WO2010087399A1 - Urotensin-ii receptor antagonists - Google Patents

Urotensin-ii receptor antagonists Download PDF

Info

Publication number
WO2010087399A1
WO2010087399A1 PCT/JP2010/051129 JP2010051129W WO2010087399A1 WO 2010087399 A1 WO2010087399 A1 WO 2010087399A1 JP 2010051129 W JP2010051129 W JP 2010051129W WO 2010087399 A1 WO2010087399 A1 WO 2010087399A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pyrrolidin
ylmethyl
ethyl
sulfonyl
Prior art date
Application number
PCT/JP2010/051129
Other languages
French (fr)
Japanese (ja)
Inventor
真志 丸本
俊宏 木方
智 松井
清明 米須
貴弘 永山
秀樹 田川
Original Assignee
第一三共株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 第一三共株式会社 filed Critical 第一三共株式会社
Publication of WO2010087399A1 publication Critical patent/WO2010087399A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel compound having urotensin II receptor antagonistic activity and useful as a pharmaceutical or a pharmacologically acceptable salt thereof, and a pharmaceutical containing these.
  • Urotensin II (Urotensin II) is a cyclic peptide molecule discovered as a neurosecretory hormone in fish in the 1960s. Thereafter, the presence of prepro-Urotensin II was reported in humans in 1998 (Non-patent Document 1). In 1999, urotensin II was identified as a ligand of GPR14, which was orphan GPCR at that time (Non-patent Document 2). . Urotensin II is one of the most powerful vasoconstrictive substances in vivo, but its efficacy varies depending on the animal species and vascular bed (Non-Patent Documents 3 and 4).
  • Non-Patent Documents 5, 6, 7 and 8 For the heart, it is thought to be involved in cardiac hypertrophy and myocardial fibrosis, as well as causing cardiac function deterioration through contraction of the coronary arteries. It is also known that blood urotensin II concentration is elevated in congestive heart failure patients, hypertensive patients, renal failure patients, and diabetic patients.
  • Non-patent Document 9 The expression level of urotensin II receptor is low in normal cardiomyocytes, but it has been confirmed that the expression level of cardiomyocytes of congestive heart failure patients increases as the heart failure progresses. In the case of myocardial infarction patients, it has been found that expression is increased in the infarcted area itself (Non-patent Document 9), suggesting a relationship between increased expression of urotensin II receptor and exacerbation of heart failure. The result is obtained.
  • Non-patent Documents 3, 10, 11, 12, 13, 14, and 15 Compounds that antagonize urotensin II receptor are congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, asthma, fibrosis, restenosis, atherosclerosis, dyslipidemia, diabetic It is considered useful for the treatment of nephropathy and renal failure.
  • Non-patent Document 2 compounds that antagonize urotensin II receptor include addiction, schizophrenia, dementia, Alzheimer's It is considered useful for the treatment of diseases, anxiety, stress, depression, Parkinson's disease, movement disorders, pain and neuromuscular dysfunction (Non-Patent Documents 16 and 17).
  • Non-patent Document 8 urotensin II is known to be involved in various metabolic diseases such as diabetes.
  • Patent Documents 1 and 2 Although compounds having urotensin II receptor antagonism have been disclosed (Patent Documents 1 and 2), the structure is greatly different from the compounds of the present invention. In addition, a compound having a superior urotensin II receptor antagonistic action is desired.
  • the present invention has excellent urotensin II receptor antagonism, congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis Treatment of atherosclerosis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, pain, neuromuscular dysfunction or diabetes An object is to provide a novel compound useful for prevention.
  • X 1 , X 2 , X 3 and X 4 are each independently a hydrogen atom, a halogeno group, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, A C1-C6 alkoxy group, a C3-C8 cycloalkyl group or a phenyl group, and * represents a bond with Y 1 );
  • Y 1 and Y 2 represent the following (a) or (b): (a) Y 1 represents —O—, —NH—, —S— or —CR 11 R 12 —, and Y 2 represents —CR 13 R 14 — is shown.
  • Y 1 represents —CR 15 R 16 —, and Y 2 represents —O—, —NH— or —S—.
  • R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently represents a hydrogen atom, a halogeno group, a hydroxyl group or a C1-C6 alkyl group);
  • Q represents a C2-C4 alkylene group which may be substituted with 1 to 3 C1-C6 alkyl groups;
  • R 1 and R 2 represent the following (c) or (d):
  • R 1 and R 2 are each independently substituted with 1 to 3 selected from the group consisting of a halogeno group and a hydroxyl group C1 to C6 alkyl group which may be used.
  • R 1 and R 2 together with the nitrogen atom to which they are attached, may be substituted with 1 to 6 groups selected from the group consisting of a halogeno group and a hydroxyl group, a pyrrolidinyl group, piperidinyl A group or a morpholinyl group.
  • R 3 and R 4 represent the following (e) or (f).
  • R 3 and R 4 are each independently a hydrogen atom, a halogeno group, a C3-C8 cycloalkyl group, a carboxy group, a carbamoyl group, a mono C1-C6 alkylcarbamoyl group, or a di-C1-C6 alkylcarbamoyl group.
  • a hydroxy group, a C1-C6 alkoxy group, an amino group, a mono-C1-C6 alkylamino group, a di-C1-C6 alkylamino group, and a C2-C6 alkanoylamino group may be substituted with 1-3. Good C1-C6 alkyl groups are indicated.
  • R 3 and R 4 together with the nitrogen atom to which they are attached, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino And a 4- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 selected from the group consisting of a group, a C2-C6 alkanoylamino group, a C1-C6 alkylsulfonyl group and an oxo group. Or a halogen
  • Ring A is
  • R 1 and R 2 together with the nitrogen atom to which they are attached represent a pyrrolidinyl group optionally substituted with 1 to 6 selected from the group consisting of a halogeno group and a hydroxyl group;
  • halogeno group means a fluoro group, a chloro group, a bromo group, or an iodo group.
  • C1-C6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl. Group, tert-butyl group, n-pentyl group, n-hexyl group, 1-ethylpropyl group, 2,2-dimethylpropyl group and the like.
  • halogeno C1-C6 alkyl group means the C1-C6 alkyl group having the halogeno group as a substituent, and the number of halogeno groups may be one or two or more.
  • the type of each halogeno group in the case of being more than one may be the same or different. For example, chloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, 2-chloroethyl group, (2,2,2-trifluoro) ethyl group, (1,1,2,2 -Tetrafluoro) ethyl group, pentafluoroethyl group and the like.
  • C1-C6 alkoxy group means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group. And isobutyloxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, 1-ethylpropoxy group, 2,2-dimethylpropoxy group and the like.
  • C3-C8 cycloalkyl group means a 3- to 8-membered saturated monocyclic hydrocarbon group, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • C2 to C4 alkylene group means an alkylene group composed of 2 to 4 methylene chains, and examples thereof include an ethylene group, a trimethylene group, and a tetramethylene group.
  • C2 to C6 alkanoyl group means a linear or branched aliphatic acyl group having 2 to 6 carbon atoms, and examples thereof include an acetyl group, a propionyl group, an isobutyryl group, and a pivaloyl group. Can do.
  • “Mono C1-C6 alkylcarbamoyl group” means a carbamoyl group having one C1-C6 alkyl group as a substituent, and examples thereof include a methylcarbamoyl group and an ethylcarbamoyl group.
  • the “di-C1-C6 alkylcarbamoyl group” means a carbamoyl group having the two C1-C6 alkyl groups as substituents, and the types of the two C1-C6 alkyl groups may be the same. And may be different. Examples thereof include a dimethylcarbamoyl group, a diethylcarbamoyl group, and an N-methyl-N-ethylcarbamoyl group.
  • “Mono C1-C6 alkylamino group” means an amino group having one C1-C6 alkyl group as a substituent, and examples thereof include a methylamino group and an ethylamino group.
  • the “di-C1-C6 alkylamino group” means an amino group having two C1-C6 alkyl groups as substituents, and the two C1-C6 alkyl groups may be the same type. And may be different. Examples thereof include a dimethylamino group and an N-methyl-N-ethylamino group.
  • C2-C6 alkanoylamino group means an amino group having the C2-C6 alkanoyl group as a substituent, and examples thereof include an acetylamino group, a propionylamino group, an isobutyrylamino group, and a pivaloylamino group. Can do.
  • C1-C6 alkylsulfonyl group means an alkylsulfonyl group composed of the C1-C6 alkyl group, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, etc. Can be mentioned.
  • the “4- to 10-membered nitrogen-containing heterocyclic group” means a group consisting of a monocyclic or condensed 4- to 10-membered heterocyclic ring containing at least one nitrogen atom. It may be saturated. Further, in addition to one nitrogen atom, it may further have 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms as heteroatoms.
  • Examples include azetidinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperidinyl group, homopiperazinyl group, indolinyl group, isoindolinyl group and the like.
  • Ring A is
  • X 1 , X 2 , X 3 and X 4 are each independently a hydrogen atom, halogeno group, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C1- A C6 alkoxy group, a C3-C8 cycloalkyl group or a phenyl group, and * represents a bond to Y 1.
  • ring A As ring A,
  • Ring A (Where X 1 , X 2 , X 3 and * are the same as described above). Below is Ring A
  • X 1 , X 2 and X 3 are each independently a hydrogen atom, halogeno group, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C1-C6 alkoxy group, C3-C8
  • a cycloalkyl group or a phenyl group is represented, and * represents a bond with Y 1 .
  • X 1 , X 2 and X 3 are preferably each independently a hydrogen atom, a halogeno group, a cyano group, an amino group or a halogeno C1-C6 alkyl group, and X 1 is a halogeno group, a cyano group or a halogeno C1-C6 More preferably, it is an alkyl group, X 2 is a hydrogen atom, a halogeno group, a cyano group or an amino group, X 3 is a halogeno group or a cyano group, X 1 is a halogeno group or a cyano group, and X 2 More preferably, X 3 and X 3 are both halogeno groups.
  • the halogeno group is preferably a chloro group or a bromo group, and more preferably a chloro group.
  • X 4 represents a hydrogen atom, a halogeno group, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group or a phenyl group, and * It shows the binding of Y 1.
  • X 4 is preferably a hydrogen atom, a halogeno group or a cyano group, more preferably a halogeno group.
  • the halogeno group is preferably a chloro group.
  • Y 1 and Y 2 represent the following (a) or (b).
  • R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently represents a hydrogen atom, a halogeno group, a hydroxyl group or a C1-C6 alkyl group); R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are preferably hydrogen atoms.
  • Y 1 and Y 2 are preferably the above (a), more preferably Y 1 is —O— or —NH—, Y 2 is more preferably —CR 13 R 14 —, and Y 1 is —O—. Or, it is more preferably —NH— and Y 2 is —CH 2 —.
  • Q represents a C2-C4 alkylene group which may be substituted with 1 to 3 C1-C6 alkyl groups. Q is preferably an unsubstituted C2-C4 alkylene group, more preferably —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —, and still more preferably —CH 2 —CH 2 —.
  • R 1 and R 2 represent the following (c) or (d).
  • R 1 and R 2 each independently represent a C1-C6 alkyl group which may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group and a hydroxyl group.
  • each substituent may be the same or different.
  • R 1 and R 2 together with the nitrogen atom to which they are attached may be substituted with 1 to 6 groups selected from the group consisting of a halogeno group and a hydroxyl group, a pyrrolidinyl group, piperidinyl A group or a morpholinyl group.
  • each substituent may be the same or different.
  • R 1 and R 2 the above (d) is preferable.
  • it is preferably a pyrrolidinyl group which may be substituted with 1 to 6 selected from the group consisting of a halogeno group and a hydroxyl group, together with the nitrogen atom to which they are bonded, and one halogeno group
  • the pyrrolidinyl group optionally substituted with is more preferable, and the pyrrolidinyl group substituted at the 3-position with one fluorine atom and the unsubstituted pyrrolidinyl group are more preferable.
  • R 3 and R 4 represent the following (e) or (f).
  • R 3 and R 4 are each independently a hydrogen atom, a halogeno group, a C3-C8 cycloalkyl group, a carboxy group, a carbamoyl group, a mono C1-C6 alkylcarbamoyl group, or a di-C1-C6 alkylcarbamoyl group.
  • a hydroxy group, a C1-C6 alkoxy group, an amino group, a mono-C1-C6 alkylamino group, a di-C1-C6 alkylamino group, and a C2-C6 alkanoylamino group may be substituted with 1-3.
  • R 3 and R 4 together with the nitrogen atom to which they are attached, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino And a 4- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 selected from the group consisting of a group, a C2-C6 alkanoylamino group, a C1-C6 alkylsulfonyl
  • R 3 and R 4 are each independently a hydrogen atom or a halogeno group, a C3-C8 cycloalkyl group, a carboxy group, a carbamoyl group, a mono-C1-C6 alkylcarbamoyl group, a di-C1-C6 alkylcarbamoyl group, a hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group and C2-C6 alkanoylamino group optionally substituted with 1-3
  • each substituent may be the same or different.
  • R 3 and R 4 are preferably each independently a hydrogen atom or a C1-C6 alkyl group optionally substituted with a hydroxyl group, and both R 3 and R 4 may be substituted with a hydroxyl group. More preferably, it is a C1-C6 alkyl group.
  • R 3 and R 4 together with the nitrogen atom to which they are attached, are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, a C2-C6 Alkanoyl group, carbamoyl group, mono C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2 A 4- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 selected from the group consisting of -C6 alkanoylamino group and oxo group, and each substitution when substituted with
  • R 3 and R 4 together with the nitrogen atom to which they are attached, are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, a C2-C6 Alkanoyl group, carbamoyl group, mono C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2 An azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, which may be substituted with 1 to 3 selected from the group consisting of
  • the position of the substituent is preferably the 3-position and the 4-position.
  • R 3 , R 4 and the nitrogen atom to which they are bonded are as follows.
  • * indicates a bond with Q.
  • the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is preferably a compound having an absolute configuration represented by the following general formula (Ia) or a pharmacologically acceptable salt thereof.
  • ring A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 are the same as described above.
  • Preferred embodiments of the ring A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 in the general formula (Ia) are as described above.
  • the compound represented by the general formula (I) or (Ia) of the present invention can form a salt, and these salts are included in the present invention.
  • the salt include potassium salt, sodium salt, lithium salt, calcium salt, magnesium salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, oxalate, malonate, fumarate.
  • Acid salt maleate, D-malate, L-malate, D-tartrate, L-tartrate, phthalate, trifluoroacetate, methanesulfonate, benzenesulfonate, p- Examples include toluene sulfonate, 2,4-dimethylbenzene sulfonate, 2,4,6-trimethylbenzene sulfonate, 4-ethylbenzene sulfonate, and naphthalene sulfonate.
  • the compound represented by the general formula (I) or (Ia) of the present invention can form a salt in any ratio, and each salt thereof (for example, diacid salt, 1/2 acid salt, etc.) These mixtures are encompassed by the present invention.
  • the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof can form a hydrate or a solvate.
  • the hydrate or solvate include hydrate, methanol solvate, ethanol solvate and the like. Their respective hydrates, solvates, or mixtures thereof are encompassed by the present invention.
  • the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof may be a geometric isomer such as a cis isomer or a trans isomer, d isomer, l
  • Various isomers such as optical isomers (including enantiomers and diastereomers), tautomers, rotational isomers and the like can exist, but the invention is not limited to all such isomers. And mixtures thereof in any proportion (including racemates).
  • the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof has an unnatural ratio of atomic isotopes at one or more of atoms constituting such a compound.
  • the compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the present invention also relates to a compound that is converted to compound (I) or (Ia) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. Also included are compounds that are changed to (I) or (Ia), or “pharmacologically acceptable prodrug compounds” that are changed to compound (I) or (Ia) by hydrolysis or the like due to gastric acid or the like. .
  • the “pharmaceutically acceptable prodrug compound” include a compound in which, when compound (I) or (Ia) has an amino group, the amino group is acylated, alkylated or phosphorylated. Can be mentioned.
  • compound (I) or (Ia) when compound (I) or (Ia) has a hydroxyl group, examples thereof include compounds in which the hydroxyl group is acylated, alkylated, phosphorylated or borated, and compound (I) or (Ia) includes When a carboxy group is present, a compound in which the carboxy group is esterified or amidated can be used.
  • the compound represented by the general formula (I) of the present invention can be produced according to the following method A to method C.
  • the compound represented by the general formula (Ia) of the present invention can also be produced by the same method.
  • rings A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 are the same as described above, and X is a halogen atom , Q ′ represents a vinyl group which may be substituted with 1 to 3 C1 to C6 alkyl groups, and Q ′′ represents C3 to C4 which may be substituted with 1 to 3 C1 to C6 alkyl groups.
  • Y 1 and Y 2 in the method B-1 represent the above (a)
  • Y 1 and Y 2 represent the above (b).
  • the Boc group means a tert-butoxycarbonyl group
  • the Z group means a benzyloxycarbonyl group.
  • a protecting group may be introduced into the group, and a protecting group introduced as appropriate may be removed as necessary.
  • a protecting group is not particularly limited as long as it is a protecting group usually used for proceeding with the reaction. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. And the like.
  • the introduction reaction of these protecting groups and the removal reaction of the protecting groups can be carried out according to conventional methods such as the methods described in the above-mentioned documents.
  • the solvent used in the reaction in each step of the following method A to method C is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting material, and is selected from the following solvent group.
  • Solvent groups include aliphatic hydrocarbons such as hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene.
  • Halogenated hydrocarbons such as: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; ethyl acetate, propyl acetate Esters such as butyl acetate; Nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; Cals such as acetic acid and propionic acid Acids; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide, dimethylformamide, dimethyl Amides such as acetamide, N-methyl-2-pyrroli
  • the acid used in the reaction of each step of the following method A or method C is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group.
  • Acid groups include organic acids such as acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid, organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, and hydrochloric acid, bromide It consists of inorganic acids such as hydroacid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.
  • Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; lithium diisopropylamide Lithium alkylamides; silylamides such as lithium diisopropylamide Lithium alkylamides; silylamides such as lithium
  • reaction temperature varies depending on the solvent, starting material, reagent, etc.
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.
  • the target compound in each step is isolated from the reaction mixture according to a conventional method. For example, (i) if necessary, insoluble matter such as a catalyst is removed by filtration, and (ii) water and a solvent immiscible with water (for example, methylene chloride, diethyl ether, ethyl acetate, etc.) are added to the reaction mixture. Compound III is extracted, (iii) the organic layer is washed with water, dried using a desiccant such as anhydrous magnesium sulfate, and (iv) the solvent is distilled off to obtain the target compound.
  • a desiccant such as anhydrous magnesium sulfate
  • the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation, silica gel column chromatography or the like, if necessary. Further, the target compound ⁇ of each step can be used as it is in the next reaction without purification.
  • Step 1 of [Method A] is a method for producing compound (4) by dehydrating condensation of compound (2) and compound (3).
  • the condensing agent used include azodicarboxylic acid di-lower alkyl ester-triphenylphosphine such as azodicarboxylic acid diethyl ester-triphenylphosphine; N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3 -Carbodiimide derivatives such as (3-dimethylaminopropyl) carbodiimide (EDCI); 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; diphenylphosphoryl azide (DPPA), Phosphoric esters such as diethyl phosphoryl chloride and diethyl phosphoryl cyanide (DEPC);
  • DPPA diphenylphosphoryl azide
  • Phosphoric esters such
  • the solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably tetrahydrofuran.
  • the reaction can be accelerated by adding a catalytic amount of 4- (N, N-dimethylamino) pyridine to the reaction solution.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 30 minutes to 24 hours, preferably 2 to 12 hours.
  • Step 2 of [Method A] is a method for producing compound (5) by reducing compound (4) with a reducing agent.
  • the reducing agent used include lithium aluminum hydride, lithium borohydride, and borane, and borane is preferable.
  • the solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether as exemplified above, and more preferably tetrahydrofuran.
  • the reaction temperature is usually 0 to 100 ° C., preferably 25 to 60 ° C.
  • the reaction time is usually 30 minutes to 12 hours, preferably 1 to 4 hours.
  • Step 1 of [Method B-1] is a method for producing compound (8) by coupling compound (6) with compound (7) in the presence of a base.
  • the solvent used is preferably an ether, amide or nitrile as exemplified above, and more preferably N, N-dimethylformamide.
  • the base used is preferably an alkali metal carbonate, alkali metal hydride or alkali metal alkoxide as exemplified above, and more preferably potassium carbonate or sodium hydride.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 1 to 24 hours, preferably 1 to 12 hours.
  • Step 2 of [Method B-1] is a step of producing carboxylic acid (9) by hydrolyzing the ester of compound (8).
  • Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
  • Step 3 of [Method B-1] is a method for producing compound (10) by reacting compound (9) with a halogenating reagent.
  • the halogenating reagent to be used include oxalyl chloride, thionyl chloride, phosphoryl chloride and the like, and preferably oxalyl chloride.
  • the reaction can be accelerated by adding a catalytic amount of N, N-dimethylformamide to the reaction solution.
  • the solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably methylene chloride.
  • the reaction temperature is usually 0 to 60 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
  • Method B-2 is a method for producing acid chloride (10) by reacting compound (11) with phosgene.
  • the solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably methylene chloride.
  • the reaction temperature is usually 0 to 60 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
  • Step 1 of [Method C-1] is a method for producing compound (12) by deprotecting the Z group from compound (5) by hydrogenation reaction.
  • Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
  • Step 2 of [Method C-1] comprises (i) dehydrating condensation of compound (12) and compound (9), or (ii) coupling compound (12) and compound (10) in the presence of a base.
  • This is a method for producing (13).
  • the condensing agent used in the method (i) include azodicarboxylic acid dilower alkyl ester-triphenylphosphine such as azodicarboxylic acid diethyl ester-triphenylphosphine; N, N′-dicyclohexylcarbodiimide (DCC) Carbodiimide derivatives such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI); 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; Phosphoric esters such as phosphoryl azide (DPPA), diethyl phosphoryl chloride, diethyl
  • the solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably tetrahydrofuran.
  • the base used is preferably triethylamine.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 30 minutes to 24 hours, preferably 2 to 12 hours.
  • the solvent used in the method (ii) is preferably ethers, halogenated hydrocarbons or amides as exemplified above, and more preferably methylene chloride.
  • the base used is preferably an organic amine as exemplified above, and more preferably triethylamine.
  • the reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 10 minutes to 12 hours, preferably 10 minutes to 2 hours.
  • Step 3 of [Method C-1] is a method for producing the compound (14) by deprotecting the Boc group from the compound (13) with an acid.
  • Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
  • Step 4 of [Method C-1] is a method for producing compound (16A) or compound (16B) by coupling compound (14) and compound (15) in the presence of a base.
  • the solvent used is preferably an ether, halogenated hydrocarbon or amide as exemplified above, and more preferably methylene chloride.
  • the base used is preferably an organic amine as exemplified above, and more preferably pyridine or 2,6-ditert-butylpyridine.
  • the reaction temperature is usually ⁇ 78 to 25 ° C., preferably ⁇ 45 to 0 ° C.
  • the reaction time is usually 10 minutes to 12 hours, preferably 10 minutes to 2 hours.
  • Step 5 of [Method C-1] is a method for producing compound (I) by reacting compound (16A) or compound (16B) with amine (17).
  • the solvent used is preferably an ether or halogenated hydrocarbon as exemplified above, and more preferably methylene chloride.
  • the reaction temperature is usually 0 to 60 ° C., preferably 0 to 40 ° C.
  • the reaction time is usually 1 to 6 days, preferably 1 to 3 days.
  • Step 1 of [Method C-2] is a method for producing compound (18) by deprotection from compound (5), and can be carried out in the same manner as Step 3 of [Method C-1] described above.
  • Step 2 of [Method C-2] is a method for producing compound (19A) or compound (19B) by reacting compound (18) with compound (15). 4 can be performed.
  • Step 3 of [Method C-2] is a method for producing compound (20) by reacting compound (19A) or compound (19B) with amine (17). 5 can be performed.
  • Step 4 of [Method C-2] is a method for producing compound (21) from compound (20) by deprotection and can be carried out in the same manner as in Step 1 of [Method C-1] described above.
  • Step 5 of [Method C-2] is a method for producing compound (I) by coupling compound (21) with compound (9) or compound (10). It can be carried out in the same manner as in step 2.
  • the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof exhibits an antagonistic action on the urotensin II receptor, so congestive heart failure, Ischemic heart disease, angina pectoris, myocardial infarction, cardiac arrhythmia, essential hypertension, pulmonary hypertension, renal disease, chronic renal failure, acute renal failure, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication Limb ischemic disease, cerebrovascular disorder, chronic obstructive pulmonary disease, restenosis, asthma, neurogenic inflammation, migraine, metabolic vascular disorder, bone / cartilage / joint disease, arthritis, inflammatory disease, fibrosis, lung Fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, pain, neuromuscular dysfunction, diabetes , Gastrointestinal motility Harm
  • congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis Useful as a medicine for the treatment or prevention of lipid metabolism disorders, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorders, pain, neuromuscular dysfunction or diabetes
  • the dose to the patient depends on the sex, age, symptom, and type of drug.
  • the appropriate dose may be determined by appropriately examining the dose, administration method, number of doses, administration timing, etc. of the drug. Usually, it is 0.1 mg to 1 g per day for adults, preferably 0.5 mg to 500 mg, but should not be limited thereto.
  • the daily dose may be administered once a day or divided into 2-6 times.
  • the pharmaceutical composition containing the compound represented by the general formula (I) or (Ia) of the present invention should be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations usually used. Can do.
  • composition mainly comprising a compound represented by the general formula (I) or (Ia) of the present invention is administered to a mammal (particularly human), systemically or locally, orally or parenterally. Can be administered.
  • oral pharmaceutical forms include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. These forms of medicines are usually mixed with a diluent, excipient or carrier as a pharmaceutically acceptable additive based on the compound of the present invention represented by the general formula (I) or (Ia).
  • a diluent, excipient or carrier as a pharmaceutically acceptable additive based on the compound of the present invention represented by the general formula (I) or (Ia).
  • Prepared as a pharmaceutical composition may be any suitable pharmaceutically acceptable binder, disintegrant, lubricant, swelling, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier.
  • Necessary from agents, swelling aids, coating agents, plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffers, wetting agents, etc. Can be carried out according to a conventional method using a material appropriately selected according to the method.
  • parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, inhalants, etc. Is mentioned.
  • These forms of medicines are usually mixed with a diluent, excipient or carrier as a pharmaceutically acceptable additive based on the compound of the present invention represented by the general formula (I) or (Ia).
  • a diluent, excipient or carrier as a pharmaceutically acceptable additive based on the compound of the present invention represented by the general formula (I) or (Ia).
  • the preparation of the pharmaceutical composition comprises any suitable pharmaceutically acceptable stabilizer, preservative, solubilizer, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier, Moisturizer, preservative, antioxidant, flavoring agent, gelling agent, neutralizing agent, solubilizing agent, buffering agent, isotonic agent, surfactant, coloring agent, buffering agent, thickener, wetting agent , A filler, an absorption accelerator, a suspending agent, a binder and the like, which are appropriately selected as necessary, can be used according to a conventional method.
  • References regarding the above-mentioned pharmaceutically acceptable carriers or diluents include, for example, “Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985)”. Further, as a reference for pharmaceutically acceptable excipients, for example, “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A. Wade and P. J. Weller” can be cited.
  • the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof exhibits an antagonistic action against the urotensin II receptor, congestive heart failure, ischemic heart disease, cardiac arrhythmia, Essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, It is useful as a medicament for the treatment or prevention of stress, depression, Parkinson's disease, movement disorders, pain, neuromuscular dysfunction or diabetes.
  • IR infrared absorption spectrum
  • NMR nuclear magnetic resonance spectrum
  • MS mass spectrometry
  • the ratio of the eluting solvent described in the section of separation and purification by chromatography indicates a volume ratio unless otherwise specified.
  • IR was measured by the ATR method or KBr tableting method.
  • the parentheses in “ 1 H-NMR” indicate the measurement solvent, and TMS (tetramethylsilane) was used as an internal standard substance.
  • the aqueous phase was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was dissolved in 200 mL of methanol under a nitrogen stream, 20 g of palladium hydroxide / carbon was added, and the mixture was stirred at 45 ° C. for 6 hours under a hydrogen stream.
  • the reaction solution was cooled to room temperature, the catalyst was filtered off, and the solvent was distilled off under reduced pressure.
  • the resulting residue was purified by column chromatography (0-50% methanol / methylene chloride) to obtain 9.55 g (79%) of the target compound.
  • the solvent of the reaction solution was distilled off under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted with methylene chloride.
  • the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 10.0 g (quant) of a crude product of the target compound.
  • the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution, the solvent was distilled off under reduced pressure, and the aqueous phase was extracted with methylene chloride. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-50% methanol / methylene chloride) to obtain 5.67 g (74%) of the target compound.
  • Example 2 4- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] morpholine dihydrochloride 200 mg (0.40 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 70 mg (0.81 mmol) of morpholine to obtain 241 mg (91%) of the target compound.
  • Example 3 4- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] thiomorpholine dihydrochloride salt 65 mg (0.13 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 27 mg (0.26 mmol) of thiomorpholine to obtain 68 mg (78%) of the target compound.
  • Example 4 N-dimethyl-2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethanamine dihydrochloride salt 65 mg (0.13 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 And 2N dimethylamine / tetrahydrofuran solution 0.13 mL (0.26 mmol) was used in the same manner as in Example 1 to obtain 78 mg (97%) of the target compound.
  • Example 6 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] piperidine-4- All dihydrochloride 98 mg (0.20 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 40 mg (0.40 mmol) of piperidin-4-ol to obtain 131 mg (99%) of the target compound.
  • Example 7 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] pyrrolidine-3- All dihydrochloride 150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 And pyrrolidin-3-ol 52 mg (0.60 mmol) was used in the same manner as in Example 1 to obtain 164 mg (83%) of the target compound.
  • Example 9 N- ⁇ 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] pyrrolidine -3-yl ⁇ acetamide dihydrochloride 150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 And N-pyrrolidin-3-yl-acetamide (77 mg, 0.60 mmol) was used in the same manner as in Example 1 to obtain 175 mg (83%) of the target compound.
  • Example 10 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] piperazine-2- ON dihydrochloride 90 mg (0.18 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 36 mg (0.36 mmol) of piperazin-2-one to obtain 107 mg (88%) of the target compound.
  • Example 11 [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] -1,4 -Diazepan-5-one dihydrochloride 150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 70 mg (0.60 mmol) of 1,4-diazepan-5-one to obtain 150 mg (72%) of the target compound.
  • Example 12 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] piperidine-3- Carboxylic acid dihydrochloride (Example 12A) 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] piperidine-3- Ethyl carboxylate 150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as
  • Example 12B 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) ethyl] piperidine-3- Carboxylic acid dihydrochloride 1- [2-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl obtained in Example 12A ) Ethyl] piperidine-3-carboxylate (116 mg, 0.18 mmol) was dissolved in dioxane (1.5 mL), 1N aqueous sodium hydroxide solution (0.36 mL) was added, and the mixture was stirred at room temperature for 10 min.
  • the reaction solution was neutralized with a 1N aqueous hydrochloric acid solution, saturated with sodium chloride added to the aqueous phase, and then extracted with ethyl acetate.
  • the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Isopropyl ether was added to the obtained crude product, and the powder was collected by filtration to obtain 29 mg (26%) of the desired compound (free form).
  • the free product was dissolved in 1.2 mL of dioxane, 1N hydrochloric acid / dioxane solution was added dropwise, and then the solvent was distilled off under reduced pressure to obtain 26 mg of hydrochloride.
  • Example 14 2- ⁇ 2-[(2S) -4- ⁇ [2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl ⁇ -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxo Ethoxy ⁇ -4,5-dichlorobenzonitrile dihydrochloride 91 mg (0.37 mmol) of (4,5-dichloro-2-cyanophenoxy) acetic acid obtained in Reference Example 2 and (3S) -1- ⁇ [2- (4-acetylpiperazine-) obtained in Reference Example 9 Using 1-yl) ethyl] sulfonyl ⁇ -3- (pyrrolidin-1-ylmethyl) piperazine (120 mg, 0.30 mmol), the reaction was carried out in the same manner as in Example 13 to obtain 110 mg (54%) of the target compound.
  • Example 18 N- ⁇ 2-[(2S) -4- ⁇ [2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl ⁇ -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl ⁇ -4,5-dichloro-2- (trifluoromethyl) aniline dihydrochloride (Example 18A) ⁇ 2-[(2S) -4- ⁇ [2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl ⁇ -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl ⁇ [ 4,5-Dichloro-2- (trifluoromethyl) phenyl] carbamic acid tert-butyl 170 mg (0.44 mmol) of N- (tert-butoxycarbonyl) -N- [4,5-dichloro-2
  • Example 18B N- ⁇ 2-[(2S) -4- ⁇ [2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl ⁇ -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl ⁇ -4,5-dichloro-2- (trifluoromethyl) aniline dihydrochloride ⁇ 2-[(2S) -4- ⁇ [2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl ⁇ -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl obtained in Example 18A ] 2-oxoethyl ⁇ [4,5-dichloro-2- (trifluoromethyl) phenyl] carbamic acid 216 mg (0.29 mmol) of tert-butyl was dissolved in 4 mL of dioxane, and 2 mL of 4N hydro
  • the reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and the aqueous phase was extracted with ethyl acetate.
  • the obtained organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography (NH silica, 2% methanol / ethyl acetate) to obtain 99 mg (53%) of the desired compound (free form).
  • the free product was dissolved in 3 mL of dioxane and 1N hydrochloric acid / dioxane solution was added dropwise, and then the solvent was distilled off under reduced pressure to obtain 90 mg of hydrochloride.
  • Example 20 4- [3-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) propyl] morpholine dihydrochloride
  • Example 20A (2S) -4-[(3-Chloropropyl) sulfonyl] -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine 114.2 mg (0.280 mmol) of (2R) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine obtained in Reference Example 6B was dissolved in dichloromethane under ice-cooling.
  • Example 20B 4- [3-( ⁇ (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl ⁇ sulfonyl) propyl] morpholine dihydrochloride (2S) -4-[(3-Chloropropyl) sulfonyl] -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine 72 obtained in Example 20A .2 mg (0.13 mmol) was dissolved in 2 mL of N, N-dimethylformamide, 58 ⁇ L of morpholine and 92 ⁇ L of triethylamine were added, and the mixture was heated and stirred at 60 ° C.
  • assay buffer [25 mM HEPES (4- (2-hydroxyethyl) -1-piperazine ethane sulfonic acid), pH 7.6, 5 mM MgCl 2 , 0.1% (w / v) NaN 3 , 0.5% (W / v) bovine serum albumin (Sigma Aldrich Japan)] and wash buffer [25 mM HEPES, pH 7.6, 5 mM MgCl 2 , 1 mM CaCl 2 , 0.5 M NaCl, 0.1% (w / v) NaN 3 , 0.5% (w / v) bovine serum albumin (Sigma Aldrich Japan)] was prepared and stored at 4 ° C. until use.
  • Human urotensin II receptor stably expressing cells were maintained in a maintenance medium [10% (v / v) fetal bovine serum (EQUITECH-BIO), 100 units / mL penicillin G sodium, 100 ⁇ g / mL streptomycin sulfate, and 400 ⁇ g / mL Geneticin ( F-12 medium containing Invitrogen) (Invitrogen)].
  • a maintenance medium 10% (v / v) fetal bovine serum (EQUITECH-BIO), 100 units / mL penicillin G sodium, 100 ⁇ g / mL streptomycin sulfate, and 400 ⁇ g / mL Geneticin ( F-12 medium containing Invitrogen) (Invitrogen)].
  • human urotensin II receptor stably expressing cells were detached with 0.25% Trypsin-EDTA (Invitrogen), resuspended in maintenance medium excluding Geneticin, and then 40,000 in a
  • Inhibition rate (%) 100 ⁇ [1 ⁇ (AB) / (CB)]
  • MeOH 7: 3 to prepare a serial dilution series consisting of 1000 times the final concentration. This was diluted 100-fold with an assay buffer to obtain a sample solution, and the assay was performed according to the method described above.
  • the compound of the present invention exhibits excellent urotensin II receptor binding inhibitory activity and is congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, Stenosis, asthma, fibrosis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, pain, neuromuscular dysfunction It is useful as a medicament for the treatment or prevention of diabetes and the like.
  • Krebs-Henseleit solution NaCl 112 mM, KCl 4.7 mM, MgSO 4 1.2 mM, KH 2 PO 4 1.2 mM, NaHCO 3 25.0 mM, CaCl 2 2.5 mM, glucose, maintained at 37 ° C.
  • the ring was suspended in a 20 mL excised organ bath filled with 11.0 mM and indomethacin (0.01 ⁇ M) and aerated with 95% O 2 and 5% CO 2 .
  • the ring was coupled to a force transducer (FD pickup: manufactured by Nihon Kohden Co., Ltd.), and isometric tension was recorded while pulling to a static tension of 2 g.
  • FD pickup manufactured by Nihon Kohden Co., Ltd.
  • a cumulative amount of human urotensin II (10 ⁇ 12 M to 10 ⁇ 6 M) is added, and the functional antagonism of the test compound is measured by concentration ratio, ie test compound 10 ⁇ 5.
  • concentration ratio ie test compound 10 ⁇ 5.
  • EC 50 is the concentration of urotensin necessary to obtain half maximum contraction, and the degree of shift of EC 50 value was used as an indicator of human urotensin II antagonism.
  • the contraction when human urotensin II was added was calculated with the maximum contraction in KCl 60 mM + Krebs-Henseleit solution being 100%. The evaluation results are shown in FIG. The test compound in FIG.
  • Example 1 represents the compound of Example 1 of the present invention.
  • the compound of the present invention inhibits urotensin II-induced vasoconstriction in the monkey aorta, congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic kidney Disease, renal failure, restenosis, asthma, fibrosis, atherosclerosis, lipid metabolism disorder, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, It is considered useful as a medicament for the treatment or prevention of pain, neuromuscular dysfunction, diabetes and the like.
  • Example 1 Using the compound of Example (10 mg), colloidal silicon dioxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (175 mg), starch (10 mg), and lactose (99.8 mg), Tablets are produced according to the method. The obtained tablets can be coated as necessary.
  • the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof has an excellent urotensin II receptor antagonistic action, and is used as a pharmaceutical, particularly congestive heart failure, ischemic.

