NO174548B - Analogous methods for the preparation of therapeutically active benzo- and thieno-3,4-dihydropyridine derivatives - Google Patents

Analogous methods for the preparation of therapeutically active benzo- and thieno-3,4-dihydropyridine derivatives Download PDF

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NO174548B
NO174548B NO881759A NO881759A NO174548B NO 174548 B NO174548 B NO 174548B NO 881759 A NO881759 A NO 881759A NO 881759 A NO881759 A NO 881759A NO 174548 B NO174548 B NO 174548B
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hydrogen
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Walter Loesel
Otto Roos
Gerd Schnorrenberg
Dietrich Arndst
Georg Speck
Ilse Streller
Franz Josef Kuhn
Guenther Schingnitz
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Boehringer Ingelheim Kg
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
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    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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    • 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
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    • 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
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    • 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
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    • C07D495/04—Ortho-condensed systems

Abstract

Benzo- and thieno-3,4-dihydropyridine derivatives of the formula I <IMAGE> in which D denotes a group of the formula Ia or Ib <IMAGE> and A and B denote a benzo or thieno radical; and R4 denotes (C1-C4)alkoxy or an -NR9R10 group in which R9 and R10 independently of one another denote (a) hydrogen, (b) branched or unbranched alkyl, alkenyl or alkynyl (where the alkyl can be substituted, for example by the group <IMAGE> (c) cycloalkyl having 3-7 ring members, (d) dimethylamino, (e) amino(C2-C4)alkyl, (f) phenyl, (g) morpholinyl or (h) pyridinyl, or R9 and R10, together with the nitrogen atom to which they are bonded, denote a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl radical; and their pharmaceutically acceptable salts. The compounds have cardioprotective and/or cerebral protective action.

Description

Forbindelsen angår fremgangsmåte for fremstilling av terapeutisk aktive, nye benzo- og tieno-3,4-dihydro-pyridin-derivater. The connection concerns a process for the production of therapeutically active, new benzo- and thieno-3,4-dihydro-pyridine derivatives.

De nye forbindelsene har den generelle formel I The new compounds have the general formula I

hvor where

A betyr en benzo- eller tienorest; A means a benzo or thienoresid;

R2 og R3 uavhengig av hverandre betyr hydrogen eller, sammen med det karbonatom som de er bundet til, danner en cyklopentanring, Rn betyr hydroksy, (C1-C4)alkoksy, tiometyloksy, metansulfonyl eller metansulfonamido, eller to nabostilte substituenter Rn sammen utgjør -0-CH2-0-; R2 and R3 independently of each other are hydrogen or, together with the carbon atom to which they are attached, form a cyclopentane ring, Rn is hydroxy, (C1-C4)alkyloxy, thiomethyloxy, methanesulfonyl or methanesulfonamido, or two adjacent substituents Rn together constitute -0 -CH 2 -O-;

m betyr 0, 1 eller 2 når A er en benzorest og 0 når A er en tienorest; m means 0, 1 or 2 when A is a benzo residue and 0 when A is a thienore residue;

og D står for en gruppe med formel Ia eller Ib and D stands for a group of formula Ia or Ib

hvor, i gruppen med formel Ia, B betyr en benzo- eller tienorest; wherein, in the group of formula Ia, B is a benzo or thienoresid;

Ri betyr hydrogen, (Ci-Cm) alkyl, fenyl, fenyl (Ci-Cs) alkyl eller -NHCOX (hvori X er ( C^ C^ alkyl); R 1 means hydrogen, (C 1 -C 8 )alkyl, phenyl, phenyl (C 1 -C 8 )alkyl or -NHCOX (wherein X is (C 1 -C 3 alkyl);

R5 betyr hydrogen, (Ci-CJ alkyl eller hydroksymetyl; R 5 means hydrogen, (C 1 -C 1 alkyl or hydroxymethyl;

R6 og R7 uavhengig av hverandre betyr hydrogen eller, sammen med det karbonatom som de er bundet til, danner en cyklopentanring, R6 and R7 independently represent hydrogen or, together with the carbon atom to which they are attached, form a cyclopentane ring,

R12 betyr (C1-C4) alkyl, hydroksy, (Ci-CJ alkoksy, metan-sulf onyloksy eller metansulfonamido, eller to nabostilte R12-substituenter sammen utgjør -0-CH2-0-; R 12 means (C 1 -C 4 ) alkyl, hydroxy, (C 1 -C 1 6 alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent R 12 substituents together form -0-CH 2 -0-;

og n betyr 0, 1 eller 2 når B er en benzorest, og 0 når B er en tienorest; and n means 0, 1 or 2 when B is a benzo residue, and 0 when B is a thienore residue;

og hvor, i gruppen med formel Ib, and where, in the group of formula Ib,

R-t er hydrogen, ( C^ C^) alkyl, fenyl ( C^- C^ alkyl eller -NHCOX (hvori X er ( C^C^ alkyl) ; R-t is hydrogen, (C₁C₁)alkyl, phenyl (C₁-C₁ alkyl) or -NHCOX (wherein X is (C₁C₁ alkyl);

R'5 betyr hydrogen eller (Ci-CJ alkyl; R' 5 means hydrogen or (C 1 -C 1 alkyl;

R4 betyr en -NR9R10-gruppe, hvori R 4 means a -NR 9 R 10 group, wherein

R9 og R10 uavhengig av hverandre kan være (a) hydrogen, (b) forgrenet eller uforgrenet alkyl, alkenyl eller alkynyl med 1-12 karbonatomer (hvor alkylgruppen kan være substituert med hydroksy, (Ci-CJ alkoksy, di(Ci-CJ alkylamino, furyl, pyrrolidinyl, morfolinyl, pyridinyl, tienyl eller dimetoksyfenyl, R9 and R10 independently of each other can be (a) hydrogen, (b) branched or unbranched alkyl, alkenyl or alkynyl with 1-12 carbon atoms (where the alkyl group can be substituted with hydroxy, (Ci-CJ alkoxy, di(Ci-CJ alkylamino , furyl, pyrrolidinyl, morpholinyl, pyridinyl, thienyl or dimethoxyphenyl,

(c) dimetylamino, (d) amino (C2-C4) alkyl (hvor aminogruppen kan være di-(C^-CJalk<y>lamino) , (e) fenyl, (f) morfolinyl, eller (g) pyridinyl, idet R9 og R10 ikke samtidig kan være hydrogen, dimetylamino eller di (C]-C4) alkylaminometyl; eller R9 og R10 sammen med nitrogenatomet som de er bundet til, betyr en pyrrolidinyl-, morfolinyl- eller piperazinylrest, hvor piperazinylringen eventuelt kan være N-substituert med usubstituert fenyl, mono- eller di-(CX-CJ alkoksyfenyl, pyrimidinyl eller f enyl (C1-C4) alkyl ; og deres farmasøytisk akseptable salter med uorganiske eller organiske syrer; med unntak av forbindelsen med formel I hvor D utgjør gruppen Ia og Rlf R2, R3, R5, R6 og R7 betyr hydrogen og A og B resten (c) dimethylamino, (d) amino (C2-C4) alkyl (where the amino group may be di-(C^-CAlk<y>lamino) , (e) phenyl, (f) morpholinyl, or (g) pyridinyl, wherein R9 and R10 cannot simultaneously be hydrogen, dimethylamino or di(C1-C4)alkylaminomethyl; or R9 and R10 together with the nitrogen atom to which they are attached means a pyrrolidinyl, morpholinyl or piperazinyl residue, where the piperazinyl ring may optionally be N-substituted with unsubstituted phenyl, mono- or di-(CX-CJ alkoxyphenyl, pyrimidinyl or phenyl (C1-C4)alkyl; and their pharmaceutically acceptable salts with inorganic or organic acids; with the exception of the compound of formula I where D forms the group Ia and Rlf R2, R3, R5, R6 and R7 means hydrogen and A and B the remainder

og and

med unntak av forbindelsen med formel I, hvor D er gruppen med formel Ib, og R1( R2, R3 og R'5 betyr hydrogen, A resten with the exception of the compound of formula I, where D is the group of formula Ib, and R1( R2, R3 and R'5 means hydrogen, A the remainder

Forbindelser med formel I, hvor D er gruppen med formel Ia, betegnes i det følgende som forbindelser med formel VIII Compounds of formula I, where D is the group of formula Ia, are referred to below as compounds of formula VIII

Forbindelser med formel VIII, hvor R5 er hydrogen, danner tautomerer med formel VIIIa og VIIIb, Compounds of formula VIII, where R5 is hydrogen, form tautomers of formula VIIIa and VIIIb,

hvor R5 likeledes er hydrogen. Definisjonen av formel I, resp. VIII, omfatter også de nevnte tautomerer. Forbindelser med formel I, hvor D er gruppen med formel Ib, betegnes i det følgende som forbindelser med formel IX Forbindelser med formel IX, hvor R'5 er hydrogen, danner tautomerer med formel IXa where R 5 is likewise hydrogen. The definition of formula I, resp. VIII, also includes the aforementioned tautomers. Compounds of formula I, where D is the group of formula Ib, are referred to below as compounds of formula IX Compounds of formula IX, where R'5 is hydrogen, form tautomers of formula IXa

Tautomerene lar seg adskille etter kjente metoder, f.eks. ved søylekromatografi eller ved selektiv reduksjon (NaBH4 eller katalytisk reduksjon). Forbindelser av begge strukturer, hvori R5 betyr (Ci-CJ alkyl, er stabile. The tautomers can be separated according to known methods, e.g. by column chromatography or by selective reduction (NaBH4 or catalytic reduction). Compounds of both structures, wherein R 5 is (C 1 -C 1 alkyl) are stable.

