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WO2006070878A1 - Derive d'acide carboxylique ou sel de ce derive - Google Patents

Derive d'acide carboxylique ou sel de ce derive Download PDF

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Publication number
WO2006070878A1
WO2006070878A1 PCT/JP2005/024096 JP2005024096W WO2006070878A1 WO 2006070878 A1 WO2006070878 A1 WO 2006070878A1 JP 2005024096 W JP2005024096 W JP 2005024096W WO 2006070878 A1 WO2006070878 A1 WO 2006070878A1
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WIPO (PCT)
Prior art keywords
amino
methyl
ring
added
tert
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/JP2005/024096
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English (en)
Japanese (ja)
Inventor
Tsukasa Ishihara
Masanori Miura
Kazuhiko Ohne
Tomofumi Takuwa
Shohei Shirakami
Ryotaro Ibuka
Kei Ohnuki
Norio Seki
Takeshi Shigenaga
Fukushi Hirayama
Akihito Hirabayashi
Yuichiro Kai
Junichi Kobayashi
Hideaki Hirasawa
Atsushi Kondou
Ken Yamada
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Astellas Pharma Inc
Original Assignee
Kissei Pharmaceutical Co Ltd
Astellas Pharma Inc
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Publication date
Application filed by Kissei Pharmaceutical Co Ltd, Astellas Pharma Inc filed Critical Kissei Pharmaceutical Co Ltd
Priority to JP2006550852A priority Critical patent/JPWO2006070878A1/ja
Publication of WO2006070878A1 publication Critical patent/WO2006070878A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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Definitions

  • the present invention relates to a novel carboxylic acid derivative or a salt thereof useful as a pharmaceutical, particularly an active blood coagulation factor VII inhibitor, and its use as a pharmaceutical.
  • the compound of the present invention is useful as an active blood coagulation factor VII inhibitor.
  • thromboembolic diseases such as myocardial infarction, cerebral thrombosis, and peripheral arterial thrombosis have increased year by year due to the westernization of lifestyle and the aging of the population.
  • Anticoagulation therapy along with fibrinolysis and antiplatelet therapy, plays a part in medical treatment in the treatment and prevention of thrombosis (Non-patent Document 1).
  • Non-patent Document 1 In particular, in the prevention of thrombosis, safety that can withstand long-term administration and the development of reliable and appropriate anticoagulant activity are essential.
  • Lufarin potassium is widely used around the world as the only oral anticoagulant, but it is difficult to control its anticoagulant ability due to its characteristic mechanism.
  • Non-patent Documents 2 and 3 it is a drug that is very difficult to use clinically, and the appearance of an anticoagulant that is more useful and easy to use is desired.
  • the blood coagulation reaction is an extrinsic pathway and an intrinsic pathway force, and thrombin is generated by any pathway.
  • Thrombin is not only responsible for the conversion of fibrinogen to fibrin, which is the final stage of coagulation, but is also deeply involved in platelet activation and aggregation (Non-patent Document 4), and its inhibitor is a target for drug discovery. As long as it has been at the center of anticoagulant research. However, there are still problems with safety, such as the occurrence of force S and bleeding (Non-patent Document 5).
  • Active ⁇ blood coagulation factor VII is an enzyme located at the start of the extrinsic clotting pathway, and its enzymatic activity increases markedly by binding to tissue factor (TF), a protein cofactor. Tissue factor is known to be upregulated in various thrombotic diseases, suggesting involvement of the extrinsic coagulation pathway in thrombotic diseases (Non-patent Document 6).
  • Activated blood coagulation Selective inhibitors of factor VII may be superior anticoagulants with less bleeding side effects by not inhibiting endogenous coagulation.
  • Patent Document 1 discloses that a novel amidino derivative represented by the following general formula has an action of inhibiting activated blood coagulation factor VII, including generalized intravascular coagulation syndrome and coronary artery thrombosis. It is described that it is useful as a preventive or therapeutic agent.
  • the E 2 ring and the E 4 ring are directly bonded to each other, and the B and C rings are bonded via the linker (L), so that the structure is different from that of the present compound. .
  • Patent Document 2 describes a wide range of compounds represented by the following general formulas as active ⁇ blood coagulation factor VII and active ⁇ blood coagulation factor X inhibitors. However, the compounds described as examples are limited to compounds having a biaryl structure in which X is a bond, and the compounds of the present invention having a linker are not disclosed.
  • E 1 and L represent carbocycle, heterocycle, etc.
  • X represents a bond, unsubstituted or substituted C-methylene, etc.
  • Patent Document 3 describes the following as inhibitors of active blood coagulation factor VII, activated blood coagulation factor IX, activated blood coagulation factor X, activated blood coagulation factor XI and the like.
  • General Compounds of the formula are described. However, these compounds differ in structure from the compounds of the present invention in that there is no ring or linker corresponding to the B ring of the compounds of the present invention.
  • Patent Document 4 describes a compound represented by the following general formula as a serine protease inhibitor. However, there is no description that these compounds selectively inhibit active blood coagulation factor VII. Further, these compounds differ in structure from the compounds of the present invention in that there is no ring corresponding to the B ring of the compounds of the present invention or no linker exists.
  • Patent Document 5 describes a wide variety of compounds represented by the following general formulas as inhibitors of active blood coagulation factor VII, active blood coagulation factor IX and the like.
  • the example compounds having a carboxylic acid moiety which is a feature of the present invention, have vias in which Z Q is a bond. It is limited to compounds having a reel structure, and no compound having a linker is disclosed.
  • Patent Document 6 describes that a phenyldaricin derivative represented by the following general formula has an inhibitory effect on activated blood coagulation factor VII.
  • these compounds differ in structure from the present invention compounds in which the J part is not an amino acid, in that the site that connects the two rings is an amino acid.
  • Patent Document 7 describes that (thio) urea derivatives having the following general formula have an activity of inhibiting blood coagulation factor VII.
  • the structure is different from that of the compound of the present invention in that there is no ring corresponding to the ring B of the compound of the present invention.
  • Patent Document 8 describes that a compound represented by the following general formula has an inhibitory action on platelet aggregation. However, there is no description that it has an activity of inhibiting blood coagulation factor VII. In addition, these compounds have a pyrrolidine ring, but the compounds of the present invention differ in structure from the compounds of the present invention in that the C ring does not contain a pyrrolidine ring.
  • Patent Document 9 describes that a compound represented by the following general formula has an activity of inhibiting active blood coagulation factor X. However, there is no description that it has an activity of inhibiting blood coagulation factor VII. Further, these compounds are limited to the substituent force S on Q 1 corresponding to the A ring of the compound of the present invention, and there is no substituent corresponding to R 1 of the compound of the present invention. In this respect, the structure is different from the compound of the present invention.
  • Patent Document 10 a wide range of compounds represented by the following general formulas are activated blood coagulation.
  • R 4 is hydrogen, alkyl, halo, haloalkyl, nitro-nitro, -OR 5 , -C (0) OR 5 , -N (R 5 ) R 6 , -C (0) N (R 5 ) R 6 or -R 8 — N (R 5 ) R 6 , R 8 represents a straight-chain or branched alkylene, alkylidene, or alkylidyne chain (for the symbols in other formulas, see the publication of Patent Document 10).
  • Non-Patent Document 1 "General Clinical", 1989, 41st page, p.2141-2145
  • Non-Patent Document 2 “The New England Journal of Medicine”, (USA), 1991, No. 324, No. 26, p.1865- 1875
  • Non-Patent Document 3 "The Journal of CI inical Pharmacology” (USA), 1992, 32nd, p.196-209
  • Non-Patent Document 4 Osamu Matsuo, “t-PA and pro-UK”, Interdisciplinary Planning, 1986, Blood Coagulation, p.5-40
  • Non-Patent Document 5 “Biomedica Biochimica Acta” (Germany), 1985, No. 44, P.1201-1210
  • Non-Patent Document 6 “Thrombosis and Haemostasis” (Germany), 1997, 78th, No. 1, p.759-764
  • Patent Document 1 International Publication No. 99/41231 Pamphlet
  • Patent Document 2 Pamphlet of International Publication No. 02/34711
  • Patent Document 3 International Publication No. 02/37937 Pamphlet
  • Patent Document 4 International Publication No. 02/42273 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 01/87854
  • Patent Document 6 International Publication No. 00/35858 Pamphlet
  • Patent Document 7 European Patent Application Publication No. 1162194
  • Patent Document 8 European Patent Publication No. 0528369
  • Patent Document 9 International Publication No. 00/39118 Pamphlet
  • Patent Document 10 International Publication No. 99/32477 pamphlet
  • the active ⁇ blood coagulation factor VII selective inhibitor can be expected to be more efficient than the thrombin inhibitor and selectively inhibit the coagulation system in anticoagulation therapy.
  • an active ⁇ blood coagulation factor VII selective inhibitor is expected as a drug with fewer side effects. Therefore, the creation of an activated blood coagulation factor VII selective inhibitor having a chemical structure different from that of the compound described in the above-mentioned patent document and having a superior effect is eagerly desired.
