WO2000051640A1 - Agents soulageant les demangeaisons et agents de potentialisation de cet effet de soulagement - Google Patents

Agents soulageant les demangeaisons et agents de potentialisation de cet effet de soulagement Download PDF

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Publication number
WO2000051640A1
WO2000051640A1 PCT/JP2000/001135 JP0001135W WO0051640A1 WO 2000051640 A1 WO2000051640 A1 WO 2000051640A1 JP 0001135 W JP0001135 W JP 0001135W WO 0051640 A1 WO0051640 A1 WO 0051640A1
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alkyl
hydrogen atom
compound
atom
heteroaryl
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PCT/JP2000/001135
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English (en)
Japanese (ja)
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Naruyasu Komorita
Fujio Kobayashi
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Welfide Corporation
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Priority to AU26942/00A priority Critical patent/AU2694200A/en
Publication of WO2000051640A1 publication Critical patent/WO2000051640A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics

Definitions

  • 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.
  • “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.
  • 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.
  • Non-allergic factors include physical factors, such as skin dryness, sweating, pressurization and weighting of the skin, and rupture of the skin.
  • 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. .
  • 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.
  • 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.
  • the present invention has been made in view of the above circumstances, and aims to provide an excellent itching inhibitor.
  • 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.
  • An itching inhibitor comprising a compound having a chimase inhibitory activity as an active ingredient.
  • the compound having chymase inhibitory activity is represented by the following general formula (1):
  • R represents a hydrogen atom, an alkyl, One CHO, - COOH, - CONH 2 , -COR 1, - COOR 1 ⁇ -CONHOR 1, -C0NHR -CONR ⁇ 1 ' ,
  • 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—
  • 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
  • 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 heteroarylalky
  • 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_ ⁇ _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
  • n 0 or 1.
  • alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, and heterocyclylalkyl are each It may have one or more substituents.
  • 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
  • R 12a is a hydrogen atom, nitro, represented in - CONH 2, - C_ ⁇ _NHEt, C_ ⁇ _NMe 2, -CONE t 2, showing one C 00 M e or a C 00 E t. :), formula (a 5)
  • n a is 1.
  • the pharmacologically acceptable salt thereof represented by [1] or [2].
  • a compound having a chimase inhibitory action is represented by the following general formula (lb):
  • 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_ ⁇ _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 )
  • n b represents 1. Or the pharmacologically acceptable salt thereof represented by [1] or [2].
  • 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 is a preventive agent for atopic dermatitis or a therapeutic agent for atopic dermatitis
  • 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.
  • steroid agent is a corticosteroid or a synthetic steroid having the same action as the corticosteroid.
  • 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.
  • 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).
  • 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.
  • substance P bathoactive 'intestinal'
  • VIP polypeptide
  • 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.
  • 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.
  • 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.
  • 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.
  • itch is not particularly limited, and includes allergic itch and non-allergic itch.
  • itching that can be caused by chimaze, dermatitis dermatitis, eczema, urticaria, prurigo, insect bites, floor rubbing, xerosis, etc. are included.
  • 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.
  • 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.
  • itch due to non-allergic factors includes itch that may involve chymase released when mast cells degranulate.
  • non-allergic factors include skin dryness, sweating, pressurization / loading of the skin, rupture of the skin, and changes in air temperature and body temperature.
  • antirgic factors examples 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. .
  • 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
  • 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.
  • 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).
  • 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 (! ⁇ ⁇ ⁇ obi! ⁇ 1 ′)
  • 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 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".
  • 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).
  • substituted 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 ⁇ -CH 2 CONR b R ° s — 0 CH 2 C 0 NR b R c ⁇ -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 ⁇ NR k S0 2 T 3 , -S 0 2
  • 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 ,
  • 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.
  • 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.
  • 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.
  • 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
  • D 1 is the following equation (i V)
  • 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.
  • 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,,)
  • R,,,, R 5 ′, R 6 ′, R 7 ′, M,, ⁇ ′ 5 and ⁇ ′ ′ are R, R 5 , R 6 , R 7 , M, Synonymous with n and Y, Z, is — CF 2 CON (R 9 ")-
  • 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)
  • 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”.
  • 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.
  • R A1 for example indicates such Ariru
  • R A2 represents a carbonyl or sulfonyl
  • R A3, for example alkyl shows the like
  • 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.
  • a 1 represents 1 or 2.
  • 1 133 represents ⁇ -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, R B2 is a hydrogen
  • 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.
  • R C3 is represented by the following formula (5-1)
  • 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 s
  • Example 8 Quinazoline derivative disclosed in WO 97/1 1941.
  • ring E represents a benzene ring, a pyridine ring, a pyrroyl ring or a pyrazolyl ring;
  • 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.
  • 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.
  • 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?
  • R E4 is a hydrogen atom;
  • Example 9 A peptide compound disclosed in JP-A-9-124691.
  • 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
  • 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
  • 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.)
  • the ring B F represents an aromatic ring
  • 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
  • the pharmacologically acceptable salt is not particularly limited, and those commonly used in this field can be used.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a suitable administration form for example, powder
  • Injections for example, tablets, capsules, topical preparations, etc.
  • the appropriate administration method for example, intravenous administration, oral administration, dermal administration, topical administration, etc.
  • 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.
  • 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.
  • 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.
  • oil bases for example, petrolatum, lanolin, etc.
  • surfactants for example, surfactants, emulsifiers and the like.
  • 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.
  • a hydrophilic fatty acid ester such as glycerin ester of a saturated fatty acid (eg, Adeps solidus) and polyethylene glycol (eg, macrogol).
  • glycerin ester of a saturated fatty acid eg, Adeps solidus
  • polyethylene glycol eg, macrogol
  • the gel base component examples include organic hydrogel bases such as colloid-dispersed starch, tragacanth, alginate, and cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, etc.), and colloidal bases.
  • organic hydrogel bases containing clay for example, silicates such as bentonite and veegum are included.
  • surfactant examples 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, ethylene
  • 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.).
  • 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.).
  • ester of a polyvalent carboxylic acid and an alcohol examples 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).
  • higher alcohols examples include benzyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, 2-year-old tyldodecanol, and the like.
  • suspending agents and thickeners examples 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.
  • polysaccharides for example, gum arabic, tragacanth, pullulan, oral custingham, bingham, pectin, xanthan gum, guar gum, etc.
  • methylcellulose carboxymethylcellulose
  • polyvinyl alcohol polyvinyl alcohol
  • polyvinyl alcohol examples include pyrrolidone, acrylic acid copolymer, carboxyvinyl polymer, and colloidal microcrystalline cellulose.
  • powdery inorganic substance examples include talc, calcium anhydride, calcium carbonate, magnesium carbonate, colloidal silica, bentonite and the like.
  • the gel forming agent examples 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.
  • components of the propellant include low-boiling fluorocarbons (eg, Freon 22) and aliphatic hydrocarbons (eg, propane, butane, etc.).
  • low-boiling fluorocarbons eg, Freon 22
  • aliphatic hydrocarbons eg, propane, butane, etc.
  • 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.
  • topical agent is a liquid
  • a surfactant emulsifier
  • emulsifier emulsifier
  • higher fatty acid ester higher alcohol
  • suspending agent emulsifier
  • thickener emulsifier
  • 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.
  • a solvent for example, ethanol, glycerin, propylene glycol, etc.
  • 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.
  • excipients eg, lactose and starch
  • binders e.g., binders
  • disintegrants e.g., binders
  • other suitable additives e.g., 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.
  • an oil emulsion eg, fatty oil, stone, gum arabic, tragacanth, etc.
  • alcohol stone e.g., 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 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.
  • additive eg, sucrose, Lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chi
  • 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.
  • a diluent for example, distilled water, physiological saline, an aqueous glucose solution, etc.
  • an excipient for example, carboxymethylcellulose (CMC), sodium alginate, etc., preservatives (e
  • 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
  • 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.
  • 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.
  • the itching inhibitor of the present invention when administered orally to an adult, 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.
  • the itch inhibitor of the present invention 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.
  • 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.
  • adrenocortical hormone for example, glucocorticoid
  • synthetic steroids having the same action as adrenocortical hormone for example, prednisolone, dexamethasone, methanozone, hydrocortisone.
  • Triamcinolone and the like Triamcinolone and the like
  • any combination may be used as long as both coexist in a living body at the same time.
  • living body 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.
  • the itch inhibitor of the present invention and the steroid agent may be administered by the same or different administration methods.
  • the itch inhibitor of the present invention is orally administered, and the steroid agent is administered locally (external agent) Coating).
  • 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.
  • it 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.
  • the dose when administered, 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • THF tetrahydrofuran
  • 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)
  • a solution of sodium dihydrogen phosphate dihydrate (180 g, 1.15 ⁇ 1) 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.
  • 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.
  • DMS0 dimethylsulfoxide
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%].
  • 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
  • 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,
  • 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.
  • 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
  • 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.
  • 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
  • 6% sodium hypochlorite aqueous solution 56 mL, 46.2 thigh ol
  • 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.
  • Step (1) 2- [5-benzyloxycarbonylamino-2- (3-chlorophenyl) -6-oxo-1,6-dihydro- obtained by the same method as in Reference Example 1.
  • 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.
  • dichloromethane 270 mL
  • 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 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.
  • concentration series (5 xM, ⁇ x10, ⁇ ) 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.
  • Kiapp apparent inhibition constant
  • Ki inhibition constant
  • the reaction solution was prepared by dissolving Compounds 1 and 20 dissolved in 20% of 10% dimethyl sulfoxide (DMS0) in 140 ⁇ l of a buffer (pH 7.5) having a composition of Tris-HC1 (100 mM) -KCl (2M).
  • DMS0 dimethyl sulfoxide
  • a buffer pH 7.5
  • Tris-HC1 100 mM
  • KCl 2M
  • the chymase inhibitory activity (Ki) was 0.023 M.
  • mice 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.
  • IGELb4 Hypridoma (TIB141, ATCC) was treated with penicillin 50 U / mK streptomycin 50 ⁇ g / ml, N-2-hydroxyethylpiperazine- ⁇ '-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
  • 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.
  • mice 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.
  • 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.
  • 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.
  • PSL was dissolved in physiological saline (Otsuka Pharmaceutical) and used for the test.
  • the chimaze inhibitor was administered after the administration of the steroid agent.
  • IgE (-) group was also performed for comparison.
  • 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
  • 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).
  • h-l to k-l the number of catching behaviors in the combination administration group
  • d-l to g-1 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.
  • 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).
  • h-3 to k-3 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).
  • 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.
  • itch inhibitor of the present invention 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.
  • mice 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.
  • a locomotor measurement device Shiadzu Corporation: ANIMEX II IA
  • 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.
  • CYP Nacalai Lot No. V8B3507
  • PSL Sigma Lot No. 27H0169
  • Chlo rpromaz ine CPZ: 0.5 mg Winteramine Injection 25 mg, Lot No. 5008, manufactured by Shionogi
  • Table 6 and FIG. 5 show the results of measuring the locomotor activity of normal mice after administration of each test drug.
  • Compound 1 and PSL had no effect on mouse locomotor activity, even at doses that significantly suppressed pruritic behavior in mice.
  • (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
  • 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.
  • a commonly used gastric-soluble film coating agent for example, polyvinyl acetate or rubetylamino acetate
  • an edible coloring agent for example, polyvinyl acetate or rubetylamino acetate
  • the mixed powder was filled into hard gelatin capsules in an amount of 20 mg each.
  • An ointment was prepared using the above compound according to a conventional method.
  • a cream was prepared from the above compound according to a conventional method.
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

Ces agents soulageant les démangeaisons sont caractérisés en ce qu'ils contiennent en tant que principe actif des composés possédant un effet inhibiteur des chymases. En tant que composés possédant un effet inhibiteur des chymases, on peut utiliser, par exemple, des composés représentés par la formule générale suivante (I) dans laquelle chaque symbole possède les notations données dans la description. Ces agents soulageant les démangeaisons peuvent être utilisés dans les démangeaisons d'ordre allergique ou non (par exemple, les démangeaisons dans lesquelles les chymases jouent un rôle, les dermatites atopiques, l'eczéma, l'urticaire, le prurit, les morsures d'insectes, les escarres et xéridermies, etc.). Ces composés sont notamment efficaces en tant que traitement préventif et curatif des dermatites atopiques. L'utilisation combinée de ces agents et de stéroïdes permet d'accroître l'effet régulateur anti-démangeaison des stéroïdes, et donc de réduire la dose d'administration des stéroïdes.
PCT/JP2000/001135 1999-03-01 2000-02-25 Agents soulageant les demangeaisons et agents de potentialisation de cet effet de soulagement WO2000051640A1 (fr)

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WO2001062294A1 (fr) * 2000-02-22 2001-08-30 Suntory Limited Medicaments preventifs ou therapeutiques contenant des inhibiteurs de chymase en tant que principe actif, pour traiter des dermatites
WO2005018672A1 (fr) * 2003-08-22 2005-03-03 Teijin Pharma Limited Medicament contenant un inhibiteur de chymase en tant qu'agent actif
US7888348B2 (en) 2004-12-02 2011-02-15 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
US8049006B2 (en) 2006-05-31 2011-11-01 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062294A1 (fr) * 2000-02-22 2001-08-30 Suntory Limited Medicaments preventifs ou therapeutiques contenant des inhibiteurs de chymase en tant que principe actif, pour traiter des dermatites
US7618977B2 (en) 2000-02-22 2009-11-17 Asubio Pharma Co., Ltd. Method of treating dermatitis comprising administering a chymase inhibitor
WO2005018672A1 (fr) * 2003-08-22 2005-03-03 Teijin Pharma Limited Medicament contenant un inhibiteur de chymase en tant qu'agent actif
US7888348B2 (en) 2004-12-02 2011-02-15 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
EP2463268A1 (fr) 2004-12-02 2012-06-13 Daiichi Sankyo Company, Limited Acides aromatiques aminométhyl-substitués comme intermédiaires pour la préparation de composés 1,4-diazépan-2,5-dione inhibant la chymase
US8507714B2 (en) 2004-12-02 2013-08-13 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
US8049006B2 (en) 2006-05-31 2011-11-01 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof

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