Definisjonen av den generelle formel I, resp. IX, skal forstås slik at de også omfatter forbindelser med struktur IXa, hvor R'5 betyr hydrogen eller ( C-^- C^) alkyl. Kobor, Jeno har i Szegedi Tonarkepzo Foiskola Tud. Kozl., 1975, sidene 145-153 (sml. Chem. Abstr. 87; 134980Z) beskrevet en forbindelse med den generelle formel VIII og fremstilling av slike, hvor Rlf R2, R3, R5, R6 og R7 betyr hydrogen og de substituerte gruppene A og B betyr resten The definition of the general formula I, resp. IX, shall be understood to also include compounds of structure IXa, where R'5 means hydrogen or (C-^-C^) alkyl. Kobor, Jeno has in Szegedi Tonarkepzo Foiskola Tud. Kozl., 1975, pages 145-153 (cf. Chem. Abstr. 87; 134980Z) described a compound of the general formula VIII and preparation thereof, where R1f R2, R3, R5, R6 and R7 are hydrogen and the substituted groups A and B mean the rest

Publikasjonen inneholder imidlertid ingen angivelse av fysiologiske virkninger av disse forbindelsene. Forbindelser av typen med formel IX, hvor Rx imidlertid er fenyl, er beskrevet i EP 37934 og EP 251194 med sin fysiologiske virkning. However, the publication contains no indication of the physiological effects of these compounds. Compounds of the type with formula IX, where Rx is, however, phenyl, are described in EP 37934 and EP 251194 with their physiological action.

Det har nå overraskende vist seg at de nye forbindelser med den generelle formel I har verdifulle terapeutiske egenskaper så vel i baseform som i saltform. It has now surprisingly been shown that the new compounds of the general formula I have valuable therapeutic properties both in base form and in salt form.

Dessuten er forbindelser med den generelle formel IX, hvor R4 er gruppen med den generelle formel X Also are compounds of the general formula IX, where R 4 is the group of the general formula X

viktige mellomtrinn ved fremstillingen av forbindelser med den generelle formel VIII og tautomerer og salter derav. important intermediate steps in the preparation of compounds of the general formula VIII and their tautomers and salts.

Av forbindelser med formel VIII kan følgende fremheves som spesielt interessante: -) VIII-forbindelser, hvor Rx betyr hydrogen, ( C^ C^)alkyl, fenyl, fenyl (C^-Cs) alkyl eller -NHCOX (hvori X er Of compounds of formula VIII, the following can be highlighted as particularly interesting: -) VIII compounds, where Rx means hydrogen, (C^C^)alkyl, phenyl, phenyl (C^-Cs)alkyl or -NHCOX (where X is

(CV-C5) alkyl; (C 5 -C 5 ) alkyl;

Rn og R12 uavhengig av hverandre betyr hydroksy, (Cx-CJ alkoksy, metansulfonyl eller metansulfonamido, eller to nabostilte substituenter Ru, resp. R12, sammen Rn and R12 independently of each other mean hydroxy, (Cx-CJ alkoxy, methanesulfonyl or methanesulfonamido, or two adjacent substituents Ru, respectively R12, together

utgjør -0-CH2-0-; -) Vlll-forbindelser, hvor Rx betyr hydrogen, (Ci-Cio) alkyl eller -NHCOX (hvor X er (C^Cs) alkyl) ; constitutes -0-CH2-0-; -) VIII compounds, where R x means hydrogen, (C 1 -C 10 ) alkyl or -NHCOX (where X is (C 1 -C 8 ) alkyl);

R2, R3, R6 og R7 uavhengig av hverandre betyr hydrogen, eller R2 sammen med R3 og/eller R6 sammen med R7 og det respektive karbonatom som de er bundet til, betyr en cyklopentanring; R 2 , R 3 , R 6 and R 7 independently of each other means hydrogen, or R 2 together with R 3 and/or R 6 together with R 7 and the respective carbon atom to which they are attached means a cyclopentane ring;

Rn°9 Ri2 betyr uavhengig av hverandre hydroksy, ( C^ C,,)-alkoksy, metansulfonyl eller metansulfonamido, eller to nabostilte substituenter Rn, resp. R12 sammen utgjør -0-CH2-0- ; Rn°9 R12 independently of each other means hydroxy, (C1-C1,)-alkoxy, methanesulfonyl or methanesulfonamido, or two adjacent substituents Rn, resp. R12 together form -0-CH2-0-;

-) spesielt forbindelser hvor Rx betyr hydrogen, (C^-C,;) alkyl eller -NHCOCH3 og/eller -) especially compounds where Rx means hydrogen, (C^-C,;) alkyl or -NHCOCH3 and/or

R5 betyr hydrogen, metyl eller hydroksymetyl og/eller R5 means hydrogen, methyl or hydroxymethyl and/or

R2, R3, R6 og R7 uavhengig av hverandre betyr hydrogen, eller R2 sammen med R3 og/eller R6 sammen med R7 og det respektive karbonatom som de er bundet til, utgjør en cyklopentanring og/eller R 2 , R 3 , R 6 and R 7 independently of each other mean hydrogen, or R 2 together with R 3 and/or R 6 together with R 7 and the respective carbon atom to which they are attached form a cyclopentane ring and/or

Rn og R12 uavhengig av hverandre betyr hydroksy, metoksy, metansulfonyloksy eller metansulfonamido, eller to nabostilte substituenter Rn, resp. R12 sammen utgjør -0-CH2- Rn and R12 independently of each other mean hydroxy, methoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent substituents Rn, resp. R12 together form -0-CH2-

Foretrukket er forbindelser VIII, hvor, når A og B er benzo, m og n betyr 2, idet de to substituentene R1]L og R12 i benzoresten fortrinnsvis befinner seg i meta-, resp. para-stilling til kondensasjonspunktene av resten A, resp. B. Compounds VIII are preferred, where, when A and B are benzo, m and n mean 2, the two substituents R1]L and R12 in the benzo residue preferably being in the meta-, resp. para position to the condensation points of the residue A, resp. B.

Forbindelser hvor Rn og R12 er metoksy, skal fremheves. Compounds where Rn and R12 are methoxy must be emphasized.

Eksempler på spesifikke forbindelser fremstillet i henhold til oppfinnelsen er de som er angitt i senere følgende tabeller, hvorav 1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl) -1-(3,4-dihydro-6,7-dimetoksyisokinolin-l-yliden)etan eller den fysiologisk akseptable salter, skal fremheves. Examples of specific compounds produced according to the invention are those indicated in later following tables, of which 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(3,4-dihydro -6,7-dimethoxyisoquinolin-1-ylidene)ethane or the physiologically acceptable salts, shall be emphasized.

Andre særlig foretrukkende forbindelser er de som har formlene: Other particularly preferred compounds are those having the formulas:

og deres fysiologisk akseptable salter. and their physiologically acceptable salts.

Forbindelse (a) er første forbindelse i tabell 1. Forbindelse (b) er andre forbindelse i tabell 2. Forbindelse (c) er tredje forbindelse i tabell 3. Forbindelse (d) er andre forbindelse i tabell 3. Forbindelsene i tabellene 2 og 3 er angitt i en av de tauto-mere fonner. Compound (a) is the first compound in Table 1. Compound (b) is the second compound in Table 2. Compound (c) is the third compound in Table 3. Compound (d) is the second compound in Table 3. The compounds in Tables 2 and 3 is stated in one of the tautomer forms.

Av forbindelser med formel IX kan følgende fremheves som særlig interessante: Foretrukket er forbindelser hvor A betyr benzo, Rn metoksy, m to, R1 hydrogen eller ( C^ Cs) alkyl, R2, R3 og R'5 hydrogen og RA morfolino, metylamino, dietylamino eller fenetylamino. Of compounds with formula IX, the following can be highlighted as particularly interesting: Preferred are compounds where A means benzo, Rn methoxy, m to, R1 hydrogen or (C^Cs) alkyl, R2, R3 and R'5 hydrogen and RA morpholino, methylamino, diethylamino or phenethylamino.

Eksempler på spesifikke forbindelser fremstillet i henhold til oppfinnelsen er angitt i de senere følgende tabeller, hvorav følgende skal fremheves: morfolinokarbonylmetyl-6,7-dimetoksy-3,4-dihydro-isokinolin, 6,7-dimetoksy-3,4-dihydro-isokinolineddiksyremetylamid, Examples of specific compounds produced according to the invention are indicated in the later following tables, of which the following should be highlighted: morpholinocarbonylmethyl-6,7-dimethoxy-3,4-dihydro-isoquinoline, 6,7-dimethoxy-3,4-dihydro- isoquinoline acetic acid methylamide,

6,7-dimetoksy-3,4-dihydro-isokinolineddiksyredietylamid og 6,7-dimethoxy-3,4-dihydro-isoquinoline dioxydiethylamide and

6,7-dimetoksy-3,4-dihydro-isokinolineddiksyrefenyletylamid, så vel som deres fysiologisk akseptable salter. 6,7-dimethoxy-3,4-dihydro-isoquinolineacetic acid phenylethylamide, as well as their physiologically acceptable salts.

