MXPA95004895A - Derivatives of beta-aril- and beta-heteroaril-alpha-cianoacrilamide n-substitute and process to supreparate - Google Patents
Derivatives of beta-aril- and beta-heteroaril-alpha-cianoacrilamide n-substitute and process to supreparateInfo
- Publication number
- MXPA95004895A MXPA95004895A MXPA95004895A MX PA95004895 A MXPA95004895 A MX PA95004895A MX PA95004895 A MXPA95004895 A MX PA95004895A
- Authority
- MX
- Mexico
- Prior art keywords
- cyanoacrylamide
- hydroxy
- indolyl
- compound
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 11
- -1 cyano, carboxy Chemical group 0.000 claims abstract description 239
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 41
- 239000011780 sodium chloride Substances 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000001257 hydrogen Substances 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 19
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims abstract description 14
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N Tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 13
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 12
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
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- 239000000203 mixture Substances 0.000 claims description 26
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- 238000002360 preparation method Methods 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
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- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The present invention relates to novel compounds of the formula (I), wherein A is a bicyclic ring selected from naphthalene, tetrahydronaphthalene, quinoline, isoquinoline and indole, B is a benzene ring substituted with R2 or a thiophene ring or unsubstituted pyridine: R is hydrogen, alkyl having 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy or a group NR3R4 wherein each of R3 and R4 is independently hydrogen or alkyl with 1 to 6 carbon atoms; R1 is hydrogen , alkyl with 1 to 6 carbon atoms or alkanoyl with 1 to 6 carbon atoms, R2 is hydrogen, alkyl with 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy, hydroxy, alkoxy, with 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 carbon atoms or a group NR3R4 wherein R3 and R4 are as defined above, n is zero or an integer from 1 to 2, x is zero or an integer from 1 to 5, and salts thereof pharmaceutically acceptable The compounds of the invention are useful as inhibitors of tyrosine
Description
"DERIVATIVES DE BETA-ARIL- AND BETA-HETEROARIL-ALFA- CIANOACRILAMIDA N-SUBSTITUIDOS AND PROCESS FOR ITS PREPARATION"
Invention (s): FRANCO BUZZETTI, Italian, domiciled in Via della Gallarana 4, 20052 Monza (Milan), Italy; ANGELO CRUGNOLA, Italian, domiciled in Via Ruggiero Settimo 30, 21100 Várese, Italy, - ANTONIO LONGO, Italian, domiciled in Via N.A. Porpora 160, 20131 Milan, Italy; MARIA GABRIELLA BRASCA, Italian, domiciled in Via Dante Alighieri 15, 20090 Cusago (Milan), Italy and DARÍO BALLINARI, Italian, domiciled in Via C. Jannozzi 8, 20097 San Donato Milanese (Milan), Italy.
Causabiente: PHARMACIA S.P.A., Italian company, domiciled in Via Robert Koch 1.2, 20152 Milan, Italy
DERIVATIVES OF -ARIL- AND -HETEROARIL- Q-CIANOACRILAMIDE N-SUBSTITUTE AND PROCESS FOR ITS PREPARATION
The present invention relates to new derivatives of N-substituted aryl-and-β-heteroaryl-cyanoacrylamide, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents. The present invention provides compounds having the following general formula (I)
wherein A is a bicyclic ring selected from naphthalene, tetrahydronaphthalene, quinoline, isoquinoline and indole; 2 B is a ring of benzene substituted with R or a ring of thiophene or unsubstituted pyridine; R is hydrogen, alkyl having 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy or a group NR3R4
wherein each of R 3 and R 4 is independently hydrogen or alkyl having 1 to 6 carbon atoms; R 1 is hydrogen, alkyl having 1 to 6 carbon atoms or alkanoyl having 1 to 6 carbon atoms;
R2 is hydrogen, alkyl having 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy, hydroxy, alkoxy with 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 carbon atoms, or a group NR3R4 wherein R 3 and R4 are as defined above; n is zero or an integer from 1 to 2; x is zero or an integer from 1 to 5; and pharmaceutically acceptable salts thereof.
In the compounds of the formula (I) when A is naphthalene, quinoline, isoquinoline or indole, then each of the substituents R and OR 'can be independently on any of the two rings that make up the bicyclic system, when A is tetrahydronaphthalene while -because they are only on the benzene ring of the bicyclic system. When n is 2, the OR 'groups may be the same or different. The invention includes within its scope all possible isomers, stereoisomers, in particular the Z and E isomers and their mixtures, and the metabolites and metabolic precursors or bio-precursors (otherwise known as prodrugs) of the compounds of the formula (I) The alkyl groups and the alkyl portions in the alkoxy, alkanoyl or alkanoyloxy groups can be straight or branched alkyl chains. An alkyl with 1 to 6 carbon atoms is preferably an alkyl with 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, in particular methyl or ethyl. An alkoxy group with 1 to 6 carbon atoms is preferably an alkoxy with 1 to 3 carbon atoms, in particular methoxy. An alkanoyl group with 1 to 6 carbon atoms is preferably an alkanoyl group with 2 to 3 carbon atoms, in particular acetyl or propionyl. An alkanoyloxy group having 1 to 6 carbon atoms is preferably an alkanoyloxy group having 2 to 3 carbon atoms, in particular acetyloxy or propionyloxy. A halogen is preferably fluorine, chlorine or bromine, in particular fluorine or chlorine.
