WO2011118672A1 - Plasma kallikrein inhibitor - Google Patents

Abstract

Disclosed is a pharmaceutical product, particularly a pharmaceutical composition having a plasma kallikrein inhibition activity and is useful as a prophylactic or therapeutic agent for edemas (particularly hereditary vascular edema and cerebral edema) and hematomas (particularly intracranial hematoma) and is useful for the prevention of bleeding during surgery. It is found that a carboxylic acid compound characterized by having three ring groups, which is an active ingredient of the pharmaceutical product, has a good plasma kallikrein inhibition activity. A pharmaceutical composition containing the carboxylic acid derivative as an active ingredient has a good plasma kallikrein inhibition activity and is therefore useful as a prophylactic or therapeutic agent for edemas (particularly hereditary vascular edema and cerebral edema) and hematomas (particularly intracranial hematoma) and an agent for preventing bleeding during surgery.

Description

Plasma kallikrein inhibitor

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. There are two types of kallikrein: glandular (or tissue) kallikrein and plasma kallikrein. Generally, 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. . 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. On the other hand, 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 α2-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. Conventionally, therapeutic agents for edema have been studied, but clinical satisfaction is not sufficient. For example, 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). For brain edema, hypertonic solutions such as mannitol are used, but the effect is not sufficient (Stroke 2000; 31 (11): 2719-22).
It is known that 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).

On the other hand, 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 .

In Patent Document 1, 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. However, 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. Moreover, there is no description regarding 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 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. However, 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. Moreover, there is no description regarding 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. For symbols in other formulas, refer to this publication.)

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. However, 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. Moreover, there is no description regarding plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.

(See the official gazette for symbols in the formula.)
Or

(See the official gazette for symbols in the formula.)

In Patent Document 4, 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. However, 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. Moreover, there is no description regarding plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.

(See the official gazette for symbols in the formula.)

In Patent Document 5, 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. However, in the compound of the formula (E), 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. Moreover, there is no description regarding plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.

(K is (CR ^4A R ^4B ) _n , n is 1 or 2, E ⁰ is a bond, C (O), C (S), C (O) N (R ⁷ ), (R ⁷ ) NC (O) , S (O) ₂ , (R ⁷ ) NS (O) ₂ , or S (O) ₂ N (R ⁷ ) (refer to this publication for symbols in other formulas)

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. . However, there is no description regarding 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. However, in the compound of formula (G), 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. Moreover, there is no description regarding plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.

(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. Specifically, 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 reocclusion and restenosis after thrombolytic therapy (PTCR), thrombus formation after heart valve replacement, coagulation or inflammation of perfused blood during extracorporeal circulation, intermittentness Lameness, arteriosclerosis, cancer are described. However, there is no description regarding plasma kallikrein inhibitory action, edema, prevention / treatment of hematoma, and suppression of bleeding during surgery.

(See the official gazette for symbols in the formula.)

WO99 / 41231 pamphlet International Publication No. 02/34711 Pamphlet International Publication No. 02/37937 Pamphlet International Publication No. 02/42273 Pamphlet International Publication No. 01/87854 Pamphlet US Pat. No. 5,455,348 International Publication No. 00/39118 Pamphlet WO99 / 32477 pamphlet International Publication No. 2006/070878 Pamphlet

Providing a drug that has plasma kallikrein inhibitory action, and 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.

The inventors of the present invention have intensively studied compounds having plasma kallikrein inhibitory action. As a result, the carboxylic acid compound represented by the following formula (I), which has three ring groups, has a good plasma kallikrein inhibitory action and is useful for prevention and treatment of edema and hematoma, and for suppression of bleeding As a result, the present invention was completed.
That is, 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 ¹ : -NH ₂ , -CH ₂ NH ₂ , -C (O) NH ₂ , -C (= NH) NH ₂ , -C (= NOH) NH ₂ , -C (= NH) NH-CO _2- (Optionally substituted lower alkyl) or 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl.
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. However, the lower alkyl, cycloalkyl, aryl, or heterocyclic group in R ² and R ³ may be substituted.
Alternatively, 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 : each independently lower alkyl, lower alkenyl, cycloalkyl, aryl, heterocyclic group, halogen, oxo, —CN, —NO ₂ , —OR ⁶ , —N (R ⁶ ) ₂ , —SR ⁶ , -S (O) R ⁶ , -S (O) ₂ R ⁶ , -S (O) ₂ N (R ⁶ ) ₂ , -N (R ⁶ ) S (O) ₂ R ⁶ , -N (R ⁶ ) S (O) ₂ -N (R ⁶ ) ₂ , -N (R ⁶ ) S (O) ₂ -N (R ⁶ ) C (O) OR ⁶ , -C (O) R ⁶ , -CO ₂ R ⁶ , -C (O) N (R ⁶ ) ₂ , -C (O) N (R ⁶ ) -lower alkylene-N (R ⁶ ) ₂ , -NH-C (= NH-CN) NH ₂ , -C ( O) -N = C (NH ₂ ) ₂ , -C (O) -N = C (R ⁶ ) -NH ₂ , -C (O) N (R ⁶ ) -S (O) ₂ -N (R ⁶ ) ₂ , -C (O) N (R ⁶ ) -S (O) ₂ R ⁶ , -OC (O) R ⁶ , -OC (O) OR ⁶ , -OC (O) N (R ⁶ ) ₂ , ^{-N (R 6) C (O} ) R 6, -N (R 6) C (O) oR 6, ^{or, -N (R 6) C (} O) N (R 6) 2. However, the lower alkyl, lower alkenyl, cycloalkyl, aryl and heterocyclic groups in 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 .
J: * -N (R ⁰ ) C (O)-, * -C (O) N (R ⁰ )-, -N (R ⁰ ) C (O) N (R ⁰ )-, * -N (R ⁰ ) -lower alkylene- or * -lower alkylene-N (R ⁰ ) C (O)-. However, * shows the coupling | bonding to A ring.
L: * -NR ⁰ -lower alkylene-, * -NR ⁰ -lower alkenylene-, -lower alkylene- or -lower alkenylene-. * Indicates a bond to the B ring.
X: single bond, -O-, -N (R ⁷ )-, -S-, -C (O)-, -S (O)-, -S (O) _2- , * -lower alkylene-O- Or * -lower alkylene-N (R ⁷ )-. However, * shows the coupling | bonding to C ring.
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.
That is,
(1) A pharmaceutical composition which is a prophylactic or therapeutic agent for edema, hematoma, or a hemorrhage suppressant, comprising as an active ingredient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(2) The pharmaceutical composition according to (1), which is an agent for preventing or treating edema or a bleeding inhibitor.
(3) The pharmaceutical composition according to (2), which is an agent for preventing or treating edema.
(4) The pharmaceutical composition according to (3), which is a preventive or therapeutic agent for hereditary angioedema.
(5) The pharmaceutical composition according to (3), which is a preventive or therapeutic agent for cerebral edema.
(6) The pharmaceutical composition according to (2), which is a bleeding inhibitor.
(7) The pharmaceutical composition according to (6), which is a bleeding inhibitor during surgery.
(8) The pharmaceutical composition according to (1), which is a prophylactic or therapeutic agent for hematoma.
(9) The pharmaceutical composition according to (8), which is a preventive or therapeutic agent for intracranial hematoma.
(10) Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a plasma kallikrein inhibitor, an edema, a prophylactic or therapeutic agent for hematoma, or a bleeding inhibitor.
(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.
(12) Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of edema, hematoma, or suppression of bleeding.
(13) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating edema and hematoma, or for suppressing bleeding.
About.

