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WO1991012251A1 - Nouveau compose heterocyclique condense et agent anti-asthme prepare a partir de ce compose - Google Patents

Nouveau compose heterocyclique condense et agent anti-asthme prepare a partir de ce compose Download PDF

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Publication number
WO1991012251A1
WO1991012251A1 PCT/JP1991/000210 JP9100210W WO9112251A1 WO 1991012251 A1 WO1991012251 A1 WO 1991012251A1 JP 9100210 W JP9100210 W JP 9100210W WO 9112251 A1 WO9112251 A1 WO 9112251A1
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Prior art keywords
group
phthalazinone
value
halogen
lower alkyl
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PCT/JP1991/000210
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English (en)
Japanese (ja)
Inventor
Nobuhiro Ohi
Toshio Kuroki
Masahisa Yamaguchi
Michitaka Akima
Takaki Koga
Kenshi Kamei
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Priority to JP03504019A priority Critical patent/JP3120857B2/ja
Publication of WO1991012251A1 publication Critical patent/WO1991012251A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention has combined both bronchodilation and preparative ⁇ Nbokisa emissions
  • a 2 synthetase bile adverse effects, anti-asthmatic agents relates to a bronchodilator useful novel condensed heterocyclic compound.
  • the present invention also relates to an anti-asthmatic agent using such a condensed heterocyclic compound.
  • Bronchial asthma can be regarded as a disease associated with an immediate asthmatic response (hereinafter abbreviated as IAR) and a delayed asthmatic response (hereinafter abbreviated as LAR) and airway hypersensitivity (J. Allergy Clin. Immunol. 54, 244-254, 1974 and Am. Rev. Respir. Dis. 112, 829-859, 1975.)
  • IAR immediate asthmatic response
  • LAR delayed asthmatic response
  • airway hypersensitivity J. Allergy Clin. Immunol. 54, 244-254, 1974 and Am. Rev. Respir. Dis. 112, 829-859, 1975.
  • IAR can be controlled by stimulants and other bronchodilators.
  • LAR is thought to be a response caused by airway inflammation, and it is difficult to control this response with conventional bronchodilators (Am.Kev.Respir. Dis. 136, 740-751, 1987).
  • TX TX collected by filtration Nbokisa emissions
  • a z is believed to be deeply involved in B
  • PAF platelet activating factor
  • LAR and airway hypersensitivity of expression I have.
  • PAF platelet activating factor
  • D-X synthase inhibitors This has been reported. '(Am. Rev. Respir. Dis. 134, 258-261, 1986; Allergy, 35 (7) s 437-446, 1986, Thorax, 41, 955-959, 1986, J. sthma, 25 .. 117-124, 1988).
  • Clarification-The present inventors have conducted intensive studies to search for an excellent anti-asthmatic drug capable of suppressing IAR and LAR and enhanced airway hyperreactivity with the same drug, and as a result, suppressed the IAR and acting as a bronchodilator, a compound represented Te general formula (I) simultaneously having both action as LAR and suppress the enhanced airway hyperresponsiveness TXA 2 synthetase inhibitors were synthesized and completed the present invention . That is, the present inventors, the general formula [1 compound represented by ⁇ may have subjected both bronchodilation and T XA 2 synthase inhibitory action, anti-asthmatic agents, useful as a gas Kan ⁇ extender That was found.
  • the compound of the present invention has the general formula (I)
  • -A ⁇ is an unsaturated 5- or 6-membered ring having 0 or 1 nitrogen atom and 0 or] sulfur atoms
  • R is a hydrogen atom, a halogen, a carboxyl group, a lower alkoxyl propyl group, a nitro group or a lower alkoxy group;
  • R 2 a lower alkyl group, a cyclohexyl group, a benzyl group which may be substituted with a halogen, a phenyl group, a phenyl group, a lower alkyl group
  • K is a hydrogen atom
  • C ⁇ Gen force Rupokishiru group a lower ⁇ ⁇ co emissions' Ca carbonyl group
  • C ⁇ Gen force Rupokishiru group is then c androgenic as a two collected by filtration group also lower alcohol key sheet group, full source containing chlorine, bromine, and the e-lower an alkoxy group tio ⁇ containing a capable to twenty-one is exemplified, i rk 'Rubonino, preparative key deer Lupo sulfonyl, blanking opening Boki scolding - O: nil ⁇ top' - carbon The carbonyl group substituted with the number 1 to G
  • Examples of such a compound include: 3 ⁇ 4; -a phenyl group having a noroxy group; and trifluor, '+ :; a phenyl group.
  • R 3 lower alkyl group, lower alkenyl group, lower alkenyl group: group .. alkaryl group, cycloalkyl group,;> quartyl group masyl group.