A group N is, preferably, amino. . 5,6,7,8-tetrahydronaphthalene is more precisely proposed for tetrahydronaphthalene. When A is naphthalene the substituents R and R O and the acrylamide side chain are preferably on the same benzene portion. When A is 5, 6, 7, 8-tetrahydronaphthalene, the 1 substituents R and R O and the acrylamide side chain are preferably on the aromatic benzene portion. When A is quinoline, the acrylamide side chain is preferably attached to position 4 or 5 of the quinoline ring and the substituents R and R 0 are preferably on the same aryl or heteroaryl portion of the ring. When A is isoquinoline the acrylamide side chain is preferably attached to the 3- or 5-position of the isoquinoline ring and the substituents R and R O are preferably on the benzene portion of the ring. When A is an indole ring, the acrylamide side chain is preferably attached to the pyrrolo portion and the substituents R and R O are preferably on the benzene portion of the ring. In this case preferably A is a group of 3-indolyl. Of course, only one of the substituents iR, R O and the acrylamide side chain can be attached or linked to the same carbon atom of ring A. The substituent R 2 is preferably in the para position on the benzene ring. When one of R and R2 is N02, COOH or NR3R4, then the other preferably has a different meaning. The pharmaceutically acceptable salts of the compounds of the invention include the acid addition salts, with inorganic acids, for example hydrochloric, sulfuric, perchloric and phosphoric acids, or organic acids, for example acetic, glycolic, lactic, oxalic acid. , malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic, and the salts with inorganic bases, for example sodium, potassium, calcium or magnesium bases, or with organic bases, for example alkylamines, preferably triethylamine. As noted above, the present invention also includes within its scope the pharmaceutically acceptable bioprecursors (otherwise known as prodrugs) of the compounds of the formula (I), ie the compounds having a formula other than the formula (i) ) above, but which, however, during administration to the human being are converted directly or indirectly in vivo into a compound of the formula (I). Preferred compounds of the invention are the compounds of the formula (I), wherein A is tetrahydronaphthalene, quinoline, isoquinoline and indole; B is benzene substituted with R 2 or unsubstituted pyridine; R is hydrogen or halogen with the exception of the indole derivatives wherein R can also be carboxy or amino; -i R is hydrogen or methyl; 2 R is hydrogen, halogen, cyano, hydroxy, carboxy or amino; n is 0, 1 or 2 and x is 0, 1, 2 or 3; and the pharmaceutically acceptable salts thereof. A particularly preferred class of the compounds of the invention are the compounds of the formula (I) in which: A is tetrahydronaphthalene, quinoline, isoquinoline and indole; 2 B is benzene substituted with R or an unsubstituted pyridine; R is hydrogen with the exception of indole derivatives wherein R can also be carboxy or amino;
R is hydrogen or methyl; 2 «> R is hydrogen or hydroxy; n is 0, 1 or 2; and x is 0, 1 or 2; and pharmaceutically acceptable salts thereof. i More preferably the OR substituents are attached or linked to the 3 and 4 position when A is the
5,6, 7,8-tetrahydronaphth-1-yl and to position 4 when A is 5, 6, 7, 8-tetrahydronaphth-2-yl. When A is quinoline, 1 the OR substituent is more preferably linked or linked to the 8-position. When A is indole, the R or OR substituent is more preferably linked or linked to the 5-position. In all the above-mentioned cases, the - substituent R is bonded or linked more preferably to the 4 'position. Examples of the specific compounds of the invention are the following compounds, which can be either the Z or E isomers or the Z, E mixtures of the isomers: N-phenyl / $ - (4-hydroxy-5.6 , 7, 8-tetrahydronaphth-1 -yl) - C -cyanoacrylamide; N- (4 '-hydroxyphenyl) -β (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) - or "i-cyanoacrylamide; N-phenyl-β- (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -e > ? -cyanoacrylamide; N- (4 * -hydroxyphenyl) -β- (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -0? -cyanoacrylamide; N-benzyl- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyano-acrylamide; N- (4 '-hydroxybenzyl) ß- (4-hydroxy-5,6,7,8-tetrahydronaphth-1 -yl) - oC-cyanoacrylamide; N-benzyl β (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -P-cyanoacrylamide; N- (4 '-hydroxybenzyl) -β- (3,4-dihydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -ocyanoacrylamide; N-phenethyl β- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -O-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (4-hydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -CC-cyanoacrylamide; N-phenethyl-β (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -O-cyanoacrylamide; N- (4 '-hydroxyphenethyl) -β- (3,4-dihydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -oc-cyanoacrylamide; N-phenyl-β- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -β-cyano-acrylamide; N- (4 '-hydroxyphenyl) - β- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) - o -cyanoacrylamide; N-benzyl β- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) - oC -cyanoacrylamide; N- (4 '-hydroxybenzyl) ß • - (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -oc-cyanoacrylamide; N-phenethyl β- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -c-cyanoacrylamide; N-phenyl ß - (4-quinolyl) - «OC-cyanoacrylamide; N- (4 '-hydroxyphenyl) S- (4-quinolyl) -O-cyanoacrylamide; N-benzyl- (4-quinolyl) - ^ -cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (4-quinolyl) -OC-cyanoacrylamide;
N-phenethyl- (4-quinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxifenethyl) β- (4-quinolyl) -OC-cyanoacrylamide;
N-phenyl-β- (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenyl) - (8-hydroxy-5-quinol1) -Q-cyanoacrylamide; N-benzyl fi- (8-hydroxy-5-quinol1) -oc-cyanoacrylamide; N- (4 '-hydroxy-benzyl) -β- (8-hydroxy-5-quinolyl) - (X-cyanoacrylamide; N-phenethyl-β- (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) -β- (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide; N-phenyl-β- (3-isoquinolyl) -pc-cyanoacrylamide; N- (4'-hydroxyphenyl) - (3-isoquinolyl) - OC-cyanoacrylamide;
N-benzyl- (3-isoquinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (3-isoquinolyl) -OC-cyanoacrylamide;
N-phenethyl β- (3-isoquinolyl) -CC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) β- (3-isoquinolyl) -OC-cyanoacrylamide;
N-phenyl-β- (5-isoquinolyl) -OC-cyanoacrylamide; N- (4-hydroxyphenyl) -β- (5-isoquinolyl) -0-cyanoacrylamide; N-benzyl & - (5-isoquinolyl) -oc-cyanoacrylamide; N- (4'-Hydroxybenzyl) - - (5-isoquinolyl) -CP-cyanoacrylamide;
N-phenethyl ß - (5-isoquinolyl) - «í > C-cyanoacrylamide; N- (4 '-hydroxyphenethyl) β- (5-isoquinolyl) -OC-cyanoacrylamide;
N-phenyl-β- (3-indolyl) -OC-cyanoacrylamide; N-benzyl β- (3-indolyl) -oc-cyanoacrylamide; N-phenethyl β- (3-indolyl) - «OC-cyanoacrylamide;
N-phenyl-β- (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-benzyl- (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-phenethyl-β- (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-phenyl-β- (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-benzyl- (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-phenethyl β - (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-phenyl-β- (5-amino-3-indolyl) - "oc-cyanoacrylamide; N-benzyl- (5-amino-3-indolyl) -OC-cyanoacrylamide; N-phenethyl β - (5-amino-3-indolyl) -pc-cyanoacrylamide; N- (4 '-hydroxyphenyl) -β- (3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) ß- (3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxifenethyl) 6 * - (3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (5-hydroxy-3-indolyl) - < ? -cyanoacrylamide; N- (4 '-hydroxy-benzyl) -β- (5-hydroxy-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - (5-hydroxy-3-indolyl) -Oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (5-carboxy-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxybenzyl) ß - (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (5-amino-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (5-amino-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (5-amino-3-indolyl) -oc-cyanoacrylamide; N-phenyl-β- (5-methoxy-3-indolyl) -pc-cyanoacrylamide; N-benzyl- (5-methoxy-3-indolyl) -OC-cyanoacrylamide; N- (3-pyridyl) β- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) - • OC-cyanoacrylamide; N- (3-pyridyl) - β- (3-indolyl) -OC-cyanoacrylamide; N- (3-pyridyl) - - (5-methoxy-3-indolyl) -OC-cyanoacrylamide;
N- (3-pyridyl) - β- (4-quinolyl) -OC-cyanoacrylamide; N- (3-pyridylmethyl) - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (3-pyridylmethyl) - - (3-indolyl) -OC-cyanoacrylamide; N- (3-pyridylmethyl) - - (5-methoxy-3-indolyl) -0C-cyanoacrylamide; N- (3-pyridylmethyl) - - (4-quinolyl) -OC-cyanoacrylamide; N- (2-pyridylmethyl) - - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (2-pyridylmethyl) - - (3-indolyl) -oc-cyanoacrylamide; N- (2-pyridylmethyl) - - (5-methoxy-3-indolyl) -OC-cyanoacrylamide; N- (2-pyridylmethyl) - (4-quinolyl) -OC-cyanoacrylamide, and, where appropriate, the pharmaceutically acceptable salts thereof. The compounds of the invention, and pharmaceutically acceptable salts thereof, can be obtained by a process comprising the condensation of an aldehyde of the formula (II)
wherein A, R, R and n are as defined above, with a compound of the formula (III)
