Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/48—Nitrogen atoms not forming part of a nitro radical
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• he invention relates to suifonyloxazoiamines of the general formula I.
• R 1 , R 2 each independently of one another H, A, - (CH 2 ) n -Ar or alkenyl having 2 to 6 C atoms,
• R 1 and R 2 together also form a mononuclear saturated heterocycle with 1 to 2 N, O and / or S atoms, ZH, A, CF 3 , N0 2 , shark, OH, OA, NH 2 , NHA or NA 2 ,
• Ar is mono- or disubstituted phenyl by Z
• the invention further relates to the use of the sulfonyloxazolamines of the general formula I as therapeutic active ingredients.
• the invention also relates to the use of the sulfonyloxazolamines of the general formula I for the production of pharmaceutical preparations for combating diseases of the central nervous system.
• the object of the invention was to find new valuable properties of sulfonyloxazolamines, in particular those which prove the compounds as therapeutic active ingredients and / or which can lead to the use of sulfonyloxazolamines as therapeutic active ingredients and / or to the production of pharmaceutical preparations.
• 5-HT6 receptors form a subfamily of 5-HT receptors.
• Neurotransmitter 5-hydroxytryptamine (5-HT) also known as serotonin, is an important regulating neurotransmitter in the brain, the effects of which are supported by a family of receptors that currently contain 13 G protein-coupled receptors and an ion channel.
• the greatest density of serotonin 5-HT6 receptors in the brain is found in the olfactory tubercle, in the nucleus accumbens, in the striatum, in the dentate gyrus and in the CA1-3 regions of the hippocampus. These regions are particularly affected by psychiatric disorders such as the Involved in schizophrenia or depression. It is also known from animal experiments that the administration of 5-HT6 antisense oligonucleotides causes a behavioral syndrome which corresponds to that of dopamine agonists. Furthermore, an overfunction of the dopaminergic neurotransmitter system in schizophrenia (dopamine hypothesis of schizophrenia) is confirmed pathophysiologically. Dysfunction of the dopamine system in various forms of depression has also been demonstrated. A large number of the established or newer therapeutic agents used to treat these psychiatric disorders in clinical practice also bind to the 5-HT6
• the atypical neuroleptics e.g. clozapine
• the tricyclic antidepressants e.g. amitriptyline
• the compounds of the formula I and their physiologically acceptable salts are therefore suitable as therapeutic active ingredients for diseases of the central nervous system.
• the compounds of the formula I and their physiologically acceptable salts or solvates are particularly suitable for the treatment of psychoses, schizophrenia, manic depression (BL Roth et al., J. Pharmacol. Exp. Ther. 1994, 268, 1403-1410), depression ( DR Sibley et al., Mol. Pharmacol. 1993, 43, 320-327), neurological disorders (A. Bourson et al., J. Pharmacol. Exp. Ther.
• the invention relates to the compounds of formula I or their physiologically acceptable salts or solvates as therapeutic active ingredients.
• the invention relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as active therapeutic substances.
• the invention furthermore relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active substances for diseases of the central nervous system.
• Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
• A is alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms.
• A is preferably methyl, furthermore ethyl, propyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1 -, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2, 2-dimethylpropyl, 1-ethylpropyl or hexyl. Methyl is particularly preferred.
• Alkenyl is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, further preferred is 4-pentenyl, isopentyl or 5-hexenyl.
• Allyl is particularly preferred for alkenyl.
• Ar is preferably phenyl mono- or disubstituted by Z, where ZH, A, CF 3 , N0 2 , shark, OH, OA, NH 2 , NHA or NA 2 can mean.
• Ar therefore preferably denotes phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m - or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or pN, N-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl , o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p-t ⁇ fluoromethylphenyl, o-, m- or p-fluorophen
• Ar is particularly preferably phenyl, o- or p-methylphenyl, o- or p-chlorophenyl, p-bromophenyl, p-methoxyphenyl or 2,4-dichlorophenyl.
• n - (CH 2 ) n -Ar has one of the preferred meanings given above, where n can be 1 or 2.
• Benzyl is particularly preferred for - (CH 2 ) n -Ar.
• Shark preferably means fluorine, chlorine or bromine.
• Z means H, A, CF 3 , NO 2 , shark, OH, OA, NH 2 , NHA or NA 2 , where A and shark have one of the preferred meanings given above.
• H, methyl, chlorine, bromine or methoxy is particularly preferred for Z.
• n is preferably 1 or 2, particularly preferably 1
• R 1 and R 2 independently of one another denote H, A, - (CH 2 ) n -Ar or alkenyl having 2 to 6 C atoms, where A, Ar, alkenyl and n have one of the preferred or particularly preferred meanings given above.
• R 1 and R 2 together also mean a mononuclear saturated heterocycle having 1 to 2 N, 0 and / or S atoms.
• R 1 and R 2 together preferably mean tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yi, tetrahydro-2- or -3-thienyl, 1-, 2- or 3-pyrrolidinyl,
• 1-Piperidinyl or 4-morpholinyl is particularly preferred for R 1 and R 2 together.
