HK1055117B - 8,8a-dihydro-indeno[1,2-d]thiazole derivatives, a method for their production and their use as medicaments - Google Patents
8,8a-dihydro-indeno[1,2-d]thiazole derivatives, a method for their production and their use as medicaments Download PDFInfo
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Description
The invention relates to polycyclic dihydrothiazoles and their physiologically acceptable salts and physiologically functional derivatives.
Thiazolidine derivatives with an anorectic effect have been described in the prior art (austria patent No. 365181).
It is an object of the present invention to provide other compounds having a therapeutically useful appetite-reducing effect.
The present invention therefore relates to compounds of the formula I,
wherein
R1, R1' are each independently of the other H, F, Cl, Br, I, CF3、NO2、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) -alkyl radical]2、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynesBase, O- (C)1-C6) -alkyl, wherein one or more or all of the hydrogens of the alkyl radical may be replaced by fluoro, or one hydrogen may be replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph、NH2、NH-CO-CH3Or N (COOCH)2Ph)2Replacing;
is SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)n-phenyl, SO- (C)1-C6) Alkyl, SO- (CH)2)n-phenyl, SO2-(C1-C6) Alkyl, SO2-(CH2)nPhenyl, where n may be 0 to 6, the phenyl radical may be substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
is NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) -alkyl radical]2、NH(C1-C7) -acyl, phenyl, biphenyl, O- (CH)2)n-phenyl, wherein n may be 0-6-, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furyl or 2-or 3-thienyl, wherein the phenyl, biphenyl, naphthyl, pyridyl, furyl or thienyl rings may each be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) -alkyl radical]2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH21 to 3 times;
is 1, 2, 3-triazol-5-yl, wherein the triazol ring may be substituted at the 1-, 2-or 3-position with methyl or benzyl;
is tetrazol-5-yl, wherein the tetrazole ring may be substituted at the 1-or 2-position with methyl or benzyl;
r2 is H, (C)1-C6) Alkyl radicals, (C)3-C6) -cycloalkyl, (CH)2)n-phenyl, (CH)2)n-thienyl, (CH)2)n-pyridyl, (CH)2)nFuryl, C (O) - (C)1-C6) Alkyl, C (O) - (C)3-C6) Cycloalkyl, C (O) - (CH)2)n-phenyl, C (O) - (CH)2)n-thienyl, C (O) - (CH)2)n-pyridyl, C (O) - (CH)2)nFuryl, where n may be 0 to 5, in which phenyl, thienyl, pyridyl and furyl may each be substituted by Cl, F, CN, CF3、(C1-C3) Alkyl, OH, O- (C)1-C6) -alkyl substitution up to 2 times;
r3 is Cl, Br, CH2-COO(C1-C6) -alkyl, CH2-COOH、CH2-CONH2；
R4 is (C)1-C8) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)4-C7) Cycloalkenyl in which one or more or all of the hydrogens of the alkyl radical may be replaced by fluorine, or one hydrogen may be replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph or O- (C)1-C4) -alkyl substitution;
is (CH)2)n-pyrrolidin-1-yl, (CH)2)n-piperidin-1-yl group, (CH)2)n-morpholin-4-yl, (CH)2)n-piperazin-1-yl, (CH)2)n-N-4-methylpiperazin-1-yl group, (CH)2)n-N-4-benzylpiperazin-1-yl group, (CH)2)n-a phthalimido group, wherein n may be 1-6;