NC-CH2-CONH- (CH2)? - B (III)
2 wherein R and x are as defined above, and, if desired, converting a compound of the formula (I) to another compound of the formula (I), and / or, if desired, converting a compound of the formula (I) in a pharmaceutically acceptable salt thereof, and / or, if desired, converting a salt to a free compound, and / or, if desired, separating a mixture of isomers of a compound of the formula (I) into the individual isomers. Each of the substituents R, RO and -CHO in a compound of the formula (II) can be independently on any of the rings in naphthalene, quinoline, isoquinoline and indole, while in the case of tetra-hydronaphthalene they are preferably on the same aromatic ring. The condensation of a compound of the formula
(II) with a compound of the formula (III) can be carried out according to known methods as will be described hereinafter. For example, it can be carried out under the conditions of the Knoevanagel reaction which was described, for example, by G. Jones in Organic Reactions _15_, 204 (1967). Suitable or suitable catalysts are organic bases such as pyridine, piperidine or diethylamine. The condensation can be carried out in an inert organic solvent, for example, pyridine, ethanol; methanol, benzene or dioxane at temperatures ranging from approximately 0 ° C to approximately 100 ° C. Preferably the reaction is carried out in a hot ethanol solution in the presence of the piperidine catalyst. A compound of the formula (I) can be converted to another compound of the formula (I) according to the known methods. For example, the deesterification of a compound of the formula (I) wherein RO is methoxy, so that a compound of the formula (I) wherein RO is hydroxy is obtained, can be carried out for example with boron tribromide as it was described for example by JFN McOmie in Tetrahedron 2_4, 2289 (1968). The reaction can be carried out in an inert organic solvent such as dichloromethane or benzene under an inert atmosphere (for example nitrogen) at temperatures ranging from about -78 ° C to about room temperature. The conversion of a compound of the formula (I) 2 in which R or R is nitro, in the corresponding compound 2 of the formula (I), wherein R or R is amino, can be carried out following known methods, for example with a variety of reducing agents, for example sodium sulfide in a hydroalcoholic solution, metallic iron with ammonium chloride in an aqueous solvent, or for example, catalytic hydrogenation using for example a palladium on carbon catalyst at a hydrogenation pressure. low in an inert organic solvent. The alkylation of a compound of the formula (I),
1 2 wherein RO or R is hydroxy, to obtain the corresponding compound - • 1 2 of the formula (I), wherein RO or R is alkoxy with 1 to 6 carbon atoms, can be obtained, for example, by the reaction with sodium hydride and alkyl iodide with 1 to 6 carbon atoms in a high-boiling aromatic solvent such as xylene. The acylation of a compound of the formula (I), wherein R 2 or R 1 O is hydroxy, to obtain the corresponding compound of the formula (I), wherein R or R 0 is an alkanoyloxy with 1 to 6 carbon atoms , it can be effected, for example, by the reaction with a suitable carboxylic acid anhydride in the presence of a basic agent at temperatures ranging from room temperature to reflux temperatures. The optional salification of a compound of the formula (I) as well as the conversion of a salt to a free compound, and the separation of a mixture of isomers in the individual isomers can be carried out by conventional methods. For example, the separation of a mixture of geometric isomers, for example, the cis and trans isomers, can be carried out by fractional crystallization from a suitable solvent or by chromatography, either column chromatography or HPLC. The compounds of the formula (II) can be obtained according to the known methods from the compounds of the formula (IV)
where A, R and R are as defined above. For example, when the compound (IV) contains 1 phenolic groups, ie R 0 is hydroxy, the well-known Reimer-Tiemann method can be applied. Accordingly, the phenolic compound is treated with chloroform and alkali hydroxides in an aqueous or hydroalcoholic solution. Another useful method for the synthesis of aromatic or phenolic aldehydes has been described by H. Gross et al. in Chem.
Ber. 96_, 308 (1963). Accordingly, a compound of formula (IV), in which the OR group may or may not be present, may be treated with a dichloromethyl ether, for example dichloromethyl methyl ether, in the presence of a Friedel catalyst. Crafts such as titanium tetrachloride or aluminum trichloride in an inert solvent similar to dichloromethane or nitrobenzene at temperatures ranging from about 0 ° C to about 60 ° C. The 3-formylindole derivatives of the formula
(II) can be obtained, for example, from the compounds of the formula (IV) by formylation with N-methyl-formanilide and phosphorus oxychloride according to the well-known Vilsmeyer-Haack method [for a review see .G. Jackson et al. in J. Am. Chem. Soc. 103, 533 (1981)]. The compounds of the formula (III) can be obtained by known methods from a compound of the formula (V)
CN-CH2-COOR5 (V) 5 wherein R is an alkyl group of 1 to 6 carbon atoms, in particular a methyl group, by condensation with a compound of the formula (VI)
H2N- (CH2)? - B (VI)
2 where R and x are as defined above. Preferably, the condensation is carried out by heating equimolar amounts of the compound (VI) and the compound (V) in the form of its methyl ester at temperatures ranging from about 100 ° C to 200 ° C for several hours without adding a solvent. Alternatively, a compound of the formula (III) can be obtained by reacting a compound of the formula (V) wherein R is H with a compound of the formula (VI) wherein β and C are as previously defined using dicyclohexylcarbodiimide as the binding agent and conducting the reaction in an inert solvent such as THF or benzene at temperatures ranging from ambient to reflux temperatures. The compounds of the formulas (IV), (V) and (VI) are already known or can be obtained by known methods. When in the compounds of the formula (I) and in the intermediates thereof, there are present groups that are needed to be protected before subjecting them to the reactions illustrated hereinabove, they may be protected before the reaction It is carried out and then unprotected at the end of the reaction, according to methods well known in organic chemistry.
PHARMACOLOGY
The compounds of the invention possess a specific tyrosine kinase inhibitory activity. It is believed that tyrosine kinase inhibitors can be of great importance in the control of uncontrolled cell reproduction, that is, in the disorders of cell reproduction. Hence, the compounds according to the present invention may be useful in the treatment of pathological proliferation disorders in mammals, including humans. They may be useful, for example, in the treatment of benign and malignant tumors. They are able to cause the regression of tumors and prevent tumor metastasis and the growth of micrometastases. In addition, they may also be useful for the treatment of leukemia and psoriasis. They also have utility in the control of diseases of the immune system (immunosuppressive), angiogenesis and atherosclerosis (atheromatous plaque) because the kinases of the protein are involved in these diseases. Recent studies on the molecular basis of neoplastic transformation have identified a family of genes, designated oncogenes, whose aberrant expression causes tumorigenesis. For example, tumorigenic RNA viruses possess such an oncogene sequence whose expression determines the neoplastic conversion of infected cells. Several of its encoded oncogene proteins, such as pp60v ~, p70gag_yes, p130g g_P and p70g g ~~ g exhibit protein tyrosine kinase activity, ie they catalyze the transfer of ^ -phosphate from the triphosphate of the protein. adenosine (ATP) to tyrosine residues in the protein substrate. In normal cells, several growth factor receptors, for example the receptors for PDGF, EGF, OC-TGF and insulin, exhibit tyrosine kinase activity. Growth factor binding (GF) activates receptor tyrosine kinase to undergo autophosphorylation and to closely phosphorylate adjacent molecules on tyrosine. Therefore, it is thought that phosphorylation of these tyrosine kinase receptors play an important role in signal transduction and that the main function of tyrosine kinase activity in normal cells is to regulate cell growth. The disruption of this activity by oncogenic tyrosine kinases that are either overproduced and / or exhibit altered substrate specificity, can result in loss of growth control and / or neoplastic transformation. Accordingly, a specific inhibitor of tyrosine kinases may be useful in the investigation of the mechanism of carcinogenesis, cell proliferation and differentiation and may be effective in the prevention and chemotherapy of cancer and other pathological proliferative conditions. In particular, the compounds of the invention can be used in the treatment of cancers, metastasis, leukemia, psoriasis, angiogenesis, atherosclerosis (atheromatous plaque) and diseases of the immune system because the protein kinases are involved in these diseases. The kinase activity of the tyrosine-specific protein of the compounds of the invention is shown, for example, by the fact that they are active in the in-vitro and in-vivo test described hereinafter.
