EP1200410A1 - Isochinolin-verbindungen, diese enthaltende pharmazeutische zusammensetzungen und ein verfahren zur herstellung der wirksamen substanz - Google Patents

Isochinolin-verbindungen, diese enthaltende pharmazeutische zusammensetzungen und ein verfahren zur herstellung der wirksamen substanz

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Publication number
EP1200410A1
EP1200410A1 EP00949830A EP00949830A EP1200410A1 EP 1200410 A1 EP1200410 A1 EP 1200410A1 EP 00949830 A EP00949830 A EP 00949830A EP 00949830 A EP00949830 A EP 00949830A EP 1200410 A1 EP1200410 A1 EP 1200410A1
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EP
European Patent Office
Prior art keywords
formula
group
hydrogen atom
derivative
independently
Prior art date
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Application number
EP00949830A
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English (en)
French (fr)
Inventor
Imre Dom N
József BARK CZY
Gyula Simig
László POSZ V CZ
Csaba Sz Ntay
Mária Incze
Gábor DÖRNYEI
László BAL ZS
Zoltán Greff
Péter; K TAY-NAGY
Zoltán R TKAI
Péter SERES
András BILKEI-GORZ
István GACS LYI
György L VAY
Károly TIHANYI
Judit; R Czn Barn Gel
András Egyed
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Egis Pharmaceuticals PLC
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Egis Pharmaceuticals PLC
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Publication date
Priority claimed from HU9902590A external-priority patent/HUP9902590A3/hu
Priority claimed from HU9902592A external-priority patent/HUP9902592A3/hu
Priority claimed from HU9902591A external-priority patent/HUP9902591A3/hu
Application filed by Egis Pharmaceuticals PLC filed Critical Egis Pharmaceuticals PLC
Publication of EP1200410A1 publication Critical patent/EP1200410A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Definitions

  • the invention refers to novel isoquinohne derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient
  • novel compounds have an influence on the central nervous system, and possess especially anxiolytic effect
  • the invention refers to a novel isoquinohne derivative of the formula wherein
  • R 1 ⁇ R 2 and R 3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group, R 4 stands for a hydrogen atom, a C 1-4 alkoxy group or a t ⁇ fluoromethyl group R 7 means a hydrogen atom or a C ⁇ -4 alkyl group,
  • R 8 is a hydrogen atom or a C ⁇ - 4 alkyl group
  • R5, Re, R9 represent, independently, a hydrogen atom, or
  • R 5 forms with R 6 a valence bond, and simultaneously
  • R 8 forms with R 9 a valence bond
  • R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C 1-4 alkoxy group, a trifluoromethyl group or a cyano group
  • X T and X 2 mean, independently, a hydrogen atom, or X T forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula
  • Ri, R 2 , R3, R , R5, Re, R7, Re, R9, R10, R11, X1 s ⁇ d X 2 are as defined above,
  • R' ⁇ stands for a C ⁇ - 4 alkyl group
  • A represents a residue of an inorganic or organic acid of the formula HA, or, in formula I,
  • R 3 , R 6 and R 7 represent, independently, a hydrogen atom
  • R 8 forms with R 9 a valence bond
  • R 4 stands for a hydrogen atom, a C ⁇ -4 alkoxy group or a C ⁇ -6 alkyl group
  • R 5 means a hidrogen atom or a t ⁇ fluoromethyl group
  • R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C 1- alkoxy group or a tnfluoro- methyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof,
  • R 3 , R 5 , Re and R 7 represent, independently, a hydrogen atom
  • R 8 forms with R 9 a valence bond
  • R 4 stands for a hydrogen atom or a C ⁇ -6 alkyl group
  • R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a C ⁇ . 4 alkoxy group or a t ⁇ fluoromethyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond
  • R's represents a C ⁇ -4 alkyl group
  • A represents a residue of an inorganic or organic acid of the formula HA