is (CH)2)nAryl, where n may be 0 to 6, is phenyl, biphenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl, 2-, 4-or 5-thiazolyl, 2-, 4-or 5-oxazolyl, 1-pyrazolyl, 3-or 5-isoxazolyl, 2-or 3-pyrrolyl, 2-or 3-pyridazinyl, 2-, 4-or 5-pyrimidinyl, 2-pyrazinyl, 2- (1, 3, 5-triazinyl) -, 2-or 5-benzimidazolyl, 2-benzothiazolyl, 1, 2, 4-triazol-3-yl, 1-or 2-triazol-3-yl, 2-or 5-oxazolyl, 1-pyrazolyl, 3-isoxazolyl, 2-or 3-pyrrolyl, 2-or 3-pyridazinyl, 2-, 4-or 5-pyrimidinyl, 2, 1, 2, 4-triazol-5-yl, tetrazol-5-yl, indol-3-yl, indol-5-yl or N-methylimidazol-2-, -4-or-5-yl, the aryl or heteroaryl radical being optionally substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, S- (C)1-C6) Alkyl, SO- (C)1-C6) Alkyl, (CH)2)n-SO2-(C1-C6) Alkyl, (CH)2)n-SO2-NH2、(CH2)n-SO2-N(＝CH-N(CH3)2) -wherein n may be 0-6- (C)1-C6) Alkyl radicals, (C)3-C6) Cycloalkyl, COOH, COO (C)1-C6) -alkyl, COO (C)3-C6) -cycloalkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) -alkyl radical]2、CONH(C3-C6) -cycloalkyl, NH2、NH-CO-(C1-C6) Alkyl, NH-CO-phenyl, NH-SO2-(C1-C6) -alkyl, NH-SO2-phenyl is substituted up to 2 times, wherein the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、COOH、COO(C1-C6) -alkyl or CONH2Up to 2 substitutions;
is pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH)2)n-phenyl, O- (CH)2)n-phenyl, S- (CH)2)n-phenyl, SO2-(CH2)n-phenyl, wherein n may be 0-3;
is (CH)2)n-a-R8, wherein n may be 1-6;
a is O, NH, N- (C)1-C6) Alkyl, NCHO, N (CO-CH)3)、S、SO、SO2；
R8 is (C)1-C8) Alkyl radicals, (C)3-C8) Cycloalkyl, in which one or more hydrogens of the alkyl radical may be replaced by fluorine, or a hydrogen may be replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph or O- (C)1-C4) -alkyl substitution;
is (CH)2)m-aryl, where m may be 0-6, which may be phenyl, thienyl or pyridyl, which aryl moiety may be substituted up to 2 times with: F. cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl, S- (C)1-C6) Alkyl, SO- (C)1-C6) Alkyl, (CH)2)n-SO2-(C1-C6) Alkyl, (CH)2)n-SO2-NH2、(CH2)n-SO2-N(＝CH-N(CH3)2)、(CH2)n-SO2-NH(C1-C8) Alkyl, (CH)2)n-SO2-N[(C1-C8) -alkyl radical]2、(CH2)n-SO2-NH(C3-C8) -cycloalkyl, (CH)2)n-SO2-N[(C3-C8) -cycloalkyl radical]2-wherein n may be 0-6- (C)1-C6) Alkyl radicals, (C)3-C6) Cycloalkyl, COOH, COO (C)1-C6) -alkyl, COO (C)3-C6) -cycloalkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) -alkyl radical]2、CONH(C3-C6) -cycloalkyl, NH2、NH(C1-C6) Alkyl, N [ (C)1-C6) -alkyl radical]2、NH-CO-(C1-C6) Alkyl, NH-CO-phenyl, NH-SO2-phenyl-wherein the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、COOH、COO(C1-C6) -alkyl or CONH2Substituted up to 2 times-;
NH-SO2-(C1-C8) Alkyl, N (C)1-C6) -alkyl-SO2-(C1-C8) -alkyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH)2)p-phenyl, O- (CH)2)p-phenyl, S- (CH)2)p-phenyl or SO2-(CH2)p-phenyl-wherein p may be 0-3-;
and physiologically acceptable salts and physiologically functional derivatives thereof.
Preference is given to compounds of the formula I in which
R1, R1' are each independently of the other H, F, Cl, Br, I, CF3、NO2、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) -alkyl radical]2、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, O- (C)1-C6) -alkyl, wherein one or more or all of the hydrogens of the alkyl radical may be replaced by fluoro, or one hydrogen may be replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph、NH2、NH-CO-CH3Or N (COOCH)2Ph)2Replacing;
is SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)n-phenyl, SO- (C)1-C6) Alkyl, SO- (CH)2)n-phenyl, SO2-(C1-C6) Alkyl, SO2-(CH2)nPhenyl, where n may be 0 to 6, the phenyl radical may be substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
is NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) -alkyl radical]2、NH(C1-C7) -acyl, phenyl, biphenyl, O- (CH)2)n-phenyl, wherein n may be 0-6-, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl, 2-or 3-furyl or 2-or 3-thienyl, wherein the phenyl, biphenyl, naphthyl, pyridyl, furyl or thienyl rings may each be substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) -alkyl radical]2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH21 to 3 times;
is 1, 2, 3-triazol-5-yl, wherein the triazol ring may be substituted at the 1-, 2-or 3-position with methyl or benzyl;
is tetrazol-5-yl, wherein the tetrazole ring may be substituted at the 1-or 2-position with methyl or benzyl;
