IE45850B1 - Pyrimido (6,1-a) isoquinolin-4-one derivatives - Google Patents

Pyrimido (6,1-a) isoquinolin-4-one derivatives

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Publication number
IE45850B1
IE45850B1 IE2498/77A IE249877A IE45850B1 IE 45850 B1 IE45850 B1 IE 45850B1 IE 2498/77 A IE2498/77 A IE 2498/77A IE 249877 A IE249877 A IE 249877A IE 45850 B1 IE45850 B1 IE 45850B1
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compound
formula
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pyrimido
alkyl
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IE2498/77A
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IE45850L (en
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Hoechst Ag
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Priority claimed from IN433/BOM/76A external-priority patent/IN147624B/en
Priority claimed from DE19772720085 external-priority patent/DE2720085A1/en
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of IE45850L publication Critical patent/IE45850L/en
Publication of IE45850B1 publication Critical patent/IE45850B1/en

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    • 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
    • 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
    • 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
    • C07D491/12—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 three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

HOE 77/F 091 PYRIMIDO (6,1-a)ISOQUINOLIN-4-ONE DERIVATIVES of the disclosure: A novel class of pyrimido (6,1-a)isoquinolin-4-one derivatives, new intermediates used in their preparation and processes for the preparation of the intermediates and the compounds of the invention are described. The pyrimido(6,1-a)isouqinolin-4-one derivatives of the invention possess valuable pharmacologicla properties, for example blood pressure lowering properties, bronchodilatory properties and anti-allergic properties.

Description

This invention relates to pyrimidine derivatives, to intermediates used in their preparation and to processes for the preparation of the intermediates and the compounds of the invention.
The present invention provides pyrimido(6,1-a) isoquino lin-4-one derivatives of the general formula I each stands for a hydrogen atom, a hydroxy, alkoxy, dialkyl10 '* phosphinylalkoxy, or acyloxy group, or a halogen atom, and 14 5 two of the radicals R , R and R when in adjacent positions together may form a methylenedioxy or an ethylenedioxy group; 2 3 R and R , which may be the same or different, each stands for a hydrogen atom, a hydroxy, alkoxy, amino, alkylamino, dialkylamino, or arylamino group, or an amino or alkyl group - 3 substituted by a 5- or 6-membered* ring containing up to 3 hetero atoms, which may be the same or different, selected from nitrogen, oxygen and sulphur atoms, or an alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl, halogenoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkyl, dialkylphosphinylalkyl, acyl or optionally substituted aryl group, aryl denoting an aromatic hydrocarbon radical having up to 10 carbon atoms, a heterocyclic radical, prefer2 ably as defined above, or R represents a pair of electrons 2 if R stands for one of the radicals defined below, or R 3 and R when taken together with the nitrogen atom to which they are bound may form an optionally substituted nitrogen containing heterocycle which may contain a further nitrogen or oxygen atom; and R6 stands for a hydrogen atom or an alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl, halogenoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkyl, heterocyclically substituted alkyl, dialkylphosphinylalkyl, acyl or optionally substituted aryl group, .,.2 or R represents a pair of electrons if R represents one of the radicals defined above; and the acid addition salts and quaternary ammonium salts thereof.
In the case when at least one of the two radicals R 3 and R represents a hydrogen atom, the above definition of the pyrimido(6,1-2)isoquinolin-4-one derivatives also en25 compasses the isomers of the following formula Xb, which may be obtained, by complete isomerization of the corresponding compound of formula Ia or which is in equilibrium with the corresponding compound of formula Ia.
The definition of the pyrimido(6,1-a)isoquinolin-4-one derivatives of the invention also encompasses the isomer of formula Ic having up to 3 carbon atoms are preferred 4S8S0 s Preferred agylojfy radicals R , R and/or R are those in which the acyl group is a linear or branched c.—c. o alkanoyl group, for example an acetyl group, or an aroyl group, especially a benzoyl group, in which the phenyl nucleus may be substituted one to three times by the same or different substituents selected from halogen atoms, nitro, hydroxy, alkoxy and —c3 alkyl groups.
If R , R and/or R stands for a halogen atom, chlorine is preferred.
A dialkylphosphinylalkoxy radical R , R and/or R is preferably one in which the alkyl and alkoxy moieties each contains at most 6, advantageously up to 3 carbon atoms, for example dimethylphosphinylmethoxy.
Preferred alkylamino and dialkylamio radicals for R and/or R are those in which the alkyl groups have at most 3 carbon atoms, for example, methylamino or dimethylamino. 3 Preferred arylamino radicals R and/or R are phenylamino radicals in which the phenyl residue may be substituted one or several times by the same or different substituents selected from halogen atoms, for example, chlorine, alkyl groups, for example methyl, and nitro groups. A suit2 able nitrogen-containing heterocyclic-ammo radical for R 3 or R is, for example, an N-morpholinoamino radical. 3 6 An alkyl radical R , R and/or R is especially one 25 having at most 6 carbon atoms, for example a methyl, ethyl, n-propyl, isopropyl, butyl, iscibutyl, see.butyl or tert, butyl radical. 3 6 A cyeloalkyl radical R , R and/or R is preferably one having at most 6 carbon atoms, for example, cyclohexyl. 3 6 · If R , R and/or R represents a substituted alkyl radical this is, for example, an alkyl group having up to 6 carbon atoms and substituted by one or two hydroxy or —C3 alkoxy groups, halogen atoms, for example chlorine, amino Or di(C^—alkyl)amino groups or dialkylphosphinylalkyl groups, for example dimethylphosphinylmethyl. 3 6 Examples of aralkyl radicals R , R and/or R are those having at most 8 carbon atoms, in which the aryl radical may be mono- or polysubstituted, especially substituted one, two, or three times by the substituents defined above for r\ 3 6 Heterocyclic-alkyl radicals R , R and/or R are, for example, furfuryl and tetrahydrofurfuryl radicals. 3 6 Examples of aryl radicals R , R and/or R are phenyl radicals optionally substituted one or several times, prefer15 ably one, two or three times, by the same or different substituents selected from halogen atoms, for example fluorine, chlorine and bromine atoms, C.—C. alkyl and C—C alkoxy X J X J groups, for example methyl, ethyl, methoxy and ethoxy groups, halogenoalkyl.· groups, for example, trifluoromethyl groups, amino and hydroxy groups, in the latter the hydrogen atom optionally being replaced by an alkali metal atom, for example, a sodium atom.
A nitrogen-containing heterocyclic radical is, for example, a pyrrolidino, piperidino, morpholino, or piperazino radical, which may be substituted by one or more substituents selected from alkyl, alkoxy-carbonyl, aryl, and nitrogen containing heterocyclic radicals, the terms alkyl, alkoxy, aryl and nitrogen-containing heterocycle preferably having the above preferred meanings. 3 6 Examples of acyl radicals for R , R and/or R are linear and branched C—C alkanoyl radicals, for example, acetyl radicals, and aroyl for example, benzoyl radicals, wherein the phenyl residue may be substituted one or several 2 3 6 times by the substituents defined above for R , R and/or R when they represent an aryl radical.
As salts of the pyrimido(6,1-a)isoquinolin-4-one derivatives of the invention there are mentioned by way of example those of inorganic or organic acids, for example, the hydrochlorides, hydrobromides, sulphates, phosphates, acetates, oxalates, tartrates, citrates, maleates, and fumarates.
Suitable quaternary ammonium salts of the pyrimido(6,1-a) isoquinolin-4-one derivatives of the invention are, for example, the salts derived from alkyl halides, for example, methiodides.