  • the aim of the invention is to prepare novel isoquinohne derivatives having more favourable activity than that of the known compounds
  • a Ci -4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert -butyl or isobutyl group, preferably a methyl group
  • a C1-6 alkyl group can represent, for example, also an n-pentyl or an n-hexyl group in addition to the ones listed above under the definition of the C ⁇ - 4 alkyl group
  • a C ⁇ - alkoxy group is primarily a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group
  • a pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrochloric acid, hydrogen bromide, sulfu ⁇ c acid, phosphoric acid etc , or with a pharmaceutically suitable organic acid such as formic acid, acetic acid, fuma ⁇ c acid, maleic acid, lactic acid, malic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid etc
  • the acid of the formula HA is, preferably, a ann iinnoorrggaanniicc aacciidd ssuucchh aass hhyyddrogen chloride, hydrogen bromide, hydrogen iodide etc
  • a subgroup of the compounds of the invention consists of 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nol ⁇ ne derivatives of the formula wherein
  • Ri, R 2 and R 3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 4 stands for a hydrogen atom or a C 1- alkoxy group
  • R 7 means a hydrogen atom or a C ⁇ - alkyl group
  • R 8 is a hydrogen atom or a C 1-4 alkyl group
  • R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a Ci 4 alkoxy group or a t ⁇ fluoromethyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula wherein
  • Ri, R 2 , 3, R4, R5, R ⁇ , R7, e, R9, R10, R11, Xi and X 2 are as defined above,
  • R'a stands for a C ⁇ - alkyl group
  • A represents a residue of an inorganic or organic acid of the formula HA
  • Preferred 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nol ⁇ ne derivatives of the formula la are those, wherein
  • Ri and R 2 represent, independently, a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 3 stands for a hydrogen atom
  • R 4 means a hydrogen atom
  • R 7 is a hydrogen atom
  • R 8 represents a hydrogen atom or a methyl group
  • R 10 stands for a halo atom, a tnfluoromethyl group or a methoxy group
  • Rn means a hydrogen atom or a methoxy group
  • Xi and X 2 mean, independently, a hydrogen atom or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and quaternary derivatives of the formula I'a, wherein R-i, R 2 , R3, R 4 , R5, e, R7, R 8 , R9, R10, R11, Xi and X 2 are as defined above,
  • R's stands for a methyl group, and A represents a hahde ion
  • a further subgroup of the compounds of the invention consists of the isoquinohne derivatives of the formula
  • Ri, R 2 and R 3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 4 stands for a hydrogen atom, a C 1- alkoxy group or a tnfluoromethyl group
  • R 7 means a hydrogen atom or a C ⁇ - alkyl group
  • R1 0 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C ⁇ - alkoxy group, a tnfluoromethyl group or a cyano group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula
  • R-i, R 2 , R 3 , R 4 , R 7 , R10, Rn, Xi and X 2 are as defined above,
  • R' 8 stands for a C ⁇ - alkyl group
  • A represents a residue of an inorganic or organic acid of the formula HA
  • Preferred isoquinohne derivatives of the formula lb are those, wherein
  • Ri, R 2 and R 3 represent, independently, a hydrogen atom or a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 4 stands for a hydrogen atom, a C ⁇ _ 4 alkoxy group or a tnfluoromethyl group
  • R 7 means a hydrogen atom or a methyl group
  • R 10 represent a hydrogen atom, a halo atom, a nitro group, a methoxy group, a tnfluoromethyl group or a cyano group
  • Rn is a hydrogen atom or a methoxy group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula I'b, wherein
