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CA1336715C - 8-(4-piperidinyl)-4h-1-benzopyran-4-one derivatives and their use - Google Patents

8-(4-piperidinyl)-4h-1-benzopyran-4-one derivatives and their use

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Publication number
CA1336715C
CA1336715C CA000614537A CA614537A CA1336715C CA 1336715 C CA1336715 C CA 1336715C CA 000614537 A CA000614537 A CA 000614537A CA 614537 A CA614537 A CA 614537A CA 1336715 C CA1336715 C CA 1336715C
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alkyl
alkylamino
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aryl
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Ramchandra Ganapati Naik
Bansi Lal
Richard Helmut Rupp
Hans Harald Sedlacek
Gerhard Dickneite
Jorg Czech
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

The use of 4H-1-benzopyran-4-one derivatives, novel 4H-1-benzopyran-4-one derivatives, and pharmaceuticals containing them Compounds of the formula I

I

in which the substituents R1-R5 and n and m are as defined are suitable for controlling tumors.

Description

13~671S

Deacription~

8-(4-Piperidinyl)-4H-l-Benzo~ an-4-One Derivatives and Their Use The present invention relates to the use of 4H-l-benzopyran-4-one derivatives, to novel 4H-l-benzopyran-~-one derivatives, and to pharmaceuticalg cont~i n i ng them.

Benzopyran derivatives have already been described in European Patent Specification No. 0,137,193 (published 04 Apr 85) and in German Offenlegungsschrift 3,612,337 (published 15 Oct 87). The latter discloses compounds of the formula a~.

~I(CH2)n R4~
o in which the substituents R~ to Rs and m and n are as defined; the compounds have an antiinflammatory analgesic and immune-modifying action.

Surpri~ingly, it has now been found that certain 4H-1-benzopyran-4-one derivatives inhibit oncogene-encoded kina~es and are therefore suitable for controlling tumoral disea~es.

The expre~sion of oncogenes in a mammalian cell entails transition from the norm~l cell type to the transformed cell type, which then becomes a cancer cell. The trans-formation was caused by infecting a cell with a retro-virus. A well known example was the infection of chickenswith Rous-fiarcoma virus, and these chickens then developed cancer. The corre~ponding oncogene, which was -1~
- 2 - 1 33 6 7~ ~

responsible for the malign transformation, was named "SRC n ( sarcoma) gene (J-S- Brugge, R.L. Erikson; Nature 269, 346-348 (1977)). A characteristic feature of many oncogenes known to date is the expression of a protein having kinase activity. The enzymes catalyze the transfer of the terminal phosphate group of ATP to an amino acid.
In contrast to many other protein kinases which transfer the phosphate group to a seryl radical or threonyl radical, most of the oncogene-encoded kinases phospho-rylate a tyrosyl radical of the protein chain. Besides,it is known that products of oncogenes, namely those of the v-mos, v-mil and v-raf oncogenes, have serin/-threonin-specific protein kinase activity. (R. Molling et al., Nature (London) 312, 558-561 (1984); B. Singh et al., Journal of Virology 60, 1149-1152 (1986)).

Tyrosin kinase activity is also expressed in growth factor receptors; new findings now show that the growth of many tumors is dependent on the presence of growth factors, such as Epidermal Growth Factor (EGF), Trans-forming Growth Factor ~ (TGF~) or Platelet Derived GrowthFactor (POGF) (A.S. Goustin, G.D. Shipley, H.L. Moses, Cancer Research 46, 1015-1029 (1986). Once the growth factor is bound to its receptor, tyrosin kinase, which is an intrinsic component of the growth factor receptor, is stimulated.

A tyrosin kinase inhibitor and possibly a serin/threonin kinase inhibitor might therefore inhibit the growth and ~preading of tumors, and it could be employed in tumor therapy.

The present invention therefore relates to the use of 4H-l-benzopyran-4-one derivatives of the formula I for inhibiting oncogene-encoded kinases and growth factor receptor tyrosin kinases and for the control of tumoral diseases. Formula I reads ~ 3 ~ 1336715 ~ ~ (CH2)1~
O

and is defined as follows: R1 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl-C1-C4-alkyl, substituted C1-C6-alkyl, C3-C6-cycloalkyl, a C3-C~-heterocyclic ring having 1, 2 or 3 hetero atoms, ~uch as N, S, O or any combina-tions thereof, or else C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl including polycyclic rings, or aromatic heterocyclic radicals, substituted aryl, carboxyl or an aldehyde or COO-C1-C4-alkyl group, a primary amino, alkylamino, aralkylamino, dialkylamino, arylamino or diarylamino group, or -CH2O-C1-C4-alkyl;
R2 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl, nitro, amino, di-C1-C4-alkylamino or a halogen, or hydroxyl, alkoxy, -COOH, -COO-C1-C4-alkyl, -CHO, -CH2OH or -CH2O-C1-C4-alkyl;
R3 is hydrogen, C1-C4-alkyl, substituted Cl-C4-alkyl, hydroxyl, carboxyl, C1-C4-alkyl, nitro, amino, a C1-C4-alkylamino or di-C1-C4-alkylamino group, or halogen, o -CHO, -CH2OH, -CH2O-C1-C4-alkyl, R-N-C-O-, where R
R is H, C1-C6-alkyl, cycloalkyl and aryl;
R4 is hydrogen, hydroxyl, C1-C4-alkoxy, Cl-c4-~lk~noyloxy~
C1-C4-alkoxycarbonyl, aryloxy or amino, or a Cl-C4-alkyl-amino or di-C1-C4-alkylamino group, or is R-N-~-O-, where R i~ H, C1-C6-alkyl, cycloalkyl or aryl;
R5 is hydrogen, C1-C6-alkyl, aryl-C1-C4-alkyl, C3-C6-cyclo-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, alkylamino, C1-C4-~lk~noyl or aroyl, where the aryl group is unsubstituted or mono- or polysubstituted phenyl;

m is an integer between 0 and 3 and 133 6 71~
n is an integer between 0 and 2, and pharmacologically acceptable acid addition salts thereof.

