[go: up one dir, main page]

DE4220369A1 - Novel fused dihydropyridine acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them (C.V.) - Google Patents

Novel fused dihydropyridine acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them (C.V.)

Info

Publication number
DE4220369A1
DE4220369A1 DE19924220369 DE4220369A DE4220369A1 DE 4220369 A1 DE4220369 A1 DE 4220369A1 DE 19924220369 DE19924220369 DE 19924220369 DE 4220369 A DE4220369 A DE 4220369A DE 4220369 A1 DE4220369 A1 DE 4220369A1
Authority
DE
Germany
Prior art keywords
alkyl
phenyl
alkoxy
hydrogen
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
DE19924220369
Other languages
German (de)
Inventor
Dietrich Dr Arndts
Walter Dipl Chem Dr Loesel
Otto Dipl Chem Dr Roos
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim GmbH
Original Assignee
Boehringer Ingelheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim GmbH
Priority to DE19924220369 priority Critical patent/DE4220369A1/en
Priority to AU43273/93A priority patent/AU691468B2/en
Priority to JP6502020A priority patent/JPH07508513A/en
Priority to KR1019940704684A priority patent/KR100291706B1/en
Priority to RU95105584A priority patent/RU2127736C1/en
Priority to EP99112223A priority patent/EP0957092A1/en
Priority to CA002138788A priority patent/CA2138788A1/en
Priority to EP93913009A priority patent/EP0647220A1/en
Priority to PCT/EP1993/001554 priority patent/WO1994000435A1/en
Priority to PL93306804A priority patent/PL177745B1/en
Priority to IL106097A priority patent/IL106097A0/en
Priority to MX9303753A priority patent/MX9303753A/en
Publication of DE4220369A1 publication Critical patent/DE4220369A1/en
Priority to US08/477,214 priority patent/US5674878A/en
Priority to US08/475,154 priority patent/US5643919A/en
Priority to US08/872,584 priority patent/US5861412A/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Fused-ring dihydropyridine acetic acid derivs. of formula (I) and their acid-addn. salts are new. A = benzo, thieno or indolo (also pyrrolo in disclosure); when A = benzo, m = 2 and R11 = OH, 1-4C alkoxy, mesyloxy or NHSO2Me, or adjacent R11+R11 = OCH2O or OCH2CH2O (M and R11 are not otherwise defined); R1 = 4-6C cycloalkyl or (4-6C)cycloalkyl(1-5C)alkyl, or when A = pyrrolo, R1 may also be H, 1-10C alkyl, phenyl(1-5C)alkyl, 1-4C alkoxy or NHCOX (X - 1-5C alkyl); R2 and R3 = H or 1-5C alkyl, or CR2R3 is a 5- or 6-membered carbocyclic ring; R5 = H or 1-4C alkyl; R4 = 1-4C alkoxy or NR9R10; R9 and R10 = H, 3-6C alkenyl, 3-6C alkynyl, or 1-12C alkyl opt. substd. by OH, 1-4C alkoxy, di(1-4C alkyl)amino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, CN, thienyl or phenyl (opt. substd. by OH, OMe, F, NHSO2Me, mesyloxy or OCH2O); or R9 = H and R10 = phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl; or NR9R10 = pyrrolidino, piperidino, morpholino or 1-piperazinyl opt. 4-substd. by Me, Ph, mono- or di(1-4C alkoxy)phenyl, pyrimidinyl or phenyl(1-4C)alkyl. USE/ADVANTAGE - (I) are cardioprotective and cerebroprotective agents, antiinflammatory agents (e.g. for treating asthma and arthritis), and anticoagulants or platelet aggregation inhibitors.

Description

Die Erfindung betrifft anellierte Dihydropyridinessig­ säurederivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel. Die Verbindungen besitzen die allgemeine Formel IThe invention relates to fused Dihydropyridinessig acid derivatives, process for their preparation and containing these compounds. The Compounds have the general formula I.

worin
A einen Benzo-, Thieno-, Pyrrolo- oder Indolorest bedeutet; worin, wenn A Benzo ist, m 2 und R11 Hydroxy (C1-C4) Alkoxy, Methansulfonyloxy oder Methansulfonamido, oder zwei benachbarte Substituenten R11 zusammen -O-CH2-O- oder -O-CH2-CH2-O- sein können;
R1 (C4-C6)Cycloalkyl oder (C4-C6) Cycloalkyl (C1-C5)alkyl bedeutet oder wenn A Pyrrolo bedeutet, R1 auch Wasserstoff, (C1-C10)Alkyl, Phenyl (C1-C5)alkyl, (C1-C4)Alkoxy oder -NHCOX (worin X (C1-C5)Alkyl ist) bedeuten kann;
R2 und R3 unabhängig voneinander Wasserstoff oder (C1-C5)Alkyl oder gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Carbocyclus bedeuten;
R5 Wasserstoff oder (C1-C4)Alkyl bedeutet;
R4 (C1-C4)Alkoxy oder eine -NR9R10-Gruppe bedeutet, worin
R9 und R10 unabhängig voneinander R4 (C1-C4)Alkoxy oder eine -NR9 R 10-Gruppe bedeutet, worin
R9 und R10 unabhängig voneinanderwherein
A is a benzo, thieno, pyrrolo or indolo radical; wherein when A is benzo, m 2 and R 11 are hydroxy (C 1 -C 4 ) alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 11 together represent -O-CH 2 -O- or -O-CH 2 -CH 2 -O- can be;
R 1 is (C 4 -C 6 ) cycloalkyl or (C 4 -C 6 ) cycloalkyl (C 1 -C 5 ) alkyl or when A is pyrrolo, R 1 is also hydrogen, (C 1 -C 10 ) alkyl, phenyl ( C 1 -C 5 ) alkyl, (C 1 -C 4 ) alkoxy or -NHCOX (wherein X is (C 1 -C 5 ) alkyl);
R 2 and R 3 are independently hydrogen or (C 1 -C 5 ) alkyl or together with the carbon atom to which they are attached denote a 5- or 6-membered carbocycle;
R 5 is hydrogen or (C 1 -C 4 ) alkyl;
R 4 is (C 1 -C 4 ) alkoxy or a -NR 9 R 10 group in which
R 9 and R 10 independently of one another R 4 (C 1 -C 4 ) alkoxy or a -NR 9 R 10 group, in which
R 9 and R 10 are independent of each other