Preferred meanings for R1 to R6 are: alkoxy for R1 and 4 5 R , hydrogen for R , C,—C. alkyl or phenyl optionally subX o 2 stituted one to three times as defined above for R , hydrogen, C,—Cc alkyl, cycloalkyl, substituted alkyl, aralkyl, hetero3 cyclic alkyl, substituted aryl and C—alkanoyl for R and R6. 1 θ Particularly preferred compounds of the invention are: 9,10 - dimethoxy - 2 - tert - butylamino - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one hydrochloride, 9,10 - dimethoxy - 2 - sec - butylamino - 6,7 - dihydro4H - pyrimido(6,1-a)isoquinolin - 4 - one hydrochloride, 9,10 - dimethoxy - 2 - (2,6 - dimethylanilino) - 6,7dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one, 9,10 - dimethoxy - 2 - (2,4 - dimethylanilino) - 6,745850 - θ % dihydro - 4Η - pyrimido(6,1-a)isoquinolin - 4 - one, 9,10 - dimethoxy - 2 - (2 - chloroanilino) - 6,7dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one hydrochloride mdnohydrate, 9,10 - dimethoxy - 2 - (2,4,6 - trimethylanilino) 6.7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one hydrochloride dihydrate, 9,10 - dimethoxy - 3 - methyl - 2 - mesitylimino2.3.6.7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one hydrochloride, 9,10 - dimethoxy - 3 - acetyl - 2 - mesitylimino2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one, 9,10 - dimethoxy - 2 - (N - methyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one hydrochloride, . 9,10 - dimethoxy - 2 - (N - isopropyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one, 9,10 - dimethoxy - 3 - isopropyl - 2 - mesitylimino2.3.6.7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one, 9,10 - dimethoxy - 2 - (N - ethyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one, 9,10 - dimethojy - 3 - ethyl - 2 - mesitylimino3.4.6.7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one 9,10 - dimethoxy - 2 - (Ν - acetyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one.
In the following Table I there are listed some of the pyrimido(6,1-a)isoquinolin-4-one derivatives of the invention. 438 50 - 10 +J fi —H U 0 0 a — tn +i fi H •H IB +1 0) rH φ MH 6 O CO <0 co i-H Cl m I ci 1 kO kO co CM Cl TABLE fl r-1 ti CO β Ο M *—· am o o cn φ β 43 •rl fl Q) fl n rH m ti 2 θ A ε pH a rH + m K ίβ Cl Cl Cl Cl «—. n n ΓΌ D a y a y a y o K—* o •m· o o O o o r-H rH i-H r-H ·» ch cn Ch σι os a a a - 11 Ρ C +> fi ~ •rt □ 00 a*-* tn -p fi rt •rl flj +) (0 l's (fl ω irt · Γ- Γ- irt m in · in 00 IX Ο m co cn OJ Qi CO rt £ oi rt , , F . OJ § rrt I o 1 β I u | I , L 1 1 a 1 σ> qj in o o 00 Φ cn Γ*. IQ 0 cn 00 cn rrt »0 cn rrt Ol OJ irt OJ OJ ι—1 o o OJ CM ffl ffl , irt o rt I rt 1 rt 1 I 1 rt I rrt rt w □ U U □ y y Ol w 1 ffi 1 ffi 1 1 1 ffi 1 tfi ffi melting point M r-. M-l □ irt in O o m o o rf r* σι CM 0Ί cn IQ ϋ . T I irt . f 1 irt I I 1 rfi •Ρ Φ IQ t 1 1 1 cn 1 1 1 i 1 Γ- 1 m 1 1 r* 1 1 M-l fd cn o· co rrt <£> on tn Ο Λ OI rt rrt OJ OJ rrt cn ω ffi 8 Ol u 0 z-w cn CO OJ CM cn cn cn ffi ffi ffi 8 ffi ffi OJ ffi cn m o a 8 O O 8 U <—% a ffi 8 s x OJ OJ OJ CM cn OJ OJ cn '-Z’ □ o (*) Z ffl ffi ffi S3 ffi ffi ffi ffi ffi OJ OJ ti 1 I o 8 O a O U a o u ffi ffi I J cn OJ OJ OI CM ω OJ OJ OJ OJ cn ϋ cn o X / ffi ffi ffi K ffl ffi ffi ffi ffl ffi ffi ffi ffi ffiXJzZ a U 8 O u υ U 8 u u u U- •0 □—o CM pj m co IS w u o n CM CM S ffi s ϋ u o ffl CM CM CM ’ ffi ffi ffi ffi „ ffiffiffiUUQUffiffi ffi OJ Ol OJ Ol Ol Ol Ol OJ OJ Ol OJ z—s z-> z~x z··» Z—·» z<—» cn cn cn cn cn cn cn cn OJ m cn cn ffi κ ffi ffi ffi as z-s ffi ffi ffi rf 8 8 y a a y y y ffi y δ y ffi Q ¢5 o o o o 0 o o o 0 o j. —z> «-Ζ» »>wZ *-z — s_z SZ T rrt o o o o o o O o o o o o ffi rt rrt rrt irt rrt rt rt rt rrt rt rt rt «I - ffi * * * * <· * * cn cn cn σι OI cn σ σι cn σι cn σι ffiffiffiffiffiffiffiffiffiffi ffi μ G *—» •rt U 00 o in O «Φ 10 o CO • ft'-' o cp r- CQ o in *Φ & cn rrt 91 91 91 rrt cq ε tp μ I | ί 0 G irt 1 1 1 1 1 1 Γ- 1 0 •rt Rj o cn in CQ in co 0) μ ra σ» cn 10 CM O rrt <φ Ό rrt CQ irt CM CQ CQ CQ s_z irt m cq <Η Ο m CQ Ιβ CO JJ C CD rl M — Οι Ή U Ol φ — C Λ rl JJ φ JJ ra rJ MJ « a ο λ rrt as rrt o 0 CQ tU • rrt u rrt tu rrt ί frt o CQ o □ tU tu 1 tu in • «Φ in r* (rt Qi O in co φ 6 , . 91 , trt rrt O | 1 I 1 0 I II II 1 1 1 m Φ cn co O Ό O in 10 cn sm* CQ irt irt CQ in tU CQ Ο nO m u tU ffl tU W ϋ—ϋ ϋ—ο w Sm* rrt tu tu B u cn m ω 3 u o o o z—s z—» »-x CQ CQ CM CM CN B cn cn cn tu tu ffi tu B U SU tu B u □ U u □ CM u u U CM CM CM CQ CN B tu tu tu tu B υ υ o υ υ υ υ υ υ CQ 05 B tu B tu tu B tu tu tu B B tu° υ CQ CM CQ CM CQ CQ CQ Z-X Z—S. z—·» z—» z—·» CN cn CN cn cn m cn cn cn B B tu m B B B B 2 S’ 2 o □ a 2 2 O O o o o o o o o 05 sy Sm* Sm* o O o o o o o o 0 rrt irt irt irt irt irt irt irt ι—1 rrt 05 '« w s. s B s s· s B B - * CP CP CP CP cn CN CP CP CP CN CN CP cn \· cn tu tu a U P in sJ 1 rrt · I rrt 05 tu irt B B irt & B B B B B B - 13 melting point melting point . . _ , of the free of salt R +R4 RZ R3 base (°C) Salt (°C) 1O(OCH ) - HCl 233—235 G •fc u 0 0 Ch'-* r* ro co in Cn «Ρ ro vo i—I in G «fc oi oj ifc •fc rt •P CO 1 1 I 1 1 rfc ro in ro 1 0 ro VO «fc in OJ OJ OJ «fc +1 C O ta •μ rfc (tf w •P C 0) •fc Φ O fc ~ Ch M-l U O Οι φ *-* G 43 •fc -Ρ Φ P W fc ΨΙ rt Φ Ο Λ «fc u w (O co (fc «fc CM o CM CM GOG( \ / v / CF OJ OJ OJ OJ Ol s. . 