WO1998042672A1 - Derives benzeniques - Google Patents

Derives benzeniques Download PDF

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Publication number
WO1998042672A1
WO1998042672A1 PCT/JP1998/001265 JP9801265W WO9842672A1 WO 1998042672 A1 WO1998042672 A1 WO 1998042672A1 JP 9801265 W JP9801265 W JP 9801265W WO 9842672 A1 WO9842672 A1 WO 9842672A1
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Prior art keywords
compound
hydrogen
defined above
acceptable salt
pharmaceutically acceptable
Prior art date
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PCT/JP1998/001265
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English (en)
Japanese (ja)
Inventor
Koji Hagihara
Masashi Yanase
Koji Suzuki
Chihiro Nosaka
Michio Ichimura
Hiromi Murakami
Akira Horiguchi
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
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Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU64220/98A priority Critical patent/AU6422098A/en
Publication of WO1998042672A1 publication Critical patent/WO1998042672A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof

Definitions

  • the present invention has an activity as a bradykinin antagonist, and is useful for treating various diseases induced by bradykinin or its analogs such as allergy, inflammation, autoimmune disease, shock, pancreatitis, asthma, and pain. It relates to a benzene derivative and a salt thereof.
  • BACKGROUND ART-It is disclosed that mono- or dihalogen-substituted benzene derivatives to which quinoline, quinoxaline, quinazoline and cinnoline derivatives are bound have an activity as a bradykinin antagonist JP-A-7-002780, 7-242666
  • the other substituents on the benzene ring of the benzene derivative are limited to substituted amino groups or substituted heterocycles, and are substituted or unsubstituted.
  • No benzene derivative substituted with an alkyl, alkenyl or phenyl has any activity as a bradykinin antagonist.
  • the substituents on the heterocyclic ring of the benzene derivative are halogen, lower alkyl, acyl, aryl, oxo, nitro, amino, aralkyl (benzyl, phenethyl, etc.) and lower alkoxycarbonyl lower alkyl (methoxycarbonylmethyl, methoxycarbonyl).
  • Benzene derivatives substituted with a pyrrole ring substituted with lower alkoxymethyl, hydroxymethyl, substituted or unsubstituted aminomethyl, lower alkoxycarbonyl, carbonyl, nitrile, carbamoyl, etc. It is not known that it has any activity as an agent.
  • An object of the present invention is to provide a benzene derivative having activity as a bradykinin antagonist and a salt thereof.
  • the present invention provides a compound represented by the general formula (I):
  • R 6 represents hydrogen, lower alkyl, hydroxy, lower alkoxy, nitro, or halogen
  • R 7 represents hydrogen or lower alkyl
  • X 1 represents ⁇ , S, or NR 9 (wherein, R 9 represents hydrogen, lower alkyl, lower alkanoyl, or aroyl).
  • X 2 is a substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, or CHZ 3 R 1G (wherein, R 1 ( ⁇ has the same meaning as R 7, Z 3 represents represents.) the bond becomes either Z 1 and integrally represents hydrogen, Z 1 Contact And Z 2 both represent hydrogen, or Z 1 and Z 2 together represent a bond. ] Or the following expression
  • RR 2 , and R 3 are the same or different and each represents hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanol, aroyl, carboxy, lower alkoxycarbonyl, halogen, nitro, or NR 11A R 12A (wherein R 11A and R 12A is the same or different and has the same meaning as R 7. ).
  • W 1 and W 2 both represent hydrogen, W 1 and W 2 together represent ⁇ , or W 1 and W 2 together with E represent N.
  • n is an integer of 0-2, when B is B 2 m is 1.
  • U 2 is NR 14 R 15 (wherein R 14 and R 15 are the same or different and represent hydrogen or lower alkyl, or R 14 and R 15 sandwich the nitrogen atom and are other than carbon Child, for example, 0, S, or NR 16A , where R 16A represents a nitrogen-containing heterocyclic group consisting of the same meaning as R 7.) May 3-8 membered ring which may contain.] Or the following formula U 2A
  • Y 2 represents N or CH
  • R 17 is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanol, aroyl, carboxyl, lower alkoxycarbonyl, halogen, nitro, NR 11B R 12B (wherein, R 11B and R 12B are the same as R 7 ), ⁇ (CH 2 ) P NR 11C R 12C (wherein, R 11C and R 12C have the same meanings as R 7 , and p represents an integer of 0 to 5.
  • U 4 U 5 wherein , U 4 is NHCO (CH 2 ) ql (wherein, Q 1 represents an integer of 0 to 5.)
  • Y 3 and Q 2 have the same meanings as Y 2A and Q 1 , respectively, and R 2Q is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyl, aroyl, lower alkoxypropyl, halogen, nitro, or NR 11D R 12D (wherein, R 11D and R 12D have the same meanings as R 7 ).
  • R 4 and R 5 may include S, 0, or NR 16B (where R 16B has the same meaning as R 16A ) other than a carbon atom in the middle of the nitrogen atom.
  • A, B, X 1 , RR 2 , R 3 , W 2 , and m are as defined above.
  • J represents hydrogen, NH 2 , OR 21 (wherein R 21 has the same meaning as described above), or represents N together with W 1 and W 2 .
  • the compound represented by the formula (1) itself has a bradykinin antagonistic activity and is useful, and is also useful as an intermediate in synthesizing the compound (I).
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by the formula (I).
  • B is B 2 (B 2 is as defined above), X 3 is N, and W 1 , W 2 and E are N- Certain compounds or pharmacologically acceptable salts thereof.
  • B is B 2 (B 2 has the same meaning as described above), X 3 is N, W 1 and W 2 are in the form of O, A compound wherein E is hydrogen or a pharmaceutically acceptable salt thereof.
  • B is B 2 (B 2 has the same meaning as described above), W 1 and W 2 are in the form of O, and R 21 is hydrogen Compound or pharmacologically acceptable salt thereof.
  • B is B 2 (B 2 is as defined above), W 1 and W 2 are in the form of O, and R 21 is lower alkyl. Certain compounds or pharmacologically acceptable salts thereof.
  • B is B 1 (B 1 has the same meaning as described above), and W 2 is — and is O, m is 1, E is NR 4 R 5 wherein R 4 and R 5 are as defined above, and U 1 is (CH 2 ) nl (nl is as defined above) or a pharmacologically active compound thereof. Acceptable salt.
  • B is B 1 (B 1 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (where R 5 is Wherein U 1 is C ⁇ U 3 (wherein U 3 has the same meaning as described above), or a pharmaceutically acceptable salt thereof.
  • B is B 1 (B 1 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (where R 5 is Wherein U 1 is CONR 13 (CH 2 ) n2 (wherein R 13 and n 2 are as defined above), or a pharmaceutically acceptable salt thereof. .
  • B is B 1 (B 1 is as defined above), m is 0, and E is NHR 5 (where R 5 is as defined above) Or a pharmaceutically acceptable salt thereof, wherein U 1 is CON R 13 (CH 2 ) n 2 (wherein R 13 and n 2 are as defined above).
  • B is B 2 (B 2 is as defined above), W 1 and W 2 are hydrogen, m is 1, E is NR 4 R 5 (Wherein, R 4 and R 5 are as defined above.), And U 1 is (CH 2 ) nl (n 1 is as defined above). Or a pharmaceutically acceptable salt thereof.
  • B is B 2 (B 2 is as defined above), and W 2 is hydrogen, and E is NR 4 R 5 (wherein R 4 and R 5 is the same as defined above; R 4 is a lower alkanol; and U 1 is (CH 2 ) nl (nl is as defined above), or a pharmaceutically acceptable compound thereof. salt.
  • B is B 2 (B 2 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (wherein R 5 is Wherein U 1 is CONR 13 (CH 2 ) n2 (wherein R 13 and n 2 have the same meanings as described above), or a pharmaceutically acceptable salt thereof.
