WO1993009780A1 - Utilisation de composes de sulfonyle - Google Patents

Utilisation de composes de sulfonyle Download PDF

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Publication number
WO1993009780A1
WO1993009780A1 PCT/EP1992/002583 EP9202583W WO9309780A1 WO 1993009780 A1 WO1993009780 A1 WO 1993009780A1 EP 9202583 W EP9202583 W EP 9202583W WO 9309780 A1 WO9309780 A1 WO 9309780A1
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WO
WIPO (PCT)
Prior art keywords
compounds
methyl
formula
hydrogen
alkyl
Prior art date
Application number
PCT/EP1992/002583
Other languages
German (de)
English (en)
Inventor
Dieter Flockerzi
Christian Schudt
Hermann Amschler
Rolf Beume
Richard Riedel
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to EP92923587A priority Critical patent/EP0612247A1/fr
Priority to AU29349/92A priority patent/AU2934992A/en
Publication of WO1993009780A1 publication Critical patent/WO1993009780A1/fr

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Classifications

    • 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

Definitions

  • the invention relates to the use of sulfonyl compounds for the manufacture of new drugs.
  • the invention relates to the use of compounds of the formula I.
  • R2 is hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy
  • R3 is hydrogen (H), 1-4C-alkyl or 1-4C-alkoxy
  • R4 is hydrogen (H), methyl or methoxy
  • R5 is hydrogen (H) or 1-4C-alkyl
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially methyl est.
  • 1-4C-Al oxy radicals contain, in addition to the oxygen atom, one of the above-mentioned I-4C-alkyl radicals.
  • the methoxy radical is preferred.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • substituted phenyl radicals R6 which may be mentioned are: 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,5-dichloropheny and 4-hydroxyphenyl.
  • Suitable pharmacologically acceptable salts for compounds of the formula I are preferably all acid addition salts with inorganic acids customarily used in galenics. Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, maleinosalicylic acid ⁇ acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, e bonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a one or polyacid acts and, depending on which salt is desired - be used in an e
  • proliferative, inflammatory and allergic skin diseases are mentioned as dermatoses.
  • the compounds of the formula I can be used for the prevention and treatment of the following skin diseases. The following are used: psoriasis vulgaris, toxic and allergic contact dermatitis, atopic dermatitis, seborrheic dermatitis, follicular and extensive pyoderma, endogenous and exogenous acne, rosacea and other proliferative, inflammatory and allergic skin diseases.
  • Another object of the invention is thus the use of compounds of formula I and their pharmacologically acceptable salts for the treatment of such individuals who are suffering from dermatoses.
  • the compounds of the formula I are used in particular in the form of those medicaments which are suitable for topical application.
  • suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions in which the active substance content is advantageously between 0.1 and 99%.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
  • R4 is hydrogen or methyl
  • R5 is hydrogen or 1-4C-alkyl
  • R6 denotes 1-4C-A1kyl, phenyl or substituted phenyl with a substituent from the group 1-4C-A1kyl, 1-4C-alkoxy and halogen, and their pharmacologically acceptable salts. Of particular note is the use of such in accordance with the invention
  • R4 is hydrogen or methyl
  • the radical -N (R5) SC R6 is in the 4-position on the phenyl radical bonded in the 6-position on the benzo-naphthyridine ring
  • R5 is hydrogen, methyl or ethyl
  • R6 is methyl, 4-methylphenyl, 4-methoxyphenyl or 4-fluorophenyl, and their pharmacologically acceptable salts.
  • the benzo-naphthyridine cycle has (at positions 4a and 10b) two centers of chirality.
  • the invention therefore includes all conceivable enantiomers and diastereomers as well as the racemates and mixtures thereof.
  • Preferred compounds of the formula I are those in which the hydrogen atoms in positions 4a and 10b are in the cis position.
  • the separation of the trans compounds from the (additionally diastereomeric) cis compounds is carried out - as is the separation of the (+) - and (-) - enantiomers - in a manner familiar to the person skilled in the art, e.g. as described in European patent application 247971.
  • the compounds of formula I and their salts are prepared by a process which is characterized in that a) Compounds of the formula II (see attached formula sheet), in which Rl, R2, R3, R4 and R5 have the meanings indicated above, with sulfonyl compounds of the formula III (see attached formula sheet), in which R6 has the meaning indicated above and X represents a suitable leaving group, um ⁇ , or that one
  • the reaction of the compounds II with the compounds III takes place in inert solvents in a manner known to the person skilled in the art for the production of sulfonates.
  • the leaving group X is preferably a halogen atom, in particular a chlorine atom.
