MXPA01004272A - Chromenone and chromanone derivatives as integrin inhibitors - Google Patents
Chromenone and chromanone derivatives as integrin inhibitorsInfo
- Publication number
- MXPA01004272A MXPA01004272A MXPA/A/2001/004272A MXPA01004272A MXPA01004272A MX PA01004272 A MXPA01004272 A MX PA01004272A MX PA01004272 A MXPA01004272 A MX PA01004272A MX PA01004272 A MXPA01004272 A MX PA01004272A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- compounds
- acid
- solvates
- oxo
- Prior art date
Links
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- 108010044426 integrins Proteins 0.000 title claims abstract description 12
- 102000006495 integrins Human genes 0.000 title claims abstract description 12
- 239000003112 inhibitor Substances 0.000 title claims abstract description 8
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Abstract
The invention relates to compounds having formula (I), wherein R1, R2, R3, R4, R5, R7, R8, R11, Z, m and n have the meaning cited in claim 1, and to the physiologically acceptable salts and solvates which can be used as integrin inhibitors, especially in the prophylaxis and treatment of circulatory diseases, in case of thrombosis, myocardial infarction, coronary heart diseases, arteriosclerosis, osteoporosis, pathologic processes caused or propagated by angiogenesis and in tumor therapy.
Description
DERIVATIVES OF CROMENONE AND CHROMANONE
The invention relates to the compounds of formula
wherein R1 represents CH2OR10, COOR10, CONHR10 or C0N (R1) 2,
R2 represents R10, CO-R10, CO-R6, COOR6, COOR10, S02R6, S02R10, CONHR6, CON. { R6) 2, CONHR10 or CON (R12) 2, R3 represents H, Hal, NHR10, N (R12) 2, -NH-acyl, -O-acyl, CN, N02, OR10, SR10, S02R10, SO3R10, COOR10, CONHR6, CON (R6) 2, CONHR10 or CON (R12) 2, R4 represents H, A, Ar or aralkylene of 7 to 14 carbon atoms, R5 represents NH2, H2N-C (= NH) or H2N- (C = NH) -NH, wherein the primary amino groups may also be protected with conventional amino protecting groups or may be mono, di or trisubstituted with R10, CO-R10, COOR10 or S02R10, or represents R6-NH-, R6 represents a heterocycle of one or two cores that
Ref: 128169
it contains 1 to 4 N, O and / or S atoms, and may be unsubstituted or mono, di or trisitu- dited with Hal, A, -CO-A, OH, CN, COOH, COOA, CONH2, N02 , = NH 0 = 0, R7, R8, independently of one another, are absent or represent H, R7 and R8 / together, also represent a bond, Z is absent or represents 0, S, NH, NR1, C (= 0), CONH, NHCO, C (= S) NH, NHC (= S), C (= S), S02NH, NHS02 O CA = CA ', R9 represents H, Hal, OR11, NH2, NHR12, N (R12 ) 2, NHacyl, Oacyl, CN, N02, SR11, SOR12, S02R12 or S03H, R10 represents H, A, Ar or aralkylene of 7 to 14 carbon atoms, R11 represents H or alkyl of 1 to 6 carbon atoms,
R12 represents alkyl of 1 to 6 carbon atoms,
Á represents H or alkyl of 1 to 15 C atoms or cycloalkyl of 3 to 15 C atoms unsubstituted or mono, di or trisus with R9, and wherein one, two or three methylene groups may be replaced by N, 0 and / or S, Ar represents a one or two nucleus aromatic ring system containing 0, 1, 2, 3 or 4 N, 0 and / or S atoms and which may be unsubstituted or mono, di or trisubstituted with A and / or R9,
Hal represents F, Cl, Br or I and m, n are independently 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates. In the world patents n ° 94/29273, 96/00730 and
96/18602 similar compositions are described. The aim of the invention was to develop new compounds with valuable properties, in particular compounds that can be used in the manufacture of medicines. It was found that the compounds of formula I, their salts and solvates possess very valuable pharmacological properties and are well tolerated. First of all, they act as integrin inhibitors, in particular by inhibiting the interactions of the integrin av receptors with the ligands. These compounds have a particular effect in the case of integrins avß3 and avß5. They are particularly effective as antagonists of the adhesion receptor for the β-tronectin receptor "β3". This effect can be checked, for example, according to the method described by J.W. Smith et al. in J. Biol. Chem. 2 £ ¿, pgs. 11008 to 11013 and 12267 to 12271 (1990). B. Felding-Habermann and D.A. Cheresh describes in Curr. Opin. Cell. Biol., P. 864 (1993) the importance of integrins as adhesion receptors for
phenomena and clinical pictures more diverse, in particular with reference to the receiver of vitrónectina? v 3. P.C. Brooks, R.A. Clark and D.A. Cheresh describes in Science 2Sá., Pgs. 569-71 (1994), the dependence of the beginning of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins. The possibility of inhibiting this exchange and thus introducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described in Cell 22, pp. 1157-64 (1994), by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T. -Hu, G. Klier and D.A. Cheresh The experimental verification that the compounds of the invention also prevent living cells from being fixed on the corresponding matrix proteins and, therefore, also that the tumor cells are fixed on the matrix proteins, can be performed by an adhesion assay of cells similar to the method employed by F. Mitjans et al. in J. Cell Science 108 p. 2825 to 2838 (1995). P.C. Brooks et al. describe in J. Clin. Invest.
96. p. 1815 to 1822 (1995) avß3 antagonists used to combat cancer and for the treatment of angiogenic diseases induced by tumors. Therefore, the compounds of formula I of the invention can be used as active substances
of drugs intended, in particular, for the treatment of tumor diseases, Osteoporosis, osteolytic diseases and also to suppress angiogenesis. The compounds of formula I which block the interaction of integrin receptors with ligands such as, for example, the binding of fibrinogen to the fibrinogen receptor (glycoprotein Ilb / IIIa), act as GPIIb / IIIA antagonists and prevent the proliferation of tumor cells by metastasis. This concept is supported by the following observations: the spread of tumor cells from a local tumor to the vascular system occurs due to the formation of microaggregates (microthrombi) by the interaction of tumor cells with platelets. The tumor cells are protected and camouflaged in the microaggregate and are not recognized by the cells of the immune system. The . Microaggregates can be fixed to the vessel walls, which facilitates the in ternalization of the tumor cells in the tissue. Since the formation of microthrombi is facilitated by the binding of fibrinogen to fibrinogen receptors on activated platelets, GPIIa / IIIb antagonists can be considered active inhibitors of metastasis. The compounds of formula I inhibit both the binding of fibrinogen, fibronectin and Willebrand factor to the platelet fibrinogen receptor as well as the
binding of other adhesive proteins such as vitronectin, collagen and laminin to the corresponding receptors located on the surface of different cell types. In particular, they inhibit the formation of plaque thrombi and, therefore, can be used for the treatment of thrombosis, strokes, myocardial infarction, inflammations and arteriosclerosis. The properties of the compounds can also be checked according to the methods described in the European document Al-0 462 960. The inhibition of the fibrinogen binding to the fibrinogen receptor can be checked according to the method described in the European document Al-0 381 033 The inhibitory effect of thrombocyte aggregation can be checked in vitro according to the Born method (Nature 4832, pp. 927-929, 1962). Accordingly, they constitute, the object of the invention, the compounds of formula I, according to claim 1, and physiologically acceptable salts and solvates thereof which act as GPIIb / IIIa antagonists and are suitable for the control of thrombosis, myocardial infarction, coronary heart disease and arteriosclerosis. Also object of the invention are compounds of formula I, according to claim 1, and physiologically acceptable salts and solvates thereof which are used
to prepare a drug and are used as integrin inhibitors. A particular object of the invention are the compounds of formula I, according to claim 1, and physiologically acceptable salts and solvents which are used to prepare a medicament for the control of pathological angiogenic diseases, tumors, osteoporosis, inflammations and infections. The compounds of formula I can be used in medicine and veterinary medicine as active substances of drugs, for the prophylaxis and / or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, tumor diseases, osteolytic diseases such such as osteoporosis, pathological angiogenic diseases such as, for example, inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's Morbus, atherosclerosis, psoriasis , restenosis after angioplasty, viral infection, bacterial infection, fungal infection, acute renal insufficiency and in wound healing to help healing processes. The compounds of formula I can be used as substances with antimicrobial effect in operations in
those that use biological materials, implants, a catheter or a pacemaker. In these cases they act as antiseptic substances. The effect of the antimicrobial activity can be checked according to the procedure described by P.Valentin-Weigund et al. in "Infection and Immunity", pgs. 2851 to 2855 (1988). Another object of the invention is a process for preparing the compounds of formula I, according to claim 1, and their salts and solvates, characterized in that (a) a compound of formula I is liberated from one of its functional derivatives by treatment with an agent of solvolysis or hydrogenolysis, or (b) a residue R1, R2 and / or Rs is transformed into another residue R1, R2 and / or Rs either, for example, i) by transforming an amino group into a guanidino group by reaction with an amidation agent, ii) saponifying an ester, iii) reducing a carboxylic acid to an alcohol, iv) transforming a hydroxyamidine into an amidine by hydrogenation, and / or transforming a base or an acid of formula I into a of its salts.
