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WO1998009967A1 - Derives de pyrrolocarbazole - Google Patents

Derives de pyrrolocarbazole Download PDF

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Publication number
WO1998009967A1
WO1998009967A1 PCT/JP1997/003153 JP9703153W WO9809967A1 WO 1998009967 A1 WO1998009967 A1 WO 1998009967A1 JP 9703153 W JP9703153 W JP 9703153W WO 9809967 A1 WO9809967 A1 WO 9809967A1
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WO
WIPO (PCT)
Prior art keywords
compound
mmo
substituted
nmr
fabms
Prior art date
Application number
PCT/JP1997/003153
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English (en)
Japanese (ja)
Inventor
Yoji Ino
Fumihiko Kanai
Satoru Murakami
Chikara Murakata
Tsutomu Akama
Yukimasa Shiotsu
Kinya Yamashita
Shiro Akinaga
Tatsuya Tamaoki
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
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Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU41361/97A priority Critical patent/AU4136197A/en
Publication of WO1998009967A1 publication Critical patent/WO1998009967A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel pyrrolocarbazolyl derivative or a pharmaceutically acceptable salt thereof useful for treating thrombocytopenia.
  • Platelet depletion due to various hematopoietic disorders causes severe symptoms such as bleeding tendency.
  • platelet transfusion is the dominant tool, but there is no sufficient platelet supply and there is no marketed drug that directly restores platelet loss.
  • other compounds that promote the production of platelets include proteinaceous hematopoietic factors such as inuichi-leukin (IL) -16, IL-11, c-Mpl ligand, or indolorubazol compounds, conagenin , 2-Viranone derivative, FK5
  • the pyrrolocarbazole derivative disclosed in Japanese Patent Application Laid-Open No. 2-142971 is characterized in that R ′ in the general formula (I) described below is hydrogen.
  • Examples 385 is a compound in which a substituted phenyl group is bonded to the 5-position of a pyrazole rubazole skeleton and RA is 2- (dimethylamino) ethyl. Is limited to Furthermore, in these cases: (1) when X 1 and Y 1 are carbonyl, R B is hydrogen, 9-hydroxy or 9-methoxy, R c is hydrogen, and R D is hydrogen or or 2,4-difluoro. (2) When X 1 is methylene and Y ′ is carbonyl, R B is hydrogen, R c is methyl, and R D is restricted to hydrogen.
  • Compound R A moiety is a lower alkyl or Ararukiru is only described compounds (D) and the compound (E) is known as a raw material of the compound (B) and the compound (A).
  • Compound (A) is known to have antitumor activity, but is not known to have a platelet production promoting effect. There is no report on the platelet production promoting effect of compound (B).
  • the present invention provides a compound represented by the general formula (I):
  • ring C is a benzene ring or cyclohexene ring
  • X and Y are the same or different and are carbonyl or methylene
  • R 1 is lower alkyl or aralkyl
  • R z is hydrogen
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R ie and R 11 are the same or different and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, halogen, nitro, substituted or unsubstituted lower alkanol
  • NR 12 R 13 wherein, R 12 and R ′ 3 are the same or different and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl
  • R 9 and R 11 is OR 21 (where R 21 is a higher alkanol, a substituted or unsubstituted heterocyclic group, a lower alkyl substituted with a substituted or unsubstituted heterocyclic group, CONHR 15 Wherein R 15 is as defined above, or tri-loweralkylsilyl; NHCONHR 16 (where R ' 6 is as defined above), substituted or unsubstituted lower alkyl, substituted or unsubstituted A substituted lower alkenyl or COR 17 wherein R 11 is as defined above; (2) X and Y are carbonyl, R 1 is benzyl, R 2 is hydrogen when R 3 and R 5 are simultaneously black opening, R 4, R 6, R 7, R 8,
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by the formula (I).
  • lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter. Represents t-butyl, pentyl, neopentyl, hexyl, etc.
  • Lower alkenyl represents a group having 2 to 6 carbon atoms, for example, vinyl, aryl, butenyl, pentenyl, hexenyl, pentenyl, hexenyl, and the like.
  • aralkyl moiety in aralkyl and aralkyloxycarbonyl represents a carbon number of 7 to 15, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.
  • Lower alkanoyl represents a straight or branched chain having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, vivaloyl, hexanoyl and the like.
  • the alkanol is the lower alkanol, and the carbon number? Represents up to 20 straight-chain or branched higher alkanols, for example, octanoyl, nanonoyl, palmitoyl, stearoyl and the like.
  • the aryl and the aryl portion of the aryl represent, for example, phenyl, naphthyl and the like.
  • the lower alkyl moiety in lower alkoxycarbonyl, lower alkoxy and tri-lower alkylsilyl has the same meaning as the lower alkyl, and the three lower alkyls in tri-lower alkyl may be the same or different.
  • the heterocyclic group represents an aliphatic heterocyclic group such as pyrrolidinyl, piberidinyl, morpholinyl and the like, and an aromatic heterocyclic group such as furyl, phenyl, pyrrolyl, pyridyl, imidazolyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl and quinazolinyl.
  • a heterocyclic group formed by sandwiching N is pyrrolidinyl, morpholino, thiomorpholino, N-methylbiperazinyl, birazolidinyl , Piperidino, piperazinyl, homopi Represents perazinyl, indolyl, isoindolyl, etc.
  • Halogen represents each atom of fluorine, chlorine, bromine or iodine.
  • Amino acids represent natural amino acids such as glycine, alanine, proline, glutamic acid, lysine, serine, cysteine, phenylalanine, and tyrosine.
  • Amino protecting groups for amino acids are those usually used in peptide synthesis, and include, for example, benzyloxycarbonyl, t-butoxycarbonyl and the like.
  • Substituents in the substituted lower alkyl may be the same or different and have 1 to 3 substituents, for example, hydroxy, halogen, oxo, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyloxy, aroyloxy, p-toluenesulfonyloxy , Methanesulfonyloxy, aryl, heterocyclic group, NR 27 R 28 (wherein R 27 and R 28 are the same or different and are hydrogen, lower alkyl, cycloalkyl, aralkyloxycarbonyl, or A heterocyclic group formed by sandwiching N (the heterocyclic group may contain an oxygen atom, a sulfur atom or another nitrogen atom) ⁇ , CONR 29 R 30 (wherein R 29 and R 3 ° Are the same or different and are hydrogen, hydroxy, aralkyl, lower alkyl, or a heterocyclic group formed together by N (The heterocyclic group may contain an oxygen atom,
  • the lower alkyl moiety in the lower alkyl, lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl described above.
  • the lower alkanoyl moiety in the lower alkanoyloxy has the same meaning as the lower alkanoyl.
  • the cycloalkyl has 3 to 6 carbon atoms, for example, cyclopropyl, Represents aryl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • the aryl moiety in the aryl and the aryloxy has the same meaning as the aryl
  • the aralkyl moiety in the aralkyl and the aralkyloxycarbonyl has the same meaning as the above aralkyl.
  • the heterocyclic group has the same meaning as the above heterocyclic group
  • the heterocyclic group formed by sandwiching N is a heterocyclic group formed by sandwiching N. Synonymous with ring group.
  • the substituent in the substituted lower alkenyl has the same meaning as the substituent in the substituted lower alkyl.
  • the substituents in the substituted aralkyl are the same or different and have 1 to 3 substituents, for example, halogen, nitro, amino, lower alkylamino, di-lower alkylamino and the like.
  • the lower alkyl moiety in the lower alkylamino or di-lower alkylamino has the same meaning as the lower alkyl.
  • the halogen has the same meaning as the halogen.
  • the substituted lower Arukanoiru are the same or different number of substituted 1 to 3, for example in a halogen or NR 27A R Z 8A (formula as defined above, R 27A and R 28A are the same meanings as defined above R 2 7 and R 28 , Etc.).
  • Substituents in the substituted heterocyclic group are the same or different and represent lower alkyl, aralkyl and the like having 1 to 3 substituents.
  • the lower alkyl has the same meaning as the lower alkyl
  • the aralkyl has the same meaning as the aralkyl.
  • the lower alkyl moiety has the same meaning as the lower alkyl
  • the heterocyclic group has the same meaning as the heterocyclic group
  • the substituted heterocyclic group has the same meaning. Has the same meaning as the above-mentioned substituted heterocyclic group.