De nye forbindelsene kan fremstilles på i og for seg kjent måte. The new compounds can be produced in a manner known per se.

Fremstilling av forbindelser med formel VIII: Preparation of compounds of formula VIII:

A. I nærvær av et kondensasjonsmiddel kan et amid med den generelle formel II, A. In the presence of a condensing agent, an amide of the general formula II,

hvor A, Rlf R2, R3, R6, R7, Rn, R12 og m er som ovenfor definert, where A, Rlf R2, R3, R6, R7, Rn, R12 and m are as defined above,

Ar betyr fenyl eller tienyl og n' betyr 0, 1 eller 2, når Ar er fenyl, og 0 når Ar er tienyl, og hvor R5 betyr hydrogen eller (Ci-CJ alkyl, cykliseres til en tilsvarende forbindelse Ar means phenyl or thienyl and n' means 0, 1 or 2, when Ar is phenyl, and 0 when Ar is thienyl, and where R5 means hydrogen or (Ci-CJ alkyl, cyclized to a corresponding compound

(VIII). (VIII).

Egnede kondensasjonsmidler er sterke Lewis-syrer, som f.eks. fosforoksyklorid, fosforpentaklorid, fosfortriklorid, fosforpentoksyd, titantetraklorid, bortrifluorid, tinntetraklorid eller uorganiske syrer som f.eks. polyfosforsyre, svovelsyre, fluorsulfonsyre og hydrogenfluoridsyre, eller blandinger av kondensasjonsmidler, som f.eks. en blanding av fosforoksyklorid og fosforpentaklorid, eller en blanding av fosf orpentoksyd og (Ci-CJ alkylsulfonylsyre, f. eks. med en P205-andel på ca. 10 vektprosent. Suitable condensing agents are strong Lewis acids, such as e.g. phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride or inorganic acids such as e.g. polyphosphoric acid, sulfuric acid, fluorosulfonic acid and hydrofluoric acid, or mixtures of condensing agents, such as e.g. a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (Ci-CJ alkylsulfonyl acid, e.g. with a P205 proportion of about 10 percent by weight.

Cykliseres en forbindelse II, hvor R5 er hydrogen, i nærvær.av blandingen av fosforpentoksyd og ( C^ C)alkylsulfonsyre, oppnår man ved siden av den tilsvarende forbindelse VIII, hvor R5 er hydrogen, også den analoge forbindelse VIII, hvor R5 er (Cx-C*,) alkyl. Fortrinnsvis foretas denne fremgangs-måtevariant med metansulfonsyre. ;Cykliseringen kan foretas med eller uten oppløsnings-midler. Egnet for dette formål er alle inerte oppløsnings-midler som har tilstrekkelig oppløselighet for reaktantene og tilstrekkelig høyt kokepunkt, f.eks. benzen, alkylbenzener, (f.eks. toluen, xylen), klorbenzener, kloroform, acetonitril, dekalin. En foretrukket variant av fremgangsmåten består i at kondensasjonsmiddel, eksempelvis fosforoksyklorid eller en (Ci-CJ alkylsulfonsyre/fosforpentoksyd-blanding benyttes uten tilsetning av oppløsningsmiddel. ;Fortrinnsvis skjer cykliseringen med fosforoksyklorid eller i kompliserte tilfeller med en blanding av fosforpentoksyd og (Cj-CJ alkylsulfonsyre (fortrinnsvis metansulfonsyre) . ;Omsetningen kan utføres innenfor et bredt temperaturområde, fortrinnsvis under oppvarming fra 50°C og opptil reaksjonsblandingens kokepunkt. ;Den nødvendige reaksjonstid utgjør alt etter utgangs-forbindelsen II, mellom flere dager og noen timer. ;Forbindelsene med den ovenfor definerte generelle formel II er nye forbindelser. De kan fremstilles ved cyklisering av det tilsvarende malonsyre-diamid med formel Illa ;;hvor R5 er hydrogen og Rx, R2, R3, R6, R7, Rn og R12 er som ovenfor definert, Ar betyr fenyl eller tienyl og m' og n' uavhengig av hverandre betyr 0, 1 eller 2 når den tilhørende Ar-gruppe er fenyl, og 0 når den tilhørende Ar-gruppe er tienyl. ;Omsetningen skjer som ovenfor beskrevet for cykliseringen av forbindelse II til forbindelse III. Foretas reaksjonen med en blanding av fosforpentoksyd og (Cj-CO alkylsulfonsyre, oppnår man ved siden av den tilsvarende forbindelse II, hvor R5 er hydrogen, også den analoge forbindelse II, hvor R5 er (C1-C4)alkyl. (Se i den forbindelse også fremgangsmåte C). ;B. Omsetningen, utgående fra forbindelse Illa, kan gjennom-føres in situ uten isolering av mellomproduktet II helt til fremstillingen av VIII. ;Da ringslutningen for isokinolin-, resp. tienopyridin-ringen er meget vanskelig for mange forbindelser, kan man om nødvendig eller ønskelig, isolere mellomforbindelsene med formel II eller deres tautomerer som dannes under cykliser-ingsreaksjonen, frigjøre basen og underkaste den en ny cykliseringsreaksjon. I så fall benyttes fosforoksyklorid under svak oppvarming i første trinn. I det neste trinn sluttes ringen med fosforpentaklorid, med en blanding av fosforoksyklorid og fosforpentaklorid eller med en metan-sulf onsy re- / P205-blanding . ;Forbindelsene med den generelle formel Illa er i det vesentlige kjente forbindelser og kan fremstilles etter i og for seg kjente fremgangsmåter. ;Fremstilling av forbindelser med formel IX: ;C. I nærvær av et kondensasjonsmiddel kan et malonsyre-diamid med den generelle formel III ;hvor Ttll R2, R3/ R4 og Rn er som ovenfor definert, R<*>5 er hydrogen, Ar betyr fenyl eller tienyl og m' betyr 0, 1 eller 2 når Ar er fenyl, og 0 når Ar er tienyl, cykliseres til tilsvarende forbindelser IX og IXa. Gjennomføringen av fremgangsmåten blir mer utførlig omtalt nedenfor. Utføres reaksjonen med en blanding av fosforpentoksyd og (C1-C4)alkylsulfonsyre, oppnår man ved siden av de tilsvarende forbindelsene IX og IXa, hvori R'5 er hydrogen, også de analoge forbindelsene IX og IXa, hvori R'5 er ( C-^- C^) alkyl. Egnede kondensasjonsmidler for denne fremgangsmåte er sterke Lewis-syrer, som f.eks. fosforoksyklorid, fosforpentaklorid, fosfortriklorid, fosforpentoksyd, titantetraklorid, bortrifluorid, tinntetraklorid, eller organiske syrer, som f.eks. polyfosforsyre, svovelsyre, fluorsulfonsyre og hydrogenfluoridsyre, eller blandinger av kondensasjonsmidler, som f.eks. en blanding av fosforoksyklorid og fosforpentaklorid eller en blanding av fosforpentoksyd og If a compound II, where R5 is hydrogen, is cyclized in the presence of the mixture of phosphorus pentoxide and (C1-C)alkylsulfonic acid, one obtains next to the corresponding compound VIII, where R5 is hydrogen, also the analogous compound VIII, where R5 is ( C 1 -C 4 ) alkyl. Preferably, this method variant is carried out with methanesulfonic acid. The cyclization can be carried out with or without solvents. Suitable for this purpose are all inert solvents that have sufficient solubility for the reactants and a sufficiently high boiling point, e.g. benzene, alkylbenzenes, (eg toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin. A preferred variant of the method is that a condensing agent, for example phosphorus oxychloride or a (Ci-CJ alkylsulphonic acid/phosphorus pentoxide mixture) is used without the addition of a solvent. (preferably methanesulfonic acid). ;The reaction can be carried out within a wide temperature range, preferably under heating from 50°C and up to the boiling point of the reaction mixture. ;The required reaction time is, depending on the starting compound II, between several days and a few hours. ;The compounds with the above defined general formula II are new compounds. They can be prepared by cyclization of the corresponding malonic acid diamide of formula IIa;; where R5 is hydrogen and Rx, R2, R3, R6, R7, Rn and R12 are as defined above, Ar means phenyl or thienyl and m' and n' independently of each other mean 0, 1 or 2 when the associated Ar group is pheny 1, and 0 when the associated Ar group is thienyl. The reaction takes place as described above for the cyclization of compound II to compound III. If the reaction is carried out with a mixture of phosphorus pentoxide and (Cj-CO alkylsulfonic acid), one obtains next to the corresponding compound II, where R5 is hydrogen, also the analogous compound II, where R5 is (C1-C4)alkyl. (See in that connection also method C). ;B. The reaction, starting from compound Illa, can be carried out in situ without isolating the intermediate II all the way to the preparation of VIII. ;Since the ring closure of the isoquinoline or thienopyridine ring is very difficult for many compounds , one can, if necessary or desirable, isolate the intermediate compounds of formula II or their tautomers that are formed during the cyclization reaction, free the base and subject it to a new cyclization reaction. In this case, phosphorus oxychloride is used under gentle heating in the first step. In the next step, the ring is closed with phosphorus pentachloride, with a mixture of phosphorus oxychloride and phosphorus pentachloride or with a methane-sulfonic acid re- / P 2 O 5 mixture. ;The compounds of the general formula Illa are essentially known compounds and can be prepared according to per se known methods. ;Preparation of compounds of formula IX: ;C. In the presence of a condensing agent, a malonic acid diamide of the general formula III; where Ttll R2, R3/R4 and Rn are as defined above, R<*>5 is hydrogen, Ar means phenyl or thienyl and m' means 0, 1 or 2 when Ar is phenyl, and 0 when Ar is thienyl, are cyclized to corresponding compounds IX and IXa. The implementation of the procedure is discussed in more detail below. If the reaction is carried out with a mixture of phosphorus pentoxide and (C1-C4)alkylsulfonic acid, one obtains next to the corresponding compounds IX and IXa, in which R'5 is hydrogen, also the analogous compounds IX and IXa, in which R'5 is ( C- 3 - C 4 ) alkyl. Suitable condensing agents for this method are strong Lewis acids, such as e.g. phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, stannous tetrachloride, or organic acids, such as e.g. polyphosphoric acid, sulfuric acid, fluorosulfonic acid and hydrofluoric acid, or mixtures of condensing agents, such as e.g. a mixture of phosphorus oxychloride and phosphorus pentachloride or a mixture of phosphorus pentoxide and