The compounds according to the invention have two centers of asymmetry, one where the heterocyclic ring contAining nitrogen is fused to the benzopyran moiety (C-4'), the other at the R4-substituted carbon atom (C-3'), which means that two pairs of optical isomers are possible. The definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures.
It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity.
The two racemates can be resolved by physical methods, such as, for example, fractional crystallization. The individual optical isomers can be obtAine~ from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

Examples of alkyl groups which are suitable for Rl to R5 are straight-chain or branched radicals having up to 6, preferably up to 5, carbon atoms, for example methyl, ethyl, propyl, isopropyl, t-butyl, pentyl or isopentyl groups.

Examples of substituted alkyl groups which are suitable for R1 to R5 are haloalkyl, such as trifluoromethyl, hydroxyalkyl, such as hydroxyethyl, or carboxyalkyl, such as carboxyethyl.

Suitable examples of a cycloalkyl group which has 3 to 6 carbon atoms and is represented by Rl and R5 are cyclo-propyl, cyclobutyl, cyclopentyl or cyclohexyl. Cyclo-propylmethyl is an example of cycloalkylalkyl.

An example of an aralkyl group which is represented by R
and R5 is a phenylalkyl group in which the phenyl group is unsubstituted or monosubstituted or polysubstituted by substituents such as halogen, Cl-C4-alkyl, Cl-C4-alkoxy or nitro or by a trifluoromethyl group, amino group and substituted amino group.

An example of an aryl group which i8 represented by Rl and R5 is a phenyl group which is unsubstituted or monosub-stituted or polysubstituted by substituents such as halogen, Cl-C4-alkyl, Cl-C4-alkoxy, hydroxyl, carboxyl, nitro or trifluoromethyl, amino, Cl-C4-alkylamino, di-Cl-C4-alkylamino, aromatic heterocyclic groups such as pyridyl groups, and polycyclic aromatic radicals, such as naphthyl groups.

A suitable example of an alkylamino group which is represented by Rl and R5 is (CH2)n-NR6R7, where n is 1 to 3 and R6 and R7 are alkyl and are as defined as above in the case of alkyl R1 to R5; moreoever, R6 and R7 together with the nitrogen atom to which they are bonded can be a heterocyclic ring having one or more hetero atoms.
Suitable examples of heterocyclic rings which are formed by R6 and R7 together with the nitrogen to which they are bonded are piperidine, pyrrolidine, morpholine, piperazine or imidazole, all of which can be unsubstituted or substituted in one or more positions by Cl-C4-alkyl, Cl-C~-alkoxy or aryl or by a hydroxyl or amino group.

Suitable examples of salts of the compounds according to the invention with inorganic or organic acids are hydrochloride, hydrobromide, sulfate, phosphate, acetate, oxalate, tartrate, citrate, maleate or fumarate.

The use of compounds of the formula Ia HC~ ~ R1 Ia OH O
in which Rl is hydrogen or Cl-C3-alkyl, naphthyl, aryl, substituted aryl or a C3-C8-heterocyclic ring, R2 is hydrogen or Cl-C3-alkyl, R5 is Cl-C3-alkyl or C3-C5-cycloalkyl, or C3-C5-cycloalkyl-Cl-C4-alkyl, or of pharmacologically acceptable acid addition salts thereof, is preferred.

The use of compounds of the formula Ia as claimed in claim 2, wherein Rl is phenyl, thienyl, pyridyl, chloro-phenyl, dichlorophenyl, methylphenyl, aminophenyl,bromophenyl, hydroxyphenyl or naphthyl, R2 is hydrogen and R5 is methyl, or of pharmacologically acceptable acid addition salts thereof, is very particularly preferred.

Also part of the subject-matter of the invention are the novel compound~ of the formula Ib ~ ( CH2 )n ~ Rl Ib ~W R2 in which at least one of the substituents has one of the meanings below, while the other substituents in each case can be as defined in claim 1: R1 is C3-C6-cycloalkyl, a C3-C8-heterocyclic ring having 1, 2 or 3 hetero atoms, such as N, S, 0 or any combinations thereof, or is C3-C6-cycloalkyl-C1-C4-alkyl, or polycyclic rings, aromatic ~ 7 ~ 1336715 heterocyclic radicals, substituted aryl, a primary amino, alkylamino, aralkylamino, dialkylamino, arylamino or diarylamino group, or -CH2O-C1-C4-alkyl;
R2 is aryl, hydroxyl, alkoxy, COOH, COO-Cl-C"-alkyl, -CHO, -CH2OH or -CH2O-Cl-C4-alkyl;
R3 is carboxyl, a halogen, -CHO, -CH2OH, -CH2O-C1-C4-alkyl or R-N-C-O- group, where R is H, C1-C6-alkyl, cycloalkyl and aryl;

R4 is R-~l-C-O-, where R is H, Cl-C6-alkyl, cycloalkyl or aryl;
R5 is aroyl, where the aryl group is monosubstitued or polysubstituted phenyl, and m is an integer between 0 and 3 and n is an integer between 0 and 2, and pharmacologically acceptable acid addition salts thereof. These compounds can be prepared, for example, as described in European Patent 0,157,193 or in DE 3,612,337.