  • the pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • acid addition salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate, glutamate, etc.
  • Organic acid salts such as sodium salts, potassium salts, etc .; alkaline earth metal salts, such as alkali metal salts, magnesium salts, calcium salts, etc .; aluminum salts, zinc salts, etc .; and ammonium salts.
  • Salts include salts such as ammonium and tetramethylammonium; organic amine addition salts include addition salts such as morpholine and piperidine; and amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.
  • Me, Et, n—Pr, n—Bu, t—Bu, Bn, Ac, Ph, Ts, Ms, TBS, Bz are methyl, ethyl, n-propyl, n-butyl, t-butyl, benzyl, acetyl, phenyl, p — Means toluenesulfonyl, methanesulfonyl, t-butyldimethylsilyl, benzoyl.
  • the ring C including a dotted line in the structural formula represents a benzene or cyclohexene ring.
  • the definition of each group in each step is synonymous with each of the above groups unless otherwise specified.
  • Compound (I) can be produced according to the following reaction steps.
  • Compound (Ia) in which ring C is a cyclohexene ring and X and Y are carbonyl in compound (I) can be produced by the following steps.
  • Compound (Ia) can be obtained by reacting compound (F) with compound (G) in a solvent such as xylene, toluene, dichlorobenzene or the like or without solvent.
  • Compound (G) is used in an amount of 1 to 20 equivalents based on compound (F). The reaction is carried out between 60 and 200 and ends between 1 minute and 48 hours.
  • Compound (F) may be substituted or unsubstituted benzaldehyde in a known manner [eg, Canadian Journal of Chemistry (Can. J. Cem.), 51, 792 (1973)].
  • a Wittig reaction with a substituted or unsubstituted halogenated indole-2-methyltriphenylphosphonium salt obtained in the same manner (the halogen is as defined above for Ha1) or by a known method [for example, ⁇ Substituted or unsubstituted 2-fluoro-2-carboxaldehyde and substituted or unsubstituted compounds obtained according to Journal of Organic Chemistry (j org. Chem.), 52, 104 (1987)].
  • Compound (Ic) in which ring C is a benzene ring in compound (I) can be produced from compound (Ib) in which ring C is a cyclohexene ring by the following steps.
  • the compound (lb) obtained by the above-mentioned production method 1 or the following production method 4 is converted to 2,3-dichloro-1,5,6 in a single or mixed solvent such as methylene chloride, ethyl acetate (AcOEt), toluene and dioxane.
  • Compound (Ic) can be obtained by reacting with a dehydrogenating agent such as -dicyanor-1,4-benzoquinone (DDQ), 10% PdZC.
  • the dehydrogenating agent is used in an amount of 2 to 10 equivalents based on compound (lb).
  • the reaction is carried out at a temperature of 120 to 180 ° C. and is completed in 1 minute to 24 hours.
  • the compound (Ie) having a functional group at the R 3 , R 4 , R 5 , R fc , R *, R fl , R 9 , R 10 or R ′ 1 site is represented by R 3 , R 4, R 5, R , R 7, R B, R 9 , or compounds having other functional groups in R 11 sites, from (I d), can be prepared by the following Symbol steps.
  • R 7 & R 8A > 10a Rl) a ⁇ 3b 4 b 5b 6 b 7b 8b R
  • a and R ' la are at least one carboxy, and at least one of R 3b , R 4b , R Sb , R 6b , R 7b , R 8b , R 9b , R , 0 and R lb is CONR 18 R ' 9 (wherein, R ie and R 19 are as defined above) or C ⁇ SR 2C (wherein, R 2C is as defined above)
  • Compound (Id) can be obtained by converting thionyl chloride, phosphoryl chloride, pentachloride in the presence or absence of a base such as triethylamine, pyridine, or the like, alone or in a mixed solvent such as methylene chloride, tetrahydrofuran (THF) or a solvent. Reaction with a halogenating agent such as phosphorus or phosphorus trichloride, and then in a solvent such as methylene chloride, THF, or dimethylformamide (DMF) alone or in the presence or absence of a salt such as triethylamine or pyridine.
  • a base such as triethylamine, pyridine, or the like
  • Compound (Ie) can be obtained by reacting with compound (II) or compound (III) represented by
  • the base is used in an amount of 0 to 100 equivalents
  • the halogenating agent is used in an amount of 1 to 200 equivalents or a solvent
  • the compound (II) or the compound (III) is used in an amount of 1 to 100 equivalents, respectively.
  • the reactions are each performed at between 80 and 120 and are completed within 1 minute to 24 hours.
  • R 3a, R 4a, R 5a , R 6a, R 7a, R 8a, R, a is one even R IOa and R l la is no less carboxy
  • R 3b, R 4b, R 5b , R tb, R 7b, R 8b, R 9b, R, ob and R l lb is at least one of C_ ⁇ _NR 18 R 19 (wherein, R '8 and R 19 are the same as defined above) or COS R 2 ° (wherein R 2C is as defined above) ⁇
  • Compound (Id) is used alone or in a mixed solvent such as THF, DMF, methylene chloride, etc., in 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazol hydrate (HOB t), p-nitrophenol 1- (3-dimethylaminopropyl) _3-ethylcarbodiimide hydrochloride (WS C ⁇ HC 1), N, N'-dicyclohexylcarpoimimid in the presence or absence of additives such as triethylamine and triethylamine
  • DMAP 4-dimethylaminopyridine
  • HAB t 1-hydroxybenzotriazol hydrate
  • WS C ⁇ HC 1 4-dimethylaminopyridine
  • HOB t 1-hydroxybenzotriazol hydrate
  • the additive is used in an amount of 0 to 10 equivalents to the compound (Id), and the condensing agent and the compound (II) or the compound (III) are each used in an amount of 1 to 50 equivalents.
  • the reaction is carried out at —80 to 200: and is completed in 5 minutes to 120 hours.
  • R 3a, R 4a, R 5a, R fca, R 7 a, R 8a, R, a, R, 0a and R 'lower of la was one is lower alk force Noiru or hydroxy-substituted even without least Alkyl, wherein R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R , b , R 10b and R lb are at least one hydroxy-substituted lower alkyl or lower alkyl)
  • Compound (Id) is reacted with a reducing agent alone or in a mixture of THF, dioxane, methylene chloride, chloroform, DMF, methanol, water, trifluoroacetic acid, hydrochloric acid, acetic acid, etc., or 10% PdZC Compound (Ie) can be obtained by performing catalytic reduction in the presence of such a catalyst.
  • the reducing agent sodium borohydride, sodium cyanoborohydride, triethylsilane and the like are used.
  • the reducing agent is 1 to 10
  • the reduction catalyst is used 10 to 100% (weight).
  • the reaction is — 80-12
  • R 3a , R 4a , R 5a , R ba , R 7a .R ea , R 9a , R 10a and R la are at least one formyl or a lower alkyl substituted with formyl
  • R 3b , R 4b , R 5b , R 6b , R 7b , R eb , R 9b , R , 0 and R'lb are at least one NR 2 a R z8a (wherein, R 27a and R 28a are groups other than the definition of R 27 and R 28 except for aralkyloxycarbonyl) are substituted lower alkyls ⁇
  • Compound (Id) is treated with a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride in a solvent alone or in a mixed solvent such as chloroform, THF, methanol, acetonitrile, water, acetic acid and hydrochloric acid.
  • a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride in a solvent alone or in a mixed solvent such as chloroform, THF, methanol, acetonitrile, water, acetic acid and hydrochloric acid.
  • R z7a and R 28a are as defined above
  • Compound (Ie) can be obtained by performing a reductive amination reaction using compound (IV) represented by
  • the reducing agent and the compound (IV) are each used in an amount of 1 to 200 equivalents relative to the compound (Id).
  • the reaction is carried out at a temperature of 120 to 100 ° C. and is completed in 5 minutes to 24 hours.
  • a base and a substituted or unsubstituted halogenated lower alkyltriphenylphosphonium salt (the halogen is as defined above for Ha 1) or a substituted or unsubstituted lower alkyl
  • the halogen is as defined above for Ha 1
  • the phase transfer catalyst is used in an amount of 0 to 1 equivalent.