  • Ri, 2, R3, R , R7, R10, R11, Xi and X 2 are as defined above,
  • R'a stands for a methyl group
  • A represents a ha de ion
  • Another subgroup of the compounds of the invention consists of the 3,4-d ⁇ hydro ⁇ soqu ⁇ nohne derivatives of the formula
  • Ri and R 2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C1-4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 4 stands for a hydrogen atom, a C ⁇ - alkoxy group or a C ⁇ -6 alkyl group
  • R 5 means a hydrogen atom or a t ⁇ fluoromethyl group
  • R1 0 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C ⁇ - alkoxy group or a t ⁇ fluoro- methyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
  • Preferred 3,4-d ⁇ hydro ⁇ soqu ⁇ nohne derivatives of the formula XIV are those, wherein
  • Ri and R 2 represent, independently, a hydrogen atom, a chloro atom, a hydroxy group or a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 4 stands for a hydrogen atom or a C ⁇ - 6 alkyl group
  • R 5 means a hydrogen atom
  • R 10 and R represent, independently, a hydrogen ator , a fluoro atom, a methoxy group or a tnfluoromethyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or X T forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
  • Especially preferred 3,4-d ⁇ hydro ⁇ soqu ⁇ noh ⁇ e derivatives of the formula XIV are those, wherein Ri forms with R 2 a methylenedioxy group, R 4 stands for a C ⁇ . 6 alkyl group, R 5 means a hydrogen atom or a tnfluoromethyl group, R 10 and Rn represent, independently, a hydrogen atom, a methoxy group or a tnfluoromethyl group, Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
  • a still further subgroup of the compounds of the invention consists of the 3,4-d ⁇ hydro ⁇ soqu ⁇ ol ⁇ n ⁇ um derivatives of the formula
  • Ri and R 2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 4 stands for a hydrogen atom or a d- 6 alkyl group
  • R's means a C ⁇ - alkyl group
  • R-io and Rn represent, independently, a hydrogen atom, a halo atom, a Ci alkoxy group or a tnfluoromethyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or X T forms with X 2 a valence bond
  • A represents a residue of an inorganic or organic acid of the formula HA
  • Ri and R 2 represent, independently, a hydroxy group, a chloro atom or a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
  • R 4 stands for a hydrogen atom or a C ⁇ -3 alkyl group
  • R's means a methyl group
  • R 10 and Rn represent, independently, a hydrogen atom, a halo atom or a tnfluoromethyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond
  • A represents a residue of an inorganic acid of the formula HA
  • Especially preferred 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ n ⁇ um derivatives of the formula XI are those, wherein
  • R 4 stands for a hydrogen atom or a C ⁇ . 3 alkyl group
  • R's means a methyl group
  • R 10 and Rn represent, independently, a hydrogen atom, a fluoro atom or a tnfluoromethyl group
  • Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond
  • A represents a bromide ion or a iodide ion
  • the compounds of the invention are prepared as follows:
  • R ⁇ 3 stands for a hydrogen atom, to catalytical dehydrogenation
  • R ⁇ 2 stands for a C 1 4 alkyl group
  • A is as defined in connection with formula I', with a reducing agent, or
  • R 4 stands for a tnfluoromethyl group, reacting a 3,4-d ⁇ hydro ⁇ soqu ⁇ nohne derivative of the formula IV, wherein R 1 ( R 2 , R 3 , R 4 , R 7 , R10 Rn, Xi and X 2 are as stated above, R 13 represents a C ⁇ -4 alkoxy group, with an alkali metal hydroxide, or
  • R 1 R 2 , R 3 , R and R 7 are as stated above
  • R ⁇ 3 stands for a C ⁇ -4 alkyl group, with an aldehyde of the formula III, wherein R 10 and Rn are as stated above, in the presence of a condensing agent, or
  • R 3 stands for a hydrogen atom, and R 3 represents a hydrogen atom or a tnfluoromethyl group, or