  • X-forceRubonyl group A lower alkyl group or BN which may have a pyrimidinylthio group; a carbamoyl group, a phthalimid group, a tetrazolyl group, a thiophenoxy-thiazolinylthio group, and a pyrimidinylthio group.
  • the lower alkyl group and the like as exemplified in the paragraph of R 2.
  • Examples of the lower alkenyl group include alkenyl groups having 2 to 6 carbon atoms, such as butyl, aryl, 1-methylaryl, butyr, and pentyl.
  • Examples of the lower alkynyl group include alkynyl groups having 2 to 6 carbon atoms such as ethur and provalgyl.
  • Examples of the aralkyl group include substituted or unsubstituted benzyl.
  • Examples of the cycloalkyl group include a cycloalkyl group having 3 to "/ carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Examples of such a group include a methyl group substituted with a cycloalkyl group having 4 to 8 carbon atoms, such as cyclopentylmethyl, cyclohexylmethyl, and cyclohexylmethyl. And alkenyl groups such as acetyl, etc.
  • a lower alkyl group substituted with a fluoromethyl group That is, by reacting a compound represented by the formula ( ⁇ ) as a starting material with a compound represented by the following formula in an inert solvent in the presence of a base:
  • the compound of the present invention can be obtained using a base such as a hydrogenated alcohol, a carbonated alkaline carbonate, or a hydroxylated alcohol. Is it preferable? Sodium hydride, hydrogenation power
  • inactive solvent examples include, but are not limited to, I-, which is not particularly limited as long as it is inert in the reaction, dimethylformamide, titra, and the like. Hidden mouth:,iff.
  • the compound of the present invention represented by the formula (VI) can be obtained by hydrolysis of the compound to be obtained with a base.
  • the base used herein include alkali hydroxide and alkali carbonate, and preferably, sodium hydroxide, potassium hydroxide and the like.
  • the reaction time proceeds from 0 to the reflux temperature, preferably from 20 to 60.
  • the anti-time is from 0.5 to 12 hours, preferably from 0.5 to 3 hours.
  • a compound represented by the formula (V;) obtained by the method C is led to an acid halide with a halogenating agent, and then reacted with a compound represented by the formula ReN! K to obtain a compound represented by the formula:
  • the compound of the present invention represented by (1) can be obtained as the oxidizing agent used herein is phosphorus pentachloride, phosphorous trichloride, thionyl chloride or phosphorous oxychloride.
  • the reaction temperature is from 10'C to the reflux temperature, preferably from 15 to room temperature, and the reaction time is from 0 to 24 hours-The preferred is from 3 to 8 hours
  • the reaction temperature is from 10'C to the reflux temperature, preferably from 15 to room temperature, and the reaction time is from 0 to 24 hours
  • R or 2 represents a substituted lower alkyl group substituted by a sulfonate group, that is, a compound represented by the formula (K) as a starting material, and the presence of a base. standing under an inert solvent, wherein, by the this reacting a compound represented by S0 2 C1, used. here which can on this to obtain the compound of the present invention represented by the formula (X! bases And the same solvent used for the inert solvent A.
  • the reaction proceeds from the reaction temperature to the reflux temperature, preferably to 050 ° C.-The reaction time: 0.5 to 24 hours, preferably The duration is 15 hours
  • the acid anhydride (( ⁇ ) is used as a starting material and the base is preserved.
  • the compound is further hydrolyzed with acid.
  • the base is butyllithium.
  • reaction time I ⁇ 5 hours is preferred
  • Z represents a halogen atom
  • R '! 5 is an alcohol earth group
  • the reaction temperature is between 110 and 120, preferably between 80 and -40.
  • the reaction time is 0.5 to: 12 hours, preferably 0.5 to 3 hours.
  • Ring closure reaction by heat Dora Jin-hee Dollar metropolitan desirable to carry out ring closure reaction and ⁇ one condition in (G method) correct e
  • R and 7 each represent an unsaturated C ′ 5- or 6-membered heterocyclic ring having i to 3 nitrogen atoms and 0 or 1 sulfur atom.
  • R 1 B represents a lower alkyl group. That is, the compound represented by the general formula (XXI) is reacted with a substituted hydrazine ( ⁇ ⁇ ⁇ ⁇ ) in an alcohol solvent to obtain a compound represented by the general formula (XXI): xx m)
  • the reaction temperature at which the compound of the present invention can be obtained is preferably a reflux temperature, and the reaction time is preferably 1 to 6 hours.
  • the compound represented by the general formula (I) of the present invention is used as an anti-asthmatic drug
  • the compound is in the range of 0.1 mg / kg to 100 mg / k body weight / day, preferably 0.1 to 30 mg / kg body weight.