  • B is B 2 (B 2 has the same meaning as described above), and W 2 is in the form of O, and E is NR 4 R 5 (formula Wherein R 4 and R 5 have the same meanings as described above.) And U 1 is (CH 2 ) nl (n 1 has the same meaning as described above), or a pharmaceutically acceptable compound thereof. salt.
  • B is B 2 (B 2 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (where R 5 is Wherein U 1 is COU 3 (where U 3 is as defined above), or a pharmaceutically acceptable salt thereof.
  • B is B 1 (B 1 is as defined above), Z 1 and Z 2 are hydrogen, W 1 and W 2 are hydrogen, m Is 1 and E is NH 2 , or a pharmaceutically acceptable salt thereof.
  • B is B 1 (B 1 has the same meaning as described above), Z 1 and Z 2 are in the form of a bond, Z 2 is hydrogen, A compound or a pharmaceutically acceptable salt thereof, wherein W 1 and W 2 are hydrogen, m is 1, and E is NH 2 .
  • B is B 1 (B 1 is as defined above), Z 1 and Z 2 are hydrogen, m is 0, and E is NH 2 Certain compounds or pharmacologically acceptable salts thereof.
  • B is B 1 (B 1 is as defined above), Z 1 and Z 2 are hydrogen, and W 1 and W 2 are ⁇ , m is 1 and R 21 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • B is B 1 (B 1 has the same meaning as described above), Z 1 and Z 2 are in the form of a bond, Z 3 is hydrogen, A compound or a pharmaceutically acceptable salt thereof, wherein W 1 and W 2 are in the form of R, m is 1, and R 21 is hydrogen.
  • B is B 1 (B 1 has the same meaning as described above), Z 1 and Z 3 are a bond to form a bond, Z 2 is hydrogen, A compound or a pharmaceutically acceptable salt thereof, wherein W 1 and W 2 are in the form of m, m is 1, and R 21 is hydrogen.
  • B is B 1 (B 1 has the same meaning as described above), W 1 and W 2 are in the form of O, m is 1, E is NR 4 R 5 (wherein R 4 and R 5 are as defined above), and U 1 is (CH 2 ) nl (nl is as defined above); A compound wherein U 2 is U 2A (U 2A is as defined above), and R 17 is NH 2 , or a pharmaceutically acceptable salt thereof.
  • B is B 1 (B 1 has the same meaning as described above), W 1 and W 2 are in the form of O, m is 1, E is NR 4 R 5 (wherein R 4 and R 5 are as defined above), and U 1 is (CH 2 ) nl (nl is as defined above); U 2 is U 2A (U 2A is as defined above), and U 4 is NHCO
  • B is B 1 (B 1 is as defined above), And W 2 is O, m is 1, E is NR 4 R 5 (wherein R 4 and R 5 are as defined above), and U 1 is (CH 2 ) nl (nl is as defined above), U 2 is U 2A (U 2A is as defined above), and U 4 is CONH
  • B is B 1 (B 1 has the same meaning as described above), W 1 and W 2 are in the form of O, m is 1, E is NR 4 R 5 (wherein, -R 4 and R 5 are as defined above), and U 1 is (CH 2 ) nl (nl is as defined above). Or a pharmaceutically acceptable salt thereof, wherein U 2 is U 2A (U 2A is as defined above), and R 17 is carboxyl.
  • B is B 1 (B 1 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (where R 5 is Wherein U 1 is COU 3 (where U 3 has the same meaning as described above), and U 2 is U 2A (where U 2A has the same meaning as described above).
  • R 17 is NH 2 or a pharmaceutically acceptable compound thereof
  • B is B 1 (B 1 is as defined above), and W 2 is hydrogen, and E is NHR 5 (where R 5 is as defined above)
  • U 1 is COU 3 (wherein U 3 is as defined above), and U 2 is U 2A (U 2A is as defined above), and U Or a pharmaceutically acceptable salt thereof, wherein 4 is NHC ⁇ (CH 2 ) ql U 5 (wherein Q 1 and U 5 are as defined above).
  • B is B 1 (B 1 is as defined above), and W 2 is hydrogen, and E is NHR 5 (where R 5 is as defined above)
  • B is B 1 (B 1 is as defined above), and W 2 is hydrogen, and E is NHR 5 (where R 5 is as defined above) U 2 is U 2A (U 2A is as defined above.), U 1 is COU 3 (where U 3 is as defined above.), And R 17 Is carboxy or a pharmaceutically acceptable compound thereof Salt.
  • B is B 1 (B 1 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (where R 5 is Wherein U 1 is C ⁇ NR 13 (CH 2 ) n2 (wherein R 13 and n 2 are as defined above), and U 2 is U 2A (U 2A Is the same as defined above, and R 17 is NH 2 or a pharmacologically acceptable salt thereof.
  • B is B 1 (B 1 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (where R 5 is Wherein U 1 is CONR 13 (CH 2 ) n2 (wherein R 13 and n 2 have the same meanings as described above), and U 2 is U 2A (U 2A is Wherein U 4 is NHC ⁇ (CH 2 ) ql U 5 (wherein Q 1 and U 5 have the same meaning as described above), or a pharmaceutically acceptable salt thereof. salt.
  • B is B 1 (B 1 is as defined above), W 1 and W 2 are hydrogen, and E is NHR 5 (where R 5 is Wherein U 1 is CONR 13 (CH 2 ) n2 (wherein R 13 and n 2 have the same meanings as described above), and U 2 is U 2A (U 2A is And R 17 is carboxy, or a pharmaceutically acceptable salt thereof.
  • the alkyl portion of lower alkyl, lower alkoxy, and lower alkoxycarbonyl includes methyl having 1 to 6 carbon atoms, methyl, propyl, isopropyl, butyl, isobutyl, J ⁇ i-butyl, pentyl, carboxymethyl Le like a straight-chain or branched ⁇ like can be mentioned to, preferable one is a C i ⁇ C 4 alkyl methyl, Echiru, propyl, isobutyl, and butyl.
  • Lower alkanols are straight-chain or branched having 1 to 7 carbon atoms, such as formyl, Acetyl, propionyl, butyryl, isoptyryl, valeryl and the like.
  • halogen include fluorine, chlorine, bromine, and iodine atoms.
  • Specific examples of aryl and the aryl moiety of aryloyl include phenyl, naphthyl and the like. Examples include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, and purinyl.
  • Examples of the alicyclic heterocycle include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidino, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, bilanyl, tetrahydrofuranyl and the like.
  • Examples of the substituent of aryl, aromatic heterocyclic ring, and alicyclic heterocyclic ring include lower alkyl, nitro, amino, aryl substituted with amino, aryl, carboxy, lower alkoxycarbonyl, lower alkanol, and arylo. No. Here, lower alkyl, aryl, lower alkoxycarbonyl, lower alkanoyl, and arylo are as defined above.
  • nitrogen-containing heterocyclic ring consisting of a 3- to 8-membered ring, which may contain S, 0, or NR 16 A or NR 16 B other than carbon in the middle of the nitrogen atom, Lysinyl, imidazolidinyl, birazolidinyl, piperidino, piperazinyl, homopiperazinyl, morpholino, thiomorpholino and the like.
  • Pharmaceutically acceptable salts of compound (I) include, for example, inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, and citrate Organic salts such as lactate, oxalate, methanesulfonate, benzenesulfonate and monotoluenesulfonate; alkali metal salts such as sodium and potassium salts; alkaline earth such as magnesium salts and potassium salts Metal salts, ammonium salts such as ammonium and tetramethylammonium, and organic amine addition salts such as morpholine addition salt and piperidine addition salt.
  • inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, and citrate
  • Organic salts such as lactate, oxalate, methanesulfonate, benzenesul
  • Carboxylic acid (X 2 COOH), carboxylic acid derivative such as acid anhydride, acid halide, etc. and 1 equivalent to solvent amount of toluene derivative (III) can be used without solvent or with nitrobenzene, carbon disulfide, dichloromethane
  • an inert solvent such as 1 to 10 equivalents, preferably 3 to 4 equivalents
  • an acid catalyst such as aluminum chloride at 0 to 200 ° C. (when a solvent is used, the boiling point of the solvent used)
  • the compound (IV) is obtained by reacting at 90 to 120 ° C (when using a solvent, the boiling point of the solvent used) for 1 to 12 hours, preferably for 2 to 3 hours.