  • the present invention relates to a carboxylic acid derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • Ring A Aaryl ring or heteroaryl ring.
  • Ring B benzene ring, naphthalene ring, monocyclic to bicyclic heteroaryl ring.
  • Ring C a cycloalkyl ring, an aryl ring or a hetero ring.
  • n, and p each independently an integer from 0 to 3. However, if m, n or p is 2 or more, R 2 , R 3 or R 4 are the same or different from each other! /
  • R °°, -NR ° C ( 0) _halogeno lower alkyl, cycloalkyl, aryl or hetero ring group.
  • the lower alkyl, cycloalkyl, aryl or hetero ring group in R 2 and R 3 may be substituted.
  • each of two R 2 or R 3 may be in the form of -0-lower alkylene-0-.
  • R Q and R QQ each independently -H or lower alkyl.
  • the lower alkyl, lower alkenyl, cycloalkyl, aryl, and heterocyclic groups in R 4 may each be substituted.
  • R 6 , R 6a and R 6b each independently -H, or an optionally substituted lower alkyl, lower alkenyl, cycloalkyl, aryl or heterocyclic group.
  • R 5 -OR 0 , -NR ° R. . Or -N (R °) -lower alkylene-0R. . .
  • Y Single bond, each substituted, may be lower alkylene or lower alkylene. However, when C ring is a hetero ring, pyrrolidine is excluded. The same applies below. ]
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a carboxylic acid derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in particular, activated.
  • Diseases caused by blood coagulation factor VII inhibition, blood coagulation inhibitors, or thrombus or embolism especially ischemic heart disease, restenosis after angioplasty, cerebral thrombosis, transient ischemic attack, peripheral Arterial occlusion, intermittent claudication, deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation syndrome (DIC), thrombus formation after heart valve replacement, coagulation or inflammation of perfused blood during extracorporeal circulation, arteries
  • the present invention also relates to a pharmaceutical composition that is a prophylactic or therapeutic agent for sclerosis and cancer.
  • composition comprising the compound of the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
  • composition according to (1) which is a preventive or therapeutic agent for diseases caused by thrombus or embolism;
  • composition according to (1) which is a preventive or therapeutic agent for syndrome (DIC), thrombus formation after heart valve replacement, blood coagulation or inflammation during arterial circulation, arteriosclerosis, and cancer;
  • Ischemic heart disease restenosis after angioplasty, cerebral thrombosis, transient ischemic attack, peripheral arterial occlusion, intermittent claudication, deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation Claims (1) for the manufacture of drugs for the prevention or treatment of syndrome (DIC), thrombus formation after heart valve replacement, coagulation or inflammation of perfused blood during extracorporeal circulation, arteriosclerosis, cancer Use of the described compounds or pharmaceutically acceptable salts thereof;
  • a method for preventing or treating a disease caused by thrombus or embolism comprising administering to a patient a therapeutically effective amount of a compound of the general formula (I) or a salt thereof;
  • (10) Ischemic heart disease, restenosis after angioplasty, cerebral thrombosis, transient cerebral imagination, including administering to a patient a therapeutically effective amount of a compound of general formula (I) or a salt thereof Blood attack, peripheral arterial occlusion, intermittent claudication, deep vein thrombosis, pulmonary embolism, disseminated intravascular coagulation syndrome (DIC), thrombus formation after heart valve replacement, blood coagulation of perfused blood during extracorporeal circulation Or prevention or treatment of inflammation, arteriosclerosis, cancer
  • lower means 1 to 6 carbon atoms (hereinafter referred to as “C” unless otherwise specified).
  • Alkyl alkylene
  • alkylene alkylene
  • alkylene may each be linear or branched.
  • lower alkyl means C alkyl. Specifically, methyl,
  • Examples include til, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, normal hexyl and the like.
  • C til, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, normal hexyl and the like.
  • “Lower alkellule” is a C alkell having one or more double bonds at any position.
  • “Lower alkylene” means a divalent group formed by removing one hydrogen at any position of the “lower alkyl”. Specifically,-(CH)-,-CH (CH)-,-C (CH)-,-CH CH (C
  • Cycloalkyl means a non-aromatic hydrocarbon ring of C, and a bridged ring spiro ring.
  • Specific examples include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexenole, cycloheptinole, cyclooctyl, cyclohexenyl, cyclooctanegel, adamantyl and norbol.
  • Preferred is C cycloalkyl, more preferred is cyclobuty
  • Halogen means a halogen atom. Specific examples include fluoro, black mouth, bromo and iodine. Preferred are fluoro, black mouth and bromo, and more preferred are fluoro and black mouth.
  • halogeno lower alkyl means one or more arbitrary hydrogen atom forces of the “lower alkyl” which are the same or different from each other and substituted with the “halogen”. Specific examples include trifluoromethyl, pentafluoroethyl and the like. Preferred is trifluoromethyl.
  • aryl means a monocyclic to tricyclic C aromatic hydrocarbon ring, specifically
  • Examples include phenyl and naphthyl, and is preferably phenyl.
  • the cycloalkyl ring may be condensed.
  • indanyl or tetrahydronaphthyl may be formed.
  • “Monocyclic heteroreel” means a group power consisting of N, O, and S forces.
  • the ring atom S or N may be oxidized to form an oxide or dioxide.
  • Specific examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, furyl, chael, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl and the like.
  • Pyridyl and birazinyl are preferable, and pyridyl is more preferable.
  • Heteroaryl refers to the above-mentioned “monocyclic heteroreel", the monocyclic heteroreel or “bicyclic heteroreel” in which the monocyclic heteroreel is fused with a benzene ring, and
  • the bicyclic heteroaryl is a monocyclic heteroaryl or a tricyclic heteroaryl fused with a benzene ring.
  • the ring atom S or N may be oxidized to form a dioxide.
  • bicyclic heteroaryl examples include benzofuranyl, benzochel, benzoxazolyl, benzoimidazolyl, indolyl, benzothiazolyl, quinolinyl, quinazolyl, quinoxalinyl, cinnolyl and the like. Indolyl and benzimidazolyl are preferred.
  • Specific examples of the tricyclic heteroaryl include carbazolyl and fluorenyl.
  • Specific examples of the hetero reel include the groups described in the above-mentioned “monocyclic hetero reel”, “bicyclic hetero reel”, and “tricyclic hetero reel”. Pyridyl, pyradyl, indolyl and benzimidazolyl are preferable, and pyridyl is more preferable.
  • Heterocycle refers to a 3- to 8-membered monocyclic heterocycle having 1 to 4 heteroatoms in which a group force consisting of N, O and S is also selected.
  • the ring atom N or S may be oxidized to form an oxydoxide or a bridged ring or a spiro ring.
  • Substituents which may be substituted in R 2 and R 3 and are allowed by “lower alkyl” are preferably groups selected from the following group P 1 .
  • Q Group 1 lower alkyl, halogeno lower alkyl, halogen, oxo, -OR. And -0-halogeno lower alkyl.
  • R 4, R 6, R 6a and R may be substituted in 6b "lower alkyl” and "lower Aruke - Le" As preferred substituents allowed in, include groups selected from the following P 2 group Be
  • R 6A and R 6B which may be substituted, respectively, in R 6A and R 6B "cycloalkyl", as preferred substituents allowed in " ⁇ Re window” and “heterocyclic group” is a group selected from the Q 2 group Can be mentioned.
  • the A ring is preferably a benzene ring, a pyridine ring or a benzoimidazole ring, more preferably a benzene ring or a pyridine ring, and still more preferably a benzene ring.
  • B ring is preferably a monocyclic 6-membered aromatic ring, and more preferably a benzene ring or a pyridine ring.
  • the C ring is preferably a benzene ring, piperidine ring, piperazine ring or morpholine ring, and more preferably a benzene ring or piperidine ring.
  • R 2 is preferably halogen.
  • R 3 is preferably lower alkyl, -0-lower alkyl, or halogen, and more preferably methyl, -0-methyl, black mouth, or fluoro.
  • R 4 is preferably a heterocyclic group, -0-lower alkyl, -lower alkylene-OH, -0- Cycloalkyl or —O-lower alkylene- (substituted with lower alkyl !, may! /, Heterocycle), more preferably —0-lower alkyl, —lower alkylene-OH, or —0— Lower alkylene- (which may be substituted with lower alkyl, or a heterocycle), and more preferably is 0-ethyl, -0-isopropyl or -lower alkylene-OH.
  • R 5 is preferably -0H or -0-lower alkyl, more preferably -0H or -0-ethyl.
  • L is preferably * -NHCH- (where * represents a bond to the B ring).
  • X is preferably a single bond or -0-, more preferably -0-.
  • Y is preferably lower alkylene, more preferably methylene or ethylene.
  • B 2 , B 3 , B 4 each independently CH, CR 3 , N or N (0). However, among B 4 , CR 3 is 3 or less, and each CR 3 may be the same or different from each other. The same applies below. ]
  • the group force which also has power The compound or its pharmaceutically acceptable salt as described in (1) selected. Further, other preferred compounds in the compound of the present invention represented by the general formula (I) are shown below.
