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WO2011118672A1 - Inhibiteur de la kallicréine plasmatique - Google Patents

Inhibiteur de la kallicréine plasmatique Download PDF

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Publication number
WO2011118672A1
WO2011118672A1 PCT/JP2011/057078 JP2011057078W WO2011118672A1 WO 2011118672 A1 WO2011118672 A1 WO 2011118672A1 JP 2011057078 W JP2011057078 W JP 2011057078W WO 2011118672 A1 WO2011118672 A1 WO 2011118672A1
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Prior art keywords
methyl
amino
phenyl
imino
carbamoyl
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Ceased
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PCT/JP2011/057078
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English (en)
Japanese (ja)
Inventor
健詞 重永
佳正 今村
大輔 鈴木
知文 宅和
俊樹 本間
明仁 平林
秀明 平澤
敦志 近藤
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Astellas Pharma Inc
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Astellas Pharma Inc
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Publication of WO2011118672A1 publication Critical patent/WO2011118672A1/fr
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
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    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
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Definitions

  • the present invention is a carboxyl, which has a drug, particularly plasma kallikrein inhibitory action, and is particularly useful for prevention / treatment of edema (hereditary angioedema, brain edema), hematoma (intracranial hematoma), and bleeding suppression during surgery. It relates to an acid compound.
  • Kallikrein acts enzymatically on the substrate kininogen to release bioactive peptide kinin.
  • This kallikrein-kinin system is thought to play many physiological and pathophysiological roles in circulatory regulation, edema, inflammation / allergy, pain, shock, and the like.
  • glandular kallikrein releases high-molecular-weight kininogen and low-molecular-weight kininogen, and kalidine (lysyl bradykinin), and plasma kallikrein releases bradykinin from high-molecular-weight kininogen. .
  • B1 and B2 Two types of kinin receptors, B1 and B2, have been known so far, and kinins, including bradykinin, act through these receptors.
  • the B2 receptor is constitutively expressed in many tissues and is thought to mediate most of the physiological activities of kinin.
  • expression of B1 receptor is induced by inflammatory reaction or tissue injury, and it has been suggested that it is involved in maintenance of inflammatory reaction and associated pain (Pharmacol Rev. 1992; 44: 1-80).
  • the main inhibitors of plasma kallikrein in human plasma are C1-inhibitor and ⁇ 2-macroglobulin (Biochemistry 1993; 32 (45): 12136-47).
  • Edema is a state in which water is excessively stored in the interstitial tissue, and is a pathological state in which the body fluid balance in the living body is broken.
  • Diseases include hereditary angioedema and brain edema.
  • therapeutic agents for edema have been studied, but clinical satisfaction is not sufficient.
  • the C1-inhibitor preparation used for the treatment of hereditary angioedema attacks is a high-molecular-weight protein preparation, which is a drug that is injected intravenously and has low convenience (Trends Mol. Med. 2009; 15 (2): 69-78).
  • bradykinin produced by the kallikrein-kinin system works on vascular endothelial cells and enhances vascular permeability and acts as a cause or an exacerbation factor of edema. Therefore, a drug having a plasma kallikrein inhibitory action inhibits the release of bradykinin and is considered effective for edema (Expert Opin. Investig. Drugs 2006; 15 (9): 1077-90, J. Pharmacol. Exp. Ther. 2006; 318 (2): 849-54).
  • aprotinin an enzyme-inhibiting protein derived from bovine lung with a wide enzyme selectivity, has been used as a drug to suppress excessive bleeding during surgery. Now recovered from the market (N. Engl. J. Med. 2008; 358 (22): 2319-31). Regarding blood transfusion, there are always problems such as supply shortage, blood product storage work / cost burden, infection risk, and drugs that reduce the need for blood transfusion by suppressing bleeding during and after surgery are medical economics and iatrogenic diseases It is also useful from the point of avoidance (Semin. Hematol. 2004; 41 (Suppl. 1): 117-24). Plasma kallikrein has been reported to promote plasmin production and promote thrombolysis. Therefore, a drug having a plasma kallikrein inhibitory action is considered to be effective in suppressing bleeding (Thromb. Res. 1990; 57 (6): 889-95).
  • a hematoma is a pathological state in which a blood pool is formed in a tissue by bleeding, and examples of the disease include intracranial hematoma (intracerebral hematoma, subdural hematoma, etc.).
  • Intracranial hematoma is a disease that causes hematoma by bleeding in the skull, and there is currently no effective medical treatment or prevention for intracranial hematoma.
  • Involvement of plasma kallikrein has been reported in intracerebral hematoma and subdural hematoma (Nat. Med. 2011; 17 (2): 206-210, J. Neurol. Pneuchiatry. 1995; 59 (4): 388-94). Since a plasma kallikrein inhibitor is considered to be effective for suppressing bleeding, it can be expected to be effective for hematoma.
  • Ecallantide has been reported as a specific plasma kallikrein inhibitor, but ecarantide is a recombinant protein and anaphylaxis and antibody production have been reported as side effects (Expert Opin. Biol. Ther. 2008; 8 (8 ): 1187-99). Based on the above, low-molecular-weight plasma kallikrein inhibitors with little concern for anaphylaxis and antibody production are expected to be highly effective and safe therapeutic agents for edema and hematoma and suppressive bleeding during surgery .
  • an amidino derivative represented by the following general formula (A) has an inhibitory action on activated blood coagulation factor VII, and is used for prevention and treatment of generalized intravascular coagulation syndrome, coronary artery thrombosis and the like. It is described as being useful.
  • the active ingredient of the medicament of the present invention has B ring and C ring bonded through linker L, but E 2 ring and E 4 ring are directly bonded.
  • Patent Document 2 discloses a wide range of compounds represented by the following general formula (B): thrombin, activated blood coagulation factor VII, tissue factor / activated blood coagulation factor VII complex, activated blood coagulation factor X, It is described that it has a trypsin-like serine protease inhibitory action such as trypsin and is useful as an anticoagulant.
  • the compounds described as examples are limited to compounds having a biaryl structure in which X is a bond, and no active ingredient of the pharmaceutical agent of the present invention having a linker is disclosed.
  • plasma kallikrein inhibitory action edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.
  • E 1 and L represent a carbocycle, a heterocycle, etc.
  • X represents a bond, unsubstituted or substituted C 1-4 methylene, etc.
  • Patent Document 3 discloses that compounds represented by the following general formulas (C-1) and (C-2) are activated blood coagulation factor VII, activated blood coagulation factor IX, activated blood coagulation factor X, It is described that it has serine protease inhibitory action such as activated blood coagulation factor XI, tryptase, urokinase and the like, and is useful as an anticoagulant, an anti-inflammatory agent, and a cancer therapeutic agent.
