WO2001035936A2 - Use of substituted (quinolin-2-yl-methoxy)phenyl-acyl-sulphonamides and -cyanamides for the treatment of diseases - Google Patents

Use of substituted (quinolin-2-yl-methoxy)phenyl-acyl-sulphonamides and -cyanamides for the treatment of diseases Download PDF

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WO2001035936A2
WO2001035936A2 PCT/EP2000/010919 EP0010919W WO0135936A2 WO 2001035936 A2 WO2001035936 A2 WO 2001035936A2 EP 0010919 W EP0010919 W EP 0010919W WO 0135936 A2 WO0135936 A2 WO 0135936A2
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carbon atoms
chain
straight
branched alkyl
substituted
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PCT/EP2000/010919
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French (fr)
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WO2001035936A3 (en
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William Taylor
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Bayer Aktiengesellschaft
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to the use of known substituted (quinolin-2-yl-methoxy)phenyl- acyl-sulphonamides and -cyanamides for the treatment of diseases.
  • A, B, D, E, L and G are identical or different and represent hydrogen, hydroxyl, halogen, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or a group of the formula -NR 3 R 4 ,
  • R 3 and R 4 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms,
  • R 3 and R 4 have the abovementioned meanings, represent aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms or by a group of the formula -NR 3 R 4 , in which
  • R 3 and R 4 have the abovementioned meanings
  • R 1 represents cycloalkyl having 3 to 14 carbon atoms, which is optionally substituted by straight-chain or branched alkyl having up to 8 carbon atoms,
  • R 2 represents hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, alkoxy having up to 8 carbon atoms, halogen or by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn may be substituted by straight-chain or branched alkyl having up to 8 carbon atoms, halogen, nitro, hydroxyl or cyano, or represents cycloalkyl having 3 to 8 carbon atoms which is optionally substituted by straight-chain or branched alkyl having up to 8 carbon atoms, or
  • X - represents a group of the formula -SO 2 -R 5 , in which
  • R 5 denotes trifluoromethyl or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, halogen, cyano, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen, nitro, cyano or straight-chain or branched alkyl or alkoxy in each case having up to 8 carbon atoms, or denotes aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro, cyano, hydroxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, trifluoromethyl or trifluoro- mefhoxy, or
  • X represents cyano
  • physiologically acceptable salts are preferred.
  • Physiologically acceptable salts of the substituted (quinolin-2-yl-methoxy)phenyl- acyl-sulphonamides and -cyanamides may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids.
  • Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Salts in the context of the present invention are also salts of the monovalent metals, such as alkali metals, and the ammonium salts. Sodium salts, potassium salts and ammonium salts are preferred.
  • the compounds according to the invention may exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers).
  • the invention relates both to the antipodes and to the racemates, and also to the diastereomeric mixtures.
  • the racemates like the diastereomers, can be separated into the stereoisomerically homogeneous constituents in a known manner (cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).
  • Preferred compounds of the general formula (I) are those in which
  • A, B, D, E, L and G are identical or different and
  • R 3 and R 4 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl,
  • R 3 and R 4 have the abovementioned meanings, represent phenyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms or by a group of the formula -NR 3 R 4 , in which R 3 and R 4 have the abovementioned meanings,
  • R 1 represents cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cyclooctyl, cyclodecyl or cyclododecyl, each of which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms,
  • R 2 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, alkoxy having up to 6 carbon atoms, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl or phenyl, which in turn may be substituted by straight-chain or branched alkyl having up to 6 carbon atoms, fluorine, chlorine or bromine or represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms, or represents sodium or potassium
  • X - represents a group of the formula -SO 2 -R 5 , in which
  • R 5 denotes trifluoromethyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, alkoxycarbonyl in each case having up to 6 carbon atoms or by phenyl, which in turn may be substituted by fluorine, chlorine, bromine or by straight- chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms, or - denotes phenyl which is optionally substituted by fluorine, chlorine, bromine, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, trifluoromethyl or
  • X represents cyano
  • A, B, D, E, L and G are identical or different and represent hydrogen, fluorine, chlorine, bromine, nitro and trifluoromethyl, represent methyl, ethyl, propyl, isopropyl, butyl or tert.butyl, R 1 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclodecyl or cyclododecyl, each of which is optionally substituted by methyl, ethyl, propyl or isopropyl,
  • R 2 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl or - represents sodium,
  • X - represents a group of the formula -SO 2 -R 5 , in which
  • R 5 denotes trifluoromethyl, straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, which in turn is substituted by fluorine, chlorine or by straight-chain or branched alkyl having up to 4 carbon atoms, or denotes phenyl which may optionally be substituted by fluorine, chlorine or straight-chain or branched alkyl having up to 4 carbon atoms, or
  • X represents cyano
  • acylsulphonamides and acylcyanamides of the general formula (I) according to the invention can be employed as active compounds in medicaments.
