WO2003000697A1 - Furoisoquinoline derivative, process for producing the same, and use - Google Patents

Abstract

A compound having the partial structure represented by the formula (I) or a salt thereof; and a compound represented by the formula (II) [wherein R1 represents an optionally substituted hydrocarbon group, etc.; R2 and R3 each represents an optionally substituted hydrocarbon group, etc.; R4 and R5 each represents hydrogen, etc.; R6 and R7 each represents an optionally substituted hydrocarbon group, etc.; R8 represents hydrogen, -OR10 (R10 represents an optionally substituted hydrocarbon group, etc.), etc.; R9 represents hydrogen, etc.; X represents optionally substituted methylene, etc.; and n is 0 or 1] or a salt thereof. They have excellent phosphodiesterase IV inhibitory activity and are useful as preventives/remedies for inflammatory diseases, asthma, chronic obstructive pulmonary diseases, chronic rheumatoid arthritis, autoimmune diseases, depression, senile dementia of Alzheimer type, memory disorders, diabetes, and arteriosclerosis.

Description

 Specification

 Phosphorus derivatives, their production methods and applications

 The present invention has a phosphodiesterase (PDE) IV inhibitory effect, and has an inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory impairment, diabetes, arteriosclerosis The present invention relates to novel freusoquinoline derivatives useful as preventive and therapeutic agents, their production methods and uses. Background art

 Today, many hormones and neurotransmitters regulate their cellular functions by increasing or decreasing the intracellular concentration of the intracellular second messenger syn-3 ', 5'-phosphate (cAMP). are doing. The intracellular concentration of cAMP is controlled by synthases and degradative enzymes. That is, cAMP is produced by adenyl cyclase and degraded by PDE. This degrading enzyme also controls the degradation of cyclic guanosine-3 ', 5'-phosphate (cGMP).

 To date, the PDE has identified 11 isozymes, [Proceedings of the National Academy of Sciences of the National Academy of Sciences of the United States. 97, p. 3702 (2000).], in various cells such as the central, circulatory, respiratory, digestive, genital, blood cells, and tracheal smooth muscle. Regulates intracellular cAMP and cGMP levels and regulates cell functions. It is known that inflammatory cells such as eosinophils, neutrophils, monocytes, T-lymphocytes, and macrophages mainly contain PDE IV, one of the isozymes of PDE. Perimental allergy (Clinical and Experimental Allergy), 22, 337 (1992).].

As a treatment for asthma, three main types of drugs are used. That is, bronchodilators (e.g., beta-adrenergic receptor agonists), anti-inflammatory drugs (e.g., corticosteroids), and xanthine derivatives having both bronchodilator and anti-inflammatory effects (e.g., For example, theophylline). In particular, theophylline has been widely used as a therapeutic agent for asthma since ancient times. It has been shown that theophylline's bronchodilator activity is based on PDE inhibitory activity, and has recently attracted attention. However, theophylline is a non-selective PDE inhibitor, and cardiovascular side effects are often observed and require strict control of blood levels. Therefore, there is a demand for a therapeutic drug for inflammatory diseases such as asthma that selectively inhibits only PDE IV and does not act on other PDE isozymes.

 Studies have shown that PDE IV selective inhibitors may be effective therapeutic agents for inflammatory diseases such as asthma [Pulmonary Pharmacology, 7, 1 (1994) ·]. As a compound having a PDE IV selective inhibitory action,

Rolipram (JP-A 50-157 7 360) and formulas represented by

SB 2 0 7 4 9 9 [The Journal of Pharmacology and Experimental Therapeutics], 287, 988 (1998) ·, Journal Journal of Medicinal Chemistry, vol. 41, p. 821 (1998).] Is known. However, it has not been applied clinically to date.

で表される部分構造を有する化合物が開示されている。 In addition, W001 / 70746 includes, as a compound having a PDE IV selective inhibitory action,

The compound which has the partial structure represented by these is disclosed.

 On the other hand, Bulletin De La Societe Chimique De France 4201 (1972)

[— Represents a single bond or a double bond].

 In addition, W002 / 04455 includes a formula as a therapeutic agent for neurological and psychiatric deficiencies based on the reuptake inhibitory effect of the norepinephrine transporter protein.

Wherein, R ¹ is - 6 have alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C _{3 6} consequent opening alkyl, a C ₄ _ ₇ cycloalkylalkyl or base Njiru (These particular substituent May be)

R ² is a hydrogen atom, alkyl, C ₂₆ alkenyl, C ₂ _ ₆ alkynyl, C. ₆ A cycloalkyl, C _{4 7} cycloalkylalkyl or C ^ ₆ eight-necked alkyl,

R ³ is a hydrogen atom, a halogen atom, alkyl, haloalkyl or C ₃ _ ₆ cycloalkyl (said C i ₆ alkyl, ₍₆ haloalkyl, C _{3 6} cycloalkyl may have a specific substituent),

R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, nitro, etc., and R ⁷ represents a hydrogen atom, a halogen atom, etc.)

Are disclosed.

 Strong selective PDE IV inhibitors can be expected to be fully effective in preventing or treating a wide range of diseases involving inflammation. The present invention provides a novel heterocyclic compound having a selective inhibitory effect on PDE IV, a bronchodilator effect and an anti-inflammatory effect by increasing the intracellular cAMP concentration, and further having excellent safety and other aspects. To provide. Disclosure of the invention

 The present inventors have conducted various studies and found that the formula

[Wherein, ring A, ring B and ring C may each have a substituent.] A novel furoisoquinoline compound having a partial structure represented by the following formula (hereinafter abbreviated as compound (I) ) In particular, it has a great chemical structural characteristic when a substituent is introduced at the 1st, 2nd, 4th, 5th, 6th, 7th, 8th, 9th, etc. positions of the furoisoquinoline skeleton , Expression

[In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ² and R ³ each represent a hydrogen atom or a substituent. R ² and R ³ may have a substituent together with adjacent carbon atoms to form a 3- to 8-membered ring. R ⁴ and R ⁵ each represent a hydrogen atom or a hydrocarbon group which may have a substituent; R ⁶ and R ⁷ each represent a hydrogen atom or a hydrocarbon group which may have a substituent; 1¾ ⁶ and 1 ^ ⁷ may form a 8-membered ring to 3 which may have a substituent together with the adjacent carbon atoms, R ⁸ is (1) a hydrogen atom, Yure (2) substituent hydrocarbon group which may be substituted, (3) Ashiru group, (4) an optionally substituted heterocyclic group, (5) halogen atom, (6) -OR ¹⁰ (R ^1Q is a hydrogen atom Substituent has optionally may hydrocarbon group, was Ashiru group or indicates a heterocyclic group which may have a ^{substituent), (7) -SR 11 (} R 11 is a hydrogen atom, a substituent A hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), (8) -S (0) R ¹² (where R ¹² has a substituent A hydrocarbon group or a heterocyclic group which may have a substituent), (9) one S (O) ₂ R ¹³ (R ¹³ is a hydrocarbon group which may have a substituent or (Shows an optionally substituted heterocyclic group) or (10) — NR ¹⁴ R ¹⁵ (R ¹⁴ and R ¹⁵ are each a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group Or R ⁹ represents a hydrogen atom, a cyano group, a hydrocarbon group optionally having a substituent, an acyl group or a substituent. Moyo A hydroxyl group, X represents a methylene group or an oleponyl group which may have a substituent, and n represents 0 or 1.] A novel furisoquinoline compound represented by the following formula (hereinafter sometimes referred to as compound (): A) or its salt or its prodrug or its hydrate for the first time Synthesized successfully, these compounds have unexpectedly excellent PDE inhibitory activity, especially PDE IV inhibitory activity, based on their unique chemical structure, and have inflammatory disease, asthma, chronic obstructive pulmonary disease It has been found that it can be used as a drug for the prevention and treatment of rheumatoid arthritis, autoimmune diseases, depression, Alzheimer's dementia, memory impairment, diabetes, arteriosclerosis and the like. The present inventors have further studied based on these findings, and as a result, completed the present invention.

 That is, the present invention

 〔1 set

A compound having a partial structure represented by (hereinafter sometimes abbreviated as compound (A)) or a salt thereof;

 (2) Expression

[Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent] or a salt thereof. ;

(3) Expression ()

[In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ² and R ³ each represent a hydrogen atom or a substituent. Represents a hydrocarbon group or an acyl group which may be possessed; R ² and R ³ may form a 3- to 8-membered ring which may have a substituent together with an adjacent carbon atom; ⁴ and R ⁵ hydrocarbon group which may have a each represent a hydrogen atom or a substituent, R ⁶ and R ⁷ each represent a hydrogen atom or an optionally substituted hydrocarbon group, R ⁶ And R ⁷ may form a 3- to 8-membered ring which may have a substituent together with an adjacent carbon atom, and R ⁸ is (1) a hydrogen atom, or (2) A good hydrocarbon group, (3) an acyl group, (4) an optionally substituted heterocyclic group, (5) a halogen atom, (6) -OR ¹⁰ (R ^1Q is a hydrogen atom, A hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), (7) -SR ¹¹ (R ¹¹ is a hydrogen atom or a substituent A hydrocarbon group, an acyl group, or an optionally substituted heterocyclic group), (8) — S (O) R ¹² (where R ¹² has a substituent A hydrocarbon group or a heterocyclic group optionally having substituent (s)), O) -S (O) ₂ R ¹³ (R ¹³ is a hydrocarbon group optionally having substituent (s)) Or a heterocyclic group which may have a substituent) or (10) — NR ¹⁴ R ¹⁵ (R ¹⁴ and R ¹⁵ are each a hydrogen atom, a hydrocarbon group which may have a substituent, R ⁹ represents a hydrogen atom, a cyano group, a hydrocarbon group which may have a substituent, an acyl group or a substituent. May A hydroxyl group, X represents a methylene group or a carbonyl group which may have a substituent, and n represents 0 or 1.] or a salt thereof;

[4] R ¹ represents any of the following (i) or (ii): (i) (1) halogen atom, (2) alkylenedioxy group, (3) nitro group,

(4) cyano group, (5) optionally halogenated — 6 alkyl group, (6) optionally halogenated C ₂ _ ₆ alkenyl group, (7) optionally halogenated C ₂ _ ₆ alkynyl group, (8) C ₃ _ ₆ cycloalkyl group, (9) C ₆ - ₁₄ Ariru group, (10) optionally halogenated C ^ - ₆ alkoxy group, a (11) halogenated Alkylthio group, (12) hydroxy group, (13) amino group, (14) mono-

_6- alkylamino group, (15) MONO C ₆ — ₁₄ arylamino group, (16)

_ ₆ alkylamino group, (17) di - C ₆ - ₁₄ Ariruamino group, (18) formyl, force Rupokishi force Rubamoiru, alkyl Ichiriki Ruponiru, C ₃ - ₆ cycloalkyl Ichiriki Ruponiru, alkoxy - force Ruponiru, C 6 ^ ₄ Ariru Ichiriki Ruponiru, c ₇ - ₁₆ Ararukiru Ichiriki Ruponiru, c ₆ _ ₁₄ Ariruokishi Ichiriki Ruponiru, c ₇ _ ₁₆ § La Rukiruokishi - force Ruponiru, nitrogen atom in addition to carbon atoms, or a sulfur atom and an oxygen atom et 1 to 5 or 6-membered heterocyclic carbonyl containing heteroatoms three of the selected, mono _C alkyl Ichiriki Rubamoiru, di Ji alkyl Ichiriki Rubamoiru, C ₆ _ ₁₄ Ariru Ichiriki Rubamoiru, nitrogen in addition to carbon atoms 5- or 6-membered heterocyclic carbamoyl containing 1 to 3 heteroatoms selected from atoms, sulfur atoms and oxygen atoms, C- ₆ alkyl-thiocal Boniru, C ₃ - ₆ cycloalkyl one Chiokaruponiru,

C ^ 6 alkoxy one Chiokaruponiru, C ₆ _ ₁₄ Ariru - Chiokaruponiru, C ₇ _ ₁₆ Ararukiru one Chiokaruponiru, C ₆ - ₁₄ Ariruokishi - Chio force Ruponiru, C ₇ _ ₁₆ Ararukiruokishi one Chiokaruponiru, nitrogen atom in addition to carbon atom, a sulfur atom and to 1 selected from oxygen radicals containing heteroatoms three of the 5 or 6-membered heterocyclic Ji Sairyoku Ruponiru, Chiokarubamoiru, mono- (^ _ ₆ alkyl one Chiokarubamoiru, di one CI- ₆ alkyl one Chio carbamoyl, C ₆ _ ₁₄ § reel over Chio Scarpa moil, nitrogen atom in addition to carbon atom, a sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic ring Chiokarubamoiru selected from oxygen atom, sulfamoyl, mono - C丄-6 alkylsulfamoyl, di - - 6 alkylsulfamoyl, C ₆ one ₁₄ § Li one Rusurufamo Le, alkylsulfonyl, C ₆ - ₁₄ § reel sulfonyl, C, _ ₆ alkylsulfinyl, C ₆ _ ₁₄ § reel sulfide El, sulfino, sulfo, C - ₆ alkoxysulfinyl sulfinyl, C ₆ _ ₁₄ § Li one Ruo carboxymethyl sulfinyl, C to ₆ Al Kokishisuruhoniru and 〇 ₆ _ ₁₄ Ashiru group selected from § reel O carboxymethyl sulfonyl, (19) Horumiruamino, alkyl Ichiriki Rupokisamido, C ₆ - ₁₄ Ariru - Cal Pokisamido, (^ -6 alkoxy Ichiriki Rupokisamido, CI- ₆ alkylsulfonyl amino, and C ₆ - i ₄ § Li one Le sulfonyl Ashiruamino group selected from § amino, (20) (:. ₆ alkyl - force Ruponiruokishi, C ₆ - ₁₄ Ariru Ichiriki Ruponiruokishi, (: City ₆ a ^ / Kokishi Ichiriki Ruponiruokishi, mono- ci _ ₆ alkyl - force Rubamoiruokishi, di one C ₆ alkyl Ichiriki Rubamoiruokishi, C ₆ - _{1 4} § Li one Roux force Rubamoiruokishi per cent and Ashiruokishi group selected from nicotinyl Noi Ruo alkoxy, (21) 4 to 14 containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Membered heterocyclic group, (22) phosphono group, (23) C 64 ₄ Ariruokishi group, (24) di - CI- ₆ alkoxy one phosphoryl group, (25) C ₆ - ₁₄ § Li one thio group, (26) hydrazino group, (27) imino group, (28) Okiso group, (29) an ureido group, (30) C _x _ ₆ alkyl one ureido group, (31) G ₍₆ alkyl chromatography © raid group, (32) Okishi de group And (33) a group selected from the group consisting of two or three groups selected from the groups (1) to (32) and the like (hereinafter, abbreviated as substituent group A); Do stone five good C _ ₆ alkyl group which may have, respectively, C ₂ - ₆ alkenyl, C ₂ one ₆ alkynyl group, C ₃ _ ₆ cycloalkyl group, C ₃ - ₆ cycloalkenyl group, C ₆ _ ₁₄ T reel base or the C ₇ _ ₁₆ Ararukiru group,

 (ii) 5 to 14 containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to the carbon atom which may have 1 to 5 substituents selected from the substituent group A. Membered heterocyclic group;

R ² and R ³ each represent one of the following (i) to (iii):

 (i) a hydrogen atom,

(ii) the 1 a substituent selected from the substituent group A to 5 but it may also have each an alkyl group, C ₂ - ₆ alkenyl group, C ₂ _ ₆ alkynyl, C ₃ - ₆ a cycloalkyl group , C ₃ _ ₆ cycloalkenyl group, C ₆ - ₁₄ Ariru group or C ₇ _ ₁₆ Ararukiru

(iii) said may have 1 to 5 substituents selected from the substituent group A, E mill, force Rupokishi force Rubamoiru, alkyl Ichiriki Ruponiru, C ₃ - ₆ cycloalkyl Alkyl - carbonyl, C ₆ alkoxy Ichiriki Ruponiru, c ₆ _ ₁₄ § Li one Rukarubo alkenyl, C ₇ _ ₁₆ Ararukiru Ichiriki Ruponiru, C ₆ _ ₁₄ Ariruokishi Ichiriki Ruponiru, C

Ichiriki ₇ _ ₁₆ Ararukiruokishi Ruponiru, nitrogen atom in addition to carbon atom, a sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic force Ruponiru selected from oxygen atom, mono- C - ₆ alkyl Ichiriki Rubamoiru, di - 6 alkyl - power resolver moil, c ₆ - ₁₄ Ariru Ichiriki Rubamoiru, nitrogen atom in addition to carbon atoms, 5 or containing 1 to heteroatoms three of the selected sulfur atom Contact and oxygen atom 6 membered double ring force Rubamoiru, C _ ₆ alkyl one Chiokaruponiru, C ₃ _ ₆ cycloalkyl over Ji Okaruboniru, C ₆ alkoxy - Chio force Ruponiru, C ₆ _ ₁₄ § Li one Ruchiokarupo alkenyl, c ₇ _ ₁₆ Ararukiru one Chiokaruponiru, c ₆ _ ₁₄ Ariruokishi one Chiokarupo el, c ₇ - ₁₆ § Lal kill O Kishi Chio carbonyl, nitrogen atom in addition to carbon atoms, sulfur atoms and 5 or 6 membered heterocyclic ring Chiokaruponiru containing hetero atoms to 1 selected from atom 3 of the, Chiokarubamoiru, mono- C _ ₆ alkyl one Chioka Rubamoiru, di- (^ _ ₆ alkyl one Chiokarubamoiru, C ₆ - _14- Rutical Bamoyl, 5- or 6-membered heterocyclic thiocarpamoyl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, sulfamoyl, mono-C i— e alkylsulfamoyl, di-C alkylsulfamoyl, C ₆ one ₁₄ § reel sulfamoyl, ₆ alkylsulfonyl, C ₆ - ₁₄ Arirusu Ruhoniru, Ci-e alkylsulfinyl, C ₆ - ₁₄ § Li one Rusurufiniru, Surufi Bruno, sulfo, C i_ ₆ alkoxysulfinyl sulfide El, C ₆ _ ₁₄ § Li one Ruo alkoxy sulfinyl, C ^ 6 alkoxysulfonyl And C 6 ₄ Ashiru group § reel O carboxymethyl Ru selected from sulfo El;

R ² and R ³ together with the adjacent carbon atom, alkyl, C ₆ _ ₁₄ 7 reel, C ₇ - ₁₆ Ararukiru, Amino, mono- Arukiruamino, mono- C ₆ - ₁₄ Arirua amino, di- (: Preparative ₆ Arukiruamino, di one C ₆ — ₁₄ arylamino and a C ₃ _ ₈ cycloalkane optionally having 1 to 3 substituents selected from a 4- to 10-membered aromatic heterocyclic group or a 3- to 8-membered heterocyclic group Often ;

R ⁴ and R ⁵ may have, respectively (i) a hydrogen atom or (ii) the substituent, 1 to selected Ru substituents from group A 5 each - 6 alkyl group, C ₂ _ ₆ Al Kenyir group, c ₂ - ₆ alkynyl group, c ₃ _ ₆ cycloalkyl group, c ₃ - ₆ Shikuroaruke two Le group, c ₆ _ ₁₄ Ariru group or c ₇ - ₁₆ Ararukiru group;

R ⁶ and R ⁷ are each (i) a hydrogen atom or (ii) an alkyl group, a C ₂ _ ₆ alkenyl group which may have 1 to 5 substituents each selected from the aforementioned substituent group A, C ₂ _ ₆ alkynyl, C ₃ - ₆ cycloalkyl group, C ₃ _ ₆ Shikuroaruke two Le group, C ₆ - ₁₄ Ariru radical or C ₇ - ₁₆ show the Ararukiru group,

R ⁶ and R ⁷ together with the adjacent carbon atom, alkyl, C ₆ one ₁₄ Ariru, C ₇ _ _{1 6} Ararukiru, Amino, mono- - 6 Arukiruamino, mono- C ₆ _ ₁₄ Arirua amino, di- ₍₆ Arukiruamino, di C ₆ - ₁₄ to Ariruamino and 3 good C ₃ no one ₈ cycloalkane or 3 have respectively, 1 to substituents selected from 4- to 10-membered aromatic heterocyclic group may form a 8-membered heterocyclic ring;

R ⁸ represents one of the following (i) to (X):

 (i) a hydrogen atom,

(ii) but it may also have the, 1 to substituents selected from the substituent group A 5 each - ₆ alkyl group, C ₂ one ₆ alkenyl, C ₂ - ₆ alkynyl group, C ₃ _ ₆ cycloalk kill group, C ₃ _ ₆ cycloalkenyl group, C ₆ - ₁₄ Ariru radical or C ₇ - ₁₆ Ararukiru

(iii) the substituents selected from substituent group A may have 1 to have five, Ho mill, carboxy, force Rubamoiru, CI- ₆ alkyl one carbonyl, C ₃ one ₆ cycloalkyl - Power Ruponiru, C丄_ ₆ alkoxy Ichiriki Ruponiru, C ₆ _ ₁₄ Ariru Ichiriki Lupo El, C ₇ _ ₁₆ Ararukiru Ichiriki Ruponiru, C ₆ - ₁₄ Ariruokishi Ichiriki Ruponiru, C ₇ _ ₁₆ Ararukiruokishi Ichiriki Ruponiru, in addition to carbon atoms nitrogen atom, sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic force Ruponiru selected from oxygen atom, mono-one C DOO ₆ alkyl - force Rubamoiru, di - alkyl Ichiriki resolver moil, C ₆ - ₁₄ Ariru Ichiriki Rubamoiru, nitrogen atom, to 1 selected from nitrogen atom Contact and oxygen atoms containing hetero atoms 3 of the 5 or 6 membered double ring force Rubamoiru in addition to carbon atoms C丄_ ₆ alkyl one Chiokaruponiru, C ₃ _ ₆ cycloalkyl - Chi Sairyoku Ruponiru, C ^ - ₆ alkoxy - Chio carbonyl, C ₆ _ ₁₄ Ariru one Chiokarupo El, C ₇ _ ₁₆ Ararukiru - Chio carbonyl, C ₆ - ₁₄ Aryloxy-Carbo Alkenyl, C ₇ one ₁₆ Ararukiruokishi - Chio force Ruponiru, 5 or 6 membered heterocyclic ring Chiokaruponiru containing 1 to heteroatoms three of the selected from a nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms, Chiokarubamoiru , mono- alkyl one Chioka Rubamoiru, di-alkyl one Chiokarubamoiru, C ₆ - ₁₄ § reel over Chio local Bamoiru, nitrogen atom in addition to carbon atoms, a sulfur atom and 1 to heteroatoms three of the selected oxygen atom 5 or 6 membered heterocyclic ring Chiokarubamoiru, Surufamo I Le, mono- C _i-6 alkylsulfamoyl, _di-6 alkylsulfamoyl, C ₆ _ ₁₄ § Li one Rusurufamoiru, alkylsulfonyl, C ₆ one ₁₄ Arirusu Ruhoniru, CI_ ₆ alkyl sulfide El, C ₆ _ ₁₄ § reel sulfinyl, Surufi Roh, sulfo, (^ _ ₆ Arco Shisurufiniru, c ₆ - ₁₄ § Li one Ruo carboxymethyl sulfide El,

Ci- e alkoxysulfonyl and C ₆ - ₁₄ § Li one Ruo carboxymethyl sulfonyl El from selected Ru Ashiru group,

 (iv) In addition to the carbon atom which may have 1 to 5 substituents selected from the aforementioned substituent group A, including 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms, 5 to 5 14-membered heterocycle,

 (v) a halogen atom,

(vi) -OR ¹⁰ (R ^1Q is (i ′) a hydrogen atom, and (ii ′) a C i-6 alkyl group which may have 1 to 5 substituents each selected from the aforementioned substituent group A. , C ₂ _ ₆ alkenyl group, C ₂ _ ₆ alkynyl, C ₃ - ₆ cycloalkyl group, C ₃ - ₆ cycloalkenyl group, _{(6 "14} Ariru group or C ₇ _ ₁₆ Ararukiru group, (iii ' ) wherein, 1 to substituents selected from the substituent group a may have five, formyl, force Rubamoiru, E _ ₆ alkyl Ichiriki Ruponiru, C ₃ - ₆ cycloalkyl - power Ruponiru, - 6 alkoxy - carbonyl, C ₆ - ₁₄ Ariru - force Ruponiru, C ₇ - ₁₆ Ararukiru - force Ruponiru, C ₆ _ ₁₄ § Li one Ruo Kishi carbonyl, C ₇ _ ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom besides carbon atom, a sulfur atom Contains 1 to 3 hetero atoms selected from That 5 or 6 membered heterocyclic force Ruponiru, mono- C bets ₆ alkyl - Power resolver moil, di - 6 alkyl Ichiriki Rubamoiru, C ₆ _ ₁₄ Ariru - force Rubamoiru, nitrogen atom besides carbon atom, sulfur atom and oxygen atom 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from: rubamoyl, alkyl monocarbo Alkenyl, C ₃ _ ₆ cycloalkyl one Chiokaruponiru, alkoxycarbonyl Kishi Chio carbonylation Le, C ₆ _ ₁₄ Ariru - Chio carbonyl, C ₇ one ₁₆ Ararukiru - Chio carbonyl, C

₆ _ ₁₄ Ariruokishi one Chiokaruponiru, C ₇ - ₁₆ Ararukiruokishi one Chiokarupo two Le, nitrogen atom, sulfur atom and to 1 selected from an oxygen atom containing heteroatoms three of the 5 or 6-membered heterocyclic ring Chio in addition to carbon atoms selected ₆ alkyl one Chiokarubamoi le, c ₆ _ ₁₄ § Li one Roux Chio carbamoyl, nitrogen atom in addition to carbon atoms, a sulfur atom Contact and oxygen atom - carbonyl, Chiokarubamoiru, mono- C WINCH ₆ alkyl one Chiokarubamoiru, di C 1 to 3 containing heteroatoms of 5 or 6 membered double ring Chiokarubamoiru, sulfamoyl, mono- C i one ₆ alkylsulfamoyl, di C _ ₆ alkylsulfamoyl, C ₆ - ₁₄ § Li one Rusurufamoiru , C ₆ Al alkylsulfonyl, C ₆ - ₁₄ § Li one Rusuruhoniru, ₆ alkylsulfide El, C ₆

アルコキシスルホニルおよび C₆— ₁₄ァリ一ルォキシスルホ エルから選ばれるァシル基または （iv') 前記置換基 A群から選ばれる置換基を 1 ないし 5個有していてもよい炭素原子以外に窒素原子、硫黄原子および酸素原子か ら選ばれるヘテロ原子を 1ないし 4個含む 5ないし 14員複素環を示す） 、 (vii) -SR¹¹ (R¹¹は、 （i，） 水素原子、 （iiゥ 前記置換基 A群から選ばれる 置換基を 1ないし 5個それぞれ有していてもよいじ ₆アルキル基、 C₂_₆アルケ ニル基、 C₂_₆アルキニル基、 C ₃— ₆シクロアルキル基、 C₃— ₆シクロアルケニル 基、 C₆— ₁₄ァリール基または C₇_₁₆ァラルキル基、 （iii') 前記置換基 A群から 選ばれる置換基を 1ないし 5個有していてもよい、 ホルミル、 力ルバモイル、 d-14 § reel sulfide El, C - ₆ alkoxysulfinyl Luffy El, C ₆ _ ₁₄ § Li one Ruoki Shisurufieru,

Alkoxysulfonyl and C ₆ - ₁₄ Ashiru group or (iv ') the substituent A 1 without a substituent selected from the group to five has optionally a nitrogen atom in addition also be carbon atoms selected from § Li one Ruokishisuruho El, A 5- to 14-membered heterocyclic ring containing 1 to 4 hetero atoms selected from a sulfur atom and an oxygen atom), (vii) -SR ¹¹ (R ¹¹ is a (i,) hydrogen atom, (ii 1 to 5 Ji may have respectively ₆ alkyl group a substituent selected from group a, C ₂ _ ₆ alkenyl group, C ₂ _ ₆ alkynyl, C ₃ - ₆ cycloalkyl group, C ₃ - ₆ cycloalkenyl group, C ₆ - ₁₄ Ariru group or C ₇ _ ₁₆ Ararukiru group, which may have five to 1 substituent selected from (iii ') the substituent group a, formyl, force Rubamoiru , D

- ₆ alkyl - carbonyl, C ₃ - ₆ cycloalkyl Ichiriki Ruponiru one ₆ alkoxy Ichiriki Ruponiru, C ₆ - ₁₄ Ariru Ichiriki Ruponiru, C ₇ _ ₁₆ Ararukiru one carbonyl, C ₆ _ ₁₄ Ariruokishi - Power Lupo: I Le, C ₇ - ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom besides carbon atom, a sulfur atom and to 1 selected from an oxygen atom containing terrorist atom 3 of the 5 'or 6-membered heterocyclic ring force Ruponiru, mono- C i_ ₆ alkyl Ichiriki resolver moil, di _ C _ ₆ alkyl Ichiriki Rubamoiru, C ₆ _ ₁₄ Ariru - Karupamoiru, nitrogen atom in addition to carbon atom, to 1 selected from sulfur atom and an oxygen atom Te to three of 5- or 6-membered heterocyclic moieties containing an orbital atom Lubamoyl, alkyl monocarbo Alkylsulfonyl, C ₃ - ₆ cycloalkyl over Chio carbonyl, (^ alkoxy one Chiokarupo two Le, C ₆ - ₁₄ Ariru one Chiokaruponiru, C ₇ _ ₁₆ Ararukiru - Chiokaruponiru, C

6 ^ ₄ aralkyloxyl talc, C7 ^ ₆ aralkyloxyl oxyl, containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon 5 or 6-membered heterocyclic ring Chiokaruponiru, Chiokarubamoiru, mono- C i _ ₆ alkyl one Chiokarubamoiru, di C i _ ₆ alkyl one Chiokarubamoi Le, C ₆ _ ₁₄ § Li one Roux Chio carbamoyl, nitrogen atom in addition to carbon atom, a sulfur atom 1 to 3 containing heteroatoms of 5 or 6 membered double ring Chiokarubamoiru selected from Contact and oxygen atoms, sulfamoyl, mono- C _i-6 alkylsulfamoyl, di - 6 alkylsulfamoyl, C ₆ _ ₁₄ § reel sulfamoyl, C - ₆ Al alkylsulfonyl, C ₆ _ ₁₄ § Li one Rusuruhoniru, (^ _ ₆ alkyl sulfide El, C ₆

-14 § reel sulfinyl substitutions, alkoxysulfinyl sulfide El, C ₆ one ₁₄ Ariruoki Shisurufiniru, selected from alkoxysulfonyl and C 6 ^ ₄ § reel O alkoxy or Ashiru selected from sulfonyl group (ίν ') the substituent Α group A 5- to 14-membered heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have 1 to 5 groups),

(viii) -S (〇) R ¹² (R ¹² is (i,) a Ci- ₆ alkyl group optionally having 1 to 5 substituents selected from the aforementioned substituent group A, C ₂ - ₆ alkenyl, C ₂ one ₆ alkynyl group, C ₃ _ ₆ cycloalkyl group, C ₃ - ₆ cycloalkenyl group, C ₆ - ₁₄ § aryl group or C ₇ - ₁₆ Ararukiru group or (ii ') the substituent Group A 5- to 14-membered heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have 1 to 5 substituents selected from group A ),

(ix) -S (〇) ₂ R ¹³ (R ¹³ is (i,) an alkyl group optionally having 1 to 5 substituents selected from the above-mentioned substituent group A, C ₂ _ ₆ alkenyl group, C ₂ _ ₆ alkynyl, C ₃ _ ₆ cycloalkyl group, C ₃ - ₆ cycloalkenyl group, ₍₆ - ₁₄ § aryl group or 〇 ₇ _ ₁₆ Ararukiru group or (ii,) the substituent group A A 5- to 14-membered heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have 1 to 5 substituents selected from) ,

(X) — NR ¹⁴ R ¹⁵ (R ¹⁴ and R ¹⁵ are each a (ί ′) hydrogen atom, (ii,) the above substitution , 1 to substituents selected from group A five may have respective C ^ ₆ Al kill groups, C ₂ - ₆ alkenyl groups, C ₂ - ₆ alkynyl groups, C ₃ _ ₆ cycloalkyl groups, C ₃ - ₆ cycloalkenyl group, ₍₆ _ ₁₄ Ariru group or C ₇ _ ₁₆ Ararukiru group, (iii ⁵⁾ said may have 1 to 5 substituents selected from the substituent group a, formyl, Karupamoiru , alkyl Ichiriki Ruponiru, C ₃ - ₆ cycloalkyl - force Ruponiru, alkoxy Ichiriki Ruponiru, C ₆ - ₁₄ Ariru Ichiriki Ruponiru, C ₇ - ₁₆ Araruki Lou force Ruponiru, C ₆ _ ₁₄ § Li one Ruokishi - power Ruponiru , C ₇ _ ₁₆ aralkyloxycarbonyl, containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. 5- or 6-membered heterocyclic carbonyl, mono-C alkyl. Force rubamo Le, di alkyl Ichiriki Rubamoiru, C ₆ - ₁₄ Ariru Ichiriki Rubamoiru, nitrogen atom in addition to carbon atom, a sulfur atom and 1 to 5 or 6-membered heterocyclic ring force containing heteroatoms three of the selected oxygen atom Rubamoiru, (^ _ ₆ Al kill one Chiokaruponiru, C ₃ -. ₆ cycloalkyl one Chiokaruponiru, DOO ₆ alkoxy Sea Chio carbonyl, C ₆ _ ₁₄ § Li one Roux Chio local Poni Le, C ₇ - ₁₆ Ararukiruchi Sairyoku Ruponiru, C ₆ - ₁₄ Ariruokishi - Chio carbonyl, C ₇ _ ₁₆ Ararukiruoki sheet - Chi Sairyoku Ruponiru, nitrogen atom in addition to carbon atoms, 5 or 6 membered heterocyclic containing 1 to heteroatoms three of the selected sulfur atom and an oxygen atom ring Chio carbonyl, Ji Sairyoku Rubamoiru, mono- C i _ ₆ alkyl one Chiokarubamoiru, di one C ₆ alkyl - Chio force Rubamoiru, C ₆ _ ₁₄ § Li Luciocarbamoyl, 5- or 6-membered heterocyclic thiocarbamoyl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, thiocarbamoyl, sulfamoyl, mono--6 alkylsulfamoyl, di _C - ₆ alkylsulfamoyl, C ₆ _ ₁₄ § reel sulfamoyl Le, C WINCH ₆ alkylsulfonyl, C ₆ - ₁₄ § reel sulfonyl, alkylsulfinyl Fier, C ₆ _ ₁₄ § Li one Rusurufiniru, C one ₆ alkoxysulfinyl sulfinyl , C ₆ —e