  • the compound is in the range of days 5 O
  • the administration method can be oral, intravenous, intramuscular or subcutaneous rectus, and also as an aerosol.
  • Example 2 The same procedure as in Example 1 was carried out using 41- (4-cyclophenyl) -1]-(2 ⁇ ) phthalazinone as a raw material to obtain the desired product.
  • Example 2 The same procedure as in Example 1 was carried out using 4- (4-ethylphenyl) -111 (2H) phthalazinone as a raw material to obtain the desired product.
  • Example 2 The same procedure as in Example 1 was carried out using 4- (4-methoxyethoxy) -1-1 (2H) phthalazinone as the starting material, and the desired product was obtained. I got
  • Example 2 The same procedure as in Example 1 was carried out using 4-((4-ethoxyethoxyunyl) -11- (2H) phthalazinone as a raw material to obtain the desired product.
  • Example 2 The same operation as in Example 1 was carried out using 4- (3,4-dimethyoxyfuran) 1 1- (2H:) phthalazinone as the raw material. I got .
  • N.1R (CDC1 2 3 values;. 3.91 - 4 ⁇ 3-4 Ryo UH, n;
  • Example 2 The same procedure as in Example 1 was carried out using 4- (4-methylthioethyl) 1) — (2H; phthalazinone) as a raw material to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 1 using 4- (4-fluorophenyl) -1-1 (2H) phthalazinone as a raw material.
  • Example 2 The same operation as in Example 1 was carried out using 6-chloro-4 (3-fluoro-4-methoxykiphenyl) 1-1-1 (2H) phthalazinone as the raw material. I got something.
  • Example 2 The same procedure as in Example 1 was performed using 41- (4-chlorobenzyl) -11- (2H) phthalazinone as a raw material to obtain the desired product.
  • the intended product was obtained by performing the same operation as in Example 1 using the above method.
  • 80% hydrazine hydrate 1.7 S is added to 7 O ml of an ethanol suspension containing 3.9 g of 2-nicotinoylbenzoic acid, and the mixture is stirred under reflux for 4 hours. After standing overnight, the precipitated crystals are collected to obtain 2.7 g of the desired product.
  • the desired product was obtained by performing the same operation as in Example 1 using 4- (3-pyridyl) -111 (2H) phthalazine as a raw material. 9. C
  • Example 2 The same procedure as in Example 1 was carried out using 4-((4-viridyl) -111 (2H) phthalazinone as a raw material to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 1 using 4- (: ⁇ —bilge / re) 1-11 (2H) phthalazinone as a raw material-mp 11 3 to 1 15 V
  • the desired product was obtained by performing the same operation as in Example 1 using 4- (2-furyl ')-11 (2H) phthalazinone as a raw material.
  • the desired product was obtained by performing the same operation as in Example 1 using 4-methyl-11- (2H) -phthalazi'none as a raw material.
  • Example 3 4-cyclohexyl 1 2— [2-(_ 1.H—imigzo'lyl) ethyl] — 1- (2H) phthalazinone
  • the desired product was obtained by performing the same operation as in Example 1 using 4-cyclohexyl-1- (2H) phthalazino as a raw material.
  • the desired product was obtained by performing the same operation as in Example 1 using 6-chloro-1-41 [2- (5-methyl-2- / L)]-111 (2H) phthalazinone as the raw material. .
  • the raw material is Ding —Nitro 1 4— [2— (5-Echi 'Che 2) j 1-
  • the same procedure as in Example 1 was performed using 1- (2H) phthalazinone to obtain the desired product.
  • Example 2 The same procedure as in Example 1 was carried out using 6-methoxy-1-41- (2-chenyl) -11- (2H) phthalazinone as the starting material to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 1 using phthalazinone as the raw material, 6-toki 4- 1 [2-(5-chininii ⁇ .): -1-(2 ⁇ ) phthalazinone. Was.
  • the desired product was obtained by performing the same operation as in Example 1 using cinna — cinnamon 4 — [2 — (— ⁇ tyltinini) — 11-2H) phthalazinone as a raw material. rn p 9 9, 1 0 2
  • Phthalazinone 2.0 g was dissolved in ethanol 200 ml, and a catalytic amount of Port Ryuic acid was added. Reflux for hours. The solvent was distilled off under reduced pressure, and a mixed solution of ethyl ethyl acetate 200% and a 5% aqueous solution of carbon dioxide 10 Oml was added to the residue. After stirring, the organic layer was separated. After drying over magnesium sulfate, the ethyl acetate is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography.
