WO1991017144A1 - Compose amide, utilisation pharmaceutique de ce compose et nouvelles pyrrolidinemethyl-amines 1-substituee - Google Patents

Compose amide, utilisation pharmaceutique de ce compose et nouvelles pyrrolidinemethyl-amines 1-substituee Download PDF

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Publication number
WO1991017144A1
WO1991017144A1 PCT/JP1991/000593 JP9100593W WO9117144A1 WO 1991017144 A1 WO1991017144 A1 WO 1991017144A1 JP 9100593 W JP9100593 W JP 9100593W WO 9117144 A1 WO9117144 A1 WO 9117144A1
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WO
WIPO (PCT)
Prior art keywords
methyl
pyrrolidinyl
reduced pressure
under reduced
same temperature
Prior art date
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PCT/JP1991/000593
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English (en)
Japanese (ja)
Inventor
Shu Murakami
Tsuguo Ikebe
Yasuto Morimoto
Shuzo Takehara
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Yoshitomi Pharmaceutical Industries, Ltd.
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Publication of WO1991017144A1 publication Critical patent/WO1991017144A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present invention relates to a benzamide and a 2,3-dihydrobenzofuran-7-potassium lipoxamide compound, a pharmacologically acceptable salt thereof, or an optical agent thereof, which is effective for treating psychiatric disorders and mental disorders.
  • Benzamide compounds having a pyrrolidine ring in the amine moiety are described in U.S. Pat. No. 3,342,826, British Patent No. 1,394,559, or Drugs of the Future. Chiyua (Drugs oft he Future) Vol. 1, Vol. 1, pp. 944-948, pp. 1986, etc.
  • 2,3—dihidrobenzofuran 1—7—Rupoxamide compound Products are disclosed in U.S. Pat. No. 4,617,314 and U.S. Pat. No. 4,888,353.
  • These Ami de compounds exhibit a psychotropic work by selectively blocking the de Pami down D 2 receptor has been characterized as an anti-schizophrenic drugs, non-typically (atypi ca l).
  • the number of carbon atoms of the alkyl group at the 1-position of pyrrolidine is 5 or less regardless of the type of the substituent on the benzene ring.
  • pyrrolidine is a compound having a phenylalkyl group which may be substituted at the 1-position.
  • 2,2-Dialkyl-1,2,3-dihydrobenzofuran-17-carboxamide compounds in which is substituted with a sulfamoyl or alkylthio group is not known.
  • pyrrolidine-2-methylamines no compound having 6 or more alkyl groups at the 1-position has been synthesized.
  • EPS extrapyramidal disorders
  • R 1 is an alkoxy group having 1 to 4 carbon atoms
  • R 2 is hydrogen or R 1 and R 2 are bonded to each other and substituted by at least one alkyl having 1 to 4 carbon atoms
  • R 3 is a group forming the oxyethylene which may be
  • R represents an alkyl group having 1 to 4 carbon atoms or a phenylalkyl group which may be substituted, and m represents 0, 1, or 2.
  • m represents 0, 1, or 2.
  • R 6 and R 7 are each hydrogen or an alkyl group having 1 to 4 carbon atoms.
  • R 4 is an alkyl group having a carbon number of 6 to 15 or a substituted or unsubstituted alkyl group. And represents a phenylalkyl group.
  • R 1 and R 2 are bonded to each other to form oxishethylene which is substituted by two alkyl having 1 to 4 carbon atoms.
  • R 4 a is. Represents an alkyl group having carbon chain number 6-1 5) about 1 monosubstituted pyromellitic lysine one 2- Mechirua Mi emissions such and its optical isomers are represented by.
  • the C 1 -C 4 A kill group is methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc., and an alkoxy group having 1 to 4 carbon atoms is methoxy, ethoxy, propoxy, isopropoxy, butoxy, No.
  • Alkyl groups having 6 to 15 carbon atoms include hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pendudecyl and the like. Further, a cycloalkyl group having 3 to 7 carbon atoms (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) may be bonded to these groups.