Abstract

Provided are novel compounds which show excellent urotensin II receptor antagonism and are useful in treating or preventing congestive heart failure, ischemic heart diseases and so on. A compound represented by general formula (I) or a pharmacologically acceptable salt of the same. In general formula (I), ring A represents a group represented by formula (1) or (2) [wherein X1, X2, X3 and X4 represent each a hydrogen atom, a halogeno group, etc.]; Y1 represents -O-, -NH-, -S-, -CR11R12-, etc.; Y2 represents -CR13R14-, etc.; Q represents a C2-4 alkylene group optionally substituted by one to three C1-6 alkyl groups; R1 and R2 form, together with the nitrogen atom to which R1 and R2 are bonded, a pyrrolidinyl group etc. optionally substituted by a halogeno group and a hydroxyl group; and R3 and R4 form, together with the nitrogen atom to which R3 and R4 are bonded, a 4- to 10-membered nitrogen-containing heterocyclic group etc. optionally substituted by a halogeno group, a C1-6 alkyl group, etc.

Description

ウロテンシンＩＩ受容体拮抗薬Urotensin II receptor antagonist
　本発明は、ウロテンシンＩＩ受容体拮抗作用を有し、医薬として有用な新規な化合物またはその薬理上許容される塩、およびこれらを含有する医薬に関する。 The present invention relates to a novel compound having urotensin II receptor antagonistic activity and useful as a pharmaceutical or a pharmacologically acceptable salt thereof, and a pharmaceutical containing these.
　ウロテンシンＩＩ（ＵｒｏｔｅｎｓｉｎＩＩ）は１９６０年代に魚類の神経分泌ホルモンとして発見された環状ペプチド分子である。その後、１９９８年にヒトにおいてｐｒｅｐｒｏ－ＵｒｏｔｅｎｓｉｎＩＩの存在が報告され（非特許文献１) 、翌１９９９年にはウロテンシンＩＩが当時オーファンＧＰＣＲであったＧＰＲ１４のリガンドとして同定された（非特許文献２)。ウロテンシンＩＩは生体内における最も強力な血管収縮性物質の一つであるが、その効力は動物種や血管床に応じて多様である（非特許文献３、４）。心臓に対しては、冠動脈の収縮を介して心機能低下を惹起する他、心肥大や心筋繊維化に関与すると考えられている。また鬱血性心不全患者、高血圧患者、腎不全患者、及び糖尿病患者において血中ウロテンシンＩＩ濃度が上昇していることが知られている（非特許文献５、６、７および８）。 Urotensin II (Urotensin II) is a cyclic peptide molecule discovered as a neurosecretory hormone in fish in the 1960s. Thereafter, the presence of prepro-Urotensin II was reported in humans in 1998 (Non-patent Document 1). In 1999, urotensin II was identified as a ligand of GPR14, which was orphan GPCR at that time (Non-patent Document 2). . Urotensin II is one of the most powerful vasoconstrictive substances in vivo, but its efficacy varies depending on the animal species and vascular bed (Non-Patent Documents 3 and 4). For the heart, it is thought to be involved in cardiac hypertrophy and myocardial fibrosis, as well as causing cardiac function deterioration through contraction of the coronary arteries. It is also known that blood urotensin II concentration is elevated in congestive heart failure patients, hypertensive patients, renal failure patients, and diabetic patients ( Non-Patent Documents 5, 6, 7 and 8).
　ウロテンシンＩＩ受容体は、正常な心筋細胞では発現量は低いが、鬱血性心不全患者の心筋細胞においては心不全の進行に従って発現量が増加することが確認されている（非特許文献９) 。また心筋梗塞患者の場合は梗塞域そのものにおいて発現が上昇していることが見出されており（非特許文献９)、ウロテンシンＩＩ受容体の発現上昇と心不全の増悪との関連を示唆するような結果が得られている。 The expression level of urotensin II receptor is low in normal cardiomyocytes, but it has been confirmed that the expression level of cardiomyocytes of congestive heart failure patients increases as the heart failure progresses (Non-patent Document 9). In the case of myocardial infarction patients, it has been found that expression is increased in the infarcted area itself (Non-patent Document 9), suggesting a relationship between increased expression of urotensin II receptor and exacerbation of heart failure. The result is obtained.
　ウロテンシンＩＩ受容体に拮抗する化合物は、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、喘息、線維症、再狭窄、アテローム性動脈硬化症、脂質代謝異常、糖尿病性腎症、腎不全の治療に有用であると考えられる（非特許文献３、１０、１１、１２、１３、１４および１５）。 Compounds that antagonize urotensin II receptor are congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, asthma, fibrosis, restenosis, atherosclerosis, dyslipidemia, diabetic It is considered useful for the treatment of nephropathy and renal failure ( Non-patent Documents 3, 10, 11, 12, 13, 14, and 15).
　また、ウロテンシンＩＩおよびウロテンシンＩＩ受容体は哺乳動物の中枢神経系で発現されることから（非特許文献２）、ウロテンシンＩＩ受容体に拮抗する化合物は、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛および神経筋機能障害の治療に有用であると考えられる（非特許文献１６および１７）。 In addition, since urotensin II and urotensin II receptor are expressed in the central nervous system of mammals (Non-patent Document 2), compounds that antagonize urotensin II receptor include addiction, schizophrenia, dementia, Alzheimer's It is considered useful for the treatment of diseases, anxiety, stress, depression, Parkinson's disease, movement disorders, pain and neuromuscular dysfunction (Non-Patent Documents 16 and 17).
　さらに、ウロテンシンＩＩは糖尿病のような種々の代謝性疾患に関与していることが知られている（非特許文献８）。 Furthermore, urotensin II is known to be involved in various metabolic diseases such as diabetes (Non-patent Document 8).
　ウロテンシンＩＩ受容体拮抗作用を有する化合物が開示されているが（特許文献１および２）、本発明の化合物とは構造が大きく異なる。また、より優れたウロテンシンＩＩ受容体拮抗作用を有する化合物が望まれている。 Although compounds having urotensin II receptor antagonism have been disclosed (Patent Documents 1 and 2), the structure is greatly different from the compounds of the present invention. In addition, a compound having a superior urotensin II receptor antagonistic action is desired.
国際公開第２００２／０８９７９２号パンフレットInternational Publication No. 2002/089792 Pamphlet 国際公開第２００３／０４８１５４号パンフレットInternational Publication No. 2003/048154 Pamphlet
　本発明は、優れたウロテンシンＩＩ受容体拮抗作用を有し、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害または糖尿病の治療または予防に有用な、新規な化合物を提供することを目的とする。 The present invention has excellent urotensin II receptor antagonism, congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis Treatment of atherosclerosis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, pain, neuromuscular dysfunction or diabetes An object is to provide a novel compound useful for prevention.
　本発明者らは上記の課題を解決するため鋭意研究を行なった結果、以下の一般式（Ｉ）および（Ｉａ）で表される新規な化合物が優れたウロテンシンＩＩ受容体拮抗作用を有することを見い出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that the novel compounds represented by the following general formulas (I) and (Ia) have an excellent urotensin II receptor antagonistic action. As a result, the present invention has been completed.
　すなわち本発明は、
（１）一般式（Ｉ） That is, the present invention
(1) General formula (I)
Figure JPOXMLDOC01-appb-C000005
［式中、環Ａは、
Figure JPOXMLDOC01-appb-C000005
[Wherein ring A is
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
を示し（ここで、Ｘ１、Ｘ２、Ｘ３およびＸ４はそれぞれ独立して、水素原子、ハロゲノ基、水酸基、シアノ基、アミノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ１～Ｃ６アルコキシ基、Ｃ３～Ｃ８シクロアルキル基またはフェニル基を示し、＊はＹ１との結合を示す。）；
Ｙ１およびＹ２は、次の（ａ）または（ｂ）を示し
　（ａ）Ｙ１は－Ｏ－、－ＮＨ－、－Ｓ－または－ＣＲ１１Ｒ１２－を示し、Ｙ２は－ＣＲ１３Ｒ１４－を示す。
　（ｂ）Ｙ１は－ＣＲ１５Ｒ１６－を示し、Ｙ２は－Ｏ－、－ＮＨ－または－Ｓ－を示す。
（ここで、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５およびＲ１６はそれぞれ独立して、水素原子、ハロゲノ基、水酸基またはＣ１～Ｃ６アルキル基を示す。）；
Ｑは、１～３個のＣ１～Ｃ６アルキル基で置換されていてもよい、Ｃ２～Ｃ４アルキレン基を示し；
Ｒ１およびＲ２は、次の（ｃ）または（ｄ）を示し
　（ｃ）Ｒ１およびＲ２はそれぞれ独立して、ハロゲノ基および水酸基からなる群より選ばれる１～３個で置換されていてもよい、Ｃ１～Ｃ６アルキル基を示す。
　（ｄ）Ｒ１およびＲ２は、それらが結合している窒素原子と一緒になって、ハロゲノ基および水酸基からなる群より選ばれる１～６個で置換されていてもよい、ピロリジニル基、ピペリジニル基またはモルホリニル基を示す。；
Ｒ３およびＲ４は、次の（ｅ）または（ｆ）を示す。
　（ｅ）Ｒ３およびＲ４はそれぞれ独立して、水素原子、または、ハロゲノ基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基およびＣ２～Ｃ６アルカノイルアミノ基からなる群より選ばれる１～３個で置換されていてもよいＣ１～Ｃ６アルキル基を示す。
　（ｆ）Ｒ３およびＲ４は、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい４～１０員の含窒素複素環基を示す。］で表される化合物、またはその薬理上許容される塩、
（２）一般式（Ｉａ） Wherein X 1 , X 2 , X 3 and X 4 are each independently a hydrogen atom, a halogeno group, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, A C1-C6 alkoxy group, a C3-C8 cycloalkyl group or a phenyl group, and * represents a bond with Y 1 );
Y 1 and Y 2 represent the following (a) or (b): (a) Y 1 represents —O—, —NH—, —S— or —CR 11 R 12 —, and Y 2 represents —CR 13 R 14 — is shown.
(B) Y 1 represents —CR 15 R 16 —, and Y 2 represents —O—, —NH— or —S—.
(Wherein R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently represents a hydrogen atom, a halogeno group, a hydroxyl group or a C1-C6 alkyl group);
Q represents a C2-C4 alkylene group which may be substituted with 1 to 3 C1-C6 alkyl groups;
R 1 and R 2 represent the following (c) or (d): (c) R 1 and R 2 are each independently substituted with 1 to 3 selected from the group consisting of a halogeno group and a hydroxyl group C1 to C6 alkyl group which may be used.
(D) R 1 and R 2 together with the nitrogen atom to which they are attached, may be substituted with 1 to 6 groups selected from the group consisting of a halogeno group and a hydroxyl group, a pyrrolidinyl group, piperidinyl A group or a morpholinyl group. ;
R 3 and R 4 represent the following (e) or (f).
(E) R 3 and R 4 are each independently a hydrogen atom, a halogeno group, a C3-C8 cycloalkyl group, a carboxy group, a carbamoyl group, a mono C1-C6 alkylcarbamoyl group, or a di-C1-C6 alkylcarbamoyl group. A hydroxy group, a C1-C6 alkoxy group, an amino group, a mono-C1-C6 alkylamino group, a di-C1-C6 alkylamino group, and a C2-C6 alkanoylamino group may be substituted with 1-3. Good C1-C6 alkyl groups are indicated.
(F) R 3 and R 4 together with the nitrogen atom to which they are attached, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino And a 4- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 selected from the group consisting of a group, a C2-C6 alkanoylamino group, a C1-C6 alkylsulfonyl group and an oxo group. Or a pharmacologically acceptable salt thereof,
(2) General formula (Ia)
Figure JPOXMLDOC01-appb-C000007
　　　
［式中、環Ａ、Ｙ１、Ｙ２、Ｑ、Ｒ１、Ｒ２、Ｒ３およびＲ４は、前記（１）と同様のものを示す。］で表される化合物、またはその薬理上許容される塩、
（３）
環Ａが、
Figure JPOXMLDOC01-appb-C000007