  • [B 5 , B, B 7 and B are each independently CH, CR or N. However, among B 5 , B, B 7 and B, CR 3a is 3 or less, and each CR 3a may be the same or different from each other.
  • R QQ cycloalkyl, aryl or heterocyclic group.
  • the cycloalkyl, aryl, and heterocyclic groups in R 2a and R 3a may be substituted with lower alkyl, halogeno lower alkyl, halogen, oxo, -OR °, or 0-0-norogeno lower alkyl. .
  • each of two R 2a or R 3a may be in the form of -0-lower alkylene-0-.
  • R 6e lower alkyl in R 1 ⁇ 2 is substituted with a group selected also P a group force and may, cycloalkyl, be the heterocyclic group Ariru and to be substituted with a group selected respectively Q a group force Good.
  • R 6c , R 6d and R 6e each independently —H, lower alkyl, cycloalkyl, aryl or hetero ring group.
  • R 6e , R 6d and R 6e is a cycloalkyl, aryl and hetero ring group which may be substituted with a group selected from group P a and each is selected from group Q a May be substituted with a group.
  • cycloalkyl, aryl or heterocycle 0
  • R °° cycloalkyl, aryl or heterocycle.
  • the cycloalkyl, aryl and hetero ring group in the P a group may be substituted with a group selected from the Q a group.
  • R 5a —OH or —0-lower alkyl.
  • Y a lower alkylene substituted with halogen or —OR °. ]
  • the compound of the present invention may have various stereoisomers such as geometric isomers, tautomers and optical isomers.
  • the present invention includes mixtures thereof and isolated ones.
  • the compound of the present invention may form an acid addition salt. It may also form a salt with a base.
  • strong salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid and other organic acids, acid addition salts with aspartic acid, glutamic acid and other acidic amino acids, sodium, Examples thereof include inorganic bases such as potassium, magnesium, calcium, and aluminum, organic bases such as methylamine, ethylamine, and ethanolamine, salts with basic amino acids such as lysine and oltin, and ammonium salts.
  • the present invention includes hydrates of the compounds of the present invention, various pharmaceutically acceptable solvates, crystal polymorphs, and the like. It should be understood that the present invention is not limited to the compounds described in the examples below, and all of the carboxylic acid derivatives represented by the general formula (I) or pharmaceutically acceptable salts thereof. Is included.
  • the compounds of the present invention also include all compounds that are metabolized in vivo and converted to the compounds having general formula (I) or salts thereof, so-called prodrugs. Examples of the group that forms a prodrug of the compound of the present invention include those described in Prog. Med.
  • a prodrug of the compound of the present invention a prodrug having a hydroxyl group and an ester group that undergoes metabolism in a living body and becomes a carboxylic acid derivative represented by the general formula (I) can be considered.
  • a prodrug having a hydroxyl group and an ester group that undergoes metabolism in a living body and becomes a carboxylic acid derivative represented by the general formula (I) can be considered.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent.
  • a typical production method is illustrated below.
  • it is effective in terms of production technology to replace the functional group with a suitable protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. There is a case. Thereafter, the protecting group can be removed as necessary to obtain the desired compound.
  • functional groups include a hydroxyl group, a carboxyl group, an amino group, and the like, and examples of protective groups thereof include those described in “Protective Groups in Organic Synthesis (third) by Greene and Wuts”. edition) ”, and these may be appropriately used depending on the reaction conditions.
  • R 8 , R 9 , R 1Q , R U , R 12 and X 1 are R 1 R 2 , R 3 , A substituent that can be converted to R 5 and X.
  • J 2 and J 3 are substituents that can be converted into a bond J through a process that can be usually employed by those skilled in the art, and specifically include methyl, hydroxymethyl, halogenomethyl, and the like. Group, formyl group, alkoxymethyl group, acetoxymethyl group, amino group, alkoxycarboamino group, nitro group, carboxyl group, alkoxycarbo group and the like.
  • L 1 and L 2 mean a substituent that can be converted to a bond L through a process that can be usually employed by those skilled in the art, and specifically include a methyl group, a hydroxymethyl group, and a halogenomethyl group.
  • R 8 , R 9 , R 1Q , R u , R 12 and X 1 are each It may be the same as R 5 and X. The same shall apply hereinafter. ) [0048] Process A
  • any step that can be usually employed by those skilled in the art for example, halogenation reaction, oxidation reaction, reduction reaction, hydrolysis reaction, hydrogenolysis reaction, amidation reaction, alkylation reaction, reductive alkyl-rich reaction, etc. It can be implemented by combining with.
  • This process is not limited to a one-step reaction and may be composed of a multi-step reaction.
  • the halogenation reaction can be a halogenation reaction that can be usually used by those skilled in the art.
  • the method described in “Chemical Experiment Course (4th edition)” edited by The Chemical Society of Japan, 19 ⁇ (1992) (Maruzen) can be applied.
  • N-promosuccinimide or the like can be used as a halogenating agent in the presence of 2,2′-azobisisobutyryl-tolyl or peroxybenzoyl.
  • Reactions include aromatic hydrocarbons such as benzene, toluene, xylene, esters such as ethyl acetate, ethers such as dimethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as black mouth form, alcohols such as methanol and ethanol, ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA), ⁇ -methylpyrrolidone ( ⁇ ), dimethyl sulfoxide
  • the reaction can be carried out in a solvent inert to the reaction such as (DMSO), acetonitrile, pyridine, water, etc. under cooling to heating under reflux.
  • an acid-acid reaction that can be usually used by those skilled in the art can be used.
  • the method described in “Chemical Experiment Course (4th edition)” edited by The Chemical Society of Japan, 23 ⁇ (1992) (Maruzen) can be applied.
  • a reduction reaction which can be usually used by those skilled in the art can be adopted.
  • a reducing agent such as lithium aluminum hydride and sodium borohydride
  • Room temperature to Caro in solvent It can be carried out under heat reflux.
  • a hydrolysis reaction which can be usually used by those skilled in the art can be used.
  • sulfuric acid, hydrochloric acid, hydrobromic acid in a solvent inert to the reaction such as the above aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, etc.
  • an acid such as mineral acid such as formic acid and acetic acid
  • a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia.
  • the reaction can be carried out under cooling to heating under reflux.
  • the hydrogenolysis reaction such as debenzylation
  • a hydrogenolysis reaction which can be usually used by those skilled in the art can be used.
  • a catalyst use is made of noradium carbon, Raney nickel, platinum, etc., and the above-mentioned aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF.
  • the reaction can be carried out in a solvent inert to the reaction, such as DMA, NMP, ethyl acetate, acetonitrile, and acetic acid, from room temperature to under reflux.
  • an acid preferably hydrochloric acid, acetic acid, etc.
  • amidy salt which can be usually used by those skilled in the art can be adopted.
  • methods using acid chloride, carbodiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC 'HCl), dicyclohexylcarbodiimide, diphenylphosphoryl A method using a condensing agent such as ruazide and jetylphosphyl cyanide, and a method using a mixed acid anhydride using isobutyl chloroformate, ethyl ethyl formate, and the like are preferable.
  • reaction is carried out in a solvent inert to the reaction such as the above-mentioned halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMA, NMP, DMSO or the like, under cooling or under reflux with heating.
  • a solvent inert such as the above-mentioned halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMA, NMP, DMSO or the like, under cooling or under reflux with heating.
  • a base preferably triethylamine, di-sodium pyrethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.
  • alkyl groups such as a hydroxyl group and an amino group
  • alkyl groups generally used by those skilled in the art can be employed.
  • solvent or inactive solvents such as aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, DMSO, and acetonitrile, or alcohols
  • the reaction can be carried out in a solvent such as a mixture at room temperature or under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used
  • metal salt bases potassium carbonate
  • reductive alkyl group a reductive alkyl group commonly used by those skilled in the art can be adopted.
  • solvents inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, alcohols, acetic acid, sodium borohydride, sodium triacetoxyborohydride, etc. It is preferable to use a reducing agent under cooling and at room temperature or under reflux with heating.
  • the reaction in the presence of an acid such as a mineral acid such as sulfuric acid, hydrochloric acid or hydrobromic acid, or an organic acid such as formic acid or acetic acid.
  • an acid such as a mineral acid such as sulfuric acid, hydrochloric acid or hydrobromic acid, or an organic acid such as formic acid or acetic acid.
  • the reductive alkyl group uses, for example, noradium carbon, Raney nickel, platinum or the like as a catalyst, and the above-mentioned aromatic hydrocarbons, esters, ethers, halogenated substances in a hydrogen atmosphere of normal pressure to pressure.
  • the reaction can be carried out in a solvent inert to the reaction, such as hydrocarbons, DMF, DMA, NMP, acetonitrile, and acetic acid, at room temperature to under reflux.
  • an acid preferably hydrochloric acid, acetic acid, etc.
