EP0350846B1
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Condensed heterocyclic compounds and their use in therapy
Assignee: F Hoffmann La Roche AG
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Filing: 1989-07-10
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Granted: 1995-10-11
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Expires: 2009-07-10
Abstract
Abstract Compounds of the formula <IMAGE> in which the symbols R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, n, X and Y have the meaning indicated in the description, can be used as medicines for oncological and dermatological indications.
Inventors
- 👤 Michael Dr. Klaus
- 👤 Peter Dr. Mohr
- 👤 Ekkehard Dr. Weiss
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-30 16:34
CPC Classifications
C; C07; C07D; C07D223/00; C07D223/14; C07D223/16; C07D311/00; C07D311/02; C07D311/04; A; A61; A61P; A61P17/00; A61P29/00; A61P35/00; A61P43/00; C07D215/00; C07D215/02; C07D215/04; C07D215/06; C07D215/12; C07D215/16; C07D215/48; C07D241/00; C07D241/36; C07D241/50; C07D241/52; C07D243/00; C07D243/06; C07D243/10; C07D243/12; C07D281/00; C07D281/02; C07D281/04; C07D281/08; C07D281/10; C07D311/58; C07D315/00; C07D317/00; C07D317/08; C07D317/44; C07D317/46; C07D317/48; C07D317/50; C07D317/54; C07D317/60; C07D319/00; C07D319/10; C07D319/14; C07D319/16; C07D319/18; C07D321/00; C07D321/02; C07D321/10; C07D327/00; C07D327/02; C07D327/04; C07D327/06; C07D335/00; C07D335/04; C07D335/06; C07D337/00; C07D337/02; C07D337/06; C07D337/08; C07D339/00; C07D339/02; C07D339/06; C07D339/08; C07D417/00; C07D417/02; C07D417/12
Claims Analysis
Total Claims: 14
Claim 1
Independent Claim
399 words
A process for the manufacture of compounds of the general formula wherein R¹ signifies acyl or a group -CHO, -CH₂OR¹⁰, -COR⁷ or OR¹³; R², R³ and R⁴ signify hydrogen, lower-alkyl, lower-alkoxy or halogen; R⁵ and R⁶ signify hydrogen or lower-alkyl; R⁷ signifies hydroxy, lower-alkoxy or NR⁸R⁹; R⁸ and R⁹ signify hydrogen or lower-alkyl; X signifies >CR¹⁴R¹⁵, -O-, -S-, >SO, >SO₂ or >NR¹⁸; Y signifies -O-, -S-, >SO, >SO₂ or >NR¹⁸; R¹⁰ and R¹⁸ signify hydrogen, lower-alkyl or acyl; M signifies -C(CH₃)=CH-, -CONH- or -NH-CO-; R¹⁴ and R¹⁵ signify hydrogen or lower-alkyl; R¹³ signifies lower-alkyl, which is substituted by amino, mono- or di-alkylamino, morpholino, thiamorpholino or piperazino, or lower-alkoxycarbonyl; and n signifies 1, 2, 3 or 4; and wherein "lower" denotes groups with 1-6 C atoms, and salts of compounds of formula I in which R¹ represents a carboxy group, characterized by a) reacting a compound of the general formula with a compound of the general formula in which either A represents the residue -CH(CH₃)P⁺(Q)₃Z⁻ or -CH(CH₃)-P(O)(OAlk)₂ and B represents a formyl residue; or A represents a residue CH₃CO and B represents the residue -CH₂P⁺(Q)₃Z⁻ or -CH₂-P-(O)(OAlk)₂; Q represents aryl; Z⁻ represents the anion of an organic or inorganic acid; Alk represents a lower alkyl group; and R¹⁶ represents a residue R¹ with the exception of the formyl, carboxyl and hydroxymethyl group; or b) reacting a compound of the general formula with a compound of the general formula in which either D signifies a carboxyl group or a reactive derivative thereof and E signifies an amino group or D signifies an amino group and E signifies a carboxyl group or a reactive derivative thereof and R¹⁹ signifies a residue R¹ with the exception of the carboxyl and hydroxymethyl group; or c) reacting a compound of the general formula with a compound of the general formula in which either F represents a residue -CH(CH₃)MgHal and G represents a formyl residue; or F represents a formyl residue and G represents a residue -CH₂-MgHal; Hal represents halogen; and wherein "lower" denotes groups with 1-6 C atoms, and the remaining symbols have the significance given earlier in formulae II-VII; and dehydrating the reaction product; whereupon, if desired, in the resulting reaction product of formula I the residue R¹ is functionally modified and/or the sulphur atom in a compound I in which X and/or Y is -S- is oxidized to a sulphoxyl or sulphonyl group.