In-vitro assay
Purification of the kinase p45 v-abl
The enzyme used in this test was tyrosine kinase p45 v-abl, which represents the catalytic domain "" of Abelson tyrosine kinase (isolated from murine leukemia virus, Abelson). The p45 v-abl kinase was produced and isolated as described by Wang et al. in J. Biol. Chem. 260, 64 (1985) and by Ferguson et al. in J. Biol. Chem. 26, 3652 (1985) and in Biochem. J. 2j > 7, 321 (1989).
Kinease Assay p45 v-abl
Phosphorylation of (Val) -ngiotensin II was effected by incubation with 40 ng of the purified abl-kinase and (# 32P) -ATP, in 50 uZl of the buffer solution containing 25 mM Tris-HCl, pH 8.0, 10 mM MgCl2 and 0.1 mM dithiothreitol (kinase buffer). The reaction mixture is incubated for the indicated period of time at 30 ° C and the reaction stopped by adding 50 μl of 5% trichloroacetic acid. After a brief incubation on ice, the tubes were centrifuged. The supernatants were placed on squares of phosphocellulose paper (Whatman P-81) and rinsed abunclarly in acetic acid. The radioactivity bound to the dry phosphocellulose squares is measured in a liquid scintillation counter. The IC, -n values were calculated from triplicate determinations of each experimental point. Each inhibitor was tested at concentrations ranging from 0 to 400 jxq in the presence of fixed concentrations of peptide (2 mM) and ATP (50 μM).
In-vivo test
Growth Inhibition Test of K562 Cells
K562 cells, a cell line of human myelogenous leukemia, were seeded in a tissue culture plate of 24 cavities (Falcon 3047) (10000 / cavity) in the presence of increasing concentrations of the compounds. After 72 hours, the cells were collected and counted using a cell counter (Coulter Counter-ZM). The percent inhibition was evaluated with respect to the untreated control cells. The data of the inhibitory activity for a representative compound according to the present invention, obtained both in the p45 v-abl in-vivo kinase assay and in the growth inhibition assay of the K562 cells of human chronic myeloid leukemia in-vivo described above, are shown in Table 1.
"" Table I Inhibition of p45 v-abl kinase and growth of K562 cells
N-phenyl ß - (8-hydroxy-5-quinolyl) - v-abl K562 oc-cyanoacrylamide 3.4 0.66
In view of their high activity and low toxicity, the compounds of the invention can be used safely in medicine. For example, the approximate acute toxicity (LD, -0) of the compounds of the invention in the mouse, determined by the single administration of increasing doses and measured on the seventh day after treatment, was found to be negligible. The compounds of the invention can be administered in a variety of dosage forms, for example orally, in the form of tablets, capsules, tablets coated with sugar or with a film, liquid solutions or suspensions, rectally, in the form of suppositories; parenterally, for example intramuscularly, or by intravenous injection or infusion; or topically. The dose depends on the age, weight, condition of the patient and the route of administration; for example, the "dosage" adopted for oral administration to human adults may vary from about 10 to about 150-200 mg per dose, from 1 to 5 times daily. Of course, these dosage regimens can be adjusted to provide the optimal therapeutic response. The invention includes pharmaceutical compositions comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, in association with an accretable excipient fa-rttra < The "substances" or "pharmaceutical compositions" containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form, for example, solid oral forms. "may" contain, together with the active compound, diluents, for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch, lubricants, for example silica, talc, stearic acid, magnesium stearate or calcium and / or polyethylene glycol-0 agglutinating agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone, disaggregation agents, for example a starch, alginic acid, alginates or sodium starch glycollate, effervescent mixtures; dyes or colorants; sweetening agents or sweeteners; wetting agents, such as lecithin, polysorbates, lauryl sulfates; al, pharmacologically inactive and non-toxic substances used in pharmaceutical formulations. The pharmaceutical preparations can be manufactured in a known manner, for example, by means of mixing, granulating, tabletting, coating processes with sugar or coating with a film.
The liquid dispersion for oral administration can be, for example, syrups, emulsions and suspensions. The syrup may contain as a carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol. Suspensions and emulsions can contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methyl cellulose, carboxymethyl cellulose or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol, and, if desired, an appropriate amount of Lidocaine hydrochloride. The solutions for intravenous injections or infusion may contain as carrier, for example, sterile water or, preferably, they may be in the form of aqueous, sterile, isotonic saline solutions. The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The compositions for topical application, for example creams, lotions or pastes, can be prepared by mixing the active ingredient with a conventional oily or emulsifying excipient. A further object of the present invention is a combined method for the treatment of cancer in mammals, including humans, in need of such treatment, the method comprising administering 1) a compound of the formula (I), or a salt of the same pharmaceutically acceptable, and 2) an additional antitumor agent, in amounts and together in a sufficiently linked or narrow period of time to produce a therapeutically useful effect. It is an object of the present invention also to provide products containing a compound of the formula (I), or a pharmaceutically acceptable salt, and an additional antitumor agent as a combined preparation for simultaneous, separate or sequential use in anticancer therapy. The term "antitumor agent" is intended to encompass both a single antitumor drug and "cocktails" ie a mixture of such drugs, in accordance with clinical practice. The antitumorigenic agents which can be formulated with a compound of the invention or alternatively, which can be administered in a combined method of treatment, are for example doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, bleomycin, vinblastine and mitomycin or a mixture of two or more thereof. The compounds of the invention can therefore be used in a treatment to improve a cancer pathology. They can be administered to a patient suffering from a cancer treatable with an anti-tumor agent, for example an anthracycline glycoside such as doxorubicin, daunomycin, epirubicin or idarubicin as mentioned above, together with the antitumor agent. A compound of the invention and an antitumor-antigen agent such as an anthracycline glycoside can be administered to improve the condition of a patient having a leukemia such as myeloblastic leukemia, lymphoma, sarcoma, neuroblastoma, Wilm's tumor or malignant neoplasm of the bladder, chest, lung or thyroid. The following examples illustrate but do not limit >;-""' the invention.
