WO2001083452A1 - Nouveaux composes tricycliques - Google Patents

Nouveaux composes tricycliques

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Publication number
WO2001083452A1
WO2001083452A1 PCT/JP2001/003576 JP0103576W WO0183452A1 WO 2001083452 A1 WO2001083452 A1 WO 2001083452A1 JP 0103576 W JP0103576 W JP 0103576W WO 0183452 A1 WO0183452 A1 WO 0183452A1
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WIPO (PCT)
Prior art keywords
group
atom
compound
carbon atoms
general formula
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PCT/JP2001/003576
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English (en)
Japanese (ja)
Inventor
Shunichi Ikuta
Shiro Miyoshi
Kohei Ogawa
Original Assignee
Asahi Kasei Kabushiki Kaisha
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Application filed by Asahi Kasei Kabushiki Kaisha filed Critical Asahi Kasei Kabushiki Kaisha
Priority to AU2001252575A priority Critical patent/AU2001252575A1/en
Publication of WO2001083452A1 publication Critical patent/WO2001083452A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a novel compound useful as a preventive and therapeutic drug for diabetes, obesity, hyperlipidemia, digestive system diseases, depression, and dysuria.
  • Adrenergic receptors are classified into] 31, ⁇ 2, and] 33; stimulation of / 31 increases the number of beats, and stimulation of 82 induces relaxation of smooth muscle tissue, and blood pressure.
  • ⁇ 3 is thought to promote adipocyte lipolysis and increase thermogenesis. Therefore, it has been shown that; 33 agonists are useful as preventive and therapeutic agents for diabetes, obesity, and hyperlipidemia (Nature, Vol. 309, ppl63-165, 1984, Int. Obes. Relat. Metab. Disord., Vol. 20, ppl91-199, 1996, Drug Development Research, Vol. 32, pp69-76, 1994, J. Clin. Invest., Vol. 101, pp2387-2393, 1998).
  • this compound is a compound that acts on the heart, and differs from the compound of the present invention in that it has a different structure and a stronger effect on the heart. Further, as a compound having a blocking action, ie, a blood pressure lowering action, the following structural formulas described in JP-A-55-53262 and JP-A-58-41860
  • German Patent DE2651572 is known as a compound having a vasodilator action.
  • the present invention provides a compound represented by the general formula (I):
  • R 1 represents a hydrogen atom, a hydroxyl group, or a halogen atom
  • R 2 represents NH S 0 2 R : Or SO 2 NR 4 R 4 ′
  • R 3 represents an alkyl group having 1 to 6 carbon atoms, a benzyl group, a phenyl group or NR 4 R 4 ′
  • R 4 and R 4 ′ may be the same or different, and each is independently Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • X represents NH, oxygen atom, sulfur atom or methylene group.
  • Y represents NR 5 , a sulfur atom, a methylene group or a bond.
  • R 5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, or an alkoxycarbonyl group having 2 to 6 carbon atoms.
  • Z is HH (two hydrogen atoms) or an oxygen atom when Y is NR 5 (R 5 is a hydrogen atom or an alkyl group), and Y is NR 5 (R 5 is an acyl group or an alkoxycarbonyl group) ,
  • a sulfur atom, a methylene group or a bond indicates HH.
  • G is a halogen atom, G 1 OG NG 2 COG 2 , NG 3 G 4 , NG 2 S0 2 R 3 , CO 2 G 2 , CONG 3 G 4 , SO 2 NG 3 G 4 , SG 2 , cyano group or nitro group Is shown.
  • G 1 represents a hydrogen atom, a benzyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 6 carbon atoms
  • G 2 , G 3 and G 4 are the same and Each independently represents a hydrogen atom, a benzyl group, a phenyl group or an alkyl group having 1 to 6 carbon atoms, and the benzyl group, the phenyl group and the alkyl group each have one or more halogen atoms. It may be substituted by an atom.
  • G 3 and G 4 may form a saturated heterocyclic ring having 3 to 7 carbon atoms together with the nitrogen atom to which they are bonded, even if one of the methylene groups is replaced with an oxygen atom, a sulfur atom or NH. Good. Or a salt thereof.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • an alkyl group having 1 to 6 carbon atoms means a linear or branched saturated hydrocarbon group containing 1 to 6 carbon atoms, specifically, methyl, ethyl, n-propyl, i-Propyl, n-butyl, i-butynole, s-butyl, t-butynole, n-pentyl, i-pentynole, neopentynole, n-hexyl, etc.
  • an acyl group having 1 to 6 carbon atoms means a carbonyl group bonded to a hydrogen atom or a linear or branched saturated hydrocarbon group containing 1 to 5 carbon atoms. Specifically, it means formyl, acetyl, propionyl, butanol, pentanoyl, hexanoyl and the like.
  • R 1 represents a hydrogen atom, a hydroxyl group or a halogen atom; Nitrogen, chlorine and bromine are mentioned as preferred examples.
  • the substitution position of R 1 on the benzene ring is not particularly limited, but is preferably an ortho position or a para position with respect to the aminoethanol side chain, and particularly preferably the substitution position is the para position (2 position). .
  • R 2 is NHS0 2 R 3 or S0 2 NR 4 R 4, indicates, R 3 represents ⁇ alkyl group of 1 to 6 carbon atoms, a benzyl group, a phenyl group or NR 4 R 4 ', 1 4 Oyobi 1 4 'may be the same or different and each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • X represents NH, oxygen atom, sulfur atom or methylene group.
  • Y represents NR 5 , a sulfur atom, a methylene group or a bond, preferably NH.
  • R 5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, or an alkoxycarbonyl group having 2 to 6 carbon atoms.
  • Specific examples of the alkoxycarbonyl group include methoxycarbonyl., Ethoxycarbonyl, n-propoxycanoleboninole, i-propoxycanoleboninole, n-butoxycanoleboninole, sec-butoxynol / reponinole. , T-butoxycarbonyl, n-pentoxycarboe and the like.
  • Z is HH or oxygen atom when Y is NR 5 (hydrogen atom or alkyl group), and when Y is NR 5 (R 5 is acyl group or alkoxycarbonyl group), sulfur atom, methylene group or bond.
  • Y is at R 5 or a sulfur atom, preferably a combination Z is HH, Y is NH, and the combination Z is HH is particularly preferred.
  • G is a halogen atom, G 1 OG NG 2 COG 2 , NG 3 G 4 , NG 2 S ⁇ 2 R 3 , C 0 2 G 2 , CONG 3 G 4 , SO 2 NG 3 G 4 , SG 2 , cyano group or nitro Represents a group.
