WO2016148135A1

WO2016148135A1 - Therapeutic agent

Info

Publication number: WO2016148135A1
Application number: PCT/JP2016/058129
Authority: WO
Inventors: 前川　毅志; 正教渡部; 博昭矢代; 佐々木　実
Original assignee: 武田薬品工業株式会社
Priority date: 2015-03-16
Filing date: 2016-03-15
Publication date: 2016-09-22
Also published as: JP2018080109A

Abstract

The present invention relates to an agent for treating or preventing obesity or diabetes, the agent containing a compound represented by general formula (I): (R₁)(R₂)N-X-Y-A-O-C(O)-B-Z [In the formula: R₁ and R₂ each independently represent a hydrogen atom or a substituent; R₁ and R₂ may form a nitrogen-containing heterocycle, and, together with nitrogen atoms adjacent thereto, may be substituted; X represents –C(O)-, a C_1-6 akylene group, or C_1-6alkylene group-C(O)-; Y represents an atomic bond, a C_1-6 alkylene group, N(R₃), or C_1-6 alkylene group-N(R₃)-; R₃ represents a C_1-6 alkyl group or a hydrogen atom; ring A represents a ring which may be substituted (excluding dihydrobenzofuran); ring B represents an aromatic hydrocarbon ring which may be substituted; and Z represents an amino group which may be substituted.], or a salt thereof, and to a method for preventing or treating obesity or diabetes, the method characterized by comprising administering an effective dose of the aforementioned compound or salt thereof.

Description

Therapeutic agent

(Related application)
This application claims priority based on Japanese Patent Application No. 2015-052255 (filed on Mar. 16, 2015), the contents of which are incorporated herein by reference.
The present invention relates to a preventive or therapeutic agent for obesity, diabetes and the like, which contains a compound having an optionally substituted amino group.

(Background of the Invention)
Diabetes is a lifestyle-related disease that induces various complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, etc.) and is a risk factor for the onset of heart disease and cerebrovascular disorder. Therefore, it is desired to provide a therapeutic agent having an excellent blood glucose lowering effect. In addition, obesity is a risk factor for various diseases including lifestyle-related diseases, and therefore, it is desired to provide a therapeutic agent having an excellent weight reduction effect.

On the other hand, as compounds having an optionally substituted amino group, compounds described in the following prior art documents and the like have been known so far.

An object of the present invention is to provide a novel preventive or therapeutic agent for obesity, diabetes and the like.

As a result of intensive studies to solve the above problems, the present inventors have found that the compound represented by the following formula (I) has excellent anti-obesity action, anti-diabetic action, and the like, and completes the present invention. It came.

That is, the present invention is as described in [1] to [11] below.
[1] Formula (I):
General formula:
(R ₁ ) (R ₂ ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R ₁ and R ₂ each independently represent a hydrogen atom or a substituent;
R ₁ and R ₂ may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C _1-6 alkylene group or a C _1-6 alkylene group —C (O) —;
Y represents a bond, a C _1-6 alkylene group, N (R ₃ ) or a C _1-6 alkylene group —N (R ₃ ) —;
R ₃ represents a C _1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
A prophylactic or therapeutic agent for obesity or diabetes comprising a compound represented by the formula (I) or a salt thereof (hereinafter sometimes abbreviated as compound (I));
[2] The agent according to the above [1], wherein R ₁ is a C _1-6 alkyl group optionally substituted with a hydrogen atom or a carboxy group;
[3] R ₂ is
(1) i) a carboxy group, and
ii) a carboxy group, or a C _1-14 aryl group which may be substituted with a C _1-6 alkyl group which may be substituted with a carboxy group, or a 1 to 1 member selected from a 5- to 14-membered aromatic heterocyclic group; A C _1-6 alkyl group substituted with three substituents, or
(2) The agent according to [1] or [2] above, which is a C _6-14 aryl group optionally substituted with a C _1-6 alkyl group optionally substituted with a carboxy group;
[4] The agent according to any one of [1] to [3] above, wherein X is —C (O) — and Y is a bond or a C _1-6 alkylene group;
[5] Any of the above-mentioned [1] to [4], wherein the ring A is a hydrocarbon ring optionally substituted with 1 to 3 halogen atoms, or a 5- to 14-membered aromatic heterocyclic ring The agent described.
[6] The agent according to any one of [1] to [5] above, wherein ring B is a benzene ring optionally substituted with a halogen atom;
[7] The agent according to any one of the above [1] to [6], wherein Z is a guanidino group;
[8] R ₁ is a C _1-6 alkyl group which may be substituted with a hydrogen atom or a carboxy group,
R ₂ is
(1) i) a carboxy group, and
ii) a carboxy group, or a C _1-14 aryl group which may be substituted with a C _1-6 alkyl group which may be substituted with a carboxy group, or a 1 to 1 member selected from a 5- to 14-membered aromatic heterocyclic group; A C _1-6 alkyl group substituted with three substituents, or
(2) a C _6-14 aryl group which may be substituted with a C _1-6 alkyl group which may be substituted with a carboxy group,
X is —C (O) —, Y is a bond or a C _1-6 alkylene group,
Ring A is a hydrocarbon ring optionally substituted with 1 to 3 halogen atoms, or a 5- to 14-membered aromatic heterocycle,
Ring B is a benzene ring optionally substituted with a halogen atom,
The agent according to [1] above, wherein Z is a guanidino group;
[9] General formula for mammals:
(R ₁ ) (R ₂ ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R ₁ and R ₂ each independently represent a hydrogen atom or a substituent;
R ₁ and R ₂ may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C _1-6 alkylene group or a C _1-6 alkylene group —C (O) —;
Y represents a bond, a C _1-6 alkylene group, N (R ₃ ) or a C _1-6 alkylene group —N (R ₃ ) —;
R ₃ represents a C _1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
A method for preventing or treating obesity or diabetes in the mammal, which comprises administering an effective amount of a compound represented by the formula:
[10] For producing a prophylactic or therapeutic agent for obesity or diabetes,
General formula:
(R ₁ ) (R ₂ ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R ₁ and R ₂ each independently represent a hydrogen atom or a substituent;
R ₁ and R ₂ may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C _1-6 alkylene group or a C _1-6 alkylene group —C (O) —;
Y represents a bond, a C _1-6 alkylene group, N (R ₃ ) or a C _1-6 alkylene group —N (R ₃ ) —;
R ₃ represents a C _1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
Or a salt thereof;
[11] For use in the prevention or treatment of obesity or diabetes,
General formula:
(R ₁ ) (R ₂ ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R ₁ and R ₂ each independently represent a hydrogen atom or a substituent;
R ₁ and R ₂ may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C _1-6 alkylene group or a C _1-6 alkylene group —C (O) —;
Y represents a bond, a C _1-6 alkylene group, N (R ₃ ) or a C _1-6 alkylene group —N (R ₃ ) —;
R ₃ represents a C _1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
Or a salt thereof.