• the therapeutic active compounds of the formula I or their physiologically acceptable salts or solvates, the use of the compounds of the formula I or their physiological Safe salts or solvates as therapeutic agents or the preparation of a pharmaceutical preparation for the treatment of diseases of the central nervous system are particularly preferred those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings given above.
• Some preferred groups of compounds can be expressed by the following partial forms in Ia to Ic, which correspond to the formula i and in which the radicals not specified have the meaning given for the formula I, but in which
• R 1 and R 2 each independently represent H, A, - (CH 2 ) n -Ar or alkenyl having 2 to 6 C atoms;
• R 1 and R 2 in formula I together mean 1-piperidinyl
• the invention further relates to the use of the following compounds, selected from the group a) dimethyl- [2-phenyl-4- (toluene-4-sulfonyl) -oxazol-5-yl] amine, b) [2- (2nd , 4-dichloro-phenyl) -4- (toluen-4-sulfonyl) -oxazol-5-yl] - dimethylamine, c) benzyl- [4- (4-chloro-benzenesulfonyl) -2- (2-chloro-phenyl ) -oxazol-5-yl] amine, d) (4-benzenesulfonyl-2-o-tolyl-oxazol-5-yi) methylamine, e) benzyl- [2- (2,4-dichloro-phenyl) -4- (toluene-4-sulfonyl) oxazol-5-yl]
• the compounds of the formula I are generally commercially available or can be synthesized according to the following synthesis scheme (cf. VA Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57 (4), 415-418 or VA Chervonyi et al., Zh. Org. Khim. 1988, 24 (2), 453-4 corresponding to VA Chervonyi et al., J. Org. Chem. USSR (English transl.) 1988, 24, 401).
• a base of formula I can with an acid in the associated
• Acid addition salt are transferred, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
• acids that provide physiologically acceptable salts are suitable for this implementation.
• So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfonic or
• Sulfuric acids e.g. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or toluenesulfonic acid, p-
• Naphthalene mono- and disulfonic acids or lauryl sulfuric acid can be used for the isolation and / or purification of the compounds of the formula I.
• Salts with physiologically unacceptable acids, for example picrates can be used for the isolation and / or purification of the compounds of the formula I.
• the binding of the compounds of the formula I to 5-HT6 receptors was determined as follows:
• the substances to be tested were dissolved in DMSO at a concentration of 1 mM and diluted to the desired concentrations (0.1 nM to 10 ⁇ M) with test buffer (20 mM HEPES, 0.1% ascorbic acid, adjusted to pH 7.4 with NaOH).
• the reaction mixture was filtered through GFB filters (Whatman), which had been pretreated with 0.1% aqueous polyethyleneimine solution for one hour.
• the filters were washed 3 times with 3 ml of test buffer, the filters were transferred to minivials and, after adding Ultima Gold (Packard, Frankfurt), the radioactivity was determined in a liquid scintillation counter.
• the evaluation and IC 50 determination was carried out using our own programs in RS1 (BBN software cooperation).
• the compounds of formula I have a selective affinity for 5-HT6 receptors with an inhibition constant IC 50 of less than 4 ⁇ mol / l.
• the invention furthermore relates to the use of the compounds of the general formula I for the production of a pharmaceutical preparation for combating diseases of the central nervous system.
• the invention furthermore relates to the use of compounds of the general formula I for the preparation of a pharmaceutical preparation for the treatment of psychoses, schizophrenia, manic depression, depression, neurological disorders, Memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, bulimia, nervous anorexia or other eating disorders, compulsive acts or premenstrual syndrome.
• the invention further relates to pharmaceutical preparations for combating diseases of the central nervous system, comprising at least one compound of the formula I or one of its physiologically acceptable salts or solvates.
• Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
• Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder.
• the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
• the specified preparations can be sterilized and / or can contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, for example one or more Vitamins. / 37452. -, g. PCT / EP99 / 09335
• the invention also relates to a process for the preparation of these pharmaceutical preparations, characterized in that a compound of the formula I or one of its physiologically tolerable salts or solvates together with at least one solid, liquid or semi-liquid carrier or auxiliary and, if appropriate, in combination with brings one or more other active ingredients into a suitable dosage form.
• Salts or solvates can be used to combat diseases of the central nervous system.
• the substances according to the invention are generally administered in the dosage preferably between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
• the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
• the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred.
• the following examples relate to pharmaceutical preparations:
• Example A Injection glasses
• a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
• a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
• a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 P0 4 -2 H 2 0, 28.48 g of Na 2 HP0 4 -12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
• Example D ointment
• 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions. / 37452. -, g _ PCT / EP99 / 09335
• a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
• Example F coated tablets
• Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
• Example G capsules
• each capsule contains 20 mg of the active ingredient.
• a solution of 1 kg of active ingredient of the formula I in 60 ml of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
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• Veterinary Medicine (AREA)
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• Animal Behavior & Ethology (AREA)
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• General Chemical & Material Sciences (AREA)
• Psychiatry (AREA)
• Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1998
  • 1998-12-18 DE DE19858593A patent/DE19858593A1/de not_active Withdrawn
• 1999
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  • 1999-12-01 WO PCT/EP1999/009335 patent/WO2000037452A1/de not_active Application Discontinuation
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