  • G 1 represents a hydrogen atom, a benzyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 6 carbon atoms
  • G 2 , G 3 and G 4 are the same and Each independently represents a hydrogen atom, a benzyl group, a phenyl group or an alkyl group having 1 to 6 carbon atoms, and these benzyl, phenyl, and alkyl groups each have one or more halogen atoms. It may be substituted by an atom.
  • G 3 and G 4 may form a saturated heterocyclic ring having 3 to 7 carbon atoms together with the nitrogen atom to which they are attached, in which one methylene group has been replaced by an oxygen atom, a sulfur atom or NH. Is also good.
  • Specific examples of NG 3 G 4 include NH 2 , NHMe, NHEt, NMe 2 , NEt 2 , pyrrolidinyl, piberidinyl, piperazur, homopiperazinyl, morphonyl and the like.
  • the position of the substituent G is not particularly limited, but when X is NH, the position 6 or 7 is preferable.
  • * is an asymmetric carbon, and exists as an enantiomer of either the R configuration or the S configuration. Any optically pure isomer as well as mixtures of the two isomers in any ratio are included within the scope of the invention.
  • the preferred configuration of the asymmetric carbon * is the R configuration.
  • X represents ⁇ , an oxygen atom, a sulfur atom or a methylene group
  • ⁇ represents NR 5 , a sulfur atom, a methylene group or a bond
  • R 5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 carbon atom, 6 carbon atoms or an alkoxycarbonyl group having 2 carbon atoms to 6 carbon atoms.
  • Z is HH or an oxygen atom when Y is NR 5 (R 5 is a hydrogen atom or an alkyl group); Y is NR 5 (R 5 is an acryl or alkoxycarbonyl group), a sulfur atom, a methylene group or a bond.
  • W represents a hydrogen atom or an amino-protecting group
  • G represents a halogen atom
  • G 1 represents a hydrogen atom, a benzyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 6 carbon atoms
  • G 2 , G 3 and G 4 may be the same.
  • G 3 and G 4 may also form a saturated heterocyclic ring having 3 to 7 carbon atoms together with the nitrogen atom to which they are bonded, in which one methylene group has been replaced by an oxygen atom, sulfur atom or NH. Is also good.
  • R 1 ′ represents a hydrogen atom, OR 6 or a halogen atom, and R 6 represents protection of a hydroxyl group.
  • L 2 represents a leaving group.
  • R 2 ′ represents NW 2 S 0 2 R 3 or S 0 2 NR 4 R 4 ′, W 2 represents a hydrogen atom or a protecting group for an amino group, and
  • R 3 , R 4 and R 4 ′ each represent Has the same meaning as To the aminoketone (one CO—CH 2 —NW_).
  • the resulting amino ketone is reduced to aminoanolecol (one CHOH—CH 2 —NW—).
  • the target compound represented by I) is obtained.
  • Chlorine atom Examples of leaving groups L 2, such as a bromine atom or an iodine atom.
  • W and W 2 are a protecting group for an amino group, the protecting group is not particularly limited as long as it is a protecting group used in ordinary organic synthesis. Preferred examples include a benzyl group and a benzyl group having a substituent. .
  • the protecting group R 6 for the hydroxyl group when R 1 ′ is ⁇ R 6 is not limited as long as it is a substance used for ordinary organic synthesis, but preferred examples include a benzyl group and a benzyl group having a substituent. Is mentioned.
  • the amount of the compound represented by the general formula ( ⁇ ) used in the first step is from equimolar to 5 times the molar amount of the compound represented by the general formula (III).
  • a base may be added to neutralize the acid generated by the reaction, and in this case, the base used is an organic base such as triethylamine, diisopropylethylamine, pyridine, or the like, Examples include inorganic bases such as sodium hydrogen carbonate and sodium hydroxide.
  • the compound represented by the general formula (II) can be used even in the form of a salt, in which case the base exemplified above must be added without fail.
  • solvents used in the reaction include methanol, lower alcohols such as ethanol and isopropyl alcohol, methylene chloride, chloroform, chlorinated hydrocarbons such as 1,2-dichloroethane, tetrahydrofuran, and dimethylformamide. And dimethylsulfoxide, and preferably dimethylformamide.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is carried out at a temperature between 130 ° C. and the boiling point of the selected solvent, preferably at 0 ° C. (at a temperature between 30 ° C. and 10 minutes.
  • the aminoketone generated in the first step can be used in the second step of the reduction reaction without being taken out of the reaction mixture, but after extraction and purification as necessary, It may be subjected to a reduction reaction.
  • the reducing agent to be used include sodium borohydride, sodium cyanoborohydride, and poran.
  • the solvent used for the reaction include lower anocols such as methanol, ethanol, and isopropyl alcohol, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and the like, and preferably, ethanol and dimethylformamide.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is carried out at a temperature between 130 ° C.
  • the reaction conditions usually used for removing the protecting groups used are used, but the benzyl group or the benzyl group having a substituent is used as the protecting group.
  • it can be removed by hydrogenation using palladium activated carbon as a catalyst. Since the compound represented by the general formula (I) has an asymmetric carbon represented by *, it can be obtained as a racemic mixture by the above method.
  • the racemic mixture can be separated into two optically active substances by forming an addition salt with an optically active acid such as camphor sulfonic acid or mandelic acid, and then performing fractional crystallization. Separation can also be performed using a commercially available optically active column.
  • optically active acid such as camphor sulfonic acid or mandelic acid
  • an optically active substance can be obtained by carrying out asymmetric reduction together with a hydrogen supply compound in the presence of an asymmetric reduction catalyst in accordance with the method described in WO05088287.
  • L 2 represents a leaving group
  • R 7 represents a hydroxyl-protecting group.
  • R 1 'and R 2 ' are Each has the same meaning as above. * Means an asymmetric carbon atom.
  • To the amino ether one CHOR 7 — CH 2 — NHW—).
  • deprotection of the hydroxyl-protecting group R 7 and, if necessary, deprotection of the hydroxyl-protecting group R 6 , and if W and W 2 are not hydrogen atoms but amino-protecting groups, this is the case.
  • the target compound represented by the general formula (I) is obtained.
  • Examples of leaving groups L 2 is chlorine atom, bromine atom or iodine atom and the like, if these are iodine atoms are particularly preferred.
  • W, W 2 and the hydroxyl-protecting group R 6 are as described in the above-mentioned Production Method A.
