WO2001064647A1 - Isoquinoline derivatives as pde4 inhibitors - Google Patents

Isoquinoline derivatives as pde4 inhibitors Download PDF

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Publication number
WO2001064647A1
WO2001064647A1 PCT/HU2001/000024 HU0100024W WO0164647A1 WO 2001064647 A1 WO2001064647 A1 WO 2001064647A1 HU 0100024 W HU0100024 W HU 0100024W WO 0164647 A1 WO0164647 A1 WO 0164647A1
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stands
hydrogen atom
general formula
salts
group
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PCT/HU2001/000024
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French (fr)
Inventor
Sándor BÁTORI
Ágnes BEHR
Éva BORONKAY
Erzsébet FEJÉR
István HERMECZ
Zoltán Kapui
Gyuláné KISS
Endre Mikus
Marc Pascal
Kálmán Takács
Katalin URBÁN SZABÓ
Attila BARANYI
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Sanofi-Synthelabo
BARANYI, Attiláné
BARANYI, Krisztina
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Priority to AU2001240939A priority Critical patent/AU2001240939A1/en
Publication of WO2001064647A1 publication Critical patent/WO2001064647A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C07D221/12—Phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C07D217/14—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
    • C07D217/16—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 substituted by oxygen atoms

Definitions

  • the invention relates to the PDE4 inhibitors of the general formula (I), to the salts. solvates, geometric and optically active isomers thereof, to the pharmaceutical compositions containing them, to the use of the compounds of the general formula (I) and their salts, solvates, geometric and optically active isomers, to the preparation of the compounds of the general formula (I) ( Figure 1 ) and to the new intermediates of the general formula (II) ( Figure 2) and their preparation.
  • PDE4 inhibitors are presumed useful in the treatment of diseases like for instance asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiplex sclerosis and dermatological diseases.
  • COPD chronic obstructive pulmonary disease
  • PDE4 inhibitory compounds that were selected for development, in the course of the clinical studies, turned out to exert several side effects, precluding or strongly limiting their therapeutic application. Such side effects are vomiting and cardiovascular reactions.
  • These side effects are supposed to be consequences of weak selectivity and unfavourable side-effect profile of the PDE4 inhibitors described in the literature. Additional disadvantages of the known compounds are toxicity, insufficient bioavailability and weak stability.
  • R 1 stands for straight or branched C]. alkyl or C 4 . 6 cycloalkyl group,
  • R 2 stands for straight or branched Cj_ alkyl or C . 6 cycloalkyl group
  • R J stands for hydrogen atom or straight or branched Cj. 4 alkyl
  • R 4 stands for hydrogen atom or straight or branched C alkyl
  • R 5 stands for hydrogen atom or straight or branched C ⁇ _ 4 alkyl
  • R 6 stands for hydrogen atom or straight or branched C alkyl
  • R 7 stands for hydrogen atom or straight or branched C]. 4 with the proviso that one substituent selected from the groups of R 4 , R 5 , R 1 or R 7 always has a meaning different from hydrogen atom, or R ? and R 1 mean together a -(CH 2 ) Z - group - wherein z is 3 or 4 or 5,
  • R 8 stands for hydrogen atom or a straight or branched C
  • R 9 stands for hydrogen atom or a straight or branched C alkyl group
  • R 10 means saturated 4 to 7 membered saturated ring containing one or two nitrogen atom(s) connecting through the nitrogen atom and optionally substituted by a C ⁇ _ alkyl group; or a saturated 4 to 7 membered ring containing one nitrogen atom and one oxygen atom connecting through the nitrogen atom and optionally substituted by a Cj. alkyl group
  • X stands for sulfur atom or oxygen atom
  • m is zero or 1
  • n is 1 - and their salts, solvates, isomers and their salt surprisingly fulfil the desired criteria.
  • Cj. 4 alkyl group we mean butyl, isobutyl, sec. -butyl, terc- butyl, propyl group, preferably ethyl or methyl group.
  • C 4 . 6 cycloalkyl group we mean cyclobutyl, cyclopentyl or cyclohexyl group.
  • the saturated 4 to 7 membered ring containing one nitrogen atom means azetidine, pyrrolidine, piperidine or perhydroazepine ring connected to the other part of the molecule through the nitrogen atom.
  • the ring may optionally be substituted by a C]. alkyl group.
  • the saturated 4 to 7 membered ring containing one nitrogen and one oxygen atom means saturated derivatives of 1,4-oxazine 1 ,3-oxazine, 1,2-oxazine, isoxazol or oxazol ring, saturated 2-oxa-azetidine or 3-oxa-azetidine ring, or perhydro- oxazepine ring, connected to the other part of the molecule through the nitrogen atom.
  • the ring containing two nitrogen atoms may be for instance imidazoline or piperazine ring.
  • the rings may optionally be substituted by a C ⁇ _ 4 alkyl group.
  • salts of the compounds of the general formula (I) we mean salts formed with organic or inorganic acids or salts formed with bases.
  • the salts formed with pharmaceutically acceptable acids as for instance with hydrochloric acid. sulfuric acid, phosphoric acid, tartaric acid, maleic acid, alkyl-sulphonic acids and citric acid.
  • solvates we mean solvates formed with various solvents, as for instance with water, or with ethanol.
  • the compounds of the general formula (I) show geometrical and optical isomerism, therefore the invention also relates to the mixtures of the geometric isomers. to the racemic or optically active geometric isomers, and the salts and solvates thereof.
  • R' means methyl- or ethyl group
  • R ⁇ means methyl- or ethyl group
  • R J means hydrogen atom
  • R 4 means hydrogen atom
  • R 3 and R 6 mean together a - (CH ) Z - group - wherein z is 3, 4 or 5
  • R means hydrogen atom
  • R means hydrogen atom or methyl group
  • R 9 means hydrogen atom, or methyl group
  • R means pyrrolidino, piperidino, piperazino, 4-mefhylpiperazino or morpholino- group
  • m is 1
  • n is 1 - and their salts and solvates. or their racemic or optically active geometric isomers, and the salts and solvates thereof.
  • compositions containing the compounds of the general formula (I), their isomers, salts, solvates preferably oral compositions, but inhalable, parenteral and transdermal compositions also form the subjects of the present invention.
  • the above pharmaceutical compositions may be solids or liquids, for instance tablets, pellets, capsules, solutions, suspensions, or emulsions. Preferable are the solid compositions, first of all tablets and capsules.
  • the above drug products are prepared by applying excipients and technological operations conventionally used in the pharmaceutical production.
  • the compounds of the general formula (I) according to the present invention are useful for the treatment of diseases connected with abnormally high PDE4 enzyme activity.
  • diseases are for instance asthma, chronic obstructive pulmonary disease (COPD), allergic diseases, inflammatory diseases, bronchitis, atopic dermatitis, arthritis, emphysema, sclerosis multiplex, septic shock, Crohn-disease, liver damages, pulmonary hypertension, kidney and ureteral diseases, urogenital diseases and osteoporosis.