Compound (I) has an excellent anti-obesity action and is useful as a prophylactic or therapeutic agent for obesity. Compound (I) has an excellent antidiabetic action and is useful as a preventive or therapeutic agent for diabetes. Furthermore, compound (I) has an excellent antihyperlipidemic action and is useful as a prophylactic or therapeutic agent for hyperlipidemia.

(Detailed description of the invention)
The present invention is described in detail below.

Hereinafter, the definition of each substituent used in the present specification will be described in detail. Unless otherwise specified, each substituent has the following definition.
In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
In the present specification, examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
In the present specification, the "optionally halogenated C _1-6 alkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkyl group is mentioned. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
In the present specification, examples of the “C _2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, examples of the “C _2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
In the present specification, examples of the “C _3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
In the present specification, the "optionally halogenated C _3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{3- A 10} cycloalkyl group. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
In the present specification, examples of the “C _3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
In the present specification, examples of the “C _6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
In the present specification, examples of the “C _7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

In the present specification, examples of the “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, the "optionally halogenated C _1-6 alkoxy group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkoxy group is mentioned. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl. Examples include oxy and hexyloxy.
In the present specification, examples of the “C _3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
In the present specification, examples of the “C _1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, the "optionally halogenated C _1-6 alkylthio group optionally", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkylthio group is mentioned. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
In the present specification, examples of the “C _1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
In the present specification, examples of the “ _optionally halogenated C _1-6 alkyl-carbonyl group” include C ₁ optionally having 1 to 7, preferably 1 to 5 halogen atoms. _{A -6} alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, examples of the “C _1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
In the present specification, examples of the “C _6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the “C _7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
In the present specification, examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
In the present specification, examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C _1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
In the present specification, examples of the “mono- or di-C _7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
In the present specification, examples of the “C _1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
In the present specification, the "optionally halogenated C _1-6 alkyl sulfonyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{1- 6} alkylsulfonyl group is mentioned. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
In the present specification, examples of the “C _6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group. An optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
In the present specification, examples of the “hydrocarbon group” (including the “hydrocarbon group” in the “optionally substituted hydrocarbon group”) include, for example, a C _1-6 alkyl group, a C _2-6 alkenyl group, Examples thereof include a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group, and a C _7-16 aralkyl group.

In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
[Substituent group A]
(1) a halogen atom,
(2) Nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally halogenated C _1-6 alkoxy group,
(7) C _6-14 aryloxy group (eg, phenoxy, naphthoxy),
(8) C _7-16 aralkyloxy group (eg, benzyloxy),
(9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy),
(10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy),
(11) C _1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy),
(12) C _6-14 aryl-carbonyloxy group (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
(13) C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),
(14) mono- or di-C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
(15) C _6-14 aryl-carbamoyloxy group (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy),
(16) a 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyloxy),
(17) 3 to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, morpholinylcarbonyloxy, piperidinylcarbonyloxy),
(18) an optionally halogenated C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy),
(19) a C _6-14 arylsulfonyloxy group (eg, phenylsulfonyloxy, toluenesulfonyloxy) _optionally substituted with a C _1-6 alkyl group,
(20) an optionally halogenated C _1-6 alkylthio group,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3 to 14-membered non-aromatic heterocyclic group,
(23) formyl group,
(24) a carboxy group,
(25) an optionally halogenated C _1-6 alkyl-carbonyl group,
(26) a C _6-14 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclic carbonyl group,
(28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group,
(29) a C _1-6 alkoxy-carbonyl group,
(30) C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
(31) C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl),
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) mono- or di-C _1-6 alkyl-carbamoyl group,
(35) C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl),
(36) 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl, thienylcarbamoyl),
(37) 3 to 14-membered non-aromatic heterocyclic carbamoyl group (eg, morpholinylcarbamoyl, piperidinylcarbamoyl),
(38) an optionally halogenated C _1-6 alkylsulfonyl group,
(39) a C _6-14 arylsulfonyl group,
(40) 5- to 14-membered aromatic heterocyclic sulfonyl group (eg, pyridylsulfonyl, thienylsulfonyl),
(41) an optionally halogenated C _1-6 alkylsulfinyl group,
(42) C _6-14 arylsulfinyl group (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) a 5- to 14-membered aromatic heterocyclic sulfinyl group (eg, pyridylsulfinyl, thienylsulfinyl),
(44) an amino group,
(45) Mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N -Methylamino),
(46) mono- or di-C _6-14 arylamino group (eg, phenylamino),
(47) a 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino),
(48) C _7-16 aralkylamino group (eg, benzylamino),
(49) formylamino group,
(50) C _1-6 alkyl-carbonylamino group (eg, acetylamino, propanoylamino, butanoylamino),
(51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino),
(52) C _6-14 aryl-carbonylamino group (eg, phenylcarbonylamino, naphthylcarbonylamino),
(53) C _1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
(54) C _7-16 aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino),
(55) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino),
(56) a C _6-14 arylsulfonylamino group (eg, phenylsulfonylamino, toluenesulfonylamino) _optionally substituted with a C _1-6 alkyl group,
(57) an optionally halogenated C _1-6 alkyl group,
(58) a C _2-6 alkenyl group,
(59) C _2-6 alkynyl group,
(60) C _3-10 cycloalkyl group,
(61) a C _3-10 cycloalkenyl group, and (62) a C _6-14 aryl group.

The number of the substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
In the present specification, examples of the “heterocyclic group” (including the “heterocyclic group” in the “optionally substituted heterocyclic group”) include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom. (I) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .

In the present specification, the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. And 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms.
Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2,3 -B] thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quina And 8- to 14-membered condensed polycyclic (preferably 2 or 3 ring) aromatic heterocyclic groups such as linyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl .

In the present specification, examples of the “non-aromatic heterocyclic group” (including the “3- to 14-membered non-aromatic heterocyclic group”) include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from
Suitable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyrani , Tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diaze Cycloalkenyl, azepinyl, oxepanyl, azocanyl, 3 to 8-membered monocyclic non-aromatic heterocyclic group such as Jiazokaniru;
Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho [2,3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, Indolinyl, isoindolinyl, tetrahydrothieno [2,3-c] pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydro Naphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydro Rofenajiniru, tetrahydrothiophenyl key Sante alkenyl, 9 to 14 membered fused polycyclic, such as octahydro-isoquinolylmethyl (preferably 2 or tricyclic), and the non-aromatic heterocyclic group.

In the present specification, preferable examples of the “7 to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
In the present specification, examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic groups”.
In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
The number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

In the present specification, the “acyl group” is, for example, “1 selected from a halogen atom, an optionally halogenated C _1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group. C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl each optionally having 3 substituents Formyl optionally having 1 or 2 substituents selected from the group, a C _7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group ” Group, carboxy group, carbamoyl group, thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group and phosphono group.
The “acyl group” also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
Here, the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded, and the hydrocarbon-sulfinyl group is a hydrocarbon group. A sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
As preferable examples of the “acyl group”, a formyl group, a carboxy group, a C _1-6 alkyl-carbonyl group, a C _2-6 alkenyl-carbonyl group (eg, crotonoyl), a C _3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C _3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C _6-14 aryl-carbonyl group, C _7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl) , _{naphthyloxycarbonyl), C 7- 6} aralkyloxy - carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl carbonyl), a carbamoyl group, mono- - or di _{-C 1-6} alkyl - carbamoyl group, mono- - or di _{-C 2-6} alkenyl - carbamoyl group (e.g. , Diallylcarbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di _{-C 2-6} alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di _{-C 3-10} cycloalkyl - thiocarbamoyl group (e.g., cyclopropyl thiocarbamoyl, cyclohexyl Thiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl group (eg, benzylthiocarbamoyl, phenethylthiocarbamoyl) ) 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (eg, pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 alkylsulfonyl _{group, C 6- 4} arylsulfonyl group, a phosphono group, a mono - or di -C _1-6 alkyl phosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) and the like.

In the present specification, examples of the “optionally substituted amino group” include, for example, a C _1-6 alkyl group each having 1 to 3 substituents selected from the substituent group A, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7- 16-} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group Mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _1-6 alkylsulfonyl group and C _{6-1 And an} amino group optionally having 1 or 2 substituents selected from ₄ arylsulfonyl groups.
Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C _1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-6 alkenylamino groups (eg, diallylamino), mono- or di-C _3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C _6-14 arylamino group (eg, phenylamino), mono- or di-C _7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C _1-6 alkyl) - carbonyl amino group (e.g., a Chiruamino, propionylamino), mono- - or di _{-C 6-14} aryl - carbonyl amino group (e.g., benzoylamino), mono - or di _{-C 7-16} aralkyl - carbonyl amino group (e.g., benzyl carbonyl amino), mono -Or di-5 to 14-membered aromatic heterocyclic carbonylamino group (eg, nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino group (eg, piperidyl) Nylcarbonylamino), mono- or di-C _1-6 alkoxy-carbonylamino group (eg, tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino), carbamoylamino group, ( mono - or di _{-C 1-6} alkyl - carbamoyl) amino group (e.g., methylcarbamoyl Carbamoylamino), (mono - or di _{-C 7-16} aralkyl - carbamoyl) amino group (e.g., benzylcarbamoyl _{amino), C 1-6} alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), _{C 6 -14} arylsulfonylamino group (eg, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino), (C _1-6 Alkyl) (C _6-14 aryl-carbonyl) amino group (eg, N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substituted carbamoyl group” include, for example, a “C _1-6 alkyl group _optionally having 1 to 3 substituents selected from the substituent group A” C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group The have include a carbamoyl group which may.
Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group, a mono- or di-C _2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group). ), Mono- or di-C _3-10 cycloalkyl-carbamoyl groups (eg cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl groups (eg phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, mono- or di-C _1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C _6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl) A 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl) can be mentioned.

In the present specification, examples of the “optionally substituted thiocarbamoyl group” include, for example, “C _1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - one or two location selected from a carbamoyl group Have a group "include good thiocarbamoyl group.
Suitable examples of the thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio). Carbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group ( Examples, cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl group (eg, , Benzylthioca Bamoiru, phenethyl thio carbamoyl), mono - or di _{-C 1-6} alkyl - carbonyl - thiocarbamoyl group (e.g., acetyl thiocarbamoyl, propionylthio carbamoyl), mono - or di _{-C 6-14} aryl - carbonyl - thiocarbamoyl Groups (eg, benzoylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substituted sulfamoyl group” include a “C _1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”. C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group Have a "include sulfamoyl group.
Preferable examples of the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C _1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl). Sulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _2-6 alkenyl-sulfamoyl groups (eg diallylsulfamoyl), mono- or di-C _3-10 cycloalkyl- Sulfamoyl group (eg, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14 aryl-sulfamoyl group (eg, phenylsulfamoyl), mono- or di-C _7-16 aralkyl- Sulfamoyl group (eg, benzylsulfamoyl, phenethylsulfamoy) ), Mono - or di _{-C 1-6} alkyl - carbonyl - sulfamoyl group (e.g., acetyl sulfamoyl, propionitrile acylsulfamoyl), mono - or di _{-C 6-14} aryl - carbonyl - sulfamoyl group (e.g., benzoyl Sulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

In the present specification, examples of the “optionally substituted hydroxy group” include a “C _1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”. C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Groups, mono- or di-C _1-6 alkyl-carbamoyl groups, mono- or di-C _7-16 aralkyl-carbamoyl groups, C _1-6 alkylsulfonyl groups and C _{And a} hydroxy group optionally having a substituent selected from _6-14 arylsulfonyl groups.
Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C _1-6 alkoxy group, a C _2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy). ), C _3-10 cycloalkyloxy group (eg, cyclohexyloxy), C _6-14 aryloxy group (eg, phenoxy, naphthyloxy), C _7-16 aralkyloxy group (eg, benzyloxy, phenethyloxy), C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 aryl-carbonyloxy group (eg, benzoyloxy), C _7-16 aralkyl- A carbonyloxy group (eg benzylcarbonyloxy) ), 5 to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyl oxy), 3 to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., piperidinylcarbonyl oxy), C _1-6 alkoxy - carbonyl An oxy group (eg, tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), a carbamoyloxy group, a C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy), C _7-16 aralkyl-carbamoyloxy group (eg, benzylcarbamoyloxy), C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy), C _6-14 arylsulfonyloxy group (eg, phenylsulfonyl) Oxy).