  • a) Wasserstoff,a) hydrogen,
  • b) verzweigtes oder unverzweigtes Alkenyl mit 3 bis 6 Kohlenstoffatomen,b) branched or unbranched alkenyl with 3 to 6 carbon atoms,
  • c) verzweigtes oder unverzweigtes Alkinyl mit 3 bis 6 Kohlenstoffatomen, oderc) branched or unbranched alkynyl having 3 to 6 carbon atoms, or
  • d) verzweigtes oder unverzweigtes Alkyl mit 1-12 Kohlenstoffatomen bedeuten, wobei das Alkyl substituiert sein kann durch Hydroxy, (C1-C4)Alkoxy, Di(C1-C4)Alkylamino, Furyl, Pyridyl, Pyrrolidinyl, Morpholino, Indolyl, Nitrilo, Thienyl, Phenyl oder Phenyl, das ein oder mehrfach durch Hydroxy, Methoxy, Fluor -NHSO2CH3 oder CH3SO2O- oder durch die Brücke -O-CH2-O- substituiert ist;
    oder R9 Wasserstoff bedeutet und R10 Phenyl, Fluorophenyl, Pyridyl oder N-Benzylpiperidyl;
    oder R9 und R10 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind,
    Pyrrolidinyl, Piperidinyl, Morpholinyl- oder Piperazinyl bedeuten, wobei der Piperazinylring gegebenenfalls durch Methyl, unsubstituiertes Phenyl, Mono- oder Di(C1-C4)Alkoxyphenyl, Pyrimidinyl oder Phenyl (C1-C4)Alkyl N-substituiert sein kann;    d) branched or unbranched alkyl having 1-12 carbon atoms, wherein the alkyl may be substituted by hydroxy, (C 1 -C 4 ) alkoxy, di (C 1 -C 4 ) alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl , Nitrilo, thienyl, phenyl or phenyl which is mono- or polysubstituted by hydroxy, methoxy, fluorine -NHSO 2 CH 3 or CH 3 SO 2 O- or by the bridge -O-CH 2 -O-;
    or R 9 is hydrogen and R 10 is phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl;
    or R 9 and R 10 together with the nitrogen atom to which they are attached,
    Pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, where the piperazinyl ring may optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di (C 1 -C 4 ) alkoxyphenyl, pyrimidinyl or phenyl (C 1 -C 4 ) alkyl;

und ihre physiologisch unbedenklichen Salze mit anorganischen und organischen Säuren.and their physiologically acceptable salts with inorganic and organic acids.

Verbindungen der Formel 1, worin R5 Wasserstoff ist, bilden Tautomere der Formel Ia.Compounds of the formula 1 in which R 5 is hydrogen form tautomers of the formula Ia.

Die Tautomeren sind nach bekannten Methoden trennbar z. B. durch Säulenchromatographie oder selektive Reduktion (NaBH4 beziehungsweise katalytische Reduktion). Verbindungen beider Strukturen, in denen R5 (C1-C4) Alkyl bedeutet, sind stabil.The tautomers are separable by known methods, for. Example, by column chromatography or selective reduction (NaBH 4 or catalytic reduction). Compounds of both structures in which R 5 is (C 1 -C 4 ) alkyl are stable.

Die Definition der allgemeinen Formel I ist so zu verstehen, daß sie auch die Verbindungen der Struktur Ia, worin R5 Wasserstoff oder (C1-C4) Alkyl bedeutet, umfaßt.The definition of general formula I is to be understood as including also the compounds of structure Ia in which R 5 is hydrogen or (C 1 -C 4 ) alkyl.

Der Pyrrolo- und Indolorest (A) kann in Stellung 1 durch (C1-C4)Alkyl substituiert sein. The pyrrolo and indolo radical (A) can be substituted in position 1 by (C 1 -C 4 ) alkyl.

Die neuen Verbindungen haben wertvolle therapeutisch nutzbare Eigenschaften. Sie sind als cardioprotektive Mittel, als hirnprotektive Mittel (insbesondere bei der Behandlung von Patienten, die einen Schlaganfall erlitten haben oder gefährdet sind, einen Schlaganfall zu erleiden), als Mittel für die Behandlung chronisch inflammatorischer Prozesse (z. B. Bronchialasthma, Arthritis) und als Mittel zur Hemmung der Blutgerinnung bzw. Blutplättchenaggregation verwendbar.The new compounds have valuable therapeutic usable properties. They are considered cardioprotective Agents, as brain-protective agents (especially in the treatment of patients who have a stroke have suffered or are at risk of having a stroke to suffer), as a means of treatment chronic inflammatory processes (eg bronchial asthma, Arthritis) and as a means of inhibiting the Blood coagulation or platelet aggregation usable.

Ferner können diese Verbindungen als Mittel zur Behandlung der Colitis Ulcerosa und des Morbus Crohn verwendet werden. Furthermore, these compounds can be used as agents for Treatment of ulcerative colitis and Crohn's disease be used.  