The compounds of formula I have at least one chiral center and, therefore, can have several stereoisomeric forms. Formula I covers all of these forms (for example, forms D and L) and their mixtures (for example, DL forms). Compounds of the invention also include so-called "pro-drugs", that is, compounds of formula I that have been derivatized with, for example, alkyl or acyl groups, sugars or oligopépidos, which are rapidly cleaved in the body by releasing thus the active compounds of the invention. The compounds of the invention also include the solvates of the compounds, by which are meant compounds formed by the addition of, for example, water (hydrates) or alcohols such as methanol or ethanol. The abbreviations indicated in this text mean the following: Ac acetyl BOC terbutoxycarbonyl CBZ or Z benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DMF dimethylformamide DOPA (3,4-dihydroxyphenyl) -alanine DPFN 3,5-dimethyl-limazole-1-formamidinium nitrate DMAP dimethylaminopyridine
EDCl N-ethyl-N, N '- (dimethylaminopropyl) -carbodiimide
Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Methyl MTB-methyl-tertiary butyl ether Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide Np neopentyl OBn benzyl ester OBut terbutyl ester Oct octanoyl OMe ester methyl OEt ethyl ester • Orn Ornithine POA phenoxyacetyl TBTU O- (benzotriazol-1-yl) - N, N,, N-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid p-ATS salt para-toluenesulfonic acid salt trityl Trt (triphenylmethyl) Z or CBZ benzyloxycarbonyl. All the remains that are mentioned in the text of the invention and that appear repeatedly can be the same or different, that is, they are independent of each other.
In the formulas indicated above, alkyl preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tertbutyl, then also pentyl, 1-, 2- or 3-ylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2 , 3- or 3, 3-dimethyl-butyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl , octyl, nonyl or decyl. Cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or 3-menthyl. In particular, cycloalkyl represents the remainder of a bicyclic terpene and more preferably the canfo-10-yl moiety. Alkylene preferably represents methylene, ethylene, propylene, butylene, pentylene,. then also hexylene, heptylene, octylene, nonylene or decylene. Aralkylene preferably represents alkylenephene and is, for example, preferably benzyl or phenethyl. Cycloalkylene preferably represents cyclopro-pylene, 1,2- or 1,3-cyclobutylene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene, then 1,2- , 1,3- or 1,4-cycloheptylene. CO-A is alkanoyl or cycloalkanoyl and preferably represents formyl, acetyl, propionyl, butyryl, pen-
tanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, deca-noyl, undecanoyl, dodecanoyl, tridecanoyl, tetradeca-noyl, pentadecanoyl, hexadecanoyl, heptadecanoyl or octa-decanoyl. Acyl is acyl (C1-7) having 1, 2,
3, 4, 5, 6 or 7 C atoms and preferably represents, for example, formyl, acetyl, propionyl, butyryl, trifluoroacetyl or benzoyl. Preferred R9 substituents of alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl, cycloalkanoyl and aryl are, for example, Hal, OR11, NHR12, N (R12) 2, CN, N02, SR11, SOR12, S02R12 and / or S03H, in particular, for example, F, Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl. In each of the alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl moieties there may be one, two or three methylene groups which are replaced by N, 0 and / or S. Ar-CO is aroyl and preferably represents benzene. zoilo or naphthoyl. Ar represents unsubstituted phenyl, preferably
- as indicated above - monosubstituted phenyl, in particular, preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, or-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-
cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, ni- or p-bromophenyl, o-, m- or p chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methyl-sulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, or-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, then preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4 - or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2 , 5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro -6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl- , 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6 -methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3 -bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl or, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3, 4, 5-trichlorophenyl, 2,4,6-triterbutylphenyl, 2,5- dimethyl-phenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromo-phenyl, 2,4-dichloro- 5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, # 2-methoxy-5-methylphenyl, 2,4,6-triiso-propylphenyl, naphthyl, 1,3-benzodioxol-5-yl , • 1,4-benzodio-xan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.