  • COPD chronic obstructive pulmonary disease
  • the compounds of the general formula (I) - wherein X stands for sulfur atom and the meaning of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and the value of m and n are as defined above - can be prepared starting from the compounds of the general formula (VI), by brominating them to the compounds of the general formula (III), transforming them into the isothiuronium salts of the general formula (II) and reacting them with the halogen derivatives of the general formula (V) or their salts.
  • a halogen derivative of the general formula (III) - wherein the meanings of R 1 . R 2 , R ⁇ R 4 , R 5 , R 6 , R 7 are as defined in claim 1 - is reacted with a hydroxy derivative of the general formula (IV) - wherein the meanings of R 8 , R 9 , R 10 and the value of m and are as defined in claim 1 - and, if desired, the resulting compound of the general formula (I) is transformed into its salt, liberated from its salt, separated into its isomers, transformed into its solvate, or liberated from its solvate.
  • the synthetic route leading to optically active (VI) (DE- 19613091. W097/35854) is chosen.
  • the compounds of the general formula (II) can be prepared by reacting a compound of the general formula (III) - wherein the meanings of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined in claim 1 - with thiocarbamide.
  • the compounds of the general formula (III) are prepared by reacting a compound of the general formula (VI) - wherein the meanings of R 1 , R", R J , R 4 . R 5 , R 6 , R' are as defined in claim 1 - with bromine or with a brominating agent.
  • the compounds of the general formula (VI) can be prepared by methods described in J. Chem. Soc. P. 36-49 (1931), DE-19613091, J. Chem. Soc. p. 4939-4944 (1961).
  • R stands for ethyl group, R for methyl group, R J for hydrogen atom, R 4 for methyl group, R 5 for hydrogen atom.
  • R 6 for hydrogen atom, R 7 for hydrogen atom, R 8 for hydrogen atom, R 9 for hydrogen atom.
  • R 10 means morpholino group, X means sulfur atom, m is 1 , n is 1.
  • R 1 stands for ethyl group
  • R 2 for methyl group
  • R J for hydrogen atom
  • R 4 for methyl group
  • R 5 for hydrogen atom
  • R 6 for methyl group
  • R 7 for methyl group
  • R 8 for hydrogen atom
  • R 9 for hydrogen atom
  • R 10 means mo holino group
  • X means sulfur atom
  • m is 1
  • n is 1.
  • Example 2a The bromo derivative obtained in Example 2a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 145-148 °C.
  • R stands for ethoxy group, R ⁇ for methoxy group, R " for hydrogen atom, R 4 for hydrogen atom, R 5 and R 6 form together a - (CH 2 )z-group
  • R stands for hydrogen atom
  • R and R stand for hydrogen atoms
  • R means morpholino group
  • X means sulfur atom
  • m is 1.
  • n is 1.
  • Example 3a The bromo derivative obtained in Example 3a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180-182 °C.
  • R stands for ethoxy group, R " for methoxy group, R J for hydrogen atom, R 4 for hydrogen atom, R 5 and R 6 form together a - (CH 2 ) 7 -group
  • R stands for hydrogen atom.
  • R 9 stands for methyl group, R ° means morpholino group.
  • X means sulfur atom, m is 1 , n is 1.
  • Example 4a The bromo derivative obtained in Example 4a) was treated as described in Example lb) to obtain the title isothiuronium salt, mp: 180-182 °C.
  • R stands for ethoxy group.
  • R ⁇ for methoxy group
  • R J for hydrogen atom
  • R 4 for hydrogen atom
  • R 5 and R 6 form together a - (CH 2 ) z -group
  • R stands for hydrogen atom
  • R stands for methyl group
  • R 9 stands for methyl group
  • R 10 means morpholino group
  • X means sulfur atom
  • m is 1
  • n is 1.
  • Example 5a The bromo derivative obtained in Example 5a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180- 182 °C.
  • R stands for ethoxy group
  • R " for methoxy group
  • R J for hydrogen atom
  • R 4 for hydrogen atom
  • R 5 and R form together a - (CH 2 ) z -group, wherein the value of z is 4,
  • R 7 stands for hydrogen atom
  • R 8 and R 9 stand for hydrogen atoms,
  • R means pyrrolidino group.
  • X means sulfur atom
  • m is 1.
  • n is 1.
  • Example 6a The bromo derivative obtained in Example 6a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180-182 °C.
  • R stands for ethoxy group
  • R ⁇ for methoxy group
  • R ⁇ for hydrogen atom
  • R 4 for hydrogen atom
  • R 5 and R 6 form together a - (CH 2 ) z -g ⁇ oup
  • R stands for hydrogen atom
  • R and R stand for hydrogen atoms
  • R means piperidino group
  • X means sulfur atom
  • m is 1
  • n is 1.
  • Example 7a The bromo derivative obtained in Example 7a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180-182 °C.
  • R stands for ethoxy group.
  • R " for methoxy group
  • R J for hydrogen atom
  • R 4 for hydrogen atom
  • R 5 and R 6 form together a - (CH 2 ) z -group, wherein the value of z is 4.
  • R 7 stands for hydrogen atom.
  • R 8 and R 9 stand for hydrogen atoms
  • R 1 means pyrrolidino group
  • X means oxygen atom
  • m is 1
  • n is 1.
  • R stands for ethoxy group, R for methox ⁇ group, R J for hydrogen atom, R 4 for hydrogen atom, R 3 and R 6 form together a - (CH 2 ) z -group,
  • R stands for hydrogen atom
  • R and R stand for hydrogen atoms
  • R 10 means piperididino group
  • X means oxygen atom
  • m is 1.
  • n is 1. a.) 2-bromo-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6, 10b-octahydrophenanthridin-6- ylidene)acetonitrile
  • R stands for ethoxy group
  • R ⁇ for methoxy group
  • R J for hydrogen atom
  • R 4 for hydrogen atom
  • R 5 and R 6 form together a - (CH 2 ) -group.
  • (+)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy- l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile was obtained, mp: 1 18-120 °C.
  • PDE4 enzyme inhibitory activities of the compounds of the general formula (I) were determined by the following two-step method:
  • the standard assay mixture contains: 30 ⁇ l human PDE4 enzyme
  • 1x8 (chloride form) ion-exchange resin 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min. The mixture of 500 ml supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [ ⁇ ] adenosine.
  • the standard assay mixture contains: 30 ⁇ l human PDE2 enzyme
  • the reaction is initiated by addition of the substrate.
  • the samples are incubated at 30 °C for 20 min., then the reaction is stopped by boiling the assay tubes for 2 min.
  • 50 ⁇ l of the poison of the Crotalux atrox snake species 0.5 mg/ml distilled water
  • the nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min.