Von den Verbindungen der Formel I können folgende als besonders interessant hervorgehoben werden:Of the compounds of the formula I, the following may be mentioned particularly interesting to highlight:

Verbindungen
- worin R4 Methoxy oder Ethoxy ist;
- worin R4 eine -NR9R10-Gruppe bedeutet, worin R9 und R10 unabhängig voneinander (a) Wasserstoff, (b) Alkyl mit 1 bis 8 Kohlenstoffatomen, Alkenyl oder Alkinyl mit 2 oder 3 Kohlenstoffatomen (wobei das Alkyl substituiert sein kann durch Hydroxy, (C1-C4)Alkoxy, Di(C1-C4)Alkylamino, Furyl, Pyrrolidinyl, Morpholinyl, Pyridinyl oder die Gruppelinks
wherein R 4 is methoxy or ethoxy;
wherein R 4 is an -NR 9 R 10 group, wherein R 9 and R 10 are independently (a) hydrogen, (b) alkyl of 1 to 8 carbon atoms, alkenyl or alkynyl of 2 or 3 carbon atoms (wherein the alkyl substitutes may be hydroxy, (C 1 -C 4 ) alkoxy, di (C 1 -C 4 ) alkylamino, furyl, pyrrolidinyl, morpholinyl, pyridinyl or the group

worin Ar, R₁₂ und n′ wie nachstehend definiert sind, (d) Dimethylamino, (f) Phenyl, (g) Morpholinyl, (h) Pyridyl bedeuten, wobei R9 und R10 nicht gleichzeitig Wasserstoff, Dimethylamino oder Di(C1-C4)alkylaminomethyl sein können;
oder R9 und R10 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolidinyl-, Morpholinyl- oder Piperazinylrest bedeuten, wobei der Piperazinylring gegebenenfalls durch unsubstituiertes Phenyl, Mono- oder Di(C1-C4)alkoxyphenyl, Pyrimidinyl oder Phenyl-(C1-C4)alkyl N-substituiert sein kann;
insbesondere Verbindungen, worin R4 eine -NR9R10-Gruppe ist, worin R9 und/oder R10 unsubstituiertes Phenyl, Fluorphenyl, Morpholino oder 2- oder 3-Pyridyl bedeutet;
worin R4 eine -NR9R10-Gruppe ist, worin R9 und/oder R10 (C1-C4)Alkyl, vorzugsweise Methyl oder Ethyl, bedeutet; oderwherein Ar, R₁₂ and n 'are as defined below, (d) dimethylamino, (f) phenyl, (g) morpholinyl, (h) pyridyl, where R 9 and R 10 are not simultaneously hydrogen, dimethylamino or di (C 1 - C 4 ) alkylaminomethyl;
or R 9 and R 10 together with the nitrogen atom to which they are attached represent a pyrrolidinyl, morpholinyl or piperazinyl radical, where the piperazinyl ring is optionally substituted by unsubstituted phenyl, mono- or di (C 1 -C 4 ) alkoxyphenyl, pyrimidinyl or Phenyl (C 1 -C 4 ) alkyl N-substituted;
in particular compounds wherein R 4 is a -NR 9 R 10 group, wherein R 9 and / or R 10 is unsubstituted phenyl, fluorophenyl, morpholino or 2- or 3-pyridyl;
wherein R 4 is a -NR 9 R 10 group, wherein R 9 and / or R 10 is (C 1 -C 4 ) alkyl, preferably methyl or ethyl; or

worin R4 eine -NR9R10-Gruppe ist, worin R9 und/oder R10 (C2 oder C3)Alkyl bedeutet, das durch Hydroxy, Methoxy, Dimethylamin, Furyl, Morpholino, Pyrrolidinyl oder Pyridyl substituiert ist;
worin R4 eine -NR9R10-Gruppe ist, worin R9 Wasserstoff ist.wherein R 4 is a -NR 9 R 10 group, wherein R 9 and / or R 10 is (C 2 or C 3 ) alkyl substituted by hydroxy, methoxy, dimethylamine, furyl, morpholino, pyrrolidinyl or pyridyl;
wherein R 4 is a -NR 9 R 10 group, wherein R 9 is hydrogen.

Ferner sind Verbindungen (I) hervorzuheben,
worin R4 eine -NR9R10-Gruppe ist, worin R9 Wasserstoff ist und R10 ein substituiertes Alkyl der Formel VII ist,Furthermore, compounds (I) should be emphasized
wherein R 4 is a -NR 9 R 10 group, wherein R 9 is hydrogen and R 10 is a substituted alkyl of formula VII,