  • Compound (VII) is obtained by reacting at the boiling point of the solvent used, preferably at 0 ° C. to room temperature for 1 to 12 hours, preferably for 2 to 3 hours.
  • arptyrolactone and 1 equivalent to a solvent amount of the toluene derivative (III) are mixed without solvent or in an inert solvent such as nitrobenzene, carbon disulfide, or dichloromethane, and 1 to 10 equivalents, preferably 3 0 to 200 ° C (boiling point of the solvent used when a solvent is used), preferably 90 to 120 ° C (boiling point of the solvent used when a solvent is used) in the presence of an acid catalyst such as aluminum chloride of up to 4 equivalents For 1 to 12 hours, preferably for 2 to 3 hours to obtain a carboxylic acid (here, the benzene ring can be further nitrated.
  • an inert solvent such as nitrobenzene, carbon disulfide, or dichloromethane
  • 1 to 10 equivalents preferably 3 0 to 200 ° C (boiling point of the solvent used when a solvent is used), preferably 90 to 120 ° C (boiling point of the solvent used
  • an acidic solvent such as sulfuric acid
  • 1 to 5 equivalents preferably By reacting with 1 to 3 equivalents of fuming nitric acid at 0 ° C. to room temperature, preferably at 0 ° C., a nitro form of a benzene ring can be obtained.
  • the obtained carboxylic acid is dissolved in a solvent such as methanol or ethanol using thionyl chloride or the like at 0 ° C to the boiling point of the solvent used, preferably at 50 ° C to the boiling point of the solvent used, for 1 to 5 hours.
  • the compound (VII) is obtained preferably by reacting for 1 to 2 hours.
  • the compound (VII) is prepared by heating the compound (VII) in an inert solvent such as carbon tetrachloride or dichloroethane using a halogenating agent such as 1-bromo succinimide at o ° c to the boiling point of the solvent used.
  • an inert solvent such as carbon tetrachloride or dichloroethane
  • a halogenating agent such as 1-bromo succinimide
  • the reaction is carried out at 50 ° C. to the boiling point of the solvent to be used for 1 to 72 hours, preferably 3 to 12 hours to obtain a compound (VIII).
  • Compound (VIII) is mixed with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (IX), in the presence of 1 to 5 equivalents, preferably 1 to 2 equivalents of a base such as sodium hydride, —dimethylformamide
  • Compound (X) is reacted in an inert solvent such as tetrahydrofuran or ether at 0 ° C to the boiling point of the solvent used, preferably at 0 ° C to room temperature for 1 to 12 hours, and preferably for 2 to 3 hours. obtain.
  • Compound (X) is dissolved in an alcohol such as methanol, an inert solvent such as , ⁇ -dimethylformamide, dimethyl sulfoxide or the like at 0 to 100 ° C using an aqueous base solution such as 1 to 4N sodium hydroxide or the like.
  • the compound (II-a) is obtained by treating for 1 to 12 hours, preferably 2 to 3 hours, at the boiling point of the solvent used.
  • Compound (X) is dissolved in an inert solvent such as tetrahydrofuran or ether at a temperature of from 1 to 78 ° C, preferably from 1 to 10 equivalents, preferably from 1 to 2 equivalents of hydrogen at a boiling point of the solvent used, preferably from 0 ° C to room temperature.
  • the compound (XI) is obtained by reduction with a suitable reducing agent such as lithium aluminum chloride for 1 to 12 hours, preferably 2 to 3 hours.
  • Compound (XI) is converted into ether, tetrahydrofuran, dichloromethane, toluene,
  • a base such as triethylamine or pyridine is used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, and 1 to 5 equivalents, preferably 1 to 3 equivalents, toluenesulfonyl chloride, chloride
  • the compound (XII) is reacted with an acid derivative having a functional group which can be a leaving group such as methanesulfonyl or an acid anhydride thereof at 0 ° C for 1 to 12 hours, preferably for 2 to 3 hours at the boiling point of the solvent used. ).
  • compound (XI) is prepared by using a halogenating agent such as thionyl chloride / phosphorus tribromide in an inert solvent such as ether, tetrahydrofuran, dichloromethane, toluene or pyridine in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents. 0 ° C to boiling point of solvent used 1 to 1
  • a halogenating agent such as thionyl chloride / phosphorus tribromide
  • an inert solvent such as ether, tetrahydrofuran, dichloromethane, toluene or pyridine in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents. 0 ° C to boiling point of solvent used 1 to 1
  • the compound (XII) is obtained by reacting for 2 hours, preferably for 2 to 3 hours.
  • the compound (XII) is obtained by reacting in carbon tetrachloride in the presence of 1 to 5 equivalents of triphenylphosphine, using 1 equivalent to a large excess of carbon tetrabromide at 0 to 80 ° C, if necessary. .
  • Compound (XII) is reacted with an azidating agent such as sodium azide in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents, in an inert solvent such as 1,2-dimethylformamide, ether, or tetrahydrofuran.
  • an azidating agent such as sodium azide in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents
  • an inert solvent such as 1,2-dimethylformamide, ether, or tetrahydrofuran.
  • the compound (XIII) is obtained by reacting at C or the boiling point of the solvent used for 1 to 12 hours, preferably 2 to 3 hours.
  • the compound (II-b) is obtained by reacting in an inert solvent such as toluene at 0 ° C. to the boiling point of the solvent used for 1 to 12 hours, preferably 2 to 3 hours.
  • compound (XIII) is prepared by using 1 to 5 equivalents, preferably 1 to 2 equivalents of triphenylphosphine and 1 to 5 equivalents, preferably 1 to 2 equivalents of water in an inert solvent such as ether, tetrahydrofuran, and ethyl acetate.
  • the compound (II-b) is obtained by reacting at 0 ° C to the boiling point of the solvent used for 1 to 12 hours, preferably for 2 to 3 hours.
  • Compound (XI) is mixed with 1 to 5 equivalents, preferably 1 to 2 equivalents of triphenylphosphine and 1 to 5 equivalents, preferably 1 to 2 equivalents, in an inert solvent such as tetrahydrofuran.
  • the compound (XIV) is obtained by reacting phthalimide at 0 ° C to the boiling point of the solvent used, preferably at 0 ° C to room temperature for 0.5 to 24 hours.
  • compound (XII) is prepared by adding 1 to 5 equivalents, preferably 1 to 2 equivalents of phthalimide in an inert solvent such as dimethylformamide, ether, tetrahydrofuran, methanol, ethanol, or the like at 0 ° C to the boiling point of the solvent used.
  • Compound (XIV) is obtained by reacting the compound with an alkali metal salt such as sodium and potassium.
  • Compound (XIV) is prepared by adding 1 to 5 equivalents, preferably 1 to 2 equivalents of hydrazine monohydrate in an inert solvent such as alcohols such as methanol and ethanol, and 0 ° C to the boiling point of the solvent used. And reacting for 1 to 12 hours to obtain compound (II-b).
  • B is B 1 , Z 1 and Z 2 are in the form of a bond, W 1 and W 2 are in the form of O, m is 1,
  • the compound (II-d) in which m is 1 and J is hydroxy can be produced according to the following reaction steps.
  • Compound (XVI) can be obtained by using compound (XV)
  • Compound (XV II) was synthesized from compound (XVI) by the method described in Production method 111. It is obtained according to the method of obtaining compound (VI) from compound (IV). The stereoisomer at the double bond obtained at this time can be separated by a purification method such as silica gel column chromatography if desired.
  • Compound (II-c) and compound (II-d) can be obtained from compound (XV II) according to the method for obtaining compound (II-a) from compound (X) described in Production Method 11 .