  • the compounds act particularly as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism, in particular lipoxygenase.
  • the pharmacological activity data of the substances according to the invention are determined by the following method:
  • LTB 4 leucotriene B 4
  • PMNL polymorphonuclear rats leucocytes
  • the active compounds can be administered orally or parenterally.
  • parenteral administration forms of administration to the mucous membranes (i.e. buccal, lingual, sublingual, rectal, nasal, pulmonary, conjunctival or intravaginal) or into the interior of the body are particularly suitable.
  • Administration can be carried out by avoiding absorption (i.e. intracardiac, intra-arterial, intravenous, intraspinal or intralumbar administration) or by including absorption (i.e. intracutaneous, subcutaneous, percutaneous, intramuscular or intraperitoneal administration).
  • the active compounds can be administered per se or in administration forms.
  • Suitable administration forms for oral administration are, inter alia, normal and enteric-coated tablets, capsules, coated tablets, pills, granules, pellets, powders, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
  • Suitable administration forms for parenteral administration are injection and infusion solutions.
  • the active compound can be presented in the administration forms in concentrations of from 0 - 100% by weight; preferably the concentration of the active compound should be 0.5-90% by weight, i.e. quantities which are sufficient to allow the specified range of dosage.
  • the active compounds can be converted in the known manner into the abovementioned administration forms using inert non-toxic pharmaceutically suitable auxiliaries, such as for example excipients, solvents, vehicles, emulsifiers and/or dispersants.
  • auxiliaries such as for example excipients, solvents, vehicles, emulsifiers and/or dispersants.
  • auxiliaries can be mentioned as examples: water, solid excipients such as ground natural or synthetic minerals (e.g. talcum or silicates), sugar (e.g. lactose), non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), emulsifying agents, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulphate).
  • ground natural or synthetic minerals e.g. talcum or silicates
  • sugar e.g. lactose
  • non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), emulsifying agents, dispersants (e.g. polyvinylpyrrolidone) and
  • tablets can of course also contain additives such as sodium citrate as well as additives such as starch, gelatin and the like.
  • Flavour enhancers or colorants can also be added to aqueous preparations for oral administration.
  • the quantity is about 0.01 to 100 mg/kg, preferably about 0.1 to 10 mg/kg of body weight.

Abstract

Use of (quinolin-2-yl-methoxy)phenylacyl-sulphonamides and -cyanamides of formula (I), in which A, B, D, E, L and G are identical or different and represent hydrogen, hydroxyl, halogen, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or a group of the formula -NR3R4, in which R?3 and R4¿ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms, represent straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 12 carbon atoms, represent aryl having 6 to 10 carbon atoms, R1 represents cycloalkyl having 3 to 8 carbon atoms; R2 represents hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, represents an alkali metal, represents cycloalkyl having 3 to 8 carbon atoms; X represents a group of the formula -SO2-R5, in which R5 denotes trifluoromethyl or straight-chain or branched alkyl having up to 10 carbon atoms, or denotes aryl having 6 to 10 carbon atoms; or X represents cyano for the treatment and prevention of glomerular nephritis, lung cancer, multiple sclerosis, ocular inflammation, osteoporosis, reperfusion injury and tinnitus.

Description

Use of substituted (quinolin-2-vI-methoxy)phenyl-acyl-sulphonamides and -cvanamides for the treatment of diseases
Field of the Invention
The invention relates to the use of known substituted (quinolin-2-yl-methoxy)phenyl- acyl-sulphonamides and -cyanamides for the treatment of diseases.