Examples of preferred compounds according to the invention, or of compounds which are particularly suitable for the use according to the invention, are:
(~)-cis-5,7-dihydroxy-2-(2-thienyl)-8-[4-(3-hydroxy-1-methyl)piperidinyl]-4H-l-(benzopyran-4-one, (-)-cis-5~7-dihydroxy-2-phenyl-8-[4-(3-hydroxy-1-methyl)-piperidinyl]-4H-l-benzopyran-4-one hydrochloride, (+)-cis-5,7-dihydroxy-2-phenyl-8-[4-(3-hydroxy-1-methyl)-piperidinyl]-4H-l-benzopyran-4-one hydrochloride, (+)-cis-5,7-dihydroxy-2-phenyl-8-[4-(3-hydlciAy-l-methyl) piperidinyl]-4H-l-benzopyran-4-one hydrochloride, (-)-cis-5,7-dihydroxy-2-(2-pyridyl)-8-[4-(3-hydroxy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one hy~oc:hloride, (~)-cis-5,7-dihydroxy-2-(2-pyridyl)-8-[4-(3-hydroxy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one hydrochloride, (+)-cis-5,7-dihydroxy-2-(3-pyridyl)-8-[4-(3-hydroxy-1-- 8 - 1 ~ 36715 methyl ) piperidinyl ] -4H- l-benzopyran-4 -one hydrochloride, (+)-cis-5,7-dihydroxy-2-(4-pyridyl)-8-[4-(3-hydroxy-1-methyl ) piperidinyl ] -4H- l-benzopyran-4 -one hydrochloride, ( - ) -cis-S, 7-dihydroxy-5- ( 2-chlorophenyl ) -8- t 4- ( 3-hydroxy-1 -methyl ) piperidinyl ] -4H- 1 -benzopyran-4 -one hydrochloride, ( + ) -c is -5, 7 -dihydroxy-2 - ( 2 -chlorophenyl ) -8- [ 4 - ( 3-hydroxy-1 -methyl ) piperidinyl ] -4H- l-benzopyran-4 -one hydrochloride, ( + ) -cis-5, 7-dihydroxy-2- ( 2-chlorophenyl ) -8- [ 4- ( 3-hydroxy-1 -methyl ) piperidinyl ] -4H- l-benzopyran-4 -one hydrochloride, ( + ) -cis-5, 7 -dihydroxy-2 - ( 2, 5-dichlorophenyl ) - 8 - ~ 4 - ( 3 -hydroxy-l-methyl ) piperidinyl ] -4H-l-benzopyran-4-one hydrochloride, ( ~ ) -cis-5, 7-dihydroxy-2- ( 2, 4-dichlorophenyl ) -8- [ 4- ( 3-hydroxy- l-methyl ) piperidinyl ] -4H- 1 -benzopyran-4 -one hydrochloride, ( + ) -cis-5, 7-dihydroxy-2- ( 4-methylphenyl ) -8- [ 4- ( 3-hydroxy-1 -methyl ) piperidinyl ] - 4H- 1 -benzopyran- 4 -one hydrochloride, ( + ) -cis-5, 7-dihydroxy-2- ( 3-methylphenyl ) -8- [ 4- ( 3-hydroxy-1 -methyl ) piperidinyl ] -4H- l-benzopyran-4 -one hydrochloride, ( + ) -cis-5, 7-dihydroxy-2- ( 4-aminophenyl ) -8- [ 4- ( 3-hydroxy-l-methyl ) piperidinyl ] -4H-l-benzopyran-4-one hydrochloride, ( + ) -cis-5, 7-dihydroxy-2- ( 3-bromophenyl ) -8- [ 4- ( 3-hydroxy-l-methyl ) piperidinyl ] -4H- l-benzopyran-4-one 3 0 hydrochloride, ( + ) -cis-5, 7-dihydroxy-2- ( 2-naphthyl ) -8- [ 4- ( 3-hydroxy-1-methyl ) piperidinyl ] -4H-l-benzopyran-4-one hydrochloride, ( + ) -cis-5, 7-dihydroxy-2- ( 4-hydroxyphenyl ) -8- [ 4- ( 3-hydroxy-l-methyl ) piperidinyl ] -4H-l-benzopyran-4-one and ( ~ ) -cis-5, 7-dihydroxy-2- ( 2-hydroxyphenyl ) -8- [ 4- ( 3-hydroxy- l-methyl ) piperidinyl ] -4H- 1 -benzopyran-4 -one .

Other 4H- l-benzopyran-4-one derivatives according to the invention or compounds according to the invention which are particularly suitable for the use according to the invention are listed in Tables 1 and 2 below together with their physical data. Table 1 relates to formula Ic l l R4 ~ Ic RgO ~ R2 X