[Wherein, ring A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 are the same as those in the above (1). Or a pharmacologically acceptable salt thereof,
(3)
Ring A is
Figure JPOXMLDOC01-appb-C000008
（ここで、Ｘ１、Ｘ２、Ｘ３および＊は前記（１）と同じものを示す。）である、前記（１）または（２）に記載の化合物、またはその薬理上許容される塩、
（４）Ｘ１がハロゲノ基またはシアノ基であり、Ｘ２およびＸ３がともにハロゲノ基である、前記（３）に記載の化合物、またはその薬理上許容される塩、
（５）Ｙ１が－Ｏ－、－ＮＨ－、－Ｓ－または－ＣＲ１１Ｒ１２－であり、Ｙ２が－ＣＲ１３Ｒ１４－である（ここで、Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は前記（１）と同じ
ものを示す。）、前記（１）から（４）のいずれかに記載の化合物、またはその薬理上許容される塩、
（６）Ｙ１が－Ｏ－または－ＮＨ－であり、Ｙ２が－ＣＲ１３Ｒ１４－である（ここで、Ｒ１３およびＲ１４は前記（１）と同じものを示す。）、前記（１）から（４）のいずれかに記載の化合物、またはその薬理上許容される塩、
（７）Ｑが、－ＣＨ２－ＣＨ２－である、前記（１）から（６）のいずれかに記載の化合物、またはその薬理上許容される塩、
（８）Ｒ１およびＲ２が、それらが結合している窒素原子と一緒になって、ハロゲノ基および水酸基からなる群より選ばれる１～６個で置換されていてもよいピロリジニル基を示す、前記（１）から（７）のいずれかに記載の化合物、またはその薬理上許容される塩、（９）Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい４～１０員の含窒素複素環基を示す、前記（１）から（８）のいずれかに記載の化合物、またはその薬理上許容される塩、
（１０）Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい、アゼチジニル基、ピロリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、ホモピペリジニル基およびホモピペラジニル基からなる群より選ばれるいずれか１つの基を示す、前記（１）から（８）のいずれかに記載の化合物、またはその薬理上許容される塩、
（１１）Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、Ｃ１～Ｃ６アルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、水酸基、アミノ基、Ｃ２～Ｃ６アルカノイルアミノ基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい、ピペリジニル基またはピペラジニル基を示す、前記（１）から（８）のいずれかに記載の化合物、またはその薬理上許容される塩、
（１２）（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン、４－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］モルホリン、４－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］チオモルホリン、Ｎ，Ｎ－ジメチル－２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エタンアミン、２，２’－｛［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］イミノ｝ジエタノール、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－４－オール、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピロリジン－３－オール、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］アゼチジン－３－オール、Ｎ－｛１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピロリジン－３－イル｝アセトアミド、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペラジン－２－オン、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］－１，４－ジアゼパン－５－オン、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－３－カルボン酸、（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－１－［（２－ブロモ－４，５－ジクロロフェノキシ）アセチル］－２－（ピロリジン－１－イルメチル）ピペラジン、２－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエトキシ｝－４，５－ジクロロベンゾニトリル、（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－１－｛［（３－クロロ－２－ナフチル）オキシ］アセチル｝－２－（ピロリジン－１－イルメチル）ピペラジン、３－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエトキシ｝－２－ナフトニトリル、Ｎ－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝－２，４，５－トリクロロアニリン、Ｎ－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝－４，５－ジクロロ－２－（トリフルオロメチル）アニリン、（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン、および、４－［３－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）プロピル］モルホリンからなる群より選ばれる前記（１）に記載の化合物、またはその薬理上許容される塩、
（１３）前記（１）から（１２）のいずれかに記載の化合物、またはその薬理学上許容される塩を含有する医薬、
（１４）ウロテンシンＩＩ受容体拮抗作用により、治療または予防され得る疾患の治療または予防のための前記（１３）に記載された医薬、
（１５）鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害または糖尿病の治療または予防のための前記（１３）に記載された医薬、
（１６）疾患の治療または予防のための医薬を製造するための前記（１）から（１２）のいずれかに記載の化合物、またはその薬理上許容される塩の使用、ならびに、
（１７）前記（１）から（１２）のいずれかに記載の化合物、またはその薬理上許容される塩の薬理学的有効量を人に投与することにより疾患を治療または予防する方法、を提供する。
Figure JPOXMLDOC01-appb-C000008
(Wherein X 1 , X 2 , X 3 and * are the same as those in (1) above), or a pharmacologically acceptable salt thereof as described in (1) or (2) above ,
(4) The compound according to the above (3), or a pharmacologically acceptable salt thereof, wherein X 1 is a halogeno group or a cyano group, and X 2 and X 3 are both halogeno groups,
(5) Y 1 is —O—, —NH—, —S— or —CR 11 R 12 —, and Y 2 is —CR 13 R 14 — (where R 11 , R 12 , R 13 And R 14 represents the same as (1) above), the compound according to any one of (1) to (4), or a pharmacologically acceptable salt thereof,
(6) Y 1 is —O— or —NH—, and Y 2 is —CR 13 R 14 — (wherein R 13 and R 14 are the same as those in (1) above), The compound according to any one of (1) to (4), or a pharmacologically acceptable salt thereof,
(7) The compound according to any one of (1) to (6), or a pharmacologically acceptable salt thereof, wherein Q is —CH 2 —CH 2 —.
(8) R 1 and R 2 together with the nitrogen atom to which they are attached represent a pyrrolidinyl group optionally substituted with 1 to 6 selected from the group consisting of a halogeno group and a hydroxyl group; The compound according to any one of (1) to (7), or a pharmacologically acceptable salt thereof, (9) R 3 and R 4 together with the nitrogen atom to which they are bonded, Group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C3-C8 cycloalkyl group, carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, Hydroxyl group, C1-C6 alkoxy group, amino group, mono C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2-C6 alkanoylamino group Any one of (1) to (8) above, which represents a 4- to 10-membered nitrogen-containing heterocyclic group optionally substituted with 1 to 3 selected from the group consisting of a C1-C6 alkylsulfonyl group and an oxo group Or a pharmacologically acceptable salt thereof,
(10) R 3 and R 4 together with the nitrogen atom to which they are attached, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino An azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, which may be substituted with 1 to 3 groups selected from the group consisting of a group, a C2-C6 alkanoylamino group, a C1-C6 alkylsulfonyl group and an oxo group , Thiomorpholinyl group, homopiperidinyl group and homopiperazini Indicates any one group selected from the group consisting of group A compound or a pharmacologically acceptable salt thereof, according to any one of (1) to (8),
(11) R 3 and R 4 together with the nitrogen atom to which they are attached, together with a C1-C6 alkyl group, a carboxy group, a C2-C6 alkanoyl group, a carbamoyl group, a hydroxyl group, an amino group, C2-C6 The compound according to any one of (1) to (8) above, which represents a piperidinyl group or piperazinyl group optionally substituted with 1 to 3 selected from the group consisting of an alkanoylamino group and an oxo group, or A pharmacologically acceptable salt,
(12) (2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy ) Acetyl] piperazine, 4- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl ] Morpholine, 4- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] thio Morpholine, N, N-dimethyl-2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazine-1-y } Sulfonyl) ethanamine, 2,2 ′-{[2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl } Sulfonyl) ethyl] imino} diethanol, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl } Sulfonyl) ethyl] piperidin-4-ol, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazine-1 -Yl} sulfonyl) ethyl] pyrrolidin-3-ol, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) ) Acetyl] piperazin-1-yl} sulfonyl) ethyl] azetidin-3-ol, N- {1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4 , 5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] pyrrolidin-3-yl} acetamide, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4- [ (2,4,5-Trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperazin-2-one, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4 -[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] -1,4-diazepan-5-one, 1- [2-({(3S) -3- Pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperidine-3-carboxylic acid, (2S) -4-{[2- ( 4-acetylpiperazin-1-yl) ethyl] sulfonyl} -1-[(2-bromo-4,5-dichlorophenoxy) acetyl] -2- (pyrrolidin-1-ylmethyl) piperazine, 2- {2-[( 2S) -4-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethoxy} -4,5- Dichlorobenzonitrile, (2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -1-{[(3-chloro-2-naphthyl) oxy] Acetyl} -2- (pyrrolidin-1-ylmethyl) piperazine, 3- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidine- 1-ylmethyl) piperazin-1-yl] -2-oxoethoxy} -2-naphthonitrile, N- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] Sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl} -2,4,5-trichloroaniline, N- {2-[(2S) -4-{[2- ( 4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl} -4,5-dichloro-2- (trifluoromethyl) Nilin, (2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2-{[(3S) -3-fluoropyrrolidin-1-yl] methyl} -1- [ (2,4,5-trichlorophenoxy) acetyl] piperazine and 4- [3-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) [Acetyl] piperazin-1-yl} sulfonyl) propyl] morpholine, or a pharmacologically acceptable salt thereof as described in (1) above,
(13) A pharmaceutical comprising the compound according to any one of (1) to (12) above, or a pharmacologically acceptable salt thereof,
(14) The medicament described in (13) above for treating or preventing a disease that can be treated or prevented by urotensin II receptor antagonism,
(15) Congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis, abnormal lipid metabolism, dependence The medicament described in (13) for the treatment or prevention of symptom, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, pain, neuromuscular dysfunction or diabetes ,
(16) Use of the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof for producing a medicament for treating or preventing a disease, and
(17) Provided is a method for treating or preventing a disease by administering to a human a pharmacologically effective amount of the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof. To do.
　以下に、本発明の一般式（Ｉ）および（Ｉａ）について説明する。
　「ハロゲノ基」は、フルオロ基、クロロ基、ブロモ基、またはヨード基を意味する。
　「Ｃ１～Ｃ６アルキル基」とは、炭素数１から６の直鎖または分岐鎖の飽和炭化水素基を意味し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基、１－エチルプロピル基、２，２－ジメチルプロピル基などが挙げられる。 The general formulas (I) and (Ia) of the present invention will be described below.
The “halogeno group” means a fluoro group, a chloro group, a bromo group, or an iodo group.
“C1-C6 alkyl group” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl. Group, tert-butyl group, n-pentyl group, n-hexyl group, 1-ethylpropyl group, 2,2-dimethylpropyl group and the like.
　「ハロゲノＣ１～Ｃ６アルキル基」とは、前記ハロゲノ基を置換基として有する前記Ｃ１～Ｃ６アルキル基を意味し、ハロゲノ基の数は１個であっても２個以上であってもよく、２個以上である場合の各ハロゲノ基の種類は同じであってもよいし、異なっていてもよい。例えば、クロロメチル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、クロロジフルオロメチル基、２－クロロエチル基、（２，２，２－トリフルオロ）エチル基、（１，１，２，２－テトラフルオロ）エチル基、ペンタフルオロエチル基などが挙げられる。 The “halogeno C1-C6 alkyl group” means the C1-C6 alkyl group having the halogeno group as a substituent, and the number of halogeno groups may be one or two or more. The type of each halogeno group in the case of being more than one may be the same or different. For example, chloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, 2-chloroethyl group, (2,2,2-trifluoro) ethyl group, (1,1,2,2 -Tetrafluoro) ethyl group, pentafluoroethyl group and the like.
　「Ｃ１～Ｃ６アルコキシ基」とは、炭素数１～６の直鎖状または分岐鎖状のアルキルオキシ基を意味し、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブチルオキシ基、ｔｅｒｔ－ブトキシ基、ｎ－ペンチルオキシ基、ｎ－ヘキシルオキシ基、１－エチルプロポキシ基、２，２－ジメチルプロポキシ基などが挙げられる。 “C1-C6 alkoxy group” means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group. And isobutyloxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, 1-ethylpropoxy group, 2,2-dimethylpropoxy group and the like.
　「Ｃ３～Ｃ８シクロアルキル基」とは、３～８員の飽和の単環性炭化水素基を示し、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基などが挙げられる。 “C3-C8 cycloalkyl group” means a 3- to 8-membered saturated monocyclic hydrocarbon group, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
　「Ｃ２～Ｃ４アルキレン基」とは、２～４個のメチレン鎖からなるアルキレン基を意味し、エチレン基、トリメチレン基、テトラメチレン基などが挙げられる。 “C2 to C4 alkylene group” means an alkylene group composed of 2 to 4 methylene chains, and examples thereof include an ethylene group, a trimethylene group, and a tetramethylene group.
　「Ｃ２～Ｃ６アルカノイル基」とは、炭素数２から６の直鎖状もしくは分枝鎖状の脂肪族アシル基を意味し、例えば、アセチル基、プロピオニル基、イソブチリル基、ピバロイル基などを挙げることができる。 “C2 to C6 alkanoyl group” means a linear or branched aliphatic acyl group having 2 to 6 carbon atoms, and examples thereof include an acetyl group, a propionyl group, an isobutyryl group, and a pivaloyl group. Can do.
　「モノＣ１～Ｃ６アルキルカルバモイル基」とは、１個の前記Ｃ１～Ｃ６アルキル基を置換基として有するカルバモイル基を意味し、例えば、メチルカルバモイル基、エチルカルバモイル基などが挙げられる。 “Mono C1-C6 alkylcarbamoyl group” means a carbamoyl group having one C1-C6 alkyl group as a substituent, and examples thereof include a methylcarbamoyl group and an ethylcarbamoyl group.
　「ジＣ１～Ｃ６アルキルカルバモイル基」とは、２個の前記Ｃ１～Ｃ６アルキル基を置換基として有するカルバモイル基を意味し、２個の各Ｃ１～Ｃ６アルキル基の種類は同じであってもよいし、異なっていてもよい。例えば、ジメチルカルバモイル基、ジエチルカルバモイル基、Ｎ－メチル－Ｎ－エチルカルバモイル基などが挙げられる。 The “di-C1-C6 alkylcarbamoyl group” means a carbamoyl group having the two C1-C6 alkyl groups as substituents, and the types of the two C1-C6 alkyl groups may be the same. And may be different. Examples thereof include a dimethylcarbamoyl group, a diethylcarbamoyl group, and an N-methyl-N-ethylcarbamoyl group.
　「モノＣ１～Ｃ６アルキルアミノ基」とは、１個の前記Ｃ１～Ｃ６アルキル基を置換基として有するアミノ基を意味し、例えば、メチルアミノ基、エチルアミノ基などが挙げられる。 “Mono C1-C6 alkylamino group” means an amino group having one C1-C6 alkyl group as a substituent, and examples thereof include a methylamino group and an ethylamino group.
　「ジＣ１～Ｃ６アルキルアミノ基」とは、２個の前記Ｃ１～Ｃ６アルキル基を置換基として有するアミノ基を意味し、２個の各Ｃ１～Ｃ６アルキル基の種類は同じであってもよいし、異なっていてもよい。例えば、ジメチルアミノ基、Ｎ－メチル－Ｎ－エチルアミノ基などが挙げられる。 The “di-C1-C6 alkylamino group” means an amino group having two C1-C6 alkyl groups as substituents, and the two C1-C6 alkyl groups may be the same type. And may be different. Examples thereof include a dimethylamino group and an N-methyl-N-ethylamino group.
　「Ｃ２～Ｃ６アルカノイルアミノ基」とは、前記Ｃ２～Ｃ６アルカノイル基を置換基として有するアミノ基を意味し、例えば、アセチルアミノ基、プロピオニルアミノ基、イソブチリルアミノ基、ピバロイルアミノ基などを挙げることができる。 The “C2-C6 alkanoylamino group” means an amino group having the C2-C6 alkanoyl group as a substituent, and examples thereof include an acetylamino group, a propionylamino group, an isobutyrylamino group, and a pivaloylamino group. Can do.
　「Ｃ１～Ｃ６アルキルスルホニル基」とは、前記Ｃ１～Ｃ６アルキル基から構成されるアルキルスルホニル基を意味し、例えば、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、イソプロピルスルホニル基、ブチルスルホニル基などを挙げることができる。 “C1-C6 alkylsulfonyl group” means an alkylsulfonyl group composed of the C1-C6 alkyl group, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, etc. Can be mentioned.
　「４～１０員の含窒素複素環基」とは、少なくとも１個の窒素原子を含む、単環または縮合環の４～１０員の複素環からなる基を意味し、飽和であっても不飽和であってもよい。また、窒素原子１個以外に更にヘテロ原子として窒素原子、酸素原子または硫黄原子などを１～３個有していてもよい。例えば、アゼチジニル基、ピロリジニル基、イミダゾリジニル基、ピラゾリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、ホモピペリジニル基、ホモピペラジニル基、インドリニル基、イソインドリニル基等が挙げられる。 The “4- to 10-membered nitrogen-containing heterocyclic group” means a group consisting of a monocyclic or condensed 4- to 10-membered heterocyclic ring containing at least one nitrogen atom. It may be saturated. Further, in addition to one nitrogen atom, it may further have 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms as heteroatoms. Examples include azetidinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperidinyl group, homopiperazinyl group, indolinyl group, isoindolinyl group and the like.
　以下に、本発明の一般式（Ｉ）および（Ｉａ）について詳述する。
　環Ａは、 The general formulas (I) and (Ia) of the present invention are described in detail below.
Ring A is
Figure JPOXMLDOC01-appb-C000009
を示す。（ここで、Ｘ１、Ｘ２、Ｘ３およびＸ４はそれぞれ独立して、水素原子、ハロゲノ基、水酸基、シアノ基、アミノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ１～Ｃ６アルコキシ基、Ｃ３～Ｃ８シクロアルキル基またはフェニル基を示し、＊はＹ１との結合を示す。）
　環Ａとしては、
Figure JPOXMLDOC01-appb-C000009
Indicates. (Wherein X 1 , X 2 , X 3 and X 4 are each independently a hydrogen atom, halogeno group, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C1- A C6 alkoxy group, a C3-C8 cycloalkyl group or a phenyl group, and * represents a bond to Y 1. )
As ring A,
Figure JPOXMLDOC01-appb-C000010
（ここでＸ１、Ｘ２、Ｘ３および＊は前記と同じものを示す。）が好ましい。
　以下に環Ａが
Figure JPOXMLDOC01-appb-C000010
(Where X 1 , X 2 , X 3 and * are the same as described above).
Below is Ring A
Figure JPOXMLDOC01-appb-C000011
である場合について詳述する。
Figure JPOXMLDOC01-appb-C000011
The case where
　Ｘ１、Ｘ２およびＸ３はそれぞれ独立して、水素原子、ハロゲノ基、水酸基、シアノ基、アミノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ１～Ｃ６アルコキシ基、Ｃ３～Ｃ８シクロアルキル基またはフェニル基を示し、＊はＹ１との結合を示す。Ｘ１、Ｘ２およびＸ３はそれぞれ独立して水素原子、ハロゲノ基、シアノ基、アミノ基またはハロゲノＣ１～Ｃ６アルキル基であることが好ましく、Ｘ１がハロゲノ基、シアノ基またはハロゲノＣ１～Ｃ６アルキル基であり、Ｘ２が水素原子、ハロゲノ基、シアノ基またはアミノ基であり、Ｘ３がハロゲノ基またはシアノ基であることがより好ましく、Ｘ１がハロゲノ基またはシアノ基であり、Ｘ２およびＸ３がともにハロゲノ基であることがさらに好ましい。ここでハロゲノ基としては、クロロ基およびブロモ基が好ましく、クロロ基がさらに好ましい。
　以下に環Ａが X 1 , X 2 and X 3 are each independently a hydrogen atom, halogeno group, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C1-C6 alkoxy group, C3-C8 A cycloalkyl group or a phenyl group is represented, and * represents a bond with Y 1 . X 1 , X 2 and X 3 are preferably each independently a hydrogen atom, a halogeno group, a cyano group, an amino group or a halogeno C1-C6 alkyl group, and X 1 is a halogeno group, a cyano group or a halogeno C1-C6 More preferably, it is an alkyl group, X 2 is a hydrogen atom, a halogeno group, a cyano group or an amino group, X 3 is a halogeno group or a cyano group, X 1 is a halogeno group or a cyano group, and X 2 More preferably, X 3 and X 3 are both halogeno groups. Here, the halogeno group is preferably a chloro group or a bromo group, and more preferably a chloro group.
Below is Ring A
Figure JPOXMLDOC01-appb-C000012
である場合について詳述する。
Figure JPOXMLDOC01-appb-C000012
The case where
　Ｘ４は水素原子、ハロゲノ基、水酸基、シアノ基、アミノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ１～Ｃ６アルコキシ基、Ｃ３～Ｃ８シクロアルキル基またはフェニル基を示し、＊はＹ１との結合を示す。Ｘ４は水素原子、ハロゲノ基またはシアノ基であることが好ましく、ハロゲノ基であることがさらに好ましい。ここでハロゲノ基としてはクロロ基が好ましい。 X 4 represents a hydrogen atom, a halogeno group, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group or a phenyl group, and * It shows the binding of Y 1. X 4 is preferably a hydrogen atom, a halogeno group or a cyano group, more preferably a halogeno group. Here, the halogeno group is preferably a chloro group.
　Ｙ１およびＹ２は次の（ａ）または（ｂ）を示す。
　（ａ）Ｙ１は－Ｏ－、－ＮＨ－、－Ｓ－または－ＣＲ１１Ｒ１２－を示し、Ｙ２は－ＣＲ１３Ｒ１４－を示す。
　（ｂ）Ｙ１は－ＣＲ１５Ｒ１６－を示し、Ｙ２は－Ｏ－、－ＮＨ－または－Ｓ－を示す。
　（ここで、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５およびＲ１６はそれぞれ独立して、水素原子、ハロゲノ基、水酸基またはＣ１～Ｃ６アルキル基を示す。）；
　Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５およびＲ１６としては水素原子が好ましい。
　Ｙ１およびＹ２としては前記（ａ）が好ましく、中でも、Ｙ１が－Ｏ－または－ＮＨ－でありＹ２が－ＣＲ１３Ｒ１４－であることがより好ましく、Ｙ１が－Ｏ－または－ＮＨ－でありＹ２が－ＣＨ２－であることがさらに好ましい。
　Ｑは、１～３個のＣ１～Ｃ６アルキル基で置換されていてもよい、Ｃ２～Ｃ４アルキレン基を示す。Ｑとしては、置換されていないＣ２～Ｃ４アルキレン基が好ましく、－ＣＨ２－ＣＨ２－ＣＨ２－および－ＣＨ２－ＣＨ２－がより好ましく、－ＣＨ２－ＣＨ２－が更に好ましい。
　Ｒ１およびＲ２は、次の（ｃ）または（ｄ）を示す。
　（ｃ）Ｒ１およびＲ２はそれぞれ独立して、ハロゲノ基および水酸基からなる群より選ばれる１～３個で置換されていてもよい、Ｃ１～Ｃ６アルキル基を示す。ここでＣ１～Ｃ６アルキル基が２個以上で置換されている場合の各置換基は同じであってもよいし、異なっていてもよい。
　（ｄ）Ｒ１およびＲ２は、それらが結合している窒素原子と一緒になって、ハロゲノ基および水酸基からなる群より選ばれる１～６個で置換されていてもよい、ピロリジニル基、ピペリジニル基またはモルホリニル基を示す。ここでピロリジニル基、ピペリジニル基またはモルホリニル基が２個以上で置換されている場合の各置換基は同じであってもよいし、異なっていてもよい。
　Ｒ１およびＲ２としては前記（ｄ）が好ましい。中でも、それらが結合している窒素原子と一緒になって、ハロゲノ基および水酸基からなる群より選ばれる１～６個で置換されていてもよいピロリジニル基であることが好ましく、１個のハロゲノ基で置換されていてもよいピロリジニル基であることがより好ましく、１個のフッ素原子で３位が置換されたピロリジニル基および無置換のピロリジニル基がさらに好ましい。
　Ｒ３およびＲ４は、次の（ｅ）または（ｆ）を示す。
　（ｅ）Ｒ３およびＲ４はそれぞれ独立して、水素原子、または、ハロゲノ基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基およびＣ２～Ｃ６アルカノイルアミノ基からなる群より選ばれる１～３個で置換されていてもよいＣ１～Ｃ６アルキル基を示す。
　（ｆ）Ｒ３およびＲ４は、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい４～１０員の含窒素複素環基を示す。
　Ｒ３およびＲ４としては、前記（ｆ）が好ましい。 Y 1 and Y 2 represent the following (a) or (b).
(A) Y 1 represents —O—, —NH—, —S— or —CR 11 R 12 —, and Y 2 represents —CR 13 R 14 —.
(B) Y 1 represents —CR 15 R 16 —, and Y 2 represents —O—, —NH— or —S—.
(Wherein R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently represents a hydrogen atom, a halogeno group, a hydroxyl group or a C1-C6 alkyl group);
R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are preferably hydrogen atoms.
Y 1 and Y 2 are preferably the above (a), more preferably Y 1 is —O— or —NH—, Y 2 is more preferably —CR 13 R 14 —, and Y 1 is —O—. Or, it is more preferably —NH— and Y 2 is —CH 2 —.
Q represents a C2-C4 alkylene group which may be substituted with 1 to 3 C1-C6 alkyl groups. Q is preferably an unsubstituted C2-C4 alkylene group, more preferably —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —, and still more preferably —CH 2 —CH 2 —.
R 1 and R 2 represent the following (c) or (d).
(C) R 1 and R 2 each independently represent a C1-C6 alkyl group which may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group and a hydroxyl group. Here, when two or more C1-C6 alkyl groups are substituted, each substituent may be the same or different.
(D) R 1 and R 2 together with the nitrogen atom to which they are attached, may be substituted with 1 to 6 groups selected from the group consisting of a halogeno group and a hydroxyl group, a pyrrolidinyl group, piperidinyl A group or a morpholinyl group. Here, when the pyrrolidinyl group, piperidinyl group or morpholinyl group is substituted with two or more, each substituent may be the same or different.
As R 1 and R 2 , the above (d) is preferable. Among them, it is preferably a pyrrolidinyl group which may be substituted with 1 to 6 selected from the group consisting of a halogeno group and a hydroxyl group, together with the nitrogen atom to which they are bonded, and one halogeno group The pyrrolidinyl group optionally substituted with is more preferable, and the pyrrolidinyl group substituted at the 3-position with one fluorine atom and the unsubstituted pyrrolidinyl group are more preferable.
R 3 and R 4 represent the following (e) or (f).
(E) R 3 and R 4 are each independently a hydrogen atom, a halogeno group, a C3-C8 cycloalkyl group, a carboxy group, a carbamoyl group, a mono C1-C6 alkylcarbamoyl group, or a di-C1-C6 alkylcarbamoyl group. A hydroxy group, a C1-C6 alkoxy group, an amino group, a mono-C1-C6 alkylamino group, a di-C1-C6 alkylamino group, and a C2-C6 alkanoylamino group may be substituted with 1-3. Good C1-C6 alkyl groups are indicated.
(F) R 3 and R 4 together with the nitrogen atom to which they are attached, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino And a 4- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 selected from the group consisting of a group, a C2-C6 alkanoylamino group, a C1-C6 alkylsulfonyl group and an oxo group.
As R 3 and R 4 , the above (f) is preferable.
　以下にＲ３およびＲ４が前記（ｅ）である場合について詳述する。
　Ｒ３およびＲ４はそれぞれ独立して、水素原子、または、ハロゲノ基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基およびＣ２～Ｃ６アルカノイルアミノ基からなる群より選ばれる１～３個で置換されていてもよいＣ１～Ｃ６アルキル基を示し、２個以上で置換されている場合の各置換基は同じであってもよいし、異なっていてもよい。Ｒ３およびＲ４はそれぞれ独立して、水素原子、または、水酸基で置換されていてもよいＣ１～Ｃ６アルキル基であることが好ましく、Ｒ３およびＲ４はともに水酸基で置換されていてもよいＣ１～Ｃ６アルキル基であることがさらに好ましい。 The case where R 3 and R 4 are the above (e) will be described in detail below.
R 3 and R 4 are each independently a hydrogen atom or a halogeno group, a C3-C8 cycloalkyl group, a carboxy group, a carbamoyl group, a mono-C1-C6 alkylcarbamoyl group, a di-C1-C6 alkylcarbamoyl group, a hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group and C2-C6 alkanoylamino group optionally substituted with 1-3 When a C6 alkyl group is represented and substituted with two or more, each substituent may be the same or different. R 3 and R 4 are preferably each independently a hydrogen atom or a C1-C6 alkyl group optionally substituted with a hydroxyl group, and both R 3 and R 4 may be substituted with a hydroxyl group. More preferably, it is a C1-C6 alkyl group.
　以下にＲ３およびＲ４が前記（ｆ）である場合について詳述する。
　Ｒ３およびＲ４は、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい４～１０員の含窒素複素環基を示し、２個以上で置換されている場合の各置換基は同じであってもよいし、異なっていてもよい。Ｒ３およびＲ４は、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい、アゼチジニル基、ピロリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、ホモピペリジニル基およびホモピペラジニル基からなる群より選ばれるいずれか１つの基であることが好ましく、Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい、ピペリジニル基またはピペラジニル基であることがより好ましく、Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、Ｃ１～Ｃ６アルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、水酸基、アミノ基、Ｃ２～Ｃ６アルカノイルアミノ基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい、ピペリジニル基またはピペラジニル基であることがさらに好ましい。ピペリジニル基またはピペラジニル基が１個の置換基で置換されている場合の置換基の位置は３位および４位が好ましい。Ｒ３、Ｒ４およびそれらが結合している窒素原子のさらなる具体的な例は以下の通りである。ここで、＊はＱとの結合を示す。 The case where R 3 and R 4 are the above (f) will be described in detail below.
R 3 and R 4 together with the nitrogen atom to which they are attached, are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, a C2-C6 Alkanoyl group, carbamoyl group, mono C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2 A 4- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 selected from the group consisting of -C6 alkanoylamino group and oxo group, and each substitution when substituted with 2 or more The groups may be the same or different. R 3 and R 4 together with the nitrogen atom to which they are attached, are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, a C2-C6 Alkanoyl group, carbamoyl group, mono C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2 An azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, which may be substituted with 1 to 3 selected from the group consisting of a -C6 alkanoylamino group, a C1-C6 alkylsulfonyl group and an oxo group , Homopiperidinyl group and homopiperazinyl group Is preferably any one group selected from the group that, R 3 and R 4 together with the nitrogen atom to which they are attached, a halogeno group, C1 ~ C6 alkyl group, a halogeno C1 ~ C6 Alkyl group, C3-C8 cycloalkyl group, carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono group Piperidinyl optionally substituted with 1 to 3 selected from the group consisting of C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2-C6 alkanoylamino group, C1-C6 alkylsulfonyl group and oxo group more preferably a group or piperazinyl group, R 3 and R 4, they are attached Selected from the group consisting of a C1-C6 alkyl group, a carboxy group, a C2-C6 alkanoyl group, a carbamoyl group, a hydroxyl group, an amino group, a C2-C6 alkanoylamino group and an oxo group A piperidinyl group or a piperazinyl group which may be substituted with three is more preferable. When the piperidinyl group or piperazinyl group is substituted with one substituent, the position of the substituent is preferably the 3-position and the 4-position. Further specific examples of R 3 , R 4 and the nitrogen atom to which they are bonded are as follows. Here, * indicates a bond with Q.
Figure JPOXMLDOC01-appb-C000013
　一般式（Ｉ）で表される化合物、またはその薬理上許容される塩は、下記の一般式（Ｉａ）で表される絶対配置の化合物、またはその薬理上許容される塩が好ましい。
Figure JPOXMLDOC01-appb-C000013
The compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is preferably a compound having an absolute configuration represented by the following general formula (Ia) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000014
（式中、環Ａ、Ｙ１、Ｙ２、Ｑ、Ｒ１、Ｒ２、Ｒ３およびＲ４は、前記と同様のものを示す。）
　一般式（Ｉａ）における環Ａ、Ｙ１、Ｙ２、Ｑ、Ｒ１、Ｒ２、Ｒ３およびＲ４の好ましい態様は、前述のとおりである。
Figure JPOXMLDOC01-appb-C000014
(In the formula, ring A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 are the same as described above.)
Preferred embodiments of the ring A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 in the general formula (Ia) are as described above.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物は塩を形成することができ、これらの塩は本発明に包含される。塩としては例えば、カリウム塩、ナトリウム塩、リチウム塩、カルシウム塩、マグネシウム塩、塩酸塩、臭化水素酸塩、硫酸塩、硝酸塩、リン酸塩、酢酸塩、シュウ酸塩、マロン酸塩、フマル酸塩、マレイン酸塩、Ｄ－リンゴ酸塩、Ｌ－リンゴ酸塩、Ｄ－酒石酸塩、Ｌ－酒石酸塩、フタル酸塩、トリフルオロ酢酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、２，４－ジメチルベンゼンスルホン酸塩、２，４，６－トリメチルベンゼンスルホン酸塩、４－エチルベンゼンスルホン酸塩、ナフタレンスルホン酸塩などが挙げられる。本発明の一般式（Ｉ）または（Ｉａ）で表される化合物は、任意の割合の塩を形成することができ、その各々の塩（例えば２酸塩、１／２酸塩など）またはそれらの混合物は、本発明に包含される。 The compound represented by the general formula (I) or (Ia) of the present invention can form a salt, and these salts are included in the present invention. Examples of the salt include potassium salt, sodium salt, lithium salt, calcium salt, magnesium salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, oxalate, malonate, fumarate. Acid salt, maleate, D-malate, L-malate, D-tartrate, L-tartrate, phthalate, trifluoroacetate, methanesulfonate, benzenesulfonate, p- Examples include toluene sulfonate, 2,4-dimethylbenzene sulfonate, 2,4,6-trimethylbenzene sulfonate, 4-ethylbenzene sulfonate, and naphthalene sulfonate. The compound represented by the general formula (I) or (Ia) of the present invention can form a salt in any ratio, and each salt thereof (for example, diacid salt, 1/2 acid salt, etc.) These mixtures are encompassed by the present invention.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物はまたはその薬理上許容される塩は、水和物または溶媒和物を形成することができる。水和物または溶媒和物としては例えば、水和物、メタノール和物、エタノール和物などが挙げられる。その各々の水和物、溶媒和物、またはそれらの混合物は、本発明に包含される。 The compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof can form a hydrate or a solvate. Examples of the hydrate or solvate include hydrate, methanol solvate, ethanol solvate and the like. Their respective hydrates, solvates, or mixtures thereof are encompassed by the present invention.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物又はその薬理上許容される塩は、置換基の種類や組み合わせによって、シス体、トランス体等の幾何異性体、ｄ体、ｌ体等の光学異性体（エナンチオマーおよびジアステレオマーを含む）、互変異性体、回転異性体などの各種異性体が存在し得るが、本発明は、特に限定していない場合はそれら全ての異性体および任意の割合のそれらの混合物（ラセミ体を含む）も包含する。
また、本発明の一般式（Ｉ）または（Ｉａ）で表される化合物又はその薬理上許容される塩は、このような化合物を構成する原子の１以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素（２Ｈ）、トリチウム（３Ｈ）、炭素－１３（１３Ｃ）、炭素－１４（１４Ｃ）、窒素－１５（１５Ｎ）、硫黄－３４（３４Ｓ）、塩素－３７（３７Ｃｌ）、臭素－８１（８１Ｂｒ）またはヨウ素－１２５（１２５Ｉ）などが挙げられる。また、前記化合物は、例えば、トリチウム（３Ｈ）、ヨウ素－１２５（１２５Ｉ）又は炭素－１４（１４Ｃ）などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 The compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof may be a geometric isomer such as a cis isomer or a trans isomer, d isomer, l Various isomers such as optical isomers (including enantiomers and diastereomers), tautomers, rotational isomers and the like can exist, but the invention is not limited to all such isomers. And mixtures thereof in any proportion (including racemates).
In addition, the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof has an unnatural ratio of atomic isotopes at one or more of atoms constituting such a compound. May be contained. As atomic isotopes, for example, deuterium ( 2 H), tritium ( 3 H), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-15 ( 15 N), sulfur-34 ( 34 S), chlorine-37 ( 37 Cl), bromine-81 ( 81 Br) or iodine-125 ( 125 I). The compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
　また、本発明は、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）または（Ｉａ）に変換される化合物、すなわち、酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）または（Ｉａ）に変化される化合物、または胃酸等により加水分解等を起こして化合物（Ｉ）または（Ｉａ）に変化される「薬理学的に許容されるプロドラッグ化合物」も包含する。「薬学上許容されるプロドラッグ化合物」としては、例えば、化合物（Ｉ）または（Ｉａ）にアミノ基が存在する場合には、そのアミノ基がアシル化、アルキル化、リン酸化された化合物などが挙げられる。また、化合物（Ｉ）または（Ｉａ）に水酸基が存在する場合には、その水酸基がアシル化、アルキル化、リン酸化、ホウ酸化された化合物などを挙げられ、化合物（Ｉ）または（Ｉａ）にカルボキシ基が存在する場合には、そのカルボキシ基がエステル化、アミド化された化合物などが挙げられる。 The present invention also relates to a compound that is converted to compound (I) or (Ia) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. Also included are compounds that are changed to (I) or (Ia), or “pharmacologically acceptable prodrug compounds” that are changed to compound (I) or (Ia) by hydrolysis or the like due to gastric acid or the like. . Examples of the “pharmaceutically acceptable prodrug compound” include a compound in which, when compound (I) or (Ia) has an amino group, the amino group is acylated, alkylated or phosphorylated. Can be mentioned. In addition, when compound (I) or (Ia) has a hydroxyl group, examples thereof include compounds in which the hydroxyl group is acylated, alkylated, phosphorylated or borated, and compound (I) or (Ia) includes When a carboxy group is present, a compound in which the carboxy group is esterified or amidated can be used.
　本発明の一般式（Ｉ）で表される化合物は、以下のＡ法ないしＣ法に従って製造することができる。本発明の一般式（Ｉａ）で表される化合物も、これと同様の方法で製造することができる。 The compound represented by the general formula (I) of the present invention can be produced according to the following method A to method C. The compound represented by the general formula (Ia) of the present invention can also be produced by the same method.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　上記Ａ法ないしＣ法の化合物の構造式において、環Ａ、Ｙ１、Ｙ２、Ｑ、Ｒ１、Ｒ２、Ｒ３およびＲ４は前記と同様のものを示し、Ｘはハロゲン原子を示し、Ｑ’は１～３個のＣ１～Ｃ６アルキル基で置換されていてもよいビニル基を示し、Ｑ’’は１～３個のＣ１～Ｃ６アルキル基で置換されていてもよいＣ３～Ｃ４アルキレン基を示し、Ｒ２１はＣ１～Ｃ６アルキル基を示す。ただし、Ｂ法においては、Ｂ法－１ではＹ１およびＹ２は前記の（ａ）を示し、Ｂ法－２ではＹ１およびＹ２は前記の（ｂ）を示す。Ｂｏｃ基はｔｅｒｔ－ブトキシカルボニル基を意味し、Ｚ基はベンジルオキシカルボニル基を意味する。 In the structural formulas of the compounds of Method A to Method C, rings A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 are the same as described above, and X is a halogen atom , Q ′ represents a vinyl group which may be substituted with 1 to 3 C1 to C6 alkyl groups, and Q ″ represents C3 to C4 which may be substituted with 1 to 3 C1 to C6 alkyl groups. Represents an alkylene group, and R 21 represents a C1-C6 alkyl group. However, in method B, Y 1 and Y 2 in the method B-1 represent the above (a), and in the method B-2, Y 1 and Y 2 represent the above (b). The Boc group means a tert-butoxycarbonyl group, and the Z group means a benzyloxycarbonyl group.
　下記Ａ法ないしＣ法の各工程の反応において、反応基質となる化合物が、アミノ基、水酸基またはカルボキシル基等のような、目的の反応を阻害する基を有する場合、必要に応じて適宜それらの基への保護基の導入を行ってもよく、また、必要に応じて適宜導入した保護基の除去を行なってもよい。そのような保護基は、通常反応を進行させるために用いられる保護基であれば特に限定はなく、例えば、Ｔ．　Ｗ．　Ｇｒｅｅｎｅ，　Ｐ．　Ｇ．　Ｗｕｔｓ，　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ．　Ｔｈｉｒｄ　Ｅｄｉｔｉｏｎ，　１９９９年，　Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，　Ｉｎｃ．等に記載された保護基であり得る。それらの保護基の導入反応、および、当該保護基の除去反応は、上記文献に記載された方法のような常法に従って行うことができる。 In the reaction of each step of the following methods A to C, when the compound serving as a reaction substrate has a group that inhibits the desired reaction such as an amino group, a hydroxyl group, or a carboxyl group, those compounds are appropriately selected as necessary. A protecting group may be introduced into the group, and a protecting group introduced as appropriate may be removed as necessary. Such a protecting group is not particularly limited as long as it is a protecting group usually used for proceeding with the reaction. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. And the like. The introduction reaction of these protecting groups and the removal reaction of the protecting groups can be carried out according to conventional methods such as the methods described in the above-mentioned documents.
　下記Ａ法ないしＣ法の各工程の反応において使用される溶媒は、反応を阻害せず、出発原料を一部溶解するものであれば特に限定はなく、下記溶媒群より選択される。溶媒群は、ヘキサン、ペンタン、石油エーテル、シクロヘキサンのような脂肪族炭化水素類；ベンゼン、トルエン、キシレンのような芳香族炭化水素類；塩化メチレン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルのようなエーテル類；アセトン、メチルエチルケトン、メチルイソブチルケトン、シクロヘキサノンのようなケトン類；酢酸エチル、酢酸プロピル、酢酸ブチルのようなエステル類；アセトニトリル、プロピオニトリル、ブチロニトリル、イソブチロニトリルのようなニトリル類；酢酸、プロピオン酸のようなカルボン酸類；メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、２－メチル－１－プロパノール、２－メチル－２－プロパノールのようなアルコール類；ホルムアミド、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、ヘキサメチルホスホロトリアミドのようなアミド類；ジメチルスルホキシド、スルホランのようなスルホキシド類；水；および、これらの混合物からなる。 The solvent used in the reaction in each step of the following method A to method C is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting material, and is selected from the following solvent group. Solvent groups include aliphatic hydrocarbons such as hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene. Halogenated hydrocarbons such as: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; ethyl acetate, propyl acetate Esters such as butyl acetate; Nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; Cals such as acetic acid and propionic acid Acids; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide, dimethylformamide, dimethyl Amides such as acetamide, N-methyl-2-pyrrolidone and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; water; and mixtures thereof.
　下記Ａ法ないしＣ法の各工程の反応において使用される酸は、反応を阻害しないものであれば特に限定はなく、下記酸群より選択される。酸群は、酢酸、プロピオン酸、トリフルオロ酢酸、ペンタフルオロプロピオン酸のような有機酸、ｐ－トルエンスルホン酸、カンファースルホン酸、トリフルオロメタンスルホン酸のような有機スルホン酸、および、塩酸、臭化水素酸、ヨウ化水素酸、リン酸、硫酸、硝酸のような無機酸からなる。 The acid used in the reaction of each step of the following method A or method C is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group. Acid groups include organic acids such as acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid, organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, and hydrochloric acid, bromide It consists of inorganic acids such as hydroacid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.
　下記Ａ法ないしＣ法の各工程の反応において使用される塩基は、反応を阻害しないものであれば特に限定はなく、下記塩基群より選択される。塩基群は、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムのようなアルカリ金属炭酸塩；炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウムのようなアルカリ金属炭酸水素塩；水酸化リチウム、水酸化ナトリウム、水酸化カリウムのようなアルカリ金属水酸化物；水酸化カルシウム、水酸化バリウムのようなアルカリ土類金属水酸化物；水素化リチウム、水素化ナトリウム、水素化カリウムのようなアルカリ金属水素化物；リチウムアミド、ナトリウムアミド、カリウムアミドのようなアルカリ金属アミド；リチウムメトキシド、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシドのようなアルカリ金属アルコキシド；リチウムジイソプロピルアミドのようなリチウムアルキルアミド；リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミドのようなシリルアミド；ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウムのようなアルキルリチウム；塩化メチルマグネシウム、臭化メチルマグネシウム、ヨウ化メチルマグネシウム、塩化エチルマグネシウム、臭化エチルマグネシウム、塩化イソプロピルマグネシウム、臭化イソプロピルマグネシウム、塩化イソブチルマグネシウムのようなハロゲン化アルキルマグネシウム；および、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、Ｎ－エチルモルホリン、ピリジン、ピコリン、４－(Ｎ,Ｎ－ジメチルアミノ)ピリジン、４－ピロリジノピリジン、２,６－ジ(ｔｅｒｔ－ブチル)－４－ピリジン、キノリン、Ｎ,Ｎ－ジメチルアニリン、Ｎ,Ｎ－ジエチルアニリン、１,５－ジアザビシクロ[４,３,０]ノナ－５－エン（ＤＢＮ）、１,４－ジアザビシクロ[２,２,２]オクタン（ＤＡＢＣＯ）、１,８－ジアザビシクロ[５,４,０]ウンデカ－７－エン（ＤＢＵ）のような有機アミンからなる。 The base used in the reaction of each step of the following method A or method C is not particularly limited as long as it does not inhibit the reaction, and is selected from the following group of bases. Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; lithium diisopropylamide Lithium alkylamides; silylamides such as lithium bistrimethylsilylamide and sodium bistrimethylsilylamide; alkyllithiums such as n-butyllithium, sec-butyllithium and tert-butyllithium; methylmagnesium chloride, methylmagnesium bromide, iodide Alkyl magnesium halides such as methyl magnesium, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, isobutyl magnesium chloride; and triethylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, N-methyl Morpholine, N-ethylmorpholine, pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 4-pi Lydinopyridine, 2,6-di (tert-butyl) -4-pyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4,3,0] non-5-ene It consists of an organic amine such as (DBN) 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU).