₄ § Li - Ruo alkoxy sulfinyl, C DOO ₆ alkoxysulfonyl and C ₆ - ₁₄ Ari Ruo carboxymethyl sulfo Ashiru selected from sulfonyl group or (ίν ') wherein have 1 to 5 substituents selected from substituent group Α group A 5- to 14-membered heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may be present) R ⁹ is (i) a hydrogen atom, (ii) a cyano group,

(iii) said, 1 to substituents selected from the substituent group A may have five, respectively - 6 alkyl group, C ₂ _ ₆ alkenyl, C ₂ - ₆ alkynyl group, C ₃ - ₆ Shikuroa alkyl group, C ₃ _ ₆ cycloalkenyl group, C ₆ _ ₁₄ Ariru group or C ₇ - ₁₆ Araruki group,

(iv) the substituents selected from substituent group A may have 1-5 amino acids, formyl, carboxy, force Rubamoiru, ^ - ₆ alkyl - carbonyl, C ₃ _ ₆ Shikuroa Ruki Lou carbonyl, C _ ₆ alkoxy - force Ruponiru, C ₆ _ ₁₄ § Li one Roux force Lupo two Le, C ₇ _ ₆ Ararukiru Ichiriki Ruponiru, C ₆ - ₁₄ § Li one Ruokishi - force Ruponiru, C ₇ - ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atoms, to 1 selected from sulfur atom and oxygen radicals three of the 5 or 6-membered heterocyclic ring force containing heteroatoms Ruponiru, mono one C Bok ₆ alkyl - force Rubamoiru, di - CI- _6- alkyl-carbamoyl, _4- aryl-lubamoyl, 5- or 6-membered heterocyclic lubamoyl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, C ₆ Alkyl - Chiokaruponiru, C ₃ - ₆ cycloalkyl - Chio force Ruponiru, - 6 alkoxy - Chio force Ruponiru, C ₆ _ ₁₄ § Li one Ruchiokarupo two Le, C ₇ - ₁₆ Ararukiru - Chiokaruponiru, C ₆ - ₁₄ Ariruokishi - Chio force Lupo two Le, C ₇ - ₁₆ § Lal kill O Kishi Chio carbonyl, nitrogen atom in addition to carbon atom, a sulfur atom and 1 to 5 or 6-membered heterocyclic ring Chio carbonyl containing heteroatoms three of the selected oxygen atom , terrorism Chiokarubamoiru, mono- C ^ 6 alkyl one Chiokaru Bamoiru, di one ₆ alkyl one Chiokarubamoiru, C ₄ Ariru one Chiokaruba moil, nitrogen atom in addition to carbon atoms, to 1 selected from sulfur and oxygen atoms to three of containing an atom 5 or 6-membered heterocyclic ring Chiokarubamoiru, Surufamoi Le, mono- C E _ ₆ alkylsulfamoyl Famo Le, di - 6 alkylsulfamoyl, C ₆ - ₁₄ § reel sulfamoyl, alkylsulfonyl, C ₆ one _{1 4} Arirusu Ruhoniru, alkylsulfide El, _<6 _ ₁₄ § reel sulfinyl, Surufi Bruno, sulfo, C ₆ alkoxy sulfinyl, C ₆ - ₁₄ § Li one Ruo alkoxy sulfinyl, _d-6 alkoxy sulfonyl Oyobi C ₆ one ₁₄ § Li one Ruo carboxymethyl sulfonyl from Ru selected Ashiru group or, (v) Formula 1 OR ⁹ '

(R ⁹ 'is a ① hydrogen atom,

② said, 1 to substituents selected from the substituent group A may have five each C Bok ₆ alkyl group, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₆ cycloalkyl Le group , C ₃ - ₆ cycloalkenyl group, C ₆ _ ₁₄ § Li Ichiru group or C ₇ _ ₁₆ Ararukiru group or,

③ said substituent selected from the substituent group A may have 1-5 amino acids, formyl, force Rubamoiru, C WINCH ₆ alkyl one carbonyl, C ₃ - ₆ cycloalkyl Ichiriki Ruponiru, c i_ ₆ alkoxy one power Ruponiru, c ₆ _ ₁₄ § Li one Roux carbonyl, c ₇ _ ₁₆ Araruki Lou force Ruponiru, c ₆ - ₁₄ Ariruokishi - force Ruponiru, c ₇ - ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atom, sulfur atom and 5- or 6-membered heterocyclic carbonyl containing 1 to 3 heteroatoms selected from oxygen atoms, mono-C ₆ alkyl mono-rubamoyl, di-C _r — ₆ alkyl mono-rubamoyl, C ₆ — ₁₄ aryl mono-rubamoyl , nitrogen atom in addition to carbon atom, a sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic force Rubamoiru selected from oxygen atom, ₆ Al Kiruchio Carbonyl, C ₃ _ ₆ cycloalkyl over Chio carbonyl, ₆ alkoxy Sich Sairyoku Ruponiru, c ₆ - ₁₄ Ariru - Chio carbonyl, c ₇ _ ₁₆ Ararukiru - Chi Sairyoku Ruponiru, 〇 _{6, 14} Ariruokishi - Chio force Lupo sulfonyl , c ₇ - ₁₆ Ararukiruoki Sea Chio carbonyl, nitrogen atom in addition to carbon atoms, 1 selected from sulfur atom and an oxygen atom to 3 for containing heteroatoms 5 or 6-membered heterocyclic ring Chiokaruponiru, Ji Sairyoku Rubamoiru, mono- - 6 alkyl chromatography Chio Scarpa moil, di _Ci- ₆ alkyl one Chiokarubamoiru, c ₆ _ ₁₄ Ariru one Chiokarubamoiru, nitrogen atom in addition to carbon atoms, 1 to heteroatoms three of the selected sulfur atom and an oxygen atom Contains 5- or 6-membered heterocyclic thiocarbamoyl, sulfamoyl, mono-^- ₆ alkylsulfamoyl, di Alkylsulfamoyl, C ₆ - ₁₄ § reel sulfamoyl Le, (^ _ ₆ alkylsulphonyl, C 6 ₄ § reel sulfonyl, - 6 alkylsulfinyl Finiru, C ₆ _ ₁₄ § Li one Rusurufiniru, - 6 alkoxysulfinyl sulfinyl, C _Q _ ₁

₄ § Li one Ruo alkoxy sulfinyl, C - ₆ alkoxysulfonyl and C ₆ _ ₁₄ group represented by Ashiru a group) selected from § Li one Ruo carboxymethyl sulfonyl; X is ①a methylene group which may have a substituent selected from the above-mentioned substituent group A or ②a carpenyl group;

 The compound according to the above [3], wherein n represents 0 or 1;

[5] The indicating the R ² and R ³ are each (^ _ ₆ alkyl group [3] The compound according; [6] R ⁴ and R ⁵ are the represents a hydrogen atom, respectively [3] The compound according;

'[7] The compound according to the above [3], wherein R ⁶ and R ⁷ each represent an alkyl group; [8] the compound according to the above [3], wherein R ⁹ represents a hydrogen atom;

 [9] the compound of the above-mentioned [3], wherein n represents 0;

[10] R ¹ is the formula

Wherein, R ¹⁶ is a hydrogen atom, which may have a substituent C ₆ - ₁₄ Ariru group, an optionally substituted amino group, heterocyclic group which may have a substituent R ² and R ³ each represent an alkyl group; R ⁴ and R ⁵ each represent a hydrogen atom; R ⁶ and R ⁷ each represent a Ci- ₆ alkyl group; and R ^{8 represents a} halogen atom. A hydrogen atom or a monovalent R ^1Q (R ^1Q represents a hydrogen atom, which may have a substituent—a 6-alkyl group or an acyl group), R ⁹ represents a hydrogen atom, and n represents 0; 3] The compound as described;

[11] R ^{1 ()} is (1) a hydrogen atom, (2) a C— ₆ alkyl group optionally substituted with pyridyl, or (3) a Ct- ₆ alkylsulfonyl substituted with a halogen atom, R ¹⁶ is selected from (1) hydrogen atom, (2) phenyl substituted by acetylamino, (S Ci- ₆ alkylsulfonyl group, (ii) pyridyl carpoel or (iii) sulfamoyl-Ci-e alkyl group The compound of the above-mentioned [10], which represents an amino which may be mono- or di-substituted by a substituent, (4) a pyridyl or (5) a halogen atom;

 [12] A prodrug of the compound according to [3];

(13) Expression

[Wherein, R ¹⁷ represents a vinyl group or an aryl group which may have a substituent] or a compound having a partial structure represented by the formula:

R ¹ -CN

[Wherein R ¹ has the same meaning as described in the above [2]] or a salt thereof.

Wherein R ¹ is as defined above; or a method for producing a compound having a partial structure represented by the formula:

 (14) Expression

[Wherein each symbol is as defined in the above [3]] or a salt thereof and a compound represented by the formula R ¹ — CN

[Wherein, R ¹ has the same meaning as described in the above [3].] Or a salt thereof, the method for producing the compound according to the above [3]; (15) Expression

[Wherein, ninini represents a single bond or a double bond] (hereinafter sometimes abbreviated as compound (A-1)) or a salt thereof. A pharmaceutical composition;

 (16) Expression

^{Wherein, R 2 ,, R 3 ,, R} 6 ' and R ^7, respectively, a ₆ alkyl group, R ^16' is hydrogen atom, which may have a substituent 〇 ₆ _ ₁₄ Ariru group, a substituted An amino group which may have a group, a heterocyclic group which may have a substituent or a halogen atom], or a salt thereof.

 [17] a pharmaceutical composition comprising the compound of the above-mentioned [3], a salt thereof, or a prodrug thereof;

 (18) Expression

(A-2)

〔式中、 は、 単結合または二重結合を示す〕 で表される部分構造を有する化 合物 （以下、 化合物 （A— 2 ) と略記する塲合がある） またはその塩を含有してな るホスホジエステラーゼ IV阻害剤；

[In the formula, represents a single bond or a double bond] (hereinafter, there is a compound abbreviated as compound (A-2)) or a salt thereof. Phosphodiesterase IV inhibitors;

 (19) Expression

 [Wherein, JI represents a single bond or a double bond] .Inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis containing a compound having a partial structure represented by Prophylactic / therapeutic agents for autoimmune diseases, depression, Alzheimer's dementia, memory impairment, diabetes or arteriosclerosis;

 [20] the pharmaceutical composition of the above-mentioned [15] to [17], which is a phosphodiesterase IV inhibitor;

 [21] The above-mentioned [15] which is an agent for preventing or treating inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis. Or the pharmaceutical composition of [17];

 [22] Formula for mammals

 [Wherein represents a single bond or a double bond] a method for inhibiting phosphodiesterase IV, which comprises administering an effective amount of a compound having a partial structure represented by the following formula or a salt thereof:

[23] Formula for mammals '

^{Wherein, R 2 ', R 3 ,,} R 6' and R ⁷ 'is a C ^ 6 alkyl groups, respectively, R ^16, are hydrogen atoms, which may have a substituent C ₆ _ ₁₄ Ariru group Represents an amino group which may have a substituent, a heterocyclic group which may have a substituent or a halogen atom), or an effective amount of a salt thereof. A method for inhibiting phosphodiesterase IV;

 [24] Formula for mammals

 (Wherein, ninii represents a single bond or a double bond), characterized by administering an effective amount of a compound having a partial structure represented by Prevention and treatment of obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, dementia of aruhaimai type, memory impairment, diabetes or arteriosclerosis;

[25] Formula for mammals

[Wherein R ² , R ³ , R ⁶ , and R ⁷ ′ are each —6 alkyl groups, R ¹⁶ is a hydrogen atom, and a C _{6 14} aryl group which may have a substituent. An aryl group, an amino group which may have a substituent, a heterocyclic group which may have a substituent or a halogen atom) or a salt thereof. Administering inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory impairment, diabetes or arteriosclerosis;

[26] Formula for producing phosphodiesterase IV inhibitor

 [In the formula, ^ represents a single bond or a double bond] Use of a compound having a partial structure represented by the following formula or a salt thereof;

 (27) Formula for producing a therapeutic agent for preventing inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis

(A-2)

〔式中、 ^ Zは、 単結合または二重結合を示す〕 で表される部分構造を有する化 合物またはその塩の使用；

[In the formula, ^ Z represents a single bond or a double bond] Use of a compound having a partial structure represented by the following formula or a salt thereof;

 [28]

[Wherein, R ^2a and an R ^3a are each an aliphatic substituted hydrocarbon group, R ^4a and R ^{5 a} may hydrocarbons which also each have a hydrogen atom or a substituent group, R ^{6 a} and R ^7a each represents a hydrogen atom or an optionally substituted carbon hydrocarbon radical, R ^6a and R ^7a are optionally substituted with adjacent carbon atoms R ^8a may form a (1) hydrogen atom, (2) a hydrocarbon group which may have a substituent, (3) an acyl group, or (4) a substituent. (5) a halogen atom, (6) -OR ^10a (R ^1Ga represents a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or a substituent. shows also heterocyclic group optionally ^{having), (7) - SR lla} (R lla is hydrogen atom, which may have a substituent charcoal hydrocarbon group, a Ashiru group or substituent ) Shows a heterocyclic group which may have (8) - S (O) R 12a (R 12a is may have may have a substituent hydrocarbon group or an optionally substituted heterocyclic Represents a cyclic group), (9) one S (O) ₂ R ^13a (R ^13a represents a hydrogen atom which may have a substituent or a heterocyclic group which may have a substituent; Or (10) — NR ^14a R ^15a (R ^14a and R ^15a are each a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent.) R ^9a represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxyl group which may have a substituent] or a salt thereof; And so on. ·

Further, the present invention provides (29) Expression

 [In the formula, ring A, ring B and ring C may each have a substituent. Or a salt thereof;

 (30) The substituents on ring A, ring B and ring C are (1) a hydrocarbon group which may have a substituent, (2) a heterocyclic group which may have a substituent, 3) an amino group which may have a substituent, (4) an acyl group, (5) a hydroxyl group which may have a substituent, (6) a sulfenyl group which may have a substituent, (7) halogen atom, (8) lower alkylene dioxy group, (9) nitro group, (10) cyano group, (11) imino group which may have a substituent, (12) oxo group, (13) A ureido group which may have a substituent, (14) an azide group, (15) an amidino group which may have a substituent, (16) a guanidino group which may have a substituent, ( 17) The compound according to the above [29], wherein the compound is 1-5 substituents selected from the group consisting of a hydrazino group which may have a substituent and (18) an oxoxide group;

 [31] the compound of the above-mentioned [29], wherein the substituent is a group selected from substituent group A; [323 compound (A-1) is a compound of the formula:

 [In the formula,---may have a single bond or a double bond, and ring A, ring B and ring C may each have a substituent. (Hereinafter may be abbreviated as compound (1-1)), wherein the pharmaceutical composition according to the above [15],

[33] Compound (A-1) has the formula (-1)

 [Wherein the symbols have the same meanings as described in the above [3]] (hereinafter sometimes abbreviated as compound (-1)). I do.

 Further, the compound (A), (.1), (Γ), (Α-1), (1-1), (I, 1-1), (A-2) or a salt thereof has an asymmetric carbon in the structure. When included, both optically active forms and racemic forms are included in the scope of the present invention, and the compounds (A), (I), (Γ), (A-1), (1-1), (1 , ー 1), (A-2) or salts thereof may be either hydrates or anhydrides.

 The compounds of the present invention have the formula

Having a partial structure represented by the formula:

 Wherein each symbol is as defined above. The molecular weight of the compounds of the invention is about

It is 1000 or less, preferably about 900 or less, more preferably about 800 or less, and particularly preferably about 700 or less.

In the above formula, ring A, ring B and ring C have a substitutable number of substituents at substitutable positions. You may have.

 The substituents on the ring A, ring B and ring C are respectively

 (1) a hydrocarbon group which may have a substituent,

 (2) a heterocyclic group which may have a substituent,

 (3) an amino group which may have a substituent,

 (4) an acyl group,

 (5) a hydroxyl group which may have a substituent,

 (6) a sulfenyl group which may have a substituent,

 (7) halogen atoms (eg, fluorine, chlorine, bromine, iodine),

(8) lower alkylenedioxy O carboxymethyl group (e.g., Mechirenjiokishi, etc. 〇 ₃ alkylenedioxy O alkoxy groups such Echirenjiokishi)

 (9) Motoki Nitoguchi,

 (10) a cyano group,

 (11) an imino group which may have a substituent,

 (12) an oxo group,

 (13) an ureido group which may have a substituent,

 (14) an azide group,

 (15) an amidino group which may have a substituent,

 (16) a guanidino group which may have a substituent,

 (17) a hydrazino group which may have a substituent,

 (18) An oxide group or the like is used.

 Examples of the “optionally substituted hydrocarbon group” used as a substituent on the ring A, ring B and ring C include, for example, an alkyl group, an alkenyl group, an alkynyl group, and a cycloalkyl group. A chain or cyclic hydrocarbon group such as a cycloalkenyl group, an aryl group or an aralkyl group is used. Among them, a linear (branched or branched) or cyclic hydrocarbon group having 1 to 16 carbon atoms is used. (Eg, aromatic hydrocarbon group, aliphatic cyclic hydrocarbon group) and the like. Specifically, the following are used.

 (1) Chain hydrocarbon group:

a) an alkyl group [preferably a lower alkyl group (eg, methyl, ethyl, propyl) Le, isopropyl, butyl, isobutyl, sec- butyl, ter t-butyl, pentyl, (such as ^ _-6 alkyl group) such as cyclohexyl,

b) an alkenyl group [preferably a lower alkenyl group (for example, C ₂ _ such as vinyl, aryl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl, 5-hexenyl and the like); ₆ alkenyl groups)],

c) alkynyl groups [preferably, lower alkynyl group (e.g., propargyl, E Ji sulfonyl, 2-Bucheru, C ₂ such hexynyl to 2 - such as ₆ alkynyl group)]

 (2) Aliphatic cyclic hydrocarbon group:

a) cycloalkyl groups [preferably, a lower cycloalkyl group (e.g., Shikuropuro pills, cyclobutyl, cyclopentyl, c ₃ _ ₆ cycloalkyl Le group such as cyclohexyl), may be condensed with a benzene ring,

b) a cycloalkenyl group [preferably, a lower cycloalkenyl group (for example, 1 over sheet Kuropuro Bae cycloalkenyl, 1 Shikurobuteniru, -1-cyclopentenyl, C ₃ _ ₆ cycloalkenyl group such as xenon alkenyl to 1 Shikuro) benzene May be condensed with a ring]. (3) Aromatic hydrocarbon group:

Ariru group (e.g., phenyl, 1 one-naphthyl, 2-Nafuchirire, 1 one anthryl, 2-anthryl, 9 one anthryl, 1 one Fuenantoriru, 2 Fuenantoriru, three to Fuenantoriru, C _6, such as 4 _ Fuenantoriru or 9 one Fuenantoriru such as _ _{1 4} Ariru group, preferably a phenyl group)

 (4) Aralkyl group:

Lower aralkyl groups (e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3 - phenylpropyl, 4 one Hue Nirupuchiru, etc. Flip ₇ _ _{1 6} Ararukiru groups such as 5-phenylene Rupenchiru, preferably benzyl group).

Examples of the substituent of these hydrocarbon groups include (1) a halogen atom (for example, fluorine, chlorine, bromine, and iodine), and (2) a lower alkylenedioxy group (for example, methylenedioxy, ethylenedioxy and the like). (3) nitro group, (4) cyano group, (5) lower alkyl group which may be halogenated, (6) Lower alkenyl group which may be halogenated, (7) lower alkynyl group which may be halogenated, (8) lower cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. C, such as ₃ _ ₆ cycloalkyl group), (9) C ₆ - _{1 4} § Li Ichiru group (e.g., phenyl, 2 - naphthyl), (10) optionally halogenated substituted lower alkoxy group, (11 ) Lower alkylthio group which may be halogenated, (12) hydroxy group, (13) amino group, (14) mono-lower alkylamino group (e.g., monoamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) C, such as E _ ₆ Arukiruamino group), (15) mono- C ₆ one _{1 4} Ariruamino group (eg, Fueniruamino, 2 - etc. Nafuchiruamino), (16) di-one lower A Kiruamino group (eg, Jimechiruamino, Jechiruamino, Jipuropiruamino, Jibuchiruamino, such as di-ci- ₆ Arukiruamino groups such as E chill methyl § Mino),

(17) G C ₆ - _{1 4} Ariruamino group (eg, Jifueeruamino, di (2-naphthyl) Amino etc.), (18) Ashiru group, (19) Ashiruamino group, (20) Ashiruokishi group,

(21) 4- to 14-membered heterocyclic group (preferably 4- to 10-membered, more preferably 4- or 7-membered heterocyclic group, particularly preferably 5- or 6-membered heterocyclic group) (eg, 4-pyridyl, 2 1-Cenyl, 2-furyl, 2-thiazolyl, 3-indolyl, morpholino, 1-piperazinyl, piperidino, 1-pyrrolidinyl, 2-isoindolyl, etc., other than carbon, nitrogen, sulfur, oxygen, etc. 1 A 4- to 14-membered, preferably 4- to 7-membered, more preferably a 5- or 6-membered heterocyclic group containing from 4 to 4 heteroatoms), (22) a phosphono group, (23) a C ₆ -aryloxy group (eg, Fe phenoxy), (24) Jiju alkoxy one phosphoryl group (e.g., dimethoxyphosphoryl, _{diethoxyphosphoryl), (25) C 6 -} 1 4 Ariruchio group (e.g., phenylene thio), (26) hydrazino Base (. Except when making However, Ashiru group Okiso group bonded to a hydrocarbon group) (27) imino group, (28) Okiso group, (29) an ureido _{group, (30) C ^ - 6} ' alkyl —Ureido group (eg, methyl ureide, ethyl pereide, etc.), (31) di6-alkyl-pereide group (eg, dimethyl ureide, getyl ureide, etc.), (32) oxide group, (33) above (1) to (32) One to five, and preferably one to three, selected from the group consisting of a group formed by combining two to three groups selected from groups (substituent group A) is used. As the “optionally halogenated lower alkyl group” in the above-mentioned substituent group A, for example, a lower alkyl group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec - heptyl, tert- butyl, pentyl, etc. (^ _ ₆ alkyl groups such as hexyl) and the like are used, as a specific example, Methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ether, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluorotrifluoropropyl, isopropyl, butyl, 4 , 4,4-Trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neope Chill, 5, 5, 5-triflate Ruo b hexyl pentyl to,, 6, 6, etc. hexyl and the like to 6 Torifuruo port.

The “lower alkenyl group optionally octogenated” in the substituent group A may have, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) lower alkenyl groups (e.g., vinyl, Ariru, isoproterenol base alkenyl, 2-butenyl, 2-methyl-2 _ propenyl, 4 one-pentenyl, 5 one hexenyl such which C ₂ - ₆ alkenyl group) and the like.

The “lower alkynyl group optionally octogenated” in the substituent group A may have, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) a lower alkynyl group (e.g., propargyl, Echiniru, 2-Petit El and C ₂ _ ₆ alkynyl group such as hexynyl to 2) and the like.

Examples of the “optionally halogenated lower alkoxy group” in the above-mentioned substituent group A include, for example, lower optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) an alkoxy group (e.g., methoxy, ethoxy, Purobokishi, iso-propoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyl Ruokishi, isopentyl Ruo alkoxy, neopentyl Ruo alkoxy, to a C丄_ ₆ alkoxy group such as Kishiruokishi Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trichloromethoxy, 3,3,3-trifluoropropoxy, 4,4, 4 Trifluorobutoxy, 5, 5, 5—Trifluoropentyloxy, 6, 6 6-Trifluohexyloxy is used.

As the “optionally halogenated lower alkylthio group” in the above-mentioned Substituent group A, for example, may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) ( ^ - 6 alkylthio group (e.g., methylthio, Echiruchio, pro Piruchio, isopropylthio, Puchiruchio, isobutylthio, sec- butylthio, ter t one Puchiruchio, pentylthio, cyclohexylthio C WINCH ₆ alkylthio group such as to) and the like are used, specifically Examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like. Examples of the "acyl group" include formyl, Alkoxy, force Rubamoiru, (3 ^ 6 alkyl - Karuponiru (eg, Asechiru, propionyl, etc.),

C ₃ _ ₆ cycloalkyl - Karuponiru (e.g., cyclopentyl Luca Lupo, cycloalkenyl, cycloheteroalkyl, etc. keys Shirukaruponiru), C丄- ₆ alkoxy Ichiriki Ruponiru (e.g., methoxy Cal Poni le, X Tokishikaruponiru, Isopuropokishi force Ruponiru, t er t-butoxycarbonyl etc.), C ₆ _ _{1 4} Ariru - Karuponiru (eg, Benzoiru and 2 one naphthoyl), C ₇ _ _{1 6} Ararukiru Ichiriki Ruponiru (eg, phenylene Ruasechiru, 3-phenylpropyl propionyl, etc.), C ₆ _ _{1 4} Aryloxy-one-strand (eg, phenoxy-th, 2-naphthyl-thoxyl-ponyl), C 7 ^ ₆ Arar-l-oxy-strand-thruponyl (eg, benzyloxy-carbonyl, 2-naphthylmethyloxy-thyl), 5- or 6-membered Ring carbonyl (e.g., 1-pyrrolidinylcarbonyl, 4-piperidylcarbonyl, 1 -From carbon atoms such as piperazinylcarbonyl, 2-morpholinylcarbonyl, 4-pyridylcarbonyl, 3-phenylcarbonyl, 2-furylcarbonyl, 2-thiazolylcarbonyl, nitrogen, sulfur, oxygen, etc. chosen such 1 to 3 for 5 or 6-membered heterocyclic ring Karuponiru containing heteroatoms are) mono- ₆ § alkyl Ichiriki Rubamoiru (e.g., methylcarbamoyl, etc. E Ji carbamoyl), di one C ₆ alkyl Ichiriki Rubamoiru (eg, dimethylcarbamoyl, etc. Jechirukarubamo I le), C ₆ - _{1 4} § Li one Roux force Rubamoiru (e.g., Hue carbamoylmethyl, 2-naphthylcarbamoyl etc.), 5- or 6-membered heterocyclic ring force Rubamoiru (eg, 1 one Pyrrolidinylcarbamoyl, 4-piberidylcarbamoyl, 1-piperazinylcarbamoy Selected from nitrogen atoms, sulfur atoms, oxygen atoms, etc., in addition to carbon atoms such as 1, 2-morpholinylcarbamoyl, 4-pyridylcarbamoyl, 3-chlorocarbamoyl, 2-furyl-rubamoyl, 2-thiazolylcarbamoyl, etc. is a 5- or 6-membered heterocyclic force Rubamoiru containing 1 to heteroatoms 3 of the) (^ _ ₆ alkyl chromatography Chio carboxymethyl sulfonyl (e.g., methyl thio Cal Poni Le), Ji ₃ _ ₆ cycloalkyl over Chio local Poni Le ( E.g., pentyl thiol carbonyl, cyclohexyl thiocarbonyl, etc., C ₆ alkoxy-thio carbonyl (e.g., methoxy thiol, ethoxy luponyl, propoxy thiol, butoxy carbonyl, etc.), c ₆ _ ₁₄ Aryl-thiocarbonyl (eg, phenylthiocarbonyl, 21-naphthylthiocarbonyl Etc.), c ₇ _ _{1 6} § Lal kills over Chio carbonyl (e.g., benzylthio force Lupo two Le, Hue phenethyl Lucio carbonitrile El, etc.), C ₆ - _{1 4} § reel O Kishi Chio carbonyl

(Eg, phenoxyethanol Chio Cal Poni le, etc. 2 one Nafuchiruokishichi Sairyoku Ruponiru), C ₇ _ _{1 6} Ararukiruokishi - Chio carbonyl (e.g., Benjiruokishichi Sairyoku Ruponiru, 2-naphthylmethyl O carboxymethyl like Chi Sairyoku Ruponiru), 5 or 6-membered heterocyclic thiocarbonyl (e.g., 1-pyrrolidinyl thiol propyl, 4-piperidyl thiol, 1-piperazinyl thiol, 2-morpholinyl thiol, 4-pyridyl thiol, 3-pyridyl thiol, 3 5- or 6-membered heterocyclic thiocarbonyl containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as 2-furylthiocarbonyl and 2-thiazolylthiocarbonyl ), Thiocarbamoyl, mono-alkyl-thiocarbamoyl (eg, methyl thiocarbayl) Yl, etc. Echiruchio force Rubamoiru), di -C e alkyl one Chiokarubamoiru (e.g., dimethylthio force Rubamoiru, etc. Jechiruchio force Rubamoi Le), C ₆ - _{1 4} Ariru one Chiokarubamoiru (eg, phenylene Lucio force Rubamoiru, 2- 5- or 6-membered heterocyclic thiocarbamoyl (e.g., 2-pyrrolidinylthio-potassium, 2-piperidylthio-potassium, 2-piperazinyl-thio-potsubamoyl, 2-morpholinyl-thio-potsubamoyl, 4-pyridylthio-potassium) Containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon atoms such as 3-chlorothiocarbamoyl, 2-furylthiocarbamoyl, 2-thiazolylthiocarbamoyl, etc. 5 Or 6-membered heterocyclic ring Sairyoku etc. Rubamoiru), sulfamoyl, mono- C i-6 alkyl loose sulfamoyl (e.g., methylsulfamoyl, etc. E chill sulfamoyl), G ^ - ₆ alkyl Surufamoiru (e.g., dimethylsulfamoyl, Jefferies chill sulfamoyl Such),

C ₆ — ₁₄ arylsulfamoyl (eg, phenylsulfamoyl), 0 _: _ ₆ alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C ₆ _ ₁₄ arylsulfonyl (eg, phenyl) sulfonyl, such as 2 one-naphthylsulfonyl), (G ₆ alkylsulfinyl (e.g., methylsulfinyl, etc. E chill sulfide El), C ₆ - ₁₄ § reel sulfinyl (e.g., Hue Nils sulfinyl, such as 2 one Nafuchirusurufu Iniru), sulfino, sulfo, C丄_ ₆ alkoxysulfinyl sulfinyl (e.g., methoxide Shisurufiniru, e Toki cis sulfinyl), Ji ₆ _ ₁₄ § reel O carboxymethyl sulfinyl (e.g., full enoki cis sulfinyl), Ci-e alkoxy sulfonyl (e.g., main Bok Kishisu Ruhoniru , E butoxy-benzenesulfonyl) and C ₆ - ₁₄ § reel O carboxymethyl sulfonyl (e.g., Fueno Shisuruhoniru) and the like Among them, formyl, force Rupokishi, C i_ ₆ alkyl -.. Force Ruponiru, C i_ ₆ alkoxy Ichiriki Ruponiru force Rubamoiru, mono one C i _ ₆ alkyl force Rubamoiru, sulfamoyl, mono- et An acyl group such as alkyl-sulfamoyl is preferred.

Said the "Ashiruamino group" in Substituent Group A, for example, Horumiruamino, C ^ ₆ alkyl Ichiriki Rupokisamido (eg, Asetoamido and propionamide), C ₆ - ₁₄ Ariru Ichiriki Rupokisamido (e.g., benzamide, 2- naphthyl Cal poke Sami Donado), alkoxy Ichiriki Rupokisamido (e.g., methoxy carboxamide, X Toki deer Lupo alkylcarboxamide, isopropoxycarbonyl carboxamide, such as tert- Butokishikarupoki Samido), C ₆ alkylsulfonyl § amino (e.g., methylsulfonyl § Mino, E such as chill sulfonyl § Mino), bis ((^ - 6 alkylsulfonyl) amino (e.g., bis (methylsulfonyl) amino, bis (Edjirusuruhoniru) amino etc.), C ₆ - ₁₄ § Li one Le sulfonyl § Mino (eg , Phenylsulfonylamino, 2-naphthylsulfonylamino Etc.) and the like Of these, Horumiruamino, DOO ₆ Al kill -.. Karupokisamido, (^ _ ₆ alkoxy Ichiriki Rupokisamido, (^ - ₆ alkylsulfanyl Honiruamino, bis alkylsulfonyl) of Flip Ashiruami amino group such as Amino? preferable. Examples of the "Ashiruokishi group" in Substituent Group A, for example, C ^ - ₆ alkyl Ichiriki Ruponiruokishi (eg, Asechiruokishi propionyloxy, etc. Ruo carboxymethyl), C ₆ one _{1 4} § Li one Luca Lupo sulfonyl O carboxymethyl (e.g., Benzoyloxy, 2-naphthoyloxy, etc.), alkoxy monopropyloxy (e.g., methoxycarboxy, ethoxypropyloxy, isopropoxyoxy, tert-butoxycarboxy), mono-Ci- ₆ alkyl monorubamoyloxy (e.g. examples, Mechirukarubamo Iruokishi, E Ji carbamoyl O carboxymethyl, etc.), di-primary alkyl Ichiriki Rubamoi Ruokishi (eg, dimethylcarbamoyl O carboxymethyl, Jefferies Chi carbamoyl O carboxymethyl, etc.), C ₆ - _{1 4} Ariru Ichiriki Rubamoiruokishi (eg, phenylene Rucarbamoyloxy, 21-Nakhchi Such as carbamoyl O carboxymethyl), such as nicotinyl Noi Ruo alkoxy is used. Among, ₍₆ alkyl Ichiriki Ruponiruokishi, - 6 C ₂ _ ₇ Ashiruokishi groups such as alkoxy Ichiriki Ruponiruokishi are preferred.