worin p O, 1 oder 2 ist;
R6 und R7 unabhängig voneinander Wasserstoff oder (C1-C5)Alkyl oder gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Carbocyclus bedeuten;
Ar Phenyl oder Thienyl bedeutet;
R12 (C1-C4)Alkyl, Halogen (F, Cl, Br, J), Hydroxy, (C1-C4)Alkoxy, Amino, Thiomethyl, Methansulfonyloxy oder Methansulfonamido bedeutet, oder zwei benachbarte Substituenten R12 zusammen -O-CH2-O- oder -O-CH2-CH2 -O- sind und
n′ O, 1, 2 oder 3 bedeutet, wenn Ar Phenyl ist, und
n′, O, 1 oder 2 bedeutet, wenn Ar Thienyl ist; insbesondere Verbindungen
worin R12 (C1-C4)Alkyl, Hydroxy, (C1-C4 ) Alkoxy, Methansulfonyloxy oder Methansulfonamido bedeutet, oder zwei benachbarte Substituenten R12 zusammen -O-CH2 -O- oder -O-CH2-CH2 -O- sind;
worin R12 Hydroxy, (C1-C4)Alkoxy, Methansulfonyloxy oder Methansulfonamido bedeutet, oder zwei benachbarte Substituenten R12 zusammen -O-CH2 -O- oder -O-CH2-CH2 -O- sind;
worin R12 Hydroxy, Methoxy, Methansulfonyloxy oder Methansulfonamido bedeuten, oder zwei benachbarte Substituenten R12 zusammen -O-CH2 -O- sind; besonders Verbindungen
worin R12 Methoxy ist; worin n′ null ist; worin Ar Phenyl und n′ zwei ist, vorzugsweise worin die beiden Sustituenten R12 in den Positionen 2 und 3 sind.wherein p is O, 1 or 2;
R 6 and R 7 are independently hydrogen or (C 1 -C 5 ) alkyl or together with the carbon atom to which they are attached denote a 5- or 6-membered carbocycle;
Ar is phenyl or thienyl;
R 12 is (C 1 -C 4 ) alkyl, halogen (F, Cl, Br, I), hydroxy, (C 1 -C 4 ) alkoxy, amino, thiomethyl, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 12 together - O-CH 2 -O- or -O-CH 2 -CH 2 -O- are and
n 'is O, 1, 2 or 3 when Ar is phenyl, and
n ', O, 1 or 2, when Ar is thienyl; especially connections
wherein R 12 is (C 1 -C 4 ) alkyl, hydroxy, (C 1 -C 4 ) alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 12 together -O-CH 2 -O- or -O-CH 2 - CH 2 -O-;
wherein R 12 is hydroxy, (C 1 -C 4 ) alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 12 together are -O-CH 2 -O- or -O-CH 2 -CH 2 -O-;
wherein R 12 is hydroxy, methoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 12 together are -O-CH 2 -O-; especially connections
wherein R 12 is methoxy; where n 'is zero; wherein Ar is phenyl and n 'is two, preferably wherein the two substituents R 12 are in positions 2 and 3.

Hervorzuheben sind ferner Verbindungen (1), worin R4 eine -NR9R10-Gruppe ist, worin R9 und R10 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, Morpholino, Pyrrolidinyl oder Piperazinyl (das durch Methoxyphenyl, Phenethyl oder 2-Pyrimidinyl N-substituiert ist) bedeuten;
Von den genannten Verbindungsgruppen sind solche bevorzugt,Also noteworthy are compounds (1) wherein R 4 is a -NR 9 R 10 group wherein R 9 and R 10 together with the nitrogen atom to which they are attached are morpholino, pyrrolidinyl or piperazinyl (represented by methoxyphenyl, phenethyl or 2-pyrimidinyl is N-substituted);
Of the named linking groups, those are preferred

  • - worin R1 Wasserstoff, (C1-C10)Alkyl, Phenyl (C1-C5)alkyl oder -NHCOX (worin X (C1-C5)Alkyl ist) bedeutet; und
    R11 (C1-C4)Alkyl, Hydroxy, (C1-C4)Alkoxy, Methansulfonyloxy oder Methansulfonamido bedeutet, oder zwei benachbarte Substituenten R 11 zusammen -O-CH2-O- oder -O-CH2-CH2-O- sind;    wherein R 1 is hydrogen, (C 1 -C 10 ) alkyl, phenyl (C 1 -C 5 ) alkyl or -NHCOX (wherein X is (C 1 -C 5 ) alkyl); and
    R 11 is (C 1 -C 4 ) alkyl, hydroxy, (C 1 -C 4 ) alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 11 together represent -O-CH 2 -O- or -O-CH 2 -CH 2 -O-;
  • - worin R1 Wasserstoff, (C1-C10)Alkyl oder -NHCOX (worin X (C1-C5Alkyl ist) bedeutet;
    R2 und R3 Wasserstoff bedeuten oder zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Carbocyclus bedeuten;
    R11 Hydroxy, (C1-C4)Alkoxy, Methansulfonyloxy oder Methansulfonamido bedeutet, oder zwei benachbarte Substituenten R11 zusammen -O-CH2-O- oder -O-CH2-CH2-O- sind;    wherein R 1 is hydrogen, (C 1 -C 10 ) alkyl or -NHCOX (wherein X is (C 1 -C 5 alkyl);
    R 2 and R 3 are hydrogen or together with the carbon atom to which they are attached denote a 5- or 6-membered carbocycle;
    R 11 is hydroxy, (C 1 -C 4 ) alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 11 together are -O-CH 2 -O- or -O-CH 2 -CH 2 -O-;
  • - worin R1 Wasserstoff, (C1-C6)Alkyl, oder -NHCOCH3 bedeutet;wherein R 1 is hydrogen, (C 1 -C 6 ) alkyl, or -NHCOCH 3 ;
  • - worin R5 Wasserstoff, Methyl oder Ethyl bedeutet; - wherein R 5 is hydrogen, methyl or ethyl;
  • - worin R2 und R3 Wasserstoff bedeuten oder gemeinsam mit dem Kohlenstoffatom, an das sie, gebunden sind, einen 5-gliedrigen Carbocyclus bedeuten;wherein R 2 and R 3 are hydrogen or, together with the carbon atom to which they are bonded, denote a 5-membered carbocycle;
  • - worin R11 Hydroxy, Methoxy, Methansulfonyloxy oder Methansulfonamido bedeutet, oder zwei benachbarte Substituenten R11 zusammen -O-CH2-O- sind;wherein R 11 is hydroxy, methoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 11 together are -O-CH 2 -O-;
  • - worin, wenn A ein Benzorest ist, m 2 bedeutet, und vorzugsweise die beiden Substituenten R11 in meta- beziehungsweise para-Position zu den Fusionspunkten des Restes A stehen;wherein, when A is a benzo radical, m is 2, and preferably the two substituents R 11 are in meta or para position to the fusion points of the radical A;
  • - worin R11 Methoxy ist.wherein R 11 is methoxy.