　下記Ａ法ないしＣ法の各工程の反応において、反応温度は、溶媒、出発原料、試薬等により異なり、反応時間は、溶媒、出発原料、試薬、反応温度等により異なる。 In the reaction of each step of Method A to Method C below, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.
　下記Ａ法ないしＣ法の各工程の反応において、反応終了後、各工程の目的化合物は、常法に従って反応混合物から単離される。例えば、（i）必要に応じて触媒等の不溶物を濾去し、（ii）反応混合物に水および水と混和しない溶媒（例えば、塩化メチレン、ジエチルエーテル、酢酸エチル等）を加えて、目的化合物 を抽出し、（iii）有機層を水洗して、無水硫酸マグネシウム等の乾燥剤を用いて乾燥させ、（iv）溶媒を留去することによって、目的化合物が得られる。得られた目的化合物 は、必要に応じ、常法、例えば、再結晶、再沈澱、または、シリカゲルカラムクロマトグラフィー等により、更に精製することができる。また、各工程の目的化合物 は精製することなくそのまま次の反応に使用することもできる。 In the reaction of each step of Method A or Method C below, after completion of the reaction, the target compound in each step is isolated from the reaction mixture according to a conventional method. For example, (i) if necessary, insoluble matter such as a catalyst is removed by filtration, and (ii) water and a solvent immiscible with water (for example, methylene chloride, diethyl ether, ethyl acetate, etc.) are added to the reaction mixture. Compound III is extracted, (iii) the organic layer is washed with water, dried using a desiccant such as anhydrous magnesium sulfate, and (iv) the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation, silica gel column chromatography or the like, if necessary. Further, the target compound の of each step can be used as it is in the next reaction without purification.
　以下にＡ法ないしＣ法の各工程の反応を説明する。
　［Ａ法］
　［Ａ法］の工程１は化合物（２）と化合物（３）を脱水縮合することにより化合物（４）を製造する方法である。使用される縮合剤としては例えば、アゾジカルボン酸ジエチルエステル－トリフェニルホスフィンのようなアゾジカルボン酸ジ低級アルキルエステル－トリフェニルホスフィン類；Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＥＤＣＩ）のようなカルボジイミド誘導体；２－クロル－１－メチルピリジニウムヨージドのような２－ハロ－１－低級アルキルピリジニウムハライド類；ジフェニルホスホリルアジド（ＤＰＰＡ）、ジエチルホスホリルクロリド、ジエチルホスホリルシアニド（ＤＥＰＣ）のようなリン酸エステル類；クロロ蟻酸エチル、クロロ蟻酸イソブチルのようなクロロ蟻酸エステル類；Ｎ，Ｎ’－カルボジイミダゾール（ＣＤＩ）のようなイミダゾール誘導体；Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスフェート（ＨＡＴＵ）、（１Ｈ－ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウムヘキサフルオロホスフェート（ＰｙＢＯＰ）のようなベンゾトリアゾール誘導体などであり、好適にはカルボジイミド誘導体であり、より好適にはＥＤＣＩである。使用される溶媒は好適には前記例示のようなハロゲン化炭化水素類あるいはエーテル類であり、より好適にはテトラヒドロフランである。なお、反応溶液に４－（Ｎ，Ｎ－ジメチルアミノ）ピリジンを触媒量加えることにより、反応を加速することができる。反応温度は通常０～１００℃であり、好適には０～４０℃である。反応時間は通常３０分～２４時間であり、好適には２～１２時間である。 The reaction in each step of Method A to Method C will be described below.
[Method A]
Step 1 of [Method A] is a method for producing compound (4) by dehydrating condensation of compound (2) and compound (3). Examples of the condensing agent used include azodicarboxylic acid di-lower alkyl ester-triphenylphosphine such as azodicarboxylic acid diethyl ester-triphenylphosphine; N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3 -Carbodiimide derivatives such as (3-dimethylaminopropyl) carbodiimide (EDCI); 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; diphenylphosphoryl azide (DPPA), Phosphoric esters such as diethyl phosphoryl chloride and diethyl phosphoryl cyanide (DEPC); Chloroformates such as ethyl chloroformate and isobutyl chloroformate; Imines such as N, N′-carbodiimidazole (CDI) Zole derivatives; O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), (1H-benzotriazol-1-yloxy) tripyrrolyl A benzotriazole derivative such as dinophosphonium hexafluorophosphate (PyBOP), a carbodiimide derivative, and more preferably EDCI. The solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably tetrahydrofuran. The reaction can be accelerated by adding a catalytic amount of 4- (N, N-dimethylamino) pyridine to the reaction solution. The reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 2 to 12 hours.
　［Ａ法］の工程２は化合物（４）を還元剤で還元することにより化合物（５）を製造する方法である。使用される還元剤としては例えば水素化リチウムアルミニウム、水素化ホウ素リチウム、ボランなどであり、好適にはボランである。使用される溶媒は、好適には前記例示のような脂肪族炭化水素類、芳香族炭化水素類あるいはエーテル類であり、より好適にはテトラヒドロフランである。反応温度は通常０～１００℃であり、好適には２５～６０℃である。反応時間は通常３０分～１２時間であり、好適には１～４時間である。 Step 2 of [Method A] is a method for producing compound (5) by reducing compound (4) with a reducing agent. Examples of the reducing agent used include lithium aluminum hydride, lithium borohydride, and borane, and borane is preferable. The solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether as exemplified above, and more preferably tetrahydrofuran. The reaction temperature is usually 0 to 100 ° C., preferably 25 to 60 ° C. The reaction time is usually 30 minutes to 12 hours, preferably 1 to 4 hours.
　［Ｂ法－１］
　［Ｂ法－１］の工程１は化合物（６）を塩基存在下化合物（７）とカップリングし、化合物（８）を製造する方法である。使用される溶媒としては、好適には前記例示のようなエーテル類、アミド類あるいはニトリル類であり、より好適にはＮ，Ｎ－ジメチルホルムアミドである。使用される塩基は、好適には前記例示のようなアルカリ金属炭酸塩、アルカリ金属水素化物あるいはアルカリ金属アルコキシドであり、より好適には炭酸カリウムあるいは水素化ナトリウムである。反応温度は通常０～１００℃であり、好適には０～４０℃である。反応時間は通常１～２４時間であり、好適には１～１２時間である。 [Method B-1]
Step 1 of [Method B-1] is a method for producing compound (8) by coupling compound (6) with compound (7) in the presence of a base. The solvent used is preferably an ether, amide or nitrile as exemplified above, and more preferably N, N-dimethylformamide. The base used is preferably an alkali metal carbonate, alkali metal hydride or alkali metal alkoxide as exemplified above, and more preferably potassium carbonate or sodium hydride. The reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C. The reaction time is usually 1 to 24 hours, preferably 1 to 12 hours.
　［Ｂ法－１］の工程２は化合物（８）のエステルを加水分解することによりカルボン酸（９）を製造する工程である。反応としては例えばＴ．　Ｗ．　Ｇｒｅｅｎｅ，　Ｐ．　Ｇ．　Ｗｕｔｓ，　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ．　Ｔｈｉｒｄ　Ｅｄｉｔｉｏｎ，　１９９９年，　Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，　Ｉｎｃ．などの総説書に記載の文献を参考にすることができる。 Step 2 of [Method B-1] is a step of producing carboxylic acid (9) by hydrolyzing the ester of compound (8). Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
　［Ｂ法－１］の工程３は化合物（９）をハロゲン化試薬と反応させることにより化合物（１０）を製造する方法である。使用されるハロゲン化試薬としては例えば塩化オキザリル、塩化チオニル、塩化ホスホリルなどであり、好適には塩化オキザリルである。なお、反応溶液にＮ，Ｎ－ジメチルホルムアミドを触媒量加えることにより、反応を加速することができる。使用される溶媒としては、好適には前記例示のようなハロゲン化炭化水素類あるいはエーテル類であり、より好適には塩化メチレンである。反応温度は通常０～６０℃であり、好適には０～４０℃である。反応時間は通常１０分～１２時間であり、好適には３０分～６時間である。 Step 3 of [Method B-1] is a method for producing compound (10) by reacting compound (9) with a halogenating reagent. Examples of the halogenating reagent to be used include oxalyl chloride, thionyl chloride, phosphoryl chloride and the like, and preferably oxalyl chloride. The reaction can be accelerated by adding a catalytic amount of N, N-dimethylformamide to the reaction solution. The solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably methylene chloride. The reaction temperature is usually 0 to 60 ° C., preferably 0 to 40 ° C. The reaction time is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
　［Ｂ法－２］
　［Ｂ法－２］は化合物（１１）をホスゲンと反応させ酸クロリド（１０）を製造する方法である。使用される溶媒としては好適には前記例示のようなハロゲン化炭化水素類あるいはエーテル類であり、より好適には塩化メチレンである。反応温度は通常０～６０℃であり、好適には０～４０℃である。反応時間は通常１０分～１２時間であり、好適には３０分～６時間である。 [Method B-2]
[Method B-2] is a method for producing acid chloride (10) by reacting compound (11) with phosgene. The solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably methylene chloride. The reaction temperature is usually 0 to 60 ° C., preferably 0 to 40 ° C. The reaction time is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
　［Ｃ法－１］
　［Ｃ法－１］の工程１は化合物（５）からＺ基を水素添加反応により脱保護し、化合物（１２）を製造する方法である。反応としては例えばＴ．　Ｗ．　Ｇｒｅｅｎｅ，　Ｐ．　Ｇ．　Ｗｕｔｓ，　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ．　Ｔｈｉｒｄ　Ｅｄｉｔｉｏｎ，　１９９９年，　Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，　Ｉｎｃ．などの総説書に記載の文献を参考にすることができる。 [Method C-1]
Step 1 of [Method C-1] is a method for producing compound (12) by deprotecting the Z group from compound (5) by hydrogenation reaction. Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
　［Ｃ法－１］の工程２は（ｉ）化合物（１２）と化合物（９）を脱水縮合、あるいは（ｉｉ）化合物（１２）と化合物（１０）を塩基存在下でカップリングすることにより化合物（１３）を製造する方法である。
（ｉ）の方法として使用される縮合剤としては例えば、アゾジカルボン酸ジエチルエステル－トリフェニルホスフィンのようなアゾジカルボン酸ジ低級アルキルエステル－トリフェニルホスフィン類；Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＥＤＣＩ）のようなカルボジイミド誘導体；２－クロル－１－メチルピリジニウムヨージドのような２－ハロ－１－低級アルキルピリジニウムハライド類；ジフェニルホスホリルアジド（ＤＰＰＡ）、ジエチルホスホリルクロリド、ジエチルホスホリルシアニド（ＤＥＰＣ）のようなリン酸エステル類；クロロ蟻酸エチル、クロロ蟻酸イソブチルのようなクロロ蟻酸エステル類；Ｎ，Ｎ’－カルボジイミダゾール（ＣＤＩ）のようなイミダゾール誘導体；Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスフェート（ＨＡＴＵ）、（１Ｈ－ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウムヘキサフルオロホスフェート（ＰｙＢＯＰ）のようなベンゾトリアゾール誘導体などであり、好適には、ＤＥＰＣである。使用される溶媒は好適には前記例示のようなハロゲン化炭化水素類あるいはエーテル類であり、より好適にはテトラヒドロフランである。使用される塩基は好適にはトリエチルアミンである。反応温度は通常０～１００℃であり、好適には０～４０℃である。反応時間は通常３０分～２４時間であり、好適には２～１２時間である。
（ｉｉ）の方法として用いられる溶媒としては、好適には前記例示のようなエーテル類、ハロゲン化炭化水素類あるいはアミド類であり、より好適には塩化メチレンである。使用される塩基としては、好適には前記例示のような有機アミンであり、より好適にはトリエチルアミンである。反応温度は通常０～１００℃であり、好適には０～４０℃である。反応時間は通常１０分～１２時間であり、好適には１０分～２時間である。 Step 2 of [Method C-1] comprises (i) dehydrating condensation of compound (12) and compound (9), or (ii) coupling compound (12) and compound (10) in the presence of a base. This is a method for producing (13).
Examples of the condensing agent used in the method (i) include azodicarboxylic acid dilower alkyl ester-triphenylphosphine such as azodicarboxylic acid diethyl ester-triphenylphosphine; N, N′-dicyclohexylcarbodiimide (DCC) Carbodiimide derivatives such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI); 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; Phosphoric esters such as phosphoryl azide (DPPA), diethyl phosphoryl chloride, diethyl phosphoryl cyanide (DEPC); chloroformates such as ethyl chloroformate and isobutyl chloroformate; N, N′-carbodiimidazole (C I) imidazole derivatives; O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), (1H-benzotriazole-1 A benzotriazole derivative such as -yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and preferably DEPC. The solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably tetrahydrofuran. The base used is preferably triethylamine. The reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 2 to 12 hours.
The solvent used in the method (ii) is preferably ethers, halogenated hydrocarbons or amides as exemplified above, and more preferably methylene chloride. The base used is preferably an organic amine as exemplified above, and more preferably triethylamine. The reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C. The reaction time is usually 10 minutes to 12 hours, preferably 10 minutes to 2 hours.
　［Ｃ法－１］の工程３は化合物（１３）からＢｏｃ基を酸により脱保護し、化合物（１４）を製造する方法である。反応としては例えばＴ．　Ｗ．　Ｇｒｅｅｎｅ，　Ｐ．　Ｇ．　Ｗｕｔｓ，　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ．　Ｔｈｉｒｄ　Ｅｄｉｔｉｏｎ，　１９９９年，　Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，　Ｉｎｃ．などの総説書に記載の文献を参考にすることができる。 Step 3 of [Method C-1] is a method for producing the compound (14) by deprotecting the Boc group from the compound (13) with an acid. Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
　［Ｃ法－１］の工程４は化合物（１４）と化合物（１５）を塩基存在下カップリングすることにより化合物（１６Ａ）あるいは化合物（１６Ｂ）を製造する方法である。使用される溶媒としては好適には前記例示のようなエーテル類、ハロゲン化炭化水素類あるいはアミド類であり、より好適には塩化メチレンである。使用される塩基としては、好適には前記例示のような有機アミンであり、より好適にはピリジンあるいは２，６－ジｔｅｒｔ－ブチルピリジンである。反応温度は通常－７８～２５℃であり、好適には－４５～０℃である。反応時間は通常１０分～１２時間であり、好適には１０分～２時間である。 Step 4 of [Method C-1] is a method for producing compound (16A) or compound (16B) by coupling compound (14) and compound (15) in the presence of a base. The solvent used is preferably an ether, halogenated hydrocarbon or amide as exemplified above, and more preferably methylene chloride. The base used is preferably an organic amine as exemplified above, and more preferably pyridine or 2,6-ditert-butylpyridine. The reaction temperature is usually −78 to 25 ° C., preferably −45 to 0 ° C. The reaction time is usually 10 minutes to 12 hours, preferably 10 minutes to 2 hours.
　［Ｃ法－１］の工程５は化合物（１６Ａ）または化合物（１６Ｂ）をアミン（１７）と反応させることにより化合物（Ｉ）を製造する方法である。使用される溶媒としては好適には前記例示のようなエーテル類あるいはハロゲン化炭化水素類であり、より好適には塩化メチレンである。反応温度は通常０～６０℃であり、好適には０～４０℃である。反応時間は通常１～６日であり、好適には１～３日である。 Step 5 of [Method C-1] is a method for producing compound (I) by reacting compound (16A) or compound (16B) with amine (17). The solvent used is preferably an ether or halogenated hydrocarbon as exemplified above, and more preferably methylene chloride. The reaction temperature is usually 0 to 60 ° C., preferably 0 to 40 ° C. The reaction time is usually 1 to 6 days, preferably 1 to 3 days.
　［Ｃ法－２］
　［Ｃ法－２］の工程１は化合物（５）から脱保護により化合物（１８）を製造する方法であり、前述の［Ｃ法－１］の工程３と同様に行うことができる。 [Method C-2]
Step 1 of [Method C-2] is a method for producing compound (18) by deprotection from compound (5), and can be carried out in the same manner as Step 3 of [Method C-1] described above.
　［Ｃ法－２］の工程２は化合物（１８）を化合物（１５）と反応させることにより化合物（１９Ａ）又は化合物（１９Ｂ）を製造する方法であり、前述の［Ｃ法－１］の工程４と同様に行うことができる。 Step 2 of [Method C-2] is a method for producing compound (19A) or compound (19B) by reacting compound (18) with compound (15). 4 can be performed.
　［Ｃ法－２］の工程３は化合物（１９Ａ）または化合物（１９Ｂ）をアミン（１７）と反応させることにより化合物（２０）を製造する方法であり、前述の［Ｃ法－１］の工程５と同様に行うことができる。 Step 3 of [Method C-2] is a method for producing compound (20) by reacting compound (19A) or compound (19B) with amine (17). 5 can be performed.
　［Ｃ法－２］の工程４は化合物（２０）から脱保護により化合物（２１）を製造する方法であり、前述の［Ｃ法－１］の工程１と同様に行うことができる。 Step 4 of [Method C-2] is a method for producing compound (21) from compound (20) by deprotection and can be carried out in the same manner as in Step 1 of [Method C-1] described above.
　［Ｃ法－２］の工程５は化合物（２１）と化合物（９）又は化合物（１０）をカップリングすることにより化合物（Ｉ）を製造する方法であり、前述の［Ｃ法－１］の工程２と同様に行うことができる。 Step 5 of [Method C-2] is a method for producing compound (I) by coupling compound (21) with compound (9) or compound (10). It can be carried out in the same manner as in step 2.
　後述の実施例に示す通り、本発明の一般式（Ｉ）または（Ｉａ）で表される化合物またはその薬理上許容される塩は、ウロテンシンＩＩ受容体に対する拮抗作用を示すので、鬱血性心不全、虚血性心疾患、狭心症、心筋梗塞、心不整脈、本態性高血圧、肺性高血圧、腎疾患、慢性腎不全、急性腎不全、末梢血管疾患、男性***不全、糖尿病性網膜症、間欠性跛行、四肢虚血性疾患、脳血管障害、慢性閉塞性肺疾患、再狭窄、喘息、神経性炎症、片頭痛、代謝性血管障害、骨／軟骨／関節疾患、関節炎、炎症性疾患、線維症、肺線維症、敗血症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害、糖尿病、消化管運動障害、潰瘍または泌尿生殖器疾患の治療または予防のための医薬として有用である。また、本発明の一般式（Ｉ）または（Ｉａ）で表される化合物またはその薬理上許容される塩は、サルの大動脈においてウロテンシンＩＩに誘発される血管収縮を有意に阻害するので、前述の背景技術からも明らかなように、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害または糖尿病の治療または予防のための医薬として有用であり、特に、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常または糖尿病の治療または予防のための医薬として有用である。 As shown in the examples described later, the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof exhibits an antagonistic action on the urotensin II receptor, so congestive heart failure, Ischemic heart disease, angina pectoris, myocardial infarction, cardiac arrhythmia, essential hypertension, pulmonary hypertension, renal disease, chronic renal failure, acute renal failure, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication Limb ischemic disease, cerebrovascular disorder, chronic obstructive pulmonary disease, restenosis, asthma, neurogenic inflammation, migraine, metabolic vascular disorder, bone / cartilage / joint disease, arthritis, inflammatory disease, fibrosis, lung Fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, pain, neuromuscular dysfunction, diabetes , Gastrointestinal motility Harm, are useful as pharmaceuticals for the treatment or prophylaxis of ulcers or genitourinary disease. In addition, since the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof significantly inhibits vasoconstriction induced by urotensin II in the monkey aorta, As is clear from the background art, congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis Useful as a medicine for the treatment or prevention of lipid metabolism disorders, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorders, pain, neuromuscular dysfunction or diabetes In particular, congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis, lipid Useful as Xie abnormality or a medicament for the treatment or prevention of diabetes.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物またはその薬理上許容される塩を医薬として使用する場合、患者への投与量は、患者の性別、年齢、症状、薬物の種類、薬物の投与量、投与方法、投与回数、投与時期等により適宜検討を行い、適当な投与量を決めればよい。通常、成人一日当たり０．１ｍｇ～１ｇであり、０．５ｍｇ～５００ｍｇが好ましいが、これに限定されるべきものではない。一日の投与量は、一日１回、または２～６回程度に分割して投与してもよい。 When the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof is used as a medicine, the dose to the patient depends on the sex, age, symptom, and type of drug. The appropriate dose may be determined by appropriately examining the dose, administration method, number of doses, administration timing, etc. of the drug. Usually, it is 0.1 mg to 1 g per day for adults, preferably 0.5 mg to 500 mg, but should not be limited thereto. The daily dose may be administered once a day or divided into 2-6 times.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物を含有する医薬組成物は、投与法に応じ適当な製剤を選択し、通常用いられている各種製剤の調製法で調製することができる。 The pharmaceutical composition containing the compound represented by the general formula (I) or (Ia) of the present invention should be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations usually used. Can do.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物を主剤とする医薬組成物を哺乳動物（特にヒト）に投与する場合には、全身的又は局所的に、経口又は非経口で投与することができる。 When a pharmaceutical composition mainly comprising a compound represented by the general formula (I) or (Ia) of the present invention is administered to a mammal (particularly human), systemically or locally, orally or parenterally. Can be administered.
　経口用の医薬の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬は、通常、一般式（Ｉ）または（Ｉａ）で表される本発明化合物を主剤とし、薬学的に許容される添加物としての希釈剤、賦形剤又は担体と混合された医薬組成物として調製される。医薬組成物の調製は、薬学的に許容される希釈剤、賦形剤又は担体として、又はそれらに加えて、任意の適切な薬学的に許容される結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、湿潤剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 Examples of oral pharmaceutical forms include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. These forms of medicines are usually mixed with a diluent, excipient or carrier as a pharmaceutically acceptable additive based on the compound of the present invention represented by the general formula (I) or (Ia). Prepared as a pharmaceutical composition. The preparation of the pharmaceutical composition may be any suitable pharmaceutically acceptable binder, disintegrant, lubricant, swelling, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier. Necessary from agents, swelling aids, coating agents, plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffers, wetting agents, etc. Can be carried out according to a conventional method using a material appropriately selected according to the method.
　非経口用の医薬の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、点鼻剤、座剤、吸入剤等が挙げられる。これら形態の医薬は、通常、一般式（Ｉ）または（Ｉａ）で表される本発明化合物を主剤とし、薬学的に許容される添加物としての希釈剤、賦形剤又は担体と混合された医薬組成物として調製される。 The parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, inhalants, etc. Is mentioned. These forms of medicines are usually mixed with a diluent, excipient or carrier as a pharmaceutically acceptable additive based on the compound of the present invention represented by the general formula (I) or (Ia). Prepared as a pharmaceutical composition.
　医薬組成物の調製は、薬学的に許容される希釈剤、賦形剤又は担体として、又はそれらに加えて、任意の適切な薬学的に許容される安定化剤、防腐剤、溶解補助剤、保湿剤、保存剤、抗酸化剤、着香剤、ゲル化剤、中和剤、溶解補助剤、緩衝剤、等張剤、界面活性剤、着色剤、緩衝化剤、増粘剤、湿潤剤、充填剤、吸収促進剤、懸濁化剤、結合剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。　上記の薬学的に許容される担体又は希釈剤に関する参考文献としては、例えば、「Ｒｅｍｉｎｇｔｏｎ’ｓ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｍａｃｋ　Ｐｕｂｌｉｓｈｉｎｇ　Ｃｏ．（Ａ．Ｒ．Ｇｅｎｎａｒｏ　ｅｄｉｔ．１９８５）」を挙げることができる。　また、薬学的に許容される賦形剤に関する参考文献としては、例えば「Ｈａｎｄｂｏｏｋ　ｏｆ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｅｘｃｉｐｉｅｎｔｓ，　２ｎｄ　Ｅｄｉｔｉｏｎ，（１９９４），Ｅｄｉｔｅｄ　ｂｙ　Ａ．Ｗａｄｅ　ａｎｄ　Ｐ．Ｊ．Ｗｅｌｌｅｒ」を挙げることができる。 The preparation of the pharmaceutical composition comprises any suitable pharmaceutically acceptable stabilizer, preservative, solubilizer, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier, Moisturizer, preservative, antioxidant, flavoring agent, gelling agent, neutralizing agent, solubilizing agent, buffering agent, isotonic agent, surfactant, coloring agent, buffering agent, thickener, wetting agent , A filler, an absorption accelerator, a suspending agent, a binder and the like, which are appropriately selected as necessary, can be used according to a conventional method. References regarding the above-mentioned pharmaceutically acceptable carriers or diluents include, for example, “Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985)”. Further, as a reference for pharmaceutically acceptable excipients, for example, “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A. Wade and P. J. Weller” can be cited.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物またはその薬理上許容される塩は、ウロテンシンＩＩ受容体に対する拮抗作用を示すので、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害または糖尿病の治療または予防のための医薬として有用である。 Since the compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof exhibits an antagonistic action against the urotensin II receptor, congestive heart failure, ischemic heart disease, cardiac arrhythmia, Essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, It is useful as a medicament for the treatment or prevention of stress, depression, Parkinson's disease, movement disorders, pain, neuromuscular dysfunction or diabetes.
カニクイザル摘出血管におけるヒトウロテンシンＩＩ誘発収縮の阻害評価結果を示した図である。It is the figure which showed the inhibition evaluation result of the human urotensin II induced contraction in the cynomolgus monkey excised blood vessel.
　以下に実施例、試験例および製剤例を挙げて本発明をさらに詳細に説明するが、本発明はこれに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples, but the present invention is not limited thereto.
　以下、実施例により本発明を具体的に説明するが、この方法に何ら限定されるものではない。 Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to these methods.
　実施例中の「ＩＲ」、「１Ｈ－ＮＭＲ」、「ＭＳ」の記号は、各々「赤外吸収スペクトル」、「核磁気共鳴スペクトル」、「質量分析」を意味する。クロマトグラフィーによる分離精製の箇所に記載の溶出溶媒の割合は、特に記載のない場合は体積比を示す。「ＩＲ」はＡＴＲ法またはＫＢｒ打錠法によって測定した。「１Ｈ－ＮＭＲ」の括弧内は測定溶媒を示し、全て内部標準物質としてＴＭＳ（テトラメチルシラン）を用いた。１Ｈ－ＮＭＲにおける多重度は、ｓ＝ｓｉｎｇｌｅｔ、ｄ＝ｄｏｕｂｌｅｔ、ｔ＝ｔｒｉｐｌｅｔ、ｑ＝ｑｕａｒｔｅｔ、ｍ＝ｍｕｌｔｉｐｌｅｔ、およびｂｒ　ｓ＝ｂｒｏａｄ　ｓｉｎｇｌｅｔを意味する。また、本明細書中において、以下の略語を使用した。
Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル
Ｚ：ベンジルオキシカルボニル
ＣＤＣｌ３：重クロロホルム
ＤＭＳＯ－Ｄ６：ジメチルスルホキシドＤ６
（参考例１）
（２－ブロモ－４，５－ジクロロフェノキシ）酢酸
（参考例１Ａ）
２－ブロモ－４，５－ジクロロフェノール The symbols “IR”, “ 1 H-NMR”, and “MS” in the examples mean “infrared absorption spectrum”, “nuclear magnetic resonance spectrum”, and “mass spectrometry”, respectively. The ratio of the eluting solvent described in the section of separation and purification by chromatography indicates a volume ratio unless otherwise specified. “IR” was measured by the ATR method or KBr tableting method. The parentheses in “ 1 H-NMR” indicate the measurement solvent, and TMS (tetramethylsilane) was used as an internal standard substance. Multiplicity in 1 H-NMR means s = singlet, d = doublelet, t = triplet, q = quartet, m = multiplet, and br s = broad singlet. Moreover, the following abbreviations were used in this specification.
Boc: tert-butoxycarbonyl Z: benzyloxycarbonyl CDCl 3 : deuterated chloroform DMSO-D 6 : dimethyl sulfoxide D6
(Reference Example 1)
(2-Bromo-4,5-dichlorophenoxy) acetic acid (Reference Example 1A)
2-Bromo-4,5-dichlorophenol
Figure JPOXMLDOC01-appb-C000020
３，４－ジクロロフェノール１．００ｇ（６．１ｍｍｏｌ）をクロロホルム２０ｍＬに溶解し、Ｎ－ブロモコハク酸イミド１．２０ｇ（６．７ｍｍｏｌ）を加え、５０℃で１時間撹拌した。反応溶液を室温に冷却した後、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー（５０－８０％トルエン／ヘキサン）及び（１０－１５％酢酸エチル／ヘキサン）により生成し、目的化合物１６４ｍｇ（１１％）を得た。
1H-NMR (CDCl3) δ: 5.52 (1H, s), 7.15 (1H, s), 7.56 (1H,s).
（参考例１Ｂ）
（２－ブロモ－４，５－ジクロロフェノキシ）酢酸　エチル
Figure JPOXMLDOC01-appb-C000020
1.00 g (6.1 mmol) of 3,4-dichlorophenol was dissolved in 20 mL of chloroform, 1.20 g (6.7 mmol) of N-bromosuccinimide was added, and the mixture was stirred at 50 ° C. for 1 hour. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was produced by column chromatography (50-80% toluene / hexane) and (10-15% ethyl acetate / hexane) to give 164 mg (11%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 5.52 (1H, s), 7.15 (1H, s), 7.56 (1H, s).
(Reference Example 1B)
(2-Bromo-4,5-dichlorophenoxy) ethyl acetate
Figure JPOXMLDOC01-appb-C000021
参考例１Ａで得られた２－ブロモ－４，５－ジクロロフェノール１５０ｍｇ（０．６２ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド２ｍＬに溶解し、炭酸カリウム１０３ｍｇ（０．７４ｍｍｏｌ）及びブロモ酢酸エチル７６μＬ（０．６８ｍｍｏｌ）を加え、室温で終夜撹拌した。反応溶液に水を加え、水相をエーテルで抽出し、有機相を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－８％酢酸エチル／ヘキサン）により精製し、目的化合物を１９０ｍｇ（９４％）得た。
1H-NMR (CDCl3) δ: 1.31 (3H, t, J = 7.1 Hz), 4.28 (2H, q,J = 7.1 Hz), 4.68 (2H,s), 6.89 (1H, s), 7.65 (1H, s).
（参考例１Ｃ）
（２－ブロモ－４，５－ジクロロフェノキシ）酢酸
Figure JPOXMLDOC01-appb-C000021
150 mg (0.62 mmol) of 2-bromo-4,5-dichlorophenol obtained in Reference Example 1A was dissolved in 2 mL of N, N-dimethylformamide, and 103 mg (0.74 mmol) of potassium carbonate and 76 μL of ethyl bromoacetate (0 .68 mmol) was added and stirred at room temperature overnight. Water was added to the reaction solution, the aqueous phase was extracted with ether, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-8% ethyl acetate / hexane) to obtain 190 mg (94%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.31 (3H, t, J = 7.1 Hz), 4.28 (2H, q, J = 7.1 Hz), 4.68 (2H, s), 6.89 (1H, s), 7.65 ( 1H, s).
(Reference Example 1C)
(2-Bromo-4,5-dichlorophenoxy) acetic acid
Figure JPOXMLDOC01-appb-C000022
参考例１Ｂで得られた（２－ブロモ－４，５－ジクロロフェノキシ）酢酸　エチル１９０ｍｇ（０．５８ｍｍｏｌ）をエタノール５ｍＬ及びテトラヒドロフラン５ｍＬの混合溶媒に溶解し、１規定水酸化ナトリウム水溶液５ｍＬを加え、室温で３０分間撹拌した。反応溶液を１規定塩酸水溶液で中和し、溶媒を減圧下留去し、水相を酢酸エチルで抽出した。得られた有機相を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより目的化合物の粗生成物１６８ｍｇ（９７％）を得た。得られた粗生成物はクロロホルム／ヘキサン混合溶媒で再結晶可能であった。
1H-NMR (CDCl3) δ: 4.75 (2H, s), 6.94 (1H, s), 7.67 (1H,s).
（参考例２）
（４，５－ジクロロ－２－シアノフェノキシ）酢酸
（参考例２Ａ）
４，５－ジクロロ－２－ヨードフェノール
Figure JPOXMLDOC01-appb-C000022
190 mg (0.58 mmol) of ethyl (2-bromo-4,5-dichlorophenoxy) acetate obtained in Reference Example 1B was dissolved in a mixed solvent of 5 mL of ethanol and 5 mL of tetrahydrofuran, and 5 mL of 1N aqueous sodium hydroxide solution was added. Stir at room temperature for 30 minutes. The reaction solution was neutralized with 1N aqueous hydrochloric acid, the solvent was evaporated under reduced pressure, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 168 mg (97%) of a crude product of the target compound. The obtained crude product could be recrystallized with a chloroform / hexane mixed solvent.
1 H-NMR (CDCl 3 ) δ: 4.75 (2H, s), 6.94 (1H, s), 7.67 (1H, s).
(Reference Example 2)
(4,5-dichloro-2-cyanophenoxy) acetic acid (Reference Example 2A)
4,5-dichloro-2-iodophenol
Figure JPOXMLDOC01-appb-C000023
３，４－ジクロロフェノール２．４２ｇ（１５ｍｍｏｌ）及びＮ－ヨードコハク酸イミド３．６７ｇ（１６ｍｍｏｌ）を用いて参考例１Ａと同様に反応を行い、目的化合物１．２３ｇ（２９％）を得た。
1H-NMR (CDCl3) δ: 5.32 (1H, s), 7.10 (1H, s), 7.72 (1H,s).
（参考例２Ｂ）
（４，５－ジクロロ－２－ヨードフェノキシ）酢酸　エチル
Figure JPOXMLDOC01-appb-C000023
The reaction was conducted in the same manner as in Reference Example 1A using 2.42 g (15 mmol) of 3,4-dichlorophenol and 3.67 g (16 mmol) of N-iodosuccinimide, to obtain 1.23 g (29%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 5.32 (1H, s), 7.10 (1H, s), 7.72 (1H, s).
(Reference Example 2B)
(4,5-dichloro-2-iodophenoxy) ethyl acetate
Figure JPOXMLDOC01-appb-C000024
参考例２Ａで得られた４，５－ジクロロ－２－ヨードフェノール１．００ｇ（３．５ｍｍｏｌ）を用いて、参考例１Ｂと同様に反応を行い、目的化合物１．２０ｇ（９３％）を得た。
1H-NMR (CDCl3) δ: 1.31 (3H, t, J = 7.2 Hz), 4.29 (2H, q,J = 7.2 Hz), 4.66 (2H,s), 6.79 (1H, s), 7.85 (1H, s).
（参考例２Ｃ）
（４，５－ジクロロ－２－シアノフェノキシ）酢酸　エチル
Figure JPOXMLDOC01-appb-C000024
Using 1.00 g (3.5 mmol) of 4,5-dichloro-2-iodophenol obtained in Reference Example 2A, the reaction was conducted in the same manner as in Reference Example 1B to obtain 1.20 g (93%) of the target compound. It was.
1 H-NMR (CDCl 3 ) δ: 1.31 (3H, t, J = 7.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 4.66 (2H, s), 6.79 (1H, s), 7.85 ( 1H, s).
(Reference Example 2C)
(4,5-dichloro-2-cyanophenoxy) ethyl acetate
Figure JPOXMLDOC01-appb-C000025
参考例２Ｂで得られた（４，５－ジクロロ－２－ヨードフェノキシ）酢酸　エチル１．２０ｇ（３．２ｍｍｏｌ）を窒素気流下Ｎ，Ｎ－ジメチルホルムアミド５ｍＬに溶解し、シアン化亜鉛２１０ｍｇ（１．８ｍｍｏｌ）及びテトラキストリフェニルホスフィンパラジウム２６０ｍｇ（０．２３ｍｍｏｌ）を加え、１００℃で４時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液及び酢酸エチルを加え、不溶物をろ過により除いた後、ろ液の水相を酢酸エチルで抽出した。得られた有機相を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（１５％酢酸エチル／ヘキサン）により精製し、目的化合物を０．５５ｇ（６３％）得た。
1H-NMR (CDCl3) δ: 1.28 (3H, t, J = 7.1 Hz), 4.25 (2H, q,J = 7.1 Hz), 4.72 (2H,s), 6.92 (1H, s), 7.62 (1H, s).
（参考例２Ｄ）
（４，５－ジクロロ－２－シアノフェノキシ）酢酸
Figure JPOXMLDOC01-appb-C000025
1.20 g (3.2 mmol) of ethyl (4,5-dichloro-2-iodophenoxy) acetate obtained in Reference Example 2B was dissolved in 5 mL of N, N-dimethylformamide under a nitrogen stream, and 210 mg (1 0.8 mmol) and 260 mg (0.23 mmol) of tetrakistriphenylphosphine palladium were added and stirred at 100 ° C. for 4 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, insoluble matters were removed by filtration, and the aqueous phase of the filtrate was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (15% ethyl acetate / hexane) to obtain 0.55 g (63%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.28 (3H, t, J = 7.1 Hz), 4.25 (2H, q, J = 7.1 Hz), 4.72 (2H, s), 6.92 (1H, s), 7.62 ( 1H, s).
(Reference Example 2D)
(4,5-dichloro-2-cyanophenoxy) acetic acid
Figure JPOXMLDOC01-appb-C000026
参考例２Ｃで得られた（４，５－ジクロロ－２－シアノフェノキシ）酢酸　エチル５４９ｍｇ（２．０ｍｍｏｌ）を用いて参考例１Ｃと同様に反応を行い、目的化合物４３９ｍｇ（９０％）を得た。
1H-NMR (DMSO-D6) δ: 5.00 (2H, s), 7.63 (1H, s), 8.20 (1H,s).
（参考例３）
Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－（２，４，５－トリクロロフェニル）グリシン
（参考例３Ａ）
（２，４，５－トリクロロフェニル）カルバミン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000026
The reaction was conducted in the same manner as in Reference Example 1C using 549 mg (2.0 mmol) of (4,5-dichloro-2-cyanophenoxy) acetic acid obtained in Reference Example 2C to obtain 439 mg (90%) of the target compound. .
1 H-NMR (DMSO-D 6 ) δ: 5.00 (2H, s), 7.63 (1H, s), 8.20 (1H, s).
(Reference Example 3)
N- (tert-butoxycarbonyl) -N- (2,4,5-trichlorophenyl) glycine (Reference Example 3A)
Tert-Butyl (2,4,5-trichlorophenyl) carbamate
Figure JPOXMLDOC01-appb-C000027
２，４，５－トリクロロアニリン４．４９ｇ（２３ｍｍｏｌ）をテトラヒドロフラン６０ｍＬに溶解し、トリエチルアミン１ｍＬ及び二炭酸ジｔｅｒｔ－ブチル６．９３ｇ（３２ｍｍｏｌ）を加え、１日間加熱還流した。反応溶液の溶媒を減圧下留去し、得られた固体をヘキサンで洗浄することにより、目的化合物２．２６ｇ（３３％）を得た。
1H-NMR (CDCl3) δ: 1.54 (9H, s), 6.95 (1H, s), 7.43 (1H,s), 8.40 (1H, s).
（参考例３Ｂ）
Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－（２，４，５－トリクロロフェニル）グリシン　エチル
Figure JPOXMLDOC01-appb-C000027
2.49 g (23 mmol) of 2,4,5-trichloroaniline was dissolved in 60 mL of tetrahydrofuran, 1 mL of triethylamine and 6.93 g (32 mmol) of ditert-butyl dicarbonate were added, and the mixture was heated to reflux for 1 day. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting solid was washed with hexane to obtain 2.26 g (33%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.54 (9H, s), 6.95 (1H, s), 7.43 (1H, s), 8.40 (1H, s).
(Reference Example 3B)
N- (tert-butoxycarbonyl) -N- (2,4,5-trichlorophenyl) glycine ethyl
Figure JPOXMLDOC01-appb-C000028
参考例３Ａで得られた（２，４，５－トリクロロフェニル）カルバミン酸　ｔｅｒｔ－ブチル１．５０ｇ（５．１ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド１５ｍＬに溶解し、水素化ナトリウム３３０ｍｇ（６０％，７．６ｍｍｏｌ）を加え、室温で３０分間撹拌した。反応溶液にブロモ酢酸エチル０．６２ｍＬ（５．６ｍｍｏｌ）を加え、室温でさらに４時間撹拌した。反応溶液に水を加え、水相を酢酸エチルで抽出し、有機相を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－５％酢酸エチル／ヘキサン）により精製し、目的化合物を２．００ｇ（ｑｕａｎｔ）得た。
IR (Liquid film) νmax2981, 1752, 1717, 1469, 1370, 1206, 1158, 1093,1050, 1027cm-1;
1H-NMR (CDCl3) δ: 1.26-1.33 (3H, m), 1.38 (6H, s), 1.49(3H, s), 3.68 (1H, d, J= 17.3 Hz), 4.19-4.28 (2H, m), 4.73 (1H, d, J = 17.3 Hz), 7.53 (0.67H, s), 7.54(0.33H, s), 7.68 (0.67H, s), 7.72 (0.33H, s); 
MS (EI) m/z: 381 [M+].
（参考例３Ｃ）
Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－（２，４，５－トリクロロフェニル）グリシン
Figure JPOXMLDOC01-appb-C000028
Tert-butyl (2,4,5-trichlorophenyl) carbamate obtained in Reference Example 3A (1.50 g, 5.1 mmol) was dissolved in 15 mL of N, N-dimethylformamide, and sodium hydride (330 mg, 60%, 7.6 mmol) was added and stirred at room temperature for 30 minutes. To the reaction solution, 0.62 mL (5.6 mmol) of ethyl bromoacetate was added, and the mixture was further stirred at room temperature for 4 hours. Water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (0-5% ethyl acetate / hexane) to obtain 2.00 g (quant) of the target compound.
IR (Liquid film) ν max 2981, 1752, 1717, 1469, 1370, 1206, 1158, 1093,1050, 1027cm -1 ;
1 H-NMR (CDCl 3 ) δ: 1.26-1.33 (3H, m), 1.38 (6H, s), 1.49 (3H, s), 3.68 (1H, d, J = 17.3 Hz), 4.19-4.28 (2H , m), 4.73 (1H, d, J = 17.3 Hz), 7.53 (0.67H, s), 7.54 (0.33H, s), 7.68 (0.67H, s), 7.72 (0.33H, s);
MS (EI) m / z: 381 [M + ].
(Reference Example 3C)
N- (tert-butoxycarbonyl) -N- (2,4,5-trichlorophenyl) glycine
Figure JPOXMLDOC01-appb-C000029
参考例３Ｂで得られたＮ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－（２，４，５－トリクロロフェニル）グリシン　エチル２．００ｇ（５．２ｍｍｏｌ）を用いて参考例１Ｃと同様に反応を行い、目的化合物１．７０ｇ（９２％）を得た。
1H-NMR (CDCl3) δ:1.38 (6H, s), 1.49 (3H, s), 3.74 (1H, d,J = 18.1 Hz), 4.78 (1H, d, J = 18.1 Hz), 7.55 (0.67H, s), 7.55 (0.33H, s), 7.64 (0.67H, s), 7.69(0.33H, s). 
（参考例４）
Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］グリシン
（参考例４Ａ）
４，５－ジクロロ－２－（トリフルオロメチル）アニリン
Figure JPOXMLDOC01-appb-C000029
Using 2.00 g (5.2 mmol) of ethyl N- (tert-butoxycarbonyl) -N- (2,4,5-trichlorophenyl) glycine obtained in Reference Example 3B, the reaction was performed in the same manner as in Reference Example 1C. This gave 1.70 g (92%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.38 (6H, s), 1.49 (3H, s), 3.74 (1H, d, J = 18.1 Hz), 4.78 (1H, d, J = 18.1 Hz), 7.55 ( 0.67H, s), 7.55 (0.33H, s), 7.64 (0.67H, s), 7.69 (0.33H, s).
(Reference Example 4)
N- (tert-butoxycarbonyl) -N- [4,5-dichloro-2- (trifluoromethyl) phenyl] glycine (Reference Example 4A)
4,5-dichloro-2- (trifluoromethyl) aniline
Figure JPOXMLDOC01-appb-C000030
１，２－ジクロロ－４－ニトロ－５－（トリフルオロメチル）ベンゼン６．３４ｇ（２４ｍｍｏｌ）をメタノール１２０ｍＬに溶解し、氷冷下濃塩酸２０ｍＬを滴下後塩化スズ（Ｉ）１８．５ｇ（９８ｍｍｏｌ）を加え、２時間加熱還流した。反応溶液に水及び塩化メチレンを加え、４規定水酸化ナトリウム水溶液で中和し、生成した無機物をろ別した。得られたろ液の溶媒を減圧下留去し、水相を酢酸エチルで抽出し、有機相を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（１５％酢酸エチル／ヘキサン）により精製し、目的化合物を５．４４ｇ（９７％）得た。
1H-NMR (CDCl3) δ: 4.22 (2H, br s), 6.85 (1H, s), 7.48(1H, s).
（参考例４Ｂ）
［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］イミドジカルボン酸　ジｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000030
6.34 g (24 mmol) of 1,2-dichloro-4-nitro-5- (trifluoromethyl) benzene was dissolved in 120 mL of methanol, and 20 mL of concentrated hydrochloric acid was added dropwise under ice cooling, and then 18.5 g (98 mmol) of tin (I) chloride. ) And heated to reflux for 2 hours. Water and methylene chloride were added to the reaction solution, neutralized with 4N aqueous sodium hydroxide solution, and the produced inorganic substance was filtered off. The solvent of the obtained filtrate was distilled off under reduced pressure, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (15% ethyl acetate / hexane) to obtain 5.44 g (97%) of the desired compound.
1 H-NMR (CDCl 3 ) δ: 4.22 (2H, br s), 6.85 (1H, s), 7.48 (1H, s).
(Reference Example 4B)
[4,5-Dichloro-2- (trifluoromethyl) phenyl] imidodicarboxylic acid ditert-butyl
Figure JPOXMLDOC01-appb-C000031
参考例４Ａで得られた４，５－ジクロロ－２－（トリフルオロメチル）アニリン１．５０ｇ（６．５ｍｍｏｌ）をテトラヒドロフラン３０ｍＬに溶解し、二炭酸ジｔｅｒｔ－ブチル３．１３ｇ（１４ｍｍｏｌ）及びＮ，Ｎ－ジメチルアミノピリジン８０ｍｇ（０．６６ｍｍｏｌ）を加え、２時間加熱還流した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、水相を酢酸エチルで抽出した。得られた有機相を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（１０％酢酸エチル／ヘキサン）により精製し、目的化合物を１．１８ｇ（４２％）
得た。
1H-NMR (CDCl3) δ: 1.40 (18H, s), 7.38 (1H, s), 7.76 (1H,s).
（参考例４Ｃ）
［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］カルバミン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000031
1.50 g (6.5 mmol) of 4,5-dichloro-2- (trifluoromethyl) aniline obtained in Reference Example 4A was dissolved in 30 mL of tetrahydrofuran, and 3.13 g (14 mmol) of ditert-butyl dicarbonate and N , N-dimethylaminopyridine (80 mg, 0.66 mmol) was added, and the mixture was heated to reflux for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (10% ethyl acetate / hexane) to obtain 1.18 g (42%) of the target compound.
Obtained.
1 H-NMR (CDCl 3 ) δ: 1.40 (18H, s), 7.38 (1H, s), 7.76 (1H, s).
(Reference Example 4C)
[4,5-Dichloro-2- (trifluoromethyl) phenyl] carbamic acid tert-butyl
Figure JPOXMLDOC01-appb-C000032
参考例４Ｂで得られた［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］イミドジカルボン酸　ジｔｅｒｔ－ブチル１．１８ｇ（２．７ｍｍｏｌ）をメタノール１２ｍＬに溶解し、２規定水酸化カリウム水溶液２．７ｍＬ(５．５ｍｍｏｌ)を加え、室温で１０分撹拌した。反応溶液の溶媒を減圧下留去し、硫酸水素カリウム水溶液で中和し、水相を酢酸エチルで抽出した。得られた有機相を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（２－３％酢酸エチル／ヘキサン）により精製し、目的化合物を６１７ｍｇ（６８％）得た。
1H-NMR (CDCl3) δ: 1.53 (9H, s), 6.78 (1H, br s), 7.62(1H, s), 8.43 (1H, s).
（参考例４Ｄ）
Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］グリシン　エチル
Figure JPOXMLDOC01-appb-C000032
Dissolve 1.18 g (2.7 mmol) of ditert-butyl [4,5-dichloro-2- (trifluoromethyl) phenyl] imide dicarboxylate obtained in Reference Example 4B in 12 mL of methanol, and add 2N potassium hydroxide. 2.7 mL (5.5 mmol) of an aqueous solution was added and stirred at room temperature for 10 minutes. The solvent of the reaction solution was distilled off under reduced pressure, neutralized with an aqueous potassium hydrogen sulfate solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (2-3% ethyl acetate / hexane) to obtain 617 mg (68%) of the desired compound.