  • This step is a step that can be usually employed by those skilled in the art, for example, halogenation reaction, oxidation reaction, reduction reaction, hydrolysis reaction, hydrogenolysis reaction, amidation reaction,
  • the reaction can be carried out by arbitrarily combining a rukylation reaction, a reductive alkyl reaction or the like. This process is not limited to a one-step reaction and may be composed of a multi-step reaction.
  • Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A to 8 in Step A, respectively.
  • any step that can be usually employed by those skilled in the art for example, halogenation reaction, oxidation reaction, reduction reaction, hydrolysis reaction, hydrogenolysis reaction, amidation reaction, alkylation reaction, reductive alkylation reaction, etc. It can implement by combining.
  • This process is not limited to a one-step reaction and may be composed of a multi-step reaction.
  • Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A to 8 in Step A, respectively.
  • the compounds of the present invention can also be produced by the following typical production methods.
  • any step that can be usually employed by those skilled in the art for example, halogenation reaction, oxidation reaction, reduction reaction, hydrolysis reaction, hydrogenolysis reaction, amidation reaction, alkylation reaction, reductive alkyl-rich reaction, etc. It can be implemented by combining with.
  • This process is not limited to a one-step reaction and may be composed of a multi-step reaction.
  • Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A to 8 in Step A, respectively.
  • This step is a step usually employed by those skilled in the art, such as halogen.
  • the reaction can be carried out by arbitrarily combining oxidization reaction, oxidation reaction, reduction reaction, hydrolysis reaction, hydrogenolysis reaction, amidation reaction, alkylation reaction, reductive alkyl reaction, and the like. This process is not limited to a one-step reaction and may be composed of a multi-step reaction.
  • Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A to 8 in Step A, respectively.
  • R 9 , R 1Q , R U , R 12 or X 1 are each R 8 , R 9 , R 1Q , R U , R 12 or X 1 as required if different from R 5 and X
  • This step is a step that can be usually employed by those skilled in the art, such as halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, reductive alkylation, etc. It can implement by combining arbitrarily.
  • This process is not limited to a one-step reaction and may be composed of a multi-step reaction.
  • Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A to 8 in Step A, respectively.
  • R 8 , R 9 , R 1Q , R U , R 12 or X 1 is R 8 , R 9 , R 1Q , R U , R 12 or X 1 as R 1 R 2 , if different from R 4 , R 5 and X, respectively, as required
  • Process C or process F converted to R 5 and X is process
  • the raw material used for the production of the compound of the present invention can be produced, for example, by using the method described in the Reference Examples described below, a known method, a method obvious to those skilled in the art, or a modification thereof. it can.
  • the compound of the present invention thus produced can be isolated and purified by a known method such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization and the like.
  • the salt of this invention compound can be guide
  • optical isomer when the compound of the present invention has an asymmetric carbon, an optical isomer exists. These optical isomers can be used for fractional crystallization, column chromatography, etc. It can be divided by conventional methods. Moreover, it can manufacture by using a suitable optically active raw material.
  • a pharmaceutical composition containing, as an active ingredient, one or more of the compounds of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof, Prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc. using carriers and excipients and other additives, and orally Or administered parenterally.
  • the clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the patient's symptoms, body weight, age, sex, etc., but it is usually 0.1 to 500 mg orally per day for adults and 0 to parenterally.
  • 01 ⁇ : LOOmg which is administered once or in several divided doses. Since the dosage varies depending on various conditions, the dosage may be less than the above dosage range.
  • the solid composition for oral administration according to the present invention tablets, powders, granules and the like are used.
  • one or more active substance forces at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, poly It is mixed with bull pyrrolidone and magnesium aluminate metasilicate.
  • the composition may contain an additive other than the inert diluent, for example, a lubricant, a disintegrant, a stabilizer, a solubilizer, or a solubilizing agent according to a conventional method.
  • tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc., or gastric soluble sputum may be coated with an enteric film!
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents, Examples include purified water and ethyl alcohol.
  • This composition may contain solubilizers, solubilizers, wetting agents, suspending agents, sweeteners, flavors, fragrances, preservatives in addition to the inert diluent. Good.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous solution and suspension diluent include distilled water for injection and physiological saline.
  • diluents for non-aqueous solutions and suspensions include Examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (a pharmacopeia name).
  • Such compositions may further contain additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers or solubilizers.
  • These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation.
  • These can be prepared by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.
  • Me methyl, Et: ethyl, cPr: cyclopropyl, iPr: isopropyl, nBu: normal butyl, iBu: isobutyl, tBu: tert-butyl, cBu: cyclobutyl, cHex: cyclohexyl, Ac: acetyl, Ph: phenyl, Bn: benzyl, Bo tert-butoxycarbonyl, TFA: trifluoroacetic acid, Ms: methanesulfonyl, null: unsubstituted, bond: bond.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (4: 1) as an elution solvent to obtain 1.08 g of 5-cyan-3-methoxysalicylaldehyde as a colorless solid.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (4: 1) as the elution solvent, and 3.9 g of 4-chloro-2- (hydroxymethyl) -6-odophenol was obtained. Obtained as a colorless oil (EP: 285). 841 mg of the resulting oil was dissolved in 6 mL of ⁇ , ⁇ -dimethylformamide, 496 mg of benzaldehyde dimethylacetal and 10 mg of p-toluenesulfonic acid were added at room temperature, and then 1 at 100 ° C. Stir for hours.
  • the flask was charged with 22.6 mL of concentrated hydrochloric acid, 2.7 g of zinc chloride and 4.1 g of paraformaldehyde and bubbled with saline and hydrogen until dissolved.
  • a solution of 15 g of 3-ethoxysalicylaldehyde in toluene (68 mL) was added thereto, and hydrogen chloride was blown in at room temperature for 2 hours with vigorous stirring.
  • To the reaction mixture 45 mL of toluene was added and poured into about 150 g of ice. After stirring at room temperature for 20 minutes, the insoluble material was filtered off through Celite. After washing with toluene, the filtrate was separated.
  • the organic layer was washed twice with water and then dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure to obtain a red-black solid.
  • 29.6 g of sodium acetate was added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours.
  • About 300 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (about 300 mL).
  • the organic layer was washed twice with water, twice with saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate.
  • the obtained crude product was dissolved in 2 mL of ⁇ , ⁇ -dimethylformamide, 112 mg of potassium carbonate and 169 mg of tert-butyl bromoacetate were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the suspension (8.5 mL) was stirred at 70 ° C. for 14 hours under an argon atmosphere.
  • the reaction mixture was allowed to cool, filtered through celite, and washed with ethyl acetate.
  • the filtrate was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Ethyl (2-formyl-6-isopropoxy-4-butylphenoxy) acetate was added dropwise to a solution of AD-MIX- ⁇ 7.7 g in tert-butyl alcohol (15 mL) at 0 ° C. The mixture was warmed to room temperature and stirred for 12 hours. After adding 865 mg of sodium thiosulfate and stirring for 1 hour, 15 mL of water was added and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • Tetrahydrofuran (5 mL) solution of tert-butyl (4-acetoxymethyl-2-formyl-6-hydroxyphenoxy) acetate 0.32 4 g, 1-tert-butoxy-2-propanol 0.145 g, triphenylphosphine 0.288 g
  • 0.48 mL of a toluene solution (2.30 M) of jetillazodicarboxylate was added at room temperature and stirred at the same temperature for 1.5 hours.
  • reaction mixture was purified by silica gel column chromatography using n-hexane / ethyl acetate (4: 1) as an elution solvent, and tert-butyl [4-acetoxymethyl-2- (2-tert-butoxy-1-methyl) was obtained. Ethoxy) -6-formylphenoxy] ase A tarte of 0.085 g was obtained.
  • NMR (CDC1): 1.20 (9H, s), 1.36 (3H, d, J 6.5 Hz), 1.49 (9
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate / n-hexane (1: 3) as an elution solvent to obtain 11.24 g of a yellow oily substance.
  • 11.24 g of the obtained yellow oily substance was dissolved in 300 mL of ethanol, added with 4.384 g of potassium carbonate, and stirred at room temperature for 5.5 hours. Potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the residue was diluted with ethyl acetate and washed successively with 0.5N hydrochloric acid, water and saturated brine.
  • the reaction mixture was washed successively with water, diluted hydrochloric acid three times, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate / n-hexane (1:10) as an elution solvent to obtain 10.985 g of a yellow oily substance. 100 mg of the obtained yellow oily substance was dissolved in ethanol (2 mL), 156 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours and allowed to stand for 13 hours. Potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the reaction mixture was diluted with ethyl acetate, poured into 1N hydrochloric acid and extracted. Organic layer with water and saturated saline After washing, it was dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography using ethyl acetate / n-hexane (1: 2) as the elution solvent, and tert-butyl 3- (4-acetoxymethyl-2- 148 mg of hydroxymethyl-6-isopropoxyphenol) propanoate was obtained as a colorless oil.