0 co co co co ro ffl ffl ffl ffl ffl c 8 8 8 8 8 s •m· taX o o o o o q «fc rfc rfc «fc ifc o a » ifc ω cn 01 ω 01 •b 01 - 15 . , - , of the free melting point RL+R4 R2 R base (°C) Salt of salt (°C) 03 OL ΰ O o LO O Γ Γ Γ 7 i, I co λ o o o <*) OL 03 OL w ffl ffi 03 03 03 03 »·>. *—> ro i*L m OL ffl O s g ffl y O o £ o •w* O o O o rrt rrt rrt rM »« K K OL OL OL OL ffi ffi ffi ffl 43850 - 16 +> fi •rt ϋ οο a*- tn -ρ fi rrt •rt fij •P tQ So +i rrt (ti w •P fi •rt Φ a 9) M Ή □ tn o C (U •rt £3 © © CN rt x CN X ω CN +> +J Φ ( rrt ra rt •P ΰ cti © fi B 0 rQ CN 0 X © CN CN X CN © n CN a ca g ffl + ffl ffl ffl ffl CN CN CN CN cn cn cn cn ffl B ffl ffl 8 8 8 8 o o o o irt jrt irt rrt κ k © © © © - 17 melting point of the free melting point r +R R2 R base (°C) Salt of salt (°C) 45830 ft CJ ,-' •rt U OO C- ft co rt tnft | | d rt 1 I •rt (tf + 01 in rt co ffl Ή rt Jo ft rt rt co 1 ΰ a ί 1 ft d •rt Q} 0 rt ft M ft u LO 1—I co tn 0 c· in ro Cj φ *—' 21 •rt X ft ft rt 1 1 rt rt O in rt ft rt r> in m B 0 X ci Cl ci +J a o υ rt U n ffl •p Cl ffl ffl + ffl ffl ffl ffl Cl · Cl Cl <*» O CI f*l ro I*) ffi ffi ffi CI 8 8 u o ffl u o o o O rt rt rt Ο» d σ» σ> rt cn in _ ffl ffl ffl ffl ffl - 19 meIting point , of the free melting point R^+r R R base (°C) Salt of salt (°C) CM co i-l cn O rH cn 6 Cl Cl s s Cl d 8 8 ci X—» Cl o co x—* N K JH a 8 a o 8 o o o rH rH rH * * cn cn lO(OC0CH ) CH CH CH CH„CH„CH 1O1-103 «μ β Ο Ο μ β *> •π α ο ο 0^ tp «μ β rH •ri ti •μ ra »ri 0) Ή Β Ο +J rH ti w 4J β •ri OJ 0 Φ & μ ~ O MH □ fO &Ϊ 0 CM β Φ | •ri J3 1 μ •μ Φ ω pH ra CM SI MH ti CM £ 0 Λ in rH P- σι Φ Γ T Γ A 00 J) σι co σι 03 03 CM o O Ol 03 tf tf rH , , υ as rH rH a u tf ffl tf .+ M · o rH * σι § melting point 45830 - 22 +J c ~ •h u 00 Ih'b< +J ΰ <-< •H (8 +> ra ti co •P fi •rl 0 Φ 0 0 α fi —. CO © Mrt □ X © tn 0 rl rrt fi Φ — I I •rl £3 1 1 •Ρ •Ρ Φ X rt rl ω X © 1 rrt rrt 4J fi υ ffl g B U g70\ m Β Ο σι Β r os + Β ·«/ ο r·I § Ν·Ζ Ο rrt - 23 In the following table Ia are listed pyrimido(6,1-a)isoquinolin-2-one derivatives according to the invention the structure Of which corresponds to that of isomer Ic. The melting points of the free bases or of the salts are likewise indicated. +> d »—» •π □ 00 ft'-' o CJ tJL ft o Cl d rt rt rt ft co Γ T rt co rt rt ft OL ci g 0 1“I Cl ft H rt rt ro rt □ ffl CQ ffl a ffl Cl Γ0 ffl + in ffl Ο rt 0? OL ffl ffl TABLE Ia (cont. 43850 - 26 meIting point .., _ of the free melting point R +R R R bases (°C) Salt of salt (°C) 121-021 εΗ>·ε?Η3)-π- £HO 2{EHOO)OI'6 - 27 The present invention also provides novel intermediates and their salts suitable for the preparation of the pyrimido(6,1-a)isoquinolin-2-one derivatives of the invention. The intermediates have the formulae III and IV (III) (IV) in which r\ R4, R5 and R6 have the above meanings, X represents an oxygen or sulphur atom and Y represents a halogen atom, for example chlorine, or an alkoxy or alkylthio group, alkoxy and alkyl having the meanings given earlier in this text, with the exception of the compound of formula III in which R^, R4 and R^ are all hydrogen atoms and X is an oxygen atom (cf. L. Capuano and K. Mueller, Chem. Ber. 108 1541 (1975)).
Intermediates of formulae III and IV are listed in Table II, which also includes the melting points of these compounds. 45830 - 28 - rW R5 TABLE R6 II X Y melting point (°C) 2H H H 0 - 260°C 2H H H s - - 2H H - - Cl 179—180° 9,1O(OCH3)2 H H 0 - 323—325° 9,1O(OCH3)2 H H s - 236—237° 9,1O(OCH3)2 H - - SCH3 203—205° 9,1O(OCH3)2 H - - Cl 235—236° 9,1O(OCH3)2 H - - OBu 158—159° 9,10(OH) 2 H H 0 - >260° 9,1O(OCH3)2 11—och3 H 0 - 215—218° 9,10(OCH3)2 11—och3 - - Cl 176—178° H, 10—Cl Η H 0 - >250° H, 10—Cl H - - ci >250° 9,1O(OCH3)2 H CH3 0 - 260—262° 9,1O(OCH3)2 H c» s - 230—231° 9,io(och3)2 H ch(ch3)2 0 - 190—192° The present invention further provides a process 20 for the preparation of the intermediates of formula III in which X is an oxygen atom, which comprises reacting a compound of formula V 4S850 - 29 14 5 6 in which R , R , R and R have the aforesaid meanings with a compound of the formula R' X in which X represents an oxygen atom, R' and Rn', which may be the same or different, each represents a halogen atom or an amino or alkoxy group, or R' is alkoxy and R is a halogen atom.
This reaction may be carried out according to known methods (cf. Shaw + Wooley, J. Biol. Chem. 181, 89 (1949); A. Dornow + D. Wille, Chem. Ber. 98.? 1505 (1965)). As an alkyl halogenoformate, ethyl chloroformate and as a dialkyl carbonate, diethyl carbonate may be used. The preferred base for the reaction is an alkali metal alkoxide, for example, sodium methylate, sodium ethylate, potassium methylate, or potassium ethylate, an alkali metal hydride, for example sodium hydride, or an organic base, for example an alkyl amine, for example, triethylamine. The reaction may be carried out in a non-polar or a polar solvent, for example, an aromatic hydrocarbon for example, benzene, toluene, or xylene, an alkanol having from 1 to 6 carbon atoms, for example, methanol or ethanol, an ether, for example dioxane or tetrahydrofuran, or another solvent, for example, dimethylsulphoxide, dimethylformamide or hexamethylphosphortriamide. The reaction can be accelerated or completed by the application of heat, for example, by heating to the boiling point of the solvent.
The present invention also provides a process for the preparation of an intermediate of formula III in which '45850 X is an oxygen atom and R has the above meaning, which comprises alkylating or acylating a compound of formula θ III in which X is an oxygen atom and R stands for a hydrogen atom.