In the present specification, examples of the “optionally substituted sulfanyl group” include a “C _1-6 alkyl group _optionally having 1 to 3 substituents selected from the substituent group A”. C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C _1-6 alkylthio group, a C _2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C _3-10 cycloalkylthio group (eg, cyclohexylthio), C _6-14 arylthio group (eg, phenylthio, naphthylthio), C _7-16 aralkylthio group (eg, benzylthio, phenethylthio), C _1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C _6-14 aryl-carbonylthio group (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio group (Eg, pyridylthio), halogenated thio groups (eg, pentafluorothio) E).

In the present specification, examples of the “optionally substituted silyl group” include a “C _1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A” A silyl group optionally having 1 to 3 substituents selected from a C _2-6 alkenyl group, a C _3-10 cycloalkyl group, a C _6-14 aryl group and a C _7-16 aralkyl group ” Can be mentioned.
Preferable examples of the optionally substituted silyl group include a tri-C _1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).

In this specification, examples of the “C _1-6 alkylene group” include —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — (CH ₂ ) ₆ —, —CH (CH ₃ ) —, —C (CH ₃ ) ₂ —, —CH (C ₂ H ₅ ) —, —CH (C ₃ H ₇ ) —, —CH (CH (CH ₃ ) ₂ ) —, — (CH (CH ₃ )) ₂ —, —CH ₂ —CH (CH ₃ ) —, —CH (CH ₃ ) —CH ₂ —, —CH ₂ —CH _{_{_{_{2 -C (CH 3) 2 -}}}} , - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2 And —CH ₂ —CH ₂ —CH ₂ —.

In the present specification, examples of the “hydrocarbon ring” include a C _6-14 aromatic hydrocarbon ring, a C _3-10 cycloalkane, and a C _3-10 cycloalkene.
In the present specification, examples of the “C _6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
In the present specification, examples of “C _3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
In the present specification, examples of “C _3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
In the present specification, examples of the “heterocycle” include aromatic heterocycles each containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. Non-aromatic heterocycles may be mentioned.

In the present specification, the “aromatic heterocycle” is, for example, a 5- to 14-membered member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom ( Preferred is a 5- to 10-membered aromatic heterocyclic ring. Preferable examples of the “aromatic heterocyclic ring” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi 5- to 6-membered monocyclic aromatic heterocycle such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine;
Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, Imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2,3-b] thiophene, phenoxathiin, indol, Isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, cal Tetrazole, beta-carboline, phenanthridine, acridine, phenazine, phenothiazine, 8 to 14 membered fused polycyclic, such as phenoxazine (preferably 2 or tricyclic) and aromatic heterocycle.

In the present specification, the “non-aromatic heterocycle” includes, for example, a 3 to 14 member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. (Preferably 4 to 10 membered) non-aromatic heterocycle. Suitable examples of the “non-aromatic heterocycle” include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline. , Thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, 3 types such as diazepan, azepine, azocan, diazocan, oxepane 8-membered monocyclic non-aromatic heterocyclic ring and;
Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho [2,3-b] thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, tetrahydrothieno [2 , 3-c] pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline Tetrahydroacridine, tetrahydrophenazine, tetrahydrothi Xanthene, 9 to 14 membered fused polycyclic, such as octahydro-isoquinoline (preferably 2 or tricyclic) non-aromatic heterocyclic ring.
In the present specification, examples of the “nitrogen-containing heterocycle” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocycle”.

Hereinafter, each symbol of the formula (I) will be described.

R ₁ and R ₂ each independently represent a hydrogen atom or a substituent.
R ₁ and R ₂ may form a nitrogen-containing heterocyclic ring which may be substituted with an adjacent nitrogen atom.

Examples of the “substituent” represented by R ₁ or R ₂ include substituent group A.
Preferably, the “substituent” represented by R ₁ or R ₂ is
(1) i) a carboxy group, and
ii) a carboxy group or a C _6-14 aryl group (eg phenyl) optionally substituted with a C _1-6 alkyl group (eg methyl) optionally substituted with a carboxy group or a 5- to 14-membered aromatic Group heterocyclic group (eg thienyl)
A C _1-6 alkyl group (for example, methyl, ethyl) optionally substituted with 1 to 3 (preferably 1 or 2) substituents selected from
(2) A C _6-14 aryl group (eg, phenyl) _optionally substituted with a C _1-6 alkyl group (eg, methyl) _optionally substituted with a carboxy group.

R ₁ is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl, ethyl) optionally substituted with a carboxy group, more preferably a hydrogen atom or —CH ₂ COOH.

R ₂ is preferably
(1) i) a carboxy group, and
ii) a carboxy group or a C _6-14 aryl group (eg phenyl) optionally substituted with a C _1-6 alkyl group (eg methyl) optionally substituted with a carboxy group or a 5- to 14-membered aromatic Group heterocyclic groups (eg thienyl)
A C _1-6 alkyl group (eg, methyl, ethyl) substituted with 1 to 3 (preferably 1 or 2) substituents selected from
(2) a C _6-14 aryl group (eg, phenyl) _optionally substituted with a C _1-6 alkyl group (eg, methyl) _optionally substituted with a carboxy group
And
More preferably,
(1) i) a carboxy group, and
ii) a carboxy group or phenyl or thienyl optionally substituted with —CH ₂ COOH,
Methyl or ethyl substituted with 1 or 2 substituents selected from
(2) Phenyl substituted with methyl substituted with a carboxy group, and specific examples include the following groups.

X represents —C (O) —, a C _1-6 alkylene group or a C _1-6 alkylene group —C (O) —,
Y represents a bond, a C _1-6 alkylene group, N (R ₃ ) or a C _1-6 alkylene group —N (R ₃ ) —, and R ₃ represents a C _1-6 alkyl group or a hydrogen atom. .