  • the obtained colorless solid 500 mg and phenylboronic acid 317 mg were dissolved in ⁇ , ⁇ -dimethylformamide 10 mL, and potassium phosphate 552 mg and tetrakis (triphosphine) palladium 150 mg were dissolved at room temperature. The mixture was stirred at 100 ° C for 1.5 hours. Ethyl acetate and water were added to the reaction solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was dissolved in 100 mL of ⁇ , dimethylformamide, and 4.15 g of imidazole and 9.18 g of tert-butyldimethylchlorosilane were sequentially stirred at room temperature for 17 hours.
  • the reaction solution was diluted with water and extracted with ethyl acetate.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (8: 1) as an elution solvent.
  • the obtained yellow oil was dissolved in 100 mL of ethanol, an ethanol suspension of Raney nickel (3 mL) was added, and the mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere of 1 atm.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained orange oil was dissolved in 50 mL of 1,2-dichloroethane, and 1.24 g of acetic acid and 4.30 g of 37% formaldehyde aqueous solution were prepared at room temperature, and then 3.30 g of sodium triacetoxyhydrogen hydride was brought to room temperature. And stirred for 1 hour.
  • Nickel chloride hexahydrate A solution of 607 mg of methanol (50 mL) in sodium borohydride (300 mg) stirred at room temperature for 30 minutes was mixed with tert-butyl (2-formyl-6-methoxy-4- To a solution of 1.59 g of nitrophenoxy) acetate in methanol (30 mL) was added 193 mg of sodium borohydride under ice cooling, and the mixture was stirred for 5 minutes. To the reaction solution, 950 mg of sodium borohydride was added and stirred at room temperature for 1 hour. The reaction mixture was filtered through celite and concentrated under reduced pressure.
  • tert-Butyl [4-amino-2- (hydroxymethyl) -6-methoxyphenoxy] acetate 480 mg in ⁇ , ⁇ -dimethylformamide (1 mL) solution, imidazole 230 mg and tert-butyldimethylchlorosilane 281 mg Were sequentially stirred at room temperature for 20 minutes. The reaction mixture was diluted with jetyl ether-ethyl acetate (1: 1), and the organic layer was washed successively with 5% aqueous citrate and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was dissolved in 0.5 mL of pyridine, 0.08 mL of acetic anhydride was added at room temperature, and the mixture was stirred for 10 minutes.
  • the reaction solution was concentrated under reduced pressure.
  • Ammonium 555 mg was added and stirred at room temperature for 30 minutes.
  • the reaction mixture was diluted with ethyl acetate, washed successively with saturated brine, aqueous ammonia and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Jetyl ether was added to the residue, and the resulting precipitate was collected by filtration, and the filtrate was dried under reduced pressure to obtain 4.72 g of a pale yellow solid.
  • the same procedure as in Reference Example 14 was performed to obtain tert-butyl ⁇ 4-[(dimethylamino) methyl] -2-ethoxy-6-formylphenoxy ⁇ acetate 1.12 g was obtained as a pale yellow solid.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (9: 1) as an elution solvent to obtain a colorless oil.
  • the obtained colorless oil was dissolved in a mixed solvent of methylene chloride and ethanol (1: 1, 40 mL), and ozone gas was blown into the solution at ⁇ 78 ° C. for 1.5 hours, followed by stirring. After adding 355 mg of thiourea to the reaction solution at room temperature and stirring for 2 hours, insoluble matters were filtered off.
  • the obtained red solid (2.00 g) was dissolved in 2-butanone (20 mL), potassium carbonate (4.88 g) and methyl iodide (1.95 g) were added at room temperature, and the mixture was heated to reflux for 2 hours. Add ethyl acetate and water to the reaction solution. And extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (4: 1) as an eluent to obtain 1.02 g of a yellow solid.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (4: 1) as an elution solvent to obtain 475 mg of a yellow foam. Dissolve the resulting yellow foam in 10 mL of ethanol and add Raney A water suspension (3 g) of Kell was added, and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere of 1 atm. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 365 mg of tert-butyl [ ⁇ 4-[(2-amino-5-chlorobenzyl) amino] phenol ⁇ (imino) methyl] force rubamate. It was. FP: 375
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product as a pale yellow solid.
  • the obtained pale yellow solid 0.37 g, ammonium chloride 0.23 g, 1-hydroxybenzotriazole hydrate 0.16 g, (3-dimethylaminopropyl) ethylcarbodiimide monohydrochloride 0.20 g and ⁇ ,
  • a solution of 0.55 g of) -diisopropylethylamine in ⁇ , N-dimethylformamide (1.5 mL) was stirred at room temperature for 13 hours. Water was added to the reaction solution and extracted with ethyl acetate.
  • tert-Butyl [ ⁇ 4- [(5-Chromium-2-2-nitrobenzene) amino] phenol ⁇ (imino) methyl] strength rubamate 5.00 g of Raney nickel in a solution of 5.00 g of 1,4-dioxane (100 mL) 1.0 g of the water suspension was added and stirred for 2 days at room temperature in a hydrogen atmosphere of 1 atm. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4.43 g of tert-butyl [ ⁇ 4-[(2-amino-5-chlorobenzoyl) amino] phenol ⁇ (imino) methyl] force rubamate. Obtained.
  • N- (4-Chanophenol) -5-methyl-2--trobensamide 14.3 g, hydroxylamine hydrochloride 4.9 g, ⁇ , ⁇ -diisopropylethylamine 14 mL and ethanol 100 mL Stir at ° C overnight.
  • the reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the precipitate was collected by filtration to obtain 12.5 g of a yellow solid.
  • the obtained yellow solid was dissolved in tetrahydrofuran (50 mL) and ethanol (50 mL), 10% palladium-carbon (4.23 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere of 1 atm.
  • the obtained colorless oil was dissolved in 20 mL of ⁇ , ⁇ -dimethylformamide, and 0.29 g of 4-cyanobenzoic acid, 0.40 g of 1-hydroxybenzotriazole and 1-ethyl-3- (3-dimethylaminopropyl) carpositimide 17 hours of monohydrochloride 0.57 g at room temperature Stir.
  • the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed successively with water and saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the solvent was distilled off under reduced pressure.
  • the obtained residue was suspended in 35 mL of acetic acid, 1.60 g of sodium acetate was added, and the mixture was heated to reflux for 16 hours. After naturally cooling to room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated Japanese brine and dried over anhydrous magnesium sulfate.
  • Example 1 In the same manner as in Reference Examples 1 to 87, Reference Example compounds 88 to 230 shown in Tables 4 to 24 below were produced using the corresponding raw materials. Tables 4 to 24 show the structures and physicochemical data of the reference compounds. [0158] Example 1
  • tert-Butyl ⁇ 2-Ethoxy-6-[[hydroxyimino) methyl] phenoxy ⁇ acetate 50 mg of 10% palladium carbon powder is added to an ethanol solution (17 mL) of 500 mg at room temperature under a hydrogen atmosphere of 3 atm. Stir for hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Dissolve the resulting colorless oil in 15 mL of ⁇ , ⁇ -dimethylformamide, and add tert-butyl [ ⁇ 4- [(5-ciano-2-fluorobenzoyl) amino] phenol ⁇ (imino) methyl.
  • tert-butyl ⁇ 2-[( ⁇ 2-[( ⁇ 4-[[(tert-butoxycarbonyl) amino] (imino) methyl] phenol ⁇ amino was prepared in the same manner as in Reference Example 61. ) Carboxyl] -4-chlorophenol ⁇ amino) methyl] -6-hydroxyphenoxy ⁇ acetate was obtained as a yellow solid.
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by ODS column chromatography using ethanol / water (1: 2) as the elution solvent, and ethyl [ 2 — ( ⁇ [ 2 — ( ⁇ 4 — [amino ( Imino) methyl] Benzoiru ⁇ Amino) - 4 - chloro port Hue - Le] Amino) methyl) -6-ethoxy-phenoxyethanol] Asetato 0.70 g as a yellow solid.
  • the obtained residue was purified by silica gel column chromatography using methanol / ethyl acetate-hexane (1: 4: 4) as an elution solvent, and tert-butyl [2-[( ⁇ 2-[( ⁇ 4-[[ (tert-butoxycarbonyl) amino] (imino) methyl] phenyl ⁇ amino) carbonyl] -4-chloro-amino ⁇ methyl) methyl] -4-chloro-6- (4-methyl-2-o Xisopiperazine-1-yl) phenoxy] acetate 27 mg was obtained as a colorless oil.
  • the obtained residue was purified by ODS column chromatography using 0.1% aqueous formic acid / acetonitrile as a solvent, and tert-butyl ⁇ 2-[( ⁇ 2-[( ⁇ 6- [amino (imino) methyl] pyridine- 3-yl ⁇ amino) carbonyl] -4-chlorophenyl ⁇ amino) methyl] -6-ethoxyphenoxy ⁇ acetoformate 16 mg (Example 8) and tert-butyl ⁇ 2-[( ⁇ 2 -[( ⁇ 6- [Amino (imino) methyl] pyridine-3-yl ⁇ amino) carbol] phenyl ⁇ amino) methyl] -6-ethoxyphenoxy ⁇ acetate formate 5 mg (Example) 9) was obtained.