  • the standard assay mixture contains: 30 ⁇ l human PDE3 enzyme
  • the reaction is initiated by addition of the substrate.
  • the samples are incubated at 30 °C for 20 min., then the reaction is stopped by boiling the assay tubes for 2 min.
  • 50 ⁇ l of the poison of the Crotalux atrox snake species (0,5 mg/ml distilled water) is added and the samples are incubated at 37°C for 30 min.
  • the nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min.
  • the mixture of 500 ml supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [ ⁇ ] adenosine.
  • the standard assay mixture contains: 30 ⁇ l human PDE5 enzyme
  • the nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min. The mixture of 500 ⁇ l supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [ J FI] guanosine.
  • the compounds of the general formula (I) exhibit very high selectivity for the PDE4 enzyme.
  • the compounds of the general formula (I) show favourable chemical stability, in biological media they have favourable metabolic stability both in vitro and in vivo, they are readily absorbed in vitro on CaCo2 model, as well as in vivo after oral administration as compared to the known PDE4 inhibitors. They exhibit good bioavailability and isoenzyme selectivity. Furthermore, their duration of effect after intravenous and oral administration is long, their ED 50 value is low and they have favourable toxicology- and side-effect profile. All the above features make the compounds of the general formula (I) in all probability suitable for therapeutic use and demonstrate their advantage over the known PDE4 inhibitory compounds.

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Abstract

Compounds of the general formula (I) wherein R10 means saturated 4 to 7 membered ring containing one or two nitrogen atom(s) connecting through the nitrogen atom and optionally substituted by a C¿1-4? alkyl group or a satured 4 to 7 membered ring containing one nitrogen atom and one oxygen atom connecting through the nitrogen atom and optionally substituted by a C1-4 alkyl group, X stands for sulfur atom or oxygen atom, are strong and selective inhibitors of PDE4 enzyme and they are presumably suitable for the treatment of for instance asthma, chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis.

Description

ISOQUINO INE DERIVATIVES AS PDE4 INHIBITORS
The invention relates to the PDE4 inhibitors of the general formula (I), to the salts. solvates, geometric and optically active isomers thereof, to the pharmaceutical compositions containing them, to the use of the compounds of the general formula (I) and their salts, solvates, geometric and optically active isomers, to the preparation of the compounds of the general formula (I) (Figure 1 ) and to the new intermediates of the general formula (II) (Figure 2) and their preparation.
A number of compounds and groups of compounds with PDE4 inhibitory activity are known from the literature (Drug News and Perspectives 8_(8) p 514-520 (1995)). PDE4 inhibitors are presumed useful in the treatment of diseases like for instance asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiplex sclerosis and dermatological diseases. However, PDE4 inhibitory compounds, that were selected for development, in the course of the clinical studies, turned out to exert several side effects, precluding or strongly limiting their therapeutic application. Such side effects are vomiting and cardiovascular reactions. These side effects are supposed to be consequences of weak selectivity and unfavourable side-effect profile of the PDE4 inhibitors described in the literature. Additional disadvantages of the known compounds are toxicity, insufficient bioavailability and weak stability.
We aimed to develop isoquinoline type PDE4 inhibitors that exhibit strong inhibitory activity and are selective to the PDE4 enzyme, i.e. they inhibit the PDE4 enzyme in much smaller concentration than the enzymes PDE1, PDE2, PDE3 and PDE5. Further aims were good stability, bioavailability, therapeutic index and low toxicity favouring drug development, and good enteric absorption allowing oral application. We have found that the compounds of the general formula (I),
- wherein
R1 stands for straight or branched C]. alkyl or C4.6 cycloalkyl group,
R2 stands for straight or branched Cj_ alkyl or C .6 cycloalkyl group, RJ stands for hydrogen atom or straight or branched Cj.4 alkyl,
R4 stands for hydrogen atom or straight or branched C alkyl,
R5 stands for hydrogen atom or straight or branched Cι_4 alkyl,
R6 stands for hydrogen atom or straight or branched C alkyl,
R7 stands for hydrogen atom or straight or branched C].4 with the proviso that one substituent selected from the groups of R4, R5, R1 or R7 always has a meaning different from hydrogen atom, or R? and R1 mean together a -(CH2)Z- group - wherein z is 3 or 4 or 5,
R8 stands for hydrogen atom or a straight or branched C|.4 alkyl group, R9 stands for hydrogen atom or a straight or branched C alkyl group, R10 means saturated 4 to 7 membered saturated ring containing one or two nitrogen atom(s) connecting through the nitrogen atom and optionally substituted by a Cι_ alkyl group; or a saturated 4 to 7 membered ring containing one nitrogen atom and one oxygen atom connecting through the nitrogen atom and optionally substituted by a Cj. alkyl group, X stands for sulfur atom or oxygen atom, m is zero or 1, n is 1 - and their salts, solvates, isomers and their salt surprisingly fulfil the desired criteria.
Detailed meanings of the above listed substituents are as follows: By straight or branched Cj.4 alkyl group we mean butyl, isobutyl, sec. -butyl, terc- butyl, propyl group, preferably ethyl or methyl group. By C4.6 cycloalkyl group we mean cyclobutyl, cyclopentyl or cyclohexyl group.
The saturated 4 to 7 membered ring containing one nitrogen atom means azetidine, pyrrolidine, piperidine or perhydroazepine ring connected to the other part of the molecule through the nitrogen atom. The ring may optionally be substituted by a C]. alkyl group. The saturated 4 to 7 membered ring containing one nitrogen and one oxygen atom means saturated derivatives of 1,4-oxazine 1 ,3-oxazine, 1,2-oxazine, isoxazol or oxazol ring, saturated 2-oxa-azetidine or 3-oxa-azetidine ring, or perhydro- oxazepine ring, connected to the other part of the molecule through the nitrogen atom.
The ring containing two nitrogen atoms may be for instance imidazoline or piperazine ring.
The rings may optionally be substituted by a Cι_4 alkyl group.
By salts of the compounds of the general formula (I) we mean salts formed with organic or inorganic acids or salts formed with bases. Preferable are the salts formed with pharmaceutically acceptable acids, as for instance with hydrochloric acid. sulfuric acid, phosphoric acid, tartaric acid, maleic acid, alkyl-sulphonic acids and citric acid.
By solvates we mean solvates formed with various solvents, as for instance with water, or with ethanol.
The compounds of the general formula (I) show geometrical and optical isomerism, therefore the invention also relates to the mixtures of the geometric isomers. to the racemic or optically active geometric isomers, and the salts and solvates thereof.
Especially favourable group of the compounds of the general formula (I) are those - wherein
R' means methyl- or ethyl group,
R~ means methyl- or ethyl group,
RJ means hydrogen atom,
R4 means hydrogen atom, R3 and R6 mean together a - (CH )Z - group - wherein z is 3, 4 or 5,
R means hydrogen atom,
R means hydrogen atom or methyl group, R9 means hydrogen atom, or methyl group, R means pyrrolidino, piperidino, piperazino, 4-mefhylpiperazino or morpholino- group, m is 1, n is 1 - and their salts and solvates. or their racemic or optically active geometric isomers, and the salts and solvates thereof.