Preferably, X is —C (O) — and Y is a bond or a C _1-6 alkylene group (eg, methylene, ethylene). More preferably, X is —C (O) — and Y is a bond, —CH ₂ —, — (CH ₂ ) ₂ — or —CH (CH ₃ ) —. More preferably, X is —C (O) — and Y is —CH ₂ — or — (CH ₂ ) ₂ —.

Ring A represents an optionally substituted ring. However, dihydrobenzofuran is excluded from the ring.

Examples of the “optionally substituted ring” represented by ring A include a ring optionally having a substituent selected from substituent group A. The number of substituents in the “optionally substituted ring” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

The “ring” constituting ring A includes a hydrocarbon ring (eg, benzene ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene ring), a 5- to 14-membered aromatic heterocyclic ring (eg, quinoline ring) , Indole ring) and the like.

Preferably, ring A is a hydrocarbon ring (eg, benzene ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene ring) optionally substituted with 1 to 3 halogen atoms (eg, chlorine atom). Or a 5- to 14-membered aromatic heterocycle (eg, quinoline ring, indole ring), more preferably a chlorobenzene ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene (tetralin) ring, quinoline Ring, indole ring, more preferably chlorobenzene ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene (tetralin) ring, quinoline ring, most preferably chlorobenzene ring or 1,2,3,4. 4-tetrahydronaphthalene (tetralin) ring.

Ring B represents an optionally substituted aromatic hydrocarbon ring.

Examples of the “optionally substituted aromatic hydrocarbon ring” represented by ring B include an aromatic hydrocarbon ring which may have a substituent selected from substituent group A. The number of substituents in the “optionally substituted aromatic hydrocarbon ring” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

Examples of the “aromatic hydrocarbon ring” constituting the ring B include a C _6-14 aromatic hydrocarbon ring.

Preferably, ring B is a benzene ring optionally substituted with a halogen atom (for example, a fluorine atom), more preferably a benzene ring.

Z represents an amino group which may be substituted.
Preferably Z is a guanidino group. In the formula (I), when ring B is a benzene ring, Z is preferably bonded to the 4-position. That is, the relationship between —O—C (O) — and Z on the benzene ring is preferably para.

Preferred examples of compound (I) include the following:

[Compound A]
R ₁ is a C _1-6 alkyl group (eg, methyl, ethyl) optionally substituted with a hydrogen atom or a carboxy group;
R ₂ is
(1) i) a carboxy group, and
ii) a carboxy group, or a C _6-14 aryl group (eg, phenyl) optionally substituted with a C _1-6 alkyl group (eg, methyl) optionally substituted with a carboxy group or 5 to 14 members Aromatic heterocyclic groups (eg thienyl)
A C _1-6 alkyl group (eg, methyl, ethyl) substituted with 1 to 3 substituents selected from:
(2) a C _6-14 aryl group (eg, phenyl) _optionally substituted with a C _1-6 alkyl group (eg, methyl) _optionally substituted with a carboxy group
Is;
X is —C (O) — and Y is a bond or a C _1-6 alkylene group (eg, methylene, ethylene);
Ring A is a hydrocarbon ring (eg, benzene ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene ring) optionally substituted with 1 to 3 halogen atoms (eg, chlorine atom), or A 5- to 14-membered aromatic heterocycle (eg, quinoline ring, indole ring);
Ring B is a benzene ring optionally substituted with a halogen atom (for example, a fluorine atom);
Compound (I) wherein Z is a guanidino group.

[Compound B]
R ₁ is a hydrogen atom or —CH ₂ COOH;
R ₂ is
(1) i) a carboxy group, and
ii) phenyl or thienyl, each optionally substituted with a carboxy group or —CH ₂ COOH,
Methyl or ethyl substituted with 1 or 2 substituents selected from
(2) phenyl substituted with methyl substituted with a carboxy group;
X is —C (O) — and Y is a bond, —CH ₂ —, — (CH ₂ ) ₂ — or —CH (CH ₃ ) —;
Ring A is a chlorobenzene ring, naphthalene ring, 1,2,3,4-tetrahydronaphthalene (tetralin) ring or quinoline ring;
Ring B is a benzene ring;
Z is a guanidino group, which is bonded to the 4-position of the benzene ring constituting ring B (I).

[Compound C]
R ₁ is a hydrogen atom or —CH ₂ COOH;
R ₂ is any group shown below;

X is —C (O) — and Y is —CH ₂ — or — (CH ₂ ) ₂ —;
Ring A is a chlorobenzene ring or a 1,2,3,4-tetrahydronaphthalene (tetralin) ring;
Ring B is a benzene ring;
Z is a guanidino group, which is bonded to the 4-position of the benzene ring constituting ring B (I).

[Compound D]
The compound of Example 1 described later.
The compound of Example 2 described later.

Examples of the salt of the compound represented by the formula (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Can be mentioned.

Suitable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.

Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. And the salt.

Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.

Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

Of the above-mentioned salts, pharmaceutically acceptable salts are preferable.

Compound (I) may be a prodrug.
The prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).

The prodrug of compound (I) includes a compound in which amino of compound (I) is acylated, alkylated or phosphorylated (for example, amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds); compounds (I ) In which the hydroxy is acylated, alkylated, phosphorylated or borated (eg, hydroxy in compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethyl Aminomethylcarbonylated compound); compound (I) cal Carboxy is esterified or amidated compound (e.g., carboxy C _1-6 alkyl ester of the compound (I), phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification , Ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamidation compound); Among them, compounds in which the carboxy of the compound (I) is esterified with C _1-6 alkyl such as methyl, ethyl, tert-butyl and the like are preferably used. These compounds can be produced from compound (I) by a method known per se.

The prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
In the present specification, the prodrug may form a salt, and examples of the salt include those exemplified as the salt of the compound represented by the aforementioned formula (I).

The production method of compound (I) will be described below.

Compound (I) can be specifically produced based on the method described in the above-mentioned prior art document.

When the compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., any one of the isomers and a mixture are included in the compound (I). For example, when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also encompassed in compound (I). These isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) Etc., each can be obtained as a single item.

Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture. The crystal can be produced by crystallization by applying a crystallization method known per se.
Furthermore, Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). Means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
The above crystals are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), drug efficacy), and extremely useful as pharmaceuticals. It is.
Compound (I) may be a solvate (eg, hydrate etc.) or non-solvate (eg, non-hydrate etc.), both of which are encompassed in compound (I). The
Compounds labeled with isotopes (eg, ³ H, ¹³ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ²⁵ I, etc.) are also encompassed in compound (I).
A deuterium conversion form in which ¹ H is converted to ² H (D) is also encompassed in compound (I).
Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis.

Compound (I) and a prodrug thereof (sometimes abbreviated as a compound of the present invention in the present specification) have an anti-obesity action (weight-reducing action), an anti-diabetic action (blood glucose-lowering action), and an anti-hyperlipidemic action. (Blood triglyceride lowering action) and the like.

The compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), and is used as it is or mixed with a pharmacologically acceptable carrier or the like. By so doing, it can be safely administered to mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans).

Specifically, the compound of the present invention is symptomatic obesity, obesity based on simple obesity, pathology or disease associated with obesity, eating disorders, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type) Diabetes), hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, high LDL cholesterolemia, low HDL cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (hypertriglyceride (TG) emia, It can be used as a prophylactic / therapeutic agent for low HDL cholesterol (HDL-C) blood pressure, hypertension, abdominal obesity and glucose tolerance, and other conditions.

Symptomatic obesity includes endocrine obesity (eg Cushing syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudohypoparathyroidism, hypogonadism), central obesity (eg hypothalamic) Obesity, frontal lobe syndrome, Kleine-Levin syndrome, hereditary obesity (eg, Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), drug-induced obesity (eg, steroids, phenothiazine, insulin, sulfonylurea (SU), β -Obesity due to blockers).

Examples of conditions or diseases associated with obesity include impaired glucose tolerance, diabetes (especially type 2 diabetes, obesity type diabetes), lipid metabolism abnormality (same meaning as hyperlipidemia described above), hypertension, heart failure, hyperuricemia Disease / gout, fatty liver (including non-alcoholic steato-hepatitis), coronary artery disease (myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack), bone / joint disease (degenerative) Knee osteoarthritis, hip osteoarthritis, osteoarthritis, low back pain, sleep apnea syndrome / Pickwick syndrome, abnormal menstrual cycle (abnormal menstrual cycle, abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms) ), Metabolic syndrome and the like.

Regarding the criteria for determining diabetes, the criteria was reported in 1999 by the Japan Diabetes Society.

According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, it does not correspond to the above-mentioned diabetes, and “a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.

In addition, as for the criteria for determining diabetes, the criteria were reported from ADA (American Diabetes Association) in 1997 and from WHO (World Health Organization) in 1998.

According to these reports, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.

Further, according to the above reports of ADA and WHO, impaired glucose tolerance means that fasting blood glucose level (glucose concentration in venous plasma) is less than 126 mg / dl and 75 g oral glucose tolerance test 2 hour value (venous plasma Is a state in which the glucose concentration is 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.

The compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.

In this specification, obesity refers to, for example, BMI (body mass index: body weight (kg) ÷ [height (m)] ² ) of 25 or more (according to the standards of the Japanese Society of Obesity) in Japanese, BMI is defined as 30 or more (according to WHO standards).

The compound of the present invention is also useful as a prophylactic / therapeutic agent for metabolic syndrome (metabolic syndrome). Patients with metabolic syndrome have a significantly higher rate of developing cardiovascular disease than patients with a single lifestyle-related disease, so preventing or treating metabolic syndrome prevents cardiovascular disease It is extremely important to do.
Criteria for metabolic syndrome were published by WHO in 1999 and NCEP in 2001. According to WHO criteria, metabolic syndrome is diagnosed in patients with visceral obesity, dyslipidemia (high TG or low HDL), or hypertension based on hyperinsulinemia or impaired glucose tolerance. (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999). According to the criteria of the Adult Treatment Panel III of the National Cholesterol Education Program, which is a management index for ischemic heart disease in the United States, 3 of visceral obesity, hypertriglyceridemia, low HDL cholesterolemia, hypertension, and impaired glucose tolerance (National Cholesterol Education Program: Executive Summary of the Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III). The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001).

The prophylactic or therapeutic agent containing the compound of the present invention can be used alone or pharmacologically in accordance with a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). For example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, oral) Disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), instillation, transdermal preparation, ointment, lotion, patch Suppositories, suppositories ( , Rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc., for mammals orally or parenterally (eg, intravenous, intramuscular, It is safely administered subcutaneously, into organs, intranasally, intradermally, instilled, intracerebral, intrarectally, intravaginally, intraperitoneally, intratumorally, within the tumor, and directly into the lesion. be able to.

When manufacturing an oral preparation, if necessary, coating may be performed for the purpose of taste masking, enteric properties or sustainability.

Examples of the coating base used for coating include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.

As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.

Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ] Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.

Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].

The above-mentioned coating bases may be used by mixing two or more thereof in an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.

The content of the compound of the present invention in the preventive or therapeutic agent is about 0.01 to about 100% by weight of the entire preventive or therapeutic agent. The dose of the compound of the present invention varies depending on the administration subject, administration route, disease, symptom, and the like. For example, when administered orally to an obese or diabetic patient (body weight of about 60 kg), the active ingredient per day About 0.01 to about 30 mg / kg body weight, preferably about 0.1 to about 20 mg / kg body weight, more preferably about 1 to about 20 mg / kg body weight. This amount may be administered once or several times a day (eg, 1 to 3 times a day).

Examples of the pharmacologically acceptable carrier described above include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials. For example, excipients, lubricants, binders and disintegrants in solid preparations, or liquid preparations Solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. Further, if necessary, additives such as ordinary preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used.

Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.

Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, and L-hydroxypropyl cellulose.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, and citrate.

Examples of soothing agents include benzyl alcohol.

Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.
Examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blue Nos. 1 and 2), water-insoluble lake dyes (eg, : Aluminum salt of the water-soluble edible tar pigment), natural pigments (eg, β-carotene, chlorophyll, Bengala) and the like.
Examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

Furthermore, the compound of the present invention can be used in combination with a drug other than the compound of the present invention.

Examples of a drug that can be used in combination with the compound of the present invention (hereinafter sometimes abbreviated as a concomitant drug) include, for example, an anti-obesity agent, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a hypotensive agent, Examples include diuretics, anti-inflammatory drugs, and antithrombotic agents. Specific examples include the following.

Anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators , GABA modulators (eg, topiramate), neuropeptide Y antagonists (eg, Berneperit), cannabinoid receptor antagonists (eg, rimonabant, taranaban), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylase inhibitor Drugs, opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (eg, Orlistat, cetilistat), β3 agonists (eg, N-5984) , Diacylglycerol acyltransferase 1 (DGAT1) inhibitor, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibitor, microsomal triglyceride transfer protein inhibitor (eg, R-256918), Na-glucose co-transport carrier Inhibitors (eg, JNJ-28431754, remogliflozin), NFκ inhibitors (eg, HE-3286), PPAR agonists (eg, GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (eg, sodium vanadate, Trodaschemin ( Trodusquemin)), GPR119 agonists (eg, PSN821, MBX-2982, APD597), glucokinase activators (eg, AZD-1656), leptin, leptin derivatives (eg, metreleptin), CNTF (ciliary neurotrophic factor) ), BDNF (brain-derived neurotrophic factor), cholecystokinin agonist, glucagon-like peptide-1 (GLP-1) preparation (eg, bovine or porcine pancreas) Extracted animal GLP-1 preparation; human GLP-1 preparation genetically engineered using E. coli and yeast; GLP-1 fragment or derivative (eg, exenatide, liraglutide)), amylin preparation (eg, pramlintide) , AC-2307), neuropeptide Y agonist (eg, PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparation: FGF21 preparation (eg, from bovine, porcine pancreas) Extracted animal FGF21 preparations; human FGF21 preparations synthesized by genetic engineering using Escherichia coli and yeast; FGF21 fragments or derivatives), feeding inhibitors (eg, P-57), and the like.

Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragments or Derivatives (eg, INS-1), oral insulin preparations, insulin resistance improvers (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), metaglidacene ( Metaglidasen), AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT- 505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 099794 Compound), α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate), biguanide (eg, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinate)), insulin Secretion promoter (eg, sulfonylurea (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybazole), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate) Dipeptidyl peptidase IV inhibitors (eg, alogliptin or a salt thereof (preferably benzoate), trelagliptin or a salt thereof (preferably succinate), vildaglip (Vildagliptin), Sitagliptin, Saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, β3 Agonist (eg, N-5984), GPR40 agonist (eg, fasiglifam, WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 or WO2008 / 001931 compound), GLP-1 receptor agonist (eg, GLP-1, GLP-1 MR agent, Liraglutide, Exenatide, AVE-0010, BIM-51077, Aib (8,35) hGLP -1 (7,37) NH ₂ , CJC-1131, Albiglutide), amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose) -6-phosphatase inhibitor, glucagon Anti-agent, FBPase inhibitor), SGLT2 (sodium-glucose cotransporter 2) inhibitor (eg, depagliflozin (Dapagliflozin), AVE2268, TS-033, YM543, TA-7284, remogliflozin (ASP1941)), SGLT1 inhibitor Drugs, 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, INCB-13739), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin sensitizers, somatostatin receptor agonists, Glucokinase activator (eg, compound described in Piragliatin, AZD1656, AZD6370, TTP-355, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 or WO2008 / 156757), GIP (Glucose-dependent insulinotropic peptide), GPR119 agonist (eg, PSN821, MBX-2982, APD597), FGF21, FGF analog and the like.

Diabetes complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factors and their increasing drugs (eg, , NGF, NT-3, BDNF, neurotrophin production / secretion promoters described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3 -(2-methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-phenacylthia) Zorium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor agonist (eg, gabapentin, pregabalin), serotonin / noradrenaline reuptake Inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiaprid, mexiletine), somatostatin receptor agonists (eg, BIM23190 ), Apoptosis signal regulating kinase-1 (ASK-1) inhibitors and the like.

Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or their salts (eg, sodium salt, calcium salt)), squalene synthesis Enzyme inhibitors (eg, compounds described in WO97 / 10224, for example, N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- ( 2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (eg, Bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol), niceritrol (niceritr) ol), niaspan), ethyl icosapentate, plant sterols (eg, soysterol, gamma-oryzanol), cholesterol absorption inhibitors (eg, zetia), CETP inhibitors (eg, dalcetrapib) (Dalcetrapib), anacetrapib), ω-3 fatty acid preparation (eg, ω-3-acid ethyl ester 90), and the like.

Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan , Olmesartan, olmesartan medoxomil, azilsartan, azilsartan, medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, nihondipine, amlodipine, amlodipine, cilnidipine, etc.), β-blockers (eg, metoprolol, atenolol, propranolol, propranolol) Pindolol), clonidine and the like.

Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penfluolide. Thiazide, poly-5 thiazide, meticlotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.) ), Azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of anti-inflammatory drugs include non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.

Antithrombotic agents include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban) , Dabigatran, FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504 Compounds), thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor (eg, ticlopidine hydrochloride) (ticlopidine hydrochloride), clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.

When the compound of the present invention is used in combination with a concomitant drug, the amount of each drug can be reduced within a safe range considering the side effects of those drugs. In addition, since the dose of the concomitant drug can be reduced, side effects that may be caused by the concomitant drug can be effectively prevented.

By combining the compound of the present invention and a concomitant drug,
(1) The dose can be reduced compared to the case where the compound of the present invention or the concomitant drug is administered alone.
(2) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer.
(3) By selecting a concomitant drug having a mechanism of action different from that of the compound of the present invention, the therapeutic effect can be sustained.
(4) By using the compound of the present invention and the concomitant drug in combination, excellent effects such as a synergistic effect can be obtained.

When the compound of the present invention and a concomitant drug are used in combination, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject, or a time difference May be administered at any time. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

As the administration form of the compound of the present invention and the concomitant drug, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) separate administration of the compound of the present invention and the concomitant drug Simultaneous administration of the two preparations obtained by formulation into the same administration route, (3) Time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Formulating the compound of the present invention and the concomitant drug separately Administration of the two types of preparations obtained at different times by different administration routes (for example, the compound of the present invention; administration in the order of concomitant drugs, or administration in the reverse order).