  • the hydroxyl-protecting group R 6 when R 1 ′ is OR 6 is also as described in the above-mentioned Production Method A.
  • the other protecting group R 7 for the hydroxyl group is not particularly limited as long as it is a protecting group used in ordinary organic synthesis. Examples of the protecting group that can be easily and selectively deprotected include a trialkylsilyl group and an alkoxy group.
  • Alkyl groups, acyl groups and the like are exemplified as preferred examples. Further, a preferable example is a triethylsilyl group.
  • a written document for example, TW Greene, PGM Wuts, et al., Protective Groupsin Organic Synthesis
  • Thesis "Wiley—Interscience Science”
  • TDMS t_butyldimethylsilinole
  • alcohol is added to an alcohol in the presence of an acid scavenger.
  • Examples include the reaction of a silylating agent such as t-butyldimethyl silane or t-butyldimethylsilyltrifluoromethanesulfonate, etc.
  • the amount of the silylating agent added is usually 1 to alcohol.
  • the reaction is usually preferably carried out in an inert medium, such as dichloromethane or tetrahydrogen.
  • Preferred examples include N, N-dimethylformamide, such as drofuran, acetonitrinole, pyridine, etc.
  • the amount of the inert medium used is, for example, about 1 to 5 ml per lg of alcohol.
  • the acid scavenger examples include triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like, and a preferable example is imidazole.
  • the amount of The amount is usually about 1 to 3 moles relative to the alcohol. This reaction is usually carried out preferably at a temperature of from 120 to 80 ° C., particularly preferably from 0 ° C. to room temperature, for example, preferably from 1 to 5 hours.
  • the amount of the compound represented by the general formula (II) to be used is equimolar to 1.5-fold the molar amount of the compound represented by the general formula (IV).
  • a base may be added to neutralize the acid generated by the reaction, and examples of the base used in this case include triethylamine, diisopropylethylamine and the like. Further, the compound represented by the general formula (II) can be used even in the form of a salt, in which case the base exemplified above is always added.
  • the solvent used in the reaction include dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like, and preferably dimethylformamide.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is carried out at a temperature between 0 ° C. and 90 ° C., preferably at 60 ° C., for between 10 minutes and 24 hours.
  • Removal of the protecting group R 7 for the hydroxyl group and, if necessary, other protecting groups are performed, and reaction conditions generally used for removing the protecting group used at that time can be used. If triethylsilyl group are used as R 7 may be, for example, tetra-Petit Ruan monitor ⁇ beam fluoride as this removal.
  • the production method of the optically active substance may be fractional crystallization as an addition salt with an optically active acid, or resolution using a commercially available optically active column.
  • an optically active substance represented by the general formula (IV) produced according to the method described in WO97253111 and WO0104092.
  • An optically active compound of the general formula (I) can be produced.
  • the compound represented by the general formula (III) is known and can be synthesized, for example, by the method described in Japanese Patent Laid-Open Publication No. 9-249623 or J. Med. Chem., Vol. 10, p462, 1966. .
  • the compound represented by the general formula (IV) is known, and can be synthesized, for example, by the method described in Japanese Patent Laid-Open Publication No. 9-1249623.
  • the compound represented by the general formula (V) is known, and can be synthesized, for example, by the method described in WO 0104092.
  • the compound represented by the general formula (II) is characteristic as an important intermediate for the synthesis of the compound represented by the general formula (I).
  • the method for producing the compound represented by the general formula (II) is exemplified below.
  • w 1 represents a protecting group for an amino group. Is reacted in the presence of a reducing agent. Then the protective group W 1 of the amino group is deprotected as the second step. Finally, the desired product can be obtained by reprotecting this amino group with another protecting group w, if necessary. Even if W is a hydrogen atom, that is, an amino group is free, it can be subjected to the next reaction.
  • Protecting group W 1 of Amino group is not limited as long as it is used in conventional organic synthesis, base Nji Ruo carboxymethyl carbonylation Le group Preferred examples include benzyl O alkoxycarbonyl group having a substituent, t one butoxycarbonyl And the like.
  • the selection of W is as described in the production method A of the general formula (I).
  • the amount of the compound represented by the general formula (VII) used in the first step is from equimolar to 1.5 times the molar amount of the compound represented by the general formula (VI).
  • the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium cyanoborohydride and the like.
  • the solvent used in the reaction include lower alcohols such as methanol, ethanol, and isopropyl alcohol, acetic acid, methylene chloride, chloroform, chlorinated hydrocarbons such as 1,2-dichloroethane, and tetrahydrofuran.
  • reaction temperature and reaction time are not particularly limited, but the reaction is carried out at a temperature between -30 ° C and the boiling point of the selected solvent, preferably at a temperature between ⁇ ° C and 30 ° C, for 10 minutes to Take place between 24 hours.
  • the reaction conditions conventionally used for the removal of the protecting group in use is used, benzyl O propoxycarbonyl - group, benzylidene having substituent
  • a carbonyl group when used as a protecting group, it can be removed, for example, by hydrogenation using palladium on activated carbon as a catalyst.
  • a t-butoxycarbonyl group when used, trifluoroacetic acid or hydrochloric acid can be used. And the like.
  • ⁇ represents an oxygen atom
  • L 1 represents a leaving group
  • W 1 has the same meaning as described above.
  • the protective group W 1 of the amino group is deprotected as the second step.
  • the amino group is re-protected with another protecting group W to obtain the desired product.
  • W is a hydrogen atom, that is, an amino group is in a free state, it can be subjected to the next reaction (production of general formula (I)).
  • the protecting group W 1 for the amino group is not limited as long as it is a protecting group used in ordinary organic synthesis.
  • Preferred examples thereof include a benzyloxycarbonyl group, a benzyloxycarbonyl group having a substituent, and t-butoxycarbonyl. Groups and the like.
  • W is as described in the production method of the general formula (I).
  • the amount of the compound represented by the general formula (VIII) used in the first step is 1 mole to 2 times the molar amount of the compound represented by the general formula (VI). If L 1 is a hydroxyl group the reaction is carried out in the presence of a condensing agent in the first step.
  • a condensing agent usually used in the synthesis of peptides and the like can be used, and examples thereof include dicyclohexylcarbodiimide, diisopropylcarbodiimide, and water-soluble carbodiimide.
  • the solvent for the condensation reaction include chlorinated hydrocarbons such as dimethylene chloride, chloroform, 1,2-dichloroethane, and the like, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and the like.