Background
It is known that substituted (quinolin-2-yl-methoxy)phenylacyl-sulphonamides and -cyanamides are useful in the treatment of inflammatory diseases (EP-A-399 291).
Summary of the Invention
It has now been found that substituted (quinolin-2-yl-methoxy)phenylacyl-sulphon- amides and -cyanamides of the general formula (I)
Figure imgf000002_0001
in which
A, B, D, E, L and G are identical or different and represent hydrogen, hydroxyl, halogen, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or a group of the formula -NR3R4,
in which
R3 and R4 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms,
- represent straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 12 carbon atoms, and each of which is optionally substituted by hydroxyl, halogen, nitro, cyano or a group of the formula -NR3R4, in which R3 and R4 have the abovementioned meanings, represent aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms or by a group of the formula -NR3R4, in which
R3 and R4 have the abovementioned meanings,
R1 represents cycloalkyl having 3 to 14 carbon atoms, which is optionally substituted by straight-chain or branched alkyl having up to 8 carbon atoms,
R2 represents hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, alkoxy having up to 8 carbon atoms, halogen or by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn may be substituted by straight-chain or branched alkyl having up to 8 carbon atoms, halogen, nitro, hydroxyl or cyano, or represents cycloalkyl having 3 to 8 carbon atoms which is optionally substituted by straight-chain or branched alkyl having up to 8 carbon atoms, or
X - represents a group of the formula -SO2-R5, in which
R5 denotes trifluoromethyl or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by hydroxyl, halogen, cyano, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in turn may be substituted by halogen, nitro, cyano or straight-chain or branched alkyl or alkoxy in each case having up to 8 carbon atoms, or denotes aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, nitro, cyano, hydroxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, trifluoromethyl or trifluoro- mefhoxy, or
X represents cyano
and their physiologically acceptable salts can be used for the treatment and prevention of glomerular nephritic, lung cancer, multiple sclerosis, ocular inflammation, osteoporosis, reperfusion injury and tinnitus. Detailed Description of the Invention
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the substituted (quinolin-2-yl-methoxy)phenyl- acyl-sulphonamides and -cyanamides may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Salts in the context of the present invention are also salts of the monovalent metals, such as alkali metals, and the ammonium salts. Sodium salts, potassium salts and ammonium salts are preferred.
The compounds according to the invention may exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemates, and also to the diastereomeric mixtures. The racemates, like the diastereomers, can be separated into the stereoisomerically homogeneous constituents in a known manner (cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).
Preferred compounds of the general formula (I) are those in which
A, B, D, E, L and G are identical or different and
represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or a group of the formula -NR3R4, in which
R3 and R4 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl,
represent straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 10 carbon atoms, and each of which is optionally substituted by hydroxyl, fluorine, chlorine, bromine, nitro, cyano or a group of the formula -NR3R4, in which
R3 and R4 have the abovementioned meanings, represent phenyl which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms or by a group of the formula -NR3R4, in which R3 and R4 have the abovementioned meanings,
R1 represents cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cyclooctyl, cyclodecyl or cyclododecyl, each of which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms,
R2 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, alkoxy having up to 6 carbon atoms, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl or phenyl, which in turn may be substituted by straight-chain or branched alkyl having up to 6 carbon atoms, fluorine, chlorine or bromine or represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms, or represents sodium or potassium, X - represents a group of the formula -SO2-R5, in which
R5 denotes trifluoromethyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, alkoxycarbonyl in each case having up to 6 carbon atoms or by phenyl, which in turn may be substituted by fluorine, chlorine, bromine or by straight- chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms, or - denotes phenyl which is optionally substituted by fluorine, chlorine, bromine, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, trifluoromethyl or
X represents cyano
and their physiologically acceptable salts.