r2 is H, (C)1-C6) Alkyl radicals, (C)3-C6) -cycloalkyl, (CH)2)n-phenyl, (CH)2)n-thienyl, (CH)2)n-pyridyl, (CH)2)nFuryl, C (O) - (C)1-C6)-Alkyl, C (O) - (C)3-C6) Cycloalkyl, C (O) - (CH)2)n-phenyl, C (O) - (CH)2)n-thienyl, C (O) - (CH)2)n-pyridyl, C (O) - (CH)2)nFuryl, where n may be 0 to 5, in which phenyl, thienyl, pyridyl and furyl may each be substituted by Cl, F, CN, CF3、(C1-C3) Alkyl, OH, O- (C)1-C6) -alkyl substitution up to 2 times;
r3 is Cl, Br, CH2-COO(C1-C6) -alkyl, CH2-COOH、CH2-CONH2；
R4 is (C)1-C8) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)4-C7) Cycloalkenyl in which one or more or all of the hydrogens of the alkyl radical may be replaced by fluorine, or one hydrogen may be replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph or O- (C)1-C4) -alkyl substitution;
is (CH)2)n-pyrrolidin-1-yl, (CH)2)n-piperidin-1-yl group, (CH)2)n-morpholin-4-yl, (CH)2)n-piperazin-1-yl, (CH)2)n-N-4-methylpiperazin-1-yl group, (CH)2)n-N-4-benzylpiperazin-1-yl group, (CH)2)n-a phthalimido group, wherein n may be 1-6;
is (CH)2)nAryl, where n may be 0 to 6, phenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl or 2-or 3-thienyl, which aryl radical or heteroaryl radical may be substituted by F, Cl, Br, OH, CF3、O-(C1-C6) Alkyl, (CH)2)n-SO2-(C1-C6) Alkyl, (CH)2)n-SO2-NH2、(CH2)n-SO2-N(＝CH-N(CH3)2) -wherein n may be 0-6-, NH-SO2-(C1-C6) -alkyl, NH-SO2-phenyl-wherein the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、COOH、COO(C1-C6) -alkyl or CONH2Up to 2 substitutions — (C)1-C6) Alkyl, COOH, COO (C)1-C6) -alkyl or CONH2Up to 2 substitutions;
is (CH)2)n-a-R8, wherein n may be 1-6;
a is O, NH, N- (C)1-C6) Alkyl, SO2；
R8 is (C)1-C8) Alkyl radicals, (C)3-C8) Cycloalkyl, in which one or more hydrogens of the alkyl radical may be replaced by fluorine, or a hydrogen may be replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph or O- (C)1-C4) -alkyl substitution;
is (CH)2)m-aryl, where m may be O-6, aryl may be phenyl, thienyl or pyridyl, the aryl moiety may be substituted up to 2 times with: F. cl, Br, OH, CF3、O-(C1-C6) Alkyl, (CH)2)n-SO2-(C1-C6) Alkyl, (CH)2)n-SO2-NH2、(CH2)n-SO2-N(＝CH-N(CH3)2) -wherein n may be 0-6-;
NH-SO2-(C1-C6) -alkyl, NH-SO2-phenyl-wherein the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、COOH、COO(C1-C6) -alkyl or CONH2Substituted up to 2 times- (COOH), COO (C)1-C6) -alkyl or CONH2；
And physiologically acceptable salts and physiologically functional derivatives thereof.
Particular preference is given to compounds of the formula I in which
R1, R1' are each independently of the other H, F, Cl, Br, -OH, O-C1-C6) Alkyl radicals, (C)1-C6) -alkyl, wherein one hydrogen in the alkyl radical may be replaced by OH;
r2 is H, (C)1-C6) Alkyl, C (O) - (C)1-C6) -an alkyl group;
r3 is Cl, Br, CH2-COO(C1-C6) -alkyl, CH2-COOH、CH2-CONH2；
R4 is (C)1-C4) -alkyl or (C)3-C6) -cycloalkyl, wherein one hydrogen in the alkyl radical may be replaced by OH;
is (CH)2)nAryl, where n may be 0 to 6, phenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl or 2-or 3-thienyl, which aryl radical or heteroaryl radical may be substituted by F, Cl, Br, OH, CF3、O-(C1-C6) Alkyl, SO2-(C1-C6) Alkyl, (CH)2)n-SO2-NH2-wherein n may be 0-6- (C)1-C6) Alkyl, COOH, COO (C)1-C6) -alkyl or CONH2Up to 2 substitutions;
is (CH)2)n-a-R8, wherein n may be 1-6;
a is O, SO2；
R8 is (C)1-C8) Alkyl radicals, (C)3-C8) -cycloalkyl, wherein one hydrogen in the alkyl radical may be replaced by OH;
is (CH)2)mAryl, where m may be 0 to 6, aryl may be phenyl or thienyl, the aryl moiety may be substituted by F, Cl, Br, OH, CF3、O-(C1-C6) Alkyl, SO2-(C1-C6) Alkyl, SO2-NH2、COOH、COO(C1-C6) -alkyl or CONH2Up to 2 substitutions;
and physiologically acceptable salts thereof.
