EP1456179A1 - Pyrazolyl-benzolsulfonamides substitues deuteries et medicaments contenant ces composes - Google Patents

Pyrazolyl-benzolsulfonamides substitues deuteries et medicaments contenant ces composes

Info

Publication number
EP1456179A1
EP1456179A1 EP02791628A EP02791628A EP1456179A1 EP 1456179 A1 EP1456179 A1 EP 1456179A1 EP 02791628 A EP02791628 A EP 02791628A EP 02791628 A EP02791628 A EP 02791628A EP 1456179 A1 EP1456179 A1 EP 1456179A1
Authority
EP
European Patent Office
Prior art keywords
deuterated
methyl
treatment
tetradeutero
independently
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02791628A
Other languages
German (de)
English (en)
Inventor
Rudolf-Giesbert Alken
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Turicum Drug Development AG
Original Assignee
Turicum Drug Development AG
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 Turicum Drug Development AG filed Critical Turicum Drug Development AG
Publication of EP1456179A1 publication Critical patent/EP1456179A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to deuterated substituted
  • a well-known representative of the substituted pyrazolylbenzenesulfona ide is celecoxib (EP 731795,
  • the object of the present invention is to provide substituted pyrazolyl-benzenesulfonamides which have improved pharmacokinetic and / or pharmacodynamic properties compared to the already known compounds.
  • the deuterated substituted pyrazolylbenzenesulfonamides according to the invention have significantly better pharmacokinetic and / or pharmacodynamic properties than the undeuterated compounds.
  • the object is therefore achieved by providing deuterated substituted pyrazolylbenzenesulfonamides of the general formula I:
  • R 1 is methyl or partially or completely deuterated methyl
  • R 2 is independently H or D
  • R 3 is independently H or D and wherein at least one of the radicals R 1 to R 3 is D or contains D.
  • Deuterated substituted pyrazolylbenzenesulfonamides according to the general formula I are preferred, where R 1 is partially or completely deuterated methyl, R 2 is independently H or D and R 3 is independently H or D.
  • Deuterated substituted pyrazolyl-benzenesulfonamides according to the general formula I are particularly preferred, where R 1 is methyl or partially or completely deuterated methyl, R 2 is deuterium and R 3 is independently H or D. Particularly preferred are deuterated substituted pyrazolyl-benzenesulfonamides according to the general formula I, where R 1 is methyl or partially or completely deuterated methyl, R 2 is independently H or
  • R 3 is deuterium
  • Deuterated substituted pyrazolylbenzenesulfonamides according to the general formula I are advantageous, where R 1 is partially or completely deuterated methyl, R 2 is deuterium and R 3 is independently H or D.
  • Deuterated substituted pyrazolyl-benzenesulfonamides of the general formula I are particularly advantageous, where R 1 is methyl or partially or completely deuterated methyl and R 2 and R 3 are deuterium.
  • Deuterated substituted pyrazolyl-benzenesulfonamides according to the general formula I are particularly advantageous, where R 1 is partially or completely deuterated methyl, R 2 is independently H or D and R 3 is deuterium.
  • Deuterated substituted pyrazolyl-benzenesulfonamides according to the general formula I are furthermore advantageous, where R 1 is partially or completely deuterated methyl and R 2 and R 3 are deuterium.
  • Polyposis for the treatment of pain, especially acute pain and dysmenorrhea, especially primary dysmenorrhea.
  • deuterated substituted pyrazolylbenzenesulfonamides for the preparation of medicaments for the symptomatic treatment of osteoarthritis and rheumatoid arthritis and for the prevention and Treatment of neoplasia, in particular adenomatous colorectal polyps in familial adenomatous polyposis, for the treatment of pain, in particular acute pain and dysmenorrhea, in particular primary dysmenorrhea.
  • compositions which contain the deuterated substituted pyrazolyl-benzenesulfonamides according to the invention and their physiologically tolerable salts for the symptomatic treatment of osteoarthritis and rheumatoid arthritis and for the prevention and treatment of neoplasia, in particular adenomatous colorectal polyps in familial adenomatous polyposis, for the treatment of pain, in particular acute Pain and dysmenorrhea, especially primary dysmenorrhea, in addition to pharmaceutically acceptable auxiliaries and / or additives.
  • deuterated substituted pyrazolyl-benzenesulfonamides according to the invention are prepared analogously to known production processes for the undeuterated compounds using deuterated starting materials with a degree of deuteration above 98%.
  • deuterated l- (4-methylphenyl) butane-1, 3-dione and the deuterated 4-hydrazinobenzenesulfonamides such as deuterated chlorobenzene and / or deuterated 4-methylacetophenone, are commercially available and, for example, from production processes known to the person skilled in the art deuterated benzene or deuterated toluene.
  • Hydrazinobenzenesulfonamide is converted into deuterated 4-chlorobenzenesulfochloride by reaction with chlorosulfonic acid and thionyl chloride in deuterated chlorobenzene analogously to EP 115328. Without further purification, the deuterated 4-chlorobenzenesulfonyl chloride obtained can be converted to the deuterated 4-chlorobenzenesulfonamide by reaction with ammonium hydroxide solution.
  • the deuterated 4-chlorobenzenesulfonamide thus obtained is analogous to US 3839325 with an aqueous
  • deuterated 1- (4-methylphenyl) butane-1,3-diones are prepared from correspondingly deuterated 4-
  • Methyl acetophenones in the presence of sodium methoxide with ethyl trifluoroacetate see e.g. EP 731795.
  • physiologically compatible salts of the deuterated substituted pyrazolylbenzenesulfonamides for the preparation of physiologically compatible salts of the deuterated substituted pyrazolylbenzenesulfonamides according to the invention, customary physiologically compatible inorganic and organic acids can be used become.
