WO1998037083A1 - Thiophenes substitues par un sulfamide, mode de fabrication et utilisation en tant que medicament ou agent diagnostique, et medicament contenant de tels thiophenes - Google Patents

Thiophenes substitues par un sulfamide, mode de fabrication et utilisation en tant que medicament ou agent diagnostique, et medicament contenant de tels thiophenes Download PDF

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Publication number
WO1998037083A1
WO1998037083A1 PCT/EP1998/000878 EP9800878W WO9837083A1 WO 1998037083 A1 WO1998037083 A1 WO 1998037083A1 EP 9800878 W EP9800878 W EP 9800878W WO 9837083 A1 WO9837083 A1 WO 9837083A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
group
hydrogen
replaced
alkylene group
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Application number
PCT/EP1998/000878
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German (de)
English (en)
Inventor
Uwe Gerlach
Joachim Brendel
Hans Jochen Lang
Klaus Weidmann
Original Assignee
Hoechst Aktiengesellschaft
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 Hoechst Aktiengesellschaft filed Critical Hoechst Aktiengesellschaft
Priority to AU64978/98A priority Critical patent/AU6497898A/en
Publication of WO1998037083A1 publication Critical patent/WO1998037083A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds of the formula I.
  • R (8) is hydrogen or - (C r H 2r ) -R (9); r zero, 1, 2, 3, 4, 5, 6, 7 or to 8;
  • R (5) H, OH, Cl, F, Br, NR (10), alkoxy with 1, 2, 3 or 4 carbon atoms or alkyl with
  • R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms -Atoms, alkylsulfonyl with 1,
  • R (8) is hydrogen or - (C r H 2r ) -R (9); r zero, 1, 2, 3, 4, 5, 6, 7 or to 8;
  • C 2 F 5 or C 3 F 7 n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein a CH2 group of the alkylene group C n H 2n can be replaced by -O-, SO Nu n or 2 -, -CO- or -NR (10) -;
  • R (1) and R (2) independently of one another are hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together are an alkylene group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C n H 2n [NR (12)] zero or r ;
  • R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF 3 ,
  • n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein a CH2 group of the alkylene group C n H 2n can be replaced by -O-, SO Nuü or 2 -, -CO- or -NR (10) -;
  • R (6) and R (7) independently of one another are hydrogen, Cl, Br, F, nitro, cyano, alkyl having 1, 2, 3 or 4 carbon atoms, acyl having 1, 2, 3 or 4 carbon atoms, alkylsulfonyl with 1, 2, 3, 4, 5 or 6 carbon atoms or NR (10); and their physiologically tolerable salts.
  • R (1) and R (2) independently of one another are hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, sulfamoyl and methylsulfonyl; or R (1) and R (2) together an alkylene group with 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R (3) R (11) -C n H 2n [NR (12)] zero or r ;
  • R (11) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, CF 3 ,
  • C 2 F 5 or C 3 F 7 n zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein a CH2 group of the alkylene group C n H 2n can be replaced by -O-, SO Nu n 1 or 2 - or -NR (10) -;
  • the compounds I contain an acidic or basic group or a basic heterocycle, the corresponding pharmacologically and toxicologically tolerable salts are also a subject of the invention.
  • the compounds I which carry one or more -COOH groups can be used, for example, as alkali salts, preferably as sodium or potassium salts.
  • Compounds I which carry a basic, protonatable group or a basic heterocyclic radical can also be used in the form of their organic or inorganic, pharmacologically and toxicologically tolerable acid addition salts, for example as hydrochlorides, methanesulfonates, acetates, lactates, maleinates, fumarates, malates , Gluconates etc.
  • the compounds I contain an acidic and basic group in the same molecule, in addition to the salt forms described, internal salts, so-called betaines, also belong to the invention.
  • the substituents of the compounds I contain groups with different stereochemical possibilities, the individual possible stereoisomers also belong to the invention, so that in the case of optical isomerism the individual pure enantiomers and any mixtures of these optical isomers are part of the invention.
  • Alkyl and alkylene radicals can be straight-chain or branched.
  • the compounds of formula I can be prepared by different chemical processes, which are also part of the invention.
  • R (1), R (2), R (5), R (6), R (7) and X have the meaning given and L is a customary nucleofugic escape group, in particular F, Cl, Br, I, MeSO 2 -O -, a p-toluenesulfonyloxy radical, or R (5) and L form an epoxy ring, means with a sulfonamide or its salt of the formula III
  • R (3) and R (4) have the meaning indicated and M represents hydrogen or preferably a metal atom, particularly preferably lithium, sodium or potassium;
  • R (3) has the meaning given and W is a nucleofugic leaving group such as fluorine, bromine, 1-imidazolyl, but especially chlorine;
  • R (1), R (2), R (3), R (5), R (6), R (7), X and M have the meaning given, in a manner known per se with an alkylating agent of the formula VII
  • R (4) -L VII in the sense of an alkylation reaction in which R (4) with the exception of hydrogen and L have the meaning given;