Bevorzugt sind Verbindungen, worin A Benzo, R11 Methoxy, m zwei, R1 Wasserstoff oder (C1-C5)Alkyl, R2, R3 und R5 Wasserstoff und R4 Morpholino, Methylamino, Diethylamino oder Phenethylamino bedeuten. Preference is given to compounds in which A is benzo, R 11 is methoxy, m is two, R 1 is hydrogen or (C 1 -C 5 ) alkyl, R 2 , R 3 and R 5 are hydrogen and R 4 is morpholino, methylamino, diethylamino or phenethylamino.

Die Verbindungen der Formel I können nach an sich bekannten Verfahren hergestellt werden, vorzugsweise nach der in der deutschen Patentanmeldung P 37 18 570.5 und EP 358 957 beschriebenen Methode.The compounds of the formula I can be prepared per se are prepared, preferably after in the German patent application P 37 18 570.5 and EP 358 957 described method.

In Gegenwart eines Kondensationsmittels kann ein Malonsäurediamid der allgemeinen Formel IVIn the presence of a condensing agent, a Malonic acid diamide of general formula IV

in der R, m, R5 und R6 wie oben definiert sind und Ar Phenyl, 2- oder 3-Indolyl oder 2- oder 3-Thienyl oder 2- oder 3-Pyrrolyl bedeutet, zu den entsprechenden Verbindungen cyclisiert werden.wherein R, m, R 5 and R 6 are as defined above and Ar is phenyl, 2- or 3-indolyl or 2- or 3-thienyl or 2- or 3-pyrrolyl, to the corresponding compounds.

Als Kondensationsmittel für dieses Verfahren eignen sich starke Lewis-Säuren, wie z. B. Phosphoroxychlorid, Phosphorpentachlorid, Phosphortrichlorid, Phosphorpentoxid, Titantetrachlorid, Bortrifluorid, Zinntetrachlorid, aber auch anorganische Säuren, wie z . B. Polyphosphorsäure, Schwefelsäure, Fluorsulfonsäure und Fluorwasserstoffsäure, oder Gemische von Kondensationsmitteln wie z. B. ein Gemisch von Phorphoroxychlorid und Phosphorpentachlorid, oder ein Gemisch von Phosphorpentoxid und (C1-C4) Alkylsulfonsäure z. B. mit einem P2O5-Anteil von ca. 10 Gewichtsprozenten. As condensing agent for this method are strong Lewis acids, such as. As phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride, but also inorganic acids, such as. As polyphosphoric acid, sulfuric acid, fluorosulfonic acid and hydrofluoric acid, or mixtures of condensing agents such. As a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C 1 -C 4 ) alkylsulfonic acid z. B. with a P 2 O 5 content of about 10 weight percent.

Die Cyclisierung kann in Gegenwart oder Abwesenheit eines Lösungsmittels durchgeführt werden. Geeignet sind alle inerten Lösungsmittel, soweit sie eine ausreichende Löslichkeit für die Reaktionspartner besitzen und einen ausreichend hohen Siedepunkt aufweisen, beispielsweise Benzol, Alkylbenzole (z. B. Toluol, Xylol), Chlorbenzole, Chloroform, Acetonitril, Dekalin. Eine bevorzugte Variante des Verfahrens besteht darin, das Kondensationsmittel, beispielsweise Phosphoroxychlorid oder ein (C1-C4)Alkylsulfonsäure-/Phosphorpentoxid-Gemisch, ohne Zusatz von Lösungsmittel zu verwenden.The cyclization may be carried out in the presence or absence of a solvent. All inert solvents are suitable, provided they have sufficient solubility for the reactants and have a sufficiently high boiling point, for example benzene, alkylbenzenes (eg toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin. A preferred variant of the process consists in using the condensing agent, for example phosphorus oxychloride or a (C 1 -C 4 ) alkylsulfonic acid / phosphorus pentoxide mixture, without the addition of solvent.

Bevorzugt erfolgt die Cyclisierung mit Phosphoroxychlorid oder in schwierigen Fällen mit einem Gemisch von Phosphorpentoxid und (C1-C4)Alkylsulfonsäure (bevorzugt Methansulfonsäure).Preferably, the cyclization is carried out with phosphorus oxychloride or in difficult cases with a mixture of phosphorus pentoxide and (C 1 -C 4 ) alkylsulfonic acid (preferably methanesulfonic acid).

Die Umsetzung kann innerhalb eines großen Temperaturbereichs, vorzugsweise unter Erwärmen oder Erhitzen auf 50°C bis etwa den Siedepunkt des Reaktionsgemisches, durchgeführt werden.The implementation can be done within a large Temperature range, preferably with heating or Heat to 50 ° C until about the boiling point of Reaction mixture, be carried out.

Die erforderliche Reaktionsdauer liegt je nach Ausgangsverbindung IV zwischen 2 und 15 Stunden.The required reaction time is depending on Starting compound IV between 2 and 15 hours.

Die Tautomeren der allgemeinen Formeln II und II′, worin R4 Wasserstoff ist, können nach bekannten Verfahren getrennt werden, wie z. B. durch Säulenchromatographie. The tautomers of general formulas II and II ', wherein R 4 is hydrogen, can be separated by known methods, such as. B. by column chromatography.