and Table 2 relates to formula Id R4 ~ R 1 o OR8 Id 133671s Table 1 Verb. Rl R2 R4 R8 Rg X Melting point Optical (C) rotation H H OH H H - 298 (decompJ (+) 2 H H OH CH3 CH3 HCl, 1,5H2O 173-175 (+) 3 CH3 H OH H H HCl, 237-240 (+) 4 CH3 H OH H H HCl, 241-43 (+) CH3 H OH H H HCl, 241-42 (-) 6 CH3 H OH H CH3 HCl, 230-232 (+) 7 CH3 H OH CH3 CH3 2HCl, 2H2O 236-239 (+) 8 CH3 H H H H H2O 232-233 (+) 9 C2H5 H OH H H HCl, 1.5H2O 230-233 (+) C2H5 H OH CH3 CH3 HCl, 1.5H2O 240-242 (+) 11 n-c3H7 CH3 OH H H - 191-192 (+) 12 n-c3H7 H OH H H HCl, 190-192 (+) 13 n-c3H7 H OH H H HCl, 0.5H2O 197-200 (+) 14 n-c3H7 H OH H H HCl, 0.5H2O 198-201 (-) n-c4H9 H OH H H HCl, H2O 157-159 (+) 16 CH3 CH3 OH H H H2O 232-233 (+) 17 2-Pyridyl H OH H H HCl, 0,5H2O 229C (+) 18 3-Pyridyl H OH H H 2HCl, 2H2O 278-280 (+) 19 4-Pyridyl H OH H H 2HCl, 1.5H2O 236-238 (+) 21 2-Thienyl H OH H H 2H2O 243-244 (+) 22 2-Thienyl H OH CH3 CH3 - 207-208 (+) 23 2-Pyridyl H OH H H 2HCl,2H2O 220-228 (-) 24 ~-Styryl H OH H H HCl, 1.5H2O >300 (+) 1-Naphthyl H OH H H HCl, H2O 195-200 (+) 26 2-Naphtyl H OH H H HCl, 0.5H2O 280-282 (+) 27 (2-Chloro' H OH H H HCl 270-275 (+) phenyl)methyl Table 2 Verb. R1o R8 Rg X Melting point Optical (C) rotation 28 H H H HCl, 2H2O 273-275 (+) 29 4-No2 H H HCl, 3H2O 249 (decomp~ (+) 4-NO2 CH3 CH3 HCl, 2H2O 257-260(decomp~(+) 31 2-Cl H H HCl, H2O 198-200 (+) 32 2-Cl CH3 CH3 1.5HCl, H2O 190-191 (+) 33 4-NH2 H H 2HCl, 2H2O 240-242 (+) 31 3,5-Dimethoxy CH3 CH3 2HCl, 2H2O 180-182 (+) 32 4-Br H H HCl, 2H2O 215 (+) 33 4-Cl H H HCl, 1.5H2O 225 (+) 34 2,4-Dichlor H H HCl, 2.5H2O 165-166 (+) 4-F H H HCl, H2O 285-287 (+) 36 2-F H H HCl, 2H2O 263-265 (+) 37 4-Methyl H H HCl, 1.5H2O 247-49 (+) 38 3,5-Dihydroxy H H HCl, 3H2O 300-302 (+) 39 3-Cl H H HCl, 2H2O 288-290 (+) 3-Methyl H H HCl, 2H2O 268 (+) 41 2-Methyl H H 204-205 (+) 42 2-Cl H H HCl, 2H2O 190-192 (+) 43 H H H HCl 269-271 (+) 44 3-Br H H HCl, 2H2O 285 (+) 3-CO2Me CH3 CH3 1.5HCl, 3H2O 235 (+) 46 2,5-Dichloro' H H HCl, H2O 251-252 (+) 47 3-COOH CH3 CH3 HCl, 1.5H2O 270 (+) 48 2-Cl H H HCl, 1.5H2O 190-194 (-) 49 H H H HCl, O.5H2O 266-269 (-) H H H HCl 270-271 (+) 51 4-OH H H H2O > 340 (+) 52 4-Phenyl H H HCl 240-242 (+) 53 2-Br H H 1.5H2O 250-252 (+) 54 2-OH H H HzO 265-270 (+) The preparation of some of the compounds which can be used according to the invention and the preparation of the necessary starting materials are described in detail in German Offenlegungsschrift 3,612,337, to which reference is made at this point. Another subject-matter of the present invention is a process for the preparation of the novel compounds of the formula as claimed in claim 4. In this process, a compound of the formula II

~ ( C H2 ) n R4/~ II

o where R4 is hydroxyl or acetoxy and R3, R5, n and m are as defined, is reacted, for example with an alkali metal and the alkyl ester of an acid of the formula Rl-COOalkyl, where Rl is as defined in formula I, to give a diketone of the formula III

(CH2 )n O III, lS and the resulting compound is cyclized by reaction with a mineral acid to give a compound of the formula Ib, where Rl, R3, R5, m and n are as defined, R4 is the hydroxyl or acetoxy group and R2 i8 hydrogen, and, if appropriate, a compound of the formula Ib where R5 is CH3 is reacted with cyanogen bromide after the hydroxyl groups have been protected, and the resulting compound is reacted under acid or alkaline conditions to give a compound of the formula Ib where R5 is hydrogen, and, if appropriate, a compound of the formula Ib where R5 is hydrogen is reacted with suitable electrophilic reagents, such as halides, acid chlorides, tosylates or enones, to give compounds of the formula Ib where R5 is unsubstituted or substituted C1-C6-alkyl, aryl-C1-C4-alkyl, C3-C6-cyclo-alkyl or C3-C6-cycloalkyl-C1-C4-alkyl, and, if appropriate, S a compound of the formula Ib where R2 is hydrogen is reacted with a secondary amine hydrochloride and para-formaldehyde to give a compound of the formula Ib where R2 is dialkylaminomethyl, or, if appropriate, a compound of the formula Ib where R2 is hydrogen is nitrated to give a compound of the formula Ib where R2 is NO2, and, if appropriate, a compound of the formula Ib where R2 is NO2, is hydrogenated to give a compound of the formula Ib where R2 i8 the amino group.

The conditions for the individual reaction steps are as described in German Offenlegungsschrift 3,612,337. A
particularly preferred method for the preparation of compounds according to the invention i8 the reaction of a compound of the formula IV

l l R-O/~ IV
H3CO~ OH
~ CH3 in which R i8 -COCH3 or H, with a compound of the formula Rl-COO X
in which X is hydrogen or halogen, preferably hydrogen or chloride. This esterification takes place under generally known conditions, as described, for example, in Organikum [Laboratory Practice in Organic Chemistry], VEB, Deutscher Verlag der Wissenschaften, 15th edition, Berlin 1977, Chapter D7. The resulting esters are treated in an inert atmosphere with bases, for example sodium hydride, or preferably in aprotic ~olvents, for example tetra-hydrofuran, dioxane or N,N-dimethylformamide, this giving diketones which are usually not isolated. On ~tirring with a mineral acid, for example HCl, the ketone cyclize, and benzopyran-4-one derivatives of the formula Ib are formed. The process is widely applicable and is particularly useful for the preparation of compounds such as formula Ib where Rl is aryl and heteroaryl groups. The above reaction will be illustrated in greater detail in the Examples.

The compounds according to the invention have pharmacological properties; in particular, they inhibit oncogene-encoded kinases, such as tyrosin kinase, serin/threonin kinase and growth factor receptor tyrosin kinase, and it can therefore be expected that they inhibit growth and spreading of tumors and that they can be used in the therapy of tumors.

Further subject-matter of the invention are therefore also pharmaceuticals for controlling tumors, which contain at least one compound of the formula I as claimed in claim 1 or at least one of its pharmacologically acceptable acid addition salts, and the use of a compound as claimed in claim 1 for the preparation of a pharmaceutical having an antitumoral action.