The present invention additionally provides a process for preparing an intermediate of formula III in which X is a sulphur atom, which comprises converting a compound of formula III in which X is an oxygen atom to the desired compound, for example, by treatment with an inorganic sulphide.
. The present invention further provides a process for the preparation of an intermediate of formula III in which X is a sulphur atom and R stands for an acyl group, which comprises acylating a compound of formula III in which X θ is a sulphur atom and R stahds for a hydrogen atom.
. The present invention provides a process for preparing an intermediate of formula IV in which Y is a halogen atom, which comprises converting a compound of formula III in which X is an oxygen atom into the desired compound, for example, with an inorganic halide.
The present invention further provides a process for preparing an intermediate of formula IV in which Y is an alkoxy group, preferably, having at most 6 carbon atoms, which comprises alkoxylating a compound of formula IV in which Y stands for a halogen atom, preferably chlorine, for example, by treatment with an alkali metal alcoholate.
An intermediate of formula IV in which Y is an alkoxy group, preferably having at most 6 carbon atoms, may also be prepared by a different process according to - 31 which a compound of formula III in which X ia an oxygen atom is reacted with a trialkyloxonium fluoroborate, for example triethyloxonium fluoroborate. The reaction may be carried out in the presence of a solvent, for example a halogenated aliphatic hydrocarbon, for example dichloromethane.
An intermediate of formula IV in which Y is an alkylthio group may be prepared by alkylating a compound of formula III in which X is a sulphur atom, for example, with an alkyl halide, for example methyl iodide.
The compounds of formula V may be prepared by known methods (cf, C.A. 64, 6627, (1966); Hoffmann La Roche + Co. AG., Netherlands Patent Specification No. 6,401,827, 27th August, 1965). θ A starting compound of formula V in which R is a hydrogen atom may also be prepared by the following process, which comprises treating a compound of formula VI appropriate acid, for example, formic acid, trifluoroacetic acid or polyphosphoric acid. The reaction can be accelerated or completed by heating, for example, to 80 to 150°C. - 32 The compounds of formula VI can be prepared by known methods (cf. C.A. 64, 6627 (1966), Hoffmann La Roche + Co. AG., Netherlands Patent Specification No. 6,401,827, 27th August, 1965; K. Harsanyi, K. Takaes, E. Bendeh + A.
Neszmelyi, Liebigs Ann. Chem. 1606 (1973).
The present invention provides a process for preparing a pyrimido(6,1-a)isoquinolin-4-one derivative of formula I and salts thereof, which comprises reacting a compound of formula III or IV in which r\ R4, RR and R^ have the meanings given for formula I and X and Y are as defined for formulae III and IV, with a compound of the formula HN 3 in which R and R have the aforesaid meaning, with the proviso, however, that they do not represent acyl groups, preferably in the presence of a base and, if desired, acylating the resulting compound. The compound of the formula R' z itself can be used as the base, in which case it is added in excess of that required for the reaction, or the base may be an alkali metal hydride, for example sodium hydride, a tertiary amine, for example triethyl amine, or an acid acceptor, for example diazabieyclononene. The reaction may be carried out in the presence of a polar solvent for example, dimethylformamide, dimethyl sulphoxide, a halogenated - 33 aliphatic hydrocarbon, for example chloroform, or an alkanol, for example butanol, or in the presence of an aprotic solvent, for example, a high boiling ether, for example, diethylene glycol dimethyl ether. The reaction may be accelerated or completed by the application of heat, for example, by heating to the boiling point of any solvent used.
A. further, optional step is the conversion of a resulresulting ting free base into a salt or a / salt into the free base. 6 A compound of formula I xn whxch exther R or R represents an alkyl, cycloalkyl, substituted alkyl, aryl, aralkyl, or heterocyclic alkyl group as defined above can be prepared 2 6 from a compound of formula I in which either R or R is a hydrogen atom by treatment in the presence of a base or of a 2 6 2 salt, with a halide of the formula R X or R X in which R θ and R are as defined above, and X is a halogen, for example, 2 6 chlorine bromine or iodine. If R or R represents a phenyl radical, the phenyl nucleus should carry appropriate substituents in order that the halide has a sufficient reactivity. The preferred bases are alkali metal carbonates, for example potassium carbonate, alkali metal hydrides, for example sodium hydride, tertiary amines, such as triethylamine, and acid scavengers, for example, diazabicyclononene. The preferred salts are metal fluorides, for example potassium fluoride. The reaction may be carried out in the presence of a polar solvent, for exanple dimethylformamide or dimethyl sulphoxide, a halogenated aliphatic hydrocarbon, for example, chloroform, or a ketone for example, acetone, or in the presence of an aprotic solvent, for example a high boiling point ether, for example, diethylene glycol dimethyl ether. The reaction can be - 34 accelerated or completed by the application of heat, for example by heating to the boiling point of the solvent.
This process is especially suitable for transforming a com2 6 pound of formula I, in which either R or R denotes a 3 hydrogen atom and R an aryl radical, into the corresponding 2 6 compound of formula I in which either R or R denotes an 3 alkyl or substituted alkyl group and R stands for an aryl radical.
The process described in the preceding paragraph may lead to quaternary ammonium salts of the isomers of formula I. Alternatively, a resulting free base of formula I can be transformed into a quaternary ammonium salt or an acid addition salt.
A compound of formula I in which R2 or R6 stands for an acyl radical can be prepared from a compound of formula 2 3 6 I in which at least one of the radicals R , R and R represents a hydrogen atom by a treatment with an acyl halide or acyl anhydride in which the acyl radical is preferably an alkanoyl group having at most 6 carbon atoms; for example acetyl, or an aroyl group, for example benzoyl, in which the phenyl nucleus can be substituted as defined above, and the halogen may be chlorine. The reaction may be carried out in the presence of a base, for example ah alkali metal carbonate, for example, potassium carbonate, or a tertiary amine, for example, triethylamine. The reaction can be accelerated by heating to the boiling point of the acylating agent. Again, a resulting salt may be cohverted into the free base or a resulting free base into a salt. Physiologically tolerable acid addition salts are, for example, formed with the following acids: hydrochloric acid, hydrobromic acid and hydriodic acid, phosphoric acid. 4saso - 35 sulphuric acid, methylsulphuric acid, amidosulphonic acid, nitric acid, tartaric acid, lactic acid, malonic acid, fumaric acid, oxalic acid, citric acid, malic acid, mucic acid, benzoic acid, salicylic acid, aceturic acid, elribonic acid, naphthalene-l,5-disulphonic acid, ascorbic acid, phenylacetic acid, £-aminosalicylic acid, hydroxyethanesulphonic acid, benzenesulphonic acid, and synthetic resins containing acid groups, for example those having an ion exchange effect.
In both of the above procedures, if R in the starting material is a hydrogen atom, this will be substituted, too, in the same way as R or R .
The pyrimido(6,1-a)isoquinolin-2-one derivatives of the invention and their salts possess valuable pharmacological properties, for example blood pressure lowering properties as demonstrated in cats and dogs, bronchodilatory properties as demonstrated by antagonism to histamine-induced bronchoconstriction in guinea pigs and anti-allergic properties as demonstrated by the inhibition of passive cutaneous anaphylaxis (pea) in rats.
Because of their hypotensive activity, the compounds of the invention and their physiologically tolerable salts are suitable for the treatment and prevention of heart and circulatory diseases, for example essential and malignant hypertonia, heart insufficiency, Angina pectoris and disturbances of the peripheral circulation. The compounds and salts can also be used in combination with other pharmacologically active substances, for example, diuretics, anti-arrhythmic agents, β-blockers, tranquilizers, heart vasodilating agents and hypolipidemics. 8ΰθ - 36 Because of their bronchodilatory and antiallergic effect, the compounds of the invention and their physiologically tolerable salts can be used for the treatment and prevention of diseases of the respiratory system, for example, bronchial asthma, chronic bronchitis, amphysema and allergies, for example, allergic asthma, hay fever, I * allergic rhinitis and conjunctivitis urticaria. The compounds and salts can also be used in combination with other pharmacologically active substances, for example, corticosteroids, sympathomimetios, xanthine derivatives, antihistamines, tranquilizers, and cardiac stimulants.
