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EP1233963A2 - Novel sulfonyl oxazole amines - Google Patents

Novel sulfonyl oxazole amines

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Publication number
EP1233963A2
EP1233963A2 EP00990614A EP00990614A EP1233963A2 EP 1233963 A2 EP1233963 A2 EP 1233963A2 EP 00990614 A EP00990614 A EP 00990614A EP 00990614 A EP00990614 A EP 00990614A EP 1233963 A2 EP1233963 A2 EP 1233963A2
Authority
EP
European Patent Office
Prior art keywords
general formula
compound
hai
compounds according
solvates
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Withdrawn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
EP00990614A
Other languages
German (de)
French (fr)
Inventor
Rolf Gericke
Henning Böttcher
Michael Gassen
Hartmut Greiner
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.)
Merck Patent GmbH
Original Assignee
Merck Patent 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
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Publication of EP1233963A2 publication Critical patent/EP1233963A2/en
Withdrawn legal-status Critical Current

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
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    • A61P25/08—Antiepileptics; Anticonvulsants
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P25/36—Opioid-abuse
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to sulfonyloxazolamines of the general formula I and their use as medicaments and a process for their preparation, the intermediates used in the production process and a process for the preparation of the intermediates.
  • the sulfonyloxazolamines according to the invention are compounds of the general formula I
  • Ri and R independently of one another H, -R ⁇ , C 3 -C 8 cycloalkyl, - (CH) n -R, - (CH 2 ) n O-R6, - (CH 2 ) n -NH 2 , - ( CH 2 ) n -NHR 6 , - (CH 2 ) -N (R 6 ) 2 , C 2 -C 6 alkenyl or optionally together form a mononuclear saturated heterocycle with one or two nitrogen, oxygen and / or sulfur atoms,
  • R 3 and Ri independently of one another are H, -R $, -CF, -NO 2 , -Hai, -OH, -OR ⁇ , -NH 2 , -NH-R ⁇ or -N (R 6 ) 2
  • R 5 represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -R ⁇ , -CF 3 , -NO 2 , -Hai, -OH, -OR * , -NH 2 , -NH-R ⁇ , or -N (R 6 ) is mono- or disubstituted, and
  • R ⁇ means Ci-C ö alkyl
  • R7 means phenyl substituted with R and / or R
  • n means 0 to 2
  • physiologically acceptable salts or solvates
  • the object of the invention was to find sulfonyloxazolamines with valuable properties. In particular, it was necessary to find pharmacologically active sulfonyloxazolamines.
  • the compounds of the formula I and their pharmacologically active salts with good tolerability, surprisingly have a selective affinity for 5-HT6 receptors, that is to say 5-HT6 receptor ligands. They have 5-HT6 antagonistic or 5-HT6 agonistic effects.
  • 5-HT6 receptors form a subfamily of 5-HT receptors.
  • the 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 5-HT6 receptors also belong to the group of G protein-coupled receptors.
  • 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 involved in psychiatric disorders such as 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. However, 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 receptor.
  • the atypical new roleptics e.g. clozapine
  • the tricyclic antidepressants e.g. amitriptyline
  • the 5-HT6 receptor is involved in psychiatric and neurological diseases such as preferably schizophrenia, depression and Alzheimer's.
  • 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.
  • 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, for example, mono- or dihydrates or alcoholates.
  • R 3 and j are preferably independently of one another methyl, methoxy, chlorine and bromine or hydrogen.
  • R3 is phenyl, o- or p-methylphenyl, o- or p-chlorophenyl, p-bromophenyl, p-methoxyphenyl or 2,4-dichlorophenyl.
  • R and R together can also form a mononuclear saturated heterocycle having 1 to 2 N, O and / or S atoms.
  • This heterocycle is preferably tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro- 1-, -2- or 4-imidazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-perhydro -azepinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1, 4-dioxanyl, l, 3-dioxan-2-, -4- or -5-yl , Hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl or 1-, 2- or 3-pipe
  • R 3 and / or R 4 are preferably H.
  • R preferably represents 2-furyl, 2-thienyl or 3- or 4-pyridyl.
  • R ⁇ is linear or branched and has 1 to 6, preferably 1, 2, 3 or 4 carbon atoms.
  • R ⁇ preferably means 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.
  • a base of the general formula I can be converted into the associated acid addition salt using an acid, 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, furthermore organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, 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, methanoic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid,
  • Another object of the invention is the use of the compounds of the general formula I and their physiologically acceptable salts and solvates for the production of medicaments, in particular for the production of anticonvulsants, nootropics, anti-inflammatories, neuro- and cerebroprotectives, and of medicaments for the treatment of Central nervous system disorders, in particular for the treatment of schizophrenia, depression, pathological anxiety, epilepsy, pathological memory disorders such as Alzheimer's disease, neurological disorders, amyotrophic lateral sclerosis, Huntigton's disease, disorders of the gastrointestinal tract, irritable stomach, irritable bowel syndrome, bulimia, nervous anorexia , Compulsive acts (obsessive-compulsive disorder, OCD), premenstrual syndrome, migraines, pharmacological dependencies, sleep disorders and / or for the treatment of head and spine injuries.
  • Compulsive acts obsessive-compulsive disorder, OCD
  • premenstrual syndrome migraines, pharmacological dependencies, sleep
  • 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 wide 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 excretion and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • the compounds of the general formula I can also be used as pesticide.
  • Another object of the invention is a pharmaceutical preparation containing at least one compound according to general formula I and its physiologically acceptable salts and solvates, and optionally carriers and / or auxiliaries.
  • 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 auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or one or more further active substances contain, for example, one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or one or more further active substances contain, for example, one or more vitamins.
  • the therapeutic agents of formula I or their physiologically acceptable salts or solvates, the use of compounds of formula I or their physiologically acceptable salts or solvates as therapeutic agents or the preparation of a pharmaceutical preparation for the treatment of diseases of the central nervous system Compounds of formula I the more preferred, the more radicals have one of the preferred or particularly preferred meanings given above.
  • Another object of the invention is the preparation of compounds of general formula I, wherein R 2 R 2 NH are reacted with compounds of general formula II or III.
  • R 3 and t independently of one another stand for H, -R ⁇ , -CF 3 , -NO 2 , -Hai, -OH, -OR ⁇ , -NH, - NH-Re or N (Re) 2 ,
  • R 5 represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -R ⁇ , -CF 3 , -NO 2 , -Hai, -OH, -O -Re, -NH 2 , -NH-R ⁇ , or N (R ⁇ ) is mono- or disubstituted, and ⁇ C ⁇ -C 6 alkyl.
  • R 3 and R 4 independently of one another represent H, -R ⁇ , -CF 3 , -NO 2 , -Hai, -OH, -OR 6 , -NH, - NH-Re or N (R 6 ) 2 ,
  • Rs represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -R «, -CF 3 , -NO 2 , -Hai, -OH, -O -Re, -NH 2 , -NH-R ö , or N (R ⁇ ) 2 is mono- or disubstituted, and
  • R5 C 1 -C 6 alkyl.
  • the compounds of general formula I can be synthesized according to the following synthetic scheme (reference is made to VA Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57 (4), 415-418; VA Chervonyi et al., Zh. Org. Khim. 1988, 24 (2), 453-4 according to VA Chervonyi et al., J Org. Chem. USSR (English transl.) 1988, 24, 401; F. Weygand et al. Chem. Ber. 1966, 99, 1944-1956; H. Böhme et al. Arch Pharmaz., 1961, 294, 307-311; AN Meldrum and GM Vad Jndian Chem. Soc. 1936, 13, 117-118; DZ Barczynski and Z. Eckstein Przem Chem., 1978, 57, 176-177; F. Kasper and H. Böttger Z Chem. 1987, 27, 710-71):
  • the invention thus also relates to a process for the preparation of a compound of the general formula (II), characterized in that a) R 5 -CONH- 2 is added to chloral, b) the product from a) is chlorinated with thionyl chloride, c ) the product from b) with an alkali metal salt of a compound of the general formula (IV)
  • R 3 (IV) is reacted, where R 3 and R 4 have the meanings given above and Me + is an alkali metal cation, preferably Na + .
  • N- (l-Phenylsulfonyl-2,2-dichloro-vinyl) -nicotinamide (0.4 g, 1.120 mmol) is dissolved in tetrahydrofiiran, methylamine (2.607 ml, 2M in tetrahydrofiirane, 4.480 mmol) is added and the mixture is overnight at room temperature touched. The resulting precipitate was filtered off with suction and discarded, the mother liquor was concentrated on a rotary evaporator and the residue was crystallized with a small amount of isopropanol, filtered off with suction and dried in air. Mp: 191-193 ° C, decomposes
  • Example 4-40 The following compounds were prepared analogously.
  • Ph phenyl decomp .: decomposition
  • 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 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 nmol / 1.
  • 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.
  • Example 44 Solution A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 -2 HO, 28.48 g of Na 2 HPO 4 T2 H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distillation Water. The pH is adjusted to 6.8, and the solution is made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
  • 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 E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example 48 Capsules 2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that 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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Abstract

The invention relates to compounds of the general formula (I), wherein R1 and R2 independently of one another represent H, -R6, C3-C8-cycloalkyl, -(CH2)n-R7, -(CH2)n-O-R6, -(CH2)n-NH2, -(CH2)n-NHR6, -(CH2)-N(R6)2, C2-C6-alkenyl or optionally together form a mononuclear saturated heterocycle with one or two nitrogen, oxygen and/or sulphur atoms; R3 and R4 independently of one another represent H, -R6, -CF3, -NO2, -Hal, -OH, -O-R6, -NH2, -NH-R6, or -N(R6)2; R5 represents a 5- or 6-member, saturated or unsaturated heterocycle with one or two nitrogen, oxygen and/or sulphur atoms, which is optionally monosubstituted or disubstituted by -R6, -CF3, -NO2, -Hal, -OH, -O-R6, -NH2, -NH-R6, or -N(R6)2; and R6 represents C1-C6-alkyl; R7 together with R3 and/or R4 represents substituted phenyl, n represents 0 to 2. The invention also relates to the physiologically safe salts or solvates of said compounds and to the use of the compounds of the general formula (I) as medicaments.

Description

Neue Sulfonyloxazolamine New sulfonyloxazolamines
Die Erfindung betrifft Sulfonyloxazolamine der allgemeinen Formel I und deren Verwendung als Arzneimittel sowie ein Verfahren zu deren Herstellung, die in dem Herstellungsverfahren eingesetzten Zwischenprodukte sowie ein Verfahren zur Herstellung der Zwischenprodukte.The invention relates to sulfonyloxazolamines of the general formula I and their use as medicaments and a process for their preparation, the intermediates used in the production process and a process for the preparation of the intermediates.
Bei den erfindunggemäßen Sulfonyloxazolaminen handelt es sich um Verbindungen der allgemeinen Formel I,The sulfonyloxazolamines according to the invention are compounds of the general formula I
wobei Ri und R unabhängig voneinander H, -Rό, C3-C8-Cycloalkyl, -(CH )n-R , -(CH2)nO-R6, -(CH2)n-NH2, -(CH2)n-NHR6, -(CH2)-N(R6)2, C2-C6-Alkenyl bedeuten oder gegebenenfalls zusammen einen einkernigen gesättigten Heterocyclus mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelatomen bilden, where Ri and R independently of one another H, -R ό , C 3 -C 8 cycloalkyl, - (CH) n -R, - (CH 2 ) n O-R6, - (CH 2 ) n -NH 2 , - ( CH 2 ) n -NHR 6 , - (CH 2 ) -N (R 6 ) 2 , C 2 -C 6 alkenyl or optionally together form a mononuclear saturated heterocycle with one or two nitrogen, oxygen and / or sulfur atoms,
R3 und R-i unabhängig voneinander für H, -R$, -CF , -NO2, -Hai, -OH, -O-Rό, -NH2, -NH-Rό oder -N(R6)2 stehen, R5 einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten Heterocyclus darstellt, mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelatomen, der gegebenenfalls durch -Rβ, -CF3, -NO2, -Hai, -OH, -O-R*, -NH2, -NH-RÖ, oder -N(R6) mono- oder disubstituiert ist, undR 3 and Ri independently of one another are H, -R $, -CF, -NO 2 , -Hai, -OH, -OR ό , -NH 2 , -NH-R ό or -N (R 6 ) 2 , R 5 represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -Rβ, -CF 3 , -NO 2 , -Hai, -OH, -OR * , -NH 2 , -NH-R Ö , or -N (R 6 ) is mono- or disubstituted, and
Rδ Ci-Cö-Alkyl bedeutet, R7 mit R und/oder R substituiertes Phenyl bedeutet, n 0 bis 2 bedeutet, sowie deren physiologisch unbedenklichen Salze oder Solvate.Rδ means Ci-C ö alkyl, R7 means phenyl substituted with R and / or R, n means 0 to 2, and their physiologically acceptable salts or solvates.
Einige Sulfonyloxazolamine sind aus verschiedenen früheren Veröffentlichungen bekannt: V. A. Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57(4), 415-418 oder V. A. Chervonyi et al., Zh. Org. Khim. 1988, 24(2), 453-4 entsprechend V. A. Chervonyi et al, J Org. Chem. USSR (engl. transl.) 1988, 24, 401. In der letztgenennten Veröffentlichung wird zum Beispiel die Herstellung von 4-Toloylsulfonyl-5-dimethylamino-2-phenyl-l,3- oxazol beschrieben.Some sulfonyloxazolamines are known from various previous publications: 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 according to VA Chervonyi et al, J Org. Chem. USSR (English transl.) 1988, 24, 401. In the latter publication For example, the preparation of 4-toloylsulfonyl-5-dimethylamino-2-phenyl-1,3-oxazole is described.
Der Erfindung lag die Aufgabe zugrunde, Sulfonyloxazolamine mit wertvollen Eigen- schaften aufzufinden. Insbesondere galt es, pharmakologisch wirksame Sulfonyloxazolamine aufzufinden.The object of the invention was to find sulfonyloxazolamines with valuable properties. In particular, it was necessary to find pharmacologically active sulfonyloxazolamines.
Die Aufgabe wird gelöst durch Verbindungen der vorstehend beschriebenen allgemeinen Formel I, sowie deren physiologisch unbedenklichen Salze oder Solvate.The object is achieved by compounds of the general formula I described above, and their physiologically acceptable salts or solvates.
Es wurde gefunden, daß die Verbindungen der Formel I und ihre pharmakologisch wirksamen Salze bei guter Verträglichkeit überraschenderweise eine selektive Affinität zu 5- HT6 Rezeptoren besitzen, also 5-HT6 Rezeptorliganden darstellen. Sie weisen 5-HT6- antagonistische oder 5-HT6 agonistische Wirkungen auf.It has been found that the compounds of the formula I and their pharmacologically active salts, with good tolerability, surprisingly have a selective affinity for 5-HT6 receptors, that is to say 5-HT6 receptor ligands. They have 5-HT6 antagonistic or 5-HT6 agonistic effects.
5-HT6 Rezeptoren bilden eine Subfamilie der 5-HT Rezeptoren. Der Neurotransmitter 5- Hydroxytryptamin (5-HT), auch bekannt als Serotonin, ist ein bedeutender regulierender Neurotransmitter im Gehirn, dessen Wirkungen von einer Familie von Rezeptoren unterstützt werden, die zum jetzigen Wissenstand 13 G-Protein gekoppelte Rezeptoren und ei- nen Ionenkanal enthält. Zur Gruppe der G-Protein gekoppelten Rezeptoren gehören auch die 5-HT6 Rezeptoren. Einige Vertreter sind kloniert und zum Teil histologisch und biochemisch untersucht (siehe zum Beispiel Kohen et al. (1996) J. Neurochem 66, 47-56; Ruart et al. (1993), 193, 268-76).5-HT6 receptors form a subfamily of 5-HT receptors. The 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 5-HT6 receptors also belong to the group of G protein-coupled receptors. Some representatives have been cloned and in part histologically and biochemically examined (see, for example, Kohen et al. (1996) J. Neurochem 66, 47-56; Ruart et al. (1993), 193, 268-76).
Die größte Dichte der Serotonin 5-HT6 Rezeptoren im Gehirn findet sich im Tuberculum olfactorium, im Nucleus accumbens, im Striatum, im Gyrus dentatus und in den CA1-3 Regionen des Hippocampus. Diese Regionen sind in besonderem Maße bei psychiatrischen Erkrankungen wie etwa der Schizophrenie oder der Depression beteiligt. Aus dem Tierversuch weiß man überdies, daß die Gabe von 5-HT6-Antisense-Oligonukleotiden ein Ver- haltenssyndrom hervorruft, das dem von Dopamin-Agonisten entspricht. Weiterhin ist eine Überfunktion des dopaminergen Neurotransmittersystems bei der Schizophrenie (Dopa- min-Hypothese der Schizophrenie) pathophysiologisch gesichert. Aber auch Dysfunktio- nen des Dopaminsystems bei verschiedenen Erkrankungsformen der Depression sind nachgewiesen. Von den etablierten oder auch neueren Therapeutika, die zur Behandlung dieser psychiatrischen Erkrankungen in der klinischen Praxis eingesetzt werden, binden zudem eine Vielzahl an den 5-HT6 Rezeptor. Hier sind insbesondere die atypischen Neu- roleptika (z.B. Clozapin) und die trizyklischen Antidepressiva (z.B. Amitriptylin) zu nennen.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 involved in psychiatric disorders such as 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. However, 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 receptor. Here in particular the atypical new roleptics (e.g. clozapine) and the tricyclic antidepressants (e.g. amitriptyline).
Darüber hinaus wurde in tierexperimentellen Untersuchungen festgestellt, daß 5-HT6 Re- zeptoren im Gehirn die cholinerge Neurotransmission kontrollieren. Cholinergika werden bei Erkrankungen mit Gedächtnisstörungen wie etwa der Alzheimerschen Krankheit eingesetzt.In addition, animal experiments have shown that 5-HT6 receptors in the brain control cholinergic neurotransmission. Cholinergics are used for diseases with memory disorders such as Alzheimer's disease.
Aus diesen Gründen kann auf eine Beteiligung des 5-HT6 Rezeptors bei psychiatrischen und neurologischen Erkrankungen wie vorzugsweise Schizophrenie, Depression und Alzheimer geschlossen werden.For these reasons it can be concluded that the 5-HT6 receptor is involved in psychiatric and neurological diseases such as preferably schizophrenia, depression and Alzheimer's.
Deshalb eignen sich die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze als therapeutische Wirkstoffe für Erkrankungen des Zentralnervensystems. Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze oder Solvate eignen sich besonders zur Behandlung von Psychosen, Schizophrenie, manischen Depressionen (B. L. Roth et al., J Pharmacol. Exp. Ther. 1994, 268, 1403-1410), Depressionen (D. R. Sibley et al., Mol. Pharmacol. 1993, 43, 320-327), neurologischen Störungen (A. Bourson et al, J Pharmacol. Exp. Ther. 1995, 274, 173-180), Gedächtnisstörungen, der Parkinson'schen Krankheit, der amyotrophen Lateralsklerose, der Alzheimer'schen Krankheit, der Huntington'schen Krankheit (A. J. Sleight et al., Neurotransmissions 1995, 11, 1- 5), Bulimie, nervöser Anorexie oder anderen Eßstörungen, Zwangshandlungen oder des prämenstruellen Syndroms.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. 1995, 274, 173-180), memory disorders, Parkinson's disease , amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease (AJ Sleight et al., Neurotransmissions 1995, 11, 1-5), bulimia, nervous anorexia or other eating disorders, compulsive acts or premenstrual syndrome.
Unter Solvaten der Verbindungen der Formel I werden Anlagerungen von „inerten" Lösungsmittelmolekülen an die Verbindungen der Formel I verstanden, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oder Alkoholate.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, for example, mono- or dihydrates or alcoholates.
Für alle Reste, die mehrfach auftreten, gilt, daß deren Bedeutungen unabhängig voneinander sind.For all radicals that occur several times, the meaning is independent of one another.
R3 und j sind bevorzugt unabhängig voneinander Methyl, Methoxy, Chlor und Brom oder Wasserstoff.R 3 and j are preferably independently of one another methyl, methoxy, chlorine and bromine or hydrogen.
bedeutet bevorzugt Phenyl, o-, r - oder p-Methylphenyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-Isopropylphenyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Aminophenyl, o-, tn- oder p-N,N-Dimethylaminophenyl, o-, m- oder p- Nitrophenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p- Ethoxyphenyl, o-, m-, p-Trifluormethylphenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-Bromphenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dichlorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dibromphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5- Dimethoxyphenyl. preferably means phenyl, o-, r- 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-, tn- 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-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o -, m- or p-bromophenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4 -, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl.
Besonders bevorzugt fürParticularly preferred for
R3 ist Phenyl, o- oder p-Methylphenyl, o- oder p-Chlorphenyl, p-Bromphenyl, p- Methoxyphenyl oder 2,4-Dichlorphenyl.R3 is phenyl, o- or p-methylphenyl, o- or p-chlorophenyl, p-bromophenyl, p-methoxyphenyl or 2,4-dichlorophenyl.
Hai bedeutet Fluor, Chlor oder Brom.Shark means fluorine, chlorine or bromine.
R und R können zusammen auch einen einkernigen gesättigten Heterocyclus mit 1 bis 2 N-, O- und/oder S-Atomen bilden.R and R together can also form a mononuclear saturated heterocycle having 1 to 2 N, O and / or S atoms.
Bei diesem Heterocyclus handelt es sich vorzugsweise um Tetrahydro-2- oder -3-furyl, l,3-Dioxolan-4-yl, Tetrahydro-2- oder -3-thienyl, 1-, 2- oder 3-Pyrrolidinyl, Tetrahydro-1-, -2- oder 4-imidazolyl, Tetrahydro-1-, -3- oder -4-pyrazolyl, 1-, 2-, 3- oder 4-Piperidinyl, 1-, 2-, 3- oder 4-Perhydro-azepinyl, 2-, 3- oder 4-Morpholinyl, Tetrahydro-2-, -3- oder -4- pyranyl, 1 ,4-Dioxanyl, l,3-Dioxan-2-, -4- oder -5-yl, Hexahydro-1-, -3- oder -4- pyridazinyl, Hexahydro-1-, -2-, -4- oder -5-pyrimidinyl oder 1-, 2- oder 3- Piperazinyl.This heterocycle is preferably tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro- 1-, -2- or 4-imidazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-perhydro -azepinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1, 4-dioxanyl, l, 3-dioxan-2-, -4- or -5-yl , Hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl or 1-, 2- or 3-piperazinyl.
Besonders bevorzugt ist 1-Piperidinyl oder 4-Morpholinyl.1-Piperidinyl or 4-morpholinyl is particularly preferred.
Bevorzugt sind Verbindungen, bei denen R- H darstellt.Compounds in which R represents H are preferred.
Ferner sind Verbindungen der allgemeinen Formel I bevorzugt, bei denen R Rό darstellt.Furthermore, compounds of the general formula I are preferred in which RR represents ό .
Im übrigen bedeuten R3 und/oder R4 bevorzugt H. R stellt bevorzugt 2-Furyl, 2-Thienyl oder 3- oder 4- Pyridyl dar.Otherwise, R 3 and / or R 4 are preferably H. R preferably represents 2-furyl, 2-thienyl or 3- or 4-pyridyl.
Rό ist linear oder verzweigt und hat 1 bis 6, vorzugsweise 1, 2, 3 oder 4 C-Atome. RÖ be- deutet vorzugsweise Methyl, weiterhin Ethyl, Propyl, Butyl, Isobutyl, sek.-Butyl oder tert.- Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyl, 1,1-, 1,2- oder 2,2-Dimethylpropyl, 1-Ethylpropyl oder Hexyl. Besonders bevorzugt ist Methyl.Rό is linear or branched and has 1 to 6, preferably 1, 2, 3 or 4 carbon atoms. R Ö preferably means 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 steht vorzugsweise für Allyl, 2- oder 3-Butenyl, Isobutenyl, sek.-Butenyl, ferner bevorzugt ist 4-Pentenyl, iso-Pentenyl oder 5-Hexenyl. Besonders bevorzugt für Alkenyl ist Allyl.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.
Eine Base der allgemeinen Formel I kann mit einer Säure in das zugehörige Säureadditionssalz überführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder heterocy- clische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäu- re, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfon- säure, p-Toluolsulfonsäure, Naphthalin-mono- und disulfonsäuren oder Laurylschwefel- säure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und/oder Aufreinigung der Verbindungen der Formel I verwendet werden.A base of the general formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, 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, furthermore organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, 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, methanoic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid and toluenesulfonic acid, -mono- and disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
Ein weiterer Gegenstand der Erfindung ist die Verwendung der Verbindungen gemäß der allgemeinen Formel I sowie deren physiologisch unbedenklichen Salze und Solvate zur Herstellung von Arzneimitteln, insbesondere zur Herstellung von Antikonvulsiva, Nootro- pica, Entzündungshemmer, Neuro- und Cerebroprotektiva, sowie von Arzneimitteln zur Behandlung von Erkrankungen des Zentralnervensystems, insbesondere zur Behandlung von Schizophrenie, Depression, krankhaften Angstzuständen, Epilepsie, krankhaften Ge- dächtnisstörungen wie Morbus Alzheimer, neurologischen Störungen, amyotrophe Lateralsklerosen, Morbus Huntigton, Störungen im Magen-Darm-Trakt, Reizmagen, Reizkolon, Bulimie, nervöse Anorexie, Zwangshandlungen (obsessive-compulsive disorder, OCD), prämenstruelles Syndrom, Migräne, pharmakologischen Abhängigkeiten, Schlafstörungen und/oder zur Behandlung von Kopf- und Wirbelsäulenverletzungen.Another object of the invention is the use of the compounds of the general formula I and their physiologically acceptable salts and solvates for the production of medicaments, in particular for the production of anticonvulsants, nootropics, anti-inflammatories, neuro- and cerebroprotectives, and of medicaments for the treatment of Central nervous system disorders, in particular for the treatment of schizophrenia, depression, pathological anxiety, epilepsy, pathological memory disorders such as Alzheimer's disease, neurological disorders, amyotrophic lateral sclerosis, Huntigton's disease, disorders of the gastrointestinal tract, irritable stomach, irritable bowel syndrome, bulimia, nervous anorexia , Compulsive acts (obsessive-compulsive disorder, OCD), premenstrual syndrome, migraines, pharmacological dependencies, sleep disorders and / or for the treatment of head and spine injuries.
Dabei werden die erfindungsgemäßen Substanzen in der Regel in der Dosierung vorzugs- weise zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Ge- schlecht, von der Kost, vom Verabreichungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.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, however, depends on a wide 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 excretion and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
Als Pestizid können die Verbindungen der allgemeinen Formel I ebenfalls eingesetzt wer- den.The compounds of the general formula I can also be used as pesticide.
Ein weiterer Gegenstand der Erfindung ist eine pharmazeutische Zubereitung, enthaltend mindestens eine Verbindung gemäß der allgemeinen Formel I sowie deren physiologisch unbedenklichen Salze und Solvate, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.Another object of the invention is a pharmaceutical preparation containing at least one compound according to general formula I and its physiologically acceptable salts and solvates, and optionally carriers and / or auxiliaries.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylalkohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlenhydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Suppositorien, zur parenteralen Anwendung Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyophilisate z.B. zur Herstellung von Injektionspräparaten verwendet werden. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersub- stanzen, Färb-, Geschmacks- und/oder einen oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine. Für den Gegenstand der Erfindung, der therapeutischen Wirkstoffe der Formel I oder deren physiologisch unbedenklichen Salze oder Solvate, der Verwendung der Verbindungen der Formel I oder deren physiologisch unbedenklichen Salze oder Solvate als therapeutische Wirkstoffe oder der Herstellung einer pharmazeutischen Zubereitung zur Behandlung von Erkrankungen des Zentralnervensystems sind Verbindungen der Formel I um so stärker bevorzugt, je mehr Reste eine der vorstehend angegebenen bevorzugten oder besonders bevorzugten Bedeutungen haben.These preparations can be used as medicinal products in human or veterinary medicine. 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 auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or one or more further active substances contain, for example, one or more vitamins. For the subject of the invention, the therapeutic agents of formula I or their physiologically acceptable salts or solvates, the use of compounds of formula I or their physiologically acceptable salts or solvates as therapeutic agents or the preparation of a pharmaceutical preparation for the treatment of diseases of the central nervous system Compounds of formula I the more preferred, the more radicals have one of the preferred or particularly preferred meanings given above.
Ein weiterer Gegenstand der Erfindung ist die Herstellung von Verbindungen der allge- meinen Formel I, wobei RιR2NH mit Verbindungen der allgemeinen Formel II oder III umgesetzt werden.Another object of the invention is the preparation of compounds of general formula I, wherein R 2 R 2 NH are reacted with compounds of general formula II or III.
Die Verbindungen der allgemeinen Formel II sind ebenfalls Gegenstand der Erfindung:The compounds of the general formula II are also a subject of the invention:
wobei R3 und t unabhängig voneinander für H, -RÖ, -CF3, -NO2, -Hai, -OH, -O-RÖ, -NH , - NH-Re oder N(Re)2 stehen, where R 3 and t independently of one another stand for H, -R Ö , -CF 3 , -NO 2 , -Hai, -OH, -OR Ö , -NH, - NH-Re or N (Re) 2 ,
R5 einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten Heterocyklus darstellt, mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelatomen, der gegebenenfalls durch -Rβ, -CF3, -NO2, -Hai, -OH, -O-Re, -NH2, -NH-Rβ, oder N(Rό) mono- oder disubstituiert ist, und Ö Cι-C6-Alkyl bedeutet.R 5 represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -Rβ, -CF 3 , -NO 2 , -Hai, -OH, -O -Re, -NH 2 , -NH-Rβ, or N (R ό ) is mono- or disubstituted, and Ö Cι-C 6 alkyl.
Die Verbindungen der allgemeinen Formel III stellen einen weiteren Gegenstand der Er- findung darThe compounds of the general formula III are a further subject of the invention
wobei R3 und R4 unabhängig voneinander für H, -R^, -CF3, -NO2, -Hai, -OH, -O-R6, -NH , - NH-Re oder N(R6)2 stehen,in which R 3 and R 4 independently of one another represent H, -R ^, -CF 3 , -NO 2 , -Hai, -OH, -OR 6 , -NH, - NH-Re or N (R 6 ) 2 ,
Rs einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten Heterocyklus darstellt, mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelatomen, der gegebenenfalls durch -R«, -CF3, -NO2, -Hai, -OH, -O-Re, -NH2, -NH-Rö, oder N(Rό)2 mono- oder disubstituiert ist, undRs represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -R «, -CF 3 , -NO 2 , -Hai, -OH, -O -Re, -NH 2 , -NH-R ö , or N (R ό ) 2 is mono- or disubstituted, and
R5 Cι-C6-Alkyl bedeutet.R5 C 1 -C 6 alkyl.
Die Verbindungen der allgemeinen Formel I können nach folgendem Syntheseschema synthetisiert werden (es wird Bezug genommen auf V. A. Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57(4), 415-418; V. A. Chervonyi et al., Zh. Org. Khim. 1988, 24(2), 453- 4 entsprechend V. A. Chervonyi et al., J Org. Chem. USSR (engl. transl.) 1988, 24, 401; F. Weygand et al. Chem. Ber. 1966, 99, 1944-1956; H. Böhme et al. Arch Pharmaz., 1961, 294, 307-311; A.N. Meldrum und G.M. Vad J lndian Chem. Soc.1936, 13, 117-118; D.Z. Barczynski und Z. Eckstein Przem Chem., 1978, 57, 176-177; F.Kasper und H. Böttger Z Chem. 1987, 27, 710-71):The compounds of general formula I can be synthesized according to the following synthetic scheme (reference is made to VA Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57 (4), 415-418; VA Chervonyi et al., Zh. Org. Khim. 1988, 24 (2), 453-4 according to VA Chervonyi et al., J Org. Chem. USSR (English transl.) 1988, 24, 401; F. Weygand et al. Chem. Ber. 1966, 99, 1944-1956; H. Böhme et al. Arch Pharmaz., 1961, 294, 307-311; AN Meldrum and GM Vad Jndian Chem. Soc. 1936, 13, 117-118; DZ Barczynski and Z. Eckstein Przem Chem., 1978, 57, 176-177; F. Kasper and H. Böttger Z Chem. 1987, 27, 710-71):
Syntheseschema:Synthesis scheme:
In dem zuvor gezeigten Syntheseschema wird ein Amid der Formel R5CONH mit Chloral umgesetzt, wobei der korrespondierende „Aldehydammoniak" entsteht. Dieser wird mit Thionylchlorid umgesetzt, wobei das enstprechende Tetrachlorethyl-Derivat gebildet wird. Anschließend erfolgt Umsetzung mit einem gegebenenfalls substituierten Natriumbenzol- sulfmat. Dabei entsteht eine Verbindung der allgemeinen Formel II oder III. Sowohl Verbindungen der Formel II als auch der Formel III reagieren mit einem Amin der Formel RjR2NH unter Cyclisierung zu Sulfonyloxazolaminen der allgemeinen Formel I.In the synthesis scheme shown above, an amide of the formula R 5 CONH is reacted with chloral, giving the corresponding “aldehyde ammonia”. This is reacted with thionyl chloride, the corresponding tetrachloroethyl derivative being formed. The reaction is then carried out with an optionally substituted sodium benzene sulfate This produces a compound of the general formula II or III. Both compounds of the formula II and of the formula III react with an amine of the formula RjR 2 NH with cyclization to give sulfonyloxazolamines of the general formula I.
Die geeigneten Reaktionsbedingungen der genannten Umsetzungen aus dem Syntheseschema sind aus den Literaturzitaten V. A. Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57(4), 415-418 oder V. A. Chervonyi et al., Zh. Org. Khim. 1988, 24(2), 453-4 entsprechend V. A. Chervonyi et al., J Org. Chem. USSR (engl. transl.) 1988, 24, 401 oder aus Standard-werken wie z.B. Houben-Weyl, Methoden der organischen Chemie, Georg- Thieme- Verlag, Stuttgart) bekannt. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.The suitable reaction conditions of the reactions mentioned from the synthesis scheme are from the literature quotes 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 according to VA Chervonyi et al., J Org. Chem. USSR (English transl.) 1988, 24, 401 or from standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart). Use can also be made of variants which are known per se and are not mentioned here in detail.
Gegenstand der Erfindung ist also auch ein Verfahren zur Herstellung einer Verbindung gemäß der allgemeinen Formel (II), dadurch gekennzeichnet, daß a) R5-CONH-2 an Chloral addiert wird, b) das Produkt aus a) mit Thionylchlorid chloriert wird, c) das Produkt aus b) mit einem Alkalimetallsalz einer Verbindung der allgemeinen Formel (IV)The invention thus also relates to a process for the preparation of a compound of the general formula (II), characterized in that a) R 5 -CONH- 2 is added to chloral, b) the product from a) is chlorinated with thionyl chloride, c ) the product from b) with an alkali metal salt of a compound of the general formula (IV)
R3 (IV), umgesetzt wird, wobei R3 und R4 die vorstehend aufgeführten Bedeutungen haben und Me+ ein Alkalimetallkation, vorzugsweise Na+ darstellt. R 3 (IV) is reacted, where R 3 and R 4 have the meanings given above and Me + is an alkali metal cation, preferably Na + .
Beispiel 1:Example 1:
Herstellung von (4-Phenylsulfonyl-2-pyridin-3-yl-oxazol-5-yI)-methylaminPreparation of (4-phenylsulfonyl-2-pyridin-3-yl-oxazol-5-yI) methylamine
N-(l-Phenylsulfonyl-2,2-dichloro-vinyl)-nicotinamid (0,4 g, 1,120 mmol) wird in Tetrahydrofiiran gelöst, mit Methylamin (2,607 ml, 2M in Tetrahydrofiiran, 4,480 mmol) versetzt und über Nacht bei Raumtemperatur gerührt. Der entstandene Niederschlag wurde abgesaugt und verworfen, die Mutterlauge am Rotationsverdampfer eingeengt und der Rück- stand mit einer geringen Menge Isopropanol kristallisiert, abgesaugt und an der Luft getrocknet. Fp: 191-193 °C, ZersetzungN- (l-Phenylsulfonyl-2,2-dichloro-vinyl) -nicotinamide (0.4 g, 1.120 mmol) is dissolved in tetrahydrofiiran, methylamine (2.607 ml, 2M in tetrahydrofiirane, 4.480 mmol) is added and the mixture is overnight at room temperature touched. The resulting precipitate was filtered off with suction and discarded, the mother liquor was concentrated on a rotary evaporator and the residue was crystallized with a small amount of isopropanol, filtered off with suction and dried in air. Mp: 191-193 ° C, decomposes
Beispiel 2: Herstellung von (4-Phenylsulfonyl-2-thiophen-2-yl-oxazol-5-yl)-benzylaminExample 2: Preparation of (4-phenylsulfonyl-2-thiophene-2-yl-oxazol-5-yl) benzylamine
Thiophen-2-carbonsäure-(l-Phenylsulfonyl-2,2,2-trichlorethyl)-amid (0,4 g, 1,003 mmol) wird in Tetrahydrofiiran gelöst, mit Benzylamin (0,428 g, 4,012 mmol) versetzt und über Nacht bei Raumtemperatur gerührt. Der entstandene Niederschlag wurde abgesaugt und verworfen, die Mutterlauge am Rotationsverdampfer eingeengt und der Rückstand mit 15 ml Petrolether kristallisiert, abgesaugt und an der Luft getrocknet. Fp: 137-139 °CThiophene-2-carboxylic acid (l-phenylsulfonyl-2,2,2-trichloroethyl) amide (0.4 g, 1.003 mmol) is dissolved in tetrahydrofiirane, benzylamine (0.428 g, 4.012 mmol) is added and the mixture is overnight at room temperature touched. The resulting precipitate was filtered off and discarded, the mother liquor concentrated on a rotary evaporator and the residue crystallized with 15 ml of petroleum ether, suction filtered and air dried. Mp: 137-139 ° C
Beispiel 3:Example 3:
Herstellung von l-(4-PhenylsuIfonyl-2-o-toIyl-oxazol-5-yl)-piperazinhydrochloridPreparation of 1- (4-phenylsulfonyl-2-o-toyl-oxazol-5-yl) piperazine hydrochloride
l-(4-Phenylsulfonyl-2-o-tolyl-oxazol-5-yl)-piperazin (0,2 g, 0,556 mmol) wurde in Tetrahydrofiiran (15 ml) und Methanol (15 ml) gelöst, bei Raumtemperatur mit methanolischer Salzsäure versetzt (2 ml) und 1 h nachgerührt. Die ausgefallenen Kristalle wurden abgesaugt, mit etwas Tetrahydrofiiran nachgewaschen und an der Luft getrocknet. Fp: 239-240 °C, Zersetzung1- (4-Phenylsulfonyl-2-o-tolyl-oxazol-5-yl) piperazine (0.2 g, 0.556 mmol) was dissolved in tetrahydrofiirane (15 ml) and methanol (15 ml) at room temperature with methanolic hydrochloric acid mixed (2 ml) and stirred for 1 h. The precipitated crystals were filtered off, washed with a little tetrahydrofiiran and air-dried. Mp: 239-240 ° C, decomposes
Beispiel 4-40: Die folgenden Verbindungen wurden analog hergestellt.Example 4-40: The following compounds were prepared analogously.
Abkürzungen:Abbreviations:
Me: MethylMe: methyl
Et: EthylEt: ethyl
Ph: Phenyl Zers.: ZersetzungPh: phenyl decomp .: decomposition
Beispiel 41: Affinitätsbestimmung Example 41: Affinity determination
Die Bindung der Verbindungen der Formel I an 5-HT6 Rezeptoren wurde wie folgt bestimmt:The binding of the compounds of the formula I to 5-HT6 receptors was determined as follows:
Die zu testenden Substanzen wurden in DMSO mit einer Konzentration von 1 mM gelöst und mit Testpuffer (20 mM HEPES, 0.1% Ascorbinsäure, mit NaOH eingestellt auf pH 7.4) auf die gewünschten Konzentrationen verdünnt (0.1 nM bis 10 μM).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 μM) with test buffer (20 mM HEPES, 0.1% ascorbic acid, adjusted to pH 7.4 with NaOH).
20 μl der jeweiligen Substanzlösung wurden mit 80 μl 3H-LSD-Lösung (TRK-1041, Amersham Pharmacia, Freiburg, spez. Akt. 80 - 90 Ci/mMol, 1 nM im Ansatz) und 100 μl Membransuspension (5-HT6 Rezeptoren, RB-HS6, Fa. Biotrend, Köln, 25-30 μg Protein) eine Stunde bei 37°C inkubiert. Das Reaktionsgemisch wurde über GFB-Filter (Whatman), die eine Stunde mit 0.1%-iger wässriger Polyethylenimin-Lösung vorbehandelt waren, gefiltert. Die Filter wurden 3 mal mit 3 ml Testpuffer gewaschen, die Filter in Minivials überfuhrt und nach Zugabe von Ultima Gold (Packard, Frankfurt) im Flüssigszintillations- zähler die Radioaktivität bestimmt. Die Auswertung und IC50-Bestimmung erfolgte mittels eigener Programme in RS1 (BBN Software Cooperation).20 μl of the respective substance solution were mixed with 80 μl 3 H-LSD solution (TRK-1041, Amersham Pharmacia, Freiburg, spec. Act. 80 - 90 Ci / mmol, 1 nM in the batch) and 100 μl membrane suspension (5-HT6 receptors , RB-HS6, from Biotrend, Cologne, 25-30 μg protein) incubated at 37 ° C. for one hour. 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).
Die Verbindungen der Formel I besitzen eine selektive Affinität zu 5-HT6 Rezeptoren mit einer Inhibierungskonstante IC50 von kleiner 4 nmol/1.The compounds of formula I have a selective affinity for 5-HT6 receptors with an inhibition constant IC 50 of less than 4 nmol / 1.
Beispiel 42: InjektionsgläserExample 42: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 1 zweifach destilliertem Wasser mit 2N Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophili- siert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.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.
Beispiel 43: SuppositorienExample 43: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel 44: Lösung Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4-2 H O, 28,48 g Na2HPO4T2 H2O und 0,1 g Benzalkonium-chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 1 auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.Example 44: Solution A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 -2 HO, 28.48 g of Na 2 HPO 4 T2 H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distillation Water. The pH is adjusted to 6.8, and the solution is made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel 45: SalbeExample 45: Ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly with aseptic
Bedingungen.Conditions.
Beispiel 46: TablettenExample 46: Tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 g Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.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.
Beispiel 47: DrageesExample 47: Dragees
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel 48: Kapseln 2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatine-kapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.Example 48: Capsules 2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel 49: AmpullenExample 49: Ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 ml zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. 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.

Claims

Patentansprüche claims
1. Verbindungen der allgemeinen F ormel (I)1. Compounds of the general formula (I)
wobeiin which
Ri und R unabhängig voneinander H, -Rό, -C3-C8-Cycloalkyl, -(CH2)n-R7, - (CH2)„-O-R6, -(CH2)n-NH2, -(CH.VNHR,, -(CH2)-N(R6)2, -C2-C6- Alkenyl bedeuten oder gegebenenfalls zusammen einen einkernigen gesättigten Heterocyclus mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelatomen bilden,Ri and R independently of one another H, -Rό, -C 3 -C 8 cycloalkyl, - (CH 2 ) n -R 7 , - (CH 2 ) „- O-R6, - (CH 2 ) n -NH 2 , - (CH.VNHR ,, - (CH 2 ) -N (R 6 ) 2 , -C 2 -C 6 - alkenyl or optionally together form a mononuclear saturated heterocycle with one or two nitrogen, oxygen and / or sulfur atoms,
R3 und j unabhängig voneinander für H, -Rβ, -CF3, -NO2, -Hai, -OH, -O—R^, - NH2, -NH-Re oder -N(Re)2 stehen,R 3 and j independently of one another represent H, -Rβ, -CF 3 , -NO 2 , -Hai, -OH, -O — R ^, - NH 2 , -NH-Re or -N (Re) 2 ,
R5 einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten Heterocyclus darstellt, mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelatomen, der gegebenenfalls durch -Re, -CF3, -NO2, -Hai, -OH, -O-Re, -NH2, -NH-Rö, oder -N(R$)2 mono- oder disubstituiert ist, undR 5 represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -Re, -CF 3 , -NO 2 , -Hai, -OH, -O -Re, -NH 2 , -NH-R ö , or -N (R $) 2 is mono- or disubstituted, and
R* Cι-C6-Alkyl bedeutet,R * is -C 6 alkyl,
R7 mit R3 und/oder * substituiertes Phenyl bedeutet, n 0 bis 2 bedeutet, sowie deren physiologisch unbedenklichen Salze oder Solvate.R 7 is phenyl substituted with R 3 and / or *, n is 0 to 2, and their physiologically acceptable salts or solvates.
2. Verbindungen gemäß Anspruch 1, dadurch gekennzeichnet, daß R\ H darstellt.2. Compounds according to claim 1, characterized in that R represents \ H.
3. Verbindungen gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß R2 -Rό darstellt.3. Compounds according to claim 1 or 2, characterized in that R 2 represents -R ό .
4. Verbindungen gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß R3 und R H bedeuten. 4. Compounds according to any one of claims 1 to 3, characterized in that R 3 and RH are.
5. Verbindungen gemäß einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß R5 2-Furyl, 2-Thienyl oder 3- oder 4- Pyridyl bedeuten.5. Compounds according to any one of claims 1 to 4, characterized in that R 5 is 2-furyl, 2-thienyl or 3- or 4-pyridyl.
6. Verwendung der Verbindungen gemäß einem der Ansprüche 1 bis 5 sowie deren phy- siologisch unbedenklichen Salze und Solvate zur Hersteilimg von Arzneimitteln, insbesondere zur Herstellung von Antikonvulsiva, Nootropica, Entzündungshemmer, Neuro- und Cerebroprotektiva.6. Use of the compounds according to any one of claims 1 to 5 and their physiologically acceptable salts and solvates for the manufacture of medicaments, in particular for the production of anticonvulsants, nootropics, anti-inflammatories, neuro- and cerebroprotectives.