  • B is B 1 , Z 1 and Z 2 are in the form of a bond, W 1 and W 2 are hydrogen, and m is 1.
  • the compound (II-e) wherein J is NH 2 can be produced according to the following reaction steps.
  • the compound (XVII) is treated with 1 to 5 equivalents, preferably 1 to 3 equivalents of a reducing agent such as diisobutylaluminum hydride in an inert solvent such as tetrahydrofuran, ether, or toluene at —78 to 80 ° C., preferably 1 to 20 equivalents.
  • a reducing agent such as diisobutylaluminum hydride
  • an inert solvent such as tetrahydrofuran, ether, or toluene
  • Compound (II-e) is obtained according to the method for obtaining compound (II-b) from compound (XI) described in Production Method 1-2.
  • the production method 1 one 5 ⁇ compound (II), B is B 1, a Z 1 and Z 2 are hydrogen, m is 0, compound J is NH 2 (II one I), the following It can be produced according to the following reaction steps.
  • the compound (II-a) is used in an inert solvent such as acetone in an amount of 1 to 5 equivalents, preferably In the presence of 1 to 2 equivalents of a base such as triethylamine, add 0 to 2 equivalents of ethyl ethyl chloroformate at 0 ° C to room temperature, preferably 0 to 5 ° C, for 0.5 to 12 hours, preferably The reaction is carried out for 0.5 to 2 hours. To give an azide of the compound (II-a).
  • the compound (II-f) is obtained by treating the azide in an inert solvent such as toluene at the boiling point of the solvent to be used for 1 to 48 hours, and further with an aqueous solution of a base such as potassium hydroxide or sodium hydroxide.
  • a base such as potassium hydroxide or sodium hydroxide.
  • Diphenylphosphoryl is added, and the mixture is reacted at 0 ° C to the boiling point of the solvent used, preferably at room temperature to the boiling point of the solvent used for 0.5 to 12 hours, preferably 0.5 to 2 hours.
  • Compounds can be treated with an aqueous solution of a base such as sodium oxide
  • an inert solvent such as toluene, tetrahydrofuran, etc.
  • 0.01-1 equivalents preferably 0.1 equivalents.
  • 01 to 0.5 equivalents of a palladium catalyst such as tetrakistriphenylphosphine palladium and a base such as potassium carbonate
  • a palladium catalyst such as tetrakistriphenylphosphine palladium
  • a base such as potassium carbonate
  • the compound (XX) is dissolved in an inert solvent such as carbon tetrachloride or dichloroethane by using 1 to 8 equivalents, preferably 3 to 5 equivalents of the compound (XX) at 0 ° using a halogenating agent such as -bromosuccinimide.
  • a halogenating agent such as -bromosuccinimide.
  • C to the boiling point of the solvent used preferably 50 ° C to the boiling point of the solvent used, 1 to 72 hours
  • Compound (XXI) is obtained by halogenation for a period of preferably 3 to 12 hours.
  • B is B 2 , X 3 is N, and, and J are in the form of a compound (II-h), and B is B 2 and X 3 Is N, W 1 and W 2 are in the form of O, and J is hydrogen.
  • the compound (II-i) can be produced according to the following reaction steps.
  • R 7A has the same meaning as R 7.
  • a pyrrole derivative (XXIII) obtained by the method described in European Patent Application Publication No. EP34945 is mixed with 1 to 5 equivalents, preferably 1 to 2 equivalents of titanium tetrachloride or the like in an inert solvent such as dichloromethane.
  • 1 to 5 equivalents, preferably 1 to 2 equivalents of dichloromethyl methyl ether is added at 15 ° C to room temperature, preferably at 15 ° C to 0 ° C.
  • the compound (XXIV) is obtained by reacting for -12 hours, preferably 2-3 hours.
  • halogenating agent such as -bromosuccinimide in an inert solvent such as carbon tetrachloride or dichloroethane
  • the compound (XXVI) is obtained by halogenating at preferably 50 ° C to the boiling point of the solvent used for 1 to 72 hours, preferably 3 to 12 hours.
  • Compound (II-h) is reacted with 1 to 15 equivalents, preferably 1 to 5 equivalents of a reducing agent such as hydrogenated diisobutylamine in an inert solvent such as tetrahydrofuran under an inert gas atmosphere such as argon at a temperature of 78 ° C To 1 to 12 hours, preferably 2 to 3 hours at room temperature to room temperature, preferably 0 ° C. to room temperature, to obtain compound (II-i).
  • a reducing agent such as hydrogenated diisobutylamine
  • an inert solvent such as tetrahydrofuran
  • an inert gas atmosphere such as argon
  • B is B 2
  • X 3 is N
  • W 1 and W 2 are in the form of O
  • J is hydrogen.
  • the compound (II-i-11) having a limited group position can also be produced by following the following reaction steps.
  • the compound (II—g) or the compound (II-i) is converted to an inert compound such as methanol.
  • an inert compound such as methanol.
  • 1 to 5 equivalents, preferably 1 to 2 equivalents of a suitable reducing agent such as sodium borohydride for 1 to 12 hours the compound (II-j) is obtained by preferably reducing for 2 to 3 hours.
  • the compound (II-1j) is preferably used in an inert solvent such as tetrahydrofuran in an amount of 1 to 5 equivalents. 1 to 2 equivalents of triphenylphosphine, 1 to 5 equivalents, preferably 1 to 2 equivalents of phthalimide and 0 ° C to the boiling point of the solvent used, preferably 0.5 ° C to 0.5 ° C to room temperature.
  • an inert solvent such as methanol or ethanol
  • 1 to 5 equivalents, preferably 1 to 2 equivalents of hydrazine monohydrate, and a compound (XXV I I I) are added at 0 ° C to the boiling point of the solvent used.
  • the compound (IIk) is obtained by reacting for 1 to 12 hours.
  • Compound (II-g) or (Il-i) ( ⁇ -1) (Wherein, A, X 1 , X 3 , RR 2 , and R 3 have the same meanings as described above.)
  • Compound (II—g) or compound (II-i) is prepared by reacting the compound in an inert solvent such as acetone.
  • the compound (II_1) is obtained by reacting with an oxidizing agent such as Jones reagent at 0 ° C to room temperature for 0.5 to 24 hours.
  • Compound (II—m) in which B is B 2 , W 1 and W 2 are in the form of O in compound (II), and R 21 is lower alkyl, can be prepared according to the following reaction steps. Can be.
  • Compound (XXIX) can be obtained according to the method of Production Method 111.
  • Compound (XXX) is obtained by converting compound (III) from compound (III) described in Production Method 11 to compound (V II) can be obtained according to the esterification method in the method for producing Alternatively, compound (XX IX) is reacted with 1 to 10 equivalents, preferably 1 to 3 equivalents of an alkyl such as methyl iodide in an inert solvent such as tetrahydrofuran or dimethylformamide in the presence of a base such as potassium carbonate.
  • the compound (XXX) is obtained by reacting with the agent at o ° c to the boiling point of the solvent used, desirably at o ° c to room temperature for 1 to 72 hours, desirably 1 to 10 hours.
  • Compound (XXXI) can be obtained according to the method for producing compound (VIII) from compound (VII) described in Production method 11-11.
  • Compound (II-m) is obtained according to the method for producing compound (X) from compound (VIII) described in Production method 11-11.
  • Compound (II-g) or compound (II-i) is prepared by converting compound (II-i) into an inert solvent such as tetrahydrofuran under an inert gas atmosphere such as argon in an amount of 1 to 15 equivalents, preferably 1 to 15 equivalents. It is obtained by reacting with 5 equivalents of a reducing agent such as diisobutylaluminum hydride at -78 ° C to room temperature, preferably 0 ° C to room temperature for 1 to 12 hours, preferably 2 to 3 hours.
  • a reducing agent such as diisobutylaluminum hydride
  • the compound (II-11) is obtained according to the method for producing a compound (II-a) from the compound (X) described in the production method 11-11.