  • the compounds (C-1) and (C-2) have no ring or linker L corresponding to the B ring of the active ingredient of the medicament of the present invention.
  • a compound represented by the following general formula (D) includes activated blood coagulation factor VII, activated blood coagulation factor IX, activated blood coagulation factor X, activated blood coagulation factor XI, It has a serine protease inhibitory action such as tryptase and urokinase, and is described as being useful as an anticoagulant, anti-inflammatory agent, or cancer therapeutic agent.
  • the compound of formula (D) does not have the B ring or linker L as the active ingredient of the medicament of the present invention.
  • plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery See the official gazette for symbols in the formula.
  • compound (E) represented by a wide range of the following general formulas inhibits serine proteases involved in blood coagulation cascades such as activated blood coagulation factor VII, activated blood coagulation factor X, thrombin, and trypsin. And is useful for the prevention and treatment of coronary artery disease, cerebrovascular disease and the like.
  • K is inserted in the corresponding part between the B ring and the linker J of the active ingredient of the medicament of the present invention.
  • plasma kallikrein inhibitory action edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.
  • Patent Document 6 describes that a wide range of compounds represented by the following general formula (F) have an anticoagulant action and are useful for the prevention and treatment of diseases such as venous / arterial thrombosis and cerebrovascular diseases. .
  • diseases such as venous / arterial thrombosis and cerebrovascular diseases.
  • plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery See the official gazette for symbols in the formula.
  • Patent Document 7 describes that a compound represented by the following general formula (G) has an activated blood coagulation factor X inhibitory action and is useful for the prevention / treatment of thrombosis and the like.
  • the substituent on Q 1 corresponding to the A ring of the compound of the present invention is limited to methyl, fluoro or chloro, and there is no substituent corresponding to R 1 of the compound of the present invention.
  • Q 1 is 2-pyridinyl optionally substituted with methyl, fluoro or chloro at the 5-position, 3-pyridinyl optionally substituted with methyl, fluoro or chloro at the 6-position, or methyl, fluoro or (This represents pyridanyl optionally substituted with chloro. For symbols in other formulas, refer to this publication.)
  • Patent Document 8 describes that a wide range of compounds represented by the following general formula (H) have serine protease, activated blood coagulation factor X inhibitory action and are useful as antithrombotic agents. However, there is no description regarding plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.
  • R 4 is hydrogen, alkyl, halo, haloalkyl, cyano, nitro, —OR 5 , —C (O) OR 5 , —N (R 5 ) R 6 , —C (O) N (R 5 ) R 6 or -R 8 -N (R 5 ) R 6 , where R 8 represents a linear or branched alkylene, alkylidene, or alkylidyne chain (see the publication for symbols in other formulas)
  • Patent Document 9 describes that a carboxylic acid derivative represented by the following formula (J) has an activated blood coagulation factor VII inhibitory action and is useful for diseases caused by thrombus or embolism.
  • diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vasospasm), acute and chronic myocardial infarction, unstable narrow Diseases in ischemic heart diseases such as heart disease, coronary artery thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, disseminated intravascular coagulation syndrome (DIC) coagulation), generalized intravascular coagulation syndrome, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty (PTCA) and other revascularization and restenosis after coronary angioplasty Diseases in various vascular disorders such as reo
  • Providing a drug that has plasma kallikrein inhibitory action is particularly useful for the prevention and treatment of edema (especially hereditary angioedema and brain edema) and hematoma (especially intracranial hematoma), and for suppressing bleeding during surgery.
  • edema especially hereditary angioedema and brain edema
  • hematoma especially intracranial hematoma
  • the present invention relates to a plasma kallikrein inhibitor containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a ring An aryl ring or a heteroaryl ring.
  • Ring B a benzene ring, a naphthalene ring, or a monocyclic to bicyclic heteroaryl ring.
  • Ring C a cycloalkyl ring, an aryl ring, or a hetero ring.
  • m, n and p each independently an integer of 0 to 3.
  • R 2 and R 3 each independently lower alkyl, halogeno lower alkyl, halogen, oxo, —CN, —NO 2 , —OR 0 , —O-halogeno lower alkyl, —N (R 0 ) 2 , —SR 0 , -S (O) R 0 , -S (O) 2 R 0 , -S (O) 2 N (R 0 ) 2 , -N (R 0 ) S (O) 2 R 0 , -C (O ) R 0 , -CO 2 R 0 , -C (O) N (R 0 ) 2 , -N (R 0 ) C (O) R 0 , -N (R 0 ) C (O) -halogeno lower alkyl, A cycloalkyl, aryl, or heterocyclic group.
  • R 2 and R 3 may be substituted.
  • each of two R 2 or R 3 may be combined to form —O-lower alkylene-O—.
  • R 0 each independently -H or lower alkyl.
  • R 4 may each be substituted.
  • R 6 each independently -H or an optionally substituted lower alkyl, lower alkenyl, cycloalkyl, aryl or heterocyclic group.
  • R 5 —OR 0 , —N (R 0 ) 2 , or —N (R 0 ) -lower alkylene-OR 0 .
  • X single bond, -O-, -N (R 7 )-, -S-, -C (O)-, -S (O)-, -S (O) 2- , * -lower alkylene-O- Or * -lower alkylene-N (R 7 )-.
  • * shows the coupling
  • R 7 —R 0 , —C (O) -lower alkyl, or —C (O) -halogeno lower alkyl.
  • Y A single bond, or lower alkylene or lower alkenylene, each of which may be substituted. The same applies hereinafter. ]
  • the present invention also provides an edema (especially hereditary angioedema, cerebral edema), hematoma (especially intracranial hematoma) containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to a pharmaceutical composition that is a prophylactic / therapeutic agent, or a hemorrhage inhibitor during surgery.
  • the present invention also provides a plasma kallikrein inhibitor, an edema, a prophylactic or therapeutic agent for hematoma, or a compound of the formula (I) or a salt thereof for the production of a hemorrhage suppressant; a prophylactic or therapeutic agent for edema, hematoma, or A compound of formula (I) or a salt thereof for use in inhibiting bleeding; prevention or treatment of edema, hematoma, or use of a compound of formula (I) or salt thereof for inhibiting bleeding; and formula (I)
  • the present invention relates to a method for preventing or treating edema, hematoma, or suppressing bleeding, comprising administering an effective amount of the compound or a salt thereof to a patient.
  • the pharmaceutical composition according to (1) which is an agent for preventing or treating edema or a bleeding inhibitor.
  • the pharmaceutical composition according to (2) which is an agent for preventing or treating edema.