Example 1
N-Phenyl - (8-hydroxy-5-quinolyl) - OC-cyanoacrylamide
A solution of 8-hydroxy-5-quinolinecarboxaldehyde (1732 g, 0.010 mole), N-phenyl cyanoacetamide (1602 g, 0.010 mole) and piperidine (0.255 g, 0.003 mole) in absolute ethanol (50 ml) is heated for 3 hours. it has ebbed. The reaction mixture is cooled to about 10-15 ° C, the precipitate is filtered, the residue is washed with ice-cold ethanol and dried under vacuum. The almost pure title compound is obtained with a yield of about 75% (2365 g). The high purity compounds are obtained by crystallization from ethanol.
C19H13N3 ° 2 calculated: C 72.37 H 4.15 N 13.33 0 found: C 72.40 H 4.20 N 13.30 EM m / z 315. IR cm "1: 3300-3600 (NH, OH), 2210 (CN), 1680, 1600 (CONH ), 1530, 1510 (C = C) NMR <? Ppm (DMSO): 5 7.0-7.5 (m, 4H), 7.6-7.8 (m, 3H), 8.36 (d, J = 8.4 Hz, 1H), 8.80 (dd, J = 1.4 and 8.6 Hz, 1H), 8.83 (s, 1H), 8.95 (dd, J = 1.4 and 1.4 Hz, 1H), 10.4 (s amp., 1H).
According to the process described above and starting from the appropriate compounds of the formula
(II) and of the formula (III) the following compounds can be prepared as the individual E or Z isomers, as well as their mixtures E, Z:
N-phenyl-β- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide. C20H18N2 ° 2 calculated: C 75.45 H 5.70 N 8.80 found: C 75.35 H 5.65 N 8.75 MS m / z 318. RMN ppm (DMSO): 1.77 (m, 4H), 2.55, 2.80 (two m, 4H), 6.78 ( d, J = 8.6 Hz, 1H), 7.11 (m, 1H), 7.34 (m, 2H), 7.64 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 8.31 (s, 1H), 10.18 (s, 1H), 10.3 (s amp., 1H).
N- (4 '-hydroxyphenyl) -β (4-hydroxy-5,6,7,8-tetrahydronaphth-1 -yl) - o -cyanoacrylamide; N-phenyl-β- (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (3,4-dihydroxy-5,6,7,8-tetrahydro-* "* naphth-1-yl) -OC-cyanoacrylamide; N-benzyl- (4-hydroxy) 5, 6,7, 8-tetrahydronaphth-1-yl) -occyanoacrylamide; N- (4'-hydroxybenzyl) - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -o -cyanoacrylamide; N-benzyl- (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (4'-hydroxybenzyl) - (3,4-dihydroxy) 5, 6,7, 8-tetrahydro-naphth-1-yl) -oc-cyanoacrylamide; 0 N-phenethyl-β- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc- cyanoacrylamide; N- (4 '-hydroxifenethyl) - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -c-cyanoacrylamide; N-phenethyl- (3,4-dihydroxy-5,6,7) , 8-tetrahydronaphth-1-yl) -5-occyanoacrylamide, N- (4'-hydroxyphenethyl) - (3,4-dihydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -oc -cyanoacrylamide; N-phenyl-β- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -OC-cyanoacrylamide; 0 N- (4'-hydroxyphenyl) - - (4-hydroxy-5, 6, 7, 8-tetrahid ronaft-2- il) - «© C-cyanoacrylamide; N-benzyl β - (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) - (4-hydroxy-5,6,7,8-tetrahydronaphth-5-yl) -oc-cyanoacrylamide;
• "" 'N-phenethyl β - (4-hydroxy-5,6,7,8-tetrahydronapht-2-yl) -OC-cyanoacrylate ida; N- (4 '-hydroxyphenethyl) - (4-hydroxy-5, 6, 7, 8-tetrahydro-napht-2-yl) -' ^ c-cyanoacrylamide;
N-Phenyl-β- (4-quinolyl) -OC-cyanoacrylamide. C1 9H1 3N3 ° calculated: C 76. 24 H 4.38 N 1 4. 04 found: CHN MS m / z 299. NMR 6 ppm (DMSO): 7.17 (m, 1H), 7.40 (m, 2H), 7.6-8.0 (m, 5H), 8.1-8.4 (m, 2H), 8.95 (s, 1H), 9.09 (d, J = 4.4 Hz, 1H), 10.65 (s, 1H).
N- (4 '-hydroxyphenyl) - (4-quinolyl) -OC-cyanoacrylamide; N-benzyl- (4-quinolyl) - oC-cyanoacrylamide; N- (4 '-hydroxybenzyl) ß - (4-quinolyl) -OC-cyanoacrylamide;
N-phenethyl- (4-quinolyl) - (C-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (4-quinolyl) -oC-cyanoacrylamide; N- (4 '-hydroxyphenyl) - (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide; N-benzyl- (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide; N-phenethyl β - (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide;
N- (4 '-hydroxyphenethyl) - - (8-hydroxy-5-quinolyl) -CC-cyanoacrylamide;
N-phenyl-β- (3-isoquinolyl) - cc-cyanoacrylamide. -.QHnN-. ° calculated: C 76.24 H 4.38 N 14.04 found: C 76.15 H 4.27 N 13.95
MS m / z 299. IR cm 1: 3500-3300 (NH); 2215 (CN); 1675, 1605 (CONH); 1580, 1530 (arom).
N- (4 '-hydroxyphenyl) - - (3-isoquinolyl) -OC-cyanoacrylamide;
N-benzyl β - (3-isoquinolyl) -oc-cyanoacrylamide. C20H15N3 ° calculated: C 76.66 H 4.83 N 13.41 found: C 76.51 H 4.75 N 13.36
MS m / z 313 IR cm "1: 3500-3300 (NH), 2210 (CN), 1680, 1610 (CONH); 1585, 1530 (arom.).
N- (4 '-hydroxybenzyl) - - (3-isoquinolyl) -o-cyanoacrylamide; N-phenethyl β - (3-isoquinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (3-isoquinolyl) -OC-cyanoacrylamide;
N-phenyl-β- (5-isoquinolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) -β- (5-isoquinolyl) -OC-cyanoacrylamide;
N-benzyl- (5-isoquinolyl) -oc-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (5-isoquinolyl) -OC-cyanoacrylamide; N-phenethyl β - (5-isoquinolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (5-isoquinolyl) -OC-cyanoacrylamide; N-phenyl-β- (3-indolyl) -OC-cyanoacrylamide; N-benzyl- (3-indolyl) -oc-cyanoacrylamide; N-phenethyl β - (3-indolyl) -OC-cyanoacrylamide; N-phenyl- (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-benzyl- (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-phenethyl- (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-phenyl-β- (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-benzyl- (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-phenethyl β - (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-phenyl-β- (5-amino-3-indolyl) -oc-cyanoacrylamide; N-benzyl- (5-amino-3-indolyl) -oc-cyanoacrylamide; N-phenethyl β - (5-amino-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) ß - (3-indolyl) -OC-cyanoacrylamide;
N- (4 '-hydroxyphenethyl) S- (3-indolyl) -OC-cyanoacrylamide;
N- (4 '-hydroxyphenyl) - - (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) fi- (5-hydroxy-3-indolyl) -OC-cyano-acrylamide; N- (4 '-hydroxyphenethyl) - - (5-hydroxy-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (5-carboxy-3-indolyl) -oc-cyano-acrylamide; N- (4 '-hydroxybenzyl) - - (5-carboxy-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (5-amino-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (5-amino-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (5-amino-3-indolyl) -OC-cyanoacrylamide;
N-Phenyl-β- (5-methoxy-3-indolyl) -OC-cyanoacrylamide. C19H16N3 ° 2 calculated: C 71.68 H 5.07 N 13.20 found: C H N MS m / z 318. NMR < 5 ppm (DMSO): 3.82 (s, 3H), 7.09 (m, 1H), 6.88 (dd, J = 2.4 and 8.8 Hz, 1H), 7.34 (m, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.67 (m, 2H), 8.45 (s, 1H), 8.55 (s, 1H), 10.1 (S amp., 1H).