The present invention relates to the racemates, racemic mixtures and pure enantiomeric forms of the compounds of formula I, and to the diastereomers and mixtures thereof.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R1', R2, R3, R4, R8 and A may be straight-chain or branched.
Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications compared to the starting materials or the basic compounds, due to their higher water solubility. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and salts of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid. Chloride salts are particularly preferred for pharmaceutical purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts).
Salts with pharmaceutically unacceptable anions are likewise included within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic applications, for example in vitro applications.
The term "physiologically functional derivative" as used herein relates to any physiologically acceptable derivative of a compound of formula I according to the invention, such as an ester, which upon administration to a mammal, such as a human, is capable of (directly or indirectly) producing a compound of formula I or an active metabolite thereof. Physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to compounds according to the invention. These prodrugs may themselves be active or inactive.
The compounds according to the invention may also exist in various polymorphic forms, such as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention are included within the scope of the invention and are further aspects of the invention.
In the following, all references to "compounds according to formula (I)" relate to compounds of formula (I) as described above and their salts, solvates and physiologically functional derivatives as described herein.
The amount of a compound according to formula (I) necessary to achieve a desired biological effect depends on a number of factors, such as the particular compound selected, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dosage will be in the range of from 0.3mg to 100mg (usually from 3mg to 50mg) per kg of body weight per day, for example 3-10 mg/kg/day. Intravenous doses may for example be in the range 0.3mg to 1.0mg/kg, which is suitable for administration as an infusion of 10ng to 100ng per kilogram per minute. Infusion solutions suitable for these purposes may contain, for example, 0.1ng to 10mg, usually from 1ng to 10mg per ml. A single dose may, for example, contain from 1mg to 10g of active compound. Thus, ampoules for injection may, for example, contain from 1mg to 100mg, and single-dose preparations for oral administration, such as tablets or capsules, may, for example, contain from 1.0 to 1000mg, usually from 10 to 600 mg. In the case of a pharmaceutically acceptable salt, the weight details described above relate to the weight of the dihydrothiazole counterion derived from the salt. With regard to the prevention or treatment of the above-mentioned diseases, the compounds according to formula (I) may be used as such, but are preferably used in the form of pharmaceutical compositions with tolerable excipients. Excipients must of course be tolerable in the sense of being compatible with the other ingredients of the composition and not deleterious to the health of the patient. The excipient may be solid or liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05 to 95% by weight of the active compound. Other pharmaceutically active substances may also be present, including other compounds according to formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist of mixing the components with pharmaceutically acceptable excipients and/or auxiliaries.
The pharmaceutical compositions according to the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each particular case depends on the nature and severity of the disease to be treated in each case and on the nature of the compound according to formula (I) used. Sugar coated formulations and sugar coated sustained release formulations are also included within the scope of the present invention. Acid resistant and enteric coated formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.
Pharmaceutical compounds suitable for oral administration may be presented as discrete units such as capsules, cachets, lozenges or tablets, each containing an amount of a compound according to formula (I); powder or granules; solutions or suspensions in aqueous or anhydrous liquids; oil-in-water or water-in-oil emulsions. It has been mentioned that these compositions may be prepared by any suitable pharmaceutical process comprising the step of bringing into contact the active compound with the excipient (which may consist of one or more additional ingredients). In general, the compositions are prepared by uniformly and consistently mixing the active compound with liquid and/or finely divided solid excipients and then, if necessary, shaping the product. Thus, for example, tablets may be prepared by compressing or molding a powder or granules of the compound, if appropriate with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form, e.g. in powder or granular form, optionally mixed with a binder, lubricant, inert diluent and/or a (bulk) surfactant/dispersant. Molded tablets may be prepared by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for peroral (sublingual) administration include lozenges, which comprise a compound according to formula (I) and a flavoring agent, customarily sucrose and acacia or tragacanth, and pastilles, which comprise the compound in an inert base, the former being, for example, gelatin and glycerol or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula (I), which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, although administration may also take the form of subcutaneous, intramuscular or intradermal injection. These formulations can preferably be prepared by mixing the compound with water, rendering the resulting solution sterile and isotonic with blood. The injectable compositions according to the invention generally contain from 0.1 to 5% by weight of active compound.