1 H-NMR (CDCl 3 ) δ: 1.53 (9H, s), 6.78 (1H, br s), 7.62 (1H, s), 8.43 (1H, s).
(Reference Example 4D)
N- (tert-butoxycarbonyl) -N- [4,5-dichloro-2- (trifluoromethyl) phenyl] glycine ethyl
Figure JPOXMLDOC01-appb-C000033
参考例４Ｃで得られた［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］カルバミン酸　ｔｅｒｔ－ブチル６２０ｍｇ（１．９ｍｍｏｌ）を用いて参考例１Ｂと同様に反応を行い、目的化合物６９０ｍｇ（８９％）を得た。
1H-NMR (CDCl3) δ: 1.27-1.35 (3H, m), 1.34 (6H, s), 1.54(3H, s), 3.56 (0.67H, d, J = 18.0 Hz), 3.61 (0.33H, d, J = 18.0 Hz), 4.19-4.32 (2H, m), 4.53 (0.33H,d,J = 18.0 Hz), 4.71 (0.67H, d, J = 18.0 Hz), 7.74 (0.67H, s), 7.75 (0.33H, s), 7.89 (1H, s).
（参考例４Ｅ）
Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］グリシン
Figure JPOXMLDOC01-appb-C000033
Using 620 mg (1.9 mmol) of tert-butyl [4,5-dichloro-2- (trifluoromethyl) phenyl] carbamate obtained in Reference Example 4C, the reaction was performed in the same manner as in Reference Example 1B to obtain 690 mg of the target compound. (89%) was obtained.
1 H-NMR (CDCl 3 ) δ: 1.27-1.35 (3H, m), 1.34 (6H, s), 1.54 (3H, s), 3.56 (0.67H, d, J = 18.0 Hz), 3.61 (0.33H , d, J = 18.0 Hz), 4.19-4.32 (2H, m), 4.53 (0.33H, d, J = 18.0 Hz), 4.71 (0.67H, d, J = 18.0 Hz), 7.74 (0.67H, s ), 7.75 (0.33H, s), 7.89 (1H, s).
(Reference Example 4E)
N- (tert-butoxycarbonyl) -N- [4,5-dichloro-2- (trifluoromethyl) phenyl] glycine
Figure JPOXMLDOC01-appb-C000034
参考例４Ｄで得られたＮ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］グリシン　エチル６９０ｍｇ（１．７ｍｍｏｌ）を用いて参考例１Ｃと同様に反応を行い、目的化合物５３２ｍｇ（８３％）を得た。
1H-NMR (CDCl3) δ: 1.35 (6H, s), 1.49 (3H, s), 3.65(0.67H, d, J = 18.0 Hz), 3.70 (0.33H, d, J= 18.0 Hz), 4.63 (0.33H, d, J = 18.0 Hz), 4.77 (0.67H, d, J =18.0Hz), 7.76 (0.67H, s), 7.77 (0.33H, s), 7.83 (0.67H, s), 7.86 (0.33H, s).
（参考例５）
（３Ｓ）－３－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル
（参考例５Ａ）
（２Ｒ）－１－［（ベンジルオキシ）カルボニル］－４－（ｔｅｒｔ－ブトキシカルボニル）ピペラジン－２－カルボン酸
Figure JPOXMLDOC01-appb-C000034
Similar to Reference Example 1C using 690 mg (1.7 mmol) of ethyl N- (tert-butoxycarbonyl) -N- [4,5-dichloro-2- (trifluoromethyl) phenyl] glycine obtained in Reference Example 4D To give 532 mg (83%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.35 (6H, s), 1.49 (3H, s), 3.65 (0.67H, d, J = 18.0 Hz), 3.70 (0.33H, d, J = 18.0 Hz), 4.63 (0.33H, d, J = 18.0 Hz), 4.77 (0.67H, d, J = 18.0Hz), 7.76 (0.67H, s), 7.77 (0.33H, s), 7.83 (0.67H, s), 7.86 (0.33H, s).
(Reference Example 5)
(3S) -3- (Pyrrolidin-1-ylmethyl) piperazine-1-carboxylate tert-butyl (Reference Example 5A)
(2R) -1-[(Benzyloxy) carbonyl] -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid
Figure JPOXMLDOC01-appb-C000035
（２Ｒ）－ピペラジン－２－カルボン酸２塩酸塩２０．０ｇ（９８ｍｍｏｌ）をジオキサン２００ｍＬ及び水８０ｍＬに溶解し、氷冷下水酸化ナトリウム水溶液７．８８ｇ（１９７ｍｍｏｌ）の４０ｍＬ溶液を加え、０℃で３０分間撹拌した。Ｂｏｃ２Ｏ２２．５７ｇ（１０３ｍｍｏｌ）を加え、室温に昇温した後終夜撹拌した。次いでトリエチルアミン２７ｍＬ（１９７ｍｍｏｌ）及びＮ－（ベンジルオキシカルボニルオキシ）スクシンイミド２７．０ｇ（１０８ｍｍｏｌ）を加え、室温で更に５時間撹拌した。減圧下溶媒を留去し、水相を硫酸水素カリウム水溶液で酸性とし、酢酸エチルで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより表記化合物の粗生成物４０．４ｇ（ｑｕａｎｔ）を得た。
1H-NMR (CDCl3) δ: 1.43 (9H, s), 2.78-3.36 (3H, m),3.86-4.09 (2H, m), 4.54-4.86(2H, m), 5.10-5.23 (2H, m), 7.29-7.41 (5H, m).
（参考例５Ｂ）
（２Ｒ）－２－（ピロリジン－１－イルカルボニル）ピペラジン－１，４－ジカルボン酸　１－ベンジル　４－ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000035
20.0 g (98 mmol) of (2R) -piperazine-2-carboxylic acid dihydrochloride is dissolved in 200 mL of dioxane and 80 mL of water, and a 40 mL solution of 7.88 g (197 mmol) of an aqueous sodium hydroxide solution is added under ice-cooling. Stir for 30 minutes. 2.57 g (103 mmol) of Boc 2 O 2 was added, and the mixture was warmed to room temperature and stirred overnight. Next, 27 mL (197 mmol) of triethylamine and 27.0 g (108 mmol) of N- (benzyloxycarbonyloxy) succinimide were added, and the mixture was further stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the aqueous phase was acidified with an aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 40.4 g (quant) of a crude product of the title compound.
1 H-NMR (CDCl 3 ) δ: 1.43 (9H, s), 2.78-3.36 (3H, m), 3.86-4.09 (2H, m), 4.54-4.86 (2H, m), 5.10-5.23 (2H, m), 7.29-7.41 (5H, m).
(Reference Example 5B)
(2R) -2- (Pyrrolidin-1-ylcarbonyl) piperazine-1,4-dicarboxylic acid 1-benzyl 4-tert-butyl
Figure JPOXMLDOC01-appb-C000036
参考例５Ａで得られた（２Ｒ）－１－［（ベンジルオキシ）カルボニル］－４－（ｔｅｒｔ－ブトキシカルボニル）ピペラジン－２－カルボン酸の粗生成物２０．１ｇ（４９ｍｍｏｌ）を塩化メチレン２００ｍＬに溶解し、ピロリジン８．２ｍＬ（９８ｍｍｏｌ）、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン１．２０ｇ（９．８ｍｍｏｌ）、ＥＤＣＩ１２．３ｇ（６４ｍｍｏｌ）を順次加え、室温で終夜撹拌した。反応溶液に硫酸水素ナトリウム水溶液を加えて中和し、水相を塩化メチレンで抽出した。得られた有機相を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－５％メタノール／塩化メチレン）により精製し、目的化合物を１８．７ｇ（９１％）得た。
1H-NMR (CDCl3) δ: 1.44 (9H, s), 1.72-2.03 (4H, m),2.84-4.26 (10H, m), 4.49-4.79 (1H, m), 4.95-5.22 (2H, m), 7.21-7.41 (5H, m).
（参考例５Ｃ）
（３Ｓ）－３－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000036
20.1 g (49 mmol) of the crude product of (2R) -1-[(benzyloxy) carbonyl] -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid obtained in Reference Example 5A was added to 200 mL of methylene chloride. After dissolution, 8.2 mL (98 mmol) of pyrrolidine, 1.20 g (9.8 mmol) of 4- (N, N-dimethylamino) pyridine and 12.3 g (64 mmol) of EDCI were sequentially added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with an aqueous sodium hydrogen sulfate solution, and the aqueous phase was extracted with methylene chloride. The obtained organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (0-5% methanol / methylene chloride) to obtain 18.7 g (91%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 1.72-2.03 (4H, m), 2.84-4.26 (10H, m), 4.49-4.79 (1H, m), 4.95-5.22 (2H, m), 7.21-7.41 (5H, m).
(Reference Example 5C)
(3S) -3- (Pyrrolidin-1-ylmethyl) piperazine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000037
参考例５Ｂで得られた（２Ｒ）－２－（ピロリジン－１－イルカルボニル）ピペラジン－１，４－ジカルボン酸　１－ベンジル　４－ｔｅｒｔ－ブチル１８．７ｇ（４５ｍｍｏｌ）を窒素気流下テトラヒドロフラン１００ｍＬに溶解し、ボラン（１．１Ｍテトラヒドロフラン溶液）９０ｍＬ（９８ｍｍｏｌ）を滴下した後、５０℃で２時間撹拌した。反応溶液を０℃に冷却し、水を加えた後減圧下溶媒を留去した。水相を酢酸エチルで抽出し、得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣を窒素気流下メタノール２００ｍＬに溶解し、２０％水酸化パラジウム／炭素１ｇを加え、水素気流下４５℃で６時間撹拌した。反応溶液を室温に冷却し、触媒をろ別し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー（０－５０％メタノール／塩化メチレン）により精製し、目的化合物を９．５５ｇ（７９％）得た。
1H-NMR (CDCl3) δ: 1.46 (9H, s), 1.73-1.79 (4H, m),1.83-1.92 (3H, m), 2.23 (1H,dd, J = 11.7, 3.5 Hz), 2.39-2.51 (2H, m), 2.53-2.63 (3H, m), 2.66-2.76 (2H,m),2.81-3.00 (2H, m), 3.94 (1H, br s).
Figure JPOXMLDOC01-appb-C000037
18.7 g (45 mmol) of 1-benzyl 4-tert-butyl (2R) -2- (pyrrolidin-1-ylcarbonyl) piperazine-1,4-dicarboxylate obtained in Reference Example 5B was added to 100 mL of tetrahydrofuran under a nitrogen stream. After dissolution, 90 mL (98 mmol) of borane (1.1 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was cooled to 0 ° C., water was added, and the solvent was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 200 mL of methanol under a nitrogen stream, 20 g of palladium hydroxide / carbon was added, and the mixture was stirred at 45 ° C. for 6 hours under a hydrogen stream. The reaction solution was cooled to room temperature, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-50% methanol / methylene chloride) to obtain 9.55 g (79%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.73-1.79 (4H, m), 1.83-1.92 (3H, m), 2.23 (1H, dd, J = 11.7, 3.5 Hz), 2.39 -2.51 (2H, m), 2.53-2.63 (3H, m), 2.66-2.76 (2H, m), 2.81-3.00 (2H, m), 3.94 (1H, br s).
（参考例６）
（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン
（参考例６Ａ）
（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000038
（２，４，５－トリクロロフェノキシ）酢酸７．２５ｇ（２９ｍｍｏｌ）を塩化メチレン１００ｍＬに溶解し、氷冷下オキザリルクロリド２．９ｍＬ（３４ｍｍｏｌ）を滴下した後Ｎ，Ｎ－ジメチルホルムアミドを一滴加え、室温で３時間撹拌した。反応溶液の溶媒を減圧下留去し、酸クロリドの粗生成物を得た。
参考例５で得られた（３Ｓ）－３－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル７．００ｇ（２６ｍｍｏｌ）を塩化メチレン５０ｍＬに溶解し、トリエチルアミン７．３ｍＬ（５２ｍｍｏｌ）を加え、氷冷下酸クロリドの塩化メチレン５０ｍＬ溶液を滴下し、室温で１時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、水相を塩化メチレンで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－４％メタノール／塩化メチレン）により精製し、目的化合物を１２．４ｇ（９４％）得た。
1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.65-1.83 (4H, m),2.42-3.01 (10H, m), 3.30 (0.5H, t, J = 11.5 Hz), 3.69 (0.5H, d, J = 12.7 Hz), 3.91-4.23 (2.5H, m), 4.34(0.5H, d, J= 13.2 Hz), 4.60-4.97 (1H, m), 4.75 (1H, d, J = 13.7 Hz), 4.81 (1H, d,J=14.6 Hz), 7.04 (0.5H, s), 7.09 (0.5H, s), 7.47 (1H, s).
（参考例６Ｂ）
（２Ｒ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン
Figure JPOXMLDOC01-appb-C000039
参考例６Ａで得られた（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル１２．４ｇ（２４ｍｍｏｌ）をジオキサン４０ｍＬ及びメタノール４０ｍＬの混合溶媒に溶解し、４規定塩酸／ジオキサン溶液を加え、室温で１時間撹拌した。反応溶液の溶媒を減圧下留去し、飽和炭酸水素ナトリウム水溶液で中和し、水相を塩化メチレンで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去することにより目的化合物の粗生成物１０．０ｇ（ｑｕａｎｔ）を得た。
1H-NMR (CDCl3) δ: 1.67-1.85 (4H, m), 2.45-3.14 (10H, m),3.27-3.41 (0.5H, m), 3.57-3.67 (0.5H, m), 3.81-3.90 (0.5H, m), 4.26-4.37 (0.5H, m), 4.58-4.95 (3H,m),7.05 (0.5H, s), 7.11 (0.5H, s), 7.46 (1H, s).
（参考例６Ｃ）
（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン
Figure JPOXMLDOC01-appb-C000040
２－クロロエタンスルホニルクロリド０．１０ｍＬ（０．９９ｍｍｏｌ）を塩化メチレン３ｍＬに溶解し、－４５℃で２，６－ジｔｅｒｔ－ブチルピリジン０．２２ｍＬ（０．９９ｍｍｏｌ）を加えた後、参考例６Ｂで得られた（２Ｒ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン２０１ｍｇ（０．４９ｍｍｏｌ）の塩化メチレン２ｍＬ溶液を滴下し、－４５℃で１時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、水相を塩化メチレンで抽出し、有機相を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－５％メタノール／塩化メチレン）により精製し、目的化合物を１１４ｍｇ（４７％）得た。
1H-NMR (CDCl3) δ: 1.63-1.83 (4H, m), 2.39-2.85 (7H, m),2.88-3.11 (1H, m), 3.36-3.50 (0.5H, m), 3.67-3.81 (2H, m), 3.81-3.90 (0.5H, m), 4.04-4.16 (0.5H, m),4.41-4.52 (0.5H, m), 4.65-4.95 (3H, m), 6.08 (1H, d, J = 9.8 Hz), 6.26 (1H, d, J=16.4 Hz), 6.39 (1H, dd, J = 16.4, 9.8 Hz), 7.04 (0.5H, s), 7.09 (0.5H, s), 7.47(1H, s). (Reference Example 6)
(2S) -2- (Pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine (Reference Example 6A)
(3S) -3- (Pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000038
Dissolve 7.25 g (29 mmol) of (2,4,5-trichlorophenoxy) acetic acid in 100 mL of methylene chloride, drop 2.9 mL (34 mmol) of oxalyl chloride under ice-cooling, and then add one drop of N, N-dimethylformamide. And stirred at room temperature for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product of acid chloride.
7.03 g (26 mmol) of tert-butyl (3S) -3- (pyrrolidin-1-ylmethyl) piperazine-1-carboxylate obtained in Reference Example 5 was dissolved in 50 mL of methylene chloride, and 7.3 mL (52 mmol) of triethylamine was dissolved. Then, 50 mL of methylene chloride in acid chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous phase was extracted with methylene chloride. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-4% methanol / methylene chloride) to obtain 12.4 g (94%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.65-1.83 (4H, m), 2.42-3.01 (10H, m), 3.30 (0.5H, t, J = 11.5 Hz), 3.69 ( 0.5H, d, J = 12.7 Hz), 3.91-4.23 (2.5H, m), 4.34 (0.5H, d, J = 13.2 Hz), 4.60-4.97 (1H, m), 4.75 (1H, d, J = 13.7 Hz), 4.81 (1H, d, J = 14.6 Hz), 7.04 (0.5H, s), 7.09 (0.5H, s), 7.47 (1H, s).
(Reference Example 6B)
(2R) -2- (Pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine
Figure JPOXMLDOC01-appb-C000039
12.4 g (24 mmol) of tert-butyl (3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazine-1-carboxylate obtained in Reference Example 6A Was dissolved in a mixed solvent of 40 mL of dioxane and 40 mL of methanol, 4N hydrochloric acid / dioxane solution was added, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted with methylene chloride. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 10.0 g (quant) of a crude product of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.67-1.85 (4H, m), 2.45-3.14 (10H, m), 3.27-3.41 (0.5H, m), 3.57-3.67 (0.5H, m), 3.81- 3.90 (0.5H, m), 4.26-4.37 (0.5H, m), 4.58-4.95 (3H, m), 7.05 (0.5H, s), 7.11 (0.5H, s), 7.46 (1H, s).
(Reference Example 6C)
(2S) -2- (Pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine
Figure JPOXMLDOC01-appb-C000040
0.10 mL (0.99 mmol) of 2-chloroethanesulfonyl chloride was dissolved in 3 mL of methylene chloride, 0.22 mL (0.99 mmol) of 2,6-ditert-butylpyridine was added at −45 ° C., and then Reference Example 6B A solution of 201 mg (0.49 mmol) of (2R) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine obtained in 1 above in methylene chloride was added dropwise, Stir at 45 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the aqueous phase was extracted with methylene chloride, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-5% methanol / methylene chloride) to obtain 114 mg (47%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.63-1.83 (4H, m), 2.39-2.85 (7H, m), 2.88-3.11 (1H, m), 3.36-3.50 (0.5H, m), 3.67-3.81 (2H, m), 3.81-3.90 (0.5H, m), 4.04-4.16 (0.5H, m), 4.41-4.52 (0.5H, m), 4.65-4.95 (3H, m), 6.08 (1H, d , J = 9.8 Hz), 6.26 (1H, d, J = 16.4 Hz), 6.39 (1H, dd, J = 16.4, 9.8 Hz), 7.04 (0.5H, s), 7.09 (0.5H, s), 7.47 (1H, s).
（参考例７）
２，４，５－トリクロロ－Ｎ－｛２－オキソ－２－［（２Ｓ）－２－（ピロリジン－１－イルメチル）－４－（ビニルスルホニル）ピペラジン－１－イル］エチル｝アニリン
（参考例７Ａ）
（３Ｓ）－４－［Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－（２，４，５－トリクロロフェニル）グリシル］－３－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000041
参考例３で得られたＮ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－（２，４，５－トリクロロフェニル）グリシン１．００ｇ（２．８ｍｍｏｌ）及び参考例５で得られた（３Ｓ）－３－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル７６０ｍｇ（２．８ｍｍｏｌ）をテトラヒドロフラン１５ｍＬに溶解し、トリエチルアミン０．７９ｍＬ（５．６ｍｍｏｌ）及びシアノリン酸ジエチル０．５６ｍＬ（３．７ｍｍｏｌ）を加え、室温で３時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、溶媒を減圧下留去し、水相を酢酸エチルで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－４％メタノール／塩化メチレン）により精製し、目的化合物を１．４７ｇ（８６％）得た。
1H-NMR (CDCl3) δ: 1.37 (9H, s), 1.46 (9H, s), 1.57-1.81(4H, m), 2.35-4.40 (13H, m), 4.61-4.98 (2H, m), 7.51 (1H, s), 7.81-7.90 (1H, m).
（参考例７Ｂ）
２，４，５－トリクロロ－Ｎ－｛２－オキソ－２－［（２Ｒ）－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］エチル｝アニリン
Figure JPOXMLDOC01-appb-C000042
参考例７Ａで得られた（３Ｓ）－４－［Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－（２，４，５－トリクロロフェニル）グリシル］－３－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル１．４７ｇ（２．４ｍｍｏｌ）を用いて、参考例６Ｂと同様に反応を行い、目的化合物９６３ｍｇ（７８％）を得た。
1H-NMR (CDCl3) δ: 1.76 (4H, br s), 2.52-3.49 (11H, m),3.69-4.07 (3H, m), 4.39-4.74 (1H, m), 5.68 (0.5H, br s), 5.75 (0.5H, br s), 6.56 (1H, br s), 7.34 (1H,s).
（参考例７Ｃ）
２，４，５－トリクロロ－Ｎ－｛２－オキソ－２－［（２Ｓ）－２－（ピロリジン－１－イルメチル）－４－（ビニルスルホニル）ピペラジン－１－イル］エチル｝アニリン
Figure JPOXMLDOC01-appb-C000043
参考例７Ｂで得られた２，４，５－トリクロロ－Ｎ－｛２－オキソ－２－［（２Ｒ）－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］エチル｝アニリン２０３ｍｇ（０．５０ｍｍｏｌ）を用いて、参考例６Ｃと同様に反応を行い、目的化合物１０１ｍｇ（４１％）を得た。
1H-NMR (CDCl3) δ: 1.75 (4H, br s), 2.53-3.11 (9H, m),3.42-4.09 (5H, m), 4.57-4.63 (0.5H, m), 4.88 (0.5H, br s), 5.57 (0.5H, br s), 5.64 (0.5H, br s), 6.09(1H, d, J = 10.0 Hz), 6.28 (1H, d, J = 16.6 Hz), 6.42 (1H, dd, J = 16.6, 10.0 Hz),6.54 (0.5H, br s), 6.57 (0.5H, br s), 7.36 (1H, s). (Reference Example 7)
2,4,5-Trichloro-N- {2-oxo-2-[(2S) -2- (pyrrolidin-1-ylmethyl) -4- (vinylsulfonyl) piperazin-1-yl] ethyl} aniline (reference example) 7A)
(3S) -4- [N- (tert-butoxycarbonyl) -N- (2,4,5-trichlorophenyl) glycyl] -3- (pyrrolidin-1-ylmethyl) piperazine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000041
1.00 g (2.8 mmol) of N- (tert-butoxycarbonyl) -N- (2,4,5-trichlorophenyl) glycine obtained in Reference Example 3 and (3S) -3 obtained in Reference Example 5 760 mg (2.8 mmol) of tert-butyl- (pyrrolidin-1-ylmethyl) piperazine-1-carboxylate was dissolved in 15 mL of tetrahydrofuran, 0.79 mL (5.6 mmol) of triethylamine and 0.56 mL (3.7 mmol) of diethyl cyanophosphate. ) And stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the solvent was distilled off under reduced pressure, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (0-4% methanol / methylene chloride) to obtain 1.47 g (86%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.37 (9H, s), 1.46 (9H, s), 1.57-1.81 (4H, m), 2.35-4.40 (13H, m), 4.61-4.98 (2H, m) , 7.51 (1H, s), 7.81-7.90 (1H, m).
(Reference Example 7B)
2,4,5-trichloro-N- {2-oxo-2-[(2R) -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] ethyl} aniline
Figure JPOXMLDOC01-appb-C000042
(3S) -4- [N- (tert-butoxycarbonyl) -N- (2,4,5-trichlorophenyl) glycyl] -3- (pyrrolidin-1-ylmethyl) piperazine-1 obtained in Reference Example 7A -Carboxylic acid The reaction was carried out in the same manner as in Reference Example 6B using 1.47 g (2.4 mmol) of tert-butyl to obtain 963 mg (78%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.76 (4H, br s), 2.52-3.49 (11H, m), 3.69-4.07 (3H, m), 4.39-4.74 (1H, m), 5.68 (0.5H, br s), 5.75 (0.5H, br s), 6.56 (1H, br s), 7.34 (1H, s).
(Reference Example 7C)
2,4,5-trichloro-N- {2-oxo-2-[(2S) -2- (pyrrolidin-1-ylmethyl) -4- (vinylsulfonyl) piperazin-1-yl] ethyl} aniline
Figure JPOXMLDOC01-appb-C000043
2,4,5-Trichloro-N- {2-oxo-2-[(2R) -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] ethyl} aniline obtained in Reference Example 7B 203 mg (0 The compound was reacted in the same manner as in Reference Example 6C to obtain 101 mg (41%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.75 (4H, br s), 2.53-3.11 (9H, m), 3.42-4.09 (5H, m), 4.57-4.63 (0.5H, m), 4.88 (0.5H , br s), 5.57 (0.5H, br s), 5.64 (0.5H, br s), 6.09 (1H, d, J = 10.0 Hz), 6.28 (1H, d, J = 16.6 Hz), 6.42 (1H , dd, J = 16.6, 10.0 Hz), 6.54 (0.5H, br s), 6.57 (0.5H, br s), 7.36 (1H, s).
（参考例８）
（２Ｓ）－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン
（参考例８Ａ）
（２Ｒ）－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］カルボニル｝ピペラジン－１，４－ジカルボン酸　１－ベンジル　４－ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000044
参考例５Ａで得られた（２Ｒ）－１－［（ベンジルオキシ）カルボニル］－４－（ｔｅｒｔ－ブトキシカルボニル）ピペラジン－２－カルボン酸４．８４ｇ（１３ｍｍｏｌ）及び（３Ｓ）－３－フルオロピロリジン塩酸塩２．００ｇ（１６ｍｍｏｌ）を用いて参考例５Ｂと同様に反応を行い、目的化合物４．１７ｇ（７３％）を得た。
1H-NMR (CDCl3) δ: 1.43 (9H, br s), 2.02-2.19 (2H, m),2.86-4.31 (9H, m), 4.55-4.80 (1H, m), 4.96-5.38 (4H, m), 7.27-7.38 (5H, m).
（参考例８Ｂ）
（３Ｓ）－３－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000045
参考例８Ａで得られた（２Ｒ）－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］カルボニル｝ピペラジン－１，４－ジカルボン酸　１－ベンジル　４－ｔｅｒｔ－ブチル４．００ｇ（９．２ｍｍｏｌ）を用いて参考例５Ｃと同様に反応を行い、目的化合物２．３６ｇ（８９％）を得た。
1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.95-2.99 (13H, m), 3.93(2H, br s), 5.06-5.11 (1H, m), 5.20-5.25 (1H, m).
（参考例８Ｃ）
（３Ｓ）－３－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000046
参考例８Ｂで得られた（３Ｓ）－３－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル９４０ｍｇ（３．３ｍｍｏｌ）を用いて参考例６Ａと同様に反応を行い、目的化合物１．６１ｇ（９４％）を得た1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.94-2.15 (2H, m),2.45-3.01 (8H, m), 3.23-3.33(0.5H, m), 3.68-3.75 (0.5H, m), 3.99-4.05 (0.5H, m), 4.09-4.20 (2.5H, m), 4.32-4.38 (0.5H, m), 4.61-5.24 (4H, m), 7.07 (1H, br s), 7.47 (1H, s).
（参考例８Ｄ）
（２Ｒ）－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン
Figure JPOXMLDOC01-appb-C000047
参考例８Ｃで得られた（３Ｓ）－３－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－カルボン酸　ｔｅｒｔ－ブチル１．６１ｇ（３．１ｍｍｏｌ）を用いて参考例６Ｂと同様に反応を行い、目的化合物１．３０ｇ（１００％）を得た。
1H-NMR (CDCl3) δ: 1.96-2.17 (2H, m), 2.49-3.15 (10H, m),3.25-3.37 (0.5H, m), 3.61-3.68 (0.5H, m), 3.88-3.95 (0.5H, m), 4.29-4.37 (0.5H, m), 4.57-5.25 (4H,m),7.07 (1H, br s), 7.46 (1H, s).
（参考例８Ｅ）
（２Ｓ）－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン
Figure JPOXMLDOC01-appb-C000048
参考例８Ｄで得られた（２Ｒ）－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン１．３０ｇ（３．１ｍｍｏｌ）を用いて参考例６Ｃと同様に反応を行い、目的化合物７６６ｍｇ（４９％）を得た。
1H-NMR (CDCl3) δ: 1.95-2.17 (2H, m), 2.51-3.11 (8.5H, m),3.38-3.46 (0.5H, m), 3.69-3.81 (2H, m), 3.85-3.91 (0.5H, m), 4.14-4.21 (0.5H, m), 4.45-4.51 (0.5H,m), 4.69-4.84 (2H, m), 4.94-5.24 (1.5H, m), 6.08 (1H, d, J = 10.2 Hz), 6.26 (1H,d, J = 16.6 Hz), 6.39 (1H, dd, J = 16.6, 10.2 Hz), 7.06 (1H, s), 7.08 (1H, s),7.47 (1H, s). (Reference Example 8)
(2S) -2-{[(3S) -3-Fluoropyrrolidin-1-yl] methyl} -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine (Reference Example) 8A)
(2R) -2-{[(3S) -3-fluoropyrrolidin-1-yl] carbonyl} piperazine-1,4-dicarboxylic acid 1-benzyl 4-tert-butyl
Figure JPOXMLDOC01-appb-C000044
4.84 g (13 mmol) of (2R) -1-[(benzyloxy) carbonyl] -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid obtained in Reference Example 5A and (3S) -3-fluoropyrrolidine The reaction was conducted in the same manner as in Reference Example 5B using 2.00 g (16 mmol) of hydrochloride, to obtain 4.17 g (73%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.43 (9H, br s), 2.02-2.19 (2H, m), 2.86-4.31 (9H, m), 4.55-4.80 (1H, m), 4.96-5.38 (4H , m), 7.27-7.38 (5H, m).
(Reference Example 8B)
(3S) -3-{[(3S) -3-Fluoropyrrolidin-1-yl] methyl} piperazine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000045
(2R) -2-{[(3S) -3-fluoropyrrolidin-1-yl] carbonyl} piperazine-1,4-dicarboxylic acid 1-benzyl 4-tert-butyl obtained in Reference Example 8A (4.00 g) (9.2 mmol) was used in the same manner as in Reference Example 5C to obtain 2.36 g (89%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.95-2.99 (13H, m), 3.93 (2H, br s), 5.06-5.11 (1H, m), 5.20-5.25 (1H, m ).
(Reference Example 8C)
(3S) -3-{[(3S) -3-Fluoropyrrolidin-1-yl] methyl} -4-[(2,4,5-trichlorophenoxy) acetyl] piperazine-1-carboxylic acid tert-butyl
Figure JPOXMLDOC01-appb-C000046
Reference Example Using 940 mg (3.3 mmol) of tert-butyl (3S) -3-{[(3S) -3-fluoropyrrolidin-1-yl] methyl} piperazine-1-carboxylate obtained in Reference Example 8B 1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.94-2.15 (2H, m), 2.45-3.01 (1.61 g (94%) of the target compound was reacted in the same manner as 6A. 8H, m), 3.23-3.33 (0.5H, m), 3.68-3.75 (0.5H, m), 3.99-4.05 (0.5H, m), 4.09-4.20 (2.5H, m), 4.32-4.38 (0.5 H, m), 4.61-5.24 (4H, m), 7.07 (1H, br s), 7.47 (1H, s).
(Reference Example 8D)
(2R) -2-{[(3S) -3-Fluoropyrrolidin-1-yl] methyl} -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine
Figure JPOXMLDOC01-appb-C000047
(3S) -3-{[(3S) -3-Fluoropyrrolidin-1-yl] methyl} -4-[(2,4,5-trichlorophenoxy) acetyl] piperazine-1- obtained in Reference Example 8C The reaction was carried out in the same manner as in Reference Example 6B using 1.61 g (3.1 mmol) of tert-butyl carboxylate to obtain 1.30 g (100%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.96-2.17 (2H, m), 2.49-3.15 (10H, m), 3.25-3.37 (0.5H, m), 3.61-3.68 (0.5H, m), 3.88- 3.95 (0.5H, m), 4.29-4.37 (0.5H, m), 4.57-5.25 (4H, m), 7.07 (1H, br s), 7.46 (1H, s).
(Reference Example 8E)
(2S) -2-{[(3S) -3-Fluoropyrrolidin-1-yl] methyl} -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine
Figure JPOXMLDOC01-appb-C000048
1.30 g of (2R) -2-{[(3S) -3-fluoropyrrolidin-1-yl] methyl} -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine obtained in Reference Example 8D (3.1 mmol) was used in the same manner as in Reference Example 6C to obtain 766 mg (49%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.95-2.17 (2H, m), 2.51-3.11 (8.5H, m), 3.38-3.46 (0.5H, m), 3.69-3.81 (2H, m), 3.85- 3.91 (0.5H, m), 4.14-4.21 (0.5H, m), 4.45-4.51 (0.5H, m), 4.69-4.84 (2H, m), 4.94-5.24 (1.5H, m), 6.08 (1H , d, J = 10.2 Hz), 6.26 (1H, d, J = 16.6 Hz), 6.39 (1H, dd, J = 16.6, 10.2 Hz), 7.06 (1H, s), 7.08 (1H, s), 7.47 (1H, s).
（参考例９）
（３Ｓ）－１－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－３－（ピロリジン－１－イルメチル）ピペラジン
（参考例９Ａ）
（２Ｒ）－２－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ベンジル　　
Figure JPOXMLDOC01-appb-C000049
参考例５Ｂで得られた（２Ｒ）－２－（ピロリジン－１－イルカルボニル）ピペラジン－１，４－ジカルボン酸　１－ベンジル　４－ｔｅｒｔ－ブチル１０．５ｇ（２５ｍｍｏｌ）を窒素気流下テトラヒドロフラン５０ｍＬに溶解し、ボラン（１．１Ｍテトラヒドロフラン溶液）４６ｍＬ（５０ｍｍｏｌ）を滴下した後、５０℃で２時間撹拌した。反応溶液を０℃に冷却し、水を加えた後減圧下溶媒を留去した。水相を酢酸エチルで抽出し、得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をメタノール５０ｍＬに溶解し、４規定塩酸水溶液を加え、室温で２日間撹拌した。反応溶液を飽和炭酸水素ナトリウム水溶液で中和し、溶媒を減圧下留去し、水相を塩化メチレンで抽出した。得られた有機相を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－５０％メタノール／塩化メチレン）により精製し、目的化合物を５．６７ｇ（７４％）得た。
1H-NMR (CDCl3) δ: 1.72 (4H, br s), 2.41-2.63 (5H, m),2.70 (1H, td, J = 12.6, 3.5 Hz), 2.79 (1H, dd, J = 12.0, 3.5 Hz), 2.98 (3H, dd, J = 11.7, 9.3 Hz), 3.13(1H, d, J= 11.7 Hz), 3.92 (1H, d, J = 12.6 Hz), 4.18 (1H, br s), 5.11 (1H, d, J=12.2 Hz), 5.17 (1H, d, J = 12.2 Hz), 7.28-7.38 (5H, m).
（参考例９Ｂ）
（２Ｓ）－２－（ピロリジン－１－イルメチル）－４－（ビニルスルホニル）ピペラジン－１－カルボン酸　ベンジル
Figure JPOXMLDOC01-appb-C000050
参考例９Ａで得られた（２Ｒ）－２－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ベンジル３．０３ｇ（１０ｍｍｏｌ）を用いて参考例６Ｃと同様に反応を行い、目的化合物１．１７ｇ（３０％）を得た。
1H-NMR (CDCl3) δ: 1.71 (4H, br s), 2.40-2.66 (6H, m),2.69 (1H, dd, J = 11.7, 3.9 Hz), 2.81 (1H, dd, J = 12.3, 8.4 Hz), 3.14 (1H, t, J = 11.3 Hz), 3.63 (1H,d,J= 11.3 Hz), 3.79 (1H, d, J = 11.7 Hz), 4.01-4.15 (1H, m), 4.34 (1H, br s), 5.12 (2H, d, J = 12.5 Hz), 5.16 (2H, d, J = 12.5 Hz), 6.05 (1H, d, J = 10.1 Hz),6.24 (1H, d, J = 16.7 Hz), 6.40 (1H, dd, J= 16.7, 10.1 Hz), 7.29-7.41 (5H, m).
（参考例９Ｃ）
（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ベンジル
Figure JPOXMLDOC01-appb-C000051
参考例９Ｂで得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－４－（ビニルスルホニル）ピペラジン－１－カルボン酸　ベンジル２．１７ｇ（５．５ｍｍｏｌ）を塩化メチレン２０ｍＬに溶解し、４－アセチルピペラジン１．４１ｇ（１１ｍｍｏｌ）を加え、室温で３日間撹拌した。反応溶液の溶媒を減圧下留去し、得られた残渣をカラムクロマトグラフィー（０－６％メタノール／塩化メチレン）により精製し、目的化合物２．４６ｇ（８５％）を得た。
1H-NMR (CDCl3) δ: 1.71 (4H, br s), 2.08 (3H, s),2.36-2.60 (10H, m), 2.75-2.91 (5H, m), 3.04-3.16 (3H, m), 3.45 (2H, t, J = 5.1 Hz), 3.60 (2H, br s), 3.70(1H,d, J = 10.6 Hz), 3.88 (1H, d, J = 11.7 Hz), 4.00-4.13 (1H, m), 4.31 (1H, br s),5.12 (2H, d, J = 12.1 Hz), 5.17 (2H, d, J = 12.1 Hz), 7.29-7.40 (5H, m).
（参考例９Ｄ）
（３Ｓ）－１－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－３－（ピロリジン－１－イルメチル）ピペラジン
Figure JPOXMLDOC01-appb-C000052
参考例９Ｃで得られた（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－カルボン酸　ベンジル１．９６ｇ（３．８ｍｍｏｌ）を窒素気流下メタノール１０ｍＬに溶解し、１０％パラジウム／炭素２００ｍｇを加え、水素気流下室温で６時間撹拌した。触媒をろ別し、減圧下溶媒を留去することにより、目的化合物の粗生成物１．４５ｇ（９９％）を得た。
1H-NMR (CDCl3) δ: 1.72-1.79 (4H, m), 2.09 (3H, s), 2.27(1H, dd, J = 12.0, 4.2 Hz), 2.40-2.59 (10H, m), 2.83-2.92 (5H, m), 3.05-3.13 (3H, m), 3.45-3.49 (2H,m), 3.60-3.70 (4H, m). (Reference Example 9)
(3S) -1-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -3- (pyrrolidin-1-ylmethyl) piperazine (Reference Example 9A)
(2R) -2- (Pyrrolidin-1-ylmethyl) piperazine-1-carboxylic acid benzyl
Figure JPOXMLDOC01-appb-C000049
10.5 g (25 mmol) of 1-benzyl 4-tert-butyl (2R) -2- (pyrrolidin-1-ylcarbonyl) piperazine-1,4-dicarboxylate obtained in Reference Example 5B was added to 50 mL of tetrahydrofuran under a nitrogen stream. After dissolution, 46 mL (50 mmol) of borane (1.1 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was cooled to 0 ° C., water was added, and the solvent was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 50 mL of methanol, 4N aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution, the solvent was distilled off under reduced pressure, and the aqueous phase was extracted with methylene chloride. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-50% methanol / methylene chloride) to obtain 5.67 g (74%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.72 (4H, br s), 2.41-2.63 (5H, m), 2.70 (1H, td, J = 12.6, 3.5 Hz), 2.79 (1H, dd, J = 12.0 , 3.5 Hz), 2.98 (3H, dd, J = 11.7, 9.3 Hz), 3.13 (1H, d, J = 11.7 Hz), 3.92 (1H, d, J = 12.6 Hz), 4.18 (1H, br s) , 5.11 (1H, d, J = 12.2 Hz), 5.17 (1H, d, J = 12.2 Hz), 7.28-7.38 (5H, m).
(Reference Example 9B)
(2S) -2- (Pyrrolidin-1-ylmethyl) -4- (vinylsulfonyl) piperazine-1-carboxylic acid benzyl
Figure JPOXMLDOC01-appb-C000050
The reaction was conducted in the same manner as in Reference Example 6C using 3.03 g (10 mmol) of benzyl (2R) -2- (pyrrolidin-1-ylmethyl) piperazine-1-carboxylate obtained in Reference Example 9A. 17 g (30%) were obtained.
1 H-NMR (CDCl 3 ) δ: 1.71 (4H, br s), 2.40-2.66 (6H, m), 2.69 (1H, dd, J = 11.7, 3.9 Hz), 2.81 (1H, dd, J = 12.3 , 8.4 Hz), 3.14 (1H, t, J = 11.3 Hz), 3.63 (1H, d, J = 11.3 Hz), 3.79 (1H, d, J = 11.7 Hz), 4.01-4.15 (1H, m), 4.34 (1H, br s), 5.12 (2H, d, J = 12.5 Hz), 5.16 (2H, d, J = 12.5 Hz), 6.05 (1H, d, J = 10.1 Hz), 6.24 (1H, d, J = 16.7 Hz), 6.40 (1H, dd, J = 16.7, 10.1 Hz), 7.29-7.41 (5H, m).
(Reference Example 9C)
(2S) -4-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazine-1-carboxylate benzyl
Figure JPOXMLDOC01-appb-C000051
2.17 g (5.5 mmol) of benzyl (2S) -2- (pyrrolidin-1-ylmethyl) -4- (vinylsulfonyl) piperazine-1-carboxylate obtained in Reference Example 9B was dissolved in 20 mL of methylene chloride. 4-Acetylpiperazine (1.41 g, 11 mmol) was added, and the mixture was stirred at room temperature for 3 days. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (0-6% methanol / methylene chloride) to obtain 2.46 g (85%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.71 (4H, br s), 2.08 (3H, s), 2.36-2.60 (10H, m), 2.75-2.91 (5H, m), 3.04-3.16 (3H, m ), 3.45 (2H, t, J = 5.1 Hz), 3.60 (2H, br s), 3.70 (1H, d, J = 10.6 Hz), 3.88 (1H, d, J = 11.7 Hz), 4.00-4.13 ( 1H, m), 4.31 (1H, br s), 5.12 (2H, d, J = 12.1 Hz), 5.17 (2H, d, J = 12.1 Hz), 7.29-7.40 (5H, m).
(Reference Example 9D)
(3S) -1-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -3- (pyrrolidin-1-ylmethyl) piperazine
Figure JPOXMLDOC01-appb-C000052
(2S) -4-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazine-1-carboxylate obtained in Reference Example 9C 96 g (3.8 mmol) was dissolved in 10 mL of methanol under a nitrogen stream, 200 mg of 10% palladium / carbon was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen stream. The catalyst was filtered off, and the solvent was distilled off under reduced pressure to obtain 1.45 g (99%) of a crude product of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.72-1.79 (4H, m), 2.09 (3H, s), 2.27 (1H, dd, J = 12.0, 4.2 Hz), 2.40-2.59 (10H, m), 2.83 -2.92 (5H, m), 3.05-3.13 (3H, m), 3.45-3.49 (2H, m), 3.60-3.70 (4H, m).
（実施例１） 
（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン　２塩酸塩
Figure JPOXMLDOC01-appb-C000053
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン２８６ｍｇ（０．５８ｍｍｏｌ）を塩化メチレン５ｍＬに溶解し、４－アセチルピペラジン１１１ｍｇ（０．８６ｍｍｏｌ）を加え、室温で３日間撹拌した。反応溶液の溶媒を減圧下留去し、得られた残渣をカラムクロマトグラフィー（０－５％メタノール／塩化メチレン）により精製し、目的化合物のフリー体３６０ｍｇ（８３％）を得た。本フリー体をジオキサン５ｍＬに溶解し、１規定塩酸／ジオキサン溶液を滴下した後、溶媒を減圧下留去して目的化合物（塩酸塩）３３５ｍｇを得た。
1H-NMR (DMSO-D6) δ: 1.87-2.04 (4H, m), 2.05 (3H, s),2.81-3.26 (8H, m), 3.26-4.13 (15H, m), 4.36-4.53 (1H, m), 4.99-5.06 (1H, m), 5.16-5.25 (1H, m), 5.29 (1H,d, J = 15.6 Hz), 7.72-7.79 (1H, m), 7.80 (1H, s), 10.09-10.34 (1H, m),11.63-11.94 (1H, m);
IR(KBr) vmax 3430, 2927, 1657, 1468, 1429, 1352, 1254, 1158, 1086, 992, 929 cm-1;
MS(FAB)m/z:624 (M+H)+. Example 1
(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] Piperazine dihydrochloride
Figure JPOXMLDOC01-appb-C000053
286 mg (0.58 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Was dissolved in 5 mL of methylene chloride, 111 mg (0.86 mmol) of 4-acetylpiperazine was added, and the mixture was stirred at room temperature for 3 days. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (0-5% methanol / methylene chloride) to obtain 360 mg (83%) of the desired compound free form. This free compound was dissolved in 5 mL of dioxane and 1N hydrochloric acid / dioxane solution was added dropwise, and then the solvent was distilled off under reduced pressure to obtain 335 mg of the target compound (hydrochloride).
1 H-NMR (DMSO-D 6 ) δ: 1.87-2.04 (4H, m), 2.05 (3H, s), 2.81-3.26 (8H, m), 3.26-4.13 (15H, m), 4.36-4.53 ( 1H, m), 4.99-5.06 (1H, m), 5.16-5.25 (1H, m), 5.29 (1H, d, J = 15.6 Hz), 7.72-7.79 (1H, m), 7.80 (1H, s) , 10.09-10.34 (1H, m), 11.63-11.94 (1H, m);
IR (KBr) vmax 3430, 2927, 1657, 1468, 1429, 1352, 1254, 1158, 1086, 992, 929 cm -1 ;
MS (FAB) m / z: 624 (M + H) + .
（実施例２）
４－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］モルホリン　２塩酸塩
Figure JPOXMLDOC01-appb-C000054
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン２００ｍｇ（０．４０ｍｍｏｌ）及びモルホリン７０ｍｇ（０．８１ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物２４１ｍｇ（９１％）を得た。
1H-NMR (DMSO-D6) δ: 1.87-2.04 (4H, m), 2.99-3.25 (7H, m),3.32-3.84 (14H, m), 3.93-4.04 (3H, m), 5.03 (1H, d, J = 11.2 Hz), 5.21 (1H, d, J = 15.8 Hz), 5.29(1H, d, J = 15.8 Hz), 7.76 (0.5H, s), 7.77 (0.5H, s), 7.80 (1H, s), 10.22 (1H,s),11.73 (1H, s);
MS(FAB)m/z:583 (M+H)+. (Example 2)
4- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] morpholine dihydrochloride
Figure JPOXMLDOC01-appb-C000054
200 mg (0.40 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 70 mg (0.81 mmol) of morpholine to obtain 241 mg (91%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.87-2.04 (4H, m), 2.99-3.25 (7H, m), 3.32-3.84 (14H, m), 3.93-4.04 (3H, m), 5.03 ( 1H, d, J = 11.2 Hz), 5.21 (1H, d, J = 15.8 Hz), 5.29 (1H, d, J = 15.8 Hz), 7.76 (0.5H, s), 7.77 (0.5H, s), 7.80 (1H, s), 10.22 (1H, s), 11.73 (1H, s);
MS (FAB) m / z: 583 (M + H) + .
（実施例３）
４－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］チオモルホリン　２塩酸塩
Figure JPOXMLDOC01-appb-C000055
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン６５ｍｇ（０．１３ｍｍｏｌ）及びチオモルホリン２７ｍｇ（０．２６ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物６８ｍｇ（７８％）を得た。
1H-NMR (DMSO-D6) δ: 1.88-2.03 (4H, m), 2.80-4.02 (24H,m), 4.99-5.05 (1H, m), 5.16 (1H, d, J = 16.2 Hz), 5.28 (1H, d, J = 16.2 Hz), 7.70 (1H, s), 7.80 (1H,s),10.00 (1H, br s);
MS(FAB)m/z:599 (M+H)+. (Example 3)
4- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] thiomorpholine dihydrochloride salt
Figure JPOXMLDOC01-appb-C000055
65 mg (0.13 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 27 mg (0.26 mmol) of thiomorpholine to obtain 68 mg (78%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.88-2.03 (4H, m), 2.80-4.02 (24H, m), 4.99-5.05 (1H, m), 5.16 (1H, d, J = 16.2 Hz) , 5.28 (1H, d, J = 16.2 Hz), 7.70 (1H, s), 7.80 (1H, s), 10.00 (1H, br s);
MS (FAB) m / z: 599 (M + H) + .
（実施例４）
Ｎ，Ｎ－ジメチル－２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エタンアミン　２塩酸塩
Figure JPOXMLDOC01-appb-C000056
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン６５ｍｇ（０．１３ｍｍｏｌ）及び２規定ジメチルアミン／テトラヒドロフラン溶液０．１３ｍＬ（０．２６ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物７８ｍｇ（９７％）を得た。
1H-NMR (DMSO-D6) δ: 1.88-2.03 (4H, m), 2.80 (6H, s),2.97-3.75 (17H, m), 3.92-4.02 (1H, m), 4.99-5.05 (1H, m), 5.20 (1H, d, J = 16.0 Hz), 5.29 (1H, d, J =16.0Hz), 7.75 (1H, s), 7.80 (1H, s), 10.19 (1H, br s), 10.83 (1H, br s);
MS(FAB)m/z:541 (M+H)+. Example 4
N, N-dimethyl-2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethanamine dihydrochloride salt
Figure JPOXMLDOC01-appb-C000056
65 mg (0.13 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 And 2N dimethylamine / tetrahydrofuran solution 0.13 mL (0.26 mmol) was used in the same manner as in Example 1 to obtain 78 mg (97%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.88-2.03 (4H, m), 2.80 (6H, s), 2.97-3.75 (17H, m), 3.92-4.02 (1H, m), 4.99-5.05 ( 1H, m), 5.20 (1H, d, J = 16.0 Hz), 5.29 (1H, d, J = 16.0Hz), 7.75 (1H, s), 7.80 (1H, s), 10.19 (1H, br s) , 10.83 (1H, br s);
MS (FAB) m / z: 541 (M + H) + .
（実施例５）
２，２’－｛［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］イミノ｝ジエタノール　２塩酸塩
Figure JPOXMLDOC01-appb-C000057
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン５０ｍｇ（０．１０ｍｍｏｌ）及びジエタノールアミン２１ｍｇ（０．２０ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物６１ｍｇ（８３％）を得た。
1H-NMR (DMSO-D6) δ: 1.89-2.04 (4H, m), 3.00-4.00 (24.5H,m), 4.99-5.46 (4.5H, m), 7.71-7.84 (2H, m), 10.00-10.44 (2H, m);
MS(FAB)m/z:601 (M+H)+. (Example 5)
2,2 ′-{[2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] Imino} diethanol dihydrochloride
Figure JPOXMLDOC01-appb-C000057
50 mg (0.10 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 And 21 mg (0.20 mmol) of diethanolamine was reacted in the same manner as in Example 1 to obtain 61 mg (83%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.89-2.04 (4H, m), 3.00-4.00 (24.5H, m), 4.99-5.46 (4.5H, m), 7.71-7.84 (2H, m), 10.00-10.44 (2H, m);
MS (FAB) m / z: 601 (M + H) + .
（実施例６）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－４－オール　２塩酸塩
Figure JPOXMLDOC01-appb-C000058
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン９８ｍｇ（０．２０ｍｍｏｌ）及びピペリジン－４－オール４０ｍｇ（０．４０ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物１３１ｍｇ（９９％）を得た。
1H-NMR (DMSO-D6) δ: 1.64-1.77 (2H, m), 1.89-2.04 (6H, m),2.95-4.03 (20H, m), 4.99-5.11 (2H, m), 5.19 (1H, d, J = 16.1 Hz), 5.28 (1H, d, J = 16.1 Hz), 7.74(1H, br s), 7.80 (1H, s), 10.13 (1H, br s), 10.89 (1H, br s);
MS(FAB)m/z:597 (M+H)+. (Example 6)
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperidine-4- All dihydrochloride
Figure JPOXMLDOC01-appb-C000058
98 mg (0.20 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 40 mg (0.40 mmol) of piperidin-4-ol to obtain 131 mg (99%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.64-1.77 (2H, m), 1.89-2.04 (6H, m), 2.95-4.03 (20H, m), 4.99-5.11 (2H, m), 5.19 ( 1H, d, J = 16.1 Hz), 5.28 (1H, d, J = 16.1 Hz), 7.74 (1H, br s), 7.80 (1H, s), 10.13 (1H, br s), 10.89 (1H, br s);
MS (FAB) m / z: 597 (M + H) + .
（実施例７）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピロリジン－３－オール　２塩酸塩
Figure JPOXMLDOC01-appb-C000059
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン１５０ｍｇ（０．３０ｍｍｏｌ）及びピロリジン－３－オール５２ｍｇ（０．６０ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物１６４ｍｇ（８３％）を得た。
1H-NMR (DMSO-D6) δ: 1.80-2.03 (6H, m), 3.01-3.74 (18H,m), 3.94-4.02 (1H, m), 4.38-4.47 (1H, m), 5.00-5.05 (1H, m), 5.14-5.22 (1H, m), 5.28 (1H, d, J = 15.6Hz), 5.48-5.55 (1H, m), 7.70 (0.5H, br s), 7.73 (0.5H, br s), 7.81 (1H, s);IR(KBr) vmax 3379, 2953, 2684, 2590, 1663, 1468, 1352, 1154, 1088, 992, 928cm-1;
MS(FAB)m/z:583 (M+H)+. (Example 7)
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] pyrrolidine-3- All dihydrochloride