Ar also preferably represents 2- or 3-fu-ryl, 2- or 3-thienyl, 1-, 2- 'd 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, then preferably 1,2,3-triazole-l-, -4- or -5-yl, 1,2,4- triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazole-3- or 5- ilo, 1,3, 4-thiadiazol-2- or. -5-yl, l, 2,4-thiadiazol-3- or -5-yl, l, 2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6 -2H-thiopy-nyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl , 1-, 3-, 4-, 5-, 6- or 7-benzcpyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzoisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benzo-2, 1 , 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinoleyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3 -, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. Arylene has the same meanings as Ar, but with the proviso that there is a further union from the aromatic system to the nearest neighbor. Heterocycloalkylene preferably represents 1,2-, 2,3- or 1,3-pyrrolidinyl, 1,2-, 2,4-, 4,5- or 1,5-
imidazolidinyl, 1,2-, 2,3- or 1,3-pyrazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-oxazolidinyl,?, 2-, 2,3-, 3 , 4- or 1,4-iso-xazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-thiazolidinyl, 2,3-, 3,4-, 4,5- or 2, 5-isothiazolidinyl, 1,2-, 2,3-, 3,4- or 1,4-piperidinyl, 1,4- or 1,2-piperazinyl, then preferably l, 2,3-tetrahydro-triazol-1, 2- or 1,4-yl, 1,2,4-tetrahydro-triazole-1,2- or 3,5-yl, 1,2- or 2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydro-oxadiazole -2,3-, -3,4-, -4,5- or -1,5-ilo, l, 2,4-tetrahydro-oxadiazol-2,3-, -3,4- or -4,5 -yl, 1,3,4-tetrahydro-thiadiazole-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydro-thiadiazole-2,3 -, -3,4-, -4,5- or -1,5-yl, 1,2,3-thiadiazol-2, 3-, -3,4-, -4,5- or -1,5 -yl, 2,3- or 3,4-morpholinyl, 2,3-, 3,4- or 2,4-thiomorpholinyl. R6 is a heterocycle of one or two nuclei and preferably represents 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, -, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5- isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, then preferably 1,2,3-triazole-1, -4- or -5-yl, 1, 2 , 4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazole-3 or 5-yl, 1, 3, 4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazole-4- or -5 -yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4- , 5-, 6- or 7-benzofuryl,
2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-Benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzoisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benzo- 2, 1, 3-oxadiazolyl ?, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinoline, 1-, 3-, 4-, 5-, 6-, 7- or 8 -isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinaz-olinyl. The heterocyclic moieties may also be partially or totally hydrogenated. Thus, R6 can also represent, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or - 5-furyl, tetrahydro-2- or -3-furyl, l, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l-, -2-, -3- , -4- or -5-pyrrolyl, 2,5-dihydro-1-,.-2-, -3-, -4- or -5-pi'rrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro -1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4 -pyrazolyl, 1,4-dihydro-l-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- orpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1, 4-dioxanyl, 1,3-dioxan-2-, 4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5 -pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2, 3,4-tetrahydro-l-, -2-, -3-, -4-, -
-, -6-, -7- or -8-quinoline, 1,2, 3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, - 7- or -8-isoquinolyl. The aforementioned heterocyclic rings can also be mono, di or trisubstituted with Hal, A, -CO-A, OH, CN, COOH, COOA, CONH2, N02, = NH u = 0. Particularly preferred meanings of R6 are 1H-imidazol-2-yl, thiazol-2-yl, lH-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolin -4-one-5-yl, l-alkyl-l, 5-dihydro-imidazol-4-one-2-yl, pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6 -tetrahydro-pyrimidin-2-yl. R1 represents, in particular, for example, hydroxymethyl, carbcxy, methoxycarbonyl, ethoxycarbonyl, C0NH2, CONHMe, CONH? T, C0NMeS or C0NEt2. A particularly preferred meaning of R 1 is that of carboxy or ethoxycarbonyl. R 2 represents, in particular, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertiary butyloxycarbonyl, isobutyloxycarbonyl, 2,2-dimethylpropoxycarbonyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfo-nyl, isobutylsulfonyl, 2,2-dimethylpropylsulfonyl, phenylsulfonyl or benzylsulfonyl. Particularly preferred meanings of R2 are 2,2-dimethylpropoxycarbonyl, 2,2-dimethylpropylsulfonyl, butylsulfonyl, phenylsulfonyl or benzylsulfonyl.
R3 preferably represents, for example, H, F, Cl, Br, amino, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, acetoxy, cyano, nitro, methoxy, ethoxy, methylsulfonyl, phenylsulfonyl, p-tolylsulfonyl, carboxy, -toxycarbonyl, ethoxycarbonyl, CONH2, CONHMe or CONMe2. The particularly preferred meaning of R 3 is H. R 4 preferably represents, for example, H, methyl, ethyl, propyl, isopropyl or butyl. The particularly preferred meaning of R 4 is H. R 9 preferably represents, for example, H, F,
Cl, Br, methoxy, ethoxy, propoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetamido, acetoxy, cyano, nitro, methylsulfonyl, phenylsulfonyl, p-tolylsulfonyl or S03H. The particularly preferred meaning of R 9 is H. R 11 represents H or alkyl of 1 to 6 C atoms, but preferably H. Therefore, a particular object of the invention are those compounds of formula I in which at least one of the residues mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the partial formulas .la to In indicated below, which correspond to formula I and in which the moieties which are not explicitly detailed have the meanings indicated for formula I, namely:
in the) R3 represents H; in Ib) R3 represents H and R2 represents COOR10 or S02R10; in le) R3 represents H, R2 represents COOR10 or S02R10 and R10 represents H, A, Ar or aralkylene of 7 to 14 C atoms; in Id) m is 0; in le) m is 0 and R3 represents H; in If) R3 represents H, R2 represents COOR10 or S02R10 and m is 0; in Ig) R3 represents H, R2 represents COOR10 or S02R10 and R10 represents H, A, Ar or aralkylene of 7 to 14 C atoms and m is 0; in Ih) R3 represents H, R2 represents COOR10 or S02R10, R10 represents H, A, Ar or aralkylene of 7 to 14 carbon atoms, A represents H or an unsubstituted group of alkyl of 1 to 15 carbon atoms or cycloalkyl from 3 to 15 C atoms,
Ar represents phenyl or naphthyl and m is 0; in Ii) Rβ represents a heterocyclic of one or two nuclei having 1 to 4 N atoms and which may be unsubstituted or mono, di or trisubstituted with Hal, A, -CO-A, OH, CN, COOH, COOA , C0NH2, N02, = NH O = 0, in Ij) R3 represents H, R2 represents COOR10 or S02R10, R10 represents H, A, Ar or aralkylene of 7 to 14 C atoms, m is 0, R6 represents a heterocycle of one or two nuclei having 1 to 4 N atoms and which may be unsubstituted or mono, di or trisubstituted with Hal, A, -CO-A, OH, CN, COOH, COOA, C0NH2, N02, = NH or = 0, in Ik) Z is absent; in 11) Z is absent and R R-3 * represents H; in Im) Z is absent, R3 represents H and R2 represents COOR10 or S02R10; in In) Z is absent, R3 represents H,
represents H, represents COOR10 or S02R10, R10 represents H, A, Ar or aralkylene of 7 to 14 carbon atoms, R6 represents a heterocycle of one or two nuclei having 1 to 4 N atoms and which may be unsubstituted or be mono, di or trisubstituted with Hal, A, -CO-A, OH, CN, COOH, COOA, CONH2, N02, = NH or = 0, A represents H or unsubstituted alkyl of 1 to 6 carbon atoms, Ar represents phenyl or naphthyl and m is 0. Particularly preferred are the groups of compounds described below and corresponding to formula I indicated in each case a)
wherein R1 represents CH20R10, COOR10, CONHR10 or C0N (R12) 2,
represents COOR10 or S02R10, represents NH2, H2N-C (= NH) or H2N- (C = NH) -NH or R6-NH-, represents lH-irnidazol-2-yl, lH-benzimidazol-2-yl, pyrimidin- 2-yl or pyridin-2-yl, independently of one another, are absent or represent H, R7 and R8, together, they also represent a bond, z is absent, R10 represents H, A, Ar or benzyl, R11 represents H , R12 represents alkyl of 1 to 6 carbon atoms, A represents H or alkyl of 1 to 15 carbon atoms or cycloalkyl of 3 to 15 unsubstituted C atoms,