  • the implementation is preferably carried out in the presence of an auxiliary base, e.g. an organic amine such as triethylamine or pyridine, or e.g. a carbonate, such as potassium carbonate or sodium carbonate.
  • the deprotonating agents that can be used are those agents for which the acidity of the proton on the nitrogen is high enough to achieve anion formation.
  • organometallic compounds such as, for example, butyl lithium
  • metal hydrides in particular sodium hydride, or alkali metal alcoholates, for example sodium methylate or potassium tert-butoxide, or Alihydroxide, such as sodium hydroxide or potassium hydroxide, or alkali carbonates, such as sodium carbonate mentioned.
  • the leaving group Y of the compounds IV is a group which is easily split off when Y-R5 is reacted with the deprotonated I, for example a halogen atom, such as chlorine, bromine or iodine, or the alkyl sulfate group.
  • the deprotonation and subsequent N-alkylation is carried out in inert, water-free solvents, such as are suitable for working with strong deprotonating agents, or in water-solvent mixtures, such as are used when working under phase transfer conditions.
  • inert, water-free solvents such as are suitable for working with strong deprotonating agents, or in water-solvent mixtures, such as are used when working under phase transfer conditions.
  • examples include open-chain or cyclic ethers, such as diethyl ether, doxane or tetrahydrofuran, or solvents such as DMF or DMSO.
  • water / solvent mixtures are the mixtures of water with chloroform, dichloromethane or benzene.
  • the reaction is preferably carried out under mild reaction conditions at temperatures around or below 0 ⁇ C.
  • cyclocondensation according to process variant c) is carried out in a manner known per se to the person skilled in the art according to Bisch! Er-Napieralski in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus pentoxide or preferably phosphorus oxychloride, in a suitable inert solvent, e.g.
  • a chlorinated hydrocarbon such as chloroform
  • a cyclic hydrocarbon such as toluene or xylene
  • another inert solvent such as acetonitrile
  • an excess of condensing agent preferably at elevated temperature, especially at Boiling temperature of the solvent or condensation agent used.
  • the compounds of the formula V are obtained in a manner known per se from the compounds VI and VII (see reaction scheme of the formula sheet) in which R 1, R 2, R 3, R 4, R 5 and R 6 have the meanings indicated above and Z is a suitable leaving group, for example represents a chlorine atom.
  • Compounds VI are e.g. known from DE-OS 21 23 328 or EP-A-247 971 or they can be prepared in an analogous manner.
  • the compounds VII are also known or can be prepared in a manner known to the person skilled in the art.
  • the trans compounds are separated from the cis compounds and the (+) and (-) enantiomers are advantageously separated at the stage of the preliminary and intermediate products prepared analogously to EP-A-247 971 .
  • the starting compound rac-cis-3- (3,4-dimethoxyphenyl) -l-methl-4- [4-methyl-3- (p-toluenesulfonamido) -benzamido] -piperidine is obtained by reacting 4, 6 g of 4-methyl-3- (p-toluenesulfonamido) -benzoic acid chloride with 3.0 g of rac-cis-4-amino-3- (3,4-dimethoxyphenyl) -l-methylpiperidine (produced in a manner analogous to that in DE -OS 21 23328 described procedure) and 4 ml of triethylamine in 50 ml of anhydrous dichloromethane. After shaking out with NaHCO 3 solution, drying the organic phase over sodium sulfate and concentrating, the residue is recrystallized in methanol. Yield: 4.2 g, mp 142-146 ° C.
  • the starting compound rac-cis-3- (3,4-dimethoxyphenyl) -l-methyl-4- [2- (p-toluenesulfonamido) -benzamido] -piperidine is obtained analogously to Example 3 from 2- (p-toluo! Sulfonamido) -benzoic acid chloride and the corresponding piperidine. Yield: 70%.
  • Example 2 The title compound is obtained analogously to Example 1 when p-methoxyphenylsulfonic acid chloride is used. Yield: 66%, mp. 210-217 ° C (crystallized as carbonate hydrate from methanol).
  • the title compound is obtained analogously to Example 3 if rac-cis- -3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(4-p-methoxyphenylsulfonamido) benzamido] piperidine is cyclocondensed.
  • This starting compound is obtained Analogously to Example 3, if 4- (p-methoxyphenylsulfonamido) benzoic acid chloride is used.
  • Example 3 Analogously to Example 3, the title compound is obtained when rac-cis-3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(p-fluorophenylsulfonamido) benzamido] piperidine is used. Yield: 69%, mp 163-165 ⁇ C.
  • the starting compound is obtainable analogously to Example 3 from 4- (p-fluorophenylsulfonamido) benzoic acid chloride. Yield: 60%, m.p. 108-113'C.
  • Example 3 Analogously to Example 3, the title compound is obtained from rac-cis-3- (3,4-dimethoxyphenyl) -1-methyl-4 - [(p-toluenesulfone-N-methylamido) benzamido] piperidine; Yield: 53%, mp. 157-158 ⁇ C (from methanol / ether).
  • the starting compound is obtainable analogously to Example 3 from 4- (p-toluenesulfone-N-methylamido) benzoic acid chloride.