  • dimethylformamide or tetrahydrofuran is used.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is carried out at a temperature between 130 ° C and the boiling point of the selected solvent, preferably at a temperature between 0 ° C and 30 ° C for 10 minutes. Done between ⁇ 24 hours.
  • the leaving group L 1 may be a chlorine atom, a bromine atom or an iodine atom, or a 2,5-dioxopyrrolidine-11-yloxy group (—OSu group). Is unnecessary, and the reaction is carried out by adding a base instead. Removal of the protecting group W 1 of Amino groups in the second step is the manufacturing method described above As described in a.
  • Z represents HH
  • W 1 represents a hydrogen atom
  • L 1 represents a chlorine atom or a bromine atom.
  • the hydrochloride or hydrobromide of the compound of the formula (1) is reacted to obtain the desired compound.
  • the amount of the compound represented by the general formula (VIII) to be used is equimolar to 1.5-fold the molar amount of the compound represented by the general formula (VI).
  • the reaction is usually performed in the presence of a base.
  • the base include organic bases such as triethylamine, diisopropylethylamine and pyridine, and inorganic bases such as potassium carbonate, sodium hydrogencarbonate and sodium hydroxide.
  • Examples of the solvent used for the reaction include lower alcohols such as methanol, ethanol and isopropyl alcohol, acetic acid, chlorinated hydrocarbons such as 1,2-dichloroethane, acetic acid, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, and dimethylform. Amides, dimethyl sulfoxide and the like are used alone or in a mixture of a plurality of solvents, and a mixed solvent of tetrahydrofuran and methanol is preferable.
  • Reaction temperature and anti The reaction time is not particularly limited, but the reaction is carried out at a temperature between 130 ° C. and the boiling point of the selected solvent, preferably at a temperature between 0 ° C. and 30 ° C., for 10 minutes to 24 hours. Done between.
  • the raw material aryl ketone, aqueous ammonium sulfide solution (yellow, sulfur content 6 to 7.5%) and sulfur powder are suspended in 1,4-dioxane, and sealed in a sealed tube at 160 ° C for 1 hour. Reaction conditions such as heating and stirring for 0 hour can be exemplified.
  • the dehydration reaction in the second step is performed by a known method, for example, Harrison and Harrison, ompendium of Organic Synthesis Methods, Vol. 1, pp464-465, Richard et al., C. Anadian. J. Res. Sec. B, Vol. 28, pp. 443-452, 1950, can be carried out in accordance with the method shown or a method analogous thereto.
  • heating in phosphoryl chloride at 100 ° C. for 10 to 30 minutes can be exemplified.
  • the reducing agent used in the reduction reaction in the third step include borane, lithium aluminum hydride, hydrogen-Raney-nickel catalyst, and the like. Specific examples include conditions such as a reaction in a borane-tetrahydrofuran solution at room temperature for 12 to 24 hours.
  • R 5 is an alkyl group having 1 to 6 carbon atoms other than a hydrogen atom
  • the compound of the general formula (VI) having a tricyclic group can be produced by the following method. That is, the general formula (VI)
  • Y denotes a NR 5, G, X and R 5 that each have a same meaning as described above.
  • the amino group of the compound represented by the general formula (VI) in which Y is NH can be obtained by a known method, for example, a method described in the literature (Cheng et al., J. Org. Chem., Vol. 56, p2436, 1991). by the method described in), it can be converted to thiols groups through Jiazoniumu salt, an S- CS- OC 2 H 5 group.
  • the substituent G is other than a hydrogen atom, that is, G is a halogen atom, G 1 OG NG 2 C ⁇ G 2 , NG 3 G 4 , NG 2 SO 2 R 3 , C ⁇ 2
  • G is a halogen atom
  • the above-mentioned G is a hydrogen atom
  • the object can be achieved by applying a method for synthesizing the compound represented by the general formula (VI) or other known synthetic methods.
  • the substituent represented by G is selected for the substituent represented by G.
  • the substituent is protected by an appropriate protecting group.
  • the reaction of each step is performed with G ', and then this G' is deprotected and converted to G to obtain the desired compound.
  • the reaction of each step is performed in the state of another substituent G ′ ′ that can be finally converted to the desired substituent G, and then G ′ and are converted to G.
  • the desired compound is obtained.
  • G and R 8 each have the same meaning as described above.
  • X represents NH.
  • R 8 represents a commonly used protecting group for an amino group, preferably an acetyl group.
  • the leaving group L 3 is exemplified by a chlorine atom, a bromine atom or an iodine atom.
  • the compounds of the general formulas (XIII) and (XIV) or the compounds of the general formulas (XVII) and (XVIII) can be obtained by obtaining a commercial product or by adding a protecting group to the commercial product. Or can be synthesized according to known literature.
  • the Suzuki reaction has been published in magazines (Norio Takaura, Akira Suzuki, Journal of Synthetic Organic Chemistry, vol. 46, p. 848 (1988); Yuki Gosei Kagaku Kyoukaishi, vol. 46, 848 (1988)). Described method or literature (CW
  • the compound of the general formula (XVI) can be synthesized by applying the method described in the literature (J.I.G. Cadogan et al., J. Chem. Soc., 1965,4831). That is, the general formula
  • the carpazole derivative of I) can be obtained.
  • the phosphite used is preferably triethyl phosphite, and the amount used is, for example, 2 to 10 equivalents, and more preferably 2 to 4 equivalents.
  • the reaction temperature is, for example, from 80 ° C. to 180 ° C., and more preferably, from 130 ° C. to 170 ° C.
  • the reaction time is, for example, 1 hour to 24 hours, preferably 3 to 10 hours.
  • R 8 is selectively deprotected according to a conventional method to obtain a compound represented by the general formula (VI).
  • a substituent that could cause a side reaction under the reaction conditions used in the production process was selected for the substituent represented by G, the substituent was protected by an appropriate protecting group.
  • the reaction of each step is performed in the state G ', and then the G' is deprotected and converted to G to obtain the desired compound.
  • the reaction of each step is performed in the state of another substituent G ′ ′ which can be finally converted to the desired substituent G, and then this G ′ ′ is converted to G.
  • the desired compound is obtained.
  • the thus-obtained compound of the present invention and the respective starting compounds and intermediates can be isolated and purified according to a conventional method such as extraction, crystallization, distillation, chromatography and recrystallization.
  • the salt of the compound of the general formula (I) in the present invention includes known salts, for example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, Includes maleate, tartrate, fumarate, dalconate, methanesulfonate, or addition salts with optically active acids such as camphorsulfonic, mandelic, and substituted mandelic acids
  • pharmaceutically acceptable salts are particularly preferred.