Particularly preferred compounds of the general formula (I) are those in which
A, B, D, E, L and G are identical or different and represent hydrogen, fluorine, chlorine, bromine, nitro and trifluoromethyl, represent methyl, ethyl, propyl, isopropyl, butyl or tert.butyl, R1 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclodecyl or cyclododecyl, each of which is optionally substituted by methyl, ethyl, propyl or isopropyl,
R2 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl or - represents sodium,
X - represents a group of the formula -SO2-R5, in which
R5 denotes trifluoromethyl, straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, which in turn is substituted by fluorine, chlorine or by straight-chain or branched alkyl having up to 4 carbon atoms, or denotes phenyl which may optionally be substituted by fluorine, chlorine or straight-chain or branched alkyl having up to 4 carbon atoms, or
X represents cyano
and their physiologically acceptable salts.
The compounds of the general formula (I) according to the invention are known from EP-A-399 291.
The acylsulphonamides and acylcyanamides of the general formula (I) according to the invention can be employed as active compounds in medicaments. The compounds act particularly as inhibitors of enzymatic reactions in the context of arachidonic acid metabolism, in particular lipoxygenase.
They are thus suitable for the treatment and prevention of glomerular nephritis, lung cancer, multiple sclerosis, ocular inflammation, osteoporosis, reperfusion injury and tinnitus.
The pharmacological activity data of the substances according to the invention are determined by the following method:
As a measure of the lipoxygenase inhibition, the release of leucotriene B4 (LTB4) from polymorphonuclear rats leucocytes (PMNL) was determined after addition of substances and Ca ionophore by means of reverse phase HPLC according to Borgeat, P. et al, Proc. Nat. Acad. Sci., 76, 2148-2152 (1979). The in vivo activity of the compounds was detected using the mouse ear inflammation model according to Young, J.M. et al, J. of Investigative Dermatology, 82, 367-371 (1984).
In Table 1, the values obtained by this test for some compounds according to the invention are shown by way of example:
Table 1
Figure imgf000009_0001
For the obtainment of systemic activity the active compounds can be administered orally or parenterally.
For parenteral administration, forms of administration to the mucous membranes (i.e. buccal, lingual, sublingual, rectal, nasal, pulmonary, conjunctival or intravaginal) or into the interior of the body are particularly suitable. Administration can be carried out by avoiding absorption (i.e. intracardiac, intra-arterial, intravenous, intraspinal or intralumbar administration) or by including absorption (i.e. intracutaneous, subcutaneous, percutaneous, intramuscular or intraperitoneal administration).
For the above purpose the active compounds can be administered per se or in administration forms.
Suitable administration forms for oral administration are, inter alia, normal and enteric-coated tablets, capsules, coated tablets, pills, granules, pellets, powders, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. Suitable administration forms for parenteral administration are injection and infusion solutions.
The active compound can be presented in the administration forms in concentrations of from 0 - 100% by weight; preferably the concentration of the active compound should be 0.5-90% by weight, i.e. quantities which are sufficient to allow the specified range of dosage.
The active compounds can be converted in the known manner into the abovementioned administration forms using inert non-toxic pharmaceutically suitable auxiliaries, such as for example excipients, solvents, vehicles, emulsifiers and/or dispersants.
The following auxiliaries can be mentioned as examples: water, solid excipients such as ground natural or synthetic minerals (e.g. talcum or silicates), sugar (e.g. lactose), non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), emulsifying agents, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulphate).
In the case of oral administration tablets can of course also contain additives such as sodium citrate as well as additives such as starch, gelatin and the like. Flavour enhancers or colorants can also be added to aqueous preparations for oral administration.
For the obtainment of effective results in the case of parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to lO mg/kg, preferably about 0.01 to 1 mg/kg of body weight. In the case of oral administration the quantity is about 0.01 to 100 mg/kg, preferably about 0.1 to 10 mg/kg of body weight.
It may nevertheless be necessary to use quantities other than those mentioned above, depending on the body weight concerned, the method of administration, the individual response to the active compound, the type of preparation and the time or interval of administration.