  • R (1) to R (5) and X have the meaning given, carries out an electrophilic substitution reaction in at least one of the positions R (6) and R (7) of the thiophene ring system, provided that this position is hydrogen and the other of the substituents R ( 6) and R (7) has the meaning given.
  • the sulfonamide is deprotonated to the salt in situ using preferred bases which are themselves not or only slightly alkylated, such as sodium carbonate, potassium carbonate, a sterically hindered amine, e.g. B. dicyclohexylamine, N, N, N-dicyclohexyl-ethylamine or other strong nitrogen bases with low nucleophilicity, for example DBU, N, N ', N , "-Triisopropylguanidin etc.
  • preferred bases which are themselves not or only slightly alkylated, such as sodium carbonate, potassium carbonate, a sterically hindered amine, e.g. B. dicyclohexylamine, N, N, N-dicyclohexyl-ethylamine or other strong nitrogen bases with low nucleophilicity, for example DBU, N, N ', N , "-Triisopropylguanidin etc.
  • polar organic solvents such as dimethylformamide, dimethylacetamide, tetramethyl urea, hexamethylphosphoric triamide, tetrahydrofuran, dimethoxyethane, toluene, a halogenated hydrocarbon such as chloroform or methylene chloride etc.
  • polar protic solvents such as water, methanol, ethanol , Isopropanol, ethylene glycol or its oligomers and their corresponding shark ethers and ethers.
  • the reaction is carried out in a preferred temperature range from -10 to 140 ° C, particularly preferably from 20 to 100 ° C.
  • Procedure a) can also be carried out in a favorable manner under the conditions of a two-phase catalysis.
  • the compounds of the formula II are obtained by methods known from the literature, for example from the corresponding unsaturated compounds of the formula X. by the action of an inorganic or organic peroxide, such as H 2 O 2 , metachloroperbenzoic acid, peracetic acid.
  • an inorganic or organic peroxide such as H 2 O 2 , metachloroperbenzoic acid, peracetic acid.
  • halogen / hydroxy is also possible by the reaction of compound X with NCS, NBS, chlorine or bromine in aqueous solvents.
  • a solvent which is sufficiently inert to these halogenating, high-energy reagents, such as, for example, in DMSO or a halogenated hydrocarbon, e.g. in chloroform, methylene chloride.
  • the reaction can in principle be carried out without Solvents are carried out, but in most cases such reactions are carried out using a solvent.
  • the reaction is preferably carried out using a polar solvent, preferably in the presence of a base which itself can advantageously be used as a solvent, for example when using triethylamine, in particular pyridine and its homologues.
  • Solvents also used are, for example, water, aliphatic alcohols, for example methanol, ethanol, isopropanol, sec. Butanol, ethylene glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA, as well as TMU and HMPT.
  • the process is carried out at a temperature of from 0 to 160 ° C., preferably from 20 to 100 ° C.
  • the amino derivatives of the formula IV are obtained in a manner known per se, preferably by reacting the reactive compounds of the formula II with R (1), R (2), R (5), R (6) and L in the meaning given, either with ammonia or an amine of formula XI
  • Procedure c) represents the known alkylation reaction of a sulfonamide or one of its salts VI with an alkylating agent of the formula VII.
  • the reaction analogy with procedure a) the reaction conditions already described in detail under procedure a) apply to procedure c).
  • the preparation of the sulfonamide derivatives VI and their precursors has already been described in procedure b).
  • the alkylating agents VII are prepared according to the analogous instructions in the literature or as described under procedure a), preferably from the corresponding hydroxy compounds (formula VII with L equal to -OH).
  • the compounds I are related to the class of 4-acylaminochroman derivatives, in particular 2,2-dialkyl-4-acylamino-3-chromanols, which has been intensively worked on in pharmaceutical chemistry in the last decade.
  • 4-acylaminochromanes is the cromakalim of formula XII
  • Cromakalim and other related 4-acylaminochroman derivatives are compounds with a relaxing effect on smooth muscle organs, so that they are used to lower the increased blood pressure due to vascular muscle relaxation and in the treatment of asthma due to the relaxation of the smooth muscles of the airways. All these preparations have in common that they act on the cellular level, for example of smooth muscle cells, and there lead to the opening of certain ATP-sensitive K + channels.
  • the increase in negative charge induced in the cell by the emergence of K + ions (“hyperpolarization”) acts via secondary mechanisms of increasing intracellular Ca2 + and thus cell activation, e.g. B. a muscle contraction.
  • cAMP cyclic adenosine monophosphate
  • the compounds are characterized as a new class of active ingredients, potent inhibitors of stimulated gastric acid secretion.
  • the compounds of the formula I are therefore valuable medicaments for the treatment of gastric and intestinal ulcers, for example the duodenum. Due to their strong gastric secretion-inhibiting effect, they are also suitable as excellent therapeutic agents for the treatment of reflux oesophagitis.
  • the compounds are furthermore distinguished by an antidiarrheal effect and are therefore suitable as medicaments for the treatment of diarrheal diseases.