Zur Salzbildung geeignete Säuren sind beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Salpetersäure, Essigsäure, Propionsäure, Buttersäure, Oxalsäure, Malonsäure, Bernsteinsäure, Maleinsäure, Fumarsäure, Milchsäure, Weinsäure, Zitronensäure, Apfelsäure, Benzoesäure, Zimtsäure, Ascorbinsäure, Methansulfonsäure. Suitable acids for salt formation are, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, nitric acid, acetic acid, Propionic acid, butyric acid, oxalic acid, malonic acid, Succinic acid, maleic acid, fumaric acid, lactic acid, Tartaric acid, citric acid, malic acid, benzoic acid, Cinnamic acid, ascorbic acid, methanesulfonic acid.  

Die Verbindungen können sowohl enteral als auch parenteral verabreicht werden. Als Dosis für die orale Anwendung werden 0,1 bis 500 mg Wirkstoff pro Dosis, für die i.v.-Anwendung von 0,05 bis 150 mg pro Dosis vorgeschlagen. Die gewünschte therapeutische Dosis ist von der Indikation und Darreichungsform abhängig und kann experimentell bestimmt werden.The compounds can be both enteral as well parenterally. As a dose for the oral Application, 0.1 to 500 mg of active ingredient per dose, for i.v. use from 0.05 to 150 mg per dose proposed. The desired therapeutic dose is depends on the indication and dosage form and can be determined experimentally.

Die Arzneimittel sind für orale oder parenterale Verabreichung geeignet. Als Arzneimittelformen dienen vorwiegend Tabletten, Dragees, Ampullen und Saftzubereitungen. Die Einzeldosis zu diesen Arzneimittelformen beträgt zwischen 1,0 und 200 mg, vorzugsweise 20 und 50 mg pro 75 kg Körpergewicht. Je nach der Schwere des Falles sind täglich im allgemeinen 1 bis 3 Einzeldosen zu verabreichen.The medicines are for oral or parenteral Suitable administration. To serve as drug forms mainly tablets, dragees, ampoules and Juice preparations. The single dose to these Pharmaceutical forms is between 1.0 and 200 mg, preferably 20 and 50 mg per 75 kg body weight. ever According to the seriousness of the case are daily in the general 1 to 3 single doses.

Die folgenden Beispiele sollen die Erfindung näher erläutern: The following examples are intended to illustrate the invention in more detail explain:  

Pharmazeutische AnwendungsbeisspielePharmaceutical application bites

a) Drageesa) dragees 1 Drageekern enthält:1 drag core contains: Wirkstoff der allgemeinen Formel IActive ingredient of the general formula I. 30,0 mg30.0 mg Milchzuckerlactose 100,0 mg100.0 mg Maisstärkecorn starch 75,0 mg75.0 mg Gelatinegelatin 3,0 mg3.0 mg Magnesiumstearatmagnesium stearate 2,0 mg 2.0 mg 210,0 mg210.0 mg

Herstellungmanufacturing

Die Mischung der Wirksubstanz mit Milchzucker und Maisstärke wird mit einer 10%igen wässerigen Gelatinelösung durch ein Sieb mit 1 mm Maschenweite granuliert, bei 40°C getrocknet und nochmals durch ein Sieb gerieben. Das so erhaltene Granulat wird mit Magnesiumstearat gemischt und verpreßt. Die so erhaltenen Kerne werden in üblicher Weise mit einer Hülle überzogen, die mit Hilfe einer wässerigen Suspension von Zucker, Titandioxyd, Talkum und Gummi­ arabicum aufgebracht wird. Die fertigen Dragees werden mit Bienenwachs poliert.The mixture of the active substance with milk sugar and Cornstarch is mixed with a 10% aqueous Gelatin solution through a sieve with 1 mm mesh size granulated, dried at 40 ° C and again through a Grated sieve. The granules thus obtained is with Magnesium stearate mixed and pressed. The way obtained cores are in the usual way with a Envelope coated with the help of a watery Suspension of sugar, titanium dioxide, talc and gum Arabic is applied. The finished dragees will be polished with beeswax.

b) Tablettenb) tablets Wirkstoff der allgemeinen Formel I|30,0 mgActive ingredient of the general formula I | 30.0 mg Milchzuckerlactose 100,0 mg100.0 mg Maisstärkecorn starch 70,0 mg70.0 mg lösliche Stärkesoluble starch 7,0 mg7.0 mg Magnesiumstearatmagnesium stearate 3,0 mg 3.0 mg 210,0 mg210.0 mg

Herstellungmanufacturing

Wirkstoff und Magnesiumstearat werden mit einer wässerigen Lösung der löslichen Stärke granuliert, das Granulat getrocknet und innig mit Milchzucker und Maisstärke vermischt. Das Gemisch wird sodann zu Tabletten von 210 mg Gewicht verpreßt.Active ingredient and magnesium stearate are combined with a granulated soluble solution of soluble starch Granules dried and intimately with milk sugar and Cornstarch mixed. The mixture is then added Tablets of 210 mg weight pressed.

c) Kapselnc) capsules Wirkstoff gemäß Formel I|20,0 mgActive substance according to formula I | 20.0 mg Milchzuckerlactose 230,0 mg230.0 mg Maisstärkecorn starch 40,0 mg40.0 mg Talktalc 10,0 mg 10.0 mg 300,0 mg300.0 mg

Herstellungmanufacturing

Wirkstoff, Milchzucker und Maisstärke werden zunächst in einem Mischer und dann in einer Zerkleinerungsmaschine vermengt. Das Gemisch wird nochmals in den Mischer gegeben, gründlich mit dem Talk vermengt und maschinell in Hartgelatinekapseln abgefüllt.Active ingredient, lactose and corn starch are first in a mixer and then in one Crushing machine mixed. The mixture is again in the mixer, thoroughly with the Blended talc and machine into hard gelatine capsules bottled.