Claim 2
Dependent Claim
43 words
A process in accordance with claim 1 for the manufacture of compounds of formula I in which R¹³ represents lower-alkyl, which is substituted by amino, mono- or di-alkylamino, morpholino, thiamorpholino or piperazino, and the remaining symbols have the significance given in claim 1.
Claim 3
Dependent Claim
22 words
A process in accordance with claim 1 or 2 for the manufacture of compounds of formula I in which M represents -C(CH₃)=CH-.
Claim 4
Dependent Claim
22 words
A process in accordance with claim 1 or 2 for the manufacture of compounds of formula I in which M represents -CONH-.
Claim 5
Dependent Claim
27 words
A process in accordance with claim 1-4 for the manufacture of compounds of formula I in which X and Y are -O-, -S-, >SO, >SO₂ or >NR¹⁸.
Claim 6
Dependent Claim
22 words
A process in accordance with claims 1-5 for the manufacture of compounds of formula I in which X and Y are -S-.
Claim 7
Dependent Claim
46 words
A process in accordance with claim 5 for the manufacture of the compounds ethyl p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-yl)-propenyl]benzoate, p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-yl)propenyl]benzoic acid, ethyl p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)propenyl]benzoate, p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)propenyl]benzoic acid, ethyl p-[2-(3',4'-dihydro-4',4'-dimethyl-2'H-1-benzothiopyran-7'-yl)propenyl]benzoate 1',1'-dioxide, p-[2-(3',4'-dihydro-4',4'-dimethyl-2'H-1-benzothiopyran-7'-yl)-propenyl]benzoic acid 1',1'-dioxide, methyl p-[(E)-2-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-8-yl)propenyl]benzoate, ethyl p-[2-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)propenyl]benzoate, p-[2-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)propenyl]benzoic acid, ethyl p-[(E)-2-(2,3,4,5-tetrahydro-1-benzoxepin-8-yl)propenyl]benzoate, methyl p-[(E)-2-(2,3,4,5-tetrahydro-3,3-dimethyl-2H-1-benzothiepin-8-yl)propenyl]benzoate, ethyl p-[(E)-2-(2,3,4,5-tetrahydro-1-benzothiepin-8-yl)propenyl)benzoate, p-[(E)-2-(2',3',4',5'-tetrahydro-1-benzothiepin-8'-yl)propenyl]benzoic acid 1',1'-dioxide, p-[(E)-2-(2,3,4,5-tetrahydro-1-benzothiepin-8-yl)propenyl]benzoic acid, ethyl p-(2,3,4,5-tetrahydro-1-benzothiepin-8-carboxamido)benzoate.
Claim 8
Dependent Claim
82 words
A process in accordance with claim 5 for the manufacture of the compounds ethyl p-[(E)-2-(1,4-benzodioxan-6-yl)propenyl]benzoate, p-[(E)-2-(1,4-benzodioxan-6-yl)propenyl]benzoic acid, ethyl p-[(E)-2-(1,4-benzodithian-6-yl)propenyl]benzoate, p-[(E)-2-(1,4-benzodithian-6-yl)propenyl)benzoic acid, methyl p-[(E)-2-(2,2-dimethyl-1,3-benzodioxol-5-yl)propenyl]benzoate, ethyl p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]benzoate, ethyl p-[(E)-2-(3,4-dihydro-3-methyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoate, ethyl p-[(E)-2-(3,4-dihydro-2H-1,5-benzodithiepin-7-yl)propenyl]benzoate, ethyl p-[(E)-2-(3',4'-dihydro-3',3'-dimethyl-2'H-1,5-benzodithiepin-7'-yl)propenyl]benzoate 1',1',5',5'-tetroxide, p-[(E)-2-(3,4-dihydro-3-methyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoic acid, p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]benzoic acid, methyl p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]benzoate, ethyl p-[(E)-2-(2,3-dihydro-3,3-dimethyl-1,4-benzoxathiin-7-yl)propenyl]benzoate, methyl p-[(E)-2-(2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-1H-1,5-benzodiazepin-7-yl)propenyl]benzoate, 4-[2-[p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]phenoxy]ethyl]morpholine, 4-[2-[p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]phenoxy]ethyl]morpholine, p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepin-7-yl)propenyl]phenyl ethyl carbonate, methyl p-[(E)-2-(3,4-dihydro-5-methyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoate, methyl p-[(E)-2-(3,4-dihydro-3,5-dimethyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoate, N,N-dimethyl-2-[p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]phenoxy]ethylamine, p-[(E)-2-(2,3-dihydro-3,3-dimethyl-1,4-benzoxathiin-7-yl)propenyl]benzoic acid, p-[(E)-2-(3,4-dihydro-2H-1,5-benzodithiepin-7-yl)propenyl]benzoic acid, p-[(E)-2-(3,4-dihydro-5-methyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoic acid, p-[(E)-2-(3,4-dihydro-3,5-dimethyl-2H-1,5-benzothiazepin-8-yl)propenyl]benzoic acid, methyl p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]benzoate, 4-[2-[p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenoxy]ethyl]morpholine, ethyl p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenyl carbonate, p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]benzoic acid, methyl p-[(E)-2-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinyl)propenyl]benzoate, p-[(E)-2-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinyl)propenyl]benzoic acid, methyl p-[(E)-2-(2-methyl-1,3-benzodithiol-5-yl)propenyl]benzoate, p-[(E)-2-(2-methyl-1,3-benzodithiol-5-yl)propenyl]benzoic acid, methyl p-[(E)-2-(1,2,3,4-tetrahydro-1,2,3,4-tetramethylquinoxalin-6-yl)propenyl]benzoate, p-[(E)-2-(2,2-dimethyl-1,3-benzodioxol-5-yl)propenyl]benzoic acid, p-(2,2-dimethyl-1,3-benzodioxol-5-carboxamido)benzoic acid.