Furthermore, the present invention relates to a compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof.

[The symbols in the formula have the following meanings.
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- . However, * 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.

However,
When R ^4A is lower alkylene-OH, R ^3A is —O-lower alkyl and —X ^A —Y ^A — is — (CH ₂ ) ₂ —.
However,
Excluding [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl) -4- (aminomethyl) -6-isopropoxyphenoxy] acetic acid . The same applies hereinafter. ]
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.

Since 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.

The present invention is described in further detail as follows.
In the present specification, the term “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” and “alkenylene” may each be linear or branched.
Thus, “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. Preferred are C _1-4 alkyl methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl and tert-butyl, and more preferred are methyl, ethyl, normal propyl and isopropyl.

“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- .

“Lower alkenylene” means a divalent group formed by removing one hydrogen at any position of the “lower alkenyl”. Specifically, -CH = CH-, -CH = C (CH ₃ )-, -C (CH ₃ ) = C (CH ₃ )-, -CH = CH-CH _2- , -CH = CH-CH = CH- and the like. C _2-3 alkenylene is preferable, and vinylene is more preferable.

“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.

The “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. Specific examples of “bicyclic heteroaryl” 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. In addition, 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. Specifically, the group described in the above “monocyclic heteroaryl” or “heteroaryl”, dihydropyridyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, Examples include pyrazolidinyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrimidinyl, chromanyl, dioxolanyl, homomorpholinyl, dihydroindolyl and the like. 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. Specific 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.

«" May be substituted "means" unsubstituted "or" substituted with 1 to 5 substituents that are the same or different ". “Substituted” means “substituted with 1 to 5 substituents which are the same or different”. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.

In the present specification, 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 .
P ¹ group: halogen, —OR ⁰ , —N (R ⁰ ) ₂ , —CO ₂ R ⁰ and —C (O) N (R ⁰ ) ₂ .
In 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.
In 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 , -C (O) N (R ⁰ ) ₂ , -C (O) N (R ⁰ ) -hetero Cyclic group, -C (O) N (R ⁰ ) -lower alkylene-OR ⁰ , -C (O) NH-lower alkylene-N (R ⁰ ) ₂ , -C (O) N (lower alkyl) -lower alkylene -N (R ⁰ ) ₂ , -C (O) N (R ⁰ ) -lower alkylene-cycloalkyl, -C (O) -heterocyclic group, -N (R ⁰ ) C (O) R ⁰ , cycloalkyl , Aryl and heterocyclic groups. However, 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 .
In the ^optionally substituted “heterocyclic group” in R ^{4a and the optionally} substituted “heterocyclic group” in R ^4b , the permissible substituent is preferably lower alkyl, halogeno lower alkyl, Halogen, —OR ⁰ , or —O-halogeno lower alkyl, more preferably lower alkyl.

Preferred embodiments of the active ingredient of the medicament of the present invention represented by the formula (I) are shown below.
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 ¹ is preferably -C (= NH) NH ₂ , -C (= NOH) NH ₂ or -C (= NH) NH-CO ₂ -lower alkyl, more preferably -C (= NH) NH _{There are two} .
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 alkyl, halogen, —OR ⁰ , or , -O-halogeno lower alkyl may be substituted). More preferably, lower alkylene-CN, -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). Even more preferably, -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.
J is preferably * -NHC (= O)-(where * represents a bond to the A ring).
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.

Another preferred embodiment of the compound represented by formula (I), which is an active ingredient in the medicament of the present invention, is shown below.
(1) A compound represented by the formula (I-1).

[Wherein m, n, p and R ⁰ represent the meanings described in formula (I). Other symbols have the following meanings.
A ^a ring: a benzene ring or a 6-membered monocyclic heteroaryl ring.
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 ) C (O) -lower alkylene-OR ⁰ , Or, -N (R ⁰ ) C (O) -lower alkylene-N (R ⁰ ) ₂ .
However, the heterocyclic group in R ^4a may be substituted. ]
(2) A compound represented by formula (I-2).

[Wherein p, R ⁰ , R ^3a and R ^4a have the same meaning as in (1). Other symbols have the following meanings.
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- . However, * means a bond to the ^Cb ring. ]
(3)

But,

[However, the symbols in the formula have the following meanings.
-X ^c -Y ^c- : * -O-CH ₂ -or-(CH ₂ ) _2- . However, * means a bond to a benzene ring.
R ^6a : lower alkyl or lower alkylene-OR ⁰ .
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 . However, 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).

[The symbols in the formula have the following meanings.
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- . However, * 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.
However,
When R ^4A is lower alkylene-OH, R ^3A is —O-lower alkyl and —X ^A —Y ^A — is — (CH ₂ ) ₂ —.
However,
Excluding [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl) -4- (aminomethyl) -6-isopropoxyphenoxy] acetic acid . ]
(5)
[2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenoxy] acetic acid,
[4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
{2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-ethoxy-4-[(4-methylpiperazin-1-yl) Methyl] phenoxy} acetic acid,
[2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -4- (glycylamino) -6-isopropoxyphenoxy] acetic acid,
{2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-isopropoxy-4-[(N-methylglycyl) amino] phenoxy} Acetic acid,
[4- (L-alanylamino) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid,
[4- (β-alanylamino) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid,
[4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
[7-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -1H-indol-1-yl] acetic acid,
[2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4,5-difluorophenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenoxy] acetic acid ,
3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenyl] propane acid,
[2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -4-{[2- (dimethylamino) ethyl] carbamoyl} -6- Isopropoxyphenoxy] acetic acid,
[7-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -3- (cyanomethyl) -1H-indol-1-yl] acetic acid
3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenyl] propane acid,
3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (hydroxymethyl) -6- (2-hydroxy- 1-methylethoxy) phenyl] propanoic acid,
3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-fluoro-5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-iso Propoxyphenyl] propanoic acid,
3- [4- (2-Aminoethoxy) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid,
3- [4- (2-aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid and
3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (aminomethyl) -6-isopropoxyphenyl] propane A compound selected from the group consisting of acids.

Another preferred embodiment of the compound of the present invention represented by the formula (IA) is shown below.
[4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
[4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenyl] propane acid,
3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-fluoro-5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-iso Propoxyphenyl] propanoic acid,
3- [4- (2-Aminoethoxy) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid,
3- [4- (2-aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid,
3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (aminomethyl) -6-isopropoxyphenyl] propane acid,
{2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) phenyl] amino} methyl) -6-ethoxy-4-[(4-methylpiperazin-1-yl) methyl] phenoxy } Acetic acid,
[2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) phenyl] amino} methyl) -6-ethoxy-4- (piperazin-1-ylmethyl) phenoxy] acetic acid, and
[2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) phenyl] amino} methyl) -6-isopropoxy-4- (morpholin-4-ylmethyl) phenoxy] acetic acid A compound selected from:

In the compounds of formula (I) and formula (IA), there may exist tautomers and geometric isomers depending on the type of substituent. In the present specification, 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.
In addition, 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.

Furthermore, 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). , May form acid addition salts or salts with bases. Specifically, 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, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.