  • the compound of the general formula (I) When the compound of the general formula (I) is converted to a salt thereof, the compound of the general formula (I) is dissolved in an alcohol such as methanol or ethanol, and an equivalent or several-fold amount of an acid component is added. Can be obtained.
  • the acid component used is pharmaceutically acceptable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen sulfate, dihydrogen phosphate, citric acid, maleic acid, tartaric acid, fumaric acid, dalconic acid, methanesulfonic acid, etc.
  • Mineral acids or organic acids can be mentioned.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof are useful as medicaments without toxicity, and have, for example, a 33 receptor agonistic activity. It can be used as a drug for treatment and prevention.
  • jS 3 receptor Related diseases are a general term for diseases that can be ameliorated by agonistic activity mediated by this receptor, and include, for example, diabetes, obesity, hyperlipidemia, and digestive diseases (preferably abnormal gastrointestinal motility or ulcers). , Depression, dysuria.
  • the compound and the pharmaceutically acceptable salt thereof of the present invention may be obtained by a synthetic method or may be formed as a result of metabolism in a living body. Having. Therefore, it is also useful to use a compound that produces the compound of the present invention as a result of metabolism in a living body as a medicine.
  • a pharmaceutically acceptable carrier In producing the medicament of the present invention, it is preferable to add a pharmaceutically acceptable carrier, if necessary, to an effective amount of the compound represented by the general formula (I) or a salt thereof to form a pharmaceutical composition.
  • Pharmaceutically acceptable carriers include excipients, binders such as carboxymethyl cellulose, disintegrants, lubricants, additives and the like.
  • the compound of the present invention When the compound of the present invention is administered to humans, it can be orally administered in the form of tablets, powders, granules, capsules, dragees, solutions, syrups and the like. In addition, parenteral administration such as injections is also possible.
  • the dosage varies depending on the age, weight, and degree of symptoms of the patient, but generally 0.01 to 200 mg of Omg is administered once or several times a day for an adult.
  • the administration period is generally daily for several weeks to several months. Both the daily dose and the administration period can be increased or decreased depending on the symptoms of the patient.
  • the measurement was performed using a JMS-AX500 type mass spectrometer manufactured by JEOL Ltd. of Japan or a JMS-SX102 type mass spectrometer manufactured by the same company.
  • the matrix used was m-butene benzyl alcohol.
  • a Platoon-LC mass spectrometer manufactured by Micromass (UK) electromass (ESI) method was used for ionization) was used.
  • the liquid chromatograph used was a device manufactured by GILS0N of France.
  • As a separation column Mightysil RP-18 GP50-4.6 (product number 25468-96) manufactured by Kanto Chemical Co., Ltd. of Japan was used. The elution conditions are described below.
  • Solution B diacetonitrile, containing 0.1% ( ⁇ / ⁇ ) acetic acid
  • solution B was a 5-100% (v / v) linear gradient.
  • the elution time was shown in minutes.
  • the measurement was performed using a Gemini-300 type nuclear magnetic resonance apparatus manufactured by Varian, USA. Tetramethylsilane was used as the internal standard. Chemical shifts were expressed as ⁇ values (ppm).
  • the division pattern is abbreviated as in the following example. s: double line, d: double line, t: triple line, quartet: quadruple line, quintet: quintet, m: multiple line, dd: double double line, dt: double triple line, brs: Wide single line.
  • a TLC plate (Silica Genole 60 F 254 , product number 1, 05715) manufactured by Merck, Germany was used. Compounds were detected by irradiating the developed TLC plate with ultraviolet light having a wavelength of 254 nm.
  • Solution 8 acetonitrile, 0.1% ( ⁇ / ⁇ ) containing trifluoroacetic acid Solution B maintained at 5% (v / v) from 0 to 1 minute
  • Solution B was purified by 50-100% linear Dallagent porous polystyrene beads using a CHP20P resin manufactured by Mitsubishi Chemical Corporation of Japan using a mixed solvent (acetonitrile / water, 5% (v / v ) Acetic acid) eluted the desired product.
  • 2-Aminocarpazole 600 mg was suspended in water (5 ml), and concentrated hydrochloric acid (576 ml) was added.
  • methylene chloride 50 ml was added, the organic layer was separated, washed with water (50 ml) and dried over anhydrous sodium sulfate (5 g).
  • Example 2 The compound (200 mg) obtained in Example 2 was dissolved in a mixture of THF and methanol (2: 1) (17 ml), and 10% palladium on activated carbon (50 mg) was added. Stirred for hours. After adding DMF (10 ml) and stirring, palladium activated carbon was filtered off. The solvent was distilled off under reduced pressure, and water was added to the residue to precipitate crystals. The crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12 lmg) as colorless crystals.
  • 2-Aminocarbazonole (synthesized by the method described in the literature (Kyziol et al., Tetrahedron, Vol. 36, pp. 3017-3019, 1980) (500 mg) was dissolved in anhydrous THF (5 ml) and stirred. , Nt-butoxycarbonylglycine (528 mg) was added, followed by diisopropylcarbodiimide (472 ⁇ l). After stirring at room temperature for 15 minutes, ethanol (50 ml) was added.
  • the deposited precipitate was collected by filtration and dried under reduced pressure to obtain a crude product (5.4 g) of N- (3-acetyl-5-ditrophenyl) methanesulfonamide. The whole amount was dissolved in ethanol (40 ml), and zinc dust (20 g) was added. After addition of concentrated hydrochloric acid (2 ml), the mixture was heated under reflux for 4 hours. The reaction solution was filtered, ethyl acetate (100 ml) was added to the filtrate, and the mixture was washed three times with water (100 ml).
  • N-methyl- [2-benzyloxy-5-bromoacetyl] benzenesulfonamide (20 mg), the compound (39 mg) obtained in Example 6 and triethylamine (28 ⁇ l) synthesized according to the method described in WO 9725311 were used. It was added to DMF (lml) and stirred at room temperature for 1 hour. Then, a solution of sodium borohydride (9.5 mg) in ethanol (lml) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was washed twice with dilute aqueous ammonia (2.5% (w / v), lml) and dried under reduced pressure.
  • Step B (R) _N— [5-[2— [2— (9H-carpazol-1-2-inoleamino) ethynoleamino] —1-hydrodoxetyl] —2-cycloethylphenyl] methansulfonamide Synthesis of hydrochloride
  • the compound (198.7 mg) obtained in the above step A was dissolved in THF (5 ml), and tetra-n-butylammonium fluoride (1 M concentrated) was added thereto. THF solution, 0.77 ml) and acetic acid (77.5 ⁇ l) were added. The reaction solution was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed twice with aqueous sodium bicarbonate and then with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 41 Step B was repeated in the same manner as in Example 41, except that the compound (606.3 mg) obtained in Step A was used instead of the compound (198.7 mg) obtained in Step A, to give the title compound (215. 2 mg).