 In the above-mentioned Substituent group A, examples of the group formed by bonding two or three members selected from the groups (1) to (32) include, for example,

(33a) substituted (^ _ ₆ alkyl group [this alkyl group, Shiano force Rubamoiru, C

^ 6 Alkyl Lubamoyl, C i _ ₆ Alkyl Lponyloxy,. Preparative ₆ alkoxy Ichiriki Lupo two Lou alkyl Ichiriki Rubamoiru, 5 or 6-membered heterocyclic ring (e.g., nitrogen atom in addition to carbon atoms, such as pin lysyl, sulfur atom, to 1 selected from oxygen atom, such as 3 to the 5- or 6-membered heterocycle containing terror atom) _1-6 alkyl-carbamoyl, C! _ ₆ having a substituent selected from alkylsulfonylamino, Ci- ₆ alkoxy-carbonyl, carboxy and the like],

(33b) substituted C ₆ - _{1 4} Ariru group [this C ₆ one _{1 4} Ariru groups, Amino, optionally halogenated C - ₆ alkyl - force Ruponiruamino, ureido, _alkyl Suruhoniruamino, (C ^ e alkyl) (C _i-6 alkylsulfonyl) Amino, - ₆ alkoxy Ichiriki Ruponiru - to have a substituent selected from such Arukiruamino,

(33c) ( ₆ alkoxy _ C ₆ — ₁₄ aryl — ₆ alkoxy group,

(33d) a 5- to 14-membered heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen and the like in addition to the carbon atom having a substituent [this heterocyclic group Is Okiso force Rupokishi alkyl, (^ -6 alkyl Ichiriki Ruponiruokishi - C ₆ alkyl, C ₆ alkyl, C alkoxy - force Lupo two Lou C ₆ alkyl, such as C DOO ₆ alkyl Ichiriki Rubamoiru C _t _ ₆ alkyl Selected substituents],

Formula (33e) — a group represented by NR ¹⁸ R ¹⁹

[R ¹⁸ and R ¹⁹ each represent (i) a 5- or 6-membered heterocyclic ring (eg, a 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, etc., in addition to a carbon atom) Or 6-membered heterocycle) monoalkyl, (iDCi-ealkoxy mono-propionyl-alkyl), (iii) dialkyl _6- alkylamino-methylene-sulfamoyl-alkyl, (iv) di-rubmoyl-C _6- alkyl, (V) sulfamoyl - ₆ alkyl le, (vi) C ₆ alkyl chromatography alkylsulfonyl, (VIOC -e alkoxy - carbonyl, (viii) di - C i_ ₆ alkoxy Ichiriki Lupo two Lou C ₂ _ ₆ alkenyl, (ix) 5 or 6-membered Heterocyclic group (e.g., a 5- or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms) [This 5- or 6-membered heterocyclic group Is, amino, Ci- ₆ alkyl-carboxamide, Ci- ₆ alkyl-sulfonylamino, etc.), and (X) may be halogenated

₆アルキルチオ一 C — ₆アルキル一力ルポニル、_ 6 alkyl-potassium,

_6- alkylthio-C-- _6- alkyl-luponyl,

(xii) C Medicine ₆ alkylsulfinyl Lou C Bok ₆ alkyl Ichiriki Ruponiru, (xiiOC ^ eT Le kills sulfonyl over C ₆ alkyl Ichiriki Ruponiru, (xiv) Amino one C ₆ alkyl Ichiriki Ruponiru, are (XV) halide alkyl Ichiriki be Lupo two Ruami Bruno - C ₆ alkyl Ichiriki Ruponiru, (xvi) C ₆ _ ₁₄ § Li one Roux carbonyl, (xvii) force Rupokishi C ₆ one ₁₄ § Li one Roux force Ruponiru, (xvi ii ) - ₆ alkyl which may optionally be esterified with a phosphono - (^ alkyl one C ₆ - ₁₄ Ariru - power Ruponiru, (ix) alkoxy Ichiriki may 5 or 6 membered heterocyclic ring which may have a Ruponiru (eg , A 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to a carbon atom. For example, besides carbon atom, nitrogen atom, sulfur atom, oxygen atom 1 to 3 5 or 6-membered heterocyclic ring containing terrorist atom to the) -C ^ e alkyl Ichiriki Ruponiru, (xxi) C ₆ _ ₁₄ Ariru one Okishi Ichiriki Ruponiru selected from such, (xxii) Power Rupoxy — 6-alkyl, (xxiii) Indicates the power of Lubamoyle, etc.],

 A group represented by the formula (33f) —C〇_Ha 1 (Ha 1 represents a halogen atom),

(33 g) substituted sulfamoyl group [this sulfamoyl group may force Rubamoiru § alkyl, 5 or 6-membered heterocycle - (with a substituent selected from such ^ _ ₆ alkyl], (33h) formula -C (= 0) NR Group represented by ²⁰ R ²¹

[R ^2Q and R ²¹ each represent (i) a 5- or 6-membered heterocyclic ring (eg, 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as pyridyl and imidazolyl) 5 or 6 membered heterocyclic ring containing) -C ^ e alkyl, (ii) Karupoki sheet - - ₆ alkyl, (iii) C Les ₆ alkoxy - force Lupo two Lou C ₆ alkyl, (iv) di - C e _ _6- Alkylamino—C _6- Alkyl, (V) Alkyl C ₆ Alkyl, (vi) Alkyl Rubamoyl—— 6 Alkyl, (vii) 5- or 6-membered Heterocycle

(Eg, nitrogen atom in addition to carbon atoms, such as pyridyl, sulfur atom, 5 or 6-membered heterocyclic ring containing hetero atoms to 1 Ru selected from oxygen atom, such as 3 to the) - alkyl force Rubamoiru (^ _ ₆ alkyl , (Viii) 5- or 6-membered heterocyclic ring (eg, containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyridyl, etc. ring) Single-amino alkyl, (ix) Sulf Amoiru C ₆ _ ₁₄ § Li one Roux ₆ alkyl, (X) which may have an alkoxy C ₆ - ₁₄ Ariru, esterified with (xi) C _i-6 alkyl which may be e Suhono - C ^ e alkyl -C ₆ _ ₁₄ Ariru, (xii) 4 to 10-membered Hajime Tamaki (e.g., nitrogen atom in addition to carbon atom, a sulfur atom, to 1 selected from oxygen atom, etc. 4- to 10-membered heterocycle containing three heteroatoms) [this The 4- to 10-membered heterocyclic group may have one or two substituents selected from a halogen atom, alkyl, oxo, etc.], (xiii) C ₆ — ₁₄ arylene ₆ alkyl, etc.],

(33i) halogenated C ^ - ₆ alkyl Cal poke Sami de (e.g., 2-Kuroroaseta bromide, 2, 2-dichloro-acetamide, 2, 2, 2-trichloro acetamide, etc.) and the like.

The `` optionally substituted heterocyclic group '' used as a substituent on the ring A, ring B and ring C includes, for example, nitrogen, sulfur, oxygen and the like in addition to carbon. A 4- to 14-membered heterocyclic group containing 1 to 4 (preferably 1 to 3) heteroatoms to be selected and the like are used. Specifically, (a) a 4- to 14-membered aromatic heterocyclic group,

(b) 4- to 14-membered aliphatic heterocyclic group, (c) 2- or 3-cyclic fused ring group of 4- to 14-membered heterocyclic ring and benzene ring, etc. are used.

 The 4- to 14-membered aromatic heterocyclic group includes, for example, 1 to 4 (preferably 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom and the like in addition to a carbon atom. Or a 14-membered aromatic heterocyclic group or the like. Specific examples thereof include thiophene, furan, indolizine, pyrrole, imidazole, triazole, thiazole, thixazole, pyrazole, pyridine, and N-dioxide. Pyridine, pyrazine, pyrimidine, pyridazine, purine, 4H-quinolidine, naphthyridine, isothiazole, isoxazole, and furazane. Among them, pyridine, thiophene, furan and the like are preferably used.

 Examples of the 4- to 14-membered aliphatic heterocyclic group include 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms. A 4-membered aliphatic heterocyclic group or the like is used, and specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,2-dihydropyridine, imidazolidine and the like.

The bicyclic or tricyclic fused ring group of a 4- to 14-membered heterocyclic ring and a benzene ring may include, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (preferably (1 to 3) and a bicyclic or tricyclic fused ring group of a benzene ring and a heterocyclic ring, such as benzo [b] thiophene, benzofuran, 1H-benzimidazole, and benzzo Xazole, benzothiazole, 1,2-benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, xanthene, phenoxatiin, indole, isoindole, 1H-indazole, isoquinoline, quinoline, phthalazine, quinoxaline, Quinazoline, cinnoline, carbazole,) 3-caprolactin, phenanthridine, acridine, phenazine, hue Chia Jin, Fuenokisajin, isochroman, such as dihydro base Nzofuran and the like. As the substituent of these heterocyclic groups, 1 to 5, preferably 1 to 3 selected from the above-mentioned substituent group A are used. The “optionally substituted amino group” used as a substituent on the A ring, the B ring and the C ring includes the “optionally substituted hydrocarbon group” and the “optionally substituted hydrocarbon group”. A heterocyclic group which may have a group '', an `` acyl group '' in the substituent group A (the `` acyl group '' is 1 to 5, preferably 1 to 3, further selected from the substituent group A) And an amino group which may have one or two substituent (s) selected from the above.

 As the “acyl group” used as a substituent of the ring A, ring B and ring C, those similar to the “acyl group” in the aforementioned substituent group A can be used. This “acyl group” may further have 1 to 5, preferably 1 to 3 substituents selected from substituent group A.

 `` Hydroxy group optionally having substituent (s) '', `` Sulfenyl group optionally having substituent (s) '', and `` Having substituent (s) '' used as substituents of ring A, ring B and ring C An optionally substituted imino group ", an" optionally substituted ureido group ", an" optionally substituted amidino group ", a" optionally substituted guanidino group "and" Examples of the substituent of the “hydrazino group optionally having a substituent” include the above “hydrocarbon group optionally having a substituent”, the above “heterocyclic group optionally having a substituent”, The “acyl group” in the substituent group A (this “acyl group” may further have 1 to 5, preferably 1 to 3 substituents selected from the substituent group A) and the like Used.

 Examples of the compound in which ring A, ring B and ring C each have a substituent include, for example,

[Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent]. Typically, the expression

 [Wherein each symbol has the same meaning as described above], and the like.

In the above formula, R ¹ represents (1) a hydrogen atom, (2) a hydrocarbon group optionally having a substituent, or (3) a heterocyclic group optionally having a substituent.

As the “optionally substituted hydrocarbon group” for R ¹ , those similar to the “optionally substituted hydrocarbon group” exemplified as the substituent for the ring can be used. It is required.

As the `` heterocyclic group optionally having substituent (s) '' for R <sup>1</sup> , the same as the `` heterocyclic group optionally having substituent (s) '' exemplified as the substituent for the ring A is used. Can be

As R ¹ , (1) an aromatic hydrocarbon group optionally having a substituent, (2) a heterocyclic group optionally having a substituent, (3) an optionally substituted substituent A good aliphatic cyclic hydrocarbon group, (4) Formula 1: L—R ^{la wherein} L is methylene or carbonyl, R ^la is a hydrogen atom, an aromatic group which may have a substituent, a substituent A hydroxyl group optionally having a substituent or an amino group optionally having a substituent]. The “aromatic hydrocarbon group optionally having substituent (s)” and the “heterocyclic group optionally having substituent (s)” are represented by the formula:

[Wherein, R ^lb represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and the ring D is an aromatic which may have a substituent. Group E is a bond, methylene, oxygen atom, acid Optionally substituted sulfur atom, optionally substituted nitrogen atom or formula —CS—O—, one CO—O—, one S—CO—, one (CH ₂ ) _k —CO—, one _{^{NR lc - CO - (CH 2}} ) m -, -NR lc -S0 2 - (CH 2) m -, one S_〇 _{^{2 - NR lc - (CH 2}} ) m -, one 〇- CS-NR ^lc - (CH ₂ ) _m- , one NR ^lc — CO-NR ^lc — (CH ₂ ) _m —, — NR ^lc _C〇 one CH ₂ — (CH ₂ ) _m -NR ^lc-where R ^lc is a hydrogen atom An alkyl group or an acyl group which may have a substituent, k represents 0 or 1, and m represents an integer of 0 to 3.)

[Wherein, Ha 1 represents a halogen atom, and ring D has the same meaning as described above].

The preferred groups for R ¹ "aromatic hydrocarbon group", for example, etc. C 6 -C 14 membered monocyclic or condensed polycyclic aromatic hydrocarbon group (C ₆ _ ₁₄ Ariru group) Is used. The C ₆ _ ₁₄ Ariru group, e.g., phenyl, 1 one-naphthyl, 2-naphthyl, 1 one anthryl, 2 one anthryl, 9 _ anthryl, 1 one Fouesnant tolyl, 2 _ Fuenantoriru, 3 Fuenantoriru, 4 one Fuenantoriru, 9-phenanthryl and the like are used, and among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable, and phenyl and the like are particularly preferable.

 As the substituent for the “aromatic hydrocarbon group”, 1 to 5, preferably 1 to 3 selected from the above-mentioned substituent group A is used. Among these substituents, (1) a halogen atom,

 (2) nitro group,

(3) ₆ alkyl groups (methyl, isopropyl, tert-butyl, etc.)

[The (^ -6 alkyl group is a halogen atom, cyano, carbamoyl, _6- alkaryl pamoyl, C i _ ₆ alkyl monopropylamine, alkoxy-carbonyl- 6 alkyl monorubumoyl, 5- or 6-membered heterocycle (Eg, 1 to 3 carbon atoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon such as pyridyl 5 or 6 membered heterocyclic ring) -C _x _ ₆ alkyl Ichiriki Rubamoiru containing hetero atoms,

— Which may have a substituent selected from _6- alkylsulfonylamino, C ^ _6- alkoxy-carbonyl, carboxy, etc.],

(4) C ₃ - ₆ cycloalkyl group (e.g., cyclohexyl),

(5) C ₆ - ₁₄ § Li Ichiru group (e.g., phenyl)

[The C ₆ - ₁₄ Ariru groups, Amino, force Rupokishi, C - ₆ alkoxy - force Ruponiru, Karupamoiru, mono - or di C i _ ₆ alkyl force Rubamoiru, Horumiruamino may have a halogen atom or carboxy alkyl - carbonyl amino (eg, Asechiruamino, propionyl Rua Mino, triflumizole Ruo b acetylide relay amino, Bibaroiruamino), c ₆ one ₁₄ Ariru Ichiriki Ruponiruamino (eg, Benzoiruami Bruno), (^ _ ₆ alkoxy - power Ruponiruamino (e.g., methoxy Karuponiruamino), ureido, mono- or di- (: e alkylureido, ₆ alkylsulfonyl amino (e.g., methylsulfonyl § Mino), (C ^ e alkyl) (C ₆ Arukirusu Ruhoniru) amino (e.g., methyl (methylsulfonyl) Amino, etc.), alkyl) (C ^ 6 alkyl Power Ruponiru) Amino etc. (e.g., methyl (Asechiru) Amino), ₍₆ alkoxy Ichiriki Ruponiru -Ci- ₆ alkylamino (e.g., 2-d butoxy force Lupo two Lu 2 Puropiruamino), C ₇ - ₁₅ Ararukiruokishi - Karuponiru amino (e.g., benzyl O carboxymethyl Cal Poni Rua amino), C WINCH ₆ alkyl Ichiriki Ruponirua amino - C, _ ₆ alkyl Ichiriki Ruponiruamino (eg, § cetyl § amino § cetyl § amino) ^ - ₆ alkylthio one _6- alkyl-l-ponylamino (eg, methylthioacetylamino), alkyl-sulfiel-Ci- _6- alkyl-1-carbonylamino

(Eg, Mechirusurufi two Ruasechiruamino), C Interview _ ₆ alkyl chromatography alkylsulfonyl over C! One ₆ alkyl - carbonylamino (e.g., methylsulfonyl § cetyl § Mino), C ₆ one ₁₄ Ariruokishi - Power Ruponiruamino (e.g., phenoxy force Ruponiruamino), human Dorokishi C E _ ₆ alkyl - Power Rubamoiru (e.g., hydroxy methylcarbamoyl, hydroxy Edji carbamoyl) may have a substituent selected from such as Amino especially, the force Rupokishi, alkoxy Ichiriki Ruponiru force Rubamoiru, mono- or is G (^ _ ₆ alkyl force Rubamoiru, Horumiruamino, eight androgenic Optionally having an atom or a carboxy group, Ci_ ₆ alkyl monophenylamine (eg, acetylamino , Propionylamino, trifluoroacetylamino, pivaloylamino), C

^ 6 alkoxy Ichiriki Ruponiruamino (e.g., methoxy Cal Poni Rua Mino), ureido, C i _ ₆ alkylsulphonyl § amino (e.g., methylsulfonyl § Mino), Al kill) ((^ - 6 alkylsulfonyl) Amino (e.g., methyl (Methylsulfonyl) amino, etc.), (C 6 alkyl) alkyl-aminopropyl, amino (eg, methyl (acetyl) amino, etc.), alkoxy monoalkylamine (eg, 2-ethoxycarbonyl-12-) Puropiruamino etc.), C ₇ - _{1 5} § La Rukiruokishi Ichiriki Ruponiruamino (e.g., may have a benzyl O carboxymethyl Cal Poni Rua mino) such as pressurized al substituents selected,

(6) A halogen atom or a Ci- ₆ alkoxy group which may have a —6 alkoxy-C ₆ _ ₁₄ aryl (eg, methoxy, trifluoromethoxy, isopropoxy, 2- (4-methoxy Phenyl) ethoxy)),

(7) C ₆ one _{1 4} Ariruokishi group (e.g., phenoxy),

(8) C- ₆ alkylthio group which may have carbamoyl (eg, methylthio, carbamoylmethylthio),

 (9) an alkylsulfinyl group which may have a carpamoyl (eg, methylsulfinyl, carbamoylmethylsulfinyl),

(10) C ₆ - _{1 4} § Li one thio group (e.g., phenylene thio)

 (11) a hydroxy group,

 (12) 4- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen and the like in addition to carbon atoms (eg, pyrrolidinyl, piperidyl, isoindolyl, (Furyl, chenyl, pyridyl, quinolyl, benzofurale, pyrimidinyl, tetrazolyl, imidazolidinyl, isothiazolidinyl, thiadiazolidinyl, azethinyl, etc.)

[The heterocyclic group is old Kiso, Karubokishi alkyl, alkyl Ichiriki Honoré Boniruokishi - C i _ ₆ alkyl, ₍₆ alkyl, C _i-6 alkoxy - Karuponiru - alkyl, C _x _ ₆ alkoxy Ichiriki Ruponiru force Rubamoiru - C - ₆ alkyl Le, C _x _ ₆ alkyl - may have a force Rubamoiru C i _ ₆ substituents selected from an alkyl, (13) a carboxy group,

 A group represented by the formula (14) —CO—Ha 1 (where Ha 1 represents a halogen atom) (eg, formyl chloromethyl),

 (15) — 6-alkyl monopropanol group (eg, acetyl, etc.),

(16) alkyl-sulfonyl group (eg, methylsulfonyl, etc.),

 (17) C ^ 6 alkoxy monocarbonyl group (eg, methoxycarbonyl etc.),

 (18) Sulfamoyl group

[The sulfamoyl group, (_ ₆ alkyl, force Rubamoiru C Bok ₆ alkyl, C, ^ - ₆ alkoxy Ichiriki Ruponiru - d_ ₆ alkyl, 5 to may have Okiso group 7-membered Hajime Tamaki ( Example: 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyridyl, pyrrolidinyl, hexahydroazepier) — ^ - ₆ alkyl, (^ _ ₆ alkyl - which may have 1 or 2 substituents selected from such ₍₆ _ ₁₄ Ariru], - Cal Poniruamino

される基 (19) Formula 1

Group

[R ^a and R ^b each represent (i) a hydrogen atom, (iO ^ -e alkyl, (iii) a 5- or 6-membered heterocyclic ring (eg, a nitrogen atom, a sulfur atom, an oxygen atom, etc. selected 1 to 5 or 6-membered heterocyclic ring containing hetero atoms 3 of the being) - Les ₆ Al kill, (iv) ₆ alkoxy - power Ruponiru - ₆ alkyl, (V) di - alkyl Rua plasminogen methylene chromatography sul Famo Ilu — _6- alkyl, (vi) Rubimoyl — _6- alkyl, (vii) Sulfamoyl- _6- alkyl, (viii) Ci- _6- alkylsulfonyl, (ix) — 6-alkoxy-low-proponyl, (X) Di-alkoxy-low-power-ponyl - C ₂ one ₆ Arukenisore, (xi) C ₆ - ₁₄ Ariru, a 1 to be chosen (xii) 5 or 6-membered Hajime Tamaki (e.g., nitrogen atom in addition to carbon atoms, such as pyridyl, sulfur atom, oxygen atom, etc. Chair 5 containing 5 heteroatoms 6-membered heterocyclic group) [this 5- or 6-membered heterocyclic group, Amino, alkyl - Karupokisamido, ₆ alkyl - which may have a substituent group selected from a sulfonyl Amino] is (xiii) halide Tei be alkyl - power Ruponiru, (xiv) ^ - ₆ alkylthio primary alkyl Ichiriki Ruponiru, (XV) C preparative ₆ alkylsulfinyl Lou C ₆ alkyl Ichiriki Ruponiru, (xvi) C ₆ alkylsulfonyl C ^ 6 alkyl one-strand, (xv ii) amino-C! ― ₆ alkyl-carbonyl, (xvi ii) optionally halogenated C i- ₆ alkyl-potassium ruamino- ^ alkyl mono-potassium, (xix) C ₆ _ ₁₄ aryl-carbonyl, (XX) Rupokishi - Ji _6-14 Ariru Ichiriki Ruponiru, (xxi) ₆ alkyl which may optionally be esterified phosphono - CI_ ₆ alkyl one C ₆ _ ₁₄ Ariru one local Poniru, (xxii) a halogen atom, Okiso or alkoxy - power 5- or 6-membered heterocyclic ring optionally having luponyl (eg, containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyrrolidinyl, pyridyl, etc.) 5- or 6-membered heterocyclic ring One-strand ruponyl, (xxii i) 5- or 6-membered heterocyclic ring (eg, one or three selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyridyl) A heteroatom 5 or 6 membered heterocyclic ring) i (^ _ ₆ alkyl Ichiriki Lupo two Le has, fcdv) C ₆ - ₁₄ Ariru one Okishi Ichiriki Ruponiru, (XXV) force Rupokishi - C - ₆ § alkyl, (xxvi) force Rubamoiru , (xxvii) optionally halogenated good alkylcarbamoyl, (xxviii) C丄alkyl one carbonyl § Mino but it may also have a C ₆ _ ₁₄ § Lee carbamoyl, (xxix) 5 or 6-membered heterocyclic ring ( examples, nitrogen atom in addition to a pyridyl that any carbon atom, a sulfur atom, 1 selected from oxygen atom, etc. to three 5 or 6-membered heterocyclic ring containing a heteroatom) Ichiriki Rubamoiru, (XXX) C ₂ _ ₆ Al Kenyl-Ruponyl, (XXXi) 5- or 6-membered heterocyclic ring optionally having an oxo group (eg, 1 to 3 members selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyrrolidinyl) 5 or 6 members containing hetero atoms Elementary ring) —amino—C ₆ alkyl—caprolponyl, (xxxii) (5- or 6-membered heterocyclic ring optionally having an oxo group (eg, a nitrogen atom, a sulfur atom, 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen atoms, etc.)) — ₆ alkyl) amino- ( _6- alkyl-carbonyl), (xxxiii) (even if it has an oxo group Good 5- or 6-membered heterocycle (eg, a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as pyrrolidinyl)) C ₆ alkyl force ruponyl) amino-Cis-alkyl-carbonyl,

(xxx iv) CI_ ₆ alkylthio one ₆ alkylcarbonyl (sulfur atom may be oxidized), (XXXV) eight halogenated which may be alkylsulfonyl, (xxxvi) sulfamoyl, (XXXV ii) C _a _ ₆ alkylsulfamoyl, etc.], (20) a group represented by the formula C (= 0) NR ^c R ^d

[Rc and R ^d are each (i) hydrogen atom, (i C ^ - ₆ alkyl, (iii) 5 or 6-membered heterocyclic ring (e.g., pyridyl, nitrogen atom in addition to carbon atoms, such as imidazolyl, sulfur atom, an oxygen atom 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of: 1 Ci- ₆ alkyl, (iv) carboxy-alkyl, WCi- ₆ alkoxy-carbocarbonyl C ₆ alkyl, (vi) G C ^ 6 alkylamino one C Bok ₆ alkyl, (vii) force Rubamoiru ₆ alkyl, (viii) C ₆ alkyl force Rubamoiru - C E _ ₆ alkyl, (ix) 5 or 6-membered heterocyclic ring (e.g., carbon, such as pyridyl A 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to the atom) 1 C— ₆ alkyl rubamoyl-C— ₆ alkyl, (X) 5 Or 6-membered heterocycle (eg, charcoal such as pyridyl) Nitrogen atom besides atom, a sulfur atom, 5 or 6-membered heterocyclic ring containing hetero atoms to 1 selected from SansoHara child like to three of) - § amino - C - ₆ alkyl, (xi) Surufamoiru C ₆ — ₁₄ aryl — (: ₆ alkyl, (xii) — 6 alkoxy optionally having C ₆ — ₁₄ aryl, (xiii) C ^ — ₆ phosphono optionally esterified with alkyl C i _ ₆ Alkyl-C ₆ _ J ₄ aryl, (xiv) 4- to 10-membered heterocyclic group (e.g., azechel, pyrrolidinyl, piberidile, hexahydroazepier, pyridyl, pyrimigel, pyrazinyl, pyridazinyl, 1-azabicyclo [2. 2.2] 4- to 10-membered heterocycle containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as oct-3-yl The 10-membered heterocyclic group is halo Emissions atom, ^ - ₆ § alkyl may have two, 1 to substituents selected from such _{Okiso], (XV) 6 -.} 14 Ariru - Power Rubamoiru - 6 alkyl, (xvi) hydroxy-C ^ — _6- alkyl, (xvii) 5- or 6-membered heterocyclic ring which may have an oxo group (eg, selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyrrolidinyl, pyridyl, etc. 1 to 3 of 5 or 6 membered heterocyclic ring) Ichiriki containing heteroatoms Rubamoiru C - ₆ alkyl shows the like. Rc is preferably a hydrogen atom. ],

(22) Mono- or di-C ₆ alkyl rubamoylthio group (eg, dimethylcarbamo Iruchio),

 (23) Mono- or di-C ^ -ealkylthiolrubamoyloxy groups (eg, dimethylthiolrubamoyloxy) and the like are preferable.

Examples of the “heterocyclic group” represented as a preferable group of R ¹ include pyridyl, phenyl, furyl, imidazolyl, thiazolyl, quinolyl, 1,2-dihydropyridyl, dihydrobenzofuranyl, benzodioxolyl, and benzothiazolyl. , Piperidyl, piperazinyl and the like are preferable, and pyridyl, 1,2-dihydropyridyl and the like are particularly preferable.

 As the substituent of the “heterocyclic group”,

 (1) a halogen atom,

(2) Ci- ₆ alkyl group (eg, methyl, ethyl, etc.)

[Wherein alkyl, force Rupokishi, ₆ alkoxy, alkoxy - has Karupamoiru, a Okiso - force Lupo two Le, mono one C ^ - ₆ Arukiruamino, di - ₆ Arukiruamino force Rubamoiru, alkyl which may have hydroxy A 4- to 10-membered heterocyclic group (e.g., containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyridyl and quinolyl) 10-membered heterocyclic group), 4- to 10-membered heterocyclic ring (eg, containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as pyridyl and quinolyl) Or a 10-membered heterocyclic ring) —which may have a substituent selected from rubamoyl, rubamoyl-C ₆ -alkyl monobutylammonium, etc.]

(3) (: ₆ alkoxy groups (eg, methoxy),

(4) C ₆ - _{1 4} Ariru group (e.g., phenyl), -

(5) C ₇ — ₁₆ aralkyl group (eg, benzyl)

[The C ₇ _ _{1 6} Ararukiru is carboxy, alkoxy one carbonyl, force Luba moil, hydroxy may have - 6 alkyl Ichiriki Rubamoiru, 4 to 1 0-membered heterocyclic ring (e.g., carbon atoms, such as pyridyl A 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc.) — Which may have a substituent selected from rubamoyl, etc.] ,

(6) 4- to 10-membered heterocyclic group (eg, charcoal such as pyridyl, quinolyl, isoquinolyl, etc.) 4- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc., in addition to elemental atoms)

[This 4 to 1 0-membered heterocyclic group, alkyl, C ^ - ₆ alkoxy - carbonylation Le force Rubamoiru, Okiso, 4 to 1 0-membered Hajime Tamaki (e.g., nitrogen atom besides carbon atom, such as pyridyl , A sulfur atom, a 4- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from oxygen atoms, etc.), and the like.)

 (7) an oxo group,

 (8) One to five, preferably one to three substituents selected from an oxoxide group and the like are preferable.

As the heterocyclic group in which R ¹ has an oxoxide group, for example, N-aminopyridyl pyridyl and the like are preferable.

"Aliphatic cyclic hydrocarbon group" represented as preferable groups for R ^1, for example, cyclopropyl, cyclobutyl, cyclopentyl, C ₃ _ ₆ shea click port alkyl groups such as cyclohexyl may be used, in particular cyclopentyl, Cyclohexyl is preferred. This “aliphatic cyclic hydrocarbon group” may have the same substituent as the substituent that the hydrocarbon group represented by R ¹ may have.

Examples of the preferred group for R ¹ include an “optionally substituted aromatic hydrocarbon group” and an “optionally substituted heterocyclic group”.

[The symbols have the same meanings as described above] are preferably used.

The “optionally substituted hydrocarbon group” represented by R ^lb may be the same as the “optionally substituted optionally substituted hydrocarbon group” exemplified as the substituent for the ring A. Is used. Above all,

(1) Ci- ₆ alkyl group (methyl, isopropyl, tert-butyl, etc.)

[This alkyl group is a halogen atom, cyano, hydroxy, C- ₆ alkoxy Sheet - Power Ruponiru, di - C ^ e Arukiruamino may be halogenated - 6 alkyl - force Lupo two Ruamino force Rupokishi force Rubamoiru, C ^ -e alkyl Ichiriki 'Rubamoiru, C ₆ alkyl one Karuboniruo Xy, alkoxy-carbonyl-alkyl-alkanoyl, 5- or 6-membered heterocyclic ring (eg, 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyridyl, imidazolyl, etc.) A 5- or 6-membered heterocyclic ring containing) 1-C ^ _6- alkyl mono-rubbamoyl, alkylthio, C _6- alkylsulfiel, — 6-alkylsulfonylamino, 5- or 6-membered heterocyclic ring (eg other than carbon atoms such as pyridyl) A 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc.) Yl, 5- or 6-membered heterocycle (eg, 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as pyridyl) —amino Sulfamoyl C ₆ — ₁₄ aryls, carboxy _C ₆ _ ₁₄ aryls, — 6 alkoxy-carbonyl _C ₆ — ₄ aryls, power rubamoyl C ₆ _ ₁₄ aryles, optionally with hydroxy _ ₆ alkyl mono-functional rubamoyl — C ₆ _ ₁₄ aryl, 4- to 10-membered heterocyclic ring (eg, 4- to 10-membered heterocyclic ring containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyridyl) ) may have a substituent selected from such as single force Rubamoiru C ₆ _ ₁₄ § reel,

(2) C ₃ - ₆ cycloalkyl group (e.g., cyclohexyl),

(3) C ₆ - ₁₄ Ariru group (e.g., phenyl)

[The C ₆ _ ₁₄ Ariru groups, - 6 alkoxy (e.g., methoxy) Amino, carboxy, may be halogenated _d-6 alkyl Ichiriki Ruponiruamino (eg, § Se Chiruamino, triflumizole Ruo b acetyl § Mino ), C ^ -e alkoxy - Karuponiruami Bruno (e.g., methoxy Cal Poni Rua Mino), Horumiruamino, ureido, ₆ alkynyl Le sulfonyl § amino (e.g., methylsulfonyl § Mino), (CI- ₆ alkyl) (d - ₆ alkyl Sulfonyl) amino (eg, methyl (methylsulfonyl) amino, etc.), C ₆ alkoxy-potassium C ₆ alkylamino (eg, 2-ethoxycarbo 2-ru-propylamino, etc.), esterified with Ci ₆ alkyl is optionally Hosuhono 〇, _ ₆ alkyl, mono- - or di - alkyl Ichiriki Rubamoiru, C ₇ _ _{1 6} Ararukiruokishi Ichiriki Ruponiruamino (e.g., benzyl O carboxymethyl Cal Poni Rua mino) may have a substituent group selected from, etc.] or the

(4) A C ₂ _ ₆ alkenyl group is preferred.

