JPH11246437A - Gastrointestinal mucosa protecting agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent having excellent gastrointestinal mucosa atrophy preventive activity and gastrointestinal mucosa hyperlucent sthenia suppressing activity by using a compound having chymase inhibiting activity as an active component. SOLUTION: This agent contains a compound having chymase inhibiting activity as an active component. An example of the compound is a compound of the formula [R is hydrogen, -CHO or the like; R<5> to R<7> are each hydrogen, an alkyl or the like; M is carbon or nitrogen, and when M is nitrogen, R<6> is absent; Y is a cycloalkyl, an aryl or the like; Z is -CF2 R<8> , -COOR<9> (R<8> is hydrogen, a halogen or the like; R<9> is hydrogen, an alkenyl or the like) or the like; (n) is 0 or 1]. The objective compound is administered preferably at a daily dose of 0.05-500 mg/kg-body weight in one or several divided doses for an adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a gastrointestinal mucosa protective agent containing a compound having a chymase inhibitory activity as an active ingredient.

[0002]

2. Description of the Related Art Total parenteral nutrition (Total Pare)
In recent years, natural nutrition (TPN) has been actively used in clinical settings as an emergency nutrition supplementation method. This TPN is impossible or inadequate for oral or enteral nutrition, such as patients who have undergone surgery on the gastrointestinal tract or have lost the function of the gastrointestinal tract. It has been used as a nutritional supplementation method, and has a great clinical effect by improving the prognosis of surgery and improving the survival effect.

[0003] As described above, TPN is an extremely useful method, but when TPN is performed, atrophy of the digestive tract mucosa occurs, and bacterial translocation (Ba) occurs.
cterial Translation) (B
T) occurs, and it is necessary to take various measures. This BT breaks down the gastrointestinal tract barrier during invasion, and resident intestinal bacteria pass through the gastrointestinal mucosa and migrate into local lymph nodes and other organs. It has been seen.

[0004] Therefore, by protecting the gastrointestinal mucosa itself, complications at the time of TPN administration can be prevented beforehand and effective T
Although the development of a TPN complication preventive agent that realizes PN is desired, a gastrointestinal mucosal protective agent sufficiently effective to exhibit such an effect has not yet been found.

On the other hand, as is well known, the incidence of allergic diseases such as atopic dermatitis and pediatric asthma has been increasing in recent years, and the number of patients has rapidly increased, which has led to social problems. In particular, food-related allergic symptoms often occur from infants to childhood, but are attracting great interest because the symptoms are likely to be aggravated and the number of adult patients is gradually increasing.

Various studies have been made on the mechanism of the onset of such food allergy. One of the factors is suspected of invasion of the allergen into the body from the digestive tract mucosa such as the intestinal mucosa. In order to prevent and treat such food allergies, various measures are taken to avoid taking allergens, especially dietary restrictions. However, there are many problems due to adverse effects such as a loss of nutritional balance. Therefore, it is considered that the development of a therapeutic agent for allergic diseases by protecting the gastrointestinal mucosa itself and preventing the invasion of allergen from the gastrointestinal mucosa is considered to be effective, and various studies have been made. No gastrointestinal mucosal protective agent sufficiently effective to exert such an effect has been found.

In addition, inflammatory gastrointestinal diseases typified by ulcerative colitis and Crohn's disease, atrophy of the gastrointestinal mucosa and the like after laparotomy and transplantation surgery accompanied by gastrointestinal ischemia and reperfusion. However, the occurrence of BT has been regarded as a problem, and the development of these preventive and therapeutic agents has been desired. However, a gastrointestinal mucosa protective agent sufficiently effective to exert such an effect has not yet been found.

[0008]

SUMMARY OF THE INVENTION In view of the above situation, the present invention has an excellent effect of preventing atrophy of the gastrointestinal mucosa and an effect of suppressing the increase in permeability of the gastrointestinal mucosa, thereby protecting the gastrointestinal mucosa itself. Protective agent for gastrointestinal mucosa, further preventive and therapeutic agent for TPN complications based on such action, preventive and therapeutic agent for allergic disease, inflammatory gastrointestinal disease preventive and therapeutic agent, and gastrointestinal tract associated with ischemia / reperfusion An object of the present invention is to provide a prophylactic / therapeutic agent for postoperative disorders and the like.

[0009]

The present inventors have conducted various studies to solve the above-mentioned problems, and as a result, surprisingly, a compound having a chymase inhibitory action has been found to be an excellent gastrointestinal tract suitable for the above-mentioned purpose. The present inventors have found that they have a mucosal atrophy preventing action and a gastrointestinal mucosal hyperpermeability suppressing action, and have completed the present invention. That is, the present invention is a gastrointestinal mucosa protective agent comprising a compound having a chymase inhibitory activity as an active ingredient. Hereinafter, the present invention will be described in detail.

[0010] Chymase is one of the in vivo enzymes found in mast cell secretory granules and one of a subfamily of chymotrypsin-like serine proteases. Chymase, when released extracellularly, rapidly binds to the surrounding cell membrane, cleaves the extracellular matrix of type IV collagen and fibronectin, enhances vascular permeability together with histamine, enhances histamine action, and increases serum albumin. To produce histamine-releasing peptides, and also cleave intracellular substrates such as collagen and proteoglycans.
It has an in vivo action such as limited degradation of G, formation of leukocyte chemotactic factor, and activation of a precursor of interleukin-1-β, one of inflammatory cytokines.

Chymase has also been shown to be involved in the formation process of angiotensin I to angiotensin II without being dependent on angiotensin converting enzyme, and in addition to extracellular matrix, substance P, and bathoactive intestinal. -It has been found that many physiologically active substances such as polypeptide (VIP) and apoprotein B are used as substrates, and that they are also involved in the activation of other in vivo proteases such as collagenase. ing.

As used herein, "chymase inhibitory action"
The term means not only the actions of the various chymases described above, but also the actions of inhibiting and suppressing all in vivo reactions involving chymase. Further, in the present specification, the “compound having a chymase inhibitory action” may be a compound having an action of inhibiting or suppressing at least one of the actions of the various chymases described above. And compounds having an action of inhibiting or suppressing at least one of all in vivo reactions involving chymase other than the action of.

[0013] In the present specification, the above-mentioned "chymase inhibitory action" is a generic term for various actions and is used to mean only one of these actions. Is also used to mean the combined action of In the present specification, the “compound having a chymase inhibitory action” means a compound that expresses the chymase inhibitory action at a normal dose, and the “normal dose” includes, for example, , 0.01 to 1000 mg / k
g human / day means an amount comparable to the amount of a compound administered orally or parenterally as a normal pharmaceutical.

In connection with the above, rat mast cell protease type II (Type 1), a kind of chymase, is used.
II rat must cell proteas
e) (hereinafter also referred to as “RMCP-II”) has been reported as follows.

The American Journal of Physiology (Am. J. Physiol.) 267 [Gastrointestinal River Physiology (G)
astrointest. Liver Physio
l. Vol. 30] G316-G321, 1994, RMCP-induced rat ischemia-reperfusion injury in intestinal mucosa.
It has been reported that the blood concentration of II is elevated.

Also, shock (SHOCK) 13 volumes, 2
No., pp. 125-131, 1995, it is reported that the amount of RMCP-II is increased in the intestinal mucosal tissue atrophy due to the above-mentioned disorder. In addition, the Journal of Experimental Medicine (J. Ex
p. Med. 182, December, 1871-188
1, 1995, reports the involvement of RMCP-II in the enhancement of intestinal mucosal permeability in anaphylaxis with rapid enhancement of intestinal mucosal permeability to macromolecules of the rat jejunum.

[0017] In these documents, since there is no information or discussion other than the above regarding the relationship between chymase and the gastrointestinal mucosa, suggestions relating the chymase inhibitory effect to the gastrointestinal mucosal protective effect are made. I don't think it is. This is because these documents only report the involvement of mucosal mast cells and chymase in gastrointestinal mucosal injury.

Therefore, it was not known at all before the present invention was completed that the compound having a chymase inhibitory effect has a protective effect on the gastrointestinal mucosa, and it can be expected at all. As such, the present invention is sufficiently novel and inventive.

As described above, the compound having a chymase inhibitory action used in the present invention is characterized by having only a chymase inhibitory action, and is not particularly limited.

Examples of the compound having a chymase inhibitory action include a compound represented by the following general formula (1).

[0021]

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Wherein R is a hydrogen atom, alkyl, --CH
_{O, -COOH, -CONH 2, -COR} 1, -COO
^{R 1, -CONHOR 1, -CONHR 1} , CONR 1
R ¹ ', -CONHSO ₂ R ¹ , -COSR ¹ , -CO
COR ² , -COCOOR ² , -CONHCOOR ² ,
^{-COCONR 3 R 4, -CSXR 1,} -SO 2 W
R ^{1 represents} —SO ₂ NR ¹ R ¹ ′ or —SO ₂ E. R ¹ and R ¹ ′ are the same or different and represent alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom, alkyl or arylalkyl;
R ^{3 and} R ⁴ in R ³ R ⁴ may together represent a heterocycle. X represents a single bond, an oxygen atom, a sulfur atom, or -NH-. W is a single bond, -NH
-, -NHCO-, -NHCOO-, or -NHCO
Represents NH-. E represents a hydroxyl group or amino.

R ⁵ , R ⁶ and R ⁷ are the same or different,
Represents a hydrogen atom or an alkyl, or R ⁵ ,
One of R ⁶ and R ⁷ represents aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, and the other two represent a hydrogen atom. M represents a carbon atom or a nitrogen atom. When M represents a nitrogen atom, R ⁶ represents
Does not exist. Y represents cycloalkyl, aryl, or heteroaryl. Z is -CF ₂ R ⁸ , -C
_{^{F 2 CONR 9 R 10, -CF}} 2 COOR 9, -COOR
⁹ , -CONR ⁹ R ¹⁰ , a group represented by the following formula (i), a group represented by the following formula (ii), or a group represented by the following formula (iii).

R ⁸ is a hydrogen atom, halogen, alkyl,
Represents perfluoroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl. R ⁹ and R ¹⁰ are the same or different, and each represents a hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl. the stands, R ⁹ and R ¹⁰ in -NR ⁹ R ^10, may represent a heterocycle together.

[0025]

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In the formula, a, b, c, and d all represent a carbon atom, or one of them represents a nitrogen atom, and the remaining three represent carbon atoms. R ¹¹ , R ¹² , R ¹³ , R
¹⁴ is the same or different and is a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano,
^{Nitro, -NR 17 R 17 ', -NHSO} 2 R 17, -O
R ¹⁷ , —COOR ¹⁷ , —CONHSO ₂ R ¹⁷ , or —
CONR ¹⁷ R ¹⁷ ′. However, when any one of a, b, c and d represents a nitrogen atom, R ¹¹ , R ¹² , R ¹³ and R ¹⁴ bonded to a, b, c and d representing the nitrogen atom do not exist. .

R ¹⁵ and R ¹⁶ are the same or different and each represents a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano, nitro, -NR ¹⁷ R ¹⁷ ',- NH
_{^{SO 2 R 17, -OR 17,}} -COOR 17, -CONHSO
₂ R ^17, or represents a -CONR ¹⁷ R ¹⁷ '. R ¹⁷ ,
R ¹⁷ ′ are the same or different and represent a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or trifluoromethyl;
¹⁷ The 'R ¹⁷ and R ¹⁷ in the' R ^17, may represent a heterocycle together. A represents an oxygen atom, a sulfur atom, or, -NR ¹⁸ - represents a. R ¹⁸ represents a hydrogen atom, alkyl, cycloalkyl, or cycloalkylalkyl. n represents 0 or 1. The above alkyl,
The cycloalkyl, the cycloalkylalkyl, the aryl, the arylalkyl, the arylalkenyl, the heteroaryl, the heteroarylalkyl, the heteroarylalkenyl, the heterocycle, and the heterocyclealkyl are one or more. It may be substituted by a substituent.

R, R ¹ , R ¹ ', R ² , R ³ , R ⁴ , R
^{5, R 6, R 7,} R 8, R 9, R 10, R 11, R 12,
The alkyl in R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁷ ′ and R ¹⁸ is not particularly limited, but has 1 to 6 carbon atoms.
Is preferably a linear or branched one. In particular,
For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ter
Examples thereof include t-butyl, n-pentyl, isopentyl, and n-hexyl.

R ¹ , R ¹ ', R ⁹ , R ¹⁰ , R ¹⁷ ,
The cycloalkyl for R ¹⁷ ′, R ¹⁸ and Y is not particularly limited, but is preferably a cycloalkyl having 3 to 7 carbon atoms. Specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl and the like can be mentioned.

R ¹ , R ¹ ′, R ⁹ , R ¹⁰ , R ¹⁷ , R ¹⁷ ′
And it is not particularly restricted but includes cycloalkylalkyl at R ^18, and the like which the cycloalkyl portion is described above, the alkyl portion preferably has 1 to 3 carbon atoms. Specifically, for example, cyclopropylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like can be mentioned.

R ¹ , R ¹ ', R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R
The aryl for ¹⁷ , R ¹⁷ 'and Y is not particularly limited, and is, for example, an ortho-fused bicyclic group such as phenyl, naphthyl or indenyl, having 8 to 10 ring atoms and having at least 1 One in which one ring is an aromatic ring can be exemplified.

R ¹ , R ¹ ', R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R
The arylalkyl in ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁷ ′ is not particularly limited, but the aryl portion is as described above, and the alkyl portion is a straight or branched chain having 1 to 3 carbon atoms. Is preferred. Specifically, for example, benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (1-
Naphthyl) propyl, 3- (2-naphthyl) propyl and the like.

The arylalkenyl in R ⁵ , R ⁶ , and R ⁷ is not particularly limited, but may be those having an aryl moiety as described above and an alkenyl moiety having a straight or branched chain having 2 to 6 carbon atoms. Is preferred. Specifically, for example,
3-phenyl-2-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6-phenyl-5-hexenyl, 3- (1-naphthyl) -2-propenyl, 4- (2-naphthyl ) -3-butenyl and the like.

The arylalkenyl in R ⁸ , R ⁹ , and R ¹⁰ is not particularly limited. The aryl alkenyl is as described above, and the alkenyl moiety is a straight or branched chain having 3 to 6 carbon atoms. Is preferred. Specifically, for example,
Examples thereof include 3-phenyl-2-propenyl and 4-phenyl-3-butenyl.

R ¹ , R ¹ ', R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R
The heteroaryl represented by R ¹⁷ , R ¹⁷ ′ and Y is not particularly limited, but is, for example, a group having 5 carbon atoms and 1 to 4 hetero atoms (oxygen, sulfur or nitrogen)
A 6-membered ring group; an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom; a benz derivative; a benz derivative fused with a propenylene, trimethylene or tetramethylene group; What can be done;
Benz derivative N-oxide and the like are preferable. Specifically, for example, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4 -Thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl,
Benzothiazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, chromenil, isoindolyl, indolyl,
Indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzoxazinyl and the like can be mentioned.

R ¹ , R ¹ ', R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R
The heteroarylalkyl for ¹⁷ and R ¹⁷ ′ is not particularly limited, but is preferably a heteroaryl moiety described above or the like, and an alkyl moiety having a straight or branched chain having 1 to 3 carbon atoms is preferred. Specifically, for example, 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl,
Examples thereof include (2-pyridyl) ethyl, 2- (3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, and 3- (2-pyrrolyl) propyl.

The heteroarylalkenyl in R ⁵ , R ⁶ and R ⁷ is not particularly limited, but the heteroaryl moiety is as described above and the alkenyl moiety has 2 carbon atoms.
6 to 6 are preferred. Specifically, for example, 3- (2-pyridyl) -2-propenyl,
4- (3-pyridyl) -3-butenyl, 5- (2-pyrrolyl) -4-pentenyl, 6- (2-thienyl) -5
Hexenyl and the like can be mentioned.

The heteroarylalkenyl in R ⁸ , R ⁹ and R ¹⁰ is not particularly limited, but the heteroaryl moiety is as described above and the alkenyl moiety has 3 carbon atoms.
6 to 6 are preferred. Specifically, for example, 3- (2-pyridyl) -2-propenyl,
4- (2-pyridyl) -3-butenyl and the like can be mentioned.

The heterocycle in R ¹ and R ¹ ′ is a 4- to 6-membered ring group having a carbon atom and 1 to 4 hetero atoms (oxygen, sulfur or nitrogen). The heterocycle is not particularly limited, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperidino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl, tetrahydropyranyl, dioxacyclohexyl and the like Can be mentioned.

-NR ³ R ⁴ , -NR ⁹ R ¹⁰ and -NR ¹⁷
The heterocycle represented by R ¹⁷ ′ is a 4- to 6-membered ring group having a carbon atom and at least one nitrogen atom and optionally having another hetero atom (an oxygen atom or a sulfur atom). It is. The ^{-NR 3 R 4, -NR 9 R} 10 and -N
The heterocycle represented by R ¹⁷ R ¹⁷ ′ is not particularly limited, and includes azetidinyl, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, and the like.

The heterocycle alkyl in R ¹ , R ¹ ′, R ⁹ and R ¹⁰ is not particularly limited, but the heterocycle portion is exemplified by the heterocycle in R ¹ and R ¹ ′ described above. Those having a straight-chain or branched chain having 1 to 3 carbon atoms are preferred. Specifically, for example, azetidinylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinoethyl, piperazinylethyl, morpholinylpropyl, morpholinomethyl, thiomorpholinylethyl, oxothiomorpholinylethyl, Dioxothiomorpholinylethyl, tetrahydropyranylpropyl, dioxacyclohexylmethyl, and the like can be mentioned.

The halogen in R ⁸ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ is not particularly restricted but includes, for example, fluorine, chlorine, bromine and iodine. The perfluoroalkyl for R ⁸ is not particularly limited, but is preferably a linear or branched one having 1 to 6 carbon atoms. Specifically, for example, trifluoromethyl, pentafluoroethyl, heptafluoropropyl and the like can be mentioned.

The aminoalkyl for R ⁸ is not particularly limited, but is preferably a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms. Specifically, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl and the like can be mentioned. The alkylaminoalkyl for R ⁸ is not particularly limited, but each of the alkyl portions has 1 carbon atom.
6 to 6 are preferred. Specifically, examples include methylaminomethyl, methylaminoethyl, ethylaminopropyl, ethylaminobutyl, methylaminopentyl, methylaminohexyl and the like.

The dialkylaminoalkyl for R ⁸ is not particularly limited, but is preferably a straight-chain or branched-chain alkyl moiety having 1 to 6 carbon atoms. Specifically, for example, dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl, diethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl and the like can be mentioned. The alkoxyalkyl in R ⁸ is not particularly limited, but is preferably a straight-chain or branched-chain alkoxy moiety having 1 to 6 carbon atoms, and the alkyl moiety of the alkoxy moiety is preferably a straight-chain having 1 to 6 carbon atoms. Alternatively, a branched one is preferred. Specific examples include methoxymethyl, methoxyethyl, ethoxypropyl, ethoxybutyl, methoxypentyl, methoxyhexyl and the like.

The hydroxyalkyl for R ⁸ is not particularly limited, but is preferably a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms. Specifically, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like can be mentioned. R ⁹ and R
The alkenyl in ¹⁰ is not particularly limited, but is preferably a straight or branched one having 3 to 6 carbon atoms. Specifically, for example, 2-propenyl, 3-butenyl, 4
-Pentenyl, 5-hexenyl and the like.

The above alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle, and heterocycle Cycle alkyl is one of the substituents shown below.
It may be substituted by two or more substituents.

Examples of the substituent include halogen,
Hydroxyl group, nitro, cyano, trifluoromethyl, alkyl, alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, -COOR
_{^{a, -CH 2 COOR a, -OCH}} 2 COOR a, -C
_{^{ONR b R c, -CH 2 CONR}} b R c, -OCH 2 C
^{ONR b R c, -COO (CH} 2) 2 NR e R f, -S
_{^{O 2 T 1, -CONR d SO}} 2 T 1, -NR e R f, -
NR ^g CHO, -NR ^g COT ² , -NR ^g COO
T ² , -NR ^h CQNR ⁱ R ^j , -NR ^k SO ₂ T ³ ,
-SO ₂ NR ^l R ^m, can be mentioned -SO ₂ NR ⁿ COT ^4, and the like.

The halogen is not particularly limited, and examples thereof include those exemplified in the description of the general formula (1). The alkyl is not particularly limited, and examples thereof include those exemplified in the description of the general formula (1). The arylalkyl is not particularly limited, and may be, for example, the above-mentioned general formula (1)
And the like exemplified in the description.
The alkoxy is not particularly limited, but has 1 carbon atom.
6 to 6 are preferred. Specific examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

The alkylthio is not particularly limited, but is preferably a straight or branched one having 1 to 6 carbon atoms. Specifically, for example, methylthio, ethylthio,
Examples thereof include propylthio, butylthio, pentylthio, and hexylthio. The acyloxy is not particularly limited, but is preferably a straight-chain or branched-chain acyloxy having 1 to 6 carbon atoms. Specific examples include formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, hexanoyloxy and the like.

R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R
^g , R ^h , R ⁱ , R ^j , R ^k , R ^l , R ^m and R ⁿ are
Represents a hydrogen atom, alkyl or arylalkyl.
The alkyl is not particularly limited, and examples thereof include those exemplified in the description of the general formula (1). The arylalkyl is not particularly limited, and examples thereof include those exemplified in the description of the general formula (1).

[0051] In ^{addition, -NR b R c, -NR e} R f, -N
R ⁱ R ^j and —NR ^l R ^m together with the adjacent nitrogen atom may represent a heterocycle. The not particularly restricted but includes heterocycle, for example, can be cited such as those exemplified as -NR ³ R ^4, heterocycle represented by -NR ⁹ R ¹⁰ and -NR ¹⁷ R ¹⁷ 'described above.

Further, —NR ^e R ^f may represent a heteroaryl having ＯO. The heteroaryl is not particularly limited and includes, for example, 2-pyrrolidinone-1-yl, succinimide, oxazolidin-2-one-3-
Yl, 2-benzoxazolinone-3-yl, phthalimide, cis-hexahydrophthalimide and the like.

T ¹ , T ² , T ³ and T ⁴ are R
Represents the same group as ¹ . T ¹ , T ² , T ³ and T ⁴ may be further substituted by the above substituents. Q is = O
Or represents = S.

For example, when R in the above formula (1) is alkyl, when R is —COR ¹ (R ¹ is alkyl), a compound in which the alkyl is substituted by —COOR ^a is mentioned. Can be.

Further, in Z of the general formula (1),-
CF ₂ CONR ⁹ R ¹⁰ is —CF ₂ CON (R ⁹ ′) —
It may be a group represented by D ¹ -CONR ¹⁹ R ²⁰ . In this case, R ⁹ ′ represents a hydrogen atom, alkyl or arylalkyl. R ¹⁹ and R ²⁰ are the same or different,
Hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, or represents a heteroaryl alkenyl, and R ¹⁹ in -NR ¹⁹ R ²⁰ R
²⁰ may together represent a heterocycle.

D ¹ represents a group represented by the following formula (iv), a group represented by the following formula (v), or a group represented by the following formula (vi).

[0057]

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In the formula, R ²¹ and R ²² are the same or different,
Represents a hydrogen atom, alkyl, arylalkyl, or heteroarylalkyl. R ²¹ and R ²² may together represent a methylene chain having 2 to 6 carbon atoms.
m represents 1, 2, 3, 4, 5, or 6. G represents a single bond, an oxygen atom, a sulfur atom, or —NR ²³ —.
R ²³ represents a hydrogen atom, alkyl or arylalkyl. p and r are the same or different and represent 0, 1, 2, or 3. s and t represent integers whose sum is 1 to 6.

The alkyl, the arylalkyl, the alkenyl, the cycloalkyl, the cycloalkylalkyl, the heterocyclealkyl, the aryl, the arylalkyl, the arylalkenyl,
The heteroaryl, the heteroarylalkyl, the heteroarylalkenyl, and the heterocycle are not particularly limited, and include, for example, those exemplified in the description of the general formula (1). These may be further substituted by the above substituents.

Further, in Z of the general formula (1),-
CF ₂ CONR ⁹ R ¹⁰ is —CF ₂ CON (R ⁹ ″)
A group represented by — (CH ₂ ) _u —COOR ²⁴ or —C
It may be a group represented by F ₂ CON (R ⁹ ″) -D ² . In this case, R ⁹ ″ represents a hydrogen atom, alkyl or arylalkyl. R ²⁴ represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. u represents 1, 2, or 3. D ²
Represents a group represented by the following formula (vii).

[0061]

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In the formula, R ²⁵ represents a hydrogen atom, alkyl, alkoxy, or halogen. The alkyl, the cycloalkyl, the cycloalkylalkyl, the aryl, the arylalkyl, the heteroaryl, the heteroarylalkyl, the heterocycle, the heterocyclealkyl, the alkoxy, and the halogen are not particularly limited, and include, for example, , The above general formula (1)
And the like exemplified in the description.
These may be further substituted by the above substituents.

The compound represented by the above general formula (1) is
Due to the asymmetric carbon to which the (CH ₂ ) _n -Y group is bonded, it can exist as an optically active substance and a racemic form.
The racemate can be separated into each optically active substance by a known method. When the compound represented by the general formula (1) further has an additional asymmetric carbon,
It can exist as a mixture of diastereomers or as a single diastereomer. These are also
Each of them can be separated by a known method.

The compound represented by the above general formula (1) can exhibit polymorphism and can exist as more than one tautomer. Further, the compound represented by the general formula (1) can exist as a solvate such as a ketone solvate and a hydrate. Therefore, the compound represented by the general formula (1) includes any of the above-mentioned stereoisomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof. Is what you do.

The compound represented by the general formula (1) includes, for example, International Publication No. WO96 / 39373.
No.), Japanese Patent Application Laid-Open No. 10-7661, PCT / JP97
No./03839 International Application, Japanese Patent Application No. 9-35357.
Compounds described in Patent No. 2 can be exemplified. The production methods and chymase inhibitory effects of these compounds are described in the above-mentioned publications and the above-mentioned specification.

The compound having a chymase inhibitory action according to the present invention may also include a compound represented by the following general formula (2).

[0067]

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In the formula, R, R ⁵ , R ⁶ , R ⁷ , M, Y and n represent the same substituent as the compound represented by the above general formula (1).