  • examples include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid.
  • Other acids that can be used are, for example, in the progress of
  • the acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone such as Acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane.
  • a lower alcohol such as methanol, ethanol, n-propanol or isopropanol
  • a lower ketone such as Acetone, methyl ethyl ketone or methyl isobutyl ketone
  • an ether such as diethyl ether, tetrahydrofuran or dioxane.
  • physiologically compatible aqueous solutions of acid addition salts of the compounds used according to the invention can be prepared in an aqueous acid solution.
  • the acid addition salts of the compounds according to the invention can be converted into the free base in a manner known per se, for example using alkalis or ion exchangers.
  • the free base can be reacted with inorganic or organic acids, in particular those which form therapeutically usable salts are suitable, win more salts.
  • These or other salts of the new compound such as, for example, the picrate, can also be used to purify the free base by converting the free base into a salt, separating it and releasing the base from the salt.
  • the present invention also relates to pharmaceuticals for oral, rectal, topical (percutaneous, transdermal, local), subcutaneous, intravenous or intramuscular application, which, in addition to conventional carriers and diluents, contain a compound of the general formula I or its acid addition salt as active ingredient.
  • the medicaments of the invention are mixed with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries according to the desired type of application with a suitable one
  • the preferred preparations are in a dosage form which is suitable for oral administration.
  • Such dosage forms are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.
  • Topical application can take place, for example, in the form of ointments, creams, gels, solutions or by plasters.
  • parenteral preparations such as injection solutions are also suitable.
  • Suppositories may also be mentioned as preparations.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve one Depot effects such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
  • auxiliaries for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve one Depot effects such as carboxyl
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the active ingredient used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and e.g. Contain flavorings such as vanillin or orange extract. You can also taste-improving agents such as saccharin, cyclamate or sugar and e.g. Contain flavorings such as vanillin or orange extract. You can also taste-improving agents such as saccharin, cyclamate or sugar and e.g. Contain flavorings such as vanillin or orange extract. You can also
  • Suspending aids such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates contain.
  • Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
  • Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
  • the preparation of the pharmaceuticals according to the invention for topical application is known to the person skilled in the art.
  • the auxiliaries and enhancers known per se are used in the production of the medicaments according to the invention for transdermal use.
  • the compounds according to the invention have a number of advantages over the compounds known in the prior art which contain deuterium only in the natural distribution.
  • deuteration slows down the metabolism in the organism. This makes it possible to change the dosage and to create longer-lasting preparations, which can also improve compliance in the form of depot preparations.
  • the pharmacodynamics have also changed, since the deuterated compounds according to the invention form other hydration shells, so that their distribution in the organism differs from that of the undeuterated compounds.
  • reaction mixture is cooled to room temperature and 21 g of crude product are obtained, which is reacted further without further purification.
  • Example 1 as a by-product, deuterated
  • the filtrate is brought to pH 5-6 by adding hydrochloric acid, the temperature of the reaction mixture being kept at 20-25 ° C. by cooling.
  • the reaction product which has precipitated is separated off, washed with water and dried. 17.25 g of product are isolated as a white solid.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des pyrazolyl-benzolsulfonamides substitués deutériés, des médicaments contenant ces composés, et l'utilisation de pyrazolyl-benzolsulfonamides substitués deutériés pour le traitement symptomatique de l'ostéoarthrite et de l'arthrite rhumatismale ainsi que pour prévenir et traiter la néoplasie, notamment les polypes colorectaux adénomateux en cas de polypose adénomateuse familiale, pour traiter la douleur, en particulier la douleur aiguë, et la dysménorrhée, notamment la dysménorrhée primaire. La présente invention porte également sur des compositions pharmaceutiques comprenant des pyrazolyl-benzolsulfonamides substitués deutériés et leur sels physiologiquement acceptables, outre des auxiliaires et/ou additifs pharmaceutiquement acceptables, pour le traitement symptomatique de l'ostéoarthrite et de l'arthrite rhumatismale ainsi que pour prévenir et traiter la néoplasie, notamment les polypes colorectaux adénomateux en cas de polypose adénomateuse familiale, pour traiter la douleur, en particulier la douleur aiguë, et la dysménorrhée, notamment la dysménorrhée primaire.
EP02791628A 2001-12-12 2002-12-11 Pyrazolyl-benzolsulfonamides substitues deuteries et medicaments contenant ces composes Withdrawn EP1456179A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10162121A DE10162121A1 (de) 2001-12-12 2001-12-12 Deuterierte substituierte Pyrazolyl-Benzolsulfonamide sowie diese Verbindungen enthaltende Arzneimittel
DE10162121 2001-12-12
PCT/DE2002/004600 WO2003050091A1 (fr) 2001-12-12 2002-12-11 Pyrazolyl-benzolsulfonamides substitues deuteries et medicaments contenant ces composes