  • the pharmaceutical composition according to (3) which is a preventive or therapeutic agent for hereditary angioedema.
  • the pharmaceutical composition according to (6) which is a bleeding inhibitor during surgery.
  • the pharmaceutical composition according to (1) which is a prophylactic or therapeutic agent for hematoma.
  • the pharmaceutical composition according to (8) which is a preventive or therapeutic agent for intracranial hematoma.
  • (11) A method for preventing or treating edema, hematoma, or inhibiting bleeding, comprising administering an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a patient.
  • the present invention relates to a compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof.
  • B A CH or N.
  • R 3A —H or —O-lower alkyl.
  • R 3B —H, F, or lower alkyl.
  • -X A -Y A- * -O-CH 2 -or-(CH 2 ) 2- .
  • * means the bond to a benzene ring.
  • R 4A lower alkylene-OH, lower alkylene-NH 2 , —O-lower alkylene-NH 2 , or lower alkylene- (nitrogen-containing saturated heterocyclic group optionally substituted with lower alkyl).
  • R 6A Lower alkyl.
  • R 4A is lower alkylene-OH
  • R 3A is —O-lower alkyl
  • —X A —Y A — is — (CH 2 ) 2 —.
  • Excluding [2-( ⁇ [2-( ⁇ 4- [Amino (imino) methyl] phenyl ⁇ carbamoyl) -4-methylphenyl] amino ⁇ methyl) -4- (aminomethyl) -6-isopropoxyphenoxy] acetic acid .
  • the present invention also relates to a pharmaceutical composition comprising a compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the carboxylic acid compound represented by the formula (I) which is an active ingredient of the medicament of the present invention, has a plasma kallikrein inhibitory action, edema (especially hereditary angioedema, brain edema), hematoma (especially intracranial hematoma) It is useful for the prevention and treatment of bleeding and the suppression of bleeding during surgery.
  • edema especially hereditary angioedema, brain edema
  • hematoma especially intracranial hematoma
  • lower means a hydrocarbon chain having 1 to 6 carbon atoms (hereinafter sometimes referred to as C 1-6 ) unless otherwise specified.
  • Alkyl alkenyl
  • alkylene alkenylene
  • lower alkyl means C 1-6 alkyl. Specific examples include methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, normal hexyl and the like.
  • “Lower alkenyl” means C 2-6 alkenyl having one or more double bonds at any position. Specific examples include vinyl, 1-propen-1-yl, allyl, isopropenyl, 3-buten-1-yl, 1,3-butadienyl and the like. Preferred are C 2-3 alkenyl vinyl, 1-propen-1-yl, allyl and isopropenyl, and more preferred are vinyl and allyl.
  • the “lower alkylene” means a divalent group formed by removing one hydrogen at any position of the “lower alkyl”. Specifically,-(CH 2 ) 1-6- , -CH (CH 3 )-, -C (CH 3 ) 2- , -CH 2 CH (CH 3 )-, -CH 2 C (CH 3 ) 2 -Etc. Preferred are C 1-3 alkylene-(CH 2 ) 1-3- , -CH (CH 3 )-, -C (CH 3 ) 2- , -CH 2 CH (CH 3 )-, more preferably Is- (CH 2 ) 1-3- .
  • Cycloalkyl means a C 3-10 non-aromatic hydrocarbon ring, which may form a bridged ring or a spiro ring, or may have a partially unsaturated bond. . Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclooctadienyl, adamantyl and norbornyl. C 3-6 cycloalkyl is preferable, and cyclobutyl, cyclopentyl, or cyclohexyl is more preferable.
  • Halogen means a halogen atom. Specific examples include fluoro, chloro, bromo and iodo. Preferred are fluoro, chloro and bromo, and more preferred is fluoro and chloro.
  • halogeno lower alkyl means a group in which one or more arbitrary hydrogen atoms of the “lower alkyl” are the same or different from each other and substituted with the “halogen”. Specific examples include trifluoromethyl and pentafluoroethyl. Preferably, it is trifluoromethyl.
  • Aryl means a monocyclic to tricyclic C 6-14 aromatic hydrocarbon ring group, and specific examples thereof include phenyl, naphthyl and the like, preferably phenyl. Further, the C 5-8 cycloalkyl ring may be condensed, and for example, indanyl or tetrahydronaphthyl may be formed.
  • “Monocyclic heteroaryl” means a 5- to 6-membered monocyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of N, O and S.
  • the ring atom S or N may be oxidized to form an oxide or a dioxide.
  • Specific examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl and the like.
  • Pyridyl and pyrazinyl are preferable, and pyridyl is more preferable.
  • Heteroaryl refers to the above “monocyclic heteroaryl”, “bicyclic heteroaryl” in which the monocyclic heteroaryls or the monocyclic heteroaryl are condensed with a benzene ring, and the bicyclic heteroaryl Means a monocyclic heteroaryl or a tricyclic heteroaryl condensed with a benzene ring.
  • the ring atom S or N may be oxidized to form an oxide or a dioxide.
  • bicyclic heteroaryl examples include benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl and the like. Indolyl and benzimidazolyl are preferred.
  • Specific examples of the tricyclic heteroaryl include carbazolyl.
  • Specific examples of the heteroaryl include the groups described in the above “monocyclic heteroaryl”, “bicyclic heteroaryl” and “tricyclic heteroaryl”. Pyridyl, pyrazinyl, indolyl, and benzimidazolyl are preferable, and pyridyl is more preferable.
  • Heterocycle means a 3- to 8-membered monocyclic heterocycle having 1 to 4 heteroatoms selected from the group consisting of N, O and S, and the monocyclic heterocycles And a bicyclic heterocycle in which the monocyclic heterocycle is fused with a benzene ring or a cycloalkyl ring, and the bicyclic heterocycle is fused with the monocyclic heterocycle, benzene ring or cycloalkyl ring Means a tricyclic heterocycle, and includes saturated, partially unsaturated, and aromatic heterocycles.
  • ring atoms N or S may be oxidized to form an oxide or a dioxide, or a bridged ring or a spiro ring may be formed.
  • pyridyl Preferred are pyridyl, pyrazinyl, benzimidazolyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl, indolyl, dihydroindolyl, and more preferred are pyridyl, piperidyl, morpholinyl, piperazinyl.
  • the “nitrogen-containing saturated heterocycle” means a saturated heterocycle in which at least one of heteroatoms constituting the ring is a nitrogen atom among the above heterocycles.
  • pyrrolidinyl examples include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, homomorpholinyl, decahydroquinolinyl and the like.
  • Preferred are monocyclic nitrogen-containing saturated heterocycles, more preferred are 5- to 7-membered monocyclic nitrogen-containing saturated heterocycles, and even more preferred are pyrrolidinyl, piperidyl, piperazinyl, and morpholinyl.