  • Step A (R) —N-Methylenone [5-—2- [2- (9H-carpazol-2-ylamino) ethylamino] —1-triethylsilyloxyxetyl] —2-benzyloxylbenzene Synthesis of mid
  • Example 41 In Step A, substitute for (R) -N- [5- (2-hydroxy-1-triethylsilylloxicetinole) -12-chlorophenyl] methansnolefonamide (236 mg) , (R) -N-methyl- [5- (2-node_1-triethylsilinoleoxyethyl) -1-2-benzyloxy] benzenesnolephonamide (323.8 mg) (93. Omg).
  • Step B (R) — N-methinole [5- [2-] [2- (9H-carpazole-2_ylamino) ethylamino] 1-hydroxyloxetyl] 12-benzyloxy] benzenesulfonamide hydrochloride Synthesis of
  • Example 41 Step B, the compound obtained in Example 41, Step A (198.7 The title compound (183.2 mg) was obtained in the same manner except that the compound (223. Omg) obtained in the above step A was used instead of (mg).
  • the compound (183.2 mg) obtained in the above step B was dissolved in methanol (10 ml), and 10% palladium carbon (41.4 mg) was added.
  • the reaction solution was stirred at room temperature under a hydrogen atmosphere for 6 hours.
  • the reaction solution was diluted with THF, and 10% palladium carbon was filtered off and washed with a mixed solvent of methanol and THF.
  • the washing solution and the filtrate were combined, and the solvent was distilled off under reduced pressure.
  • the residue was dissolved in methanol and converted into a hydrochloride with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. This was suspended in ethyl acetate, collected by filtration, and dried under reduced pressure to give the title compound (36.lmg).
  • Step A Synthesis of N-ethoxycanoleponinole N- [2- (benzyloxycarbinoleamino) ethyl] -N- (9H-carbazol-2-yl) amine
  • Compound of Example 2 1.04 g was dissolved in acetonitrile (10 ml), and thereto was added ethylethyl chloroformate (2 ml), and the mixture was heated under reflux for 2 hours.
  • the reaction solution was diluted with ethyl acetate and washed with water and saturated saline.
  • the organic layer was dried and the solvent was distilled off under reduced pressure.
  • Step B Synthesis of N-ethoxycarbonyl-N- (2-aminoethyl) -1-N- (9H-carbazol-2-yl) amine
  • Step C Synthesis of N-methyl-N- (2-aminoethyl) -1-N- (9H-carpazo-nor-2--1-inole) amine
  • the compound (331 mg) obtained in the above step B was dissolved in dehydrated THF (25 ml), and a solution of lithium aluminum hydride (161 mg) and aluminum chloride (197 mg) in dehydrated THF (25 ml) was added at 0 ° C for 10 minutes. The mixture was added over minutes and stirred at room temperature for 50 minutes. The solvent of the reaction solution was distilled off under reduced pressure, 5% aqueous ammonia was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and dried to obtain the title compound (189 mg).
  • Step D (R) — N— [3-—2- [2 -— [N- (9 H—carpazol-2-yl) -1-N_methylamino] ethyl] amino-1—triethylsilyloxy Synthesis of [ethyl] phenyl] methanesulfonamide
  • Example 44 Compound (322 mg) obtained in step ⁇ was treated with acetone (6 m 1) (R) — N— [3- (2-dodecyl-1-triethylsilyloxyxethyl) phenyl] methanesulfonamide (543 mg) and diisopropylethyl (307 mg) was added, and the mixture was heated under reflux for 21.5 hours.
  • the reaction solution was diluted with ethyl acetate and washed with water and saturated saline. The organic layer was dried and the solvent was distilled off under reduced pressure.
  • Step B (R) — N— [3-—2- [2 -— [N- (9 H—carpazol-2-yl) 1-N-ethoxycarbonylamino] ethyl] amino-1—hydroxethyl Synthesis of phenyl] methanesulfonamide
  • Step B Synthesis of 7-methoxy-2-acetylamino-19H-carpazole
  • the compound (2.674 g) obtained in the above step A was added to triethyl phosphite (35 ml), and the mixture was added at 160 ° C. Stir for 75 hours. After the reaction, the mixture was cooled to room temperature, and further cooled with ice. 7.5% aqueous hydrogen peroxide (75 ml) was slowly added dropwise. After the dropwise addition, the precipitated crystals were separated by filtration and dried under reduced pressure to obtain the title compound (959 mg ).
  • Step C Synthesis of 7-Methoxy-12-amino-9H-caprolupazole hydrochloride Dissolve the compound (369 mg) obtained in Step B above in methanol (25 ml), add 1N aqueous hydrochloric acid, and add 80 ° C. Stirred at C for 2 days. After the completion of the reaction, the solvent was distilled off at 40 ° C. under reduced pressure to obtain the title compound (369 mg).
  • the compound (369 mg) obtained in the above step C was suspended in THF (3.5 ml), and diisopropylethylamine ⁇ (558 ⁇ l) was added. Under ice-cooling, cloacetyl lochloride (136 ⁇ l) was added, and the mixture was heated to room temperature and stirred for 3 hours and 40 minutes. After the reaction was completed, water (14 ml) was added, and the precipitated crystals were collected by filtration. The obtained crude crystals were washed with methanol to give the title compound (330 mg).
  • Step E Synthesis of N- (7-Methoxy-9H-carpazol-2-yl) 2- (benzinoleamino) acetamide
  • the compound (330 mg) obtained in the above step D was suspended in a mixed solvent of THF (10 ml) and chloroform (10 ml), benzylamine (1.0 ml) was added, and the mixture was heated at 100 ° C and the solvent was distilled off. Then, the reaction was continued for 3 hours. After completion of the reaction, water (5 ml) and diisopropyl ether (3 ml) were added, and the crystals were collected by filtration. Drying under reduced pressure at 40 ° C gave the title compound (347mg).