  • the reaction is performed at —80 to 120 and ends in 5 minutes to 24 hours.
  • R 3a, R 4a, R Sa , R 6a, R 7a, R 8a, R, R 10a and R '' a lower alkenyl one substituted or unsubstituted even without less, R 3b, At least one of R 4b , R Sb , R 6b , R 7b , R Bb , R 9b , R , 0 and R llb is a substituted or unsubstituted lower alkyl
  • the reduction catalyst is used in an amount of 10 to 500% (by weight) and the base is used in an amount of 0 to 10 equivalents.
  • the reaction is carried out at a temperature of 20 to 120 ° C and is completed in 5 minutes to 24 hours.
  • R 3a, R 4a, R 5a, R ba, R 7a, a R 8a, R 9 a, R , 0a and R l la one is lower alkoxycarbonyl Biel even without less, R 3b, R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R , 0b and R ' lb are at least one of formylmethyl.
  • Compound (Id) is dissolved in a solvent such as acetonitrile in a solvent such as acetonitrile.
  • Compound (Ie) can be obtained by reacting with trimethylsilane in the presence of silane or sodium iodide in the presence of trimethylsilane.
  • Iodotrimethylsilane or sodium iodide and chlorotrimethylsilane are each used in an amount of 1 to 10 equivalents to the compound (Id).
  • the reaction is carried out between 180 and 100 and ends in 5 minutes to 24 hours.
  • R 3a , R a , R 5a , R fca , R 7a , R 8a , R 9a , R , 0a and R ′ la are at least one hydrogen
  • R 3b , R 4b , R 5b R 6b , R ⁇ R 8b , R 9b , R ′ ° b and R l lb are methyl substituted with at least one of NR 27a R 28a , wherein R 27a and R 28a are as defined above. is there ⁇
  • Compound (Ie) can be obtained by reacting with compound (V) represented by
  • Formalin and compound (IV) or compound (V) are each used in an amount of 1 to 100 equivalents based on compound (Id). The reaction is performed at 0-180 and ends in 5 minutes to 24 hours.
  • R 3a is R 4a, R 5a, R fca , R 7a, R 8a, R 9a, R, 0a and R l la one hydroxy or carboxy even without less, R 3b, R 4b, At least one of R 5b , R 6b , R, b , R 8 ⁇ R 9 R 10b and R ' lb is OR' 4a (where R
  • 4a is substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, heteroaralkyl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclic group substituted lower alkyl) or lower alkoxycarbonyl is there ⁇
  • R ′ ′′ and Ha 1 are as defined above, R 36 is T s or M s, and R 37 is lower alkyl.
  • the compound (Ie) can be obtained by reacting with the compound (VI) or the compound (VIII) represented by the following or with the compound (VIII).
  • the compound (VI) or the compound (VII), or the compound (VIII) and the base are each used in an amount of 1 to 20 equivalents based on the compound (Id).
  • the reaction is carried out at —20-120 ⁇ and ends in 5 minutes-24 hours.
  • Process 3 10 (Wherein, at least one of R 3a , R 4a , R 5a , ba .R 7a , R Ba , R , a , R 103 and R lla is at least one of NR 31 R 3Z (where R 3 ′ and R 3Z is the same as defined above, wherein R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R ′ ° b and R Mb are at least one of NR 31 R 32 R 33 H a 1 (wherein, R 3 ′, R 32 , R 33 and Ha 1 have the same meanings as defined above).
  • the compound (Id) is DMF, In a solvent such as form, the following formula
  • the compound (IX) is used in an amount of 1 to 20 equivalents based on the compound (Id).
  • the reaction is carried out between 0 and 180 and ends in 5 minutes to 24 hours.
  • R 3a, R 4a, R 5a, R 6a, R 7a, R ea, R 9a, R, 0a and R l la One is NR 3 even without least 'R 3Z R 33 H a 1 ( formula Wherein R 3 R 3Z , R 33 and HaI are the same as defined above, and R 3b , R 4 , R Sb , R 6b , R 7b , R 8b , R 9b , R 10b and R l lb are at least one lower alkanoyloxy-substituted lower alkyl ⁇
  • the compound (XI) is used in an amount of 1 to 100 equivalents based on the compound (Id).
  • the reaction is carried out between 0 and 200 and is completed between 5 minutes and 48 hours.
  • R 3a, R 4a, R 5a, in R 6a, R 7a, R ea , R 9a, R, 0a and R l la is even no less one is ⁇ _R 14b (wherein, R 14b is substituted or R 3b , R 4b , R 5b , R 6b , R 7 ⁇ R 8b , R 9b , R 10b and R ′ lb, which are unsubstituted lower alkanoyl) or lower alkanoyloxy-substituted lower alkyl. Is at least one hydroxy or hydroxy-substituted lower alkyl.
  • the compound (Ie) can be obtained by reacting the compound (Id) with an acid or a base in a single or mixed solvent such as methylene chloride, THF, methanol, dioxane, and water.
  • a single or mixed solvent such as methylene chloride, THF, methanol, dioxane, and water.
  • R 3a, R 4a, R 5a, R 6a, R 7a, R 8a, R, a, R, 0a and R l la One is NR 3l even without least R 32 R 33 Ha 1 (wherein , R 31 , R 32 , R 33 and H a1 have the same meanings as defined above, or a lower alkyl or halogen substituted with a halogen (the halogen has the same definition as the above Ha 1); And R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R , 0b and R ′′ b are at least one of lower alkyl or hydrogen.
  • Compound (Ie) can be obtained from compound (Id) by the same steps as in Steps 3-6.
  • R 3a is R 4a, R Sa, R fca , R 7a, R ea, R 9a, R 10a and R '' a is the one even without least Amino or hydroxy, R 3b, R 4b, At least one of R 5b , R 6 R 7b , R 8b , R 9b , R , 0b and R ′ lb is NHCONHR 16 (wherein R ′ 6 is as defined above) or OCONHR ′ 5 (wherein R 15 is as defined above.)
  • Compound (Id) can be prepared by reacting compound (Id) alone or in a mixed solvent such as methylene chloride, DMF or THF in the presence or absence of a base such as triethylamine or pyridine, with the following formula R 38 NCO (XII)
  • R 3B has the same meaning as R 1S or R lb )
  • Compound (Ie) can be obtained by reacting with compound (XII) represented by
  • R 3a, R 4a, R sa, R fca, in R 7a, R ea, R, R, 0a and R l la is even no less one is lower alkoxycarbonyl or OR 1 "(wherein, R 1 "Is lower alkoxycarbonyl-substituted lower alkyl), and R 3b , R 4b , R 5b , R 6b , R 7b , R eb , R 9b , R , ob and R lb are at least one of carboxy or ⁇ lb.
  • R 14d wherein R ′ 4d is carboxy-substituted lower alkyl.
  • Compound (Ie) can be obtained by reacting compound (Id) with an acid such as hydrochloric acid or sulfuric acid in a single or mixed solvent such as methylene chloride, dioxane and THF.
  • an acid such as hydrochloric acid or sulfuric acid
  • a single or mixed solvent such as methylene chloride, dioxane and THF.
  • the acid is used in 0.1 to 100 equivalents relative to compound (Id).
  • the reaction is carried out at 0 to 120 and ends in 5 minutes to 120 hours.
  • R 3a, R 4a, R 5a , R 6a, R 7a, R ea, R, a, R is one even oa and R l la is no less hydrogen
  • R 3b, R ⁇ R Sb , R 6b , R 7b , R 8b , R 9 R ′ ° b and R 1 are at least one octalogene (the halogen is as defined above for Ha 1) ⁇
  • Compound (Id) is used alone or in a mixed solvent such as chloroform, methylene chloride, methanol, and THF, in the presence or absence of a base such as t-butylamine, in the presence or absence of sulfuryl chloride, tetra-n-butylammonium salt.
  • the compound (Ie) can be obtained by reacting with an octalogizing agent such as a rib mouth mid, N-bromosuccinimide, ⁇ '-succinimide and the like.
  • the base is used in an amount of 0 to 10 equivalents, and the halogenating agent is used in an amount of 1 to 10 equivalents based on compound (Id). The reaction is performed at —20 to 100 and ends in 5 minutes to 24 hours.
