WO1997021691A1 - Derives thiazole - Google Patents

Derives thiazole Download PDF

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Publication number
WO1997021691A1
WO1997021691A1 PCT/JP1996/003637 JP9603637W WO9721691A1 WO 1997021691 A1 WO1997021691 A1 WO 1997021691A1 JP 9603637 W JP9603637 W JP 9603637W WO 9721691 A1 WO9721691 A1 WO 9721691A1
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WO
WIPO (PCT)
Prior art keywords
group
general formula
salt
thiazole
reaction
Prior art date
Application number
PCT/JP1996/003637
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English (en)
Japanese (ja)
Inventor
Jun Nakano
Satoshi Murai
Hiroshi Yamamoto
Yoshihiro Ichikawa
Masaru Ogawa
Mitsuru Watanuki
Kimie Debuchi
Tsutomu Nakamura
Original Assignee
Kaken Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kaken Pharmaceutical Co., Ltd. filed Critical Kaken Pharmaceutical Co., Ltd.
Priority to AU11104/97A priority Critical patent/AU1110497A/en
Publication of WO1997021691A1 publication Critical patent/WO1997021691A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to a novel thiazol derivative having leukotriene D (hereinafter abbreviated as LTD) receptor antagonism and thromboxane A 2 (hereinafter abbreviated as TXA 2 ) receptor antagonism, and a synthetic intermediate thereof.
  • LTD leukotriene D
  • TXA 2 thromboxane A 2
  • an anti-allergic agent such as a histamine receptor antagonist or a mediator release inhibitor from mast cells, or steroids.
  • Bronchodilators such as tin derivatives and tri-exchanger receptor stimulants have been used.
  • bronchial asthma is characterized by increased airway responsiveness to various stimuli, with reversible airway narrowing, airway mucosal edema, increased mucus secretion, and infiltration of inflammatory cells into the airway wall. It is recognized as a disease.
  • LTD has a strong bronchoconstrictive effect
  • TXA 2 supports not only a strong bronchoconstrictive effect but also airway hyperreactivity.
  • allergic diseases such as bronchial asthma
  • LTD receptor antagonists and TXA 2 synthesis inhibitors have been launched on the market, and TXA 2 receptor antagonists have been clinically applied. Higher efficacy has been confirmed compared to conventional antiallergic agents.
  • allergic diseases such as bronchial asthma are caused by the simultaneous involvement of various mediators, resulting in their pathology. Its efficacy is limited, and by simultaneously suppressing both the mediators, LT Da and TXA 2 , which are the major mediators in allergic conditions, a new anti-allergic agent that can be expected to have superior therapeutic effects Development is desired.
  • LTD. And as a compound having both a receptor antagonism for both mediators TXA 2, JP-3 258 759, JP-A No. 4 one 1 54757, JP-A No. 4-1 54766, JP-A No. 5 26 2736 And Japanese Patent Application Laid-Open Nos. 5-279336 and 6-41 051, which are structurally different from the compounds of the present invention.
  • Receptor antagonism of LTD which is considered to be a major mediator, is considered to have insufficient potency to expect a sufficient therapeutic effect as an antiallergic agent.
  • the present invention has been made in view of the current state of treatment and therapeutic research for such allergic diseases, and it is an object of the present invention to provide LTD 4 and TXA which play a major role in the development of allergic diseases.
  • An object of the present invention is to provide a novel compound which has a potent therapeutic effect on both of the two mediators and which can be expected to have a more excellent therapeutic effect, and an antiallergic agent comprising these as active ingredients. Disclosure of the invention
  • the present inventors have conducted intensive studies in order to achieve the above-mentioned object in the treatment of allergic diseases and the above-mentioned research trends.
  • the thiazole derivative of the present invention is mainly used for the development of allergic diseases.
  • superior antagonistic activity against both mediators, LTD 4 and TXA 2 which play an important role, and are superior to single mediator-receptor antagonists or synthetic inhibitors mentioned above.
  • the inventors have found that the present invention has an effect, and have completed the present invention.
  • the present invention provides a compound represented by the general formula (I):
  • X is the force Ruponiru group or a sulfonyl group, ⁇ is a carboxyl groups, C 5 alkoxycarbonyl group, or 1 H- Te Torazoru 5 I le group