  • the mixture is developed and eluted with a mixture of chloroform and methanol (20: 1, V / V) to obtain 7-ethoxycarbonyl-2- [2- (5-ethylethyl)]-111 (2H) phthalazinone.
  • the same operation as in Example 1 was carried out by using 7-ethoxycarbonyl 4- [2- (5-ethylthienyl)] — 1— (2H) phthalazinone as a raw material. I got something.
  • Example 2 The same operation as in Example 1 was carried out using 8-ri [2— (5-chlorozenyl)] — 5— (6H pyrido [2,3 le d) pidazinone as the raw material. I got something.
  • Example 2 The same process as in Example 1 was performed using 11- [2— (5—methyl'handi-nil >>) 43H-H-d'lide '[3,4-1d] pyridazinone as the raw material. As a result, the desired product was obtained.
  • Example 2 The same procedure as in Example 1 was carried out using 41-[(2-phenyl) methyl] -1- (2H) phthalazinone as a raw material to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 1 using 1,5-dibromopentane instead of 1,2-dibromopentane.
  • the desired product was obtained by performing the same operation as in Example 1 except that 1,6-dibromohexane was used instead of 1,2-dibromoethane.
  • Example 2 The same procedure as in Example 1 was carried out except that 1,4-dibromo-2-butene was used instead of 1,2-dibromethane to obtain the objective ⁇ .
  • the target compound was obtained by performing the same operation as in Example 1 using 1,4-dibromo-2-butyne instead of 1,2-dibromethane.
  • Example 2 The same procedure as in Example 1 was carried out using 1,4-bis (bromomethyl) cyclohexane instead of 1,2-dibromoethane to obtain the desired product.
  • Example 2 Same as in Example 1, except that 1,3-dibutene pan was used instead of 1,2-dibromogetane, and 4- (2-Chenyl) —1— (2H phthalazinone was used as a raw material.
  • the desired object was obtained by performing the above operations.
  • Example 2 Same as in Example 1, except that 1,5-dibromomethane was used instead of 1,2-dibromomethane, and 6,7-dimethoxy-14-phenyl-11- (2H) phthalazinone was used as a raw material. By performing the above operation, the desired product was obtained as a colorless oily substance.
  • the desired hydrochloride was obtained by performing the same operation as in Example 53.
  • Example 2 The same as in Example 1 except that 1,5-dibutene methane was used instead of 1,2-dibromomethane, and 4- (3-pyridyl) 111 (2H) phthalazinone was used as a raw material. The objective was obtained by performing the operation.
  • Example 1 using 1,5—dibutene methane in place of 1,2-dibromomethane and 4- (4-pyridyl) —1— (2H) phthalazinone as raw material
  • the target product was obtained by performing the same operation as in.
  • Example 2 The same operation as in Example 1 is performed using 1,5-dibromopentane instead of 1,2-dibromomethane and 4- (2-pyridyl) 111 (2H) phthalazinone as a raw material. Thus, the target substance was obtained as an oily substance.
  • Example 2 The same procedure as in Example 1 was carried out using 4- (3-ethoxycarbonylphenyl) 111 (2H) phthalazinone as a raw material to obtain the desired product.
  • the target compound was obtained by performing the same operation as in Example 61 using methyl iodide instead of ethyl amide.
  • Example 61 The same procedure as in Example 61 was carried out using 2-methoxyl chloride instead of ethyl bromide to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 61 using ethyl bromoacetate instead of ethyl bromide.
  • the desired product was obtained by performing the same operation as in Example 61, using ethyl bromobromide instead of ethylpromide.
  • the desired product was obtained by performing the same operation as in Example 61, using an isolopi / reb mouth guide instead of ethyl bromide.
  • the desired product was obtained by performing the same operation as in Example 61 using arylpromide instead of ethylpromide.
  • the desired product was obtained by performing the same operation as in Example 61 using an acetilk mouth ride instead of ethylpromide.
  • the desired product was obtained by performing the same operation as in Example 61, using ⁇ -propyl bromide instead of ethyl bromide, to obtain mp 142.5 to 143.5.
  • the desired product was obtained by performing the same operation as in Example 61 using n-butyl bromide instead of ethyl bromide.
  • the desired product was obtained by performing the same operation as in Example 61 using 4-bromo-2-methyl-2-butene instead of ethyl bromide.
  • the desired product was obtained by performing the same operation as in Example 61 using cyclohexylmethyl bromide instead of ethyl bromide.
  • n- Okuchirupuromai de have use of, N MR to obtain a particularly good Ri desired product carrying out the same operation as in Example 6 1 (CDC 1 3) ⁇ J value; 1.6 ⁇ 2,2 ( 15H, m>, 4.28 (2H, t, J-7Hz) 7.2-8.1 (5H, m), 8.3-8.9 (3H, m)
  • Example 61 Using benzyl bromide instead of ethyl bromide, the same procedure as in Example 61 was carried out to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 61 using black mouth acetone instead of ethylpromide.