Ar represents phenyl or naphthyl, m is 0, n is 2, 3 or 4, and physiologically acceptable salts and solvates thereof; b)
R * - (CH2) m- Z- (CH2) "
wherein R1 represents CH2OR10, COOR10, CONHR10 or CON (R12) 2,
R2 represents R10, CO-R10, COOR10 or S02R10, R4 represents H or R12, R5 represents NH2, H2N-C (= * NH) or H2N- (C = NH) -NH, wherein the primary amino groups can also be protected with conventional amino protecting groups or may be mono, di or trisubstituted with R10, CO-R10, COOR10 or S02R10, or represents R6-NH-, R6 represents 1H-imidazol-2-yl, lH-benzimidazole- 2- ilo, 2H-pyrazol-2-yl, lH-tetrazol-5-yl, 2-imino-imidazolidin-4-one-5-yl, 1-alkyl-1,5-dihydro-imidazol-4-one-2- ilo, pyridin-2-yl, pyrimidin-2-yl or 1, 4, 5, 6-tetrahydro-pyrimidin-2-yl, R7, R8, independently of one another, are absent or represent H, R7 and 8 » together, they also represent a bond, Z is absent, R10 represents H, A, Ar or aralkylene, of 7 to 14 carbon atoms, R11 represents H, R12 represents alkyl of 1 to 6 carbon atoms, A represents H or alkyl of 1 to 6 C atoms not
substituted, Ar represents phenyl or hafethyl, Hal represents F, Cl, Br or I and m is 0, n is 2, 3 or 4, and their physiologically acceptable salts and solvates; OR
where R- represents CH2OR10, COOR10, CONHR10 or C0N (R12) 2,
R 'represents R10, CO-R10, COOR10 or S02R10, represents H or R12, represents NH2, H2N-C (= NH) or H2N- (C = NH) -NH, where the primary ammo groups may also be protected with conventional amino protecting groups or can be mono, di or trisubstituted with R10, CO-R10, COOR10 or S02R10, or represents R6-NH-,
R6 represents 1H-imidazol-2-yl, lH-benzimidazol-2-yl, 2H-pyrazol-2-yl, lH-tetrazol-5-yl, 2-imino-imidazolidin-4-one-5-yl, 1- alkyl-1,5-dihydro-imidazol-4-one-2-yl, pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6,6-tetrahydro-pyrimidin-2-yl, R7, R8, independently of one another, they are absent or represent H, R7 and R8 'together, they also represent a bond, Z is absent or represents 0, C (= 0) or CH = CH, R9 represents H, Hal, OR11, NH2 NHR12 , N (R12) 2, NHacyl, Oacyl, CN, N02, SR11, SOR12, S02R12 or S03H,
R10 represents H, A, Ar or aralkylene of 7 to 14 carbon atoms, R1 'represents H, R12 represents alkyl of 1 to 6 -al carbon atoms,
A * represents H or alkyl of 1 to 6 unsubstituted C atoms, Ar represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A and / or R9, Hal represents F, Cl, Br or I and m is 0, n is 2, 3 or 4, and their salts and solvates acceptable from the physiological point of view;
d)
R ^ - (CH2) m- Z- (CH2) 0
where it represents CH20R, 10, COOR, C0NHRiü or C0N (R?) 2,
R2 represents R10, CO-R10, COOR10 or S02R10, R4 represents H or R12, represents NH2, H2N-C (= NH) or H2N- (C = NH) -NH, wherein the primary amino groups may also be protected with conventional amino protecting groups or can be mono, di or trisubstituted with R10, CO-R10, COOR10 or S02R10, or represents R6-NH-, represents lH-imidazol-2-yl, lH-benzimidazol-2-yl, 2H -pyrazol-2-yl, lH-tetrazol-5-yl, 2-imino-imidazolidin-4-yne-5-yl, 1-alkyl-1,5-dihydro-imidazol-4-yne-2-yl, pyridine -2-yl, pyrimidin-2-yl or 1, 4, 5, 6-tetrahydro-pyrimidin-2-yl, R ', R8 independently of one another, are absent or represent H,
R7 and 8 together, also represent a bond, Z is absent, R9 represents H, Hal, OR11, NH2, NHR12, N (R12) 2, NHacyl, Oacyl, CN, N02, SR11, SOR12, S02R12 or S03H, R10 represents H, A, Ar or aralkylene of 7 to 14 C atoms, R 11 represents H or alkyl of 1 to 6 C atoms, R 12 represents alkyl of 1 to 6 carbon atoms, A represents H or alkyl of 1 to 6 atoms of unsubstituted C, A represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A and / or R9, Hal represents F, Cl, Br or I and m is 0, n is 1, 2, 3 or 4, and its Salts and solvates acceptable from the physiological point of view. In general, both the compounds of formula I and the starting materials for their preparation are prepared according to known methods, as described in the literature (for example, in certain works such as Houben-Weyl, "Methoden der organischen Chemie "(Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use ofknown variants of these methods that are not detailed in this text. If desired, the starting materials can be prepared in situ, but in such a way that instead of isolating them from the reaction mixture they are directly reacted to form the compounds of formula I. To obtain the compounds of formula I they can be released from one of their functional derivatives by treatment with a solvolysis or hydrogenolysis agent. As starting substances for solvolysis or hydrogenolysis, those substances which respond to formula I are preferred, but instead of one or more free amino groups and / or free hydroxyl groups they contain amino and / or hydroxyl groups correspondingly protected, preferably those which instead of an H atom attached to an N atom carry a group. amino-protecting agents, in particular those which, instead of a group of NH, carry a group of R'-N, where R 'is an amino-protecting group, and / or those which, instead of the H atom of a hydroxyl group, carry an amino-protecting group; a protective group of. hydroxyl, for example, those that respond to formula I, but instead of a group of COOH carry a group of COOR '', R '' being a hydroxyl protecting group. In the molecule of the starting substance there may also be several groups, the same or different, of amino
and / or protected hydroxyl. If the protective groups present are different from each other, then they can be removed in many cases selectively. The term "amino protecting group" is known and refers to groups that are adapted to protect (block) an amino group from chemical reactions, but which can be easily removed after having carried out the desired chemical reaction in other places of the molecule. Typical examples of these groups are, in particular, the unsubstituted or substituted groups of acyl, aryl, aralkoxymethyl or aralkyl. Since the amino protecting groups are removed after the desired reaction (or sequence of reactions) has elapsed, the type and size thereof is not a critical point; however, those groups from 1 to 20, in particular from 1 to 8, C atoms are preferred. In the context of the process of the present invention, the expression "acyl group" has a very broad interpretation. It encompasses acyl groups deriving from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids such as, in particular, the alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are the alkpoyl groups such as acetyl, propionyl and butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA;
alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; arisulphonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, then CBZ, Fmoc, benzyl and acetyl. The cleavage of the amino protecting group is carried out - depending on the protective group used - for example with strong acids, conveniently with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, with carboxylic acids strong organics such as trichloroacetic acid, or with sulfonic acids such as benzenesulfonic or p-toluenesulfonic. It is possible to carry out the reaction in an additional inert solvent, but the presence thereof is not indispensable in all cases; As inert solvents, organic solvents such as, for example, carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons, such as sodium hydroxide, can be used. dichloromethane, also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of these solvents can also be used. The TFA is preferably used in excess and without the additional addition of another solvent; the acid per-