  • Compound (Ie) can be obtained by reacting compound (Id) with a reducing agent such as borane Z dimethyl sulfide complex or borane ZT HF complex in a solvent such as THF.
  • a reducing agent such as borane Z dimethyl sulfide complex or borane ZT HF complex
  • a solvent such as THF.
  • the reducing agent is used in an amount of 0.3 to 50 equivalents based on compound (Id).
  • the reaction is performed at between 20 and 10 Ot: and is completed in 5 minutes to 24 hours.
  • R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R ′ ° a and R lla is OR 14d (where R 14d is as defined above)
  • At least one of R 3b , R 4b , R Sb , R 6b , R 7b , R 8b , R, R 10b and R llb is OR , 4e (wherein, R 14e is as defined above) Is) is ⁇
  • the compound (Id) is reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride in a solvent alone or in a mixed solvent such as methylene chloride and THF, and then dioxane and methylene chloride.
  • a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride in a solvent alone or in a mixed solvent such as methylene chloride and THF, and then dioxane and methylene chloride.
  • Compound (Ie) can be obtained by reacting with a reducing agent such as sodium borohydride alone or in a mixed solvent such as methanol and methanol.
  • the compound (Id) is used in an amount of 1 to 200 equivalents of the halogenating agent or as a solvent, and 1 to 100 equivalents of the reducing agent. Each reaction is carried out at a temperature of 120 to 120 ° C and is completed in 5 minutes to 24 hours. Process 3-19
  • R 3a , R a , R 5a , R 6a , R 7a , R 8a , R , a , R , 0a and R la are at least one hydroxy-substituted lower alkyl, R 3b , R 4b, R 5, R 6b , R 7b, R 8b, R,, R 10b and R '' b is at least one is black port substituted lower alkyl)
  • the halogenating agent is used in an amount of 1 to 200 equivalents or a solvent with respect to the compound (Id).
  • the reaction is carried out at —20 to 120 and ends in 5 minutes to 24 hours.
  • R 3a, R 4a, R 5a , R 6a, R 7a, R 8a, R 9a is one even R IOa and R l la is no less hydroxy
  • R 3b, R 4b, R 5b, R 6b , R 7b , R eb , R 9b , R , 0b and R lb are at least one of tri-lower-alkylsilyloxy
  • Compound (Id) in a solvent such as DMF, imidazole, triethylamine, etc.
  • the base and the tri-lower alkylsilane are each used in an amount of 1 to 20 equivalents.
  • the reaction is carried out in a period of 20-100, and is completed in 5 minutes to 24 hours.
  • R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R IOa and R ′ la is OR 14f (where R 14i is aralkyl, N— R 3b , R 4b , R Sb , R 6b , R 7b , R Bb , R 9b , R , 0b and R ′ lb , which are lower alkyl substituted with an aralkyl heterocyclic group or an N-aralkyl heterocyclic group.
  • OR 149 where is hydrogen, a heterocyclic group or a heteroalkyl-substituted lower alkyl.
  • Compound (Ie) can be obtained from compound (Id) by the same steps as in Steps 3-6.
  • a and R l la is one hydroxy even without less
  • R 3b, R 4b, R 5b, R 6b, R 7b, R 8b, R 9b, R, ob and R 'lb is at least one of OR 14h ( Wherein R 14h is a substituted or unsubstituted lower or higher alkanoyl)
  • the compound (Id) can be prepared by adding the compound (Id) in a solvent such as THF, DMF, or methylene chloride, alone or in a mixed solvent, in the presence or absence of DMAP, in the presence of a base such as pyridine, triethylamine, or the like.
  • Compound (Ie) can be obtained by reacting with compound (XIII) or compound (XIV) represented by
  • the base and the compound (XII) or the compound (XIV) are each used in an amount of 1 to 50 equivalents, and DMAP is used in an amount of 0 to 1 equivalent.
  • the reaction is carried out in 20 to 120 hours and is completed in 5 minutes to 24 hours.
  • Compound (Ie) can be obtained by reacting compound (Id) with an oxidizing agent such as manganese dioxide in a single or mixed solvent such as methylene chloride, toluene and DMF.
  • an oxidizing agent such as manganese dioxide in a single or mixed solvent such as methylene chloride, toluene and DMF.
  • the oxidizing agent is used in an amount of 100 to 2000% (by weight) based on the compound (Id).
  • the reaction is carried out at about 20 to 12 O: and is completed in 30 minutes to 120 hours.
  • R 3a , R 4a , R sa , R 6a , R 7a , R 8a , R 9a , R , 0a and R ′ la are at least one carboxy
  • R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R , 0b and R lb are at least one lower alkoxycarbonyl
  • the acid is used in an amount of 0.01 to 1 equivalent, and the lower alkyl alcohol is used in an amount of 1 to 100 equivalents or a solvent, based on the compound (Id).
  • the reaction is carried out between 0 and 120 and ends in between 5 minutes and 120 hours.
  • R 3a , R 4a , R 5a , R fca , R 7a , R ea , R 9a , R ′ ° a and R lla are at least one of carboxy or hydroxy, and R 3b , R 4b , R Sb , R 6b , R 7b , R 8b , R q R ' 0 and R llb are at least one methoxycarbonyl or methoxy)
  • the compound (Id) is reacted with diazomethane in a single or mixed solvent such as methylene chloride, methanol, acetate nitrile, and ether, or in the presence or absence of a base such as diisopropylethylamine in the presence or absence of (trimethylsilyl) diazometa.
  • a single or mixed solvent such as methylene chloride, methanol, acetate nitrile, and ether
  • a base such as diisopropylethylamine in the presence or absence of (trimethylsilyl) diazometa.
  • Compound (Ie) can be obtained by reacting with
  • Diazomethane or (trimethylsilyl) diazomethane is used in an amount of 1 to 50 equivalents and the base is used in an amount of 0 to 50 equivalents based on compound (Id).
  • the reaction is carried out between 120 and 80 and ends between 1 minute and 24 hours.
  • R 3a, R 4a, R 5a, in R 6a, R 7a, R 8a , R 9a, R, 0a and R l la one is OR 14e even without least is (wherein, R 14e is defined as above a is a), R 3b, R 4 b , R 5b, in R fcb, R ⁇ R 8b, R 9b, R, 0b and R '' b is at least one of ⁇ R "1 (wherein, R 14i is Methanesulfonyloxy, p-toluenesulfonyloxy or cycloalkyl-substituted lower alkyl) ⁇
  • R 3a R 4a R 5a R 6a R 7a R ea R 9a R 103 and R l la has one even without least OR L4i (wherein, R L4i is as defined above), R 3b R 4b R Sb R fcb R 7b R 8b R 9b R 10b and at least one of R ' lb are O R' 4j (wherein, R 14j is NR 27a R 28a (wherein, R 27a and R 28a are as defined above) Is lower alkyl substituted with ⁇ )
  • Compound (Id) is reacted with compound (IV) in the presence or absence of sodium iodide or potassium iodide, alone or in a mixed solvent of DMF, methylene chloride, etc., or DMF, methylene chloride, etc.
  • sodium iodide or potassium iodide in a single or mixed solvent of the above, and then reacting with compound (IV) alone or in a mixed solvent of DMF, methylene chloride, etc. to obtain compound (I e) be able to.
  • R 3a R 4a R Sa R fca R 7a R 8a R 9a, R, 0a and R l la is one nitro even without less
  • R 3b R 4b R 5b R tb R 7b R eb RR 10b and R '' b is (wherein, R at least one of NR l2a R, 3a '2a and R 13 a are the same or different, hydrogen, a substituted or unsubstituted lower alkyl) ⁇
  • the compound (Id) is subjected to catalytic reduction using a catalyst such as 10% Pd ZC in a single or mixed solvent such as DMF or ethanol, or under the catalytic reduction, to perform a reductive amination reaction using the corresponding aldehyde.
  • a catalyst such as 10% Pd ZC in a single or mixed solvent such as DMF or ethanol
  • a reductive amination reaction using the corresponding aldehyde.
  • the reduction catalyst is used at 100% by weight, and the aldehyde is used at 1,200 equivalents.
  • the reaction takes place between 20 and 120 minutes, 5 minutes to 48 hours Ends in between.