The present invention is further explained in detail by the following examples, test examples and formulation examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
The following abbreviations are used in the following examples.
MS: Mass spectrum
[M + H] ⁺ , [M + Na] ⁺ , [MH] ⁻ : Molecular ion peak
LC / MS: Liquid chromatograph mass spectrometer
TFA: trifluoroacetic acid MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. The data is the actual measurement (found). Usually, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group, a peak from which a tert-butoxycarbonyl group or a tert-butyl group is eliminated may be observed as a fragment ion. In the case of a compound having a hydroxyl group, a peak from which H ₂ O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.

Examples The compounds listed in Table 1 (Examples 1 to 4) were prepared by known methods described in the prior art literature.

Further compounds of the invention (Examples 5 and 6) are described below.

Test example Anti-obesity action test using ob / ob mice Obese type 2 diabetes model, ob / ob mice (male, 7 weeks old), powder diet containing test compound at a concentration of 0.1% (w / w) ( A compound-administered group, 5 mice per group) or a feed containing no compound (a compound non-administered group (vehicle group), 5 mice per group) was fed for 7 days (CE2 of CLEA Japan). The average doses calculated from food intake and body weight during the test period were 63.7 and 66.5 mg / kg / day in Examples 1 and 2, respectively. Blood indicators (blood glucose level, blood triglyceride level) were measured using an automatic analyzer 7180 (Hitachi). The average values and standard deviations of body weight, blood glucose level, and blood triglyceride level at the start of administration and after 7 days of continuous administration are shown below. The significance of each compound administration group relative to the Vehicle group was evaluated by Dunnett's test. The significant difference level with respect to the vehicle is shown as **: p <0.01 and ***: p <0.001.

As described above, it was shown that the compound of the present invention has an anti-obesity action (weight reduction action), an anti-diabetic action (blood sugar reduction action), and an antihyperlipidemic action (blood triglyceride reduction action).

The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

The compound of the present invention has an excellent anti-obesity action and is useful for the prevention or treatment of obesity. The compound of the present invention has an excellent antidiabetic action and is useful as a preventive or therapeutic agent for diabetes. Furthermore, the compound of the present invention has an excellent antihyperlipidemic action and is useful as a prophylactic or therapeutic agent for hyperlipidemia.

All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

Claims

General formula:
(R 1 ) (R 2 ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R 1 and R 2 each independently represent a hydrogen atom or a substituent;
R 1 and R 2 may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C 1-6 alkylene group or a C 1-6 alkylene group —C (O) —;
Y represents a bond, a C 1-6 alkylene group, N (R 3 ) or a C 1-6 alkylene group —N (R 3 ) —;
R 3 represents a C 1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
A prophylactic or therapeutic agent for obesity or diabetes comprising a compound represented by the formula:
The agent according to claim 1 , wherein R 1 is a C 1-6 alkyl group which may be substituted with a hydrogen atom or a carboxy group.
R 2 is
(1) i) a carboxy group, and
ii) a carboxy group, or a C 1-14 aryl group which may be substituted with a C 1-6 alkyl group which may be substituted with a carboxy group, or a 1 to 1 member selected from a 5- to 14-membered aromatic heterocyclic group; A C 1-6 alkyl group substituted with three substituents, or
(2) The agent according to claim 1, which is a C 6-14 aryl group optionally substituted with a C 1-6 alkyl group optionally substituted with a carboxy group.
The agent according to claim 1, wherein X is -C (O)-and Y is a bond or a C 1-6 alkylene group.
The agent according to claim 1, wherein ring A is a hydrocarbon ring optionally substituted with 1 to 3 halogen atoms, or a 5- to 14-membered aromatic heterocyclic ring.
The agent according to claim 1, wherein ring B is a benzene ring optionally substituted with a halogen atom.
The agent according to claim 1, wherein Z is a guanidino group.
R 1 is a C 1-6 alkyl group which may be substituted with a hydrogen atom or a carboxy group,
R 2 is
(1) i) a carboxy group, and
ii) a carboxy group, or a C 1-14 aryl group which may be substituted with a C 1-6 alkyl group which may be substituted with a carboxy group, or a 1 to 1 member selected from a 5- to 14-membered aromatic heterocyclic group; A C 1-6 alkyl group substituted with three substituents, or
(2) a C 6-14 aryl group which may be substituted with a C 1-6 alkyl group which may be substituted with a carboxy group,
X is —C (O) —, Y is a bond or a C 1-6 alkylene group,
Ring A is a hydrocarbon ring optionally substituted with 1 to 3 halogen atoms, or a 5- to 14-membered aromatic heterocycle,
Ring B is a benzene ring optionally substituted with a halogen atom,
The agent according to claim 1, wherein Z is a guanidino group.
General formula for mammals:
(R 1 ) (R 2 ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R 1 and R 2 each independently represent a hydrogen atom or a substituent;
R 1 and R 2 may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C 1-6 alkylene group or a C 1-6 alkylene group —C (O) —;
Y represents a bond, a C 1-6 alkylene group, N (R 3 ) or a C 1-6 alkylene group —N (R 3 ) —;
R 3 represents a C 1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
A method for preventing or treating obesity or diabetes in the mammal, comprising administering an effective amount of a compound represented by the formula:
For producing a prophylactic or therapeutic agent for obesity or diabetes,
General formula:
(R 1 ) (R 2 ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R 1 and R 2 each independently represent a hydrogen atom or a substituent;
R 1 and R 2 may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C 1-6 alkylene group or a C 1-6 alkylene group —C (O) —;
Y represents a bond, a C 1-6 alkylene group, N (R 3 ) or a C 1-6 alkylene group —N (R 3 ) —;
R 3 represents a C 1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
Or a salt thereof.
For use in the prevention or treatment of obesity or diabetes,
General formula:
(R 1 ) (R 2 ) N—X—Y—A—O—C (O) —BZ (I)
[Where,
R 1 and R 2 each independently represent a hydrogen atom or a substituent;
R 1 and R 2 may form a nitrogen-containing heterocycle in which they may be substituted with the adjacent nitrogen atom;
X represents —C (O) —, a C 1-6 alkylene group or a C 1-6 alkylene group —C (O) —;
Y represents a bond, a C 1-6 alkylene group, N (R 3 ) or a C 1-6 alkylene group —N (R 3 ) —;
R 3 represents a C 1-6 alkyl group or a hydrogen atom;
Ring A represents an optionally substituted ring (excluding dihydrobenzofuran);
Ring B represents an optionally substituted aromatic hydrocarbon ring;
Z represents an amino group which may be substituted. ]
Or a salt thereof.