  • the permissible substituent of the word “which may be substituted” may be any substituent as long as it is a commonly used substituent in the technical field.
  • the substituent on the lower alkyl allowed by “—C ( ⁇ NH) NH—CO 2- (optionally substituted lower alkyl)” in R 1 is preferably —OC (O) -lower alkyl. It is done.
  • Preferred examples of the substituent allowed by “lower alkyl” which may be substituted in R 2 and R 3 include groups selected from the following group P 1 .
  • R 2 and R 3 which may be substituted respectively "cycloalkyl", preferably the permissible substituents in the "aryl” and “heterocyclic group” include groups selected from the following Q 1 group .
  • Q group 1 lower alkyl, halogeno lower alkyl, halogen, oxo, —OR 0 and —O-halogeno lower alkyl.
  • R 4 and R 6 the preferred substituents are permissible in which may be substituted are “lower alkyl” and "lower alkenyl” includes groups selected from the following P 2 groups.
  • P 2 group halogen, —CN, —OR 0 , —O-halogeno lower alkyl, —OC (O) R 0 , —OC (O) N (R 0 ) 2 , —oxo, —SR 0 , —S ( O) R 0 , -S (O) 2 R 0 , -S (O) 2 N (R 0 ) 2 , -N (R 0 ) S (O) 2 R 00 , -NHS (O) 2 N (R 0 ) 2 , -N (lower alkyl) -S (O) 2 N (R 0 ) 2 , -N (R 0 ) 2 , -NH-lower alkylene-N (R 0 ) 2 , -N (lower alkyl) -Lower alkylene-N (R 0 ) 2 , -C (O) R 0 , -CO 2 R 0
  • cycloalkyl, aryl and heterocyclic group in P 2 group may be substituted with a group selected from Q 2 groups.
  • Q 2 group lower alkyl, halogeno lower alkyl, halogen, oxo, -OR 0 , -O-halogeno lower alkyl, -N (R 0 ) 2 , -C (O) R 0 , -CO 2 R 0 , -N (R 0 ) S (O) 2 R 0 , -C (O) N (R 0 ) 2 , -N (R 0 ) C (O) R 0 , lower alkylene-N (R 0 ) 2 , lower alkylene- CO 2 R 0 and -lower alkylene-C (O) N (R 0 ) 2 .
  • Preferred examples of the substituent allowed for “cycloalkyl”, “aryl” and “heterocyclic group” which may be substituted in R 4 and R 6 include groups selected from the group Q 2 above.
  • Preferred examples of the substituent allowed for “lower alkylene” and “lower alkenylene” in Y which may be substituted include a group selected from halogen and —OR 0 .
  • the permissible substituent is preferably lower alkyl, halogeno lower alkyl, Halogen, —OR 0 , or —O-halogeno lower alkyl, more preferably lower alkyl.
  • the A ring is preferably a benzene ring or a 6-membered monocyclic heteroaryl ring, more preferably a benzene ring or a pyridine ring, and more preferably a benzene ring.
  • the B ring is preferably a benzene ring or a 6-membered monocyclic heteroaryl ring, more preferably a benzene ring or a pyridine ring, and still more preferably a benzene ring.
  • the C ring is preferably an aryl ring or a heteroaryl ring, more preferably a benzene ring or an indole ring, and still more preferably a benzene ring.
  • R 2 is preferably lower alkyl, halogeno lower alkyl, halogen, —OR 0 , —O-halogeno lower alkyl, or —C (O) N (R 0 ) 2 , and more preferably halogen.
  • R 3 is preferably lower alkyl, halogeno lower alkyl, halogen, —OR 0 , —O-halogeno lower alkyl, or —C (O) N (R 0 ) 2 , more preferably lower alkyl, halogen Or -O-lower alkyl.
  • R 4 is preferably lower alkyl optionally substituted with -OR 0 , lower alkylene-N (R 0 ) 2 , lower alkylene-CO 2 R 0 , lower alkylene-heterocyclic group, lower alkylene-CN,- OR 0, -O- lower alkylene -OR 0, -O- lower alkylene -N (R 0) 2, -N (R 0) - (- lower alkyl optionally substituted with OR 0), - N ( R 0 ) S (O) 2 N (R 0 ) 2 , -C (O) N (R 0 ) -lower alkylene-N (R 0 ) 2 , -N (R 0 ) C (O) -lower alkylene- OR 0 , or —N (R 0 ) C (O) -lower alkylene-N (R 0 ) 2 (wherein the heterocyclic group is lower alkyl, halogeno lower
  • -OR 0 lower alkyl optionally substituted with -OR 0 , lower alkylene-N (R 0 ) 2 , lower alkylene-heterocyclic group, -O-lower alkylene-OR 0 , -O -Lower alkylene-N (R 0 ) 2 , -C (O) N (R 0 ) -lower alkylene-N (R 0 ) 2 and -N (R 0 ) C (O) -lower alkylene-N ( R 0 ) 2 (wherein the heterocyclic group may be substituted with lower alkyl, halogeno lower alkyl, halogen, —OR 0 , or —O-halogeno lower alkyl).
  • R 5 is preferably —OR 0 , more preferably —OH.
  • L is preferably * —NHCH 2 — (where * represents a bond to the B ring).
  • X is preferably a single bond or —O—, more preferably —O—.
  • Y is preferably lower alkylene, more preferably —CH 2 — or — (CH 2 ) 2 —.
  • —X—Y— is preferably —CH 2 —, — (CH 2 ) 2 — or * —O—CH 2 — (* means a bond to the C ring), more preferably — (CH 2 ) 2 — or * —O—CH 2 — (* means a bond to the C ring).
  • m is preferably 0 or 1, and more preferably 0.
  • n is preferably 0, 1 or 2.
  • p is preferably 0, 1 or 2, more preferably 1 or 2, and more preferably 2.
  • a compound represented by the formula (I-1) is shown below.
  • B a ring a benzene ring or a 6-membered monocyclic heteroaryl ring.
  • C a ring an aryl ring or a heteroaryl ring.
  • X a a single bond or —O—.
  • Y a lower alkylene.
  • R 2a and R 3a lower alkyl, halogeno lower alkyl, halogen, —OR 0 , —O-halogeno lower alkyl, or —C (O) N (R 0 ) 2 .
  • R 4a lower alkyl optionally substituted by —OR 0 , lower alkylene-N (R 0 ) 2 , lower alkylene-CO 2 R 0 , lower alkylene-heterocyclic group, lower alkylene-CN, —OR 0 , -O- lower alkylene -OR 0, -O- lower alkylene -N (R 0) 2, -N (R 0) - (- OR 0 lower alkyl which may be substituted with), - N (R 0) S (O) 2 N (R 0 ) 2 , -C (O) N (R 0 ) -lower alkylene-N (R 0 ) 2 , -N (R 0 )
  • R 4a may be substituted.