  • Z is C, - 5 alkyl groups, C 3 - 6 cycloalkyl or phenyl group
  • W is C 2 - a 5 alkylene group or a 1, 4 xylene group to Shikuro
  • R represents an optionally substituted phenylpropyl sulfonyl amino group, Fuweniru sulfonyl group, N '- off We two Ruchiourei de group or C, -.
  • alkylsulfonyl is alkylsulfonyl ⁇ Mi amino group) represented by thiazole derivative or a salt thereof and the general formula (I) thiazole derivative or a pharmacologically in An antiallergic agent containing an acceptable salt as an active ingredient and a general formula (II) which is a synthetic intermediate of a thiazole derivative of the general formula (I)
  • Z is C, - 5 alkyl group, a C 3- 6 cycloalkyl group or a phenylene Le group
  • W is C 2 - a 5 alkylene group or a 1, 4-xylene group to Shikuro
  • R represents a substituted which may be full I sulfonyl sulfonyl ⁇ Mi amino group, full Wenirusuruhoniru group, N '- off We two Ruchiourei de group or C, -. 5 is Al kill sulfonyl ⁇ Mi amino group
  • the C, -5 alkoxycarbonyl group represented by ⁇ is a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group. , N-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, n-pentoxycarbonyl group and the like. Preferably, it is a methoxycarbonyl group.
  • Examples of the C 5 alkyl group represented by Z include straight groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, and n-pentyl group. Or a branched alkyl group. Particularly preferred are an isopropyl group and a tert-butyl group.
  • C 2 represented by W - The 5 alkylene group, an ethylene group, trimethylene down group, Te Toramechiren group, pentamethylene group. Particularly preferred is a tetramethylene group.
  • R which may be substituted represented by R: r-nylsulfonylamino group, r-inylsulfonyl group, N'-f: L-dithiothioureido group includes a fluorine atom, a chlorine atom, a bromine atom Halogen atoms such as iodine atoms, alkyl groups such as methyl and ethyl groups, and ethoxy groups and ethoxy groups. And a lucoxy group. Particularly preferred are a fluorine atom, a chlorine atom, a bromine atom, a methyl group and a methoxy group.
  • any of the racemic forms, diastereoisomers and individual optical isomers may be used. It is included in the present invention, and when a geometric isomer is present, the (E) -form, the (Z) -form and a mixture thereof are all included in the present invention.
  • Salts of the compounds of the present invention represented by the general formulas (I) and (II) are also included in the compounds of the present invention. These salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates, phosphates, carbonates, etc.
  • Inorganic acid salts lower alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, and arylsulfonates such as P-toluenesulfonate
  • Organic salts such as fumarate, succinate, citrate, tartrate, oxalate, and maleate; amino acids such as glycine, alanine, glutamate, and aspartate; and sodium And alkali metal salts such as salts and potassium salts. Preference is given to sodium salts or hydrochlorides.
  • the thiazole derivative of the general formula (I) can be produced by the following method. Manufacturing a method ⁇
  • the compound represented by the general formula (III) (which can be produced by the production method described in JP-A-6-80654) and the compound represented by the general formula (IV) are subjected to a dehydration reaction in an inert solvent.
  • the compound represented by the general formula (II) can be produced by a reduction reaction with a reducing agent.
  • the compound represented by the general formula (II) is a useful synthetic intermediate of the compound represented by the general formula (I).
  • the inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction, and for example, ethanol, methanol, and the like are preferable.
  • the reducing agent to be used is not particularly limited as long as it is a normal reducing agent for reducing an imino group to an amino group, but for example, sodium borohydride, lithium aluminum hydride and the like are preferable.
  • This reaction uses 1 to 1.3 equivalents of the compound represented by the general formula (IV) and 1 to 3 equivalents of the reducing agent with respect to the compound represented by the general formula (III).
  • a molecular sieve may be present in the reaction solution in order to promote the dehydration reaction.
  • the amount of the molecular sieve is usually 20 Omg for the compound ⁇ mm 0 I represented by the general formula (I I I).