Doric is used in the form of a mixture composed of acetic acid and. 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are conveniently between about 0 and about 50 ° C, preferably between 15 and 30 ° C (room temperature). The groups BOC, OBut and Mtr can be cleaved preferably with, for example, TFA in dichloromethane or with HCl approx. 3N to 5N in dioxane, at a temperature between 15 and 30 ° C; The FMOC group can be cleaved using a 5-50% solution of dimethylamine, diethylamine or piperidine in DMF, at a temperature between 15 and 30 ° C. Protective groups that are separated by hydrogenolysis (eg, CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (for example, a noble metal catalyst such as palladium, conveniently on a support like coal). Suitable solvents are the same as mentioned above, in particular alcohols such as methanol or ethanol, or amides such as DMF. In general, hydrogenolysis is carried out at temperatures between approximately 0 and 100 ° C and pressures between approximately 1 and 200 bar, preferably at temperatures between 20 and 30 ° C and pressures between 1 and 10 bar. The hydrogenolysis of the CBZ group
it proceeds favorably with, for example, 5-10% Pd / C in methanol or with ammonium formate (instead of hydrogen) over Pd / C in methanol / DMF, at temperatures between 20 and 30 ° C. The compounds of formula I, in which R5 represents R6-NH-, can be obtained, for example, analogously to that described in reaction schemes 1 to 3. Suitable inert solvents include, for example, hydrocarbons such as hexa-no, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether "(methyl glycol) or ethylene glycol monoethyl ether (ethyl glycol), ethylene glycol dimethyl ether (diglyme), ketones such as acetone or butanone, amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); such as acetonitrile, sulfoxides such as dimethyl sulfoxide (DMSO), carbon disulfide, carboxylic acids such as formic or acetic acid, nitro compounds such as nitromethane or nitrobenzene;
esters such as ethyl acetate, water or mixtures of the solvents mentioned. It is also possible to transform a radical R1, R2 and / or R5 into another radical R1, R2 and / or Rs. In particular, carboxylic acid ester can be converted to a carboxylic acid. For this, an ester of formula I can be saponified. This reaction is conveniently carried out by solvolysis or hydrogenolysis, as indicated above, for example, with NaOH or KOH in dioxane-water, and at temperatures between 0 and 60 ° C, preferably between 10 and 40 ° C. The transformation of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and then by reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd / C. It is also possible to replace a conventional amino protecting group with hydrogen by cleaving the protecting group by solvolysis or hydrogenolysis, as described above, or by solvolysis or hydrogenolysis to release an amino group protected with a conventional protecting group. To prepare compounds of formula I, wherein Rs represents H2N-C (= NH) -NH-, an amino compound can be treated correspondingly with an amidination agent. As
amidination agent is preferred l-amidino-3,5-dimethylpyrazole (DPFN), which is preferably used in the form of nitrate. It is convenient to work in the presence of a base such as triethylamine or ethyl-diisopropylamine, in an inert solvent or a mixture of inert solvents, for example water / dioxane, and at temperatures between 0 and 120 ° C, preferably between 60 and 120 °. C. To prepare an amidine of formula I (R5 = -C (= NH) -NH2), ammonia can be added to a nitrile of form-mule I (Rs = CN). The addition is preferably carried out in several steps, a) by transforming the nitrile in a manner known per se into a thioamide with H2S, which is reacted with an alkylating agent, for example, CH3I to obtain the S-alkyl- corresponding imidothioester, which in turn reacts with NH3 to give amidine, b) by reacting the nitrile with an alcohol, - for example ethanol, in the presence of HCl to obtain the corresponding imidoester which is then treated with ammonia, or c) react the nitrile with lithium bis- (trimethylsilyl) -amide and then hydrolyze the product obtained. The free amino groups can also be acylated in the usual manner with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, conveniently in an inert solvent such as the
Chloromethane or THF and / or in the presence of a base such as triethylamine or pyridine, at temperatures between -60 and + 30 °. A base of formula I can be converted into its salt by the addition of an acid, for example, by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol and then by evaporation of the latter. For this reaction, acids that form physiologically acceptable salts are particularly suitable. Therefore, inorganic acids such as, for example, sulfuric acid, nitric acid, hydrocides such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, then also organic acids can be used, in particular the carboxylic, sulphonic or sulfuric acids mono- or polybasic aliphatic, alicyclic, araliphatic, aromatic or etherocyclic acids such as, for example, formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic, naphthalenedisulfonic and lauryl sulphuric. Salts of acids that are not physiologically acceptable, for example picrates, can be
employed to isolate and / or purify the compounds of formula I. An acid of formula I can also be converted to one of its physiologically acceptable metal or ammonium salts by treatment with a base. Among the salts, the sodium, potassium, magnesium, calcium and ammonium salts are particularly preferred, and also the substituted ammonium salts, for example the dimethylammonium, diethylammonium or diisopropylammonium salts, the monoe-tanolamonium or diethanolammonium salts, the cyclohexylammonium salts , dicyclohexylammonium, dibenzylethylenediamonium, and also, for example, the salts formed with arginine or lysine. The compounds of formula I have one or several chiral centers, whereby they can be obtained as ra-cemates or in their optically active forms. The obtained racemates can be separated into their enantiomers by means of known chemical or mechanical methods. The diastereomers are formed from the racemic mixture, preferably by reaction with an optically active separation agent. Examples of suitable separation agents are optically active acids such as the D and L forms of tartaric, diacetyltartaric, dibenzoyltartaric, mandelic, malic, lactic acids, or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. It is also convenient to separate the enantiomers through a
column filled with an optically active separation agent (eg, dinitrobenzoyl-phen'yl-glycine); As the mobile phase, a hexane / isopropanol / acetonitrile mixture can be used, for example, in a volume ratio of, for example, 82: 15: 3. Of course it is also possible to obtain optically active compounds of formula I according to the methods described above, using optically active starting substances. The invention also relates to the use of the compounds of formula I and / or their physiologically acceptable salts for preparing pharmaceutical compositions, in particular by a non-chemical route. For these purposes, the compounds can be brought into a suitable dosage form, together with at least one solid, liquid and / or semi-liquid auxiliary excipient or auxiliary product and, optionally, in combination with one or more additional active substances. . The invention also relates to pharmaceutical compositions containing at least one compound of formula I and / or one of its physiologically acceptable salts. These compositions can be used in medicine and veterinary medicine as a medicine. Among the excipients, organic substances can be mentioned or
inorganic substances that are suitable for enteral (for example, oral), parenteral, topical application or for application in the form of aerosol inhaling solution, and which do not react with the new compounds. Examples of these excipients are water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. For oral administration, in particular, tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for the rectal application of suppositories, for parenteral application the solutions, preferably the oily solutions or aqueous, and also suspensions, emulsions or implants, and for topical application, ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilized products can be used, for example, for the preparation of injectable preparations. The mentioned compositions can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, pH regulating substances, dyes, flavor correction substances and / or various additional active substances such as, for example, one or several vitamins.