Especially favourable are the racemic or optically active cis-isomers of the above compounds, as for instance the
(±)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy-l ,2,3.4.4a.5.6.10b- octahydrophenanthridin-6-ylidene)acetonitrile,
(-)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy- 1.2,3.4.4a.5.6, 10b- octahydrophenanthridin-6-ylidene)acetonitrile,
(+)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy-l,2.3.4.4a,5.6, 10b- octahydrophenanthridin-6-ylidene)acetonitrile, (±)-cis-2-[2-Morpholino-( 1 -methyl)ethylthio]-2-(9-ethoxy-8-methoxy- l,2,3,4,4a,5,6, 10b-octahydrophenanthridin-6-ylidene)acetonitrile.
(+)-cis-2-[2-Morpholino-( 1.1 -dimethyl)ethylthio]-2-(9-ethoxy-8-methoxy- l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile.
(±)-cis-2-(2-Pyrrolidinoethylthio)-2-(9-ethoxy-8-methoxy- 1,2,3, 4.4a.5,6.10b- octahydrophenanthridin-6-ylidene)acetonitrile,
(±)-cis-2-(2-Piperidinoethylthio)-2-(9-ethoxy-8-methoxy-1.2,3,4.4a.5,6.10b- octahydrophenanthridin-6-ylidene)acetonitrile,
(+)-cis-2-(2-Pyrrolidinoethoxy)-2-(9-ethoxy-8-methoxy- 1,2.3, 4,4a.5.6,10b- octahydrophenanthridin-6-ylidene)acetonitrile, (±)-cis-2-(2-Piperidinoethoxy)-2-(9-ethoxy-8-methoxy- 1 ,2,3 ,4,4a.5.6, 10b- octahydrophenanthridin-6-ylidene)acetonitrile,
(±)-cis-2-(2-Morpholinoethoxy)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a.5.6.10b- octahydrophenanthridin-6-ylidene)acetonitrile.
Further subjects of the present invention are pharmaceutical compositions containing the compounds of the general formula (I), their isomers, salts, solvates, preferably oral compositions, but inhalable, parenteral and transdermal compositions also form the subjects of the present invention. The above pharmaceutical compositions may be solids or liquids, for instance tablets, pellets, capsules, solutions, suspensions, or emulsions. Preferable are the solid compositions, first of all tablets and capsules.
The above drug products are prepared by applying excipients and technological operations conventionally used in the pharmaceutical production.
The compounds of the general formula (I) according to the present invention are useful for the treatment of diseases connected with abnormally high PDE4 enzyme activity. Such diseases are for instance asthma, chronic obstructive pulmonary disease (COPD), allergic diseases, inflammatory diseases, bronchitis, atopic dermatitis, arthritis, emphysema, sclerosis multiplex, septic shock, Crohn-disease, liver damages, pulmonary hypertension, kidney and ureteral diseases, urogenital diseases and osteoporosis. A further subject of the invention is the use of the compounds of the general formula (I) in the treatment of the diseases listed above.
In another aspect of the present invention there is provided a process for the preparation of the compounds of the general formula (I): synthesis of the compounds of the general formula (I) - wherein X stands for sulfur atom - is demonstrated on Reaction Scheme 1 (Figures 6 and 7), synthesis of the compounds of the general formula (I) - wherein X stands for oxygen atom - is demonstrated on Reaction Scheme 2 (Figure 8).
The compounds of the general formula (I) - wherein X stands for sulfur atom and the meaning of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and the value of m and n are as defined above - can be prepared starting from the compounds of the general formula (VI), by brominating them to the compounds of the general formula (III), transforming them into the isothiuronium salts of the general formula (II) and reacting them with the halogen derivatives of the general formula (V) or their salts. The compounds of the general formula (I) - wherein X stands for oxygen atom - can be prepared by reacting the bromo derivatives of the general formula (III) (Figure 3) with the hydroxy derivatives of the general formula (IV) (Figure 4), in the following way:
a.) An isothiuronium salt of the general formula (II) - wherein the meanings of R1. R2, R R4, R5, R6, R7 are as defined in claim 1- is reacted with a halogen derivative of the general formula (V) (Figure 5) - wherein the meanings of R8, R9, R10 and the value of m and n are as defined in claim 1 - or with its salt, or
b.) A halogen derivative of the general formula (III) - wherein the meanings of R1. R2, R\ R4, R5, R6, R7 are as defined in claim 1 - is reacted with a hydroxy derivative of the general formula (IV) - wherein the meanings of R8, R9, R10 and the value of m and are as defined in claim 1 - and, if desired, the resulting compound of the general formula (I) is transformed into its salt, liberated from its salt, separated into its isomers, transformed into its solvate, or liberated from its solvate.
If an optically active compound of the general formula (I) is prepared, the appropriate racemic compound of the general formula (I) or one of the intermediates of the general formulae (VI), (III) or (II) is resolved by a method known per se.
Preferably the synthetic route leading to optically active (VI) (DE- 19613091. W097/35854) is chosen.
Further subjects of the invention are the intermediates of the general formulae (II) and (III) - wherein the meanings of R1, R2, R3, R4, R5, R6, R7 are as defined in claim 1 - and their preparation. The compounds of the general formula (II) can be prepared by reacting a compound of the general formula (III) - wherein the meanings of R1, R2, R3, R4, R5, R6, R7 are as defined in claim 1 - with thiocarbamide. The compounds of the general formula (III) are prepared by reacting a compound of the general formula (VI) - wherein the meanings of R1, R", RJ, R4. R5, R6, R' are as defined in claim 1 - with bromine or with a brominating agent.
The compounds of the general formula (VI) can be prepared by methods described in J. Chem. Soc. P. 36-49 (1931), DE-19613091, J. Chem. Soc. p. 4939-4944 (1961).