'' • "'N-benzyl ß - (5-methoxy-3-indolyl) - OC-cyanoacrylamide C20H18N3 ° 2 calculated: C 72.27 H 5.96 N 12.64 found: C 72.15 H 5.35 N 12.63 MS m / z 332. NMR d ppm (DMSO): 3.80 (s, 3H), 4.42 (d, J = 5.9 Hz, 2H), 6.87 (dd, J = 2.2 and 8.8 Hz, 1H), 7.2-7.5 (m, 7H), 8.39 ( s, 1H), 8.47 (s, 1H), 8.75 (t, J = 5.9 Hz, 1H), 12.2 (s amp., 1H).
10 N- (3-pyridyl) - - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (3-pyridyl) - - (3-indolyl) -OC-cyanoacrylamide; N- (3-pyridyl) - - (5-methoxy-3-indolyl) -cyanoacrylamide;
N- (3-pyridyl) - - (4-quinolyl) -OC-cyanoacrylamide; N- (3-pyridylmethyl) - - (4-hydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -C-cyanoacrylamide; N- (3-pyridylmethyl) - (3-indolyl) -c-cyanoacrylamide;
N- (3-pyridylmethyl) - - (5-methoxy-3-indolyl) -oc-cyanoacryl-20-amide. C19H16N4 ° 2: calculated: C 68.66 H 4.85 N 16.86 found: C 68.53 H 4.76 N 16.73 MS m / z 332. NMR S ppm (DMSO) 25 3.80 (s, 3H), 4.43 (d, J = 5.9 Hz, 2H ), 6.87 (dd, J = 2.4 and 8.8 Hz, 1H), 7.35 (ddd, J = 1.9 and 4.8 and 7.9 Hz, 1H), 7.42 (m, 2H), 7.72 (ddd, J = 7.9 and 1.8 and 2.3 Hz, 1H), 8.39, 8.46 (two s, 2H), 8.45 (dd, J = 1.8 and 4.8 Hz, 1H), 8.54 (dd, J = 2.3 and 1.9 Hz, 1H), 8.80 (t, J = 6.0 Hz, 1H), 12.2 (s amp., 1 H).
N- (3-pyridylmethyl) ß- (4-quinolyl) -oc-cyanoacrylamide; N- (2- (pyridylmethyl) ß - (4-hydroxy-5,6,7,8-tetrahydro-napht-1-yl) -oC-cyanoacrylamide; N- (2-pyridylmethyl) β- (3-indolyl) ) - oc-cyanoacrylamide: N- (2-pyridylmethyl) - (5-methoxy-3-indolyl) -OC-cyanoacrylamide; N- (2-pyridylmethyl) - (4-quinolyl) - «OC-cyanoacrylamide.
Example 2
N-Phenyl- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide.
A stirred solution of the N-phenyl-β- (4-methoxy-5,6,7,8-tetrahydronaphth-1-yl) -c-cyanoacrylamide (3324 g, 0.01 mole) in anhydrous dichloromethane (100 ml) is added to -78 ° C under nitrogen, over a period of 20 min, a solution of 1 M boron tribromide in dichloromethane (30 ml, 0.030 mol). The resulting mixture is stirred for another 1 hour at -78 ° C and then allowed to warm to room temperature. After stirring for 1.5 h at room temperature, the mixture is cooled to -10 ° C and then quenched or the temperature is rapidly reduced by the dropwise addition of water (100 ml) over a period of 10 min. After the addition of ethyl acetate (100 ml) the organic layer is separated, washed with water, dried over Na_SO. and evaporate under vacuum to dryness. The residue is crystallized from ethanol, giving as a
Followed by the pure title compound with a 65% yield (2.070 g). calculated: C 75.45 H 5.70 N 8.80 found: C, 75.80 H 5.40 N 8.75 MS m / z 318, 5 IR cm 1: 3100-3500 (NH, OH), 2210 (CN), 1685, 1610 (CONH), 1585 , 1560, 1520 (C = C).
Following the procedure described above and starting from a phenolic methyl ether of the formula (I), which can be obtained according to the procedure described in example 1, the corresponding phenolic compound of the formula (I) can be obtained.
25 Example 3
N-Phenyl-β- (5-amino-3-indolyl) -oc-cyanoacrylamide.
To a solution of the N-phenyl-β- (5-nitro-3-indo-lyl) - o -cyanoacrylamide (3324 g, 0.010 mole) in anhydrous ethanol (200 ml) is added palladium on carbon (0.200 g) and the The mixture is hydrogenated at room temperature and atmospheric pressure until 3 equivalents of hydrogen are absorbed. Hydrogen absorption is plotted as a function of time. The catalyst is filtered and the solution is concentrated under vacuum until crystallization begins. The mixture is cooled to 0-5 ° C, filtered, the residue is washed with ice-cold ethanol and dried under vacuum. Accordingly, the almost pure title compound is obtained with a yield of about 80% (2416 g). A pure analytical sample is obtained by crystallization from ethanol. Calculated Cl8H14N40: C 71.51 H 4.67 N 18.53 found: C 71.45 H 4.55 N 18.45 MS m / z 302. IR cm 1: 3400, 3300 (NH), 2220 (CN), 1680, 1620 (CONH), 1590, 1510 ( C = C).
By proceeding analogously and starting from a nitro compound of the formula (I), which can be obtained according to the procedure described in Example 1, the corresponding amino compound of the formula (I) can be obtained.
Example 4
N-Phenyl-β- (4-acetoxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide.
To a cooled solution of N-phenyl-β- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide (3,184 g, 0.010 mol) in dry pyridine (5 ml) is added anhydride acetic (2.040 g, 0.020 mol) and the mixture is kept at 0-5 ° C overnight. After this the mixture is concentrated under vacuum, the residue is dissolved in dichloromethane, the organic layer is washed with water and then evaporated under reduced pressure. The crude product is crystallized from chloroform / methanol to give the pure title compound in a yield of about 80%. C22H20N2 ° 3 calculated: C 73.32 H 5.59 N 7.77 found: C 73.25 H 5.45 N 7.65 MS m / z 360. -1 IR cm 3300 (NH), 2200 (CN), 1755 (ester), 1690 (amide), 1620 (amide).
According to this process, the phenols of the formula (I) obtained in Example 1 can be converted into the corresponding acetoxy derivatives of the formula (I).