(C1-C4) alkylsulf onsyre, f.eks. med en P205-andel på ca. 10 vektprosent. (C1-C4) alkylsulfonic acid, e.g. with a P205 share of approx. 10 percent by weight.

Cykliseres en forbindelse III, hvori R'5 er hydrogen, i nærvær av blandingen av fosforpentoksyd og (Cx-C4)alkylsulfonsyre, oppnår man som nevnt ovenfor, ved siden av de tilsvarende forbindelsene IX og IXa, hvor R'5 er hydrogen, også de analoge forbindelsene IX og IXa, hvor R'5 er (C-l-CJalkyl. Fortrinnsvis utføres denne variant med metansulfonsyre. If a compound III, in which R'5 is hydrogen, is cyclized in the presence of the mixture of phosphorus pentoxide and (Cx-C4)alkylsulfonic acid, one obtains, as mentioned above, next to the corresponding compounds IX and IXa, where R'5 is hydrogen, also the analogous compounds IX and IXa, where R'5 is (C-1-C alkyl. Preferably, this variant is carried out with methanesulfonic acid.

Cykliseringen kan utføres med eller uten oppløsnings-middel. Alle inerte oppløsningsmidler som har en tilstrekkelig oppløselighet for reaktantene og et tiltrekkelig høyt kokepunkt, f.eks. benzen, alkylbenzener (f.eks. toluen, xylen), klorbenzener, kloroform, acetonitril, dekalin, er egnet. En foretrukket variant av fremgangsmåten består i anvendelse av kondensasjonsmidlet, f.eks. fosforoksyklorid eller en (CX-CA)alkylsulfonsyre/fosforpentoksyd-blanding, uten tilsetning av oppløsningsmiddel. The cyclization can be carried out with or without a solvent. All inert solvents that have a sufficient solubility for the reactants and an attractively high boiling point, e.g. benzene, alkylbenzenes (eg toluene, xylene), chlorobenzenes, chloroform, acetonitrile, decalin, are suitable. A preferred variant of the method consists in using the condensation agent, e.g. phosphorus oxychloride or a (CX-CA)alkylsulfonic acid/phosphorus pentoxide mixture, without the addition of solvent.

Cykliseringen foretas fortrinnsvis med fosforoksyklorid eller, i mer kompliserte tilfeller, med en blanding av fosforpentoksyd og (Ci-CJ alkylsulfonsyre (fortrinnsvis metansulfonsyre. The cyclization is preferably carried out with phosphorus oxychloride or, in more complicated cases, with a mixture of phosphorus pentoxide and (Ci-CJ alkylsulfonic acid (preferably methanesulfonic acid.

Omsetningen kan utføres innenfor et bredt temperaturområde, fortrinnsvis under oppvarming fra 50°C opptil reaksjonsblandingens kokepunkt. The reaction can be carried out within a wide temperature range, preferably under heating from 50°C up to the boiling point of the reaction mixture.

Den nødvendige reaksjonstid utgjør, avhengig av utgangs-forbindelsene III, mellom 2 og 15 timer. The required reaction time is, depending on the starting compounds III, between 2 and 15 hours.

Tautomerene med den generelle formel IX og IXa, hvor R'5 er hydrogen, kan spaltes etter kjente fremgangsmåter, som f.eks. ved søylekromatografi eller selektiv reduksjon med f.eks. NaBHA (reduserer tautomerene IX), ved katalytisk reduksjon reduseres tautomerene IX og IXa. The tautomers with the general formula IX and IXa, where R'5 is hydrogen, can be cleaved according to known methods, such as, for example by column chromatography or selective reduction with e.g. NaBHA (reduces tautomers IX), by catalytic reduction, tautomers IX and IXa are reduced.

Forbindelser med formel I, hvor R5 er hydrogen, blir eventuelt N-alkylert. For N-alkyleringen er i prinsippet alle kjente alkyleringsmidler egnet såfremt de har de har en tilstrekkelig reaktivitet, f.eks. aktive alkylestere som dialkyl-sulfat, toluensulfonsyrealkylester eller fluormetansulfonsyre-alkylester. Reaksjonen skjer ved temperaturer opptil reaksjonsblandingens kokepunkt (alkyl står her for (Cj-C4)-alkyl). Compounds of formula I, where R 5 is hydrogen, are optionally N-alkylated. For the N-alkylation, in principle, all known alkylating agents are suitable as long as they have sufficient reactivity, e.g. active alkyl esters such as dialkyl sulfate, toluenesulfonic acid alkyl ester or fluoromethanesulfonic acid alkyl ester. The reaction takes place at temperatures up to the reaction mixture's boiling point (alkyl here stands for (Cj-C4)-alkyl).

N-hydroksymetyleringen foretas under aminoalkylerings-betingelser ifølge Leuckart-Wallach (Ber. dtsch. Chem. Ges., 18, (1885) 2341) eller Eschweiler-Clarke (Teilheimer 2, (1948) Nr. 352; 4 (1950) Nr. 378). I alminnelighet behandles forbindelsen med en f.eks. 3 0% formaldehydoppløsning i nærvær av maursyre ved romtemperatur. The N-hydroxymethylation is carried out under aminoalkylation conditions according to Leuckart-Wallach (Ber. dtsch. Chem. Ges., 18, (1885) 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; 4 (1950) No. 378). In general, the compound is treated with an e.g. 3 0% formaldehyde solution in the presence of formic acid at room temperature.

Overføringen av den frie base med den generelle formel I i dens syreaddisjonssalter, skjer på kjent måte. The transfer of the free base of the general formula I into its acid addition salts takes place in a known manner.

Egnede syrer for saltdannelse er eksempelvis saltsyre, hydrogenbromidsyre, svovelsyre, fosforsyre, salpetersyre, eddiksyre, propionsyre, smørsyre, oksalsyre, malonsyre, rav-syre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, benzosyre, kanelsyre, ascorbinsyre, metansulfonsyre. 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.

Som allerede nevnt har de nye bis-(3,4-dihydro-l-pyridinyl)-metan-forbindelsene med formel I både som baser og i form av salter, verdifulle terapeutiske egenskaper. As already mentioned, the new bis-(3,4-dihydro-1-pyridinyl)-methane compounds of formula I both as bases and in the form of salts have valuable therapeutic properties.

Spesielt har forbindelsene oppvist en tydelig kardio-protektiv virkning som ble bestemt på følgende måte: Som kjent er det myokardiale Ca(2+)-innhold et mål for hjertelidelser forårsaket av hypoksi eller toksiske katekolamindoser, (Higgins et al., Mol. Cell. Cardiol. 10. 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242, 437-449, 1982; Fleckenstein, A. Vortråge der Erlanger Physiol. Tagung 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Omvendt er hemmingen av det hypoksiske- eller isoprenalin-betingede myokardiale kalsiumopptak et mål for den kardioprotektive effektivitet av kalsiumantagonister (Fleckenstein, se ovenfor), av calmodulin-hemmere (Higgins) og av andre farmaka, f.eks. beta-adrenolytika (Arndts, Arzneimittelforschung 25, 1279-1284, 1975). Den kardioprotektive virkning ble bestemt på bevisste rotter etter subkutan eller peroral virkestoffadministrasjon i henhold til fremgangsmåten beskrevet av Arndts (se ovenfor) og styrken av testsubstansens virkning angitt som H50-verdi. Denne verdi tilsvarer den dose som gir 50% hemming av det myokardiale radiokalsiumopptak som forårsakes av 30 mg/kg s.c. isoprenalin. In particular, the compounds have shown a clear cardio-protective effect which was determined in the following way: As is known, the myocardial Ca(2+) content is a measure of heart disorders caused by hypoxia or toxic catecholamine doses, (Higgins et al., Mol. Cell. Cardiol. 10. 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242, 437-449, 1982; Fleckenstein, A. Vortråge der Erlanger Physiol. Tagung 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg , New York, 1971). Conversely, the inhibition of hypoxic- or isoprenaline-induced myocardial calcium uptake is a measure of the cardioprotective effectiveness of calcium antagonists (Fleckenstein, see above), of calmodulin inhibitors (Higgins) and of other drugs, e.g. beta-adrenolytics (Arndts, Arzneimittelforschung 25, 1279-1284, 1975). The cardioprotective effect was determined in conscious rats after subcutaneous or oral active substance administration according to the method described by Arndts (see above) and the strength of the test substance's effect indicated as H50 value. This value corresponds to the dose which produces 50% inhibition of the myocardial radiocalcium uptake caused by 30 mg/kg s.c. isoprenaline.