Examples
Example 1
2-(2-MorphoIinoethylthio)-2-(3-methyl-6 ethoxy-7-methoxy-l,2,3,4-tetrahydro isoquinolinylidene)acetonitrile
In the general formula (I) R stands for ethyl group, R for methyl group, RJ for hydrogen atom, R4 for methyl group, R5 for hydrogen atom. R6 for hydrogen atom, R7 for hydrogen atom, R8 for hydrogen atom, R9 for hydrogen atom. R10 means morpholino group, X means sulfur atom, m is 1 , n is 1.
a.) 2-bromo-2-(3-methyl-6-ethoxy-7-methoxy-l,2,3,4-tetrahλ dro- isoquinolinylidene)acetonitrile
The solution of 1,35 g (0.0043 mol) of
Figure imgf000010_0001
-7-mefhoxy- 1,2,3,4- tetrahydroisoquinolinylidene)acetonitrile and 0,93 g (0.0052 mol) of N- bromosuccinimide in 40 ml of dichloromethane is stirred for 1 hour at room temperature, then it is extracted with 2x60 ml of water. The organic layer is dried over sodium sulfate and evaporated in vacuo. The solide residue is digerated with ethanol, filtered off, to obtain 1,25 g of the title compound, mp: 1 17-120 °C.
b.) S-[α-cyano-α-(3-methyl-6-ethoxy-7-methoxy-l,2,3,4-tetrahydro- isoquinoliny lidene)methy 1] isothiuronium bromide
The solution of 1 ,25 g (0,0032 mol) of 2-bromo-2-(3-methyl-6-ethoxy-7-methoxy- l,2,3,4-tetrahydroisoquinolinylidene)acetonitrile and 0,27 g (0.0035 mol) of thiocarbamide in 50 ml of methanol is refluxed for 10 minutes, then it is evaporated in vacuo. The residue is crystallized from ethyl acetate to obtain 1.5 g of the title compound, mp: 158-163 °C. (decomp.) The solution of 1,7 g (0,0036 mol) of S-[α-cyano-α-(3-methyl-6-ethoxy-7- methoxy-l,2,3,4-tetrahydro-isoquinolinylidene)methyl]isothiuronium bromide in 50 ml of methanol and 25 ml of 5 m/m% sodium hydroxide is refluxed for 1.5 hours, then to the reaction mixture 0,76 g (0,004 mol) of 4-(2-chloroethyl)morpholinium chloride is added and refluxed for 3 hours. Methanol is removed in vacuum, the residue is extracted with the mixture of 30 ml of water and 30 ml of dichloromethane. The organic layer is dried over sodium sulfate, evaporated and chromatographed on a silicagel column using toluene/m ethanol 10: 1 eluent. Thus
0,16 g of the title compound of the general formula (I) is obtained, mp: 104-105 °C.
Example 2
2-(2-Morpholinoethylthio)-2-(4,4-dimethyl-6-ethoxy-7-methoxy-l,2,3,4- tetrahydroisoquinoIinylidene)acetonitriIe monohydrochloride
In the general formula (I) R1 stands for ethyl group, R2 for methyl group, RJ for hydrogen atom, R4 for methyl group, R5 for hydrogen atom, R6 for methyl group, R7 for methyl group, R8 for hydrogen atom. R9 for hydrogen atom, R10 means mo holino group, X means sulfur atom, m is 1 , n is 1.
a.) 2-bromo-2-(4,4-dimethyl-6-ethoxy-7-methoxy- 1,2.3, 4-tetrahydro- isoquinolinylidene)acetonitrile
In a similar manner as described in Example 1, starting from 2-(4,4-dimethyl-6- ethoxy-7-methoxy- 1 ,2,3,4-tetrahydroisoquinolinylidene)acetonitrile the title compound was obtained, mp.: 158-160 °C.
b.) S-[α-cyano-α-(4,4-dimethyl-6-ethoxy-7-methoxy-l,2.3,4-tetrahydro- isoquinolinylidene)methyl]isothiuronium bromide
The bromo derivative obtained in Example 2a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 145-148 °C.
c.) The above isothiuronium salt was treated as described in Example lc), to obtain the title compound, mp.: 206-209 °C.
d.) 1.61 g (0.0036 mol) of the compound obtained in 2c) was dissolved in 20 ml of water-free ethanol and the solution was acidified with ethanolic hydrogen chloride solution to pH=2 and cooled down. The precipitated title monohydrochloride salt was filtered off, washed with ethanol to obtain 1.35 g of the salt, mp.: 210-212 °C. Example 3
(±)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
In the general formula (I) R stands for ethoxy group, R~ for methoxy group, R" for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2)z-group
7 S O
- wherein the value of z is 4, R stands for hydrogen atom, R and R stand for hydrogen atoms, R means morpholino group, X means sulfur atom, m is 1. n is 1.
a.) 2-bromo-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
In a similar manner as described in Example 1, starting from 2-(9-ethoxy-8- methoxy-l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C.
b.) S-[α-cyano-α-(9-ethoxy-8-methoxy-l,2.3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)methyl]isothiuronium bromide
The bromo derivative obtained in Example 3a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180-182 °C.
c.) The above isothiuronium salt was treated as described in Example lc). to obtain the title compound, mp.: 103-106 °C. Example 4
(±)-cis-2-[2-Morpholino-(l-methyl)ethylthio]-2-(9-ethoxy-8-methoxy- 1,2,3, 4,4a, 5,6, 10b-octahydrophenanthridin-6-yIidene)acetonitrile
In the general formula (I) R stands for ethoxy group, R" for methoxy group, RJ for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2)7-group
7 8
- wherein the value of z is 4. R stands for hydrogen atom. R stands for hydrogen atom, R9 stands for methyl group, R ° means morpholino group. X means sulfur atom, m is 1 , n is 1.
a.) 2-bromo-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6, 10b-octahydrophenanthridin-6- ylidene)acetonitrile
In a similar manner as described in Example 1 , starting from 2-(9-ethoxy-8- methoxy-l,2,3,4,4a,5,6, 10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C.
a.) S-[α-cyano-α-(9-ethoxy-8-methoxy- 1 ,2.3,4,4a,5,6, 10b- octahydrophenanthridin-6-ylidene)methyl]isothiuronium bromide
The bromo derivative obtained in Example 4a) was treated as described in Example lb) to obtain the title isothiuronium salt, mp: 180-182 °C.
c.) The above isothiuronium salt was treated with 4-[(2-chloro-l- methyl)ethyl]morpholinium chloride in a similar manner as described in Example lc) to obtain the title compound, mp.: 59-60 °C. Example 5
(±)-cis-2-[2-Morpholino-(l,l-dimethyl)ethyIthio]-2-(9-ethoxy-8-methoxy- l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-yIidene)acetonitrile
1 9 In the general formula (I) R stands for ethoxy group. R~ for methoxy group, RJ for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2)z-group
7 R
- wherein the value of z is 4, R stands for hydrogen atom, R stands for methyl group, R9 stands for methyl group, R10 means morpholino group, X means sulfur atom, m is 1 , n is 1.
a.) 2-bromo-2-(9-ethoxy-8-methoxy-l,2,3,4,4a.5.6.10b-octahydrophenanthridin-6- ylidene)acetonitrile
In a similar manner as described in Example 1. starting from 2-(9-ethoxy-8- methoxy-l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C.
b.) S-[α-cyano-α-(9-ethoxy-8-methoxy-l,2,3,4.4a.5,6, 10b- octahydrophenanthridin-6-ylidene)methyl] isothiuronium bromide
The bromo derivative obtained in Example 5a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180- 182 °C.