The 4H-l-benzopyran-4-one derivatives are used according to the invention in the generally known fashion which is known to the expert. For pharmaceuticals, an effective amount of the active substance mentioned is employed either per se or preferably in combination with suitable - pharmaceutical auxiliaries in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the active compound content being up to about 95%, preferably between 10 and 75%.

The expert will know which auxiliaries are suitable for the desired formulation of the pharmaceutical because of his expert knowledge. Besides auxiliaries for tablets, or solvents, gel formers, ba~es for suppositories, and other excipients for the active substance, it is possible to use, for example, antioxidants, dispersants, emulsifiers, defoamers, flavor corrigants, preservatives, solubilizers or colorants.

The active substance can be administered orally, parenterally, intravenously or rectally, intravenous administration being preferred. For a form of oral administration, the active substance may be mixed with other compounds together with the additives which are suitable for this purpose, such as excipients, stabilizers or inert diluents, and customary methods can be used for bringing it into suitable administration forms, such as tablets, coated tablets, hard-gelatin capsules, and aqueous alcoholic or oily suspensions or solutions. Examples of inert excipients which can be used are gum arabic, magnesia, lactose, glucose or starch, in particular corn starch. In this context, the formulation can be prepared as dry granules or moist granules.
Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or codliver oil.

For subcutaneous or intravenous administration, a solution, suspension or emulsion of the active substance is formed, if appropriate using substances which are conventional for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, and also sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.

The dose of 4H-l-benzopyran-4-one derivatives which is to be administered can cover a wide range. The dose to be administered daily is to be selected to suit the desired effect. About 50 to 1,000 mg are preferably administered daily per patient, preferably intravenously. If required, higher or lower daily doses can also be administered, but a maximum amount of 2,000 mg should only be exceeded for - a short time.

The pharmacological properties of the compounds mentioned are confirmed by the pharmacological assays which follow and which have been carried out with compounds according to the invention and their salts; the results obtained are listed in Table III.

Test methods Tyrosin ~i n^~^ inhibition assays Testing procedure:

In the case of tyrosin kinase activity, the starting material was the rat tumor cell line RR 1022 (ATCC CCL47) which had been grown in RPMI 1640 medium + 10% of FCS.
This cell line has been transformed with RSV (Rous sarcoma virus) and contains the oncogene product PP60~rC, which has tyrosin kinase activity.

The cells were grown until nearly confluent, washed with PBS (phosphate-buffered saline), scraped off from the culture bottle and repeatedly washed twice (0.85%
strength NaCl solution) and centrifuged (200 x g).

100 ~1 of buffer (10% of glycerol, 25 mM of Tris-HCl pH 7.4, 10 mM of RCl, 1 mM of EDTA, 1% of ~Triton X-100, surfactant manufactured by Rohm & Haas, Philadelphia, USA, 2 mM PMSF (phenylmethyl sulfonyl fluoride), 100 kallikrein-inactivating units of aprotinin/ml, 2 mM of dithiotreitol) were then added per 1 x 106 cells in order to lyze the cells. After 5' at 4C, the lyzate was centrifuged at 10,000 x g for 10', and the supernatant was used as a starting material for tyrison kinase activity.

Tyrosin kinase activity of the lyzate was measured with poly(Glu, Tyr), 4:1, as a substrate. The inhibitor was preincubated with cell lyzate, substrate ( 2 mg/ml) and Mg2+ (10 mM) in 100 mM of HEPEA (N-2-hydroxyethyl-piperazin-N'-2-ethanesulfonic acid), pH 7.2, and the reaction was initiated by adding 7_32p ATP (40 ~M). After 15' at 30C, the substrate was precipitated using 10%
strength TCA (trichloroacetic acid), filtered over a Millititer Filtration Plate (Millipore Corporation, Mass., USA), washed and dried. The incorporation of 32p was determined by means of a liquid scintillation counter.

Results:

The substances were tested at a maximum concentration of 45 ~g/ml and diluted stepwise in the ratio 1:10. ICSo denoted the concentration at which 50% of the initial enzyme activity were inhibited (see Table III).

A~ay for 3~5~-cAMp-derQn~nt protein ~in~ inhibition p~ re:

The catalytic sub-unit of cAMP-dependent protein kinase (Sigma) was reconstituted as described by Sigma (Sigma Chemical Co., St. Louis, MO, USA). The enzyme activity was measured with kemptide (Sigma) (Leu-Arg-Arg-Ala-Ser-Leu-Gly) as the substrate. The inhibitor was preincubated with the enzyme, substrate (190 ~M), Mg2+ (5 mN), 0.25 mg/ml of BSA and 3.75 mM of mercaptoethanol in 50 mM of MOPA (4-morpholinopropanesulfonic acid), pH 6.9. The reaction was initiated by adding ~_32p ATP (40 ~M). After 15 minutes at 30C, an aliquot amount was transferred to p81 ion exchange paper (2 x 2 cm; Whatman Paper Ltd., Great Britain), the paper was immersed in 75 mM H3PO4, washed and dried, and the incorporation of 32p was determined by means of a liquid scintillation counter.

RRsult~:

The results are expressed as % inhibition of the initial enzyme activity at an inhibitor concentration of 45 ~g/ml (see Table III).