Example 5
1,4-dihydroxy-5,6,7,8-tetrahydro-2-naphthaldehyde.
To a solution of 1,4-dihydroxy-5,6,7,8-tetrahydro-naphthalene (1640 g, 0.010 mol) in dichloromethane (50 ml) is added titanium tetrachloride (5.69 g, 0.03 mol). The 1,1-dichlorodimethyl ether (1.73 g, 0.015 mol) is then added dropwise under vigorous stirring and the reaction mixture is stirred for a further 3 h at room temperature. Finally, 5% hydrochloric acid (10 ml) is added under cooling with ice. The organic phase is separated and the residual aqueous phase is extracted repeatedly with ether. The combined organic phases are washed with saturated brine solution, dried over sodium sulfate and evaporated under vacuum. The residue is crystallized from benzene or alternatively subjected to flash chromatography on silica gel with benzene / ethyl acetate 85:15 to give the pure title compound in a yield of about 60% (1.080 g), mp 145 ° C.
MS m / z 180. NMR d ppm: 10.4 (s amp., OH), 9.7 (s, CHO), 9.1 (s amp., OH), 6.9 (s, H arom.), 2.8 (m, 5- CH2, 8-CH2), 1.9 (m, 6-CH2, 7-CH2).
Example 6
5-Nitro-3-indolaldehyde.
A mixture of N-methylformanilide (1.76 g, 0.013 mol) and phosphorus oxychloride (1.99 g, 0.013 mol) is stirred for 15 minutes at 20-25 ° C under nitrogen. Then a solution of 5-nitroindole (1.62 g, 0.01 mol) in 1,2-dichloroethane (50 ml) is added and the mixture is refluxed for 3 hours. After cooling the mixture is poured into ice water, the precipitate is filtered off and washed with water. After this the residue is chromatographed on silica gel using benzene / ethyl acetate as eluent. Accordingly, the pure title compound was obtained with a yield of 80% (1.52 g). CnyHcoN ¿_0j calculated: C 56.85 H 3.18 N 14.73 found: C 56.79 H 3.01 N 14.51 MS m / z 190. IR cm -1 3140, 3090 (NH), 1650 (CO), 1511, 1345 (N02) Example 7
N-benzyl OC-cyanoacetamide
To the benzylamine (1.07 g, 0.01 mole) is added methyl cyanoacetate (0.99 g, 0.01 mole) and the mixture is heated for 16 h at 100 ° C without a condenser to allow evaporation of the methanol formed. Cooling gave a dark red solid which was triturated with ethanol, filtered and recrystallized from ethanol to give the pure title compound in a yield of about 40% (0.70 g). mp 123-4 ° C. MS m / z 174.
According to the process described above and starting from the appropriate compounds of the formula (V) and the formula (VI), the corresponding compounds of the formula (III) can be prepared.
Example 8
The tablets each weighing 0.150 g and containing 25 mg of the active substance, can be manufactured as follows: composition (for 10,000 tablets):
N-phenyl ß - (8-hydroxy-5-quinolyl) - OC-cyanoacrylamide 250 g Lactose 800 g Corn starch 415 g Talc powder 30 g Magnesium stearate 5 g
The N-phenyl > S- (8-hydroxy-5-quinolyl) -oc-cyanoacrylamide, lactose and half of maize starch are mixed; The mixture is then forced through a sieve with a mesh size of 0.5 mm. The corn starch (10 g) is converted into a suspension in hot water (90 ml) and the resulting paste is used to granulate the powder. The granulate is dried, crushed or shredded on a sieve of 1.4 mm mesh size, then the remaining amounts of starch, talc and magnesium stearate are added, mixed thoroughly and processed into tablets.
Example 9
The capsules, each dosed at 0.200 g and containing 20 mg of the active substance, can be prepared. Composition for 500 capsules:
N-benzyl ß - (5-methoxy-3-indolyl) - OC-cyanoacrylamide 10 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g
This formulation is encapsulated in two-piece hard gelatin capsules and is dosed with 0.200 g for each capsule.
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.
Having described the invention as above, property is claimed as contained in the following
Claims (14)
- A compound of the formula (I) characterized in that: A is a bicyclic ring selected from naphthalene, tetrahydronaphthalene, quinoline, isoquinoline and indole. B is a ring of benzene substituted with R or a ring of thiophene or pyridine not substituted? R is hydrogen, alkyl having 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy or a group NR 3 R 4 wherein each of R 3 and R 4 is independently hydrogen or alkyl having 1 to 6 carbon atoms; R is hydrogen, alkyl having 1 to 6 carbon atoms or alkanoyl having 1 to 6 carbon atoms; R 2 is hydrogen, alkyl having 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy, hydroxy, alkoxy with 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 carbon atoms or a group NR R are as defined previously; n is zero or an integer from 1 to 2; x is zero or an integer from 1 to 5; and pharmaceutically acceptable salts thereof.
- 2. A compound of the formula (I), according to vindication 1, characterized in that A is tetrahydronaphthalene, quinoline, isoquinoline and indole; 2 B is benzene substituted with R or unsubstituted pyridine; R is hydrogen or halogen with the exception of the indole derivatives wherein R can also be carboxy or amino; 1 R is hydrogen or methyl; R 2 is hydrogen, halogen, cyano, hydroxy, carboxy or amino; n is 0, 1 or 2; and x is 0, 1, 2 or 3; and pharmaceutically acceptable salts thereof.
- 3. A compound of the formula (I) in accordance vindication 2, characterized in that: A is tetrahydronaphthalene, quinoline, isoquinoline and indole; 2 B is benzene substituted with R or an unsubstituted pyridine; R is hydrogen with the exception of the indole derivatives wherein R can also be carboxy or amino; R is hydrogen or methyl; 2 R is hydrogen or hydroxy; n is 0 or 1 and x is 0, 1 or 2, and pharmaceutically acceptable salts thereof.