  • R 1 ? R 2 , R 3 , R 4 , R 7 , R10, Rn, X T and X 2 are as defined in connection with formula I,
  • R 8 stands for a hydrogen atom, to a compound of the formula la, wherein R 8 represents a C 1- alkyl group, by reaction with a C ⁇ - alkyl hahde, or
  • R 1 R 2 , R 3 , R 4 , R5, Re, R7, Re, R9, R10, R11, Xi and X 2 are as defined in connection with formula I
  • R' 8 represents a C ⁇ -4 alkyl group
  • A stands for a residue of an inorganic or organic acid of the formula HA, by reaction with a compound of the formula R' 8 -A, wherein R' 8 and A are as stated above, or
  • R-, R 2 , R 3 , R 4 , R 7 , R ⁇ 0 , Rn, Xi and X 2 are as defined in connection with formula I
  • R' 8 stands for a C ⁇ - alkyl group
  • A represents a residue of an inorganic or organic acid of the formula HA, to a compound of the formula la, wherein Ri, R 2 , R 3 , R 4 , R 7 , R ⁇ 0 , Rn, Xi and X 2 are as stated above, R 8 stands for a C ⁇ . alkyl group, by reaction with a reducing agent
  • the 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne derivative is hydrogenized using known literature processes [Houben-Weyl Meth Org Chem , 4/1 c, 121 , 271 -281 , 365, 401 , Georg Thieme Verlag, Stuttgart, (1981 )]
  • the alkoxy group in position 4 is eliminated with an alkali metal hydroxide, preferably potassium hydroxide
  • Process f) of the invention can be performed in a similar way as process a)
  • condensing agent preferably a carboxylic anhydride, suitably acetic anhydride is used
  • the acid amide of the formula VIII is cyc zed in a manner known from the literature [Heterocyclic compounds, Ed J Wiley and Sons, Inc , 38/3. 85-89 (1994), 38/1 , 173-175 (1994)]
  • a C ⁇ -4 alkyl hahde suitably methyl iodide or methyl bromide is used as the reagent of the formula R' 8 -A, and the reaction is carried out in the presence of an indifferent organic solvent at 10 to 160 °C, in general
  • the organic solvent can be apolar such as benzene, toluene, xylene, dichloromethane, etc , or polar protic such as methanol, ethanol etc
  • Process i) of the invention is performed in an analogous manner as the processes known from the literature [Houben- Weyl, Meth Org Chem , Georg Thieme Verlag, Stuttgart, 4/1 c. 517-518 (1981)] An obtained isoquinohne derivative can be converted to another compound of the formula I in a manner known perse
  • a styryl derivative wherein X forms with X 2 a valence bond
  • a compound of the formula I wherein Xi and X 2 stand for a hydrogen atom by catalytical hydrogenation [Houben-Weyl Meth Org Chem , 4/1 d, 580-581 , Georg Thieme Verlag, Stuttgart, (1981 )]
  • the nitrogen atom of a 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nohne derivative of the formula la, wherein R 8 represents a hydrogen atom, can be alkylated in a manner known per se, for example using an alkyl hahde
  • the compound of the formula I can be reacted with a compound of the formula R' 8 -A, preferably a C 1 - 4 alkyl ha de to obtain a quaternary compound of the formula I'
  • the reaction is carried out in an apolar solvent such as benzene, toluene, xylene, dichloromethane, dichloroethane, etc , or a polar protic solvent such as an alkanol at a temperature from 10 to 160 °C
  • a quaternary isoquinohne derivative of the formula I'b can be reduced to obtain the corresponding 1 ,2,3,4-tetrahydro ⁇ so- quinohne of the formula la
  • the reduction is performed using the methods described in the literature cited in connection with process c)
  • the 1 -methyhsoqu ⁇ nohne derivatives of the formula II are partly known compounds
  • the compounds of the formula II, wherein R 4 stands for a tnfluoromethyl group, can be prepared by the reaction of a 1 -methyl-1 ,2-d ⁇ hydro ⁇ soqu ⁇ nohne and potassium hydroxide