Table I I I
Formula lc where Rz = R8 = H and R4 = OH

Rl X Sign of theICso in% inhibition tif A 1 ~g/TIll of ~_ rotationpp60 v-src ~r''~'"
pmtein kinase at an inhibitor ,~nn~" 1,, 1; flr~ of 45 ~,g/ml 2-thir~h~nyl (+) 1,7 14 2_h~ yl - (+) 22,3 63 (2-chlo~u~yl)- HCl( + ) >45 ~ 69 ~1 phen~1 HCl (-) 5,7 46 2{:hlo~phenyl HC1 (+) 9,2 27 2-fluor~l HC1( + ) 28,0 0 4~thylphe~1 HCl( + ) 2,7 55 3-pyridyl HCl( + ) 10,6 0 2-pyridyl HCl (+) 34,8 0 Eih~rl HCl( + ) 0,7 13 4-pyridyl HCl( + ) 4,2 12 n-pmE~l HCl (_) 45, O O
2-chlo~u~lyl HCl (+) 3~3 29 ethyl HCl (+) >45,0 0 p~nyl HCl (+) 1,9 48 4-br ~ rhf-nyl HCl (+) 3,4 65 4--hi~ yl HCl (+) 39,0 37 n-butyl HCl (+) 0,0 n.b.
2-pyridyl HCl (-) 7,8 6 2-nAphthyl HCl (+) 3 ~ 4 0 4-f~ enyl HCl (+) 2,7 25 4-chluLu~yl HCl( + ) 1,6 37 n-pr ~ 1 HCl (- ) >45,O S

The Example below illustrates the invention without restricting its scope.

- 19a - 1336~15 SRC tumor test:

Single cell suspensions (from cell culture A 549 or disaggregated human tumor xenografts LXF 529) in Beriplast (Behringwerke AG) were diluted 1:2 with RPMI 1640 supplemented with 15 ~ FCS to a final cell concentration of 107 cells/50 ~l. This suspension was sucked quickly into 50 ~l glass capillaries (diameter 1.5 mm), of which the inner walls had been moistered with a thrombin/CaCl2 solution (500 units thrombin in 1 ml 40 mmol CaCl2).

After solidification of the cell-fibrin mixture (about 5 min at RT) the fibrin clot has been removed from the glass capillary into a petridish by air pressure. The fibrin clot was cut into 2 mm pieces (s~ 5 x 105 cells per piece) and the pieces were stored in RPMI 1640 supplemented with 15 ~ FCS
until implantation.

A single fibrin piece was transferred under the renal capsule of a nude mouse and, subsequently, two perpendicular diameters of the implanted piece were measured by microscope with an ocular micrometer (day 0). The tumor size was calculated according to V = a x b V = tumor size a = largest diameter b = diameter perpendicular to a The substance was given i.v. or p.o. daily on day 2 - 15 with the maximal tolerable dose (MTD) and a dose 2/3 of the MTD value according to the pretests. 5 mice/group were used.

_ 19b -On day 21 after implantation the animals were sacrificed, the kidney was exteriorized and the tumor size was measured again. The effectivity of the test drug was calculated from the tumor growth inhibition.

The relative tumor size VR was calculated according the formula Vt VR
Vo Vt = tumor size at the end of experiment (day 21) Vo = tumor/fibrin size at day of implantation Subsequently the median relative tumor size of the treated group (VT) was related to the corresponding median relative tumor size of controls (Vc) according to the formula T/C ~ = - x 100 VC

The statistical significance ( p 0.05) of the antitumoral effects was calculated using the Wilcoxon U test.

Table IV shows the test results.

19c 1336715 Table IV

compound tumor dose schedule T/C
(mg/kg/day) (days) (~) broncho-genic carcinomas (Exmp. 17) LXF 52925 i.v. 2-15 81 n.s.
35 i.v. 2-15 67 A 549 35 i.v. 2-15 70 100 p.o. 2-15 73 (Exmp. 9) LXF 529 2 i.v. 2-15 59 4 i.v. 2-15 51 (Exmp. 19) LXF 529100 i.v. 2-15 98 n.s.
150 i.v. 2-15 80 n.s. = not significant (P 0.05) Example 1 ( +/- ) -Ci8-5,7-dimetho y-2-(2-thienyl)-8-t4-(3-acetosy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one 2-Thiophenecarboxylic acid (2.73 g) was added at 0C to a æolution of (~)-cis-3-acetoxy-1-methyl-4-(3-acetyl-4,6-dimethoxy-2-hydroxy)phenylpiperidine of the formula IV, R = COCH3, (3.0 g) in dry pyridine (30 ml), and POCl3 (2.2 ml) was then added. The reaction mixture was stirred for two hours at room temperature. Water (50 ml) was added slowly to the reaction mixture, and the reaction solution was later rendered alkaline by adding sodium carbonate (pH 8). The reaction mixture was extracted using ethyl acetate (3 x 40 ml). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and the solvent removed in vacuo. The residue was chromatographed on silica gel (4% of MeOH in CHCl3); yield 2.7 g of (+)-cis-3-acetoxy-1-methyl-4-(3-acetyl-4,6-dimethoxy-2-(2-thienyloxy)phenyl)piperidine;
melting point 153-154C.

This compound was taken up in dry dioxane (50 ml), sodium hydride (5 equivalents) was added, and the mixture was stirred for four hours at 40C. MeOH (10 ml) was added to destroy the excess sodium hydride, and dry HCl gas was passed in until the pH of the solution was clearly acid.
The reaction mixture was worked up by adding ice-cold sodium carbonate solution, and the resulting solid product was separated by filtration. Further purification was by means of column chromatography (silica gel, 2% of MeOH, 1% of NH40H in CHC13), and (+)-cis-5,7-dimethoxy-2-(2-thienyl)-8-[4-(3-acetoxy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one were obt~i n~A . Yield 2.50 g, melting point 207-208C.

The following compounds were prepared analogously to Example 1:

13~6715 Example 2 (+)-cis-5,7-Dihydroxy-2-(phenyl)-8-[4-(3-hydroxy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one hydrochloride.

Example 3 (-)-cis-5,7-Dihydroxy-2-phenyl-8-t4-3-hydroxy-1-methyl)-piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

~ample 4 (+)-cis-5,7-Dihydroxy-2-phenyl-8-[4-(3-hydroxy-1-methyl)-piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

~sample 5 (-)-cis-5,7-Dihydroxy-2-(2-pyridyl)-8-t4-(3-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

Example 6 (+)-cis-5,7-Dihydroxy-2-(2-pyridyl)-8-t4-(3-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

Example 7 ( ~ ) -Ci8-5, 7-Dihydroxy-2-(3-pyridyl)-8-t4-(3-hydroxy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one hydrochloride.