  • the reaction temperature may be appropriately selected from the range of room temperature to the boiling point of the solvent, and the reaction time may be appropriately selected from the range of 4 to 12 hours.
  • the compound represented by the general formula (III) can also be produced by the following production method.
  • the compound represented by the general formula (III) can be produced by dehydrating and condensing the compound represented by the general formula (VIII) with isophthaldialdehyde in acetic anhydride.
  • the reaction temperature may be appropriately selected from the range of 50 to 180 ° C, and the reaction time may be appropriately selected from the range of 5 to 36 hours.
  • Y is C, - 5 alkoxy process of the present invention compound represented by the general formula is a carbonyl group (I a)
  • the desired general compound is obtained.
  • the compound represented by the formula (Ia) can be produced.
  • the compound represented by the general formula (Ia) is a useful synthetic intermediate for the compound represented by the general formula (Ib).
  • the inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction. For example, dichloromethane, 1,2-dichloroethane and the like are preferable.
  • the base to be used is not particularly limited as long as it usually acts as a base, but a tertiary ammine organic base such as triethylamine or pyridine is preferable.
  • the compound represented by the general formula (V) is used in an amount of up to 3 equivalents and the base is used in an amount of 2 to 8 equivalents based on the compound represented by the general formula (II).
  • reaction temperature ranges from 0 to 80 ° C, and the reaction time is! 1 to 1 ⁇ Time may be selected as appropriate.
  • the desired compound represented by the general formula (Ib) can be produced by subjecting the compound represented by the general formula (la) to a hydrolysis reaction with a base in an inert solvent.
  • the inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.
  • methanol and ethanol are preferred.
  • the base to be used is not particularly limited as long as it is usually used for a hydrolysis reaction of an ester group.
  • a 1 N aqueous sodium hydroxide solution, a 1 N aqueous potassium hydroxide solution and the like are preferable.
  • the amount of the base is 1 to 50 equivalents to the compound represented by the general formula (la).
  • the reaction temperature may be appropriately selected from the range of 0 ° C. to the boiling point of the solvent, and the reaction time may be appropriately selected from the range of 1 to 8 hours.
  • the desired compound represented by the general formula (1c) can be produced by reacting the compound represented by the general formula (II) with phthalic anhydride in an inert solvent. This reaction may be carried out in the presence of a base in the reaction solution in advance.
  • the inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.
  • toluene and 1,2-dimethoxetane are preferable.
  • the base to be used is not particularly limited as long as it usually acts as a base, and for example, sodium acetate, potassium acetate and the like are preferable.
  • the reaction temperature may be appropriately selected from the range of room temperature to the boiling point of the solvent, and the reaction time may be appropriately selected from the range of 2 to 48 hours.
  • the compound represented by the general formula (II) and the compound represented by the general formula (VI) are condensed alone or in a solvent such as condensing agent or hydroxy 1H-benzotriazole monohydrate (hereinafter, abbreviated as HOBt).
  • HOBt hydroxy 1H-benzotriazole monohydrate
  • the inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this type of reaction.
  • N, N-dimethylformamide and the like are preferable.
  • the condensing agent to be used is not particularly limited as long as it usually acts as a dehydrating condensing agent.
  • a dehydrating condensing agent for example, 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (hereinafter abbreviated as ws C), Dicyclohexylcarbodiimide is preferred.
  • This reaction generally uses 1 equivalent of the compound represented by the general formula (VI), 1.1 equivalent of the condensing agent, and 1.1 equivalent of H 0 Bt with respect to the compound represented by the general formula (II). .
  • the reaction temperature ranges from room temperature to the boiling point of the solvent, and the reaction time is 2-30. What is necessary is just to select suitably from the range of time.