The compounds of the invention and their physiologically tolerable salts can be administered perorally, parenterally (intramuscularly, intravenously, subcutaneously) rectally, or topically, optionally in the form of an aerosol.
The following doses are used in mammals, particularly man: to Reduce the blood pressure: a daily dose of 0.1 to 200 mg. dosage unit 0.1 to 25 mg,· as bronchospasmolytic and antiallergic agent: a daily dose of 1 to 500 mg, dosage unit I to 100 mg.
The compounds of the invention and their physiologically tolerable salts can be administered either per se or in admixture or conjunction with a pharmaceutically suitable carrier material. For oral administration the active compounds may be admixed with the carrier and transformed into the usual form for administration, for example, tablets, push-fit capsules, aqueous alcoholic or oily suspensions or solutions. Suitable carrier materials are, for example, magnesium carbonate, milk sugar, maize starch, and magnesium stearate. The compositions can be prepared in the form of dry or moist granules. An oily carrier or solvents may be a vegetable or animal oil, for example sunflower oil or cod4S8S0 - 37 liver oil.
In emergency situations, the active compounds may be administered intravenously. To this end, a compound of the invention or a physiologically tolerable salt thereof, as far as it has sufficient solubility, is generally dissolved in one of the usual auxiliaries, which may also act as a dissolving intermediary or buffer.
The solvents for intravenous administration are, for example, water, physiological sodium chloride solution and dilute alcohols, for example, ethanol, propanediol and glycerol; furthermore sugar solutions, for example, glucose and mannitol solutions, or a mixture of two or more of the aforesaid solvents.
The pharmaceutical preparations are preferably in unit dosage form, the preferred unit doses of the active substances being given above.
The following Examples illustrate the invention.
EXAMPLE 1 6,7-Dimethoxy-l-carbamoylmethylene-l,2,3,4-tetrahydroisoquinoline Polyphosphoric acid (10.0 g) is heated to 100°C and 1.0 g of 6,7 - dimethoxy - 1 - cyanomethylene - 1,2,3,4tetrahydroisoquinoline is added under mechanical stirring. The reaction mixture is heated for 1 hour, poured into crushed ice and made basic with 30% sodium hydroxide. The mixture is extracted with chloroform and the extract dried over anhydrous sodium sulphate. The solvent is evaporated under reduced pressure to give a white solid, yield 0.7 g, mp. 156—158°C. - 38 EXAMPLE 2 9.10- Dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)-isoquinolin-2,4-dione A solution of 6,7 - dimethoxy’- 1 - carbamoylmethylene1,2,3,4 - tetrahydroisoquinoline (5.0 g) and an excess of sodium ethoxide (prepared from 12.0 g of sodium metal and 600 ml of ethanol) in ethanol is heated. To the solution 150.0 ml of diethyl carbonate is added. The reaction mixture is refluxed for an additional 2.5 hr. The solvent is removed under vacuum and the residue is acidified to give a white precipitate, yield 4.80 g. The product crystallizes from dimethylformamide, mp. 323—325°C.
EXAMPLE 3 9.10- Dimethoxy-3-methyl-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione A mixture of 9,10 - dimethoxy - 3,4,6,7 - tetrahydro2H - pyrimido - (6,1-a)isoquinolin-2,4-dione (4.11 g), oilfree sodium hydride (0.75 g) and dimethylformamide (100 ml) is heated for 15 minutes to 100°C and then cooled to room temperature. Mpthyl iodide (10 ml) is added and the reaction mixture is heated for 12 hours to 100°C. The solvent is removed under reduced pressure and the residue treated with cold water. The solid matter is filtered off and recrystallized from ethyl acetate/methylene chloride. Yield 4.0 g, melting point 260—262°C.
EXAMPLE 4 9.10- Dimethoxy-3-isopropyl-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione In a manner analogous to that of Example 3, 9,10 - dimethoxy - 3,4,6,7 - tetrahydro - 2H - pyrimido(6,1-a)isoquino· lin - 2,4 - dione is reacted with isopropyl iodide. Yield 50%; melting point 190—192°C. - 39 EXAMPLE 5 9.10- Dimethoxy-2-thio-2,3,6,7-tetrahydro-4H-pyrimido(6,1-a)isoquinolin-4-one A mixture of 9,10 - dimethoxy - 3,4,6,7 - tetrahydro2H - pyrimido(6,1-a)isoquinolin - 2,4 - dione (10.0 g) and phosphorus pentasulfide (9.0 g) in 200 ml of pyridine is refluxed for 5 hours. Pyridine is removed under pressure.
The residue is treated with dilute hydrochloric acid and then extracted with methylene chloride. The methylene chloride extract is dried over anhydrous sodium sulfate and evaporated to dryness leaving a white powder which is crystallized from chloroform-ether mixture, yield 10.0 g, m.p. 236—237°C.
EXAMPLE 6 9.10- Dimethoxy-3-methyl-2-thio-2,3,6,7-tetrahydro-4Hpyrimido(6,1-a)isoquinolin-4-one Phosphorus pentasulfide (1.0 g) is added to a solution of 9,10 - dimethyl - 3 - methyl - 3,4,6,7 - tetrahydro - 2Hpyrimido(6,1-a)isoquinolin - 2,4 - dione (0.5 g) in pyridine (10 ml). The mixture is refluxed for 15 hours, the solvent removed under reduced pressure and the residue repeatedly extracted with methylene chloride. The combined methylene chloride extracts are washed with dilute hydrochloric acid and with water, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed to yield the desired compound. Yield 0.25 g, m.p. 230—231°C.
EXAMPLE 7 9.10- Dimethoxy-2-chloro-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one A mixture of 30.0 g of 9,10 - dimethoxy - 3,4,6,7tetrahydro - 2H - pyrimido(6,1-a)isoquinolin - 2,4 - dione and 300 ml of phosphorus oxychloride is heated on a steam bath for 4 hours. The excess of phosphorus oxychloride is 43850 - 40 distilled under reduced pressure. The residue is poured into a cold solution of sodium hydroxide. A yellow solid precipitates which is collected by filtration. The product is purified by passage through a silica gel column using chloroform as eluent. Yield 28.0 g, m.p. 235—236°C.
EXAMPLE 8 9.10- Dimethoxy-2-butoxy-5,6-dihydro-4H-pyrimido (6,1-a)isoquinolin-4-one To a mixture of sodium hydroxide (1.0 g) and n-butanol (50.0 ml) is added 9,10 - dimethoxy - 6,7 - dihydro - 2chloro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one (1.46 g). The reaction mixture is refluxed for 6 hours. The solvent is removed under reduced pressure. The residue is treated with water and extracted with chloroform. The extract is dried over anhydrous Na^SO^ and evaporated to give a white solid. After crystallization from chloroform-ether mixture, 0.7 g of the title compound is obtained, m.p. 158—159°C.
EXAMPLE 9 9.10- Dimethoxy-2-ethoxy-6,7-dihydro-4H-pyrimido (6,1-a)20 isoquinolin-4-one A mixture of 3.0 g of 9,10 - dimethoxy - 3,4,6,7tetrahydro - 2H - pyrimido(6,1-a)isoquinolin - 2,4 - dione and 15.0 g of triethyloxonium fluoroborate in 100 ml of dichloromethane is stirred overnight. The reaction mixture is washed with a solution of sodium carbonate. The organic layer is separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gives the title compound, yield 1.8 g.