  • the resulting residue was purified by silica gel column chromatography using chloroform / methanol (20: 1) as the elution solvent, and te rt-butyl ⁇ 2-[( ⁇ 2-[( ⁇ 4- [amino (imino 1.16 g of) methyl] phenyl ⁇ amino) carbonyl] -4-chlorophenol-amino ⁇ methyl] phenoxy ⁇ acetate was obtained as a yellow foam.
  • the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography using ethyl acetate / n-hexane (7: 1) as an elution solvent, and ethyl 3- ⁇ 2-[( ⁇ 2-[( ⁇ 4- [Amino (hydroxyimino) methyl] phenol ⁇ amino) carbol] -4-chlorophine ⁇ amino) methyl] piperidine-1-yl ⁇ propanoate 28 mg was obtained as a pale yellow oil.
  • tert-Butyl ⁇ 2-[( ⁇ 2-[( ⁇ 4-[[(tert-Butoxycarbonyl) amino] (imino) methyl] phenyl ⁇ amino) carbol] -4-chlorophine ⁇ Amino) methyl] -6-hydroxyphenoxy ⁇ acetate 250 mg was dissolved in tetrahydrofuran (5 mL), and 2- (dimethylamino) ethanol (53 mg), triphenylphosphine (157 mg) and diisopropylazodicarboxylate (0.15 mL) were dissolved at room temperature. The mixture was stirred overnight.
  • the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (7: 3) as an elution solvent.
  • the obtained compound was charged with 4 mL of methylene chloride and 4 mL of trifluoroacetic acid at room temperature and stirred for 4 hours.
  • 250 mg was dissolved in 5 mL of tetrahydrofuran, and 3- (methyloxetane-3-yl) was dissolved at room temperature.
  • Methanol 61 mg, triphenylphosphine 157 mg, and diisopropylazodicarboxylate 0.15 mL were added and stirred overnight.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (7: 3) as an elution solvent.
  • the resulting compound was charged with 4 mL of methylene chloride and 4 mL of trifluoroacetic acid at room temperature and stirred for 4 hours.
  • Trifluoroacetic acid (4 mL) was stirred at room temperature for 2 hours in 300 mg of methylene chloride solution (4 mL). The reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in 20 mL of ethyl acetate, a solution of hydrogen chloride in ethyl acetate (4 N, 1 mL) was added at room temperature, and the mixture was stirred for 30 minutes.
  • Example 17 Ethyl 4- ⁇ 2- [( ⁇ 2- [( ⁇ 4- [[(tert-Butoxycarbonyl) amino] (imino) methyl] phenyl ⁇ amino) carbol] -4 ⁇ Amino) methyl] piperidine-1-yl ⁇ Pytolate
  • methylene chloride 1.5 mL
  • trifluoroacetic acid 1.5 mL
  • the reaction solution was concentrated under reduced pressure.
  • the obtained residue was dissolved in ethanol 0.80 mL, 1N aqueous sodium hydroxide solution 0.78 mL was added, and the mixture was stirred for 9 hr.
  • the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by ODS column chromatography using 0.1% aqueous formic acid / acetonitrile as the solvent, and 4- ⁇ 2-[( ⁇ 2-[( ⁇ 4- [amino ( Imino) methyl] phenyl ⁇ amino) carbol] -4-chlorophenyl ⁇ amino) methyl] piperidine-1-yl ⁇ petitic acid formate 72 mg was obtained as a pale yellow oil.
  • Trifluoroacetic acid (0.35 mL) was added to 3 mg of methylene chloride solution (0.35 mL) at room temperature and stirred for 4 hours.
  • the reaction mixture was concentrated under reduced pressure and purified by ODS column chromatography using 0.1% aqueous formic acid / acetonitrile as the solvent, and 3 [( ⁇ 2 [( ⁇ 4 [Amino (imino) methyl] phenol ⁇ amino)
  • 15 mg of (carbol-4-phenyl) amino) methyl] piperidine-1-yl ⁇ propanoic acid formate was obtained as a pale yellow solid.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate / n-hexane (1: 9) as an elution solvent to obtain 124 mg of a colorless foam.
  • the obtained colorless foam was used as a raw material, and the same operation as in Example 15 was performed.
  • tert-butyl ⁇ 4-amino- 2- [( ⁇ 2- [( ⁇ 4- [[(tert-butoxycarbonyl) amino] (imino) methyl] phenyl ⁇ amino) carbol] -4-chloro Mouthphenol ⁇ amino) methyl] -6-isopropoxyphenoxyacetate 100 mg, pyridine 13 ⁇ L, dichloromethane 1.5 mL and tetrahydrofuran 0.5 mL in a mixture (N-tert-butoxycarbol) 35 mg of sulfamyl was added and stirred overnight at room temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate.
  • the organic layer was washed with water and then saturated Japanese brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using chloroform / methanol (99: 1) as an elution solvent.
  • To the obtained residue were added 3 mL of a 1,4-dioxane solution (4 M) of hydrochloric acid and hydrogen and 0.030 mL of water at room temperature, and the mixture was stirred overnight at the same temperature.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate / n-hexane (3: 1) as an elution solvent.
  • ethanol 1.0 mL
  • 2N aqueous sodium hydroxide solution 0.04 mL
  • the reaction solution was concentrated under reduced pressure.
  • the obtained crude product was dissolved in 5 mL of 1,4-dioxane, 0.03 mL of a 1,4-dioxane solution (4 M) in hydrochloric acid and hydrogen was added at room temperature, and the mixture was stirred for 4 hours.
  • the reaction mixture was concentrated under reduced pressure, and 5 mL of 1N aqueous sodium hydroxide solution was added.
  • the resulting reaction solution was purified by ODS column chromatography using 0.1% aqueous formic acid / acetonitrile as the elution solvent, and 3- [2-[( ⁇ 2-[( ⁇ 2- [amino (imino) methyl] pyrimidine- 5-yl ⁇ amino) carbol] -4-methylphenyl ⁇ amino) methyl] -4- (hydroxymethyl) -6-isopropoxyphenyl] propanoic acid formate 5 mg was obtained.
  • tert-butyl [ ⁇ 4-[(2-amino-5-methylbenzoyl) amino] phenol ⁇ (imino) methyl] carbamate 100 mg and sodium triacetoxyborohydride 173 mg in acetic acid (3.3 mL) 4 _ ⁇ [tert-Butyl (dimethyl) silyl] oxy ⁇ -2_formyl-6_isopropoxyphenoxy) acetate 107 mg acetic acid (2.7 mL) solution at room temperature and stirred for 14 hours under the same conditions did. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate twice, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate / n-hexane (1: 3) as an elution solvent to obtain 94 mg of a yellow solid.
  • 94 mg of the obtained yellow solid was dissolved in 3 mL of tetrahydrofuran, and 0.04 mL of tetrahydrofuran solution (1 M) of n-tetraptylammonium fluoride was stored at room temperature, and 1.5 hours under the same conditions. Stir.
  • the reaction solution was purified by silica gel column chromatography using ethyl acetate / n-hexane (2: 3) as an elution solvent to obtain 47 mg of a yellow oily substance.
  • 1.6 mL of trifluoroacetic acid was added to a solution of 104 mg of the yellow oil obtained by the above method in 1,2-dichloroethane (5 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue obtained was added to 7 mL of acetonitrile. After dissolution, 0.59 mL of 1N aqueous sodium hydroxide solution was added. After stirring at room temperature for 1 hour, 1.2 mL of 1N aqueous sodium hydroxide solution was added.
  • tert-Butyl [ ⁇ 4- [(2-amino-5-methylbenzoyl) amino] phenol ⁇ (imino) methyl] carbamate In a suspension of 71 mg acetic acid (0.5 mL), 123 mg sodium triacetoxyborohydride was added. The mixture was further stirred at room temperature for 5 minutes. Next, a solution of tert-butyl [4-acetoxymethyl-2- (2-tert-butoxy-1-methylethoxy) -6-formyl] phenoxyacetate in acetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. did. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (10: 1) as an elution solvent. 4N Hydrochloric acid (10 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 5 hr.
  • the organic layer was washed successively with water, 5% aqueous sodium bicarbonate and then saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate / n_hexane (3: 1) as an elution solvent to obtain a colorless foam.
  • the obtained compound was dissolved in 4 mL of methylene chloride, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours.
  • reaction solution was purified by ODS column chromatography using 0.1% aqueous formic acid / acetonitrile as the elution solvent, and ethyl 3- [2-[( ⁇ 2-[( ⁇ 4- [amino (imino) methyl] phenol ⁇ Amino) carbol] -4-methylphenol ⁇ amino) methyl] -4_ (hydroxymethyl) _6_isopropoxyphenol] propanoate formate 16 mg was obtained as a yellow foam.