Claims (2)

Verbindung der allgemeinen Formel I worin
A einen Benzo, Thieno- oder Indolorest bedeutet;
worin, wenn A Benzo ist, m 2 und R11 Hydroxy, (C1-C4)Alkoxy, Methansulfonyloxy oder Methansulfonamido, oder zwei benachbarte Substituenten R11 zusammen -O-CH2 -O- oder -O-CH2-CH2-O- sein können;
R1 (C4-C6)Cycloalkyl oder (C4-C6) Cycloalkyl (C1-C5)alkyl bedeutet oder wenn A Pyrrolo bedeutet, R1 auch Wasserstoff, (C1-C10)Alkyl, Phenyl(C1-C5)alkyl, (C1-C4)Alkoxy oder -NHCOX (worin X (C1-C5)Alkyl ist) bedeuten kann;
R2 und R3 unabhängig voneinander Wasserstoff oder (C1-C5)Alkyl oder gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen Carbocyclus bedeuten;
R5 Wasserstoff oder (C1-C4)Alkyl bedeutet;
R4 (C1-C4)Alkoxy oder eine -NR9R10-Gruppe bedeutet, worin
R9 und R10 unabhängig voneinander
  • a) Wasserstoff,
  • b) verzweigtes oder unverzweigtes Alkenyl mit 3 bis 6 Kohlenstoffatomen,
  • c) verzweigtes oder unverzweigtes Alkinyl mit 3 bis 6 Kohlenstoffatomen, oder
  • d) verzweigtes oder unverzweigtes Alkyl mit 1-12 Kohlenstoffatomen bedeuten, wobei das Alkyl substituiert sein kann durch Hydroxy, (C1-C4) Alkoxy, Di (C1-C4) Alkylamino, Furyl, Pyridyl, Pyrrolidinyl, Morpholino, Indolyl, Nitrilo, Thienyl, Phenyl oder Phenyl, das ein oder mehrfach durch Hydroxy, Methoxy, Fluor -NHSO2CH3 oder CH3SO2O- oder durch die Brücke -O-CH2-O- substituiert ist;
    oder R9 Wasserstoff bedeutet und R10 Phenyl, Fluorophenyl, Pyridyl oder N-Benzylpiperidyl;
    oder R9 und R10 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind,
    Pyrrolidinyl, Piperidinyl, Morpholinyl- oder Piperazinyl bedeuten, wobei der Piperazinylring gegebenenfalls durch Methyl, unsubstituiertes Phenyl, Mono- oder Di(C1-C4)alkoxyphenyl, Pyrimidinyl oder Phenyl(C1-C4)alkyl N-substituiert sein kann;
Compound of the general formula I wherein
A represents a benzo, thieno or indolo radical;
wherein when A is benzo, m is 2 and R 11 is hydroxy, (C 1 -C 4 ) alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents R 11 taken together -O-CH 2 -O- or -O-CH 2 -CH 2 -O- can be;
R 1 is (C 4 -C 6 ) cycloalkyl or (C 4 -C 6 ) cycloalkyl (C 1 -C 5 ) alkyl or when A is pyrrolo, R 1 is also hydrogen, (C 1 -C 10 ) alkyl, phenyl ( C 1 -C 5 ) alkyl, (C 1 -C 4 ) alkoxy or -NHCOX (wherein X is (C 1 -C 5 ) alkyl);
R 2 and R 3 are independently hydrogen or (C 1 -C 5 ) alkyl or together with the carbon atom to which they are attached denote a 5- or 6-membered carbocycle;
R 5 is hydrogen or (C 1 -C 4 ) alkyl;
R 4 is (C 1 -C 4 ) alkoxy or a -NR 9 R 10 group in which
R 9 and R 10 are independent of each other
  • a) hydrogen,
  • b) branched or unbranched alkenyl having 3 to 6 carbon atoms,
  • c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or
  • d) branched or unbranched alkyl having 1-12 carbon atoms, wherein the alkyl may be substituted by hydroxy, (C 1 -C 4 ) alkoxy, di (C 1 -C 4 ) alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl , Nitrilo, thienyl, phenyl or phenyl which is mono- or polysubstituted by hydroxy, methoxy, fluorine -NHSO 2 CH 3 or CH 3 SO 2 O- or by the bridge -O-CH 2 -O-;
    or R 9 is hydrogen and R 10 is phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl;
    or R 9 and R 10 together with the nitrogen atom to which they are attached,
    Pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, where the piperazinyl ring may optionally be N-substituted by methyl, unsubstituted phenyl, mono- or di (C 1 -C 4 ) alkoxyphenyl, pyrimidinyl or phenyl (C 1 -C 4 ) alkyl;
und ihre physiologisch unbedenklichen Salze mit einer anorganischen und organischen Säure.and their physiologically acceptable salts with a inorganic and organic acid.
DE19924220369 1992-06-22 1992-06-22 Novel fused dihydropyridine acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them (C.V.) Ceased DE4220369A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
DE19924220369 DE4220369A1 (en) 1992-06-22 1992-06-22 Novel fused dihydropyridine acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them (C.V.)
EP93913009A EP0647220A1 (en) 1992-06-22 1993-06-18 Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions
PCT/EP1993/001554 WO1994000435A1 (en) 1992-06-22 1993-06-18 Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions
KR1019940704684A KR100291706B1 (en) 1992-06-22 1993-06-18 Closed dihydropyridine, preparation method thereof and pharmaceutical composition comprising the same
RU95105584A RU2127736C1 (en) 1992-06-22 1993-06-18 Annealed dihydropyridine derivatives or salts thereof with physiologically tolerable acids and agent blocking nonselective cationic passages
EP99112223A EP0957092A1 (en) 1992-06-22 1993-06-18 Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions
CA002138788A CA2138788A1 (en) 1992-06-22 1993-06-18 Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions
AU43273/93A AU691468B2 (en) 1992-06-22 1993-06-18 Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions
JP6502020A JPH07508513A (en) 1992-06-22 1993-06-18 Cyclized dihydropyridine and its use for the production of pharmaceutical preparations
PL93306804A PL177745B1 (en) 1992-06-22 1993-06-18 Novel condensed dihydropyridines
IL106097A IL106097A0 (en) 1992-06-22 1993-06-22 Carbocyclic and heterocyclic anellated dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them
MX9303753A MX9303753A (en) 1992-06-22 1993-06-22 DIHYDROPYRIDINE RINGS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US08/477,214 US5674878A (en) 1992-06-22 1995-06-07 Anellated dihydropyridines and the use thereof for the production of pharmaceutical preparations
US08/475,154 US5643919A (en) 1992-06-22 1995-06-07 Anellated dihydropyridines and the use thereof for the production of pharmaceutical preparation
US08/872,584 US5861412A (en) 1992-06-22 1997-06-10 Dihydro-isoquinoline compounds and their use as pharmaceuticals