  • Example 78 The same procedures as in Example 78 were carried out using thiophenol and sodium hydride instead of pyrrolidine to obtain the desired product.
  • Example 78 Using 2-mercaptopyrimidine and sodium hydride in place of pyrrolidine, the same procedure as in Example 78 was carried out. The desired product was obtained.
  • the desired product was obtained by performing the same operation as in Example 78 using phthalimidocadium instead of pyrrolidine.
  • Example 78 The same procedures as in Example 78 were carried out using 2-mercaptothiazolinyl and sodium hydride instead of vial resin to obtain the desired product.
  • Example 61 4- (3-pyridin-1 (2H) phthalazinone (0.30 s) and 2-bromoethylacetate (from 0 ⁇ 17m, 2— ( 2—acetoxityl) —4— (3—pyridyl) 111 (2H) phthalazinone (0.35 g) was synthesized, and this (0.35s) was dissolved in 5 ml of tetrahydrofuran. Then, 10% sodium hydroxide was added. 5 ml of an aqueous solution was added, and the mixture was stirred for 2.5 hours at 40.
  • reaction solution was neutralized with 3 3-hydrochloric acid under ice-cooling, and the desired product was mixed with tetrahydrofuran and chloroform-form.
  • the organic layer was washed with saturated saline solution, separated, and treated with magnesium sulfate. And dried. Next, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
  • the mixture was developed and eluted with a mixed solvent (99: 1, ⁇ / 'V) to obtain the desired product as (0.27 s) colorless crystals.
  • Example 85 By carrying out the same hydrolysis as in Example 85, the desired product was obtained from 2-ethoxycarbonylmethyl-4-1 (3-pyridyl) -111 (2 ⁇ ) phthalazinone obtained in Example 64. Obtained.
  • the foam layer was washed with water and then dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The mixture was developed and eluted with a mixture of chloroform and methanol (99: 1, v / V) to give the desired product (0.20 s) as colorless crystals.
  • Example 8 2- (3-Carboxyporyl) 1-141 (3-pyridyl) 1-111 (2H) phthalazine (0.29 S ) obtained in 7 and triethylamine (0.14 ⁇ > 1) in dichloromethane (0.14 ⁇ > 1) To the solution (10 ml) was added phosphorus pentachloride (0.21 g) under cooling, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure. After methylene chloride (10 ml) and tetrahydrofuran (10 ml) were added to the residue, the mixture was similarly compressed.
  • Example 61 The same procedure as in Example 61 was carried out, except that methyl-41- (bromomethyl) benzoate was used instead of ethylpromide, to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 61 using isobutyl bromide instead of ethylpromide.
  • Example 61 The same procedures as in Example 61 were carried out using benzenesulfonyl chloride instead of ethyl bromide to obtain the desired product.
  • the intended product was obtained by performing the same operation as in Example 61, using 2-thiophene carboxylate instead of ethylpromide.
  • the desired product was obtained by performing the same operation as in Example 61 using benzyl chloride of 3-chloro mouth instead of ethyl bromide.
  • the desired product was obtained by performing the same operation as in Example 61 using 2,2,2-trifluoroethyl chloride instead of ethyl bromide.
  • a mixed solution of diluted hydrochloric acid and ethyl acetate was added to the mixture, and the mixture was stirred for 5 minutes. After confirming that the aqueous layer was acidic, the aqueous layer was separated, and the aqueous layer was adjusted to pH 8 with a 5% aqueous sodium hydrogen carbonate solution. After standing in a refrigerator overnight, the precipitated insolubles were collected and recrystallized from ethanol to obtain the desired product (0.8 g) as pale yellow crystals.
  • the desired product was obtained by performing the same operation as in Example 100, except that 1 ⁇ -1,2,4-triazole was used instead of imidazole.
  • the obtained insoluble material was dissolved in ethanol (300 in 1), 80% hydrazine hydrate (20 ml) was added thereto, and the mixture was stirred under heating and reflux for 6 hours. After returning to room temperature, the precipitated insoluble material was collected, and then dried with water and H. The obtained insoluble matter was added to a suspension of about 0% sodium hydride (1.4 g) in dimethylformamide (200, ⁇ I) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour.
  • the aqueous layer was acidified with 31 ⁇ -salt, and extracted with ethyl acetate (400 ml): dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was ethanol (200) ml) and 80% hydrazine hydrate (1 Oml) were added, and the mixture was stirred under heating and reflux for 3 hours. After cooling, the precipitated insolubles were collected, washed with water, and recrystallized from ethanol to obtain the desired product (1.9 g).