The compound represented by the above general formula (2) is a compound described in the international application specification of PCT / JP97 / 03839, and the production method of these compounds and the chymase inhibitory activity are also described in the specification. It is described in.

The compound having a chymase inhibitory action according to the present invention includes all the above-mentioned compounds and other compounds having a chymase inhibitory action. Examples of such a compound include the following.

[A] The polypeptides disclosed in JP-T-7-5070769. For example, polypeptides represented by the following general formula (3) can be exemplified.

[0072]

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In the formula, R ^A1 represents, for example, aryl or the like. R ^A2 represents a carbonyl or sulfonyl. R
^A3 represents, for example, alkyl or the like. R ^A4 represents, for example, a heterocycle or the like. R ^A5 represents, for example, proline or the like. R
^A6 represents, for example, -BF _2, and the like. R ^A7 is, for example,-
Represents NH- or the like. A1 represents 1 or 2.

[B] Triazine derivatives disclosed in JP-A-8-208654. For example, the following general formula (4-
1) and a triazine derivative represented by the following general formula (4-2).

[0075]

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In the formula (4-1), when R ^B3 represents C-CH ₃ and R ^B4 represents N, R ^B1 represents lower alkyl or benzyl substituted by one halogen atom. . R
^B2 represents lower alkyl, benzyl substituted with one halogen atom, or lower alkoxycarbonylmethyl. Wherein (4-2), R ^B3 represents N, when R ^B4 represents CH, R ^B3 represents CH, when R ^B4 represents CH, and, R ^B3 represents a C-CH _3, When ^RB4 represents N,
R ^B1 represents lower alkyl, lower alkoxycarbonylmethyl, phenyl lower alkyl, or benzyl substituted on the phenyl ring with any one of lower alkyl, halogen, cyano, phenyl, and halo lower alkyl. R ^B2 is hydrogen atom, lower alkyl, lower alkoxycarbonylmethyl, phenyl lower alkyl, or benzyl substituted on the phenyl ring with any one of lower alkyl, halogen, cyano, phenyl, and halo lower alkyl. Represents

[C] Hydantoin derivatives disclosed in JP-A-9-31061. For example, the following general formula (5)
And the like.

[0078]

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In the formula, R ^C1 is halogen, lower alkyl having 1 to 4 carbons, lower alkoxy having 1 to 4 carbons, or
Represents a carboxyl which may be esterified with lower alkyl or allyl having 1 to 4 carbon atoms. C1 is 0,
1, 2, 3, 4 or 5 is represented. R ^C2 represents a hydrogen atom, a lower alkyl having 1 to 4 carbons, an aralkyl having 7 to 10 carbons, or a lower alkyloxycarbonyl having 2 to 5 carbons. R ^C3 represents a group represented by the following general formula (5-1), a group represented by the following general formula (5-2), or a group represented by the following general formula (5-3).

[0080]

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In the formula, R ^C4 represents a hydrogen atom, halogen, hydroxyl, or lower alkoxy having 1 to 4 carbon atoms. C2 represents 0, 1 or 2. R ^C5 represents a hydrogen atom or a lower alkyl having 1 to 4 carbon atoms. C3 represents 1 or 2. R ^C6 represents a hydrogen atom or a lower alkyl having 1 to 4 carbon atoms. C4 represents 1 or 2.

[D] An imidazolidine derivative disclosed in WO 96/04248. For example, an imidazolidine derivative represented by the following general formula (6) can be given.

[0083]

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In the formula, R ^D1 and R ^D2 are the same or different and each is halogen, alkyl having 1 to 4 carbons, 1 to 4 carbons.
Which is esterified with an alkyl having 1 to 4 carbon atoms, alkylenedioxy, phenoxy, nitro, cyano, phenyl, alkanoylamino having 2 to 5 carbon atoms, alkyl having 1 to 4 carbon atoms, or alkenyl having 1 to 4 carbon atoms. Carboxyl; alkyl having 1 to 4 carbons or 1 to 4 carbons
A carboxyalkyl which may be esterified with alkenyl; a carboxyalkyloxy which may be esterified with alkyl having 1 to 4 carbons or alkenyl having 1 to 4 carbons; N-alkylpiperazinylcarbonyl;
N-alkylpiperazinylcarbonylalkylalkyl; N-alkylpiperazinylcarbonylalkyloxy;
1-3 selected from the group consisting of morpholinocarbonyl
Represents an aromatic hydrocarbon which may be substituted by a plurality of groups. R
^D3 represents sulfonyl or carbonyl. R ^D4 is
Represents an oxygen atom or a sulfur atom.

[E] A quinazoline derivative disclosed in WO 97/11941. For example, a quinazoline derivative represented by the following general formula (7) can be given.

[0086]

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Wherein ring E is a benzene ring, a pyridine ring,
Represents a pyrrole ring or a pyrazole ring. E1 represents 0, 1 or 2. R ^E1 and R ^E2 are the same or different and are each a hydrogen atom, halogen, lower alkyl having 1 to 4 carbon atoms which may be substituted by halogen, nitro, cyano, pyrazolyl, tetrazolyl, lower alkyl having 1 to 4 carbon atoms; Or carboxyl which may be esterified with allyl,
Or, halogen, morpholino, phenylpiperazinyl,
And a lower alkoxy having 1 to 4 carbon atoms which may be substituted with at least one group selected from the group consisting of carboxyl which may be esterified with lower alkyl or allyl having 1 to 4 carbon atoms. . When ring E is a benzene ring, R ^E1 and R ^E2 represent a group that forms a naphthalene ring or a quinoline ring together with the benzene ring. R ^E3 is hydroxy, nitro, halogen, lower alkyl having 1 to 4 carbon atoms which may be substituted with halogen, lower alkoxy having 1 to 4 carbon atoms which may be substituted with halogen, or 7 to 7 carbon atoms. 12 represents an aralkyloxy or a group forming a naphthalene ring or a quinoline ring together with a benzene ring substituted by RE ³ . R ^E4 is a hydrogen atom; lower alkyl having 1 to 4 carbon atoms which may be substituted by halogen, and 2 carbon atoms.
~ 5 alkenyl, optionally substituted aralkyl,
Optionally substituted aromatic heterocyclic alkyl, carbon number 1
-4 lower alkyl or carboxymethyl optionally esterified with allyl, carbonylmethyl amidated with primary amine, secondary amine or cyclic amine, or aralkyl optionally substituted Represents oxymethyl.

[F] Peptide compounds disclosed in JP-A-9-124691. For example, a peptide compound represented by the following general formula (8) can be exemplified.

[0089]

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In the formula, R ^F1 represents alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, arylalkyl, heteroaryl, heterocycle, or heterocyclealkyl optionally substituted with —COR ^F8 . R ^F2 and R ^F3 are the same or different and are each a hydrogen atom, an alkyl ^optionally substituted with —COR ^F8 ,
Cycloalkyl, cycloalkylalkyl, aryl,
Or, represents an arylalkyl. Further, R ^F2 and R ^F3 may together represent a methylene chain having 4 to 6 carbon atoms, which may be substituted with —COR ^F8 . R ^F4 represents a hydrogen atom or alkyl. R ^F5 represents a hydrogen atom or alkyl. However, X ^F is represented by the following general formula (8)
In the case of the group represented by -2), X ^F and R ^F5 may together represent a methylene chain having 2 to 4 carbon atoms. Y
^F represents cycloalkyl, aryl, or heteroaryl. F1 represents 0, 1, 2, or 3. ^AF is
Represents carbonyl or sulfonyl. X ^F is a group represented by the following general formula (8-1), or the following general formula (8
Represents a group represented by 2).

[0091]

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In the formula, Z ^F1 and Z ^F2 are the same or different,
Represents a hydrogen atom, a hydroxyl group, -COR ^F8 , alkyl ^optionally substituted with -COR ^F8 , or -SO ₂ R ^F8 . R
^F6 and ^RF7 are the same or different and each represents a hydrogen atom, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,-
COR ^F8 , alkyl, alkenyl, alkynyl, heterocycle, or -C which may be substituted with -COR ^F8 ;
Represents a heterocycle alkyl. Further, R ^F6 and R ^F7 may together represent a methylene chain having 4 to 6 carbon atoms, which may be substituted with —COR ^F8 . However,
R ^F6 and R ^F7 do not simultaneously represent a hydrogen atom, and R ^F6 and R ^F
If one or both of ^F7 is heterocycle optionally substituted with -COR ^F8, heteroatom of the heterocycle is not bonded to the carbon atom bonded to the R ^F6, R ^F7. The ring B ^F represents an aromatic ring. R ^F8 represents a hydroxyl group,
Represents alkoxy, amino, alkylamino, dialkylamino, aryloxy or arylalkoxy.

The fact that these compounds have a chymase inhibitory action is specified in the respective publications in which these compounds are disclosed.

In the present specification, the pharmacologically acceptable salt is not particularly limited, and those commonly used in this field can be used, for example, hydrochloric acid, sulfuric acid, nitric acid, and the like.
Salts of mineral acids such as phosphoric acid, hydrofluoric acid and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid And salts of organic acids such as toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid; salts of alkali metals or alkaline earth metals such as sodium, potassium and calcium.

The compound having a chymase inhibitory action according to the present invention has an extremely good action of preventing gastrointestinal mucosal atrophy and a function of suppressing gastrointestinal mucosal hyperpermeability, as will be described later in detail in Test Examples. Therefore, the compound having a chymase inhibitory action according to the present invention is extremely useful as an active ingredient of a gastrointestinal mucosa protective agent, and furthermore, a TP based on the action described above.
It is extremely useful as an active ingredient of a preventive / therapeutic agent for N-complications, a preventive / therapeutic agent for an allergic disease, a preventive / therapeutic agent for an inflammatory gastrointestinal tract disease, and a preventive / therapeutic agent for a postoperative disorder of the gastrointestinal tract accompanied by ischemia / reperfusion. .

The gastrointestinal mucosa protective agent of the present invention comprises a compound having a chymase inhibitory activity as an active ingredient, and is prepared into a suitable formulation together with a suitable diluent and other additives usually used in formulating the compound. Thereafter, it can be administered to humans or animals by an appropriate administration method according to the formulation.

The above administration forms include, for example, powders,
Injection and the like can be mentioned, and as the administration method,
For example, intravenous administration, oral administration, transdermal administration and the like can be mentioned. The gastrointestinal mucosa protective agent of the present invention in the form of a powder can be administered intravenously by dissolving it in a physiological saline solution, a high calorie nutritional infusion or the like at the time of use. In addition, the gastrointestinal mucosa protective agent of the present invention, which is used as an injection, may be directly administered intravenously by itself, or may be intravenously administered by co-injection into a high calorie nutritional infusion.

The gastrointestinal mucosa protective agent of the present invention is prepared by mixing and dissolving the active ingredient in advance with the usual infusion components such as amino acids, carbohydrates, electrolytes and the like into one agent (injection). It can also be administered.

The above-mentioned various dosage forms can be prepared by various ordinary methods commonly used in this field, and various diluents and additives used at this time are also commonly used. be able to. The above-mentioned powder for dissolution at the time of use is prepared by dissolving an effective amount of the gastrointestinal mucosa protective agent of the present invention in a diluent such as distilled water, a physiological saline solution, or an aqueous glucose solution.
C), excipients such as sodium alginate, preservatives such as benzyl alcohol, benzalkonium chloride, phenol, soothing agents such as glucose, calcium gluconate, procaine hydrochloride, hydrochloric acid, acetic acid, citric acid, sodium hydroxide, etc. And then freeze-dried by a conventional method.

The injection is prepared by dissolving an effective amount of the gastrointestinal mucosa protective agent of the present invention in, for example, a diluent such as distilled water, physiological saline, Ringer's solution, and the like. Dissolution aids such as mannitol,
Buffers such as sodium citrate and glycerin; tonicity agents such as glucose and invert sugar; stabilizers such as human serum albumin and polyethylene glycol; preservatives such as benzyl alcohol, benzalkonium chloride and phenol; glucose and gluconic acid Soothing agents such as calcium and procaine hydrochloride, pH of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, etc.
It can be prepared by adding a regulator and the like and sterilizing the same by a usual method such as heat sterilization and sterile filtration.

The dosage of the gastrointestinal mucosa protective agent of the present invention varies depending on the administration route, the patient's condition, body weight, age and the like.
It can be set appropriately according to the purpose of administration. Normal,
When administered to an adult, it is preferable to administer 0.01 to 1000 mg / kg body weight / day, preferably 0.05 to 500 mg / kg body weight / day, once or several times a day.

[0102]

EXAMPLES The present invention will be described in more detail below with reference to Test Examples and Production Examples of the present invention, but the present invention is not limited to only these Examples.

In the Reference Examples and Examples, ¹ H-NMR was used.
Was measured at 500 MHz. The chemical shift of ¹ H-NMR was expressed by relative delta (δ) value in parts per million (ppm) using TMS as an internal standard.
Coupling constants indicate trivial multiplicity in Hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) ), Brs
(Broad singlet), ABq (AB quartet)
And so on. Thin layer chromatography (TLC) and column chromatography were performed using silica gel manufactured by Merck. Concentration was performed using a rotary evaporator manufactured by Tokyo Rika Kikai.

Reference Example 1 [5-benzyloxycarbonyl ]
Ruamino-2- (4-fluorophenyl) -6-oxo
Synthesis step of ( -1,6-dihydro-1-pyrimidinyl) acetic acid (1): 4-fluorobenzonitrile (50.9
g, 0.420 mol) in ethanol (500 ml) under ice-cooling and saturated with hydrogen chloride, followed by stirring at room temperature for 21 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with ether and dried under vacuum, and 78.8 g (yield: 92%) of ethyl 4-fluorobenzimidate hydrochloride as a target compound was obtained as white crystals. )Obtained.

Step (2): The desired compound (7
8.8 g (0.387 mol) of ethanol (350 m
l) Aminoacetaldehyde diethyl acetal (62 ml, 0.43 mol) was added dropwise to the solution under ice-cooling.
Stirred at 5 ° C. for 16 hours. Ethanol was distilled off under reduced pressure, and the obtained concentrate was concentrated in 1N aqueous sodium hydroxide solution (7%).
50 ml) and extracted with chloroform. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the target compound N- (2,2-diethoxyethyl) -4 was obtained.
-A colorless oil containing fluorobenzamidine was obtained.

Step (3): The target compound of step (2) (crude product obtained in the above reaction) was treated with ethanol (150 m
l) To the solution was added dropwise diethylethoxymethylene malonate (86 ml, 0.43 mol) at room temperature. After dripping, 1
The mixture was heated to 00 ° C and stirred for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (1: 1 ethyl acetate-hexane).
Ethyl 1- (2,2-diethoxyethyl) -2- (4-fluorophenyl) pyrimidine-6
135 g of (1H) -one-5-carboxylate was obtained as a pale yellow oily substance [yield from the target compound of step (1) 92%].

Step (4): The desired compound (1) of step (3)
Lithium iodide (120 g, 0.895 mol) was added to a pyridine (480 ml) solution of 35 g (0.358 mol), and the mixture was heated to 100 ° C. and stirred for 16 hours. After distilling off the organic solvent under reduced pressure, toluene (100 ml) was added,
The remaining traces of pyridine were distilled off under reduced pressure. The residue was added to a saturated aqueous solution of sodium hydrogen carbonate (500 ml), and organic substances other than carboxylic acid were extracted with ethyl acetate. After removing insolubles by filtration, the aqueous layer was separated. The aqueous layer and the insolubles were combined, adjusted to pH 3 with 2N hydrochloric acid (about 1 L), and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1- (2,2-diethoxyethyl) -2- (4-fluorophenyl) as a target compound. Pyrimidine-
A brown oil containing 6 (1H) -one-5-carboxylic acid was obtained.

Step (5): The target compound of Step (4) (crude product obtained in the above reaction) and triethylamine (8
7.5 ml (0.63 mol) of 1,4-dioxane (9
(00 ml) solution, diphenylphosphoryl azide (84 ml, 0.37 mol) was added dropwise at room temperature. After dripping, 11
The mixture was heated to 0 ° C and stirred for 2 hours. Cooled to room temperature and added benzyl alcohol (44 ml, 0.43 mol). The reaction solution was heated again to 110 ° C., stirred for 4 hours, cooled to room temperature, and 1,4-dioxane was distilled off under reduced pressure.
The residue was added to a saturated aqueous ammonium chloride solution (1 L), and extracted with ethyl acetate. The extract was washed successively with a 1N aqueous sodium hydroxide solution and a saturated saline solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (1: 2 ethyl acetate-hexane).
And the desired compound [5-benzyloxycarbonylamino-2- (4-fluorophenyl)-
1,6-Dihydro-6-oxo-1-pyrimidinyl] acetaldehyde A mixture of diethyl acetal and benzyl alcohol was obtained as a pale yellow oily substance (126 g, yield 69% as the target compound).

Step (6): THF (650 m) of the target compound of Step (5) (126 g of a mixture with benzyl alcohol, 0.247 mol as the target compound of Step (5))
l) 1N Hydrochloric acid (500 ml) was added to the solution, and the mixture was stirred at 70 ° C for 14 hours. The reaction solution was cooled to room temperature, and THF was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained concentrated solution to adjust the pH to 7, followed by extraction with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the target compound [5-benzyloxycarbonylamino-2- (4-fluorophenyl).
-1,6-dihydro-6-oxo-1-pyrimidinyl]
A white solid containing acetaldehyde was obtained.

Step (7): The desired compound of Step (6) (crude product obtained in the above reaction), 2-methyl-2-propanol (900 ml) and 2-methyl-2-butene (1
06 ml, 1.00 mol) in water (400 ml) of sodium dihydrogen phosphate dihydrate (180 g, 1.15 mol) and sodium chlorite (80% content, 136 g, 1.20 mol) The solution was added and stirred at room temperature for 2 hours. The insolubles were removed by filtration, the organic solvent was distilled off under reduced pressure, and the obtained concentrated solution was added to 2N hydrochloric acid (650 ml), followed by extraction with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized by adding ethyl acetate-hexane (1: 1) to give the title compound [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -6.
[Oxo-1,6-dihydro-1-pyrimidinyl] acetic acid was obtained as a white solid (10.6 g). The insoluble matter obtained above was added to 1N hydrochloric acid (500 ml) and extracted with ethyl acetate.
The extract was washed with saturated saline, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the title compound [5-benzyloxycarbonylamino-2- (4-
(Fluorophenyl) -6-oxo-1,6-dihydro-
17.7 g of 1-pyrimidinyl] acetic acid as a white solid
(Total yield: 80%).

The ¹ H-NMR and IR measurement values of the obtained compound are shown below. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ1
3.3 (brs, 1H), 8.99 (s, 1H), 8.
46 (s, 1H), 7.56 (dd, J = 5.4, 8.
9 Hz, 2H), 7.44 (d, J = 7.2 Hz, 2
H), 7.30-742 (m, 5H), 5.19 (s,
2H), 4.53 (s, 2H) IR (KBr) 3650-2300, 1720, 166
0,1600cm ^-1

Reference Example 2 2-amino-1-hydroxy-
1- [5- (methoxycarbonyl) benzoxazole
-2-yl] -3-phenylpropane synthesis step (1): 4-hydroxy-3-nitrobenzoic acid (1
To a solution of 5.8 g (86.3 mmol) in 1,2-dichloroethane (150 ml) were added methanol (14 ml) and concentrated sulfuric acid (0.5 ml), and the mixture was heated to 80 ° C. and stirred. Methanol (9 ml) was added on the way, and the mixture was stirred for 21 hours. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution
0 ml) and extracted with chloroform. The extract was washed with a saturated saline solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain the target compound, 4-hydroxy-3-
11.5 g (68% yield) of methyl nitrobenzoate was obtained as a yellow solid.

Step (2): The desired compound (1) of Step (1)
1.4 g (57.8 mmol) of ethyl acetate (300 m
1) 10% palladium on carbon (1.
80 g), and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. After removing the catalyst by filtration and washing with ethyl acetate, the filtrate was concentrated under reduced pressure. The obtained solid was washed with ether-hexane (1: 1) and dried under vacuum, and 9.34 g of the target compound, methyl 3-amino-4-hydroxybenzoate, was fixed in pale brown color (yield: 97). %)Obtained.

Step (3): L-phenylalaninol (20.2 g, 0.134 mol), sodium carbonate (2
To a mixture of 1.2 g (0.200 mol) and 1,4-dioxane (150 ml) was added a solution of benzyloxycarbonyl chloride (19.1 ml, 0.134 mol) in 1,4-dioxane (50 ml), and the mixture was stirred at room temperature. For 3 hours. Water (300 ml) was added to the reaction solution, and the resulting mixture was added to ice-cooled 0.5N hydrochloric acid (500 ml). The precipitated crystals were collected by filtration, washed with hexane, and dried to obtain 28.8 g (yield: 76%) of the target compound, N-benzyloxycarbonyl-L-phenylalaninol, as white crystals.

Step (4): The desired compound (1) of Step (3)
To a solution of 0.7 g, 37.5 mmol) and triethylamine (21.3 ml, 153 mmol) in dichloromethane (100 ml) was added sulfur trioxide pyridine complex (2
A solution of 3.9 g (150 mmol) in dimethylsulfoxide (DMSO) (100 ml) was added at -10 <0> C.
After the obtained solution was stirred at 10 to 20 ° C. for 45 minutes, it was added to saturated saline (400 ml) and extracted with ether.
The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the target compound, N-benzyloxycarbonyl-L-phenylalaninal, in white. 10.6 g (quantitative) were obtained as a solid.

Step (5): Triethylamine (1.5 mM) was added to a dichloromethane (50 ml) solution of the target compound (5.00 g, 17.6 mmol) and acetone cyanohydrin (4.8 ml, 53 mmol) in step (4).
1, 11 mmol) and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained concentrate was washed with water (100 m
l) and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (2: 1 hexane-ethyl acetate), and 5.15 g (94% yield) of the target compound, N-benzyloxycarbonyl-L-phenylalaninal cyanohydrin, as a pale yellow solid was obtained. Obtained.

Step (6): A mixture of chloroform (10 ml) and ethanol (9.5 ml, 0.16 mol) was mixed with 1 ml of acetyl chloride (10 ml, 0.14 mol) under ice-cooling.
It was dropped in 0 minutes. After stirring at 0 ° C. for 30 minutes, the target compound of step (5) (1.50 g, 4.83 mmol)
Of chloroform (10 ml) was added. After stirring at 0 ° C. for 3 hours, the solvent was distilled off under reduced pressure to obtain a pale yellow solid. Ethanol (35 ml) was added to the obtained solid and the target compound of step (2) (1.94 g, 11.6 mmol).
Was added, and the mixture was heated to 90 ° C. and stirred for 18 hours. After the solvent was distilled off under reduced pressure, the obtained concentrate was added to a 0.5N aqueous sodium hydroxide solution (50 ml) and extracted with ethyl acetate. The extract was washed sequentially with 0.5N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (100: 1 chloroform-
(Methanol).
Benzyloxycarbonylamino-1-hydroxy-1
-[5- (methoxycarbonyl) benzoxazole-
1.80 g (yield 81%) of 2-yl] -3-phenylpropane was obtained as a light brown solid.

Step (7): The desired compound (1.65 g, 3.58 mmol) of step (6) in methanol (25
10% palladium on carbon (3 ml) under a nitrogen atmosphere.
78 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. After removing the catalyst by filtration and washing with methanol, the filtrate was concentrated under reduced pressure to give 2-amino-1 which was the title compound.
1.14 g (98% yield) of -hydroxy-1- [5- (methoxycarbonyl) benzoxazol-2-yl] -3-phenylpropane was obtained as a light brown solid.

The ¹ H-NMR and IR measurement values of the obtained compound are shown below. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ8.
27 (d, J = 1.3 Hz, 0.4H), 8.25
(D, J = 1.3 Hz, 0.6 H), 8.03 (dd,
J = 8.6, 1.3 Hz, 0.4H), 8.02 (d
d, J = 8.6, 1.3 Hz, 0.6H), 7.84
(D, J = 8.6 Hz, 0.4 H), 7.81 (d, J
= 8.6 Hz, 0.6 H), 7.28-7.23 (m,
4H), 7.18-7.13 (m, 1H), 4.77-
4.73 (m, 1H), 3.89 (s, 3H), 3.5
8 (m, 0.6H), 3.50 (m, 0.4H), 3.
06 (dd, J = 13.6, 4.8 Hz, 0.4H),
2.88 (dd, J = 13.6, 7.3 Hz, 0.6
H), 2.81 (dd, J = 13.6, 6.8 Hz,
0.6H), 2.65 (dd, J = 13.6, 8.2H)
z, 0.4H) IR (KBr) 3300, 1710, 1615 cm ^-1

Example 1 2- [5-amino-2- (4-
(Fluorophenyl) -6-oxo-1,6-dihydro-
1-pyrimidinyl] -N- [1-[[5- (methoxyca
Rubonyl) benzoxazol-2-yl] carboni
L] -2-phenylethyl] acetamide (compound 1)
Synthesis step (1): [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -6 obtained in Reference Example 1.
-Oxo-1,6-dihydro-1-pyrimidinyl] acetic acid (1.30 g, 3.27 mmol) and the 2-amino-1-hydroxy-1- [5- (methoxycarbonyl) benz obtained in Reference Example 2. Oxazol-2-yl] -3-
To a solution of phenylpropane (1.08 g, 3.31 mmol) in DMF (10 ml) was added HOBT (884 mg, 6.6 mg).
54 mmol) and the hydrochloride salt of WSCI (752 mg,
(3.92 mmol) and stirred at room temperature for 4.5 hours. The reaction solution was added to 0.5N hydrochloric acid (80 ml) and extracted with ethyl acetate. At this time, the precipitated solid is collected by filtration,
After drying under vacuum, the target compound, 2- [5-benzyloxycarbonylamino-2- (4-fluorophenyl) 6-oxo-1,6-dihydro-1-pyrimidinyl] -N- [1-[[ 5- (methoxycarbonyl) benzoxazol-2-yl] hydroxymethyl] -2-
Phenylethyl] acetamide as a white solid 1.26
g was obtained. The filtrate was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and concentrated under reduced pressure. The obtained solid is washed with ether, dried under vacuum, and further subjected to 2- [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -6-oxo-1,
6-dihydro-1-pyrimidinyl] -N- [1-[[5
408 mg of-(methoxycarbonyl) benzoxazol-2-yl] hydroxymethyl] -2-phenylethyl] acetamide as a light brown solid (1.66 g in total,
(Total yield 72%).

Step (2): The target compound of Step (1) (1.56 g, 2.21 mmol) in DMSO (20 m
l) and toluene (20 ml) were added to a mixed solution of WSCI hydrochloride (5.09 g, 26.6 mmol) and dichloroacetic acid (0.87 ml, 11 mmol).
Stirred for hours. The reaction solution was added to 1N hydrochloric acid (100 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. At this time, the precipitated solid was collected by filtration and dried under vacuum to obtain the target compound, 2- [5-benzyloxycarbonylamino-2-.
(4-Fluorophenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] -N- [1-[[5- (methoxycarbonyl) benzoxazol-2-yl] carbonyl] -2-phenylethyl] acetamide Was obtained as a white solid. The filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (5: 1 dichloromethane-ethyl acetate), and the target compound, 2- [5-benzyloxycarbonylamino-
2- (4-fluorophenyl) -6-oxo-1,6-
Dihydro-1-pyrimidinyl] -N- [1-[[5-
222 mg of (methoxycarbonyl) benzoxazol-2-yl] carbonyl] -2-phenylethyl] acetamide as a pale yellow solid (1.28 g in total, yield 8)
2%).

Step (3): The desired compound (4) of Step (2)
62 mg, 0.657 mmol) and anisole (0.
21 ml, 1.9 mmol) of dichloromethane (13 m
l) To the solution was added trifluoromethanesulfonic acid (0.35 ml, 4.0 mmol) under ice-cooling,
Stirred at room temperature for 1 hour. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution (13 ml) was added, and the mixture was stirred for 30 minutes. Then, the reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution (50 ml), and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3
0: 1 chloroform-methanol).
2- [5-amino-2- (4-fluorophenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] -N- [1-[[5- (methoxycarbonyl) benzoxazole, the title compound -2-yl] carbonyl] -2
[-Phenylethyl] acetamide (compound 1) was obtained as pale yellow crystals (368 mg, yield 98%).

The melting point, ¹ H-NMR,
IR and MS measurement values are shown below. mp: 208-213 ° C ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ8.
97 (d, J = 6.7 Hz, 1H), 8.51 (d, J
= 1.6 Hz, 1H), 8.24 (dd, J = 8.7,
1.6 Hz, 1 H), 8.05 (d, J = 8.7 Hz,
1H), 7.35 (dd, J = 8.8, 5.6 Hz, 2
H), 7.28-7.17 (m, 6H), 7.08.
(T, J = 8.8 Hz, 2H), 5.50 (m, 1
H), 5.12 (s, 2H), 4.48 (d, J = 1
6.8 Hz, 1 H), 4.41 (d, J = 16.8 H)
z, 1H), 3.93 (s, 3H), 3.31 (m, 1
H), 2.97 (dd, J = 14.1, 8.9 Hz, 1
H) IR (KBr) 3370, 1705, 1655, 160
0 cm ^-1 MS (SIMS, positive) m / z 570 (M
H ⁺ )

The inhibitory activity of the obtained compound 1 on human heart chymase was measured as the inhibitory activity on human heart chymase amidase activity, and the effectiveness was evaluated as follows. In the presence of the synthetic substrate succinyl-alanyl-alanyl-prolyl-phenylalanine-p-nitroanilide at a final concentration of 2.5 mM, a defined concentration series (<× 1, <× 10, <× 100 times equivalent) for 5 nM chymase The inhibitory activity was quantified by the change in the residual activity fraction of compound 1. The analysis of the inhibitory potency was performed using an Easson-Stedman plot (Pro
c. Roy. Soc. B. 121, 141, 19
36 years). The apparent inhibition constant (Kiapp) obtained in this analysis, the inhibition constant (Kappa) calculated from the final concentration of the reaction solution substrate and the Km value obtained separately.
The inhibitory activity was evaluated according to i). For the quantification of the initial rate of the enzymatic reaction, the amount of p-nitroaniline produced by hydrolysis of the substrate was detected spectrophotometrically by increasing the absorbance at 405 nm after subtracting the absorbance at 650 nm wavelength light. The chymase inhibitory activity of Compound 1 was calculated as the residual activity in the presence of the inhibitor relative to the enzyme activity in the absence of the inhibitor, and the measured value was taken below the initial rate guaranteed absorbance at the substrate concentration used for the enzyme. And analyzed.

The composition of the reaction solution was Tris-HCl.
(100 mM) -KCl (2M) buffer (pH
7.5) To 140 μl, compound 1 dissolved in 20 μl of 10% dimethylsulfoxide (DMSO), substrate dissolved in 20 μl of DMSO, and 20 μl of chymase were added to make a total volume of 200 μl. From the absorbance immediately after addition of the enzyme, the increase in absorbance was recorded as a progressive curve at exactly equal time intervals.

From the above data, if necessary, the residual activity of the inhibitor-added sample relative to the control without the inhibitor was quantified based on the difference between the absorbance at the end of the reaction and the absorbance immediately after the addition, and analysis was performed. Alternatively, the step width for a certain time (≧ 20
Min) to calculate the reaction rate of the control and the inhibitor-added sample.
The rate calculation was shifted every 0 to 30 minutes, and the inhibitory activity was analyzed in the same manner by quantifying the residual activity fraction from each reaction rate averaged over the entire reaction time.

As a result of the human heart chymase inhibitory activity test of Compound 1, the chymase inhibitory activity (Ki) was 0.023 μM.

Test Example 1 Pharmacological Test of Compound 1 (1) Measurement of Intestinal Wet Weight Rats fasted overnight were anesthetized with pentobarbital (AB
BOT; Nembutal injection 50 mg / kg BW: i.
p. ), And the entire jejunum / ileum was made ischemic by clipping the upstream part of the anterior mesenteric artery distributed in the small intestine. After maintaining this ischemic state for 60 minutes (the laparotomy was maintained during intestinal ischemia and additional anesthesia with pentobarbital was performed as necessary), reperfusion was performed by releasing the clipping of the anterior mesenteric artery. Was done. The restoration of blood flow to the intestinal tract tissue was visually confirmed. Thereafter, the intestinal tract was housed in the abdominal cavity, and the incision site was sutured and disinfected (isodine). Six hours after reperfusion, the mice were sacrificed with carbon dioxide, and after blood removal, the entire small intestine (from the pyloric portion of the lower stomach to the ileocecal portion of the lower ileum) was removed. The excised small intestine was washed with physiological saline, and the total wet weight was measured. A part of the ileum was fixed in formalin and subjected to histopathological examination. Free drinking and fasting during the reperfusion period,
Compound 1 was orally administered 30 minutes before intestinal ischemia treatment.
The test animals were assigned to each group by a random sampling method.

The results of measurement of the intestinal wet weight are shown in FIG. 1 (number of animals, 8 animals per group). The vertical axis represents the wet weight (g / kgB)
W). The left shows the untreated group, the middle shows the ischemic treatment group, and the right shows the group to which compound 1 was administered before the ischemic treatment. It is evident that the pre-administration of Compound 1 significantly improved the decrease in intestinal wet weight due to ischemia / reperfusion, and clearly shows the inhibitory effect of Compound 1 on gastrointestinal mucosal atrophy.

(2) Measurement of ileal mucosal area The ileum extracted in (1) above was used as a sample (fixed with 10% neutral buffered formalin), and a paraffin section of about 4 μm was prepared according to a conventional method. Using an image analyzer (LUZEX-F, manufactured by Nireco Co., Ltd.), E. FIG. Mucosal area (m
m ² / 10mm) was measured. The results are shown in FIG. The vertical axis represents the mucosa area of (mm ² / 10mm). The left shows the untreated group (7 animals), the middle shows the ischemic treatment group (6 animals), and the right shows the group to which compound 1 was administered before the ischemia treatment (7 animals). ) Respectively. It is apparent that the pre-administration of Compound 1 improved the reduction of the mucosal area due to ischemia / reperfusion, and clearly shows the preventive effect of Compound 1 on gastrointestinal mucosal atrophy.

(3) Measurement of mucosal damage The section obtained in (2) above was subjected to H. E. FIG. , PAS and toluidine blue staining, and the mucosal structure was histologically evaluated by light microscopic observation according to the following evaluation method. Criteria for mucosal damage score 0: No histological changes 1: Minor congestion in mucosa, dilation of central chyle, single cell necrosis and inflammatory cell infiltration 2: Minor mucosal mucosal changes and exfoliation 3: Medium mucosal mucosal Change and erosion 4: Widespread erosion and ulceration of mucous membranes The results are shown in Table 1.

[0132]

[Table 1]

[0133] Histopathological examination also reveals that pre-administration of Compound 1 improved ileal mucosal damage.

(4) Measurement of PSP Urinary Excretion A PSP (phenolsulfonphthalein) reagent was prepared for the intestinal mucosal permeability test, and 100 mg / 10 m
L / kg BW was orally administered 6 hours after reperfusion, and urinary excretion was measured for 24 hours by collecting urine for 24 hours under fasting and free drinking water management using a metabolic cage.
For the measurement of PSP urinary excretion, 24-hour urine was centrifuged (15000 rpm × 5 minutes), the supernatant was diluted appropriately with distilled water, and an equal volume of 0.5N sodium hydroxide was added. After color development by alkalization, colorimetric determination was performed by absorbance at 540 nm. Compound 1 is effective in treating intestinal ischemia
Oral administration (30 mg / kg BW) one minute before.

The results are shown in FIG. The vertical axis is urine PS
Represents P excretion rate (%). Left: untreated group (number of animals, 10
), The middle represents the ischemic treatment group (number of animals, 9), and the right represents the group (number of animals, 9) to which compound 1 was administered 30 minutes before the ischemic treatment. It is apparent that the pre-administration of Compound 1 reduces the urinary excretion rate of PSP and suppresses the increase in intestinal mucosal permeability associated with ischemia / reperfusion injury.

Formulation Example 1 Tablet (1) Compound 1 10 mg (2) Fine particles for direct hit 209 (manufactured by Fuji Chemical Co., Ltd.) 46.6 mg magnesium aluminate metasilicate 20% corn starch 30% lactose 50% (3) crystalline cellulose 24.0 mg (4) carboxymethylcellulose calcium 4.0 mg (5) magnesium stearate 0. Each of 4 mg (1), (3) and (4) was previously passed through a 100-mesh sieve. These (1), (3), (4) and (2) were each dried to reduce the water content to a certain level, and then mixed at the above weight ratio using a mixer. (5) is added to the mixed powder having uniform quality and mixed for a short time (30 seconds), and the mixed powder is tableted (punch: 6.3 mmφ, 6.0 mm).
R) to give a tablet of 85 mg per tablet. The tablet may be coated with a commonly used gastrosoluble film coating agent (for example, polyvinyl acetal diethylaminoacetate) or an edible colorant, if necessary.

Formulation Example 2 Capsule (1) Compound 1 50 g (2) Lactose 935 g (3) Magnesium stearate 15 g After weighing each of the above components, they are mixed uniformly, and the mixed powder is filled into hard gelatin capsules 200 mg each. did.

Formulation Example 3 Injection (1) Hydrochloride of Compound 1 5 mg (2) Sucrose 100 mg (3) Physiological saline 10 ml After filtering the above mixture through a membrane filter, sterilization filtration was performed again, and the filtration was performed. The solution was aseptically dispensed into vials, filled with nitrogen gas, and sealed to give an intravenous injection.

[0139]

Industrial Applicability The gastrointestinal mucosa protective agent comprising the compound having a chymase inhibitory activity of the present invention as an active ingredient has an extremely excellent gastrointestinal mucosal atrophy preventing action and an intestinal mucosal permeability increase suppressing action. Since it exerts a protective effect on gastrointestinal mucosa, it prevents and treats TPN complications, prevents and treats allergic diseases, prevents and treats inflammatory gastrointestinal diseases, and prevents and treats postoperative disorders of the gastrointestinal tract accompanied by ischemia and reperfusion. It is extremely useful.

[Brief description of the drawings]

FIG. 1 is a diagram showing the results of (1) measurement of intestinal wet weight in Test Example 1.

FIG. 2 is a diagram showing the results of measurement of (2) ileal mucosal area in Test Example 1.

FIG. 3 is a diagram showing the results of measurement of (4) PSP urinary excretion rate in Test Example 1.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 413/12 213 C07D 413/12 213 239 239 417/12 239 417/12 239 (72) Inventor Kazuki Murakami Invited by Hirakata City, Osaka Prefecture 2-25-1, Otani Inside Midori Cross Central Research Institute, Inc. (72) Inventor Koji Naito 2-25-1, Otani, Hirakata City, Osaka Prefecture Inside Midori Cross Central Institute, Ltd. (72) Inventor, Mitsuaki Imada Osaka Midori Cross Research Institute, Hirakata City

Claims (6)

[Claims] 1. A gastrointestinal mucosa protective agent comprising a compound having a chymase inhibitory activity as an active ingredient. 2. A compound having a chymase inhibitory activity is represented by the following general formula (1): 2. The gastrointestinal mucosa protective agent according to claim 1, which is a compound represented by the formula: or a pharmacologically acceptable salt thereof. In the formula, R is a hydrogen atom, alkyl, -CHO, -COOH, -CON
_{^{H 2, -COR 1, -COOR 1}} , -CONHOR 1,
—CONHR ¹ , CONR ¹ R ¹ ′, —CONHSO ₂
R ¹ , -COSR ¹ , -COCOR ² , -COCOOR
^{2, -CONHCOOR 2, -COCONR 3 R} 4, -
_{^{CSXR 1, -SO 2 WR 1,}} -SO 2 NR 1 R 1 ',
Or represents -SO ₂ E. R ¹ and R ¹ ′ are the same or different and are each an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or
Represents a heterocycle alkyl. R ² , R ³ and R ⁴ are
The same or different, and represents a hydrogen atom, an alkyl or an arylalkyl, and R ³ and R ⁴ in —NR ³ R ⁴ may together represent a heterocycle. X
Represents a single bond, an oxygen atom, a sulfur atom, or -NH-. W is a single bond, -NH-, -NHCO-, -NHC
OO- or -NHCONH-. E represents a hydroxyl group or amino. R ⁵ , R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom or alkyl, or one of R ⁵ , R ⁶ and R ⁷ is aryl, arylalkyl, arylalkenyl, heteroaryl, Represents a heteroarylalkyl or a heteroarylalkenyl, and the remaining two represent a hydrogen atom. M represents a carbon atom or a nitrogen atom. When M represents a nitrogen atom, R ⁶ does not exist. Y represents cycloalkyl, aryl, or heteroaryl. Z is -CF
_{^{2 R 8, -CF 2 CONR 9}} R 10, -CF 2 COO
R ⁹ , -COOR ⁹ , -CONR ⁹ R ¹⁰ , the following formula (i)
Or a group represented by the following formula (ii) or a group represented by the following formula (iii). R ⁸ is a hydrogen atom, halogen, alkyl, perfluoroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, or
Represents a heteroarylalkenyl. R ⁹ and R ¹⁰ are the same or different, and each represents a hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl. the stands, R ⁹ and R ¹⁰ in -NR ⁹ R ^10, may represent a heterocycle together. Embedded image In the formula, a, b, c, and d all represent carbon atoms, or one of them represents a nitrogen atom, and the remaining three represent carbon atoms. R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are the same or different and are each a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano, nitro, -NR ^{17
_{R 17 ', -NHSO 2 R 17}} , -OR 17, -COOR 17,
-CONHSO ₂ R ^17, or represents a -CONR ¹⁷ R ¹⁷ '. However, when any one of a, b, c and d represents a nitrogen atom, R ¹¹ , R ¹² , R ¹³ and R ¹⁴ bonded to a, b, c and d representing the nitrogen atom do not exist. . R ¹⁵ , R
¹⁶ is the same or different and is a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano,
^{Nitro, -NR 17 R 17 ', -NHSO} 2 R 17, -O
R ¹⁷ , —COOR ¹⁷ , —CONHSO ₂ R ¹⁷ , or —
CONR ¹⁷ R ¹⁷ ′. R ^17, R ¹⁷ 'are the same or different, a hydrogen atom, an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or represents trifluoromethyl, -NR ¹⁷ R ¹⁷ R ¹⁷ and R ¹⁷ 'may together represent a heterocycle. A represents an oxygen atom, a sulfur atom, or, -NR ¹⁸ - represents a. R ¹⁸ represents a hydrogen atom, alkyl, cycloalkyl, or cycloalkylalkyl. n represents 0 or 1. The alkyl, the cycloalkyl, the cycloalkylalkyl, the aryl, the arylalkyl, the arylalkenyl, the heteroaryl, the heteroarylalkyl, the heteroarylalkenyl, the heterocycle, and the heterocyclealkyl are May be substituted by one or more substituents. 3. The gastrointestinal mucosa protective agent according to claim 1, wherein the gastrointestinal mucosa protective agent is a preventive or therapeutic agent for TPN complications. 4. The gastrointestinal mucosa protective agent according to claim 1, wherein the gastrointestinal mucosa protective agent is an agent for preventing or treating allergic diseases. 5. The gastrointestinal mucosa protective agent according to claim 1, wherein the gastrointestinal mucosa protective agent is a prophylactic or therapeutic agent for inflammatory gastrointestinal diseases. 6. The method according to claim 1, wherein the gastrointestinal mucosa protective agent is a prophylactic or therapeutic agent for gastrointestinal postoperative disorders accompanied by ischemia / reperfusion.
The gastrointestinal mucosa protective agent according to the above.