Abstract

L'invention concerne l'utilisation de composés répondant à la formule (I), dans laquelle les substituants ont les propriétés énoncées dans la description, ainsi que de leurs sels compatibles sur le plan pharmacologique, pour fabriquer des médicaments destinés au traitement de dermatoses.
PCT/EP1992/002583 1991-11-15 1992-11-11 Utilisation de composes de sulfonyle WO1993009780A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92923587A EP0612247A1 (fr) 1991-11-15 1992-11-11 Utilisation de composes de sulfonyle
AU29349/92A AU2934992A (en) 1991-11-15 1992-11-11 Use of sulphonyl compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH33344/91-6 1991-11-15
CH334491 1991-11-15

Publications (1)

Publication Number Publication Date
WO1993009780A1 true WO1993009780A1 (fr) 1993-05-27

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Application Number Title Priority Date Filing Date
PCT/EP1992/002583 WO1993009780A1 (fr) 1991-11-15 1992-11-11 Utilisation de composes de sulfonyle

Country Status (2)

Country Link
EP (1) EP0612247A1 (fr)
WO (1) WO1993009780A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055481A1 (fr) * 1997-06-03 1998-12-10 Byk Gulden Lomberg Chemische Fabrik Gmbh Benzonaphthyridine
WO2003101964A1 (fr) * 2002-05-31 2003-12-11 Takeda Pharmaceutical Company Limited Derive piperidine, procede de production, et utilisation
JP2004285038A (ja) * 2002-05-31 2004-10-14 Takeda Chem Ind Ltd ピペリジン誘導体、その製造法および用途
US7776877B2 (en) 2007-06-22 2010-08-17 Chemocentryx, Inc. N-(2-(hetaryl)aryl) arylsulfonamides and N-(2-(hetaryl) hetaryl arylsulfonamides
US7932252B2 (en) 2004-05-12 2011-04-26 Chemocentryx, Inc. Aryl sulfonamides
US8153818B2 (en) 2006-07-14 2012-04-10 Chemocentryx, Inc. Triazolyl phenyl benzenesulfonamides
US8445518B2 (en) 2006-07-14 2013-05-21 Chemocentryx, Inc. Triazolyl pyridyl benzenesulfonamides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3899494A (en) * 1970-05-13 1975-08-12 Sandoz Ltd Substituted 6-phenyl benzo-naphthyridines
EP0247971A2 (fr) * 1986-05-29 1987-12-02 Sandoz Ag Compositions pharmaceutiques contenant de la cis-6-(4-acétanilido)-8,9-diméthoxy-2-méthyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphtyridine et son utilisation
WO1991017991A1 (fr) * 1990-05-16 1991-11-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux composes de sulfonyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3899494A (en) * 1970-05-13 1975-08-12 Sandoz Ltd Substituted 6-phenyl benzo-naphthyridines
EP0247971A2 (fr) * 1986-05-29 1987-12-02 Sandoz Ag Compositions pharmaceutiques contenant de la cis-6-(4-acétanilido)-8,9-diméthoxy-2-méthyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphtyridine et son utilisation
WO1991017991A1 (fr) * 1990-05-16 1991-11-28 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux composes de sulfonyle

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055481A1 (fr) * 1997-06-03 1998-12-10 Byk Gulden Lomberg Chemische Fabrik Gmbh Benzonaphthyridine
US6384047B1 (en) 1997-06-03 2002-05-07 Byk Gulden Lomberg Chemische Fabrik Gmbh Benzonaphthyridine
WO2003101964A1 (fr) * 2002-05-31 2003-12-11 Takeda Pharmaceutical Company Limited Derive piperidine, procede de production, et utilisation
JP2004285038A (ja) * 2002-05-31 2004-10-14 Takeda Chem Ind Ltd ピペリジン誘導体、その製造法および用途
US7622487B2 (en) 2002-05-31 2009-11-24 Takeda Pharmaceutical Company Limited Piperidine derivative, process for producing the same, and use
US7932252B2 (en) 2004-05-12 2011-04-26 Chemocentryx, Inc. Aryl sulfonamides
US8153818B2 (en) 2006-07-14 2012-04-10 Chemocentryx, Inc. Triazolyl phenyl benzenesulfonamides
US8445518B2 (en) 2006-07-14 2013-05-21 Chemocentryx, Inc. Triazolyl pyridyl benzenesulfonamides
US8481579B2 (en) 2006-07-14 2013-07-09 Chemocentryx, Inc. Triazolyl phenyl benzenesulfonamides
US7776877B2 (en) 2007-06-22 2010-08-17 Chemocentryx, Inc. N-(2-(hetaryl)aryl) arylsulfonamides and N-(2-(hetaryl) hetaryl arylsulfonamides
US8198309B2 (en) 2007-06-22 2012-06-12 Chemocentryx, Inc. N-(2-(hetaryl)aryl) arylsulfonamides and N-(2-(hetaryl)hetaryl arylsulfonamides
US8835468B2 (en) 2007-06-22 2014-09-16 Chemocentryx, Inc. N-(2-(hetaryl)aryl)arylsulfonamides and n-(2-(hetaryl)hetaryl) arylsulfonamides
US9409909B2 (en) 2007-06-22 2016-08-09 Chemocentryx, Inc. N-(2-(hetaryl)aryl)arylsulfonamides and N-(2-(hetaryl)hetaryl)arylsulfonamides

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