Herunder har de undersøkte nye forbindelser vist seg å være opptil 5 ganger mer virksomme enn det kjente handels-produkt propranolol. Below, the investigated new compounds have been shown to be up to 5 times more effective than the known commercial product propranolol.

Dersom et isolert hjerte etter å ha vært holdt lengre tid under ischemiske betingelser, igjen perfunderes normalt, skjer ingen øyeblikkelig normalisering av hjertefunksjonen. Det inntrer derimot en forbigående periode som er kjennetegnet ved sammentrekning og arytmier. Denne arytmifase er betinget av forandringer av funksjon og struktur av myokardceller med intracellulær kalsium-overladning (Hess et Manson, J. Moll. Cell. Cardiol. 16, 969, 1984). Kardioprotektivt virksomme forbindelser som verapamil og Diltiazem senker kalsium-over-ladningen og forbedrer kontraksjonsforholdet ved reperfusjon (Watts et al., Am. J. Physiol. 238. H 909, 1980; Meno et al., Am. J. Physiol. 247, H 380, 1984). Den kardioprotektive virkning ble undersøkt på isolerte rottehjerter under ischemi og påfølgende reperfusjon. Under kontrollbetingelsene inntrer etter 1 times ischemi (strømningshastighet 0,15 ml/min.) en periode av uregelmessig hjertevirksomhet på 10-15 minutter. Infusjon av kardioprotektive forbindelser bevirker en signi-fikant forkortelse av denne periode. If an isolated heart, after having been kept for a longer time under ischemic conditions, is again perfused normally, no immediate normalization of cardiac function occurs. There is, however, a transient period characterized by contraction and arrhythmias. This arrhythmia phase is conditioned by changes in the function and structure of myocardial cells with intracellular calcium overload (Hess et Manson, J. Moll. Cell. Cardiol. 16, 969, 1984). Cardioprotective compounds such as verapamil and diltiazem lower calcium overload and improve the contractile ratio at reperfusion (Watts et al., Am. J. Physiol. 238. H 909, 1980; Meno et al., Am. J. Physiol. 247, H 380, 1984). The cardioprotective effect was investigated on isolated rat hearts during ischemia and subsequent reperfusion. Under the control conditions, after 1 hour of ischemia (flow rate 0.15 ml/min.) a period of irregular cardiac activity of 10-15 minutes occurs. Infusion of cardioprotective compounds causes a significant shortening of this period.

Forbindelser som inngår i testresultatene Forbindelse A: forbindelse i henhold til Tabell 1 Compounds included in the test results Compound A: compound according to Table 1

Forbindelser i henhold til Tabell 4 (Strukturtype I) Connections according to Table 4 (Structure type I)

In vitro-undersøkelser på glatt muskulatur (aortastrimler) har vist at det ved forbindelsene i henhold til oppfinnelsen er tale om kalsiumantagonister med en ny virkningsmekanisme: Kalsiumantagonister hemmer den transmembrane kalsiumionestrøm inn i cellen. Denne hemming gjelder cellemembranens spennings-avhengige (langsomme) kalsiumkanal. Bestemmelse av transmembrane kalsiumionestrømmer i vevstrimler under kalium-depol-arisasjon etter fremgangsmåten beskrevet av van Breemen påviser entydig kalsiumantagonister (van Breemen et al., Chest. 78, 157 S.- 165 S, 1980; van Breemen et al., Am. J. Cardiol. 49, 507-510, 1982; Casteels et al., Pfliigers Arch. 392. 139-145, 1981; Deth. und van Breemen, J. Membrane Biol. 30, 363-380, 1977). Ved disse undersøkelser har det vist seg at de nye forbindelsene ikke er klassiske kalsiumantagonister. In vitro investigations on smooth muscle (aortic strips) have shown that the compounds according to the invention are calcium antagonists with a new mechanism of action: Calcium antagonists inhibit the transmembrane calcium ion flow into the cell. This inhibition concerns the cell membrane's voltage-dependent (slow) calcium channel. Determination of transmembrane calcium ion currents in tissue strips during potassium depolarization according to the method described by van Breemen clearly demonstrates calcium antagonists (van Breemen et al., Chest. 78, 157 S.-165 S, 1980; van Breemen et al., Am. J . Cardiol. 49, 507-510, 1982; Casteels et al., Pfliigers Arch. 392. 139-145, 1981; Deth. und van Breemen, J. Membrane Biol. 30, 363-380, 1977). These investigations have shown that the new compounds are not classic calcium antagonists.

Som følge av disse funn er forbindelsene med den generelle formel I, resp. deres syreaddisjonssalter, aktuelle som virkestoff for legemidler til behandling av koronare hjertesykdommer og akutte myokardieinfarkt. As a result of these findings, the compounds of the general formula I, resp. their acid addition salts, relevant as active ingredients for drugs for the treatment of coronary heart disease and acute myocardial infarction.

Ved undersøkelse av dyrenes evne til å overleve i et lukket kammer (hypoksi-toleransetest), som ble gjennomstrømmet med en gassblanding av 96,5% nitrogen og 3,5% oksygen, oppviste dyr som var forbehandlet med forbindelsene fremstillet i henhold til oppfinnelsen, en statistisk høyere overlevingsevne enn kontrolldyr, resp. dyr forbehandlet med Diltiazem, nifedipin eller verapamil. Ved undersøkelser etter denne metode var den hjerneprotektive virkning allerede utpreget ved en dosering på 5 mg/kg p.o. Dermed er de nye forbindelsene de nevnte kjente substanser tydelig overlegne både med hensyn til virksom dose og den dyre-eksperimentelt oppnådde ytelsesforbedring. Som følge av disse funn kan forbindelsene med den generelle formel I eller deres syre-adclisjonssalter, finne anvendelse som virkestoff for legemidler mot hjerteinsuffisiens og cerebrale stoffskifte-forstyrrelser, resp. det hjerneorganiske psykosyndrom samt post-traumatiske og alkoholbetingede hjerneskader. When examining the animals' ability to survive in a closed chamber (hypoxia tolerance test), which was perfused with a gas mixture of 96.5% nitrogen and 3.5% oxygen, animals pretreated with the compounds produced according to the invention showed, a statistically higher survival rate than control animals, resp. animals pretreated with Diltiazem, nifedipine or verapamil. In investigations using this method, the brain protective effect was already pronounced at a dosage of 5 mg/kg p.o. Thus, the new compounds are clearly superior to the aforementioned known substances both with regard to effective dose and the performance improvement obtained in animal experiments. As a result of these findings, the compounds with the general formula I or their acid addition salts can find use as active ingredients for drugs against heart insufficiency and cerebral metabolic disorders, resp. the brain-organic psychosyndrome as well as post-traumatic and alcohol-related brain damage.

Oppfinnelsen angår dessuten legemidler som inneholder forbindelser med den generelle formel I, samt deres salter med uorganiske eller organiske syrer. Legemidlene er egnet for oral eller parenteral administrasjon. Som legemiddelformer tjener først og fremst tabletter, drasjéer, ampuller og safter. Enhetsdosen for disse legemiddelformer utgjør mellom 1,0 og 200 mg, fortrinnsvis 20-50 mg per 75 kg legemsvekt. Alt etter lidelsens grad vil det vanligvis bli gitt 1 til 3 enhetsdoser per døgn. The invention also relates to medicinal products containing compounds of the general formula I, as well as their salts with inorganic or organic acids. The drugs are suitable for oral or parenteral administration. Tablets, dragees, ampoules and juices primarily serve as pharmaceutical forms. The unit dose for these pharmaceutical forms is between 1.0 and 200 mg, preferably 20-50 mg per 75 kg body weight. Depending on the degree of the disorder, 1 to 3 unit doses will usually be given per day.

Eksempel 1 Example 1

1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl) -1-(1,2,3,4-tetrahydro-6,7-dimetoksy-isokinolin-l-yliden)-pentan og 1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl)-1-(1,2,3,4-tetrahydro-6,7-dimetoksy-2-N-metylisokinolin-l-yliden)-pentan 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-1-ylidene)-pentane and 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methylisoquinolin-1-ylidene )-pentane

4,9 g n-butylmalonsyre di-N-[2-(3,4-dimetoksy-fenyl)-etyl]amid ble oppvarmet i 20 ml av en metansulfonsyre-P205-blanding (10 vektprosent P205-andel) 1-2 timer til 100°C. Etter endt omsetning (tynnskiktkrornatografi-kontroll) ble reaksjonsblandingen helt på is, gjort alkalisk med en mettet natrium-karbonatoppløsning og ekstrahert med metylenklorid. Den organiske fase ble vasket med vann, tørket over natriumsulfat, inndampet i vakuum, hvoretter residuet ble separert på kiselgel (eluent: metylenklorid:metanol = 100:5 vol./vol.). Derved elueres N-H-forbindelsen først. 4.9 g of n-butylmalonic acid di-N-[2-(3,4-dimethoxy-phenyl)-ethyl]amide was heated in 20 ml of a methanesulfonic acid-P2O5 mixture (10% by weight of P2O5) for 1-2 hours to 100°C. After completion of the reaction (thin-layer chromatography control), the reaction mixture was poured onto ice, made alkaline with a saturated sodium carbonate solution and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate, evaporated in vacuo, after which the residue was separated on silica gel (eluent: methylene chloride: methanol = 100:5 vol./vol.). Thereby, the N-H compound is eluted first.