  • Compound (II-g) or compound (II-i) is mixed with 1 to 10 equivalents, preferably 1 to 5 equivalents of sodium chlorite in a mixed solvent of 2-methyl-2-propanol and water.
  • the compound (II-11) is obtained by reacting with 10 equivalents, preferably 1 to 5 equivalents of disodium phosphate and 1 to 10 equivalents, preferably 1 to 5 equivalents of 2-methyl-2-butene.
  • Compound (I-a), (II-c) or (II-d) is condensed with compound (XXXII) to obtain compound (I-a).
  • ⁇ In an inert solvent such as dimethylformamide and dichloromethane, from 0 ° C. to the boiling point of the solvent used, preferably from 0 to 80 ° C., from 1 to 5 equivalents, preferably from 1 to 2 equivalents of 1-
  • an appropriate condensing agent such as ethyl-3- (3'-dimethylaminopropyl) carbodiimide, the mixture is reacted with 1 equivalent of the compound (XXXII) for 1 to 12 hours to obtain a compound (I_a).
  • the compound (II-a), (II-c), or (II-d) is used in an amount of 1 equivalent to a solvent, preferably 1 to 3 equivalents of a halogenating agent such as thionyl chloride, and Compound (I) obtained by reacting in an inert solvent such as methane at 0 ° C. to the boiling point of the solvent used for the reaction or the boiling point of the halogenating agent for 0.5 to 6 hours, preferably 1 to 3 hours.
  • a solvent preferably 1 to 3 equivalents of a halogenating agent such as thionyl chloride
  • Compound (I) obtained by reacting in an inert solvent such as methane at 0 ° C. to the boiling point of the solvent used for the reaction or the boiling point of the halogenating agent for 0.5 to 6 hours, preferably 1 to 3 hours.
  • An acid halide such as I_a), (II_c) or (II-d) and one equivalent of the compound (XXXII) are mixed with an pyridine, triethylamine or the like in an inert solvent such as dichloromethane or tetrahydrofuran. 1 to 10 equivalents, preferably 1 to 3 equivalents in the presence of a base, 0 ° C to the boiling point of the solvent used, preferably 0 ° C to room temperature, 0.5 to 24 hours, preferably 1 to 4 hours
  • the compound (I-a) is obtained by the reaction. Manufacturing method 2—2
  • Compound (I - a) in a U 2 is U 2A
  • compound R 17 is a nitro group (I - a - 1) and methanol, in an inert solvent such as ethanol, 3-1 0 equivalent, preferably Or 3 to 5 equivalents of a reducing agent such as tin dichloride or titanium trichloride and the presence of concentrated hydrochloric acid in an equimolar amount with the reducing agent, 0 ° C to the boiling point of the solvent used, for 0.5 to 24 hours, preferably 1 to By reacting the compound (I-a-l) under a hydrogen atmosphere with 0.05 to 0.2 equivalent, preferably 0.05 to 0.1 equivalent of palladium carbon or the like.
  • the reaction is carried out in an inert solvent such as methanol, ethanol, ether, tetrahydrofuran or toluene at 0 ° C to the boiling point of the solvent to be used, or the compound (Ia-1) is converted to methanol,
  • an inert solvent such as methanol, ethanol, ether, tetrahydrofuran or toluene at 0 ° C to the boiling point of the solvent to be used, or the compound (Ia-1) is converted to methanol
  • a mixed solvent of water and an inert solvent such as ethanol
  • B is B 1 , W 1 and W 2 are in the form of ⁇ , m is 1, U 1 is (CH 2 ) ⁇ 1 , and U 2 is U 2A
  • U 4 is NHCO (CH 2 ) q U 5 (I-a-3) can be produced according to the following reaction steps.
  • B is B 1 , W 1 and W 2 are in the form of O, m is 1, U 1 is (CH 2 ) nl , and U 2 is U 2A
  • U 5 (Ia-4) can be produced according to the following reaction steps.
  • Compound (I-a-2) is mixed with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (XXX IV) in an inert solvent such as chloroform, dichloromethane, tetrahydrofuran, ether and the like, and a solvent used at 0 ° C to 0 ° C.
  • Compound (I-a_4) can be obtained by reacting at a boiling point of preferably at room temperature for 0.5 to 24 hours, preferably for 1 to 3 hours. Manufacturing method 2-5
  • B is B 1 , W 1 and W 2 are in the form of O, m is 1, U 1 is (CH 2 ) nl , and U 2 is U 2A Wherein U 4 is CONR 19 (CH 2 ) Q 2 U 5 , and the compound (I—a_5) can be produced according to the following reaction steps.
  • (XXXV) is used to produce the compound (I-a-1) from the compound (II-a), (II-c), or the compound (II-d) described in Production method 2-1 Obtained accordingly.
  • B is B 1
  • a W 1 and W 2 are hydrogen
  • R 4 is hydrogen
  • compound U 1 is a COU 3 (I _b) is It can be produced according to the following reaction steps.
  • B is B 1
  • a W 1 and W 2 are hydrogen
  • R 4 is hydrogen
  • U 1 is C_ ⁇ _U 3
  • U 2 is U 2A
  • R 17 Is a NH 2 (I-b-2) can be produced according to the following reaction steps.
  • Compound U—b—2) is obtained according to the method for producing (I-a-2).
  • compound (I) B is B 1, a W 1 and W 2 are both hydrogen, R 4 is hydrogen, U 1 is COU 3, U 2 is U 2A, the U 4 NHC_ ⁇ (CH 2) ql U 5, compound (I one b-3) can be prepared by the following reaction steps.
  • (I-a) can be obtained according to the method for producing.
  • Preparation 2 - in 9 “Compound (I), B is B 1, a W 1 and W 2 are hydrogen, R 4 is hydrogen, U 1 is COU 3, U 2 is in U 2A There, U 4 is NH (CX 4) NH (CH 2) q 3 U 5 , compound (I one b-4) is leaving in be prepared by the following reaction steps.
  • B is B 1
  • a W 1 and W 2 are hydrogen
  • R 4 is hydrogen
  • compound U 1 is a CONR 13 (CH 2)
  • n2 U 2 (I _c) is It can be produced according to the following reaction steps.
  • the compound (II-b), (II-e) or (II-f) is dissolved in an inert solvent such as dichloromethane or tetrahydrofuran in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents of carbonyldiimidazole.
  • an inert solvent such as dichloromethane or tetrahydrofuran in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents of carbonyldiimidazole.
  • the compound (II-b), (II-e) or (II-f) is mixed with 1 to 5 equivalents, preferably 1 to 2 equivalents of the amine derivative (XXXV III) in an inert solvent such as dioxane.
  • the reaction is carried out at room temperature to the boiling point of the solvent used, preferably at room temperature to 50 ° C, for 1 to 72 hours, preferably for 1 to 5 hours to obtain the compound (I-Ic).
  • B is B 1
  • a W 1 and W 2 are hydrogen
  • R 4 is hydrogen
  • U 1 is CONR 13 (CH 2) n2
  • U 2 is located at U 2A
  • the compound (I-c-12) in which R 17 is NH 2 can be produced according to the following reaction steps.
  • Compound (Ic-1) is obtained according to the method for producing (Ia-2). Production method 2— 1 2
  • B is B 1
  • a W 1 and W 2 are hydrogen
  • R 4 is hydrogen
  • U 1 is CONR 13 (CH 2) n2
  • U 2 is located at U 2A
  • U 4 is NHCO
  • the compound (I-c-1 2) and the compound (XXXIII) are used to convert the compound (I-c-I) from the compound (II-a), (II-c), or (II-d) described in the production method 2-1.
  • Compound (I-1c-3) is obtained according to the method of obtaining 1a). Manufacturing method 2—1 3
  • B is B 1
  • a W 1 and W 2 are hydrogen
  • R 4 is hydrogen
  • U 1 is CONR 13 (CH 2) n2
  • U 2 is located at U 2A
  • NH (CH 2) q 3 U 5 compound (I one c one 4) can be prepared by the following reaction steps.