  • the 1 -methyl-1 ,2-d ⁇ hydro ⁇ soqu ⁇ nohne of the formula VI is prepared by cychzing an acid amide of the formula wherein Ri, R 2 and R 3 are as defined in connection with formula I, R 4 stands for a tnfluoromethyl group, R ⁇ 3 represents a C 1 - 4 alkoxy group
  • the cychzation reaction is carried out in a manner known from the literature [Heterocyclic Compounds, Ed J Wiley and Sons, Inc , 38/3, 65-89 (1994), 38/1 , 173-175 (1994)]
  • the aldehydes of the formula III are known compounds that are commercially available
  • the 1 ,2-d ⁇ hydro ⁇ soqu ⁇ nohne derivatives of the formula IV are novel compounds that are prepared by cychzing an acid amide of the formula VIII, wherein Ri, R 2 , R 3 , R 4 , R 10 , Rn, Xi and X 2 are as defined in connection with formula I, R 3 represents a Ci -4 alkoxy group
  • the cychzation reaction is performed an an analogous manner as the cychzation of the acid amide of the formula VII
  • the acid amide of the formula VIII can be prepared by reacting an acid derivative of the formula
  • R 10 , Rn, Xi and X 2 are as defined in connection with formula I, with a phenylethylamine of the formula wherein Ri, R 2 , R 3 and R 4 are as defined in connection with formula I, R 13 stands for a C 1 - 4 alkoxy group, in an analogous manner as described in the literature [Houben-Weyl Meth Org Chem , E5/2, 993-1 100, Georg Thieme Verlag, Stuttgart, (1981 )]
  • the acid derivatives of the formula IX and the phenylethylamines of the formula X are commercially available
  • the tnfluoromethyl derivatives of the formula X can be prepared from the corresponding cyanohyd ⁇ ne of the formula
  • the 1 ,2-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ n ⁇ um derivative of the formula V can be prepared from the corresponding 1 ,2-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne by reaction with an alkylating agent of the formula R1 2 -A, wherein R ⁇ 2 represents a C, 4 alkyl group, A is a residue of an inorganic or organic acid of the formula HA
  • the 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne derivative of the formula XII is prepared by cychzing an acid amide of the formula VIII
  • the cychzation reaction is carried out in a manner described under the cychzation of the acid amide of the formula VII
  • the pharmacological effect of the compounds of the invention have been proved by the following experiments
  • Wistar rats weighing 140 to 160 g were used for the experiments The compounds to be tested were suspended in 0 4 % methylcellulose solution and administered in 100 mg/kg daily per os dose for 3 consecutive days ⁇ -Naphthoflavone treatment was used as positive control in 25 mg/kg per os dose.
  • the typical reaction for CYP1 A isoenzyme has been monitored by the measurement of ethoxyresoruphine deethylase (EROD) activity according to the method of Pohl, R.J. and Fouts, J.R., Anal. Biochem., 107, 150-155 (1980). Control values from untreated animals have been considered as 100 %, and EROD activities have been expressed as percent of untreated control.
  • Table III 1 -(4-Trifluoromethylstyryl)-6,7- methylenedioxyisoquinohne has been used as the reference compound.
  • the compounds of the invention display marked CNS, especially anxiolytic effects
  • the anxiolytic activity is significant in the "light-dark transition” test, while the known 1 -styryhsoquinohne derivatives were found to be practically ineffective in this test Moreover, the novel compounds did not influence spontaneous motor activity in a dose more than five times higher than that of the ID 50 value of the reference compound diazepam
  • the compounds of the invention did not influence the key enzymes of hepatic drug metabolism
  • the low and insignificant enzyme induction potency of the novel compounds is of great importance from drug safety approaches
  • novel isoquinohne derivatives of the formula I can be any novel isoquinohne derivatives of the formula I.