  • All of the target compounds produced by the above-mentioned production methods a and A to D can be isolated and purified by a conventional method.
  • the thiazole derivative of the general formula (I) thus obtained has an excellent anti-allergic effect because it has both LT DA receptor antagonism and TXA 2 receptor antagonism, and has an allergic bronchial effect. It is highly effective in preventing and treating various allergic diseases such as asthma, rhinitis and conjunctivitis, atopic dermatitis, gastroenteritis, colitis, spring catarrh, and nephritis.
  • the thiazole derivative of the present invention can be used alone or in various dosage forms using a known preparation method.
  • oral preparations such as tablets, capsules, granules, powders and syrups
  • parenteral preparations such as injections, nasal drops, eye drops, ointments, suppositories and inhalants.
  • the dosage varies depending on the patient's symptoms, age, body weight, therapeutic effect, administration method, and administration period.For oral administration, it is preferable that the dose be in the range of 0.1 mg to 1 g per adult per day. is there.
  • the 'H-NMR spectrum was measured with a J NM-EX270 type spectrometer (270 MHz, manufactured by JEOL Ltd.) using tetramethylsilane (TMS) as an internal standard. Indicated by The mass spectrum was measured with a QP1 OOOEX type spectrum meter (manufactured by Shimadzu Corporation).
  • Examples 54 to 106 were produced in the same manner as in Example 53.
  • Table 2 shows the physical property values of the obtained compound.
  • Examples # 08 to 160 were produced in the same manner as in Example 107.
  • Table 3 shows the physical property values of the obtained compound.
  • Examples 162 to 192 were produced in the same manner as in Example 161.
  • Table 4 shows the physical property values of the obtained compound.
  • Examples 194 to 200 were produced in the same manner as in Example 193.
  • Table 5 shows the physical property values of the obtained compound.
  • thiazole Ichiru derivatives of the present invention will be described by way of Test Examples will be have a good receptor antagonism and anti-allergic effects on both Medellin Ieta of LT D ⁇ and TXA 2.
  • the compounds of the present invention were tested for ⁇ LTD action, anti-TXA 2 activity and ⁇ breath action.
  • the test method and test results are shown below.
  • the specimen 95% 0 2 - aerated with 5% C 0 2 mixed gas, at 37 ° C for data kept in Irodo (T yr 0 de) Magnus bath filled with liquid 2m I, load 1 g of the sample And the contraction reaction caused by the addition of LTD 4 was recorded isotonic.
  • the anti-asthmatic effect was examined by passive sensitization guinea pig immediate asthmatic response. That is, on the day before the experiment, guinea pigs were treated with anti-DN PZo V aI bumin guinea pig serum (guinea pig PCA titer; X102) 4) was administered through the ear vein for sensitization. On the day of the experiment, after pretreatment with pyrilamine (10 mg / kg i.p.), normal airway resistance was measured by the double flow plethysmograph method according to the method of Pennock et al.
  • test substance (3mgZkg) was dissolved in DMS ⁇ , then dissolved in 50% normal guinea pig serum monophysiological saline solution, and administered to the ear vein 5 minutes before inhalation of the antigen.
  • Immediate asthmatic response was induced by inhalation exposure to a 1% ovalbumin saline solution as an antigen using an ultrasonic nebulizer for 3 minutes, and airway resistance was measured 5 minutes (4 to 6 minutes) after the end of inhalation.
  • the data was represented by the inhibition rate calculated by the following equation.
  • A Airway resistance value after inhalation of antigen in the test substance group
  • Table 7 shows the results. From the results, it was confirmed that the compound of the present invention had an excellent anti-asthmatic effect.
  • a tablet containing 100 mg of the active ingredient per tablet was prepared.
  • 190 mg of the mixed ingredient containing 100 mg of the active ingredient was filled in a capsule to prepare a capsule.
  • the novel thiazol derivative represented by the general formula (I) of the present invention has both LTD4 receptor antagonism and TxAz receptor antagonism, and exhibits excellent antiasthmatic activity. Therefore, the compounds of the present invention are useful as antiallergic agents for treating and preventing various allergic diseases such as allergic bronchial asthma.