  • the compounds I can be used as medicaments for the treatment and prevention of all types of arrhythmias, including ventricular and supraventricular arrhythmias. In particular, they can be used to control reentry arrhythmias and to prevent sudden cardiac death due to ventricular fibrillation.
  • Medicaments which contain a compound I according to the invention can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred application depending on the particular appearance of the disease.
  • the compounds I can be used alone or together with pharmaceutical auxiliaries, both in veterinary medicine and in human medicine.
  • auxiliaries which are suitable for the desired pharmaceutical formulation on the basis of his specialist knowledge.
  • solvents, gel formers, suppository bases, tablet excipients and other active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers or colorants can be used.
  • the active compounds are mixed with the suitable additives, such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by the usual methods, such as tablets, dragées, push-fit capsules, aqueous, alcoholic or oily solutions.
  • suitable additives such as carriers, stabilizers or inert diluents
  • suitable dosage forms by the usual methods, such as tablets, dragées, push-fit capsules, aqueous, alcoholic or oily solutions.
  • inert carriers such.
  • the preparation can take place both as dry and as moist granules.
  • Vegetable or animal oils such as sunflower oil or cod liver oil, are suitable as oily carriers or as solvents.
  • the active compounds are brought into solution, suspension or emulsion, if desired with the usual substances such as solubilizers, emulsifiers or other auxiliaries.
  • solvents such as water, physiological saline or alcohols, e.g. As ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for. B. solutions, suspensions or emulsions of the active ingredient of formula I in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such solvents. If required, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers Contain propellant. Such a preparation usually contains the active ingredient in a concentration of approximately 0.1 to 10, in particular approximately 0.3 to 3% by weight.
  • the dosage of the active ingredient of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; but also on the type and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
  • the daily dose of a compound of the formula I in a patient weighing approximately 75 kg is at least 0.001 mg, preferably at least 0.01 mg, in particular at least 0.1 mg, up to at most 1 g, preferably up to at most 100 mg, in particular up to 10 mg per kg body weight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des thiophènes substitués par un sulfamide, un mode de fabrication et leur utilisation en tant que médicament ou agent diagnostique, et un médicament contenant de tels thiophènes. Les composés de la formule (I) sont particulièrement utiles dans la production de médicaments pour le traitement et la prévention d'une secrétion excessive de suc gastrique, des ulcers d'estomac et de l'intestin, de l'oesophagite peptique, de la diarrhée, de tous les types d'arythmie, y compris ventriculaire et supraventriculaire, et de l'arythmie de rentrée, et pour la prévention des décès par arrêt du coeur consécutif à une fibrillation ventriculaire.
PCT/EP1998/000878 1997-02-21 1998-02-16 Thiophenes substitues par un sulfamide, mode de fabrication et utilisation en tant que medicament ou agent diagnostique, et medicament contenant de tels thiophenes WO1998037083A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64978/98A AU6497898A (en) 1997-02-21 1998-02-16 Sulphonamide-substituted thiophenes and a method for their production, their useas a medicament or diagnostic agent, as well as a medicament containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19706892.8 1997-02-21
DE1997106892 DE19706892A1 (de) 1997-02-21 1997-02-21 Sulfonamid-substituierte Thiophene, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament

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Publication Number Publication Date
WO1998037083A1 true WO1998037083A1 (fr) 1998-08-27

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PCT/EP1998/000878 WO1998037083A1 (fr) 1997-02-21 1998-02-16 Thiophenes substitues par un sulfamide, mode de fabrication et utilisation en tant que medicament ou agent diagnostique, et medicament contenant de tels thiophenes

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AU (1) AU6497898A (fr)
DE (1) DE19706892A1 (fr)
WO (1) WO1998037083A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0360621A1 (fr) * 1988-09-23 1990-03-28 Ortho Pharmaceutical Corporation Thienopyrannes substitués comme agents antihypertensives
EP0389861A1 (fr) * 1989-03-28 1990-10-03 Fujisawa Pharmaceutical Co., Ltd. Dérivés de benzopyranne et procédé pour leur préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0360621A1 (fr) * 1988-09-23 1990-03-28 Ortho Pharmaceutical Corporation Thienopyrannes substitués comme agents antihypertensives
EP0389861A1 (fr) * 1989-03-28 1990-10-03 Fujisawa Pharmaceutical Co., Ltd. Dérivés de benzopyranne et procédé pour leur préparation

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AU6497898A (en) 1998-09-09
DE19706892A1 (de) 1998-08-27

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