  • Example 103 Using methyl hydrazine instead of 80% hydrazine hydrate, the same operation as in Example 103 was carried out, and purification was carried out by silica gel chromatography. The desired product was obtained.
  • the desired product was obtained by performing the same operation as in Example 107 using 1 (2H) -phthalazinone.
  • the desired product was obtained by performing the same operation as in Example 109, using arylpromide instead of ethylpromide.
  • the desired product was obtained by performing the same operation as in Example 109, except that isobutyl bromide was used instead of ethyl bromide.
  • Example 10 9 was used instead of ethyl bromide, and the reaction temperature was 70 and the reaction time was 3 hours. By performing the same operation as in the above, the desired product was obtained.
  • the desired product was obtained by performing the same operation as in Example 109, using 2,2,2-trifluoroethyl chloride instead of ethyl bromide, and setting the reaction time to 20 hours.
  • the desired product was obtained by performing the same operation as in Example 107, using 2-methoxethyl ⁇ -ite as the frit of the mouth nozzle.
  • the pH of the aqueous layer was adjusted to 3 to 4, and the mixture was extracted with ethyl acetate (40 Offl), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. (200 «I) and 80% hydrazine hydrate (10) were added, and the mixture was stirred under reflux for 6 hours.After cooling, the solvent was distilled off under quenching.
  • N M R (D M S 0-d 6) value 7.45-7.80 (ZH, rn) .8.05-S.45
  • Example 1 1 1 Production of 1-oxo-1,2-dihydro-4- (3-pyridyl) thieno “3,2-d ⁇ ⁇ pyridazine
  • a tetrahydrofuran solution (50 mi) of 2,3-dibumochiophene (18.lg) was added dropwise to a 15% butyllithium hexane solution (5 Oml) at -78 at the same temperature. For 30 minutes. Then, a solution of 3-cyanopyridine (8.0 g) in tetrahydrofuran (5 Ofni) was quickly added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes, then returned to room temperature, stirred for 15 minutes, and then again stirred at 78 ° C. C, and a 15% butyl lithium hexane solution (50 ml) was added dropwise.
  • the reaction solution was poured into finely ground dry ice (500 g). After standing overnight, the pH was adjusted to 1 with 3N-hydrochloric acid, and the mixture was stirred at 4TC for 30 minutes. Next, ethyl acetate (10 Oral) was added thereto, and the mixture was stirred, and then the aqueous layer was separated. In order to further remove impurities, the pH of the aqueous layer was adjusted to 8 with a 5% aqueous carbonated lime solution, and then ethyl ethyl perchlorate (100 ml) was added and stirred, and the aqueous layer was separated.
  • the pH of the aqueous layer was adjusted to 3 to 4 again by adding 3N-hydrochloric acid, dried over sodium sulfate extracted with ethyl acetate (40 O ml), and the solvent was distilled off under reduced pressure.
  • Ethanol (200 ml) and 80% hydrazine hydrate (10 ml) were added to the residue, and the mixture was stirred under heating and reflux for 6 hours. After cooling, the solvent was distilled off under reduced pressure.
  • water (1000) the pH is adjusted to 8 with 3N-hydrochloric acid, the insoluble material is collected, air-dried, and recrystallized from ethanol to obtain the desired product (1). 9 g) was obtained.
  • Example 120 4- (1-Imidazolyl) 12H) Instead of phthalazinone, 1-oxo-1,2-dihydro 4- (3-pyridyl) thieno [2,3-d] pyridazine obtained in Example 120 was used. The same procedure as in Example 107 was carried out to obtain the desired product.
  • the desired product was obtained by performing the same operation as in Example 61 using 2,2-dimethylpropylbutamide instead of ethyl bromide.
  • the desired product was obtained by performing the same operation as in Example 61 using 2-hydroxypropyl pyramide instead of ethylpromide.
  • the desired product was obtained by performing the same operation as in Example 61 using 2-hydroxy-2-methylpropyl bromide instead of ethylpromide.
  • the present compounds have excellent TXA 2 synthase inhibitory activity and bronchodilator activity represented by the general formula (I) Test Examples below.
  • Usagi platelets (approximately 1 0 8 ZMI>, porcine aortic Mi black, over beam (about 1 0 g ZML) and the compound represented by the general formula (I) (1 0 - £ M) and buffer containing (1 5 ⁇ ⁇ Tris-hydrochloride, 140 mM sodium chloride, 10 mM glucose, pH 7.6) was stirred, and array incubated for 3 minutes at 25. This was followed by arachidonic acid (1 to 3 M). Was added, and the mixture was incubated at 25 ° C for 3 minutes to react.Then, the reaction was stopped by adding 1N hydrochloric acid to make it acidic, and then centrifuged at 1500> g. the TXB 2 the amount of the supernatant R. IA method to measure Ri by the (Amersham kit) Was.