E~ample 8 (+)-cis-5,7-Dihydroxy-2-(4-pyridyl)-8-t4-(3-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

Example 9 (-)-cis-5,7-Dihydroxy-5-(2-chlorophenyl)-8-[4-(3-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

Example 10 (+)-cis-5~7-Dihydroxy-2-(2-chlorophenyl)-8-[4-(3-hy~loxy-l-methyl)piperidinyl]-4H-1-benzopyran-4-one S hydrochloride.

~xample 11 (~)-cis-5,7-Dihydroxy-2-(2-chlorophenyl)-8-[4-(3-hydroxy-l-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

E~ample 12 (+)-cis-5,7-Dihydroxy-2-(2,5-dichlorophenyl)-8-t4-(3-hydroxy-l-methyl)piperidinyl]-4H-l-benzopyran-4-one hydrochloride.

~xample 13 (+)-cis-5,7-Dihydroxy-2-(2,4-dichlorophenyl)-8-t4-(3-hydroxy-l-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

~ample 14 (~)-cis-5,7-Dihydroxy-2-(4-methylphenyl)-8-[4-(3-hydroxy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one hydrochloride.

~xæmple lS

(+)-cis-5,7-Dihydroxy-2-(4-methylphenyl)-8-[4-(3-hydroxy-l-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride.

E~cample 16 ( + ) -cis-5, 7-Dihydroxy-2- ( 4-aminophenyl ) -8- [ 4- ( 3-hydroxy-1 -methyl ) piperidinyl ] -4H- l-benzopyran-4 -one hydrochloride .

Example 17 ( ~ ) -cis-5, 7-Dihydroxy-2- ( 3-bromophenyl ) -8- [ 4- ( 3-hydroxy-1-methyl ) piperidinyl ] -4H-1-benzopyran-4-one hydrochloride .

Example 18 1 0 ( ~ ) -c is - 5, 7 -Dihydroxy-2 - ( 2 -naphthyl ) -8 - [ 4 - ( 3 -hydroxy- 1-methyl ) piperidinyl ] -4H-1-benzopyran-4-one hydrochloride .

E~ample 19 ( + ) -cis-5, 7-Dihydroxy-2- ( 4-hydroxyphenyl ) -8- [ 4- ( 3-hydroxy- 1-methyl ) piperidinyl ] -4H- l-benzopyran-4 -one .

l~xample 20 ( + ) -cis-5, 7-Dihydroxy-2- ( 2-hydroxyphenyl ) -8- [ 4- ( 3-hydroxy- l-methyl ) piperidinyl ] -4H- l-benzopyran-4 -one .

Esample 2 1 Active substance solutions which are suitable for in~ection contain the constituents mentioned below and can be prepared in a manner known per se by mixing the substances with each other and filling sterile ampoules with the solutions. The solutions for in~ections are used for the treatment of tumors in a dose of 1-2 in~ection units ( 1 in~ection unit = 1 ampoule) per day.

Constituents (per ampoule) Weight (+)-cis-5,7-Dimethoxy-2-(2-thienyl)-8-[4-(3-acetoxy-1-methyl)piperidinyl]-4H-l-benzopyran-4-one Sodium chloride 50 mg Methylparaben 5 mg Sterile water 5 mg

Claims (9)