N-H-forbindelse: Smp. = 158-159°C (hydroklorid) N-CH3-forbindelse: Smp. = 136-137°C (hydroklorid) . N-H compound: mp. = 158-159°C (hydrochloride) N-CH3 compound: mp. = 136-137°C (hydrochloride) .

Eksempel 2 Example 2

1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl)-1-(3,4-dihydro-6,7-dimetoksy-2-N-metyl-isokinolin-l-yliden)-pentan-hydroklorid 1 g av 1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl)-l-(1,2,3,4-tetrahydro-6,7-dimetoksy-isokinolin-l-yliden)-pentan fremstillet ifølge Eksempel 1, i 2 ml nylig destillert dimetylsulfat, ble oppvarmet i 6 timer til kokepunktet. Etter den vanlige opparbeidning ble det foretatt kromatografi på kiselgel (eluent: CH2Cl2:MeOH = 100:5 vol./vol.), hvorpå hydro-kloridet ble fremstillet og krystallisert fra etanol/eter. 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(3,4-dihydro-6,7-dimethoxy-2-N-methyl-isoquinolin-1-ylidene)- pentane hydrochloride 1 g of 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-1) -ylidene)-pentane prepared according to Example 1, in 2 ml of freshly distilled dimethylsulphate, was heated for 6 hours to the boiling point. After the usual work-up, chromatography was carried out on silica gel (eluent: CH2Cl2:MeOH = 100:5 vol./vol.), after which the hydrochloride was prepared and crystallized from ethanol/ether.

Produktet var identisk med produktet fra Eksempel 1. The product was identical to the product from Example 1.

Eksempel 3 Example 3

1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl)-1-(3,4-dihydro-6,7-dimetoksy-l-N-hydroksymetyl-isokinolin-l-yliden)-etan-hydroklorid 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(3,4-dihydro-6,7-dimethoxy-1-N-hydroxymethyl-isoquinolin-1-ylidene)-ethan- hydrochloride

12 g 1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl)-1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yliden)-etan ble hensatt i en blanding av 20 ml 30% formaldehydoppløsning og 10 ml maursyre (98%) i 20 timer ved romtemperatur. Det ble inndampet til tørrhet under vannstrålevakuum, hvorpå produktet ble tatt opp i CH2C12, vasket med fortynnet natriumkarbonat-oppløsning og deretter med vann, hvorpå den organiske fase ble tørket over Na2S04 og oppløsningsmidlet fordampet i vakuum. Residuet ble tatt opp i en akkurat tilstrekkelig mengde etanol og etter tilsetning av eterisk saltsyre, utfelt som hydroklorid. Smp. = 155°C. Eksempel 4 a-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl)-1,2,3,4-tetra-hydro-6,7-dimetoksy-l-benzyliden-isokinolin 4,9 g 1,2,3,4-tetrahydro-6,7-dimetoksy-l-a-{[2-(3,4-dimetoksyfenyl)-etyl]aminokarbonyl}-benzyl-isokinolin ble oppvarmet til kokepunktet i 20 ml nylig destillert fosforoksyklorid i 4 timer. Etter endt omsetning (tynnskiktkromatografi-kontroll) ble overskudd av P0C13 fradestillert, residuet fordelt mellom CH2C12 og fortynnet natriumkarbonatoppløsning, hvoretter den organiske fase ble vasket med vann, tørket over Na2S04 og inndampet. Residuet ble krornatografert på kiselgel (eluent: CH2Cl2:MeOH = 100:10, vol. /vol.). Den hurt ig-vandr ende gule fraksjon førte til a-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yl) -1,2,3,4-tetrahydro-6,7-dimetoksy-l-benzyliden-2-N-fosfono-isokinolin (Smp. > 270°C (hydroklorid)). Den etterfølgende røde sone førte til N-H-forbindelsen (Smp. = 95-100°C) angitt i tittelen. Eksempel 5 (4,5-dihydro-tieno[2,3-c]pyridin-l-yl)-4,5,6,7-tetrahydro-1- metyliden-tieno[2,3-c]pyridin 19 g malonsyre-di-N-[2-(3-tieno)-etyl]amid ble oppvarmet til kokepunktet i 25 ml fosforoksyklorid i 3 timer. Så snart utgangsmaterialet ikke lenger kunne påvises, ble det foretatt opparbeidning på vanlig måte, hvorpå reaksjonsproduktet ble renset på nøytral A1203, aktivitet III (Fa. Woelm) (eluent: CH2C12) og hydrokloridet fremstillet. (Smp. = 233-235°C) . Eksempel 6 a-isobutylaminokarbonyl-l-pentyl-6,7-dimetoksy-3,4-dihydro-isokinolin 3,8 g (10 mmol) a-isobutylaminokarbonyl-valeriansyre-N-[2-(3,4-dimetoksyfenyl)-etyl]-amid ble oppløst i 120 ml acetonitril og tilsatt 18 ml fosforoksyklorid. Reaksjonsblandingen ble kokt under tilbakeløpskjøling i 2 timer. Deretter ble blandingen inndampet, residuet tatt opp i 200 ml metylenklorid og gjort alkalisk ved innrøring i en isvann-kaliumkarbonat-oppløsning. Etter vanlig opparbeidning - utristing med metylenklorid, tørking av den organiske fase over Na2S04, fordampning av oppløsningsmidlet, etc. - ble produktet renset over en kiselgelsøyle (CH2Cl2/MeOH = 100:2). Smp. = 158-160°C. Eksempel 7 2- etyl-2-(3,4-dihydro-5,6-dimetoksy-l-isokinolinyl)-butan-karbonsyremetylester 22 g 2-{[2-(3,4-dimetoksyfenyl)-etyl]-aminokarbonyl}-2-etyl-butankarboksylsyremetylester ble oppvarmet til kokepunktet i en blanding av 100 ml acetonitril og 12 ml fosforoksyklorid inntil fullstendig omsetning (ca. 2 timer). Deretter ble blandingen opparbeidet på vanlig måte og produktet renset på kiselgel (eluent: CH2Cl2:CH3OH = 100:2) og hydrokloridet dannet. Smp. = 141-143°C (etanol/eter). 12 g of 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-ylidene)-ethane were placed in a mixture of 20 ml of 30% formaldehyde solution and 10 ml of formic acid (98%) for 20 hours at room temperature. It was evaporated to dryness under water jet vacuum, whereupon the product was taken up in CH 2 Cl 2 , washed with dilute sodium carbonate solution and then with water, whereupon the organic phase was dried over Na 2 SO 4 and the solvent evaporated in vacuo. The residue was taken up in a just sufficient amount of ethanol and, after addition of ethereal hydrochloric acid, precipitated as hydrochloride. Temp. = 155°C. Example 4 α-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-benzylidene-isoquinoline 4.9 g 1 ,2,3,4-tetrahydro-6,7-dimethoxy-1-a-{[2-(3,4-dimethoxyphenyl)-ethyl]aminocarbonyl}-benzyl-isoquinoline was heated to the boiling point in 20 ml of freshly distilled phosphorus oxychloride for 4 hours . After completion of the reaction (thin-layer chromatography control), excess P0C13 was distilled off, the residue distributed between CH2C12 and dilute sodium carbonate solution, after which the organic phase was washed with water, dried over Na2S04 and evaporated. The residue was chromatographed on silica gel (eluent: CH2Cl2:MeOH = 100:10, vol./vol.). The rapidly evaporating yellow fraction led to α-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1- benzylidene-2-N-phosphono-isoquinoline (M.p. > 270°C (hydrochloride)). The subsequent red zone led to the N-H compound (Mp = 95-100°C) indicated in the title. Example 5 (4,5-dihydro-thieno[2,3-c]pyridin-1-yl)-4,5,6,7-tetrahydro-1-methylidene-thieno[2,3-c]pyridine 19 g malonic acid-di -N-[2-(3-thieno)-ethyl]amide was heated to the boiling point in 25 ml of phosphorus oxychloride for 3 hours. As soon as the starting material could no longer be detected, work-up was carried out in the usual way, after which the reaction product was purified on neutral A1203, activity III (Fa. Woelm) (eluent: CH2C12) and the hydrochloride prepared. (Mp. = 233-235°C) . Example 6 α-isobutylaminocarbonyl-1-pentyl-6,7-dimethoxy-3,4-dihydro-isoquinoline 3.8 g (10 mmol) α-isobutylaminocarbonyl-valeric acid-N-[2-(3,4-dimethoxyphenyl)- ethyl]-amide was dissolved in 120 ml of acetonitrile and 18 ml of phosphorus oxychloride was added. The reaction mixture was refluxed for 2 hours. The mixture was then evaporated, the residue taken up in 200 ml of methylene chloride and made alkaline by stirring in an ice-water-potassium carbonate solution. After the usual work-up - shaking off with methylene chloride, drying the organic phase over Na2SO4, evaporation of the solvent, etc. - the product was purified over a silica gel column (CH2Cl2/MeOH = 100:2). Temp. = 158-160°C. Example 7 2-ethyl-2-(3,4-dihydro-5,6-dimethoxy-1-isoquinolinyl)-butane-carboxylic acid methyl ester 22 g 2-{[2-(3,4-dimethoxyphenyl)-ethyl]-aminocarbonyl} -2-Ethyl-butanecarboxylic acid methyl ester was heated to the boiling point in a mixture of 100 ml of acetonitrile and 12 ml of phosphorus oxychloride until complete reaction (about 2 hours). The mixture was then worked up in the usual way and the product purified on silica gel (eluent: CH2Cl2:CH3OH = 100:2) and the hydrochloride formed. Temp. = 141-143°C (ethanol/ether).