  • tert-Butyl [ ⁇ 4- [(2-amino-5-methylpyridine-3-carbol) amino] phenol ⁇ (imino) methyl] force rubamate 0.10 g and sodium triacetoxyborohydride 0.17 g acetic acid (1.0 mL) solution was charged with 0.10 g of tert-butyl 3- (4-acetoxymethyl-2-formyl-6-isopropoxyphenol) propanoate at room temperature. After stirring for 30 minutes, 0.25 g of sodium triacetoxyborohydride and 0.13 g of tert-butyl 3- (4-acetoxymethyl-2-formyl-6-isopropoxyphenyl) propanoate were obtained at room temperature.
  • the reaction solution was diluted with ethyl acetate, poured into saturated aqueous sodium bicarbonate and extracted.
  • the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography using ethyl acetate / n-hexane (3: 1) as an elution solvent to obtain 78 mg of a pale yellow oil.
  • 2 mL of trifluoroacetic acid was added at room temperature and stirred for 3 hours.
  • reaction solution was purified by ODS column chromatography using 0.1% aqueous formic acid / acetonitrile as a solvent, and 3- (2- ⁇ [(2- ⁇ 4- [amino (imino) methyl] phenol ⁇ amino) carbo- L] -4-methylphenylamino ⁇ methyl-4- (2-hydroxyethylamino) -6-isopropoxyphenol) propanoic acid formate 22 mg was obtained as a yellow solid.
  • Example 38 2-Amino-N- ⁇ 4- [Amino (hydroxyimino) methyl] phenol ⁇ -5-chlorobensamide Add 277 mg of sodium triacetoxyborohydride to a suspension of 133 mg of acetic acid (2 mL). After stirring at room temperature for 5 minutes, 129 mg of ethyl (2-formyl-4-hydroxymethyl _6_isopropoxyphenoxy) acetate was added, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (1:10) as an elution solvent to obtain 180 mg of a pale yellow solid.
  • 180 mg of the obtained pale yellow solid was dissolved in ethyl acetate, and 0.135 mL of an ethyl acetate solution (4 M) of hydrochloric acid and hydrogen salt was obtained at 0 ° C.
  • the resulting solid was collected by filtration and dried under reduced pressure to give ethyl [2-[( ⁇ 2-[( ⁇ 4- [amino (hydroxyimino) methyl] phenol ⁇ amino) carbol] -4-chloro].
  • Mouthphenol ⁇ amino) methyl] -4- (hydroxymethyl) _6_isopropoxyphenoxy] acetate hydrochloride was obtained as a pale yellow solid.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate-hexane (3: 1) as an elution solvent.
  • the obtained compound was dissolved in 8 mL of ethanol, and 2 mL of 2N sodium hydroxide aqueous solution was added at room temperature, followed by stirring for 2.5 hours.
  • 2.3 mL of 2N hydrochloric acid was added at 0 ° C, and the solvent was concentrated under reduced pressure. Water was added to the residue, and the resulting precipitate was collected by filtration.
  • the residue was washed successively with water and n-hexane and then dried under reduced pressure.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate twice, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate-hexane (2: 3) as an elution solvent to obtain 1.1 g of a yellow solid.
  • 1.1 g of the obtained yellow solid was dissolved in 33 mL of tetrahydrofuran, and 0.47 mL of tetrahydrofuran solution (1 M) of tetra n-butylammonium fluoride was prepared at room temperature and stirred for 1.5 hours under the same conditions. .
  • a tetrahydrofuran solution (1 M) of tetrahydrofuran-tetra-n-butyl ammonium (0.235 mL) was added at room temperature, and the mixture was stirred for 3 hours under the same conditions.
  • 0.141 mL of a tetrahydrofuran solution (1 M) of tetraptyl ammonium fluoride was added at room temperature, and the mixture was stirred for 2 hours under the same conditions.
  • reaction solution was purified by silica gel column chromatography using ethyl acetate / n-hexane (2: 3) as an elution solvent, and ethyl ⁇ 2-[( ⁇ 2-[( ⁇ 4- [amino (hydroxyimino 616 mg of) methyl] phenyl ⁇ amino) carbol] -4-methylphenol ⁇ amino) methyl] -4-hydroxy-6-isopropoxyphenoxy ⁇ acetate was obtained as a yellow solid.
  • the residue obtained by distilling off the solvent under reduced pressure was dissolved in 15 mL of ethanol, and 268 mg of potassium carbonate was added at room temperature, followed by stirring for 3 hours.
  • the reaction mixture was poured into 2N hydrochloric acid, and neutralized with saturated aqueous sodium hydrogen carbonate.
  • the precipitate was collected by filtration to obtain 162 mg of a colorless solid.
  • the resulting colorless solid 132 mg was purified by ODS column chromatography using 0.1% aqueous formic acid / acetonitrile as a solvent.
  • the elution fraction was concentrated under reduced pressure to about 20 mL, saturated aqueous sodium hydrogen carbonate was added, and the precipitated solid was collected by filtration.
  • the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography using ethyl acetate / n-hexane (1: 2) as an elution solvent to obtain 26 mg of a pale yellow oily substance.
  • 2 mL of trifluoroacetic acid was added at room temperature, followed by stirring for 3.5 hours.
  • the solvent was distilled off under reduced pressure, methylene chloride was added to the resulting residue, and the mixture was distilled off again under reduced pressure to obtain a pale yellow solid.
  • the obtained pale yellow solid was dissolved in 5 mL of ethanol, and 53 mg of potassium carbonate was stirred at room temperature for 1 hour and at 40 ° C. for 1 hour.
  • Potassium carbonate (53 mg) was added and stirred at 60 ° C for 30 minutes.
  • a phosphate buffer solution of PH7.4 was added, and 1N hydrochloric acid was added dropwise to adjust the pH to 6.
  • Example 43 tert-Butyl [ ⁇ 4- [(2-amino-5-chlorobenzobenzo) amino] phenol Kimino) methyl] rubamate 250 mg of sodium triacetoxyborohydride in a solution of 229 mg of acetic acid (6 mL) After stirring at room temperature and stirring for 10 minutes, 200 mg of methyl 4- (2_tert-butoxy_2_oxoethoxy) -3-ethoxy-5-formylbenzoate was added at room temperature and 3 Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water, 5% aqueous sodium bicarbonate, and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (2: 1) as an elution solvent.
  • the obtained residue was dissolved in 3 mL of methanol, 0.3 mL of 1N aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. 0.6 mL of 1N aqueous solution of sodium hydroxide and sodium chloride was stirred at room temperature for 2 hours.
  • the obtained residue was purified by silica gel column chromatography using ethyl acetate as an elution solvent, and ethyl 3- [2-[( ⁇ 3-[( ⁇ 4-[[(ethoxycarbonyl) amino] (imino) methyl [Fuel ⁇ amino) carbol] pyridine-2-yl ⁇ amino) methyl] -4- (hydroxymethyl) -6-isopropoxyphenyl] propanoate 19 mg was obtained as a pale yellow solid.
  • the resulting residue was purified by aminopropyl silica gel column chromatography using ethyl acetate-hexane (7: 1) as an elution solvent. 0.07 mL of an ethyl acetate solution (4 M) of sodium chloride and hydrogen was added to an ethyl acetate solution (1.0 mL) of the obtained compound, and the mixture was stirred for 30 minutes.
  • reaction solution was purified by ODS column chromatography using water / acetonitrile as an elution solvent, and 3- [2-[( ⁇ 2-[( ⁇ 4-[[(ethoxycarbonyl) amino] (imino) methyl] phenyl. L-amino) force] -4-methylphenol ⁇ amino) methyl] -4_ (hydroxymethyl) _6_isopropoxyphenyl] propanoic acid 42 mg was obtained as a yellow solid.
  • N- ⁇ 4- [Amino (hydroxyimino) methyl] phenol ⁇ -2-amino-5-methylbenzamide and tert-butyl 3_ (4-acetoxymethyl-2_formyl-6_isopropoxyphenyl) propanoate was used as a raw material to give a yellow solid by the same operation as in Example 54 described later.
  • 1N aqueous sodium hydroxide solution 5.5 mL was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was purified by ODS column chromatography using water / acetonitrile as an elution solvent, and sodium 3- [2-[( ⁇ 2-[( ⁇ 4- [amino (hydroxyimino) methyl] fale was obtained.
  • a yellow solid was obtained in the same manner as in Example 7, using tert-butyl [ ⁇ 4-[(2-amino-5-chlorobenzobenzo) amino] phenol Kimino) methyl] rubamate as a raw material. .
  • ⁇ 2-[( ⁇ 2-[( ⁇ 4- [amino] imino] methyl ⁇ amino) carbol] -4 was prepared in the same manner as in Example 15.
  • -Chlorophenyl ⁇ amino) methyl] -4-[(dimethylamino) methyl] -6-ethoxyphenoxy ⁇ acetic acid hydrochloride was obtained as a yellow solid.
  • Example compounds 61 to 654 shown in Tables 25 to 107 to be described later were produced using the corresponding raw materials.
  • Tables 25 to 107 show the structures and physicochemical data of the example compounds.
  • Tables 108 to 118 below show structures of other compounds of the present invention. These can be easily produced by using the production methods described above, the methods described in the examples, methods obvious to those skilled in the art, or variations thereof.