As the “heterocyclic group ^optionally having substituent (s)” represented by R ^lb , those similar to the “heterocyclic group optionally having substituent (s)” exemplified as the substituent for ring A are used. It is possible. Among them, halogen atom, C ₆ alkyl, carboxyl-C ^ -e alkyl, C ₆ alkoxy mono-potential C _6- alkyl, C ₆ alkoxy mono-proponyl, dipotamoyl, oxo, 4- to 10-member complex A ring group (eg, a 4- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as pyridyl) 1 A 5- to 14-membered heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon, which may be substituted with 1 to 2 substituents (E.g., azetinyl, piperidinyl, piperidyl, isothiazolidinyl, thiadiazolidinyl, hexahydrroazepier, frill, chenyl, pyridyl, quinolyl, isoquinolyl, benzofurel Pyrimidinyl, tetrazolyl, imidazolidinyl, pyrazinyl, etc. Piridaji yl) and the like are preferable.

The aromatic hydrocarbon ring represented by D ring, e.g., C 6 -C to 1 4-membered monocyclic or condensed polycyclic aromatic hydrocarbon ring (C _{6 1 4} Ariru ring), and the like Ru is used. As the C _{6 14} aryl ring, for example, a benzene ring, a naphthalene ring, an anthryl ring, a phenanthryl ring and the like are used, and among them, a benzene ring, a naphthylene ring and the like are preferable, and a benzene ring is particularly preferable. .

 These aromatic hydrocarbon rings may have 1 to 5, preferably 1 to 3, substituents selected from the aforementioned substituent group A.

 Examples of the heterocycle represented by the ring D include a 5- to 14-membered heterocyclic ring having 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen, sulfur, oxygen and the like in addition to carbon atoms. Heterocycles and the like are used. Specific examples include (a) a 5- to 14-membered aromatic heterocycle, (b) a 5- to 14-membered aliphatic heterocycle, and (c) a 5- to 14-membered heterocycle. A bicyclic or tricyclic fused ring with a zen ring is used.

Examples of the 5- to 14-membered aromatic heterocycle include a nitrogen atom and a sulfur atom in addition to a carbon atom. A 5- to 14-membered aromatic heterocycle containing 1 to 4 (preferably 1 to 3) heteroatoms selected from a yellow atom, an oxygen atom and the like is used, and specifically, thiophene, furan, indolizine and the like are used. , Pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, N-oxidized pyridine, pyrazine, pyrimidine, pyridazine, purine, 4H-quinolizine, naphthyridine, isothiazole, isoxazole, furazan, etc. . Among them, pyridine, thiophene, furan and the like are preferably used.

 The 5- to 14-membered aliphatic heterocycle includes 1 to 4 (preferably 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom and the like in addition to a carbon atom. A membered aliphatic heterocycle or the like is used, and specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,2-dihydropyridine, imidazolidine and the like.

 As the bi- or tricyclic fused ring of the 5- to 14-membered heterocyclic ring and a benzene ring, one to four heteroatoms (preferably one to four) selected from nitrogen, sulfur and oxygen other than carbon atoms And 3 or more condensed rings of a benzene ring with a heterocyclic ring containing benzene [b] thiophene, benzofuran, 1H-benzimidazole, benzoxazole, benzo Thiazole, 1,2-benzisothiazol, naphtho [2,3-b] thiophene, thianthrene, xanthene, phenoxatiin, indole, isoindole, 1H-indazole, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, Cinnoline, carbazole, 3-ketoporin, phenanthridine, acridine, phenazine, phenothiazine Fuenokisajin, isochroman, such as dihydro base Nzofuran and the like.

■ Among the heterocycles represented by the D ring, pyridine, thiophene, furan, imidazole, thiazole, quinoline, N-hydroxylated pyridine, 1,2-dihydropyridine, dihydrobenzofuran, benzodioxole, Benzothiazole, piperidine, piperazine and the like are preferable, and pyridine, 1,2-dihydropyridine and the like are particularly preferable.

These heterocycles may have 1 to 5, preferably 1 to 3, substituents selected from the aforementioned substituent group A. As the “optionally oxidized sulfur atom” represented by E, S, SO, and SO ₂ are used.

 Examples of the optionally substituted nitrogen atom represented by E include (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon group, and (iii) an acyl group. A nitrogen atom which may be present is used.

 As the “hydrocarbon group optionally having substituent (s)”, those similar to the “hydrocarbon group optionally having substituent (s)” exemplified as the substituent for ring A can be used.

 As the “acyl group”, those similar to the “acyl group” exemplified as the substituent for the ring A are used, and this acyl group further has 1 to 5, preferably 1 to 5, substituents selected from the substituent group A. May have one to three.

Formula expressed by E CS—〇 one, one CO— 0—, one S—CO—,-(CH ₂ ) _k — CO-, -NR ^lc -CO- (CH ₂ ) _m- , _NR ^lc _S〇 ₂ ― (CH ₂ ) _m -,-S〇 ₂ -NR ^lc — (CH ₂ ) _m ―, -O-CS-NR ^10- (CH ₂ ) _m ―, — NR ^lc- C〇— NR ^lc — ( CH ₂ ) _m —, NR ^lc —CO—CH ₂ — (CH ₂ ) _m — NR ^lc [wherein, is a hydrogen atom, an alkyl group or an acyl group which may have a substituent, and k is And m represents an integer of 0 to 3]. Examples of the alkyl group represented by R include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl - butyl, etc. C WINCH ₆ alkyl groups such as pentyl, carboxymethyl Le is used.

The alkyl group represented by R ^le may have 1 to 5, preferably 1 to 3 substituents selected from the aforementioned substituent group A.

As the acyl group represented by R ^lc , those similar to the `` acyl group '' exemplified as the substituent for the ring A are used, and the acyl group further has 1 to 5 substituents selected from the substituent group A. Preferably, it may have one to three.

 k represents 0 or 1, particularly preferably 0.

 m represents an integer of 0 to 3, and among them, 0 or 1 is preferable.

 Among the above, as E

(i) bond, (ii) methylene, (iii) 〇, (iv) S, (v) SO, (vi) S〇 ₂ , (vii) -NH—, (viii) -N (C— ₆ alkyl ) One (eg, one N (methyl) one etc.), (ix) — N alkyl-capillonyl) (eg, one N (acetyl) one), (X) N

— 6 alkoxy monopropionyl) (eg, — N (ethoxycarbonyl), etc.), (xi) -N alkyl-sulfonyl)-(eg, 1 N (methylsulfonyl), etc.), (xii) — C 〇 一 O—, (xiii) — S— C〇-1,

a group represented by (xiv)-(CH ₂ ) _k —CO—, wherein k represents 0 or 1;

^{(xv) -NR f -C0- (CH} 2) ml - [wherein, R ^f is a hydrogen atom or a C ^ - ₆ an alkoxy Ichiriki Ruponiru (e.g., methoxycarbonyl) or a nitrogen atom in addition to carbon atom, an oxygen atom , An alkyl group which may be substituted with a heterocyclic group containing 1 to 3 hetero atoms (e.g., pyridyl) selected from a sulfur atom, etc., and ml represents an integer of 0 to 3.) Group,

_{^{(xvi) -NR g -S0 2 -}} (CH 2) m2 - wherein, R ^g represents a hydrogen atom or a ₆ alkyl Rusuruhoniru group (e.g., methylsulfonyl) and, m 2 represents 0] is represented by Group, (xvi0-SO ₂ -NR ^h- (CH ₂ ) _m [where R ^h represents a hydrogen atom or a C ^ 6 alkyl group (eg, methyl), and m3 represents 0 or 1]. Group

(xviiD-O-CS-NR ^1- (CH ₂ ) _m4 — wherein R ¹ represents a hydrogen atom or a C alkyl group (eg, methyl), and m4 represents 0 or 1),

(xix) -NR ^j -CO-NR ^k- (CH ₂ ) _m5- (wherein, R ^j is a hydrogen atom or a C ₆ alkyl group (e.g., methyl); R ^k is a hydrogen atom or a ₆ alkyl group (e.g., , Methyl), and m5 represents 0 or 1.]

(xx) -NR ^L -CO-CH ₂ (CH ₂ ) _mS — 'NR ^m — (where R ^L is a hydrogen atom or C

^ 6 alkyl group (e.g., methyl), and R ^m is hydrogen or ^ - _{group 6} alkyl group (e.g., methylation) and represented by m6 is 0 or 1],

Are preferred.

Examples of the preferred group for R ¹ include an “optionally substituted aromatic hydrocarbon group” and an “optionally substituted heterocyclic group”.

〔各記号は前記と同意義を示す〕 で表わきれる基も好ましく用いられる。 CO-Hal

[Each symbol has the same meaning as described above] is also preferably used.

 As the halogen atom represented by H a1, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like are used, and among them, a chlorine atom is preferable.

 As the D ring, those similar to the above can be used.

In the group represented by the formula L-R ^la exemplified as a preferable group of R ¹ , wherein each symbol has the same meaning as described above, L is preferably methylene or heptonyl.

The aromatic group represented by R ^{1 a,} for example,

①Monocyclic or condensed polycyclic aromatic hydrocarbons, more specifically phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1.1-phenanthryl, 2- _{1 4} Ariru group (preferably, phenyl, 1 - - naphthyl or 2-naphthyl, particularly preferably phenyl) Fouesnant Bok Lil, 3 Fuenantoriru, C _6, such as 4 _ Fuenantoriru or 9 _ Fuenantoriru 6 to such 1 4 Membered monocyclic or fused polycyclic aromatic hydrocarbon group,

② Including one or more (for example, 1 to 4, preferably 1 to 3) one or more heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon atoms 4 to 14 A membered aromatic heterocyclic group or the like is used.

As the 4- to 14-membered aromatic heterocyclic group, one or more heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom and the like in addition to a carbon atom may be used. (Preferably 1 to 3) monocyclic heterocyclic group (preferably 5 to 8 members) or a fused aromatic heterocyclic group thereof, more specifically, thiophene, benzo [b] thiophene, benzofuran, 1 H-benzimidazole, benzoxazole, benzothiazole, 1,2-benzisothiazole, naphth C2,3-b] thiophene, thianthrene, furan, indolizine, xanthene, phenoxatiin, pyrrole, Imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole 1 H one-indazole, purine, 4 H- quinolizine, isoquinoline, quinoline, Futaraji down, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, beta-carboline, Hue phenanthridine, Akurijin, Fuenajin, isothiazole, Hue One or more aromatic heterocycles (preferably pyridine, thiophene or furan, more preferably pyridine) or one of these rings (preferably monocyclic heterocycles) such as nothiazine, isooxazole, furazane, phenoxazine, and isochroman; A condensed ring group of a plurality (preferably 1 or 2, more preferably 1) and an aromatic ring (for example, the above-mentioned aromatic hydrocarbon group, preferably a benzene ring) is used. As the substituent of the aromatic group, 1 to 5, preferably 1 to 3 substituents selected from the aforementioned substituent group A are used.

R ¹ The aromatic group which may have a substituent represented by ^a, alkyl, 1 to 5 optionally having C ₄ Ariru group (e.g., phenyl) substituents such as alkoxy and preferable.

As the “optionally substituted hydroxyl group” represented by R ^la , those similar to the aforementioned “optionally substituted hydroxyl group” exemplified as the substituent of the ring A described above are used. Among them, a hydroxyl group which may have a C ₆ alkyl group (eg, methyl) is preferable.

As the “optionally substituted amino group” represented by R ^la , those similar to the “optionally substituted amino group” exemplified as the substituent for the ring A can be used. .

Examples of the “amino group optionally having substituent (s)” represented by R ^la include, for example, an alkyl group optionally having a substituent, an aryl group optionally having a substituent, and the like. And an amino group which may have 2 or more, particularly preferably a 4- to 10-membered heterocyclic group (1 to 3 hetero atoms selected from nitrogen atom, oxygen atom, sulfur atom and the like in addition to carbon atom) May be substituted with a 4- to 10-membered heterocyclic group having an atom, eg, pyridyl) — 6-alkyl-amino group, ② C _{6 4} aryl-amino group, ③ 4- to 10-membered heterocyclic ring (nitrogen other than carbon atom) A 4- to 10-membered heterocyclic ring having 1 to 3 heteroatoms selected from an atom, an oxygen atom, a sulfur atom and the like, eg, pyridyl) -amino group is preferred.

Among these, as R ¹ , the formula

Wherein, R ¹⁶ is a hydrogen atom, which may have a substituent C ₆ _ ₁₄ § Li Ichiru group, an optionally substituted amino group, which may have a substituent A heterocyclic group or a halogen atom]. In particular, R ¹⁶ is a substituent selected from (1) a hydrogen atom, (2) phenyl substituted with an acetylamino group, (3) (i) an alkylsulfonyl group, (ii) pyridylcarbonyl or (iii) a sulfamoyl-alkyl group. Preferred are mono- or di-substituted amino, (4) pyridyl or (5) halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom).

The `` optionally substituted hydrocarbon group '' represented by R <sup>2</sup> and R <sup>3</sup> is the same as the `` optionally substituted hydrocarbon group '' exemplified as the substituent of ring A Is used.

 As the “optionally substituted hydrocarbon group”, for example,

① halogen atom,

② hydroxyl group which may have a substituent (e.g., ^ - ₆ alkyl, - force Ruponiru, alkylsulfonyl, C ₆ Ararukiru such like hydroxy group which may be substituted),

③ substituent amino group which may have a (e.g., one or two CI- ₆ alkyl, C ^ g alkyl - force Ruponiru, etc. In substituted C ₆ _ i ₄ § Li one Lou force Ruponiru Molypamino group),

 44- to 10-membered heterocyclic group which may have a substituent (for example, which may have an oxo group, other than carbon atom, is selected from nitrogen atom, oxygen atom, sulfur atom, etc. 4- to 10-membered heterocyclic group having one heteroatom (eg, phthalimide, imidazolyl, piperidyl, pyrrolidinyl)),

⑤ which may have a substituent Chio group (e.g., (^ _ ₆ alkyl such Yoi Chio group optionally substituted with) ⑥C i-e alkyl-sulfinyl group,

⑦ C ₆ alkyl-sulfonyl group,

A hydrocarbon group (particularly, an alkyl group) which may be substituted by, for example, is used. Among them, ① halogen atom (especially, bromine atom), ② hydroxy, ③ _ ₆ alkyl Le - Karuponiruokishi (eg, Asetokishi), ④ Amino, ⑤ 4 which may have a Okiso group to 1 0-membered heterocyclic group (Substituted with a 4- to 10-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen, sulfur, etc. in addition to carbon (eg, phthalimide, imidazolyl, piperidyl, pyrrolidinyl)) etc. good C ₆ alkyl group is preferable be news halogen atom (especially, bromine atom) may be halogenated and the like - 6 alkyl group (e.g., methyl, etc. Echiru) and the like are preferable, especially methyl Groups are preferred.

Represented by R ² and R ³ as "Ashiru group", those similar to the Ru is exemplified as the substituents for ring A "Ashiru group" is used, inter alia - ₆ alkoxy - Karuponiru groups are preferred, especially methoxycarbonyl Groups are preferred.

As the 3- to 8-membered ring formed by R ² and R ³ together with adjacent carbon atoms, for example, a 3- to 8-membered homocyclic or heterocyclic ring is used.

The 3- to 8-membered homocyclic R ² and R ³ form together with the adjacent carbon atom, 3- to consist carbon atom used cyclic hydrocarbons to 8-membered, particularly, C ₃ _ ₈ consequent Roarukan (e.g., cyclobutane, cyclopentane, cyclohexane, heptane cyclohexane, cyclooctane), C ₃ _ ₈ Shikuroarugen (e.g., cyclobutene, consequent opening pentene, cyclohexene, cycloheptene, Shikurookuten) etc. is Ru mentioned. Of these C _{3 8} cycloalkane is preferred, cyclopentane, 5 or 6-membered homocyclic ring such as key San cyclohexane (especially, cyclohexane) are preferred.

The 3- to 8-membered heterocyclic ring formed by R ² and R ³ together with adjacent carbon atoms includes, in addition to a carbon atom, one or two hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. A 5- to 8-membered aliphatic heterocycle (preferably a 5- or 6-membered aliphatic heterocycle) containing at least one (for example, 1 to 4, preferably 1 to 3) is used.

More specifically, for example, piperidine, piperazine, morpholine, thiomorphol 5 to 8 members (preferably 5 or 6) containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon and nitrogen atoms, such as a nitrogen atom, a pyrrolidine and an imidazolidine ring. Member) is used.

The 3- to 8-membered allo-heterocyclic or heterocyclic ring formed by R ² and R ³ together with the adjacent carbon atom has the same substituent as the above-mentioned substituent which the heterocyclic ring represented by R ¹ may have. It may have 1 to 5, preferably 1 to 3. Substituents include: — 6-alkyl, C ₆ — ₁₄ aryl, C ₇ — ₁₆ aralkyl, amino, mono— — 6-alkylamino, mono-C ₆ — ₁₄ arylamino, di- ₆ alkylamino, di— C ₆ — ₁₄ arylamino A 4- to 10-membered heterocyclic group (eg, a 4- to 10-membered (preferably 5- or 6-membered) containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms) 1 to 3 members selected from heterocycles) are preferred.

The Among that, as the R ² and R ^3, etc. In the optionally substituted C _ ₆ alkyl groups, respectively a halogen atom,. A _6- alkoxy-carbonyl group is preferred, and a methyl group and a methoxycarbonyl group are particularly preferred.

Furthermore, C _{3 8} cycloalkane together with the carbon atoms to which R ² and R ³ are adjacent, preferably cyclopentane, 5 or 6-membered homocyclic ring such as cyclohexane (in particular, key San cyclohexylene) may form a preferable.

As the `` optionally substituted hydrocarbon group '' represented by R <sup>4</sup> and R <sup>5</sup> , the same as the `` optionally substituted hydrocarbon group '' exemplified as the substituent of ring A Things are used. Among them, (1) halogen atom, (2) halogenated alkyl, (3) optionally halogenated — 6 alkoxy, (4) halogenated alkylthio, (5 ) May have 1 to 5 substituents selected from hydroxy, (6) amino, (7) monoalkylamino, (8) dialkylamino, etc. — 6 alkyl group, C ₂₆ alkenyl group or C preferably ₂ _ ₆ alkynyl group, particularly an alkyl group (e.g., methyl, etc. Echiru) are preferred.

As R ⁴ and R ⁵ , for example, a hydrogen atom, an alkyl group (eg, methyl, ethyl) and the like are preferable, and a hydrogen atom is particularly preferable. As the `` optionally substituted hydrocarbon group '' represented by R <sup>6</sup> and R <sup>7</sup> , the same as the `` optionally substituted hydrocarbon group '' exemplified as the substituent of the ring A Of these, a (-6) alkyl group (eg, methyl, ethyl, etc.) is preferred, and a methyl group is particularly preferred.

As the “optionally substituted 3- or 8-membered ring” formed by R ⁶ and R ⁷ together with adjacent carbon atoms, the above-mentioned “replacement formed by R ² and R ³ together with adjacent carbon atoms” have a substituent like are used and may also be 3 to 8-membered ring ", among them is preferably 8-membered homocyclic to 3 which may have a substituent, of these C ₃ _ ₈ Preferred are cycloalkanes (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane), and particularly preferred are 5- or 6-membered homocyclic rings (particularly, cyclopentane) such as cyclopentane and cyclohexane.

As the “optionally substituted hydrocarbon group” for R ⁸ , those similar to the “optionally substituted hydrocarbon group” exemplified as the substituent for the ring A can be used. It is required.

The hydrocarbon group represented by R ^8, an alkyl group (e.g., methyl, etc. Echiru), C ₂ - ₆ alkenyl group (e.g., Ariru, such as 2-methyl-2-propenyl), C ₂ _ ₆ alkynyl group (e.g., propargyl, etc.), C ₃ _ ₆ cycloalkyl group (e.g., consequent opening pentyl, etc.), C ₇ - _{1 6} Ararukiru group (e.g., benzyl, 3 _ phenylpropyl, 5 etc. phenylene Rupenchiru) etc. it is preferred, (^ _ ₆ alkyl group (particularly, methylation) are suitable.

Examples of the substituent of the hydrocarbon group include (1) a halogen atom (for example, fluorine, chlorine, bromine, and iodine), (2) a hydroxy group, (3) an amino group, (4) lipoxy, and (5) rubamoyl. , (6) C- ₆ alkoxy monopropionyl (eg, methoxycarbonyl, X toxiccarbonyl, etc.), (7) Monono C i _ ₆ alkyl monopotassium rubamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), (8) G-alkyl-carbamoyl (eg, dimethylcarbamoyl, getylcarbamoyl, etc.), (9) one to three carbon atoms which may have an oxo atom, other than nitrogen atom, sulfur atom, oxygen atom, etc. Hetero atom-containing 4- to 10-membered heterocyclic groups (eg, pyridyl, 2-isoindolyl, etc.), (10) C ₆ monoaryl groups (eg, phenyl, etc.), etc. preferable.

As the `` acyl group '' represented by R <sup>8</sup> , those similar to the `` acyl group '' exemplified as the substituent for the ring A are used, and this acyl group further has a substituent selected from the group of substituents A to 1 to 5 , Preferably one to three. Of these, (1) formyl, (2) C ₆ alkyl - Power Ruponiru group (eg, Asechiru, propionyl and the like), (3) _<6 _ _{1 4} Ariru Ichiriki Ruponiru group (eg, a Benzoiru), (4 ) C ₇ — ₁₆ aralkyl monofunctional ruponyl group (eg, phenylacetyl), (5) (:) ₆ alkoxy monofunctional group (eg, methoxycarbonyl, ethoxycarponyl, etc.), (6) functional rubamoyl group, (7) mono- or di - C i _ ₆ alkyl - power Rubamoiru group (e.g., methylcarbamoyl, dimethylcarbamoyl, etc.), (8) mono- or di-C Bok ₆ alkyl one Chiokaruba carbamoyl group (e.g., methylthio force Rubamoiru, dimethylthio force Rubamoiru etc.), (9) (^ - 6 alkyl - sulfonyl group (e.g., methylsulfonyl, etc.) or (lCD C _i-6 § alkyl - sulfinyl group (e.g., methyl sulfide El) and preferably .

As the `` heterocyclic group optionally having substituent (s) '' for R <sup>8</sup> , those similar to the `` heterocyclic group optionally having substituent (s) '' exemplified as the substituent for the ring A are used. Can be Among them, the heterocyclic group represented by R ⁸ is a 4- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. Preferred are ring groups (eg, tetrazolyl, etc.). '

The substituent of the heterocyclic group, C ₆ - _{1 4} Ariru group (e.g., phenyl etc.) and the like are preferable.

The halogen atom represented by R ^8, fluorine atom, chlorine atom, bromine atom, iodine atom are used, inter alia as chlorine atom is preferable. ,

Of formula one OR ^{1 Q} represented by R ^{8,: 1} as "optionally substituted hydrocarbon group" represented by ^G, have a "substituent exemplified as the substituent of ring A The same hydrocarbon groups as those described above may be used.

Examples of the hydrocarbon group represented by R ^{1 G} include (OC ^ -e alkyl group (eg, methyl, ethyl, isopropyl, butyl, etc.) [the _6- alkyl group is (1) halogen atom, (2) hydroxy Group, (3) amino group, (4) diluvamoyl, (5) diluvamoyl, (6) alkoxy-diluponyl, (7) monol-alkyl diluvamoyl, (8) Di--6 alkyl monorubumoyl, (9) containing from 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon which may have oxo, 10-membered aromatic Hajime Tamaki (e.g., pyridyl, 2-isoindolyl, etc.) which may have a substituent selected from _{such], (ii) C 2 _} 6 alkenyl group (e.g., § Lil, 2-methyl 2-propenyl, etc.) [this C ₂ _ ₆ alkenyl group C ₆ - ₁₄ § Li Lumpur (eg, which may have a _{phenyl)], (iii) C 2} _ 6 alkynyl group (e.g., such flop port _{Parugiru), (iv) C 3 _} 6 cycloalkyl group (e.g., cyclopentyl, _{etc.), (v) C 7 _} 16 Ararukiru group (e.g., benzyl, 3-phenylpropyl, 5-phenylene point pen chill etc. Are preferred.

The formula represented by R ⁸ — OR ^1Q , the “acyl group” represented by R ^1Q includes, for example, formyl, sorbamoyl, —6 alkyl monopropionyl (eg, acetyl, propionyl, etc.), c ₃ _ ₆ Cycloalkyl-carbonyl (eg, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C ₆ alkoxy mono-proponyl (eg, methoxy-proponyl, ethoxycarbonyl, isopropoxy-proponyl, tert-butoxycarbonyl, etc.), C ₆ _ ₁₄ Ariru - carbonyl (e.g., Benzoiru, 2 Nafutoi Le etc.), C ₇ _ ₁₆ Ararukiru - Karuponiru (eg, phenylene Ruasechiru, 3-phenylene Rupuropioniru), C 6 ^ ₄ § Li one Ruokishi Ichiriki Ruponiru ( examples, phenoxy force Ruponiru, 2 one naphthyl O carboxymethyl like Cal Poni Le), C ₇ _ ₁₆ Ararukiruokishi - power Ruponiru (eg Benzyloxycarbonyl, 2-naphthylmethyloxycarbonyl, etc., 5- or 6-membered heterocyclic carbonyl (eg, 1-pyrrolidinylcarbonyl, 4-piberidylcarbonyl, 1-piperazinylcarbonyl, 2-morpholini) 1 to 3 selected from nitrogen, sulfur, oxygen, etc., in addition to carbon atoms such as nilcarponyl, 4-pyridylcarbonyl, 3-cerylcarbonyl, 2-furylcapillon, and _2- thiazolylcarbonyl a 5- or 6-membered heterocyclic force Lupo two Le containing hetero atoms) to the mono - C E _ ₆ alkyl Ichiriki Rubamoiru (e.g., methylcarbamoyl, etc. E Ji carbamoyl), di -C - ₆ alkyl Ichiriki Rubamoiru (e.g., dimethyl carbamoyl, such as GETS Ji carbamoyl), C ₆ - ₁₄ § Li one Roux force Rubamoiru (eg, full E carbamoylmethyl Such as 2 _ naphthylcarbamoyl), 5- or 6-membered heterocyclic Cal Bamoiru (e.g., 1-pyrrolidinylmethyl carbamoyl, 4 one piperidylcarbamoyl, 1 —Selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as piperazinylcarbamoyl, 21-morpholinylcarbamoyl, 4-pyridylcarbamoyl, 3-cerylcarbamoyl, 2-furylcarbamoyl, 2-thiazolylcarbamoyl, etc. is a 5- or 6-membered heterocyclic force Rubamoiru containing 1 to 3 heteroatom), C ^ ₆ alkyl chromatography Chio local Poni Le (e.g., methyl thio Cal Poni Le), C ₃ - ₆ cycloalkyl over Chio local Poni Le (e.g., cyclopentylthio force Ruponiru, cyclohexane, etc. cyclohexyl Chiokaruponiru) alkoxy - Chiokaruponiru (e.g., methoxide ^ Chioka Ruponiru, Etokishichi Sairyoku Ruponiru, propoxycarbonyl Chio carbonyl, etc. Butokishichioka Ruponiru), C ₆ - _{1 4} § reel over Chio carbonyl (e.g., Hue Nilthiocarbonyl, 2 Na like border Lucio Cal Poni Le), C ₆ § Lal kills over Chio local Poni Le (e.g., benzyl ^^ O force Ruponiru and Hue phenethyl Lucio Cal Poni Le), C ₆ _ _{1 4} Ariruo carboxymethyl - Chio carbonyl (e.g., phenoxyethanol Chio Cal Poni Le, and 2-naphthyl O carboxymethyl Chio carbonyl), C ₇ - _{1 6} § Lal kill O Kishi Chio carbonyl (e.g., Benjiruo carboxymethyl Chio carbonyl, 2-naphthylmethyl O carboxymethyl Chio Cal Poni Le etc.), 5- or 6-membered heterocyclic ring Chiokaruponiru (eg , 1-pyrrolidinylthiocarbonyl, 4-piperidylthiothiol-ponyl, 1-piperazinylthiothiol-ponyl, 2-morpholinylthiocarbonyl, 4-pyridylthio-thiol-ponyl, 3-cherylthiocarbonyl, 2-furyl-thiocarbonyl, In addition to carbon atoms such as 2-thiazolylthiocarbonyl, nitrogen, sulfur and acid 5- or 6-membered heterocyclic thiocarbonyl containing 1 to 3 heteroatoms selected from elementary atoms, etc.), thiocarbamoyl, mono--6alkyl-thi-substituted rubamoyl (eg, methylthiolrubamoyl, ethylthiolrubamoyl, etc.) ), di-Bok ₆ alkyl one Chiokarubamoiru (e.g., dimethylthio force Rubamoiru, such as di Echiruchio force Rubamoiru), C ₄ Ariru - Chiokarubamoiru (eg, phenylene Lucio force Rubamoiru, such as 2-naphthylthio force Rubamoiru), 5 or 6-membered Heterocyclic thiocarbamoyl (eg, 2-pyrrolidinylthiolrubamoyl, 4-piperidylti talent rubamoyl, 2-piperazinylthiolrubamoyl, 2-morpholinylthiocarbamoyl, 4-pyridylthiolrubamoyl, 3-1-chelylthiolrubamoyl, 2-Ruffle Chacarbamoy Contains 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon atoms such as That a 5- or 6-membered heterocyclic Chiokarubamoiru, sulfamoyl, mono - C 3_ _ ₆ Al key loose sulfamoyl (e.g., methylsulfamoyl, etc. E chill sulfamoyl), G (^ _ ₆ alkyl - sulfamoyl (e.g., dimethylsulfamoyl, etc. Jechirusu Rufamoiru), C 6 ^ ₄ Ariru - sulfamoyl (e.g., such as Fuenirusurufa Moyle) (^ _ ₆ alkylsulfonyl (e.g., methylsulfonyl, etc. Echirusuruho sulfonyl), C ₆ - ₁₄ § reel sulfonyl ( examples, phenylalanine sulfonyl, such as 2-naphthyl Rusuruhoniru), (^ 6 alkylsulfinyl (e.g., methylsulfinyl, etc. E Chirusurufiniru), C ₆ _ ₁₄ § reel sulfinyl (e.g., Hue Nils sulfinyl, 2- Nafuchirusuru Fiel, etc.), sulfino, sulfo, alkoxys Rufiniru (e.g., methoxysulfinyl, E Toki cis sulfinyl), c ₆ - ₁₄ § reel O carboxymethyl sulfinyl (e.g., full enoki cis Luffy El), Arukokishisu Ruhoniru (e.g., methoxysulfonyl, E butoxy-benzenesulfonyl) and c ₆ _ ₁₄ Ari Ruo Xylsulfonyl (eg, phenoxysulfonyl) is used, and this acyl group may further have 1 to 5, preferably 1 to 3, substituents selected from the substituent group A. But, (i) C i-6 alkyl Ichiriki Ruponiru group (eg, a _{Asechiru), (ii) C 6 _} 14 § Li one Roux force Ruponiru group (eg, a _{Benzoiru), (iii) C 7 -} 16 § (1) alkenyl carbonyl group (eg, phenyl acetyl), (iv)! ^^ ₆ alkoxy carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (V) monomer Other di primary alkyl one Chiokarubamoiru group (e.g., methylthio Scarpa moil, such as di-methylthio force Rubamoiru), (vi) halogenated may CI_ ₆ alkyl one sulfonyl group (e.g., methyl sulfonyl), etc. are preferable.

As the `` heterocyclic group optionally having substituent (s) '' represented by R <sup>1Q</sup> of the formula 1 OR <sup>1G represented</sup> by R <sup>8</sup> , the `` optionally substituted heterocyclic group '' exemplified as the substituent on ring A The same as "good heterocyclic group" are used.

Among them, ^examples of the heterocyclic group represented by R ^1Q include a ^4- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms. (eg, such as tetrazolyl) [this double ring group C ₆ - ₁₄ Ariru (e.g., phenyl) which may have a. ] Is preferred.

In the formula (1) represented by R ⁸ , SR ¹¹ may be a `` carbonized optionally having substituent (s) '' represented by R ¹¹ As the “hydrogen group”, those similar to the “optionally substituted carbon hydride group” exemplified as the substituent for the ring A are used.

The hydrocarbon group represented by R ^11, are preferred, such as (^ _ ₆ alkyl group (e.g., methyl, etc. Echiru).

As the “acyl group” represented by R ¹¹ in the formula—31 ¹¹ of the formula—31 ^{11 represented} by the scale ⁸ , the same “acyl group” represented by R ^1Q can be used. It may have 1 to 5, preferably 1 to 3, substituents selected therefrom.

The “acyl group” represented by R ¹¹ is preferably a monol or dialkyl-carbamoyl group (eg, methylcarbamoyl, dimethylcarbamoyl, etc.).