Preparation Examples
Example 1
N- { 1 -[4-(Quinolin-2-yl-methoxy)phenyl]- 1 -cyclopentyl} -acetyl-methansulphon- amide
Example 2
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]-l -cyclopentyl} -acetyl-benzylsulphon- amide
Example 3
N-{ l-[4-(Quinolin-2-yl-methoxy)-phenyl]-l -cyclopentyl} -acetyl-p-tolylsulphon- amide
Example 4
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]- 1 -cyclopentyl} -acetyl-o-tolylsulphon- amide
Example 5
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]- 1 -cyclopentyl} -acetyl-trifluoromethane- sulphonamide Example 6
N-Methyl-N-l-[4-(quinolin-2-yl-methoxy)-phenyl]-l-cyclopentyl-acetyl-trifluoro- methanesulphonamide
Example 7
N-{l-[4-(Quinolin-2-yl-methoxy)-phenyl]-l-cyclopentyl}-acetyl-cyanamide
Example 8
Sodium-N-{l-[4-(quinolin-2-yl-methoxy)-phenyl]-l-cyclopentyl}-acetyl-trifluoro- methanesulphonamide
Example 9
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]-l -cyclohexyl} -acetyl-methanesulphon- amide
Example 10
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]- 1 -cyclohexyl} -acetyl-p-benzylsulphon- amide
Example 11
N-{l-[4-(Quinolin-2-yl-methoxy)-phenyl]-l-cyclohexyl}-acetyl-o-tolylsulphonamide Example 12
N-{l-[4-(Quinolin-2-yl-methoxy)-phenyl]-l-cyclohexyl}-acetyl-cyanamide
Example 13
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]- 1 -cycloheptyl} -acetyl-methanesulphon- amide
Example 14
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]- 1 -cycloheptyl} -acetyl-trifluoromethane- sulphonamide
Example 15
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]- 1 -cycloheptyl} -acetyl-o-tolylsulphon- amide
Example 16
N-{ l-[4-(Quinolin-2-yl-methoxy)-phenyl]-l-cyclooctyl}-acetyl-methanesulphon- amide
Example 17
N-{l-[4-(Quinolin-2-yl-methoxy)-phenyl]-cyclodecyl}-acetyl-methanesulphonamide Example 18
N- { 1 -[4-(Quinolin-2-yl-methoxy)-phenyl]-l -cyclodecyl} -acetyl-methanesulphon- amide
Example 19 and 20
(+)-N-{l-[4-(Quinolin-2-yl-methoxy)-phenyl]-l -cycloheptyl} -acetyl-methane- sulphonamide and (-)-N-{l-[4-(Quinolin-2-yl-methoxy)-phenyl]-l -cycloheptyl} -acetyl-methane- sulphonamide

Claims

WHAT IS CLAIMED IS:
Use of a compound of the general formula (I)
Figure imgf000016_0001
in which
A, B, D, E, F and G are identical or different and represent hydrogen, hydroxyl, halogen, carboxyl, nitro, trifluoromethyl, trifluoromefhoxy or a group of the formula -NR3R4,
R3 and R4 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms,
represent straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, in each case having up to 12 carbon atoms, and each of which is unsubstituted or substituted by hydroxyl, halogen, nitro, cyano or a group of the formula -NR3R4, in which
R3 and R4 have the abovementioned meanings, represent aryl having 6 to 10 carbon atoms, which is unsubstituted or substituted by halogen, hydroxyl, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms or by a group of the formula -NR3R4, in which
R3 and R4 have the abovementioned meanings,
R1 represents cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted by straight-chain or branched alkyl having up to 8 carbon atoms,
R2 represents hydrogen or
straight-chain or branched alkyl having up to 10 carbon atoms, which is unsubstituted or substituted by hydroxyl, alkoxy having up to 8 carbon atoms, halogen or by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, which in turn is unsubstituted or substituted by straight-chain or branched alkyl having 3 to 8 carbon atoms, halogen, nitro, hydroxyl or cyano, or
represents cycloalkyl having 3 to 8 carbon atoms which is unsubstituted or substituted by straight-chain or branched alkyl having up to 8 carbon atoms, or
represents an alkali metal,
X represents a group of the formula -SO2-R5, in which
R5 denotes trifluoromethyl or straight-chain or branched alkyl having up to 10 carbon atoms, which is unsubstituted or substituted by hydroxyl, halogen, cyano, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which is unsubstituted or substituted by (halogen, nitro, cyano or straight-chain or branched alkyl or alkoxy in each case having up to 8 carbon atoms, or
denotes aryl having 6 to 10 carbon atoms, which is unsubstituted or substituted by halogen, nitro, cyano, hydroxyl, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, trifluoromethyl or trifluoromefhoxy, or
X represents cyano
and physiologically acceptable salts thereof for the manufacture of a medicament for the treatment and prevention of glomerular nephritis, lung cancer, multiple sclerosis, ocular inflammation, osteoporosis, reperfusion injury and tinnitus.