  • R 3a is R 4a, R 5a, R 6a , R 7a, R ea, R 9a, R, oa and R l la has one even without least formyl
  • R 3b, R 4b, R 5b , R 6b , R 7b , R Bb , R 9b , R 10b and R llb are at least one carboxy
  • Compound (Ie) can be obtained by reacting with an oxidizing agent such as pentafluorobenzene.
  • the oxidizing agent is used in an amount of 1 to 100 equivalents based on compound (Id).
  • the reaction is carried out between 120 and 100 and ends in 5 minutes to 24 hours.
  • R 3a, R 4a, in R 5a, R 6a, R 7a , R 8a, R 9a, R, 0a and R l la has one even without least OR "k (wherein, R '4k is pyrrolidinyl R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R , ob and R ′ lb are at least one of the following: piperidinyl or pyridinyl or piperidinyl-substituted lower alkyl.
  • R ' 4m is N-lower alkylpyridinyl, N-lower alkylpiperidinyl or N-lower alkylpyridinyl or N-lower alkylpiperidinyl-substituted lower alkyl
  • Compound (Id) was treated with sodium cyanoborohydride, sodium triacetoxyborohydride, hydrogen, in a solvent alone or in a mixed solvent such as chloroform, THF, methanol, acetate, water, acetic acid and hydrochloric acid.
  • the compound (Ie) can be obtained by performing a reductive amination reaction using an aldehyde in the presence of a reducing agent such as sodium borohydride.
  • the reducing agent and the aldehyde are each used in an amount of 1 to 200 equivalents based on compound (Id).
  • the reaction is performed at —20-10 Ot: and ends in 5 minutes to 24 hours.
  • R 3a , R 4a , R 5a , R fca , R 7a , R 8a , R 9a , R 10a and R lla are small At least one is COS R 20 (where R z is as defined above), and R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b and R l lb is at least one of the holmills ⁇
  • the reduction catalyst is used in an amount of 10 to 500% (by weight), and triethylsilane is used in an amount of 1 to 20 equivalents.
  • the reaction is carried out at -20 to 120, and is completed in 5 minutes to 24 hours.
  • the compound (Ig) in which at least one of X and Y is methylene can be produced from the compound (If) in which at least one of X and Y is carbonyl by the following steps. it can.
  • R ′, R 2 , R 3 , R 4 , R s , R 6 , R 7 , R 8 , R 9 , R ′ ° and R 1 ′ are as defined above, X a and Y a is at least one carbonyl, X b and Y b are at least one methylene)
  • the compound (If) is reacted with a reducing agent such as borane-dimethylsulfide complex or borane.THF complex in a solvent such as THF, and then in a solvent such as hydrochloric acid, sulfuric acid or the like alone or in a mixed solvent of THF, dioxane, water or the like.
  • a reducing agent such as borane-dimethylsulfide complex or borane.THF complex in a solvent such as THF, and then in a solvent such as hydrochloric acid, sulfuric acid or the like alone or in a mixed solvent of THF, dioxane, water or the like.
  • the compound (Ig) can be obtained by reacting with an acid.
  • the reducing agent is used in an amount of 0.3 to: L00 equivalent, and the acid is used in an amount of 0.1 to 100 equivalents.
  • Each reaction is carried out at —80 to 12 O: and is completed in 5 minutes to 24 hours.
  • the compound (I) having a desired functional group at a desired position can be obtained by appropriately combining and carrying out the above methods.
  • the isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like.
  • the intermediate can be subjected to the next reaction without purification.
  • the compound (I) may exist as isomers such as positional isomers, geometric isomers or optical isomers, but the possible isomers and mixtures of the isomers in any ratio are also included in the present invention.
  • the compound (I) When it is desired to obtain a salt of compound (I), the compound (I) may be purified as it is when the salt is obtained, or may be dissolved or suspended in an appropriate solvent when obtained in a free form, An acid or a base may be added to form a salt.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and such adducts are also included in the present invention.
  • Specific examples of the compound (I) are shown in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10.
  • (E: Z) and (diastereomeric ratio) represent the geometric isomer ratio and diastereomeric ratio, respectively.
  • Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms depending on its pharmacological action and the purpose of administration.
  • the pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in a unit dosage form suitable for oral or parenteral administration such as ointment or injection.
  • excipients such as lactose, glucose, sucrose, mannitol, and methylcellulose; starch, sodium alginate, calcium carboxymethylcellulose, disintegrants such as crystalline cellulose, magnesium stearate, talc Lubricants such as gelatin, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, etc., and surfactants such as sucrose fatty acid ester, sorbitol fatty acid ester, etc. in accordance with ordinary methods. Good. Tablets containing 1 to 20 mg of active ingredient per tablet are preferred.
  • excipients such as lactose and sucrose, disintegrants such as starch, and binders such as gelatin may be used in a conventional manner.
  • an excipient such as lactose and mannitol may be used in a conventional manner.
  • capsules for example, gelatin, water, sucrose, acacia, sorbitol, glycerin, crystalline cellulose, magnesium stearate, talc, and the like may be used in a conventional manner.
  • Capsules containing 1-20 mg of active ingredient per capsule are preferred.
  • sugars such as sucrose, water, ethanol and the like may be used in a conventional manner.
  • ointment bases such as petrolatum, liquid paraffin, lanolin, and macgol
  • emulsifiers such as sodium lauryl lactate, benzalkonidum chloride, sorbitan monofatty acid ester, sodium carboxymethylcellulose, and gum arabic are used in the usual manner. May be used.
  • plants such as water, saline, olive oil, peanut oil, etc.
  • Oils such as ethyl oleate ⁇ propylene glycol, solubilizers such as sodium benzoate-sodium salicylate ⁇ urethane, salt tonicity agents such as sodium chloride, phenol, cresol ⁇ p-hydroxybenzoate ⁇ chlorobutanol And the like, and antioxidants such as ascorbic acid and sodium pyrosulfite may be used in a conventional manner.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered orally, or as an ointment or parenterally as an injection. Usually, it is preferable to administer 0.1 to 50 mg / kg per day.
  • Bone marrow cells were obtained from a cut piece of a femur and a tibia using an injector containing an IMDM (430-2200EA manufactured by Gibco) solution, and the marrow cells were blown into a test tube. After standing for 5 minutes, the supernatant was obtained using a pit.
  • IMDM 430-2200EA manufactured by Gibco
  • Bone marrow cells (50000 cells), bovine serum albumin (2%: Sigma A4508), transferrin (600 g / ml: Boehringer Mannheim 652202), IL-3 (100 U / ml), cholesterol (16 g / ml: A test compound of each type was added to a reaction composition comprising 036-0641) and agar (0.6%: 0142-02 manufactured by Difco), and lm 1 was added to a 35 ⁇ dish manufactured by Lux. placed at 3 7, 5% C0 2, 9 5% or more humidity conditions, and cultured for 7 days. A control obtained by adding IL-3 alone to bone marrow cells was used as a control. After completion of the culture, the agar was dried using a filter paper (100-55, manufactured by Whatman), fixed with 2.5% glutaraldehyde, and then stained with acetylcholinesterase (ACHE staining).
  • ACHE staining acetylcholinesterase
  • ACHE staining was performed by the following method.
  • ACHE staining method Acetylthiocholine iodide 0.67 mg / ml sodium citrate 2.94 mg / ml copper sulfate (U) 7.5 mg / ml and potassium ferricyanide 1.65 mg / ml are added to the sample, and the solution is added at room temperature in the dark for 4 to 4 days. Left for 6 hours. The number of colonies per dish was calculated with a microscope using 4 or more megakaryocyte cells stained red-brown as one colony, and the results are shown in Table 11 as relative values to the control. Table 11 shows the effect of compound (I) on megakaryocyte colony formation.
  • BAL BZc mice male, 7 weeks old, 4 mice / group were irradiated with 300 X-rays on Day 1 and the test compound was subcutaneously administered once daily from Day 1 for 5 days.
  • the control group received only X-ray irradiation.
  • blood was collected from the fundus vein of each individual, and the platelet count was measured using a microcell counter (F800, manufactured by Toa Medical Electronics Co., Ltd.).
  • the effect of the test compound is defined as the increase rate (%), as shown in the following formula, in which the platelet count of mice receiving the test compound at Day 11 is divided by the platelet count of the mice not receiving the test compound. expressed.