EXAMPLE 10 9,lO-Dimethoxy-2-methylmercapto-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one hydriodide To a suspension of 10.0 g of 9,10 - dimethoxy - 248830 - 41 thio - 2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one in 200 ml of tetrahydrofuran, 20 ml of methyliodide is added and the reaction mixture refluxed for 4 hours. A white solid precipitates and is collected by filtration. It is crystallized from chloroform-methanol mixture, yield 10.50 g, m.p. 220—225°C (dec.) EXAMPLE 11 General Procedure for the Preparation of Compounds of the General Formula I from Compounds of Formula III or IV Compound III (X=S) or any one of the compounds IV (Y=Cl, SCHy OBu) is heated with an about equimolar amount of the appropriate amine of the general formula HNR^R^.
The reaction is carried out in the presence of a base or an acid scavenger. The base is preferably the reacting amine itself, used in excess of that required for the reaction.
The reaction is also preferably carried out in the presence of a suitable solvent as defined in the text. The reaction mixture may be heated to refluxing temperatures for 2—10 hours. The solvent is evaporated under reduced pressure.
The residue is treated with water and extracted with an organic solvent. The extract is allowed to stand over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by chromatography and/or crystallized to give the desired compound, which, if desired, is converted to its salt.
EXAMPLE 12 9,10-Dimethoxy-2-tert-butylamino-6,7-dihydro-4H-pyrimido (6,1-a)isoquinolin-4-one hydrochloride A solution of 9,10 - dimethoxy - 2 - chloro - 6,7dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one (3.0 g) and tert.-butylamine (10.0 ml) in chloroform (75 ml) is - 42 heated under reflux for 16 hours. The solvent is evaporated under reduced pressure and the residue is triturated with a dilute solution of sodium hydroxide to give a white precipitate. The precipitate is filtered, dried and converted into its hydrochloride by treating it in solutioh in ethanol with hydrochloric acid. The hydrochloride is crystallized from ethanol-ether mixture,yield 3.0 g, m.p. 265—27O°C.
EXAMPLE 13 9.10- Dimethoxy-2-gec-butylamino-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one hydrochloride A solution of 9,10 - dimethoxy - 6,7 - dihydro - 2chloro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one (2.5 g) sec-butylamine (10 ml) and dimethylformamide (2 ml) is heated under reflux for 5 hours. The solvent and excess amine are distilled under reduced pressure. The residue is treated with water. A white solid precipitates and is collected by filtration. The precipitate is crystallized from methylene chloride-ether mixture, yield 2.10 g. The crystals are dissolved in dlchloromethane and treated with a solution of ethereal hydrochloric acid. The hydrochloride is crystallized from ethanol-ether mixture, m.p. 218—225°C, EXAMPLE 14 9.10- Dimethoxy-2-(2,6-dimethylanilino)-6,7-dihydro-4Hpyrimido-{6,1-a) isoquinolin-4-one A solution of 9,10 - dimethoxy - 2 - chloro - 6,7dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one (2.5 g), 2,6-dimethylaniline (5.0 ml) in butanol (20.0 ml) is heated under reflux for 10 hours. The solvent is evaporated under reduced pressure to give a gummy mass. Chromatography of the gummy mass over silica gel using benzene-ethyl acetate as eluent gives the required product. The compound is cry45850 - 43 stallized from methanol, yield 2.0 g, m.p. 297—299°C. EXAMPLE 15 9.10- Dimethoxy-2-(2,4-dimethylanilino)-6,7-dihydro-4Hpyrimido(6,1-a)isoquinolin-4-one The procedure described in Example 14 is followed by using 2,4-dimethylaniline in place of 2,6-dimethylaniline. Yield: 75%, m.p. 239—241°C.
EXAMPLE 16 9.10- Dimethoxy-2-(2-chloroanilino)-6,7-dihydro-4H-pyrimido(6,1-a)isoguinolin-4-one hydrochloride The procedure described in Example 14 is followed, using 2-chloroaniline in place of 2,6-dimethylaniline. The hydrochloride is prepared as described in Example 12. Yield 70%, m.p 162—196°C.
EXAMPLE 17 9.10- Dimethoxy-2-(2,4,6-trimethylanilino)-6,7-dihydro-4Hpyrimido(6,1-a)isoquinolin-4-one hydrochloride dihydrate The procedure described in Example 14 is followed using 2,4,6-trimethylaniline in place of 2,6-dimethylaniline. The hydrochloride is prepared as described in Example 12. Yield 70%, m.p. 167—169°C, EXAMPLE 18 9.10- Dimethoxy-3-methyl-2-mesitylimino-2,3 6,7-tetrahydro4H-pyrimido(6,1-a)isoquinolin-4-one A mixture of 9,10 - dimethoxy - 3 - methyl - 2 - thio2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one (0.1 g) and methyl iodide (2 ml) in tetrahydrofuran (10 ml) is refluxed for 2 hours. The solid matter is filtered off and heated for 3 hours at 100 to 11O°C together with 2 4,6-trimethylaniline (0.4 g). The excess trimethylaniline is removed by treating the reaction mixture with petroleum - 44 ether. The residue is worked up to give the desired compound, which is recrystallized from ethyl acetate/petroleum ether. Yield 80 mg, m.p. 151—152°C.
The same compound can also be'obtained by direct reac5 tion of 9,10 - dimethoxy - 3 - methyl - 2 - thio - 2 3,6,7tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one with 2,4,6-trimethylaniline.
EXAMPLE 19 9,10-Dimethoxy-3-methyl-2-n-butylimino-2,3 6,7-tetrahydro10 4H-pyrimido(6,1-a)isoquinolin-4-one In a manner analogus to that of Example 18 the compound is prepared from 9,10 - dimethoxy - 3 - methyl - 2thio - 3,4,6,7 - tetrahydro-4H - pyrimido(6,l-a)isoquinolin4 - one and n-butylamine. Yield 100%, m.p. 120—121°C.
EXAMPLE 20 General Procedure for the Preparation of Compounds of the Formula I from Compounds of Formulae la and lb The compound of formula Ia or lb, in which 7 preferably represents aryl is reacted, in the presence of a base, an acid scavenger, or a. salt with a halide of the formula 2 6 R X or R X. The halide can be used in equimolar amounts or in an excess. The reaction is preferably carried out in the presence of a solvent as defined above. The reaction mixture may be refluxed for 2 to 50 hours. The solvent is evaporated under reduced pressure. The residue is treated with water and extracted with an organic solvent. The extract is dried over anhydrous sodium sulfate and the filtrate is evaporated to dryness. The residue is purified by chromatography and/or recrystallized to give the desired oom30 pound which can be transformed into its salt, if desired. - 45 EXAMPLE 21 a) 9,10 - Dimethoxy - 3 - methyl - 2 - mesitylimino2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin4 - one, its hydrochloride and methiodide and b) 9,10 - Dimethoxy - 2 - (N - methyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one and its hydrochloride A suspension of 9,10 - dimethoxy - 2 - (2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)iso10 quinolin - 4 - one (3.0 g), anhydrous potassium carbonate (15.0 g) and methyl iodide (45.0 ml) in acetone (300.0 ml) is heated under reflux for 15 hours. The reaction mixture is cooled and filtered. The filtrate is concentrated under reduced pressure whereby a residue is obtained. Chromatography of the residue over silica gel using benzene-chloroform (1:1) as eluent gives the desired free bases a) 2.3 g, m.p. 151— 152°C and b) 0.15 g, m.p. 175—176°C. Further elution of the chromatography column with chloroform gives 0.35 g of the methiodide of base a) of m.p. 221—222°C. The hydro20 chlorides are prepared from the bases by the procedure described in Example 13. They are crystallized from dichloromethane/petroleum ether (b.p. 60—80°C) or diehloromethane/ ethyl acetate or ethanol/diethyl ether. M.p. of hydrochloride a) 198°—'200°C, m.p. of hydrochloride b) 189—191°C.