1. The use of a compound of the formula I

I

in which R1 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl-C1-C4-alkyl, C1-C6-alkyl which may be substituted by halogen, hydroxy or carboxy; C3-C6-cycloalkyl, a C3-C9-heterocyclic ring having 1, 2 or 3 hetero atoms, such as N, S, O or any combinations thereof, or else C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, aryl including polycyclic rings, or aromatic heterocyclic radicals, aryl, aryl mono- or polysubstituted by halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, carboxyl, COO-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, nitro, trifluoromethyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, or phenyl; carboxyl or an aldehyde or COO-C1-C4-alkyl group, a primary amino, alkylamino, aralkyl-amino, dialkylamino, arylamino or diarylamino group, or -CH2O-C1-C4-alkyl;
R2 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl, nitro, amino, di-C1-C4-alkylamino or a halogen, or hydroxyl, alkoxy, -COOH, -COO-C1-C4-alkyl, -CHO, -CH2OH
or -CH2O-C1-C4-alkyl;
R3 is hydrogen, C1-C4-alkyl, C1-C4-alkyl substituted by halogen, hydroxy or carboxy; hydroxyl, carboxyl, C1-C4-alkyl, nitro, amino, a C1-C4-alkylamino or di-C1-C4-alkylamino group, or halogen, -CHO, -CH2OH, -CH2O-C1-C4-alkyl, , where R is H, C1-C6-alkyl, cycloalkyl and aryl;
R4 is hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-alkanoyloxy, C1-C4-alkoxycarbonyl, aryloxy or amino, or a C1-C4-alkylamino or di-C1-C4-alkylamino group, or is , where R is H, C1-C6-alkyl, cycloalkyl or aryl;
R5 is hydrogen, C1-C6-alkyl, aryl-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, alkylamino, C1-C4-alkanoyl or aroyl, where the aryl group is unsubstituted phenyl, or phenyl that is mono- or polysubstituted by halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, carboxyl, COO-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, nitro, trifluoromethyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino or phenyl;
m is 1 or 2 and n is an integer between 0 and 2, and pharmacologically acceptable acid addition salts thereof, for the inhibition of oncogene-encoded kinases and/or growth factor receptor tyrosine kinases.
2. The use of a compound as claimed in claim 1, of the formula Ia Ia in which R1 is hydrogen or C1-C3-alkyl, naphthyl, aryl, aryl mono- or polysubstituted by halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, carboxyl, COO-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, nitro, trifluoromethyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, or phenyl; or a C3-C9-heterocyclic ring, R2 is hydrogen or C1-C3-alkyl, R5 is C1-C3-alkyl or C3-C5-cycloalkyl, or C3-C5-cycloalkyl-C1-C4-alkyl, or a pharmacologically acceptable acid addition salt thereof.
3. The use of a compound of the formula Ia as claimed in claim 2, in which R1 is phenyl, thienyl, pyridyl, chlorophenyl, dichlorophenyl, methylphenyl, aminophenyl, bromophenyl, hydroxyphenyl or naphthyl, R2 is hydrogen and R5 is methyl, or a pharmacologically acceptable acid addition salt thereof.
4. The use of a compound of the formula Ia as claimed in claim 1, wherein R1 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl-C1-C4-alkyl; C1-C6-alkyl substituted by halogen, hydroxy, or carboxy; C3-C6-cycloalkyl, pyridyl, thienyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, phenyl; phenyl mono- or polysubstituted by halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, carboxyl, COO-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, nitro, trifluoromethyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, or phenyl; naphthyl, carboxyl, -CHO, COO-C1-C4-alkyl, a primary amino, alkylamino, aralkylamino, dialkylamino, amido, arylamino, diarylamino, or -CH2-O-C1-C4-alkyl;
R2 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl, nitro, amino, di-C1-C4-alkylamino, a halogen, hydroxyl, alkoxy, -COOH, -COO-C1-C4-alkyl, -CHO, -CH2OH or -CH2O-C1-C4-alkyl;
R3 is hydrogen, C1-C4-alkyl; C1-C4-alkyl substituted by halogen, hydroxy, or carboxy; hydroxyl, carboxyl, nitro, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, halogen, , -CHO, -CH2OH, -CH2O-C1-C4-alkyl, or , where R is H, C1-C6-alkyl, cycloalkyl, or aryl;
R4 is hydrogen, hydroxyl, C1-C4-alkoxy, C1-C4-alkanoyloxy, C1-C4-alkoxycarbonyl, aryloxy, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, or , where R' is H, C1-C6-alkyl, cycloalkyl or aryl;
R5 is hydrogen, C1-C6-alkyl, aryl-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, alkylamino, C1-C4-alkanoyl, or aroyl, where the aryl group in R1, R2, R3, R4, and R5 is unsubstituted phenyl or phenyl that is mono- or polysubstituted by halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, carboxyl, COO-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, nitro, trifluoromethyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, or phenyl;
m is 1 or 2 and n is 1, or a pharmacologically acceptable acid addition salt thereof.
5. A compound of the formula Ib Ib in which at least one of the substituents is as defined below and the other substituents in each case can be as defined in claim 1: R1 is C3-C6-cycloalkyl, a C3-C9-heterocyclic ring having 1, 2 or 3 hetero atoms, such as N, S, O or any combinations thereof, or is C3-C6-cycloalkyl-C1-C4-alkyl, or polycyclic rings, aromatic heterocyclic radicals, aryl, mono- or polysubstituted by halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, carboxyl, COO-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, nitro, trifluoromethyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, or phenyl; a primary amino, alkylamino, aralkylamino, dialkylamino, arylamino or diarylamino group, or -CH2O-C1-C4-alkyl;
R2 is aryl, hydroxyl, alkoxy, COOH, COO-C1-C4-alkyl, -CHO, -CH2OH or -CH2O-C1-C4-alkyl;
R3 is carboxyl, a halogen, -CHO, -CH2OH, -CH2O-C1-C4-alkyl or group, where R is H, C1-C6-alkyl, cyclo alkyl or aryl;

R4 is , where R is H, C1-C6-alkyl, cycloalkyl or aryl;
R5 is aroyl, where the aryl group is phenyl monosubstituted or polysubstituted by halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, carboxyl, COO-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, nitro, trifluoromethyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino or phenyl;
and m is 1 or 2 and n is an integer between 0 and 2, and a pharmacologically acceptable acid addition salt thereof.
6. A process for the preparation of a compound of the formula Ib as claimed in claim 5, which comprises reacting a compound of the formula II

where R4 is hydroxyl or acetoxy and R3, R5, n and m are as defined in claim 4, to give a diketone of the formula III

III

and cyclizing the resulting compound by reaction with a mineral acid to give a compound of the formula Ib where R1, R3, R5, m and n are as defined, R4 is the hydroxyl group or acetoxy group and R2 is hydrogen and, if appropriate, reacting a compound of the formula Ib where R5 is CH3 with cyanogen bromide after the hydroxyl groups have been protected and reacting the resulting compound under acid or alkaline conditions to give a compound of the formula Ib where R5 is hydrogen, and, if appropriate, reacting a compound of the formula Ib where R5 is hydrogen with suitable electrophilic reagents, such as halides, acid chlorides, tosylates or enones to give a compound of the formula Ib where R5 is C1-C6-alkyl, aryl-C1-C4-alkyl, C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C4-alkyl which may be unsubstituted or substituted as defined in claim 4, and, if appropriate, reacting a compound of the formula Ib where R2 is hydrogen with a secondary amine hydrochloride and paraformaldehyde to give a compound of the formula Ib where R2 is dialkylamino-methyl, or, if appropriate, nitrating a compound of the formula Ib where R2 is hydrogen to give a compound of the formula Ib where R2 is NO2 and, if appropriate, hydrogenating a compound of the formula Ib where R2 is NO2 to give a compound of the formula Ib where R2 is the amino group.
7. A pharmaceutical for controlling tumors, containing at least one compound of the formula I as defined in claim 1 or at least one pharmacologically acceptable acid addition salt.
8. The use of a compound of the formula I as defined in claim 1 for the preparation of a pharmaceutical having an anti-tumoral action.
9. The use of a compound of the formula I as defined in claim 1 for the preparation of a pharmaceutical having an inhibiting action on oncogene-encoded kinases and/or growth factor receptor tyrosine kinases.
CA000614537A 1988-10-28 1989-09-29 8-(4-piperidinyl)-4h-1-benzopyran-4-one derivatives and their use Expired - Lifetime CA1336715C (en)

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DEP3836676.2 1988-10-28

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CY2026A (en) 1998-02-20
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EP0366061A1 (en) 1990-05-02
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