  • the one group form an optionally Okishiechire down even toying substituted with number 1-4 amino ⁇ alkyl carbon, Okishiechiren (an OCH 2 CH 2 -), O carboxymethyl E Chile emissions [ten CH ( CH 3 ) CH 2 mono-, mono-CH 2 CH (CH 3 ) —], oxydimethylethylene [-0C (CH 3 ) 2 CH 2- , -0CH 2 C (CH 3 ) 2- ], etc. the group forming a Okishi ethylene substituted with pieces of number 1-4 alkyl carbons - 0C (CH 3) 2 CH 2 -, the etc.
  • a phenylalkyl group refers to a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc.
  • alkyl group having 1 to 4 carbon atoms and the substituent is halogen ( Chlorine, bromine, fluorine, etc.), alkyl groups with 1 to 4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted carbon 1-4 alkyl groups (g Li off Ruoromechiru, 2, 2, 2 - Application Benefits Furuoroechiru, such as pen data off Honoré Oroechiru), two Toro, Ru is 1-3 pieces selected from such ⁇ Mi Bruno
  • R 1 is main butoxy
  • R 2 is hydrogen or R 1 and R 2 are bonded to each other - 0 C (CH 3) 2 CH 2 one
  • R 3 is methylthio
  • R 4 is hexyl, octyl, nonyl, or decyl, a pharmacologically acceptable salt thereof or an optical isomer thereof.
  • the compound of the present invention represented by the general formula (I) has the general formula (1)
  • the reaction is dicyclohexylcarbodiimide, titanium tetrachloride, halogenated phosphorus (eg, phosphorus trichloride, phosphorus oxychloride). ), Ethyl chloride phosphite, o-phenyl chloride phosphite, ethyldichlorophosphite in an inert solvent, under cooling, at room temperature or in the presence of a condensing agent. It is performed under heating.
  • the compound (Ia) may be preliminarily treated with a phosphorus halide in an inert solvent and then condensed with the compound (dish).
  • the phosphorus halide is phosphorus trichloride
  • about 1/2 mole of the phosphorus trichloride is added to the compound (Ha) in an inert solvent in advance of triethylamine, pyridine, N
  • the compound (M) is reacted with the compound (M) in an inert solvent at room temperature or under heating, preferably under heated reflux.
  • reaction is carried out in the presence of an alkali such as sodium hydroxide or hydroxylated lithium in water under cooling or at room temperature.
  • an alkali such as sodium hydroxide or hydroxylated lithium
  • a reactive derivative of the compound ( ⁇ ) a symmetrical acid anhydride or a mixed acid anhydride, for example, an alkyl carbonate mixed anhydride, an alkyl phosphoric acid mixed anhydride, or an alkyl phosphorous mixed acid anhydride
  • an acid anhydride, sulfuric acid mixed anhydride, etc. the reaction is carried out in an inert solvent under cooling or at room temperature in the presence of a tertiary base such as triethylamine, pyridine, N, N-dimethylaniline. Done under warming
  • the compounds of the general formula (I) are also novel, for example starting from 2-pyrrolidinone, alkylating, condensing with nitromethane, Alternatively, it can be produced by performing a reduction reaction.
  • Optically active compounds of the general formula (H) can be optically resolved by an ordinary method using an optically active acid (for example, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.). It can be manufactured by In addition, by using (R) or (S) -proline or pyroglutamic acid as a starting material, esterification, amidation, alkylation, and reduction are performed to obtain a general formula (stereospecifically).
  • the compound of I) can also be produced.
  • the compound (I) of the present invention can also be produced by alkylating a compound in which R 4 is hydrogen.
  • Examples of the inert solvent used in each of the above condensation reactions include, for example, benzene, toluene, xylene, methanol, ethanol, ethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, and hexamethylphosphoric acid.
  • Examples thereof include, but are not limited to, dimethylformamide, dimethylformamide, and the like, and a mixed solution thereof, which is appropriately selected depending on the type of the reactive derivative.
  • the compound of the present invention also contains a racemic mixture, diastereomer and optical isomer resulting from the asymmetric carbon at the 2-position of pyrrolidine or the asymmetric carbon at the 2-position of dihydrobenzofuran.
  • the racemic mixture can be optically resolved using an optically active acid (eg, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-commasulfonic acid, etc.) by utilizing its basicity in a conventional manner. It comes.
  • an optically active acid eg, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-commasulfonic acid, etc.