  • Step F () 1 N— (7-Methoxy 9 H—Carpazol-2-yl) 2-[ ⁇ '1-Venzinole 1 N' ⁇ [2-[3— ( ⁇ , '—benzyl- ⁇ Synthesis of 1,2-methylsulfonylamino) phenyl] -12-hydroxyhexyl] acetoamide
  • 2-butanol (10 ml) 2-butanol (10 ml)
  • the compound (477 mg) obtained in the above step G was dissolved in a mixed solvent of ethanol (70 ml) and THF (70 ml), and 20% hydroxide Radium carbon (450 mg) was added. After replacing the argon with hydrogen gas, the mixture was stirred at 70 ° C for 4 hours. The reaction solution was filtered to remove 20% palladium hydroxide carbon, and then washed with a mixed solvent of hot methanol and hot THF. The washing solution and the filtrate were combined, the solvent was distilled off under reduced pressure, and then a 10% alcoholic hydrochloric acid solution (4 ml) was added to the residue. The solvent was distilled off under reduced pressure to obtain the title compound (162 mg).
  • Step F Synthesis of N- (7-benzyloxy 9H-carpazol-2-yl) 2-(benzylamino) acetamide
  • Step G (R) —N— (7-benzyloxy-1 9H—carpazol-2-yl) 2 -— [ ⁇ '—benzylyl N '— [2— [3— ( ⁇ ', 1-benzyl-N ', Synthesis of [2-methylsulfonylamino) phenyl] -l-2-hydroxyoxethyl] acetoamide
  • Step H (R) — 2— [N '—benzyl-1-N, 1- [2 -— (7-benzyloxy 9 H—caprolupazol-2-ylamino) ethyl] amino] 1-1— [3-(N Synthesis of N-methylsulfonylamino) phenyl] ethanol
  • Step H the compound (330 mg) obtained in Step H above was dissolved in a mixed solvent of ethanol (70 ml) and THF (70 ml), and 20% palladium hydroxide carbon (300 mg) was added thereto. The same reaction as in H was performed to obtain the title compound (190 mg).
  • Step B Synthesis of 4,1-acetylamino-4-1-benzylamino_2-2-nitrobiphenyl
  • step A The compound (1.0 g) obtained in the above step A was dissolved in toluene (60 ml), and tetrakistriphenylphosphine palladium (0) (116 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) was added to a 2 M aqueous potassium carbonate solution. (3.3 ml). Further, 4′-one (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-12-yl) acetanilide (1.72 g, product of Anoledritz) and ethanol (10 ml) were added, and Example The same reaction as in step A of 46 was carried out to obtain the title compound (1.2 g).
  • Step C Synthesis of 4, -acetylamino-41- (N-benzyl-1-N-methylsulfonyl) amino-2-nitrobiphenyl
  • Step D Synthesis of 7- (N-benzyl N-methylsulfonyl) amino-2-acetylamino-9H-carpazole
  • step C The compound (2.0 g) obtained in the above step C was added to triethyl phosphite (12 ml), and the same reaction as in step B of Example 46 was carried out to obtain the title compound (222 mg).
  • Step F Synthesis of N- [7- ( ⁇ '-benzyl-1-N, monomethylsulfonyl) amino-9H-potassyl-2-yl] 2-chloroacetoamide
  • step E The compound (452 mg) obtained in the above step E was suspended in THF (8 ml). Diisopropylethylamine (470 ⁇ l) was added. Chloroacetyl chloride (131 ⁇ l) was added under ice-cooling, and the same reaction as in step D of Example 46 was performed to obtain the title compound (242 mg).
  • Step G Synthesis of N— [7— ( ⁇ '-benzylil''methylsulfonyl) amino-9H-carpazol-2-yl] 2- (benzylamino) acetamide
  • step F The compound (242 mg) obtained in the above step F was suspended in THF (10 ml), benzylamine (1.0 ml) was added thereto, and the same reaction as in step E of Example 46 was carried out to obtain the title compound (224 mg).
  • THF 10 ml
  • benzylamine 1.0 ml
  • Step H (R) — N— [7- ( ⁇ '-benzyl-N'-methylsulfonylamino) -1-9H-force-pazono-le-2-yl] 2- [ ⁇ '-one-benzyl-N ', One
  • step I Under an argon atmosphere, the compound (120 mg) obtained in the above step I was dissolved in a mixed solvent of ethanol (30 ml) and THF (30 ml), and 20% hydroxide Radium carbon (120 mg) was added, and the same reaction as in step H of Example 46 was carried out to obtain the title compound (46 mg).
  • the human / 33 agonistic activity was determined using CHO (Chinese hamster ovary) cells transfected with the human] 33 gene inserted into pcDNA3 (invitrogen). Human] The S3 gene was first isolated from human adipose tissue with the 83 primers (Krief et al., J. Clin. Invest, vol. 91, p344_349 (1993)). A human ⁇ 3 fragment was obtained by PCR using cDNA (manufactured by Clontech), and this was used as a probe to obtain a full-length human 33 gene from a human genomic library (manufactured by Clonetech). The cells were re-populated with 10% fetal serum,
  • the cells were cultured in a ham F-12 medium containing 400 ⁇ g / m 1 dienictin (Gibco BRL), 100 U / m 1 ⁇ nisilin, and 100 ⁇ g / m 1 streptomycin.
  • the cells were placed in a 6-well plate at 5 ⁇ 10 5 and cultured for 24 hours, and then left for 2 hours in serum-free Ham F-12 medium.
  • Table 1 shows the relative activity (%) to isoproterenol of 11 compounds among the examples. Isoproterenol was purchased from RBI (ResearchBiochimimica1sInternatlional). From the results in Table 4, it was found that these compounds have human ⁇ 3 activity.
  • a heart was excised from a male guinea pig weighing 180 to 250 g, a right atrial specimen was prepared, and set in an organ bath containing Krebs solution aerated with 5% C02Z95% 02 mixed gas. .
  • Automated performance was measured using an isometric transformer user (Nihon Kohden TB-6111T) connected to a polygraph (Nihon Kohden MR-60000).
  • the compounds of the Examples did not affect the motility of the right atrium specimens 1 0- 6 M. Therefore, These compounds were expected to be selective, have very little increase in heart rate, and have few side effects.
  • the compounds of the present invention can be tested for anti-obesity and anti-diabetic effects using transgenic mice according to the following procedure.
  • the epididymal white adipose tissue and the like can be obtained from this transgenic mouse according to the method of Rodbell (J. Biol. Chem., Vol. Collect the cells, use Krebs-Ringer buffer solution containing 4% serum albumin to bring the cell concentration to 2 x 10 5 cells Zm 1, and dispense 300 ⁇ l each into an Eppendorf tube. Add 3001 of the medium in which the compound is dissolved to this tube, and incubate at 37 with shaking for 1 hour. The stimulation is stopped by cooling on ice, and after centrifugation, the fat cells are removed with an aspirator, and the free glycerol is quantified with F-kit glycerol (Boehringer-Mannheim).