  • Table 1 shows the TXA 2 synthase inhibition rate based on the TXB 2 content of the control.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composé répondant à la formule générale (I) et sel d'addition acide pharmaceutiquement acceptable de celui-ci, ayant tous les deux une action de bronchodilatation et d'inhibition de la thromboxane A2 synthétase, et pouvant servir d'agent antiasthmatique et bronchodilatateur. Dans la formule (I), (a) représente un composé cyclique insaturé à cinq ou six éléments ayant 0 ou 1 atome d'azote et 0 ou 1 atome de soufre; R1 représente hydrogène, halogène, carboxyle, alcoxycarbonyle inférieur, nitro ou alcoxy inférieur; R2 représente alkyle inférieur, cyclohexyle, benzyle (non)substitué, thiénylméthyle, un composé cyclique insaturé et (non)substitué, thiénylméthyle, un composé cyclique insaturé et (non)substitué à cinq ou six éléments ayant de 1 à 3 atomes d'azote et 0 ou 1 atome de soufre, ou phényle (non)substitué; et R3 représente alkyle inférieur, alkényle inférieur, alkynyle inférieur, aralkyle, cycloalkyle, cycloalkylméthyle, acyle, acylméthyle, benzènesulfonyle, alkyle inférieur (non)substitué, ou (b), (où B représente un groupe hydrocarbure à chaîne ouverte).
PCT/JP1991/000210 1990-02-19 1991-02-19 Nouveau compose heterocyclique condense et agent anti-asthme prepare a partir de ce compose Ceased WO1991012251A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
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WO1993007146A1 (fr) * 1991-10-09 1993-04-15 Syntex (U.S.A.) Inc. Composes benzo et pyrido pyridazinones et pyridazinthiones a activite inhibant la phosphodiesterase iv
US5716954A (en) * 1991-10-09 1998-02-10 Syntex U.S.A. Inc. Benzopyridazinone and pyridopyridazinone compounds
WO1999029695A1 (fr) * 1997-12-05 1999-06-17 Astrazeneca Uk Limited Nouveaux composes
CN1045962C (zh) * 1993-01-01 1999-10-27 森德克斯(美国)股份有限公司 吡啶并哒嗪酮或吡啶并哒嗪硫酮化合物,制备它的中间体,含它的药物组合物及其用途
ES2137113A1 (es) * 1997-07-29 1999-12-01 Almirall Prodesfarma Sa Nuevos derivados de triazolo-piridazinas heterociclicos.
EP1050536A3 (fr) * 1999-05-06 2000-11-15 Wacker-Chemie GmbH Composé des silanes 2-(Benz-)Imidazol-, 2-(Benz-)Oxazol- ou 2-(Benz-)Thiazol-substitués
US6380196B1 (en) 1997-12-15 2002-04-30 Byk Gulden Lomberg Chemische Fabrik Gmbh Dihydrobenzofurans
WO2003057689A1 (fr) * 2002-01-02 2003-07-17 Fujisawa Pharmaceutical Co., Ltd. Composes aminopyrimidine, procedes de preparation de ces composes et compositions pharmaceutiques les contenant
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
CN108250150A (zh) * 2018-03-15 2018-07-06 兰州大学 一种肽嗪酮化合物及其制备方法与应用
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors
JP2020529458A (ja) * 2017-08-10 2020-10-08 中国科学院上海薬物研究所 フタラジノン系化合物、その製造方法、医薬組成物及びその使用

Families Citing this family (2)

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JPH0634558U (ja) * 1992-10-15 1994-05-10 雄作 神原 サブベッド
US20130116241A1 (en) * 2011-11-09 2013-05-09 Abbvie Inc. Novel inhibitor compounds of phosphodiesterase type 10a

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FR2478640A1 (fr) * 1980-03-24 1981-09-25 Sanofi Sa Nouvelles thieno (2,3-d) pyridazinones-4 et thieno (2,3-d) pyridazinones-7, leur procede de preparation et leur therapeutique