Figure JPOXMLDOC01-appb-C000059
150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 And pyrrolidin-3-ol 52 mg (0.60 mmol) was used in the same manner as in Example 1 to obtain 164 mg (83%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.80-2.03 (6H, m), 3.01-3.74 (18H, m), 3.94-4.02 (1H, m), 4.38-4.47 (1H, m), 5.00- 5.05 (1H, m), 5.14-5.22 (1H, m), 5.28 (1H, d, J = 15.6Hz), 5.48-5.55 (1H, m), 7.70 (0.5H, br s), 7.73 (0.5H , br s), 7.81 (1H, s); IR (KBr) vmax 3379, 2953, 2684, 2590, 1663, 1468, 1352, 1154, 1088, 992, 928cm -1 ;
MS (FAB) m / z: 583 (M + H) + .
（実施例８）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］アゼチジン－３－オール
Figure JPOXMLDOC01-appb-C000060
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン１２０ｍｇ（０．２４ｍｍｏｌ）を塩化メチレン２ｍＬに溶解し、トリエチルアミン０．１ｍＬ（０．７２ｍｍｏｌ）及びアゼチジン－３－オール塩酸塩５３ｍｇ（０．４８ｍｍｏｌ）を加え、室温で２時間撹拌した。反応溶液に水を加え、水相を酢酸エチルで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（５－１５％メタノール／塩化メチレン）により精製し、目的化合物を８８ｍｇ（６３％）得た。
1H-NMR (CDCl3) δ: 1.68-1.80 (4H, m), 2.48-3.05 (13H, m),3.60-3.66 (3H, m), 3.73-3.87 (3H, m), 4.07-4.12 (0H, m), 4.37-4.48 (2H, m), 4.72-4.94 (3H, m), 7.07(1H, br s), 7.12 (1H, br s), 7.48 (1H, s);
IR(KBr) vmax 3426, 2950, 2813, 1670, 1477, 1334, 1248, 1148, 1090, 982 cm-1;
MS(FAB)m/z:569 (M+H)+. (Example 8)
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] azetidine-3- Oar
Figure JPOXMLDOC01-appb-C000060
120 mg (0.24 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Was dissolved in 2 mL of methylene chloride, 0.1 mL (0.72 mmol) of triethylamine and 53 mg (0.48 mmol) of azetidin-3-ol hydrochloride were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (5-15% methanol / methylene chloride) to obtain 88 mg (63%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.68-1.80 (4H, m), 2.48-3.05 (13H, m), 3.60-3.66 (3H, m), 3.73-3.87 (3H, m), 4.07-4.12 ( 0H, m), 4.37-4.48 (2H, m), 4.72-4.94 (3H, m), 7.07 (1H, br s), 7.12 (1H, br s), 7.48 (1H, s);
IR (KBr) vmax 3426, 2950, 2813, 1670, 1477, 1334, 1248, 1148, 1090, 982 cm -1 ;
MS (FAB) m / z: 569 (M + H) + .
（実施例９）
Ｎ－｛１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピロリジン－３－イル｝アセトアミド　２塩酸塩
Figure JPOXMLDOC01-appb-C000061
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン１５０ｍｇ（０．３０ｍｍｏｌ）及びＮ－ピロリジン－３－イル－アセトアミド７７ｍｇ（０．６０ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物１７５ｍｇ（８３％）を得た。
1H-NMR (DMSO-D6) δ: 1.82 (1.5H, s), 1.84 (1.5H, s),1.90-2.37 (6H, m), 2.90-3.85 (19H, m), 3.93-4.04 (1H, m), 4.24-4.39 (1H, m), 4.99-5.05 (1H, m), 5.19 (1H,d, J = 16.2 Hz), 5.29 (1H, d, J = 16.2 Hz), 7.74 (1H, br s), 7.80 (1H, s), 8.29(0.5H, s), 8.47 (0.5H, s), 10.12 (1H, br s), 11.37 (1H, br s);
IR(KBr) vmax 3259, 2958, 2588, 1665, 1543, 1468, 1352, 1153, 1087, 992, 928 cm-1;
MS(FAB)m/z:624 (M+H)+. Example 9
N- {1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] pyrrolidine -3-yl} acetamide dihydrochloride
Figure JPOXMLDOC01-appb-C000061
150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 And N-pyrrolidin-3-yl-acetamide (77 mg, 0.60 mmol) was used in the same manner as in Example 1 to obtain 175 mg (83%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.82 (1.5H, s), 1.84 (1.5H, s), 1.90-2.37 (6H, m), 2.90-3.85 (19H, m), 3.93-4.04 ( 1H, m), 4.24-4.39 (1H, m), 4.99-5.05 (1H, m), 5.19 (1H, d, J = 16.2 Hz), 5.29 (1H, d, J = 16.2 Hz), 7.74 (1H , br s), 7.80 (1H, s), 8.29 (0.5H, s), 8.47 (0.5H, s), 10.12 (1H, br s), 11.37 (1H, br s);
IR (KBr) vmax 3259, 2958, 2588, 1665, 1543, 1468, 1352, 1153, 1087, 992, 928 cm -1 ;
MS (FAB) m / z: 624 (M + H) + .
（実施例１０）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペラジン－２－オン　２塩酸塩
Figure JPOXMLDOC01-appb-C000062
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン９０ｍｇ（０．１８ｍｍｏｌ）及びピペラジン－２－オン３６ｍｇ（０．３６ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物１０７ｍｇ（８８％）を得た。
1H-NMR (DMSO-D6) δ: 1.84-2.08 (4H, m), 2.98-3.90 (21H,m), 3.97 (1H, t, J = 11.5 Hz), 5.02 (2H, d, J= 11.7 Hz), 5.19 (1H, d, J = 16.1 Hz), 5.29 (1H, d, J =16.1 Hz), 7.74 (1H, s), 7.80 (1H, s), 8.36 (1H, br s), 10.13 (1H, br s);
MS(FAB)m/z:596 (M+H)+. (Example 10)
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperazine-2- ON dihydrochloride
Figure JPOXMLDOC01-appb-C000062
90 mg (0.18 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 36 mg (0.36 mmol) of piperazin-2-one to obtain 107 mg (88%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.84-2.08 (4H, m), 2.98-3.90 (21H, m), 3.97 (1H, t, J = 11.5 Hz), 5.02 (2H, d, J = 11.7 Hz), 5.19 (1H, d, J = 16.1 Hz), 5.29 (1H, d, J = 16.1 Hz), 7.74 (1H, s), 7.80 (1H, s), 8.36 (1H, br s), 10.13 (1H, br s);
MS (FAB) m / z: 596 (M + H) + .
（実施例１１）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］－１，４－ジアゼパン－５－オン　２塩酸塩
Figure JPOXMLDOC01-appb-C000063
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン１５０ｍｇ（０．３０ｍｍｏｌ）及び１，４－ジアゼパン－５－オン７０ｍｇ（０．６０ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物１５０ｍｇ（７２％）を得た。
1H-NMR (DMSO-D6) δ: 1.88-2.04 (4H, m), 2.38-2.56 (2H, m),3.01-3.80 (22H, m), 3.94-4.03 (1H, m), 4.99-5.05 (1H, m), 5.16 (1H, d, J = 15.8 Hz), 5.28 (1H, d, J=15.8 Hz), 7.69 (1H, br s), 7.81 (1H, s), 7.93 (1H, br s), 9.98 (1H, br s), 11.58 (1H, br s);
IR(KBr) vmax 3415, 2955, 2587, 1665, 1468, 1351, 1154, 1087, 992, 927 cm-1;
MS(FAB)m/z:610 (M+H)+. Example 11
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] -1,4 -Diazepan-5-one dihydrochloride
Figure JPOXMLDOC01-appb-C000063
150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 70 mg (0.60 mmol) of 1,4-diazepan-5-one to obtain 150 mg (72%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.88-2.04 (4H, m), 2.38-2.56 (2H, m), 3.01-3.80 (22H, m), 3.94-4.03 (1H, m), 4.99- 5.05 (1H, m), 5.16 (1H, d, J = 15.8 Hz), 5.28 (1H, d, J = 15.8 Hz), 7.69 (1H, br s), 7.81 (1H, s), 7.93 (1H, br s), 9.98 (1H, br s), 11.58 (1H, br s);
IR (KBr) vmax 3415, 2955, 2587, 1665, 1468, 1351, 1154, 1087, 992, 927 cm -1 ;
MS (FAB) m / z: 610 (M + H) + .
（実施例１２）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－３－カルボン酸　２塩酸塩
（実施例１２Ａ）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－３－カルボン酸　エチル
Figure JPOXMLDOC01-appb-C000064
参考例６で得られた（２Ｓ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン１５０ｍｇ（０．３０ｍｍｏｌ）及びニペコチン酸　エチル９４ｍｇ（０．６０ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物（フリー体）１９０ｍｇ（９５％）を得た。
1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.1 Hz), 1.46-1.58(2H, m), 1.68-1.79 (4H, m), 1.88-1.95 (1H, m), 2.06-2.14 (1H, m), 2.21-2.30 (1H, m), 2.45-3.14 (14.5H,m), 3.36-3.45 (0.5H, m), 3.75-3.87 (3H, m), 4.08-4.16 (3.5H, m), 4.43-4.49 (0.5H,m), 4.72-4.96 (3H, m), 7.06 (0.5H, br s), 7.12 (0.5H, br s), 7.48 (1H, s).
（実施例１２Ｂ）
１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－３－カルボン酸　２塩酸塩
Figure JPOXMLDOC01-appb-C000065
実施例１２Ａで得られた１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－３－カルボン酸　エチル１１６ｍｇ（０．１８ｍｍｏｌ）をジオキサン１．５ｍＬに溶解し、１規定水酸化ナトリウム水溶液０．３６ｍＬを加え、室温で１０分撹拌した。反応溶液を１規定塩酸水溶液で中和し、水相に塩化ナトリウムを加え飽和させた後、酢酸エチルで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた粗生成物にイソプロピルエーテルを加え、粉末をろ取することにより目的化合物（フリー体）２９ｍｇ（２６％）を得た。フリー体をジオキサン１．２ｍＬに溶解し、１規定塩酸／ジオキサン溶液を滴下した後、溶媒を減圧下留去して塩酸塩２６ｍｇを得た。
1H-NMR (DMSO-D6) δ: 1.39-1.48 (1H, m), 1.76-2.06 (7H, m),2.45-2.54 (1H, m), 2.82-3.84 (19H, m), 3.96-4.02 (1H, m), 4.99-5.05 (1H, m), 5.16 (1H, d, J = 15.6Hz), 5.28 (1H, d, J= 15.6 Hz), 7.69 (1H, br s), 7.81 (1H, s), 9.96 (1H, br s),11.02 (1H, br s), 12.90 (1H, br s);
IR(KBr) vmax 3417, 2956, 2669, 1730, 1664, 1468, 1351, 1151, 1141, 1087 cm-1;
MS(FAB)m/z:625 (M+H)+. (Example 12)
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperidine-3- Carboxylic acid dihydrochloride (Example 12A)
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperidine-3- Ethyl carboxylate
Figure JPOXMLDOC01-appb-C000064
150 mg (0.30 mmol) of (2S) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] -4- (vinylsulfonyl) piperazine obtained in Reference Example 6 Then, the reaction was carried out in the same manner as in Example 1 using 94 mg (0.60 mmol) of ethyl nipecotate to obtain 190 mg (95%) of the target compound (free form).
1 H-NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.46-1.58 (2H, m), 1.68-1.79 (4H, m), 1.88-1.95 (1H, m), 2.06 -2.14 (1H, m), 2.21-2.30 (1H, m), 2.45-3.14 (14.5H, m), 3.36-3.45 (0.5H, m), 3.75-3.87 (3H, m), 4.08-4.16 ( 3.5H, m), 4.43-4.49 (0.5H, m), 4.72-4.96 (3H, m), 7.06 (0.5H, br s), 7.12 (0.5H, br s), 7.48 (1H, s).
(Example 12B)
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperidine-3- Carboxylic acid dihydrochloride
Figure JPOXMLDOC01-appb-C000065
1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl obtained in Example 12A ) Ethyl] piperidine-3-carboxylate (116 mg, 0.18 mmol) was dissolved in dioxane (1.5 mL), 1N aqueous sodium hydroxide solution (0.36 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction solution was neutralized with a 1N aqueous hydrochloric acid solution, saturated with sodium chloride added to the aqueous phase, and then extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Isopropyl ether was added to the obtained crude product, and the powder was collected by filtration to obtain 29 mg (26%) of the desired compound (free form). The free product was dissolved in 1.2 mL of dioxane, 1N hydrochloric acid / dioxane solution was added dropwise, and then the solvent was distilled off under reduced pressure to obtain 26 mg of hydrochloride.
1 H-NMR (DMSO-D 6 ) δ: 1.39-1.48 (1H, m), 1.76-2.06 (7H, m), 2.45-2.54 (1H, m), 2.82-3.84 (19H, m), 3.96- 4.02 (1H, m), 4.99-5.05 (1H, m), 5.16 (1H, d, J = 15.6Hz), 5.28 (1H, d, J = 15.6 Hz), 7.69 (1H, br s), 7.81 ( 1H, s), 9.96 (1H, br s), 11.02 (1H, br s), 12.90 (1H, br s);
IR (KBr) vmax 3417, 2956, 2669, 1730, 1664, 1468, 1351, 1151, 1141, 1087 cm -1 ;
MS (FAB) m / z: 625 (M + H) + .
（実施例１３）
（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－１－［（２－ブロモ－４，５－ジクロロフェノキシ）アセチル］－２－（ピロリジン－１－イルメチル）ピペラジン　２塩酸塩
Figure JPOXMLDOC01-appb-C000066
参考例１で得られた（２－ブロモ－４，５－ジクロロフェノキシ）酢酸７８ｍｇ（０．２６ｍｍｏｌ）及び参考例９で得られた（３Ｓ）－１－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－３－（ピロリジン－１－イルメチル）ピペラジン９２ｍｇ（０．２４ｍｍｏｌ）をテトラヒドロフラン２ｍＬに溶解し、トリエチルアミン６６μＬ（０．４７ｍｍｏｌ）及びシアノリン酸ジエチル４７μＬ（０．３１ｍｍｏｌ）を加え、室温で終夜撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、溶媒を減圧下留去し、水相を酢酸エチルで抽出した。得られた有機相を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（０－７％メタノール／塩化メチレン）により精製し、目的化合物（フリー体）を１２７ｍｇ（８０％）得た。フリー体をジオキサン５ｍＬに溶解し、１規定塩酸／ジオキサン溶液を滴下した後、溶媒を減圧下留去して塩酸塩１４１ｍｇを得た。
1H-NMR (DMSO-D6) δ: 1.88-2.04 (4H, m), 2.05 (3H, s),2.93-4.08 (23H, m), 4.44 (1H, br s), 5.00-5.05 (1H, m), 5.14-5.22 (1H, m), 5.26-5.31 (1H, m), 7.66 (1H,brs), 7.71 (1H, br s), 7.92 (1H, s);
IR(KBr) vmax 3428, 2927, 2572, 1656, 1464, 1428, 1348, 1154, 1061, 991 cm-1;
MS(FAB)m/z:668 (M+H)+. (Example 13)
(2S) -4-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -1-[(2-bromo-4,5-dichlorophenoxy) acetyl] -2- (pyrrolidine-1- Ylmethyl) piperazine dihydrochloride
Figure JPOXMLDOC01-appb-C000066
78 mg (0.26 mmol) of (2-bromo-4,5-dichlorophenoxy) acetic acid obtained in Reference Example 1 and (3S) -1-{[2- (4-acetylpiperazine-) obtained in Reference Example 9 1-yl) ethyl] sulfonyl} -3- (pyrrolidin-1-ylmethyl) piperazine (92 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL), and triethylamine (66 μL, 0.47 mmol) and diethyl cyanophosphate (47 μL, 0.31 mmol) were dissolved. In addition, the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the solvent was distilled off under reduced pressure, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (0-7% methanol / methylene chloride) to obtain 127 mg (80%) of the desired compound (free form). The free product was dissolved in 5 mL of dioxane, 1N hydrochloric acid / dioxane solution was added dropwise, and then the solvent was distilled off under reduced pressure to obtain 141 mg of hydrochloride.
1 H-NMR (DMSO-D 6 ) δ: 1.88-2.04 (4H, m), 2.05 (3H, s), 2.93-4.08 (23H, m), 4.44 (1H, br s), 5.00-5.05 (1H , m), 5.14-5.22 (1H, m), 5.26-5.31 (1H, m), 7.66 (1H, brs), 7.71 (1H, br s), 7.92 (1H, s);
IR (KBr) vmax 3428, 2927, 2572, 1656, 1464, 1428, 1348, 1154, 1061, 991 cm -1 ;
MS (FAB) m / z: 668 (M + H) + .
（実施例１４）
２－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエトキシ｝－４，５－ジクロロベンゾニトリル　２塩酸塩
Figure JPOXMLDOC01-appb-C000067
参考例２で得られた（４，５－ジクロロ－２－シアノフェノキシ）酢酸９１ｍｇ（０．３７ｍｍｏｌ）及び参考例９で得られた（３Ｓ）－１－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－３－（ピロリジン－１－イルメチル）ピペラジン１２０ｍｇ（０．３０ｍｍｏｌ）を用いて実施例１３と同様に反応を行い、目的化合物１１０ｍｇ（５４％）を得た。
1H-NMR (DMSO-D6) δ: 1.88-2.01 (4H, m), 2.05 (3H, s),2.91-4.09 (23H, m), 4.38-4.49 (1H, m), 4.99-5.05 (1H, m), 5.30-5.43 (2H, m), 8.01 (1H, s), 8.16 (1H, s),10.30 (1H, s), 11.77 (1H, s);IR(KBr) vmax 3433, 2958, 2569, 2232, 1666, 1474, 1428, 1351, 1255, 1165, 992,925 cm-1;
MS(FAB)m/z:615 (M+H)+. (Example 14)
2- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxo Ethoxy} -4,5-dichlorobenzonitrile dihydrochloride
Figure JPOXMLDOC01-appb-C000067
91 mg (0.37 mmol) of (4,5-dichloro-2-cyanophenoxy) acetic acid obtained in Reference Example 2 and (3S) -1-{[2- (4-acetylpiperazine-) obtained in Reference Example 9 Using 1-yl) ethyl] sulfonyl} -3- (pyrrolidin-1-ylmethyl) piperazine (120 mg, 0.30 mmol), the reaction was carried out in the same manner as in Example 13 to obtain 110 mg (54%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.88-2.01 (4H, m), 2.05 (3H, s), 2.91-4.09 (23H, m), 4.38-4.49 (1H, m), 4.99-5.05 ( 1H, m), 5.30-5.43 (2H, m), 8.01 (1H, s), 8.16 (1H, s), 10.30 (1H, s), 11.77 (1H, s); IR (KBr) vmax 3433, 2958 , 2569, 2232, 1666, 1474, 1428, 1351, 1255, 1165, 992,925 cm -1 ;
MS (FAB) m / z: 615 (M + H) + .
（実施例１５）
（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－１－｛［（３－クロロ－２－ナフチル）オキシ］アセチル｝－２－（ピロリジン－１－イルメチル）ピペラジン　２塩酸塩
Figure JPOXMLDOC01-appb-C000068
Ｊ．Ｃｈｅｍ．Ｓｏｃ．１９５１，３４１８に記載の［（３－クロロ－２－ナフチル）オキシ］酢酸６７ｍｇ（０．２８ｍｍｏｌ）及び参考例９で得られた（３Ｓ）－１－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－３－（ピロリジン－１－イルメチル）ピペラジン１００ｍｇ（０．２６ｍｍｏｌ）を用いて実施例１３と同様に反応を行い、目的化合物９７ｍｇ（５５％）を得た。
1H-NMR (DMSO-D6) δ: 1.78-2.03 (4H, m), 2.05 (3H, s),2.91-4.11 (23H, m), 4.44 (1H, br s), 5.06 (1H, d, J= 12.1 Hz), 5.22 (1H, d, J = 15.6 Hz), 5.27 (1H, d, J=15.6 Hz), 7.39 (1H, t, J = 7.6 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.82 (1H, d, J= 7.6 Hz), 7.90 (1H, d, J = 7.6 Hz), 7.91 (1H, s), 8.06 (1H, s), 10.45 (1H, br s),11.70 (1H, br s);
IR(KBr) vmax 3429, 2953, 2572, 1658, 1462, 1427, 1331, 1252, 1219, 1157, 991 cm-1;
MS(FAB)m/z:606 (M+H)+. (Example 15)
(2S) -4-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -1-{[(3-chloro-2-naphthyl) oxy] acetyl} -2- (pyrrolidine-1- Ylmethyl) piperazine dihydrochloride
Figure JPOXMLDOC01-appb-C000068
J. et al. Chem. Soc. 1951,3418 [(3-chloro-2-naphthyl) oxy] acetic acid 67 mg (0.28 mmol) and (3S) -1-{[2- (4-acetylpiperazine-1) obtained in Reference Example 9 Reaction was carried out in the same manner as in Example 13 using 100 mg (0.26 mmol) of -yl) ethyl] sulfonyl} -3- (pyrrolidin-1-ylmethyl) piperazine to obtain 97 mg (55%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.78-2.03 (4H, m), 2.05 (3H, s), 2.91-4.11 (23H, m), 4.44 (1H, br s), 5.06 (1H, d , J = 12.1 Hz), 5.22 (1H, d, J = 15.6 Hz), 5.27 (1H, d, J = 15.6 Hz), 7.39 (1H, t, J = 7.6 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.82 (1H, d, J = 7.6 Hz), 7.90 (1H, d, J = 7.6 Hz), 7.91 (1H, s), 8.06 (1H, s), 10.45 (1H, br s) , 11.70 (1H, br s);
IR (KBr) vmax 3429, 2953, 2572, 1658, 1462, 1427, 1331, 1252, 1219, 1157, 991 cm -1 ;
MS (FAB) m / z: 606 (M + H) + .
（実施例１６）
３－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエトキシ｝－２－ナフトニトリル　２塩酸塩
Figure JPOXMLDOC01-appb-C000069
Ｊ．Ｃｈｅｍ．Ｓｏｃ．１９５８，４７２３に記載の［（３－シアノ－２－ナフチル）オキシ］酢酸５９ｍｇ（０．２６ｍｍｏｌ）及び参考例９で得られた（３Ｓ）－１－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－３－（ピロリジン－１－イルメチル）ピペラジン９１ｍｇ（０．２３ｍｍｏｌ）を用いて実施例１３と同様に反応を行い、目的化合物１４０ｍｇ（８９％）を得た。
1H-NMR (DMSO-D6) δ: 1.75-2.03 (4H, m), 2.05 (3H, s),2.95-4.09 (23H, m), 4.44 (1H, br s), 5.05 (1H, d, J= 12.2 Hz), 5.32 (2H, s), 7.47 (1H, t, J = 7.8 Hz),7.62 (1H, t, J= 7.8 Hz), 7.95 (2H, d, J = 7.8 Hz), 8.08 (1H, s), 8.51 (1H, s),10.56 (1H, s), 11.71 (1H, s);
IR(KBr) vmax 3430, 2957, 2927, 2570, 2228, 1657, 1428, 1336, 1257, 1155 cm-1;
MS(FAB)m/z:597 (M+H)+. (Example 16)
3- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxo Ethoxy} -2-naphthonitrile dihydrochloride
Figure JPOXMLDOC01-appb-C000069
J. et al. Chem. Soc. 1958, 4723 [(3-cyano-2-naphthyl) oxy] acetic acid 59 mg (0.26 mmol) and (3S) -1-{[2- (4-acetylpiperazine-1) obtained in Reference Example 9 The reaction was carried out in the same manner as in Example 13 using 91 mg (0.23 mmol) of -yl) ethyl] sulfonyl} -3- (pyrrolidin-1-ylmethyl) piperazine to obtain 140 mg (89%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.75-2.03 (4H, m), 2.05 (3H, s), 2.95-4.09 (23H, m), 4.44 (1H, br s), 5.05 (1H, d , J = 12.2 Hz), 5.32 (2H, s), 7.47 (1H, t, J = 7.8 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.95 (2H, d, J = 7.8 Hz), 8.08 (1H, s), 8.51 (1H, s), 10.56 (1H, s), 11.71 (1H, s);
IR (KBr) vmax 3430, 2957, 2927, 2570, 2228, 1657, 1428, 1336, 1257, 1155 cm -1 ;
MS (FAB) m / z: 597 (M + H) + .
（実施例１７）
Ｎ－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝－２，４，５－トリクロロアニリン　２塩酸塩
Figure JPOXMLDOC01-appb-C000070
参考例７で得られた２，４，５－トリクロロ－Ｎ－｛２－オキソ－２－［（２Ｓ）－２－（ピロリジン－１－イルメチル）－４－（ビニルスルホニル）ピペラジン－１－イル］エチル｝アニリン８６ｍｇ（０．１７ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物１１２ｍｇ（９３％）を得た。
1H-NMR (DMSO-D6) δ: 1.86-2.02 (4H, m), 2.04 (3H, s),2.90-4.50 (27H, m), 5.05-5.11 (1H, m), 5.80 (1H, s), 7.63 (1H, s), 10.04 (1H, br s);
IR(KBr) vmax 3393, 2926, 2567, 1654, 1595, 1503, 1430, 1334, 1153, 1063, 991 cm-1;
MS(FAB)m/z:623 (M+H)+. (Example 17)
N- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl } -2,4,5-trichloroaniline dihydrochloride
Figure JPOXMLDOC01-appb-C000070
2,4,5-Trichloro-N- {2-oxo-2-[(2S) -2- (pyrrolidin-1-ylmethyl) -4- (vinylsulfonyl) piperazin-1-yl obtained in Reference Example 7 The reaction was carried out in the same manner as in Example 1 using 86 mg (0.17 mmol) of ethyl} aniline to obtain 112 mg (93%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 1.86-2.02 (4H, m), 2.04 (3H, s), 2.90-4.50 (27H, m), 5.05-5.11 (1H, m), 5.80 (1H, s), 7.63 (1H, s), 10.04 (1H, br s);
IR (KBr) vmax 3393, 2926, 2567, 1654, 1595, 1503, 1430, 1334, 1153, 1063, 991 cm -1 ;
MS (FAB) m / z: 623 (M + H) + .
（実施例１８）
Ｎ－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝－４，５－ジクロロ－２－（トリフルオロメチル）アニリン　２塩酸塩
（実施例１８Ａ）
｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］カルバミン酸　ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000071
参考例４で得られたＮ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］グリシン１７０ｍｇ（０．４４ｍｍｏｌ）及び参考例９で得られた（３Ｓ）－１－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－３－（ピロリジン－１－イルメチル）ピペラジン１４０ｍｇ（０．３６ｍｍｏｌ）を用いて実施例１３と同様に反応を行い、目的化合物（フリー体）２１６ｍｇ（８０％）を得た。
1H-NMR (CDCl3) δ: 1.33 (9H, s), 1.64-1.81 (4H, m), 2.09(3H, s), 2.37-3.15 (16H, m), 3.39-3.90 (8.5H, m), 4.51-4.58 (0.5H, m), 4.68-4.95 (2H, m), 7.72 (1H,s),8.08 (1H, s).
（実施例１８Ｂ）
Ｎ－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝－４，５－ジクロロ－２－（トリフルオロメチル）アニリン　２塩酸塩
Figure JPOXMLDOC01-appb-C000072
実施例１８Ａで得られた｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝［４，５－ジクロロ－２－（トリフルオロメチル）フェニル］カルバミン酸　ｔｅｒｔ－ブチル２１６ｍｇ（０．２９ｍｍｏｌ）をジオキサン４ｍＬに溶解し、４規定塩酸／ジオキサン溶液２ｍLを加え、室温で１時間撹拌した。反応溶液を１規定水酸化ナトリウム水溶液で中和し、水相を酢酸エチルで抽出した。得られた有機相を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（ＮＨシリカ，２％メタノール／酢酸エチル）により精製し、目的化合物（フリー体）を９９ｍｇ（５３％）得た。フリー体をジオキサン３ｍＬに溶解し、１規定塩酸／ジオキサン溶液を滴下した後、溶媒を減圧下留去して塩酸塩９０ｍｇを得た。
1H-NMR (DMSO-D6) δ: 1.82-2.02 (4H, m), 2.02 (3H, s),2.87-4.49 (26H, m), 5.04-5.10 (1H, m), 5.93 (1H, br s), 7.29 (1H, s), 7.65 (1H, s), 10.28 (1H, br s),11.98 (1H, br s);
IR(KBr) vmax 3413, 2959, 2555, 2447, 1656, 1611, 1563, 1508, 1429, 1320, 1163,1119, 1057 cm-1;
MS(FAB)m/z:657 (M+H)+. (Example 18)
N- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl } -4,5-dichloro-2- (trifluoromethyl) aniline dihydrochloride (Example 18A)
{2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl} [ 4,5-Dichloro-2- (trifluoromethyl) phenyl] carbamic acid tert-butyl
Figure JPOXMLDOC01-appb-C000071
170 mg (0.44 mmol) of N- (tert-butoxycarbonyl) -N- [4,5-dichloro-2- (trifluoromethyl) phenyl] glycine obtained in Reference Example 4 and Reference Example 9 ( 3S) -1-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -3- (pyrrolidin-1-ylmethyl) piperazine was reacted in the same manner as in Example 13 using 140 mg (0.36 mmol). To obtain 216 mg (80%) of the target compound (free form).
1 H-NMR (CDCl 3 ) δ: 1.33 (9H, s), 1.64-1.81 (4H, m), 2.09 (3H, s), 2.37-3.15 (16H, m), 3.39-3.90 (8.5H, m ), 4.51-4.58 (0.5H, m), 4.68-4.95 (2H, m), 7.72 (1H, s), 8.08 (1H, s).
(Example 18B)
N- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl } -4,5-dichloro-2- (trifluoromethyl) aniline dihydrochloride
Figure JPOXMLDOC01-appb-C000072
{2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl obtained in Example 18A ] 2-oxoethyl} [4,5-dichloro-2- (trifluoromethyl) phenyl] carbamic acid 216 mg (0.29 mmol) of tert-butyl was dissolved in 4 mL of dioxane, and 2 mL of 4N hydrochloric acid / dioxane solution was added, Stir at room temperature for 1 hour. The reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (NH silica, 2% methanol / ethyl acetate) to obtain 99 mg (53%) of the desired compound (free form). The free product was dissolved in 3 mL of dioxane and 1N hydrochloric acid / dioxane solution was added dropwise, and then the solvent was distilled off under reduced pressure to obtain 90 mg of hydrochloride.
1 H-NMR (DMSO-D 6 ) δ: 1.82-2.02 (4H, m), 2.02 (3H, s), 2.87-4.49 (26H, m), 5.04-5.10 (1H, m), 5.93 (1H, br s), 7.29 (1H, s), 7.65 (1H, s), 10.28 (1H, br s), 11.98 (1H, br s);
IR (KBr) vmax 3413, 2959, 2555, 2447, 1656, 1611, 1563, 1508, 1429, 1320, 1163,1119, 1057 cm -1 ;
MS (FAB) m / z: 657 (M + H) + .
（実施例１９） 
（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン　２塩酸塩
Figure JPOXMLDOC01-appb-C000073
参考例８で得られた（２Ｓ）－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］－４－（ビニルスルホニル）ピペラジン１２０ｍｇ（０．２３ｍｍｏｌ）を用いて実施例１と同様に反応を行い、目的化合物１２８ｍｇ（７６％）を得た。
1H-NMR (DMSO-D6) δ: 2.05 (3H, s), 2.12-2.47 (2H, m),2.91-4.10 (23H, m), 4.38-4.49 (1H, m), 4.96-5.55 (4H, m), 7.64 (0.5H, s), 7.79 (0.5H, s), 7.80 (0.5H, s),7.87 (0.5H, s), 10.63 (1H, s), 10.99 (1H, s);
IR(KBr) vmax 3412, 2925, 2554, 1657, 1469, 1429, 1353, 1254, 1155, 1083, 992 cm-1;
MS(FAB)m/z:642 (M+H)+. Example 19
(2S) -4-{[2- (4-Acetylpiperazin-1-yl) ethyl] sulfonyl} -2-{[(3S) -3-fluoropyrrolidin-1-yl] methyl} -1-[(2 , 4,5-Trichlorophenoxy) acetyl] piperazine dihydrochloride
Figure JPOXMLDOC01-appb-C000073
(2S) -2-{[(3S) -3-fluoropyrrolidin-1-yl] methyl} -1-[(2,4,5-trichlorophenoxy) acetyl] -4- () obtained in Reference Example 8 The reaction was carried out in the same manner as in Example 1 using 120 mg (0.23 mmol) of vinylsulfonyl) piperazine to obtain 128 mg (76%) of the target compound.
1 H-NMR (DMSO-D 6 ) δ: 2.05 (3H, s), 2.12-2.47 (2H, m), 2.91-4.10 (23H, m), 4.38-4.49 (1H, m), 4.96-5.55 ( 4H, m), 7.64 (0.5H, s), 7.79 (0.5H, s), 7.80 (0.5H, s), 7.87 (0.5H, s), 10.63 (1H, s), 10.99 (1H, s) ;
IR (KBr) vmax 3412, 2925, 2554, 1657, 1469, 1429, 1353, 1254, 1155, 1083, 992 cm -1 ;
MS (FAB) m / z: 642 (M + H) + .
（実施例２０）
４－［３－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）プロピル］モルホリン　２塩酸塩
（実施例２０Ａ）
（２Ｓ）－４－［（３－クロロプロピル）スルホニル］－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン
Figure JPOXMLDOC01-appb-C000074
参考例６Ｂで得られた（２Ｒ）－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン１１４．２ｍｇ（０．２８０ｍｍｏｌ）を氷冷下ジクロロメタン５ｍＬに溶解し、３―クロロプロパン－１－スルホニルクロリド３７．８μＬ及びトリエチルアミン１５６μＬを加え、室温で終夜撹拌した。反応溶液に飽和食塩水を加え、水相を塩化メチレンで抽出した。得られた有機相を硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（２％メタノール／塩化メチレン）により精製し、目的化合物を１１１ｍｇ（７２％）得た。
1H-NMR (CDCl3) δ: 1.63-1.83 (4H, m), 2.24-2.32 (2H, m),2.45-3.19 (12H, m), 3.43 (0.5H, br t), 3.68 (2H, t, J = 12.1 Hz), 3.70 (1H, d, J = 11.7 Hz), 3.87(1H,d, J = 12.1 Hz), 4.11 (0.5H, br s), 4.47 (0.5H, br s), 4.70-4.95 (2.5H, m), 7.04 (0.5H, br s), 7.09 (0.5H, br s),7.48 (1H, s).
（実施例２０Ｂ）
４－［３－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）プロピル］モルホリン　２塩酸塩
Figure JPOXMLDOC01-appb-C000075
実施例２０Ａで得られた（２Ｓ）－４－［（３－クロロプロピル）スルホニル］－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン７２．２ｍｇ（０．１３ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド２ｍＬに溶解し、モルホリン５８μＬ及びトリエチルアミン９２μＬを加え、６０度で終夜加熱撹拌をした。反応溶液に酢酸エチルを加え、有機相を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（５％メタノール／塩化メチレン）により精製し、目的化合物（フリー体）を５８ｍｇ（７４％）得た。フリー体をジオキサン２ｍＬに溶解し、４規定塩酸／ジオキサン溶液１ｍＬを滴下した後、溶媒を減圧下留去して塩酸塩７０ｍｇを得た。
1H-NMR (DMSO-D6) δ: 1.85-2.04 (4H, m), 2.12 (2H, m),2.96-3.99 (24H, m), 4.90-5.32 (3H, m), 7.66 (1H, s), 7.76 (1H, s);
IR(KBr) vmax 3427, 2952, 2660, 2578, 2465, 1667, 1584, 1467, 1344, 1321, 1250,1152, 1086, 991, 952, 730, 678 cm-1;
MS(FAB)m/z:597 (M+H)+. (Example 20)
4- [3-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) propyl] morpholine dihydrochloride (Example 20A)
(2S) -4-[(3-Chloropropyl) sulfonyl] -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine
Figure JPOXMLDOC01-appb-C000074
114.2 mg (0.280 mmol) of (2R) -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine obtained in Reference Example 6B was dissolved in dichloromethane under ice-cooling. After dissolving in 5 mL, 37.8 μL of 3-chloropropane-1-sulfonyl chloride and 156 μL of triethylamine were added, and the mixture was stirred at room temperature overnight. Saturated saline was added to the reaction solution, and the aqueous phase was extracted with methylene chloride. The obtained organic phase was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (2% methanol / methylene chloride) to obtain 111 mg (72%) of the target compound.
1 H-NMR (CDCl 3 ) δ: 1.63-1.83 (4H, m), 2.24-2.32 (2H, m), 2.45-3.19 (12H, m), 3.43 (0.5H, br t), 3.68 (2H, t, J = 12.1 Hz), 3.70 (1H, d, J = 11.7 Hz), 3.87 (1H, d, J = 12.1 Hz), 4.11 (0.5H, br s), 4.47 (0.5H, br s), 4.70-4.95 (2.5H, m), 7.04 (0.5H, br s), 7.09 (0.5H, br s), 7.48 (1H, s).
(Example 20B)
4- [3-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) propyl] morpholine dihydrochloride
Figure JPOXMLDOC01-appb-C000075
(2S) -4-[(3-Chloropropyl) sulfonyl] -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] piperazine 72 obtained in Example 20A .2 mg (0.13 mmol) was dissolved in 2 mL of N, N-dimethylformamide, 58 μL of morpholine and 92 μL of triethylamine were added, and the mixture was heated and stirred at 60 ° C. overnight. Ethyl acetate was added to the reaction solution, and the organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (5% methanol / methylene chloride) to obtain 58 mg (74%) of the desired compound (free form). The free product was dissolved in 2 mL of dioxane, and 1 mL of 4N hydrochloric acid / dioxane solution was added dropwise, and then the solvent was distilled off under reduced pressure to obtain 70 mg of hydrochloride.
1 H-NMR (DMSO-D 6 ) δ: 1.85-2.04 (4H, m), 2.12 (2H, m), 2.96-3.99 (24H, m), 4.90-5.32 (3H, m), 7.66 (1H, s), 7.76 (1H, s);
IR (KBr) vmax 3427, 2952, 2660, 2578, 2465, 1667, 1584, 1467, 1344, 1321, 1250,1152, 1086, 991, 952, 730, 678 cm -1 ;
MS (FAB) m / z: 597 (M + H) + .
（試験例１）ウロテンシンＩＩ受容体結合阻害の評価
　ヒトウロテンシンＩＩ受容体安定発現細胞（Ｅｕｒｏｓｃｒｅｅｎ社）と［１２５Ｉ］ウロテンシンＩＩ（ＧＥヘルスケア・バイオサイエンス株式会社）を用いたｌｉｇａｎｄ　ｂｉｎｄｉｎｇ　ａｓｓａｙを以下の通りに実施した。
　［１２５Ｉ］ウロテンシンＩＩ凍結乾燥品１ボトル（９２５ｋＢｑ）に２５０μＬの蒸留水を加えて溶解し、使用時まで－２０℃に保管した。無標識ヒトウロテンシンＩＩ（株式会社ペプチド研究所）は蒸留水で溶解して４００μＭ溶液とし、使用時まで－２０℃に保管した。また、ａｓｓａｙ　ｂｕｆｆｅｒ［２５ｍＭ　ＨＥＰＥＳ（４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホニックアシッド），ｐＨ７．６，５ｍＭ　ＭｇＣｌ２，０．１％（ｗ／ｖ）ＮａＮ３，０．５％（ｗ／ｖ）ウシ血清アルブミン（シグマアルドリッチジャパン社）］およびｗａｓｈ　ｂｕｆｆｅｒ［２５ｍＭ　ＨＥＰＥＳ，ｐＨ７．６，５ｍＭ　ＭｇＣｌ２，１ｍＭ　ＣａＣｌ２，０．５Ｍ　ＮａＣｌ，０．１％（ｗ／ｖ）ＮａＮ３，０．５％（ｗ／ｖ）ウシ血清アルブミン（シグマアルドリッチジャパン社）］を作製し、使用時まで４℃に保存した。
　ヒトウロテンシンＩＩ受容体安定発現細胞は、維持培地［１０％（ｖ／ｖ）ウシ胎児血清（ＥＱＵＩＴＥＣＨ－ＢＩＯ社），１００ｕｎｉｔｓ／ｍＬ　ｐｅｎｉｃｉｌｌｉｎ　Ｇ　ｓｏｄｉｕｍ，１００μｇ／ｍＬ　ｓｔｒｅｐｔｏｍｙｃｉｎ　ｓｕｌｆａｔｅ，および４００μｇ／ｍＬ　Ｇｅｎｅｔｉｃｉｎ（Ｉｎｖｉｔｒｏｇｅｎ社）を含むＦ－１２培地（Ｉｎｖｉｔｒｏｇｅｎ社）］にて維持した。アッセイの前日に、ヒトウロテンシンＩＩ受容体安定発現細胞を０．２５％Ｔｒｙｐｓｉｎ－ＥＤＴＡ（Ｉｎｖｉｔｒｏｇｅｎ社）で剥離し、Ｇｅｎｅｔｉｃｉｎを除いた維持培地に再懸濁後、９６ウェル平底プレートに４０，０００細胞／ウェルで播種して一晩培養した。
　９６ウェル丸底プレートに分注しておいた検体にａｓｓａｙ　ｂｕｆｆｅｒを加えて希釈し、終濃度の１０倍濃度からなるサンプル溶液を作製した。コントロールのウェルには検体と同量のＤＭＳＯ：ＭｅＯＨ＝７：３を分注した。その内、半数のウェルにはａｓｓａｙ　ｂｕｆｆｅｒを加えて上記と同様に希釈し、残り半数のウェルには５μＭの無標識ヒトウロテンシンＩＩを含むａｓｓａｙ　ｂｕｆｆｅｒを加えて上記と同様に希釈した。これらをコントロール溶液とした。
　細胞を播種したプレートを取り出し、２００μＬのＦ－１２培地で細胞を３回洗浄した。ａｓｓａｙ　ｂｕｆｆｅｒを８０μＬ添加し、更にサンプル溶液またはコントロール溶液を１０μＬ添加した。プレートを穏やかに振盪して良く混和し、室温に１０分間静置した。ａｓｓａｙ　ｂｕｆｆｅｒで２５倍に希釈した［１２５Ｉ］ウロテンシンＩＩ溶液を１０μＬ添加後（終濃度０．２ｎＭ）、プレートを穏やかに振盪して良く混和し、室温に９０分間静置した。
　３００μＬのｗａｓｈ　ｂｕｆｆｅｒで細胞を５回洗浄した後、０．１％（ｖ／ｖ）Ｔｒｉｔｏｎ　Ｘ－１００（シグマアルドリッチジャパン社）を含む１Ｎ　ＮａＯＨ溶液を１５０μＬ添加し、プレートを１０分間振盪して細胞を溶解した。細胞溶解液の全量をプラスチックチューブに移し、ＲＩＡＳＴＡＲ　５４２０（株式会社パーキンエルマージャパン社）を用いて残存する放射活性（ｃｐｍ）を測定した後、以下の計算式に基づいて阻害率（％）を算出した。
　阻害率（％）＝１００×［１－（Ａ－Ｂ）／（Ｃ－Ｂ）］
　Ａ：検体を加えたウェルの放射活性
　Ｂ：無標識ヒトウロテンシンＩＩを加えたコントロールのウェルの放射活性の平均値
　Ｃ：無標識ヒトウロテンシンＩＩを加えなかったコントロールのウェルの放射活性の平均値
　結晶サンプルのＩＣ５０を求める際は、結晶サンプルをＤＭＳＯで溶解した後、ＤＭＳＯ：ＭｅＯＨ＝７：３で順次希釈して、終濃度の１０００倍濃度からなる段階希釈系列を作製した。これをａｓｓａｙ　ｂｕｆｆｅｒで１００倍希釈してサンプル溶液とし、上記の方法に従ってアッセイを実施した。 (Test Example 1) Evaluation of inhibition of binding of urotensin II receptor Binding binding assay using human urotensin II receptor stably expressing cells (Euroscreen) and [ 125 I] urotensin II (GE Healthcare Biosciences) It carried out as follows.
250 [mu] L of distilled water was added to [ 125 I] urotensin II lyophilized product (925 kBq) and dissolved, and stored at −20 ° C. until use. Unlabeled human urotensin II (Peptide Institute, Inc.) was dissolved in distilled water to make a 400 μM solution and stored at −20 ° C. until use. Further, assay buffer [25 mM HEPES (4- (2-hydroxyethyl) -1-piperazine ethane sulfonic acid), pH 7.6, 5 mM MgCl 2 , 0.1% (w / v) NaN 3 , 0.5% (W / v) bovine serum albumin (Sigma Aldrich Japan)] and wash buffer [25 mM HEPES, pH 7.6, 5 mM MgCl 2 , 1 mM CaCl 2 , 0.5 M NaCl, 0.1% (w / v) NaN 3 , 0.5% (w / v) bovine serum albumin (Sigma Aldrich Japan)] was prepared and stored at 4 ° C. until use.
Human urotensin II receptor stably expressing cells were maintained in a maintenance medium [10% (v / v) fetal bovine serum (EQUITECH-BIO), 100 units / mL penicillin G sodium, 100 μg / mL streptomycin sulfate, and 400 μg / mL Geneticin ( F-12 medium containing Invitrogen) (Invitrogen)]. On the day before the assay, human urotensin II receptor stably expressing cells were detached with 0.25% Trypsin-EDTA (Invitrogen), resuspended in maintenance medium excluding Geneticin, and then 40,000 in a 96-well flat-bottom plate. Cells / well were seeded and cultured overnight.
An assay buffer was added to the specimen dispensed in the 96-well round bottom plate and diluted to prepare a sample solution having a concentration 10 times the final concentration. The same amount of DMSO: MeOH = 7: 3 as the sample was dispensed into the control wells. Among them, assay buffer was added to half of the wells and diluted in the same manner as described above, and assay buffer containing 5 μM of unlabeled human urotensin II was added to the other half of the wells and diluted as described above. These were used as control solutions.
The plate seeded with the cells was removed and the cells were washed 3 times with 200 μL of F-12 medium. 80 μL of assay buffer was added, and 10 μL of sample solution or control solution was further added. The plate was gently shaken to mix well and left at room temperature for 10 minutes. After adding 10 μL of [ 125 I] urotensin II solution diluted 25-fold with assay buffer (final concentration 0.2 nM), the plate was gently shaken to mix well, and allowed to stand at room temperature for 90 minutes.
After washing the cells 5 times with 300 μL of wash buffer, 150 μL of 1N NaOH solution containing 0.1% (v / v) Triton X-100 (Sigma Aldrich Japan) was added, and the plate was shaken for 10 minutes. Was dissolved. After transferring the entire amount of the cell lysate to a plastic tube and measuring the remaining radioactivity (cpm) using RIASTAR 5420 (Perkin Elmer Japan Co., Ltd.), the inhibition rate (%) is calculated based on the following formula. did.
Inhibition rate (%) = 100 × [1− (AB) / (CB)]
A: Radioactivity of wells to which sample was added B: Average radioactivity of control wells to which unlabeled human urotensin II was added C: Average radioactivity of control wells to which unlabeled human urotensin II was not added Value When determining the IC 50 of the crystal sample, the crystal sample was dissolved in DMSO and then diluted sequentially with DMSO: MeOH = 7: 3 to prepare a serial dilution series consisting of 1000 times the final concentration. This was diluted 100-fold with an assay buffer to obtain a sample solution, and the assay was performed according to the method described above.
　実施例１から２０の化合物のＩＣ５０値を表１に示す。
Figure JPOXMLDOC01-appb-T000076
 　以上の通り、本発明の化合物は優れたウロテンシンＩＩ受容体結合阻害活性を示し、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害、糖尿病などの治療または予防のための医薬として有用である。 The IC 50 values for the compounds of Examples 1 to 20 are shown in Table 1.
Figure JPOXMLDOC01-appb-T000076
 As described above, the compound of the present invention exhibits excellent urotensin II receptor binding inhibitory activity and is congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, Stenosis, asthma, fibrosis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, pain, neuromuscular dysfunction It is useful as a medicament for the treatment or prevention of diabetes and the like.
（試験例２）カニクイザル摘出血管におけるヒトウロテンシンＩＩ誘発収縮の阻害評価　カニクイザルを麻酔し、放血した。大動脈を摘出した後、切開し、３～５ｍｍのリングを切り取った。内腔にタコ糸を通し、内膜表面を擦って内皮を除去した。
　３７℃に保ったクレブス-ヘンゼライト（Ｋｒｅｂｓ-Ｈｅｎｓｅｌｅｉｔ）液（ＮａＣｌ １１２ｍＭ、ＫＣｌ ４．７ｍＭ、ＭｇＳＯ４ １．２ｍＭ、ＫＨ２ＰＯ４１．２ｍＭ、ＮａＨＣＯ３ ２５.０ｍＭ、ＣａＣｌ２ ２．５ｍＭ、グルコース１１.０ｍＭ、およびｉｎｄｏｍｅｔｈａｃｉｎ ０．０１μＭ）を満たした２０ｍＬの摘出臓器浴中に前記リングを懸垂し、９５％のＯ２と５％のＣＯ２を通気した。リングを力トランスデューサ（ＦＤピックアップ：日本光電（株）社製）に結合し、静止張力２ｇまで牽引しながら、等尺性張力を記録した。試験化合物またはそのベヒクルとともに３０分間インキュベートしたのち、累積量のヒトウロテンシンＩＩ（１０-１２Ｍ～１０-６Ｍ）を加え、試験化合物の機能拮抗作用を濃度比、すなわち、試験化合物１０－５Ｍ濃度で誘発されるＥＣ５０の右へのシフトを測定することで評価した。ＥＣ５０は、半分の極大収縮を得るのに必要なウロテンシンの濃度であり、ＥＣ５０値のシフトの度合いをヒトウロテンシンＩＩ拮抗の指標として用いた。
なお、ＫＣｌ６０ｍＭ＋クレブス－ヘンゼライト液における最大収縮を１００％として、ヒトウロテンシンＩＩ添加時の収縮を算出した。評価結果を図１に示した。図１における試験化合物とは本発明の実施例１の化合物を示す。
　以上の通り、本発明の化合物はサルの大動脈においてウロテンシンＩＩに誘発される血管収縮を阻害することから、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害、糖尿病などの治療または予防のための医薬として有用であると考えられる。 (Test Example 2) Evaluation of inhibition of human urotensin II-induced contraction in cynomolgus monkey-extracted blood vessels Cynomolgus monkeys were anesthetized and exsanguinated. After removing the aorta, an incision was made and a 3-5 mm ring was cut out. An octopus thread was passed through the lumen, and the endothelium surface was rubbed to remove the endothelium.
Krebs-Henseleit solution (NaCl 112 mM, KCl 4.7 mM, MgSO 4 1.2 mM, KH 2 PO 4 1.2 mM, NaHCO 3 25.0 mM, CaCl 2 2.5 mM, glucose, maintained at 37 ° C. The ring was suspended in a 20 mL excised organ bath filled with 11.0 mM and indomethacin (0.01 μM) and aerated with 95% O 2 and 5% CO 2 . The ring was coupled to a force transducer (FD pickup: manufactured by Nihon Kohden Co., Ltd.), and isometric tension was recorded while pulling to a static tension of 2 g. After incubating with the test compound or its vehicle for 30 minutes, a cumulative amount of human urotensin II (10 −12 M to 10 −6 M) is added, and the functional antagonism of the test compound is measured by concentration ratio, ie test compound 10 −5. Evaluated by measuring the right shift of EC 50 induced by M concentration. EC 50 is the concentration of urotensin necessary to obtain half maximum contraction, and the degree of shift of EC 50 value was used as an indicator of human urotensin II antagonism.
The contraction when human urotensin II was added was calculated with the maximum contraction in KCl 60 mM + Krebs-Henseleit solution being 100%. The evaluation results are shown in FIG. The test compound in FIG. 1 represents the compound of Example 1 of the present invention.
As described above, since the compound of the present invention inhibits urotensin II-induced vasoconstriction in the monkey aorta, congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic kidney Disease, renal failure, restenosis, asthma, fibrosis, atherosclerosis, lipid metabolism disorder, addiction, schizophrenia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorder, It is considered useful as a medicament for the treatment or prevention of pain, neuromuscular dysfunction, diabetes and the like.
（製剤例１）
　実施例の化合物（１０ｍｇ）、コロイド性二酸化ケイ素（０．２ｍｇ）、ステアリン酸マグネシウム（５ｍｇ）、微結晶性セルロース（１７５ｍｇ）、デンプン（１０ｍｇ）、およびラクトース（９９．８ｍｇ）を用いて、常法に従って錠剤を製造する。得られた錠剤には、必要に応じてコーティングを施すことができる。 (Formulation example 1)
Using the compound of Example (10 mg), colloidal silicon dioxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (175 mg), starch (10 mg), and lactose (99.8 mg), Tablets are produced according to the method. The obtained tablets can be coated as necessary.
　本発明の一般式（Ｉ）または（Ｉａ）で表される化合物またはその薬理上許容される塩は、優れたウロテンシンＩＩ受容体拮抗作用を有し、医薬として、特に、鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害、糖尿病などの治療または予防のための医薬として有用である。 The compound represented by the general formula (I) or (Ia) of the present invention or a pharmacologically acceptable salt thereof has an excellent urotensin II receptor antagonistic action, and is used as a pharmaceutical, particularly congestive heart failure, ischemic. Heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis, dyslipidemia, addiction, schizophrenia, dementia, It is useful as a medicament for the treatment or prevention of Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorders, pain, neuromuscular dysfunction, diabetes and the like.