Pharmaceutical compositions suitable for rectal administration are preferably single dose suppositories. They may be prepared by mixing a compound according to formula (I) with one or more conventional solid excipients, for example cocoa butter, and shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin are preferably ointments, creams, pastes, sprays, aerosols or oils. Excipients which may be used are petroleum gels, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The concentration of active compound is generally from 0.1 to 15%, for example from 0.5 to 2% by weight of the composition.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may be presented as unitary patches adapted for prolonged intimate contact with the epidermis of the patient. Such patches suitably contain an optionally buffered aqueous solution of the active compound, the compound being dissolved and/or dispersed in the adhesive or dispersed in the polymer. Suitable active compound concentrations are from about 1% to 35%, preferably from about 3% to 15%. It is particularly possible that the active compound can be released by electron transport or iontophoresis, as described, for example, in Pharmaceutical Research, 2 (6): 318(1986).
The invention furthermore relates to a process for the preparation of a compound of the formula I, which comprises obtaining a compound of the formula I in such a way that it is processed according to the following reaction scheme:
to this end, compounds of the formula II
Formula II
Wherein R1 and R1' are as defined above,
and formula Z-CH2Reaction of a-COOR compound, where Z is, for example, halogen and R is, for example, methyl, to give a compound of formula III, where R3 is-CH2-COOR. Further reaction of the compound of formula III with a halogen, for example bromine, gives a compound of formula IV, wherein R1 and R1' are as defined above and R3 is for example-CH2-COOR. The compound of formula IV is then reacted with a thioamide of formula VI,
wherein R4 is as defined above, to give a compound of formula I. Compounds of formula I wherein R3 is chloro or bromo may be prepared by reacting a compound of formula V with a halogenating agent, for example N-chlorosuccinimide or N-bromosuccinimide.
The compounds of formula I may also form salts with acids. Suitable inorganic acids are, for example: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, and sulfuric acid, phosphoric acid and sulfamic acid. Organic acids which may be mentioned are, for example: formic acid, acetic acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic acid, isethionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 1, 2-benzisothiazol-3 (2H) -one, 6-methyl-1, 2, 3-oxathiazin-4 (3H) -one 2, 2-dioxide.
The above process is advantageously carried out such that the compound of the formula IV is reacted with the thioamide VI in a molar ratio of from 1: 1 to 1: 1.5. The reaction is advantageously carried out in an inert solvent, for example a polar organic solvent such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, dioxane, tetrahydrofuran, acetonitrile, nitromethane or diglyme. However, particularly advantageous solvents have proven to be methyl acetate and ethyl acetate, short-chain alcohols, such as methanol, ethanol, propanol, isopropanol, and lower dialkyl ketones, such as acetone, butan-2-one or hexan-2-one. Mixtures of the reaction media may also be used; mixtures of the solvents mentioned with solvents which are less suitable per se, for example mixtures of methanol with benzene, ethanol with toluene, methanol with diethyl ether or tert-butyl methyl ether, ethanol with carbon tetrachloride, acetone with chloroform, dichloromethane or 1, 2-dichloroethane, may also be used, the strongly polar solvents should preferably be used in excess in each case. The reactants may be suspended or dissolved in the respective reaction medium. In principle, the reactants can also be reacted in the absence of a solvent, in particular if the individual thioamides have as low a melting point as possible. The reaction proceeds in a slightly exothermic manner and can be carried out at between-10 ℃ and 150 ℃ and preferably at between 30 ℃ and 100 ℃. A temperature range between 50 ℃ and 90 ℃ has generally been found to be particularly desirable.
The reaction time is strongly dependent on the reaction temperature, between 2 minutes and 3 days at higher and lower temperatures, respectively. Within the desirable temperature range, the reaction time is generally between 5 minutes and 48 hours.