  • B is B 1 , W 1 and W 2 are in the form of O, m is 1, U 1 is (CH 2 ) nl , and U 2 is U 2A
  • R 17 is a carbonyl compound
  • R 22 represents lower alkyl.
  • Alkyl is as defined above.
  • Compound (II-a), (II-c) or (II-d) is mixed with 1 to 5 equivalents, preferably 1 to 2 equivalents of triethylamine in an inert solvent such as 1,2-dichlorobenzene.
  • 1 to 5 equivalents, preferably 1 to 2 equivalents of diphenylphosphonyl azide are added in the presence of a base such as a solvent, and 0 to 10 ° C to the boiling point of the solvent used, preferably room temperature to 0.5 to 12 at the boiling point of the solvent used.
  • Reaction time preferably 0.5 to 2 hours, and in the presence of 1 to 5 equivalents, preferably 1 to 2 equivalents of a base such as triethylamine, 1 to 5 equivalents, preferably 1 to 2 equivalents of the compound (XXV II) at 0 ° C to the boiling point of the solvent used, preferably at room temperature to the boiling point of the solvent used for 0.5 to 12 hours, preferably 0.5 to 2 hours, to give the compound (I-c — 1) can be obtained.
  • a base such as triethylamine
  • B is B 2 , W 1 and W 2 are hydrogen, m is 1, R 4 is hydrogen or lower alkyl, and U 1 is (CH 2 ) nl
  • Compound (I-d-1) can be produced according to the following steps.
  • R 4A is hydrogen or lower alkyl as defined for R 4
  • lower alkyl is as defined above.
  • Compound (I) wherein B is B 2 , W 1 and W 2 are hydrogen, m is 1, R 4 is a lower alkanol, and U 1 is (CH 2 ) nl I-1d-3) can be manufactured according to the following process.
  • compound (I—cl—1) compound (I—d—2) in which R 4A is hydrogen is dissolved in a basic solvent such as pyridine in 1 to 5 equivalents, preferably 1 to 3 equivalents of acetic anhydride or the like.
  • the compound (I-d-3) is obtained by reacting the acid anhydride at 0 ° C to the boiling point of the solvent used, preferably at 0 ° C to room temperature for 1 to 72 hours, preferably for 1 to 5 hours.
  • reaction in an inert solvent such as dichloromethane, in the presence of 1 to 5 equivalents, preferably 1 to 3 equivalents of an acid halide such as acetyl, and 1 to 5 equivalents, preferably 1 to 3 equivalents of a base such as triethylamine.
  • the reaction is carried out at 0 ° C. to the boiling point of the solvent to be used, preferably at 0 ° C. to room temperature, for 1 to 72 hours, preferably for 1 to 5 hours to obtain a compound (I 1 d — 3).
  • B is B 2 is W 1 and W 2 are hydrogen, R 4 is hydrogen, compound U 1 is a CONR 13 (CH 2) n2 ( I- e)
  • R 4 is hydrogen
  • compound U 1 is a CONR 13 (CH 2) n2 ( I- e) The following It can be manufactured according to the steps described above.
  • the compound (II-11) can be prepared by using a halogenating agent such as thionyl chloride in an amount of 1 equivalent to a solvent in an inert solvent such as dichloromethane, or using a solvent in a halogenating agent in an amount of 0 to the boiling point of the solvent used in the reaction, or The acid halide of the compound (II-11) obtained by reacting at 0.5 to 6 hours, preferably 1 to 3 hours at the boiling point of the halogenating agent and 1 to 5 equivalents, preferably 1 to 3 equivalents of the compound (II-11) XXXII) and in the presence of 1 to 5 equivalents, preferably 1 to 3 equivalents of a base such as pyridine or triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran at 0 ° C to the boiling point of the solvent used.
  • the reaction is carried out preferably at 0 ° C. to room temperature for 0.5 to 24 hours, preferably for
  • Compound (I_g) is obtained using compound (IIk) and carboxylic acid form (XXXVI) in the same manner as in Production method 2-21.
  • the compounds (XXXVI), (XXXVIII) and (XXVVIII) among the starting compounds can be obtained by the method described in JP-A-7-002780 or a method analogous thereto.
  • the compound (I) obtained by the above-mentioned production method there may be a case where a isomer or an optical isomer of a form exists, or a form or a stereoisomer of a form exists for a double bond. can get.
  • the isolation and purification thereof can be performed by a method generally used in organic synthetic chemistry, for example, various chromatography, resolution by diastereomerization, recrystallization, resolution by biocatalysis, and the like. It is also possible to isomerize the isomers with each other if desired. For example, for 1 to 24 hours in acetic acid reflux, and in the presence of a suitable acid catalyst such as toluenesulfonic acid or sodium hydroxide or the like. It is isomerized by processing.
  • the reaction was performed by adding 50 ⁇ L of [ 3 H] bradykinin at a final concentration of 0.3 nM and 50 L of the test drug, 400 ⁇ L of the membrane fraction, and then at 25 for 90 minutes. Bound to tissue by the end of the reaction after the reduced pressure rapid filtration of [3 Eta] bradykinin was separated from unbound bradykinin. Radioactivity on the filters was measured by a liquid scintillation counter. A buffer solution was used instead of the drug solution for calculating the total binding amount, and 1% of bradykinin was used for calculating the non-specific binding amount.
  • Drug binding inhibition rate (%) is ⁇ ;
  • the target compound (I) and its pharmacologically acceptable salt have strong activity as a bradykinin antagonist and can be used in humans or animals, for example, in the presence of allergies, inflammation and autoimmune diseases.
  • various diseases induced by bradykinin or its analogs such as breath, shock, and pain, more specifically, asthma, cough, tracheal inflammation, rhinitis, rhinorrhea, obstructive pulmonary disease (eg, emphysema, etc.) ), Sputum, pneumonia, systemic inflammation, response, syndrome Lsys temi c inf l ammatory response syndrome (S IRS)], septic shock, irritable shock, endotoxin shock, adult respiratory distress syndrome, disseminated intravascular Coagulation, arthritis, rheumatism, osteoarthritis, low back pain, proinflammatory bone resorption, conjunctivitis, spring catarrh, uve
  • the target compound (I) can It is expected to be useful for the prevention and treatment or treatment of all-day-induced diseases.
  • compound (I) of the present invention and pharmaceutically acceptable salts thereof may be administered orally, intravenously, intramuscularly, subcutaneously, or parenterally, such as intraarticularly, transdermally.
  • organic or inorganic excipients suitable for external, enteral, rectal, vaginal, inhalation, ophthalmic, nasal, sublingual, etc. It can be used in the form of a pharmaceutical preparation containing any of the compounds as the active compound in a mixture with an acceptable carrier.
  • compositions include capsules, tablets, dragees, granules, suppositories, solutions, lotions, suspensions, emulsions, ointments, gels, creams and the like. If desired, these preparations may contain auxiliary substances, stabilizers, wetting or emulsifying agents, buffers and other conventional additives.
  • the dose of compound (I) varies depending on the age and condition of the patient, but about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1,000 mg of compound (I) The average single dose is effective for prevention and prevention or treatment of the above diseases. Generally, dosages between 0.1 and about 1,000 mg / individual per day may be administered.
  • Example 44 8- [3- (2-caproloxy-1-methylethyl) -1,2,6-dichloromouth benzyloxy] _2-methylquinoline obtained in Example 44 (100 mg, 0.25 mmol) ) And 1-aminoethylpyridine (0.04 ml, 0.38 mmol) to give the title compound (69 mg, 0. Hmmol, 55%).
  • Example 44 In the same manner as in Example 1, the 8- [3- (2-caproloxy-1-methylethyl) —2,6-dichloromouth benzyloxy] -12-methylquinoline obtained in Example 44 was obtained.