c.) The above isothiuronium salt was treated with 4-[(2-chloro-l , l - dimethyl)ethyl]morpholinium chloride in a similar manner as described in Example lc) to obtain the title compound, mp.: 71-72 °C. Example 6
(±)-cis-2-(2-Pyrrolidinoethylthio)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
1 9 "* In the general formula (I) R stands for ethoxy group, R" for methoxy group. RJ for hydrogen atom, R4 for hydrogen atom, R5 and R form together a - (CH2)z-group, wherein the value of z is 4, R7 stands for hydrogen atom, R8 and R9stand for hydrogen atoms, R means pyrrolidino group. X means sulfur atom, m is 1. n is 1.
a.) 2-bromo-2-(9-ethoxy-8-methoxy- 1 ,2,3 ,4,4a.5,6, 1 Ob-octahydrophenanfhridin-6- ylidene)acetonitrile
In a similar manner as described in Example 1 , starting from 2-(9-ethoxy-8- methoxy-l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C.
b.) S-[α-cyano-α-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b-octahydrophenanthridin- 6-ylidene)methyl]isothiuronium bromide
The bromo derivative obtained in Example 6a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180-182 °C.
c.) The above isothiuronium salt was treated with 4-(2-chloroethyl)pyrrolidinium chloride in a similar manner as described in Example lc) to obtain the title compound, mp.: 102-104 °C. Example 7
(±)-cis-2-(2-Piperidinoethylthio)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-yIidene)acetonitrile
1 9 " In the general formula (I) R stands for ethoxy group, R~ for methoxy group, R~ for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2)z-gτoup,
7 S Q wherein the value of z is 4. R stands for hydrogen atom, R and R stand for hydrogen atoms, R means piperidino group, X means sulfur atom, m is 1, n is 1.
a.) 2-bromo-2-(9-ethoxy-8-methoxy- 1,2,3, 4,4a,5, 6, 1 Ob-octahydrophenanthridin-6- ylidene)acetonitrile
In a similar manner as described in Example 1, starting from 2-(9-ethoxy-8- methoxy- 1 ,2, 3, 4,4a, 5, 6, 10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C.
b.) S-[α-cyano-α-(9-ethoxy-8-methoxy-l, 2,3,4 ,4a,5,6,10b-octahydrophenanthridin- 6-ylidene)methyl]isothiuronium bromide
The bromo derivative obtained in Example 7a) was treated as described in Example lb), to obtain the title isothiuronium salt, mp: 180-182 °C.
c.) The above isothiuronium salt was treated with 4-(2-chloroethyl)piperidinium chloride in a similar manner as described in Example lc) to obtain the title compound, mp.: 98-100 °C. Example 8
(±)-cis-2-(2-Pyrrolidinoethoxy)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
1 9 ■"" In the general formula (I) R stands for ethoxy group. R" for methoxy group, RJ for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2)z-group, wherein the value of z is 4. R7 stands for hydrogen atom. R8 and R9 stand for hydrogen atoms, R1 means pyrrolidino group, X means oxygen atom, m is 1 , n is 1.
a.) 2-bromo-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6.10b-octahydrophenanthridin-6- ylidene)acetonitrile
In a similar manner as described in Example 1, starting from 2-(9-ethoxy-8- methoxy-l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C.
b.) The above 2-bromo derivative was reacted with 2-pyrrolidinoethanol to obtain the title compound, mp.: 135-136 °C.
Example 9
(±)-cis-2-(2-Piperidinoethoxy)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
In the general formula (I) R stands for ethoxy group, R for methox} group, RJ for hydrogen atom, R4 for hydrogen atom, R3 and R6 form together a - (CH2)z-group,
7 8 0 wherein the value of z is 4. R stands for hydrogen atom, R and R stand for hydrogen atoms, R10 means piperididino group, X means oxygen atom, m is 1. n is 1. a.) 2-bromo-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6, 10b-octahydrophenanthridin-6- ylidene)acetonitrile
In a similar manner as described in Example 1. starting from 2-(9-ethoxy-8- methoxy- 1 ,2.3 ,4,4a,5.6, 10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C.
b.) The above 2-bromo derivative was reacted with 2-piperidinoethanol to obtain the title compound, mp.: 104-105 °C.
Example 10 (±)-cis-2-(2-MorphoIinoethoxy)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
1 9 "*
In the general formula (I) R stands for ethoxy group, R~ for methoxy group, RJ for hydrogen atom, R4 for hydrogen atom, R5 and R6 form together a - (CH2) -group.
7 K Q wherein the value of z is 4, R stands for hydrogen atom, R and R stand for hydrogen atoms, R10 means morpholino group, X means oxygen atom, m is 1 , n is 1.
a.) 2-bromo-2-(9-ethoxy-8-methoxy- 1,2,3, 4,4a,5, 6,1 Ob-octahydrophenanthridin-6- ylidene)acetonitrile
In a similar manner as described in Example 1. starting from 2-(9-efhoxy-8- methoxy-l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile the title compound was obtained, mp.: 154-158 °C. b.) The above 2-bromo derivative was reacted with 2-morpholinoethanol to obtain the title compound, mp.: 99-101 °C.
Example 11
(-)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5,6,10b- octahydrophenanthridin-6-ylidene)acetonitrile
The (-)-cis-2-(9-ethoxy-8-methoxy- 1,2,3, 4,4a,5,l Ob-octahydrophenanthridin-6- ylidene)acetonitrile of the general formula (IV), prepared by the process described in patent application DE- 19613091, by resolution with dibenzoyl tartaric acid, was treated as described in Example 3, to obtain the title compound, mp.: 121- 122 °C, [α] - -87,8° ( c - 1.5, ethanol)
From the appropriate (+) isomer of the compound of the general formula (IV) in a similar manner the (+)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy- l,2,3,4,4a,5,6,10b-octahydrophenanthridin-6-ylidene)acetonitrile was obtained, mp: 1 18-120 °C.
Biological investigations
PDE4 enzyme inhibitory activities of the compounds of the general formula (I) were determined by the following two-step method:
The standard assay mixture contains: 30 μl human PDE4 enzyme
20 μl of one of the test compounds of the general formula (I) or its solution
20 μl [3H] cAMP substrate (220000 dpm)
30 μl 40 mM Tris buffer (pH=7,6) containing 2,5mM magnesium sulfate The reaction is initiated by addition of the substrate. The samples are incubated at
30 °C for 30 min., then the reaction is stopped by boiling the assay tubes for 2 min.
After cooling the tubes 50 μl of the poison of the Crotalux atrox snake species (0.5 mg/ml distilled water) is added and the samples are incubated at
37°C for 30 min. The nonreacted cAMP is removed by chromatography on Dowex
1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min. The mixture of 500 ml supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [Η] adenosine.
