WO2000051640A1 - Itchiness-relieving agents and itchiness-relieving effect potentiators - Google Patents

Abstract

Itchiness-relieving agents characterized by containing, as the active ingredient, compounds having a chymase inhibitory effect. As the compounds having a chymase inhibitory effect, use can be made of, for example, compounds represented by general formula (1): wherein each symbol is as defined in the description. These itchiness-relieving agents are applicable to allergic itchiness and non-allergic itchiness (for example, itchiness in which chymase participates, atopic dermatitis, eczema, urticaria, prurigo, insect bite, bedsore, xeroderma, etc.). They are particularly efficacious as preventives and remedies for atopic dermatitis. Combined use of these itchiness-relieving agents with steroids makes it possible to enhance the scratching regulatory effect of the steroids, thus enabling reduction of the administration dose of the steroids.

Description

 Specification

 Itching inhibitor and itching inhibitor

 Technical field

 The present invention relates to an itch inhibitor containing a compound having a chymase inhibitory activity as an active ingredient. Further, the present invention relates to a itch-inhibiting effect-enhancing agent comprising a compound having a chymase inhibitory activity as an active ingredient, and enhancing the itch-inhibiting effect of a steroid agent.

 Background art

 “Itching” refers to the sensation, or pruritus, caused by a weak stimulus to the pain points in the skin and mucous membranes. Itching has characteristics that differ from pain in that it occurs only on the body surface and in the oral cavity. Furthermore, itching is markedly different from pain in that it is extremely painful to withstand the discomfort caused by it, even if it is mild. Severe itching can even impair daily life, and in very severe cases requires treatment with hospitalization.

 In recent years, the number of cases of atopic dermatitis has increased dramatically with changes in the living environment. Arterial dermatitis is a disease that develops specific skin symptoms with the characteristic of persistent itching, and its diagnostic criteria are (1) pruritus, (2) rash, (3) chronic and recurrent It satisfies the following three points.

 Environmental factors greatly affect the development of atby dermatitis. Environmental factors can be broadly divided into non-allergic and allergic factors. Non-allergic factors include physical factors, such as skin dryness, sweating, pressurization and weighting of the skin, and rupture of the skin. On the other hand, allergic factors include, for example, contact with environmental factors, food allergens, mites, house dust, pet hair, metals and other allergens present in the environment, aspiration and ingestion. .

 When the above-mentioned non-allergic factors or allergic factors are further linked to a genetic predisposition such as an allergic predisposition or a dry skin predisposition, that is, atopic predisposition, it leads to the development of atopic dermatitis.

If atopic dermatitis develops due to non-allergic factors, Contact with the factor triggers itching, and skin tissue is destroyed by exposing the skin in response to the itching. This impairs the protective mechanism of the skin, which protects the human body from the outside world, and causes a barrier to the skin barrier, which makes the skin more susceptible to pathogens and the skin becomes more sensitive.搔 Broken skin becomes more susceptible to irritation, which results in the development of arthro- dermatitis. When atby dermatitis develops due to allergic factors, contact with the allergic factors causes allergic inflammation with IgE-dependent itching, which is caused by the first contact with the allergen There are immediate allergies and delayed allergies caused by re-contact, and after these are mixed, prolonged and intractable inflammation leads to the development of atby dermatitis.

 When atopic dermatitis develops, it is persistent and intense itching, so it exacerbates the affected area more violently, further increasing non-allergic factors, further destroying the skin tissue and causing skin barrier disorders. Allergic factors are further increased, leading to aggravation of the allergic factors, which in turn leads to exacerbation of allergens through the skin.

 Therefore, in the prevention and treatment of atopic dermatitis, correction of skin barrier disorder and control of skin including suppression of itching are considered as one of the important pillars, and in this case, it depends on IgE. It is important to control both itching and itching due to non-allergic factors simultaneously.

 Antihistamines, anti-allergic drugs, which have been widely used in the past because they are effective in suppressing itch, are not effective in patients with moderate or more persistent itch, and steroids Not only are they often only topical or are ineffective, they can also cause side effects such as central depression and liver damage.

 For this reason, there is a strong demand for the development of itch inhibitors with a new mechanism of action.

 The present invention has been made in view of the above circumstances, and aims to provide an excellent itching inhibitor.

 Disclosure of the invention

The present inventors have conducted intensive studies to achieve the above object, and surprisingly found that a compound having a chimase inhibitory action has an excellent itching inhibitory action suitable for the above purpose. The present inventors have further found that the combined use of a steroid inhibitor and a itch inhibitor containing a compound having a chymase inhibitory effect enhances the itch inhibitory effect of the steroid agent, and completed the present invention. Was.

 That is, the present invention

 1. An itching inhibitor comprising a compound having a chimase inhibitory activity as an active ingredient.

 2. The compound having chymase inhibitory activity is represented by the following general formula (1):

R ⁶

^R Sr ^R o

IV (? ^Η 2) η-Υ

 J. II-,

RHN 'γ ^Ν N ^Z ("

ο ^π ο

In the formula, R represents a hydrogen atom, an alkyl, One _{CHO, - COOH, - CONH 2} , -COR 1, - COOR 1ヽ ^{-CONHOR 1, -C0NHR -CONR ^ 1 '} ,

-CONHS0 ₂ R -CO SR -CO COR ² , -CO COOR ² ,

— CONHC〇OR ² , — COCONR ³ R ⁴ , -C SXR -S0 ₂ WR

— SOzNRiR ¹ 'or 1 S0 ₂ E (wherein II ¹ and R ¹ ' may be the same or different and each independently represents an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl Represents a heteroaryl, a heteroarylalkyl, a heterocycle or a heterocyclealkyl, and R ² , R ³ and R ⁴ may be the same or different and each independently represents a hydrogen atom, an alkyl or an arylalkyl. shown, there have may form a connexion hetero cycle to such together with R ³ and R ⁴ in an NR ³ R ^4, X is a single bond, an oxygen atom, a sulfur atom or - NH- indicates, W Represents a single bond, —NH—, one NHC0—, one NHC00— or one NHCQNH—, and E represents a hydroxyl group or an amino.

R \ R ⁶ and R ⁷ may be the same or different and each independently represents a hydrogen atom or an alkyl, or one of R ⁵ , R ⁶ and R ⁷ is an aryl, an aryl alkyl , Arylaryl, heteroaryl, heteroarylalkyl or heteroarylalkyl, the other two represent a hydrogen atom, M represents a carbon atom or a nitrogen atom (however, when M is a nitrogen atom, R ⁶ is not present);

 Y represents cycloalkyl, aryl or heteroaryl,

Z is —CF ₂ R ⁸ , —CF ₂ C ONR ^g R ¹⁰ , —CF ₂ COOR ⁹ , —COOR \ —CO NR ⁹ R ¹⁰ (where R ⁸ is a hydrogen atom, halogen, alkyl, perfluoroalkyl , aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, Arukokishia alkyl, hydroxyalkyl, Ariru, § reel alkyl, § reel alkenyl heteroaryl, represents a hetero § reel alkyl or hetero arylalkenyl, R ^9, R ^{1 G} is Which may be the same or different and each independently represents a hydrogen atom, an alkyl, an alkenyl, a cycloalkyl, a cycloalkylalkyl, a heterocyclealkyl, an aryl, an arylalkyl, an arylalkenyl, a heteroaryl, a heteroarylalkyl, Or represents heteroarylalkenyl, or May form a hetero cycle to together such connexion and R ⁹ and R ^1Q in an NR ⁹ R ^{1 Q.),} The following formula (i)

A group represented by the following formula (ii)

Or a group represented by the following formula (iii)

{In the formulas (i) to (iii), a, b, c and d all represent a carbon atom, or one of them represents a nitrogen atom and the rest represents a carbon atom, and R ¹ R ¹² , ¹³ and R ¹⁴ May be the same or different and each independently represents a hydrogen atom, an alkyl, an aryl, an arylalkyl, a heteroaryl, a heteroarylalkyl, a halogen, a trifluoromethyl, § Bruno, nitro, One NR ¹⁷ R ¹⁷ indicates 'one NHS0 ₂ R ^17, -OR ^17, one C_〇_OR ^17, one C ONH S 0 ₂ R ¹⁷ or a CONR ¹⁷ R ^17' (where, a, b, c, if any one of the d represents a nitrogen atom, R, that binds a, b, c, and d representing the nitrogen atom R ^12, R ^13, R ¹⁴ is absent.), R ¹⁵ , R ¹⁶ may be the same or different and each independently represents a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano, nitro, one NR ¹⁷ R ¹⁷ ', one NHS0 ₂ R ^17, -OR ^17, one COOR ^17, or one C 0 NHS 0 ₂ R ¹⁷ one CONR ¹⁷ R ^17' indicates where in the above formulas, R ^17, R ¹⁷ 's may be the same or have different dates, it it independently hydrogen atom, alkyl, cycloalkyl, cycloalk Kiruaruki , Ariru, § reel alkyl, Heteroariru represents a hetero § reel alkyl le or triflate Ruo Russia methyl, or the 'R ¹⁷ and R ¹⁷ in the' single NR ¹⁷ R ¹⁷ may form a hetero cycle to together such connexion A often represents an oxygen atom, a sulfur atom or —NR ¹⁸ — (wherein R ¹⁸ represents a hydrogen atom, alkyl, cycloalkyl or cycloalkylalkyl). } Represents a group represented by

n represents 0 or 1.

Of the above groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, and heterocyclylalkyl are each It may have one or more substituents. ]

Or the pharmacologically acceptable salt thereof represented by the formula (I). 3. The compound having a chimase inhibitory activity is represented by the following general formula (la):

Wherein, H ^a is a hydrogen atom or a base Nji Ruo alkoxycarbonyl, R ^{5 a} is phenyl, 3 one-fluorophenyl, 4-fluorophenyl, 3-black port phenyl, 4-black port phenylene le, 3- Methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl Eniru showed 3-pyridyl or 4-pyridyl, R ^7a represents a hydrogen atom, Y ^a represents an optionally phenyl which may have a substituent, Z ^a formula (ia)

Group (wherein, R ^12a is a hydrogen atom, nitro, represented in - CONH _2, - C_〇_NHEt, C_〇_NMe _2, -CONE t _2, showing one C 00 M e or a C 00 E t. :), formula (a ⁵⁾

Or a group represented by the formula (i i i a) 0, (iiia)

 Ν '

In indicates a group represented by, n ^a is 1. Or the pharmacologically acceptable salt thereof represented by [1] or [2].

 4. A compound having a chimase inhibitory action is represented by the following general formula (lb):

(1)

[Wherein, R ^b represents a hydrogen atom or benzyloxycarbonyl, one of R ^5b , R ^6b , and R ^7b represents an aryl which may have a substituent, and the remaining two are represents a hydrogen atom, M ^b represents a carbon atom or a nitrogen atom (provided that when M ^b is a nitrogen atom R ^{6 b} is absent.), Y ^b which may have a substituent Ariru are shown, Z ^b is in one CF ₂ R ^8b or a CF ₂ C_〇_NR ^9b R ^10b (wherein, R ^8b, R ^{9 b} and R ^{10 b} is a said R ^8, R ⁹ and R ^1Q synonymous ) And n ^b represents 1. Or the pharmacologically acceptable salt thereof represented by [1] or [2].

5. The anti-itch agent is a preventive agent for atopic dermatitis or a therapeutic agent for atopic dermatitis The above-mentioned itching inhibitor of 1-4.

 6. The itching inhibitor according to any one of the above items 1 to 5, further comprising a steroid agent.

 7. The itching inhibitor according to 6 above, wherein the steroid agent is a corticosteroid or a synthetic steroid having the same action as the corticosteroid.

 8. The itching inhibitor according to 6 or 7 above, wherein the steroid agent is prednisolone, dexamethasone or betamethasone. -

9. An itching inhibitory enhancer comprising a compound having a chimase inhibitory effect as an active ingredient to enhance the itch inhibitory effect of a steroid agent.

 10. The itch-inhibiting effect enhancer according to 9 above, wherein the compound having chymase inhibitory activity is the compound represented by the above general formula (1) or a pharmacologically acceptable salt thereof.

 11. The itch-inhibiting effect-enhancing agent according to 9 or 10 above, wherein the compound having a chimase inhibitory activity is a compound represented by the above general formula (1a) or a pharmacologically acceptable salt thereof.

12. The itch-inhibiting effect-enhancing agent according to 9 or 10 above, wherein the compound having a chimase inhibitory activity is the compound represented by the above general formula (lb) or a pharmacologically acceptable salt thereof. 13. The itch-inhibiting effect enhancer according to 9.-12 above, which is an agent for preventing atby dermatitis or a therapeutic agent for atopic dermatitis.

 14. The itch-inhibiting effect-enhancing agent according to any one of 9 to 13 above, wherein the steroid agent is a corticosteroid or a synthetic steroid having the same action as the corticosteroid.

 15. The itching-inhibiting effect-enhancing agent according to any of the above 9 to 14, wherein the steroid agent is prednisolone, dexamethasone or betamethasone.

 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the number of catching actions of the mice in each group in Table 3. *; P <0.05 (t-test), **; p-0.01 (t-test), #; p-0.05 (Dunnett method for IgE (+) control), ##, p- 0.01 (Dunnett method for IgE (+) control). FIG. 2 shows the catching-inhibition rates of the combination administration group (hl-k-1) and the PSL-only administration group (dl-g-1) in Table 3. *; P <0.05 (t test), **; p <0.01 (t test). FIG. 3 shows the number of catching actions of the mice of each group in Table 4. *; p <0.05 (t-test), **; p-0.01 (t-test), #; p-0.05 (Dunnett method for IgE (+) control), ##, p- 0.01 (Dunnett method for IgE (+) control). FIG. 4 shows the inhibition rate of the catching behavior of the combination administration group (h-3 to k-3) and the PSL single administration group (d-3 to g-3) in Table 4. *; P <0.05 (t-test).

 FIG. 5 shows the locomotor activity of each group of normal mice in Table 5. **; p <0.01 (Tukey test for control group).

 Hereinafter, the present invention will be described in detail.

 Chimase is one of the in vivo enzymes found in mast cell secretory granules and one of a subfamily of chymotrypsin-like serine proteases. When released from the cell, chimase immediately binds to the surrounding extracellular matrix, cleaves the extracellular matrix of type IV collagen / five-mouth nectin, enhances vascular permeability together with histamine, etc. Enhances the action of histamine, generates histamine-releasing peptides from serum albumin, and also degrades IgG to a limited extent to form leukocyte chemotactic factors, and is a precursor of interleukin-1-5, one of the inflammatory cytokines It has in vivo effects such as activating the body.

 Chymase has also been shown to be involved in the process of conversion of angiotensin I to angiotensin II, which is independent of angiotensin converting enzyme.In addition, substance P, bathoactive 'intestinal' It has also been found that many physiologically active substances such as polypeptide (VIP) apoprotein B are used as substrates, and that it is involved in the activation of other in vivo proteases such as collagenase. Has been clarified.

 In the present specification, the term “chimase inhibitory action” means an action of inhibiting and suppressing all in vivo reactions involving chymase, in addition to the various chimase actions described above. Further, in the present specification, the “compound having a chimase inhibitory action” may be a compound having an action of inhibiting or suppressing at least one of the above-mentioned various actions of chimase. The term also includes compounds having an action of inhibiting or suppressing at least one of all in vivo reactions involving chimase other than the action of these known chimases.

In the present specification, the term “chimase inhibitory effect” is a general term for various effects. It is also used to mean only one of these actions, and also to mean a combined action of two or more of those actions.

 As used herein, the term “compound having a chymase inhibitory action” means a compound that expresses the chymase inhibitory action at a normal dose, and the above “normal dose” For example, 0.01 to: L 0 mg / kg human / day, which means an amount similar to the amount of a compound administered orally or parenterally as a normal pharmaceutical product. I do.

 In the present specification, “itch” is not particularly limited, and includes allergic itch and non-allergic itch. For example, itching that can be caused by chimaze, dermatitis dermatitis, eczema, urticaria, prurigo, insect bites, floor rubbing, xerosis, etc. are included.

 In the present specification, the “itch inhibitor” is not particularly limited, and may be one that suppresses itching due to atopic dermatitis or one that suppresses itching caused by other causes.

 The above-mentioned “itch due to atopic dermatitis” is not particularly limited as long as it is caused by atopic dermatitis, and includes itch due to IgE due to allergic factors and itch due to non-allergic factors. Here, itch due to non-allergic factors includes itch that may involve chymase released when mast cells degranulate.

 Examples of the above “non-allergic factors” include skin dryness, sweating, pressurization / loading of the skin, rupture of the skin, and changes in air temperature and body temperature.

 Examples of the above “allergic factors” include environmental factors, food allergens, mites, house dust, pet hair, etc., contact with metals and other environmental allergens, sucking I, ingestion, etc. Can be mentioned.

 Among the itches due to atopic dermatitis, the inhibitory effect on IgE-dependent itch, which was mentioned as an allergic factor, is a completely different phenomenon from the inhibitory effect on IgE production, and both are independent. It is a phenomenon. This is evident, for example, from the fact that the itch-inhibiting effect of a chimase inhibitor was observed in an experimental system passively sensitized with IgE.

The compound having a chimase inhibitory effect used in the present invention is, as described above, It is characterized only by having harmful effects, and is not particularly limited.

 Examples of the compound having a chimase inhibitory action include a compound represented by the above general formula (1). There has been no report before the present invention that a compound having such a pyridone or pyrimidone skeleton is effective in suppressing itch, and the compound having a pyridone or pyrimidone skeleton according to the present invention has an anti-itch effect. The knowledge that it had was unpredictable.

 Preferred embodiments of the compound represented by the general formula (1) include a compound represented by the general formula (1a) and a compound represented by the general formula (lb).

2- [5-amino-2- (4-fluorophenyl) -6-oxo-1,6-dihydro-topyrimidinyl] -N- [l-[[5- (methoxycarbonyl) benzoxazolyl-2- Yl] carbonyl] -2-phenylethyl] asemid,

 2- [5-amino-2- (3-methoxyphenyl) -6-oxo-1, 6-dihydro-1-pyrimidinyl] -N- [l (S)-[(2-penzoxazolyl ) Carbonyl] -2-phenylethyl] acetamide and 2- [5-amino-2- (3-chlorophenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] -N- [l (S ) -Benzyl-3- (N-pendylcarbamoyl) -3,3-difluo-2-oxoprovir] asemidide is preferred.

 Hereinafter, the symbols used in the present specification will be described.

The alkyl in R, RR ¹ ′ R ² to R ¹⁷ , R ¹⁷ ′, R ¹⁸ and R ^{8b to} R ^10b is not particularly limited, and is preferably a linear or branched alkyl having 1 to 6 carbon atoms. Examples include linear alkyl, and specifically, for example, methyl, ethyl, n-propyl, isopropyl, II-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl And the like.

The cyclic alkyl in RR ¹ ′ R ⁹ , R ¹⁰ , R ¹⁷ , R ¹⁷ ′, R ¹⁸ , Y, R ^{9 b} and R ^{10 b} is not particularly limited, and is preferably a cycloalkyl having 3 to 7 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

RR ¹ ', as the Shikuroa Rukiruarukiru in ^{R 9, R 10, R 17} , R 17 \ R 18, R 9 b and R ^{10 b,} not particularly limited, but is preferably same cycloalkyl portion is the And those in which the alkyl moiety is a straight-chain or branched-chain alkyl having 1 to 3 carbon atoms. Specific examples include cyclopropylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl, 2-cyclopentylpropyl and the like.

^{RR, R 5 ~R 17, R} 17 ', Y, is a Ariru in R ^{5 b} to R ^10b and Y ^b, not particularly limited, met for example phenyl, naphthyl or ortho fused bicyclic group, Having 8 to 10 ring atoms and at least one ring is an aromatic ring (for example, indenyl and the like).

The arylalkyl in R ¹ , R ¹ ′ R ^{2 to} R ¹⁷ , R ¹⁷ ′ and R ^{8b to} R ^10b is not particularly limited, and preferably has an aryl moiety similar to the above, and the like. And the alkyl group is a straight-chain or branched-chain alkyl having 1 to 3 carbon atoms. Specific examples include benzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, and Naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (1-naphthyl) propyl, 3- (2-naphthyl) propyl, 2- (1-naphthyl) propyl ) Propyl, 2- (2-naphthyl) propyl, and the like.

The aryl alkenyl in R ^{5 to} R ⁷ is not particularly limited. Preferably, the aryl moiety is the same as described above, and the alkenyl moiety is a straight or branched chain having 2 to 6 carbon atoms. And specifically, for example, 2-phenyl, 3-phenyl-2-propenyl, 4-phenyl-1-butenyl, 5-phenyl-1-pentenyl, 6-phenyl-1-hexenyl, 3_ (1-naphthyl) -12-propenyl, 4- (2-naphthyl) -3-butenyl and the like.

The arylalkenyl in ^{18 to} 11 ^{1 ()} 1 1 ^{81) to} 11 ^{1 () 1)} is not particularly limited, and preferably has an aryl portion similar to the above. Wherein the alkenyl moiety is a straight-chain or branched alkenyl having 3 to 6 carbon atoms, specifically, for example, 3-phenyl-12-propenyl, 4-phenyl-3 —Butenyl, 5-phenyl-1-41-pentenyl, 6-phenyl 5-hexenyl, 3- (1-naphthyl) -1-propenyl, 4- (2-naphthyl) -13-butenyl and the like Can be

The heteroaryl in RR ¹ ′, R ⁵ to R ¹⁷ , R ¹⁷ ′, Y and R ^8b to R ^10b Is not particularly limited, and is preferably a 5- to 6-membered ring group having a carbon atom and 1 to 4 hetero atoms (oxygen, sulfur or nitrogen atom); Ortho-fused bicyclic heteroaryl having a ring atom; benz derivatives; those derived by fusing a probenylene group, a trimethylene group or a tetramethylene group to the benz derivative; and N-sulfoxide of a penz derivative. . Specifically, for example, pyrrolyl, furyl, chenyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, virazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4 —Thiadiazolyl, pyridyl, vilanyl, virazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, benzo [b] Chenyl, isopenzo [b] chenyl, benzofuranyl, isobenzofuranyl, chromenil, isoindolyl, indrillyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pen Kisajiniru, and the like.

The heteroaryl alkyl in R Ri ′, R ⁵ to R ¹⁷ _s R ¹⁷ ′ and R ^{8b to} R ^10b is not particularly limited, and the heteroaryl moiety is preferably the same as described above, and the alkyl moiety Is a linear or branched alkyl having 1 to 3 carbon atoms, specifically, for example, 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-Chenylmethyl, 2- (2-pyridyl) ethyl, 2- (3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, 3- (2-pyrrolyl) propyl and the like.

The heteroarylalkenyl in R ⁵ to R ⁷ is not particularly limited, and preferably has the same heteroaryl portion as described above, and the alkenyl portion has a straight or branched chain having 2 to 6 carbon atoms. And specifically, for example, 2- (2-pyridyl) ethenyl, 3- (2-pyridyl) -12-propenyl, 4- (3-pyridyl) -3-butenyl, 5- (2-pyrrolyl) -14-pentenyl, 6- (2-chenyl) -14-hexenyl and the like.

The hetero § reel alkenyl in R ⁸ to R ¹⁰ and R ^{8 b} ~R ^{10 b,} particularly limited There is no particular limitation, preferably those in which the heteroaryl moiety is the same as described above, and the alkenyl moiety is a straight-chain or branched alkenyl having 3 to 6 carbon atoms. For example, 3- (2-pyridyl) — 2-propenyl, 4- (2-pyridyl) -1-butenyl, 5- (2-pyrrolyl) -14-pentenyl, 6— (2-phenyl) — 5 —Hexenyl and the like. ,

The heterocycle in R ¹ and R ¹ ′ is not particularly limited, and is a 4- to 6-membered ring group having a carbon atom and 1 to 4 hetero atoms (an oxygen atom, a sulfur atom or a nitrogen atom). Azetidinyl, pyrrolidinyl, piberidinyl, piperidino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl, tetrahydroviranyl, dioxacyclohexyl and the like.

— A heterocycle in NR ³ R ⁴ , one NR ⁹ R ¹⁰ , -NR ¹⁷ R ¹⁷ ′ and one NR ^{9 b} R ^{10 b} is a heterocycle having a carbon atom and at least one nitrogen atom. A 4- to 6-membered ring group which may have another hetero atom (oxygen atom or sulfur atom), and is not particularly limited; azetidinyl, pyrrolidinyl, biperidino, piperazinyl, morpholino, thio Morpholino, oxothiomorpholino, dioxothiomorpholino and the like.

The heterocycle alkyl in RR ¹ ′, R ⁹ , R ¹⁰ , R ^gb and R ¹ Qb is not particularly limited, and preferably has a heterocycle portion similar to the above (! ^ ぉ ぉ obi! ^ ¹ ′) Wherein the alkyl portion is a linear or branched alkyl having 1 to 3 carbon atoms, specifically, for example, azetidinylethyl, pyrrolidinylpropyl , Biperidinylmethyl, biberidinoethyl, piperazinylethyl, morpholinylpropyl, morpholinomethyl, thiomorpholinylethyl, oxothiomorpholinylethyl, dioxothiomorpholinylethyl, tetrahydroviranylpropyl, dioxacyclo Hexylmethyl and the like.

R ^8, R ¹¹ ~: The halogen in R ¹⁶ and R ^8b, is not particularly limited, for example, fluorine, chlorine, bromine or iodine.

The perfluoroalkyl for R ⁸ and R ^8b is not particularly limited, and is preferably a straight-chain or branched-chain perfluoroalkyl having 1 to 6 carbon atoms. concrete Examples thereof include trifluoromethyl, pendufluorethyl, heptylfluoropropyl and the like.

The aminoalkyl for R ⁸ and R ^8b is not particularly limited, and preferably includes those in which the alkyl portion is a linear or branched alkyl having 1 to 6 carbon atoms. Specific examples include aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl and the like.

The alkylaminoalkyl for R ⁸ and R ^8b is not particularly limited, and preferably includes those in which each alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms. Specifically, for example, methylaminomethyl, methylaminoethyl, ethylaminopropyl, ethylaminobutyl, methylaminopentyl, methylaminohexyl, propylaminomethyl, butylaminomethyl, pentylaminomethyl, hexylaminomethyl, etc. No.

The dialkylaminoalkyl for R ⁸ and R ^8b is not particularly limited, and preferably includes those in which each alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms. Specifically, for example, dimethylaminomethyl, dimethylaminoethyl, acetylaminopropyl, dimethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl, dipropylaminomethyl, diisopropylaminomethyl, diisopropylaminoethyl, dibutylamino Methyl, dipentylaminomethyl, dihexylaminomethyl and the like.

The alkoxyalkyl in R ⁸ and R ^8b is not particularly limited, and preferably, the alkoxy moiety is a linear or branched alkoxy having 1 to 6 carbon atoms, and the alkyl moiety is 1 to 6 carbon atoms. Those which are linear or branched alkyl are mentioned. Specifically, for example, methoxymethyl, methoxethyl, ethoxypropyl, ethoxybutyl, methoxypentyl, methoxyhexyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, pentyloxymethyl, hexyloxymethyl And the like.

The hydroxyalkyl in R ⁸ and R ^8b is not particularly limited, and preferably includes those in which the alkyl portion is a linear or branched alkyl having 1 to 6 carbon atoms. You. Specific examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.

R ^9, R ^1G, the alkenyl in R ^{9 b} and R ^1Gb, not particularly limited, preferred properly may include linear or branched alkenyl of 3-6 carbon atoms. Specific examples include 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.

The substituent of the phenyl may have a substituent in Y ^a, for example, the following "location substituent".

 Of the above substituents, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle, and heterocyclealkyl are Each of them may be substituted by one or more substituents shown below (hereinafter, “substituents of the above substituents” are referred to as “substituents” to distinguish them from the above substituents).

As "substituent" of the substituents, e.g., halogen, hydroxyl, nitro, Shiano, triflumizole Ruo Russia methyl, alkyl, alkoxy, alkylthio, formyl, Ashiruokishi, Okiso, phenyl, § reel alkyl, One COOR ^a, one CH ₂ COOR ^a , -0 CH ₂ COOR ^a , one CONR ^b R ^cヽ -CH ₂ CONR ^b R ° _s — 0 CH ₂ C 0 NR ^b R ^cヽ-C 00 (CH ₂ ) ₂ NR ^e R ^f ,- S0 ₂ T -CONR ^d S0 ₂ T NR ^e R ^f , — NR ^g CH0, NR ^g C0T ² , NR ^g C gT ² , NRhCQNRiRj ヽ NR ^k S0 ₂ T ³ , -S 0 ₂ NR ¹ R ^m , one S0 ₂ NR ⁿ COT ^{4 and the} like.

 The halogen, alkyl and arylalkyl in the “substituent” are not particularly limited, and include, for example, the same as those exemplified in the description of the general formula (1).

 The alkoxy in the “substituent” is not particularly limited, and preferably includes a straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms. Specifically, for example, methoxy, ethoxy, propoxy, Isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

The alkylthio in the "substituent" is not particularly limited, and preferably includes those in which the alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

 The acyloxy in the “substituent” is not particularly limited and preferably includes a straight-chain or branched alkanoyloxy having 1 to 6 carbon atoms.Specifically, for example, formyloxy, acetyloxy, And propionyloxy, butyryloxy, valeryloxy, vivaloyloxy, hexanoyloxy and the like.

R ^{a to} R ⁿ in the “substituent” are a hydrogen atom, an alkyl (with no particular limitation, for example, the same as those exemplified in the description of the above general formula (1)), an arylalkyl (particularly, There is no limitation, and examples thereof include the same ones as exemplified in the description of the above general formula (1). Note that — NR ^b R ^c , one NR ^e R ^f ,

— In NRiRm, R ^b and R ^c , R ^e and R ^f , R ^j, and ¹¹ and ^{111 1} each form a heterocycle together with an adjacent nitrogen atom. And NR ³ R ⁴ , one NR ⁹ R ¹⁰ , —NR ¹⁷ R ¹⁷ ′ and —NR ^{9 b} R ^10b , and the same as those exemplified above, which is substituted by the above “substituent” And NR ^e R ^f is a heterocycle or a heteroaryl having = 0 (without any particular limitation, for example, 2-pyrrolidinone-11-yl, succinimide, oxazolidinone) 2-one-3-yl, 2-benzoxazolinone-13-yl, phthalimid, cis-hexahydrophthalimid, etc. can also be used.

In "substituent"! ^{1 1} ~! ¹⁴ shows the same as R ¹ described above, it may be substituted by the "substituent".

 Q in the “substituent” represents = 0 or = S.

The compound represented by the general formula (1) can exist as an optically active substance and a racemic form due to an asymmetric carbon to which a — (CH ₂ ) _n —Y group is bonded. 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 diastereomer mixture or as a single diastereomer. These can also be separated from each other by a known method.

The compound represented by the general formula (1) can exhibit polymorphism, —Can exist as more tautomers. 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 above general formula (1) in the present invention may be any of the above stereoisomers, optical isomers, polymorphs, tautomers, solvates, mixtures thereof, and the like. Is included.

 Examples of the compound represented by the general formula (1) include, for example, International Publication No. (W096 / 39373), Japanese Patent Application Laid-Open No. H10-7661, PCT / JP 97/03389, International Application Specification, The compounds described in Japanese Patent Application No. 353,572 / 1991 are exemplified. The production methods and the chimase inhibitory activity of these compounds are described in the above publications and in the above specification.

 Further, examples of compounds having a chymase inhibitory action which can be used as an active ingredient of the itch inhibitor of the present invention are shown below.

 Example 1: The following general formula (1 ')

[Wherein, R,, R ⁵ ′, R ⁶ ′, R ⁷ ′, M,, n, and Y are the same as R, RR ⁶ , R ⁷ , M, n and Y, and R ⁹ 'Represents a hydrogen atom, alkyl or arylalkyl, and R ¹⁹ and R ^{2 Q} may be the same or different and are each independently a hydrogen atom, an alkyl, an alkenyl, a cycloalkyl, a cycloalkylalkyl, a heterocyclealkyl , Ariru, § reel alkyl, § reel alkenyl, Heteroariru, hetero cycle to together such connexion and R ¹⁹ and R ^{2 Q} at the hetero § reel alkyl or to either show hetero arylalkenyl, or single NR ^{1 9} R ^{2 Q} Where D ¹ is the following equation (i V)

A group represented by the following formula (V)

Or a group represented by the following formula (vi)

Wherein, in the above three formulas, R ²¹ and R ²² may be the same or different and each independently represents a hydrogen atom, an alkyl, an arylalkyl, or a heteroarylalkyl Or may be taken together to form an alkylene 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 — (wherein R ²³ represents a hydrogen atom, alkyl, or arylalkyl), and p and r may be the same or different, and independently represent 0, 1 , 2 or 3, and s and t are integers such that their sum is 1 to 6. }. ] The compound represented by this.

Alkyl, arylalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, aryl, arylalkenyl, heteroaryl, heteroaryl in R ⁹ ′, R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ The alkyl, heteroarylalkenyl and heterocycle are not particularly limited, and include, for example, those exemplified in the description of the above general formula (1). Further, these may be substituted with the above “substituent”. Is also good. Example 2: The following general formula (1,,)

[Wherein, R,,, R ⁵ ′, R ⁶ ′, R ⁷ ′, M,, η ′ ⁵ and Υ ′ ′ are R, R ⁵ , R ⁶ , R ⁷ , M, Synonymous with n and Y, Z, is — CF ₂ CON (R ⁹ ")-

(CH _{2) u} - CO_〇_R ²⁴ or 'in -D ² {wherein, R ⁹ one ^{_{CF 2 CON (R 9')}} ',' represents a hydrogen atom, an alkyl or § reel alkyl, R ²⁴ is hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, Ariru, § reel alkyl, Heteroari Lumpur, Heteroari one Ruarukiru, heterocycle or to the hetero cycle alkyl, 11 represents 1, 2 or 3, D ² is the following Equation (vi i)

(Wherein, R ²⁴ has the same meaning as described above, and R ²⁵ represents a hydrogen atom, alkyl, alkoxy or halogen.). }. ] The compound represented by these.

Alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, alkoxy and halogen in R ⁹ ′, R ²⁴ and R ²⁵ are particularly limited. Instead, there may be mentioned those exemplified in the description of the above general formula (1), and these may be substituted with the above “substituent”.

Example 3: The following general formula (2)

(Wherein, R, R ⁵ , R ⁶ , R ⁷ , M, Y and n are as defined in the above general formula (1)).

 The compound of the above general formula (2) is a compound described in the specification of PCT / JP 97/03839 International Application, and the production method and chymase inhibitory activity of these compounds are also described in the specification. .

Example 4: Polypeptides disclosed in JP-T-7-507069.

 For example, the following general formula (3)

(Wherein, R ^A1, for example indicates such Ariru, R ^A2 represents a carbonyl or sulfonyl, R ^A3, for example alkyl shows the like, R ^A4, for example indicates such heterocycle, R ^{A 5} is For example, proline and the like, R ^A6 represents, for example, 1 BF ₂ , R ^A7 represents, for example, 1 NH—, etc., and A 1 represents 1 or 2.)

Example 5: Triazine derivative _c disclosed in JP-A-8-208654

 For example, the following general formula (4-1)

Or, the following general formula (4-2)

(In the formula (4-1), 1 ¹³³ represents 〇-Rei_11 _3, and when R ^B4 represents a N, R ^{B 1} is a lower § alkyl or benzyl substituted with one halogen atom, : ^B2 represents lower alkyl, benzyl substituted by one hagen atom, or lower alkoxycarbonylmethyl, and in formula (4-2), R ^B3 represents N and R ^B4 represents CH when, R ^B3 represents CH, and when R ^B4 represents a CH, and R ^B3 represents a C one CH _3, and when R ^B4 represents a N, R ^{B 1} is lower alkyl, lower alkoxycarbonyl-methyl, phenyl-lower alkyl, or a benzene ring on a lower alkyl, halogen, Shiano, phenyl, and shows a benzyl substituted by any one of a halo-lower al kills, R ^B2 is a hydrogen atom, lower alkyl, lower Alkoxycarbonylmethyl, phenyl lower alkyl, Other benzene ring on a lower alkyl, halogen, Shiano, phenyl, and one of halo-lower alkyl

Indicate benzyl substituted by one kind. ) A triazine derivative represented by the formula: Example 6: Hydantoin derivative disclosed in JP-A-9-131061.

 For example, the following general formula (5):

(Five)

[Wherein, ^{C 1} represents 0, 1, 2, 3, 4 or 5; R ^{C 1} represents halogen, lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, or carbon number. R ^C2 represents a hydrogen atom, a lower alkyl having 1 to 4 carbon atoms, an aralkyl having 7 to 10 carbon atoms, or a carbon atom having 2 to 4 carbon atoms which may be esterified with lower alkyl or aryl. Represents a lower alkyloxycarbonyl of ~ 5, and R ^C3 is represented by the following formula (5-1)

A group represented by the following formula (5-2)

 CH: OR

 'C3 (5-2)

Or a group represented by the following formula (5-3)

-CH ₂ —COOR ^CD (5-3)

 / C4

(In the formula (5-1), C 2 represents 0, 1 or 2, R ^C4 represents a hydrogen atom, halogen, hydroxyl or lower alkoxy having 1 to 4 carbon atoms, and in the formula (5-2) And C 3 represents 1 or 2, R ^G5 represents a hydrogen atom or lower alkyl having 1 to 4 carbon atoms, and in the formula (5-3), C 4 represents 1 or 2, R ^C6 represents hydrogen. Represents an atom or a lower alkyl having 1 to 4 carbon atoms.) Represents a group represented by. ] The compound represented by these. Example 7: An imidazolidine derivative disclosed in WO 96/04248.

 For example, the following general formula (6)

(Wherein, R ^{D 1.} R ^D2 may be the same or different, it it independently, halogen, alkyl having 1 4 carbon atoms, 1 to 4 carbon atoms alkoxy of 1 to 4 carbon atoms Alkylene dioxy, phenoxy, nitro, cyano, phenyl, alkanoylamino having 2 to 5 carbon atoms, carboxyl which may be esterified with alkyl having 1 to 4 carbons or alkenyl having 1 to 4 carbons; Carboxylalkyl which may be esterified with alkyl or alkenyl having 1 to 4 carbons; carboxyalkyloxy which may be esterified with alkyl having 1 to 4 carbons or alkenyl having 1 to 4 carbons; One to three groups selected from the group consisting of N-alkylpiperazinylcarbonyl; N-alkylpiperazinylcarbonylalkyl; and morpholinocarbonyl Conversion to an aromatic hydrocarbon but it may also have, R ^D3 represents sulfonyl or carbonyl, R ^D4 represents an oxygen atom or a sulfur atom.) The compound represented by the.

Example 8: Quinazoline derivative disclosed in WO 97/1 1941.

 For example, the following general formula (7)

[Wherein, ring E represents a benzene ring, a pyridine ring, a pyrroyl ring or a pyrazolyl ring;

1 represents 0, 1 or 2, R ^{E 1} and R ^E2 may be the same or different, and each independently represents a hydrogen atom, a halogen, or a carbon number 1 to 1 which may be substituted with a halogen. 4, lower alkyl, nitro, cyano, pyrazolyl, tetrazolyl, carboxyl which may be esterified with lower alkyl or aryl having 1 to 4 carbon atoms, or halogen, 1 to 4 carbon atoms which may be substituted with at least one group selected from the group consisting of rufolino, phenylbiperazinyl, and carboxyl which may be esterified with lower alkyl or aryl having 1 to 4 carbon atoms. shows a lower alkoxy (provided that when a ring E Gabe benzene ring, R ^{E 1} and R ^E2 is connexion such with benzene璟naphthoquinone evening was Len ring or form a quinoline ring.), R ^E3 Is hydroxy, nitro, halogen, lower alkyl having 1 to 4 carbon atoms which may be substituted by halogen, lower alkoxy having 1 to 4 carbon atoms which may be substituted by halogen, or carbon number? May represent an aralkyloxy group of from 12 to 12 or may form a naphthylene ring or a quinoline ring together with the benzene ring substituted by R ^E3 , and R ^E4 is a hydrogen atom; Lower alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 5 carbon atoms, optionally substituted aralkyl, optionally substituted aromatic heterocyclic alkyl, lower alkyl having 1 to 4 carbon atoms, Or carboxymethyl, which may be esterified with aryl, carbonylmethyl which is amidated with primary amine, secondary amine, or cyclic amine, or aralkyloxymethyl which may be substituted. Show. ] The quinazoline derivative represented by these.

Example 9: A peptide compound disclosed in JP-A-9-124691.

 For example, the following general formula (8)

[Wherein, R ^{F 1} represents alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, arylalkyl, heteroaryl, heterocycle, or heterocyclealkyl which may be substituted with —COR ^F8 ; R ^{F 2} and R ^F3 may be the same or different and each independently represents a hydrogen atom, — an alkyl, cycloalkyl, cycloalkylalkyl, aryl or aryl optionally substituted with COR ^F8 Or R ^F2 and R ^F3 are joined together and replaced by a COR ^F8 May form an alkylene chain having 4 to 6 carbon atoms, R ^F4 represents a hydrogen atom or an alkyl, and R ^F5 represents a hydrogen atom or an alkyl (provided that X ^F represents the following general formula (8— In the case of the group represented by 2), X ^F and R ^F5 may be taken together to form an alkylene chain having 2 to 4 carbon atoms.) And Y ^F is cycloalkyl, aryl or Represents teroaryl, 1 represents 0, 1, 2 or 3, A ^F represents carbonyl or sulfonyl, and X ^F represents the following general formula (8-1)

Or a group represented by the following general formula (8-2)

{In the formula (8-1), the ring B ^F represents an aromatic ring, and Z ^{F 1} and Z ^F2 may be the same or different, and each independently represents a hydrogen atom, a hydroxyl group, —C0R ^F8 , C0R ^{F8 represents} an alkyl which may be substituted, or S 0 ₂ R ^F8 , wherein in the formula (8-2), R ^F6 and R ^F7 may be the same or different; Hydrogen atom, cycloalkyl, cycloalkylalkyl, arylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, — COR ^F8 , alkyl, alkenyl, alkynyl, heterocycle or heterocycle optionally substituted by one C 0 R ^F8 May represent alkyl, or R ^F6 and R ^F7 may be taken together to form an alkylene chain having 4 to 6 carbon atoms which may be substituted by one COR ^F8 (provided that R ^F6 , the R ^F7 at the same time hydrogen atom Not be, also, either or both of R ^F6, R ^F7 is a heteroatom of the hetero cycle when it is Terosai cycle also to be substituted with -COR ^F8 is a R ^F6, R ^F7 Does not bind to the carbon atom to which it binds.) Wherein R ^F8 represents a hydroxyl group, alkoxy, amino, alkylamino, dialkylamino, aryloxy or arylalkoxy. ] The compound represented by these.

In addition, the fact that the compounds of Examples 1 to 9 have a chimase inhibitory action indicates that these compounds Are disclosed in the respective publications.

 In the present specification, the pharmacologically acceptable salt is not particularly limited, and those commonly used in this field can be used. For example, inorganic acids (for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like) , Hydrofluoric acid, hydrobromic acid, etc.), organic acids (eg, formic acid, acetic acid, tartaric acid, lactic acid, cunic acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethylsulfonic acid, benzenesulfonic acid) , P-toluenesulfonic acid, naphthylenesulfonic acid, camphorsulfuric acid, etc.), and salts of alkali metals or alkaline earth metals (eg, sodium, potassium, calcium, etc.).

 The compound having a chimase inhibitory action according to the present invention has an extremely good itching inhibitory action, as described in detail in Test Examples later. Therefore, the compound having a chimase inhibitory activity according to the present invention is extremely effective as an active ingredient of a therapeutic and prophylactic agent for itch, especially for atopic dermatitis.

 If the itching inhibitor of the present invention is administered before the onset of atopic dermatitis and after itching has occurred, it can suppress the onset of atopic dermatitis due to its excellent itch suppressing effect, and Dermatitis can be prevented. In addition, if the anti-itch agent of the present invention is administered after the onset of atopic dermatitis, its excellent itching-inhibiting action can prevent skin rupture, prevent the deterioration of symptoms, and treat atopic dermatitis. Can be. Therefore, the itching inhibitor of the present invention is an excellent therapeutic agent for atopic dermatitis and an excellent agent for preventing atopic dermatitis.

 Further, unlike the anti-histamine drug having antipruritic activity, which is an anti-allergic drug, the anti-itch agent of the present invention has no Hi antagonism, and therefore has a side effect such as a central inhibitory effect. Can be avoided.

 The itch inhibitor of the present invention comprises, as an active ingredient, a compound having a chimase inhibitory activity, and in formulating it, together with a suitable diluent and other additives which are usually used, in a suitable administration form (for example, powder) , Injections, tablets, capsules, topical preparations, etc.) and then by the appropriate administration method (for example, intravenous administration, oral administration, dermal administration, topical administration, etc.) according to the dosage form, It can be administered to animals.

The form of the topical topical formulation is not particularly limited as long as it can be applied to the affected area, including the antipruritic agent of the present invention and the topical medium (base). Examples thereof include liquids, aerosols, creams, and gels. (Jelly), powder, ointment, poultice, liniment and the like.

 Depending on its form, topical external preparations can be used in conventional bases (eg, oily bases, hydrophobic bases, emulsion bases, hydrophilic bases, water-soluble bases, gel bases, etc.) and conventional bases. Ingredients (e.g., surfactants, fatty acids or derivatives thereof, esters of polycarboxylic acids and alcohols, higher alcohols, suspending agents, thickeners, powdered inorganic substances, gelling agents, water, alcohol , Polyhydric alcohols, alkanolamines, propellants, etc.).

 The components of the oily base and the hydrophobic base include, for example, petrolatum, liquid paraffin, paraffin wax, plastibase containing liquid paraffin and polyethylene, silicone oil, triglyceride, squalene, beeswax, salami beeswax, and microcriss. Examples include waxes such as phosphorus wax, paraffin wax, and whale wax, and refined lanolin.

 The components of the emulsion base include oil bases (for example, petrolatum, lanolin, etc.), higher alcohols, surfactants, emulsifiers and the like.

 In addition, the components of the hydrophilic base and the water-soluble base include a hydrophilic fatty acid ester such as glycerin ester of a saturated fatty acid (eg, Adeps solidus) and polyethylene glycol (eg, macrogol). And other water-soluble polymers.

 Examples of the gel base component include organic hydrogel bases such as colloid-dispersed starch, tragacanth, alginate, and cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, etc.), and colloidal bases. Inorganic hydrogel bases containing clay (for example, silicates such as bentonite and veegum) are included.

Examples of the surfactant include natural emulsifiers (eg, gum arabic, gelatin, tragacanth, lecithin, cholesterol, etc.), anionic surfactants (eg, stone, sodium alkyl sulfate, etc.), polyoxyethylene sorbitan Fatty acid esters (eg, monooleyl polyoxyethylene sorbitan), glycerin fatty acid esters (eg, polyoxyethylene castor oil derivatives, polyoxyethylene hydrogenated castor oil, glycerin monostearate, sorbitan monoolate, etc.) , Sorbitan fatty acid ester (example For example, sorbitan monostearate, sorbitan sesquioleate, etc., polyoxyethylene higher alcohol ethers (eg, polyoxyethylene cetyl ether), nonionic surfactants (eg, polyoxyethylene alkylphenol, polyoxy) Examples thereof include an ethyleneoxypropylene copolymer (for example, pluronic) and the like, a cationic surfactant (for example, cetyltrimethylammonium chloride), and an amphoteric surfactant.

 Examples of the fatty acids or derivatives thereof include higher fatty acids (eg, oleic acid, stearic acid, etc.) or salts thereof, higher fatty acids (eg, hexanoic acid, octanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, etc.). ) With monohydric aliphatic alcohols (eg, isopropyl myristate, isopropyl palmitate, isopropyl stearate, decyl oleate, etc.), triglycerides (eg, triglyceride octanoate, triglyceride hexanoate, Examples include peanut oil, castor oil, cocoa oil, hydrogenated oils (eg, hydrogenated castor oil, etc.), and fatty acid esters of polyhydric alcohols (eg, Penyu erythritol fatty acid ester, etc.).

 Examples of the ester of a polyvalent carboxylic acid and an alcohol include esters of a polyvalent carboxylic acid such as adipic acid and sebacic acid with a monovalent aliphatic alcohol (for example, ethyl ethyl adipate, disopropyl adipate and the like).

 Examples of higher alcohols include benzyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, 2-year-old tyldodecanol, and the like.

 Examples of suspending agents and thickeners include polysaccharides (for example, gum arabic, tragacanth, pullulan, oral custingham, bingham, pectin, xanthan gum, guar gum, etc.), methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinyl alcohol Examples include pyrrolidone, acrylic acid copolymer, carboxyvinyl polymer, and colloidal microcrystalline cellulose.

 Examples of the powdery inorganic substance include talc, calcium anhydride, calcium carbonate, magnesium carbonate, colloidal silica, bentonite and the like.

Examples of the gel forming agent include polyacrylic acid, polymethacrylic acid or a salt thereof, Examples thereof include super-absorbent resins such as cross-linked polyvinyl alcohol, sodium oxymethylcellulose, gum arabic, xanthan gum, guar gum and the like.

 Examples of the alcohol include ethanol and isopropanol. Examples of the polyvalent alcohol include ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, 1,3-tetramethylene glycol, glycerin, and the like. Sorbitol and the like; and alkanolamines, for example, diethanolamine, triethanolamine and the like.

 Examples of components of the propellant include low-boiling fluorocarbons (eg, Freon 22) and aliphatic hydrocarbons (eg, propane, butane, etc.).

 In addition, if necessary, topical topical preparations may contain other additives such as preservatives such as methyl parabenzoate, propyl parabenzoate and other preservatives, and antioxidants such as butylhydroxytoluene. Stabilizers, coloring agents, fragrances and the like may be added.

 If the topical agent is a liquid, use a surfactant, emulsifier, and, if necessary, higher fatty acid ester, higher alcohol, suspending agent, thickener, alcohol, polyhydric alcohol, preservative, etc. You may.

 A propellant is used in the azo preparation together with the components of the liquid preparation, and a solvent (for example, ethanol, glycerin, propylene glycol, etc.), a higher fatty acid ester, a surfactant and the like can be used as necessary.

 The gel contains a gel-forming agent. The bases of the cream and ointment include the above-mentioned oily base, hydrophobic base, emulsion base, hydrophilic base, water-soluble base, and gel base. A base or the like can be used.

 Powders can be prepared with excipients (eg, lactose and starch), binders, disintegrants, and other suitable additives. The itching inhibitor of the present invention in the form of a powder can be administered intravenously by dissolving it in a physiological saline solution or a high calorie nutritional infusion at the time of use.

The base component of the poultice includes, for example, a rubber component (for example, styrene-isoprene-styrene block copolymer), a tackifier, an oil component, a water-soluble polymer, and a water-absorbing polymer. Water, antioxidants and the like.

 As the liniment, an oil emulsion (eg, fatty oil, stone, gum arabic, tragacanth, etc.), alcohol stone, and the like can be used. If necessary, glycerin, carmellose sodium, and the like may be used.

 The base, components, and additives in these preparations are appropriately selected depending on the type of the preparation, and the amounts thereof are also appropriately selected within the range usually used depending on the dosage form.

 Solid dosage forms for oral administration (eg, powders, granules, tablets, pills, capsules, etc.) can be formulated in a conventional manner, and the active ingredient contains at least one additive (eg, sucrose, Lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi- Synthetic polymers, such as glycerides, etc., and such dosage forms usually also include an inert diluent, a lubricant (eg, magnesium stearate), a preservative (eg, Parabens, sorbic acid or its salts), antioxidants (eg, ascorbic acid, Errol, etc. cysteine), disintegrator, binder, thickener, buffering agent, sweetening imparting agents, flavoring agents, Pas one fumes agents, etc.), and the like. Tablets and pills can additionally be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, and these are inert diluents commonly used in the art. For example, water) may be included.

 The powder for dissolution at the time of use is prepared by dissolving an effective amount of the itch inhibitor of the present invention in, for example, a diluent (for example, distilled water, physiological saline, an aqueous glucose solution, etc.), and adding an excipient ( For example, carboxymethylcellulose (CMC), sodium alginate, etc., preservatives (eg, benzyl alcohol, benzalkonium chloride, phenol, etc.), soothing agents (eg, glucose, calcium gluconate, proforce hydrochloride, etc.), It can be prepared by adding a pH regulator (for example, hydrochloric acid, acetic acid, citric acid, sodium hydroxide, etc.) and freeze-drying by a conventional method.

Injectables may contain an effective amount of the itching inhibitor of the present invention, for example, a diluent (eg, distilled water, raw water). Dissolved in physiological saline, Ringer's solution, etc., and if necessary, solubilizers (eg, sodium salicylate, sodium acetate, mannitol, etc.), buffers (eg, sodium citrate, glycerin, etc.), isotonicity Agents (eg, pudose, invert sugar, sucrose, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (eg, benzyl alcohol, penzalconium chloride, phenol, etc.), soothing agents (eg, For example, glucose, calcium gluconate, proforce hydrochloride, etc.) and a pH adjuster (eg, hydrochloric acid, acetic acid, citric acid, sodium hydroxide, etc.) are added, and the mixture is subjected to ordinary heat sterilization, sterile filtration, etc. Can be prepared by aseptic sterilization.

 In addition, the antipruritic agent of the present invention 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 anti-itch agent of the present invention can be prepared as a single drug (injection) by mixing and dissolving the active ingredient in advance with ordinary infusion components such as amino acids, carbohydrates, and electrolytes, and can be administered intravenously. You.

 The above-mentioned various dosage forms can be prepared by usual various methods commonly used in this field, and various diluents and additives used at this time may also be used. it can.

 Further, the itch inhibitor of the present invention may be used in combination with other antihistamines, antiallergics, and antiserotonins having an antipruritic effect.

 The dose of the itching inhibitor of the present invention varies depending on the administration route, the patient's condition, body weight, sex, age, etc., but can be appropriately set depending on the purpose of administration.

 Usually, when administered orally to an adult, the itching inhibitor of the present invention has an amount of the active ingredient of 0.01 to 100 Omg / kg body weight / day, preferably 0.05 to 25 Omg / kg body weight / day. Can be administered once to several times a day. When administered to an adult by injection, the active ingredient is administered in a dose range of about 0.01 mg / kg to about 100 Omg / kg / dose, preferably about 0.1 to 25 Omg / kg / dose. Can be administered intravenously once to several times a day, or continuously.

When the itch inhibitor of the present invention is administered as a topical agent, the itch of the present invention may be administered. The content of the active ingredient in the inhibitor is, for example, about 0.2 to 5% by weight, preferably about 0.5 to 3% by weight in the topical medium. The topical topical preparation can be applied according to the dosage form and the like, for example, by a method such as application, rubbing or spraying. The amount of the topical topical agent applied to the affected area can be selected according to the content of the active ingredient and the like.

 In addition, the itch inhibitor of the present invention is preferably used in combination with a steroid agent, because the itch inhibitory effect of the steroid agent alone can be enhanced, and the dose of the steroid agent can be reduced. . That is, it can be said that the itch inhibitor of the present invention is an itch inhibitory effect enhancer that enhances the itch inhibitory effect of the steroid agent in the presence of the steroid agent.

 Examples of the steroid agent used in the present invention include adrenocortical hormone (for example, glucocorticoid), and synthetic steroids having the same action as adrenocortical hormone (for example, prednisolone, dexamethasone, methanozone, hydrocortisone). , Triamcinolone and the like), and preferably, prednisolone, dexamethasone and betamethasone.

 Regarding the method of using the itch inhibitor and the steroid agent of the present invention in combination, any combination may be used as long as both coexist in a living body at the same time. The term "living body" as used herein refers to any part of the living body, such as the stomach and other organs, blood vessels, and skin tissue. The method of using the itch inhibitor of the present invention in combination with the steroid agent includes, specifically, (1) a method of adding a steroid agent to the itch inhibitor of the present invention and using it in a one-part form; Examples include a method in which an antipruritic agent and a steroid agent are separately formulated and administered simultaneously or with a time lag.

 In the method (2), the itch inhibitor of the present invention and the steroid agent may be administered by the same or different administration methods. For example, the itch inhibitor of the present invention is orally administered, and the steroid agent is administered locally (external agent) Coating). When administering the itch inhibitor of the present invention and the steroid agent with a time difference, the administration time difference may be usually within 6 hours, preferably within 2 hours.

The dosage of the active ingredient of the antipruritic agent of the present invention when used in combination with a steroid drug depends on the dose, administration route, patient condition, body weight, age, etc. of the steroid drug to be used in combination. In the case of (1), when administered locally to an adult, it is usually 0.01 to 100 Omg / kg body weight / day, preferably 0.05 to 50 Omg / kg body weight / day. When administered, the dose is 0.01 to: L00 Omg / kg body weight / day, preferably 0.05 to 50 Omg / kg body weight / day.

 The itch inhibitor of the present invention can be used in combination with an antihistamine and an antiserotonin in addition to a steroid agent to enhance their itch inhibitory effect.

 Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto.

 In Reference Examples and Examples, the measurement was performed at —NMI and 50 OMHz. The chemical shifts of ifi-NMR were expressed in parts per million (ppm) relative to Dermal (6) using tetramethylsilane (TMS) as the internal standard. The coupling constant indicates the obvious multiplicity in Hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet doublet) , Brs (pro-dosing let), ABq (AB quartet), etc. Bed layer chromatography— (TLC) and column chromatography were performed using Merck Siri force gel. Concentration was performed by using a low-temperature evaporator manufactured by Tokyo Rika Kikai Co., Ltd.

Reference example 1

 Synthesis of {5-benzyloxycarbonylamino-2- (4-fluorophenyl) -6-oxo-1,6-dihydroxy- mouth-1-pyrimidinyl] acetic acid

Step (1): Hydrogen chloride was blown into a solution of 4-fluorobenzonitrile (50.9 g, 0.420 mol) in ethanol (500 mL) under ice-cooling, and the mixture was stirred 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 to obtain 78.8 g (92%) of ethyl 4-fluoropenzimidate hydrochloride as white crystals.

Step (2): To a solution of the target compound (78.8 g, 0.387 mol) in step (1) in ethanol (350 mL) was added dropwise aminoacetaldehyde getylase (62 mL, 0.43 mol) under ice-cooling. After that, the mixture was stirred at 5 ° C for 16 hours. Ethanol was distilled off under reduced pressure, and the obtained concentrate was added to a 1N aqueous sodium hydroxide solution (750 mL), and extracted with chloroform. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and N- (2,2-jetoxetil) -4-fluorobenzamide was removed. A colorless oil containing gin was obtained.

Step (3): To a solution of the target compound of step (2) (the crude product obtained in the above reaction) in ethanol (150 mL), ethylethoxymethylene malonate (86 mL, 0.43 mol) was added dropwise at room temperature. Was. After the dropwise addition, the mixture was heated to 100 ° 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) to give ethyl 1- (2,2-jetoxethyl) -2- (4-fluoro Phenyl) pyrimidin-6 (1H) -one-5-carboxylate was obtained as a pale yellow oil (135 g, yield 92% from the target compound in step (1)).

Step (4): Lithium iodide (120 g, 0.895 mol) was added to a solution of the target compound of step (3) (135 g, 0.358 mol) in pyridine (480 mL), and the mixture was heated to 100 ° C and stirred for 16 hours. . After evaporating the organic solvent under reduced pressure, toluene (100 mL) was added, and 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, the pH was adjusted to 3 with 2N hydrochloric acid (about 1 L), and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give 1- (2,2-diethoxychetyl) -2- (4-fluorophenyl) pyrimidine-6 (1H)- A brown oil containing on-5-carboxylic acid was obtained.

Step (5): A solution of the target compound of Step (4) (the crude product obtained in the above reaction) and a solution of triethylamine (87.5 mL, 0.63 mol) in 1,4-dioxane (900 mL) are added at room temperature to diphenylphosphoryl. Azide (84 mL, 0.37 mol) was added dropwise. After the dropwise addition, the mixture was heated to 110 ° C and stirred for 2 hours. After cooling to room temperature, pendyl alcohol (44 mL, 0.43 mol) was added. 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 solution of ammonium chloride (1 L), and extracted with ethyl acetate. The extract was washed sequentially with a 1N aqueous sodium hydroxide solution and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography (1: 2 ethyl acetate-hexane), and [5-pentyloxycarbonylamino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo [Topirimidinyl] acetaldehyde 126 g (69% as the target compound) of a mixture of acetyl acetyl acetal and benzyl alcohol was obtained as a pale yellow oily substance. Step (6): To a solution 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)) in tetrahydrofuran (THF) (650 mL) is added IN hydrochloric acid (500 ml). And 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 give [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl. A white solid containing acetoaldehyde was obtained.

Step (7): target compound of step (6) (crude product obtained in the above reaction), 2-methyl-2-propanol (900 mL) and 2-methyl-2-butene (106 mL, 1.00 mol) To a mixture of the above, a solution of sodium dihydrogen phosphate dihydrate (180 g, 1.15πιο1) and sodium chlorite (containing 80%, 136 g, 1.20 mol 1) in water (400 mL) was added, and the mixture was added at room temperature for 2 hours. Stirred. 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. Ethyl acetate-hexane (1: 1) was added to the residue for crystallization to give 10.6 g of the title compound as a white solid. The insoluble matter obtained above was added to 1 N hydrochloric acid (500 mL), extracted with ethyl acetate, the extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Further, 67.7 g (total yield: 80%) of the title compound was obtained as a white solid.

¹ H-NMR and IR measurement values of the obtained compound are shown below.

Thigh _{(500MHz, DMS0-d 6)} (5 13.3 (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, 2H), 7.30-7.42 (m, 5H), 5.19 (s, 2H), 4.53 (s, 2H)

IR (KBr) 3650-2300, 1720, 1660, 1600 cm one ¹

Reference example 2

 Synthesis of 2-Amino-1-hydroxy-1- [5- (methoxycarbonyl) penzoxazol-2-yl] -3-phenylpropane

Step (1): To a solution of 4-hydroxy-3-nitrobenzoic acid (15.8 g, 86.3 mmol) in 1,2-dichloroethane (150 mL) was added methanol (14 mL) and concentrated sulfuric acid (0.5 mL). Warmed to ° C and stirred. On the way, methanol (9 mL) was added, and the mixture was stirred for 21 hours. Saturated carbonated water The solution was added to an aqueous solution of sodium hydrogen chloride (400 mL), and extracted with chloroform. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 11.5 g (yield: 68%) of methyl 4-hydroxy-3-nitrobenzoate as a yellow solid.

Step (2): To a solution of the target compound (11.4 g, 57.8 ol) in step (1) in ethyl acetate (300 mL) is added 10% palladium on carbon (1.80 g) under a nitrogen atmosphere, and the mixture is heated at room temperature under a hydrogen atmosphere. The mixture was stirred for 18 hours. 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), dried under vacuum, and 9.34 g of methyl 3-amino-4-hydroxybenzoate was obtained as a light brown solid (yield 97%). Obtained.

Step (3): Benziroxycarbonyl chloride was added to a mixture of phenylalaninol (20.2 g, 0.134 mol), sodium carbonate (21.2 g, 0.200 mol) and 1,4-dioxane (150 mL). (1 9.1 mL, 0.134 mol) in 1,4-dioxane (50 mL) was added, 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 (76%) of N-benzyloxycarbonyl-L-phenylalaninol as white crystals.

Step (4): In a dichloromethane (100 mL) solution of the target compound of Step (3) (10.7 g, 37.5 mmol) and triethylamine (21.3 mL, 153 mol / l), iodipyridine trioxide complex (23.9 g, 150 mol / l) Was added at −10 ° C. in dimethylsulfoxide (DMS0) (100 mL). The resulting solution was stirred at 10-20 ° C for 45 minutes, added to a saturated saline solution (400 mL), and extracted with ether. The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give N-pentyloxycarbonyl-L-phenylalanine. 10.6 g (quantitative) were obtained as a white solid.

Step (5): Triethylamine (1.5 mL) was added to a dichloromethane (50 mL) solution of the target compound (5.00 g, 17.6 t ol) and acetone cyanohydrin (4.8 mL, 53 orchid ol) in Step (4). , 11 mmol) and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained concentrate was added to water (100 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 separated and purified by silica gel column chromatography (2: 1 ethyl hexane monoacetate) to obtain 5.15 g (94) of N-pentyloxycarbonyl-L-phenylalaninylcyanohydrin as a pale yellow solid. Step (6): Acetyl chloride (10 mL, 0.14 mol) was added dropwise over 10 minutes to a mixture of chloroform (10 mL) and ethanol (9.5 mL, 0.16 mol) under ice-cooling. After stirring at 0 ° C for 30 minutes, a solution of the desired compound (1.50 g, 4.83 tmol) in step (5) in a form (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) and the target compound of step (2) (1.94 g, 11.6 mmol) were added to the obtained solid, 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 0.5 sodium hydroxide aqueous solution (50 mL), and extracted with ethyl acetate. The extract was washed successively with 0.5 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (100: 1 chloroform-methanol) to give 2-pentyloxycarbonylamino-1-hydroxy-1- [5- (methoxycarbonyl) benzoxazole-2- 1.80 g (81%) of 3-ylphenyl-3-propane as a light brown solid.

Step (7): To a solution of the target compound of Step (6) (1.65 g, 3.58 bandol) in methanol (25 mL) is added 10% palladium on carbon (378 rag) under a nitrogen atmosphere, and at room temperature under a hydrogen atmosphere. The mixture was stirred for 24 hours. After removing the catalyst by filtration and washing with methanol, the filtrate was concentrated under reduced pressure to obtain 1.14 g (yield 98%) of the title compound as a pale brown solid.

¹ H-NMR and IR measurement values of the obtained compound are shown below.

NMR-NMR (500 MHz, DMS0-d ₆ ) δ 8.27 (d, J = 1.3 Hz, 0.4H),

8.25 (d, J = 1.3 Hz, 0.6H), 8.03 (dd, J = 8.6, 1.3 Hz, 0.4H),

8.02 (dd, J = 8.6, 1.3 Hz, 0.6H), 7.84 (d, J = 8.6 Hz, 0.4H),

7.81 (d, J = 8.6 Hz, 0.6H), 7.28-7.23 (m, 4H), 7.18-7.13 (m, 1H),

4.77-4.73 (m, 1H), 3.89 (s, 3H), 3.58 (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, 0.6H),

2.81 (dd, J = 13.6, 6.8 Hz, 0.6H), 2.65 (dd, J = 13.6, 8.2 Hz, 0.4H)

IR (KBr) 3300, 1710, 1615 cm " ¹

Reference example 3

Synthesis of 2 (S) -amino-1- (2-benzoxazolyl) -1-hydroxy-3-phenylpropane Step (1): Reference compound of Reference Example 2- (3) (43.7 g, 0.153 mol), 2,2,6,6-tetramethylbibe A 6% aqueous solution of sodium hypochlorite was added to a mixed solution of lysine-toxyl free radical (240 mg, 1.54 mol) and sodium bromide (15.7 g, 0.153 mol) in ethyl acetate (450 mL) and toluene (450 mL). (205 mL, 0.17 mol) and a solution of sodium hydrogen carbonate (37.5 g, 0.446 mol) in water (270 mL) were added dropwise over 1.75 hours under ice-cooling, followed by stirring for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was extracted twice with a 10% aqueous solution of potassium hydrogen sulfate (1.25 mL, 7.5 mL) (200 mL) and a 10% aqueous solution of sodium thiosulfate (150 mL). The extract was washed successively with 0.2 M phosphate buffer (pH 7, 250 mL) and saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. Ethyl acetate (100 mL) and hexane (300 mL) were added to the residue, and the mixture was allowed to stand at room temperature. The precipitated crystals are collected by filtration, washed with hexane-ethyl acetate (3: 1, 30 mL), and dried under vacuum to give N-benzyloxycarbonyl-L-phenylalaninal as white crystals. 39.62 g (91% yield) was obtained.

Step (2): A solution of the target compound of Step (1) (24.46 g, 86.33, fraction 01) in DMF (335 mL) was added with sodium carbonate (1.83 g, 17.3 mmol) and acetone cyanohydrin (9.5 mL, 10 mol), and the mixture was stirred at 0 ° C for 2 hours. Water (1200 mL) was added, and the mixture was extracted with ethyl acetate-hexane (1: 1). The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 25.35 g of a pale yellow oily substance containing N-benzyloxycarbonyl-L-phenylalaninyl cyanohydrin.

Step (3): The same reaction as in Reference Example 2- (6) using the target compound of Step (2) (crude product obtained in the above reaction) and 0-aminophenol (11.3 g, 104 tmol) Yielded 17.7 g of 1- (2-benzoxazolyl) -2 (S) -benzyloxycarbonylamino-1-hydroxy-3-phenylpropane as a brownish solid [yield from the target compound in step (2). 51%].

Step (2): Using the target compound (17.7 g, 43.9 mmol) of step (3), the reaction was carried out in the same manner as in Reference Example 2- (7) to give 2 (S) -amino-1- (2-benzoxaxene). 13.0 g of a brown solid substance containing zolyl) -hydroxy-3-phenylpropane was obtained.

The -ΝΜΙΙ measurement values of the obtained compound are shown below.

Ή-NMR (500 MHz, DMS0-d ₆ ) d 7.74-7.68 (m, 2H), 7.41-7.15 (m, 7H), 6.17 (m, 0.4H), 6.08 (m, 0.6H), 4.61 (m , 0.6H), 4.54 (m, 0.4H), 3.34 (m, 1H), 3.05 (dd, J = 13.4, 3.8 Hz, 0.4H), 2.78 (dd, J = 13.4, 5.9 Hz, 0.6H), 2.60 (dd, J = 13.4, 7.9 Hz, 0.6H), 2.53 (dd, J = 13.4, 8.9 Hz, 0.4H), 1.47 (brs, 2H) Reference example 4

 Synthesis of 4 (S) -amino-N-benzyl-2,2-difluoro-mouth 3-hydroxy-5-phenylpentanoic acid amide

Step (1): To a suspension of zinc (8.93 g, 137 bandol) and THF (15 mL) was added dropwise ethyl bromodifluoroacetate (2.9 mL, 23 ml) at room temperature over 3 minutes. Ethyl promodifluoroacetate (1 4.6 mL, 114 marl) and a solution of the target compound of Reference Example 3-(1) (12.9 g, 45.5 tmol) in THF (72 mL) were added dropwise over 25 minutes. Stirred for minutes. The reaction solution was ice-cooled, a saturated aqueous solution of ammonium chloride (300 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (2: 1 hexane-ethyl acetate) to give 4 (S) -benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-5-phenylpentanoic acid. 13.3 g (72% yield) of ethyl was obtained as a pale yellow oil.

Step (2): To a solution of the target compound (13. Og, 31.9 mmol) in Step (1) in THF (90 mL) was added pendylamine (10.5 mL, 95.8 mmol), and the mixture was stirred at room temperature for 3 days. The reaction solution was added to 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off to give N-benzyl-4 (S) -benzyloxycarbonylamino-2,2-difluoro-3-hydroxy. 18.2 g of a pale yellow solid substance containing 5-phenylpentanoic acid amide was obtained.

Step (3): A 10% palladium carbon (5.46 g) solution is added to a methanol-dioxane (1: 1, 600 mL) solution of the target compound of Step (2) (the crude product obtained in the above reaction), and then a hydrogen atmosphere is added. The mixture was stirred at room temperature for 6 hours. The palladium carbon was removed by filtration, and the solvent of the filtrate was distilled off. The residue was separated and purified by silica gel column chromatography (10: 1 chloroform-methanol) to give 4 (S) -amino-N-benzyl-2,2-difluoro-3-hydroxy-5-phenyl. 5.78 g of lupentanoic acid amide was obtained as a white solid [yield from the target compound in step (1): 54%].

The -R measurement of the obtained compound is shown below.

Ή-NMR (300 MHz, DMS0-d ₆ ) d 9.40 (brs, 1H), 7.40-7.09 (m, 10H), 5.98 (brs, 1 H), 4.33 (s, 2H), 3.74 (dt, J = 1.8, 14.5 Hz, 1H), 3.09 (dt, J = 1.8, 7.3 Hz, 1H), 2.75-2.55 (m, 2H), 1.5 (brs, 2H) Example 1

 2- [5-Amino-2- (4-fluorophenyl) -6-oxo-1,6-dihydro-topyrimidinyl] -N- [l-[[5- (methoxycarbonyl) benzoxazol-2- Synthesis of [yl] carbonyl] -2-phenylethyl 1acetamide (Compound 1)

Step (1): HOBT (884 mg, 6.54 mmol) was added to a solution of the title compound of Reference Example 1 (1.30 g, 3.27 mmol) and the title compound of Reference Example 2 (1.08 g, 3.31 mmol) in DMF (10 mL). And WSCI hydrochloride

(752 mg, 3.92 mmol) was added and the mixture was 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. The solid precipitated at this time is collected by filtration, dried under vacuum, and dried to give 2- [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -6-oxo-1,6-dihydrido-1. 1.26 g of -pyrimidinyl] -N- [l-[[5- (methoxycarbonyl) benzoxazolyl-2-yl] hydroxymethyl] -2-phenylethyl] acetamide was obtained as a white solid. The filtrate was washed successively with an aqueous saturated sodium hydrogen carbonate solution and saturated saline, and concentrated under reduced pressure. The obtained solid is washed with ether, dried under vacuum, and further treated with 2- [5-pentyloxycarbonylamino-2- (4-fluorophenyl) -6-oxo-1,6-dihydro-. Topyrimidinyl] -N- [l-[[5- (methoxycarbonyl) benzoxazol-2-yl] hydroxymethyl] -2-phenylethyl] acemidamide as a light brown solid 408 mg (Total 1.66 g, total yield 72%).

Step (2): In a mixed solution of the target compound (1.56 g, 2.21 mmol) in DMS0 (20 mL) and toluene (20 mL) in step (1) was added WSCI hydrochloride (5.09 g, 26.6 ol) and dichloromethane. Acetic acid (0.87 mL,

1.11 mmol) and stirred at room temperature for 7 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 hydrogencarbonate and a saturated aqueous solution of sodium chloride. A white solid precipitated at this time was collected by filtration, dried under vacuum, and dried with 2- [5-benzyloxycarbonylaminoamino-2- (4- Fluorophenyl) -6-oxo-1,6-dihydro-topyrimidinyl] -N- [l-[[5- (methoxycarbonyl) benzoxazol-2-yl] carbonyl] -2-phenylene 1.06 g of [R] asemidamide was obtained as a white solid. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (5: 1 dichloromethane-ethyl acetate), and further purified with 2- [5-benzyloxycarbonylamino-2- (4- Fluorophenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] -N- [1-[[5- (methoxycarbonyl) benzoxazole-2-yl] carbonyl] -2- Phenylethyl] asemidamide as a pale yellow solid 222 mg (total 1. 28 g, yield 82%).

Step (3): To a solution of the target compound (462 mg, 0.657 mmol) and anisol (0.21 mL, 1.9 tmol) in dichloromethane (13 mL) under ice-cooling, was added trifluoromethanesulfonic acid (0%). (35 mL, 4.0 mmol) and stirred at 0 C to 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. 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 separated and purified by silica gel column chromatography (30: 1 chromatoform-methanol) to obtain 368 mg (yield: 98%) of the title compound (compound 1) as pale yellow crystals.

 The melting point, —NMR, IR, and MS measured values of the obtained compound 1 are shown below.

 mp 208-213 ° C

'H-NMR (500 MHz, DMS0-d ₆ ) δ 8.97 (d, J = 6.7 Hz, 1H),

8.51 (d, J = 1.6 Hz, 1H), 8.24 (dd, J = 8.7, 1.6 Hz, 1H),

8.05 (d, J = 8.7 Hz, 1H), 7.35 (dd, J = 8.8, 5.6 Hz, 2H),

7.28-7.17 (m, 6H), 7.08 (t, J = 8.8 Hz, 2H), 5.50 (m, 1H),

5.12 (s, 2H), 4.48 (d, J = 16.8 Hz, 1H), 4.41 (d, J = 16.8 Hz, 1H),

3.93 (s, 3H), 3.31 (m, 1H), 2.97 (dd, J = 14.1, 8.9 Hz, 1H)

IR (KBr) 3370, 1705, 1655, 1600 cm " ¹

MS (SIMS, positive) m / z 570 (MH ⁺ )

Example 2

 2- [5-amino-2- (3-methoxyphenyl) -6-oxo-1,6-dihydro-topyrimidinyl] -N- [l (S)-[(2-benzoxazolyl) Synthesis of carbonyl] -2-phenylethyl] acetamide (Compound 3)

 Step (1): 2- [5-benzyloxycarbonylamino-2- (3-methoxyphenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl obtained in the same manner as in Reference Example 1. ] Acetic acid (17.75 g, 43.30 ref.) And 2 (S) -amino-1- (2-benzoxazolyl) -1-hydroxy- obtained in Reference Example 3

By using 3-phenylpropane (13.0 g) and performing the same reaction as in Example 1_ (1), 2- [5-benzyloxycarbonylamino-2- (3-methoxyphenyl) -6-oxo -1,6-dihydro-topyri 22.35 g of [midinyl] -N- [1 (S)-[(2-benzoxazolyl) hydroxymethyl] -2-phenylethyl] acetamide was obtained as a light brown solid (yield 77%).

Step (2): To a solution of the target compound (23.42 g, 35.50 mmol) in step (1) in dichloromethane (210 mL) is added 2,2,6,6-tetramethylbiperidine 1-oxyl, free radical (55 mg, 0.35 thigh ol), 0.5 M potassium bromide aqueous solution (7.1 mL), and 6% sodium hypochlorite aqueous solution (56 mL, 46.2 thigh ol) and sodium bicarbonate (6.6 g, 78.6 mmol) in water (76 mL) The solution was added dropwise over 15 minutes under ice cooling, followed by stirring at 400 rpm for 4 hours. In addition, 2,2,6,6-tetramethylpiperidine methoxyl, free radical (27 mg, 0.17 benzyl), 6% aqueous sodium hypochlorite solution (28 mL, 23.1 ol) and sodium hydrogen carbonate ( A solution of 3.3 g, 39.3 thigh 01) in water (38 mL) was added dropwise over 15 minutes under ice cooling, and the mixture was stirred at 500 rpm for 1.5 hours. The precipitated crystals are collected by filtration, washed with water (200 mL) and ethyl acetate (300 mL), dried under vacuum, and treated with 2- [5-benzyloxycarbonylamino-2- (3-methoxyphenyl) -6- Oxo-1,6-dihydro-topyrimidinyl] -N- [1 (S)-[(2-benzoxazolyl) carbonyl] -2-phenylethyl] acetamide as white crystals 15. 57 g (yield 67%) were obtained.

Step (3): A solution of the target compound of Step (2) (15.57 g, 23.67 mmol) and anisol (8.2 mL, 75 tmol) in dichloromethane (220 mL) was added under ice-cooling to trifluoromethanesulfonic acid (12.6 mL, After adding 142 ol), the mixture was stirred at 0 ° C to room temperature for 2.5 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was stirred for 20 minutes.

(400 mL), and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

Separation and purification with (30: 1 form-methanol), ethanol (100 mL) was added to the obtained yellow amorphous, and the mixture was allowed to stand under ice-cooling to precipitate a solid. The collected brown solid was dissolved in black-mouthed form (80 mL), half of the black-mouthed form was distilled off, hexane (25 mL) was added, and the mixture was allowed to stand under ice-cooling. The precipitated crystals are collected by filtration, washed with ethanol (80 mL), dried in a vacuum, and dried at 2- [5-amino-2- (3-methoxyphenyl) -6-oxo-1,6-dihydro-1-. 6.42 g of pyrimidinyl] -N- [l (S)-[(2-penzoxazolyl) carbonyl] -2-phenylethyl] acetamide (compound 3) as pale yellow powdery crystals 52%).

The melting point, specific rotation, optical purity, NMR, and MS measurement values of Compound 3 were shown below. mp: 180-187 ° C

[a] ² + 41.13 ° (c 0.50, CHC1 ₃ )

HPLC analysis (CHIRALCEL OD-H 4.6 x 250 nun; 15 ° C; CH ₃ CN; 0.5 mL / min flow rate; 305 nm UV detection, t _E (S) ii 11.90 min, t _R (R) ii 13.19 min) : 96% ee

NMR-NMR (300 MHz, DMS0-d ₆ ) (58.92 (d, J = 6.8 Hz, 1H),

8.01 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H),

7.66 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.30-7.15 (m, 7H), 6.98-6.92 (m, 2H), 6.85 (d, J = 7.6 Hz , 1H), 5.57 (m, 1H), 5.13 (brs, 2H), 4.49 (d, J = 16.6 Hz, 1H), 4.43 (d, J = 16.6 Hz, 1H), 3.68 (s, 3H),

3.27 (dd, J = 14.0, 9.0 Hz, 1H), 2.99 (dd, 14.1, 8.6 Hz, 1H)

MS (ESI, positive) m / z 524 (MH ⁺ )

Example 3

 2- [5-amino-2- (3-chlorophenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] -N- [l (S) -benzyl-3- (N-pentylcarbamoyl) -3 Of 1,3-Difluoro-2-oxopropyl] acetamide (Compound 4)

Step (1): 2- [5-benzyloxycarbonylamino-2- (3-chlorophenyl) -6-oxo-1,6-dihydro- obtained by the same method as in Reference Example 1. 1-Pyrimidinyl] acetic acid (2.49 g, 6.02 mmol) and the 4 (S) -amino-N-benzyl-2,2-difluoro mouth-3-hydroxy-5-phenylpentanoic acid amide obtained in Reference Example 4 ( 2.0 [g, 6.02 mmol) and 2- [5-benzyloxycarbonylamino-2- (3-chlorophenyl) -6-oxo- by the same reaction as in Example 1- (1). 1,6-Dihydro-1-pyrimidinyl] -N- [1 (S) -pendyl-3- (N-benzylcarbamoyl) -3,3-difluoro- mouth-2-hydroxypropyl] acetamide as a white solid 2.7 g (61% yield) was obtained.

Step (2): To a solution of the desired compound (6.7 g, 9.18 mmol) in step (1) in dichloromethane (270 mL), add the Dess-Martin reagent (7.78 g, 18.4 mmol) under ice-cooling, and add 0 ° C to room temperature. The mixture was stirred for 18 hours. Under ice-cooling, a saturated aqueous solution of sodium hydrogencarbonate (150 mL) containing sodium thiosulfate (38 g) was added, and the mixture was stirred for 5 minutes and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol-water (19: 1, 300 mL) to give 2- [5-benzyloxycarbonylamido. No-2- (3-chlorophenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] -N- [1 (S) -pendyl-3- (N-benzylcarbamoyl) -3,3 4.66 g (70% yield) of [-difluoro-2-oxypropyl] asemidamide was obtained as a pale yellow powder.

Step (3): To a solution of the target compound of Step (2) (1.177 g, 1.62 mmol) and anisol (0.53 mL, 4.8 mmol) in dichloromethane (40 mL) under ice cooling is added trifluoromethanesulfonic acid (0.86 mL, 9. The mixture was stirred for 30 minutes. A saturated aqueous solution of sodium hydrogen carbonate (100 mL) was added to the reaction solution, and the mixture was stirred and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (10: 1 chloroform-methanol), and further precipitated from ethyl acetate-heptane to give 2- [5-amino-2- (3-chlorophenyl) -6- Oxo-1,6-dihydric mouth-1-virimidinyl] -N- [1 (S) -pendyl-3- (N-benzylcarbamoyl) -3,3-difluoro-2-oxypropyl] acetamide (compound 4) 0.473 g (yield 49%) was obtained as a white powder solid. Further, this solid (0.200 g) was crystallized from ethanol / water to give 0.148 g of the title compound (distilled compound 4) as white crystalline powder.

The melting point, specific rotation, optical purity, and measured value of @ -NMR of the obtained Compound 4 are shown below. mp: 130-133 ° C

[a] ²⁰ _D + 8.84 ° (c 0.266, MeOH)

HPLC analysis (CHIRALCEL OJ-R 4.6 × 150 wisteria; 40 ° C .; 2: 3 CH ₃ CN-H ₂₀ ;

0.5 mL / min flow rate; 305 nm UV detection, t _R (S) = 15.6 min,

t _R (R) = 21.6min): 97% ee

Ή-NMR (300 MHz, DMS0-d ₆ ) (59.71 (t, J = 6.0 Hz, 1H),

8.82 (d, J = 7.4 Hz, 1H), 7.60-7.00 (m, 15H), 5.23 (brs, 2H),

5.06-4.90 (m, 1H), 4.51-4.23 (m, 4H), 3.19-3.15 (m, 1H), 2.80-2.60 (m, 1H) The inhibitory activity of compound 1 on human cardiac chymase was The activity was measured by the inhibitory activity on the amidase activity of cardiac chimase, and the efficacy was evaluated as follows.

Defined concentration series (5 xM, <x10, く) for 5 nM chimase in the presence of the synthetic substrate succinyl-aranyl-aranyl-prolyl-phenylalanine-P-nitroanilide at a final concentration of 2.5 mM. (100 equivalents of X100) of compound 1 Quantified. The analysis of inhibitory potency was performed by least-squares regression of the Easson-Stedman plot (Proc. Roy. Soc. B., Vol. 121, p. 141, 1936) using a bimolecular equilibrium reaction linearization equation. The inhibitory activity was evaluated based on the apparent inhibition constant (Kiapp) obtained in this analysis and the inhibition constant (Ki) calculated from the final concentration of the reaction solution substrate and the Km value separately determined. To determine 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. The chymase inhibitory activity of compound 1 is 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 is taken below the guaranteed initial absorbance at the substrate concentration used for the enzyme. After that, analysis was performed.

 The reaction solution was prepared by dissolving Compounds 1 and 20 dissolved in 20% of 10% dimethyl sulfoxide (DMS0) in 140 μl of a buffer (pH 7.5) having a composition of Tris-HC1 (100 mM) -KCl (2M). The substrate dissolved in 1 DMS0 and 201 chymidase were added to make the total amount 2001.

 From the absorbance immediately after the addition of the enzyme, the increase in absorbance was recorded as a progressive force at exactly equal time intervals.

 Based on the above data, if necessary, quantitate the residual activity of the inhibitor-added sample relative to the control with no inhibitor, based on the difference between the absorbance at the end of the reaction and the absorbance immediately after addition, and perform analysis or Calculate the reaction rate of the control and inhibitor-added samples in increments (≥20 minutes), shift the rate calculation every 10 to 30 minutes, and calculate the reaction rate from each reaction rate averaged over the entire reaction time. Similarly, the inhibitory activity was analyzed by a method for quantifying the residual activity fraction.

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

Test example 1

 Pharmacological test using mouse scratch model

Six groups of 6-week-old BALB / c mice were sensitized with 10 g of anti-DNP-IgE (b4-IgE) / mouse, and 4 hours later, 0.75% of DNFB (trifluoro-2,4-dinitrobenzene) ) Was applied to the pinna to induce pruritic behavior. The pruritus behavior was quantified by video recording for 30 minutes from 1 hour after DNFB application, observing the pinna pinching behavior by the hind toes, counting the number of pinching actions. Each drug was orally administered 1 hour before DNFB administration. Compounds 1 and 2- [5-amino-2- (3-meth Toxifenyl)-6-oxo-1,6-dihydro-topyrimidinyl] -N- [l-[[5- (Methoxycarbonyl) benzoxazol-2-yl] carbonyl]- [2-Phenylethyl] acetamide (Compound 2) was administered at different concentrations, and 0.5% CMC was administered as a control. The results are shown in Table 1. The b4IgE used in the present specification was reported by Naito et al. (K. Naito et al.

Allergy Clin. Immunol., 1996; 97, 773-780). The following is a brief explanation. IGELb4 Hypridoma (TIB141, ATCC) was treated with penicillin 50 U / mK streptomycin 50 μg / ml, N-2-hydroxyethylpiperazine-Ν'-2-ethanesulfonic acid 0.01 mol / L 10% FCS (fetal calf serum, Flow Laboratories, Irv in, Scot land) were cultured in Du Ibecco's minimum medium (Nissui Pharmaceutical), and the culture supernatant was TNP (Trinitrophenyl) -BSA

(bovin serum albumin) After washing with 0.05 mol / L Tris-HCl (pH 8.0), 1.0 mol / L NaCl, and 0.1 ° NaN ₃ using a Sepharose column, 0.2 mol / L glycine (pH 2.5) and And 0.1% NaN ₃ .

 Table 1 Itching-inhibitory effects of compounds 1 and 2

 As shown in Table 1, administration of Compound 1 and Compound 2 produced a dose-dependent itching inhibitory effect. This has revealed that the itching inhibitor of the present invention effectively suppresses itching.

Furthermore, since the itch-inhibiting effects of the chymase inhibitors of Compound 1 and Compound 2 were observed in an experimental system in which IgE was passively sensitized, the itch-inhibiting effects dependent on IgE and IgE production were completely different phenomena. It is clear that both are independent phenomena. Test example 2

Combination effect of compound 1 with itching inhibitor having other mechanism of action (anti-histamine / serotonin action)

 6-week-old BALB / c mice were grouped in groups of 8, and sensitized with anti-DNP-IgE (b4-IgE) 10 g / mouse.After 24 hours, 0.75% DNFB was applied to the auricle, and itching behavior was observed. Was triggered. The pruritus behavior was quantified by videotaping for 30 minutes from 1 hour after DNFB application, observing the pinna grabbing behavior by the hind toes, counting the number of grabbing behaviors. Each drug was orally administered 1 hour before DNFB administration. Compound 1 (30 mg / kg) and the known itching inhibitor cyproheppudin (10 mg / kg) were administered as the test drug, and the inhibitory effect of the catching behavior, that is, the itching inhibitory effect, was examined. Also, 0.5% CMC was administered as a control, and 30 mg / kg of compound 130 and 1 Omg / kg of cyprohepdin were administered alone for comparison. Compound 1 was suspended in 0.5% CMC, and ciprohepdin was used as an aqueous solution. The results are shown in Table 2. Table 2 Combined effects of Compound 1 with itch suppressants having other mechanisms of action

As shown in Table 2, it was found that Compound 1 did not inhibit the effects of other drugs having a different mechanism of action and have an itch-inhibiting effect, indicating that it could be used in combination with conventional itch-inhibiting agents.

Furthermore, the above-mentioned animal experiments revealed that the compound having a chymase inhibitory activity of the present invention does not have toxicity that would pose a problem in operation. Test example 3

 Combined effect of itch inhibitor (compounds 1, 3) and steroids on DNFB-induced mouse scratch model

Eight-week-old BALB / c mice (male, producer: SLC) were divided into groups of eight, and anti-DNP-mAb (b4-IgE) l 0〃g / lmL / body was intravenously injected. After 24 hours, 0.75% Of DNFB 5 zL (prepared at the time of use at a concentration of 0.75% in a mixture of acetone and olive oil (3: 1)) was applied to both sides of the right ear to induce pruritic behavior. One hour after DNFB application, mice were housed one by one in a glass beaker, and the subsequent movement was video-recorded for 30 minutes (managed in a closed environment, avoiding direct observation). The pruritus behavior within 30 minutes was counted and integrated from the video playback image. In addition, the pruritus behavior was defined as one action of holding the back or posterior pinna for 1 second or longer by the back toe, which was distinguished from grooming by the fore toe. Each drug was administered orally or intraperitoneally 1 hour or 2 hours before DNFB application, as shown in Tables 3 and 4. Compounds 1 and 3, which are compounds having a chimase inhibitory effect in itch suppressants, were treated at 30 mg / kg BW and 100 mg / kg BW, respectively, in a single dose (10 mL / kg BW). Oral administration before. However, as the itch inhibitor, a compound in which Compound 1 and Compound 3 were suspended in 0.5% hydroxypropylmethylcellulose (HPMC: methanol) was used. Prednisolone (PSL, manufactured by Sigma: Lot No. 27H0169), a steroid agent, was administered in a single dose of 0.1 to 3 mg / kg BW (10 mL / kg BW), 2 hours before DNFB application. Was administered intraperitoneally. However, PSL was dissolved in physiological saline (Otsuka Pharmaceutical) and used for the test. When a chimase inhibitor and a steroid agent were used in combination (combination group), the chimaze inhibitor was administered after the administration of the steroid agent. It should be noted that a test using a mouse not sensitized with IgE (IgE (-) group) was also performed for comparison.

Table 3: Treatment group 1 in Test Example 3

Table 4: Treatment group 2 in Test Example 3 Group name 2 hours before DNFB 1 hour before DNFB (abbreviated name) Intraperitoneal administration Oral administration

ISE (-) (a-3) Saline only 0.5% HPMC only

IgE (+) control (b-3) Saline only 0.5% HPMC only Compound 3 (c-3) Saline only Compound 3 100 mg / kg

PSL-0.1 (d-3) PSL 0.1 mg / kg 0.5% HPMC only

PSL-0.3 (e-3) PSL 0.3 mg / kg 0.5% HPMC only

PSL-1 (f-3) PS 1 mg / kg 0.5% HPMC only

PSL-3 (g-3) PSL 3 mg / kg 0.5% HPMC only

PSL-0.1 / Compound 3 (h-3) PS 0.1 mg / kg Compound 3 100 mg / kg

PSL-0.3 / Compound 3 (i-3) PSL 0.3 mg / kg Compound 3 100 mg / kg

PSL-1 / Compound 3 (j-3) PSL 1 mg / kg Compound 3 100 mg / kg

PSL-3 / Compound 3 (k-3) PSL 3 mg / kg Compound 3 100 mg / kg Test method:

 The measured values of each group in Tables 3 and 4 were expressed as the average value of the soil SE of eight cases.

 Each group in Tables 3 and 4 was tested as follows. The difference between the IgE (-) group and the IgE (+) Control group was determined by the t-test, and the difference between the group that received the itch inhibitor (Compound 1 and Compound 3) administration group and the IgE (+) ) Difference between the control group and the PSL alone group by the Dunnett method, and the difference between the IgE (+) control group and the combination group by the Dimnett method. Was performed by t test. In each test, a significance level of less than 5% was determined to be significant.

Test results:

 1) Effect of combined use of Compound 1 and steroid agent on DNFB-induced mouse scratch model Figure 1 shows the measurement results of the number of catching actions in each group. Fig. 2 shows the rate of inhibition of the number of catching behaviors in the combination administration group (h-l to k-l) and the PSL-only group (d-l to g-1). At the dose of 30 mg / kg in the compound 1 alone administration group, and at the dose of 1 mg / kg or more in the PSL alone administration group, a significant inhibitory effect on pruritus was observed. The dose-dependent inhibitory effect on the catching behavior in the PSL-only group was significantly enhanced by the combined use of Compound 1 (30 mg / kg), and almost complete additive effects were observed with both drugs.

 2) Effect of combined use of compound 3 and a steroid agent on DNFB-induced mouse scratch model Figure 3 shows the measurement results of the number of catching actions in each group. Fig. 4 shows the suppression rate of the number of catching behaviors in the combination administration group (h-3 to k-3) and the PSL alone administration group (d-3 to g-3). At the dose of 100 mg / kg in the compound 3 alone administration group, and at the dose of 1 mg / kg or more in the PSL alone administration group, a significant antipruritic effect was observed. The dose-dependent inhibitory effect on scratching behavior in the PSL alone administration group was markedly enhanced by the combined use of Compound 3 (100 mg / kg), and almost complete additive effects were observed with both drugs.

 From the above, it was found that the use of the itching inhibitor of the present invention in the treatment of atopic dermatitis can reduce the dose of the steroid drug.

 Test example 4:

Effect of the itch inhibitor of the present invention and other drugs (anti-histamine, steroid, major tranquilizer) on locomotor activity in normal mice (presence or absence of a sedative effect) Whether the itch suppressant of the present invention has a sedative effect that is considered to affect the catching behavior was examined by evaluating the locomotor activity of normal mice after administration of each drug.

 Seven-week-old normal mice (BALB / c strain, male, producer SLC) were grouped into groups of five, and the test drugs were administered in the following group composition, and then a locomotor measurement device (Shimadzu Corporation: ANIMEX II IA) was used. The spontaneous locomotor activity for 30 minutes was accurately measured. The exercise was measured in an unmanned environment after acclimating the mouse for 5 minutes in the cage of the device. The CPZ group was set as a positive control for the test system.

 As shown in Table 5, each test drug was administered orally (PO), intraperitoneally (i.p.), or intravenously (i.v.) immediately before, 2 or 3 hours before the locomotor activity measurement. )did. The test drugs were compound 1 as a chymase inhibitor, cyprohepdudin hydrochloride (CYP: Nacalai Lot No. V8B3507) as an anti-histamine / serotonin drug, and predodizolone (PSL: Sigma Lot No. 27H0169) and Chlo rpromaz ine (CPZ: 0.5 mg Winteramine Injection 25 mg, Lot No. 5008, manufactured by Shionogi) was used as a major tranquilizer. However, Compound 1 was suspended in 0.5% CMC-Na, CYP was prepared as an aqueous solution, and PSL and CPZ were dissolved in physiological saline (Otsuka Pharmaceutical) and administered. Compound 1 and compound 3 suspended in 0.5% hydroxypropyl methylcellulose (HPMC: methanol) were used as the itch inhibitor. Table 5: Treatment groups in Test Example 4

Test method:

 The measured values of each group in Table 5 were expressed as SE, the average value of the spontaneous locomotor activity of five cases.

The comparison between the control group and the test drug administration group was tested by the Tukey method, and the It was determined that there was a significant difference.

Test results:

 Table 6 and FIG. 5 show the results of measuring the locomotor activity of normal mice after administration of each test drug.

 Table 6: Locomotor activity of normal mice in Test Example 4

In the CYP-administered group, administration of a dose (10 mg / kg) that significantly suppressed the pruritic behavior of mice significantly reduced locomotor activity, and marked sedation was observed.

 In contrast, Compound 1 and PSL had no effect on mouse locomotor activity, even at doses that significantly suppressed pruritic behavior in mice.

 As a result, it was revealed that the decrease in the catching behavior of the mice caused by the administration of the antipruritic agent of the present invention was not due to paralysis of the itch but to suppression of the itch itself.

 Hereinafter, Formulation Examples of the itching inhibitor of the present invention are shown.

Formulation Example 1 Tablet

 (1) Compound 1 10 mg

 (2) Fine particles for direct hit No. 209 (Fuji Chemical Co., Ltd.) 46.6 mg

 20% magnesium aluminate metasilicate

 Tropical sorghum starch 30%

 Lactose 50%

(3) Microcrystalline cellulose 24.0 mg (4) Carboxymethylcellulose 'calcium 4.0 mg

 (5) Magnesium stearate 0.4 mg

 (1), (3) and (4) were all passed through a 100 mesh sieve in advance. Each of (1), (3) and (4) and (2) was dried and reduced to a constant water content, and then mixed at the above weight ratio using a mixer. (5) is added to the mixed powder of uniform quality and mixed for a short time (30 seconds). The mixed powder is tableted (punch: 6.3 mm0, 6. OmmR), and 1 tablet 85 mg tablet And

 If necessary, the tablet may be coated with a commonly used gastric-soluble film coating agent (for example, polyvinyl acetate or rubetylamino acetate) or an edible coloring agent.

Formulation Example 2 Capsules

 (1) Compound 1 50 g

(2) Lactose 935 _g

 (3) Magnesium stearate 15 g

 After each of the above components was weighed and mixed uniformly, the mixed powder was filled into hard gelatin capsules in an amount of 20 mg each.

Formulation Example 3 Injection

 (1) Compound 1 hydrochloride 5mg

 (2) Sucrose 10 Omg

 (3) Physiological saline 10ml

 After filtering the above mixture through a membrane filter, sterilization filtration was performed again. The filtrate was aseptically dispensed into vials, filled with nitrogen gas, and sealed to obtain an intravenous injection. Formulation Example 4 Ointment

 (1) Compound 1 1% by weight

 (2) Macrogol 4000 49% by weight

 (3) Macrogol 400 50% by weight

 An ointment was prepared using the above compound according to a conventional method.

Formulation Example 5 Cream (1) Compound 1.

 (2) Predoni Vron 0.5% by weight

 (3) 6% by weight of glycerin monostearate

 (4) Self-emulsifying glyceryl monostearate 6.

 (5) Polyoxyethylene cetyl ether (23E0)

 (6) Liquid paraffin 4% by weight

 (7) Diisopropyl adipate

 (8) Cetostearyl alcohol 4% by weight

 (9) 1,3-tetramethylene glycol 7% by weight

 (10) Methyl paraoxybenzoate 0 1% by weight

 (1 1) Propyl paraoxybenzoate 0 1% by weight

 (12) Purified water

 A cream was prepared from the above compound according to a conventional method.

 The invention's effect

 The itch inhibitor comprising the compound having a chimase inhibitory activity of the present invention as an active ingredient has an inhibitory effect on any of itch due to atopic dermatitis and itch due to other causes. In addition, as for the itch due to atopic dermatitis, the itch caused by IgE and the stimulus caused by other internal factors including those involving chimase or by physical stimulation Is effective for both. As described above, the itch inhibitor of the present invention exerts an excellent itch inhibitory effect, and thus is extremely useful for treatment and prevention of atopic dermatitis.

 Further, the itch inhibitor of the present invention can enhance the itch inhibitory effect of a steroid agent. For this reason, it is possible to treat and prevent itch (especially atopic dermatitis) by reducing the amount of steroids that may cause side effects. This application is based on a patent application No. 52143/1999 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

 1. An itching inhibitor comprising a compound having a chimase inhibitory activity as an active ingredient.

 2. The compound having chymase inhibitory activity is represented by the following general formula (1):

[Wherein, R is a hydrogen atom, alkyl, — CHO, — COOH, -CONH _2. COR -COOR ¹ , one CONHOR ¹ヽ-CONHR-C ONR ^J R,

-CONHS0 ₂ R — COSR ¹ヽ — COCOR ² , — COCOOR ² ,

-CONHCOOR ² , — COC〇NR ³ R ⁴ , -C SXR ¹ , -S0 ₂ WR \

One SC ^ NR ¹ : ^ ¹ 'or one S0 ₂ E (wherein I ¹ and R may be the same or different and each independently represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, Represents arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl, and R ² , R ³ and R ⁴ may be the same or different, and each independently represents a hydrogen atom, an alkyl or shows the reel alkyl, there have may form a hetero cycle to together such connexion R ³ and R ⁴ in an NR ³ R ^4, X is a single bond, an oxygen atom, a sulfur atom or -NH- and W represents a single bond, —NH—, —N HCO—, one NHCOO— or one NHC0NH—, and E represents a hydroxyl group or an amino.

R ⁵ , R ⁶ and R ⁷ may be the same or different and each independently represents a hydrogen atom or an alkyl, or one of R ⁵ , R ⁶ and R ⁷ is aryl or aryl Alkyl, arylaryl, heteroaryl, heteroarylalkyl or heteroarylalkenyl; the remaining two represent a hydrogen atom;

M represents a carbon atom or a nitrogen atom (however, when M is a nitrogen atom, R ⁶ is not present);

Y represents cycloalkyl, aryl or heteroaryl, Z is CF ₂ R ⁸ -CF ₂ CONR ⁹ R ¹ CF ₂ C〇OR ⁹ -COOR \ -CO NR ⁹ R ¹⁰ (In the above formula, R ⁸ is a hydrogen atom, halogen, alkyl, perfluoroalkyl, amino alkyl, alkylaminoalkyl, dialkylaminoalkyl, Arukokishia alkyl, hydroxyalkyl, Ariru represents § reel alkyl, § reel alkenyl into, heteroaryl, heteroaryl § reel alkyl or hetero arylalkenyl, R ⁹ R ^{1 Q} are the same or May be different and each independently represents a hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroaryl indicates Aruke alkenyl, or your one NR ⁹ R ^{1 D} The that R ⁹ and R ^1G may form a hetero cycle to together such connexion.), The following formula (i)

A group represented by the following formula (ii)

Or a group represented by the following formula (iii)

(In the formulas (i) and (iii), abcd represents all carbon atoms, or one of them represents a nitrogen atom and the rest represents a carbon atom, and I ¹¹ R ¹² R ¹³ R ¹⁴ may be the same or different. well, that it independently hydrogen atom, alkyl, Ariru, Ariruaru kill, Heteroariru, heteroalkyl § reel alkyl, halogen, triflate Ruo Russia methyl, shea § Bruno, nitro, one _{^{NR 17 R 17 '_NHS0 2 R}} 17 -OR ¹⁷ , — C00R ¹⁷ — C

ONHS0 ₂ R ¹⁷ or one CONR ¹⁷ R ¹⁷ '(however, if any one of abcd represents a nitrogen atom, bond to abcd representing the nitrogen atom. II ¹¹ R ¹² , R ¹³ and R ¹⁴ are not present. ), R ¹⁵ and R ¹⁶ may be the same or different and each independently represents a hydrogen atom, an alkyl, an aryl, an arylalkyl, a heteroaryl, a heteroarylalkyl, a halogen, a trifluoromethyl, Shiano, nitro, one NR ¹⁷ R ¹⁷ ', one ^{_{NHS0 2 R 17, -OR 17,}} - COOR 17, - C 0 NHS 0 2 R 17 or one CONR ¹⁷ R ^17' indicates where in the above formulas, R ¹⁷ and R ¹⁷ ′ may be the same or different and each independently represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or trifluoromethyl are shown, or the 'R ¹⁷ and R ¹⁷ in the' single NR ¹⁷ R ¹⁷ may form a hetero cycle to together such connexion, a is an oxygen atom, a sulfur atom or a NR ¹⁸ - (wherein R ¹⁸ represents a hydrogen atom, an alkyl, a cycloalkyl or cycloalkyl § alkyl. The). } Represents a group represented by

n represents 0 or 1.

Of the above groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, and heterocyclylalkyl are each It may have one or more substituents. ]

2. The itching inhibitor according to claim 1, which is a compound represented by the formula: or a pharmacologically acceptable salt thereof.

 3. A compound having a chymase inhibitory action is represented by the following general formula (la):

[Wherein, ^Ra represents a hydrogen atom or benzyloxycarbonyl, R ^5a represents phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl , 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl, 3-pyridyl or 4-pyridyl, R ^7a represents a hydrogen atom, and Ya represents phenyl which may have ^a substituent. , Z ^a is the formula (ia)

In in a group represented by (wherein, R ^{12 a} is a hydrogen atom, nitro, One _{CONH 2, - CONHE t, -} CONMe 2 -. CONE t physician one C_〇 shows a 0 M e or a C 00 E t :) , Formula (ia ⁵ )

A group represented by or

In indicates a group represented by, n ^a is 1. 3. The itching inhibitor according to claim 1 or 2, which is a compound represented by the formula: or a pharmacologically acceptable salt thereof.

4. A compound having a chimase inhibitory action is represented by the following general formula (lb):

[Wherein, R ^b represents a hydrogen atom or benzyloxycarbonyl, and one of R ^5b , R ^6b , and R ^7b represents a aryl which may have a substituent, and the remaining two represents a hydrogen atom, M ^b represents a carbon atom or a nitrogen atom (provided that when M ^b is a nitrogen atom R ^{6 b} is absent.), Y ^b may have a substituent indicates Ariru, Z ^b is - CF ₂ R ^8b or _{^{- CF 2 CONR 9b R 1 Gb}} ( wherein, R ^8b, R ^9b and R ^1Gb may, R ⁸ of according to claim 2, wherein, R ⁹ and R ^{1 Q} And n ^b represents 1. 3. The itch inhibitor according to claim 1 or 2, which is a compound represented by the formula: or a pharmacologically acceptable salt thereof.

5. The anti-itch agent is a preventive agent for atopic dermatitis or a therapeutic agent for atopic dermatitis The itching inhibitor according to any one of claims 1 to 4.

 6. The itching inhibitor according to any one of claims 1 to 5, further comprising a steroid agent.

 7. The itching inhibitor according to claim 6, wherein the steroid agent is a corticosteroid or a synthetic steroid having the same action as a corticosteroid.

 8. The itching inhibitor according to claim 6 or 7, wherein the steroid agent is prednisolone, dexamethasone or betamethasone.

 9. An anti-itch enhancer comprising a compound having a chymase inhibitory activity as an active ingredient and enhancing the anti-itch effect of a steroid agent.

 10. The compound having chymase inhibitory activity is represented by the following general formula (1):

[Where R is a hydrogen atom, alkyl, — CHO, — COOH, — CONH ₂ , -CORK-COOR ¹ヽ one CONHOR -CONH ¹ , — CONRW s

-CONHS0 ₂ R -CO SR ¹ , — COCOR ²ヽ — COCOOR ² ,

-CONHCOOR ² , -CO C0NR ³ R \ — C SXR ¹ヽ -S0 ₂ WR

— SOsNRiR ¹ 'or 1 S0 ₂ E (where RR may be the same or different and each independently represents an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl R ² and RR ⁴ may be the same or different and each independently represents a hydrogen atom, alkyl or arylalkyl, or NR ³ may be R ³ and R ⁴ in R ⁴ to form a hetero cycle to together such connexion, X is a single bond, an oxygen atom, a sulfur atom or - NH- indicates, W is a single bond, - NH-, -N HCO—, one NHC00— or one NHCONH—, and E represents a hydroxyl group or an amino.

R ⁵ , R ⁶ and R ⁷ may be the same or different and each independently represents a hydrogen atom or Represents alkyl, or one of R ⁵ , R ⁶ , and R ⁷ represents aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkyl, and the remaining 2 One represents a hydrogen atom,

M represents a carbon atom or a nitrogen atom (however, when M is a nitrogen atom, R ⁶ is not present);

 Y represents cycloalkyl, aryl or heteroaryl,

Z is one CF ₂ R ⁸ , one CF ₂ CONR ⁹ R ¹⁰ , one CF ₂ COOR ⁹ , one CO〇R ^g , -CO NR ⁹ R ¹⁰ (In the above formula, R ⁸ is a hydrogen atom, halogen, alkyl, Monofluoroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl; R ⁹ , R ^{9 1 G} may be the same or different and each independently represents a hydrogen atom, an alkyl, an alkenyl, a cycloalkyl, a cycloalkylalkyl, a heterocyclealkyl, an aryl, an arylalkyl, an arylalkenyl, a heteroaryl, Represents heteroarylalkyl or heteroarylalkenyl, There may form a hetero cycle to together such connexion and R ⁹ and R ^1Q in an NR ⁹ R ^{1 Q.),} The following formula (i)

A group represented by the following formula (ii)

 Fifteen

 (ϋ)

 A eight R 16

Or a group represented by the following formula (iii:

{In the formulas (i) and (iii), a, b, c, and d all represent carbon atoms, or One represents a nitrogen atom and the other represents a carbon atom, and I ¹¹ , R ¹² , R ¹³ , and R ¹⁴ may be the same or different and each independently represents a hydrogen atom, an alkyl, an aryl, an arylalkyl, a heteroaryl. , heteroalkyl § reel alkyl, halogen, triflate Ruo Russia methyl, shea § Bruno, nitro, one NR ¹⁷ R ¹⁷ ', one NHS_〇 ₂ R ^17, one oR ^17, one COOR ^17, one C ONHS0 ₂ R ¹⁷ or a CONR ¹⁷ R ¹⁷ ′ (however, when any one of a, b, c, and d represents a nitrogen atom, R ¹ R ¹² , R ¹ bonded to a, b, c, or d representing the nitrogen atom ¹³ and R ¹⁴ are not present.), R ¹⁵ and R ¹⁶ may be the same or different and each independently represents a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Halogen, trifluoromethyl, Shiano, nitro, One NR ¹⁷ R ¹⁷ ', - NHS_〇 _{^{2 R 17, -OR 1 \ -COO}} 17, -CONHSO ^ 1 7 or a CONR ¹⁷ R ^17' indicates where in the above formulas, R ^17, R ¹⁷ ′ may be the same or different and each independently represents a hydrogen atom, an alkyl, a cycloalkyl, a cycloalkylalkyl, an aryl, an arylalkyl, a heteroaryl, a heteroarylalkyl or trifluoromethyl. , or single NR ¹⁷ R ¹⁷ and 'R ¹⁷ and R ¹⁷ in the' may form a hetero cycle to together such connexion, a is an oxygen atom, one was or sulfur atom NR ¹⁸ - (wherein, R ^{And 18} represents a hydrogen atom, alkyl, cycloalkyl or cycloalkylalkyl. } Represents a group represented by

n represents 0 or 1.

Of the above groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle and heterocyclealkyl are all And may have one or more substituents. ]

10. The itch suppressing effect enhancer according to claim 9, which is a compound represented by the formula: or a pharmacologically acceptable salt thereof.

1 1. A compound having chymase inhibitory activity is represented by the following general formula (la):

Wherein: ^a represents a hydrogen atom or benzyloxycarbonyl; R ^5a represents phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl , 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl, 3-pyridyl or 4-pyridyl, R ^7a represents a hydrogen atom, and Ya represents phenyl which may have ^a substituent. Where Z ^a is the formula (ia)

(wherein, ^12a represents a hydrogen atom, nitro, —C0NH ₂ , —CONHEt, —C0NMe ₂ , one C0NEt ₂ , one COOMe or one C〇0Et.) , Formula (ia ⁵ )

To N N (ia ') or the formula (i i i a) 0, (ilia)

 Ν '

In indicates a group represented by, n ^a is 1. 11. The itching suppressing effect enhancer according to claim 9 or 10, which is a compound represented by the formula: or a pharmacologically acceptable salt thereof.

 12. A compound having a chymase inhibitory action is represented by the following general formula (lb):

(1b)

[Wherein, R ^b represents a hydrogen atom or benzyloxycarbonyl, one of R ^5b , R ^6b , and R ^7b represents an aryl which may have a substituent, and the remaining two are represents a hydrogen atom, M ^b represents a carbon atom or a nitrogen atom (provided that when M ^b is a nitrogen atom R ^{6 b} is absent.), Y ^b which may have a substituent Ariru are shown, Z ^b is - CF ₂ R ^8b or - CF ₂ CONR ^9b R ^10b (wherein, R ^8b, R ^9b, and R ¹ ° ^b are claims It is the same as R ⁸ , R ^g and R ^1C) described in 10. ) And n ^b represents 1. 11. The itch suppressing effect enhancer according to claim 9 or 10, which is a compound represented by the formula: or a pharmacologically acceptable salt thereof.

 13. The itching-suppressing effect-enhancing agent according to any one of claims 9 to 12, which is a preventive agent for atopic dermatitis or a therapeutic agent for atopic dermatitis.

 14. The itch-inhibiting effect-enhancing agent according to any one of claims 9 to 13, wherein the steroid agent is a corticosteroid or a synthetic steroid having the same action as adrenocortical hormone (15. 15. The itching suppressing effect enhancer according to any one of claims 9 to 14, which is dexamethasone or betamethasone.