For the application in the form of aerosol inhaling solution, aerosols containing the active substance either dissolved or suspended in a carrier gas or a mixture of gases (for example, C02 or chlorofluorocarbons) can be used. The active substance particles usually have a micron size, and it is also possible to add one or more additional solvents that are physiologically acceptable, such as, for example, ethanol. Inhalant solutions can be administered using conventional inhalers. Another object of the invention is the use of the compounds of formula I as therapeutic active substances. The compounds of formula I and their physiologically acceptable salts can be used as integrin inhibitors to combat diseases, in particular pathological angiogenic diseases, thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, tumors, inflammations and infections. The substances of the invention are generally administered analogously to the other known and commercial peptides, in particular analogously to the compounds described in US Pat. No. 4,472,305, preferably in US Pat. Doses approximately between 0.05 and 500 mg, in particular between 0.5 and 100
mg per dosage unit. The daily dose is preferably comprised between about 0.01 and 2 mg / kg of body weight. However, the particular dose for each patient depends on a wide variety of factors, for example, the effect of the particular compound used, age, body weight, general state of health, sex, diet, of the time and method of administration, the rate of excretion, the combination of drugs and the severity of the particular disease to which the therapy is applied. Parenteral application is preferred. All temperatures of the present text are given in ° C. In the examples that follow, the expression "is worked (or treated) in a usual manner" means the following: if necessary, water is added, if necessary the pH is adjusted between 2 and 10 according to the constitution, of the final product it is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulphate, concentrated by evaporation and purified by chromatography on silica gel and / or by recrystallization. Mass spectrometry (MS): The (ionization by electronic impact) M + FAB (rapid bombardment of atoms) (M + H) +
Example 1 Acid (2S) -3-. { 2- [3- (1H-imidazol-2-ylamino) propyl] -4-oxo-4H-cro en-6-yl} -2- (2,2-dixamet-l-propoxyoxamido) -propidnico The synthesis of the compound is ied out, for example, as indicated in scheme 1. 80 g (0.31 mol) of 3- are suspended. acetyl-L-tyrosine in ll of anhydrous ethanol and heated at reflux for 12 hours, at 80 ° C and in the presence of 70 g (0.37 mol) of toluene-4-sulfonic acid. After cooling to room temperature 500 ml of MTB-ether are added, the obtained crystals are filtered off with suction and then washed with MTB-ether and dried. Yield: 99.4 g of the ethyl ester of 3-acetyl-L-tyrosine ("AB") in the form of p-ATS salt. 20 g (47.2 mmol) of "AB" are suspended in 320 ml of water and 160 ml of THF and mixed, portionwise and with stirring, with 8 g (94 mmol) of NaHCO 3. Then, a solution of 8.6 g (56 mmoles) of neopentyl chloroformate in 160 ml of THF is added drop by drop, stirred for 30 minutes at room temperature and the reaction mixture is worked up in a usual manner. The residue is recrystallized from MTB-ether. Yield: 16.1 g (93%) of the N- (2,2-dimethylpropyl-oxyhenyl) -3-acetyl-L-tyrosine ethyl ester ("AC"). Dissolve 5 g (14.2 mmol) of "AC" and 3.3 g (17 mmol) of 4-benzyloxy-butyric acid in 100 ml of DMF and mix at room temperature with 3.1 ml (28.4 mmol) ) of N-
methyl morpholine and 4.08 g (21.3 mmol) of EDCl. After 5 hours, the reaction solution is poured into 700 ml of water and the mixture is worked up in the usual manner. Yield: 7.4 g of 2-acetyl-4- (2-oxyethyl-2- (2,2-dimethylpropyl) oxyonylamino-ethyl) -phenyl ester ("AD") 4-benzyloxybutyrate. 6.2 g (11.4 mmoles) of "AD" are dissolved in 100 ml of anhydrous THF and the solution is stirred at room temperature with 342 mg (11.4 mmoles) of sodium hydride (80% in mineral oil) . After 30 minutes the solution is neutralized with an acidic ion exchanger and concentrated. Yield: 6.2 g of (2S) -3- (2-hydroxy-2- (3-benzyloxy-propyl) -4-oxo-chroman-6-yl) -2- (2,2-dimethylpropyl) oxyonylamino- ethyl non-propionate ("AE"). To a solution of 6.2 g (11.4 mmol) of - "AE" in
180 ml of dichloromethane is added 18 ml of trifluoroacetic acid and the mixture is stirred overnight at room temperature. The solution is then concentrated, concentrated 3 more times with 50 ml of toluene each time, and chromatographed on silica gel using toluene / methanol 20/1 as eluent. Yield: 4.2 g of (2S) -3- (2- (3-benzyloxy-propyl) -4-OXO-4H-chromen-6-yl) -2- (2,2-dimethylpropyl) -oxyonylaminopropium-nato of ethyl ("AF"), FAB 534.
3.5 g (6.7 mmoles) of "AF" are hydrogenated in 50 ml of ethanol, in the presence of 350 mg of palladium (10% on activated charcoal), for 1 hour and at room temperature and normal pressure. The catalyst is filtered and the solution is concentrated so that the product precipitates as an amorphous and colorless mass. Yield: 2.6 g of ethyl (2S) -3- (2- (3-hydroxypropyl) -4-oxo-4H-chromen-6-yl) -2- (2,2-dimethylpropyl) oxyonylamino-propionate ( "AG"), FAB 434. To a solution of 500 mg (1.15 mmol) of "AG" and
357 mg (1.38 mmol) of 2- (2,2,2-trichloro-ethoxycarbonyl) -amino-1H-imidazole in 20 ml of anhydrous THF are added 0.267 ml (1.72 mmol) of DEAD (diethylazadicarboxylate, azodicarboxylate diethyl) and 450 mg (172 mmol) of triphenylphosphine and the mixture is stirred overnight at 60 ° C. The solution is then concentrated and the residue is chromatographed on silica gel RP-8 with methanol / water 2: 1. Yield: 560 mg of (2S) -3- (2- (3- ((1H-imidazol-2-yl) - (2,2,2-trichloro-ethoxycarbonyl) -amino) -propyl) -4-oxo- 4H-cro-men-6-yl) -2- (2,2-dimethyl? Propyl) oxycarbonylamino-propionate ("AH") as a colorless oil, FAB 675. A solution of 280 mg (4.15 mmoles) of "AH" in 5 ml of THF with 0.5 ml of acetic acid and 0.5 ml of water is mixed with 500 mg (7.7 mmoles) of zinc powder and stirred
for 1 hour at room temperature. Then it is filtered, the solution is concentrated and the residue is dried. Yield: 210 mg of (2S) -3-. { 2- [3- (lH-imidazol-2-ylamino) -propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethylpropoxycarboxyamido) -ethyl propionate ("AI"), FAB 499. 200 mg (0.4 mmol) of "AI" are dissolved in 4 ml of dioxane and the solution is stirred with 2 ml of IN HCl for 12 hours at 75 ° C. The solution is then concentrated and the residue is purified by preparative-scale HPLC on RP-18 silica gel, using a water / acetonitrile gradient of 99: 1 to 1:99 as eluent in 60 minutes. After lyophilizing the HPLC fractions, the product is precipitated as amorphous and white powder. Yield: 103 mg of (2S) -3- acid. { 2- [3- (1H-imidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propoxy-carboxamido) -propionic acid ("AK"), m.p. 105-110 °, FAB 471. Sssuema 1:
Example 2 Acid (2S) -3-. { 2- [3- (pyridin-2-ylamino) propyl] -4-oxo-4H-cro-men-6-yl} -2- (2,2-dimethyl-propoxycarboxamido) -propionic The synthesis of the compound is carried out, for example, as indicated in scheme 2..
A solution of 0.5 g (1.47 mmol) of "AC" and 630 mg (1.77 mmol) of 4- (pyridin-2-yl- (2, 2, 2-trichloro-ethoxycarbonyl) - amino) -butyric acid in 10 ml of dichloromethane is mixed at room temperature with 420 mg (2.04 mmoles) of DCC and 20 mg of DMAP and the mixture is stirred for 15 hours. The precipitated dicyclohexylurea is then filtered, the residue is washed with dichloromethane and the solution is concentrated. The residue is chromatographed on silica gel with toluene / acetone 20: 1. Yield: 130 mg of 4- (pyridin-2-yl- (2, 2,2-trichloro-ethoxycarbonyl) -amino) -butyrate of 2-acetyl-4- (2-carboxyethyl-2- (2,2-dimethylpropyl) oxycarbonylamino-ethyl) phenyl ("BB"), FAB 704. At room temperature 130 mg (0.185 mmol) of "BB" are reacted with 5.4 mg (0.18 mmol) of sodium hydride (80% by weight). mineral oil) in 5 ml of THF. After 45 minutes it is neutralized with acetic acid and concentrated to a residue. Yield: 130 mg of (2S) -3- (2-hydroxy-2- (3-pyridin-2-yl- (2, 2, 2-trichloro-ethoxycarbonyl) -amino) -propyl) -4-oxo-chroman -6-yl) -2- (2,2-dimethylpropyl) oxycarbonylamino-propionate ("BC"). For 15 hours, 130 mg (0.18 mmol) of "BC" in 5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid are stirred at room temperature. The solution is then concentrated and the residue is chromatographed on silica gel.