  • compositions / used as active ingredients in pharmaceutical compositions
  • compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' and one or more conventional car ⁇ er(s)
  • compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid
  • the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc , and can comprise binding agents such as gelatine, sorbitol, poly(v ⁇ nylpyrrol ⁇ done) etc , filling agents such as lactose, glucose, starch, calcium phosphate etc , auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc , wetting agents such as sodium laurylsulfate etc as the carrier
  • the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e g suspending agents such as gelatine, carboxymethylcellulose etc , emulsifiers such as sorbitane monooleate etc , solvents such as water, oils, glycerol, propylene glycol, ethanol etc , preservatives such as methyl p- hydroxybenzoate etc as the carrier
  • compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general
  • compositions of the invention contain, in general, 0 1 to 95 0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'
  • a typical dose for adult patients amounts to 0 1 to 1000 mg of the compound of the formula I, daily
  • the above dose can be administered in one or more portions
  • the actual dosage depends on many factors and is determined by the doctor
  • compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' to one or more carr ⁇ er(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se Useful methods are known from the literature, e g Remington's Pharmaceutical Sciences mentioned above
  • compositions of the invention contains a 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nohne of the formula la or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'a
  • a further subgroup of the pharmaceutical compositions of the invention contains an isoquinohne derivative of the formula lb or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'b
  • compositions of the invention contains a 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne derivative of the formula XIV or a pharmaceutically suitable acid addition salt thereof
  • a still further subgroup of the pharmaceutical compositions of the invention contains a 3,4-d ⁇ hydro ⁇ soqu ⁇ nohn ⁇ um derivative of the formula XI
  • the invention includes also a method of treatment in which a patient suffering from especially a disease of the central nervous system is treated with a non-toxic dose of a 3,4- dihydroisoquino ne derivative of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'
  • the invention includes the use of an isoquinohne derivative of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' for the preparation of a pharmaceutical composition having anxiolytic effect
  • the title compound is prepared in a similar manner as the starting compound under 28)
  • the crude product is fractionated under reduced pressure At a pressure of 373 Pa, the fraction from 84 to 85 °C is separated Yield 63 % Analysis for C 9 H 5 F 3 0 3 (218 134) calculated C 49 56 %, H 2 31 %, found C 49 43 %, H 2 20 %
  • the title compound is prepared in a similar manner as the starting compound under 32)
  • the crude product is fractionated under reduced pressure At a pressure of 147 Pa, the fraction from 1 14 to 1 16 °C is collected Yield 68 %
  • the title compound is a colourless oil
  • Example 14 The procedure described in Example 14 is followed to bta ⁇ n the title compound Yield 59 % M p 256-258 °C Analysis for C 2 ⁇ H 2 ⁇ FIN0 2 (503 30) calculated C 50 31 %, H 4 21 %, N 2 78 %, found C 49 88 %, H 4 25 %, N 2 87 %
  • Example 28 1-/2-(3,4-D ⁇ methoxyphenyl)ethyl/-6,7-d ⁇ methoxy ⁇ soqu ⁇ nohne 3
  • 51 g (0 01 moles) of 1 -(3,4-d ⁇ methoxystyryl)-6,7-d ⁇ methoxy- isoquinohne are dissolved in 100 cm 3 of acetic acid
  • 0 5 g of Pd/C catalyst are added, and the mixture is hydrogenized at room temperature and 10 bar pressure until the end of hydrogen gas consumption
  • the catalyst is removed by filtration, the filtrate is evaporated under reduced pressure
  • the residue is dissolved in 50 cm 3 of methanol, and, by the addition of about 50 g of crushed ice and 10 cm 3 of 25 % aqueous ammonia, the base is prepared
  • the precipitated crystalline product is filtered, and washed with cold water
  • 1 5 g (43 %) of the title compound are obtained M p 146-147 °C
  • the solution is extracted three times using 30 cm 3 of ethyl acetate each time, the combined organic phases are dried over anhydrous magnesium sulfate, and evaporated.
  • the crude base is dissolved in 10 cm 3 of methanol, and, to the solution formed, a solution of 1.16 g (10 mmoles) of maleic acid in 10 cm 3 of methanol, then 40 cm 3 of diisopropyl ether are added, drop by drop.
  • the precipitated crystals are filtered, washed with 10 cm 3 of diisopropyl ether.
  • 2.54 g (53 %) of the title compound are obtained.