Claim 9
Dependent Claim
41 words
A process in accordance with claim 4 for the manufacture of the compounds ethyl p-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-8-carboxamido)benzoate, p-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoic acid, ethyl p-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxamido)benzoate, p-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxamido)benzoic acid, ethyl p-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoate, p-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoic acid, ethyl p-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoate 1,1-dioxide, p-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoic acid 1,1-dioxide, ethyl p-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinecarboxamido)benzoate, p-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinecarboxamido)benzoic acid, ethyl p-(1-decyl-1,2,3,4-tetrahydro-4,4-dimethyl-7-quinolinecarboxamido)benzoate, p-(1-decyl-1,2,3,4-tetrahydro-4,4-dimethyl-7-quinolinecarboxamido)benzoic acid, p-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepine-8-carboxamido)benzoic acid,
Claim 10
Dependent Claim
35 words
A process in accordance with claim 5 for the manufacture of the compounds ethyl p-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine-7-carboxamido)benzoate, ethyl p-(1,4-benzodioxane-6-carboxamido)benzoate, p-(1,4-benzodioxane-6-carboxamido)benzoic acid, p-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine-7-carboxamido)benzoic acid, p-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine-7-carboxamido)benzoic acid, ethyl p-(2,2-dimethyl-1,3-benzoxathiol-5-carboxamido)benzoate, p-(2,2-dimethyl-1,3-benzoxathiol-5-carboxamido)benzoic acid, ethyl p-(2,2-dimethyl-1,3-benzodioxol-5-carboxamido)benzoate, 2-[p-[(E)-3,4-(isopropylidenedioxy)-β-methylstyryl]phenoxy]-N,N-dimethylethylamine, p-(2,2-dimethyl-1,3-benzodioxol-5-carboxamido)benzoic acid and ethyl p-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodioxepine-7-carboxamido)benzoate.
Claim 11
Dependent Claim
17 words
A process in accordance with claim 1 for the manufacture of p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]-benzoic acid and its lower-alkyl esters.
Claim 12
Dependent Claim
13 words
A process in accordance with claim 1 for the manufacture of ethyl p-[(E)-2-(3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl)propenyl]-benzoate.
Claim 13
Dependent Claim
41 words
A process according to claim 1, characterized in that the reaction in accordance with process variants a), b) and c) is performed in an organic solvent at temperatures between 0°C and the boiling point of the reaction mixture at atmospheric pressure.
Claim 14
Dependent Claim
159 words
Use of compounds of formula I in which R¹ signifies hydrogen, acyl, lower-alkyl or a group -CHO, -CH₂OR¹⁰, -COR⁷ or OR¹³; R², R³ and R⁴ signify hydrogen, lower-alkyl, lower-alkoxy or halogen; R⁵ and R⁶ signify hydrogen or lower-alkyl; R⁷ signifies hydroxy, lower-alkoxy or NR⁸R⁹; R⁸ and R⁹ signify hydrogen or lower-alkyl; X signifies >CR¹⁴R¹⁵, -O-, -S-, >SO, >SO₂ or >NR¹⁸; Y signifies -O-, -S-, >SO, >SO₂ or >NR¹⁸; R¹⁰ and R¹⁸ signify hydrogen, lower-alkyl or acyl; M signifies -C(R¹¹)=C(R¹²)-, -CONH- or -NH-CO-; R¹¹, R¹², R¹⁴ and R¹⁵ signify hydrogen or lower-alkyl; R¹³ signifies hydrogen, lower-alkyl, which can be substituted by amino, mono- or di-alkylamino, morpholino, thiamorpholino or piperazino, or lower-alkoxycarbonyl; and n signifies 1, 2, 3 or 4; and wherein "lower" denotes groups with 1-6 C atoms, and salts of compounds of formula I in which R¹ represents a carboxy group as active ingredients in the manufacture of pharmaceutical preparations for the treatment of neoplasms, dermatoses and aged skin.
References Cited (Backward Citations)
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