Claims (17)

  1. 　一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、環Ａは、
    Figure JPOXMLDOC01-appb-C000002
    を示し（ここで、Ｘ１、Ｘ２、Ｘ３およびＸ４はそれぞれ独立して、水素原子、ハロゲノ基、水酸基、シアノ基、アミノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ１～Ｃ６アルコキシ基、Ｃ３～Ｃ８シクロアルキル基またはフェニル基を示し、＊はＹ１との結合を示す。）；
    Ｙ１およびＹ２は、次の（ａ）または（ｂ）を示し
    　（ａ）Ｙ１は－Ｏ－、－ＮＨ－、－Ｓ－または－ＣＲ１１Ｒ１２－を示し、Ｙ２は－ＣＲ１３Ｒ１４－を示す。
    　（ｂ）Ｙ１は－ＣＲ１５Ｒ１６－を示し、Ｙ２は－Ｏ－、－ＮＨ－または－Ｓ－を示す。
    （ここで、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、Ｒ１５およびＲ１６はそれぞれ独立して、
    水素原子、ハロゲノ基、水酸基またはＣ１～Ｃ６アルキル基を示す。）；
    Ｑは、１～３個のＣ１～Ｃ６アルキル基で置換されていてもよい、Ｃ２～Ｃ４アルキレン基を示し；
    Ｒ１およびＲ２は、次の（ｃ）または（ｄ）を示し
    　（ｃ）Ｒ１およびＲ２はそれぞれ独立して、ハロゲノ基および水酸基からなる群より選ばれる１～３個で置換されていてもよい、Ｃ１～Ｃ６アルキル基を示す。
    　（ｄ）Ｒ１およびＲ２は、それらが結合している窒素原子と一緒になって、ハロゲノ基および水酸基からなる群より選ばれる１～６個で置換されていてもよい、ピロリジニル基、ピペリジニル基またはモルホリニル基を示す。；
    Ｒ３およびＲ４は、次の（ｅ）または（ｆ）を示す。
    　（ｅ）Ｒ３およびＲ４はそれぞれ独立して、水素原子、または、ハロゲノ基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基およびＣ２～Ｃ６アルカノイルアミノ基からなる群より選ばれる１～３個で置換されていてもよいＣ１～Ｃ６アルキル基を示す。
    　（ｆ）Ｒ３およびＲ４は、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい４～１０員の含窒素複素環基を示す。］で表される化合物、またはその薬理上許容される塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [Wherein ring A is
    Figure JPOXMLDOC01-appb-C000002
    Wherein X 1 , X 2 , X 3 and X 4 are each independently a hydrogen atom, a halogeno group, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, A C1-C6 alkoxy group, a C3-C8 cycloalkyl group or a phenyl group, and * represents a bond with Y 1 );
    Y 1 and Y 2 represent the following (a) or (b): (a) Y 1 represents —O—, —NH—, —S— or —CR 11 R 12 —, and Y 2 represents —CR 13 R 14 — is shown.
    (B) Y 1 represents —CR 15 R 16 —, and Y 2 represents —O—, —NH— or —S—.
    (Where R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently
    A hydrogen atom, a halogeno group, a hydroxyl group or a C1-C6 alkyl group; );
    Q represents a C2-C4 alkylene group which may be substituted with 1 to 3 C1-C6 alkyl groups;
    R 1 and R 2 represent the following (c) or (d): (c) R 1 and R 2 are each independently substituted with 1 to 3 selected from the group consisting of a halogeno group and a hydroxyl group C1 to C6 alkyl group which may be used.
    (D) R 1 and R 2 together with the nitrogen atom to which they are attached, may be substituted with 1 to 6 groups selected from the group consisting of a halogeno group and a hydroxyl group, a pyrrolidinyl group, piperidinyl A group or a morpholinyl group. ;
    R 3 and R 4 represent the following (e) or (f).
    (E) R 3 and R 4 are each independently a hydrogen atom, a halogeno group, a C3-C8 cycloalkyl group, a carboxy group, a carbamoyl group, a mono C1-C6 alkylcarbamoyl group, or a di-C1-C6 alkylcarbamoyl group. A hydroxy group, a C1-C6 alkoxy group, an amino group, a mono-C1-C6 alkylamino group, a di-C1-C6 alkylamino group, and a C2-C6 alkanoylamino group may be substituted with 1-3. Good C1-C6 alkyl groups are indicated.
    (F) R 3 and R 4 together with the nitrogen atom to which they are attached, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, C2-C6 alkanoyl group, carbamoyl group, mono-C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino And a 4- to 10-membered nitrogen-containing heterocyclic group which may be substituted with 1 to 3 selected from the group consisting of a group, a C2-C6 alkanoylamino group, a C1-C6 alkylsulfonyl group and an oxo group. Or a pharmacologically acceptable salt thereof.
  2. 　一般式（Ｉａ）
    Figure JPOXMLDOC01-appb-C000003
    ［式中、環Ａ、Ｙ１、Ｙ２、Ｑ、Ｒ１、Ｒ２、Ｒ３およびＲ４は、請求項１と同様のものを示す。］で表される化合物、またはその薬理上許容される塩。     Formula (Ia)
    Figure JPOXMLDOC01-appb-C000003
    [Wherein, ring A, Y 1 , Y 2 , Q, R 1 , R 2 , R 3 and R 4 are the same as those in claim 1. Or a pharmacologically acceptable salt thereof.
  3. 　環Ａが、
    Figure JPOXMLDOC01-appb-C000004
    （ここで、Ｘ１、Ｘ２、Ｘ３および＊は請求項１と同じものを示す。）である、請求項１または２に記載の化合物、またはその薬理上許容される塩。     Ring A is
    Figure JPOXMLDOC01-appb-C000004
    (Wherein X 1 , X 2 , X 3 and * are the same as those in claim 1), or a pharmacologically acceptable salt thereof according to claim 1 or 2.
  4. 　Ｘ１がハロゲノ基またはシアノ基であり、Ｘ２およびＸ３がともにハロゲノ基である、請求項３に記載の化合物、またはその薬理上許容される塩。 The compound according to claim 3, or a pharmacologically acceptable salt thereof, wherein X 1 is a halogeno group or a cyano group, and X 2 and X 3 are both halogeno groups.
  5. 　Ｙ１が－Ｏ－、－ＮＨ－、－Ｓ－または－ＣＲ１１Ｒ１２－であり、Ｙ２が－ＣＲ１３Ｒ１４－である（ここで、Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は請求項１と同じものを示す。）、請求項１から４のいずれか１項に記載の化合物、またはその薬理上許容される塩。 Y 1 is —O—, —NH—, —S— or —CR 11 R 12 —, and Y 2 is —CR 13 R 14 — (where R 11 , R 12 , R 13 and R 14 Represents the same as in claim 1.), The compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof.
  6. 　Ｙ１が－Ｏ－または－ＮＨ－であり、Ｙ２が－ＣＲ１３Ｒ１４－である（ここで、Ｒ１３およびＲ１４は請求項１と同じものを示す。）、請求項１から４のいずれか１項に記載の化合物、またはその薬理上許容される塩。 Y 1 is —O— or —NH—, and Y 2 is —CR 13 R 14 — (wherein R 13 and R 14 are the same as in claim 1), Or a pharmacologically acceptable salt thereof.
  7. 　Ｑが、－ＣＨ２－ＣＨ２－である、請求項１から６のいずれか１項に記載の化合物、またはその薬理上許容される塩。 The compound according to any one of claims 1 to 6, or a pharmacologically acceptable salt thereof, wherein Q is -CH 2 -CH 2- .
  8. 　Ｒ１およびＲ２が、それらが結合している窒素原子と一緒になって、ハロゲノ基および水酸基からなる群より選ばれる１～６個で置換されていてもよいピロリジニル基を示す、請求項１から７のいずれか１項に記載の化合物、またはその薬理上許容される塩。 2. R 1 and R 2 together with the nitrogen atom to which they are attached represent a pyrrolidinyl group optionally substituted by 1 to 6 selected from the group consisting of a halogeno group and a hydroxyl group 8. The compound according to any one of 7 to 7, or a pharmacologically acceptable salt thereof.
  9. 　Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい４～１０員の含窒素複素環基を示す、請求項１から８のいずれか１項に記載の化合物、またはその薬理上許容される塩。 R 3 and R 4 together with the nitrogen atom to which they are attached, are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, a C2-C6 Alkanoyl group, carbamoyl group, mono C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2 9. A 4- to 10-membered nitrogen-containing heterocyclic group optionally substituted with 1 to 3 selected from the group consisting of a C6 alkanoylamino group, a C1 to C6 alkylsulfonyl group and an oxo group. Or a pharmacologically acceptable salt thereof.
  10. 　Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、ハロゲノ基、Ｃ１～Ｃ６アルキル基、ハロゲノＣ１～Ｃ６アルキル基、Ｃ３～Ｃ８シクロアルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、モノＣ１～Ｃ６アルキルカルバモイル基、ジＣ１～Ｃ６アルキルカルバモイル基、水酸基、Ｃ１～Ｃ６アルコキシ基、アミノ基、モノＣ１～Ｃ６アルキルアミノ基、ジＣ１～Ｃ６アルキルアミノ基、Ｃ２～Ｃ６アルカノイルアミノ基、Ｃ１～Ｃ６アルキルスルホニル基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい、アゼチジニル基、ピロリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、ホモピペリジニル基およびホモピペラジニル基からなる群より選ばれるいずれか１つの基を示す、請求項１から８のいずれか１項に記載の化合物、またはその薬理上許容される塩。 R 3 and R 4 together with the nitrogen atom to which they are attached, are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C3-C8 cycloalkyl group, a carboxy group, a C2-C6 Alkanoyl group, carbamoyl group, mono C1-C6 alkylcarbamoyl group, di-C1-C6 alkylcarbamoyl group, hydroxyl group, C1-C6 alkoxy group, amino group, mono-C1-C6 alkylamino group, di-C1-C6 alkylamino group, C2 An azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, which may be substituted with 1 to 3 selected from the group consisting of a -C6 alkanoylamino group, a C1-C6 alkylsulfonyl group and an oxo group , Homopiperidinyl group and homopiperazinyl group It indicates any one group selected from the group that the compound or a pharmacologically acceptable salt thereof, as claimed in any one of claims 1 to 8.
  11. 　Ｒ３およびＲ４が、それらが結合している窒素原子と一緒になって、Ｃ１～Ｃ６アルキル基、カルボキシ基、Ｃ２～Ｃ６アルカノイル基、カルバモイル基、水酸基、アミノ基、Ｃ２～Ｃ６アルカノイルアミノ基およびオキソ基からなる群より選ばれる１～３個で置換されていてもよい、ピペリジニル基またはピペラジニル基を示す、請求項１から８のいずれか１項に記載の化合物、またはその薬理上許容される塩。 R 3 and R 4 together with the nitrogen atom to which they are attached, a C1-C6 alkyl group, a carboxy group, a C2-C6 alkanoyl group, a carbamoyl group, a hydroxyl group, an amino group, a C2-C6 alkanoylamino group And a pharmacologically acceptable salt thereof, or a pharmacologically acceptable compound thereof, which represents a piperidinyl group or piperazinyl group optionally substituted with 1 to 3 groups selected from the group consisting of oxo groups and Salt.
  12. 　（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン、４－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］モルホリン、４－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］チオモルホリン、Ｎ，Ｎ－ジメチル－２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エタンアミン、２，２’－｛［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］イミノ｝ジエタノール、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－４－オール、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピロリジン－３－オール、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］アゼチジン－３－オール、Ｎ－｛１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピロリジン－３－イル｝アセトアミド、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペラジン－２－オン、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］－１，４－ジアゼパン－５－オン、１－［２－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）エチル］ピペリジン－３－カルボン酸、（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－１－［（２－ブロモ－４，５－ジクロロフェノキシ）アセチル］－２－（ピロリジン－１－イルメチル）ピペラジン、２－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエトキシ｝－４，５－ジクロロベンゾニトリル、（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－１－｛［（３－クロロ－２－ナフチル）オキシ］アセチル｝－２－（ピロリジン－１－イルメチル）ピペラジン、３－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエトキシ｝－２－ナフトニトリル、Ｎ－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝－２，４，５－トリクロロアニリン、Ｎ－｛２－［（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－（ピロリジン－１－イルメチル）ピペラジン－１－イル］－２－オキソエチル｝－４，５－ジクロロ－２－（トリフルオロメチル）アニリン、（２Ｓ）－４－｛［２－（４－アセチルピペラジン－１－イル）エチル］スルホニル｝－２－｛［（３Ｓ）－３－フルオロピロリジン－１－イル］メチル｝－１－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン、および、４－［３－（｛（３Ｓ）－３－（ピロリジン－１－イルメチル）－４－［（２，４，５－トリクロロフェノキシ）アセチル］ピペラジン－１－イル｝スルホニル）プロピル］モルホリンからなる群より選ばれる請求項１に記載の化合物、またはその薬理上許容される塩。 (2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) -1-[(2,4,5-trichlorophenoxy) acetyl] Piperazine, 4- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] morpholine, 4- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] thiomorpholine, N , N-dimethyl-2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} s Phonyl) ethanamine, 2,2 ′-{[2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} Sulfonyl) ethyl] imino} diethanol, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} Sulfonyl) ethyl] piperidin-4-ol, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazine-1- Yl} sulfonyl) ethyl] pyrrolidin-3-ol, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) Cetyl] piperazin-1-yl} sulfonyl) ethyl] azetidin-3-ol, N- {1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,4 5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] pyrrolidin-3-yl} acetamide, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[( 2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperazin-2-one, 1- [2-({(3S) -3- (pyrrolidin-1-ylmethyl) -4- [(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] -1,4-diazepan-5-one, 1- [2-({(3S) -3- (pyro Lysine-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) acetyl] piperazin-1-yl} sulfonyl) ethyl] piperidine-3-carboxylic acid, (2S) -4-{[2- ( 4-acetylpiperazin-1-yl) ethyl] sulfonyl} -1-[(2-bromo-4,5-dichlorophenoxy) acetyl] -2- (pyrrolidin-1-ylmethyl) piperazine, 2- {2-[( 2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethoxy} -4,5- Dichlorobenzonitrile, (2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -1-{[(3-chloro-2-naphthyl) oxy] ace L} -2- (pyrrolidin-1-ylmethyl) piperazine, 3- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidine- 1-ylmethyl) piperazin-1-yl] -2-oxoethoxy} -2-naphthonitrile, N- {2-[(2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] Sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl} -2,4,5-trichloroaniline, N- {2-[(2S) -4-{[2- ( 4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2- (pyrrolidin-1-ylmethyl) piperazin-1-yl] -2-oxoethyl} -4,5-dichloro-2- (trifluoromethyl) ani (2S) -4-{[2- (4-acetylpiperazin-1-yl) ethyl] sulfonyl} -2-{[(3S) -3-fluoropyrrolidin-1-yl] methyl} -1- [ (2,4,5-trichlorophenoxy) acetyl] piperazine and 4- [3-({(3S) -3- (pyrrolidin-1-ylmethyl) -4-[(2,4,5-trichlorophenoxy) The compound according to claim 1, or a pharmacologically acceptable salt thereof, selected from the group consisting of (acetyl) piperazin-1-yl} sulfonyl) propyl] morpholine.
  13. 　請求項１から１２のいずれか１項に記載の化合物、またはその薬理学上許容される塩を含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof.
  14. 　ウロテンシンＩＩ受容体拮抗作用により、治療または予防され得る疾患の治療または予防のための請求項１３に記載された医薬。 The medicament according to claim 13, for treating or preventing a disease that can be treated or prevented by urotensin II receptor antagonism.
  15. 　鬱血性心不全、虚血性心疾患、心不整脈、本態性高血圧、肺性高血圧、糖尿病性腎症、腎不全、再狭窄、喘息、線維症、アテローム性動脈硬化症、脂質代謝異常、依存症、統合失調症、認知症、アルツハイマー病、不安症、ストレス、うつ病、パーキンソン病、運動障害、疼痛、神経筋機能障害または糖尿病の治療または予防のための請求項１３に記載された医薬。 Congestive heart failure, ischemic heart disease, cardiac arrhythmia, essential hypertension, pulmonary hypertension, diabetic nephropathy, renal failure, restenosis, asthma, fibrosis, atherosclerosis, dyslipidemia, dependence, integration 14. A medicament according to claim 13 for the treatment or prevention of ataxia, dementia, Alzheimer's disease, anxiety, stress, depression, Parkinson's disease, movement disorders, pain, neuromuscular dysfunction or diabetes.
  16. 　疾患の治療または予防のための医薬を製造するための請求項１から１２のいずれか１項に記載の化合物、またはその薬理上許容される塩の使用。 Use of the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof for the manufacture of a medicament for treatment or prevention of a disease.
  17. 　請求項１から１２のいずれか１項に記載の化合物、またはその薬理上許容される塩の薬理学的有効量を人に投与することにより疾患を治療または予防する方法。 A method for treating or preventing a disease by administering to a human a pharmacologically effective amount of the compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof.
PCT/JP2010/051129 2009-01-30 2010-01-28 Urotensin-ii receptor antagonists WO2010087399A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-018987 2009-01-30
JP2009018987 2009-01-30