  • Compound (I) can also be synthesized stereoselectively.
  • the diastereomer can also be divided into each enantiomer by a known method.
  • the compounds of the present invention include conventional benzamides having an alkyl group with a carbon number of 5 or less at the 1-position of pyrrolidine and 2,3-dihydrobenzofuran 17-carboxamide. It was clearly different from the class and showed high affinity for the serotonin ⁇ receptor. Further, since higher than its affinity for affinity Dopami emissions D 2 receptors, the compounds of the present invention, not only the improvement in schizophrenic patients positive symptoms are also very effective in improving negative symptoms, also It is also useful as an anti-schizophrenia drug with very weak side effects such as EPS.
  • the compound of the present invention can be used as a therapeutic drug for depression and anxiety disorder or dyskinesia, abnormal behavior such as agitation, aggression in old age or cerebrovascular disorder and alcohol dependence.
  • depression and anxiety disorder or dyskinesia abnormal behavior such as agitation, aggression in old age or cerebrovascular disorder and alcohol dependence.
  • psychiatric disorders such as stomach and duodenal ulcers, or drugs for suppressing vomiting, or for diarrhea and unidentified complaints of gastrointestinal tract due to stress and emotional tension.
  • the crude synaptosome fraction was separated from the 9 to 10-week-old wister rat striatum, and 120 mM sodium chloride, 5 mlV [Calium chloride, 2 mM calcium chloride, ImM magnesium chloride, 1 mM The suspension was used in 50 mM Tris-HCl buffer (pH 7.1) containing 0 / M pargyline and 0.1% ascorbic acid for use in the experiment.
  • the compound of the present invention When used as a medicament, it may be used as a tablet, pill, capsule, powder, liquid, or injection prepared by appropriately mixing with excipients, bulking agents, diluents and other pharmaceutical additives. Administered.
  • the capacity depends on the compound selected, the severity of the disease, the age, etc. Normally 0.1-1 to 10 mZ kg per adult o
  • a tablet containing 10.0 mg of compound (I) can be prepared according to the following formulation.
  • Compound (I) is ground with an atomizer to give a fine powder having an average particle size of 10 u or less.
  • lactose, corn starch and crystalline cellulose are mixed in a kneading machine, hydroxypropyl cellulose is added and kneaded for 20 minutes.
  • the kneaded product was granulated through a 200-mesh sieve, dried in a hot air drier at 50 ° C until the R content was 3 to 4%, and passed through a 24-mesh sieve. Luk and magnesium stearate are mixed, and the mixture is compressed using a flat-tabletting machine using a flat punch with a diameter of 6 mm.
  • (S) -pyrroyl is obtained from L-proline by a known method. After drying over magnesium sulfate and concentrating under reduced pressure, 5.7 g of lysine-2-carboxamide, 8.3 g of hexyl bromide and 20 g of lithium carbonate were added to 50 ml of dimethylformamide. Add the mixture of m £ and toluene 40 and stir at 40 ° C for 7 hours. The mixture is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate and washed with water.
  • Dimethyl sulfate 114 is added to 2 g of 1-octyl-2-pyrrolidinone, and the mixture is heated to 50 to 70 ° C and stirred for 2 hours.
  • 23 g of a 28% sodium methoxide methanol solution was added dropwise under cooling, and the mixture was stirred at room temperature for 2 hours, and then nitromethan 657 ⁇ was added dropwise and stirred at room temperature for 2 hours. And leave overnight.
  • Add ice water and ethyl acetate to the reaction mixture. Separate the organic layer, wash with water, and reduce after drying Concentration under pressure yields 260 g of 1-octyl-2-nitromethylenepyrrolidine as an oil.
  • 1 1-year-old chillyl 2-dinitromethylenepyrrolidine 26 Og is dissolved in methanol 2 _g, about 50 g of Raney nickel is added, and the mixture is reacted in an initial hydrogen pressure of 60 atm in a 5 _g autoclave. . After completion of the reaction, Raney nickel was filtered off, the solvent was concentrated under reduced pressure, and the resulting residue was distilled. can get. 167 g of this racemic 2-aminomethyl-1-octylpyrrolidine is dissolved in 50 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ of isopropyl alcohol, and 177 g of L-(+)-tartaric acid is dissolved in 200 ml of water in this solution. And add.