  • Example 8 8-[3- ⁇ 2- [N- (4-carpoxybenzyl) capsulebamoyl] — 1-methyl-ethyl ⁇ 2,6-dichlorobenzyloxy] — 2-methylquinoline (Compound 8)
  • EI -MASS m / z calculated for C 35 H 3I 35 C1 2 N 5 0 5 , observed 672 (M + ).
  • Example 1 8-[2,6-dichloro-3-—2- (N_- ⁇ 4- ⁇ N_- [3- (1-imidazolyl) propyl] propyl rubamoyl ⁇ benzyl ⁇ rubamoyl ⁇ 1-methylethyl ⁇ benzyloxy One 2-methylquinoline (Compound 12)
  • Example 11 In the same manner as in Example 7, the 8- [2,6-dichroic-3--3- ⁇ 1-methyl-2- ⁇ N- ⁇ 4- [3-ditrophenyl)] obtained in Example 11 was obtained. Ureido] benzyl ⁇ rubamoyl ⁇ ethyl ⁇ benzyloxy] 1-2-methylquinoline (265 mg, 0.39 mmol) to give the title compound (181 mg, 0.28 bandol, 72 °).
  • Example 50 8- [3- (3-amino-1-methylpropyl) -2,6-dichlorobenzyloxy] 1-2-methylquinoline obtained in Example 50 by the same method as in Example 1
  • Example 52-2 8- ⁇ 3-[(2E) -12-carboxy-1-methylvinyl] -1,2,6-dichlorobenzenebenzyloxy obtained in Example 52-2—2-methylquinolyl
  • the title compound (321 mg, 0.65 marl ol, 53%) was obtained from benzene (500 mg, 1.24 mmol) and 3-(aminomethyl) pyridine (0.2 ml, 1.86 marl ol).
  • Example 59 In the same manner as in Example 1, 8- ⁇ 3-[(2E) —3-amino-1_phenyl_1-propynyl] -1,2,6-dichlorobenzene obtained in Example 59 was obtained. ⁇ -The title compound (91 mg, 0.10 ol, 21%) was obtained from 2-methylquinoline (220 mg, 0.49 mmol) and 4-aminocyanic acid (118 mg, 0.59 mmol).
  • Example 61 1 the 8_ ⁇ 3-[(2Z) -2-hydroxypropyl 1-methylvinyl] -1,2,6-dichroic benzyloxy) obtained in Example 61 1 —2-methyl
  • the title compound (270 mg, 0.53 bandol ol, 33%) was obtained from tylquinoline (650 mg, 1.62 mmol) and 4-aminobenzylamine (0.3 ml, 2.37 bandol).
  • Example 33-8 [2,6-dichroic mouth 3 — ⁇ (2Z) —2— [N— (4-nicotinoylaminobenzyl) capillubamoyl] 1-1-methylvinyl ⁇ benzyloxy] 1-2— Methylquinoline (compound 33)
  • Example 11- ⁇ 3-[(2Z) -13-amino-1-methyl-11-propenyl] _2,6-dichlorobenzene obtained in Example 63 was obtained.
  • Ndyloxy ⁇ -methylquinoline (1.51 & 3.86 marl ol) and 3-2-trofenyl isocyanate (640 mg, 3.87 recitation 1) gave the title compound (1.51 g, 2.74 mmol, 71%).
  • EI -MASS m / z calculated for C 35 H 3 x 35 C1 2 N 5 0 3 , observed 511 (M + ).
  • Example 42 8 [2,6-Dichroicone 3— ⁇ 3— ⁇ N- ⁇ 3— [N _- (3-pyridyl) carbamoyl] phenyl ⁇ aminomethyl ⁇ 1 1 _pyrrolyl ⁇ benzyloxy] 1 2— Methyl quinoline (compound 42)
  • the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed twice with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution.
  • the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
  • Example 45 8- [2,6-dichloro-3- (2-methoxycarbonyl-1-methylethyl) -1-5-nitrobenzoyloxy] -2-methyl obtained in Example 45
  • the title compound (60 mg, 0.13 mmol, 48%) was obtained from quinoline (100 mg, 0.28 mmol).
  • Example 47 8- [2,6-dichloro-3- (2-ethoxycarbonyl-2-l-phenylethyl) benzyloxy] -12-methylquinoline obtained in Example 47 (670 mg, 1.36 fractions) ol) to give the title compound (490 mg, 1.05 marl ol, 773 ⁇ 4) Obtained.
  • the aqueous layer was basified with an aqueous sodium hydroxide solution under ice-cooling, and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give the title compound (40 mg, 0.1 mmol, 86%).
  • Example 65 8— ⁇ 2,6-dichroic —3 — [(2E) —2-methoxycarbodilu-1-phenylvinyl] benzyloxy obtained in Example 65.
  • the title compound (753 mg, 1.68 mmol, 100%) was obtained from 1,2-methylquinoline (800 mg, 1.68 mmol).
  • Example 60 8- [2,6-dichloro-13-[(2Z) —2-ethoxycarbonyl-1-methylvinyl] benzyloxy] —2-methyl obtained in Example 60
  • the title compound (1.88 g, 4.67 mmol, 40%) was obtained from quinoline (5.00 g, 11.6 ⁇ 01).
  • Example 43 According to a method similar to that in Example 43, the title compound (15.6 g, 37.5 mmol) was obtained from 1- (2,6-dichloromethyl-3-methylphenyl) -12-cyanopyrrole (11.7 g, 46.6 mmol) obtained in Reference Example 21. , 803 ⁇ 4).
  • Example 73 8- [3- ⁇ 3- [3- (4-aminobenzyl) ureido] —1-methylpropyl ⁇ —2,6-dichroic benzoyloxy) obtained in Example 73 From 2-methylquinoline (200 mg, 0.37 bandol) and isonicotinyl chloride hydrochloride (100 mg, 0.56 fraction 1), the title compound (182 mg, 0.43 l, 1,76 mg) was obtained.
  • Example 78 In the same manner as in Example 7, 8- [2,6-dichroic-3-1- ⁇ 1-methyl-2- (3- (3-ditrobenzyl) ureido] ethyl) obtained in Example 78 was benzyloxy. The title compound (94 mg, 0.18 iM01, 100 mg) was obtained from 12-methylquinoline (100 mg, 0.18 mmol).
  • Example 79 8- [2,6-dichloro-3- ⁇ 2- [3- (3-aminobenzyl) ureido] -11-methylethyl ⁇ benzyloxy] obtained in Example 79 was obtained in Example 79.
  • Example 44 8- [3- (2-carboxy-1-methylethyl) —2,6-dichlorobenzyloxy] 1-2-methylquinoline (500 mg, 1.24) obtained in Example 44
  • the title compound (626 mg, 1.10 dragon ol, 893 ⁇ 4) was obtained from bandits ol) and ethyl 3-ethylaminobenzoate (220 mg, 1.33 bandits 01).
  • Example 61 8- ⁇ 3-[(2Z) -12-carboxy-1-methylvinyl] -12,6-dichloromethylbenzyloxy] -2-methyl obtained in Example 61 was obtained.
  • the title compound (293 mg, 0.57 mmol, 33%) was obtained from quinoline (700 mg, 1.74 mmol) and (4-aminophenyl) ethylamine (0.34 ml, 2.58 mmol).
  • Example 8 ⁇ 3-[(2Z) _2-carboxoxy-1-methylvinyl] —2,6-dichloromouth benzyloxy] —2-methylquinoline obtained in Example 61 (400 mg, 0.99 bandol) and 3_ (3-aminobenzyl) aminoviridine (0.32 g, 1.50 mmol) to give the title compound (69 mg, 0.16 mmol, 163 ⁇ 4).
  • Example 40 8- [2,6-dichloro-3- (2-formylphenyl) benzyloxy] -2-methylquinoline (198 mg, 0.47 mmol) obtained in Example 99 was used.