Of formula -SR ¹¹ represented by R ^8, as the "optionally heterocyclic group which may have a substituent" represented by R ^11, exemplified as the substituent of the ring A 'may have a substituent The same as "good heterocyclic group" are used.

In the formula _S (O) R ¹² represented by R ⁸ , the “optionally substituted hydrocarbon group” represented by R ^{12 includes} the “substituent having a substituent” exemplified as the substituent for ring A. The same hydrocarbon groups as those described above may be used.

The hydrocarbon group represented by R ^12, ^ alkyl group (e.g., methyl, etc. Echiru) is preferable.

Formula represented by R ⁸ - the S (〇) R ^12, as the "but it may also be substituted heterocyclic group" represented by R ^12, the illustrated "substituent as the substituent of ring A The same as the "heterocyclic group which may be possessed" is used.

Of formula -S (〇) ₂ R ¹³ represented by R ^8, as the "optionally substituted hydrocarbon group" represented by R ^13, the illustrated "substituent as the substituent of ring A The same as the "hydrocarbon group which may be possessed" is used.

As the hydrocarbon group represented by R ^13, (: Preparative ₆ alkyl group (e.g., methyl, etc. Echiru) is preferably such.

As the `` heterocyclic group optionally having substituent (s) '' for R <sup>13</sup> of the formula (1) S (O) <sub>2</sub> R <sup>13 represented</sup> by R <sup>8</sup> , the `` substituents '' exemplified as the substituents for ring A The same as those described for the "heterocyclic group which may be possessed" are used. As the `` optionally substituted hydrocarbon group '' represented by R <sup>14</sup> and R <sup>15</sup> of the formula 1 NR <sup>14</sup> R <sup>15 represented</sup> by R <sup>8</sup> , the `` substituents '' exemplified as the substituents for ring A The same as the "hydrocarbon group which may be possessed" is used.

Examples of the hydrocarbon group represented by R ¹⁴ and R ¹⁵ include a C ₆ alkyl group (eg, methyl, ethyl, etc.) [This alkyl group may have an alkoxyl monopropyl. And the like are preferred.

As the “acyl group” represented by R ¹⁴ and R ¹⁵ of the formula 1 NR ¹⁴ R ^{15 represented} by R ⁸ , the same as the “acyl group” represented by R ^1Q can be used. May further have 1 to 5, preferably 1 to 3, substituents selected from substituent group A. Among them, formyl, c ^ 6 alkyl-caprolponyl group (eg, acetyl, propionyl, etc.) alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarponyl, etc.), caprolvamoyl group, mono- or dialkyl Carbamoyl groups (eg, methylcarbamoyl, dimethylcarbamoyl, etc.),

C ^ - ₆ alkyl chromatography sulfonyl group (e.g., methyl sulfonyl), etc. are preferable.

Examples of the `` heterocyclic group optionally having substituent (s) '' represented by R <sup>14</sup> and R <sup>15</sup> in the formula 1 NR <sup>14</sup> R <sup>15 represented</sup> by R <sup>8</sup> include `` substituents exemplified as substituents on ring A. The same ones as those described for the "heterocyclic group which may be possessed" are used.

In the formula —NR ¹⁴ R ^{15 represented} by R ⁸ , R ¹⁴ is a hydrogen atom, (2) a _6- alkyl group (eg, methyl, ethyl, etc.) [This alkyl group has ₆ alkoxy-carbonyl Is also good. ] ③ formyl, ④ C i- ₆ alkyl-propionyl group (eg, acetyl, propionyl, etc.), (Dc ₆ alkoxy mono-propionyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), ⑥ carbamoyl group, ⑦ mono- or di- one c ^ - ₆ alkyl Ichiriki Rubamoiru group (e.g., methylcarbamoyl, dimethylcarbamyl model etc. I le) or ⑧ (^ _ ₆ alkyl chromatography sulfonyl group (e.g., methyl sulfonyl) and the like, R ¹⁵ is ① a hydrogen atom , ② (: preparative ₆ alkyl (e.g., methyl, Echiru, propyl Le, isopropyl, etc.), ③ C ₆ - ₁₄ Ariru (e.g., phenyl, 2-naphthyl, etc.) or ④ C ₇ - ₁₆ Ararukiru (e.g., benzyl, phenethyl In particular, R ¹⁴ is preferably a hydrogen atom, or an alkyl group (eg, methyl, ethyl, etc.) [this alkyl group May have alkoxy-carbonyl No. ], ③ formyl, @C _{1 →} alkyl Ichiriki Ruponiru group (eg, Asechiru, etc. propionitrile sulfonyl), ⑤ Ji ₆ alkoxy - carbonyl group (e.g., methoxy Cal Poni Le, like ethoxy alkoxycarbonyl), ⑥ a carbamoyl group, ⑦ mono - or di - - 6 alkyl Ichiriki Rubamoiru group (e.g., methylcarbamoyl, etc. dimethylcarbamoyl) or ⑧ alkyl - or a sulfonyl group (e.g., methyl sulfonyl), which R ¹⁵ is a hydrogen atom or the like or methyl are preferred.

R ⁸ represents a hydrogen atom or a formula —OR ^1Q (R ^1Q represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent) Is preferred. Among them, as R ⁸ , a hydrogen atom, a hydroxyl group (where R ^1Q is a hydrogen atom), an optionally substituted Ci-e alkoxy (R ^1G may have a substituted C Preferred are i- ₆ alkyl) or acyloxy (where R ¹⁰ is acyl). In particular, a hydrogen atom, a hydroxyl group (where R ^1Q is a hydrogen atom), an alkoxy optionally substituted with pyridyl (where R ¹⁰ is C i _ ₆ alkyl optionally substituted with pyridyl) or ha C _ ₆ Arukirusu Ruhoniruokishi substituted mouth Gen atoms (R ^1Q alkylsulfonyl der shall substituted with halogen atom) is preferable.

As the “optionally substituted hydrocarbon group” for R ⁹ , those similar to the “optionally substituted hydrocarbon group” exemplified as the substituent for the ring A can be used. It is required.

The hydrocarbon group represented by R ^9, ₆ alkyl group (e.g., methyl, Echiru, propyl, isopropyl, etc.), C ₂ - ₆ alkenyl group (e.g., 2-methyl-2-pro Bae sulfonyl) are preferred, methyl, (^ _ ₃ alkyl groups such as isopropyl good preferable.

Examples of the substituent for the hydrocarbon group include an ω halogen atom (for example, fluorine, chlorine, bromine, and iodine), (2) a cyano group, (3) a lower alkoxy group (eg, methoxy, ethoxy), and (4) hydroxy. Group, (5) amino group, (6) mono-lower alkylamino group (eg, mono-alkylamino group such as methylamino, ethylamino, etc.), (7) G-lower alkylamino group (eg, dimethylamino, dimethylamino, etc.) — C _t __ ₆ alkylamino group), (8) In addition to the carbon atom which may have oxo, Atom, one oxygen atom and hetero atom selected from sulfur atom to 4 not containing 3 to 10-membered heterocyclic ring (e.g., piperidino, _{2-isoindolyl), (9) C 6 _} 14 Ariruchio (e.g., Hue (10) ureido, (11) lipoxy, (12) rubamoyl, (13) alkoxy monopropyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (14) mono-C alkyl monorubamoyl (Eg, methyl carbamoyl, ethyl carbamoyl, etc.), (15) formylamino, (16) C ア ル キ ル -6 alkyl monol lipoxamide (eg, acetoamide, propionamide, etc.) are preferred.

As the “acyl group” represented by R ⁹ , those similar to the “acyl group” exemplified as the substituent for the ring A can be used. Specifically, (1) formyl, (2) 0 ^ 6 alkyl- power Lupo sulfonyl group (e.g., Asechiru, propionyl and the like), (3) C ₆ _ ₁₄ Ariru - power Ruponiru group (eg, a Benzoiru), (4) C ₇ - ₁₆ Ararukiru - carbonyl group (e.g., Fuenirua cetyl etc.) , (5) C ^ 6 alkoxy Ichiriki Ruponiru group (e.g., methoxy Cal Poni Le, an ethoxy Cal Poni le), (6) force Rubamoiru group, (7) mono - or di C ^ - ₆ Al kill Ichiriki Rubamoiru group (e.g., methylcarbamoyl, etc. dimethylcarbamoyl), (8) mono- or di-primary alkyl one Chiokarubamoiru group (eg, Mechiruchiokaru Bamoiru, dimethylthiocarbamoyl Kalpa moil etc.), (9) C _ ₆ alkyl one sulfonyl group (e.g. And methylsulfonyl), (10) C ₁ _ ₆ alkyl one sulfinyl group (e.g., a methylcarbamoyl Rusurufiniru) and may be used, inter alia formyl is preferred.

As the "optionally substituted hydroxy group" represented by R ^9, for example, the formula - OR ⁹ '(R ^9' may be a hydrogen atom, an optionally substituted hydrocarbon group or Ashiru group The group represented by is used.

As the optionally substituted hydrocarbon group represented by R ⁹ , those similar to the “optionally substituted hydrocarbon group” exemplified as the substituent for the ring A can be mentioned. Used, and among them, alkyl and the like are preferable.

As the acyl group represented by R ⁹ , those similar to the “acyl group” represented by R ^1Q can be used, and among them, Ci- ₆ alkyl-pyruonyl and the like are preferable.

R ⁹ is preferably a hydrogen atom, a cyano group, an alkyl group optionally substituted with cyano, formyl, and the like, and particularly preferably a hydrogen atom. X represents (1) a methylene group which may have a substituent or (2) a carbonyl group. '

 As the substituent of the methylene group, a group selected from the above-mentioned substituent group A is used, and among them, one or two alkyl groups (eg, methyl, ethyl, etc.) and a hydroxyl group are preferable.

The X, (1) one or two (^ _ ₆ alkyl group (e.g., methyl, good methylene group or (2) a carbonyl group which may have a like) or a hydroxyl group Echiru preferable, 1 or A methylene group which may have two methyl groups is preferred, and a methylene group is particularly preferred.

 n represents 0 or 1, and particularly preferably 0.

 As the compound of the present invention, the following are preferable.

 [Compound ()-I]

R ¹ is the formula

Wherein each symbol is as defined above, or a group represented by the formula:

Wherein each symbol is as defined above, R ² and R ³ each represent a hydrocarbon group which may have a substituent, and R ⁴ and R ⁵ represent A hydrogen atom, R ⁶ and R ⁷ each represent a hydrocarbon group which may have a substituent, and R ⁸ represents a hydrogen atom or a formula OR ^1Q (R ^1Q represents a hydrogen atom or a substituent A hydrocarbon group, an acyl group or a heterocyclic group which may have a substituent), R ⁹ is a hydrogen atom, X is methylene, and n is 0 (化合物) Or its salt.

[Compound (II) II] R ¹ is the formula

Wherein, R ¹⁶ is a hydrogen atom, which may have a substituent C ₆ _ ₁₄ Ariru group, an optionally substituted amino group, optionally substituted heterocyclic group Or a halogen atom), R ² and R ³ each may have an alkyl group, R ⁴ and R ⁵ may represent a hydrogen atom, and R ⁶ and R ⁷ may represent a hydrogen atom. R ⁸ represents a hydrogen atom or a group represented by the formula OR ^{1 Q} (R ¹ ° represents a hydrogen atom, a hydrocarbon group optionally having a substituent, an acyl group or A compound (Γ) or a salt thereof, wherein R ⁹ represents a hydrogen atom, X represents methylene, and n is 0.

 [Compound (Γ) -III]

R ¹ is the formula

[Wherein, R ¹⁶ represents (1) a hydrogen atom, (2) phenyl substituted with an acetylamino group, (3) (i) C i_ ₆ alkylsulfonyl group, (ii) pyridylcarponyl or (iii) sulfamoyl ^ _ _{6 represents} an amino, which may be mono- or di-substituted by a substituent selected from an alkyl group, (4) pyridyl or (5) a halogen atom], wherein R ² and R ³ are each Ce alkyl R ⁴ and R ⁵ are hydrogen atoms; R ⁶ and R ⁷ are each ₆ alkyl groups; R ⁸ is a hydrogen atom or a formula —OR ^{1 Q} (R ^1Q is (1) hydrogen atom, (2 ) Represents an alkyl group optionally substituted with pyridyl or (3) alkylsulfonyl substituted with a halogen atom), R ⁹ represents a hydrogen atom, represents methylene, and n represents 0.

[Compound () -IV] Compounds produced in Examples 1-16 or salts thereof.

 Formula used in the pharmaceutical composition of the present invention

 [In the formula,-represents a single bond or a double bond] Specifically, the compound having a partial structure represented by the formula:

 [Wherein, ring A, ring B and ring C may each have the same substituent as described above], and the like.

(-1)

 [Wherein the symbols have the same meanings as described above], and the like.

In addition, the expression '

^{Wherein, R 2 ,, R 3 ',} R 6' and R ^7, each represents an alkyl group, R ^16, are hydrogen atoms, which may have a substituent C _{6 14} Ariru group, a substituent Which may have an amino group, a heterocyclic group which may have a substituent or a halogen atom].

 As the compound (A-1), (1-1) or (Ι′-1) of the present invention, specifically, the compounds produced in Examples 1 to 16 and the like are used.

 The method for producing the compounds (I) and (II) of the present invention will be described below. Compound (la) is a compound included in compound (I).

 The compounds (I) and (Γ) of the present invention can be obtained, for example, by the method represented by the following reaction formulas 1 and 2, or a method analogous thereto.

 Compounds (A), (A-1), (1-1) and (II-1) can also be produced according to the following production method.

 Each symbol of the compounds in the following schemes has the same meaning as described above unless otherwise specified. The compounds (Π) to (VI) and (νπ ') to (ΧΙΙΓ) in the reaction formula include those in the form of a salt. Examples of the salt include the same as the salt of the compound (I) or (Γ). And the like.

 Compounds (II), (III), (IV), (VI), (VII '), (VIII'), (XI ') and (II) are readily available commercially, and It can also be produced according to a method known per se or a method analogous thereto.

As the solvent used in the following reactions and represented by a generic name, unless otherwise specified, Alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, etc. Ethers such as getyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2 —Dimethoxyethane, etc. Hydrocarbons such as benzene, toluene, cyclohexane and hexane, and amides such as N, N-dimethylformamide, N, N—dimethylacetamide, hexamethylphosphoric triamide Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ketones such as acetone and ethyl methyl ketone Organic acids such as formic acid, acetic acid, Acid, Torifuruoro acetic acid, methanesulfonic acid, aromatic Amin compounds show pyridine, 2, 6-lutidine, quinoline, etc., and etc. dimethylsulfoxide as sulfoxides.

 Unless otherwise specified, the bases used in the following reactions and represented by a generic name include sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide as inorganic bases, sodium carbonate as basic salts, and the like. Potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, ammonium acetate, etc. Pyridine, lutidine, etc. as aromatic amines, Triethylamine, trippropylamine, triptylamine, N-ethyldiisopropylamine as tertiary amines Sodium hydride, alkali metal hydrides such as amine, cyclohexyl dimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine Metals such as potassium Alkoxides such as sodium amide, lithium diisopropylamide, and lithium hexamethyldisilazide; alkyl metals such as butyllithium and tert-butyllithium; aryl metals such as phenyllithium; and metal alkoxides such as sodium methoxide and sodium ethoxide. Sodium tert-butoxide, potassium tert-butoxide and the like.

The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by a usual separation method (eg, recrystallization, distillation, chromatography, etc.). Can be easily purified. Compound (la) wherein the C ′ ring may have a substituent other than RR ² and R ³ is produced by the process shown in Reaction Scheme 1.

Rj¾, Equation 1

 (II)

 R

, P + (R ₃ (hal)-(IV)

(V)

Compound (III) is produced by converting compound (II) into an organometallic compound using magnesium or a base, and reacting the compound with a formylating agent.

 Examples of the “base” include alkyl metals, aryl metals and the like. The amount of the base to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (II).

 Examples of the "formylating agent" include N, N-dimethylformamide, 1-formylpiperidine, 4-formylmorpholine, N-methylformanilide and the like. The amount of the formylide used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (II).

 This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, but is preferably, for example, a solvent such as ethers or hydrocarbons, or a mixed solvent thereof.

 The reaction time is generally about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about −100 to about 150 ° C., preferably about 180 to about 100 ° C.

Compound (V), the compound (III) with the compound (IV) wherein, R ^{2 2} is a hydrocarbon group, hal is a halogen] Ru is prepared by reacting in the presence of a base optionally a.

As the "hydrocarbon group" include chain or cyclic hydrocarbon group (e.g., _ ₆ § alkyl (e.g., methyl, Echiru, propyl, isopropyl, butyl, Isopuchiru, sec - heptyl, ter t-heptyl, pentyl , the like hexyl), C ₃ _ ₆ cycloalkyl (eg example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylene hexyl, etc.), C ₆ - _{1 4} Ariru (e.g., phenyl, 1 one-naphthyl, 2-naphthyl, Bifue two Lilly, 2-anthryl, etc.).

 The amount of compound (IV) to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (III).

Examples of the "base" include inorganic bases, basic salts, aromatic amines, tertiary amines, alkali metal hydrides, alkyl metals, aryl metals, metal amides, metal alkoxides and the like. Is mentioned. The amount of base used is the same as that of compound (III) About 1 to about 5 moles, preferably about 1 to about 2 moles, based on

 This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but examples thereof include solvents such as alcohols, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, and water. Are preferred.

 The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours. The reaction temperature is usually about 100 to about 200 ° C, preferably about 180 to about 150 ° C.

 Compound (la) is produced by reacting compound (V) with compound (VI) in the presence of an acid.

 The amount of compound (VI) to be used is about 0.5 to about 5 mol, preferably about 0.5 to about 2 mol, per 1 mol of compound (V).

 Examples of the "acid" include mineral acids such as sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, and perchloric acid; boron trifluoride dimethyl ether complex; Lewis acids such as zinc chloride and aluminum chloride; . The amount of the acid to be used is about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (V).

 This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, but is preferably, for example, a hydrocarbon, an organic acid, a halogenated hydrocarbon, or a mixture thereof. The reaction time is generally about 10 minutes to about 48 hours, preferably about 15 minutes to about 24 hours. The reaction temperature is usually about 120 to about 150 ° C, preferably about 0 to about 10 ° C.

Compound (Γ) is produced by the process shown in Reaction Scheme 2. Reaction formula 2

(Ι ') (X = CH ₂ , n = o) The compound (ΙΧ ′) is a compound (νΐΓ) and a compound (νΐΐΓ) wherein R ²³ and R ²⁴ are a hydrocarbon group which may form a part of R ⁷ and may have a substituent. those similar to R ⁷ can be exemplified, W is is prepared by reacting in the presence of a base as desired and represents a leaving group].

Examples of the “leaving group” include hydroxy, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and optionally halogenated Ci-s alkylsulfonyloxy (eg, methanesulfonyloxy, E evening down sulfonyl O carboxymethyl, trichloro methane sulfonyl O carboxymethyl, etc.), one C ₆ which may have a substituent _{1 ()} Arirusuruhoni Ruokishi the like. ". Which may have a substituent § Li one Rusuruhoni Ruokishi" as, for example ₍₆ alkyl (e.g., methyl, Echiru etc.), selected from ₍₆ § alkoxy (e.g., methoxy, ethoxy, etc.) and nitro C ₆ _ _1Q 7 reelsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy, etc.) which may have 1 to 3 substituents, and specific examples thereof include benzenesulfonyl Xy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the like.

 The amount of compound (VIII ′) to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (VII ′).

 Examples of the “base” include inorganic bases, basic salts, aromatic amines, tertiary amines, metal hydrides, metal amides, metal alkoxides and the like. The amount of the base to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (νΐΓ).

 This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, and examples thereof include solvents such as alcohols, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, and sulfoxides. Alternatively, a mixed solvent thereof is preferable.

 The reaction time is usually about 15 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is generally about 120 to about 150 ° C, preferably about 0 to about 100 ° C.

Instead of the above reaction, Mitsunobu reaction (Synthesis, 1981, 1-27) Page) can also be used.

 In the reaction, the compound (νΐ Γ) and the compound (νΐ ΐ Γ) in which W is Ο を are reacted with an azodicarboxylate (eg, getyl azodicarboxylate, etc.) and a phosphine (Eg, triphenylphosphine, tributylphosphine, etc.).

 The amount of the compound in which W is 中 in the compound (νΐ Π ′) is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound (νΐ Π).

 The amount of the “azodicarboxylates” and “phosphines” to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound (νΐ)).

 This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but examples thereof include solvents such as ethers, hydrocarbons, amides, halogenated carbons, nitriles, ketones, and sulfoxides. Preferred are mixed solvents thereof.

 The reaction time is generally about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours. The reaction temperature is usually about 120 to about 200, preferably about 0 to about 100.

 Compound (Χ ′) is produced by subjecting compound (ΙΧ ′) to Claisen rearrangement. This reaction is advantageously performed without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols, hydrocarbons, organic acids, ethers, and anilines (eg, Ν, Ν-dimethyl aniline, Ν, Ν — Phenethylaniline, etc.), phenols (eg, 2,6-dimethylphenol), halogenated hydrocarbons, or a mixed solvent thereof.

This reaction may be performed using an acid catalyst, if desired. As the acid catalyst, Lewis acids such as aluminum chloride and boron bromide are used. The amount of the acid catalyst to be used is, for example, in the case of a Lewis acid, usually about 0.1 to about 20 mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (IX '). The reaction time is usually about 30 minutes to about 24 hours, preferably about 1 to about 8 hours. The reaction temperature is usually about -70 to About 30 Ot: preferably about 150 to about 250 ° C.

 Compound (ΧΓ) can be produced by cyclizing compound (Χ ') in the presence of a protonic acid, a Lewis acid or iodine. Examples of protic acids include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and fluorosulfonic acid. Examples of Lewis acids include aluminum chloride, aluminum bromide, and the like. Titanium chloride (ιν), tin chloride αν), zinc chloride, boron trichloride, boron tribromide, boron trifluoride and the like are used. Usually, a protonic acid or a Lewis acid is used alone, but both may be combined as desired. When using protonic acid, it is used in an amount of about 1 to about 200 mol, preferably about 1 to about 100 mol, per 1 mol of the compound α '). When a Lewis acid is used, it is used in an amount of about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (Χ ′). When iodine is used, it is used in an amount of about 0.05 to about 1 mol, preferably about 0.1 to about 0.5 mol, per 1 mol of the compound (Χ ′).

 This reaction is advantageously performed using a solvent inert to the reaction. There is no particular limitation as long as the reaction proceeds as such a solvent, but examples thereof include ethers, hydrocarbons, alcohols, amides, halogenated hydrocarbons, nitriles, ketones, and sulfoxides. Or a mixed solvent thereof is preferred. The reaction temperature is usually about -20 to about 150, preferably about 0 to about 120 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

 Compound (II) is produced from compound (II) in the same manner as when producing compound (III) from compound (II).

Compound (ΙΙΙ ') can be prepared in the same manner as in the production of compound (V) from compound (III) and compound (IV); compound αΐΓ) and compound (IV) wherein R ²² and hal are as defined above. Show the same significance].

 Compound (Γ) is produced from compound απι ′) and compound (VI) in the same manner as in the production of compound (la) from compound (V) and compound (VI).

By the above reaction, a compound in which X is methylene in compound (r) can be produced. The compound thus obtained is optionally subjected to a functional group conversion based on a reaction known per se, whereby X is a substituted methylene and a carbonyl compound. Can be converted to a compound that is

 In each of the above reactions, when the starting compound has an amino, carboxy, or hydroxy substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups. The target compound can be obtained by removing the protecting group as necessary.

The protecting group of Amino, for example, formyl or each alkyl Ichiriki be substituted Ruponiru (e.g., Asechiru, propionyl, etc.), benzo I Le, C WINCH ₆ alkoxy - carbonyl (e.g., methoxy Cal Poni Le, Etokishika Ruponiru etc.), phenylalanine O carboxymethyl Cal Poni le, c ₇ _ _{1 6} Ararukiruokishi Ichiriki Lupo two Le (e.g., benzyl O carboxymethyl cull Poni Le etc.), trityl, phthaloyl and the like Ru is used. As these substituents, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a _6- alkyl monopropanol (for example, acetyl, propionyl, parryl, etc.), nitro and the like are used. Is about one to three.

Examples of the protecting group for alkoxy include alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc. . Examples of these substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine), formyl, (^ _ ₆ Al kills one force Ruponiru (e.g., Asechiru, propionyl, butylcarbonyl, etc.), Two Toro, C - ₆ alkyl (e.g., methyl, Echiru, ter t-butyl, etc.), C ₆ - _{1 4} § Li - Le (e.g., phenyl, naphthyl and the like) and the like are used, and the number of substituents is 3 or so from 1 .

Examples of the hydroxy-protecting group include formyl, or each of which may have a substituent — 6-alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, 〇 ₇ _ _{1 6} Ararukiru (e.g., benzyl, etc.), single ₆ alkyl Ichiriki Ruponiru (e.g., Asechiru, propionyl, etc.), Fueniruo Kishikaruponiru, C ₇ - _{1 6} Ararukiruokishi Ichiriki Ruponiru (e.g., Benjiruoki aryloxycarbonyl, etc.), tetrahydronaphthalene Villa alkenyl, Tetrahydrofurel, silyl, etc. are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), _6- alkyl (eg, methyl, ethyl, tert-butyl, etc.), C ₇ - _{1 6} Ararukiru (e.g., benzyl etc.), C ₆ _ _{1 4} 7 reel (e.g., phenyl, naphthyl, etc.), nitro and the like are used, and the number of the substituents is about four from 1.

 As a method for removing the protecting group, a method known per se or a method analogous thereto is used. Examples thereof include an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, and tetrabutylammonium fluoride. , A method of treating with palladium (II) acetate or the like, or a reduction reaction is used.

 In any case, if desired, a deprotection reaction, an acylation reaction, an alkylation reaction, a hydrogenation reaction, an oxidation reaction, a reduction reaction, a carbon chain extension reaction, and a substituent exchange reaction may be used alone or in combination of two or more. By carrying out in combination, compounds (A), (I), (1 ′), (A-1), (1-1) or (Ι′-1) can be synthesized. For these reactions, for example, the methods described in New Experimental Chemistry Lectures 14, 15 and 1977 (Maruzen Publishing) are adopted.

 When the desired product is obtained in a free state by the above reaction, it may be converted to a salt according to a conventional method, and when obtained as a salt, converted to a free form or another salt according to a conventional method. You can also. The compound (A;), (1), (Γ), (Α-1), (I-1) or (-1) thus obtained can be obtained by known means such as phase transfer, concentration, solvent extraction, fractionation, It can be isolated and purified from the reaction solution by crystallization, recrystallization, chromatography and the like.

 Compound (A), (I), (), (A-1), (1-1) or (Γ-1) is a conjugated isomer (configuration isomer), diastereomer, conformer, etc. If present, each can be isolated by the above-mentioned separation and purification means, if desired. Further, when the compound (A), (I), (Γ), (A-1), (1-1) or (Γ-1) is a racemate, the S-isomer and the S-isomer are obtained by ordinary optical resolution means. Can be separated into R-forms.

 If the compound (A), (I), (Γ), (A-1), (1-1) or (1, -1) has a stereoisomer, And mixtures thereof are also included in the present invention.

Compounds (A), (I), (), (A-1), (1-1) or (I, -1) may be hydrates or non-hydrates. Compound (A), (1), (Γ), (A- 1), (I - 1) or (I, - 1) is (For example, ³ H, ^{14 35} S) isotopes are labeled with like You may.

 The compound used in the production of the compounds (A), (I), (Γ), (A-1), (1-1) or (1, -1) of the present invention

(In the formula, R ^2a and R ^3a each may be an aliphatic hydrocarbon group which may have a substituent, and R ^4a and R ^5a may each have a hydrogen atom or a substituent. the hydrocarbon group, R ^{6 a} and R ^{7 a} are each a hydrogen atom or an optionally substituted carbon hydrocarbon group, the substituent together with the carbon atoms R ^{6 a} and R ^{7 a} is adjacent May form a 3- to 8-membered ring, and R ^8a is (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent, (3) an acyl group, (4) a heterocyclic group which may have a substituent, (5) a halogen atom, (6) -OR ^10a (R ^1Qa represents a hydrogen atom, a hydrocarbon group which may have a substituent, (7) ^{—SR lla} (R ^lla is a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent.) Replace The showing a heterocyclic group which may have), (8) -. S ( 〇) R ^12a (R ^12a is have may have a substituent hydrocarbon group or a substituted group (9) — S (O) ₂ R ^13a (where R ^13a is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent) the illustrated) or ^{(10) _NR 14a R 15a (} R 14 a and R ^{15 a} are each a hydrogen atom, may be an optionally substituted hydrocarbon group, which may have a Ashiru group or substituent heterocyclic R ^9a represents a hydrogen atom, a hydrocarbon group optionally having substituent (s), an acyl group or a hydroxyl group optionally having substituent (s), or a salt thereof. Is a novel compound. Examples of the “aliphatic hydrocarbon group” of the “optionally substituted aliphatic hydrocarbon group” for R ^2a and R ”include, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and the like. And a chain (linear or branched) or aliphatic cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable. Specifically, the following are used.

 (1) Chain hydrocarbon group:

Alkyl group [preferably, a lower alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, etc. (^ _ ₆ alkyl groups such as hexyl)],

 (2) Aliphatic cyclic hydrocarbon group: ''

Cycloalkyl groups [preferably, a lower cycloalkyl group (e.g., Shikuropuropi Le, cyclobutyl, cyclopentyl, C ₃ _ ₆ cycloalkyl group such as cyclohexyl), may be condensed with a benzene ring,

Examples of the substituent of these "aliphatic hydrocarbon group", for example, (1) a halogen atom, (2) 0, _ ₃ alkylene O alkoxy group, (3) a nitro group, be (4) a halogenated good C ^ - ₆ alkyl group, (5) C ₃ _ ₆ cycloalkyl group, (6) C ₆ - ₁₄ Ariru group, (7) optionally halogenated alkoxy group, optionally be (8) halogenated also alkylthio group, (9) hydroxy group, (10) amino group, (11) mono - ₆ alkylamino group, (12) mono- C ₆ _ ₁₄ Ariruamino group, (13) G ^ - ₆ alkylamino group, (14) G C ₆ - ₁₄ § Li one Ruamino group, (15) formyl, carboxy, force Rubamoiru, alkyl one carbonyl, C ₃ - ₆ cycloalkyl one carbonyl, c I ₆ alkoxy one carbonyl, C ₆ _ ₁₄ § Li one Lou force Ruponiru, C ₇ - ₁₆ Ararukiru - carbonyl, C ₆ _ ₁₄ 7 reel Carboxymethyl - Power Ruponiru, C ₇ one _1β § la Rukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atom, a sulfur atom and an oxygen atom or al 1 to 5 or 6-membered heterocyclic ring force containing heteroatoms three of the selected Luponyl, Monobut ₆ alkyl Lubamoyl, G alkyl 1 Lubamoyl, C ₆ —

₁₄ aryl carbamoyl, a 5- or 6-membered heterocyclic carbamoyl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. E alkyl chromatography Chio carbonyl, C ₃ - ₆ cycloalkyl - Chiokaruponiru, Alkoxy - Chio force Ruponiru, (: ₆ _ ₁₄ Ariru one Chiokaruponiru, C ₇ - ₁₆ Ararukiru one Chiokaruponiru, c ₆ _ ₁₄ Ariruokishi - Chio force Ruponiru, c ₇ _ ₁₆ Ararukiruokishi one Chiokaruponiru, nitrogen atom in addition to carbon atom, a sulfur atom 5- or 6-membered heterocyclic thiophene containing 1 to 3 heteroatoms selected from and oxygen atoms, thiocarbamoyl, mono-alkyl-thiocarbamoyl, di-C-alkyl-thiocarbamoyl, C ₆ _ _14- aryl-thiocarbamoyl, 5- or 6-membered heterocyclic thiocarbamoyl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon, mono- _6- alkylsulfamoyl, di-C _i-6 alkylsulfamoyl, C ₆ _ ₁₄ § Li one Rusurufamoiru, alkyl sulfonyl , C ₆ - ₁₄ § reel sulfonyl, C - ₆ alkylsulfide alkylsulfonyl, C ₆ - ₁₄ § reel sulfide El, sulfino, sulfo, - ₆ Arukokishisuru Fier, C ₆ - ₁₄ § reel O carboxymethyl sulfinyl, alkoxysulfonyl Oyo fine C ₆ one ₁₄ Ashiru group selected from § reel O carboxymethyl sulfonyl, (16) Horumiruami Bruno, C ^ - ₆ alkyl - carboxamide, C ₆ - ₁₄ § Li one Luca Lupo alkylcarboxamide, C _x _ ₆ alkoxy - power Rupokisamido , ₆ alkylsulfonyl § amino and C ₆ _ ₁₄ Ashiruamino group selected from § Li one Le sulfonyl § amino, (17) ₆ alkyl one local Poniruokishi, C ₆ _ ₁₄ Ariru - power Ruponiruokishi, ₍₆ alkoxy Ichiriki Lupo two Ruokishi , mono- alkyl Ichiriki Rubamoiruokishi, Gee ₆ alkyl Ichiriki Rubamoiruokishi, C ₆ _ ₁₄ Ariru Ichiriki Rubamoiru An acyloxy group selected from xy and nicotinyloxy; (18) a 4- to 14-membered cyclic group containing 1 to 3 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms; (19) phosphono _{group, (20) C 6 -.} 14 Ariruokishi group, (21) G alkoxy one phosphoryl group, (22) C ₆ _ ₁₄ Ariruchio group, (23) a hydrazino group, (24) Imino group, (25 Oxo groups, (26) ureido groups, (27) alkyl-perido groups, (28) dialkyl-ureido groups, (29) oxides and (30) 2 to 2 groups selected from the above (1) to (29) A group selected from the group consisting of groups formed by bonding three groups (hereinafter, abbreviated as substituent group B) is used. Specific examples of these substituents include the same as those exemplified in the above-mentioned substituent group A.

As the `` hydrocarbon group which may have a substituent '' represented by R ^4a and R ^5a , The same ones as the “optionally substituted hydrocarbon group” represented by R ⁴ and R ⁵ are used.

As the `` optionally substituted hydrocarbon group j '' represented by R <sup>6a</sup> and R <sup>7a</sup> , the same as the `` optionally substituted hydrocarbon group '' represented by R ⁶ and R ⁷ Is used.

R ^{6 a} and R ^{7 a} it is may be formed together with the adjacent carbon atoms as "no 3 may have a substituent to 8-membered ring" formed together with the carbon atom to which R ⁶ and R ⁷ adjacent And the same as the “3- to 8-membered ring optionally having substituent (s)” may be used.

R ^{8a represents} a “hydrocarbon group which may have a substituent”, an “acyl group”, a “heterocyclic group which may have a substituent”, a “halogen atom”, or a compound represented by the formula R ^{1 () a} , “Formula — SR ^lla ”, “Formula —S (O) R ^12a J”, “Formula —S (O) ₂ R ^13a ” or “Formula — N 1 ^a R ^15a j, "optionally substituted hydrocarbon group" represented by ⁸ "Ashiru group", "substituted heterocyclic group which may have a", "halogen atom", "formula - OR ^10" The same formulas as those of “Formula—SR ¹¹ ,“ Formula—S (O) R ¹² ”,“ Formula 1 S (0) ₂ R ¹³ ”or“ Formula 1 NR ¹⁴ R ¹⁵ ”are used.

Examples of the “optionally substituted hydrocarbon group”, “acyl group” and “optionally substituted hydroxyl group” represented by R ^9a include “substituents” represented by R ⁹ The same groups as those described for the "hydrocarbon group optionally having", the "acyl group" and the "hydroxyl group optionally having a substituent" are used.

 As the compound (B), the following compounds are preferred.

アルキル基を示 し、 (1) R ^{2 a} and R ^{3 a} are each ① halogen atoms, ② Ji ₆ alkyl, - 6 Al kill one Karuboeru, substituted by C i _ ₆ alkylsulfonyl and C ₇ _ ₁₆ substituents Ru is selected from Ararukiru hydroxy which may, ③ 1 or 2 CI- ₆ alkyl, Ji E - ₆ alkyl Ichiriki Ruponiru and C e- i ₄ Ariru Ichiriki optionally substituted amino group with a substituent selected from Ruponiru, ④ A 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, a thio group optionally substituted with ア ル キ ル alkyl, ⑥ — ₆ A C ₆ alkyl group optionally substituted with an alkylsulfinyl group or a で C alkyl-sulfonyl group, R ^4a , R ^5a , R ^6a and R ^7a are each a hydrogen atom or

Represents an alkyl group,

アルキル—カルボ ニル基、 （vi)C₆— ₁₄ァリール一力ルポニル基、 （viOC^-eアルコキシ—力ルポ二 ル基、 （viii)モノーまたはジ— C^-eアルキル—チォカルバモイル基、 （ix)ハロゲ ン化されていてもよい — 6アルキルースルホニル基または (X)炭素原子以外に窒 素原子、硫黄原子および酸素原子から選ばれる 1ないし 4個のへテロ原子を含有す る 4ないし 10員複素環基 [この複素環基は < ₆_₁₄ァリールを有していてもよい] を示す） 、 ④式ー SR^lla (R^llaは、 （i) 水素原子、 （10(^— 6アルキル基また は（iii)モノ—またはジ—C^eアルキル一力ルバモイル基を示す）、⑤式— S (O) R^12a (R^12aは、 （OCi— ₆アルキル基または（ii)モノーまたはジ一 -6アルキ ルー力ルバモイル基を示す） 、 ⑥式ー S (O) ₂R^13a (： R^13aは、 （i)*^— ₆アル キル基または（ii)モノーまたはジ一C^eアルキル一力ルパモイル基を示す） また は⑦式ー NR^14aR^15a (R^14aは、 （i) 水素原子、 （i C — eアルキル基 [この C i_₆アルキル基は Cェ—6アルコキシ一力ルポニルを有していてもよい] 、 （iii) ホルミル、 （1 )0^6アルキル一力ルポニル基、 WCi— ₆アルコキシ—カルボニル 基、 （vi)力ルバモイル基、 （vii)モノ—またはジー（^— 6アルキル一力ルバモイル 基または (vii C^ ₆アルキルースルホニル基を、 R^15aは、 水素原子またはメチ レを示す） を示し、 R ^8a is ① (: ₆ alkyl group, ② Nono androgenic atoms, ③ Shiki 〇_R ^10a (R ^10a is, (i) a hydrogen atom, (ii) (^ -6 alkyl [the alkyl group (1) halogen atom, (2) hydroxy group, (3) amino group, (4) force Rupokishi, (5) force Rubamoiru, (6) (丄- ₆ alkoxy - power Ruponiru, (7) mono - alkyl Ichiriki Rubamoiru, (8 ) Di-C- _6- alkyl-rubamoyl, (9) containing from 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have oxo. a substituent selected from the 10-membered heterocyclic group which may _{have], (iii) C 3 -} 6 cycloalkyl group, (iv) C ₇ - ₁₆ Ararukiru group, (V)

Alkyl - carboxymethyl sulfonyl group, (vi) C ₆ - ₁₄ Ariru Ichiriki Ruponiru group, (VIOC ^ -e alkoxy - force Lupo two Le group, (viii) mono- or di - C ^ -e alkyl - Chiokarubamoiru group, ( ix) May be halogenated — 4 to 4 containing, in addition to the 6 alkyl-sulfonyl group or (X) carbon atom, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen 10-membered Hajime Tamaki [this heterocyclic group may have a _<6 _ ₁₄ Ariru] shows a), ④ Shiki SR ^lla (R ^lla is, (i) a hydrogen atom, (10 (^ - 6 An alkyl group or (iii) a mono- or di-C ^ e alkyl monorubamoyl group), a formula — S (O) R ^12a (R ^12a is an (OCi- ₆ alkyl group or (ii) a mono- or di one -6 showing the alkylene Lou force Rubamoiru group), ⑥ Shiki ^{_{S (O) 2 R 13a (}} : R 13a is, (i) * ^ - ₆ Al kill group or (ii) Mo Over or di illustrating an C ^ e alkyl Ichiriki Rupamoiru group) or ⑦ Shiki NR ^14a R ^15a (R ^14a is, (i) a hydrogen atom, (i C - e alkyl group [this C i_ ₆ alkyl group (Iii) formyl, (1) 0 ^ 6 alkyl monopropyl, WCi- ₆ alkoxy-carbonyl, (vi) dirubamoyl, vii) mono- or di-(^-6 alkyl monorubumoyl group or (vii C ^ ₆ alkyl-sulfonyl group, R ^15a represents a hydrogen atom or methyl),

R ^{9 a} is (i) a hydrogen atom, (ii) a C ₆ alkyl group [this — ₆ alkyl group is (1) a halogen atom, (2) ₆ alkoxy group, (3) hydroxy group,) amino group, (5 ) Mono C _1-6 alkylamino group, (6) di-alkylamino group, (7) A 4- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; (8) C ₆ _ _{1 4} Arylthio, (9) Ureido, (10) Power Lupoxyl, (11) Power Lubamoyl, (12) (: ₆ Alkoxy One Power Luponil, (13) Mono-(^ _ ₆ alkyl-Power Lubamoyl, (14) Formylamino and (15) it may have a substituent selected from alkyl-carboxamides] or (iii) a compound showing a formyl group (B)

 (2) Compound (B) produced in Reference Example 4.

The prodrugs of the compounds (I), (1 '), (1-1) and (-1) are prepared by reacting the compounds (I), (Γ), (1) (1) or (1'-1), that is, compounds (I), (Γ), (1-1) or (1, -1) which are enzymatically oxidized, reduced, hydrolyzed, etc. ), Or a compound that undergoes hydrolysis by gastric acid or the like to change to a compound (I), (Γ), (1-1) or (Γ-l). As a prodrug of the compound (I), (1,), (1-1) or (1′_1), a prodrug of the compound (I), (I ゥ, (1-1) or (1′-1) Compounds in which the group is acylated, alkylated or phosphorylated (for example, the amino group of compound (I), (I ゥ, (1-1) or (1′-1) is eicosanoylated, araellated, pentylized) Minocarbonylation, (5-methyl_2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinomethylation, pivaloyloxymethylation, tert- Compounds in which the hydroxyl group of the compound (I), (Γ), (1-1) or (1′-1) is acylated, alkylated, phosphorylated, or borated (for example, The hydroxyl group of compound (I), (Γ), (1-1) or (1'-1) is acetylated, palmitoylated, propanoylated, or pivaloylic. , Succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); the carboxy group of compound (I), ()), (1-1) or (P-1) is esterified, Amidated compounds (for example, when the carboxy group of compound (I), (), (1-1) or (Γ-1) is esterified, phenylesterified, carboxymethylesterified, dimethylamino Methyl esterification, pivalyloxymethyl esterification, ethoxycarponyloxyshethyl esterification, phthalidyl esterification, (5-methyl-2-oxo1-1,3-dioxolen-1-41) methyl esterification , Cyclohexyloxycarponylethyl esterified, methylamidated compounds Etc.). These compounds can be produced from compound (1), (1,), (1-1) or (Γ-1) by a method known per se.

 In addition, prodrugs of compounds (I), (), (1-1) or (1'-1) are disclosed in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design, 163-1. It may be changed to the compound (I), (Γ), (1-1) or (Ι'-1) under physiological conditions as described in 98.

 Examples of the salt of the compound (A), (1), (Γ), (A-1), (1-1), (Γ-1) or (B) include, for example, pharmacologically acceptable salts and the like. Used. Examples include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, and an aluminum salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine. , N, N 'salts with dibenzyldiethylenediamine and the like. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone And salts with an acid, p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ordinine, and the like. Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts.

Among them, pharmaceutically acceptable salts are preferable. Examples thereof include compounds having a basic functional group in compound (I) or (III), for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid Salts with inorganic acids such as acetic acid, fumaric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. In the case of having an acidic functional group, examples thereof include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metals such as calcium salts and magnesium salts. Genus salts, ammonium salts and the like.

 Expression

[Wherein, ninii represents a single bond or a double bond] or a salt thereof has a PDE inhibitory activity, particularly a PDE IV inhibitory activity, and is caused by PDE. It can be used as an agent for preventing and treating diseases. Examples of the salt of the compound (A-2) include the salt of the above compound (A), (1), (I,), (A-1), (1-1), (-1) or (B). Similar ones can be mentioned.

 In particular, the compounds (A), (1), (1,), (A-1), (1-1), (Γ-1) of the present invention included in the above compound (A-2) or a salt thereof Or a salt thereof (including prodrugs of compounds (I), (1-1), (Γ), and (Γ-l)) (hereinafter abbreviated as compound of the present invention) is excellent: PDE inhibitory action In particular, it has PDE IV inhibitory activity, is low in toxicity, and is safe, so it can be used in mammals (eg, humans, mice, dogs, rats, mice, etc.) for inflammatory diseases, autoimmune diseases, Diabetes, arteriosclerosis, graft-versus-host disease, multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, central dysfunction after cerebral vascular obstruction, cerebrovascular dementia, Alzheimer's dementia, memory impairment, obesity, Heart failure, pulmonary fibrosis, allergic disease, angina, myocardial infarction, hypertension, pulmonary hypertension, Disease, brain function disorders, immunodeficiency, prophylactic or therapeutic agent such as sexual dysfunction ophthalmic diseases, male or female, can be used as a PDE inhibitor. Above all, inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, diabetes, arteriosclerosis, graft-versus-host disease, multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, cerebral vascular obstruction Later central dysfunction, cerebral vascular dementia, dementia of aruhaima type 1, memory impairment, obesity, heart failure, pulmonary fibrosis, allergic diseases (eg, atopic dermatitis, allergic rhinitis, juniper measles) ) Can be used as prophylactic or therapeutic agents, and PDE IV inhibitors. The route of administration may be oral or parenteral.

Specific examples of dosage forms include, for example, tablets (including sugar-coated tablets and film-coated tablets), Pills, capsules (including microcapsules), granules, fine granules, powders, tablets, emulsions, suspensions, injections, inhalants, ointments, eye drops, aerosols, eye ointments, plasters Suppositories, troches, cataplasms, liniments and the like are used. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).

 In the preparation of the present invention, the content of the compound of the present invention varies depending on the form of the preparation, but is usually from 0.01 to 100% by weight, preferably from 0.1 to 50% by weight, based on the whole preparation. % By weight, more preferably about 0.5 to 20% by weight.

 Specifically, in the tablet manufacturing method, the drug was used as is, and excipients, binders, disintegrants, or other appropriate additives were added, and the mixture was uniformly mixed to obtain granules by an appropriate method. After that, a lubricant is added and compression molding is performed, or the medicine is directly mixed or directly mixed with excipients, binders, disintegrants or other suitable additives. Alternatively, the granules can be produced by compression-molding the granules prepared beforehand as they are, or after adding an appropriate additive thereto and mixing them uniformly. In addition, the present agent can contain a coloring agent, a flavoring agent, and the like as needed. In addition, the agent can be coated with an appropriate coating agent.

 In the method of manufacturing an injection, a certain amount of a drug is dissolved, suspended or emulsified in water for injection, physiological saline, Ringer's solution, etc. in the case of an aqueous solvent, or vegetable oil in the case of a non-aqueous solvent, to make a certain amount. Alternatively, a predetermined amount of the drug can be taken and sealed in a container for injection.

 As the pharmaceutical carrier for oral use, for example, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium propyloxymethylcellulose and the like are used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in pharmaceutical preparations can be appropriately added.

The dosage of these preparations varies depending on age, body weight, symptoms, route of administration, number of administrations, etc. For example, for adult asthma patients, it is converted into the active ingredient (compound of the present invention) per day. Usually 0.1 to 100 mg / kg, preferably 0.1 to 5.0 mg / kg, more preferably 0.5 to 10 mg / kg, divided orally once or twice daily It should be administered. Although the compound of the present invention exhibits excellent PDE IV inhibitory activity even when used as a single agent, it is also used in combination with other pharmaceutical ingredients other than the compound of the present invention (hereinafter abbreviated as concomitant drug) (multiple drug combination) You can also.

 Examples of such concomitant drugs include anti-asthmatic agents (eg, flutidinzone propionate, beclomethasone propionate, theophylline, propoterol, ketotifen, azelastine, seratrodast, etc.), antiallergic agents (eg, fexofenadine, etc.) , Epinastine, ebastine, etc.), anticholinergic agents (eg, ipratropium bromide, fructophorium pium bromide, oxotropium bromide, etc.), anti-inflammatory agents (eg, diclofenac sodium, ibuprofen, indomethacin, loxoprofen sodium, etc.), Antibacterial agents (eg, cefixime, cefdinir, ofloxacin, tosfloxacin tosylate, lepofloxacin, etc.), antifungal agents (eg, fluconazole, itraconazole, etc.), antidiabetic Use agents (e.g., Piodari Yuzo down, nateglinide, Poguriposu, etc. Akaruposu) and the like.

 When the compound of the present invention and a concomitant drug are used in combination, the timing of administration 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 simultaneously administered to a subject to be administered. It may be administered at a time interval. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination, and the like.

The administration form of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously preparing a compound of the present invention and a concomitant drug, and (2) separate administration of the compound of the present invention and the concomitant drug. Simultaneous administration of the two preparations obtained as a formulation by the same administration route, (3) the time difference between the same administration route of the two preparations obtained by separately preparing the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Separating the compound of the present invention and the concomitant drug (Eg, administration of the compound of the present invention → concomitant drug, or administration in the reverse order) of two types of preparations obtained by different preparation routes at different times. No. Hereinafter, these administration forms are collectively abbreviated as the concomitant drug of the present invention. The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se to obtain a pharmaceutical composition such as a tablet. (Including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, topical, rectal) , Intravenous administration, etc.). Injectables can be administered intravenously, intramuscularly, subcutaneously, in organs, intranasally, intradermally, instilled, in the brain, rectum, intravaginally and intraperitoneally, inside tumors, near tumors, or directly into lesions It can be administered.

 As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used in the aforementioned pharmaceutical composition of the present invention can be used.

 The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.

 For example, the content of the compound of the present invention in the combination preparation of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0. It is about 1 to about 50% by weight, more preferably about 0.5 to about 20% by weight.

 The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation. %, More preferably about 0.5 to about 20% by weight.

 The content of additives such as carriers in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to 10% by weight, based on the whole preparation. It is about 90% by weight.

 The same content may be used when the compound of the present invention and the concomitant drug are separately formulated.

 These preparations can be produced by a method known per se that is generally used in the preparation process.

For example, the compound of the present invention or the concomitant drug may be a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HC060 (manufactured by Nikko Chemicals), polyethylene) Glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, dextrin, etc., stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), possible Solvents (eg, glycerin, ethanol, etc.), buffers (eg, phosphoric acid and its alkali metal salts, citrate and its alkali metal salts, etc.), tonicity agents (eg, sodium chloride, potassium chloride, mannitol) Sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl parabenzoyl benzoate, benzoic acid, methyl paraben, propyl paraben, benzyl alcohol, etc.), dissolving agents (eg, , Concentrated glycerin, medalmin, etc.), dissolution aid ( , Propylene glycol, sucrose, etc.) and soothing agents (eg, glucose, benzyl alcohol, etc.) in aqueous injections or dissolving olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, propylene glycol, etc. It can be dissolved, suspended or emulsified in an auxiliary agent and formed into an oil-based injection to give an injection.

 In order to prepare a preparation for oral administration, the compound of the present invention or the concomitant drug is used in accordance with a method known per se, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.) , A binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 600, etc.) By compression molding and, if necessary, coating with a method known per se for taste masking, enteric coating or long-lasting purposes, a preparation for oral administration can be obtained. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, tween 80, pull mouth nick F68, cellulose acetate phthalate, and hydroxypropylmethyl cellulose. For example, tyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, copolymerization of methacrylic acid / acrylic acid), and pigments (eg, bengara, titanium dioxide, etc.) are used. The preparation for oral administration may be either a quick release preparation or a sustained release preparation.

For example, to prepare a suppository, a compound of the present invention or a concomitant drug may be prepared according to a method known per se. The product can be an oily or aqueous solid, semi-solid or liquid suppository. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cocoa butter, witepsols (manufactured by Dynamite Nobel, Germany), etc.), intermediate fatty acids [eg, migliols (manufactured by Dynamite Nobel And vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, bier polymers, and acrylic acid polymers.

 Examples of the sustained-release preparation include sustained-release micro force capsules.

 A method known per se can be used to prepare a sustained release microcapsule. For example, it is preferable to administer the composition into a sustained release preparation shown in the following [2].

 The compound of the present invention is preferably formed into a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a preparation for rectal administration such as a suppository. In particular, preparations for oral administration are preferred.

 The concomitant drug can be in the above-mentioned dosage form depending on the type of the drug.

 In the following, (1) an injection of the compound of the present invention or the concomitant drug and its preparation, (2) a sustained-release preparation or immediate-release preparation of the compound or the concomitant drug of the present invention and its preparation,

[3] Specific examples of the sublingual tablet, buccal or buccal disintegrant of the compound of the present invention or the concomitant drug and its preparation are shown below.

 [1] Injection and its preparation

 An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate.

 The injection can be obtained by dissolving the compound of the present invention or the concomitant drug and, if desired, both benzoate or Z and salicylate in water.

Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, medalmine salts, and organic acid salts such as trometamol. . The concentration of the compound of the present invention or the concomitant drug in the injection is about 0.5 to about 50 w / v%, preferably about 3 to about 20 wZV%. Also benzoate or and salic The concentration of the luate is preferably from about 0.5 to about 50 w / v%, preferably from about 3 to about 20 wZ v%.

 In addition, this agent contains additives commonly used for injections, such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), and solvents. (Glycerin, ethanol, etc.), buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), tonicity agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose, dextrin, etc.) ), PH regulators (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl ethyl parabenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.) And soothing agents (glucose, benzyl alcohol, etc.) and the like can be appropriately compounded. These additives are generally mixed in a ratio usually used for an injection.

 The pH of the injection can be adjusted to 2 to 12, preferably 2.5 to 8.0 by adding a pH regulator.

 An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, if desired, a benzoate and / or a salicylate, and if necessary, the above-mentioned additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.

 The aqueous solution for injection is preferably heated, and can be used as an injection by performing, for example, filtration sterilization or high-pressure heat sterilization in the same manner as an ordinary injection.

 The aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 ° C. to 121 ° C. for 5 minutes to 30 minutes.

 Further, a formulation having antimicrobial properties of the solution may be used so that it can be used as a multiple-dose formulation.

 [2] Sustained-release preparation or immediate-release preparation and its preparation

 A sustained-release preparation comprising a core comprising the compound of the present invention or the concomitant drug optionally coated with a film-forming agent such as a water-insoluble substance-swellable polymer is preferred. For example, a once-daily sustained release preparation for oral administration is preferred.

Examples of the water-insoluble substance used in the coating agent include ethyl cellulose and butyl cellulose. Cellulose ethers such as cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polybier acetate and polypinyl butyrate, acrylic acid Z methacrylic acid copolymer, methyl methacrylate copolymer, X toki Shetyl methacrylate / cinnamethyl methacrylate Z-aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly methacrylate, polymethacrylamide, Aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially Eudragit RS-100, RL-100, RS-3OD, RL-3OD, RL-PO, RS — PO (Acri Eudragits (Rohm Pharma Co., Ltd.) such as ethyl acrylate, methyl methacrylate, trimethyl methacrylate, and ammonium methacrylate copolymer, and Eudragit NE-30D (methyl methacrylate and ethyl acrylate acrylate). And hardened oils such as hardened castor oil (eg, Lovely wax (Freund Corporation)), carnauba wax, fatty acids glycerin ester, waxes such as paraffin, polyglycerin fatty acid esters, and the like.

 As the swellable polymer, a polymer having an acidic dissociating group and exhibiting pH-dependent swelling is preferable.Swelling is less in an acidic region such as in the stomach and swelling in a neutral region such as the small intestine and the large intestine. Polymers having an acidic dissociating group that grows are preferred.

 Examples of the polymer having such an acidic dissociating group and exhibiting pH-dependent swelling include, for example, carbomer 934P, 940, 941, 944, 980, 1342, and the like, such as polycarbophil 1 , Calcium polycarbophil (all of which are manufactured by BF Goodrich), and Hibis Pico 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.). Coalescence.

 The coating agent used in the sustained-release preparation may further contain a hydrophilic substance.

Examples of the hydrophilic substance include polysaccharides which may have a sulfate group, such as pullulan, dextrin, alkali metal alginate, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose-snadium, and the like. Polysaccharides having a hydroxyalkyl group or a carboxyalkyl group, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like.

 The content of the water-insoluble substance in the coating agent of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 4 0 to 75% (w / w), swellable polymer content of about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w) . The coating may further comprise a hydrophilic substance, in which case the content of the hydrophilic substance in the coating is not more than about 50% (w / w), preferably about 5 to about 40% (w / w), more preferably from about 5 to about 35% (w / w). Here, the above-mentioned% (w / w) refers to% by weight based on the coating composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating composition liquid.

 The sustained-release preparation is prepared by preparing a nucleus containing a drug as exemplified below, and then dissolving the obtained nucleus by heating or dissolving or dispersing a water-insoluble substance or a swellable polymer in a solvent. It is manufactured by coating with

 I. Preparation of nuclei containing drugs

 The form of the nucleus containing the drug to be coated with the coating agent (hereinafter sometimes simply referred to as the nucleus) is not particularly limited, but is preferably formed into particles such as granules or fine granules. When the core is granules or fine granules, the average particle size is preferably from about 150 to about 2,000 um, more preferably from about 500 to about 1,400 x m.

 The nucleus can be prepared by a usual production method. For example, a drug is mixed with an appropriate excipient, binder, disintegrant, lubricant, stabilizer, and the like, and the mixture is prepared by wet extrusion granulation, fluidized bed granulation, or the like. '

 The drug content of the core is about 0.5 to about 95% (w / w), preferably about 5 to about 80% (w / w), and more preferably about 30 to about 70% (w / w). w).

 Examples of excipients contained in the core include sugars such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Among them, crystalline cellulose and corn starch are preferred.

Examples of the binder include polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone, pull nick F68, and Arabic Rubber, gelatin, starch and the like are used. Disintegrants include, for example, carboxymethylcellulose calcium (ECG505), croscarmethylene monosodium sodium (Ac-Di-Sol), cross-linked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) Are used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone and low-substituted hydroxypropylcellulose are preferred. For example, talc and magnesium stearate are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol and the like are used as a lubricant. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.

 The nucleus may be formed by spraying a binder dissolved in a suitable solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) onto the inert carrier particles serving as the center of the nucleus, in addition to the above-mentioned production method. It can be prepared by the tumbling granulation method, pan coating method, fluidized bed coating method or melt granulation method, in which a small amount of a drug or a mixture of an excipient and a lubricant is added. it can. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and the average particle size is about 100 111, or about 1,500 m. Is preferred.

 To separate the drug contained in the nucleus from the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the above-mentioned hydrophilic substances, water-insoluble substances and the like are used. As the protective agent, a polysaccharide having a polyethylene glycol-hydroxyalkyl group or a carboxyalkyl group is preferably used, and hydroxypropylmethyl cellulose and hydroxypropylcellulose are more preferably used. The protective agent may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid, and a lubricant such as talc. When a protective agent is used, its coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% based on the core. (w / w).

 The protective agent can be coated by a usual coating method.Specifically, the protective agent can be coated by spray-coating the nucleus by, for example, a fluidized-bed coating method or a pan coating method. .

 I I. Coating of core with coating agent

The nuclei obtained in I above, the water-insoluble substance and a pH-dependent swellable polymer, In addition, a sustained-release preparation is produced by heating and dissolving a hydrophilic substance or coating with a coating agent solution in which a hydrophilic substance is dissolved or dispersed in a solvent.

 Examples of the method of coating the core with a coating agent solution include a spray coating method.

 The composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating solution is appropriately selected so that the content of each component in the coating becomes the above-mentioned content.

 The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), based on the core (not including the protective agent). Preferably it is about 5 to 35% (w / w).

 As the solvent for the coating agent solution, water or an organic solvent can be used alone or in a mixture of both. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be changed in the range of 1 to 100%, and is preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance. Examples thereof include lower alcohols such as methanol, ethanol, 2-propanol and 1-butanol, lower alkynones such as acetone, acetonitrile, and the like. Chloroform, dichloromethane and the like are used. Of these, lower alcohols are preferred, and ethanol and 2-propanol are particularly preferred. Water and a mixture of water and an organic solvent are preferably used as a solvent for the coating agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, or maleic acid may be added to the coating agent solution for stabilization.

 The operation for coating by spray coating can be performed by a usual coating method.Specifically, the coating agent solution is spray-coated on the nucleus by, for example, a fluidized bed coating method or a banco coating method. It can be implemented at At this time, if necessary, talc, titanium oxide, magnesium stearate, calcium stearate, light gay anhydride, etc. are used as lubricants, and glycerin fatty acid ester, hydrogenated castor oil, triethyl quenate, cetyl alcohol, stearyl alcohol are used. May be added as a plasticizer.

After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary. Immediate release preparations can be liquid (solutions, suspensions, emulsions, etc.) or solid (particles, Pills, tablets, etc.). Parenteral preparations such as oral preparations and injections are used, but oral preparations are preferred.

 Immediate release preparations may generally contain, in addition to the drug as an active ingredient, carriers, additives and excipients (hereinafter sometimes abbreviated as excipients) commonly used in the pharmaceutical field. . The formulation excipient used is not particularly limited as long as it is a commonly used excipient. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (such as Avicel PH101, manufactured by Asahi Kasei Corporation), powdered sugar, granulated sugar, mannitol, light caffeic anhydride, magnesium carbonate, carbonate Calcium, L-cysteine and the like, preferably corn starch and mannitol. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30 to It is about 97w / w%.

 The content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60%, based on the total amount of the immediate release preparation.

 When the immediate release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (eg, Asahi Kasei Co., Ltd., AXIDISOL), crospovidone (eg, BASF Corporation, Kolydone CL) , Low-substituted hydroxypropylcells (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), carboxymethyl starch sodium (Kimura Sangyo, X Kisprotab), part Pregelatinized starch (PCS, manufactured by Asahi Kasei Corporation) is used. Granules are formed by, for example, contacting with water to absorb water, swell, or create a channel between the active ingredient constituting the core and the excipient. Can be used. These disintegrants can be used alone or in combination of two or more. The blending amount of the disintegrant is appropriately selected depending on the kind and blending amount of the drug to be used, the design of the release preparation, and the like. Is from about 0.5 to about 15 w / w%.

If the immediate-release preparation is an oral solid preparation, or if it is an oral solid preparation, it is added to the above composition. Alternatively, if necessary, the solid preparation may further contain an additive for placement. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.) Sourcing agents (eg, polyethylene glycol, magnesium stearate, talc, light gay anhydride (eg, AEROSIL (Nippon AEROSIL)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters) And non-ionic surfactants such as polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, etc.), coloring agents (for example, tar pigments, caramel, bengara, acid) Titanium, riboflavins), if necessary, flavoring agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. Tartaric acid, citrate as a stabilizer Organic acids such as succinic acid and fumaric acid may be added.

 As the above-mentioned binder, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone and the like are preferably used.

 The immediate-release preparation can be prepared by mixing the above-mentioned components, kneading and molding as necessary, based on a usual preparation production technique. The mixing is performed by a generally used method such as mixing and kneading. Specifically, for example, when a rapid-release preparation is formed into particles, a vertical granulator, a universal kneading machine (Hata Tekko And fluidized-bed granulator FD-5S (manufactured by Palek Co., Ltd.), followed by granulation by wet extrusion granulation, fluidized bed granulation, or the like.

 The immediate-release preparation and the sustained-release preparation thus obtained can be administered as they are, or separately, separately and in combination with excipients, etc., according to a conventional method, and then administered simultaneously or in combination at an arbitrary administration interval. Alternatively, both preparations may be formulated as a single orally administered preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate, together with excipients. Both preparations may be made into granules or fine granules and filled in the same capsule or the like to prepare a preparation for oral administration.

[3] Sublingual tablet, puccal or oral fast disintegrating agent and its preparation The sublingual tablet, the puccal preparation, and the quick disintegrating agent in the oral cavity may be a solid preparation such as a tablet or an oral mucosa patch (film).

 As the sublingual tablet, buccal or intraoral quick disintegrating agent, a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. In addition, auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer may be contained. Further, it may contain a / 3-cyclodextrin or | 3-cyclodextrin derivative (eg, hydroxypropyl-13-cyclodextrin) for facilitating absorption and increasing bioavailability.

Examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light caffeic anhydride and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, and the like, and magnesium stearate-colloidal silica is particularly preferable. Examples of the tonicity agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, with mannitol being particularly preferred. Examples of the hydrophilic carrier include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polybierpyrrolidone, light caffeic anhydride, citric acid, dicalcium phosphate, and calcium carbonate. Microcrystal cell openings) are preferred. Water-dispersible polymers include gums (eg, tragacanth, acacia, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose) , Hydroxypropyl methylcellulose), gelatin, water-soluble starch, polyacrylic acid (eg, carpomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarpyl, ascorbic acid palmitate, and the like. Propyl methylcellulose, polyacrylic acid, alginate, gelatin, carboxymethyl cellulose, polypierpyrrolidone, polyethylene Glycol is preferred. Particularly, hydroxypropyl methylcellulose is preferable. Examples of the stabilizer include cystine, thiosorbitol, tartaric acid, cunic acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite, and the like. Good.

 The sublingual disintegrant, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug with an excipient by a method known per se. Further, if necessary, the above-mentioned auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a coloring agent, a sweetening agent and a preservative may be mixed. By mixing the above components at the same time or with a time difference, and then press-molding, sublingual tablets, buccal tablets or intraorally rapidly disintegrating tablets can be obtained. In order to obtain an appropriate hardness, it may be manufactured by humidifying and moisturizing with a solvent such as water or alcohol before and after the tableting process, if necessary, molding, and then drying.

 When molded into a mucosa-adhered tablet (film), the compound of the present invention or the concomitant drug, the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient, etc. Dissolve in a solvent and cast the resulting solution into a film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, and a sweetener may be added. Glycols such as polyethylene glycol and propylene glycol can be included to impart appropriate properties to the film, and bioadhesive polymers (eg, Polycarbophil, Carbofil, etc.) can be used to enhance the adhesion of the film to the oral mucosal lining. Paul) may be contained. Casting involves pouring the solution onto the non-adhesive surface, spreading it to a uniform thickness (preferably about 100 to 100 microns) with an application tool such as a doctor blade, and then drying the solution. This is achieved by forming a film. The film thus formed may be dried at room temperature or under heating, and cut into a desired surface area.

 A preferred rapid intraoral disintegrant is a solid rapid diffusion administration comprising a network of the compound of the present invention or the concomitant drug and a water-soluble or water-diffusible carrier inactive with the compound of the present invention or the concomitant drug. Agents. The network can be obtained by sublimating the solvent from the solid composition composed of a solution of the compound of the present invention or the concomitant drug in a suitable solvent. .

 The composition of the oral disintegrating agent preferably contains a matrix-forming agent and a secondary component in addition to the compound of the present invention or the concomitant drug.

Examples of the matrix forming agent include gelatins, dextrins, soybeans, and wheat. And animal or plant proteins such as psyl 1 ium seed protein; gums such as gum arabic, guar gum, agar and xanthan; polysaccharides; alginic acids; carboxymethylcellulose; Dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and substances derived from gelatin-gum arabic complex. Furthermore, saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, Includes amino acids with 2 to 12 carbon atoms such as L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, and L-phenylalanine. '

 One or more matrix-forming agents can be introduced into a solution or suspension before solidification. Such a matrix forming agent may be present in addition to the surfactant, or may be present without the surfactant. The matrix former, in addition to forming its matrix, can help maintain the compound or compound of the invention or the concomitant drug in a dispersed state in the solution or suspension.

 Secondary components such as preservatives, antioxidants, surfactants, thickeners, coloring agents, pH adjusters, flavors, sweeteners or taste masking agents may be included in the composition. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue No. 2 and FD & C Red 40 from Ellis' Anderbergerd. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof. Suitable pH regulators include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.

Formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of book. Comprising between about 1 minute and about 60 minutes, preferably between about 1 minute and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (in water) comprising the compound of the invention or the concomitant drug. Formulations capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (the above-mentioned sublingual tablets, puccal, etc.), and preferably within about 1 to about 60 seconds after being placed in the oral cavity Is preferably a fast disintegrating agent in the oral cavity that disintegrates within about 1 to about 30 seconds, more preferably within about 1 to about 10 seconds.

 The content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. ] The content of the 3-cyclodextrin or) 3-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight. The content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible lima in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer relative to the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The above preparations may further contain additives such as coloring agents, sweetening agents, preservatives and the like, if necessary.

The dose of the concomitant drug of the present invention varies depending on the type, age, body weight, symptom, dosage form, administration method, administration period, and the like of the compound of the present invention. Usually, about 0.01 to about 1000 mgZkg, preferably about 0.01 to about 100 mgZkg per day, as the compound of the present invention and the concomitant drug, is more preferable. 1 to about 10 Omg Zkg, especially about 0.1 to about 5 OmgZkg, especially about 1.5 to about 30 mgZkg, is administered intravenously once or several times a day. You. Of course, as described above, since the dose varies under various conditions, a dose smaller than the above dose may be sufficient, or it may be necessary to administer beyond the range. The concomitant drug can be used in any amount as long as side effects are not a problem. The daily dosage of the concomitant drug varies depending on the severity of symptoms, age, gender, body weight, sensitivity difference, administration timing, interval, characteristics of pharmaceutical preparation, preparation, type, type of active ingredient, etc. Although not particularly limited, the amount of the drug is usually The dose is about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 10 Omg per kg body weight of the mammal, and is usually administered in 1 to 4 times a day.

 When administering the concomitant drug of the present invention, the concomitant drug may be administered at the same time, but after administering the concomitant drug first, the compound of the present invention may be administered, or the compound of the present invention may be administered first. Thereafter, the concomitant drug may be administered. When administered at different times, the time difference depends on the active ingredient to be administered, dosage form, and administration method.For example, when the concomitant drug is administered first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention. Method. BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention will be further described in detail with reference to the following Reference Examples, Examples, Formulation Examples and Test Examples, which are merely examples and do not limit the present invention. It may be changed without departing from the scope.

 "Room temperature" in the following Reference Examples and Examples usually indicates about 10 ° C to about 35 ° C. % Means' mol / mol% yield, and the others indicate% by weight. As the basic silica gel, NH-DM1020 manufactured by Fuji Silicon Chemical Co., Ltd. was used. In the proton NMR spectrum, those which cannot be confirmed by broad, such as 0H and NH protons, are not described in the data.

 Abbreviations used in other texts have the following meanings.

 s u (singlet)

 d doublet

 t Triplet (triplet)

 q quartet

 m multiple (multiple!)

br broad J: Coupling constant

 Hz: Hertz

CDC1 ₃ : Double-mouthed holm

DMS0- d ₆ : heavy dimethyl sulfoxide

 Ή NMR: proton nuclear magnetic resonance

 The transformant Escherichia coli BL21ZPPDE4D3 obtained in Test Example 1 described below was deposited with the National Institute of Advanced Industrial Science and Technology (NI BH) on March 8, 2000 under the deposit number FERM BP. -Deposited with the Fermentation Research Institute (IFO) under the accession number IF 216 383 from February 24, 2000 as 7075.

 In addition, the gene manipulation method using Escherichia coli followed the method described in Molecular cloning.

 The sequence numbers in the sequence listing in the present specification indicate the following sequences.

 [SEQ ID NO: 1]

 1 shows the nucleotide sequence of a primer used in Test Example 1.

 [SEQ ID NO: 2]

 1 shows the nucleotide sequence of a primer used in Test Example 1.

 [SEQ ID NO: 3]

 1 shows the nucleotide sequence of cDNA carried by Escherichia coli BL21ZpPDE4D3 obtained in Test Example 1.

 [SEQ ID NO: 4]

 3 shows the amino acid sequence encoded by the nucleotide sequence of cDNA carried by Escherichia coli BL21 / pPDE4D3 obtained in Test Example 1. Example benzoic acid 5-bromo-2-methoxyphenyl ester

A solution of guaiacol (125 g, 1.01 mol) in pyridine (300 mL) was cooled on ice, and benzoyl chloride (149 g, 1.06 mol) was added dropwise over 30 minutes in a nitrogen atmosphere. Stirred for minutes. Water was added to the reaction mixture, which was extracted twice with ethyl acetate. The combined organic layers were washed with water, 2M hydrochloric acid (twice), and water, and concentrated to give benzoic acid 2-methoxyphenyl ester (234 g) as a solid.

 229 g of this was dissolved in acetic acid (700 mL), and a solution of bromine (176 g, 1.10 mol) in acetic acid (100 mL) was added dropwise at 15 ° C over 1.5 hours, followed by stirring at room temperature for 15.5 hours. To the resulting mixture, a solution of bromine (24 g, 0.15 mol) in acetic acid (10 mL) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under reduced pressure to obtain the title compound (267 g, yield 89%).

74-78 ° C.

_{¾ NMR (CDC1 3) 53.80 (} 3H, s), 6.89 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 2.5 Hz), 7.36 (1H, dd, J = 8.6, 2.5 Hz) , 7.46-7.56 (2H, m), 7.59-7.70 (1H, m), 8.16-8.24 (2H, m).

Reference example 2

5_bromo-2-methoxyphenol

 To a suspension of benzoic acid 5-bromo-2-methoxyphenyl ester (261 g, 0.850 mol) in tetrahydrofuran (100 mL) / methanol (100 mL) was added a 5 M aqueous sodium hydroxide solution (350 mL, 1.75 mol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with 2 M hydrochloric acid (500 mL, 1.00 mol) and neutralized by adding sodium hydrogen carbonate (10 g, 0.12 mol). The resulting mixture was extracted twice with a mixture of ethyl acetate / hexane (1: 1). The combined organic layers were washed with water and concentrated under reduced pressure. The residue was recrystallized from hexane to give the title compound (148 g, yield 86%).

Melting point 66-67.

_{Ή NMR (CDC1 3) 53.88 (} 3H, s), 5.65 (1H, br s), 6.71 (1H, d, J = 8.5 Hz), 6.97 (1H, dd, J = 8.5, 2.5 Hz), 7.07 (1H , d, J = 2.5 Hz).

Reference example 3

 2,3-dihydro-7-methoxy-2,2-dimethyl-4-benzofurancarboxaldehyde

To a solution of 5_bromo-2-methoxyphenol (102 g, 0.502 mol) in N, N-dimethylformamide (400 mL) was added 3-chloro-2-methyl-1-propene (55 mL, 0.56 mol) and Potassium carbonate (83.3 g, 0.603 mol) was added, and the mixture was stirred at 75 under a nitrogen atmosphere for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with a hexane / ethyl acetate (1: 1) mixed solution. The combined organic layers were washed twice with water, treated with activated carbon, filtered, and concentrated under reduced pressure to give 4-bromo-trimethoxy-2-[(2-methyl-2-propyl) oxy] benzene (130 g). Obtained as an oil.

 This was dissolved in N, N_ cetiraniline (100 mL) and stirred at 200 for 5.5 hours under a nitrogen atmosphere. The reaction mixture was dissolved in diisopropyl ether, washed with 1 M hydrochloric acid (twice) and water, treated with activated carbon, filtered, and concentrated under reduced pressure to give 3-bromo-6-methoxy-2- (2-methyl-2-prop. (Pinyl) phenol (129 g) was obtained as an oil.

 This was dissolved in ethanol (200 mL), a solution of concentrated hydrochloric acid (50 mL) in ethanol (50 mL) was added, and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure, hexane was added, and the aqueous layer was separated. The organic layer is washed with water, 1 M aqueous sodium hydroxide solution (3 times), water, treated with activated carbon, filtered, and concentrated under reduced pressure to give 4-bromo-2,3-dihydro-7-methoxy-2,2-dimethylene. Benzofuran (113 g) was obtained as an oil.

 This 1.37 g was dissolved in tetrahydrofuran (15 mL), cooled to -78 in a nitrogen atmosphere, 1.6 M n_butyllithium / hexane solution (4.0 mL, 6.4 mmol) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes. . Ν, Ν-Dimethylformamide (1.2 mL, 15 mmol) was added dropwise to the obtained mixture, and the mixture was stirred at -78 for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography (hexane / ethyl acetate 20: 1), and recrystallized from ethyl acetate to give the title compound (741 mg, yield 59%).

89-90 ° C.

_{¾ NMR (CDC1 3) 51.54 (} 6H, s), 3.39 (2H, s), 3.96 (3H, s), 6.88 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 8.4 Hz) , 9.90 (1H, s) _D

Reference example 4

2,3-dihydro-7-methoxy-2,2-dimethyl-4_ (2-methyl-1-propenyl) benzofuran 2,3-dihydro-7-methoxy-2,2-dimethyl-4_benzofurancarboxaldehyde (10.4 g, 50.4 imol) and isopropyltriphenylphosphonidumodizide (23.8 g, 55.1 mmol) in tetrahydrofuran (100 mL ) Sodium hydride (66% oil dispersion) (1.99 g, 55 t ol) was added to the suspension, and the mixture was refluxed for 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane / ethyl acetate (4: 1) mixture was added to the residue, the insolubles were filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate 100: 1 followed by 10: 1) to give the title compound (11.0 g, yield 94). .

Oil.

_{Ή NMR (CDC1 3) 51.51 (} 6H, s), 1.81 (3H, d, J = 1.1 Hz), 1.87 (3H, d, J = 1.1 Hz), 2.94 (2H, s), 3.86 (3H, s) , 6.03 (1H, s), 6.70 (2H, s) _D

Example 1

 1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinoline

 Of 2,3-dihydro-7-methoxy-2,2-dimethyl-4- (2-methyl-1-propenyl) benzofuran (2.09 g, 9.00 maraudal 01) and benzonitrile (1.21 g, 11.7 mmol) Concentrated sulfuric acid (1.2 mL) was added dropwise to the acetic acid (3 mL) solution at 10 and stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water and washed with diisopropyl ether. The aqueous layer was made basic with a 5 M aqueous sodium hydroxide solution, and extracted twice with a mixed solution of tetrahydrofuran / diisopropyl ether (1: 1). The combined organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (1.37 g, yield 45 »).

128-129 ° C.

_{Ή NMR (CDC1 3) (51.28} (6H, s), 1.57 (6H, s), 2.59 (2H, s), 3.01 (2H, s), 3.69 (3H, s), 6.62 (1H, s), 7.36 -7.45 (3H, m), 7.49-7.60 (2H, m).

Example 2

1,2,8,9-tetrahydro-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinolin-4-ol 48% bromination of 1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinoline (3.70 g, 11.0 mmol) The solution of hydrogen acid (25 mL) was heated under reflux for 13 hours. After cooling, the reaction mixture was neutralized with concentrated aqueous ammonia and extracted twice with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The precipitated crystals were washed with diisopropyl ether and recrystallized from ethanol-ethyl acetate to give the title compound (2.17 g, yield 61%). Softening point 187 ° C.

_{¾ NMR (CDC1 3) 51.25 (} 6H, s), 1.54 (6H, s), 2.53 (2H, s), 3.00 (2H, s), 6.56 (1H, s), 7.30-7.33 (3H, m), 7.43-7.50 (2H, m).

Example 3

 4-Ethoxy-1,2,8,9-tetrahydro_2,2,8,8-tetramethyl-6-phenylfuro [3,2-f] isoquinoline

 1,2,8,9-Tetrahydrido-2,2,8,8-tetramethyl-6-phenylphenol [3,2-f] isoquinolin-4-ol (638 mg, 1.99 t) To a solution of N-dimethylformamide (6 mL) were added iodoethane (0.19 mL, 2.4 mol) and sodium hydride (66% oil dispersion) (87 mg, 2.4 mmol), and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 20: 1 followed by 10: 1), and crystallized from hexane to give the title compound (465 mg, yield 67).

120-122 ° C.

 Ή NMR (CDCI3) δΐ.29 (6H, s), 1.32 (3Η, t, J = 7.0 Hz), 1.57 (6H, s), 2.60 (2H, s), 3.00 (2H, s), 3.93 (2H , q, J = 7.0 Hz), 6.63 (1H, s), 7.39-7.42 (3H, m), 7.52-7.57 (2H, m).

Example 4

 3- (l, 2,8,9-tetrahydrido _4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline 6-yl) benzenamine

A suspension of N- (3-cyanophenyl) -2,2,2-trifluoroacetamide (5.89 g, 27.5 mmol) in toluene (25 mL) and acetic acid (12 mL) was cooled on ice and concentrated sulfuric acid (3.0 mL). ), Next A solution of 2,3-dihydro-7-methoxy-2,2-dimethyl-4- (2-methyl-1-propenyl) benzofuran (5.81, 25.0 mmol) in toluene (25 mL) was added dropwise. Stirred for 1 hour. Ethanol (20 mL) was added dropwise to the resulting mixture at the same temperature, and the mixture was stirred for 1 hour. The reaction mixture was ice-cooled, water was added, neutralized with concentrated aqueous ammonia, and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was suspended in ethanol (30 mL), a 2 M aqueous sodium hydroxide solution (30 mL, 60 mmol) was added, and the mixture was heated under reflux for 1 hour. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 3: 1 followed by 1: 1), and crystallized from ethyl acetate-hexane to give the title compound (4.47 g, yield 51).

Melting point 163-165 V _a

_{Ή NMR (CDC1 3) δ 1.26} (6H, s), 1.56 (6H, s), 2.58 (2H, s), 3.00 (2H, s), 3.20-4.00 (2H, br), 3.71 (3H, s) , 6.68-6.76 (1H, m), 6.69 (1H, s), 6.84-6.92 (2H, m), 7.17 (1H, t, J = 7.7 Hz).

Example 5

 N- [3- (1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethylfuran [3,2-f] isoquinoline-6-ylyl) phenyl] -4- Pyridinecarboxamide

 .3- (1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethylph [3,2-f] isoquinolin-6-yl) benzenamine (701 mg, 2.00 mmol ) And 4-dimethylaminopyridine (611 mg, 5.00 mmol) in N, N-dimethylformamide (10 mL) were added with isonicotinoyl chloride hydrochloride (712 mg, 4.00 methylol) and stirred at room temperature for 20 minutes. did. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was recrystallized from ethanol lugetyl ether to give the title compound (800 mg, yield 88 »; melting point 247-249 ° C.

¾ NMR (CDCI3) 51.21 (6H, s), 1.57 (6H, s), 2.51 (2H, s), 3.00 (2H, s), 3.73 (3H, s), 6.68 (1H, s), 7.25-7.33 (1H, m), 7.42 (1H, i, J = 7.9 Hz), 7.66 (2H, d, J = 6.2 Hz), 7.74 (1H, t, J = 1.7 Hz), 7.90-7.98 (1H, m) , 8.73 (1H, br s), 8.76 (2H, d, J = 6.2 Hz Example 6

 N- [3- (1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylphenyl [3,2-f] isoquinolin-6-yl) phenyl] methanesulfone Amide

 3- (1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethylph [3,2-f] isoquinolin-6-yl) benzenamine (2.11 g, 6.02 thighs) To a solution of ol) in pyridine (15 虬), methanesulfonyl chloride (0.51 mL, 6.6 band01) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was dissolved in toluene, concentrated under reduced pressure, and crystallized from ethyl acetate-ethyl ether to give the title compound (2.28 g, yield 88%).

Melting point 211-215. C.

_{¾ NMR (CDC1 3) δΐ.34 (} 6H, s), 1.58 (6Η, s), 2.60-2.81 (5H, m), 3.02 (2H, s), 3.73 (3H, s), 6.66 (1H, s ), 7.21-7.44 (3H, m), 7.53 (1H, br s) ₀

Example 7

3-[(Methylsulfonyl) [3- (1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethyl] [3,2-f] isoquinoline-6- L) Phenyl] amino] propanesulfonamide To a suspension of 3-chloro-propanesulfonamide (788 mg, 5.00 mmol) in toluene (10 mL) was added Ν, Ν-dimethylformamide dimethyl acetal (0.73 mL, 5.5 Bandit 01) was added and stirred at 60 for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a mixture (1.15 g) containing 3-chloro-N-[(dimethylamino) methylene] -1-propanesulfonamide. 600 mg of this mixture, N- [3_ (1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) phenyl] To a suspension of methanesulfonamide (806 mg, 1.88 mmol) and sodium iodide (282 mg, 1.88 mmol) in Ν, Ν-dimethylformamide (4 niL) was added sodium hydride (66 oil dispersion) (89 mg, 2.4 mg). Orchid ol) was added, and the mixture was stirred at room temperature for 10 minutes and at 80 for 4 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 1: 1 followed by ethyl acetate) to give N-[(dimethylamino) methylene] -3-[(methylsulfonyl) [3- (1,2 , 8, 9-Tetrahydro-4-methoxy-2,2,8,8-tetra [3,2-f] isoquinoline-6-yl) phenyl] amino] propanesulfonamide (1.05 g) was obtained as amorphous.

 This was dissolved in 2 M hydrochloric acid and heated under reflux for 40 minutes. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (820 mg, yield 79%).

Mp 165-167 ° C.

_{¾ NMR (CDC1 3) δΐ.29 (} 6Η, s), 1.57 (6H, s), 1.89-2.05 (2H, m), 2.59 (2H, s), 2.96 (3H, s), 3.01 (2H, s ), 3.21 (2H, t, J = 7.3 Hz), 3.73 (3H, s), 3.91 (2H, t, J = 6.6 Hz), 5.38 (2H, br s), 6.62 (1H, s), 7.39- 7.56 (3H, m), 7.57-7.61 (1H, m).

Example 8

 6- (3-bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline

₃ one-bromobenzonitrile _{(4 47 g,} 24.6 cage ol.) And 2, 3-dihydro - 7-methoxyethanol - 2, 2 - dimethyl _4- (2_ methyl - Bok propenyl) benzofuran (5.70 g, 24.5 A toluene solution (20 mL) of dandelion (ol) was heated to 85 ° C, a solution of concentrated sulfuric acid (3.0 mL, 56 mL) in acetic acid (10 mL) was added dropwise, and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was washed with diisopropyl ether. The organic layer was extracted with 2M hydrochloric acid. The combined aqueous layer was ice-cooled, neutralized with concentrated aqueous ammonia, and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 10: 1), and condensed from hexane to obtain the title compound (2.88 g, yield 28¾).

128-130 ° C.

'HNMR (CDC <51.27 (6H, s), 1.57 (6H, s), 2.58 (2H, s), 3.01 (2H, s), 3.71 (3H, s), 6.56 (1H, s), 7.27 (1H , t, J = 7.8 Hz), 7.46 (1H, dt, J = 7.8, 1.3 Hz), 7.54 (1H, ddd, J-7.8, 2.0, LI Hz), 7.72 (1H, t, J = 1.7 Hz) _0. Example 9 1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6- [3- (4-pyridinyl) phenyl] aceto [3,2-f] isoquinoline

 6- (3-Bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-isoquinoline (3.34 g, 8.06 bandages01) and 4-pyridinylporone A suspension of acid (1.49 g, 12.1 mmol) in N, N-dimethylformamide (20 mL) was added to a solution of sodium carbonate (1.41 g, 13.3 mmol) in water (10 mL) and tetrakis (triphenylphosphine) palladium (0. ) (466 mg, 0.403 bandol) was added, and the mixture was stirred at 120 under a nitrogen atmosphere for 6 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 10: 1 followed by 2: 1) and crystallized from ethyl acetate-hexane to give the title compound (1.95 g, yield 59%). Was.

Melting point 125-127 ° Co

 Ή NMR (CDC) 51.30 (6H, s), 1.58 (6H, s), 2.62 (2H, s), 3.03 (2H, s), 3.69 (3H, s), 6.62 (1H, s), 7.48-7.57 (1H, m), 7.55 (2H, d, J = 6.2 Hz), 7.61 (1H, dt, J = 7.6, 1.7 Hz), 7.69 (1H, dt, J = 7., 1.7 Hz), 7.83 (1H , t, J = 1.7 Hz), 8.66 (2H, d, J = 6.2 Hz).

Example 10

 1,2,8,9-Tetrahydro-2,2,8,8-tetramethyl-6- [3- (4-pyridinyl) phenyl] fluoro [3,2_f] isoquinoline-4ol

 1,2,8,9-Tetrahydro-4-methoxy-2,2,8,8-tetramethyl-6_ [3- (4-pyridinyl) phenyl] furo [3,2-f] isoquinoline (1.11 g, 2.69 t) was added 48 hydrobromic acid (13 mL), and the mixture was stirred at 105 for 17 hours. The reaction mixture was ice-cooled, neutralized with concentrated aqueous ammonia, and extracted twice with a mixed solution of ethyl acetate and tetrahydrofuran. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, treated with activated carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl ether to give the title compound (766 mg, yield 71%).

Melting point 221-223. C.

_{¾ NMR (CDC1 3) (51.29} (6H, s), 1.56 (6H, s), 2.59 (2H, s), 3.02 (2H, s), 6.60 (1H, s), 7.35 (2H, d, J = 6.2 Hz), 7.45-7.54 (1H, m), 7.57-7.68 (3H, m), 8.44 (2H, d, J = 6.2 Hz

Example 11

 1,2,8,9-Tetrahydro-2,2,8,8-tetramethyl-4- [2- (2-pyridinyl) ethoxy] -6- [3- (4-pyridinyl) phenyl] furo [3 , 2-f] isoquinoline

 1,2,8,9-Tetrahydro-2,2,8,8-tetramethyl-6_ [3- (4-pyridinyl) phenyl] furo [3,2-f] isoquinolin-4-ol (598 mg, 1.50 mmol), 2- (2-hydroxyethyl) pyridine (277 mg, 2.25 mmol) and triphenylphosphine (787 mg, 3.00 mmol) in tetrahydrofuran (6 mL) under ice-cooling with diisopropyl azodicarboxylate (0.59 mL, 3.09 mmol). mmol), and the mixture was stirred at room temperature for 30 minutes and at 60 for 1 hour. The resulting mixture was added to 2- (2-hydroxyethyl) pyridine (0.17 mL, 1.5 liters), triphenylphosphine (394 mg, 1.50 mmol) and diisopropyl azodiphenol (0.30 mL, 1.5 mL). ol) and stirred at 60 for 1.5 hours. The reaction mixture was cooled on ice, acidified with 1M hydrochloric acid, and washed twice with ethyl acetate. The aqueous layer was neutralized with concentrated aqueous ammonia and extracted twice with ethyl acetate. The combined organic layer was washed with 1 M aqueous sodium hydroxide solution (twice) and water, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 10: 1, 5: 1, 3: 1 followed by 1: 1), and recrystallized from ethyl ether-hexane to give the title compound (348 mg). The yield was 46. The melting point was 110-113.

_{¾ NMR (CDC1 3) 51.29 (} 6H, s), 1.56 (6H, s), 2.60 (2H, s), 3.00 (2H, s), 3.17 (2H, t, J = 7.0 Hz), 4.28 (2H, t, J = 7.0 Hz), 6.66 (1H, s), 7.06 (1H, ddd, J = 7.6, 4.9, 1.2 Hz), 7.11-7.17 (1H, m), 7.45-7.61 (5H, m), 7.67 (1H, dt, J = 7.0, 1.9 Hz), 7.78-7.81 (1H, m), 8.45 (1H, ddd, J = 5.0, 1.9, 0.9 Hz), 8.63 (2H, d, J = 6.2 Hz) ₀

Example 12

N- [3 '-(1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuran [3,2-f] isoquinoline-6-yl) [1,1 '-Biphenyl] -4-yl] acetoamide

6- (3-bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline (207 mg, 0.500 mmol), 4 ' -(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) acetanilide (144mg, 0.551 bandol ol), sodium carbonate Thorium (133 mg, 1.25 bandol) and tetrakis (triphenylphosphine) palladium (0) (12 mg, 0.010 mmol) in 1,2-dimethoxyethane (1.5 mL), ethanol (0.8 mL) and water (0.8 mL) mL) suspension was stirred at 85 under a nitrogen atmosphere for 16 hours. Water was added to the reaction mixture, which was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate basic silica gel (eluted with ethyl acetate) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (218 rag, yield 93%).

Melting point 231-234 ° Co

_{¾ NMR (CDC1 3) 1.31 (} 6H, s), 1.58 (6H, s), 2.13 (3H, s), 2.63 (2H, s), 3.03 (2H, s), 3.69 (3H, s), 6.67 ( 1H, s), 7.40-7.61 (7H, m), 7.68-7.76 (2H, m). Example 13

 6- (3-Bromophenyl) -1,2,8,9-tetrahydro-2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-4-ol

 To 6- (3-bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline (2.08 g, 5.02 mmol) 48% Hydrobromic acid (30 mL) was added, and the mixture was stirred at 105 ° C for 14.5 hours. The reaction mixture was ice-cooled, neutralized with concentrated aqueous ammonia, and extracted twice with chloroform. The combined organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (1.09 g, yield 54¾).

236-239 ° C.

 ¾ NMR (CDCI3) δ 1.24 (6Η, s), 1.54 (6H, s), 2.54 (2H, s), 3.00 (2H, s),

5.60-5.80 (1H, br), 6.50 (1H, s), 7.19 (1H, t, J = 7.8 Hz), 7.33-7.38 (1H, m), 7.43-7.48 (1H, m), 7.61 (1H, t, J = 1.7 Hz) ₀

Example 1

N- [3 '-(1,2,8,9-tetrahydro-4-hydroxy-2,2,8,8-tetramethylfuran [3,2- -isoquinolin-6-yl] [1, Γ-bihue Nil] -4-yl] acetamide

6- (3-Bromophenyl) -1,2,8,9-tetrahydro-2,2,8,8-tetramethylfuran [3,2--] isoquinolin-4-ol (1.00 g, 2.50 mmol), 4 ' -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) acetoanilide (718 mg, 2.75 mmol), sodium carbonate Thorium (662 mg, 6.25 mol) and tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.050 mmol) in 1,2-dimethoxyethane (12 mL), ethanol (6 mL) and water (6 mL) The suspension was stirred at 85 under a nitrogen atmosphere for 21 hours. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate-basic silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (1.12 g, yield 99%).

Mp 272-275.

¾NMR (DMSO-d ₆ ) dl.17 (6Η, s), 1.46 (6H, s), 2.06 (3H, s), 2.52 (2H, s), 2.99 (2H, s), 6.58 (1H, s) , 7.37-7.44 (1H, m), 7.51 (1H, t, J = 7.7 Hz), 7.59-7.72 (6H, m), 9.03 (1H, s), 10.04 (1H, s).

Example 15

 Trifluoromethanesulfonic acid 6- [4 '-(acetylamino) [1, Γ-biphenyl] -3-yl] -1,2,8,9-tetrahydrido-2,2,8,8-tetramethylfur [ 3, 2-f] isoquinoline-4-yl ester

 N- [3 '-(1,2,8,9-tetrahydro-4-hydroxy_2,2,8,8-tetramethylfuro [3,2-f] isoquinolin-6-yl) [1,1' To a solution of [-pifenyl] -4-yl] acetoamide (546 mg, 1.20 mmol) in pyridine (6 mL) was added dropwise trifluoromethanesulfonic anhydride (0.51 mL, 3.0 tmol) under ice-cooling. The mixture was stirred at warm for 15 minutes. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 5: 1, 2: 1 followed by 1: 1) and crystallized from ethyl acetate-hexane to give the title compound (595 mg, yield 85 » I got

233-235. C.

_{¾ NMR (CDC1 3) (51.31} (6H, s), 1.58 (6H, s), 2.18 (3H, s), 2.65 (2H, s), 3.07 (2H, s), 7.02 (1H, s), 7.32 (1H, br s), 7.34-7.51 (2H, m), 7.57 (4H, s), 7.60-7.65 (1H, m), 7.69-7.71 (1H, m).

Example 16

N- [3 '-(l, 2,8,9-tetrahydro-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline -6-yl) [1, Γ-biphenyl] -1-4-yl] acetamide

 Trifluoromethanesulfonic acid 6- [4 '-(acetylamino) [1,1'-biphenyl] -3-yl] -1,2,8,9-tetrahydro-2,2,8,8-tetramethylphenyl Mouth [3,2-f] isoquinoline-4-yl ester (470 mg, 0.801 virgin ol), triethylamine (0.34 mL, 2.4 mmol), palladium (II) acetate (4.5 m. 0.020 mmol) and triphenylphosphine (10.5 mg, 0.0400 mL) of N, N-dimethylformamide (1.5 mL) was added with formic acid (60 βί, 1.6 t ol), and the mixture was stirred at 70 ° C for 4.5 hours under a nitrogen atmosphere. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate basic silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane / ethyl acetate 1: 1 followed by 1: 2), and crystallized from ethyl acetate-hexane to give the title compound (340 mg, yield 97%). . 140-152 ° C.

_{Ή NMR (CDC1 3) δ 1.31} (6Η, s), 1.53 (6H, s), 2.17 (3H, s), 2.67 (2H, s), 2.99 (2H, s), 6.53 (1H, d, J = 8.1 Hz), 7.04 (1H, d, J = 8.1 Hz), 7.40-7.49 (3H, m), 7.54 (4H, s), 7.55-7.62 (1H, m), 7.66-7.69 (1H, m).

The compounds prepared in the above examples are shown in Table 1 below.

(0 ίιίί3? ¾

[Ihara]

6ΤΙ

8ST90 / Z0df / X3d .69000 / CO OAV Formulation Example 1

 (1) Compound of Example 1 l O.O mg

 (2) Lactose 60.0 mg

 (3) Corn starch 35.0 mg

(4) Gelatin 3.0 mg

 (5) Magnesium stearate 2.0 mg

 A mixture of the compound obtained in Example 1 10. Omg, lactose 60. Omg and corn starch 35.0 fflg was granulated through a 1-mesh mesh sieve using 0.03 ml of 10% gelatin aqueous solution (3.0 mg as gelatin). Thereafter, it was dried at 40 ° C. and sieved again. The granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed. The obtained central tablets were coated with a sugar coating using an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were glazed with beeswax to obtain coated tablets.

Formulation Example 2

(1) Compound of Example 1 10.0 mg

 (2) Lactose 70.O mg

 (3) Corn starch 50.O mg

 (4) Soluble starch 7.0 mg

 (5) Magnesium stearate 3.0 mg

 10.0 mg of the compound obtained in Example 1 and 3.0 mg of magnesium stearate were granulated with 0.07 ml of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried, and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. . The mixture was compressed to give tablets.

Formulation Example 3

(1) Compound of Example 1 5.O mg

 (2) Salt 20.O mg

 (3) Total volume of distilled water is 2 ml

5.0 mg of the compound obtained in Example 1 and 20.0 mg of common salt were dissolved in distilled water, and water was added to make a total volume of 2.0 ml. Filter the solution into 2 ml ampules under aseptic conditions Filled. The ampoule was sterilized and sealed to obtain a solution for injection.

Formulation Example 4

 After uniformly mixing 1500 g of the compound obtained in Example 1, lactose 2025 g and 556.5 g of corn starch in a fluidized bed granulating drier (FD-5S, Parec Co., Ltd.), An aqueous solution in which 126 g of propylcellulose was dissolved was sprayed and granulated, and then dried in a fluidized bed granulating dryer. The obtained granules were pulverized using a power mill with a punching screen having a diameter of 1.5 mm to give sized powder. Take 3927 g of the sized powder, add 210 g of croscarmellose sodium and 63 g of magnesium stearate, and mix with a tumbler mixer to obtain granules for tableting. The granules were tableted with a tableting machine at a weight of 300 mg using a frame with a diameter of 6.5 mm to give naked tablets. The obtained uncoated tablets were prepared by dissolving hydr-methyl oxymethyl-pyrumethylcellulose 2910 (TC-5) and macrogol 6000 in a doria coater and spraying a liquid containing titanium oxide and iron sesquioxide dispersed therein. About 13500 film tablets containing lO Omg and having the following formulation were obtained.