7. Verwendung der Verbindungen gemäß einem der Ansprüche 1 bis 5 sowie deren phy- siologisch unbedenklichen Salze und Solvate zur Herstellung von Arzneimitteln zur7. Use of the compounds according to one of claims 1 to 5 and their physiologically acceptable salts and solvates for the manufacture of medicaments for
Behandlung von Erkrankungen des Zentralnervensystems, insbesondere zur Behandlung von Schizophrenie, Depression, krankhaften Angstzuständen, Epilepsie, krankhaften Gedächtnisstörungen wie Morbus Alzheimer, neurologischen Störungen, amyotrophe Lateralsklerosen, Morbus Huntington, Störungen im Magen-Darm-Trakt, Reizmagen, Reizkolon, Bulimie, nervöse Anorexie, Zwangshandlungen (obsessive- compulsive disorder, OCD), prämenstruelles Syndrom, Migräne, pharmakologischen Abhängigkeiten, Schlafstörungen und/oder zur Behandlung von Kopf- und Wirbelsäulenverletzungen.Treatment of diseases of the central nervous system, in particular for the treatment of schizophrenia, depression, pathological anxiety, epilepsy, pathological memory disorders such as Alzheimer's disease, neurological disorders, amyotrophic lateral sclerosis, Huntington's disease, disorders of the gastrointestinal tract, irritable stomach, irritable bowel syndrome, bulimia, nervous anorexia , Compulsive acts (obsessive-compulsive disorder, OCD), premenstrual syndrome, migraines, pharmacological dependencies, sleep disorders and / or for the treatment of head and spine injuries.
8. Verwendung der Verbindungen gemäß einem der Ansprüche 1 bis 5 sowie deren Salze und Solvate als Pestizid.8. Use of the compounds according to any one of claims 1 to 5 and their salts and solvates as a pesticide.
9. Pharmazeutische Zubereitung, enthaltend mindestens eine Verbindung gemäß einem der Ansprüche 1 bis 5 sowie deren physiologisch unbedenklichen Salze und Solvate, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.9. Pharmaceutical preparation containing at least one compound according to one of claims 1 to 5 and its physiologically acceptable salts and solvates, and optionally carriers and / or auxiliaries.
10. Verbindung der allgemeinen Formel (II)10. Compound of the general formula (II)
wobei R3 und R-t unabhängig voneinander für H, -Rβ, -CF3, -NO2, -Hai, -OH, -O-RÖ, -NH2, where R 3 and Rt are independently H, -Rβ, -CF 3 , -NO 2 , -Hai, -OH, -OR Ö , -NH 2 ,
-NH-Rö oder -N(Re)2 stehen, R5 einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten Heterocyclus darstellt, mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelatomen, der gegebenenfalls durch -Re, -CF3, -NO2, -Hai, -OH, -O-Re, -NH2, -NH-RÖ, oder -N(RÖ) mono- oder disubstituiert ist, und-NH-Rö or -N (Re) 2 , R 5 represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -Re, -CF 3 , -NO 2 , -Hai, -OH, -O -Re, -NH 2 , -NH-R Ö , or -N (R Ö ) is mono- or disubstituted, and
Ri Cι-C6-Alkyl bedeutet.R 1 -C 6 -alkyl means.
11. Verbindung der allgemeinen Formel (III),11. Compound of the general formula (III),
wobeiin which
R3 und R4 unabhängig voneinander für H, -R^, -CF3, -NO2, -Hai, -OH, -O-R6, -NH2,R 3 and R 4 independently of one another for H, -R ^, -CF 3 , -NO 2 , -Hai, -OH, -OR 6 , -NH 2 ,
-NH-Re oder -N(R6)2 stehen, R5 einen 5- oder 6-gliedrigen, gesättigten oder ungesättigten Heterocyclus darstellt, mit ein oder zwei Stickstoff, Sauerstoff und/oder Schwefelato- men, der gegebenenfalls durch -R^, -CF3, -NO2, -Hai, -OH, -O-R-5, -NH2,-NH-Re or -N (R 6 ) 2 , R 5 represents a 5- or 6-membered, saturated or unsaturated heterocycle, with one or two nitrogen, oxygen and / or sulfur atoms, which may be replaced by -R ^ , -CF 3 , -NO 2 , -Hai, -OH, -OR- 5 , -NH 2 ,
-NH-Rö, oder -N(Re)2 mono- oder disubstituiert ist, und RÖ d-Ce-Alkyl bedeutet.-NH-R ö , or -N (Re) 2 is mono- or disubstituted, and R Ö d-Ce-alkyl means.
12. Verfahren zur Herstellung einer Verbindung gemäß der allgemeinen Formel (II), da- durch gekennzeichnet, daß a) R5-CONH-2 an Chloral addiert wird, b) das Produkt aus a) mit Thionylchlorid chloriert wird, c) das Produkt aus b) mit einem Alkalimetallsalz einer Verbindung der allgemeinen Formel (IV)12. A process for the preparation of a compound of the general formula (II), characterized in that a) R 5 -CONH- 2 is added to chloral, b) the product from a) is chlorinated with thionyl chloride, c) the product from b) with an alkali metal salt of a compound of the general formula (IV)
K-3 (IV),K-3 (IV),
umgesetzt wird, wobei R3 und R4 die in Anspruch 10 aufgeführten Bedeutungen haben und Me+ ein Alkalimetallkation, vorzugsweise Na+ darstellt. is implemented, wherein R 3 and R 4 have the meanings listed in claim 10 and Me + is an alkali metal cation, preferably Na + .
3. Verfahren zur Herstellung einer Verbindung gemäß der allgemeinen Formel (I), dadurch gekennzeichnet, daß man eine Verbindung der allgemeinen Formel (II) oder (III) mit RιR2NH umsetzt. 3. A process for the preparation of a compound of the general formula (I), characterized in that reacting a compound of the general formula (II) or (III) with RιR 2 NH.
EP00990614A 1999-11-25 2000-11-24 Novel sulfonyl oxazole amines Withdrawn EP1233963A2 (en)

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DE19956791 1999-11-25
DE19956791A DE19956791A1 (en) 1999-11-25 1999-11-25 New 2-heterocyclyl-4-arylsulfonyl-5-amino-oxazole derivatives useful in treatment of central nervous system disorders and as pesticides
PCT/EP2000/011734 WO2001038316A2 (en) 1999-11-25 2000-11-24 Sulfonyl oxazole amines and their use as 5-ht6 receptor ligands

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US8394788B2 (en) * 2006-11-16 2013-03-12 The Regents Of The University Of California Phenylsulfoxyoxazole compound inhibitors of urea transporters
EP2016943B1 (en) * 2007-07-19 2011-02-23 Laboratorios del Dr. Esteve S.A. Substituted tetrahydro-quinoline-sulfonamide compounds, their preparation and use as medicaments
RU2443697C1 (en) 2010-12-21 2012-02-27 Александр Васильевич Иващенко Substituted methyl-amines, serotonin 5-ht6 receptor antagonists, methods of production and use
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US6194410B1 (en) 1998-03-11 2001-02-27 Hoffman-La Roche Inc. Pyrazolopyrimidine and pyrazolines and process for preparation thereof
DE19858593A1 (en) 1998-12-18 2000-06-21 Merck Patent Gmbh (2-Phenyl-4-(phenylsulfonyl)-oxazol-5-yl)-amine therapeutic agents having 5-HT6 receptor affinity, useful for treating CNS disorders such as psychosis, schizophrenia, depression or Alzheimer's disease

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