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19924220369 DE4220369A1 (en) 1992-06-22 1992-06-22 Novel fused dihydropyridine acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them (C.V.)

Publications (1)

Publication Number Publication Date
DE4220369A1 true DE4220369A1 (en) 1993-12-23

Family

ID=6461526

Family Applications (1)

Application Number Title Priority Date Filing Date
DE19924220369 Ceased DE4220369A1 (en) 1992-06-22 1992-06-22 Novel fused dihydropyridine acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them (C.V.)

Country Status (1)

Country Link
DE (1) DE4220369A1 (en)

Similar Documents

Publication Publication Date Title
DE60020994T2 (en) NEW USES AND NEW N-AZABICYCLOAMIDE COMPOUNDS
EP0528922B1 (en) New sulfonyl compounds
EP0314154A2 (en) Tetrahydrofuro- and thieno(2,3-c)pyridines, their use as a medicament and process for their preparation
DE3827253A1 (en) Esters and amides of cyclic carboxylic acids and cyclic alcohols and amines, processes for their preparation and therapeutic compositions containing them
DE3827727A1 (en) ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE OF SUCH CONNECTIONS FOR CARDIRO PROTECTION
DE19636769A1 (en) 3-Substituted pyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine derivatives, their preparation and use
DE2643753A1 (en) NEW 1H-PYRAZOLO ANGLE CLAMP ON 3.4-B ANGLE CLAMP TO PYRIDINE
DE4104257A1 (en) USE OF ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL ILLNESSES
EP0288048B1 (en) Benzo- and thieno-3,4-dihydropyridine derivates, processes for their preparation, and medicaments containing them
DE69514315T2 (en) AZABICYCLOALKYL DERIVATIVES FROM IMIDAZO [1,5-a] INDOL-3-ONE AS 5HT3 ANTAGONISTS
DE60203283T2 (en) 6H-OXAZOLO [4,5-E] INDOL DERIVATIVES AS NICOTINIC ACETYLCHOLIN RECEPTOR LIGANDS AND / OR SEROTONERGES LIGANDS
DE4220369A1 (en) Novel fused dihydropyridine acetic acid derivatives, process for their preparation and pharmaceutical compositions containing them (C.V.)
EP0190563B1 (en) 12-Amino pyridazino[4',5':3,4]pyrrolo[2,1-a]isoquinolines, process for their preparation and use
DE2724478A1 (en) NEW, 11-POSITION SUBSTITUTED 5,11-DIHYDRO-6H-PYRIDO SQUARE CLAMP ON 2.3 SQUARE BRACKET TO SQUARE BRACKET ON 1.4 SQUARE BRACKET TO BENZODIAZEPIN-6-ONE, THE PROCESS FOR THEIR PRODUCTION AND THESE JOINTS DRUG
DE4220373A1 (en) Novel fused dihydropyridine acetic acid derivatives, process for their preparation and medicaments containing these compounds (P)
DE4220368A1 (en) Novel fused dihydropyridine acetic acid derivatives, process for their preparation and medicaments containing these compounds
WO1982002891A1 (en) Amino-2,1,3-benzothiadiazol and benzoxadiazol derivatives,preparation thereof and drugs containing them
DE3718570A1 (en) Benzo- and thieno-3,4-dihydro-1-pyridinylacetic acid derivatives, process for their preparation, and medicaments containing these compounds
DE69200948T2 (en) Use of benzimidazoline-2-oxo-1-carboxylic acid derivatives in the treatment of organic brain diseases.
EP0000716A2 (en) Pyrrolo(2,1-b)(3)benzazepine derivatives, process for their preparation and pharmaceutical compositions containing them
EP0000479B1 (en) Substituted 1-piperazinyl-4h-s-triazolo (3,4-c)thieno(2,3-e)1,4-diazepines, process for their preparation and medicaments containing them
DE3302126A1 (en) Amino acid derivatives, process for their preparation and use
EP0014996B1 (en) Heterocyclic spiro-amidines, their stereoisomers and optical isomers, methods for their preparation and medicaments containing them
LU82582A1 (en) NEW 4-PHENYL-4,5,6,7-TETRAHYDRO-PYRROLO (2,3-C) PYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS
DE2322851A1 (en) N-PHENYL-N'-DIALKYLPHOSPHINYLALKYLPIPERAZINE AND THE METHOD FOR THEIR PRODUCTION

Legal Events

Date Code Title Description
8110 Request for examination paragraph 44
8125 Change of the main classification

Ipc: C07D217/12

8131 Rejection