  • BALBZc mice male, 7 weeks old, 4 mice per group
  • mice were irradiated with 300 X-rays, and the test compounds shown in Table 12 were subcutaneously administered at the doses shown in Table 12 and 24 hours later. Life or death was determined.
  • brine, CHC 1 3> Me OH represents their respective saturated brine, black hole Holm, methanol.
  • Step 1 of Example 1 iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 2.40 g (4.5 Ommo 1), 5-chloro-1,3 0.88 g (4.09 mmo 1) of methyl formylsalicylate, 1.24 g (9.0 Ommo 1) of carbonated lime and 18—crown—6, 0.10 g (0.41 mmo 1) ), 0.85 g (60%) of 2- [2- (5-chloro-2-hydroxy-3-methoxycarbonylphenyl) vinyl ⁇ 1-methylindole was obtained.
  • benzyl alcohol derivative 1 was obtained from 1.68 g (10.1 mmo 1) of methyl 4-methylsalicylate and 763 mg (20.1 mmo 1) of lithium aluminum hydride. 40 g (quantitative) were obtained.
  • Step 1 of Example 1 0.35 g (2.57 mmo 1) of 4-methyl salicylaldehyde, iodide (1-methylindole-1-yl) methyl (triphenyl) phosphonium 1. 3 9 g (2.6 Ommo 1) and potassium carbonate 1.6 From 2 g (11.73 mmo 1), 580 mg (82%) of 2- [2- (2-hydroxy-14-methylphenyl) vinyl] -1-monomethylindole was obtained.
  • step 2 of Example 1 2- [2- (2-acetoxy-4-methylphenyl) vinyl] 111-methylindole 84 mg (0.27 mmo 1) and N-methylmaleimide 91 mg ( From 0.82 mmo 1), the compound 5, 73 mg (64%) was obtained.
  • Step 6 of Example 3 1.39 g (10.Ommo 1) of 4-hydroxysalicylaldehyde, 1.53 g (1 1.Ommo 1) of potassium carbonate and benzyl chloride 1. From 31 mi (1 1. Ommo 1), 674-mg (29%) of 4-benzyloxysalicylaldehyde was obtained.
  • Step 1 of Example 1 4 O-benzyloxysalicylaldehyde 63 Omg (2.76 mmo 1), iodide (1-methylindole-2-yl) methyl (tririfenyl) phosphonium 1.55 g (2.91 mmo 1) and 1.9 g (13.8 mmo 1) of carbonic acid rim, 2— [2— (4-benzyloxy-2-hydroxyphenyl) vinyl] 1-1— 0.68 g (66%) of methylindole was obtained.
  • Step 3 of Example 3 2.43 g (12.5 mmo 1) of the acetyl derivative, 5.58 g (31.3 mmo 1) of N-bromosuccinic acid imide and benzoperoxide 5.48 g (quantitative) of the dibromomethyl compound was obtained from 305 mg (0.88 mmo 1) of the compound.
  • Step 1 of Example 1 1.38 g (8.32 mmo 1) of 2-hydroxy-4-nitrobenzaldehyde, iodide (1-methylindole-1-yl) methyl (triphenyl) From phosphonium 4.04 g (7.58 mmo 1) and potassium carbonate 5.26 g (38.1 mmo 1), 2- [2- (2-hydroxy-14-nitrophenyl) vinyl] 1-1 One methyl indole was obtained.
  • Step 1 of Example 1 13.3 g (73.6 mmo 1) of 3-formyl-methyl 4-hydroxybenzoate, iodide (1-methylindole-1-yl) methyl (triphenyl) Phosphonium 30.1 g (56.4 mmo 1), Carbonated rim 10.2 g (73.7 mmo 1) and 18—crown 1.6, 1.53 g
  • Step 1 of Example 1 (1 monomethylindole-2-yl) methyl (triphenyl) phosphonium 1.76 g (3.3 Ommo 1), 2-hydroxy-6-methoxy From 0.46 g (3.0 mmo 1) of benzaldehyde, 0.91 g (6.6 Ommo 1) of potassium carbonate and 18-crown 6, 0.07 g (0.3 Ommo 1) There was obtained 0.60 g (72%) of 2- [2- (2-hydroxy-6-methoxyphenyl) vinyl] -111-methylindole.
  • Resorcinol 11.0 g (10 Ommo 1) was dissolved in methylene chloride 300 m 1, and 3,4-dihydro-2H-pyran 27 ml (30 Ommo 1) and d 1-10 Add 0.70 g (2.99 mmo 1) of camphorsulfonic acid and add at room temperature. Stir for 1 hour. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extracted with CHC 1 3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / AcOEt 9/1) to obtain 27.1 g (97%) of a ditetrahydropyrael compound.
  • Step 1 of Example 1 iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 5.86 g (1 1.Ommo 1), 2-hydroxy-6- From benzyloxybenzaldehyde 2.28 g (10. Ommo 1), potassium carbonate 1.66 g (1 2. Ommo 1) and 18—crown 1.6, 0.26 g (1.0 Ommo 1) 1.48 g (42%) of 2- [2- (6-benzyloxy-2-hydroxyphenyl) vinyl] -111-methylindole were obtained.
  • Example 11 According to step 1 of 1, 476 mg (2.03 mmo 1) of N, N-getyl-2-formyl-13-methoxybenzamide and 1 M of boron tribromide in methylene chloride 4.10 ml From (4.1 Ommo 1), 324 mg (72%) of N, N-getyl-2-formyl-3-hydroxybenzamide was obtained.
  • Step 1 of Example 1 iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 1.76 g (3.3 Ommo 1),, N-diethyl-2- Formyl 3-hydroxybenzamide 0.46 g (3.0 Ommo1), potassium carbonate 0.91 g (6.60 mmol) and 18-crown From 6, 0.08 g (0.3 Ommo 1), 2- [2- (2-Jetylcarbamoyl 6-hydroxyphenyl) vinyl] 1.1-methylindole 0.64 g
  • Example 54 1.54 g (10. Ommo 1) of 6-fluoro-2-methoxybenzaldehyde and LM boron tribromide Z methylene chloride solution 12.0 ml (1 2. Ommo) From 1), 1.18 g (84%) of 6-fluoro-2-hydroxybenzaldehyde was obtained.
  • Step 1 of Example 1 iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 1.77 g (3.32 mmo 1), 6-fluoro 2- From 0.42 g (3.01 mmo 1) of hydroxybenzaldehyde, 0.92 g (6.63 mmo 1) of potassium carbonate and 18—crown 6, 0.085 g (0.32 mmo 1) 0.90 g (96%) of 2- [2- (6-fluoro-2-hydroxyphenyl) vinyl] -1-methylindole was obtained.
  • 6-Promo 2-methoxybenzoic acid 6.93 g (30.Ommo 1) was dissolved in THF 10 Om 1, and PORAN'dimethylsulfuric acid complex 14.3 m 1 (150.00 mmo 1) was added. 1. Heated to reflux for 5 hours. After cooling, water was added to the reaction solution, extracted with getyl ether, washed with water and then brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 5.70 g (88%) of a benzyl alcohol compound.
  • 6-bromo-2-methoxybenzaldehyde was obtained from 5.70 g (26.3 mmol) of the benzyl alcohol compound and 23.0 g (264 mmol) of manganese dioxide. 4.33 g (77%) were obtained.
  • Example 11 According to Step 1 of 1, 4.33 g (20.2 mmo 1) of 6-promo 2-methoxybenzaldehyde and 1 M boron tribromide / methylene chloride solution 2 4.Oml (24. Ommol), 2.05 g (50%) of 6-bromo-2-hydroxybenzaldehyde was obtained.
  • Step 1 of Example 1 (1-methylindole-2-yl) methyl (triphenyl) phosphonium 2.93 g (5.5 Ommo 1), 6-bromo-2-hydroxybenzaldehyde 1.0 1 g (5.02 mmo 1), potassium carbonate 1.52 g (1 1.Ommo 1) and 18—crown 6, 0.13 g (0.50 mmo 1) From 1), 1.59 g (96%) of 2- [2- (6-bromo-1-hydroxyphenyl) vinyl] -1-monomethylindole was obtained.