Publications (1)

Publication Number Publication Date
EP1456179A1 true EP1456179A1 (fr) 2004-09-15

Family

ID=7709640

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02791628A Withdrawn EP1456179A1 (fr) 2001-12-12 2002-12-11 Pyrazolyl-benzolsulfonamides substitues deuteries et medicaments contenant ces composes

Country Status (14)

Country Link
US (1) US20050222238A1 (fr)
EP (1) EP1456179A1 (fr)
JP (1) JP2005516009A (fr)
CN (1) CN1612863A (fr)
AU (1) AU2002357973A1 (fr)
CA (1) CA2471743A1 (fr)
DE (1) DE10162121A1 (fr)
HU (1) HUP0402422A2 (fr)
IL (1) IL162432A0 (fr)
IS (1) IS7304A (fr)
NO (1) NO20042906L (fr)
PL (1) PL370563A1 (fr)
RU (1) RU2004121033A (fr)
WO (1) WO2003050091A1 (fr)

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JP5448448B2 (ja) * 2005-07-26 2014-03-19 タケダ ゲゼルシャフト ミット ベシュレンクテル ハフツング 同位体置換されたプロトンポンプインヒビター
US7601737B2 (en) * 2005-07-26 2009-10-13 Nycomed Gmbh Isotopically substituted proton pump inhibitors
BRPI0617987A2 (pt) * 2005-10-06 2011-08-16 Auspex Pharmaceuticals Inc composição, composição farmacêutica, forma de dosagem efervescente, composição farmacêutica oral de comprimidos unitários múltiplos, forma de dosagem farmacêutica de liberação prolongada, forma de dosagem farmacêutica revestida entérica, forma de dosagem farmacêutica estável para administração oral a sujeitos mamìferos, método para tratamento de doenças relacionadas a ácido gástrico pela inibição de secreção de ácido gástrico, método para tratamento de uma infecção bacteriana provocada ou mediada por helicobacter pylori, processo para preparar um composto da fórmula 3, processo para preparar um composto da fórmula 5, uso de um composto da fórmula 1 para a preparação de um medicamento para tratamento de doenças relacionadas a ácido gástrico, pela inibição de secreção de ácido gástrico, uso de um composto da fórmula 1 para a preparação de um medicamento para tratamento de uma infecção bacteriana provocada ou mediada por helicobacter pylori uso de um composto da fórmula 1 para a preparação de um medicamento para tratamento de doenças relecionadas a ácido gástrico pela inibição de secreção de ácido gástrico
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Also Published As

Publication number Publication date
JP2005516009A (ja) 2005-06-02
NO20042906L (no) 2004-07-09
DE10162121A1 (de) 2003-06-18
RU2004121033A (ru) 2006-01-10
CN1612863A (zh) 2005-05-04
PL370563A1 (en) 2005-05-30
IS7304A (is) 2004-06-10
AU2002357973A1 (en) 2003-06-23
IL162432A0 (en) 2005-11-20
CA2471743A1 (fr) 2003-06-19
US20050222238A1 (en) 2005-10-06
WO2003050091A1 (fr) 2003-06-19
HUP0402422A2 (hu) 2005-03-29

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