  • the title compound (161 mg, 0.26 mmol, 55 °) was obtained from 3- (3-aminobenzyl) aminoviridine (100 mg, 0.47 mmol).
  • reaction solution was diluted with ethyl acetate and washed with water and saturated saline.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

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Abstract

Ces dérivés benzéniques, qui présentent une forte activité antagoniste de la bradykinine, sont représentés par la formule générale (I). Dans cette formule, Y1 de A est -CH=CH- ou NR8 (R8 étant hydrogène ou alkyle inférieur). X1 est O, S ou NR9 (R9 étant hydrogène ou alkyle inférieur). B est B?1 ou B2. X2¿ est aryle substitué ou non substitué ou analogue. Z1 et Z2 sont chacun hydrogène, mais Z1 et Z2 peuvent former ensemble une liaison. X3 est N ou -CH=C-. R?1, R2 et R3¿, qui peuvent être identiques ou différents les uns des autres, sont chacun hydrogène, alkyle inférieur, hydroxyle ou analogue. W1 et W2 sont chacun hydrogène ou représente ensemble O, mais W1 et W2 peuvent également, avec E, être N. 'm' est un entier valant 0, 1 ou 2, et valant 1 lorsque B est B2. E est N ensemble avec W1 et W2, mais E peut également être hydrogène, OR21 (R21 étant hydrogène, alkyle inférieur ou analogue) ou NR4R5.
PCT/JP1998/001265 1997-03-24 1998-03-24 Derives benzeniques WO1998042672A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062295A2 (fr) * 2001-02-02 2002-08-15 Icagen, Inc. Benzanilides a substitution pyridine utilises comme ouvreurs de canaux ioniques de potassium
US6737422B2 (en) 1999-08-04 2004-05-18 Icagen, Inc. Benzanilides as potassium channel openers
US6919347B2 (en) 1999-07-15 2005-07-19 Pharmacopeia Drug Discovery, Inc. Bradykinin B1 receptor antagonists
JP2006516132A (ja) * 2002-12-19 2006-06-22 エラン ファーマシューティカルズ，インコーポレイテッド 置換ｎ−フェニルスルホンアミドブラジキニン拮抗薬
AU2002238023B2 (en) * 1999-08-04 2008-03-13 Icagen, Inc Pyridine-substituted benzanilides as potassium ion channel openers
US7595343B2 (en) * 2001-09-14 2009-09-29 Methylgene, Inc. Inhibitors of histone deacetylase
US7838520B2 (en) 2001-09-14 2010-11-23 Methylgene, Inc. Inhibitors of histone deacetylase
US7868204B2 (en) 2001-09-14 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US7868205B2 (en) 2003-09-24 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
JP2011502983A (ja) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド 眼の疾患及び障害治療用のアミン誘導体化合物
US8088805B2 (en) 2004-03-26 2012-01-03 Methylgene Inc. Inhibitors of histone deacetylase
WO2013092522A1 (fr) 2011-12-20 2013-06-27 Bayer Intellectual Property Gmbh Nouveaux amides aromatiques insecticides
US8598168B2 (en) 2006-04-07 2013-12-03 Methylgene Inc. Inhibitors of histone deacetylase
JP2022533487A (ja) * 2019-05-23 2022-07-22 ファーヴァリス ゲーエムベーハー 皮膚疾患を処置するためのブラジキニン（ｂｋ）ｂ２受容体アンタゴニストとしての（ｒ）－３－（クロロ－５－フルオロ－２－（（４－（１ｈ－ピラゾール－１－イル）－２－メチルキノリン－８－イルオキシ）メチル）フェニル）モルホリン誘導体および関連化合物
JP2022534389A (ja) * 2019-05-23 2022-07-29 ファーヴァリス ゲーエムベーハー 皮膚疾患を処置するためのブラジキニン（ｂｋ）ｂ２受容体アンタゴニストとしての１－（（ｓ）－１－（３－クロロ－５－フルオロ－２－（（４－（１ｈ－ピラゾール－１－イル）－２－メチルキノリン－８－イルオキシ）メチル）フェニル）エチル）－イミダゾリジン－２，４－ジオン誘導体および関連化合物

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JPH072780A (ja) * 1993-04-28 1995-01-06 Fujisawa Pharmaceut Co Ltd 複素環化合物
WO1997007115A1 (fr) * 1995-08-17 1997-02-27 Fournier Industrie Et Sante Derives de benzenesulfonamide comme antagonistes de la bradykinine

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JPS62120365A (ja) * 1985-11-16 1987-06-01 バイエル・アクチエンゲゼルシヤフト 置換ベンジルエ−テル類、その製造法および用途
JPH072780A (ja) * 1993-04-28 1995-01-06 Fujisawa Pharmaceut Co Ltd 複素環化合物
WO1997007115A1 (fr) * 1995-08-17 1997-02-27 Fournier Industrie Et Sante Derives de benzenesulfonamide comme antagonistes de la bradykinine

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6919347B2 (en) 1999-07-15 2005-07-19 Pharmacopeia Drug Discovery, Inc. Bradykinin B1 receptor antagonists
AU2002238023B2 (en) * 1999-08-04 2008-03-13 Icagen, Inc Pyridine-substituted benzanilides as potassium ion channel openers
US6737422B2 (en) 1999-08-04 2004-05-18 Icagen, Inc. Benzanilides as potassium channel openers
US6989398B2 (en) 1999-08-04 2006-01-24 Icagen, Inc. Benzanilides as potassium channel openers
WO2002062295A3 (fr) * 2001-02-02 2003-07-03 Icagen Inc Benzanilides a substitution pyridine utilises comme ouvreurs de canaux ioniques de potassium
WO2002062295A2 (fr) * 2001-02-02 2002-08-15 Icagen, Inc. Benzanilides a substitution pyridine utilises comme ouvreurs de canaux ioniques de potassium
US7838520B2 (en) 2001-09-14 2010-11-23 Methylgene, Inc. Inhibitors of histone deacetylase
US7595343B2 (en) * 2001-09-14 2009-09-29 Methylgene, Inc. Inhibitors of histone deacetylase
US7868204B2 (en) 2001-09-14 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
JP2006516132A (ja) * 2002-12-19 2006-06-22 エラン ファーマシューティカルズ，インコーポレイテッド 置換ｎ−フェニルスルホンアミドブラジキニン拮抗薬
US7868205B2 (en) 2003-09-24 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US8088805B2 (en) 2004-03-26 2012-01-03 Methylgene Inc. Inhibitors of histone deacetylase
US8598168B2 (en) 2006-04-07 2013-12-03 Methylgene Inc. Inhibitors of histone deacetylase
JP2011502983A (ja) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド 眼の疾患及び障害治療用のアミン誘導体化合物
WO2013092522A1 (fr) 2011-12-20 2013-06-27 Bayer Intellectual Property Gmbh Nouveaux amides aromatiques insecticides
US9204645B2 (en) 2011-12-20 2015-12-08 Bayer Intellectual Property Gmbh Insecticidal aromatic amides
JP2022533487A (ja) * 2019-05-23 2022-07-22 ファーヴァリス ゲーエムベーハー 皮膚疾患を処置するためのブラジキニン（ｂｋ）ｂ２受容体アンタゴニストとしての（ｒ）－３－（クロロ－５－フルオロ－２－（（４－（１ｈ－ピラゾール－１－イル）－２－メチルキノリン－８－イルオキシ）メチル）フェニル）モルホリン誘導体および関連化合物
JP2022534389A (ja) * 2019-05-23 2022-07-29 ファーヴァリス ゲーエムベーハー 皮膚疾患を処置するためのブラジキニン（ｂｋ）ｂ２受容体アンタゴニストとしての１－（（ｓ）－１－（３－クロロ－５－フルオロ－２－（（４－（１ｈ－ピラゾール－１－イル）－２－メチルキノリン－８－イルオキシ）メチル）フェニル）エチル）－イミダゾリジン－２，４－ジオン誘導体および関連化合物

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