  • Example 41 The procedure described in Example 41 is followed to obtain the title compound Yield 81 % M p 183-185 °C
  • Example 62 1 -(4-Tr ⁇ fluoromethylstyryl)-6,7-methylened ⁇ oxy-3,4-d ⁇ hydro- isoquinohne hydrochlonde
  • the crude product obtained is dissolved in dichloromethane and the pH is adjusted to 11 by the addition of 20 % aqueous sodium hydroxide solution under stirring
  • the separated aqueous phase is extracted with dichloromethane twice using 50 cm 3 of dichloromethane each time
  • the combined organic phases are dried over anhydrous sodium sulfate, evaporated to obtain 2.9 g (45 %) of oily product
  • the crude product is dissolved in absolute ether, and, to the solution, an equimolar amount of anhydrous oxalic acid is added
  • the crystalline salt is filtered. Thus, 3 22 g (41 %) of the title compound are obtained.
  • Example 66 1 -(2-Phenylethyl)-6,7-methylened ⁇ oxy-3,4-d ⁇ hydro ⁇ soqu ⁇ nohne
  • Example 67, section A The procedure described in Example 67, section A) is followed starting from 1 12 g (2 5 mmoles) of N-/3-(4-tr ⁇ fluoromethyl- phenyl)propanoyl/-3,3,3-t ⁇ fluoro-2-methoxy-2-(3-metho ⁇ y- phenyl)propylam ⁇ ne and 2 0 cm 3 (3 36 g, 22 mmoles) of phosphor(V) trichloride oxide The crude base is dissolved in

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EP00949830A 1999-07-29 2000-07-28 Isochinolin-verbindungen, diese enthaltende pharmazeutische zusammensetzungen und ein verfahren zur herstellung der wirksamen substanz Withdrawn EP1200410A1 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
HU9902590A HUP9902590A3 (en) 1999-07-29 1999-07-29 3,4-dihydro isoquinolinium derivatives, pharmaceutical compositions containing them and process for producing them
HU9902591 1999-07-29
HU9902592 1999-07-29
HU9902592A HUP9902592A3 (en) 1999-07-29 1999-07-29 Isoquinoline derivatives, pharmaceutical compositions containing such active ingredients and process for producing them
HU9902590 1999-07-29
HU9902591A HUP9902591A3 (en) 1999-07-29 1999-07-29 3,4-dihydro isoquinolinium derivatives, pharmaceutical compositions containing such active ingredients and process for producing them
PCT/HU2000/000087 WO2001009101A1 (en) 1999-07-29 2000-07-28 Isoquinoline derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substance

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US20210163453A1 (en) * 2018-07-23 2021-06-03 Ohio State Innovation Foundation Derivatives of papaverine that are effective hypoxic tumor radiosensitizers

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CH410007A (de) * 1961-04-21 1966-03-31 Hoffmann La Roche Verfahren zur Herstellung von tertiären Aminen
DE1902402A1 (de) * 1968-05-21 1969-11-27 Dresden Arzneimittel Verfahren zur Herstellung von 1-substituierten 6.7-Dimethoxy-isochinolinen
DE1902559A1 (de) * 1968-07-05 1970-03-26 Dresden Arzneimittel Verfahren zur Herstellung von 1-substituierten 3,4-Dihydro-6,7-dimethoxy-isochinolinen
GB1181959A (en) * 1969-01-30 1970-02-18 Dresden Arzneimittel 6,7-Dimethoxy-3,4-Dihydroisoquinoline Derivatives
GB8419658D0 (en) * 1984-08-01 1984-09-05 Wellcome Found Nitrogen containing heterocyclic compounds
HUT71407A (en) * 1994-05-03 1995-11-28 Egyt Gyogyszervegyeszeti Gyar Heterocyclic compounds, pharmaceutical compositions containing them, and process for producing the active components
EP0787493A1 (de) * 1996-02-03 1997-08-06 F. Hoffmann-La Roche Ag Tetrahydroisochinolin-Derivate

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