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WO2010087399A1 - Antagonistes du récepteur de l'urotensine ii - Google Patents

Antagonistes du récepteur de l'urotensine ii Download PDF

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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
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pyrrolidin
ylmethyl
ethyl
sulfonyl
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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
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Daiichi Sankyo Co Ltd
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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.

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Abstract

L'invention porte sur de nouveaux composés qui présentent un excellent antagonisme au récepteur de l'urotensine II et qui sont utiles dans le traitement ou la prévention d'une insuffisance cardiaque congestive, de maladies cardiaques ischémiques, etc. L'invention porte sur un composé représenté par la formule générale (I) ou un sel pharmacologiquement acceptable de celui-ci. Dans la formule générale (I), le cycle A désigne un groupe représenté par la formule (1) ou (2) [dans laquelle X1, X2, X3 et X4 représentent chacun un atome d'hydrogène, un groupe halogéno, etc.]; Y1 représente -O-, -NH-, -S-, -CR11R12-, etc.; Y2 représente -CR13R14-, etc.; Q représente un groupe alkylène en C2-4 facultativement substitué par un à trois groupes alkyle en C1-6; R1 et R2 forment, conjointement avec l'atome d'azote auquel R1 et R2 sont liés, un groupe pyrrolidinyle etc., facultativement substitué par un groupe halogéno et un groupe hydroxyle; et R3 et R4 forment, conjointement avec l'atome d'azote auquel R3 et R4 sont liés, un groupe hétérocyclique contenant de l'azote à 4 à 10 chaînons etc., facultativement substitué par un groupe halogéno, un groupe alkyle en C1-6, etc.
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JP2015519308A (ja) * 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 癌治療用組成物および方法
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US9862701B2 (en) 2014-09-25 2018-01-09 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
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US9988357B2 (en) 2015-12-09 2018-06-05 Araxes Pharma Llc Methods for preparation of quinazoline derivatives
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