  • a test compound dissolved in 10% hydroxypropyl- ⁇ -cyclodextrin (Aldrich) is orally administered to a transgenic mouse fasted for 4 hours at a dose of 0.1 ml per 10 g body weight. Blood is collected from the fundus venous plexus at 0 minutes, 30 minutes, 1 hour, and 2 hours.
  • transgous mice fasted overnight were intraperitoneally administered with Ug / kg of dulose (manufactured by Wako Pure Chemical Industries) and dissolved in 10% hydroxypropyl-10-cyclodextrin (Aldrich).
  • the test subject's ligature was added at 0.
  • Blood is collected from the fundus venous plexus at 0, 30, 60, 1 and 2 hours.
  • the serum glucose concentration in the sample is measured by using a glucose test B test (Co) (Wako Pure Chemical Industries, Ltd.).
  • the lipolytic effect was determined by adding a test conjugate dissolved in 10% hydroxy pill-cyclodextrin (Aldrich) to a transgenic mouse fasted for 4 hours at a dose of 0.1 lm 1 per 10 g body weight. Administer orally. Blood is collected from the fundus venous plexus at 0 minutes, 30 minutes, 1 hour, and 2 hours. Using the serum obtained from the above sample, the amount of free fatty acids in the sample is measured using NEFA HA Test Co. (Wako Pure Chemical Industries, Ltd.). Thermogenesis is measured using the 0XYMAX system (Columbus) according to the method of Largis II (Drug Development Research, vol. 32, pp. 69-76, 1994).
  • This device calculates the heat production from the oxygen consumption and the carbon dioxide production by power source calculation. After administration of the drug, measure for 120 minutes (15 points), and convert the average value for the following 9 minutes (10 points) into body weight to obtain the heat production value.
  • body weight, blood glucose, and insulin levels can be followed over time, as in Largis et al. (Drug Development Research, vol. 32, pp. 69-76, 1994). Then, the weight of fat can be measured and slices can be prepared for microscopic observation.
  • the expression level of UCP-1 can be tested by the method of Nagase et al. (J. Clin. Invest., Vol. 97, pp. 2898-2904, 1996).
  • the compound of the present invention is a novel compound and has a strong activity of stimulating human; 83 adrenergic receptor. Therefore, it is useful as a medicament used for treatment and prevention of jS 3 adrenergic receptor-related diseases such as diabetic drugs, obesity drugs, hyperlipidemic drugs, and dysuria.

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Abstract

L'invention concerne des composés correspondant à la formule générale (I) ou leurs sels, utiles en tant que médicaments préventifs et thérapeutiques contre le diabète, l'obésité, l'hyperlipidémie, les maladies digestives, la dépression et les troubles urinaires. Dans la formule, R1 représente un groupe hydrogène, hydroxyl ou halogéno ; R2 représente un groupe méthylsulfonylamino, phénylsulfonylamino ou analogue ; X représente un groupe NH, oxygène, soufre ou méthylène ; Y représente un groupe NH, soufre ou analogue, Z représente un groupe HH (deux atomes d'hydrogène), oxygène ou analogue ; et G représente un groupe hydrogène, méthoxy, hydroxyl, méthylsulfonylamino, benzyloxy ou analogue.
PCT/JP2001/003576 2000-04-28 2001-04-25 Nouveaux composes tricycliques WO2001083452A1 (fr)

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DE10252650A1 (de) * 2002-11-11 2004-05-27 Grünenthal GmbH Cyclohexyl-Harnstoff-Derivate
WO2005108373A1 (fr) * 2004-04-30 2005-11-17 Boehringer Ingelheim International Gmbh Nouveaux beta-agonistes, leur procede de production et leur utilisation en tant que medicament
US7271190B2 (en) 2001-10-25 2007-09-18 Asahi Kasei Pharma Corporation Indazole compounds as β3 adrenoceptor agonist
WO2008051523A3 (fr) * 2006-10-23 2008-08-21 Univ Georgetown Thérapie anticancéreuse
US7754756B2 (en) 2005-10-28 2010-07-13 Boehringer Ingelheim International Gmbh Indol-containing beta-agonists, methods for the preparation thereof and their use as pharmaceutical compositions
US8008506B2 (en) 2008-10-09 2011-08-30 Asahi Kasei Pharma Corporation Indazole compounds
CN102382037A (zh) * 2010-09-03 2012-03-21 中国医学科学院药物研究所 苯丙酸类化合物及其制法和药物用途
US8304443B2 (en) 2008-10-09 2012-11-06 Asahi Kasei Pharma Corporation Indazole derivatives
US10457639B2 (en) 2008-08-15 2019-10-29 Georgetown University Fluorescent regulators of RASSF1A expression and human cancer cell proliferation
US11053255B2 (en) 2015-06-22 2021-07-06 Georgetown University Synthesis of mahanine and related compounds

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JP4662979B2 (ja) * 2004-04-30 2011-03-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規なβ−アゴニスト、その製造方法及びその薬物としての使用
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JP2007535512A (ja) * 2004-04-30 2007-12-06 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規なβ−アゴニスト、その製造方法及びその薬物としての使用
US7977334B2 (en) 2004-04-30 2011-07-12 Boehringer Ingelheim International Gmbh Beta-agonists, methods for the preparation thereof and their use as pharmaceutical compositions
US7754756B2 (en) 2005-10-28 2010-07-13 Boehringer Ingelheim International Gmbh Indol-containing beta-agonists, methods for the preparation thereof and their use as pharmaceutical compositions
WO2008051523A3 (fr) * 2006-10-23 2008-08-21 Univ Georgetown Thérapie anticancéreuse
US10457639B2 (en) 2008-08-15 2019-10-29 Georgetown University Fluorescent regulators of RASSF1A expression and human cancer cell proliferation
US8008506B2 (en) 2008-10-09 2011-08-30 Asahi Kasei Pharma Corporation Indazole compounds
US8304443B2 (en) 2008-10-09 2012-11-06 Asahi Kasei Pharma Corporation Indazole derivatives
CN102382037A (zh) * 2010-09-03 2012-03-21 中国医学科学院药物研究所 苯丙酸类化合物及其制法和药物用途
US11053255B2 (en) 2015-06-22 2021-07-06 Georgetown University Synthesis of mahanine and related compounds

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