- 4. A compound selected from the group consisting of compound elements, the compound is the Z or E isomer, or a mixture of the Z and E isomers: N-phenyl-β- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide; N- (4 * -hydroxyphenyl) - ß - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -Occ-cyanoacrylamide; N-phenyl-β- (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide; N-benzyl- (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (4 '-hydroxy-benzyl) -β- (4-hydroxy-5, 6,7,8-tetra-hydronaphth-1-yl) -oc-cyanoacrylamide; N-benzyl- (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) ß - (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N-phenethyl β - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -OC-cyanoacrylamide; N- (4 * -hydroxyphenethyl) - - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide; N-phenethyl β - (3,4-dihydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (3,4-dihydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide; N-phenyl-β- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) - O-cyanoacrylamide; N-benzyl- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -oC-cyanoacrylamide; N- (4 '-hydroxybenzyl) ß - (4-hydroxy-5,6,7,8-tetrahydroaphth-2-yl) -oc-cyanoacrylamide; N-phenethyl β - (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) -oc-cyanoacrylamide; N-phenyl-β- (4-quinolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) -β- (4-quinolyl) -OC-cyanoacrylamide; N-benzyl- (4-quinolyl) - "OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) β- (4-quinolyl) -OC-cyanoacrylamide; N-phenethyl β- (4-quinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxifenethyl) - - (4-quinolyl) - oc-cyano-acrylamide; N-phenyl-β- (8-hydroxy-5-quinolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) -β (8-hydroxy-5-quinolyl) -oc-cyanoacrylamide; N-benzyl- (8-hydroxy-5-quinolyl) -O-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (8-hydroxy-5-quinolyl) - "OC-cyanoacrylamide; N-phenethyl β- (8-hydroxy-5-quinolyl) -oc-cyano-acrylamide; N- (4 '-hydroxyphenethyl) - (8-hydroxy-5-quinolyl) -OC-cyanoacrylamide; N-phenyl-β- (3-isoquinolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (3-isoquinolyl) -OC-cyanoacrylamide; N-benzyl- (3-isoquinolyl) -oc-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (3-isoquinolyl) -OC-cyanoacrylamide; N-phenethyl β - (3-isoquinolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) / ^ - (3-isoquinolyl) -OC-cyanoacrylamide; N-phenyl-β- (5-isoquinolyl) -OC-cyanoacrylamide; N- (4-hydroxyphenyl) - - (5-isoquinolyl) -cc-cyano-acrylamide; N-benzyl ß - (5-isoquinolyl) - «OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) - (5-isoquinolyl) - (X-cyano-acrylamide; N-phenethyl-β- (5-isoquinolyl) -OC-cyanoacrylamide; N- (4'-hydroxifenethyl) - (5- isoquinolyl) -.OC-cyano-acrylamide; N-phenyl-β- (3-indolyl) -OC-cyanoacrylamide; N-benzyl- (3-indolyl) -0C-cyanoacrylamide; N-phenethyl-β- (3-indolyl) - OC-cyanoacrylamide; N-phenyl-β- (5-hydroxy-3-indolyl) -oc-cyanoacrylamide; N-benzyl- (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-phenethyl β - (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N-phenyl-β- (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-benzyl- (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N-phenethyl β - (5-carboxy-3-indolyl) -oC-cyano-acrylamide; N-phenyl-β- (5-amino-3-indolyl) -oc-cyanoacrylamide; N-benzyl- (5-amino-3-indolyl) - cc-cyanoacrylamide; N-phenethyl β - (5-amino-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (3-indolyl) - O-cyanoacrylamide; N- (4 '-hydroxybenzyl) - - (3-indolyl) - cc-cyano-acrylamide; N- (4 '-hydroxifenethyl)? - (3-indolyl) - ec-cyano-acrylamide; N- (4 '-hydroxyphenyl) & - (5-hydroxy-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) B - (5-hydroxy-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (5-hydroxy-3-indolyl) -oc-cyanoacrylamide; N- (4 '-hydroxyphenyl) - - (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxybenzyl) ß - (5-carboxy-3-indolyl) -OC-cyanoacrylamide; N- (4 '-hydroxyphenethyl) - - (5-carboxy-3-indolyl) -s-cyanoacrylamide; N-. { 4 '-hydroxyphenyl) ß - (5-amino-3-indolyl) -oc-cyano-acrylamide; N- (4 '-hydroxybenzyl) - - (5-amino-3-indolyl) -o-cyano-acrylamide; N- (4 '-hydroxyphenethyl) - - (5-amino-3-indolyl) -c-cyanoacrylamide; N-phenyl-β- (5-methoxy-3-indolyl) -OC-cyanoacrylamide; N-benzyl- (5-methoxy-3-indolyl) -OC-cyanoacrylamide; N- (3-pyridyl) - - (4-hydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -OC-cyanoacrylamide; N- (3-pyridyl) - - (3-indolyl) -oc-cyanoacrylamide; N- (3-pyridyl) - - (5-methoxy-3-indolyl) - (C-cyano-acrylamide; N- (3-pyridyl) - - (4-quinolyl) -OC-cyanoacrylamide; N- (3-pyridylmethyl) - - (4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) -oc-cyanoacrylamide; N- (3-pyridylmethyl) / & - (3-indolyl) -oc-cyanoacrylamide; N- (3-pyridylmethyl) / 8 - (5-methoxy-3-indolyl) -oc-cyano-acrylamide; N- (3-pyridylmethyl) - - (4-quinolyl) -oc-cyanoacrylamide; N- (2-pyridylmethyl) - - (4-hydroxy-5,6,7,8-tetrahydro-naphth-1-yl) -CC-cyanoacrylamide; N- (2-pyridylmethyl) - - (3-indolyl) -oc-cyanoacrylamide; N- (2-pyridylmethyl) - - (5-methoxy-3-indolyl) -OC-cyanoacrylamide; N- (2-pyridylmethyl) -β- (4-quinolyl) -OC-cyanoacrylamide, and, where appropriate, the pharmaceutically acceptable salts thereof.
- 5. A process for preparing a compound of the formula (I), according to claim 1, characterized in that it comprises the condensation of an aldehyde of the formula (II) 1 wherein A, R, R and n are as defined in claim 1, with a compound of the formula (III) NC-CH 2_-CONH- (CH2") x-B (III) ' where R 2 and x are as defined in the claim 1, and, if desired, converting a compound of the formula (I) to another compound of the formula (I), and / or, if desired, converting a compound of the formula (I) to a salt thereof acceptable pharmaceutically, and / or, if desired, converting a salt into a free compound, and / or, if desired, separating a mixture of isomers of a compound of the formula (I) into the individual isomers.
- 6. A pharmaceutical composition, characterized in that it comprises a suitable carrier and / or diluent and, as an active ingredient, a compound of the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
- 7. A compound of the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use as a tyrosine kinase inhibitor.
- 8. A compound of the formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that it is used as an anticancer agent or in the treatment of leukemia, psoriasis or the atheromatous plaque.
- 9. A compound of the formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that it is used as an immunosuppressive agent.
- 10. The use of a compound of the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as a tyrosine kinase inhibitor.
- 11. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, in the preparation of a medicament for use as an anti-cancer agent or in the treatment of leukemia, psoriasis or the atheromatous plaque.
- 12. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, in the preparation of a medicament for use as an immunosuppressive agent.
- 13. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, for use in a method of treating the body of the human or animal, by therapy.
- 14. The products containing a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and an antitumor agent as a combined preparation for simultaneous, separate or sequential use in anticancer therapy. In testimony of which I sign the present in this City of Mexico, D.F., on November 24, 1995. Representative SUMMARY OF THE INVENTION The present invention relates to novel compounds of the formula (I) wherein A is a bicyclic ring selected from naphthalene, tetrahydronaphthalene, quinoline, isoquinoline and indole. 2 B is a benzene ring substituted with R or an unsubstituted thiophene or pyridine ring; R is hydrogen, alkyl having 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy or a group NR3R4 wherein each of R and R is independently hydrogen or alkyl having 1 to 6 carbon atoms; R is hydrogen, alkyl having 1 to 6 carbon atoms or alkanoyl having 1 to 6 carbon atoms; R 2 is hydrogen, alkyl having 1 to 6 carbon atoms, halogen, nitro, cyano, carboxy, hydroxy, alkoxy with 1 to 6 carbon atoms, alkanoyloxy with 1 to 6 carbon atoms or a group NR R wherein R 3 and R4 are as defined above; n is zero or an integer from 1 to 2; x is zero or an integer from 1 to 5; and pharmaceutically acceptable salts thereof. The compounds of the invention are useful as tyrosine kinase inhibitors.
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