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JPS62298573A (ja) * 1986-06-10 1987-12-25 バイエル・アクチエンゲゼルシヤフト 酸化還元反応指示薬としてのトリアリ−ル−及びトリヘタリルメタン誘導体及びそれらの使用
JPS63150278A (ja) * 1986-11-24 1988-06-22 ファイザー・インコーポレーテッド イミダゾリジンジオン誘導体
JPS63280078A (ja) * 1987-04-21 1988-11-17 ファイザー・リミテッド ヘテロニ環式キノロン誘導体
JPS6419077A (en) * 1987-07-13 1989-01-23 Yamanouchi Pharma Co Ltd Thiazolidine derivative

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FR1453897A (fr) * 1965-06-16 1966-07-22 Dérivés du thiophène et de thiéno pyridazines
FR2478640A1 (fr) * 1980-03-24 1981-09-25 Sanofi Sa Nouvelles thieno (2,3-d) pyridazinones-4 et thieno (2,3-d) pyridazinones-7, leur procede de preparation et leur therapeutique
JPS6051173A (ja) * 1982-11-05 1985-03-22 ヒルトン　―　デービィス　ケミカル　カンパニー 発色物質の製造方法およびこれを使用した基材
JPS62298573A (ja) * 1986-06-10 1987-12-25 バイエル・アクチエンゲゼルシヤフト 酸化還元反応指示薬としてのトリアリ−ル−及びトリヘタリルメタン誘導体及びそれらの使用
JPS63150278A (ja) * 1986-11-24 1988-06-22 ファイザー・インコーポレーテッド イミダゾリジンジオン誘導体
JPS63280078A (ja) * 1987-04-21 1988-11-17 ファイザー・リミテッド ヘテロニ環式キノロン誘導体
JPS6419077A (en) * 1987-07-13 1989-01-23 Yamanouchi Pharma Co Ltd Thiazolidine derivative

Cited By (19)

* Cited by examiner, † Cited by third party
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JP3245165B2 (ja) 1991-10-09 2002-01-07 シンテックス（ユー・エス・エイ）・インコーポレイテッド ピリドピリダジノンおよびピリダジンチオン化合物
AU670544B2 (en) * 1991-10-09 1996-07-25 Syntex (U.S.A.) Inc. Benzo and pyrido pyridazinone and pyridazinthione compounds with PDE IV inhibiting activity
ES2105920A1 (es) * 1991-10-09 1997-10-16 Syntex Inc Procedimiento para preparar compuestos de benzo-y piridopiridazinona y piridazinationa.
US5716954A (en) * 1991-10-09 1998-02-10 Syntex U.S.A. Inc. Benzopyridazinone and pyridopyridazinone compounds
WO1993007146A1 (fr) * 1991-10-09 1993-04-15 Syntex (U.S.A.) Inc. Composes benzo et pyrido pyridazinones et pyridazinthiones a activite inhibant la phosphodiesterase iv
CN1045962C (zh) * 1993-01-01 1999-10-27 森德克斯(美国)股份有限公司 吡啶并哒嗪酮或吡啶并哒嗪硫酮化合物,制备它的中间体,含它的药物组合物及其用途
ES2137113A1 (es) * 1997-07-29 1999-12-01 Almirall Prodesfarma Sa Nuevos derivados de triazolo-piridazinas heterociclicos.
US6407108B1 (en) 1997-07-29 2002-06-18 Almirall Prodesfarma, S.A. 1,2,4-triazolo(4,3-b)pyrido(3,2-d)pyridazine derivatives and pharmaceutical compositions containing them
WO1999029695A1 (fr) * 1997-12-05 1999-06-17 Astrazeneca Uk Limited Nouveaux composes
US6342601B1 (en) 1997-12-05 2002-01-29 Astrazeneca Ab Compounds
US6770646B2 (en) 1997-12-05 2004-08-03 Astrazeneca Ab Substituted fused pyridazinone compounds; composition and use thereof
US6380196B1 (en) 1997-12-15 2002-04-30 Byk Gulden Lomberg Chemische Fabrik Gmbh Dihydrobenzofurans
EP1050536A3 (fr) * 1999-05-06 2000-11-15 Wacker-Chemie GmbH Composé des silanes 2-(Benz-)Imidazol-, 2-(Benz-)Oxazol- ou 2-(Benz-)Thiazol-substitués
WO2003057689A1 (fr) * 2002-01-02 2003-07-17 Fujisawa Pharmaceutical Co., Ltd. Composes aminopyrimidine, procedes de preparation de ces composes et compositions pharmaceutiques les contenant
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors
JP2020529458A (ja) * 2017-08-10 2020-10-08 中国科学院上海薬物研究所 フタラジノン系化合物、その製造方法、医薬組成物及びその使用
CN108250150A (zh) * 2018-03-15 2018-07-06 兰州大学 一种肽嗪酮化合物及其制备方法与应用
CN108250150B (zh) * 2018-03-15 2020-12-29 兰州大学 一种肽嗪酮化合物及其制备方法与应用

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