and rheumatoid arthritis.
- 7. A pharmaceutical composition characterized in that it contains at least one compound of the formula I according to claim 1 and/or one of its physiologically acceptable salts or solvates.
- 8. A process for the production of a pharmaceutical composition characterized in that a compound of formula I according to claim 1 and/or one of its physiologically acceptable salts or solvates is brought into a suitable dose form together with at least one solid, liquid or semi-liquid vehicle or excipient.
- 9. A method for treatment of a disease or condition affected by αv integrin inhibition which comprises administering an αv integrin inhibition effective amount of a compound of the formula I of claim 1 or physiologically acceptable salt or solvate thereof.
- 10. The method of claim 9, wherein the disease or condition is cancer, a tumor-induced angiogenic disease, oncoses, osteoporosis, an osteolytic disorder, angiogenesis, thromboses, cardiac infarct, coronary heart disorder, arteriosclerosis or rheumatoid arthritis.
- 11. Compounds of claim 1, wherein:Aralk is benzyl or phenethyl, A is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl, Ar is unsubstituted or mono-substituted phenyl, and R5 is 1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl, 5-oxo-4,5-dihydro-1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolin-4-on-5-yl, 1-alkyl-1,5-dihydroimidazol-4-on-2-yl, pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro-pyrimidin-2-yl.
- 12. Compounds of claim 1, wherein R2 is H.
- 13. Compounds of claim 1, wherein R2 is H, R1 is OR4 and R4 is H or A.
- 14. Compounds of claim 1, wherein R2 is H, R1 is OR4, R4 is H or A and R3 is H2N—C(═NH), H2N—(C═NH)—NH, 1H-imidazol-2-ylamino, 4,5dihydro-1H-imidazol-2-ylamino, 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-yl-amino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydro-pyrimidin-2-ylamino.
- 15. Compounds of claim 1, wherein m is 0 or 1.
- 16. Compounds of claim 1, wherein m is 0 or 1 and R2 is H.
- 17. Compounds of claim 1, wherein R2 is H; R1 is OR4, R4 is H or A and m is 0 or 1.
- 18. Compounds of claim 1, wherein R2 is H, R1 is OR4, R4 is H or A and A is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl and m is 0 or 1.
- 19. Compounds of claim 1, wherein R2 is H, R1 is OR4, R4 is H or A, A is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl, R3 is H2N—C(═NH), H2N—(C═NH), H2N—(C═NH)—NH, 1H-imidazol-2-ylamino, 4,5dihydro-1H-imidazol-2-ylamino, 5-oxo4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-on-5-ylamino, 1-methyl-1,5-dihydroimidazol-4-on-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6,-tetrahydropyrimidin-2-ylamino;m is 0 or 1 and n is 2, 3 or 4.
- 20. Compounds of claim 1, wherein the amino protective group, if present, is an unsubstituted or substituted acyl, aralkoxymethyl or aralkyl group.
- 21. Compounds of claim 20, wherein the amino protective group, if present, is BOC, Mtr, CBZ, Fmoc, benzyl or acetyl.
Priority Claims (1)
Number |
Date |
Country |
Kind |
199 16 837 |
Apr 1999 |
DE |
|
Parent Case Info
This application is a 371 of PCT/EP00/02925 filed Apr. 1, 2000.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/EP00/02925 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO00/63178 |
10/26/2000 |
WO |
A |
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
3795709 |
Frey et al. |
Mar 1974 |
A |
6069158 |
Miller et al. |
May 2000 |
A |