  • B 1 and B 2 C (H), C (R 3a ), or N. However, at least one of B 1 and B 2 is not N.
  • q 0, 1 or 2.
  • Cb ring benzene ring or indole ring.
  • -X b -Y b- -CH 2 -,-(CH 2 ) 2- , * -O-CH 2- .
  • * means a bond to the Cb ring.
  • R 4b Lower alkyl optionally substituted with —OR 0 , lower alkylene-N (R 0 ) 2 , lower alkylene-heterocyclic group, —O-lower alkylene-N (R 0 ) 2 , —C (O ) N (R 0 ) -lower alkylene-N (R 0 ) 2 and —N (R 0 ) C (O) -lower alkylene-N (R 0 ) 2 .
  • the heterocyclic group in R 4b may be substituted.
  • R 4c —H or lower alkylene —CN.
  • a compound that is (4) A compound represented by the formula (IA).
  • B A CH or N.
  • R 3A —H or —O-lower alkyl.
  • R 3B —H, F, or lower alkyl.
  • -X A -Y A- * -O-CH 2 -or-(CH 2 ) 2- .
  • * means the bond to a benzene ring.
  • R 4A lower alkylene-OH, lower alkylene-NH 2 , —O-lower alkylene-NH 2 , or lower alkylene- (nitrogen-containing saturated heterocyclic group optionally substituted with lower alkyl).
  • R 6A Lower alkyl.
  • R 4A is lower alkylene-OH
  • R 3A is —O-lower alkyl
  • —X A —Y A — is — (CH 2 ) 2 —.
  • Excluding [2-( ⁇ [2-( ⁇ 4- [Amino (imino) methyl] phenyl ⁇ carbamoyl) -4-methylphenyl] amino ⁇ methyl) -4- (aminomethyl) -6-isopropoxyphenoxy] acetic acid .
  • the compounds of formula (I) and formula (IA) there may exist tautomers and geometric isomers depending on the type of substituent.
  • the compounds of formula (I) and formula (IA) may be described in only one form of isomer, but the present invention encompasses other isomers, Also included are those separated, or mixtures thereof.
  • the compounds of formula (I) and formula (IA) may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on these may exist.
  • the present invention also includes separated optical isomers of the compounds of formula (I) and formula (IA), or mixtures thereof.
  • the active ingredient of the medicament of the present invention and the compound of the present invention also include pharmaceutically acceptable prodrugs of the compounds represented by formula (I) and formula (IA), respectively.
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.
  • the salts of the compounds of formula (I) and formula (IA) are pharmaceutically acceptable salts of the compounds of formula (I) and formula (IA).
  • inorganic 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
  • Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum
  • the active ingredient of the medicament of the present invention and the compound of the present invention include various hydrates and solvates of the compounds of the formula (I) and formula (IA) and their salts, and polymorphic substances, respectively. Includes.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • diseases involving plasma kallikrein include: (1) Edema. Specifically, hereditary angioedema and brain edema. In particular, hereditary angioedema. (2) Hematoma. Specifically, intracranial hematomas such as intracerebral hematoma and subdural hematoma. , (3) Bleeding (including fluid leakage). Specifically, bleeding during surgery and trauma. Bleeding especially during surgery (especially during cardiac surgery such as CABG (coronary artery bypass grafting) and valve replacement). Etc.
  • Edema Specifically, hereditary angioedema and brain edema. In particular, hereditary angioedema.
  • Hematoma Specifically, intracranial hematomas such as intracerebral hematoma and subdural hematoma.
  • Bleeding including fluid leakage. Specifically, bleeding during surgery and trauma. Bleeding especially during surgery (especially during cardiac surgery such as CABG (coronary artery bypass
  • the compounds of formula (I) and formula (IA) and salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic structure or the type of substituent.
  • it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate.
  • protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected and used according to the reaction conditions.
  • the desired compound after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
  • the prodrugs of the compounds of the formula (I) and the formula (IA) introduce a specific group at the stage from the raw material to the intermediate, or the obtained formula (I) and formula It can be produced by further reacting with the compound of (IA).
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • typical production methods of the compounds of formula (I) and formula (IA) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
  • the manufacturing method of this invention is not limited to the example shown below.
  • R 8 , R 9 , R 10 , R 11 , R 12 and X 1 are R 1 , R 2 , R 3 , R 4 , R 1 , respectively, through steps that can be generally employed by those skilled in the art, if necessary.
  • J 2 and J 3 mean a substituent that can be converted into a bond J through a process that can be usually employed by those skilled in the art, and Examples include methyl group, hydroxymethyl group, halogenomethyl group, formyl group, alkoxymethyl group, acetoxymethyl group, amino group, alkoxycarbonylamino group, nitro group, carboxyl group, alkoxycarbonyl group, etc.
  • L 1 and L 2 are substituents that can be converted to a bond L through a process that can be generally employed by those skilled in the art as needed. Specifically, a methyl group, a hydroxymethyl group, a halogenomethyl group, a formyl group , Alkoxymethyl group, a Tokishimechiru group, an amino group, an alkoxycarbonylamino group, a nitro group, a carboxyl group, an alkoxycarbonyl group, or the like.
  • R 8, R 9, R 10, R 11, R 12 and X 1 are each R 1, R 2 , R 3 , R 4 , R 5 and X may be the same, and so on.
  • compound (IV) is synthesized from two compounds consisting of a combination of compound (II) and compound (III).
  • any step that can be generally 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 with.
  • This process is not limited to a one-step reaction, and may be constituted by a multi-step reaction.
  • A-1 Halogenation As the halogenation reaction, a halogenation reaction that can be usually used by those skilled in the art can be used. For example, the method described in “Chemical Experiment Course (4th edition)” volume 19 (1992) (Maruzen) edited by the Chemical Society of Japan can be applied.
  • the halogenation of alkyl for example, N-bromosuccinimide or the like can be used as a halogenating agent in the presence of 2,2′-azobisisobutyronitrile or benzoyl peroxide.
  • Reaction includes aromatic hydrocarbons such as benzene, toluene, xylene, esters such as ethyl acetate, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, etc.
  • aromatic hydrocarbons such as benzene, toluene, xylene, esters such as ethyl acetate, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, etc.
  • Halogenated hydrocarbons alcohols such as methanol, ethanol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), acetonitrile
  • a solvent inert to the reaction such as pyridine, water, etc.
  • the reaction can be carried out under cooling to heating under reflux.
  • halogenation of the hydroxyl group for example, methanesulfonyl chloride, carbon tetrabromide / triphenylphosphine, or the like can be used.
  • the reaction proceeds smoothly by reacting in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.).
  • a base preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.
  • a base preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.
  • a solvent inert to the reaction such as the above-mentioned aromatic hydrocarbons, ethers, halogenated hydrocarbons, etc. under cooling to heating under reflux.
  • A-2 Oxidation For the oxidation reaction of alcohol, aldehyde, etc., an oxidation reaction that can be usually used by those skilled in the art can be used. For example, the method described in “Chemical Experiment Course (4th edition)” volume 23 (1992) (Maruzen) edited by the Chemical Society of Japan can be applied.
  • A-3 Reduction For the reduction reaction of ester, amide, nitrile and the like, a reduction reaction that can be usually used by those skilled in the art can be adopted. For example, using a reducing agent such as lithium aluminum hydride and sodium borohydride, the above aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMA, NMP, DMSO, acetonitrile, alcohols, etc. The reaction can be performed in a solvent at room temperature to heating under reflux.
  • a reducing agent such as lithium aluminum hydride and sodium borohydride
  • the reaction can be performed in a solvent at room temperature to heating under reflux.
  • A-4 Hydrolysis Hydrolysis reactions such as ester, amide, nitrile and the like that can be used by those skilled in the art can be used.
  • sulfuric acid, hydrochloric acid, hydrogen bromide in a solvent inert to the reaction such as the above aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, water, etc.
  • acids such as mineral acids such as acids, organic acids such as formic acid and acetic acid; or in the presence of bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia, under cooling To heating under reflux.
  • the hydrogenolysis reaction such as debenzylation can be a hydrogenolysis reaction that can be used by those skilled in the art.
  • a catalyst palladium-carbon, Raney nickel, platinum or the like is used, and the above aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA.
  • the reaction can be carried out in a solvent inert to the reaction such as NMP, ethyl acetate, acetonitrile, acetic acid or the like at room temperature to heating under reflux.
  • an acid preferably hydrochloric acid, acetic acid, etc.
  • amidation reaction amidation which can be usually used by those skilled in the art can be adopted.
  • condensing agents such as carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride (WSC ⁇ HCl), dicyclohexylcarbodiimide, diphenylphosphoryl azide, diethylphosphoryl cyanide
  • CDI carbonyldiimidazole
  • WSC ⁇ HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride
  • dicyclohexylcarbodiimide diphenylphosphoryl azide
  • diethylphosphoryl cyanide A method of using a compound, a method of passing through a mixed acid anhydride using isobutyl chloroformate, ethyl chloroformate or the like, or a method of passing through an acid halide using
  • the reaction is carried out in a solvent inert to the reaction such as the aforementioned halogenated hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, DMF, DMA, NMP, DMSO, etc., under cooling to heating under reflux.
  • a solvent inert such as the aforementioned halogenated hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, DMF, DMA, NMP, DMSO, etc.
  • the reaction proceeds smoothly by reacting in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.). In some cases, it may be advantageous.
  • A-7 Alkylation Alkylation which can be usually used by those skilled in the art can be employed for alkylation of hydroxyl group, amino group and the like.
  • a solvent or a solvent inert to the reaction such as the aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, DMSO, acetonitrile, etc.
  • the reaction can be performed in a solvent at room temperature to heating under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.
  • metal salt bases potassium carbonate, cesium carbonate, water
  • Performing in the presence of sodium oxide, potassium hydroxide, sodium hydride, tert-butoxypotassium, etc. may be advantageous for allowing the reaction to proceed smoothly.
  • A-8 Reductive alkylation
  • the reductive alkylation can employ a reductive alkylation that can be commonly used by those skilled in the art.
  • a reductive alkylation that can be commonly used by those skilled in the art.
  • the method described in “Chemical Experiment Course (4th edition)” volume 20 (1992) (Maruzen) edited by the Chemical Society of Japan can be cited.
  • reduction of sodium borohydride, sodium triacetoxyborohydride, etc. in a solvent inert to the reaction of the aforementioned halogenated hydrocarbons, aromatic hydrocarbons, esters, ethers, alcohols, acetic acid, etc. It is preferable to use an agent under cooling and at room temperature to heating under reflux.
  • 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 alkylation uses, for example, palladium-carbon, Raney nickel, platinum or the like as a catalyst in a hydrogen atmosphere of normal pressure to pressure under the above-mentioned aromatic hydrocarbons, esters, ethers, halogenated carbonization.
  • the reaction can be carried out in a solvent inert to the reaction such as hydrogen, DMF, DMA, NMP, acetonitrile, acetic acid or the like at room temperature to under reflux.
  • an acid preferably hydrochloric acid, acetic acid, etc.
  • Process B In this step, compound (VI) is synthesized from two compounds consisting of a combination of compound (IV) and compound (V).
  • any step that can be generally 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 with.
  • This process is not limited to a one-step reaction, and may be constituted by a multi-step reaction. Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A-1 to A-8 in step A, respectively.
  • R 8 , R 9 , R 10 , R 11 , R 12 or X 1 is different from R 1 , R 2 , R 3 , R 4 , R 5, and X, respectively.
  • step of synthesizing the compound (I) of the present invention by converting 8 , R 9 , R 10 , R 11 , R 12 or X 1 into R 1 , R 2 , R 3 , R 4 , R 5 and X, respectively. is there.
  • 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.
  • This process is not limited to a one-step reaction, and may be constituted by a multi-step reaction.
  • Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A-1 to A-8 in step A, respectively.
  • the compound of formula (I) can also be produced by the following typical production method.
  • step D compound (VII) is synthesized from two compounds comprising a combination of compound (III) and compound (V).
  • any step that can be generally 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 with.
  • This process is not limited to a one-step reaction, and may be constituted by a multi-step reaction. Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A-1 to A-8 in step A, respectively.
  • step E compound (VIII) is synthesized from two compounds comprising a combination of compound (VII) and compound (II).
  • any step that can be generally 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 with.
  • This process is not limited to a one-step reaction, and may be constituted by a multi-step reaction. Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A-1 to A-8 in step A, respectively.
  • This process is not limited to a one-step reaction, and may be constituted by a multi-step reaction.
  • Halogenation, oxidation, reduction, hydrolysis, hydrogenolysis, amidation, alkylation, and reductive alkylation can be carried out according to steps A-1 to A-8 in step A, respectively.
  • the raw materials used for the production of the compound of formula (I) can be produced, for example, by using the methods described in the production examples described later, known methods, methods obvious to those skilled in the art, or variations thereof. .
  • the compounds of formula (I) and formula (IA) are isolated and purified as free compounds, their salts, hydrates, solvates, or crystalline polymorphic substances.
  • the salts of the compounds of formula (I) and formula (IA) can also be produced by subjecting them to a conventional salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers.
  • optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
  • a pharmaceutical composition containing one or more of the compounds of formula (I) and formula (IA) or a salt thereof as an active ingredient is an excipient normally used in the art, that is, for pharmaceutical use. It can be prepared by a commonly used method using an excipient, a pharmaceutical carrier and the like.
  • Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • a solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. .
  • tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. In addition to the inert diluent, the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • aqueous solvent include distilled water for injection or physiological saline.
  • non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
  • a transmucosal agent such as an inhalant or a nasal agent is used in a solid, liquid or semi-solid form, and can be produced according to a conventionally known method.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer
  • the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the compounds of formula (I) and formula (IA) can be used in combination with various therapeutic or prophylactic agents for diseases for which plasma kallikrein inhibitors are considered effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography using n-hexane / ethyl acetate (1: 1) as an elution solvent, and ethyl (E) -3 -(2-Diethoxymethyl-6-isopropoxy-4-nitrophenyl) acrylate (7.4 g) was obtained as a yellow oil.
  • the obtained residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (55:45) as an elution solvent, and ethyl 3- (4- ⁇ 2-[(tert-butoxycarbonyl) amino] ethoxy ⁇ - 2-Formyl-6-isopropoxyphenyl) propanoate (0.10 g) was obtained as a yellow oil.
  • N, N-dimethylformamide (6 mL) and imidazole (374 mg) were added to the residue, tert-butyldiphenylchlorosilane (0.79 mL) was added under ice cooling, and the mixture was stirred at room temperature for 20 min.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in ethanol (10 mL), potassium carbonate (569 mg) was added at room temperature, and the mixture was stirred at 50 ° C. for 1.5 hr.
  • the obtained compound was dissolved in dimethyl sulfoxide (6 mL), sodium cyanide (148 mg) was added at room temperature, and the mixture was stirred for 2 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain tert-butyl 3- ⁇ 2-[(tert-butyldiphenylsilyloxy) methyl] -4-cyanomethyl-6-isopropoxyphenyl ⁇ propanoate (1.0 g) as a yellow oil.
  • Example 1 tert-butyl ⁇ 2-[( ⁇ 2-[(4- ⁇ [(tert-butoxycarbonyl) amino] (imino) methyl ⁇ phenyl) carbamoyl] phenyl ⁇ amino) methyl] -6-ethoxy-4-[(4 -Methylpiperazin-1-yl) methyl] phenoxy ⁇ acetate (320 mg) was dissolved in 4M hydrogen chloride / dioxane solution (5 mL) and water (0.5 mL) and stirred at room temperature for 5 hours.
  • Example 3 3- [4- (Acetoxymethyl) -2-formyl-6-isopropoxyphenyl] propanoic acid (120 mg) and tert-butyl [ ⁇ 4-[(2-amino-4-methoxybenzoyl) amino] phenyl ⁇ (Imino) methyl] carbamate (150 mg) was dissolved in an acetic acid (8 mL) solution, sodium triacetoxyborohydride (248 mg) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off, ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate.
  • Example 4 tert-butyl (2-[( ⁇ 2-[(4- ⁇ (Z) -amino [(tert-butoxycarbonyl) imino] methyl ⁇ phenyl) carbamoyl] -4-methylphenyl ⁇ amino) methyl] -4- ⁇ 2-[(tert-butoxycarbonyl) amino] ethyl ⁇ -6-isopropoxyphenoxy) acetate (180 mg) is dissolved in 1,2-dichloroethane (2 mL), trifluoroacetic acid (2 mL) is added, and the mixture is stirred at room temperature. Stir for 3 hours.
  • Example 5 3- [4- (Acetoxymethyl) -2-( ⁇ [2-( ⁇ 4- [amino (imino) methyl] phenyl ⁇ carbamoyl) -4-fluoro-5-methoxyphenyl] amino ⁇ methyl) -6-iso
  • ethanol 0.8 mL
  • Trifluoroacetic acid 18 ⁇ L was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Water / ethanol (20: 1) was added to the residue, and the precipitate was collected by filtration.
  • Example 6 3- (4- ⁇ 2-[(tert-butoxycarbonyl) amino] ethoxy ⁇ -2-[( ⁇ 2-[(4- ⁇ [(tert-butoxycarbonyl) amino] (imino) methyl ⁇ phenyl) carbamoyl]
  • a solution of -4-fluorophenyl ⁇ amino) methyl] -6-isopropoxyphenyl) propanoic acid (115 mg) and trifluoroacetic acid (1 mL) in dichloromethane (1 mL) was stirred at room temperature for 3 hours.
  • the reaction mixture was concentrated under reduced pressure, diethyl ether (5 mL) was added to the resulting residue, and the resulting precipitate was powdered and collected by filtration.
  • Example 8 3- ⁇ 4- (aminomethyl) -2-[( ⁇ 3-[(4- ⁇ [(tert-butoxycarbonyl) amino] (imino) methyl ⁇ phenyl) carbamoyl] pyridin-2-yl ⁇ amino) methyl]
  • Trifluoroacetic acid 0.6 mL was added to a solution of ⁇ 6-isopropoxyphenyl ⁇ propanoic acid (72 mg) in dichloromethane (0.6 mL) at room temperature, and the mixture was stirred for 30 minutes.
  • reaction mixture was concentrated under reduced pressure, toluene and ethyl acetate were added to the residue, and trifluoroacetic acid was distilled off under reduced pressure by azeotropy of toluene and ethyl acetate. Diethyl ether / ethyl acetate (1: 1) was added to the residue.
  • Example compounds 9 to 10 were produced in the same manner as in Examples 1 to 8.
  • the structures of the example compounds are shown in Tables 19 to 21 below, and the production methods and physicochemical data are shown in Tables 22 to 23 below.
  • Reference Example Compounds 1 to 40 are shown in Tables 24 to 33 below. These compounds can be produced by the method described in International Publication WO2006 / 070878 Pamphlet. For example, Reference Example 34 can be produced using the corresponding raw material in the same manner as Example 12 of the pamphlet of International Publication WO2006 / 070878.
  • Tables 34 to 181 below show the structures of other compounds as the active ingredients of the present invention. These compounds can be produced by the method described in International Publication WO2006 / 070878 Pamphlet.
  • Example 11 Human Plasma Kallikrein Inhibition Experiment In a 96-well microplate, reaction buffer (pH 7.4) 50 ⁇ L, test compound solution 10 ⁇ L, 2 mM synthetic substrate S-2302 (Chromogenix) 20 ⁇ L, human plasma kallikrein (Sigma) 20 ⁇ L was added and allowed to react at room temperature for 1 hour. The change in absorbance at 405 nm was measured with a microplate reader (trade name: SPECTRAmax340PC384, Molecular Devices), and IC 50 was calculated. The results are shown in Tables 1-2. Ex means Example Compound Number, REx means Reference Example Compound Number (the same applies hereinafter).
  • Example 12 Extended partial thromboplastin time (APTT) extension experiment 50 ⁇ L of test compound solution and 50 ⁇ L of Hemoliance (registered trademark) SynthASil (Instrumentation Laboratory) were added to 50 ⁇ L of human or guinea pig plasma, and heated at 37 ° C. for 3 minutes. did. Furthermore, 50 ⁇ L of 20 mM CaCl 2 was added and the coagulation time was measured. For measurement of the clotting time, a blood clotting time measuring device KC10 (Amelung) was used. The concentration that doubles the human plasma activated partial thromboplastin time was calculated as CT2. The results are shown in Table 3.
  • Example 13 Inhibitory Effect on Dextran Sulfate-Induced Increase in Vascular Permeability in Guinea Pig
  • the dextran known as a pathological model involving endogenous bradykinin was used as an inhibitory effect on the increased vascular permeability of the active ingredient of the drug of the present invention and the compound of the present invention.
  • Sulfuric acid-induced increase in vascular permeability was evaluated. Specifically, the method described in “Jpn J Pharmacol, 72, 217-221, 1996” was partially modified. The animals were male Hartley guinea pigs weighing around 500 g, and the number of animals in each group was 4 to 6. Under wakefulness, the compound solution was subcutaneously administered to the back, and then anesthetized with pentobarbital.
  • Example 14 Inhibitory effect on hepatic incision blood in guinea pigs
  • the active ingredient of the pharmaceutical composition of the present invention and the anti-bleeding effect of the compound of the present invention are measured in a model in which the incision is created in the liver and bleeding is induced. It was evaluated by.
  • the animals were male Hartley guinea pigs weighing around 500 g, and the number of animals in each group was 4 to 6. Under wakefulness, the compound solution was subcutaneously administered to the back, and then anesthetized with pentobarbital.
  • Example 15 Inhibitory Effect on Increased Vascular Permeability in C1-Inhibitor-Deficient Mice
  • the inhibitory effect on the increase in vascular permeability in C1-inhibitor-deficient mice of a compound as an active ingredient of the medicament of the present invention is described in “The Journal of Clinical Investigation, 109 ( 8), 1057-1063, 2002 ”. That is, Evans blue 30 mg / kg is intravenously injected into C1-inhibitor-deficient mice. It can be confirmed by isolating tissues (foot, small intestine, auricles stimulated with 5% mustard oil) after euthanasia, extracting Evans blue into formamide and measuring vascular permeability.
  • the active ingredient of the medicament of the present invention and the compound of the present invention are useful for the treatment or prevention of diseases involving plasma kallikrein, particularly edema (especially hereditary angioedema, brain edema), hematoma (especially, It is useful for prevention / treatment of intracranial hematoma), suppression of bleeding / fluid leakage during surgery (especially during cardiac surgery such as CABG (coronary artery bypass grafting), valve replacement), and bleeding / fluid leakage during trauma. Is obvious.
  • Sal Salt The numbers before the mean molar ratio, for example when 2HCl is mentioned it indicates that the compound is dihydrochloride, TFA: trifluoroacetate.
  • Syn Production method (Indicates that the product was produced using the corresponding raw material in the same manner as the Example compound having the numeric number as the Example number.)
  • PSyn Production method (The numeric number was designated as the Production Example number.) It shows that it manufactured using the corresponding raw material similarly to the manufacture example compound which has).
  • the compound of formula (I) which is an active ingredient of the medicament of the present invention and the compound of formula (IA) which is a compound of the present invention have plasma kallikrein inhibitory activity, Prevention, especially prevention / treatment of edema (especially hereditary angioedema, brain edema), hematoma (especially intracranial hematoma), during surgery (especially during CABG (coronary artery bypass grafting), valve replacement, etc.) ) Is useful for suppressing bleeding.
  • edema especially hereditary angioedema, brain edema
  • hematoma especially intracranial hematoma
  • CABG coronary artery bypass grafting
  • valve replacement etc.

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  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un produit pharmaceutique, particulièrement une composition pharmaceutique qui a une activité d'inhibition de la kallicréine plasmatique, qui est utile comme agent prophylactique ou thérapeutique pour les oedèmes (particulièrement les oedèmes vasculaires et les oedèmes cérébraux héréditaires) et les hématomes (particulièrement les hématomes intracrâniaux), et qui est utile pour la prévention des hémorragies pendant les opérations chirurgicales. Il a été découvert qu'un composé d'acide carboxylique caractérisé par le fait qu'il présente trois groupes annulaires, qui est un principe actif dans le produit pharmaceutique, a une bonne activité d'inhibition de la kallicréine plasmatique. Une composition pharmaceutique contenant le dérivé d'acide carboxylique comme principe actif présente une bonne activité d'inhibition de la kallicréine plasmatique et est par conséquent utile comme agent prophylactique ou thérapeutique pour les oedèmes (particulièrement les oedèmes vasculaires et les oedèmes cérébraux héréditaires) et les hématomes (particulièrement les hématomes intracrâniaux), et comme agent pour la prévention des hémorragies pendant les opérations chirurgicales.
PCT/JP2011/057078 2010-03-25 2011-03-24 Inhibiteur de la kallicréine plasmatique Ceased WO2011118672A1 (fr)

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WO2015022547A1 (fr) * 2013-08-14 2015-02-19 Kalvista Pharmaceuticals Limited Inhibiteurs bicycliques
US9051249B2 (en) 2011-07-07 2015-06-09 Kalvista Pharmaceuticals Limited Benzylamine derivatives as inhibitors of plasma kallikrein
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WO2021028645A1 (fr) 2019-08-09 2021-02-18 Kalvista Pharmaceuticals Limited Inhibiteurs de la kallicréine plasmatique
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US11234939B2 (en) 2017-11-29 2022-02-01 Kalvista Pharmaceuticals Limited Dosage forms comprising a plasma kallikrein inhibitor
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WO2023209381A1 (fr) 2022-04-27 2023-11-02 Kalvista Pharmaceuticals Limited Formulations d'un inhibiteur de la kallicréine plasmatique
WO2024180100A1 (fr) 2023-02-27 2024-09-06 Kalvista Pharmaceuticals Limited Nouvelle forme solide d'un inhibiteur de la kallicréine plasmatique
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