EXAMPLE 22 a) 9,10 - Dimethoxy - 2 - (N - isopropyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one and b) 9,10 - dimethoxy - 3 - isopropyl - 2 - mesitylimino30 2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin4 - one 9,10 - Dimethoxy - 2 - (2,4,6 - trimethylanilino)6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one - 46 (5.85 g) and dimethylformamide (30 ml) are added to oilfree sodium hydride (1.5 g). The mixture is heated for 5 minutes to 110°C and then cooled to room temperature. Isopropyl iodide (2.55 g) is added and the whole is heated to 110°C for 40 hours. After cooling, methanol is added to the reaction mixture and the solvents are removed under reduced pressure. The residue is extracted with chloroform, the extract washed with water,' dried over sodium sulfate and evaporated to dryness. The residue is chromatographed to give the bases a) m.p. 182—183°C and b) m.p. 178—179°C. EXAMPLE 23 -. Y a) 9,10 - Dimethoxy - 2 - (N - ethyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoguinolin 4 - one and b) 9,10 - d/imethoxy - 3 - ethyl.- 2 - mesitylimino - 2,3,6,7tetrahydro - 4H - pyrimido(6,1-a)isoguinolin - 4 - one Procedure A Example 22 is repeated with the exception that ethyl iodide is used instead of methyl iodide.
Procedure B 9,10 - Dimethoxy - 2 - (2,4,6 - trimethylanilino)6,7 -dihydro - 4H - pyrimido(6,1-a)isoguinolin - 4 - one (0.5 g) and potassium fluoride (0.5 g) are added to dimethylformamide (10 ml). The mixture is heated to 100°C for 1 hour and then cooled. Ethyl iodide (0.2 g) is added and the whole is heated to 100°C for 40 hours. The .solvent is removed under reduced pressure and the residue worked up as described in Example 22.
The procedures A and B yield the two isomers in diffe30 rent proportions. Free base a) m.p. 164—165°C? free base b) m.p. 142—143°C. 458 50 - 47 EXAMPLE 24 9,10-dimethoxy-2- (N-aeetyl-2,4,6-trimethylanilino)-6,7dihydro-4H-pyrimido-(6,1-a)isoquinolin-4-one To an ice-cold solution of 9,10 - dimethoxy - 2 5 (2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one (1.6 g) in chloroform (40.0 ml, is added first triethylamine (1.2 ml) and then dropwise a solution of acetyl chloride (0.64 ml) in chloroform (10.0 ml). The mixture is stirred for 2 hours. The chloroform solution is washed successively with water, sodium carbonate solution and water, and is then dried over anhydrous sodium sulfate. The solution is filtered and the filtrate evaporated to dryness in vacuo. The residue is triturated with diethyl ether to yield the desired compound in solid form.
Yield 1.6 g, m.p. 210—212°C (dichloromethane-petroleum ether b.p. 60—80°c). 4S850

Claims (31)

1. CLAIMS :1. Pyrimido(6,1-a)isoquinolin-4-one derivatives of the formula I 14 5 5 in v/hich R , R and R , which may be the same or different, each stands for a hydrogen atom, a hydroxy, alkoxy, dialkylphosphinylalkoxy, or acyloxy group, or a halogen atom, and 14 5 two of the radicals R , R and R when in adjacent positions together may form a methylenedioxy or an ethylenedioxy group; 2 3 10 R and R , which may be the same or different, each stands for a hydrogen atom, a hydroxy, alkoxy, amino, alkylamino, dialkylamino, or arylamino group, or an amino or alkyl group substituted by a 5- or 6-membered ring containing up to 3 hetero atoms, which may be the same or different, 15 selected from nitrogen, oxygen and sulphur atoms, or an alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl, halogenoalkyl, aminoaikyl, alkylaminoalkyl, dialkylaminoalkyl, aralkyl, dialkylphosphinylalkyl, acyl or optionally substituted aryl group, aryl denoting an aromatic 20 hydrocarbon radical having up to 10 carbon atoms, a hetero45850 - 49 2 6 cyclic radical, or R represents a pair of electrons if R 2. 3 stands for one of the radicals defined below, or R and R when taken together with the nitrogen atom to which they are bound may form an optionally substituted nitrogen-containing heterocycle which may contain a further nitrogen or oxygen atom; and R stands for a hydrogen atom or an alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl, halogenoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkyl, heterocyclically substituted alkyl, dialkylphosphinylalkyl, acyl or optionally substituted aryl group, or 6 2 R represents a pair of electrons if R represents one of the radicals defined above; and the acid addition salts and quaternary ammonium salts thereof.
2. A compound as claimed in claim 1, wherein a halogen 14 5 atom represented by R , R and/or R is a chlorine atom and a dialkylphosphinylalkoxy radical is one in which the alkyl and alkoxy moieties contain at most 3 carbon atoms.
3. A compound as claimed in claim 1 or claim 2, wherein 2 3 6 R , R and/or R , as appropriate represents an alkylamino or dialkylamino radical in which the alkyl groups having at most 3 carbon atoms; a phenylamino radical in which the phenyl residue is substituted one or more times, by the same or different substituents selected from halogen atoms, —C 3 alkyl groups, and nitro groups; an N-morpholinoamino radical; an alkyl group having at most 6 carbon atoms, which may be substituted by one or two hydroxy or —C 3 alkoxy groups, halogen atoms, amino or di(C^—c 4 alkyl)amino groups; - 50 a dialkylphosphinylalkyl group; a cycloalkyl group having at most 6 carbon atoms; an aralkyl group having at most 8 carbon atoms and which may be mono- or poly-substituted; 5 a furfuryl or tetrahydrofurfuryl radical; a phenyl radical optionally substituted one or several timas by the same or different substituents selected from halogen atoms, alkyl and alkoxy groups, halogenoalkyl groups, amino, hydroxy and alkali‘metaloxy groups; 10 a pyrrolidipo, piperidino, morpholino or piperazino radical which may be substituted by one or more substituents selected from alkyl, alkoxyearbonyl and aryl groups, and nitrogen-containing heterocycles; or a linear or branched, C—c, alkanoyl group, or a 1 6 15 benzoyl radical the phenyl residue of which may be substituted as defined above. 1 4
4. R compound as claimed in claim 1, wherein R and R each represents an alkoxy group; R 3 represents a hydrogen atom; 20 R represents a C,—alkyl group or a phenyl group, 1 Ό optionally substituted as defined in claim 3; and 3 6 R and R , which may be the same or different, each represents a hydrogen atom, a C.—C, alkyl group, a cyclo1 o alkyl, substituted alkyl, aralkyl, heterocyclic alkyl, sub25 stituted aryl or C—C, alkanoyl group.
5. 9,10 - Dimethoxy - 2 - tert. - butylamino -
6. ,7dihydro - 4H - pyrimido(6,1-a)isoquinoline - 4 - one hydrochloride. 9,10 - Dimethoxy - 2 - (2,4,6 - trimethylanilino)6. - 51 6.7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one hydrochloride dihydrate.
7. 9,10 - Dimethoxy - 3 - methyl - 2 - mesitylimino2.3.6.7 - tetrahydro - 2H - pyrimido(6,1-a)isoquinolin - 4one hydrochloride.
8. 9,10 - Dimethoxy - 2 - (N - methyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one hydrochloride.