Eksempler på forbindelser fremstillet ifølge oppfinnelsen, som kan fremstilles analogt med de beskrevne eksempler, er samlet i de følgende tabeller. Examples of compounds produced according to the invention, which can be produced analogously to the described examples, are collected in the following tables.

1. Analogifremgangsmåte for fremstilling av en terapeutisk aktiv forbindelse med den generelle formel I 1. Analogous process for the preparation of a therapeutically active compound of the general formula I

hvor where

A betyr en benzo- eller tienorest; A means a benzo or thienoresid;

R2 og R3 uavhengig av hverandre betyr hydrogen eller, sammen med det karbonatom som de er bundet til, danner en cyklopentanring, Ru betyr hydroksy, (Ci-CJ alkoksy, tiometyloksy, metansulfonyl eller metansulfonamido, eller to nabostilte substituenter Rn sammen utgjør -0-CH2-0-; R 2 and R 3 independently of each other are hydrogen or, together with the carbon atom to which they are attached, form a cyclopentane ring, Ru is hydroxy, (C 1 -C 6 alkoxy, thiomethyloxy, methanesulfonyl or methanesulfonamido, or two adjacent substituents Rn together form -0- CH2-0-;

m betyr 0, 1 eller 2 når A er en benzorest og 0 når A er en tienorest; m means 0, 1 or 2 when A is a benzo residue and 0 when A is a thienore residue;

og D står for en gruppe med formel Ia eller Ib and D stands for a group of formula Ia or Ib

hvor, i gruppen med formel Ia, where, in the group of formula Ia,

B betyr en benzo- eller tienorest; B means a benzo or thienore residue;

Rx betyr hydrogen, (Ci-C^) alkyl, fenyl, fenyl (C^-Cs) alkyl eller -NHCOX (hvori X er (Cx-Cj) alkyl) ; R x means hydrogen, (C 1 -C 8 )alkyl, phenyl, phenyl (C 1 -C 8 )alkyl or -NHCOX (wherein X is (C 1 -C 8 )alkyl);

R5 betyr hydrogen, (C^-C,,) alkyl eller hydroksymetyl; R 5 means hydrogen, (C 1 -C 1 , ) alkyl or hydroxymethyl;

R6 og R7 uavhengig av hverandre betyr hydrogen eller, sammen med det karbonatom som de er bundet til, danner en cyklopentanring, R6 and R7 independently represent hydrogen or, together with the carbon atom to which they are attached, form a cyclopentane ring,

R12 betyr ( C^ C,,) alkyl, hydroksy, (C^-C,,) alkoksy, metansulfonyloksy eller metansulfonamido, eller to nabostilte R12-substituenter sammen utgjør -O-CH2-C—; R 12 means (C 1 -C 12 ) alkyl, hydroxy, (C 1 -C 12 ) alkoxy, methanesulfonyloxy or methanesulfonamido, or two adjacent R 12 substituents together form -O-CH 2 -C—;

og n betyr 0, 1 eller 2 når B er en benzorest, og 0 når B er en tienorest; and n means 0, 1 or 2 when B is a benzo residue, and 0 when B is a thienore residue;

og hvor, i gruppen med formel Ib, and where, in the group of formula Ib,

Rx er hydrogen, (C^-Ck)) alkyl, fenyl (Cx-C5) alkyl eller -NHCOX (hvori X er ( C^ C^ alkyl) ; R x is hydrogen, (C 1 -C 5 ) alkyl, phenyl (C 1 -C 5 ) alkyl or -NHCOX (where X is (C 1 -C 5 ) alkyl);

R'5 betyr hydrogen eller (Cx-C4) alkyl ; R'5 means hydrogen or (Cx-C4)alkyl;

RA betyr en -NR9R10-gruppe, hvori RA means a -NR9R10 group, wherein

R9 og R10 uavhengig av hverandre kan være (a) hydrogen, (b) forgrenet eller uforgrenet alkyl, alkenyl eller alkynyl med 1-12 karbonatomer (hvor alkylgruppen kan være substituert med hydroksy, (Cj-CJ alkoksy, di (C^-C,,) alkylamino, furyl, pyrrolidinyl, morfolinyl, pyridinyl, tienyl eller dimetoksyfenyl, R9 and R10 independently of each other can be (a) hydrogen, (b) branched or unbranched alkyl, alkenyl or alkynyl with 1-12 carbon atoms (where the alkyl group can be substituted with hydroxy, (Cj-CJ alkoxy, di (C^-C ,,) alkylamino, furyl, pyrrolidinyl, morpholinyl, pyridinyl, thienyl or dimethoxyphenyl,

(c) dimetylamino, (d) amino(C2-C4)alkyl (hvor aminogruppen kan være di-(C]-C4) alkylamino) , (e) fenyl, (f) morfolinyl, eller (g) pyridinyl, idet R9 og R10 ikke samtidig kan være hydrogen, dimetylamino eller di (Ci-Cj alkylaminometyl ; eller R9 og R10 sammen med nitrogenatomet som de er bundet til, betyr en pyrrolidinyl-, morfolinyl- eller piperazinylrest, hvor piperazinylringen eventuelt kan være N-substituert med usubstituert fenyl, mono- eller di- (C^-C^,) alkoksy f enyl, pyrimidinyl eller f enyl (Ci-CJ alkyl; og deres farmasøytisk akseptable salter med uorganiske eller organiske syrer; med unntak av forbindelsen med formel I hvor D utgjør gruppen Ia og R1( R2, R3, R5; R6 og R7 betyr hydrogen og A og B resten (c) dimethylamino, (d) amino(C2-C4)alkyl (where the amino group can be di-(C]-C4)alkylamino), (e) phenyl, (f) morpholinyl, or (g) pyridinyl, wherein R9 and R10 cannot simultaneously be hydrogen, dimethylamino or di(Ci-Cj alkylaminomethyl ; or R9 and R10 together with the nitrogen atom to which they are attached means a pyrrolidinyl, morpholinyl or piperazinyl residue, where the piperazinyl ring may optionally be N-substituted with unsubstituted phenyl, mono- or di-(C^-C^) alkoxy f phenyl, pyrimidinyl or phenyl (C 1 -C 1 alkyl; and their pharmaceutically acceptable salts with inorganic or organic acids; with the exception of the compound of formula I where D forms the group Ia and R1( R2, R3, R5; R6 and R7 mean hydrogen and A and B the rest

og and

med unntak av forbindelsen med formel I, hvor D er gruppen med formel Ib, og Rx, R2, R3 og R's betyr hydrogen, A resten with the exception of the compound of formula I, where D is the group of formula Ib, and Rx, R2, R3 and R's mean hydrogen, A the remainder

karakterisert ved at characterized by that

A; (for fremstilling av en forbindelse med formel I, hvor D utgjør gruppen med formel Ia), en forbindelse (II) A; (for the preparation of a compound of formula I, where D constitutes the group of formula Ia), a compound (II)

hvor A, Rx, R2, R3, R6, R7, Rn, Ri2 og m er som ovenfor definert, Ar betyr fenyl eller tienyl og n' betyr 0, 1 eller 2 når Ar er fenyl, og 0 når Ar er tienyl, og R5 betyr hydrogen eller (Cx-C4)alkyl, kondenseres i nærvær av et kondensasjonsmiddel; where A, Rx, R2, R3, R6, R7, Rn, Ri2 and m are as defined above, Ar means phenyl or thienyl and n' means 0, 1 or 2 when Ar is phenyl, and 0 when Ar is thienyl, and R 5 means hydrogen or (C x -C 4 )alkyl, condensed in the presence of a condensing agent;