Abstract

Les dérivés thiazole représentés par la formule générale (I) et certains de leurs sels font preuve d'antagonisme aux récepteurs aussi bien du leucotriène D4 que de la thromboxane A2. Dans cette formule générale, X est carbonyle ou sulfonyle; Y est carboxyle, alcoxycarbonyle C1-C5 ou 1H-tétrazol-5-yle; Z est alkyle C1-C5, cycloalkyle C3-C6 ou phényle; W est alkylène C2-C5 ou 1,4-cycloxyhexylène, et R est phénylsulfonylamino, phénylsulfonyle, N'-phénylthiouréïdo ou alkylsulfonylamino C1-C5 éventuellement substitués.
PCT/JP1996/003637 1995-12-14 1996-12-13 Derives thiazole WO1997021691A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11104/97A AU1110497A (en) 1995-12-14 1996-12-13 Thiazole derivatives

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JP34735295 1995-12-14
JP7/347352 1995-12-14

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WO1997021691A1 true WO1997021691A1 (fr) 1997-06-19

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0999209A1 (fr) * 1997-06-17 2000-05-10 Kaken Pharmaceutical Co., Ltd. Derives d'acide 2-sulfamoylbenzoique
WO2009090976A1 (fr) * 2008-01-16 2009-07-23 Kaken Pharmaceutical Co., Ltd. Préparation thérapeutique transmucosale pour une obstruction nasale
JP2011517665A (ja) * 2008-03-11 2011-06-16 メルク パテント ゲーエムベーハー エレクトロルミネセント特性または電子輸送特性を有する化合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62142168A (ja) * 1985-10-16 1987-06-25 Mitsubishi Chem Ind Ltd チアゾ−ル誘導体及びそれを有効成分とするロイコトリエンきつ抗剤
JPH03258759A (ja) * 1990-03-09 1991-11-19 Terumo Corp フェノキシ酢酸誘導体およびこれを含有する医薬製剤
JPH04154757A (ja) * 1990-10-16 1992-05-27 Terumo Corp フェノキシ酢酸誘導体及びこれを含有する医薬製剤
JPH05262736A (ja) * 1992-03-23 1993-10-12 Terumo Corp フェノキシ酢酸誘導体
JPH05279336A (ja) * 1992-03-23 1993-10-26 Terumo Corp フェノキシ酢酸誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62142168A (ja) * 1985-10-16 1987-06-25 Mitsubishi Chem Ind Ltd チアゾ−ル誘導体及びそれを有効成分とするロイコトリエンきつ抗剤
JPH03258759A (ja) * 1990-03-09 1991-11-19 Terumo Corp フェノキシ酢酸誘導体およびこれを含有する医薬製剤
JPH04154757A (ja) * 1990-10-16 1992-05-27 Terumo Corp フェノキシ酢酸誘導体及びこれを含有する医薬製剤
JPH05262736A (ja) * 1992-03-23 1993-10-12 Terumo Corp フェノキシ酢酸誘導体
JPH05279336A (ja) * 1992-03-23 1993-10-26 Terumo Corp フェノキシ酢酸誘導体

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0999209A1 (fr) * 1997-06-17 2000-05-10 Kaken Pharmaceutical Co., Ltd. Derives d'acide 2-sulfamoylbenzoique
EP0999209A4 (fr) * 1997-06-17 2004-09-15 Kaken Pharma Co Ltd Derives d'acide 2-sulfamoylbenzoique
WO2009090976A1 (fr) * 2008-01-16 2009-07-23 Kaken Pharmaceutical Co., Ltd. Préparation thérapeutique transmucosale pour une obstruction nasale
JP2011517665A (ja) * 2008-03-11 2011-06-16 メルク パテント ゲーエムベーハー エレクトロルミネセント特性または電子輸送特性を有する化合物

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