  • Step 2 of Example 12 2.5-ml (20.0 mmol) of 3-chlorodisole, 1.6 M n-butyllithium / n-hexane solution 16 m 1 ( 2.35 g (35%) of 6-n-butyl-2-methoxybenzaldehyde was obtained from 26 ml of Oml and DMF 3.1 ml (40 ml of Oml).
  • Example 11 According to Step 1 of 1, 1.34 g (6.98 mmo 1) of 6-n-butyl-2-methoxybenzaldehyde and 8.4 ml of a 1 M boron tribromide Z methylene chloride solution ( 8. 40 mm 01) gave 94 g (76%) of 6-n-butyl-2-hydroxybenzaldehyde.
  • Step 1 of Example 1 iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 1.8 1 g (3.4 Ommo 1), 6-n-butyl-2 —From 0.55 g (3.1 Ommo 1) of hydroxybenzaldehyde, 0.95 g (6.88 mmo 1) of potassium carbonate and 18—crown 6, 0.08 g (0.31 mmo 1) There was obtained 0.73 g (77%) of 2- [2- (6-n-butyl-2-hydroxyphenyl) vinyl] -11-methylindole.
  • Step 1 of Example 1 (1-methylindole-2-yl) methyl (triphenyl) phosphonium 3.20 g (6.0 Ommo 1), 2-hydroxy 6-bivaloylaminobenz Aldehyde 1.llg (5.0 2mmo 1), From 2.42 g (17.5 mmo 1) and 18—crown 6, 0.14 g (0.5 Ommo 1) of potassium carbonate, 2-— 2-(2-hydroxy-1-6-pivaloy) Laminophenyl) vinyl] —1.02 g (49%) of 1-methylindole.
  • Step 1 of Example 1 2.39 g (10.6 mmo 1) of 6-fluoro-2- (1-methoxycarbonylethoxy) benzaldehyde, iodide (1-methylindole-2-yl) ) Methyl (triphenyl) phosphonium 6.76 g (12.7 mmo 1), potassium carbonate 4.38 g (3.1.7 mmo 1) and 18—crown 1.6, 0. ⁇ 8 g (2.2 From 1 mmo 1), 2- ⁇ 2- [6-Fluoro-2- (1-methoxycarbonyldioxy) phenyl] vinyl ⁇ 3.45 g (93%) of indole were obtained.
  • Step 1 of Example 1 (1 monomethylindole-2-yl) methyl (triphenyl) phosphonium (267 mg, 0.93 mm 01), 6-bromo—2- (1- —Methoxycarbonylethoxy) benzaldehyde 597 mg (1.12 mmo 1), potassium carbonate 193 mg (1.4 Ommo 1) and 18- Round — From 26 mg (0.10 mmo 1), 2- ⁇ 2- [6-bromo-2- (1-methoxycarbonyl-2-ethoxy) phenyl] vinyl ⁇ 1-methylindole 29 Omg (75%).
  • Example 21 According to Step 1 of 1, from 20 and 62 mg (0.16 mmol) of compound 20 and 2.0 ml of thionyl chloride, an acid chloride was obtained. The compound 22 was reacted with 0.10 ml (0.79 mmo 1) of N′-trimethylethylenediamine to obtain 64 mg (85%) of compound 22.
  • Example 21 An acid chloride was obtained from compound 64, 64 mg (0.17 mmol) and thionyl chloride 5.0 ml according to Step 1 of Example 1 and then converted the acid chloride to N-methylbiperazine 0 By reacting with 18 ml (1.6 mmo 1), compound 23 free base, 38 mg (49%) was obtained.
  • step 2 of Example 2 compound 23 free base 38 mg (0.081 mm 0 1)
  • Compound 0.87N Hydrogen chloride ZAc OEt solution 0.13 ml (0.17 mmol) of compound 23 gave 17 mg (42%) of compound 23.
  • Example 21 An acid chloride was obtained from compound 20, 19 Omg (0.494 mmo 1) and thionyl chloride lm 1 according to Step 1 of Example 1, and then the acid chloride was converted to 2-pi By reacting with 55 mg (0.5 Ommo 1) of lysine thiol and 0.069 m 1 (0.5 Ommo 1) of triethylamine, compounds 24 and 38 mg (33%) were obtained.
  • Example 30 Compounds 34 and 67 mg (78%) were obtained from Compounds 33 and 86 mg (0.2 Ommo 1) and 10% PdZC and 46 mg, respectively.
  • Example 21 According to step 1 of 1, from 25,1 mg (0.846 mmol) of compound 20, 325 mg and 25 ml of thionyl chloride, an acid chloride was obtained, and then N, N-getyl ethylenediamine 1.2 ml (8 By reacting with 5 mmol 1), 33 Omg (81%) of the compound 38 free base was obtained.
  • Example 38 Compound 38 free base 33 Omg (0.684 m 1110 1) Compound 38, 297 mg (84%) were obtained from 1.55 ml (1.4 mmol) of a 0.98 N hydrogen chloride / AcOEt solution.
  • Step 1 of Example 1 iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 8.91 g (16.7 mmo 1), salicylaldehyde 2.00 g (16.4 mmo 1), potassium carbonate 3.40 g (24.6 mmo 1) and 18—crown 6, 0.04 g (0.16 mmo 1), 2-[2-( 2.60 g (88%) of 2-hydroxyphenyl) vinyl] 111-methylindole were obtained.
  • Example 20 4- (2-acetoxoxyphenyl) 1-1,3-dioxo-2,6-dimethyl-1,2,3,3a, 4,5,6,10c From the hydropyrro [3,4-c] hydrorubazole 6.97 g (17.32 mm 01) and DDQ 7.88 g (34.7 Ommo 1), 4 Cetoxyphenyl) 1,1,3-dioxo-2,6-dimethyl-1,1,2,3,6-tetrahydropyrro [3,4-c] potassium 6.78 g (98%) Was.
  • Step 6 of Example 37 4- (2-acetoxyphenyl) -1,1,3-dioxo-1,2,6-dimethyl_1,2,3,6-tetrahydropyrro [3,4- c] From 2.50 g (6.28 mmo 1) of potassium hydroxide and 1.74 g (12.6 mmo 1) of potassium carbonate, 1,3-dioxo-1- (2-hydroxyphenyl) 1.83 g (82%) of 2,6-dimethyl-1- (1,2,3,6-tetrahydropyrro [3,4-c] caproluvazole) was obtained.
  • the compound 48 was obtained from 73 mg (0.14 mmo 1) of free base and 4 N hydrogen chloride ZA c OEt solution 0.039 ml (0.16 mmo 1). 48, 76 mg (97%) were obtained.
  • Example 30 1,3-dioxo-1-4- [2- (2-dimethylaminoethoxy) -3--3-trophenyl] -12,6-dimethyl-1,2,3,6-tetra Hydropyrrole [3,4-c] sorbazole From 1.15 g (2.43mmo I) and 10% PdZC, 0.30g, 4- [3-amino-2- (2- Dimethylaminoethoxy) phenyl] 1,1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyrrole [3,4-c] -caproluvazole 0.97 g (90%) Was.
  • Example 30 Compound 48 free base 545 mg (1.05 mmol) and 10% Pd / C (50 wt%), 276 mg, Compound 50 free base 41 6 mg (82%) were obtained.
  • Example 2 According to Step 2 of 1, from Compound 50 free base 82 mg (0.17 mmo 1) and 4N hydrogen chloride ZAc OEt solution 0.04 7 ml (0.19 mmo 1), Compound 50, 79 mg (90%) was obtained.
  • Example 5 According to Step 2 of Example 1, Compound 5 was obtained from 8 Omg (0.17 mmo 1) of free base and 4 N hydrogen chloride ZA c OEt solution 0.047 ml (0.19 mmo 1) to obtain Compound 5 1, 83 mg (96%) were obtained.
  • Example 25 compound 51 1 free base 1 24 mg (0.26 mmo 1), WSC'HC and 15 1 mg (0.79 mmo 1) and getylamine 0.05 5 ml (0. From 53 mmol), 68 mg (49%) of compound 52 free base was obtained.
  • Example 2 According to step 2 of 1, from compound 52 free base, 64 mg (0.12 mmo 1) and 4N hydrogen chloride ZA c ⁇ Et solution 0.033 ml (0.13 mmo l) Compound 52, 65 mg (95%) was obtained.