During the course of the reaction, compound I often forms a poorly soluble precipitate in the form of its acid addition salt, suitably followed by the addition of a suitable precipitating agent. The precipitant used is, for example, hydrocarbons, such as benzene, toluene, cyclohexane or heptane, or carbon tetrachloride; in particular alkyl acetates, such as ethyl acetate or n-butyl acetate, or dialkyl ethers, such as diethyl ether, diisopropyl ether, di-n-butyl ether or tert-butyl methyl ether, have proven particularly suitable. If the reaction mixture remains in solution after the end of the reaction, the salt of compound I can be precipitated out using one of the precipitating agents, if appropriate after concentration of the reaction solution. In addition, it is also possible to filter the solution of the reaction mixture into the solution of one of the precipitants, advantageously with stirring. Since the reaction of the compound of the formula IV with the thioamide of the formula VI is almost quantitative, the crude product obtained is almost analytically pure. The work-up of the reaction mixture can also be carried out in such a way that an organic base is added to render the reaction mixture basic, for example triethylamine or diisobutylamine or ammonia or morpholine or piperidine or 1, 8-diazabicyclo [5.4.0] undec-7-ene, and after concentration the crude reaction product is purified by chromatography, for example silica gel column chromatography. Eluents suitable for this purpose have proven to be, for example, mixtures of ethyl acetate and methanol, mixtures of dichloromethane and methanol, mixtures of toluene and methanol or ethyl acetate or mixtures of ethyl acetate and hydrocarbons, for example heptane. If the purification of the crude product is carried out as just described, the acid addition product of formula I can be obtained from the pure base of the compound of formula I obtained by dissolving or suspending the base in an organic protic solvent, such as methanol, ethanol, propanol or isopropanol, or in an organic aprotic solvent, such as ethyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, acetone or butan-2-one, and treating the mixture with an at least equimolar amount of a mineral acid, such as hydrochloric acid, dissolved in an inert solvent, such as diethyl ether or ethanol, or with another mineral or organic acid as further described above.
The compound of formula I may be recrystallised from a suitable inert solvent, such as acetone, butan-2-one, acetonitrile or nitromethane. However, it is particularly advantageous to reprecipitate from a solvent such as dimethylformamide, dimethylacetamide, nitromethane, acetonitrile, preferably methanol or ethanol.
The reaction of the compound of the formula IV with the thioamide of the formula VI can also be carried out in such a way that an at least equimolar amount of a base, for example triethylamine, is added to the reaction mixture and the resulting compounds of the formula I are then optionally converted into their acid addition products.
By base treatment, the acid addition product I can be converted to give the compound of formula I (free base). Suitable bases are, for example, solutions of the following bases: inorganic hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, or barium hydroxide; carbonates or bicarbonates, such as sodium or potassium carbonate, sodium or potassium bicarbonate; ammonia and amines, such as triethylamine, diisopropylamine, dicyclohexylamine, piperidine, morpholine, methyldicyclohexylamine.
Thioamides of the formula VI are commercially available or can be obtained, for example, by reacting the corresponding formamide V with phosphorus pentasulfide in pyridine (R.N.hurd.G.Delameter, chem.Rev. (chem.Rev.). 61, 45(1961)), or with Lawesson's reagent in toluene, pyridine, hexamethylphosphoric triamide (Scheibye, Pedersen and Lawesson: Bull.Soc.Chim.Belges (Belgium Chemicals) 87, 229(1978)), preferably in a mixture of tetrahydrofuran with 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone or 1, 3-dimethyl-2-imidazolidinone. In this case it is appropriate to protect the hydroxyl, amino or further carbonyl function with a removable protective function, for example a benzyl, tert-butoxycarbonyl or benzyloxycarbonyl radical, or to convert it into an alternative cyclic acetal. This method is described, for example, in Th.W.Greene and P.G.M.Wuts, Protective Groups in organic Synthesis, second edition, 1991, John Wiley & Sons, New York.
Thioamides of the formula VI can also be obtained by reacting nitriles of the formula VII
N≡C-R4
Formula VII
With hydrogen sulfide (Houben-Weyl IX, 762) or thioacetamide (E.C.Taylor, J.A.Zoltewicz, J.Am.chem.Soc. (J.S. chem.Soc.) (J.Am.) 82, 2656(1960)) or O, O-diethyldithiophosphoric acid. The reaction with hydrogen sulfide is preferably carried out in an organic solvent such as methanol or ethanol, the reaction with thioacetamide is carried out in a solvent such as dimethylformamide, and hydrochloric acid is added, and the reaction with O, O-diethyldithiophosphoric acid is carried out in a solvent such as ethyl acetate under acidic conditions such as HCl at room temperature or under heating.
The following examples serve to illustrate the invention without limiting it. The measured melting point or decomposition temperature (m.p.) is uncorrected, and generally depends on the heating rate.
Table 1: examples
Formula I
| Examples | R1；R1’ | R2 | R3 | R4 | Salt (salt) | m.p.[℃] |
| 1 | 6-C1；H | H | Br | Phenyl radical | - | 148 |
| 2 | 6-Cl；H | H | Cl | Phenyl radical | - | 88 |
The compounds of formula I are distinguished by favorable effects on lipid metabolism; in particular, they are suitable as anorectics. The compounds may be used by themselves or in combination with other anorectically active compounds. Such other anorexigenic active compounds are mentioned, for example, under the Rote Liste Chaptera 01 preparations/anorectics. The compounds are suitable for the prophylaxis, in particular for the treatment of obesity. The compounds are further suitable for the prophylaxis, in particular for the treatment of type II diabetes.
The efficacy of the compounds was tested as follows:
biological test model:
female NMRI mice were tested for appetite reducing effects. After 24 hours of fasting, the test formulations were administered via gastric tube. The animals were kept separate and free to drink water, and 30 minutes after dosing were provided with condensed milk. The consumption of condensed milk was measured every half hour, at 7 hours, and the general conditions of the animals were observed. The measured milk consumption was compared to untreated control animals.
Table 2: appetite-reducing effect, i.e. reduction of cumulative milk consumption in treated animals compared to untreated animals
From this table it can be concluded that the compounds of formula I show a very good appetite reducing effect.
The preparation of some of the examples is described in detail below; other compounds of formula I are obtained in a similar manner.
Example 1 (Compound 1)
8 a-bromo-6-chloro-2-phenyl-8, 8 a-dihydroindeno [1, 2-d ] thiazol-3 a-ol
a) 2-bromo-5-chloroindan-1-ones
10g (0.06mol) of 5-chloroindan-1-one are dissolved in 120ml of glacial acetic acid at room temperature with stirring. 0.05ml of 48% aqueous HBr and 3.074ml (0.06mol) of bromine in 25ml of glacial acetic acid are added dropwise. After stirring at room temperature for 2 hours, the reaction was complete (TLC). The solution of the crude product was slowly added dropwise to 300ml of ice water with stirring. The precipitated crude product was filtered off with suction and washed thoroughly with water. The moist residue on the filter paper was removed with ethyl acetate and the phases of the filtrate were separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 120ml hot n-heptane; the hot solution was filtered through pleated filter paper and then the solution was allowed to crystallize at 0 ℃. The crystallized product was filtered off with suction and dried under reduced pressure. The melting point is 94-96 ℃.
b) 6-chloro-2-phenyl-8, 8 a-dihydroindeno [1, 2-d ] thiazol-3 a-ol
1.0g of 2-bromo-5-chloroindan-1-one are dissolved in 20ml of anhydrous acetone at room temperature and mixed with 620mg of thiobenzamide. The mixture is stirred at room temperature for 6 hours, the hydrobromide of the crystallized product is filtered off with suction, and the residue is washed with acetone and dried under reduced pressure. The salt was added to a mixture of 30ml ethyl acetate and 20ml saturated sodium bicarbonate solution and stirred for 20 minutes to give the free base. The organic phase is separated, washed with saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. 6-chloro-2-phenyl-8, 8 a-dihydroindeno [1, 2-d ] thiazole-3 a-ol is obtained, melting point 164-.
c)8 a-bromo-6-chloro-2-phenyl-8, 8 a-dihydroindeno [1, 2-d ] thiazol-3 a-ol
1.51g of the compound from example 1b and 0.89g N-bromosuccinimide were dissolved in 20ml of carbon tetrachloride and mixed with 50mg of benzoyl peroxide, and the mixture was stirred under reflux for 3 hours. The reaction solution was cooled, extracted twice with 20ml of water, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography with dichloromethane as the mobile phase gave 8 a-bromo-6-chloro-2-phenyl-8, 8 a-dihydroindeno [1, 2-d ] thiazol-3 a-ol, mp 148 ℃.
Claims (5)
1. A compound of the formula I,
wherein
R1, R1' are each independently H, F, Cl, Br, I, NO2、CN、COOH、COO(C1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) -alkyl radical]2、(C1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, O- (C)1-C6) -alkyl, wherein one or more or all of the hydrogens of the alkyl radical are unsubstituted or replaced by fluorine, or one hydrogen is replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph、NH2、NH-CO-CH3Or N (COOCH)2Ph)2Replacing;
is SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) -alkyl radical]2、S-(C1-C6) Alkyl, S- (CH)2)n-phenyl, SO- (C)1-C6) Alkyl, SO- (CH)2)n-phenyl, SO2-(C1-C6) Alkyl, SO2-(CH2)n-phenyl, wherein n is 0 to 6, the phenyl radical being unsubstituted or substituted by F, Cl, Br, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2Up to 2 substitutions;
is NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) -alkyl radical]2、NH(C1-C7) -acyl, phenyl, biphenyl, O- (CH) wherein n is 0-62)nPhenyl, 1-or 2-naphthyl, where the phenyl, biphenyl, naphthyl are each unsubstituted or substituted by F, Cl, Br, I, OH, CF3、NO2、CN、OCF3、O-(C1-C6) Alkyl radicals, (C)1-C6) -alkyl, NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) -alkyl radical]2、SO2-CH3、COOH、COO-(C1-C6) Alkyl, CONH21 to 3 times;
r2 is H, (C)1-C6) Alkyl radicals, (C)3-C6) -cycloalkyl, (CH)2)n-phenyl, C (O) - (C)1-C6) Alkyl, C (O) - (C)3-C6) Cycloalkyl, C (O) - (CH)2)n-phenyl, wherein n is 0-5, wherein phenyl is unsubstituted or substituted by Cl, F, CN, CF3、(C1-C3) Alkyl, OH, O- (C)1-C6) -alkyl substitution up to 2 times;
r3 is Cl, Br, CH2-COO(C1-C6) -alkyl, CH2-COOH、CH2-CONH2；
R4 is (C)1-C8) Alkyl radicals, (C)3-C7) -cycloalkyl, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)4-C7) Cycloalkenyl in which one or more or all of the hydrogens of the alkyl radical are unsubstituted or replaced by fluorine, or one hydrogen is replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph or O- (C)1-C4) -alkyl substitution; is (CH)2)n-pyrrolidin-1-yl, (CH)2)n-piperidin-1-yl group, (CH)2)n-morpholin-4-yl, (CH)2)n-piperazin-1-yl, (CH)2)n-N-4-methylpiperazin-1-yl group, (CH)2)n-N-4-benzylpiperazin-1-yl group, (CH)2)n-a phthalimido group, wherein n is 1-6;
is (CH)2)nAryl, where n is 0 to 6, phenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridyl or 2-or 3-thienyl, which aryl radical is unsubstituted or substituted by F, Cl, Br, OH, CF3、O-(C1-C6) Alkyl, (CH)2)n-SO2-(C1-C6) Alkyl, (CH)2)n-SO2-NH2、(CH2)n-SO2-N(＝CH-N(CH3)2)、NH-SO2-(C1-C6) -alkyl, NH-SO2-phenyl-wherein the phenyl ring is unsubstituted or substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、COOH、COO(C1-C6) -alkyl or CONH2Substituted at most 2 times with (C)1-C6) Alkyl radical, COOH、COO(C1-C6) -alkyl or CONH2The substitution is carried out at most 2 times,
wherein n is 0 to 6;
is (CH)2)n-a-R8, wherein n is 1-6;
a is O, NH, N- (C)1-C6) Alkyl, SO2；
R8 is (C)1-C8) Alkyl radicals, (C)3-C8) Cycloalkyl in which one or more hydrogens of the alkyl radical are unsubstituted or replaced by fluorine, or one hydrogen is replaced by OH, OC (O) CH3、OC(O)H、O-CH2-Ph or O- (C)1-C4) -alkyl substitution; is (CH)2)m-aryl, wherein m is 0-6, aryl is phenyl, thienyl or pyridyl, the aryl moiety being unsubstituted or substituted up to 2 times by: F. cl, Br, OH, CF3、O-(C1-C6) Alkyl, (CH)2)n-SO2-(C1-C6) Alkyl, (CH)2)n-SO2-NH2、(CH2)n-SO2-N(＝CH-N(CH3)2) Wherein n is 0 to 6;
is NH-SO2-(C1-C6) -alkyl, NH-SO2-phenyl-wherein the phenyl ring is unsubstituted or substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、COOH、COO(C1-C6) -alkyl or CONH2Substituted up to 2 times- - - -, COOH, COO (C)1-C6) -alkyl or CONH2(ii) a And physiologically acceptable salts thereof.
2. A pharmaceutical composition comprising a compound as claimed in claim 1.
3. A process for preparing a pharmaceutical composition comprising a compound as claimed in claim 1, which process comprises mixing a compound as claimed in claim 1 with pharmaceutically suitable excipients and formulating the mixture into a form suitable for administration.
4. Use of a compound as claimed in claim 1 for the manufacture of a medicament for the prevention or treatment of obesity.
5. Use of a compound as claimed in claim 1 for the manufacture of a medicament for the prophylaxis or treatment of type II diabetes.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10008275.0 | 2000-02-23 | ||
| DE10008275 | 2000-02-23 | ||
| PCT/EP2001/001499 WO2001062746A1 (en) | 2000-02-23 | 2001-02-12 | 8,8a-dihydro-indeno[1,2-d]thiazole derivatives, substituted in position 8a, a method for their production and their use as medicaments, e.g. anorectic agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1055117A1 HK1055117A1 (en) | 2003-12-24 |
| HK1055117B true HK1055117B (en) | 2005-07-29 |
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