Yield: 55 mg of (2S) -3- (2- (3- ((pyridin-2-yl) - (2,2,2-trichloroethoxycarbonyl) -amino) -propyl) -4-oxo-4H-chromen- 6-yl) -2- (2,2-dimethylpropyl) oxycarbonylamino-propionate ("BD"), FAB 686. After removing the TROC group in a manner analogous to that described for "Al" and working the mixture of 40 mg of (2S) -3- are obtained in the usual manner. { 2- [3- (pyridin-2-ylamino) -propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propoxycarboxa-mido) -ethyl propionate ("BE"). 40 mg (78 umoles) of "BE" are stirred in 2 ml of dioxane with 1 ml of IN HCl for 60 hours at 70 ° C. The solution is then concentrated and the residue is purified by preparative-scale HPLC on RP-18 silica gel. Yield: 20 mg of acid (2S) -3-. { 2- [3- (pyridin-2-ylamido-no) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propoxycarboxamido) -propionic ("BF") which after freeze-drying forms an amorphous and white powder, m.p. 80-85 °, FAB 482. Scheme 2:
"BA"
E-iprpnlo 3 Acid (2S) -3-. { 2- [3- (lH-benzimidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propoxycarboxamido) -propionic The synthesis of the compound is carried out, for example, as indicated in scheme 3.
In the same manner as in Example 1, 6.5 g (17.8 mmol) of "AD" are reacted with 5.2 g (35.6 mmol) of acetoxy-butyric acid in the presence of 7.5 g ( 39.1 mmol) of EDCI and 5.9 mL (53.6 mmol) of NMP in 100 mL of DMF. The product is purified by chromatography on silica gel with toluene / acetone 6: 1 as eluent. Yield: 7.7 g of 2-acetyl-4- (2-carboxyethyl-2- (2,2-dimethylpropyl) oxycarbonylamino-ethyl) -phenyl ester ("CA") 4-acetoxybutyrate obtained in the form of colorless oil, FAB 494. In the same manner as in Example 1, 7.7 g (15.7 mmoles) of "CA" are reacted with 489 mg (16.3 mmol) of sodium hydride (80% in oil). mineral) in 200 ml of THF for 16 hours and at room temperature, and then work the reaction mixture in a manner analogous to, 1a of example 1. Yield: 7.2 g of (2S) -3- (2-hydroxy) Ethyl 2- (3-acetoxy-propyl) -4-oxo-chroman-6-yl) -2- (2,2-dimethylpropyl) -oxycarbonylamino-propionate ("CB") as a crude product that can maintain its transformation without prior purification. Analogously to that described in Example 1, 7.2 g (15.7 mmol) of "CB" were dehydrated with 18 ml of trifluoroacetic acid in 180 ml of dichloromethane for 48 hours and at room temperature. The reaction solution is concentrated
and the product obtained is dried and used directly for the next reaction. Yield: 7.0 g of (2S) -3- (2- (3-acetoxy-propyl) -4-oxo-4H-chromen-6-yl) -2- (2,2-dimethylpropyl) -oxycarbonylamino-propion -ethyl ester ("CC") obtained in the form of a colorless oil. For 1 hour, 7.0 g (14.7 mmol) of "CC" in 200 ml of anhydrous ethanol are stirred at room temperature with 1.9 g (28 mmol) of sodium methoxide. Then it is neutralized with an acidic ion exchanger, the solution is concentrated until a residue is obtained and the latter is chromatographed on silica gel with toluene / acetone 2: 1. Yield: 2.4 g of (2S) -3- (2- (3-hydroxy-propyl) -4-oxo-4H-chromen-6-yl) -2- (2,2-dimethylpropyl) -oxycarbonylamino-propion -ethyl ethyl ester ("CD"), FAB 434. 500 mg (1.15 mmol) of "CD" are dissolved in 20 ml of dichloromethane and oxidized for 1.5 hours at room temperature with 370 mg (1.73 mM). mmol) of pyridinium chlorochromate. The reaction solution is filtered over 30 g of silica gel, the filter cake is washed with ethyl acetate and the solution is concentrated. The crude product is further processed without further purification. Yield: 392 mg of (2S) -3- (2- (3-oxopropyl) -4-oxo-4H-chromen-6-yl) -2- (2,2-dimethylpropyl) -oxycarbonylamino-propionate ethyl ester ("CE").
The crude product "CE" (100 mg, 0.23 mmol) is dissolved in 10 ml of pyridine and. Reacted with 33 mg (0.25 mmol) of 2-amino-benzimidazole in the presence of 0.13 ml (0.93 mmol) of triethylamine. After the reaction has ended (3 hours at room temperature), 18 mg (0.46 mmol) of sodium borohydride are added and the mixture is stirred at room temperature for a further 3 hours. It is then neutralized with dilute acetic acid, the solution is concentrated and the residue is purified by preparative-scale HPLC on RP-18. Yield: 64 mg of (2S) -3-. { 2- [3-lH-benzimidazol-2-ylamino) -propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propoxycarboxamido) -ethyl propionate ("CF") which after freeze-drying forms an amorphous and colorless powder, FAB 549. 50 mg (0.09 mmol) of "CF "in 2 ml of dioxane with 1 ml of IN HCl for 12 hours at 80 ° C and then the reaction mixture is concentrated .. Yield-. 45 mg of (2S) -3- acid. { 2- [3- (lH-benzimidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2, 2-dimethyl-propoxy-carboxamido) -propionic ("CG") FAB 521. Scheme 3:
Example 4 The chromenones and chromanones of formula I, in which R 1 represents an amide, can be prepared, for example, analogously to that indicated in scheme 4. Scheme 4:
H, / Pd / C / EtOH
Example 5 The chromenones of formula I, in which R represents CH 2 OH, can be prepared, for example, analogously to that indicated in scheme 5.
Scheme 5:
t-, THF
Example 6 The chromenones of formula I, in which Rs represents a guanidino group, can be prepared, for example, in a manner analogous to that indicated in scheme 6. Scheme 6:
EDCl, DMF
NaH cyclization, THF
Cleavage of the ester HCl / dioxane Cleavage of the phthalimide with hydrazine
Guanilación DPFN or S-metilisotiourea
Example 7 The chromenones of formula I, in which R represents an amidino group, can be prepared, for example, analogously to that indicated in scheme 7.