To investigate the selectivity of the compounds of the general formula (I) inhibitory activities against PDE2, PDE3 and PDE5 enzymes were also determined- Inhibitory activity against PDE2 enzyme was determined by the following two-step method:
The standard assay mixture contains: 30 μl human PDE2 enzyme
20 μl of one of the test compounds of the general formula (I) or its solution 20 μl [3H] cAMP substrate (220000 dpm) 30 μl 40 mM Tris buffer (pH=7.6) containing 2,5mM magnesium sulfate
The reaction is initiated by addition of the substrate. The samples are incubated at 30 °C for 20 min., then the reaction is stopped by boiling the assay tubes for 2 min. After cooling the tubes 50 μl of the poison of the Crotalux atrox snake species (0.5 mg/ml distilled water) is added and the samples are incubated at 37°C for 30 min. The nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min. The mixture of 500 ml supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [Η] guanosine. Inhibitory activity of the compounds of the general formula (I) against PDE3 enzyme was determined by the following two-step method:
The standard assay mixture contains: 30 μl human PDE3 enzyme
20 μl of one of the test compounds of the general formula (I) or its solution 20 μl [3H] cAMP substrate (220000 dpm) 30 μl 40 mM Tris buffer (pFI=7.6) containing 2,5mM magnesium sulfate.
The reaction is initiated by addition of the substrate. The samples are incubated at 30 °C for 20 min., then the reaction is stopped by boiling the assay tubes for 2 min. After cooling the tubes 50 μl of the poison of the Crotalux atrox snake species (0,5 mg/ml distilled water) is added and the samples are incubated at 37°C for 30 min. The nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min. The mixture of 500 ml supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [Η] adenosine.
Inhibitory activity of the compounds of the general formula (I) against PDE5 enzyme was determined by the following two-step method:
The standard assay mixture contains: 30 μl human PDE5 enzyme
20 μl of one of the test compounds of the general formula (I) or its solution 20 μl [3H] cAMP substrate (220000 dpm) 30 μl 40 mM Tris buffer (pH=7.6) containing 2.5mM magnesium sulfate. The reaction is initiated by addition of the substrate. The samples are incubated at 30 °C for 20 min., then the reaction is stopped by boiling the assay tubes for 2 min. After cooling the tubes 50 μl of the poison of the Crotalux atrox snake species (0,5 mg/ml distilled water) is added and the samples are incubated at 37°C for 30 min. The nonreacted cAMP is removed by chromatography on Dowex 1x8 (chloride form) ion-exchange resin: 1 ml of Dowex is added to the sample and after vortex-mixing the resin is left to settle at room temperature for 60 min. The mixture of 500 μl supernatant and of 2 ml of the liquid scintillation cocktail is measured to determine the amount of formed [JFI] guanosine.
The following results were obtained: (the investigated compounds of the general formula (I) are designated with the number of the Example of their preparation).
Figure imgf000023_0001
The compounds of the general formula (I) exhibit very high selectivity for the PDE4 enzyme.
The compounds of the general formula (I) show favourable chemical stability, in biological media they have favourable metabolic stability both in vitro and in vivo, they are readily absorbed in vitro on CaCo2 model, as well as in vivo after oral administration as compared to the known PDE4 inhibitors. They exhibit good bioavailability and isoenzyme selectivity. Furthermore, their duration of effect after intravenous and oral administration is long, their ED50 value is low and they have favourable toxicology- and side-effect profile. All the above features make the compounds of the general formula (I) in all probability suitable for therapeutic use and demonstrate their advantage over the known PDE4 inhibitory compounds.

Claims

Claims
1. Compounds of the general formula (I)
- wherein
R1 stands for straight or branched Cμ alkyl or C4.6 cycloalkyl group. R~ stands for straight or branched Cι.4 alkyl or C4.6 cycloalkyl group.
R3 stands for hydrogen atom or straight or branched Ct. alkyl,
R4 stands for hydrogen atom or straight or branched C].4 alkyl,
R5 stands for hydrogen atom or straight or branched Cj.4 alkyl,
R6 stands for hydrogen atom or straight or branched Cj.4 alkyl, R7 stands for hydrogen atom or straight or branched C]_4 alkyl, with the proviso that one substituent selected from the groups of R , R , R or R always has a meaning different from hydrogen atom, or R5 or R6 mean together a
-(CH2)Z- group - wherein z is 3 or 4 or 5,
R stands for hydrogen atom or a straight or branched Cι_4 alkyl group, R9 stands for hydrogen atom or a straight or branched Cj. alkyl group,
R10 means saturated 4 to 7 membered ring containing one or two nitrogen atom(s) connecting through the nitrogen atom and optionally substituted by a Cj.4 alkyl group or a saturated 4 to 7 membered ring containing one nitrogen atom and one oxygen atom connecting through the nitrogen atom and optionally substituted by a C]_4 alkyl group,
X stands for sulfur atom or oxygen atom, m is zero or 1, n is 1 - and their salts, solvates, isomers and their salts.
2. Compounds of the general formula (I) according to Claim 1
- wherein
R stands for methyl or ethyl group,
R stands for methyl or ethyl group,
R stands for hydrogen atom, R stands for hydrogen atom or methyl group, R5 stands for hydrogen atom or methyl group,
R6 stands for hydrogen atom or methyl group,
R7 stands for hydrogen atom or methyl group, with the proviso that one substituent selected from the groups of R4, R\ R6 or R7 always has a meaning different from hydrogen atom, or R3 and R6 mean together a
-(CH2)Z- group - wherein z is 3 or 4 or 5, with the proviso that in that case the meaning of R and R7 is different from methyl group.
R8 stands for hydrogen atom or methyl group,
R9 stands for hydrogen atom or methyl group, R10 stands for pyrrolidino, piperidino, piperazino or 4-methylpiperazino or morpholino group,
X stands for sulfur atom, m is 1, n is 1 - and their salts, solvates, isomers and their salts.
3. Compounds of the general formula (I) according to Claim 1
- wherein
R1 stands for methyl or ethyl group, R stands for methyl or ethyl group,
RJ stands for hydrogen atom,
R4 stands for hydrogen atom or methyl group,
R5 stands for hydrogen atom or methyl group,
R6 stands for hydrogen atom or methyl group, R7 stands for hydrogen atom or methyl group, with the proviso that one substituent selected from the groups of R4, R\ R6 or R7 always has a meaning different from hydrogen atom, or R~ and R mean together a
-(CH2)Z- group - wherein z is 3 or 4 or 5, with the proviso that in that case the meaning of R4 and R7 is different from methyl group, R stands for hydrogen atom or methyl group, R9 stands for hydrogen atom or methyl group.
R10 stands for pyrrolidino, piperidino, or morpholino group,
X stands for oxygen atom, m is 1 , n is 1 - and their salts, solvates, isomers and their salts.
4. 2-(2-Morpholinoethylthio)-2-(3-methyl-6-ethoxy-7-methoxy-l ,2,3.4- tetrahydroisoquinolinyliden)acetonitrile and its salts and solvates.