Further, 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.

Specifically, 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.

(Production method)
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. In this case, depending on the type of functional group, 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. There is a case. Examples of such 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. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
Further, 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.
Hereinafter, 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. In addition, the manufacturing method of this invention is not limited to the example shown below.

(Production method)
Hereinafter, representative production methods of the compound of the formula (I) which is an active ingredient of the medicament of the present invention will be described. The compound of the present invention of formula (IA) can also be produced in the same manner as the compound of formula (I).

(In the formula, 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. Means a substituent that can be converted to ⁵ and X. In the formula, 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. In ^{addition, 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.

Process A
In this step, compound (IV) is synthesized from two compounds consisting of a combination of compound (II) and compound (III). In this step, 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. For 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. Halogenated hydrocarbons, alcohols such as methanol, ethanol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), acetonitrile In a solvent inert to the reaction, such as pyridine, water, etc., the reaction can be carried out under cooling to heating under reflux. Further, for halogenation of the hydroxyl group, for example, methanesulfonyl chloride, carbon tetrabromide / triphenylphosphine, or the like can be used. Depending on the type of reaction, 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. The reaction can be carried out in 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-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. For example, 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. In the presence of 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.

A-5: Hydrogenolysis The hydrogenolysis reaction such as debenzylation can be a hydrogenolysis reaction that can be used by those skilled in the art. For example, as 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. Further, depending on the compound, it may be advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid, etc.) in order to facilitate the reaction.
A-6: Amidation As the amidation reaction, amidation which can be usually used by those skilled in the art can be adopted. In particular, condensing agents such as carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride (WSC · HCl), 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 oxalyl chloride, thionyl chloride or the like is preferable. 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. Depending on the type of reaction, 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. For example, in the absence of 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. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or 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. For example, the method described in “Chemical Experiment Course (4th edition)” volume 20 (1992) (Maruzen) edited by the Chemical Society of Japan can be cited. Usually, 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. Depending on the compound, it may be advantageous to carry out 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. In addition, 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. Depending on the compound, it may be advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid, etc.) in order to facilitate the reaction.

Process B
In this step, compound (VI) is synthesized from two compounds consisting of a combination of compound (IV) and compound (V). In this step, 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.

Process C
In the compound (VI), 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. ^In the 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.
In this step, 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 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.

Process D
In this step, compound (VII) is synthesized from two compounds comprising a combination of compound (III) and compound (V). In this step, 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.
Process E
In this step, compound (VIII) is synthesized from two compounds comprising a combination of compound (VII) and compound (II). In this step, 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.
Process F
In the compound (VIII), when 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, R ^In the step of synthesizing the compound (I) of the present invention by converting ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² or X ¹ to R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X, respectively. is there.
In this step, 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 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.

In producing the compound (I) of the present invention, when 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. In addition, a process C or a process F for converting R 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 as required. May be carried out in the process A, B, D or E.

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. For example, 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.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, 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. . If necessary, 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. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of 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. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, 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. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using 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.

In general, in the case of oral administration, 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. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As 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.

Hereinafter, based on the examples, the production methods of the compounds of formula (I) and formula (IA) will be described in more detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown in a manufacture example, respectively. Further, the production methods of the compounds of the formula (I) and the formula (IA) are not limited to the production methods of the specific examples shown below, but the formula (I) and the formula (IA) ) Can also be produced by a combination of these production methods or by methods obvious to those skilled in the art.

Production Example 1
3-Ethoxy-2-hydroxybenzaldehyde (40 g) was dissolved in ethanol (330 mL), formaldehyde (26.9 mL) and 1-methylpiperazine (34.5 mL) were added, and the mixture was stirred overnight with heating under reflux. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure to give 3-ethoxy-2-hydroxy-5-[(4-methylpiperazin-1-yl) methyl] benzaldehyde (67 g) as a brown oil. Obtained.

Production Example 2
3-Ethoxy-2-hydroxy-5-[(4-methylpiperazin-1-yl) methyl] benzaldehyde (67 g) was dissolved in N, N-dimethylformamide (500 mL), and potassium carbonate (66.5 g) was dissolved. Under ice cooling, a solution of tert-butyl bromoacetate (35.5 mL) in N, N-dimethylformamide (30 mL) was slowly added dropwise. After the addition, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with diethyl ether (500 mL) and washed 3 times with water (500 mL) and once with saturated brine (300 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give tert-butyl {2-ethoxy-6-formyl-4-[(4-methylpiperazin-1-yl) methyl] phenoxy} acetate ( 49.7 g) was obtained as a colorless powder.

Production Example 3
Dissolve tert-butyl [{4-[(2-aminobenzoyl) amino] phenyl} (imino) methyl] carbamate (300 mg) in acetic acid (4 mL) and add sodium triacetoxyborohydride (329 mg). Stir at room temperature for 15 minutes. To this solution was added dropwise an acetic acid solution (2 mL) of tert-butyl {2-ethoxy-6-formyl-4-[(4-methylpiperazin-1-yl) methyl] phenoxy} acetate (333 mg) at room temperature. Stir for 5 hours. The solvent was distilled off under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol) and 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 (330 mg) was obtained as a pale yellow powder.

Production Example 4
tert-butyl {4- (acetoxymethyl) -2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] phenyl} amino) methyl] -6- Isopropoxyphenoxy} acetate (1.7 g) was dissolved in ethanol (35 mL), 1M aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 1 hr. After the solvent was distilled off under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give tert-butyl {2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) Methyl} phenyl) carbamoyl] phenyl} amino) methyl] -4- (hydroxymethyl) -6-isopropoxyphenoxy} acetate (335 mg) was obtained as a pale yellow powder material.

Production Example 5
tert-butyl {2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] phenyl} amino) methyl] -4- (hydroxymethyl) -6- Isopropoxyphenoxy} acetate (330 mg) was dissolved in dichloromethane (6 mL), triethylamine (125 μL) and methanesulfonyl chloride (62 μL) were added under ice cooling, and the mixture was warmed to room temperature and stirred for 5 hr. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate), and tert-butyl {2-[({2-[(4-{[(tert-butoxycarbonyl ) Amino] (imino) methyl} phenyl) carbamoyl] phenyl} amino) methyl] -4- (chloromethyl) -6-isopropoxyphenoxy} acetate (115 mg) was obtained as a pale yellow powder material.

Production Example 6
tert-butyl {2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] phenyl} amino) methyl] -4- (chloromethyl) -6- Isopropoxyphenoxy} acetate (115 mg) was dissolved in N, N-dimethylformamide (2.3 mL), diisopropylethylamine (48 μL) and morpholine (21 μL) were added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give tert-butyl {2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) Carbamoyl] phenyl} amino) methyl] -6-isopropoxy-4- (morpholin-4-ylmethyl) phenoxy} acetate (80 mg) was obtained as a pale yellow powder material.

Production Example 7
tert-Butyl 3- [4- (acetoxymethyl) -2-formyl-6-isopropoxyphenyl] propanoate (2150 mg) was dissolved in 4M hydrogen chloride / dioxane solution (50 mL) and dissolved in argon at room temperature. Stir for hours. The solvent was distilled off under reduced pressure, and the residue was again dissolved in 4M hydrogen chloride / dioxane solution (50 mL), and further stirred at room temperature for 2 hours under an argon atmosphere. The solvent was distilled off under reduced pressure to obtain 3- [4- (acetoxymethyl) -2-formyl-6-isopropoxyphenyl] propanoic acid (1800 mg) as a pale yellow oily substance.

Production Example 8
5-[(Dimethylamino) methyl] -2-hydroxy-3-isopropoxybenzaldehyde (1 g) is dissolved in acetone / methanol = 1/1 (5 mL) and methyl iodide (275 μL) is added dropwise. Stir at room temperature overnight. After distilling off the solvent under reduced pressure, the residue was suspended in diisopropyl ether, filtered, and dried under reduced pressure to give (3-formyl-4-hydroxy-5-isopropoxyphenyl) -N, N, N-trimethylmethane. Ammonium iodide (1.2 g) was obtained as a pale yellow powder material.

Production Example 9
(3-Formyl-4-hydroxy-5-isopropoxyphenyl) -N, N, N-trimethylmethaneammonium iodide (300 mg) is dissolved in N, N-dimethylformamide (3 mL), and potassium cyanide (103 mg) is added. The mixture was stirred at 100 ° C. for 1 hour. The solvent was evaporated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give (3-formyl-4-hydroxy-5-isopropoxyphenyl) acetonitrile (55 mg) as a pale yellow oil.

Production Example 10
(3-Formyl-4-hydroxy-5-isopropoxyphenyl) acetonitrile (3.09 g) was dissolved in ethanol (20 mL), sodium borohydride (1.07 g) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give [4-hydroxy-3- (hydroxymethyl) -5-isopropoxyphenyl] acetonitrile (3.039 g) as a pale yellow oil.

Production Example 11
[4-Hydroxy-3- (hydroxymethyl) -5-isopropoxyphenyl] acetonitrile (200 mg) was placed in a 50 mL Parr bottle and dissolved in ethanol (3 mL) and 50% aqueous ammonia (1 mL). Dissolved. Raney nickel (NDHT-90, Kawaken Fine Chemical) was washed 10 times each with water and ethanol, and 200 mg was added to the mixture. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere of 3 atm. Raney nickel was removed by Celite filtration, and the filtrate was concentrated under reduced pressure to obtain 4- (2-aminoethyl) -2- (hydroxymethyl) -6-isopropoxyphenol (198 mg) as a pale yellow oily substance.

Production Example 12
4- (2-Aminoethyl) -2- (hydroxymethyl) -6-isopropoxyphenol (182 mg) is dissolved in tetrahydrofuran (3 mL), triethylamine (0.35 mL) and di-tert-butyl dicarbonate (185 mg) And stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give tert-butyl {2- [4-hydroxy-3- (hydroxymethyl) -5-isopropoxyphenyl] ethyl} carbamate (212 mg) Was obtained as a pale yellow oil.

Production Example 13
tert-butyl [4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2- (hydroxymethyl) -6-isopropoxyphenoxy] acetate (210 mg) was dissolved in dichloromethane (10 mL) (830 mg) was added. After stirring at room temperature for 2 hours, manganese dioxide (415 mg) was added, and the mixture was stirred at room temperature for 1 hour. Further, manganese dioxide (830 mg) was added, and the mixture was stirred at room temperature for 1 hour. Manganese dioxide was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give tert-butyl (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2-formyl-6-isopropoxyphenoxy ) Acetate (199 mg) was obtained as a pale yellow oil.

Production Example 14
A solution of 3-fluoro-4-methoxyaniline (5.0 g) in acetic anhydride (10 mL) was stirred at room temperature for 30 minutes. Nitric acid (3.9 mL) was added dropwise to the mixed solution at room temperature and stirred for 30 minutes, and then water was added to the reaction mixture. The precipitate was collected by filtration, washed with water, and dried under reduced pressure. The obtained compound was suspended in ethanol (20 mL), 6M hydrochloric acid (100 mL) was added, and the mixture was stirred for 40 minutes under reflux with heating. The reaction mixture was cooled in an ice bath, and the deposited precipitate was collected by filtration. The obtained solid was washed with water and then dried under reduced pressure to obtain 5-fluoro-4-methoxy-2-nitroaniline (5.5 g) as a red solid.

Production Example 15
Add a solution of sodium nitrite (611 mg) in water (3 mL) to a mixed solution of 5-fluoro-4-methoxy-2-nitroaniline (1.5 g) in concentrated hydrochloric acid (3 mL) and water (6 mL) at 0 ° C. The solution was added dropwise and stirred for 30 minutes. To the reaction mixture, a solution of potassium iodide (4.0 g) in water (9 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 10 minutes and at 60 ° C. for 40 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and water, 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 elution solvent to give 2-fluoro-4-iodo-5-nitroanisole (1.9 g) as a yellow solid. It was.

Production Example 16
To a suspension of 2-fluoro-4-iodo-5-nitroanisole (1.0 g), bis (triphenylphosphine) palladium (II) dichloride (236 mg) and lithium chloride (714 mg) in tetrahydrofuran (15 mL) at room temperature Then, tri n-butylvinyltin (1.1 mL) was added, and the mixture was stirred at 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (93: 7) as an elution solvent to give 2-fluoro-5-nitro-4-vinylanisole (664 mg). Was obtained as a yellow solid.

Production Example 17
Ozone gas was blown into a solution of 2-fluoro-5-nitro-4-vinylanisole (664 mg) in dichloromethane (12 mL) at −78 ° C. for 40 minutes. Dimethyl sulfide (1.2 mL) was added to the reaction mixture at −78 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with n-hexane / ethyl acetate (4: 1) to give 5-fluoro-4-methoxy-2-nitrobenzaldehyde (535 mg). Was obtained as a yellow solid.

Production Example 18
5-fluoro-4-methoxy-2-nitrobenzaldehyde (530 mg), sodium dihydrogen phosphate dihydrate (332 mg) and 2-methyl-2-butene (0.84 mL) in water (2 mL) and tert To a mixed solution of -butanol (5 mL) and acetonitrile (2 mL) was added sodium chlorite (721 mg) at room temperature, and the mixture was stirred for 1 hour. Water was added to the reaction mixture and washed twice with diethyl ether. To the aqueous layer was added 2M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 5-fluoro-4-methoxy-2-nitrobenzoic acid (378 mg) as a white solid.

Production Example 19
Add oxalyl chloride (91 μL) to a suspension of 5-fluoro-4-methoxy-2-nitrobenzoic acid (150 mg) and N, N-dimethylformamide (3 μL) in dichloromethane (2 mL) at room temperature, Stir for 1 hour. The reaction mixture was concentrated under reduced pressure, and acetonitrile (1.5 mL) was added to the residue. The mixture was added to a suspension of tert-butyl [(4-aminophenyl) (imino) methyl] carbamate (164 mg) and pyridine (0.17 mL) in acetonitrile (1.5 mL) at room temperature and stirred overnight. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (7:13) as an elution solvent, and tert-butyl [{4-[(5-fluoro-4-methoxy-2-nitrobenzoyl) amino] Phenyl} (imino) methyl] carbamate (209 mg) was obtained as a white solid.

Production Example 20
At room temperature, tert-butyl [{4-[(5-fluoro-4-methoxy-2-nitrobenzoyl) amino] phenyl} (imino) methyl] carbamate (205 mg) in tetrahydrofuran (4 mL) and ethanol (2 mL ) Was added to a suspension of Raney nickel (300 mg) in ethanol (2 mL), and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere of 1 atm. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give tert-butyl [{4-[(2-amino-5-fluoro-4-methoxybenzoyl) amino] phenyl} (imino) methyl] carbamate (145 mg). Obtained as a red solid.

Production Example 21
tert-Butyl [{4-[(2-amino-5-fluoro-4-methoxybenzoyl) amino] phenyl} (imino) methyl] carbamate (62 mg) and sodium triacetoxyborohydride (98 mg) in acetic acid ( To a 0.4 mL) solution was added tert-butyl 3- (4-acetoxymethyl-2-formyl-6-isopropoxyphenyl) propanoate (56 mg) in acetic acid (0.2 mL), and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel using n-hexane / ethyl acetate (1: 3) as an elution solvent, and tert-butyl 3- {4- (acetoxymethyl) -2-[({2-[( 4-{[(tert-Butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] -4-fluoro-5-methoxyphenyl} amino) methyl] -6-isopropoxyphenyl} propanoate (87 mg) Obtained as a regular product.

Production Example 22
tert-butyl 3- {4- (acetoxymethyl) -2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] -4-fluoro-5- Trifluoroacetic acid (0.5 mL) was added to a solution of methoxyphenyl} amino) methyl] -6-isopropoxyphenyl} propanoate (85 mg) in dichloromethane (0.5 mL), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, toluene and ethyl acetate were added to the residue, and trifluoroacetic acid was azeotroped under reduced pressure. Ethyl acetate was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give 3- [4- (acetoxymethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluoro. -5-Methoxyphenyl] amino} methyl) -6-isopropoxyphenyl] propanoic acid trifluoroacetate (61 mg) was obtained as a pale yellow solid.

Production Example 23
tert-Butyl (E) -3- (2-formyl-6-isopropoxy-4-nitrophenyl) acrylate (8.0 g) and molecular sieves 38.0 (8.0 g) and 27.5 w / w% hydrogen chloride / ethanol (100 mL ) The mixture of solutions was stirred at an external temperature of 50 ° C. for 6 hours. The 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. Under argon atmosphere, 5% platinum carbon powder (3.7 g) in a solution of ethyl (E) -3- (2-diethoxymethyl-6-isopropoxy-4-nitrophenyl) acrylate (7.4 g) in tetrahydrofuran (100 mL) Of tetrahydrofuran (100 mL) was added and stirred at room temperature for 5 days under a hydrogen atmosphere of 1 atm. A suspension of 5% platinum carbon powder (1.3 g) in tetrahydrofuran (40 mL) was added to the reaction mixture, and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 2 days. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by aminopropyl silica gel column chromatography using n-hexane / ethyl acetate (1: 1) as an elution solvent, and ethyl 3- (4-amino-2-diethoxymethyl-6-isopropoxyphenyl) was obtained. ) Propanoate (2.6 g) was obtained as a pale red oil.

Production Example 24
To a mixture of ethyl 3- (4-amino-2-diethoxymethyl-6-isopropoxyphenyl) propanoate (0.96 g) in sulfuric acid (7 mL) and water (7 mL), sodium nitrite (0.24 g) under ice-cooling Of water (3 mL) was added dropwise and stirred at the same temperature for 5 minutes. Urea (48 mg) was added to the reaction mixture. To this solution was added ice-cooled copper (II) nitrate trihydrate (65 g) in water (120 mL), and copper (I) oxide (0.39 g) was added with vigorous stirring. Stir. Ethyl acetate was added to the reaction mixture, and the organic layer was extracted. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Of ethyl 3- (2-formyl-4-hydroxy-6-isopropoxyphenyl) propanoate (0.15 g), tert-butyl (2-hydroxyethyl) carbamate (106 μL) and triphenylphosphine (0.21 g) To a tetrahydrofuran (2.5 mL) solution was added 2.3 mol / L diethyl azodicarboxylate / toluene solution (375 μL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. 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.

Production Example 25
tert-Butyl [{4-[(2-amino-5-fluorobenzoyl) amino] phenyl} (imino) methyl] carbamate (0.09 g) and sodium triacetoxyborohydride (0.15 g) in acetic acid (1 mL) A solution of ethyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethoxy} -2-formyl-6-isopropoxyphenyl) propanoate (0.10 g) in acetic acid (1 mL) was added at room temperature. Stir for 1 hour. Saturated aqueous sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract 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 (3: 7) as an elution solvent, and ethyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethoxy}- 2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] -4-fluorophenyl} amino) methyl] -6-isopropoxyphenyl) propanoate (0.15 g) was obtained as a yellow amorphous.

Production Example 26
Ethyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethoxy} -2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl ] -4-fluorophenyl} amino) methyl] -6-isopropoxyphenyl) propanoate (0.15 g) in ethanol (1 mL) was added 2M aqueous sodium hydroxide (150 μL) at room temperature, and the external temperature was 40 ° C. For 5 hours. To the reaction mixture was added 2M aqueous sodium hydroxide solution (50 μL) at room temperature, and the mixture was stirred at an external temperature of 40 ° C. for 1 hour. To the reaction mixture was added 2M hydrochloric acid (200 μL) at room temperature. The reaction mixture was concentrated under reduced pressure. Water (5 mL) was added to the obtained residue, and the resulting precipitate was powdered and collected by filtration. The obtained precipitate was washed with water, dried under reduced pressure, and 3- (4- {2-[(tert-butoxycarbonyl) amino] ethoxy} -2-[({2-[(4-{[( tert-Butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] -4-fluorophenyl} amino) methyl] -6-isopropoxyphenyl) propanoic acid (0.13 g) was obtained as a white solid.

Production Example 27
Sodium borohydride (114 mg) was added to a solution of tert-butyl 3- (4-acetoxymethyl-2-formyl-6-isopropoxyphenyl) propanoate (1.0 g) in methanol (5 mL) under ice-cooling. The mixture was stirred for 20 minutes under the conditions. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 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 reaction mixture was concentrated under reduced pressure, 0.5M hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (1: 1) as an elution solvent, and tert-butyl 3- {2-[(tert-butyldiphenylsilyloxy) methyl] -4-hydroxymethyl. -6-Isopropoxyphenyl} propanoate (1.2 g) was obtained as a colorless oil.

Production Example 28
tert-Butyl 3- {2-[(tert-Butyldiphenylsilyloxy) methyl] -4-hydroxymethyl-6-isopropoxyphenyl} propanoate (1.2 g) and carbon tetrabromide (856 mg) in dichloromethane (6 mL ) Triphenylphosphine (677 mg) was added to the solution at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (4: 1) as an elution solvent. 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.

Production Example 29
tert-Butyl 3- {2-[(tert-Butyldiphenylsilyloxy) methyl] -4-cyanomethyl-6-isopropoxyphenyl} propanoate (1.0 g) in methanol (9 mL) at 0 ° C with ditert-butyl Dicarbonate (773 mg) and nickel (II) chloride 23 mg were added, and then sodium borohydride (469 mg) was added little by little over 1 hour. After foaming subsided, the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (7: 3) as an elution solvent, and tert-butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2 -[(tert-Butyldiphenylsilyloxy) methyl] -6-isopropoxyphenyl) propanoate (864 mg) was obtained as a pale yellow oil.

Production Example 30
tert-butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2-[(tert-butyldiphenylsilyloxy) methyl] -6-isopropoxyphenyl) propanoate (864 mg) in tetrahydrofuran To the (6 mL) solution was added 1 mol / L tetra n-butylammonium fluoride / tetrahydrofuran solution (1.5 mL) at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (1: 4) as an elution solvent, and tert-butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2 -Hydroxymethyl-6-isopropoxyphenyl) propanoate (510 mg) was obtained as a colorless oil.

Production Example 31
tert-Butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2-hydroxymethyl-6-isopropoxyphenyl) propanoate (318 mg) in dichloromethane (6 mL) at room temperature, Manganese dioxide (IV) (949 mg) was added and stirred overnight. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (1: 1) as an elution solvent, and tert-butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2 -Formyl-6-isopropoxyphenyl) propanoate (311 mg) was obtained as a colorless oil.

Production Example 32
tert-Butyl [{4-[(2-amino-5-fluorobenzoyl) amino] phenyl} (imino) methyl] carbamate (86 mg) and sodium triacetoxyborohydride (146 mg) in acetic acid (1 mL) To a solution of tert-butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2-formyl-6-isopropoxyphenyl) propanoate (100 mg) in acetic acid (0.6 mL) at room temperature The mixture was further stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (7:13) as an elution solvent. The solvent was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography using ethyl acetate as an elution solvent, and tert-butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2 -[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] -4-fluorophenyl} amino) methyl] -6-isopropoxyphenyl) propanoate (137 mg ) Was obtained as a yellow amorphous.

Production Example 33
To a solution of ethyl 3- (4-acetoxymethyl-2-formyl-6-isopropoxyphenyl) propanoate (500 mg) in ethanol (8 mL) was added potassium carbonate (308 mg) at room temperature, and the mixture was stirred for 2 hours. 0.5M hydrochloric acid 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, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained compound was dissolved in dichloromethane (8 mL), carbon tetrabromide (592 mg) and triphenylphosphine (468 mg) were sequentially added under water cooling, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (2: 1) as an elution solvent, and ethyl 3- (4-bromomethyl-2-formyl-6-isopropoxyphenyl) propanoate (310 mg) was purified. Obtained as a yellow oil.

Production Example 34
Sodium azide (73 mg) was added to a solution of ethyl 3- (4-bromomethyl-2-formyl-6-isopropoxyphenyl) propanoate (310 mg) in dimethyl sulfoxide (4 mL) at room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 3- (4-azidomethyl-2-formyl-6-isopropoxyphenyl) propanoate (255 mg) as a yellow oil. Obtained.

Production Example 35
A suspension of ethyl 3- (4-azidomethyl-2-formyl-6-isopropoxyphenyl) propanoate (255 mg), 2-aminonicotinic acid (166 mg) and sodium formate (1.1 g) in acetic acid (7 mL) Using a microwave reaction apparatus, microwave irradiation was performed at 170 ° C. for 40 minutes and stirring was performed. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed 3 times with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (1: 2) as an elution solvent, and 2-({5-azidomethyl-2- [2- (ethoxycarbonyl) ethyl] -3-isopropoxy was obtained. (Benzyl} amino) pyridine-3-carboxylic acid (150 mg) was obtained as a white solid.

Production Example 36
2-({5-azidomethyl-2- [2- (ethoxycarbonyl) ethyl] -3-isopropoxybenzyl} amino) pyridine-3-carboxylic acid (135 mg) and N, N-dimethylformamide (3 μL) Oxalyl chloride (40 μL) was added to a dichloromethane (1.5 mL) solution at room temperature, and the mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, and acetonitrile (1 mL) was added to the residue. The mixture was added to a suspension of tert-butyl [(4-aminophenyl) (imino) methyl] carbamate (108 mg) and pyridine (74 μL) in acetonitrile (2 mL) at room temperature and stirred overnight. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane / ethyl acetate (9:41) as an elution solvent, and ethyl 3- {4- (azidomethyl) -2-[({3-[(4-{[( tert-Butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] pyridin-2-yl} amino) methyl] -6-isopropoxyphenyl} propanoate (135 mg) was obtained as a yellow amorphous.

Production Example 37
Ethyl 3- {4- (azidomethyl) -2-[({3-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] pyridin-2-yl} amino) methyl] To a mixed solution of -6-isopropoxyphenyl} propanoate (135 mg) in tetrahydrofuran (1 mL) and ethanol (1 mL), add a Raney nickel (150 mg) ethanol suspension at room temperature, Stir for 6 hours. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel using ethyl acetate / methanol (17: 3) as an elution solvent, and ethyl 3- {4- (aminomethyl) -2-[({3-[(4-{[ (tert-Butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] pyridin-2-yl} amino) methyl] -6-isopropoxyphenyl} propanoate (94 mg) was obtained as a colorless amorphous product.

Production Example 38
Ethyl 3- {4- (aminomethyl) -2-[({3-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] pyridin-2-yl} amino) methyl ] -6-Isopropoxyphenyl} propanoate (92 mg) in ethanol (1.5 mL) was added with 2M aqueous sodium hydroxide (145 μL) at room temperature and stirred at 40 ° C. for 5 hours. 2M Hydrochloric acid (145 μL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitate was collected by filtration. The precipitate was washed successively with water and diethyl ether and then dried under reduced pressure to give 3- {4- (aminomethyl) -2-[({3-[(4-{[(tert-butoxycarbonyl) amino] ( Imino) methyl} phenyl) carbamoyl] pyridin-2-yl} amino) methyl] -6-isopropoxyphenyl} propanoic acid (73 mg) was obtained as a pale yellow solid.

In the same manner as in Production Examples 1 to 38, Compounds of Production Example Compounds 39 to 47 were produced. The structures of the production example compounds are shown in Tables 4 to 14 below, and the production methods and physicochemical data are shown in Tables 15 to 18 below.

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. After the solvent was distilled off under reduced pressure, the residue was purified by preparative HPLC (eluent: water / acetonitrile containing 0.1% formic acid), and {2-({[2-({4- [amino (imino) methyl ] Phenyl} carbamoyl) phenyl] amino} methyl) -6-ethoxy-4-[(4-methylpiperazin-1-yl) methyl] phenoxy} acetic acid triformate salt (160 mg) was obtained as a yellow powder.

Example 2
tert-butyl 4- {3-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) carbamoyl] phenyl} amino) methyl] -4- (2-tert- Butoxy-2-oxoethoxy) -5-ethoxybenzyl} piperazine-1-carboxylate (430 mg) is dissolved in dichloroethane (4 mL), trifluoroacetic acid (2 mL) is added at room temperature, and the mixture is stirred at room temperature for 5 hours. did. After distilling off the solvent under reduced pressure, the residue was suspended in diisopropyl ether, collected by filtration, and dried under reduced pressure to give [2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) phenyl. [Amino} methyl) -6-ethoxy-4- (piperazin-1-ylmethyl) phenoxy] acetic acid 3 trifluoroacetate (470 mg) was obtained as a pale yellow powder.

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. After concentration under reduced pressure, the residue was dissolved in ethanol (3 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solution was directly purified by reverse phase silica gel column chromatography (eluent: water: acetonitrile) to give 3- [2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -5-methoxy. [Phenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenyl] propanoic acid (35 mg) was obtained as a pale yellow solid.

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. The solvent was distilled off under reduced pressure, 4M hydrogen chloride / dioxane solution (5 mL) was added, and the mixture was stirred at room temperature for 10 min. The precipitated solid was collected by filtration, and [4- (2-aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl was collected. ) -6-Isopropoxyphenoxy] acetic acid dihydrochloride (120 mg) was obtained as a pale yellow powder.

Example 5
3- [4- (Acetoxymethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluoro-5-methoxyphenyl] amino} methyl) -6-iso To a solution of propoxyphenyl] propanoic acid trifluoroacetate (57 mg) in ethanol (0.8 mL) was added 2M aqueous sodium hydroxide solution (0.12 mL), and the mixture was stirred at room temperature for 30 min. Trifluoroacetic acid (18 μL) 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. The precipitate was dried under reduced pressure to give 3- [2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluoro-5-methoxyphenyl] amino} methyl) -4- (Hydroxymethyl) -6-isopropoxyphenyl] propanoic acid (48 mg) was obtained as a yellow solid.

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. The obtained precipitate was dried under reduced pressure to give 3- [4- (2-aminoethoxy) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] ] Amino} methyl) -6-isopropoxyphenyl] propanoic acid ditrifluoroacetate (120 mg) was obtained as a pale yellow amorphous product.

Example 7
tert-butyl 3- (4- {2-[(tert-butoxycarbonyl) amino] ethyl} -2-[({2-[(4-{[(tert-butoxycarbonyl) amino] (imino) methyl} phenyl) Trifluoroacetic acid (0.8 mL) was added to a solution of) carbamoyl] -4-fluorophenyl} amino) methyl] -6-isopropoxyphenyl} propanoate (132 mg) in dichloromethane (0.8 mL) and stirred at room temperature for 4 hours. The 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, and diethyl ether was added to the residue. 3- [4- (2-aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-iso Propoxyphenyl] propanoic acid ditrifluoroacetate (117 mg) was obtained as a yellow amorphous product.

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. The 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. The precipitate was collected by filtration and dried under reduced pressure to give 3- [2-({[3-({4- [amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl)- 4- (Aminomethyl) -6-isopropoxyphenyl] propanoic acid ditrifluoroacetate (71 mg) was obtained as a yellow amorphous product.

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.

The structures of 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.

The active ingredients of the medicament of the present invention and the pharmacological activity of the compound of the present invention were confirmed by the tests described in the following examples.
Example 11 Human Plasma Kallikrein Inhibition Experiment In a 96-well microplate, reaction buffer (pH 7.4) 50 μL, test compound solution 10 μL, 2 mM synthetic substrate S-2302 (Chromogenix) 20 μL, human plasma kallikrein (Sigma) 20 μL 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 μL of test compound solution and 50 μL of Hemoliance (registered trademark) SynthASil (Instrumentation Laboratory) were added to 50 μL of human or guinea pig plasma, and heated at 37 ° C. for 3 minutes. did. Furthermore, 50 μL 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.

From the above results, it was confirmed that the active ingredient of the medicament of the present invention and the compound of the present invention inhibit plasma kallikrein and prolong the activated partial thromboplastin time involved in plasma kallikrein.

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. 30 minutes after compound administration, Evans Blue 20 mg / kg, captopril 1 mg / kg, and sodium dextran sulfate 30 mg / kg, known to produce plasma kallikrein, were systemically administered from the femoral vein, and trachea 10 minutes later Was extracted. The excised trachea is immersed in formamide, and the amount of Evans blue extracted in formamide is measured with a spectrophotometer (trade name: SPECTRAmax340PC384, Molecular Devices), and the amount of Evans blue per tracheal weight It was used as an index.
As a result of this test, the increase in vascular permeability in guinea pigs was significantly suppressed by subcutaneous administration of Reference Example Compound 1 at 0.3 mg / kg and Reference Example Compound 6 at 0.1 mg / kg.
From the above, it was confirmed that the compound which is an active ingredient of the medicament of the present invention has an effect on diseases associated with edema due to increased vascular permeability such as hereditary angioedema and brain edema.

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. 29 minutes after compound administration, 100 U / kg of heparin was systemically administered from the femoral vein, and 1 minute later, a cut with a diameter of 5 mm and a depth of 4 mm was used on the surface of the liver using skin trepan (Delma Punch (registered trademark)) Created. Ten minutes after the creation of the cut, the blood in the abdominal cavity was blotted with absorbent cotton and the net wet weight was taken as the amount of bleeding. As a result of this test, it was found that Reference Example Compound 6 significantly suppressed bleeding from cuts in guinea pigs by subcutaneous administration of 0.1 mg / kg. From the above, it was confirmed that the compound which is an active ingredient of the medicament of the present invention has an effect of suppressing bleeding during cardiac surgery or the like.

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.

From the above test results, 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.

The following abbreviations may be used in the following tables.
Ex: Example Compound No.: PEx: Production Example Compound No., REx: Reference Example Compound No., No: compound number, Structure: structural formula, Data: physicochemical data (NMR: ¹ of the peak in the NMR δ (ppm), ESI +: ESI-MS (Pos) ([M + H] ⁺ unless otherwise noted), ESI-: ESI-MS (Neg) ([MH] ^- ), APCI / ESI +: APCI-MS (Pos) ([ M + H] ⁺ ) and ESI-MS (Pos) (means [M + H] ⁺ ). 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).

Since 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.

Claims (21)

1. A plasma kallikrein inhibitor comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
   

   

   [The symbols in the formula have the following meanings.
   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 ¹ : -NH ₂ , -CH ₂ NH ₂ , -C (O) NH ₂ , -C (= NH) NH ₂ , -C (= NOH) NH ₂ , -C (= NH) NH-CO _2- (Optionally substituted lower alkyl) or 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl.
   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. However, the lower alkyl, cycloalkyl, aryl, or heterocyclic group in R ² and R ³ may be substituted.
   Alternatively, 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 : each independently lower alkyl, lower alkenyl, cycloalkyl, aryl, heterocyclic group, halogen, oxo, —CN, —NO ₂ , —OR ⁶ , —N (R ⁶ ) ₂ , —SR ⁶ , -S (O) R ⁶ , -S (O) ₂ R ⁶ , -S (O) ₂ N (R ⁶ ) ₂ , -N (R ⁶ ) S (O) ₂ R ⁶ , -N (R ⁶ ) S (O) ₂ -N (R ⁶ ) ₂ , -N (R ⁶ ) S (O) ₂ -N (R ⁶ ) C (O) OR ⁶ , -C (O) R ⁶ , -CO ₂ R ⁶ , -C (O) N (R ⁶ ) ₂ , -C (O) N (R ⁶ ) -lower alkylene-N (R ⁶ ) ₂ , -NH-C (= NH-CN) NH ₂ , -C ( O) -N = C (NH ₂ ) ₂ , -C (O) -N = C (R ⁶ ) -NH ₂ , -C (O) N (R ⁶ ) -S (O) ₂ -N (R ⁶ ) ₂ , -C (O) N (R ⁶ ) -S (O) ₂ R ⁶ , -OC (O) R ⁶ , -OC (O) OR ⁶ , -OC (O) N (R ⁶ ) ₂ , ^{-N (R 6) C (O} ) R 6, -N (R 6) C (O) oR 6, ^{or, -N (R 6) C (} O) N (R 6) 2. However, the lower alkyl, lower alkenyl, cycloalkyl, aryl and heterocyclic groups in 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 .
   J: * -N (R ⁰ ) C (O)-, * -C (O) N (R ⁰ )-, -N (R ⁰ ) C (O) N (R ⁰ )-, * -N (R ⁰ ) -lower alkylene- or * -lower alkylene-N (R ⁰ ) C (O)-. However, * shows the coupling | bonding to A ring.
   L: * -NR ⁰ -lower alkylene-, * -NR ⁰ -lower alkenylene-, -lower alkylene- or -lower alkenylene-. * Indicates a bond to the B ring.
   X: single bond, -O-, -N (R ⁷ )-, -S-, -C (O)-, -S (O)-, -S (O) _2- , * -lower alkylene-O- Or * -lower alkylene-N (R ⁷ )-. However, * shows the coupling | bonding to C ring.
   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. ]
   
2. The plasma kallikrein inhibitor according to claim 1, wherein the compound represented by formula (I) of claim 1 is a compound represented by formula (I-1).
   

   

   [Wherein m, n, p and R ⁰ represent the meanings of claim 1. Other symbols have the following meanings.
   A ^a ring: a benzene ring or a 6-membered monocyclic heteroaryl ring.
   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 ) C (O) -lower alkylene-OR ⁰ , Or, -N (R ⁰ ) C (O) -lower alkylene-N (R ⁰ ) ₂ .
   However, the heterocyclic group in R ^4a may be substituted. ]
   
3. The plasma kallikrein inhibitor according to claim 2, wherein the compound represented by formula (I-1) of claim 2 is a compound represented by formula (I-2).
   

   

   [Wherein p, R ⁰ , R ^3a and R ^4a have the same meaning as in claim 2. Other symbols have the following meanings.
   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- . However, * means a bond to the ^Cb ring. ]
   
4. 

   But,
   

   

   [However, the symbols in the formula have the following meanings.
   -X ^c -Y ^c- : * -O-CH ₂ -or-(CH ₂ ) _2- . However, * means a bond to a benzene ring.
   R ^6a : lower alkyl or lower alkylene-OR ⁰ .
   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 . However, the heterocyclic group in R ^4b may be substituted.
   R ^4c : —H or lower alkylene —CN. ]
   The plasma kallikrein inhibitor according to claim 3, wherein
   
5. The compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof is:
   [2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenoxy] acetic acid,
   [4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
   {2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-ethoxy-4-[(4-methylpiperazin-1-yl) Methyl] phenoxy} acetic acid,
   [2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -4- (glycylamino) -6-isopropoxyphenoxy] acetic acid,
   {2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-isopropoxy-4-[(N-methylglycyl) amino] phenoxy} Acetic acid,
   [4- (L-alanylamino) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid,
   [4- (β-alanylamino) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid,
   [4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
   [7-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -1H-indol-1-yl] acetic acid,
   [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4,5-difluorophenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenoxy] acetic acid ,
   3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenyl] propane acid,
   [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -4-{[2- (dimethylamino) ethyl] carbamoyl} -6- Isopropoxyphenoxy] acetic acid,
   [7-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-chlorophenyl] amino} methyl) -3- (cyanomethyl) -1H-indol-1-yl] acetic acid,
   3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenyl] propane acid,
   3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (hydroxymethyl) -6- (2-hydroxy- 1-methylethoxy) phenyl] propanoic acid,
   3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-fluoro-5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-iso Propoxyphenyl] propanoic acid,
   3- [4- (2-Aminoethoxy) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid,
   3- [4- (2-aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid and
   3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (aminomethyl) -6-isopropoxyphenyl] propane The plasma kallikrein inhibitor according to claim 1, which is a compound selected from the group consisting of acids or a pharmaceutically acceptable salt thereof.
   
6. A pharmaceutical composition which is a prophylactic or therapeutic agent for edema, hematoma, or a hemorrhage suppressant, comprising as an active ingredient the compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof.
   
7. The pharmaceutical composition according to claim 6, which is an agent for preventing or treating edema or a bleeding inhibitor.
   
8. The pharmaceutical composition according to claim 7, which is an agent for preventing or treating edema.
   
9. The pharmaceutical composition according to claim 8, which is a prophylactic or therapeutic agent for hereditary angioedema.
   
10. The pharmaceutical composition according to claim 8, which is a preventive or therapeutic agent for brain edema.
    
11. The pharmaceutical composition according to claim 7, which is a bleeding inhibitor.
    
12. The pharmaceutical composition according to claim 11, which is a bleeding inhibitor at the time of surgery.
    
13. The pharmaceutical composition according to claim 6, which is a prophylactic or therapeutic agent for hematoma.
    
14. The pharmaceutical composition according to claim 13, which is a preventive or therapeutic agent for intracranial hematoma.
    
15. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a plasma kallikrein inhibitor, an edema, a prophylactic or therapeutic agent for hematoma, or a hemorrhage suppressant.
    
16. A method for preventing or treating edema, hematoma, or inhibiting bleeding, comprising administering an effective amount of a compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof to a patient.
    
17. Use of a compound represented by the formula (I) of claim 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of edema, hematoma, or suppression of bleeding.
    
18. A compound represented by the formula (I) of claim 1 or a pharmaceutically acceptable salt thereof for preventing or treating edema, hematoma, or suppressing bleeding.
    
19. A compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof.
    

    

    [The symbols in the formula have the following meanings.
    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- . However, * 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.
    
    However,
    When R ^4A is lower alkylene-OH, R ^3A is —O-lower alkyl and —X ^A —Y ^A — is — (CH ₂ ) ₂ —.
    However,
    Excluding [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl) -4- (aminomethyl) -6-isopropoxyphenoxy] acetic acid . ]
    
20. [4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-methylphenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
    [4- (2-Aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenoxy] acetic acid ,
    3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-isopropoxyphenyl] propane acid,
    3- [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) -4-fluoro-5-methoxyphenyl] amino} methyl) -4- (hydroxymethyl) -6-iso Propoxyphenyl] propanoic acid,
    3- [4- (2-Aminoethoxy) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid,
    3- [4- (2-aminoethyl) -2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) -4-fluorophenyl] amino} methyl) -6-isopropoxyphenyl ] Propanoic acid,
    3- [2-({[3-({4- [Amino (imino) methyl] phenyl} carbamoyl) pyridin-2-yl] amino} methyl) -4- (aminomethyl) -6-isopropoxyphenyl] propane acid,
    {2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) phenyl] amino} methyl) -6-ethoxy-4-[(4-methylpiperazin-1-yl) methyl] phenoxy } Acetic acid,
    [2-({[2-({4- [amino (imino) methyl] phenyl} carbamoyl) phenyl] amino} methyl) -6-ethoxy-4- (piperazin-1-ylmethyl) phenoxy] acetic acid, and
    [2-({[2-({4- [Amino (imino) methyl] phenyl} carbamoyl) phenyl] amino} methyl) -6-isopropoxy-4- (morpholin-4-ylmethyl) phenoxy] acetic acid 20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, which is more selected.
    
21. A pharmaceutical composition comprising the compound according to claim 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.