  • Test Method 1 Enzyme inhibition measurement test by synthetic substrate method
  • Table 1 shows the activity of the representative compounds of the present invention. Ex represents the example number (the same applies hereinafter) 0
  • the compound of Example 16 is active against blood coagulation factor X and its inhibitory activity IC is 1
  • Thrombin inhibitory activity 50 ⁇ L of reaction buffer (pH 7.4) in 96-well microplate, compound solution 10 ⁇ 2 mM synthetic substrate S-2238 (Chromogenix) 20 ⁇ L, 0.2 U / Add 20 ⁇ L of mL of human thrombin (Sigma), react for 1 hour at room temperature, and measure the change in absorbance at 405 nm.
  • the compound of Example 16 has an inhibitory activity IC of over 100 ⁇ IC against thrombin.
  • the compound (I) of the present invention has a strong activity ⁇ blood coagulation factor VII inhibitory activity, and is also active selectively against the activity ⁇ blood coagulation factor X and thrombin. It was confirmed that the blood coagulation factor VII was inhibited.
  • Test method Ex vivo clotting time measurement test using guinea pigs To male Hartley guinea pigs (5-7 weeks old, Japan SLC), a test compound dissolved in a solvent containing 1 volume of dimethylacetamide and 1 volume of 5% glucose was administered intravenously under anesthesia with jetyl ether. (1 mg / kg) After 2 minutes, 0.5 mL of blood was collected from the jugular vein with 1/10 volume of 3.13% sodium citrate, and plasma was separated by centrifugation at 3000 rpm for 10 minutes. Using this plasma, the extrinsic clotting time (PT) was measured according to the following method a).
  • Guinea pig plasma 50 / z L was warmed at 37 ° C for 1 minute, and 100 L of moth moth recombin plastin was added to measure the clotting time.
  • an automatic blood coagulation measuring device ST4 Roche Diagno Status
  • the clotting time of guinea pig plasma without the test compound was used as a control, and the activity of the test compound was shown as a relative value when this control was 1.
  • the compound of the present invention was found to prolong the extrinsic clotting time by intravenous administration.
  • Table 2 below shows the action of prolonging the extrinsic clotting time of the representative compounds of the present invention.
  • the compound (I) of the present invention includes a compound that is metabolized in vivo and exhibits an active blood coagulation factor VII inhibitory activity.
  • R 1 is —C ( ⁇ NH) NH and / or —C (0) R 5 is a carboxylic acid in vivo.
  • Test Method 3 There are compounds that have been converted to certain compounds and show active activity, blood coagulation factor VII inhibitory activity. The usefulness of such compounds is shown below in Test Method 3, and Test Methods 1 and Z or Test This can be confirmed by combining the tests of Method 2.
  • Rats Male; Sprague-Dawley (SD-IGS), 7 weeks old (purchased at 6 weeks of age), Nippon Chiyers River, food condition: free intake of water and food) were fasted from the evening before administration .
  • the compound was suspended in 0.5% MC to a concentration of 10 mg / 5 mL and administered orally once into the stomach using a sonde.
  • the compound was dissolved in ⁇ , ⁇ -dimethylacetamide to a concentration of 1 mg / 0.2 mL, diluted with the same amount of 5% glucose (Otsuka Pharmaceutical Factory), and then rat (male; Sprague-Dawley (SD_IGS), 7-week-old (purchased at 6-week-old), Nippon Chisuriba Co., Ltd., feeding conditions: free intake of water and food) Single intravenous administration via tail vein.
  • samples were collected at approximately 200 / zL with a syringe that had been parinized from the jugular vein at 15, 30 minutes, 1, 2, 4, and 8 hours after administration, and immediately stored under ice cooling.
  • intravenous administration about 200 ⁇ L of blood was collected from a jugular vein-treated syringe at 2, 10, 30 minutes, 1, 2, and 4 hours after administration, and immediately stored under ice cooling.
  • the blood was centrifuged at 10,000 rpm for 1 minute (room temperature) to collect the plasma.
  • the prepared sample was stored at about 4 ° C until measurement.
  • a plasma sample at each point was dispensed into a 25 ⁇ L tube, and 100 ⁇ L of an internal standard solution dissolved in acetonitrile and 875 ⁇ L of acetonitrile were added. Thereafter, the mixture was stirred with a mixer, centrifuged at 3300 rpm for 20 minutes, and 5 ⁇ L of the supernatant was injected into HPLC.
  • a calibration curve solution was prepared by dissolving the measurement compound in 50% aqueous acetonitrile and serially diluting with acetonitrile to 10, 50, 100, 500, 1000, 5000, 10000, 50000 ng / mL.

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Abstract

La présente invention a pour objet un composé présentant un effet anticoagulant basé sur l'inhibition du facteur VII activé de coagulation sanguine et, par conséquent, pouvant être employé en tant qu'inhibiteur de coagulation sanguine ou en tant qu'agent prophylactique/thérapeutique pour le traitement de maladies causées par un thrombus ou un embole. La substance décrite ci-avant est un dérivé d'acide carboxylique caractérisé en ce qu'il comprend trois groupements cycliques, ou un sel de qualité pharmaceutique dudit dérivé, ce composé présentant une activité inhibitrice puissante du facteur VII activé de coagulation sanguine. Du fait de son excellent effet anticoagulant, ledit dérivé d'acide carboxylique peut être employé en tant qu'agent prophylactique/thérapeutique dans le cas de maladies causées par un thrombus ou un embole.
PCT/JP2005/024096 2004-12-28 2005-12-28 Derive d'acide carboxylique ou sel de ce derive Ceased WO2006070878A1 (fr)

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WO2010088000A3 (fr) * 2009-02-02 2011-04-07 Angion Biomedica Corp. Composés antifibrotiques et leurs utilisations
WO2011118672A1 (fr) * 2010-03-25 2011-09-29 アステラス製薬株式会社 Inhibiteur de la kallicréine plasmatique
US20110263556A1 (en) * 2009-10-23 2011-10-27 Boehringer Ingelheim International Gmbh New Compounds
JP2013511482A (ja) * 2009-11-18 2013-04-04 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ダビガトランエテキシラートの製造方法
JP2013515026A (ja) * 2009-12-22 2013-05-02 エフ．ホフマン−ラ ロシュ アーゲー 置換されたベンズアミド誘導体
JP2013521278A (ja) * 2010-03-03 2013-06-10 ゲンナディエヴィッヒ トヴビン，ドミトリー 第Ｘａ因子のウレタン、尿素、アミジン、及び関連阻害剤
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
JP2019500380A (ja) * 2015-12-28 2019-01-10 セルジーン クオンティセル リサーチ，インク． ヒストンデメチラーゼ阻害剤
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US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
WO2010088000A3 (fr) * 2009-02-02 2011-04-07 Angion Biomedica Corp. Composés antifibrotiques et leurs utilisations
US8951999B2 (en) * 2009-10-23 2015-02-10 Orexo Ab Compounds
US20110263556A1 (en) * 2009-10-23 2011-10-27 Boehringer Ingelheim International Gmbh New Compounds
JP2013511482A (ja) * 2009-11-18 2013-04-04 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ダビガトランエテキシラートの製造方法
KR101802132B1 (ko) * 2009-11-18 2017-11-28 베링거 인겔하임 인터내셔날 게엠베하 다비가트란 에텍실레이트의 제조방법
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JP2016041740A (ja) * 2009-12-22 2016-03-31 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 置換されたベンズアミド誘導体
JP2013515026A (ja) * 2009-12-22 2013-05-02 エフ．ホフマン−ラ ロシュ アーゲー 置換されたベンズアミド誘導体
JP2013521278A (ja) * 2010-03-03 2013-06-10 ゲンナディエヴィッヒ トヴビン，ドミトリー 第Ｘａ因子のウレタン、尿素、アミジン、及び関連阻害剤
US9708265B2 (en) 2010-03-03 2017-07-18 Dmitry Gennadievich Tovbin Urethanes, ureas, amidines and related inhibitors of factor Xa
WO2011118672A1 (fr) * 2010-03-25 2011-09-29 アステラス製薬株式会社 Inhibiteur de la kallicréine plasmatique
JP2019500380A (ja) * 2015-12-28 2019-01-10 セルジーン クオンティセル リサーチ，インク． ヒストンデメチラーゼ阻害剤
US11001568B2 (en) 2015-12-28 2021-05-11 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
JP2021121599A (ja) * 2015-12-28 2021-08-26 セルジーン クオンティセル リサーチ，インク． ヒストンデメチラーゼ阻害剤
JP2023085300A (ja) * 2015-12-28 2023-06-20 セルジーン クオンティセル リサーチ，インク． ヒストンデメチラーゼ阻害剤
US11731954B2 (en) 2015-12-28 2023-08-22 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US10508107B2 (en) 2016-03-17 2019-12-17 Hoffmann-La Roche Inc. Morpholine derivative
US11312711B2 (en) 2016-03-17 2022-04-26 Hoffmann-La Roche Inc. Morpholine derivative

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