B. (for fremstilling av en forbindelse med formel I, hvor D er gruppen med formel Ia), en forbindelse (Illa) B. (for the preparation of a compound of formula I, where D is the group of formula Ia), a compound (Illa)

hvor R5 er hydrogen, Rx, R2, R3, R6, R7, Rn og R12 er som ovenfor definert, Ar betyr fenyl eller tienyl og m' og n' uavhengig av hverandre er 0, 1 eller 2 når den tilhørende Ar-gruppe er fenyl, og 0 når den tilhørende Ar-gruppe er tienyl; kondenseres i nærvær av et kondensasjonsmiddel uten å isolere mellomproduktet med den generelle formel (II); C. (for fremstilling av en forbindelse med formel I, hvor D er gruppen med formel Ib), en forbindelse III hvor R'5 er hydrogen, Rx, R2, R3 og Ru er som ovenfor definert, Ar betyr fenyl eller tienyl og rn' betyr 0, 1 eller 2 når Ar er fenyl, og 0 når Ar er tienyl, kondenseres i nærvær av et kondensasjonsmiddel; eventuelt etterfulgt av én eller flere av følgende behandlinger: alkylering av en forbindelse (I) hvor R5, henholdsvis R'5, er hydrogen, til en forbindelse (I) hvor R5, henholdsvis R'5, er (Ci-CJ alkyl; hydroksymetylering av en forbindelse (I) hvor D utgjør gruppen med formel Ia og R5 er hydrogen, til en forbindelse hvor R5 er hydroksymetylen; isolering av den frie forbindelse (I) fra dens salt; omsetning av en forbindelse (I) til dens farmasøytisk akseptable salt. 2. Fremgangsmåte ifølge krav l, for fremstilling av en forbindelse hvor D betyr gruppen med formel Ia, og, når A og B er en benzorest, begge substituentene Ru og/eller R12 i benzoresten står i meta-, resp. para-stilling til kondensasjonspunktene i resten A, resp. B, og hvori Ru og R12 fortrinnsvis er metoksy, where R5 is hydrogen, Rx, R2, R3, R6, R7, Rn and R12 are as defined above, Ar means phenyl or thienyl and m' and n' independently of each other are 0, 1 or 2 when the associated Ar group is phenyl, and 0 when the associated Ar group is thienyl; is condensed in the presence of a condensing agent without isolating the intermediate of the general formula (II); C. (for the preparation of a compound of formula I, where D is the group of formula Ib), a compound III where R'5 is hydrogen, Rx, R2, R3 and Ru are as defined above, Ar means phenyl or thienyl and rn ' means 0, 1 or 2 when Ar is phenyl, and 0 when Ar is thienyl, is condensed in the presence of a condensing agent; optionally followed by one or more of the following treatments: alkylation of a compound (I) in which R5, respectively R'5, is hydrogen, to a compound (I) in which R5, respectively R'5, is (Ci-CJ alkyl; hydroxymethylation of a compound (I) where D constitutes the group of formula Ia and R 5 is hydrogen, to a compound where R 5 is hydroxymethylene; isolation of the free compound (I) from its salt; reaction of a compound (I) to its pharmaceutically acceptable salt 2. Process according to claim 1, for the preparation of a compound where D means the group with formula Ia, and, when A and B are a benzo residue, both substituents Ru and/or R 12 in the benzo residue are in the meta or para position to the condensation points in the residue A, respectively B, and in which Ru and R12 are preferably methoxy,

karakterisert ved anvendelse av tilsvarende characterized by the application of the equivalent

utgangsforbindelser. output connections.

3. Fremgangsmåte ifølge krav 1, for fremstilling av 1-(3,4-dihydro-6,7-dimetoksykinolin-l-yl)-1-(3,4-dihydro-6,7-dimetoksy-isokinolin-l-yliden)-etan eller et fysiologisk akseptabelt salt derav, karakterisert ved anvendelse av tilsvarende utgangsforbindelser. 4. Fremgangsmåte ifølge krav 1, for fremstilling av en forbindelse valgt fra morfolinokarbonylmetyl- 6,7-dimetoksy-3,4-dihydro-isokinolin, 6,7-dimetoksy-3,4-dihydro-isokinolineddiksyremetylamid, 6,7-dimetoksy-3,4-dihydro-isokinolineddiksyredietylaraid og 6,7-dimetoksy-3,4-dihydro-isokinolineddiksyrefenyletylamid, karakterisert ved anvendelse av tilsvarende utgangsforbindelser. 5. Fremgangsmåte ifølge krav 1, for fremstilling av en forbindelse med en av de følgende formler 3. Process according to claim 1, for the production of 1-(3,4-dihydro-6,7-dimethoxyquinolin-1-yl)-1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-ylidene )-ethane or a physiologically acceptable salt thereof, characterized by the use of corresponding output connections. 4. Process according to claim 1, for the preparation of a compound selected from morpholinocarbonylmethyl-6,7-dimethoxy-3,4-dihydro-isoquinoline, 6,7-dimethoxy-3,4-dihydro-isoquinolineacetic acid methylamide, 6,7-dimethoxy- 3,4-dihydro-isoquinolineacetic acid diethylamide and 6,7-dimethoxy-3,4-dihydro-isoquinolineacetic acid phenylethylamide, characterized using corresponding starting compounds. 5. Method according to claim 1, for producing a compound with one of the following formulas

karakterisert ved anvendelse av tilsvarende utgangsforbindelser. characterized by the use of corresponding output connections.

NO881759A 1987-04-24 1988-04-22 Analogous Process for the Preparation of Therapeutically Active Benzo and Thieno-3,4-Dihydropyridine Derivatives NO174548C (en)

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DE3827727A1 (en) * 1988-08-16 1990-02-22 Boehringer Ingelheim Kg ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE OF SUCH CONNECTIONS FOR CARDIRO PROTECTION
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DE9017900U1 (en) * 1990-12-22 1993-01-28 Boehringer Ingelheim Kg, 6507 Ingelheim, De
DE4104257A1 (en) * 1991-02-13 1992-08-20 Boehringer Ingelheim Kg USE OF ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL ILLNESSES
DE59305890D1 (en) * 1992-06-22 1997-04-24 Boehringer Ingelheim Kg USE OF CONDENSED BIS- (3,4-DIHYDRO-PYRIDINYL) METHANE FOR THE TREATMENT OF MORBUS CROHN, COLITIS ULCEROSA, CHRONICALLY INFLAMMATORY PROCESSES AND AS AN ANTIPROLIFERATIVE AGENTS
US5643919A (en) * 1992-06-22 1997-07-01 Boehringer Ingelheim Kg Anellated dihydropyridines and the use thereof for the production of pharmaceutical preparation
CA2138788A1 (en) * 1992-06-22 1994-01-06 Dietrich Arndts Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions
CN1056832C (en) * 1992-06-22 2000-09-27 贝林格尔·英格海姆公司 Carbocyclic and heterocyclic annelleted dihydropyridine and application of same in preparation of pharmaceutical
CN1138324A (en) * 1993-12-21 1996-12-18 贝林格尔·英格海姆公司 Anellated dihydropyridines and their use in the production of pharmaceutical preparations
DE4343683A1 (en) * 1993-12-21 1995-06-22 Boehringer Ingelheim Kg Anellated dihydropyridines and their use for the preparation of pharmaceutical preparations
RU2665688C2 (en) * 2013-04-12 2018-09-04 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Dicarboxylic acid bisamide derivatives, their application, the pharmaceutical composition on their basis, methods for their production

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3007710C2 (en) * 1980-02-29 1982-04-15 Gödecke AG, 1000 Berlin 5,6; 8,9-Tetrahydro-7H-dibenz (d, f) azonine derivatives, processes for their preparation and pharmaceuticals
DE3013906A1 (en) * 1980-04-11 1981-10-15 C.H. Boehringer Sohn, 6507 Ingelheim SUBSTITUTED (ALPHA) -AMINOCARBONYL-L-BENZYL-3,4-DIHYDRO-ISOCHINOLINE, METHOD FOR THE PRODUCTION AND USE THEREOF
EP0198227A3 (en) * 1985-03-20 1988-01-13 Boehringer Ingelheim Kg Imidazo-isoquinoline and imidazo-thienopyridine compounds, medicaments containing them and process for their preparation
DE3621413A1 (en) * 1986-06-26 1988-01-07 Boehringer Ingelheim Kg USE OF CARBOCYCLIC AND HETEROCYCLICALLY FURNISHED DIHYDROPYRIDINE AS A CARDIOPROTECTIVE AGENT AND NEW HETEROCYCLIC AND CARBOCYCLICALLY FURNISHED DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND ITS ADDITIONAL PRODUCTS

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FI881889A0 (en) 1988-04-22
FI91750B (en) 1994-04-29
PL160019B1 (en) 1993-01-29
NO881759L (en) 1988-10-25
JPS63280069A (en) 1988-11-17
FI881889A (en) 1988-10-25
PL271963A1 (en) 1989-06-12
DE3850437D1 (en) 1994-08-04
AU609121B2 (en) 1991-04-26
IL86131A0 (en) 1988-11-15
CA1330798C (en) 1994-07-19
PT87300A (en) 1988-05-01
PT87300B (en) 1992-08-31
ATE107921T1 (en) 1994-07-15
EP0288048A3 (en) 1990-06-13
HU208673B (en) 1993-12-28
EP0288048A2 (en) 1988-10-26
YU80488A (en) 1990-04-30
DK219488D0 (en) 1988-04-22
JP2669468B2 (en) 1997-10-27
NO174548C (en) 1994-05-25
FI91750C (en) 1994-08-10
HUT47915A (en) 1989-04-28
EP0288048B1 (en) 1994-06-29
ES2055717T3 (en) 1994-09-01
NO881759D0 (en) 1988-04-22
AU1509088A (en) 1988-10-27
DK219488A (en) 1988-10-25
KR880012594A (en) 1988-11-28

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