WO1999054303A1 - Derives tetrahydrobenzindoles actifs au plan optique - Google Patents
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- WO1999054303A1 WO1999054303A1 PCT/JP1999/002127 JP9902127W WO9954303A1 WO 1999054303 A1 WO1999054303 A1 WO 1999054303A1 JP 9902127 W JP9902127 W JP 9902127W WO 9954303 A1 WO9954303 A1 WO 9954303A1
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- active compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
- C07D209/92—Naphthostyrils
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to an optically active tetrahydrobenzindole derivative and a pharmaceutical composition containing the optically active compound.
- the present invention also relates to a suitable optically active intermediate for producing the optically active compound, and a method for producing the optically active compound.
- 5-HT 7 is abundant in the brain, is estimated to play an important function in the control of circadian rhythm of human and animal [TW Lovenberg et Neuron, 11 449-458, 1993]. It is widely found not only in human and animal brain but also in smooth muscle tissue, such as spleen, stomach, ileum, small intestine, coronary blood vessels [AJ Sleight, DN & P, 214-223, 1997], and various physiological functions It is assumed that it plays. Thus, creation of a substance that acts on 5-HT 7 receptors, treatment of diseases caused by abnormal function in research and their organs physiological functions in these organs, is extremely beneficial in the prevention.
- the present inventors have already found a substance that have a strong ability to bind to 5-HT 7 receptor in vivo. That is, the invention relating to the present inventors (W09 8 / 0 0 4 0 0, Japanese Patent Application No. 9-35 838, 0, Japanese Patent Application No. 9-1 3 5 8 3 8 1 and Japanese Patent Application No. 10--8 5 9 13) pharmaceutical composition characterized in that it comprises a novel Tetorahi Dorobe lens indole derivatives, and its those compounds that bind strongly to 5-HT 7 receptor in the body is provided.
- the present inventors have studied the tetrahydrobenzindole derivative from various viewpoints. That is, regarding the mutual separation of optically active substances, a method using fractional crystallization and a salt composition with an optically active acid or base has been conventionally known, and recently, so-called chiral chromatography using an optically active carrier has been known. However, in each case, the conditions for separation and separation had to be determined for each compound, and they could not be applied to all related compounds.
- the present inventors have solved the above-mentioned problems by performing optical resolution at the stage of a synthesis raw material and developing a new synthesis route using an optically active raw material. That is, according to the present invention, an optically active tetrahydrobenzindole derivative, a pharmaceutical composition containing the optically active compound, a suitable optically active intermediate for producing the optically active compound, and A method for producing an optically active compound is provided. Therefore, the present invention consists of the following constitutions
- D is the following general formula (II), general formula (Ilia) general formula (IIIb), general formula (IV), general formula (V) or general formula (VI)
- RR 3 is each independently or plurally independently a hydrogen atom, a halogen atom, a lower alkyl, a cyano, a trihalomethyl, a hydroxy, an alkoxy, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, a carboxy, an alkoxycarbonyl, an acyl, an acyloxy, Stands for asilthio, sulfamoyl, nitro, amino, alkylamino, dirubamoyl, alkyl dirubamoyl, phenyl,
- R 2 and R 4 each independently represent a hydrogen atom, lower alkyl, or aralkyl; n represents an integer from 2 to 4;
- A represents N, CH, C or CR 7 having a double bond (R 7 is lower alkyl, Represents cyano, rubamoyl, alkyl carbamoyl, carboxy, acyl, acyloxy, alkoxy, alkoxycarbonyl, trihalomethyl, hydroxy),
- G represents methylene or carbonyl
- E 1 represents a group forming a benzene ring, a pyridine ring or a pyrimidine ring,
- E 2 represents a group which forms a benzene ring, a pyridine ring or a pyrimidine ring together with the double bond carbon atom of the condensed part
- J represents a group that forms a benzene ring, a thiophene ring, a furan ring, an imidazole ring, or a pyrazolyl ring together with the double bond carbon atom of the fused portion;
- X is NH 8, NC 0 NR 9 R 10, S, SO, S 0 2, it represents ⁇ (R 8 is a hydrogen atom, a lower alkyl, Ararukiru, Okisoarukiru, alkenyl, Shianoaruki Le, hydroxycarboxylic alkyl, alkoxyalkyl, aminoalkyl, alkyl Ruaminoarukiru, alkoxycarbonylalkyl, force Rubamoiruaruki Le, alkyl force Luba moil alkyl, and Table Ashiru, the alkoxycarbonyl alkylsulfonyl, R 9, R 1 G are each independently a hydrogen atom, a lower alkyl),
- Y represents CH 2 , S, ⁇ , CO,
- R 5 and R 6 each independently represent a hydrogen atom, lower alkyl, hydroxy, alkoxy, acyl, or phenyl;
- R a represents a hydrogen atom or alkyl
- n an integer from 1 to 3
- P represents 0 or an integer from 1 to 3
- q represents 0 or an integer from 1 to 3.
- p + q represents an integer from 1 to 3.
- optically active compound according to the above 1, wherein n is 4, and pharmaceutically acceptable The salt that is tolerated.
- a pharmaceutical composition comprising the optically active compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition for treating or preventing a mental disease comprising the optically active compound according to any one of the above 1 to 10 or a pharmaceutically acceptable salt thereof.
- 5-HT 7 agonist characterized in that it comprises a chemically acceptable salt thereof.
- R 11 represents aldehyde, alkoxycarbonyl, carboxyl or a salt thereof, CH 2 Z (Z is hydroxy, leaving group).
- the 5-HT 7 agent means a substance having a strong ability to bind to 5-HT 7 receptor in vivo.
- a halogen atom means each atom of fluorine, chlorine, bromine, and iodine
- a lower alkyl means a methyl group, an ethyl group, etc.
- the base used as a catalyst is defined as sodium hydroxide, potassium carbonate, etc. It means inorganic bases and organic bases such as triethylamine, pyridine and dimethylaniline.
- the substituent means a group other than a hydrogen atom.
- the substituents R 1 R 3 are each independently or plurally independently halogen atom, lower alkyl, cyano, trihalomethyl.
- the halogen atom is as defined above, and the three halogen atoms may be the same or different, preferably, for example, trifluoromethyl) Hydroxy, alkoxy (preferably having 1 to 4 carbon atoms, such as methoxy and ethoxy), alkylthio (preferably having 1 to 4 carbon atoms, such as methylthio and ethylthio), alkylsulfinyl (preferably having 1 to 4 carbon atoms, etc.) Methanesulfinyl), alkylsulfonyl (preferably having 1 to 4 carbon atoms), carboxy, alkoxycarbonyl (preferably having 1 to 4 carbon atoms), acyl (preferably having 1 to 4 carbon atoms, such as acetyl), and acyloxy (preferably alkyl)
- the moiety has 1 to 4 carbon atoms, for example, acetoxy), acylthio (preferably, 1 to 4 carbon atoms, for example, acetylthio),
- the substituents R 2 and R 4 each independently preferably represent lower alkyl or aralkyl (preferably benzyl, substituted benzyl).
- n an integer of 2 to 4, preferably 4.
- the substituents R 5 and R 6 each independently represent lower alkyl (preferably having 1 to 4 carbon atoms), hydroxy, alkoxy (preferably having 1 to 4 carbon atoms such as methoxy, ethoxy, etc.), acyl, and phenyl. Represent.
- the substituent Ra represents alkyl (preferably having 1 to 4 carbon atoms).
- A represents N, CH, C having a double bond or CR 7 (in the formula (I).
- the dotted line from A means that when A is C having a double bond, it becomes a bond.
- R 7 is lower alkyl (preferably having 1 to 4 carbon atoms), cyano, carbamoyl, alkylcarbamo Aryl (preferably methylcarbamoyl, getylcarbamoyl, etc.), carboxy, acyl (preferably, acetyl, propionyl, etc.), acyloxy, alkoxy (preferably, methoxy, ethoxy, etc.), alkoxycarbonyl (preferably, methoxycarbonyl) , Ethoxycarbonyl, etc.), trihalomethyl (preferably, trifluoromethyl, etc.), and hydroxy.
- G represents methylene or carbonyl.
- E 1 represents a group which alone forms a benzene ring, a pyridine ring or a pyrimidine ring in the general formula (II).
- E 2 represents a double bond carbon atom of the condensed portion. Represents a group which together form a benzene ring, a pyridine ring or a pyrimidine ring.
- A is preferably N.
- J represents a group that forms a benzene ring, a thiophene ring, a furan ring, an imidazole ring, or a pyrazole ring together with the double bond carbon atom of the condensed portion, and a benzene ring or a thiophene ring is preferable.
- X is a substituted or unsubstituted heteroatom in the three-ring fused heteroaromatic ring.
- the benzofuran ring and the sulfur atom In the case of a nitrogen atom, a benzothiophene ring is formed, and in the case of a nitrogen atom, an indole ring is formed.
- X When X is a sulfur atom, it may be substituted with oxygen, and when X is a nitrogen atom, it may be substituted with a substituent R 8 or CONR 9 R 10 other than a hydrogen atom.
- the substituent R 8 is a lower alkyl (preferably having 1 to 4 carbon atoms), an aralkyl (preferably benzyl or substituted benzyl), an oxoalkyl (preferably oxopropyl), an alkenyl (preferably aryl), a cyanoalkyl ( Preferably, cyanomethyl, cyanoethyl), hydroxyal (Preferably hydroxymethyl, hydroxyxetyl), alkoxyalkyl (preferably methoxymethyl, methoxyxethyl, ethoxymethyl, ethoxyxethyl), aminoalkyl (aminoethyl, methylaminoethyl, dimethylaminoethyl), alkylaminoalkyl, alkoxycarbonylalkylalkyl (Preferably methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl), rubam
- p represents 0 or an integer from 1 to 3, preferably 1 or 2
- q represents 0 or an integer from 1 to 3, preferably 0 or 1.
- p + q represents an integer of 1 to 3, preferably 2. That is, the secondary amino group bonded to the methylene chain in the general formula (VI) forms a 5- to 7-membered ring, and preferably forms a 6-membered ring.
- the substituent is condensed with a group J forming a benzene ring, a thiophene ring, a furan ring, an imidazole ring, or a pyrazole ring, and as a whole of the formula (VI), indolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 3,4,5-tetrahydro-1H-benzo [b] Zepinyl, 2,3,4,5-tetrahydro-111-benzo [0] azepinyl, 2,3,4,5-tetrahydro-1H-benzo [d] azepinyl, 4,5,6,7 -Tetrahydrocheno [3,2-c] pyridyl, 4,5,6,7-Tetrahydrofuro [3,2-c] pyridyl, 4,5,6,7-Tetrahydrobirazolo [4,3-c] Represents pyridyl or the like.
- R 11 represents aldehyde, alkoxycarbonyl, carboxyl or a salt thereof, or CH 2 Z (Z represents hydroxy or a leaving group).
- the leaving group includes a halogen atom (a chlorine atom, a bromine atom, an iodine atom, etc.), an alkylsulfonic acid ester residue (methanesulfonyloxy, ethanesulfonyloxy, etc.), an arylsulfonic acid ester residue ( Benzenesulfonyloxy, p-toluenesulfonyloxy, etc.).
- a halogen atom a chlorine atom, a bromine atom, an iodine atom, etc.
- an alkylsulfonic acid ester residue methanesulfonyloxy, ethanesulfonyloxy, etc.
- an arylsulfonic acid ester residue Benzenesulfonyloxy, p-toluenesulfonyloxy, etc.
- RR 3 in the general formulas (I) to (XII) or Ra in the general formula (VI) is a symbol capable of representing all hydrogen atoms on the ring, and RR 3 or Ra is a substituent
- all the hydrogen atoms on the ring can be independently substituted, and the substitution may be the same or different at one or more positions without any substitution.
- the optically active compound represented by the general formula (I) (hereinafter, also referred to as “compound (I)”.
- compound (I) also referred to as “compound (I)”.
- compound (XII) is The absolute configuration of the asymmetric carbon at position 2a of the drobensindole skeleton.
- optically active compound provided by the present invention is produced by a chemical synthesis method described below.
- compound (I) is prepared by reacting compound (XIII), which is a reactive optically active intermediate of the present invention, with an amine represented by DH, as shown in the following reaction formula. Obtainable.
- R 12 represents an aldehyde, CH 2 W (W is a leaving group).
- 11 12 (: 11 2 1 ⁇ cases the reaction for obtaining compound (I), the absence of a solvent, Moshiku is performed on diluted with an inert solvent in the presence or absence of a base, from room temperature to
- the inert solvent used include dioxane, tetrahydrofuran, acetonitril, dimethylformamide, etc.
- the base include alkali metal salts and carbonates (eg, In addition to sodium carbonate and potassium carbonate, bicarbonates (such as sodium bicarbonate and potassium bicarbonate), trialkylamines and pyridine bases, secondary amines used as raw materials
- the leaving group W may be the same as that described above for Z.
- a desired optically active compound (I) can be obtained by performing a reductive aminoalkylation reaction using sodium triacetoxyborohydride.
- W represents a leaving group
- n represents an integer from 2 to 4
- R 13 represents a lower alkyl group.
- Examples of the compound (XV) shown in the above reaction formula include: W represents a halogen atom (a chlorine atom, a bromine atom, an iodine atom, etc.), an alkylsulfonic acid ester residue (methanesulfonyloxy, ethanesulfonyloxy, etc.) ), Aryl sulfonic acid ester residues (benzenesulfonyloxy, P-toluenesulfonyloxy, etc.), and the like.
- Preferred examples of (XV) include chloroacetates and bromoacetates. , 3-bromopropionic esters and 4-bromobutyric esters are used.
- halogenating agents include thionyl chloride and thionyl bromide, and other examples include the use of carbon tetrachloride or carbon tetrabromide in the presence of triphenylphosphine. Further, even when a sulfonate residue such as an alkylsulfonyloxy residue or an arylsulfonyloxy residue is introduced instead of a halogen atom as w, the starting material can be similarly used.
- an alkylsulfonic acid halide such as methanesulfonyl chloride or an arylsulfonic acid halide such as benzenesulfonyl chloride can be reacted to obtain a sulfonate.
- the hydrolysis is usually carried out in the presence of an alkali, for example, sodium hydroxide, water, an organic solvent arbitrarily miscible with water (for example, alcohols such as methanol, ethers such as ethylene glycol dimethyl ether, dioxane, and tetrahydrofuran). And the like, or in a mixture of the organic solvent and water.
- an alkali for example, sodium hydroxide
- water an organic solvent arbitrarily miscible with water
- alcohols such as methanol
- ethers such as ethylene glycol dimethyl ether, dioxane, and tetrahydrofuran
- the compound (XVI I) is further separated into an optically active form (XVI I I) by forming a salt with an optically active base as shown in the following formula.
- Base is a generic term for optically active organic bases, and chiral amines (preferably optically active phenethylamine) and chiral amino alcohols (preferably optically active vallinol) are used in this step.
- chiral amines preferably optically active phenethylamine
- chiral amino alcohols preferably optically active vallinol
- other well-known natural chemicals such as cinchonine and cinchonidine, are also suitable for the purpose of separating optically active forms.
- the optically active carboxylic acid separated as a salt is converted into a free acid and then used in the next step as shown in the following reaction formula.
- the free acid (XIX) is re-esterified (XX) and then reduced to the alcohol (XXI), and the hydroxyl group is further converted to a reactive halogen or other substituent to form a reactive optically active intermediate.
- Aldehyde (XXIII) or alcohol (XXI) by direct reduction of free acid to aldehyde (XXII), or aldehyde (XXIII) by oxidation of alcohol (XXI). can also be manufactured.
- esters (XX) are converted to alcohols (XXI).
- the synthesis can be performed with well-known reducing agents such as lithium borohydride, borane, and the like.
- the alcohol (XXI) thus obtained is a compound (XXII) whose hydroxyl group is converted to a halogen derivative or activated as a sulfonic acid ester.
- aldehydes (XXIII) obtained by direct reduction of carboxylic acids or oxidation of alcohols (XXI), for example, oxidation with manganese dioxide or other oxidizing agents, are also useful substances.
- XXII oxidation with manganese dioxide or other oxidizing agents
- the optically active intermediate compound provided by the present invention has a quaternary carbon atom in the optically active center, maintains the optical activity in these steps, in other words, the loss of optical purity due to racemization is extremely small. There are features. If desired, it is also possible to introduce a substituent on the tetrahydrobenzindole ring while maintaining the optical activity.
- optically active intermediates (XII) of the present invention are a group of substances useful as raw materials for the production of pharmaceuticals, and to be more specific, provided by the present invention. -Very useful for producing the optically active compound represented by the general formula (I).
- the significance of the intermediate (XII) of the present invention has been elucidated here.
- the intermediate (XIII) of the present invention which is particularly reactive, is not limited to these examples and can be widely applied. It is noted that it is a substance suitable for the production of other drugs, especially bioactive amines.
- the details of the amines DH which are the other raw materials used in the synthesis of the optically active compound represented by the general formula (I) in the present invention are as follows.
- WO98 / 00400 and PCT / JP98 / 05827 can be referred to.
- amides in which D is represented by the general formula (II) for example, 1-phenylbiperazines, 4-phenylbiperidines, 4-phenyl-1,2,3,6-tetrahydropyridines And 1- (2-pyridyl) pidazines, 1- (2-pyrimidinyl) pidazines and the like.
- Examples thereof include 9-alkyl derivatives, 9-alkenyl derivatives, 9-acyl derivatives, 9-forcebamoyl derivatives, and 9-alkoxycarbonyl derivatives.
- the 9-position modification of 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole is 2,3,4,9-tetrahydro-1H-pyrido [3
- the secondary amino group at the 2-position of [, 4-b] indoles can be protected by a commonly used protecting group, subjected to a chemical reaction such as alkylation or acylation, and then deprotected.
- the protecting group used is preferably one which is stable under the conditions of chemical reactions such as alkylation and acylation and which is easy to deprotect, and examples thereof include t-butoxycarbonyl group and benzyloxycarbonyl group. In addition to carbamates, there are benzyl groups and the like.
- 2,3-, 4,9- Tetrahydro-1H-pyrido [3,4-b] indole derivatives 2,3-, 4,9- Tetrahydro-1H-pyrido [3,4-b] indole derivatives, tetrahydrofuran, and getyl in the presence of strong bases such as sodium hydride, n-butyllithium, and lithium diisopropylamide It is preferable to carry out the reaction at a temperature ranging from low temperature to heating after dilution with an inert solvent such as ether, toluene, 1,2-dimethoxetane, dimethylformamide and dimethylsulfoxide.
- an inert solvent such as ether, toluene, 1,2-dimethoxetane, dimethylformamide and dimethylsulfoxide.
- alkylating agent to be used examples include linear alkyl halides such as methyl iodide and butyl bromide, and branched-chain alkyl halides such as isopropyl bromide and isobutyl bromide.
- alkylating agent examples include linear alkyl halides such as methyl iodide and butyl bromide, and branched-chain alkyl halides such as isopropyl bromide and isobutyl bromide.
- examples include ether, bromoacetonitrile, benzyl bromide, bromoacetamide, methyl bromoacetate, and 2-chloro-N, N-dimethylethylamine.
- acylating agent examples include halogenated acyl such as acetyl chloride, propionyl chloride, and isobutyryl chloride, as well as dimethylcarbamoyl chloride, getylcarbamoyl chloride, methyl chloroformate, and ethyl chloroformate.
- 9-carbamoyl derivatives and 9-alkoxycarbonyl derivatives of 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole are tetrahydrofuran, getylether, toluene, 1, Strong bases such as sodium hydride, n-butyllithium and lithium diisopropylamide in inert solvents such as 2-dimethyloxetane, dimethylformamide and dimethylsulfoxide Can be synthesized by reacting with amines such as ammonia and methylamine, or reacting with alcohols such as methanol and ethanol after carrying out formalization with triphosgene in the presence of.
- amines such as ammonia and methylamine
- alcohols such as methanol and ethanol
- X represents any one of S, SO, S0 2, 0
- X represents any one of S, SO, S0 2, 0
- X represents any one of S, SO, S0 2, 0
- X represents any one of S, SO, S0 2, 0
- X represents any one of S, SO, S0 2, 0
- X represents any one of S, SO, S0 2, 0
- 3,4-dihydro-1H-benzo [4,5] thieno [2,3-c] pyridine can be obtained from substituted or unsubstituted thiophenol and 4-chloroacetoacetic acid ethyl ester.
- Ethyl (phenylthio) acetate can be synthesized through cyclization, amidation, amide reduction, and Pictet-Spengler cyclization (J. Heterocyclie Chem., 16, 1321, 1979).
- a sulfoxide derivative and a sulfone derivative can be obtained.
- the 2-position amino group of 3,4-dihydro-1H-benzo [4,5] thieno [2,3-c] pyridine is protected by a protecting group such as t-butoxycarbonyl group or benzyloxycarbonyl group.
- 3,4-dihydrazide mud by deprotecting - 9 Okiso 9 oN 4 -111 - base down zone [4,5] Cheno [2,3-0] Pyridine or 3,4 dihydric mud - 9,9 Jiokiso - 9 people 6 - 1H-benzo [4,5] thieno [2,3 c] Pyridine can be obtained.
- 3,4-dihydro-1H-benzo [4,5] fun [2,3-c] pyridin is, for example, 3- (2 ⁇ ) -benzo [b] furanone and getylcyanomethylphosphoform.
- 3-cyanomethylben V [b] furan obtained from a single batch can be synthesized through reduction of nitrile, formamidation, cyclization, and reduction of imine (Japanese Patent Application Laid-Open No. 63-22581).
- X represents any one of S, SO, S0 2
- G represents a methylene
- an amine compound having the general formula (Illb) of a sulfoxide derivative or a sulfone derivative can be obtained.
- X represents either NR 8 or NCONR 9 R 10 and G represents carbonyl or methylene
- a conventionally known compound such as 2,3,4,4a-tetrahydro-1H-virazino is used.
- a compound having the general formula (I.IIb) can be synthesized from a conductor (JP-A-52-114000) by chemical modification such as alkylation and acylation.
- the 3-position of 2,3,4,4a-tetrahydro-1H-birazino [l, 2-a] quinoxaline-5 (6H) -one is protected by a suitable protecting group such as a benzyloxycarbonyl group.
- a suitable protecting group such as a benzyloxycarbonyl group.
- the amines (IV-6) in which D is represented by the general formula (IV) are represented by the corresponding formulas (IV-1) wherein R 3 , E 2 , Y, and m represent the same as described above.
- the compound (IV-3) and the N-1-butoxycarbonyl piperazine represented by the formula (IV-4) are condensed in the presence of a base to give a compound (IV-5).
- IV-5) is synthesized by de-t-butoxycarbonylation under acidic conditions,
- a method for synthesizing an amine in which D is represented by the general formula (IV) will be described in detail.
- the amines (IV-6) in which D is represented by the general formula (IV) are represented by the corresponding formulas (IV-1) wherein R 3 , E 2 , Y, and m are as defined above. Is reduced with sodium borohydride to give an alcohol of the formula (IV-2), and then the compound (IV-2) is chlorinated with thionyl chloride to give the compound (IV-3)
- the compound (IV-3) and the Nt-butoxycarbonyl piperazine represented by the formula (IV-4) are condensed in the presence of a base to give a compound (IV-5).
- -5) is synthesized by de-t-butoxycarbonylation under acidic conditions,
- the amines (IV-9) also represented by the formula (IV) can be combined with a 4-bromopyridine represented by the formula (IV-7) and a corresponding ketone represented by the formula (IV-1).
- the compound (IV-8) is reacted in n-butyllithium in a terpolymer to reduce the compound (IV-8) under a hydrogen atmosphere using platinum oxide as a catalyst.
- Amine D is represented by the general formula (V) (V- 3), the compound (V-1) [H al wherein represents a halogen atom, R 5, and R 6 are as defined above. Is converted to a compound (V-2) by condensing the N-1-butoxycarborubiperazine represented by the formula (IV-4) in the presence of a base, and further the compound (V-2) is obtained under acidic conditions. Synthesized by de-butoxycarbonylation,
- the amines (V-6) and (V-7) represented by the general formula (V) can be obtained by reacting a compound (V-6) with a 4-bromopyridine represented by the formula (IV-7). 4)
- R 3 has the same meaning as described above, and R 5 ′ represents lower alkyl or phenyl. Is reacted with n-butyllithium in ether to give compound (V-5), and the compound (V-5) is reduced under a hydrogen atmosphere using platinum oxide as a catalyst. Or by reduction under a hydrogen atmosphere using palladium carbon as a catalyst.
- J in compound (VI) forms a furan ring together with the double bond carbon atom in the condensed part
- a conventionally known compound such as 4,5,6,7-tetrahydrofuro [ 3,2-c] pyridine, 4,5,6,7-tetrahydroph Mouth [2,3-c] pyridine, 5,6,7,8-tetrahydro-4H-furo [2,3-cl
- Various derivatives can be synthesized from zepin or 5,6,7,8-tetrahydro-4H-furo [2,3-d] azepine [Japanese Patent Laid-Open No. 9-118681].
- the optically active compound of the general formula (I) provided in the present invention is an amine, which exists as a base. Therefore, it forms salts with many inorganic and organic acids, and this property is used in the production of pure substances and in the form of delivery as pharmaceuticals. That is, by making it acidic at the time of production, it is solubilized in a polar solvent such as water, extracted and purified, and isolated as a salt having favorable physicochemical properties. It can be in the form of an acceptable salt.
- Possible salt forms include acid addition salts with inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid, or aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, and hydroxyalkanes.
- inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid
- aliphatic monocarboxylic acids dicarboxylic acids, hydroxyalkanoic acids, and hydroxyalkanes.
- acids, amino acids and the like, and salts derived from non-toxic organic acids such as aromatic acids, aliphatic and aromatic sulfonic acids.
- acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, bisulfate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, tartaric acid Salt, oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, fumarate, methanesulfonate, benzenesulfonate, toluene Sulfonate, citrate, lactate, malate, glycolate and the like.
- the above-mentioned acid addition salts have significance as a pharmacologically acceptable pharmaceutical composition, have pharmaceutical advantages as a pharmaceutical composition, and dispersibility and absorption when administered to the human body. It seems to show usefulness in aspects such as sex It is.
- compositions containing the present invention as an active ingredient can be administered in any of oral and parenteral (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal) routes of administration to humans and non-humans. It can be administered to animals. Therefore, the pharmaceutical composition containing the compound (I) as an active ingredient is in an appropriate dosage form depending on the administration route.
- parenteral eg, intravenous, intramuscular, subcutaneous, rectal, transdermal
- the pharmaceutical composition containing the compound (I) as an active ingredient is in an appropriate dosage form depending on the administration route.
- oral preparations include tablets, capsules, powders, granules, syrups, and the like.
- Parenteral preparations include injections such as intravenous injections and intramuscular injections, rectal preparations, oils and fats Suppositories, aqueous suppositories and the like.
- Excipients include, for example, lactose, glucose, corn starch, sorbite, crystalline cellulose, and the like.
- Disintegrators include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, and the like.
- dimethylcellulose, polyvinyl alcohol, polyvinylether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, polyvinylpyrrolidone, and the like lubricants such as talc, magnesium stearate, polyethylene glycol, Hardened vegetable oils and the like are each mentioned.
- the above injection can be produced by adding a buffer, a pH adjuster, a stabilizer and the like as necessary.
- the content of the compound (I) according to the present invention in the pharmaceutical composition varies depending on the dosage form, but is usually 0.1 to 50% by weight, preferably 0.1 to 20% by weight in the whole composition. It is about.
- the dose is determined as appropriate for each individual case, taking into account the patient's age, weight, sex, differences in disease, and the degree of symptoms.
- the preferred dose is 0.1 to 30 mg, which is administered once or several times a day.
- BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to the following Examples and Test Examples, but the present invention is not limited thereto.
- the following description of “(the compound of the present invention)” means the compound (I).
- the reaction solution was cooled to ⁇ 20 ° C., ethyl 3-bromobutyrate (7.15 ml, 50 mmol) was added, and the mixture was further stirred at room temperature for 18 hours. Ethyl acetate and water were added to the reaction solution, and the reaction product was extracted. The ethyl acetate solution was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.Diisopropyl ether was added to the resulting material for crystallization, and 8.01 g of the above product (yield 56%) %).
- the obtained free compound was dissolved in methanol saturated with hydrochloric acid to obtain a hydrochloric acid salt.
- ⁇ - negation (CDC1 3): ⁇ 1.10 ( lH, m), 1.33 (2H, m), 1.52 (2H, m), 1.
- the resulting glue was dissolved in methanol saturated with hydrochloric acid to obtain a hydrochloride.
- the binding experiment was carried out using a final concentration of lnM [ 3 H] -5CT (carboxamide tripumimine) and a test substance of 1 to 1000 ⁇ (the present invention compound in Synthesis Examples 1 to 26). Liquid 1001 was added to make the final volume at 300/1, and incubation was performed at 37 ° C for 30 minutes. The incubation was stopped by quick filtration over GF / B filter and washed with 6 ml of cold 50 mM Tris-HCI (pH 7.4). Radioactivity was measured with a liquid scintillation counter. Non-specific binding was determined with 10 M methylgoline, and the specific binding was calculated from the difference. The IC 50 was determined from the inhibition curve of each compound, and the binding inhibition constant Ki was calculated from this. Table 1 shows the results. 1 Shikikenrei 2 5 - binding affinity studies with HT 2 receptor
- Rat cerebral cortex was homogenized in 10 volumes of 0.32 M sucrose solution, and the supernatant obtained by centrifugation at 900 xg for 10 minutes was further centrifuged at ll, 500 xg for 20 minutes. The resulting 50mM Tris-HCl (P H7.4) to sediment after the buffer pressurized Ete resuspended, centrifuged for 20 minutes separated by 39,900Xg, resulting sediment was used as P2 fraction.
- the P2 fraction was incubated at 37 ° C for 15 minutes in a 50 mM Tris-HCl (pH 7.4) buffer containing InM [ 3 H] ensenserin and the compound of the present invention. After the reaction, Pettman GF / B The glass was filtered in the evening. The radioactivity of the fill was measured with a liquid scintillation counter. Non-specific binding was determined with 10 M quinoserine, and the specific binding was calculated from the difference. IC 5 from inhibition curve of each compound. From which the binding inhibition constant Ki was calculated.
- 5-HT 2 Ki a Ki and the ratio of 5-HT 7 obtained from Test Example 1 were shown in Table 1.
- Table 1 the compounds of the present invention revealed that more selectively binds to 5-HT 7 receptor.
- the compounds of the invention bind to human-serotonin 5-HT 7 receptor subtype expressed in clonal cell lines [3 H] strongly -5CT, and you selectively inhibit. Therefore, the compound of the present invention and a pharmaceutically acceptable salt thereof may be used for various diseases considered to be caused by abnormal central and peripheral seototonin control functions, such as mental disorders (manic depression, anxiety, schizophrenia, epilepsy) , Sleep disorders, biological rhythm disorders, migraines, etc.), circulatory diseases (such as hypertension), and gastrointestinal dysfunction are useful as drugs for the prevention or treatment. Also, from the manufacturing process and their associated invention intermediates provided by the present invention, substances that act on more selectively 5 _HT 7 receptor.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020007011690A KR20010042904A (ko) | 1998-04-22 | 1999-04-21 | 광학 활성 테트라하이드로벤즈인돌 유도체 |
EP99917087A EP1081136A4 (en) | 1998-04-22 | 1999-04-21 | OPTICALLY ACTIVE TETRAHYDROBENZINDOLES DERIVATIVES |
CA002329319A CA2329319A1 (en) | 1998-04-22 | 1999-04-21 | Optically active tetrahydrobenzindole derivatives |
US09/673,833 US6407112B1 (en) | 1998-04-22 | 1999-04-21 | Optically active tetrahydrobenzindole derivative |
NO20005271A NO318796B1 (no) | 1998-04-22 | 2000-10-19 | Optisk aktive tetrahydrobenzindolderivat, farmasoytisk preparat og 5-HT7-middel omfattende en slik forbindelse, og optisk aktivt mellomprodukt. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10/111833 | 1998-04-22 | ||
JP11183398 | 1998-04-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999054303A1 true WO1999054303A1 (fr) | 1999-10-28 |
Family
ID=14571322
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/002127 WO1999054303A1 (fr) | 1998-04-22 | 1999-04-21 | Derives tetrahydrobenzindoles actifs au plan optique |
Country Status (7)
Country | Link |
---|---|
US (1) | US6407112B1 (ja) |
EP (1) | EP1081136A4 (ja) |
KR (1) | KR20010042904A (ja) |
CN (1) | CN1168716C (ja) |
CA (1) | CA2329319A1 (ja) |
NO (1) | NO318796B1 (ja) |
WO (1) | WO1999054303A1 (ja) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1057814A1 (en) * | 1997-12-25 | 2000-12-06 | Meiji Seika Kaisha, Ltd. | Tetrahydrobenzindole derivatives |
WO2002018367A1 (fr) * | 2000-08-31 | 2002-03-07 | Meiji Seika Kaisha, Ltd. | Derives de tetrahydrobenzindole pouvant se fixer sur le recepteur 5-ht7 et metaboliquement stables |
US6762191B2 (en) | 2001-07-05 | 2004-07-13 | Pharmacia & Upjohn Company | Therapeutic compounds |
WO2005012310A1 (ja) * | 2003-08-04 | 2005-02-10 | Soda Aromatic Co.,Ltd. | チエノピリジン系化合物の香料における使用、および新規チエノピリジン系化合物 |
JP2005154291A (ja) * | 2003-11-21 | 2005-06-16 | Ajinomoto Co Inc | グルタミン酸誘導体の有機アミン塩及びその利用 |
WO2008013556A1 (en) | 2006-07-27 | 2008-01-31 | Janssen Pharmaceutical N.V. | Combination 5-ht7 receptor antagonist and serotonin reuptake inhibitor therapy |
JP2010241815A (ja) * | 2010-06-01 | 2010-10-28 | Ajinomoto Co Inc | グルタミン酸誘導体の有機アミン塩及びその利用 |
US8618288B2 (en) | 2003-09-17 | 2013-12-31 | Janssen Pharmaceutica Nv | Pyrimidine compounds as serotonin receptor modulators |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070232662A1 (en) * | 2004-05-11 | 2007-10-04 | Egis Gyogyszergyar Rt. | Indol-2-One Derivatives for the Treatment of Central Nervous Disorders, Gastrointestinal Disorders and Cardiovascular Disorders |
HU0400955D0 (en) * | 2004-05-11 | 2004-07-28 | Egyt Gyogyszervegyeszeti Gyar | Pyridine derivatives of dialkyl oxindoles |
NZ551543A (en) * | 2004-05-11 | 2009-12-24 | Egis Gyogyszergyar Nyrt | Pyridine derivatives of alkyl oxindoles as 5-HT7 receptor active agents |
DE102004042453A1 (de) | 2004-08-31 | 2006-03-02 | Basf Ag | Verfahren zur Herstellung von Triethanolamin |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998000400A1 (fr) * | 1996-06-28 | 1998-01-08 | Meiji Seika Kaisha, Ltd. | Composes de tetrahydrobenzindole |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6498251B1 (en) * | 1997-12-25 | 2002-12-24 | Meiji Seika Kaisha, Ltd. | Tetrahydrobenzindole derivatives |
-
1999
- 1999-04-21 US US09/673,833 patent/US6407112B1/en not_active Expired - Fee Related
- 1999-04-21 KR KR1020007011690A patent/KR20010042904A/ko not_active Application Discontinuation
- 1999-04-21 EP EP99917087A patent/EP1081136A4/en not_active Withdrawn
- 1999-04-21 CA CA002329319A patent/CA2329319A1/en not_active Abandoned
- 1999-04-21 CN CNB998077771A patent/CN1168716C/zh not_active Expired - Fee Related
- 1999-04-21 WO PCT/JP1999/002127 patent/WO1999054303A1/ja not_active Application Discontinuation
-
2000
- 2000-10-19 NO NO20005271A patent/NO318796B1/no unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998000400A1 (fr) * | 1996-06-28 | 1998-01-08 | Meiji Seika Kaisha, Ltd. | Composes de tetrahydrobenzindole |
Non-Patent Citations (2)
Title |
---|
KIKUCHI C, ET AL.: "TETRAHYDROBENZINDOLES: SELECTIVE ANTAGONISTS FO THE 5-HT7 RECEPTOR", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 42, no. 04, 25 February 1999 (1999-02-25), US, pages 533 - 535, XP002926539, ISSN: 0022-2623, DOI: 10.1021/jm980519u * |
See also references of EP1081136A4 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1057814A1 (en) * | 1997-12-25 | 2000-12-06 | Meiji Seika Kaisha, Ltd. | Tetrahydrobenzindole derivatives |
EP1057814A4 (en) * | 1997-12-25 | 2001-07-11 | Meiji Seika Kaisha | TETRAHYDROBENZINDOLE DERIVATIVES |
US6498251B1 (en) | 1997-12-25 | 2002-12-24 | Meiji Seika Kaisha, Ltd. | Tetrahydrobenzindole derivatives |
WO2002018367A1 (fr) * | 2000-08-31 | 2002-03-07 | Meiji Seika Kaisha, Ltd. | Derives de tetrahydrobenzindole pouvant se fixer sur le recepteur 5-ht7 et metaboliquement stables |
US6762191B2 (en) | 2001-07-05 | 2004-07-13 | Pharmacia & Upjohn Company | Therapeutic compounds |
JP4517381B2 (ja) * | 2003-08-04 | 2010-08-04 | 曽田香料株式会社 | チエノピリジン系化合物の香料における使用、および新規チエノピリジン系化合物 |
JPWO2005012310A1 (ja) * | 2003-08-04 | 2006-09-14 | 曽田香料株式会社 | チエノピリジン系化合物の香料における使用、および新規チエノピリジン系化合物 |
WO2005012310A1 (ja) * | 2003-08-04 | 2005-02-10 | Soda Aromatic Co.,Ltd. | チエノピリジン系化合物の香料における使用、および新規チエノピリジン系化合物 |
US8618288B2 (en) | 2003-09-17 | 2013-12-31 | Janssen Pharmaceutica Nv | Pyrimidine compounds as serotonin receptor modulators |
JP2005154291A (ja) * | 2003-11-21 | 2005-06-16 | Ajinomoto Co Inc | グルタミン酸誘導体の有機アミン塩及びその利用 |
US8883808B2 (en) | 2005-08-04 | 2014-11-11 | Janssen Pharmaceutica N.V. | Combination of 5-HT7 receptor antagonist and serotonin reuptake inhibitor therapy |
WO2008013556A1 (en) | 2006-07-27 | 2008-01-31 | Janssen Pharmaceutical N.V. | Combination 5-ht7 receptor antagonist and serotonin reuptake inhibitor therapy |
JP2010241815A (ja) * | 2010-06-01 | 2010-10-28 | Ajinomoto Co Inc | グルタミン酸誘導体の有機アミン塩及びその利用 |
Also Published As
Publication number | Publication date |
---|---|
EP1081136A1 (en) | 2001-03-07 |
NO20005271L (no) | 2000-12-15 |
NO318796B1 (no) | 2005-05-09 |
CA2329319A1 (en) | 1999-10-28 |
KR20010042904A (ko) | 2001-05-25 |
US6407112B1 (en) | 2002-06-18 |
CN1306510A (zh) | 2001-08-01 |
EP1081136A4 (en) | 2002-07-03 |
NO20005271D0 (no) | 2000-10-19 |
CN1168716C (zh) | 2004-09-29 |
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