2. Use of a of the general formula (I) acording to claim 1 in which
A, B, D, E, F and G are identifical or different and
- represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxyl, nitro, trifluoromethyl, trifluoromethoxy or a group of the formula -NR3R4, in which
R3 and R4 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, represent straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, in each case having up to 10 carbon atoms, and each of which is unsubstituted or substituted by hydroxyl, fluorine, chlorine, bromine, nitro, cyano or a group of the formula
-NR3R4, in which
R3 and R4 have the abovementioned meanings,
- represent phenyl, which is unsubstituted or substituted by fluorine, chlorine, bromine, hydroxyl, nitro, cyano, straight- chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms or by a group of the formula -NR3R4, in which
R3 and R4 have the abovementioned meanings,
R1 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is unsubstituted or substituted by straight- chain or branched alkyl having up to 6 carbon atoms,
R2 represents hydrogen or
straight-chain or branched alkyl having up to 8 carbon atoms, which is unsubstituted or substituted by hydroxyl, alkoxy having up to 6 carbon atoms, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, which in turn is unsubstituted or substituted by straight-chain or branched alkyl having up to 6 carbon atoms, fluorine, chlorine or bromine, or represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is unsubstituted or substituted by straight-chain or branched alkyl having up to 6 carbon atoms, or
represents sodium or potassium,
X represents a group of the formula -SO2- 5, in which
R5 denotes trifluoromethyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is unsubstituted or substituted by fluorine, chlorine, bromine, alkoxycarbonyl in each case having up to 6 carbon atoms or by phenyl, which in turn is unsubstituted or substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy in each case having up to 6 carbon atoms, or
denotes phenyl, which is unsubstituted or substituted by fluorine, chlorine, bromine, nitro, cyano, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms or trifluoromethyl, or
X represents cyano
and physiologically acceptable salts thereof for the manufacture of a medicament for the treatment and prevention of glomerular nephritis, lung cancer, multiple sclerosis, ocular inflammation, osteoporosis, reperfusion injury and tinnitus.
Use of a compound of the general formula (I) according to claim 1 in which
A, B, D, E, F and G are identical or different and represent hydrogen, fluorine, chlorine, bromine, nitro or trifluoromethyl,
represent methyl, ethyl, propyl, isopropyl, butyl or tert. -butyl,
R1 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is unsubstituted or substituted by methyl, propyl or isopropyl,
R2 represents hydrogen or
straight-chain or branched alkyl having up to 6 carbon atoms, which is unsubstituted or substituted by cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl,
represents cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, or
represents sodium,
X represents a group of the formula -SO2-R5, in which
R5 denotes trifluormethyl, straight-chain or branched alkyl having up to 6 carbon atoms, which is unsubstituted or substituted by phenyl which in turn is substituted by fluorine, chlorine or by straight-chain or branched alkyl having up to 4 carbon atoms, or
denotes phenyl which is unsubstituted or substituted by fluorine, chlorine or straight-chain or branched alkyl having up to 4 carbon atoms, or X represents cyano
and physiologically acceptable salts thereof for the manufacture of a medicament for the treatment (and prevention of glomerular nephritic, lung cancer, multiple sclerosis, ocular inflammation, osteoporosis, reperfusion injury and tinnitus.
4. Use of N-{l-[4-(Quinolin-2-yl-methoxy)phenyl]-l-cycloheptyl-acetyl-meth- anesulphonamide of the formula
Figure imgf000022_0001
for the manufacture of a medicament for the treatment and prevention of glomerular nephritis, lung cancer, multiple sclerosis, ocular inflammation, osteoporosis, reperfusion injury and tinnitus.
PCT/EP2000/010919 1999-11-15 2000-11-06 Use of substituted (quinolin-2-yl-methoxy)phenyl-acyl-sulphonamides and -cyanamides for the treatment of diseases WO2001035936A2 (en)

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