  • Example 7 (S) -Pyrrolidine-2 -carboxamide (8 g), lauryl bromide (17.5 g) and potassium carbonate (24 g) obtained from L-proline by a known method were added to dimethylformamide (13). Add to the mixture of 07 ⁇ and toluene 13 ⁇ and stir at 50 for 40 hours. The mixture is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate and washed with water. After drying over magnesium sulfate and concentrating under reduced pressure, hexane was added to the resulting residue, and the crystals were filtered to give (S) -1-dodecylpyrrolidine-12-carboxamide 1 with a melting point of 109-110 ° C.
  • Example 13 (R) —2—Methyl-5—Sulfamoyl 2,3—Dihydrobenzobenzofuran 7—Caprolubonic acid 15 Om and triethylamine 180 / ⁇ are converted to dimethylformamide 1 and tetrahydrofuran 1 Add to the mixture, cool to-15 ° C, and add 83 g of isobutyl chloroform. After stirring at the same temperature for 20 minutes, a solution of 107 mg of (S)-(—) — 2-aminoamino-1-hexylpyrrolidine in tetrahydrofuran 1 was added dropwise at the same temperature. Stir for 0 minutes.
  • Method 5 Metalthio-1,2,3-dihydrobenzenezofuran 7—Carbonic acid 0.46 g and triethylamine 0.66 are added to a mixture of dimethylformamide 5 and tetrahydrofuran 7, and ⁇ 15 ° After cooling to C, add 0.297 ⁇ of isobutyl chloroform. After stirring at the same temperature for 20 minutes, (R)-(+) _ 2—amino meth — 1 —Nonylpyrrolidine 0.5 g Tetrahydrofuran 3 solution is added dropwise at the same temperature, and the mixture is stirred at the same temperature for 30 minutes.
  • Method 5 Metalthio-1,2,3—Dihydrobenzozofuran 7—Carbonic acid 0.46 g and Triethylamine 0.66 in a mixture of dimethylformamide 5 and tetrahydrofuran 7 In addition, cool to 15 ° C and add isobutyl chloroform with 0.29 drop wise. After stirring at the same temperature for 20 minutes, 0.5 g of (S)-(1-)-2-aminomethyl-1-nonylpyrrolidine 3 m solution of tetrahydrofuran 3 m was added dropwise at the same temperature, and the same temperature was added. And stir for 30 minutes.
  • Example 6 (S) -(1) 12-Aminomethyl-1-decylpyrrolidine 2.
  • S Drop a solution of lg in tetrahydrofuran 20 at the same temperature and stir at room temperature overnight. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried and concentrated under reduced pressure.
  • (+) — 2 Aminomethyl-1- 1-benzylpyrrolidine 0.76 g of tetrahydrofuran 4 solution was added dropwise at the same temperature, and the temperature was 30 minutes. Stir. After further stirring for 2 hours, the reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, dried and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain (R) -N-[(1 benzyl-2-pyrrolidinyl) methyl] 1-2,2-dimethyl-5-sulfamoyl-2,3-dihydrobe Nzofuran-1 7-carboxamide 1.20 g is obtained.
  • 2,5-Dimethyl-5-methylthio-1,3-dihydrobenzofuran-17-carboxylic acid 0.55 g and triethylamine 0.68 were added to dimethylformamide 5 and tetrahydrofuran 7 Add to the mixture, cool to ⁇ 15 ° C, and add isobutyl chloroform with 0.30 ⁇ form. After stirring at the same temperature for 20 minutes, a solution of 0.50 g of (R)-(+)-2-aminoamino-1- (3-phenylphenol) pyrrolidine in tetrahydrofuran 3 was heated at the same temperature. And stir at the same temperature for 30 minutes.
  • Example 5 9 2,2-Dimethyl-5-methylthio-1,2,3-Dihydrobenzofuran-17-Carboxylic acid 0.55 g and triethylamine 0.68 were added to dimethylformamide 5 and tetrahydrofuran 7 Add to the mixture, cool to -15 C, and add 0.30 mL of isobutyl chloride. After stirring at the same temperature for 20 minutes, a solution of 0.50 g of (S)-(-) — 2—aminomethyl- (3-phenylphenyl) pyrrolidine in 0.50 g of tetrahydrofuran 3 was added at the same temperature. Add dropwise and stir at the same temperature for 30 minutes.