Scheme;
Hydroxy sheet, NaHCO3, EtOH, 60 °
NaOH ester
Hydrogenation / Pd / C, EtOH
EXAMPLE 8 The sulfonamide derivatives listed below are obtained analogously to that described in Examples 1, 2 and 3: (2S) -3- acid. { 2- [3- (1H-imidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propylsulfonamido) -propionic acid (2S) -3-. { 2- [3- (pyridin-2-ylamino) propyl] -4-oxo-4H-cro-men-6-yl} -2- (2,2-dimethyl-propylsulfonamido) -propionic acid (2S) -3-. { 2- [3- (lH-benzimidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propylsulfonamido) -propionic acid (2S) -3-. { 2- [3- (1H-imidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2-butylsulfonamido-propionic, (2S) -3- acid. { 2- [3- (pyridin-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2-butylsulfonamido-propionic, (2S) -3- acid. { 2- [3- (lH-benzimidazol-2-ylamino) propyl] -4-oxo-4-H-chromen-6-yl} -2-butylsulfonamido-propionic, (2S) -3- acid. { 2- [3- (1H-imidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2-phenylsulfonamido-propionic, (2S) -3- acid. { 2- [3- (pyridin-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2-phenylsulfonamido-propionic, (2S) -3- acid. { 2- [3- (lH-benzimidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2-phenylsulfonamido-propionic, (2S) -3- acid. { 2- [3- (1H-imidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2-benzylsulfonamido-propionic,
(2S) -3- acid. { 2- [3- (pyridin-2-ylamino) ropil] -4-oxo-4H-chromen-6-yl} -2-benzylsulfonamidd-propionic acid (2S) -3-. { 2- [3- (lH-benzimidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2-benzylsulfonamido-propionic. The following examples relate to pharmaceutical preparations. Example A: vials for injections The pH of a solution of 100 g of an active substance of formula I and 5 g of disodium hydrogen phosphate in 3 1 of bidistilled water is adjusted to 6.5 with 2N hydrochloric acid, then filtered in sterile conditions, this solution is introduced into the bottles, lyophilized and finally the bottles are closed in sterile conditions. Each bottle for injection contains 5 mg of the active substance. Example B: suppositories A mixture composed of 20 g of an active substance of formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of active substance. Example C: solution A solution is prepared with 1 g of active substance of formula I, 9.38 g of NaH2P04 x 2 H30, 28.48 g of Na2HP04 x 12 H20, 0.1 g of benzalkonium chloride and 940 ml of bidistilled water. The pH is adjusted to 6.8, it is brought to a volume of
1 1 and sterilized by irradiation. This solution can be used in the form of drops for the eyes. Example D: ointment Under aseptic conditions 500 mg of an active substance of formula I are mixed with 99.5 g of Vaseline. Example E: Tablets A mixture composed of 1 kg of an active substance of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablet form, such that each tablet contains 10 mg of the active substance. Example F: Dragees The tablets are formed analogously to that described in Example E and then coated in a usual manner with a sucrose bath, potato starch, talc, tragacanth and coloring. Example G: capsules With 2 kg of an active substance of formula I, hard gelatine capsules are filled, so that each capsule contains 20 mg of the active substance. Example H: ampoules A solution of 1 kg of an active substance of formula I in 60 1 of bidistilled water is filtered under sterile conditions. The ampoules are filled with this solution and then lyophilized and closed under conditions
sterile Each ampoule contains 10 mg of the active substance. Example I: aerosol inhalant solution 14 g of an active substance of formula I are dissolved in 10 1 of isotonic NaCl solution. With this solution, commercial containers that have a vaporizing mechanism are filled. The solution can be inhaled through the mouth or nose. Each spray (approx 0.1 ml) corresponds to a dose of approx. 0.14 mg. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (10)
1. Compounds of formula I wherein R1 represents CH20R10, COOR10, CONHR10 or CON (R12) 2, R2 represents R10, CO-R10, CO-R6, CCOR6, COOR10, S02R6, S02R10, CONHR6, CON (R6) 2, CONHR10 or CON (R12) 2 R3 represents H, Hal, NHR10, N (R12) 2, -NH-acyl, -0-acyl, CNf N02, OR10, SR10, S02R10, S03R10, COOR10, CONHR6, CON (R6) 2 CONHR10 or CON (R12) 2, R4 represents H, A, Ar or aralkylene of 7 to 14 carbon atoms, R5 represents NH2, H2N -C (= NH) or H2N- (C = NH) -NH, wherein the primary amino groups may also be protected with amino protecting groups conventional or can be mono, di or trisubstituted with R10, CO-R10, COOR10 or SO2R10, or represents R6-NH-, R represents a heterocyclic of one or two nuclei containing 1 to 4 atoms of N, 0 and / or S , and which may not be substituted or be mono, di or trisubstituted with Hal, A, -CO-A, OH, CN, COOH, COOA, CONH2, N02, = NH or = 0, R7, R8, independently of each other , are absent or represent H, R and R together, also represent a bond, Z is absent or represents O, S, NH, NR1, C (= 0), CONH, NHCO, C (= S) NH, NHC (= S), C (= S), S02NH, NHS02 or CA = CA ', R9 represents H, Hal, OR11, NH2, NHR12, N (R12) 2, NHacyl, Oacilo, CN, N02, SR11, SOR12, SO2R12 or SO3H, R10 represents H, A, Ar or aralkylene of 7 to 14 carbon atoms, R11 represents H or alkyl of 1 to 6 carbon atoms, R12 represents alkyl of 1 to 6 carbon atoms, A represents H or alkyl of 1 to 15 C or cycloalkyl atoms of 3 to 15 C atoms unsubstituted or mono, di or trisubstituted with R, and wherein one, two or three methylene groups may be replaced by N, O and / or S, Ar represents a of aromatic ring of one or two nuclei containing 0, 1, 2, 3 or 4 atoms of N, O and / or S and which may be unsubstituted or mono, di or trisubstituted with A and / or R9, Hal represents F, Cl, Br or I and m, n are independently 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates.
2. Enantiomers or diastereomers of the compounds of formula I, according to claim 1.
3. Compounds of formula I, according to the claim 1 a) (2S) -3- [2- (3-aminopropyl) -4-oxo-4H-chromen-6-yl] -2- (2,2-dimethyl-propoxycarboxamido) -propionic acid; b) (2S) -3- acid. { 2- [3- (1H-imidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propoxycarboxamido) -propionic; c) (2S) -3- acid. { 2- [3- (lH-imidazol-2-ylamino) propyl] -4-oxo-chroman-6-yl} -2- (2,2-dimethyl-propoxycarboxamido) -propionic; d) (2S) -3- acid. { 2- [3- (pyridin-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethyl-propoxycarboxamido) -propionic; e) (2S) -3- acid. { 2- [3- (1H-benzimidazol-2-ylamino) propyl] -4-oxo-4H-chromen-6-yl} -2- (2,2-dimethylpropoxycarboxamido) -propionic; and its salts and solvates acceptable from the physiological point of view.
4. Process for preparing the compounds of formula I, according to claim 1, and their salts and solvates, characterized in that a) a compound of formula I is released from one of its functional derivatives by treatment with a solvolysis or hydrogenolysis agent, ) a residue R1, R2 and / or R5 is transformed into another residue R1, R2 and / or R5 either, for example, i) by transforming an amino group into a guanidino group by reaction with an amidination agent, ii) saponifying an ester, iii) reducing a carboxylic acid to an alcohol, iv) transforming a hydroxyamidine into an amidine by hydrogenation, and / or transforming a base or an acid of formula I into one of its salts.
5. Compounds of formula I according to claim 1, and physiologically acceptable salts and solvates thereof, which act as GPIIb / IIIa antagonists and combat thrombosis, myocardial infarction, coronary heart disease and arteriosclerosis.
6. Compounds of formula I, according to claim 1, and its physiologically acceptable salts and solvates, which act as inhibitors of av integrin and combat pathological angiogenic diseases, thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, tumors, osteoporosis and rheumatic arthritis.
7. Pharmaceutical composition, characterized in that it contains at least one compound of formula I, according to claim 1, and / or one of its physiologically acceptable salts or solvates.
8. Process for obtaining 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 taken to a suitable dosage form, together with the less an excipient or solid, liquid or semi-liquid auxiliary product.
9. Use of the compounds of formula I, according to claim 1, and their physiologically acceptable salts and solvates, as therapeutic active substances.
10. Use of the compounds of formula I, according to claim 1, and their acceptable salts and solvates from the physiological point of view, to elaborate a medicine that is used as inhibitor of the integrin av.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19850131.5 | 1998-10-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01004272A true MXPA01004272A (en) | 2001-12-13 |
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