5. 2-(2-Moφholinoethylthio)-2-(4,4-dimethyl-6-ethoxy-7-methoxy-1.2,3,4- tetrahydoisoquinolinyliden)acetonitrile and its salts and solvates.
6. (±)-cis-2-(2-Morpholinoethylthio)-2-(9-ethoxy-8-methoxy-l,2,3,4,4a,5, 6,10b-octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
7. (-)-cis-2-(2- Morpholinoethylthio)-2-(9-ethoxy-8-methoxy-l,2.3,4.4a,5, 6,10b-octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
8. (+)-cis-2-(2-Moφholinoethylthio)-2-(9-ethoxy-8-methoxy-l,2.3.4,4a,5. 6,10b-octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
9. (±)-cis-2-[2-Morpholino-(l-methyl)ethylthio]-2-(9-ethoxy-8-methoxy- l,2,3,4,4a,5,6, 10b-octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
10. (±)-cis-2-[2-Moφholino-( 1 , 1 -dimethyl)ethylthio]-2-(9-ethoxy-8-methoxy- l,2,3.4.4a,5,6,10b-octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
11. (±)-cis-2-(2-Pyrrolidinoethylthio)-2-(9-ethoxy-8-methoxy-1.2.3,4,4a.5,6, 10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
12. (±)-cis-2-(2-Piperidinoethylthio)-2-(9-ethoxy-8-methoxy-l ,2.3.4,4a.5,6,10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
13. (±)-cis-2-(2-Pyrrolidinoethoxy)-2-(9-ethoxy-8-methoxy-l,2.3.4,4a.5,6.10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
14. (±)-cis-2-(2-Piperidinoethoxy)-2-(9-ethoxy-8-methoxy-l,2,3.4.4a,5,6, 10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
15. (+)-cis-2-(2-Morpholinoethyoxy)-2-(9-ethoxy-8-methoxy-l,2.3,4,4a,5,6,10b- octahydrophenanthridine-6-yliden)acetonitrile and its salts and solvates.
16. Pharmaceutical compositions characterized in that, they contain one or more of the compounds of the general formula (I) - wherein the meanings of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and the value of m and n are the same as defined in claim 1 - and/or their salts, solvates, racemic or optically active geometric isomers and the salts, solvates thereof, and one or more excipients used in the pharmaceutical industry.
17. Pharmaceutical compositions according to claim 16 characterized in that, they contain one or more of the compounds of the general formula (I) according to claims 2 or 3 or their racemic or optically active geometric isomers or their salts, solvates and one or more excipients used in the pharmaceutical industry.
18. Pharmaceutical compositions according to claim 16 characterized in that, they contain a compound of the general formula (I) that falls under claims 4-15.
19. Pharmaceutical composition useful in the treatment of diseases developing due to abnormally high PDE4 concentration as for instance asthma, chronic obstructive pulmonary disease (COPD) or rheumatoid arthritis characterized in that, they contain one or more of the compounds of the general formula (I) - wherein the meaning of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and the value of m and n are the same as defined in claim 1 - or their geometric or optical isomers and the salts, solvates thereof.
20. Use of the compounds of the general formula (I) - wherein the meanings of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and the value of m and n are the same as defined in claim 1 - in the treatment of diseases developing due to abnormally high PDE4 concentration, as for instance asthma, chronic obstructive pulmonary disease (COPD) or rheumatoid arthritis.
21. Process for the preparation of the compounds of the general formula (I) wherein the meanings of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10. X and the value of m and n are the same as defined in claim 1 , characterized in that,
a.) an isothiuronium salt the general formula (II) - wherein the meanings of R1. R2. RJ, R4, R3, R6, R7 are the same as defined in claim 1- is reacted with a halogen derivative of the general formula (V) or with its salt - wherein the meanings of R8. R , R10' m and n are the same as defined in claim 1 or b.) a halogen derivative of the general formula (III) - wherein the meanings of R1, R2, RJ, R4, R5, R6, R7 are the same as defined in claim 1- is reacted with a hydroxy - derivative of the general formula (IV) - wherein the meanings of R8, R9, R10' m and n are the same as defined in claim 1 - and if desired, the resulting compound of the general formula (I) is transformed into its salt, or it is liberated from its salt, it is separated into its isomers or it is transformed into its solvate or it is liberated from its solvate.
22. Compounds of the general formula (II), wherein the meanings of R1, R2, RJ R4, R3, R6 and R7 are the same as defined in claim 1.
1 9 "* 23. Compounds of the general formula (III), wherein the meanings of R , R , R" . R4, R5, R6 and R7 are the same as defined in claim 1.
24. Process for the preparation of the compounds of the general formula (II) - wherein the meanings of R1, R2, R R4, R3, R6, and R7 are the same as defined in claim 1 - characterized in that, a compound of the general formula (III) - wherein the meanings of R1. R2. RJ, R4, R5, R6, and R7 are the same as defined in claim 1 - is reacted with thiocarbamide.
25. Process for the preparation of the compounds of the general formula (III) - wherein the meanings of R1, R2, R3, R4. R\ R6, and R7 are the same as defined in claim 1 - characterized in that, a compound of the general formula (IV) - wherein the meanings of R1, R2, RJ, R4, R\ R6. and R7 are the same as defined in claim 1 - is reacted with bromine or a brominating agent.
PCT/HU2001/000024 2000-02-28 2001-02-27 Isoquinoline derivatives as pde4 inhibitors WO2001064647A1 (en)

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HU0000920A HUP0000920A3 (en) 2000-02-28 2000-02-28 Pde4 inhibitor isoquinolinylidene derivatives, process for their preparation and medicaments containing them

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US20130237527A1 (en) * 2010-04-08 2013-09-12 Boehringer Ingelheim International Gmbh Combinations of medicaments, containing pde4-inhibitors and ep4-receptor-antagonists
WO2019154395A1 (en) * 2018-02-06 2019-08-15 中国科学院上海药物研究所 Tetrahydroisoquinoline compound, preparation method therefor, pharmaceutical composition containing same, and use thereof
RU2792034C2 (en) * 2018-02-06 2023-03-15 Шангхаи Институте Оф Материа Медика, Чайнесе Академи Оф Сайнсес Tetrahydroisoquinoline compound, its production method, pharmaceutical composition containing such a compound, and its use

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EP1755589A1 (en) * 2004-04-23 2007-02-28 Celgene Corporation Methods of using and compositions comprising pde4 modulators for the treatment and management of pulmonary hypertension
EP1755589A4 (en) * 2004-04-23 2007-11-07 Celgene Corp Methods of using and compositions comprising pde4 modulators for the treatment and management of pulmonary hypertension
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CN111712491B (en) * 2018-02-06 2023-11-17 中国科学院上海药物研究所 Tetrahydroisoquinoline compounds, preparation method thereof, pharmaceutical composition containing compounds and application of compounds

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