  • 2,2—Dimethyl-5-methylthio-1,2,3-Dithionozofuran 7 0.5-g of ruboric acid and triethylamine.1 is replaced by dimethylformamide 5 and tetrahydrofura.
  • Add to it solution cool to ⁇ 15 ° C, and add isobutyl chloroformate 'J8 dropwise. After stirring at the same temperature for 20 minutes, (S)-(I) A solution of 0.50 g of aminomethyl-11- (4-phenylbutyl) pyrrolidine in tetrahydrofuran 3 was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes.

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

Abstract

L'invention se rapporte à un composé amide représenté par la formule générale (I) et à un sel ou isomère optique pharmacologiquement acceptable de ce composé. Dans la formule (I), R1 représente un alcoxy C¿1? à C4; R?2¿ représente H ou un groupe qui est combiné avec R1 pour former un groupe d'oxyéthylène qui peut être substitué par au moins un groupe alkyle C¿1? à C4; R?3¿ représente -S(O)mR?5 (où R5¿ représente un alkyle C¿1? à C4 ou un phénylalkyle éventuellement substitué, et m est égal à 0,1 ou à 2), ou -SO2NR?6R7 (où R6 et R7¿ représentent chacun H ou un alkyle C¿1? à C4); et R?4¿ représente un alkyle C¿6? à C15 ou un phénylalkyle éventuellement substitué, à condition que, lorsque R?4¿ représente un phénylalkyle éventuellement substitué, R1 et R2 sont combinés ensemble pour former un groupe d'oxyéthylène substitué par deux groupes alkyle C¿1? à C4. Ces composés sont utiles pour traiter la schizophrénie, la dystrophie, les troubles émotionnels et les maladies mentales ou physiques, pour empêcher les vomissements et pour traiter la diarrhée et les syndrômes cliniques non identifiés du système digestif causés par le stress ou par des tensions émotionnelles.
PCT/JP1991/000593 1990-05-02 1991-04-30 Compose amide, utilisation pharmaceutique de ce compose et nouvelles pyrrolidinemethyl-amines 1-substituee WO1991017144A1 (fr)

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JP2/116642 1990-05-02
JP11664290 1990-05-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4829764A (fr) * 1971-08-20 1973-04-19 Fratmann Sa
JPS4935377A (fr) * 1972-07-19 1974-04-01
JPS5248661A (en) * 1975-10-14 1977-04-18 Synthelabo 22methoxyybenzamide derivatives
JPS55113762A (en) * 1975-10-14 1980-09-02 Synthelabo 22methoxybenzamide derivative
JPS62234083A (ja) * 1986-02-28 1987-10-14 アーバモント　インク　ディビーエイ　アドリヤ　ラボラトリーズ 鎮吐薬または精神病治療薬として有用なカルボキサミド類
JPS62277376A (ja) * 1986-01-30 1987-12-02 ラボラトワ−ル・デラグランジエ 新規ジヒドロベンゾフラン・およびクロマン・カルボキサミド誘導体、それらの製造方法およびその神経弛緩剤としての適用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4829764A (fr) * 1971-08-20 1973-04-19 Fratmann Sa
JPS4935377A (fr) * 1972-07-19 1974-04-01
JPS5248661A (en) * 1975-10-14 1977-04-18 Synthelabo 22methoxyybenzamide derivatives
JPS55113762A (en) * 1975-10-14 1980-09-02 Synthelabo 22methoxybenzamide derivative
JPS62277376A (ja) * 1986-01-30 1987-12-02 ラボラトワ−ル・デラグランジエ 新規ジヒドロベンゾフラン・およびクロマン・カルボキサミド誘導体、それらの製造方法およびその神経弛緩剤としての適用
JPS62234083A (ja) * 1986-02-28 1987-10-14 アーバモント　インク　ディビーエイ　アドリヤ　ラボラトリーズ 鎮吐薬または精神病治療薬として有用なカルボキサミド類

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents

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