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Abstract

Cette invention se rapporte à des dérivés de pyrrolocarbazole représentés par la formule générale (I) ou à des sels pharmaceutiquement acceptables de ces dérivés. Dans la formule (I), le noyau C représente un noyau benzène ou cyclohexène; X et Y sont identiques ou différents et sont chacun carbonyle ou méthylène; R1 est alkyle inférieur ou aralkyle; R2 est hydrogène, alkyle inférieur éventuellement substitué, alkényle inférieur ou aralkyle éventuellement substitué; et R?3, R4, R5, R6, R7, R8, R9, R10 et R11¿ sont identiques ou différents et sont chacun hydrogène, alkyle inférieur éventuellement substitué, alkényle inférieur éventuellement substitué, halogéno, nitro, alcanoyle inférieur éventuellement substitué, NR?12R13, OR14¿, NHCONHR?16 ou COR17¿. Ces composés s'avèrent utiles s'agissant de favoriser la thrombopoïèse, et sont donc particulièrement adaptés au traitement de la thrombopénie.
PCT/JP1997/003153 1996-09-09 1997-09-08 Derives de pyrrolocarbazole WO1998009967A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2845997A1 (fr) * 2002-10-18 2004-04-23 Servier Lab Nouveaux derives de[1,4]benzodioxino[2,3-e]isoindole substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7122679B2 (en) 2000-05-09 2006-10-17 Cephalon, Inc. Multicyclic compounds and the use thereof
WO2007149451A2 (fr) 2006-06-19 2007-12-27 Cephalon, Inc. Nouveaux composés multicycliques et leur utilisation
EP2314586A1 (fr) 2002-01-18 2011-04-27 Astellas Pharma Inc. Dérivé 2-acylaminothiazole ou sel de celui-ci
KR20160094802A (ko) * 2015-02-02 2016-08-10 충남대학교산학협력단 카바졸 유레아 유도체를 함유하는 혈관 질환의 예방 또는 치료용 조성물
WO2017197083A1 (fr) 2016-05-12 2017-11-16 Global Blood Therapeutics, Inc. Procédé de synthèse de 2-hydroxy-6-((2- (1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)méthoxy)benzaldéhyde
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10806733B2 (en) 2011-12-28 2020-10-20 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10829470B2 (en) 2013-03-15 2020-11-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10858317B2 (en) 2013-03-15 2020-12-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
JP2022547196A (ja) * 2019-09-12 2022-11-10 アシムケム ラボラトリーズ （フーシン） カンパニー リミテッド ２，６－ジヒドロキシベンズアルデヒドの連続製造装置及びその使用

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JPH02142791A (ja) * 1988-09-29 1990-05-31 Goedecke Ag ピロロカルバゾール誘導体、それらの調製方法およびそれらの医薬として使用
JPH07304771A (ja) * 1994-03-18 1995-11-21 Kyowa Hakko Kogyo Co Ltd 血小板減少症治療剤及びインドロカルバゾール誘導体
WO1996028447A1 (fr) * 1995-03-09 1996-09-19 Kyowa Hakko Kogyo Co., Ltd. Derives de pyrrolocarbazole

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US7122679B2 (en) 2000-05-09 2006-10-17 Cephalon, Inc. Multicyclic compounds and the use thereof
EP1754707A2 (fr) 2000-05-09 2007-02-21 Cephalon, Inc. Composés multicycliques et leur utilisation comme inhibiteurs des enzymes PARP, VEGFR2 et MLK3
EP2050750A2 (fr) 2000-05-09 2009-04-22 Cephalon, Inc. Composés multi-cycliques et leur utilisation comme inhibiteurs des enzymes PARP, VEGFR2 et MLK3
EP2314586A1 (fr) 2002-01-18 2011-04-27 Astellas Pharma Inc. Dérivé 2-acylaminothiazole ou sel de celui-ci
WO2004037831A1 (fr) * 2002-10-18 2004-05-06 Les Laboratoires Servier NOUVEAUX DERIVES DE [1,4]BENZODIOXINO[2,3-e]ISOINDOLE SUBSTITUES, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT
KR100695600B1 (ko) * 2002-10-18 2007-03-14 르 라보레또레 쎄르비에르 치환된 [1,4]벤조디옥시노[2,3-ｅ]이소인돌 유도체, 이의제조방법 및 이를 함유하는 약제 조성물
US7202255B2 (en) 2002-10-18 2007-04-10 Les Laboratoires Servier Substituted [1,4] benzodioxino[2,3-e] isoindole derivatives, method for preparing and pharmaceutical compositions containing same
EA008498B1 (ru) * 2002-10-18 2007-06-29 Ле Лаборатуар Сервье Замещённые соединения [1,4]бенздиоксино[2,3-e]изоиндола, способ их получения и фармацевтические композиции, которые их содержат
FR2845997A1 (fr) * 2002-10-18 2004-04-23 Servier Lab Nouveaux derives de[1,4]benzodioxino[2,3-e]isoindole substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2007149451A2 (fr) 2006-06-19 2007-12-27 Cephalon, Inc. Nouveaux composés multicycliques et leur utilisation
US10806733B2 (en) 2011-12-28 2020-10-20 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11530191B2 (en) 2013-03-15 2022-12-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10829470B2 (en) 2013-03-15 2020-11-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10858317B2 (en) 2013-03-15 2020-12-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11452720B2 (en) 2014-02-07 2022-09-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
KR101652305B1 (ko) 2015-02-02 2016-08-30 충남대학교산학협력단 카바졸 유레아 유도체를 함유하는 혈관 질환의 예방 또는 치료용 조성물
KR20160094802A (ko) * 2015-02-02 2016-08-10 충남대학교산학협력단 카바졸 유레아 유도체를 함유하는 혈관 질환의 예방 또는 치료용 조성물
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11944612B2 (en) 2015-12-04 2024-04-02 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
WO2017197083A1 (fr) 2016-05-12 2017-11-16 Global Blood Therapeutics, Inc. Procédé de synthèse de 2-hydroxy-6-((2- (1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)méthoxy)benzaldéhyde
CN109152770A (zh) * 2016-05-12 2019-01-04 全球血液疗法股份有限公司 合成2-羟基-6-((2-(1-异丙基-1h-吡唑-5-基)-吡啶-3-基)甲氧基)苯甲醛的方法
JP2022088564A (ja) * 2016-05-12 2022-06-14 グローバル ブラッド セラピューティクス インコーポレイテッド ２－ヒドロキシ－６－（（２－（１－イソプロピル－１ｈ－ピラゾール－５－イル）－ピリジン－３－イル）メトキシ）ベンズアルデヒドの合成方法
EP3454854A4 (fr) * 2016-05-12 2019-12-11 Global Blood Therapeutics, Inc. Procédé de synthèse de 2-hydroxy-6-((2- (1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)méthoxy)benzaldéhyde
JP2019516692A (ja) * 2016-05-12 2019-06-20 グローバル ブラッド セラピューティクス インコーポレイテッド ２−ヒドロキシ−６−（（２−（１−イソプロピル−１ｈ−ピラゾール−５−イル）−ピリジン−３−イル）メトキシ）ベンズアルデヒドの合成方法
KR102487509B1 (ko) 2016-05-12 2023-01-12 글로벌 블러드 테라퓨틱스, 인크. 2-히드록시-6-((2-(1-이소프로필-1h-피라졸-5-일)-피리딘-3-일)메톡시)벤즈알데히드를 합성하는 방법
JP7398193B2 (ja) 2016-05-12 2023-12-14 グローバル ブラッド セラピューティクス インコーポレイテッド ２－ヒドロキシ－６－（（２－（１－イソプロピル－１ｈ－ピラゾール－５－イル）－ピリジン－３－イル）メトキシ）ベンズアルデヒドの合成方法
KR20190005917A (ko) * 2016-05-12 2019-01-16 글로벌 블러드 테라퓨틱스, 인크. 2-히드록시-6-((2-(1-이소프로필-1h-피라졸-5-일)-피리딘-3-일)메톡시)벤즈알데히드를 합성하는 방법
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
JP2022547196A (ja) * 2019-09-12 2022-11-10 アシムケム ラボラトリーズ （フーシン） カンパニー リミテッド ２，６－ジヒドロキシベンズアルデヒドの連続製造装置及びその使用

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