9. 9,10 - Dimethoxy - 3 - isopropyl - 2 - mesitylimino2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one hydrochloride.
10. 9,10 - Dimethoxy - 2 - (N - isopropyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin - 4 - one hydrochloride.
11. 9,10 - Dimethoxy - 3 - ethyl - 2 - mesitylimino2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one hydrochloride.
12. 9,10 - Dimethoxy - 2 - (N - ethyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one hydrochloride.
13. 9,10 - Dimethoxy - 3 - acetyl - 2 - mesitylimino2,3,6,7 - tetrahydro - 4H - pyrimido(6,1-a)isoquinolin - 4one.
14. 9,10 - Dimethoxy - 2 - (N - acetyl - 2,4,6 - trimethylanilino) - 6,7 - dihydro - 4H - pyrimido(6,1-a)isoquinolin4 - one.
15. A compound as claimed in claim 1, substantially as described in Table I herein. - 52
16. A compound as claimed in claim 1, substantially as described in any one of Examples 7 to 9, 13 to 16, and 20.
17. A process for the preparation of a compound as claimed in claim 1, wherein 5 (a) a compound of formula III or IV in which r\ R^, R^ and R 6 are as defined in claim 1, X represents a sulphur atom and Y represents a halogen atom or an alkoxy or alkylthio group, is reacted with a compound 10 of the formula R 2 / HN 2 3 in which R and R are as defined in claim 1, with the proviso that they cannot represent acyl groups, and the resulting compound obtained is optionally acylated to give 2 3 the corresponding compound of formula I in which R , R or R® is acyl, or 4S8 50 - 53 (b) a compound of formula Ia or Ib 13 4 5 in which R , R , R and R are as defined in claim 1, is 2 6 2 reacted with a compound of formula R X or R X, in which R θ 5 and R each represents an alkyl, cycloalkyl, substituted alkyl, heterocyclic alkyl, aralkyl or an optionally substituted aryl group and X represents a halogen atom, or is reacted with an acyl halide or acyl anhydride, to give a 2 , 6 compound of formula I xn whxch R and/or R represents an 10 acyl group and if R in formula Ia or Ib represents a hydrogen atom, R 2 3 in formula I represents an acyl group.
18. A process as claimed in claim 17, wherexn a resulting free base is converted into an acid addition salt or a quaternary ammonium salt, or a resulting salt is converted into 15 the free base or another salt.
19. A prooess as claimed in claim 17, carried out substantially as described in any one of Examples 7 to 9 and 11 to 24.
20. A compound as claimed in claim 1, whenever produced by 20 a process as claimed in any one of claims 17 to 19. - 54
21. A compound of the formula III or IV in which 14 5 6 R , R , R and R are as defined in claim 1, 5 X represents an oxygen or sulphur atom and Y represents a halogen atom or an alkoxy or alkylthio group, with the exception of the compound of formula III in which R 1 , R 4 » R 5 and R 6 are all hydrogen atoms and X is an oxygen atom. 10
22. A compound as claimed in claim 21, substantially as described in Table II herein.
23. A process for the preparation of a compound as claimed in claim 21, which comprises reacting a compound of the general formula V 43850 in which r\ R 4 , R 5 and R 6 are as defined in claim 1 with a compound of the formula RT^ X 5 in which X is an oxygen atom and R' and R are both amino groups, halogen atoms or alkoxy groups, or s' represents an alkoxy group and R a halogen atom, and, if desired, carrying out any one or more of the following reactions, in any appropriate order: 10 (i) converting a compound of formula III in which X represents an oxygen atom into a oompound of formula IV in which Y represents a halogen atom. (ii) alkoxylating a compound of formula IV in which Y represents a halogen atom to obtain the corresponding 15 compound in which Y represents an alkoxy group, (iii) alkylating a compound of formula III in which X represents an oxygen atom to give a compound of formula IV in which Y represents an alkoxy group. - 56 (iv) converting a compound of formula III in which X represents an oxygen atom into the corresponding compound in which X represents a sulphur atom, (v) alkylating a compound of formula III in which X 5 represents a sulphur atom to give a compound of formula IV in which Y represents an alkylthio group, (vi) alkylating or acylating a compound of formula β III in which X represents an oxygen atom and R represents a hydrogen atom, 10 (vii) acylating a compound of formula III in which X β represents a sulphur atom and R represents a hydrogen atom.
24. A process as claimed in claim 23, carried out substantially as described in any one of Examples 2 to 6.
25. A compound as claimed in claim 21, whenever produced 15 by a process as claimed in claim 23 or claim 24.
26. A process as claimed in claim 17, wherein a compound of formula III or IV has been produced by a process as claimed in claim 23 or claim 24, or a compound of formula V in which R^ is. a hydrogen atom, has been produced by trea20 ting a compound of formula VI (VI) 438 50 14 5 in which R , R and R are as defined in claim 1, with an acid.
27. A compound as claimed in claim 1 or a salt thereof whenever produced by a process as claimed in claim 26. 5
28. A pharmaceutical preparation which comprises, as active substance, a compound or salt as claimed in any one of claims 1 to 16, claim 20 or claim 27, or a physiologi cally tolerable acid addition or quaternary ammonium salt thereof as appropriate, in admixture or conjunction with a 10 pharmaceutically suitable carrier.
29. A pharmaceutical preparation as claimed in claim 28, in unit dosage form.
30. A pharmaceutical preparation as claimed in claim 29, for reducing the blood pressure, which comprises from 0.1 15 to 25 mg of the active substance per unit dose.
31. A pharmaceutical preparation as claimed in claim 29, for treating allergy and/or bronchiospasms, which comprises from 1 to 100 mg of the active substance per unit dose.
IE2498/77A 1976-12-10 1977-12-09 Pyrimido (6,1-a) isoquinolin-4-one derivatives IE45850B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN433/BOM/76A IN147624B (en) 1976-12-10 1976-12-10
DE19772720085 DE2720085A1 (en) 1977-05-05 1977-05-05 PYRIMIDO (6.1-A) ISOCHINOLIN-2-ON DERIVATIVES

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IE45850L IE45850L (en) 1978-06-10
IE45850B1 true IE45850B1 (en) 1982-12-15

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CA (1) CA1140123A (en)
GB (1) GB1597717A (en)
IE (1) IE45850B1 (en)
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PH (1) PH18224A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3135831A1 (en) * 1981-09-10 1983-04-28 Hoechst Ag, 6230 Frankfurt 9,10-SUBSTITUTED 2-MESITYLIMINO-3-ALKYL-3,4,6,7-TETRAHYDRO-2H-PYRIMIDO (6.1-A) ISOCHINOLIN-4-ONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT
CA1237429A (en) * 1983-05-05 1988-05-31 Frank Kienzle Pyrimidone derivatives
ES2208310T3 (en) 1999-03-31 2004-06-16 Vernalis Limited PYRIMIDATE DERIVATIVES (6,1-A) ISOQUINOLIN-4-ONA.
GB201613054D0 (en) 2016-07-28 2016-09-14 Verona Pharma Plc New compound and process
IL280075B2 (en) 2018-07-13 2024-06-01 Chia Tai Tianqing Pharmaceutical Group Co Ltd Fused tri-cyclic compound as pde3/pde4 dual inhibitor
EP4332102A1 (en) * 2021-04-29 2024-03-06 Suzhou Suncadia Biopharmaceuticals Co., Ltd. Isoquinolone compound and use thereof

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GB1597717A (en) 1981-09-09
AU1586583A (en) 1983-12-22
NZ185900A (en) 1981-04-24
PH18224A (en) 1985-04-30
AU527997B2 (en) 1983-03-31
CA1140123A (en) 1983-01-25
IE45850L (en) 1978-06-10

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