Publications (1)

Publication Number Publication Date
WO2010087399A1 true WO2010087399A1 (en) 2010-08-05

Family

ID=42395657

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/051129 WO2010087399A1 (en) 2009-01-30 2010-01-28 Urotensin-ii receptor antagonists

Country Status (1)

Country Link
WO (1) WO2010087399A1 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011026241A1 (en) * 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Substituted heterocyclic derivatives for the treatment of pain and epilepsy
JP2015519308A (en) * 2012-04-10 2015-07-09 ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア Cancer treatment compositions and methods
US9745319B2 (en) 2013-03-15 2017-08-29 Araxes Pharma Llc Irreversible covalent inhibitors of the GTPase K-Ras G12C
US9810690B2 (en) 2015-10-19 2017-11-07 Araxes Pharma Llc Method for screening inhibitors of Ras
US9840516B2 (en) 2013-10-10 2017-12-12 Araxes Pharma Llc Substituted quinazolines as inhibitors of KRAS G12C
US9862701B2 (en) 2014-09-25 2018-01-09 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US9926267B2 (en) 2013-03-15 2018-03-27 Araxes Pharma Llc Covalent inhibitors of K-Ras G12C
US9988357B2 (en) 2015-12-09 2018-06-05 Araxes Pharma Llc Methods for preparation of quinazoline derivatives
US10011600B2 (en) 2014-09-25 2018-07-03 Araxes Pharma Llc Methods and compositions for inhibition of Ras
US10111874B2 (en) 2014-09-18 2018-10-30 Araxes Pharma Llc Combination therapies for treatment of cancer
US10144724B2 (en) 2015-07-22 2018-12-04 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
CN109134204A (en) * 2018-11-16 2019-01-04 白银棓诺新材料有限公司 The synthetic method of the fluoro- 5- chlorophenol of the bromo- 4- of intermediate 2-
US10208023B2 (en) 2013-03-01 2019-02-19 Mark G. DeGiacomo Heterocyclic inhibitors of the sodium channel
US10246424B2 (en) 2015-04-10 2019-04-02 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10280172B2 (en) 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10377743B2 (en) 2016-10-07 2019-08-13 Araxes Pharma Llc Inhibitors of RAS and methods of use thereof
US10414757B2 (en) 2015-11-16 2019-09-17 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US10428064B2 (en) 2015-04-15 2019-10-01 Araxes Pharma Llc Fused-tricyclic inhibitors of KRAS and methods of use thereof
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
US10647703B2 (en) 2015-09-28 2020-05-12 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10689356B2 (en) 2015-09-28 2020-06-23 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10730867B2 (en) 2015-09-28 2020-08-04 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10736897B2 (en) 2017-05-25 2020-08-11 Araxes Pharma Llc Compounds and methods of use thereof for treatment of cancer
US10745385B2 (en) 2017-05-25 2020-08-18 Araxes Pharma Llc Covalent inhibitors of KRAS
US10822312B2 (en) 2016-03-30 2020-11-03 Araxes Pharma Llc Substituted quinazoline compounds and methods of use
US10858343B2 (en) 2015-09-28 2020-12-08 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10875842B2 (en) 2015-09-28 2020-12-29 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10882847B2 (en) 2015-09-28 2021-01-05 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10975071B2 (en) 2015-09-28 2021-04-13 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US11059819B2 (en) 2017-01-26 2021-07-13 Janssen Biotech, Inc. Fused hetero-hetero bicyclic compounds and methods of use thereof
US11136308B2 (en) 2017-01-26 2021-10-05 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
US11274093B2 (en) 2017-01-26 2022-03-15 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
US11639346B2 (en) 2017-05-25 2023-05-02 Araxes Pharma Llc Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HILFIKER, M.A. ET AL.: "Aminomethylpiperazines as selective urotensin antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 16, 2008, pages 4470 - 4473, XP023613398, DOI: doi:10.1016/j.bmcl.2008.07.067 *

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011026241A1 (en) * 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Substituted heterocyclic derivatives for the treatment of pain and epilepsy
US10023588B2 (en) 2012-04-10 2018-07-17 The Regents Of The University Of California Compositions and methods for treating cancer
US11891402B2 (en) 2012-04-10 2024-02-06 The Regents Of The University Of California Compositions and methods for treating cancer
US11718630B2 (en) 2012-04-10 2023-08-08 The Regents Of The University Of California Compositions and methods for treating cancer
JP2015519308A (en) * 2012-04-10 2015-07-09 ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア Cancer treatment compositions and methods
US11008334B2 (en) 2012-04-10 2021-05-18 The Regents Of The University Of California Compositions and methods for treating cancer
US11603376B2 (en) 2012-04-10 2023-03-14 The Regents Of The University Of California Compositions and methods for treating cancer
US10208023B2 (en) 2013-03-01 2019-02-19 Mark G. DeGiacomo Heterocyclic inhibitors of the sodium channel
US9745319B2 (en) 2013-03-15 2017-08-29 Araxes Pharma Llc Irreversible covalent inhibitors of the GTPase K-Ras G12C
US10919850B2 (en) 2013-03-15 2021-02-16 Araxes Pharma Llc Covalent inhibitors of KRas G12C
US9926267B2 (en) 2013-03-15 2018-03-27 Araxes Pharma Llc Covalent inhibitors of K-Ras G12C
US10273207B2 (en) 2013-03-15 2019-04-30 Araxes Pharma Llc Covalent inhibitors of kras G12C
US9840516B2 (en) 2013-10-10 2017-12-12 Araxes Pharma Llc Substituted quinazolines as inhibitors of KRAS G12C
US10370386B2 (en) 2013-10-10 2019-08-06 Araxes Pharma Llc Substituted quinolines as inhibitors of KRAS G12C
US10111874B2 (en) 2014-09-18 2018-10-30 Araxes Pharma Llc Combination therapies for treatment of cancer
US10011600B2 (en) 2014-09-25 2018-07-03 Araxes Pharma Llc Methods and compositions for inhibition of Ras
US9862701B2 (en) 2014-09-25 2018-01-09 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10246424B2 (en) 2015-04-10 2019-04-02 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10829458B2 (en) 2015-04-10 2020-11-10 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10428064B2 (en) 2015-04-15 2019-10-01 Araxes Pharma Llc Fused-tricyclic inhibitors of KRAS and methods of use thereof
US10144724B2 (en) 2015-07-22 2018-12-04 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10351550B2 (en) 2015-07-22 2019-07-16 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
US10689356B2 (en) 2015-09-28 2020-06-23 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10882847B2 (en) 2015-09-28 2021-01-05 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10730867B2 (en) 2015-09-28 2020-08-04 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10975071B2 (en) 2015-09-28 2021-04-13 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10647703B2 (en) 2015-09-28 2020-05-12 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10858343B2 (en) 2015-09-28 2020-12-08 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10875842B2 (en) 2015-09-28 2020-12-29 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US9810690B2 (en) 2015-10-19 2017-11-07 Araxes Pharma Llc Method for screening inhibitors of Ras
US11021470B2 (en) 2015-11-16 2021-06-01 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US10414757B2 (en) 2015-11-16 2019-09-17 Araxes Pharma Llc 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof
US9988357B2 (en) 2015-12-09 2018-06-05 Araxes Pharma Llc Methods for preparation of quinazoline derivatives
US10822312B2 (en) 2016-03-30 2020-11-03 Araxes Pharma Llc Substituted quinazoline compounds and methods of use
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
US10280172B2 (en) 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10723738B2 (en) 2016-09-29 2020-07-28 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10377743B2 (en) 2016-10-07 2019-08-13 Araxes Pharma Llc Inhibitors of RAS and methods of use thereof
US11358959B2 (en) 2017-01-26 2022-06-14 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
US11059819B2 (en) 2017-01-26 2021-07-13 Janssen Biotech, Inc. Fused hetero-hetero bicyclic compounds and methods of use thereof
US11136308B2 (en) 2017-01-26 2021-10-05 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
US11274093B2 (en) 2017-01-26 2022-03-15 Araxes Pharma Llc Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
US11279689B2 (en) 2017-01-26 2022-03-22 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
US10736897B2 (en) 2017-05-25 2020-08-11 Araxes Pharma Llc Compounds and methods of use thereof for treatment of cancer
US11377441B2 (en) 2017-05-25 2022-07-05 Araxes Pharma Llc Covalent inhibitors of KRAS
US11639346B2 (en) 2017-05-25 2023-05-02 Araxes Pharma Llc Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS
US10745385B2 (en) 2017-05-25 2020-08-18 Araxes Pharma Llc Covalent inhibitors of KRAS
CN109134204A (en) * 2018-11-16 2019-01-04 白银棓诺新材料有限公司 The synthetic method of the fluoro- 5- chlorophenol of the bromo- 4- of intermediate 2-
CN109134204B (en) * 2018-11-16 2022-03-08 棓诺(苏州)新材料有限公司 Synthesis method of intermediate 2-bromo-4-fluoro-5-chlorophenol

Similar Documents

Publication Publication Date Title
WO2010087399A1 (en) Urotensin-ii receptor antagonists
JP6153971B2 (en) Imidazole derivatives substituted with cycloalkyl groups
WO2013146970A1 (en) Novel quinoline derivative
WO2013147160A1 (en) Cyclic amine derivative and use thereof for medical purposes
WO2010131663A1 (en) Oxamide derivative
JP6409573B2 (en) Cyclic amine derivatives and their pharmaceutical use
US20120129888A1 (en) Libraries of n-(2-oxo-1-phenylpiperidin-3-yl)sulfonamides for drug discovery
US20120122950A1 (en) Libraries of 1-(sulfonyl)-n-phenylpyrrolidine-2-carboxamides for drug discovery
JP5663743B2 (en) Oxindole derivatives with motilin receptor agonist activity
JP2012519153A5 (en)
JP2011016742A (en) Cyclic amino compound, or salt thereof
US20120122920A1 (en) Libraries of n-substituted-n-phenylethylsulfonamides for drug discovery
US8476301B2 (en) Pyrrolidin-3-ylacetic acid derivative
WO2013039057A1 (en) Pyrrolidine-3-ylacetic acid derivative
KR102553613B1 (en) Phenyldifluoromethyl substituted prolinamide compounds
WO2011059080A1 (en) Isotope-substituted diamine derivative
EP3275878B1 (en) Cyclic amine derivative and use thereof for medical purposes
JP2011016743A (en) Cyclic amino compound, or salt thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10735864

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10735864

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP