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WO2002040449A1 - Dihydroisoquinolines as novel phosphodiesterase inhibitors - Google Patents

Dihydroisoquinolines as novel phosphodiesterase inhibitors Download PDF

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Publication number
WO2002040449A1
WO2002040449A1 PCT/EP2001/012909 EP0112909W WO0240449A1 WO 2002040449 A1 WO2002040449 A1 WO 2002040449A1 EP 0112909 W EP0112909 W EP 0112909W WO 0240449 A1 WO0240449 A1 WO 0240449A1
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eth
denotes
phenyl
hydrogen
denotes hydrogen
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PCT/EP2001/012909
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French (fr)
Inventor
Gerhard Grundler
Beate Schmidt
Armin Hatzelmann
Josef Stadlwieser
Geert Jan Sterk
Steffen Weinbrenner
Wolfram Steinhilber
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Altana Pharma Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano
  • R1 denotes hydrogen
  • R1 denotes hydrogen
  • R3 denotes hydrogen or methoxy
  • R2 denotes chlorine
  • R' and R" both denote hydrogen or together represent a bond
  • R2 denotes chlorine
  • R1 denotes hydrogen
  • R2 denotes hydrogen, fluorine or chlorine
  • R' and R" both denote hydrogen
  • R3 denotes hydrogen or methoxy
  • R4 denotes N(H)-C(0)-R6 in which
  • R4 denotes N(H)-C(0)-N(H)-R7 in which
  • Reaction scheme 2 shows, by way of example, how compounds of the formula I, in which R1 , R2 and R3 have the abovementioned meanings and R4 denotes N(H)-C(0)-R6 or N(H)-C(0)-N(H)-R7, can be prepared.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of the formula I, in which R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarboxyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or dl-1-4C-alkylaminocarbonyl and R4 denotes C(O)-X-R5, N(H)-C(O)-R6 or N(H)-C(O)-N(H)-R7, in which X denotes O or N(H), are effective PDE7 inhibitors.

Description

DIHYDROISOQUINOLINES AS NOVEL PHOSPHODIESTERASE INHIBITORS
Use of the invention
The invention relates to novel phosphodiesterase inhibitors which are used in the pharmaceutical industry for producing drugs.
Known technical background
The Journal of Medicinal Chemistry 1979, Vol. 22, No. 4, pp. 348-352 describes, among other compounds, 6,7-dimethoxy-1-phenyl-3,4~dihydroisoquinolines which inhibit cAMP phosphodiesterases better than the nonspecific PDE inhibitor theophylline. PDE7 inhibitors are described in the German Laid-Open specifications DE19953024, DE19953025 and DE19953414 and in the International Patent Applications WO00/68230, WO01/29049 and WO01/36425.
Description of the invention
It has now been found that the compounds of the formula I, which are described in more detail below, possess surprising and particularly advantageous properties.
The invention relates to compounds of the formula i
Figure imgf000002_0001
in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and
R2 denotes hydrogen, R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl and
R4 denotes C(0)-X-R5, N(H)-C(0)-R6 or N(H)-C(0)-N(H)-R7, in which X denotes O or N(H),
R5 denotes hydrogen, 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3,3,1]hept-2- yl, 3-7C-alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzylpiperidin-4-yl, mor- pholin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1- methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1 -methoxycarbonyl- 3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl, or 4-methylthiazol-5-yl-eth- 2-yl, or represents a benzyl-, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl,
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl,
1 -acetylpiperidin-4-yl, Ar1 or Ar2-CH=CH-, where
Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol- 5-yl, 2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3- trifluoromethylphenyl, 3-methoxyphenyl or pyridin-3-yl, R7 represents 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkylthio, 1-4C-alkoxy, 1-4C-alkoxy which is entirely or predominantly substituted by fluorine, 1-4C- alkylcarbonyl and phenoxy, and also the salts of these compounds.
1-4C-alkyl represents a straight-chain or branched alkyl radical having from 1 to 4 carbon atoms. Examples which may be mentioned are the butyl-, isobutyl-, sec-butyl-, tert-butyl-, propyl-, isopropyl- and, preferably, the ethyl and methyl radical.
3-7C-alkenyl represents straight-chain or branched alkenyl radicals having from 3 to 7 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl radical (allyl radical).
3-7C-alkynyl represents straight-chain or branched alkynyl radicals having from 3 to 7 carbon atoms. Examples which may be mentioned are the 2-pentynyl, 2-butynyl, 3-butynyl and, preferably, the 2-propynyl radical (propargyl radical).
3-7C-cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
2 3-7C-cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. The 3-5C cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl may be mentioned as being preferred.
1-4C-alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having from 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and, preferably, the ethoxy and the methoxy radical.
Examples of 1-4C-alkoxy which is entirely or predominantly substituted by fluorine which may be mentioned are the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and the 1 ,2,2-trifluoroethoxy radical, and, in particular, the 1 ,1 ,2,2-te.rafluoroethoxy, the 2,2,2-trifluoroethoxy and the trifluoromethoxy radical, and, preferably, the difluoromethoxy radical. In this connection, "predominantly" denotes that more than half the hydrogen atoms are replaced with fluorine atoms.
1-4C-alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl[CH30-C(0)~] and the ethoxycarbonyl[CH3CH20-C(0)-] radical.
In addition to the nitrogen atom, mono- or di-1-4C-alkylamino radicals contain one or two, respectively, of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the N-methyl, the N-ethyl, the N-isopropyl, the N,N-dimethyl and the N,N-disopropylamino radical.
1-4C-alkylthio represents a radical which, in addition to the sulfur atom, contains one of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the methylthio radical and the eth- ylthio radical.
1 -4C-alkylcarbonyl represents a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-4C-alkyl radicals. The acetyl radical may be mentioned by way of example.
1-4C-alkylcarbonyl-1-4C-alkyl represents a 1-4C-alkyl radical which is substituted by one of the above- mentioned 1-4C-alkylcarbonyl radicals. The 4-oxopentyl radical may be mentioned by way of example.
Aminocarbonyl-1-4C-alkyl represents a 1-4C-alkyl radical which is substituted by an aminocarbonyl radical. The 1-aminocarbonyl-eth-1-yl radical may be mentioned by way of example.
Examples of substituted phenyl radicals R7 which may be mentioned are 3-trifluoromethylphenyl, 2-tri- fluoromethylphenyl, 3,5-bis-trifluoromethylphenyl, 4-methylphenyl, 4-tert-butylphenyl, 2-acetylphenyl, 4-acetylphenyl, 4-phenoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3-cyanophenyl, 3-methylsulfanylphenyl, 3-chloro-2-methoxyphenyl and 3,4-difluorophenyl.
3 Depending on the substitution, all acid addition salts or all salts with bases are suitable salts for compounds of the formula I. Those which may in particular be mentioned are the pharmacologically tolerated salts of the inorganic and organic acids and bases which are customarily used in pharmacy. Salts which are suitable as such are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, gluconic acid, benzoic acid, 2-(4-hydroxylbenzoyl) benzoic acid, butyric acid, sulfosali- cylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, em- bonic acid, stearic acid, toluenesulfonic acid, methane sulfonic acid and 3-hydroxy-2-naphthoic acid, with the acids being employed, when preparing the salt, in an equimolar quantity ratio, or a quantity ratio which diverges from this, depending on whether the acid is monobasic or polybasic and depending on which salt is required.
On the other hand, salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali metal salts (lithium, sodium and potassium salt), or calcium, aluminum, magnesium, titanium, ammonium, meglumin or guanidinium salts, with, in this case too, the bases being employed, when preparing the salt, in an equimolar quantity ratio or in a quantity ratio which diverges from this.
Pharmacologically untolerated salts, which can be formed initially as process products, for example when preparing the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerated salts using methods with which the skilled person is familiar.
The skilled person is familiar with the fact that both the compounds according to the invention and their salts can contain varying quantities of solvents, for example when they are isolated in crystalline form. The invention therefore also encompasses all solvates, and, in particular, all hydrates, of the compounds of the formula I and also all solvates and, in particular, all hydrates, of the salts of the compounds of the formula I.
One aspect of the invention is represented by compounds of the formula I*,
Figure imgf000005_0001
in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and
R2 denotes hydrogen, and
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl,
R4 denotes C(0)-X-R5, N(H)-C(0)-R6 or N(H)-C(0)-N(H)-R7, in which X denotes O or N(H),
R5 denotes 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicycIo[3,3,1]hept-2-yl, 3-7C- alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2- yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzylpiperidin-4-yl, morpholin-4-yl- eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1- methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl- 3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl, or 4-methylthiazol-5-yl-eth- 2-yl, or represents a benzyl-, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl,
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl,
1-acetylpiperidin-4-yl, AM or Ar2-CH=CH-, where
Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol- 5-yl, 2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3- trifluoromethylphenyl, 3-methoxyphenyl or pyridin-3-yl, R7 represents 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyI-eth-1- yl, thiophen-2-yleth-1-yl or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C- alkylthio, 1-4C-alkoxy, 1-4C-alkoxy which is entirely or predominantly substituted by fluorine, 1- 4C-alkylcarbonyl and phenoxy, and also the salts of these compounds.
One embodiment (embodiment A) of the invention is represented by compounds of the formula I, in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R2 denotes hydrogen,
R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl,
R4 denotes C(0)-X-R5, in which X denotes O or NH,
R5 denotes hydrogen, 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2- yl, 3-7C-alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2- pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzyl-piperidin-4-yl, mor- pholin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1-methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxy- carbonyl-3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl, or
4-methylthiazol-5-yl-eth-2-yl, or represents a benzyl, phenyl-eth-1-yl or 1 -methoxycarbonyl-2- phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl, and also the salts of these compounds.
Compounds of embodiment A which are to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen and
R2 denotes chlorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen or 1-4C-alkoxy, and
R4 denotes C(0)-X-R5 in which X denotes O or NH,
R5 denotes hydrogen, 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2- yl, 3-7C-aIkynyl, methylcarbonyl-2-4C-alkyl, aminocarbonyl-2-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-y I methyl, N-methylpiperidin-3-yl, 1-benzyl-piperidin-4-yl, mor- pholin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1- methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl- 3-methylsulfanyl-eth-1 -yl, 1 -methoxycarbonyl-2-thiazol-2-yl-eth-1 -yl or 4-methylthiazol-5-yl-eth- 2-yl, or represents a benzyl, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl or phenyl, and also the salts of these compounds.
Compounds of embodiment A which are particularly to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen and
R2 denotes chlorine,
R' and R" both denote hydrogen,
6 R3 denotes hydrogen or methoxy, and
R4 denotes C(0)-X-R5, in which X denotes O or NH,
R5 denotes hydrogen, 1-4C-alkyl, cyclopropylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2-yl, propargyl, 2-oxopentyl, 1-aminocarbonyl-eth-1-yl, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1 -benzyl-piperidin-4-yl, morpholin-4-yl-eth-2-yl, morpholin-4-yI-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1-methoxycarbonyl-2- indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methylsulfanyl-eth- 1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl or 4-methylthiazo!-5-yl-eth-2-yl, or represents a benzyl, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl, and also the salts of these compounds.
Preferred compounds of embodiment A of the compounds of the formula I are those in which
R1 denotes hydrogen and
R2 denotes chlorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen, and
R4 denotes C(0)-X-R5 in which
X denotes O,
R5 denotes hydrogen, and also the salts of these compounds.
Another embodiment (embodiment B) of the invention is represented by compounds of the formula I in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and
R2 denotes hydrogen,
R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and
R4 denotes C(0)-X-R5 in which X denotes O or NH,
R5 denotes 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2-yl, 3-7C- alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2- yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzyl-piperidin-4-yl, morpholin-4-yl- eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl,
1 -methoxycarbonyl-2-indol-3-yl-eth-1 -yl, 1 ,3-bis-methoxycarbonylprop-1 -yl,
7 1 -methoxycarbonyl-3-methylsulfanyl-eth-1 -yl, 1 -methoxycarbonyl-2-thiazol-2-yl-eth-1 -yl or 4-methylthiazol-5-yl-eth-2-yl, or represents a benzyl, phenyl-eth-1-yl or 1-methoxycarbonyl-2- phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl or phenyl, and also the salts of these compounds.
Compounds of embodiment B which are to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen and
R2 denotes chlorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen or 1-4C-alkoxy, and
R4 denotes C(0)-X-R5 in which X denotes O or NH,
R5 denotes 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2-yl, 3-7C- alkynyl, methylcarbonyl-2-4C-alkyl, aminocarbonyl-2-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2- yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1 -benzyl-piperidin-4-yl, morpholin-4-yl- eth-2-yl, morphoiin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl,
1-methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl,
1 -methoxycarbonyl-3-methylsulfanyl-eth-1 -yl, 1 -methoxycarbonyl-2-thiazol-2-yl-eth-1 -yl, or 4-methylthiazol-5-yl-eth-2-yl, or represents a benzyl, phenyl-eth-1-yl or 1 -methoxycarbonyl-2- phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl or phenyl, and also the salts of these compounds.
Compounds of embodiment B which are particularly to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen and
R2 denotes chlorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen, and
R4 denotes C(0)-X-R5 in which X denotes O or NH,
R5 denotes n-butyl, cyclopropylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2-yl, propargyl, 2-oxopentyl, 1-aminocarbonyl-eth-1-yl, furan-2-yl methyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3- ylmethyl, N-methylpiperidin-3-yi, 1-benzyl-piperidin-4-yl, morpholin-4-yl-eth-2-yi, morpholin-4- yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1-methoxycarbonyl-2-indol-3-yl-eth- 1 -yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methylsulfanyl-eth-1-yl, 1-meth- oxycarbonyl-2-thiazol-2-yl-eth-1-yl or 4-methylthiazol-5-yl-eth-2-yl, or represents a benzyl, phe- nyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl or phenyl, and also the salts of these compounds.
Another embodiment (embodiment C) of the invention is represented by compounds of the formula I in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R2 denotes hydrogen,
R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and R4 denotes N(H)-C(0)-R6 in which
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl,
1-acetylpiperidin-4-yl, AM or Ar2-CH=CH-, where
AM represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl,
2-methyIpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl,
3-methoxyphenyl or pyridin-3-yl, and also the salts of these compounds.
Compounds of embodiment C which are to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen and
R2 denotes hydrogen, fluorine or chlorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen or 1-4C-alkoxy, and
R4 denotes N(H)-C(0)-R6 in which
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl, 1- acetylpiperidin-4-yl, AM or Ar2-CH=CH-, where
AM represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl,
2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl,
3-methoxyphenyl or pyridin-3-yl, and also the salts of these compounds.
Compounds of embodiment C which are particularly to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen, R2 denotes hydrogen, fluorine or chlorine, R' and R" both denote hydrogen, R3 denotes hydrogen or methoxy, and R4 denotes N(H)-C(0)-R6 in which
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl, 1- acetylpiperidin-4-yl, AM or Ar2-CH=CH-, where
AM represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl,
2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl,
3-methoxyphenyl or pyridin-3-yl, and also the salts of these compounds.
Another embodiment (embodiment D) of the invention is represented by compounds of the formula I in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and
R2 denotes hydrogen,
R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and
R4 denotes N(H)-C(0)-N(H)-R7 in which
R7 represents 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1- yl, thiophen-2-yleth-1-yl, or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, 1-4-C-alkyl, trifluoromethyl, 1-4C- alkylthio, 1-4C-alkoxy, 1-4C-alkoxy which is entirely or predominantly substituted by fluorine, 1- 4C-alkylcarbonyl and phenoxy, and also the salts of these compounds.
Compounds of embodiment D which are to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen and
R2 denotes hydrogen or fluorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen or 1-4C-alkoxy, and
R4 denotes N(H)-C(0)-N(H)-R7 in which
R7 denotes 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3,5-bis- trifluoromethylphenyl, 4-methylphenyl, 4-tert-butylphenyl, 2-acetylphenyl, 4-acetylphenyl, 4-phenoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3-cyanophenyl,
3-methylsulfanylphenyl, 3-chloro-2-methoxyphenyl or 3,4-difluorophenyl, and also the salts of these compounds.
Compounds of embodiment D which are particularly to be emphasized are those compounds of the formula I in which
R1 denotes hydrogen and
R2 denotes hydrogen or fluorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen, and
R4 denotes N(H)-C(0)-N(H)-R7 in which
R7 denotes n-butyl, allyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yieth-1-yI, 3-trifluoromethylphenyl, 2-trifluoromethylphenyi, 3,5-bis-trifluoromethylphenyl, 4-methylphenyl, 4-tert-butylphenyl, 2-acetylphenyl, 4-acetylphenyl, 4-phenoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3-cyanophenyl, 3-methylsulfanylphenyl, 3-chloro-2-methoxyphenyl or 3,4-difluorophenyl, and also the salts of these compounds.
The reaction schemes 1 and 2 demonstrate, by way of example, how the compounds of the formula I according to the invention can be prepared.
Reaction scheme 1 shows, by way of example, how compounds of the formula I, in which R1 , R2 and R3 have the abovementioned meanings and R4 denotes C(0)-X-R5, can be prepared. Proceeding from suitably substituted phenylethylamines (compounds of the formula IV), an acylation with mono- ester derivatives of terephthalic acid (compounds of the formulae Ilia and lllb) is carried out in a first step.
The acylation can be carried out in accordance with any known acylation method, for example activation of the acid group by converting it into the acid chloride or an acid anhydride, or else using the known amide coupling reagents, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide and N- dimethylaminoethyl-N'-ethyl-carbodiimide, etc.
In a second step, the dihydroisoquinoline ring system is constructed by means of a condensation reaction. The condensation is effected in a manner known to the skilled person, for example in accordance with BischlerNapieralski (J. Chem. Soc, 1956, 4280-4282), in the presence of a suitable condensing agent, for example polyphosphoric acid, phosphorus pentachloride, phosphorus pentoxide or, preferably, phosphorus oxytrichloride, in a suitable inert solvent, for example in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon, such as toluene or xylene, or another insert solvent, such as acetonitrile, or without any further solvents when using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling temperature of the solvent and/or condensing agent employed. The condensation of the compounds of the formula lla directly yields compounds of the formula I in which X is oxygen.
The condensation of the compounds of the formula lib leads to dihydroisoquinoline derivatives of the formula I in which X denotes oxygen and R5 represents a methyl group. These can be converted into other compounds of the formula I by hydrolysis, by reacting with amines of the formula R5-NH2 or by reacting with alcohols of the formula R5-OH.
Alcohols of the formula R5-OH, or amines of the formula R5-NH2, in which R5 has the abovementioned meanings, and compounds of the formulae Ilia, llib and IV, in which R1 , R2, R3 and R5 have the abovementioned meanings, are either known or can be prepared using methods with which the skilled person is familiar.
Reaction scheme 2 shows, by way of example, how compounds of the formula I, in which R1 , R2 and R3 have the abovementioned meanings and R4 denotes N(H)-C(0)-R6 or N(H)-C(0)-N(H)-R7, can be prepared.
Proceeding once again from suitably substituted phenylethyl amines (compounds of the formula IV), an acylation with derivatives of para-nitrobenzoic acid (compounds of the formula VIII) is carried out in a first step.
In a second step, the compounds of the formula VII are cyclocondensed to form compounds of the formula VI.
The acylation and the condensation are carried out in analogy with the method described in relation to reaction scheme 1.
By means of using selective reduction methods, the resulting nitro-substituted dihydroisoquinoline derivatives (compounds of the formula VI) are subsequently converted into the corresponding amino- substituted dihydroisoquinoline derivatives (compounds of the formula V).
Examples of suitable selective reduction methods which may be mentioned are various metal/acid systems, such as Fe/HOAc or SnCI2/HCI, or else catalytic hydrogenation. The reduction is preferably effected by means of catalytic transfer hydrogenation using ammonium formate and palladium on charcoal (e.g. as described in the following examples).
The reaction of the amino-substituted dihydroisoquinoline derivatives (compounds of the formula V) with acids of the formula R6-C(0)-OH finally yields the compounds of the formula I according to the invention in which R4 denotes N(H)-C(0)-R6.
12 Alternatively, reaction of the amino-substituted dihydroisoquinoline derivatives (compounds of the formula V) with isocyanates of the formula R7-N=C=0 yields the compounds of the formula I according to the invention in which R4 denotes N(H)-C(0)-N(H)-R7.
Compounds of the formulae IV and VII in which R1 , R2 and R3 have the abovementioned meanings, acids of the formula R6-C(0)-OH in which R6 has the abovementioned meanings, and isocyanates of the formula R7-N=C=0 in which R7 has the abovementioned meanings, are either known or can be prepared using methods with which the skilled person is familiar.
Reaction Scheme 1 :
Figure imgf000014_0001
13 Reaction Scheme 2:
Figure imgf000015_0001
Figure imgf000015_0002
14 In the above reaction schemes 1 and 2, the synthesis of compounds of the formula I, wherein R' and R" both denote hydrogen, is outlined. Compounds in which R' and R" together represent a bond are obtained by selective oxidation, e. g. with oxygen under basic conditions.
Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol, such as ethanol or isopropanol), which contains the desired acid or base, or to which the desired acid or base is subsequently added. The salts are isolated by filtering, reprecipitat- ing, precipitating with a nonsolvent for the addition salt, or by evaporating off the solvent. Salts which are obtained can be converted, by alkalinizing or acidification, into the free compounds, which can be converted once again into salts. In this way, pharmacologically untolerated salts can be converted into pharmacologically tolerated salts. .
The following examples serve to explain the invention in more detail without limiting it. It is likewise possible to prepare other compounds of the formula I, whose preparation is not explicitly described, in an analogous manner, or in a manner with which the skilled person is familiar, using customary process techniques.
In the examples, MS stands for atmospheric pressure chemical ionization mass spectrometry (APCI- MS) or electron impact ionization mass spectrometry (EI-MS), calc. for calculated and f. for found. The compounds mentioned in the examples, and their salts, are preferred subject matter of the invention.
Examples
End products
1aa. 1-[4-(3-fluorobenzyl-aminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
64.4 mg of 1-(4-carboxyphenyl)-7-chloro-3,4-dihydroisoquinoline hydrochloride (compound 1 bh), 38 μl of diisopropylethylamine and 2.5 mg of dimethylaminopyridine are dissolved in 800 μl of dichloromethane and 800 μl of a 0.25 molar solution of 3-fluorobenzylamine in dichloromethane are then added. 400 μ) of a 0.55 molar solution of N-dimethylaminoethyl-N'-ethy)-carbodiimide in dichloromethane are then added and the reaction mixture is stirred at RT for 16 h. Following flash chromatography on silica gel, 42 mg of the title compound are obtained.
1H NMR (200MHz, D6-DMSO): δ = 2.75 (m,2H), 3.78 (m,2H), 4.53 (d,J=5.9Hz,2H), 7.04-7.22 (m,4H), 7.37-7.44 (m,2H), 7.54 (dd,J=8.1 Hz,J=2.1 Hz,1 H), 7.63 (m,1 H), 7.67 (m,1 H), 7.97 (m,1 H). 8.01 (m,1 H), 9.18 (t,J=5.9Hz,1 H).
MS: calc: C23H18CIFN20 (392.86) f.: [M+1] 393.2
The following are obtained in accordance with this procedure:
1ab. 1-[4-((2-Pyridin-2-yl-eth-1-yl)oxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C23H19CIN202 (390.87) f.: [M+1] 391.0
1ac. 1-[4-((N-Methylpiperidin-3-yl)oxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C22H23ClN2θ2 (382.89) f.: [M+1] 383.1
1ad. 1-[4-((1-Aminocarbonyl-eth-1-yl)oxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C19H17CIN202 (356.81 ) f.: [M+1] 357.0
1ae. 1-[4-((Morpholin-4-yl-eth-2-yl)oxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C^HzaCINzOs (398.89) f.: [M+1] 399.0
1af. 1-[4-(Prop-2-ynoxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C19H14CIN02 (323.78) f.: [M+1] 324.1 lag. 1-[4-(4-Oxopentyloxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C21H2oCIN03 (369.85) f.: [M+1] 370.0
1ah. 1-[4-((4-Methylthiazol-5-yl-eth-2-yl)oxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C22H19CIN202S (410.93) f.: [M+1] 411.1
1ai. 1-[4-(Chroman-4-oxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C25H2oCIN03 (417.90) f.: [M+1] 417.8
1ak. 1-[4-(Cyclopropylmethyloxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C20H18CINO2 (339.82) f.: [M+1] 340.0
1al. 1-[4-(2,4-Difluorobenzyloxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C23H16CIF2N02 (411.84) f.: [M+1] 412.2
1am. 1-[4-(2,2-Dimethylpropyloxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C21H22CIN02 (355.87) f.: [M+1] 356.1
1an. 1-[4-((4-Chlorophenyleth-2-yl)oxycarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C24H19CI2N02 (424.33) f.: [M+1] 424.0
1ao. 1-[4-((1-Methoxycarbonyl-2-phenyl-eth-2-yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydro- isoquinoline
MS: calc: C26H23CIN203 (446.94) f.: [M+1] 447.1
lap. 1 -[4-((1 ,3-Bismethoxycarbonylprop-1 ■yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydro- isoquinoline
MS: calc: C23H23CIN205 (442.90) f.: [M+1] 443.1
17 1aq. 1-[4-((1-Methoxycarbonyl-3-methylsulfanyl-eth-1-yl)aminocarbonyl)phenyl]-7-chloro-3,4- dihydroisoquinoline
MS: calc: C22H23CIN203S (430.96) f.: [M+1] 431.1
1ar. 1 -[4-((1 -Methoxycarbonyl-2-indol-3-yl-eth-1 -yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihy- droisoquinoline
MS: calc: C28H24CIN303 (485.97) f.: [M+1] 486.1
1as. 1-[4-(4-(1-Benzylpiperidine)aminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C28H28CIN30 (458.01 ) f.: [M+1] 458.1
1at. 1-[4-((1- ethoxycarbonyl-2-thiazol-2-yl-eth-1-yl)aminocarbonyl)phenyl]-7-chloro-3,4-di- hydroisoquinoline
MS: calc: C24H21C1N203 (452.96) f.: [M+1] 453.0
1au. 1-[4-((1-Methoxycarbonyl-2-(3,5-bistrifluoromethylphenyl)eth-1-yl)aminocarbonyl)phenyl]- 7-chloro-3,4-dihydroisoquinoline
MS: calc: C28H21CIF6N203 (582.93) f.: [M+1] 583.1
1av. 1-[4-((6,6-Dimethylbicyclo[3,3,1]hept-2-yl)methylaminocarbonyl)phenyl]-7-chloro-3,4- dihydroisoquinoline
MS: calc: C26H29CIN20 (420.99) f.: [M+1] 421.1
law. 1-[4-((2-Methoxyeth-1-yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C19H19CIN202 (342.83) f.: [M+1] 343.1
1ax. 1-[4-(Cyclopropylmethylaminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C20H19CIN2O (338.84) f.: [M+1] 339.1
lay. 1-[4-((2-Morpholin-4-yl-eth-1-yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C22H24CIN302 (397.91) f.: [M+1] 398.1
18 1az. 1-[4-((2-Pyridin-3-yl)methylaminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C22H18CIN30 (375.86) f.: [M+1] 376.2
1ba. 1-[4-(Butylaminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C20H21CIN2O (340.86) f.: [M+1] 341.2
1bb. 1-[4-((2-Benzo[1,3]dioxol-4-yl-eth-1-yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydroiso- quinoline
MS: calc: C25H21CIN203 (432.91 ) f.: [M+1] 433.1
1bc. 1 -[4-((1 -Phenyleth-1 -yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C24H21C1N20 (388.90) f.: [M+1] 389.2
1bd. 1-[4-((2-(4-Fluorophenyl)eth-1-yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C24H20CIFN2O (406.89) f.: [M+1] 407.2
1be. 1-[4-((2-(3,4-Dichlorophenyl)eth-1-yl)aminocarbonyl)phenyl]-7-chloro-3,4-dihydroiso- quinoline
MS: calc: C24H19CI3N20 (457.79) f.: [M+1] 459.1
1bf. 1-[4-((Furan-2-yl)methylaminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C21H17CIN202 (364.83) f.: [M+1] 365.2
1bg. 1-[4-((Biphenyl-3-yl)methylaminocarbonyl)phenyl]-7-chloro-3,4-dihydroisoquinoline
MS: calc: C29H23CIN20 (450.97) f.: [M+1] 451.2
1bh. 1-(4-Carboxyphenyl)-7-chloro-3,4-dihydroisoquinoline hydrochloride
4.6 g of 1-(4-methoxycarbonylphenyl)-7-chloro-3,4-dihydroisoquinoline (Compound 1 bk) are suspended in 50 ml of water and 22 ml of cone hydrochloric acid and heated to 80°C. The reaction mixture is stirred at this temperature for 6 h. It is cooled down and the resulting precipitate is filtered off with suction, washed with water and dried. 3.98 g of the title compound are obtained. 1H NMR (200MHz, D6-DMSO): δ = 3.24 (m,2H), 4.03 (m,2H), 7.35 (d,J=2.2Hz,1 H), 7.67 (d,J=8.3Hz,1 H), 7.87-7.92 (m,3H), 8.19-8.23 (m,2H).
1bk. 1-(4- ethoxycarbonylphenyl)-7-chloro-3,4-dihydroisoquinoline
15 g of 2-(4-chlorophenyl)ethylamine and 18 g of monomethyl terephthalate are dissolved in 600 ml of dichloromethane. 22.9 g of N-dimethylaminoethyl-N'-ethylcarbodiimide are added and the reaction mixture is stirred at RT for 16 h. It is extracted with in each case 250 ml of 1 N hydrochloric acid, saturated sodium hydrogen carbonate solution and water, and the organic phase is dried over magnesium sulfate. It is concentrated and the residue is thoroughly stirred in diethyl ether/n-hexane, filtered off with suction and dried.
The resulting amide is suspended in 1500 ml of absolute toluene, after which 37 g of phosphorus pentoxide are added and the mixture is heated to boiling. After 4 h, a further 37 g of phosphorus pentoxide are added and the reaction mixture is kept at boiling temperature for a further 16 h. It is then cooled down and 300 ml of water are carefully added; the mixture is then brought to pH 8 using 40% sodium hydroxide solution. The organic phase is separated off and the aqueous phase is extracted a further 3 times with 150 ml of ethyl acetate; the combined organic extracts are then dried over magnesium sulfate. They are concentrated and the residue is purified by flash chromatography on silica gel. The product is thoroughly stirred in ethanol, filtered off with suction and dried. 15.7 g of the title compound are obtained.
1H NMR (200MHz, D6-DMSO): δ = 2.75 (m,2H), 3.78 (m,2H), 3.89 (s,3H), 7.07 (d,J=2.1 Hz,1 H), 7.49 (m,1 H), 7.55 (dd,J=8,0Hz,J=2.1 Hz,1 H), 7.66 (m,1 H), 7.70 (m,1 H), 8.04 (m,1 H), 8.08 (m,1 H).
1bl. 1-(4-Carboxy-3-methoxyphenyl)-7-chloro-3,4-dihydroisoquinoline hydrochloride
The title compound is obtained analogously to the procedure described for example 1 bh.
MS: calc: C17H14CIN03 ΗCI (315.76) f.: [M+1] 316.2
1H NMR (200MHz, D6-DMSO): δ = 3.21-3.28 (m,2H), 3.90 (s,3H), 3.96-4.02 (m,2H), 7.32 (d,J=9.3Hz,1 H), 7.43-7.67 (m,3H), 7.76-7.78 (m,1 H), 7.86 (d,J=7.8Hz,1 H).
1bm. 1-(3-Methoxy-4-methoxycarbonylphenyl)-7-chloro-3,4-dihydroisoquinoline
The title compound is obtained analogously to the procedure described for example 1 bk.
MS: calc: C18H16CIN03 (329.79) f.: [M+1] 330.2 1H NMR (200MHz, D6-DMSO): δ = 2.73-2.81 (m,2H), 3.73-3.81 (m,2H), 7.12 (dd,J=7.9Hz,J=1.3Hz,1 H), 7.19 (d,J=8.3,1 H), 7.27 (d,J=1.3Hz,1 H), 7.36 (dd,J=8.3Hz,J=2.1 Hz,1 H), 7.48 (d,J=2.1 Hz,1 H), 7.72 (d,J=7.9Hz,1 H).
2a. 1-[4-n-Butylureidophenyl]-3,4-dihydroisoquinoline
44 mg of 1-[4-aminophenyl]-3,4-dihydroisoquinoline (starting compound A1 ) are dissolved in 800 μl of dichloromethane and 800 μl of a 0.25 molar solution of butyl isocyanate in dichloromethane are then added. The reaction mixture is stirred for 16 h and purified by flash chromatography on silica gel. 19.8 mg of the title compound are obtained.
1H NMR (200MHz, D6-DMSO): δ = 0.90 (t, J=7.1 Hz, 3H), 1.23-1.49 (m,4H), 2.70 (m,2H), 3.10 (m,2H), 3.66 (m,2H), 6.17 (t,J=5.7Hz,1 H), 7.20-7.49 (m,8H), 8.57 (s,1 H).
MS: calc: C20H23N3O (321.43) f.: [M+1] 322.0
The following compounds are obtained in accordance with this procedure:
3a. 1-[4-Allylureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C19H18FN30 (323.37) f.: [M+1] 324.1
3b. 1-[4(3-Trifluoromethylbenzeneureido)phenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C23H17F4N30 (427.41 ) f.: [M+1] 428.0
3c. 1-[4-n-Butylureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C20H22FN3O (339.42) f.: [M+1] 340.0
3d. 1-[4-Cyclohexylureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C22H24FN30 (365.45) f.: [M+1] 366.1
3e. l-[4-(4-Methylbenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C23H20FN3O (373.43) f.: [M+1] 374.0
3f. 1-[4-(4-Acetylbenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline MS: calc: C24H20FN3O2 (401.44) f.: [M+1] 402.1
3g. 1-[4-(4-Phenoxybenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C28H22FN302 (451.50) f.: [M+1] 452.1
3h. 1-[4-(1-Ethoxycarbonyl-2-phenyleth-1-yl)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C27H26FN303 (459.52) f.: [M+1] 460.0
3i. 1 -[4-(1 -Ethoxycarbonyleth-1 -yl)ureidophenyl]-7-f luoro-3,4-dihydroisoquinoline
MS: calc: C21H22FN303 (383.43) f.: [M+1] 384.1
3k. 1-[4-(Thiophen-2-yleth-1-yl)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C22H20FN3OS (393.49) f.: [M+1] 394.0
31. 1-[4-Benzeneureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C22H18FN30 (359.41 ) f.: [M+1] 360.1
3m. 1-[4-(2,4-Dimethoxybenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C24H22FN303 (419.46) f.: [M+1] 420.1
3n. 1-[4-(2,5-Dimethoxybenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C24H22FN303 (419.46) f.: [M+1] 420.0
3o. 1-[4-(2-Trifluoromethylbenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C23H17F4N30 (427.41) f.: [M+1] 428.0
3p. 1-[4-(3,5-Bistrifluoromethylbenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C24H16F7N30 (495.40) f.: [M+1] 496.0
3q. 1-[4-(3-Cyanobenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C23H17FN40 (364.42) f.: [M+1] 385.1
22 3r. 1-[4-(3-Methylsulfanylbenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C23H20FN3OS (405.50) f.: [M+1] 406.0
3s. 1-[4-(3-Acetylbenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C24H20FN3O2 (401.44) f.: [M+1] 402.0
3t. 1-[4-(3-Chloro-2-methoxybenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C23H19CIFN302 (423.88) f.: [M+1] 424.0
3u. 1-[4-(2,4-Dichlorobenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C23H18CI2FN30 (442.32) f.: [M+1] 442.0
3v. 1-[4-(4-tert-Butylbenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C26H26FN30 (459.52) f.: [M+1] 416.1
3w. 1-[4-(3,4-Difluorobenzene)ureidophenyl]-7-fluoro-3,4-dihydroisoquinoline
MS: calc: C22H16F3N30 (395.39) f.: [M+1] 396.0
4a. 1-[4-(3-Chlorophenyl)carbonylamino)phenyl]-7-chloro-3,4-dihydroisoquinoline
51.3 mg of 1-[4-aminophenyl]-7-chloro-3,4-dihydroisoquinoline (starting compound C2) and 2.5 mg of dimethylaminopyridine are dissolved in 800 μl of dichloromethane and 800 μl of a 0.25 molar solution of 3-chlorobenzoic acid in dichloromethane are then added. 400 μl of a 0.55 molar solution of N-dimethylaminoethyl-N'-ethylcarbodiimide solution in dichloromethane are added and the reaction mixture is stirred at RT for 16 h. Following flash chromatography on silica gel, 49 mg of the title compound are obtained.
1H NMR (200MHz, D6-DMSO): δ = 2.73 (m,2H), 3.73 (m,2H), 7.16 (d,J=2.0Hz,1 H), 7,42 (d,J=8.1 Hz,1 H), 7.51 (d,J=2.2Hz,1 H), 7.55-7.71 (m,4H), 7.87-7.97 (m,3H), 8.03 (m,1 H),10.52 (s,1 H).
MS: calc: C22H16C12N20 (395.29) f.: [M+1] 395.1
The following compounds are obtained in accordance with this procedure: a. 1-[3-Methoxy-4-((2-furan-2-ylethen-1-yl)carbonylamino)phenyl]-7-chloro-3,4-dihydroiso- quinoline
S: calc: C23H19C1N203 (406.87) f.: [M+1] 407.1
b. 1-[3-Methoxy-4-((2-(3-methoxyphenyl)ethen-1-yl)carbonylamino)phenyl]-7-chloro-3,4-di- hydroisoquinoline
S: calc: C26H23N203 (446.94) f.: [M+1] 447.2
c. 1-[3-Methoxy-4-((2-thiophen-2-ylethen-1-yl)carbonylamino)phenyl]-7-chloro-3,4-dihydro- isoquinoline
S: calc: C23H19CIN202S (422.94) f.: [M+1] 423.2
d. 1-[3-Methoxy-4-((2-pyridin-3-ylethen-1-yl)carbonylamino)phenyl]-7-chloro-3,4-dihydroiso- quinoline
S: calc: C24H20CIN3O2 (417.90) f.: [M+1] 418.1
e. 1-[3-Methoxy-4-((2-furan-3-ylethen-1-yl)carbonylamino)phenyl]-7-chloro-3,4-dihydroiso- quinoline
S: calc: C23H19C1N203 (406.87) f.: [M+1] 407.2
f. 1-[3-Methoxy-4-((2-benzothiazol-6-ylethen-1-yl)carbonylamino)phenyl]-7-chloro-3,4-dihy- droisoquinoline
S: calc: C24H18CIN302S (447.95) f.: [M+1] 448.1
a. 1-[4-((3-Phenoxyphenyl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroisoquinoline
S: calc: C28H21FN202 (436.49) f.: [M+1] 437.3
b. 1-[4-((4-Trifluoromethoxyphenyl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroisoquinoline
S: calc: C23H16F4N202 (428.39) f.: [M+1] 429.1
c. 1-[4-((2-Furan-2-ylethen-1-yl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroisoquinoline
S: calc: C22H17FN202 (360.39) f.: [M+1] 361.2 d. 1-[4-((2,4-Dichlorophenoxymethyl)carbonylamino)phenyl]-7-fluoro-3,4- dihydroisoquinoline
S: calc: C23H17CI2FN202 (443.31) f.: [M+1] 443.0
e. 1-[4-((2-tert-Butoxycarbonyl)eth-1-yl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroiso- quinoline
S: calc: C23H26FN303 (411.48) f.: [M+1] 412.0
f. 1-[4-((2-(3-Trifluoromethylphenyl)ethen-1-yl)carbonylamino)phenyl]-7-fluoro-3,4-dihydro- isoquinoline
S: calc: C25H18F4N20 (438.43) f.: [M+1] 439.2
g. 1-[4-((indole-5-yl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroisoquinoline
S: calc: C24H18FN30 (383.43) f.: [M+1] 384.2
h. 1-[4-((2-Methylpyridin-5-yl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroisoquinoline
S: calc: C22H18FN30 (359.41) f.: [M+1] 360.2
i. 1-[4-((Quinolin-6-yl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroisoquinoline
S: calc: C25H18FN30 (395.44) f.: [M+1] 396.2
k. 1-[4-((1-Acetylpiperidin-4-yl)carbonylamino)phenyl]-7-fluoro-3,4-dihydroisoquinoline
S: calc: C23H24FN302 (393.47) f.: [M+1] 394.2
a. 1-[3-Methoxy-4-((2-furan-2-ylethen-1-yl)carbonylamino)phenyl]-3,4-dihydroisoquinoline
S: calc: C23H20N2O3 (372.43) f.: [M+1] 373.2
b. 1-[3-Methoxy-4-((2-(3-methoxyphenyl)ethen-1-yl)carbonylamino)phenyl]-3,4-dihydro- isoquinoline
S: calc: C26H24N203 (412.49) f.: [M+1] 413.2
25 c. 1-[3-IVIethoxy-4-((2-thiophen-2-ylethen-1-yl)carbonylamino)phenyl]-3,4-dihydroiso- quinoline
S: calc: C23H20N2O2S (388.49) f.: [M+1] 389.1
d. 1-[3-Methoxy-4-((2-pyridin-3-ylethen-1-yl)carbonylamino)phenyl]-3,4-dihydroisoquinoline
S: calc: C24H21N302 (383.45) f.: [M+1] 384.2
e. 1-[3-Methoxy-4-((2-furan-3-ylethen-1~yl)carbonylamino)phenyl]-3,4-dihydroisoquinoline
S: calc: C23H20N2O3 (372.43) f.: [M+1] 373.2
f. 1-[3-Methoxy-4-((2-benzothiazol-6-ylethen-1-yl)carbonylamino)phenyl]-3,4-dihydroiso- quinoline
S: calc: C24H19N302S (413.50) f.: [M+1] 414.2
Starting compounds
A1. 1-(4-Aminophenyl)-3,4-dihydroisoquinoline
7.2 g of 1-(4-nitrophenyl)-3,4-dihydroisoquinoline (starting compound B1) are suspended in methanol and 7.18 g of ammonium formate and 250 mg of palladium on charcoal (10%) are then added. The reaction mixture is stirred at RT for 5 h, filtered through Celite and concentrated. The residue is purified by flash chromatography on silica gel. It is thoroughly stirred in diethyl ether/n-hexane, filtered off with suction and dried. 4.1 g of the title compound are obtained.
1H NMR (200MHz, D6-DMSO): δ = 2.66 (m,2H), 3.60 (m,2H), 5.41 (s,2H), 6.57 (m,1 H), 6.62 (m,1 H), 7.25-7.44 (m,6H).
The following compound is obtained in accordance with this procedure:
A2. 1-(4-Aminophenyl)-7-fluoro-3,4-dihydroisoquinoline
1H NMR (200MHz, D6-DMSO): δ = 2.64 (m,2H), 3.63 (m,2H), 5.47 (s,2H), 6.60 (m,1 H), 6.64 (m,1 H), 7.00 (dd,J=9.7Hz,J=2.6Hz,1 H), 7.26-7.42 (m,4H).
B1. 1-(4-Nitrophenyl)-3,4-dihydroisoquinoline
10.0 g of 2-phenylethylamine are dissolved in 500 ml of dichloromethane and 20 ml of triethylamine. 15.4 g of 4-nitrobenzoyl chloride in dichloromethane are added dropwise while cooling with ice and the reaction mixture is stirred at RT for 16 h. The reaction mixture is then extracted with in each case 250 ml of 1 N hydrochloric acid, a saturated solution of sodium hydrogen carbonate and water, after which the organic phase is dried over magnesium sulfate. The organic phase is concentrated and the residue is thoroughly stirred in diethylether/n-hexane, filtered off with suction and dried.
The resulting amide is suspended in 700 ml of absolute toluene, after which 30 g of phosphorus pentoxide are added and the mixture is heated to boiling. After 4 h, a further 19 g of phosphorus pentoxide are added and the reaction mixture is kept at boiling temperature for a further 16 h. It is then cooled down and 300 ml of water are carefully added; the mixture is then brought to pH 11 with 40% sodium hydroxide solution. The organic phase is separated off and the aqueous phase is extracted a further 3 times with 150 ml of ethyl acetate; the combined organic extracts are then dried over magnesium sulfate. They are concentrated and the residue is purified by flash chromatography on silica gel. The product is thoroughly stirred in isopropanol/diethyl ether, filtered off with suction and dried. 11.9 g of the title compound are obtained.
27 1H NMR (200MHz, D6-DMSO): δ = 2.78 (m,2H), 3.80 (m,2H), 7.13 (d,J=7.7Hz,1H), 7.28-7.52 (m,3H), 7.78 (m,1 H), 7.82 (m,1 H), 8.28 (m,1 H), 8.32 (m,1 H).
The following compound is obtained in accordance with this procedure:
B2. 1-(4-Nitrophenyl)-7-fluoro-3,4-dihydroisoquinoline
1H NMR (200MHz, D6-DMSO): δ = 2.76 (m,2H), 3.82 (m,2H), 6.91 (dd,J=9.4Hz,J=2.4Hz,1 H), 7.29-7.49 (m,2H), 7.80 (m,1H), 7.84 (m,1 H), 8.29 (m,1 H), 8.34 (m,1 H).
C1. 1-(4-Amino-3-methoxyphenyl)-7-chloro-3,4-dihydroisoquinoline
3 g of 1-(3-methoxy-4-nitrophenyl)-7-chloro-3,4-dihydroisoquinoline (starting compound D1) are suspended in methanol and 2.4 g of ammonium formate and 60 mg of palladium on charcoal (10%) are then added. The reaction mixture is stirred at RT for 5 h, filtered through Celite and concentrated. The residue is purified by flash chromatography on silica gel. It is thoroughly stirred in diethyl ether/n- hexane, filtered off with suction and dried. 2.4 g of the title compound are obtained.
1H NMR (200MHz, D6-DMSO): δ = 2.67 (m,2H), 3.64 (m,2H), 3.79 (s,3H), 5.13 (s,2H), 6.66 (d,J=8.0Hz,1 H), 6.88 (dd,J=8.0Hz,J=1.8Hz,1 H), 7.09 (d,J=1.8Hz,1 H), 7.26 (d,J=2.2Hz,1 H), 7.38 (d,J=8.0Hz,1 H), 7.49 (dd,J=8.0Hz,J=2.2Hz,1 H).
The following compounds are obtained in accordance with this procedure:
C2. 1-(4-Aminophenyl)-7-chloro-3,4-dihydroisoquinoline
1H NMR (200MHz, D6-DMSO): δ = 2.65 (m,2H), 3.62 (m,2H), 5.47 (s,2H), 6.63 (d,J=8.6Hz,2H), 7.22- 7.38 (m,4H), 7.47 (dd,J=8.0Hz,J=2.1 Hz,1 H).
C3. 1-(4-Amino-3-methoxyphenyl)-3,4-dihydroisoquinoline
1H NMR (200MHz, D6-DMSO): δ = 2.67 (m,2H), 3.62 (m,2H), 3.78 (s,3H), 5.06 (s, 2H), 6.64 (d,J=8.0Hz,1 H), 6.89 (dd,J=8.0Hz,J=1.8Hz,1 H), 7.10 (d,J=1.8Hz,1 H), 7.29-7.45 (m,4H).
D1. 1-(3-Methoxy-4-nitrophenyl)-7-chloro-3,4-dihydroisoquinoline
6.9 g of 2-(4-chlorophenyl)ethylamine and 10.8 g of 3-methoxy-4-nitrobenzoic acid are dissolved in 400 ml of dichloromethane. 10.5 g of N-dimethylaminoethyl-N'-ethylcarbodiimide are added and the reaction mixture is stirred at RT for 16 h. It is then extracted with in each case 250 ml of 1 N hydrochloric acid, a saturated solution of sodium hydrogen carbonate and water, after which the
28 organic phase is dried over magnesium sulfate. It is concentrated and the residue is thoroughly stirred in diethyl ether/n-hexane, filtered off with suction and dried.
The resulting amide is suspended in 300 ml of absolute toluene, after which 19 g of phosphorus pentoxide are added and the mixture is heated to boiling. After 4 h, a further 19 g of phosphorus pentoxide are added and the reaction mixture is kept at boiling temperature for a further 16 h. It is then cooled down and 300 ml of water are carefully added; the reaction mixture is then brought to pH 11 with 40% sodium hydroxide solution. The organic phase is separated off and the aqueous phase is extracted a further 3 times with 150 ml of ethyl acetate; the combined organic extracts are then dried over magnesium sulfate. They are then concentrated and the residue is purified by flash chromatography on silica gel. The product is thoroughly stirred in isopropanol/diethyl ether, filtered off with suction and dried. 11.35 g of the title compound are obtained.
1H NMR (200MHz, D6-DMSO): δ = 2.77 (m,2H), 3.80 (m,2H), 3.96 (s,3H), 7.16 (d,J=2.1 Hz,1 H), 7.22 (dd,J=8.3Hz,J=1.5Hz,1 H), 7.43 (d,J=8.1 Hz,1 H), 7.48 (d,J=1.5Hz,1 H), 7.55 (dd,J=8.1 Hz,J=2.1 Hz,1 H), 7.97 (d,J=8.3Hz,1 H).
The following compounds are obtained in accordance with this procedure:
D2. 1-(4-Nitrophenyl)-7-chloro-3,4-dihydroisoquinoline
1H NMR (200MHz, D6-DMSO): δ = 2.77 (m,2H), 3.82 (m,2H), 7.09 (d,J=2.1 Hz,1 H), 7.44 (d,J=8.1 Hz,1 H), 7.56 (dd,J=8.1 Hz,J=2.1 Hz,1 H), 7.79 (m,1 H), 7.85 (m,1 H), 8.30 (m,1 H), 8.35 (m,1 H).
D3. 1-(3-Methoxy-4-nitrophenyl)-3,4-dihydroisoquinoline
The title compound was subjected directly to further processing without any physical data being collected.
29 Industrial applicability
Of the 11 phosphodiesterase (PDE) isoenzymes which are presently known, PDE7 was described for the first time, as HCP1 ("high affinity cAMP-specific PDE"), in 1993 (Michaeli T, Bloom TJ, Martins T, Loughney K, Ferguson K, Riggs M, Rodgers L, Beavo JA and Wigler M, Isolation and characterization of a previously undetected human cAMP phosphodiesterase by complementation of cAMP phosphodiesterase-deficient Saccharomyces cerevisiae, J Biol Chem 268: 12925-12932, 1993). According to today's nomenclature, HCP1 is human PDE7A1 ; in addition to this, another human splicing variant of the same gene (PDE7A2) (Han P, Zhu X and Michaeli T, Alternative splicing of the high affinity cAMP-specific phosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart. J Biol Chem 272: 16152-16157, 1997) and a second human PDE7 gene (PDE7B) (Sasaki T, Kotera J, Yuasa K and Omori K, Identification of human PDE7B, a cAMP-specific phosphodiesterase. Biochem Biophys Res Commun 271 : 575-583, 2000) were described in the subsequent years. Individual representatives of the PDE7 isoenzyme are characterized by being particularly prominently expressed in specific areas of the brain (putamen, caudate nucleus), in skeletal muscle, in leukemic T cell lines and in native CD4+ T cells. The induction of PDE7 has been described as being an essential prerequisite for activating T cells (Li L, Yee C and Beavo JA, CD3- and CD28-dependent induction of PDE7 required for T cell activation, Science 283: 848-851 , 1999).
The compounds according to the invention therefore possess valuable pharmacological properties, which make them utilizable in industry, and can be employed as therapeutic agents for the treatment and prophylaxis of diseases in human and veterinary medicine. As selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically of type 7), they are preferably suitable for treating T cell-mediated diseases of an inflammatory nature, for example of the airways (bronchial asthma, COPD), of the skin (dermatoses such as psoriasis and atopic dermatitis), of the kidney (glomerulonephritis), of the pancreas (autoimmune diabetes), of the central nervous system (multiple sclerosis), of the intestine (Crohn's disease, ulcerative colitis), of the eyes (conjunctivitis) and of the joints (rheumatoid arthritis), and, furthermore, for suppressing the T cell activity which is responsible for the rejection of transplanted organs, such as the kidney, the liver, the lung and the heart, and for inhibiting the degenerate proliferation of T cells in various forms of T cell leukemia and other tumors, and possibly for inhibiting the uptake and/or replication of HIV in connection with AIDS. In addition, said compounds are of potential value in treating certain diseases of the brain (such as epilepsy) and of the skeletal muscle (such as muscular atrophy). In this connection, the compounds according to the invention are characterized by low toxicity, good enteral absorption (high bioavailability), great therapeutic breadth and the absence of significant side-effects.
The invention furthermore relates to a method for treating mammals, including humans, which/who are suffering from one of the abovementioned diseases. The method is characterized by the fact that a therapeutically effective and pharmacologically tolerated quantity of one or more of the compounds according to the invention is administered to the affected mammal.
30
SUB ; The invention furthermore relates to the compounds according to the invention for use in the treatment and/or prophylaxis of diseases, in particular said diseases.
The invention likewise relates to the use of the compounds according to the invention for producing drugs which are employed for the treatment and/or prophylaxis of said diseases.
The invention furthermore relates to drugs for the treatment and/or prophylaxis of said diseases, which drugs comprise one or more of the compounds according to the invention.
The invention furthermore relates to a commercial product which consists of a customary secondary packaging means, a primary packaging means (for example an ampoule or a blister pack) which contains the drug, and, if desired, a patient information leaflet, with the drug exhibiting an antagonistic effect toward type 7 cyclic nucleotide phosphodiesterases (PDE7) and leading to the attenuation of the symptoms of diseases which are associated with type 7 cyclic nucleotide phosphodiesterases, and with reference being made, on the secondary packaging means and/or on the patient information leaflet of the commercial product, to the suitability of the drug for use in the prophylaxis or treatment of diseases which are associated with type 7 cyclic nucleotide phosphodiesterases, and with the drug comprising one or more compounds of the formula I according to the invention or a pharmacologically tolerated salt thereof. The secondary packaging means, the primary packaging means containing the drug and the patient information leaflet otherwise correspond to what the skilled person would regard as being the standard for drugs of this nature.
The drugs are produced using methods that are known per se and with which the skilled person is familiar. When employed as drugs, the compounds according to the invention (= active compounds) are either used as such or, preferably, in combination with suitable pharmaceutical auxiliary substances, for example in the form of tablets, sugar-coated tablets, capsules, suppositories, plasters, emulsions, suspensions, gels or solutions, with the content of active compound advantageously being between 0.1 and 95%.
On the basis of his specialist knowledge, the skilled person is familiar with the auxiliary substances which are suitable for the desired drug formulations. In addition to solvents, gel formers, ointment bases and other active compound excipients, it is also possible, for example, to use antioxidants, dispersing agents, emulsifiers, preservatives, solubilizers or permeation promoters.
For the treatment of diseases of the respiratory tract, the compounds according to the invention are preferably also administered by inhalation, preferably in the form of an aerosol, with the aerosol particles of solid, liquid or mixed composition having a diameter of from 0.5 to 10 μm, advantageously of from 2 to 6 μm.
31 The aerosol can be produced, for example, using pressure-driven nozzle nebulizers or ultrasonic nebulizers, advantageously, however, using propellant gas-driven metered aerosols or by means of the propellant gas-free use of micronized active compounds from inhalation capsules.
Depending on the inhalation system employed, the administration forms also contain, in addition to the active compounds, the requisite auxiliary substances, for example propellant gases (e.g. Frigen in the case of metered aerosol), surface-active substances, emulsifiers, stabilizers, preservatives, aromatizing agents, fillers (e.g. lactose in the case of powder inhalers) and, where appropriate, additional active compounds.
For the purposes of inhalation, there are available a large number of appliances which can be used to generate aerosols of optimal particle size and administer them using an inhalation technique which is as appropriate as possible for the patient. In addition to using attachments (spacers and expanders) and pear-shaped containers (e.g. Nebulator® and Volumatic®), and also automatic spray puff releas- ers (Autohaler®) for metered aerosols, a number of technical solutions are available, particularly in the case of the powder inhalers (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhaler described in European Patent Application 0 505 321), which technical solutions can be used to achieve optimal administration of the active compound.
For the treatment of dermatoses, the compounds according to the invention are used, in particular, in the form of drugs which are suitable for topical administration. For producing the drugs, the compounds according to the invention (= active compounds) are preferably mixed with suitable pharmaceutical auxiliary substances and further processed into suitable medicinal formulations. Suitable medicinal formulations which may be mentioned by way of example are powders, emulsions, suspensions, sprays, oils, ointments, greasy ointments, creams, pastes, gels and solutions.
The drugs according to the invention are produced using methods which are known per se. The active compounds are dosed in customary quantities. Thus, topical application forms (such as ointments) for the treatment of dermatoses comprise the active compounds at a concentration of, for example, 0.1- 99%. The dose for administration by inhalation is customarily between 0.1 and 3 mg per day. The customary dose in the case of systemic therapy (oral or i. v.) is between 0.03 and 3 mg per kilogram per day. Biological investigations
Inhibiting the activity of PDE7
Cloning and expression of PDE7: The cDNAs for PDE7A1 and 7A2 (GenBank Acc-#: L12052 and U67932, respectively) were isolated, using RT-PCR, from total cellular RNA derived from the T cell line CCRF-CEM and cloned into the cloning vector pCR2.1 (Invitrogen, Groningen, NL) under standard conditions (the manufacturer's instructions). For expression in insect cells, the cDNAs were subcloned into the baculo expression vector pCRBac (Invitrogen, Groningen, NL).
The recombinant baculoviruses were prepared, by means of homologous recombination in SF9 insect ceils, by cotransfecting the plasmids containing baculovirus DNA (wild type, wt) Bac-N-Blue (Invitrogen, Groningen, NL) for PDE7A1 and containing Baculo-Gold DNA (Pharmingen, Hamburg) using a standard protocol (Pharmingen, Hamburg). Wt virus-free recombinant virus supernatants were selected using plaque assay methods. After that, high-titer virus supernatants were prepared by amplifying 3 times. For determining the enzyme activities, the PDEs were expressed in SF21 cells by infecting 2χ106 cells/ml with an MOI (multiplicity of infection) » 5 in serum-free SF900 medium (Life Technologies, Paisley, UK) in spinner flasks. The cells were cultured at 28°C, and at a rotational speed of 75 rpm, for 48 hours, after which they were pelleted for 5-10 min at 1000 g and 4°C and then resuspended in 1 χ PBS at a concentration of 1-3χ106 cells/ml. The protein content was determined by the Bradford method (BioRad, Munich) using BSA as the standard.
The SF21 insect cells are resuspended, at a concentration of approx. 107 cells/ml, in ice-cold (4°C) homogenization buffer (20 mM Tris, pH 8.2, containing the following additions: 140 mM NaCI, 3.8 mM KCl, 1 mM EGTA, 1 mM MgCl2, 1 mM β-mercaptoethanol, 2 mM benzamidine, 0.4 mM Pefablock, 10 μM leupeptin, 10 μM pepstatin A and 5 μM trypsin inhibitor) and disrupted by ultrasonication. The homogenate is then centrifuged for 10 min at 1000χg and the supernatant is stored at -80°C until subsequent use (see below).
The PDE7 activity was inhibited by said compounds in a modified SPA (scintillation proximity assay) test, supplied by Amersham Pharmacia Biotech (see procedural instructions "Phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090"), carried out in 96-well microtiter plates (MTPs). The test volume is 100 μl and contains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg2+, 0.5 μM cAMP (including about 50,000 cpm of [3H]cAMP), 2 μl of the respective substance dilution in DMSO and sufficient recombinant PDE7A1 (1000χg supernatant, see above) to ensure that 15-20% of cAMP is converted under said experimental conditions. After a preincubation of 5 min at 37°C, the reaction is started by adding the substrate (cAMP) and the assays are incubated for a further 15 min; after that, they are stopped by adding SPA beads (50 μl). In accordance with the manufacturer's instructions, the SPA beads had previously been resuspended in water and diluted 1 :3 (v/v) and added to IBMX (3 mM). After the beads have been sedimented
33 (> 30 min), the MTPs are analyzed in commercially available measuring appliances and the corresponding IC50 values of the compounds for the inhibition of PDE7 activity are determined from concentration-effect curves by means of non-linear regression.
The inhibitory values [inhibitory concentration as -loglC50 (mol/l)] which were determined for the compounds according to the invention are shown in the following table 1 , in which the numbers of the compounds correspond to the numbers of the examples.
Table 1 : Inhibition of PDE7 activity
Figure imgf000035_0001
34

Claims

Patent Claims
1. A compound of the formula
Figure imgf000036_0001
in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R2 denotes hydrogen,
R1 and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl and
R4 denotes C(0)-X-R5, N(H)-C(0)-R6 or N(H)-C(0)-N(H)-R7, in which X denotes O or N(H),
R5 denotes hydrogen, 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3,3,1]hept-2- yl, 3-7C-alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzylpiperidin-4-yl, mor- pholin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1- methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl- 3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl, or 4-methylthiazol-5-yl-eth- 2-yl, or represents a benzyl-, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl,
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl,
1-acetylpiperidin-4-yl, Ar1 or Ar2-CH=CH-, where Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-
5-yl, 2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3- trifluoromethylphenyl, 3-methoxyphenyl or pyridin-3-yl, R7 represents 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkylthio, 1-4C-alkoxy, 1-4C-alkoxy which is entirely or predominantly substituted by fluorine, 1-4C- alkylcarbonyl and phenoxy, or a salt thereof.
2. A compound of the formula I*,
Figure imgf000037_0001
in which either
R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and
R2 denotes hydrogen,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and
R4 denotes C(0)-X-R5, N(H)-C(0)-R6 or N(H)-C(0)-N(H)-R7, in which X denotes O or N(H),
R5 denotes 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2-yl, 3-7C- alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2- yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzyl-piperidin-4-yl, morpholin-4-yl- eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yI, 1- methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl- 3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl, or 4-methylthiazol-5-yl-eth-
2-yl, or represents a benzyl-, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical
36 which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl,
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl, 1-acetylpiperidin- 4-yl, AM or Ar2-CH=CH-, where
Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl, 2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl, 3-methoxyphenyl or pyridin-3-yl,
R7 represents 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkylthio, 1- 4C-alkoxy, 1-4C-alkoxy which is entirely or predominantly substituted by fluorine, 1-4C- alkylcarbonyl and phenoxy, or a salt thereof.
3. A compound of the formula I as claimed in claim 1 , in which either R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and
R2 denotes hydrogen,
R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and
R4 denotes C(0)-X-R5, in which X denotes O or NH,
R5 denotes hydrogen, 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2- yl, 3-7C-alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2- pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1 -benzyl-piperidin-4-yl, mor- pholin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1-methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1 -methoxycar- bonyl-3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl, or 4-methylthiazol-5- yl-eth-2-yl, or represents a benzyl, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl, or a salt thereof.
4. A compound of the formula I as claimed in claim 1 , in which either R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R2 denotes hydrogen,
R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and R4 denotes N(H)-C(0)-R6 in which
R6 denotes 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl, 1-acetyl- piperidin-4-yl, Ar1 or Ar2-CH=CH-, where
Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl,
2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl,
3-methoxyphenyl or pyridin-3-yl, or a salt thereof.
5. A compound of the formula 1 as claimed in claim 1 , in which either R1 denotes hydrogen and
R2 denotes fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or
R1 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and
R2 denotes hydrogen,
R' and R" both denote hydrogen or together represent a bond,
R3 denotes hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and
R4 denotes N(H)-C(0)-N(H)-R7 in which
R7 represents 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1- yl, thiophen-2-yleth-1-yl, or a phenyl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, 1-4-C-alkyl, trifluoromethyl, 1-4C- alkylthio, 1-4C-alkoxy, 1-4C-alkoxy which is entirely or predominantly substituted by fluorine, 1- 4C-alkylcarbonyl and phenoxy, or a salt thereof.
6. A compound of the formula I as claimed in claim 1 , in which R1 denotes hydrogen,
R2 denotes chlorine, R' and R" both denote hydrogen, R3 denotes hydrogen or methoxy and R4 denotes C(0)-X-R5, in which X denotes O or NH,
38
- R5 denotes hydrogen, 1-4C-alkyl, cyclopropylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2-yl, propargyl, 2-oxopentyl, 1-aminocarbonyI-eth-1-yl, furan-2-ylmethyI, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-yImethyl, N-methylpiperidin-3-yl, 1 -benzyl-piperidin-4-yl, morphoIin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yI, chroman-4-yl, 1-methoxycarbonyl~2- indol-3-yI-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methyIsuIfanyl-eth- 1 -yl, 1-methoxycarbonyl-2-thiazol-2-yI-eth-1-yl or 4-methyIthiazol-5-yl-eth-2-yl, or represents a benzyl, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl, or a salt thereof.
7. A compound of the formula I as claimed in claim 1 , in which R1 denotes hydrogen,
R2 denotes chlorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen and
R4 denotes C(0)-X-R5 in which
X denotes O,
R5 denotes hydrogen, or a salt thereof.
8. A compound of the formula I as claimed in claim 1 , in which R1 denotes hydrogen,
R2 denotes chlorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen and
R4 denotes C(0)-X-R5 in which X denotes O or NH,
R5 denotes n-butyl, cyclopropylmethyl, 6,6-dimethylbicyclo[3.3.1]hept-2-yl, propargyl, 2-oxopentyl, 1-aminocarbonyl-eth-1-yl, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3- ylmethyl, N-methylpiperidin-3-yl, 1 -benzyi-piperidin-4-yl, morpholin-4-yl-eth-2-yl, morpholin-4-yl- eth-1-yl, 2-benzo[1 ,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1-methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1 ,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methylsulfanyl-eth-1-yl, 1 -methoxycar- bonyl-2-thiazol-2-yl-eth-1-yl or 4-methyIthiazol-5-yl-eth-2-yl, or represents a benzyl, phenyl-eth-1- yl or 1-methoxycarbonyl-2-phenyl-eth~2-yl radical which is unsubstituted or substituted by one or more radicals selected from the group halogen, trifluoromethyl and phenyl, or a salt thereof.
9. A compound of the formula I as claimed in claim 1 , in which R1 denotes hydrogen,
R2 denotes hydrogen, fluorine or chlorine,
39 R1 and R" both denote hydrogen,
R3 denotes hydrogen or methoxy, and
R4 denotes N(H)-C(0)-R6 in which
R6 denotes 2,4-dichlorophenoxymethyl, 2-.ert-butoxycarbonylamino-eth-1-yl, 1- acetylpiperidin-4-yl, Ar1 or Ar2-CH=CH-, where
Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl,
2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl,
Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl,
3-methoxyphenyl or pyridin-3-yl, or a salt thereof.
10. A compound of the formula I as claimed in claim 1 , in which R1 denotes hydrogen and
R2 denotes hydrogen or fluorine,
R' and R" both denote hydrogen,
R3 denotes hydrogen, and
R4 denotes N(H)-C(0)-N(H)-R7 in which
R7 denotes n-butyl, allyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyI, 3,5-bis-trifluoromethylphenyl, 4-methylphenyl, 4-tert-butyIphenyl, 2-acetylphenyl, 4-acetylphenyl, 4-phenoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3-cyanophenyl, 3-methylsulfanylphenyl, 3-chloro-2-methoxyphenyl or 3,4-difluorophenyl, or a salt thereof.
11. A compound of the formula I as claimed in claim 1 for use in treating diseases.
12. A drug which comprises at least one compound of the formula I as claimed in claim 1 together with customary, pharmaceutical auxiliary and/or carrier substances.
13. The use of compounds of the formula I as claimed in claim 1 , for producing drugs for treating diseases of the respiratory tract.
40
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WO2008119057A2 (en) 2007-03-27 2008-10-02 Omeros Corporation The use of pde7 inhibitors for the treatment of movement disorders
WO2012064667A2 (en) 2010-11-08 2012-05-18 Omeros Corporation Treatment of addiction and impulse-control disorders using pde7 inhibitors
US9220715B2 (en) 2010-11-08 2015-12-29 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
US11207275B2 (en) 2010-11-08 2021-12-28 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
US11464785B2 (en) 2010-11-08 2022-10-11 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
EP4275752A2 (en) 2010-11-08 2023-11-15 Omeros Corporation Treatment of addiction and impulse-control disorders using pde7 inhibitors
WO2017102014A1 (en) * 2015-12-17 2017-06-22 Universite D'aix-Marseille Propenamide thiophene derivatives as flavivirus inhibitors and their use
WO2024038089A1 (en) 2022-08-18 2024-02-22 Mitodicure Gmbh Use of a therapeutic agent with phosphodiesterase-7 inhibitory activity for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and/or exertional intolerance

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