Tablet prescription:

 Composition Formula II (mgj

 (1) Compound of Example 1 100.0

 (2) Lactose 135.0

 (3) Corn starch 37.1

 (4) Croscarmellose sodium 15.0

 (5) Hydroxypropyl cellulose 8.4

 (6) Magnesium stearate 4.5

 Total (naked tablets) 300. 0

Film tablet formula:

 (1) Nude tablets 300.0

 (Film components)

 (2) Hydroxypropyl methylcellulose 29 0 7 485

 (3) Macrogol 6000 5

(4) Titanium oxide 0 (5) Iron sesquioxide 0.015

 Total 310.0

Formulation Example 5

 According to the method described in Formulation Example 4, about 13,500 film tablets of the following formulation containing 25 mg per compound of the compound obtained in Example 1 were obtained.

Tablet prescription:

 Composition Formula (m)

 (1) Compound of Example 1 25.0

 (2) Lactose 210.0

 (3) Corn starch 37.1

 (4) Croscarmellose sodium 15.0

 (5) Hydroxypropyl cellulose 8.4

 (6) Magnesium stearate 4.5

 Total (naked tablets) 300. 0

Film tablet formula:

 (1) Nude tablets 300.0

 (Film component)

 (2) Hydroxypropyl methylcellulose 2910 7.485

 (3) Macro goal 6000 1.5

(4) Titanium oxide 1.0

 (5) Iron sesquioxide 0.015

 Total 310.0

Formulation Example 6

 According to the method described in Formulation Example 4, about 13500 film tablets of the following formulation containing 5 mg of the compound obtained in Example 1 per tablet were obtained.

Tablet prescription:

 Composition Amount (mg)

 (1) Compound of Example 1 5.0

(2) Lactose 230.0 (3) Corn starch 37.1

 (4) Croscarmellose sodium 15.0

 (5) Hydroxypropyl cellulose 8.4

 (6) Magnesium stearate 4.5

 Total (naked tablets) 300. 0

Film tablet formula:

 (1) Nude tablets 300.0

 (Film components)

 (2) Hydroxypropyl methyl cell mouth 2910 7.485

 (3) Macro goal 6000 1.5

 (4) Titanium oxide 1.0

 (5) Iron sesquioxide 0.015

 Total 310.0

Formulation Example 7

 According to the method described in Formulation Example 4, about 13500 film tablets of the following formulation containing 1 mg of the compound obtained in Example 1 per tablet were obtained.

Tablet prescription:

 Composition Amount (mg)

 (1) Compound of Example 1 1.0

 (2) Lactose 234.0

 (3) Corn starch 37.1

 (4) Croscarmellose sodium 15.0

 (5) Hydroxypropyl cellulose 8.4

 (6) Magnesium stearate 4.5

 Total (naked tablets) 300. 0

Film tablet formula:

 (1) Nude tablets 300.0

 (Film components)

(2) Hydroxypropyl methylcellulose 2910 7.485 (3) Macro goal 6000 1.5

 (4) Titanium oxide 1.0

 (5) Iron sesquioxide 0.015

 Total 310.0

Formulation Example 8

 White ginseng 40 g

 Cetanol 10 g

 5 g of beeswax

 Sorbitan sesquioleate 5 g

 Mouth Mouth Gold 0.5 g

 Methyl paraoxybenzoate 0.1 g

 Propyl paraoxybenzoate 0 1

 purified water

 A water-absorbing ointment having the above composition (100 g) was previously heated to 70 ° C, and a solution prepared by heating 1 g of the compound obtained in Example 1 in 20 ml of methanol was added to the solution. Was. The mixture was heated and mixed at the same temperature for 10 minutes to remove residual methanol, and cooled to room temperature to obtain a water-absorbing ointment.

Test Example 1 Measurement of PDE IV inhibitory action

 (1) Cloning of the gene encoding PDE 4D3 from human brain

From the human brain cDNA library, the gene encoding PDE 4D3 was cloned by the PCR method. Type 1 ng of brain QUICK-Clone ^™ cDNA (Clontech) and refer to the PDE 4D3 gene base sequence reported by emoz et al. (FEBS Letters 384, 97-102 (1996)). To the primer set, 5, _ccacgatagctgctcaaacaagag-3, (SEQ ID NO: 1) and 5'-atagaaaccccaagtccaataaac-3 '(SEQ ID NO: 2) were added to each of the prepared primer sets. PCR was performed using MiniCycler ™ (MJRESERCH) using Taq (Takara Shuzo) (reaction conditions: 0.5 min at 94 ° C, 0.5 min at 55T, 4 min at 72 ° C). 30 cycles). The PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of about 2.4 kb was recovered. After blunting the fragment with Pfu DNA polymerase (STRATAGENE), Zero Blunt PCR Cloning The PDE 4D3 gene was cloned using Kit (Invitrogen).

 (2) Construction of E. coli expression vector

 The plasmid obtained in the above (1) was digested with restriction enzyme EcoRI (Takara Shuzo), and then subjected to agarose gel electrophoresis to recover a DNA fragment of about 2.4 kb. The PNA fragment was digested with restriction enzyme EcoRI (Takara Shuzo) and ligated with pAPEX4T-3 (Pharmacia) treated with BAP (Takara Shuzo). The obtained cDNA fragment has the nucleotide sequence represented by SEQ ID NO: 3, and encodes the amino acid sequence represented by SEQ ID NO: 4 at the 74th to 2092th positions of the nucleotide sequence. I understood that it was. This cDNA fragment was transformed into Escherichia coli BL21 (Funakoshi) using a ligase solution to obtain Escherichia coli BL21ZPPDE4D3 expressing the PDE4D3 gene.

 (3) Expression and purification of recombinant human brain-derived PDE 4D3 in Escherichia coli

 Using the Escherichia coli BL21 / pPDE4D3 obtained in (2) above, a recombinant human brain-derived PDE4D3 was obtained. Expression and purification in Escherichia coli were performed according to the protocol attached to GST Gene Fusion System (Pharmacia). As a result, 34 mg of the desired recombinant human brain-derived PDE 4D3 of about 76 kDa was obtained from 1 L of E. coli culture.

 (4) Measurement of PDE IV inhibitory action

試験例 2 モルモットにおける抗原誘発気道狭窄抑制作用 96 well plates (OPT I plate, Packard) buffer [0. 5Μ T ris- HC 1 (pH7 . 5), 83mM MgC l 2, 17mM EGTA ] 10 1, recombinant obtained above (1) Human brain-derived PDE 4D3 (0.0034 mg Zm 1) 10, ultrapure water 65 1, inhibitor sample 51, [ ³ H] c AMP 101 were added, and reacted at 30 for 30 minutes. After completion of the reaction, SPA BE ad s solution C 1 Smg / m 1 Yttrium silicate beads, 18MMZnS_〇 _4] 50 1 was added Caro, about 20 minutes, allowed to stand at room temperature, scintillation one Deployment counter (the To PCOUNT, Packard ) Was measured. In contrast to the radioactivity without addition (1020 cpm), the addition of recombinant human brain-derived PDE4D3 showed a radioactivity of 28245 cpm. PDE activity was inhibited by adding rolipram (BIOMOL Research Laboratories, Inc.), which is an inhibitor of PDE IV at various concentrations, to this reaction. Rolipram inhibited this enzyme reaction by 50% at about 100 nM. Using this Assay system, the PDE inhibitory activity (IC5 ₍₎ value) of the compound of the present invention derived from recombinant human brain was measured. The results are shown in Table 2. (Table 2)

Test Example 2 Antigen-induced airway constriction in guinea pigs

 (1) Preparation of Egret anti-ovalbumin (〇A) serum

 1.0 ml of an emulsion of white ゥ egret (body weight: about 3 kg; New Zealand White: Kitayama Labes) in 10% 〇 A (Grade III, Sigma) solution 0.5 ml and Freud Complete Adjuvant (Wako Pure Chemical) 0.5 ml Was immunized by intramuscular administration. This operation was repeated once a week, for a total of four times. One week after the final immunization, whole blood was collected. The collected blood was allowed to stand at room temperature for at least 1 hour, and then left to stand in a refrigerator overnight. The next day, the serum portion was separated, centrifuged (3000 rpm, 10 min), and the supernatant was stored at 120 ° C as an antiserum.

 (2) Antigen-induced airway constriction response

The airway constriction response was measured by a modification of the Konzett-Rossler method. Hartley male guinea pigs weighing 400-500 g (Nippon S.L.C., Shizuoka) were intravenously administered with 1.0 ml of anti-OA serum diluted 8 to 16 times under ether anesthesia, and used for experiments 16 to 24 hours later. . Anesthetize with urethane (1.2 g / kg, ip) (manufactured by Aldrich), inject tracheal force in the trachea, and in order to stop spontaneous breathing, garamine trietiodide (lmg / kg, iv) ( (Sigma). Animals breathe times several 70 times with an artificial respirator (Harvard model 683) / min, ventilator at a tidal volume 2 to 3 ml and the initial load pressure 10 cm H ₂ 0, tracheal pressure from the side branch of the tracheal force Nyure Was measured via a differential pressure transducer. Mepyramine maleate (lO mg / kg) (Sigma) and propranolol (1.0 mg / kg) (Sigma) were administered intravenously two minutes after the administration of gallamine trietiodide, and two minutes later. OA antigen (1.0 mg / kg) was administered intravenously to induce airway stenosis. Example compound ling / kg was dissolved in 25% dimethylacetamide, 25% polyethylene glycol 400, and 50% physiological saline, and administered intravenously 5 minutes before antigen induction. The inhibition rate was calculated by comparing with the control group (intravenous administration of a mixture of 25% dimethylacetamide, 25% polyethylene glycol 400, and 50% saline). Table 3 shows the inhibition rates of the compounds of the present invention.

産業上の利用可能性 (Table 3)

Industrial applicability

 The furoisoquinoline derivative of the present invention has an excellent PDE IV inhibitory action, and is used for inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's disease, memory It is useful as a prophylactic and therapeutic agent for disorders, diabetes, arteriosclerosis, etc.

Claims

The scope of the claims  1 set

Or a salt thereof having a partial structure represented by the formula: 2. Expression

[Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent] or a salt thereof. . 3 expression

[Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R ² and R ³ each represent a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group, and R ² and R ³ may have a substituent together with an adjacent carbon atom May form a 3- to 8-membered ring, The R ⁴ and R ⁵ are each a hydrogen atom or an optionally substituted hydrocarbon group, R ⁶ and R ⁷ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ⁶ and R ⁷ may have a substituent together with an adjacent carbon atom and may have a 3- to 8-membered ring May be formed, R ⁸ represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent, (3) an acyl group, (4) a heterocyclic group which may have a substituent, (5 ) Halogen atom, (6) -OR ¹⁰ (R ^1G represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent) (7) -SR ¹¹ (R ¹¹ represents a hydrogen atom, a hydrocarbon group optionally having substituent (s), an acyl group or a heterocyclic group optionally having substituent (s)), (8)- S (〇) R ¹² (R ¹² represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), (9) -S (0) ₂ R ¹³ (R ¹³ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent) or (10) — NR ¹⁴ R ¹⁵ (R ¹⁴ and R ¹⁵ are each hydrogen. Atom, hydrocarbon group which may have a substituent, The shown) yl group or optionally substituted heterocyclic group, R ⁹ represents a hydrogen atom, a cyano group, a hydrocarbon group which may have a substituent, an acyl group or a hydroxyl group which may have a substituent,  X represents a methylene group or a heptonyl group which may have a substituent,  and n represents 0 or 1.] or a compound or a salt thereof. 4. R ¹ represents ^one of the following (i) or (ii): (i) (1) porogen atom, (2) C _1-3 alkylenedioxy group, (3) nitro group, (4) cyano group, (5) optionally halogenated (^ -6 alkyl group, (6) halogenation which may be C ₂ _ ₆ alkenyl group, (7) optionally halogenated C _{2 6} alkynyl group, (8) C ₃ _ ₆ cycloalkyl group, (9) C _{6 14} Ariru group, (10) optionally halogenated (^ -6 alkoxy group, (11) optionally halogenated C [Bok ₆ alkylthio group, (12) hydroxy group, (13) amino groups , (14) mono - 6 alkylamino group, (15) mono- C _{6 14} § Li one Ruamino group, (16) di - (丄- ₆ alkylamino group, (17) di-C _fi Ariruamino group, (18) formyl , Power Rupokishi force Rubamoiru, ₆ alkyl Ichiriki Ruponiru, c ₃ _ ₆ cycloalkyl Ichiriki Ruponiru, (^ alkoxy - force Ruponiru, 〇 ₆ _ _{1 4} Ariru - force Ruponiru, C ₇ - ₁₆ Ararukiru Ichiriki Ruponiru, c ₆ _ ₁₄ Ariruokishi Ichiriki Ruponiru, c ₇ - ₁₆ § la Rukiruokishi - force Ruponiru, nitrogen atom in addition to carbon atom, a sulfur atom and an oxygen atom or al 1 selected to terrorist three of the 5 or 6-membered heterocyclic carbonyl containing atoms, mono- CI_ ₆ alkyl - force Rubamoiru, di - 6 alkyl Ichiriki Rubamoiru, C ₆ - ₁₄ Ariru Ichiriki Rubamoiru, nitrogen atom in addition to carbon atom, a sulfur atom and to 1 selected from an oxygen atom containing heteroatoms three of the 5 or 6-membered heterocyclic ring Karubamo I le, DOO ₆ alkyl one Chiokaruponiru, C ₃ _ ₆ cycloalkyl-thiocarbonyl, — ₆ alkoxy-thiocarbonyl, c ₆ — ₁₄ aryl-thiocarbonyl, c ₇ _ ₁₆ arylalkyl-thiocarponyl, c ₆ _ ₁₄ aryloxy-thiocarbonyl, c ₇ — _16- aralkyloxycarbonyl, other than carbon atom nitrogen atom, sulfur atom and to 1 selected from oxygen radicals containing heteroatoms three of the 5 or 6-membered heterocyclic Ji Sairyoku Ruponiru, Chiokarubamoiru, mono- (^ - ₆ alkyl - Chiokarubamoiru, di one Ci - ₆ alkyl one Chiokarubamoiru, C ₆ - ₁₄ Ariru one Chiokarubamoiru, other than carbon atoms Nitrogen atom, sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic ring Chiokarubamoiru selected from oxygen atom, sulfamoyl, mono- C i_ ₆ alkylsulfamoyl, di - C ₆ alkylsulfamoyl , C ₆ - ₁₄ Ari Rusurufamoiru, C ₆ alkylsulfonyl, C ₆ - ₁₄ § reel sulfonyl, C, _ ₆ alkyl sulfides El, C ₆ - ₁₄ § Li one Rusurufieru, sulfino, sulfo, (:丄- ₆ alkoxysulfinyl Luffy El , C ₆ - ₁₄ § Li one Ruo carboxymethyl sulfide El, <preparative ₆ Al Kokishisuruhoniru and C ₆ - i ₄ Ashiru group selected from § Li one Ruo carboxymethyl sulfonyl, (19) Horumiruamino, alkyl - carboxamido, C ₆ - ₁₄ Ariru one local Pokisamido, ₆ alkoxy - Karupokisamido, - 6 alkylsulfonyl amino, and C ₆ - ₁₄ Ashiruamino group selected from § Li one Le sulfonyl § amino, (20) (^ -6 alkyl Ichiriki Ruponiruokishi, C ₆ - ₁₄ Ariru - Power Ruponiruokishi, (: Bok ₆ alkoxy Ichiriki Ruponiruokishi, mono - alkyl - force Rubamoiruokishi, di -C ^ e alkyl Ichiriki Rubamoiruokishi, C ₆ - ₁₄ § Li An acyloxy group selected from the group consisting of rubamoyloxy and nicotinyloxy; (21) nitrogen other than carbon atoms Atoms, 4 to 14-membered heterocyclic group containing 1 to heteroatoms four of the selected sulfur atom and oxygen atom, (22) phosphono group, (23) C ₆ _ ₁₄ Ariruokishi group, (24) G alkoxy - a phosphoryl group, (25) C ₆ - ₁₄ Ariruchio group, (26) a hydrazino group, (27) imino group, (28) Okiso group, (29) an ureido group, (30) C _x _ ₆ alkyl - ureido group, A group consisting of (31) a dialkyl monoureido group, (32) an oxide group, and (33) a group to which two or three groups selected from the groups (1) to (32) can be bonded (hereinafter, referred to as “ a substituent selected from abbreviated as substituent group a) which may have 1 a stone five each C ₆ alkyl group, C ₂ - ₆ alkenyl group, C ₂ - ₆ alkynyl group, C ₃ one ₆ cycloalkyl alkyl group, C ₃ - ₆ cycloalkenyl group, C ₆ one ₁₄ § aryl group or C ₇ - i ₆ Ararukiru group,  (ii) In addition to the carbon atom which may have 1 to 5 substituents selected from the substituent group A, the heteroatom contains 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms. 14-membered heterocyclic group; R ² and R ³ each represent one of the following (i) to (iii):  (i) a hydrogen atom, (Ii) the 1 a substituent selected from the substituent group A to 5 but it may also have respective ₆ alkyl group, C ₂ - ₆ alkenyl group, C ₂ _ ₆ alkynyl, C ₃ - ₆ a cycloalkyl Group, C. _ ₆ cycloalkenyl group, C ₆ _ ₁₄ § Li Ichiru group or C ₇ _ ₁₆ Ararukiru (iii) formyl, carboxy, carbamoyl, which may have 1 to 5 substituents selected from the above-mentioned substituent group A, (: ₆ alkyl-carbonyl, C ₃ _ ₆ cycloalkyl monopropionyl) , C丄_ ₆ alkoxy Ichiriki Ruponiru, C ₆ _ ₁₄ Ariru - force Lupo alkenyl, C ₇ _ ₁₆ Ararukiru Ichiriki Ruponiru, C ₆ - ₁₄ Ariruokishi - carbonyl, C 7 ^ ₆ Ararukiruokishi Ichiriki Ruponiru, in addition to carbon atoms nitrogen atom, 1 selected from sulfur atom and an oxygen atom to 3 containing heteroatoms of 5 or 6 membered heterocyclic force Ruponiru, mono- C ^ - ₆ alkyl - force Rubamoiru, di-alkyl - power resolver moil, C ₆ _ ₁₄ § Li one Lou force Rubamoiru, nitrogen atom in addition to carbon atom, to 1 is selected from the group consisting of sulfur atom you and oxygen atom containing heteroatoms three of the 5 or 6-membered ring double force Rubamoiru, C, - ₆ alkyl - Chiokaruponiru, C ₃ _ ₆ cycloalkyl over switch Sairyoku Ruponiru, (^ - 6 alkoxy - Chio force Ruponiru, C ₆ _ ₁₄ Ariru - Chiokarubo alkenyl, C ₇ _ ₁₆ Ararukiru - Chio carbonyl, ₍₆ _ ₁₄ Ariruokishi - Chio force Lupo cycloalkenyl, ₆ Ararukiruokishi one Chiokaruponiru, carbon atoms 5 or 6-membered heterocyclic thiocarbonyl, thiocarbamoyl, monono containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen

Alkyl - Chioka Rubamoiru, di - (^ - 6 alkyl one Chiokarubamoiru, C ₆ _ ₁₄ 7 Riruchiokaru Bamoiru, containing hetero atom a nitrogen atom in addition to carbon atoms, to 1 selected from sulfur and oxygen atoms to three of 5 or 6 membered heterocyclic ring Chiokarubamoiru to, Surufamo I Le, mono- CI- ₆ alkylsulfamoyl, di - C _ ₆ alkylsulfamoyl,, C ₆ - ₁₄ § reel sulfamoyl, (g ₆ alkylsulfonyl, c ₆ - ₁₄ Arirusu Ruhoniru, - 6 alkylsulfide El, C ₆ _ ₁₄ § reel sulfide El, Surufi Roh, sulfo, CI- e alkoxysulfinyl sulfinyl, C ₆ _ ₁₄ § reel O carboxymethyl sulfinyl, C WINCH ₆ alkoxysulfonyl and C 6 — I-Acsyl group selected from _4- aryloxysulfonyl; R ² and R ³ together with the adjacent carbon atom, alkyl, C ₆ _ ₁₄ Ariru, C ₇ - ₁₆ Ararukiru, Amino, mono- - 6 Arukiruamino, mono- C ₆ - ₁₄ Arirua amino, di one C ₆ Arukiruamino, di - a C ₆ one ₁₄ § Li one Ruamino and 4 to a substituent selected from the 10-membered aromatic heterocyclic group good C ₃ optionally having 1 to 3 substituents each - ₈ no cycloalkane or 3 to may form a 8-membered heterocyclic ring; R ⁴ and R ⁵ are each (i) hydrogen atom or (ii) the substituents Ru are selected from substituent group A may have five each from 1 (^ _ ₆ alkyl group, C ₂ _ ₆ an alkenyl group, C ₂ _ ₆ alkynyl, C ₃ - ₆ cycloalkyl group, C ₃ - ₆ Shikuroaruke two group, a c ₆ _ ₁₄ Ariru group or c ₇ _ ₁₆ Ararukiru group; R ⁶ and R ⁷ are each (i) a hydrogen atom or (ii) an alkyl group, a C ₂ _ ₆ alkenyl group which may have 1 to 5 substituents each selected from the aforementioned substituent group A, C ₂ - ₆ alkynyl group, C ₃ - ₆ cycloalkyl group, C ₃ - ₆ Shikuroaruke two Le group, C ₆ - i ₄ Ariru radical or C ₇ - shows a ₆ Ararukiru group, R ⁶ and R ⁷ together with the adjacent carbon atom, alkyl, C ₆ _ ₁₄ Ariru, C ₇ _ ₁₆ Ararukiru, Amino, mono- ₍₆ Arukiruamino, mono- C ₆ _ ₁₄ § Li one Rua Mino, di one (^ Arukiruamino, di one C ₆ one ₁₄ Ariruamino and 4 to 1 0-membered aromatic, 1 to substituents selected from the heterocyclic group three good C ₃ _ ₈ cycloalkane or have respectively May form a 3- to 8-membered heterocycle; R ⁸ represents one of the following (i) to (X):  (0 hydrogen atom, (ii) the, 1 to substituents selected from Substituent Group A but it may also have five each - 6 alkyl group, C ₂ - ₆ alkenyl group, C ₂ _ ₆ alkynyl, C ₃ - ₆ cycloalk kill group, C ₃ _ ₆ cycloalkenyl group, C ₆ _ ₁₄ Ariru group or C ₇ - ₁₆ Ararukiru (iii) a substituent selected from the substituent group a may have 1-5 amino acids, e mill force Rupokishi force Rubamoiru, alkyl one carbonyl, C ₃ _ ₆ cycloalkyl Ichiriki Ruponiru, ^ - ₆ alkoxy - force Ruponiru, C ₆ - ₁₄ Ariru - force Lupo alkenyl, C ₇ _ ₁₆ Ararukiru - force Ruponiru, C ₆ — ₁₄ Arlyoxy-Ruponil, C ₇ _ ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atoms, 5 or 6-membered heterocyclic carbonyl containing 1 to heteroatoms three of the selected sulfur atom and an oxygen atom, mono- C _ ₆ alkyl Ichiriki Rubamoiru di - C ₆ alkyl Ichiriki resolver moil, c ₆ _ ₁₄ § Li one Roux force Rubamoiru, 5 containing 1 to heteroatoms three of the selected nitrogen atom besides carbon atom, a sulfur atom Contact and oxygen atoms or 6 membered double ring force Rubamoiru, alkyl one Chiokaruponiru, C ₃ _ ₆ cycloalkyl over Ji Sairyoku Ruponiru, alkoxycarbonyl Kishi Chio carbonyl, C ₆ - ₁₄ § Li one Ruchiokarupo alkenyl, C ₇ _ ₁₆ § Lal kills over Chio carbonyl, C 6 ^ ₄ Ariruokishi - Chio force Lupo el, c ₇ _ ₁₆ § Lal kill O Kishi Chio carbonyl, nitrogen atom in addition to carbon atoms, or sulfur atoms and oxygen atoms 5 or 6 membered heterocyclic ring Chio carbonyl containing 1 selected to hetero atoms 3 of the, Chiokarubamoiru, mono- (^ - 6 alkyl one Chioka Rubamoiru, di C _ ₆ alkyl one Chiokarubamoiru, C ₆ _ ₁₄ § Linear or bamoyl, 5- or 6-membered heterocyclic thiocarbamoyl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, sulfamoyl, mono-C ^ 6 alkylsulfamoyl, di-C ₆ alkylsulfamoyl, C ₆ - ₁₄ § reel sulfamoyl, C - ₆ alkylsulfonyl, C ₆ - ₁₄ Arirusu Ruhoniru, alkylsulfide El, C ₆ - ₁₄ § reel sulfide El, Surufi Roh, sulfo, C i _ ₆ alkoxysulfinyl sulfide El, C ₆ _ ₁₄ § Li one Ruo carboxymethyl sulfinyl, _Ct-6 alkoxy sulfonyl and C ₄ § reel O carboxymethyl sulfonyl El from selected Ru Ashiru group,  (iv) In addition to the carbon atom which may have 1 to 5 substituents selected from the aforementioned substituent group A, including 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms, 5 to 5 14-membered heterocycle,  (v) octogen atoms, (vi) -OR ¹⁰ (R ^1Q is (i ′) a hydrogen atom, (ii,) an alkyl group optionally having 1 to 5 substituents selected from the aforementioned substituent group A, C ₂ — ₆ alkenyl group, C ₂ _ ₆ alkynyl, C ₃ - ₆ cycloalkyl group, C ₃ _ ₆ cycloalkenyl group, C ₆ _ ₁₄ Ariru group or C ₇ - ₁₆ Ararukiru group, (iii ') the substituent A , 1 to substituents selected from the group which may have five, formyl, force Rubamoiru, _ ₆ alkyl Ichiriki Ruponiru, C ₃ _ ₆ cycloalkyl Ichiriki Ruponiru, CI- ₆ alkoxy Ichiriki Ruponiru, C ₆ selected from ₁₄ Ariruokishi Ichiriki Ruponiru, c ₇ _ ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom besides carbon atom, sulfur atom and oxygen atom - _ ₁₄ Ariru - force Ruponiru, C ₇ - ₁₆ Ararukiru Ichiriki Ruponiru, c ₆ Containing 1 to 3 heteroatoms 6-membered heterocyclic ring force Ruponiru, mono - C E - ₆ alkyl Ichiriki resolver moil, di- C _i-6 alkyl - force Rubamoiru, C ₆ - ₁₄ Ariru - force Rubamoiru, nitrogen atom besides carbon atom, sulfur atom and 1 selected from oxygen atom to 3 containing terrorist atom to the 5- or 6-membered heterocyclic ring force Rubamoiru, alkyl - Chiokarupo alkenyl, C ₃ - ₆ cycloalkyl - Chiokaruponiru, C ₆ alkoxycarbonyl Kishi Chio carbonylation Le, C ₆ - ₁₄ § Li one Roux Chio local Poni Le, C ₇ _ ₁₆ Ararukiru one Chiokaruponiru, C ₆ one ₁₄ Ariruokishi one Chiokaruponiru, C ₆ § Lal Kill O Kishi Chio carbonylation Le, nitrogen atom in addition to carbon atoms, 5 or 6 membered heterocyclic containing 1 to heteroatoms three of the selected sulfur atom and an oxygen atom selected ₁₄ Ariru one Chiokarubamoiru, nitrogen atom in addition to carbon atoms, a sulfur atom Contact and oxygen atom - ring Chiokaruponiru, Chiokarubamoiru, mono- C - ₆ alkyl one Chiokarubamoiru, di - _d-6-alkyl one Chiokarubamoi Le, C ₆ 5 or 6 members containing 1 to 3 heteroatoms Ring Chiokarubamoiru, sulfamoyl, mono- C E _ ₆ alkylsulfamoyl, di-alkylsulfamoyl, C ₆ - ₁₄ § reel sulfamoyl, Al alkylsulfonyl, C ₆ _ ₁₄ § Li one Rusuruhoniru, (: E ^ alkylsulfide El, C ₆ _ ₁₄ § Li one Rusurufieru, (^ _ ₆ alkoxysulfinyl sulfide el, c ₆ - ₁₄ § Li one Ruoki Shisurufiniru, C ^ ₆ alkoxy sulfonyl and C ₆ - ₁₄ selected from § reel O carboxymethyl sulfonyl An aryl group or (ίν ') a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom which may have 1 to 5 substituents selected from the aforementioned substituent group A; Represents a 5- to 14-membered heterocyclic ring including 4), (vii) one SR ¹¹ (R ¹¹ is (ί ′) a hydrogen atom, (ii ′) an alkyl group optionally having 1 to 5 substituents selected from the aforementioned substituent group A, C ₂ _ ₆ alkenyl group, C ₂ - ₆ alkynyl group, C ₃ - ₆ cycloalkyl group, C ₃ _ ₆ cycloalkenyl group, C ₆ - ₁₄ Ariru group or C ₇ _ ₁₆ Ararukiru group, (iii ') the substituent A , 1 to substituents selected from the group which may have five, formyl, force Rubamoiru, - ₆ alkyl - force Ruponiru, C ₃ - ₆ cycloalkyl Ichiriki Ruponiru, alkoxy Ichiriki Ruponiru, C ₆ _ ₁₄ Ariru - carbonyl, 3 to 1 selected C ₇ _ ₁₆ Ararukiru Ichiriki Ruponiru, c ₆ _ ₁₄ Ariruokishi Ichiriki Ruponiru, c ₇ _ ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom besides carbon atom, a sulfur atom and an oxygen atom 5 or 6 containing a heteroatom Heterocyclic force Ruponiru, mono - C ^ ₆ alkyl Ichiriki resolver moil, di- (^ - 6 alkyl - force Rubamoiru, C ₆ - ₁₄ Ariru - force Rubamoiru, nitrogen atom besides carbon atom, selected from sulfur atom and an oxygen atom 1 to contain terrorist atom 3 of the 5 or 6-membered heterocyclic ring force Rubamoiru, CI- ₆ alkyl are - Chiokarupo alkenyl, C ₃ _ ₆ cycloalkyl over Chio, alkoxyl one Chiokarupo two Le, C ₆ _ ₁₄ Ariru - Chio carbonyl, C ₇ - ₁₆ Ararukiru one Chiokaruponiru, C ₆ _ ₁₄ Ariruokishi one Chiokaruponiru, C ₇ - ₆ Ararukiruokishi one Chiokarupo two Le, nitrogen atom in addition to carbon atoms, to 1 selected from sulfur atom and an oxygen atom 3 5 or 6 membered heterocyclic ring Chiokaruponiru containing heteroatoms of, Chiokarubamoiru, mono - C Bok ₆ alkyl chromatography Chio Scarpa Moi , Di C alkyl - Chiokarubamoi Le, C ₆ _ ₁₄ Ariru one Chiokarubamoiru, nitrogen atom in addition to carbon atoms, 5 or 6 membered multiple containing 1 to heteroatoms three of the selected sulfur atom Contact and oxygen atoms Ring Chiokarubamoiru, sulfamoyl, mono - C i _ ₆ alkylsulfamoyl, di - - 6 alkylsulfamoyl, C ₆ _ ₁₄ § reel sulfamoyl, _d-6 Al alkylsulfonyl, c ₆ - ₁₄ § Li one Rusulfonyl, ₆ alkylsulfinyl, c ₆ An acyl group selected from -14 arylsulfiel, C ^ 6 alkoxysulfinyl, C ₆ _ ₁₄ aryloxysulfinyl, — 6 alkoxysulfonyl and C ₆ _ ₁₄ aryloxysulfonyl, or (iv,) the substituent A A 5- to 14-membered heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to 1 to 5 carbon atoms which may have 1 to 5 substituents selected from the group) , (viii) -S (O) R 12 (R 12 is, (i,) said a substituent selected from the substituent group A may have 1 a stone five each C _ ₆ alkyl group, C ₂ _ ₆ alkenyl group, C ₂ _ ₆ alkynyl group, c ₃ _ ₆ cycloalkyl group, c ₃ _ ₆ cycloalkenyl group, c ₆ - ₁₄ § aryl group or C ₇ _ ₁₆ Ararukiru group or (ii ') the location selected from the substituent group A substituent A 5- to 14-membered heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have 1 to 5), (ix) -S (O) ₂ R ¹³ (R ¹³ is (ί ′) a substituent described above. The C _ ₆ alkyl group and the C ₂ _ ₆ alkenyl group each having 1 to 5 substituents selected from the group A C ₂ _ 6 alkynyl group, a C ₃ _ ₆ cycloalkyl group, a C ₃ _ ₆ cycloalkenyl group, a C ₆ _ ₁₄ T reel group or a C ₇ _ ₁₆ aralkyl group or (ii ') a substituent selected from the group A Heteroatom selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom which may have 1 to 5 substituents (Shows a 5- to 14-membered heterocyclic ring containing 1 to 4 atoms), (X) -NR ¹⁴ R ¹⁵ (R ¹⁴ and R ¹⁵ are each a (i ′) hydrogen atom, and (ii ′) the substituent A group 1 a substituent selected to 5 have may d_ ₆ Al kill group having respectively, C ₂ _ ₆ alkenyl, C ₂ one ₆ alkynyl group, C ₃ - ₆ cycloalkyl group, C ₃ - ₆ cycloalkenyl group, C ₆ _ i ₄ § Li Ichiru group or C ₇ -! ₆ Ararukiru group, (out) 'a substituent selected from the substituent group a may have 1-5 amino acids, formyl, power Rubamoiru, - 6 alkyl Ichiriki Ruponiru, C ₃ - ₆ cycloalkyl - carbonyl, alkoxy - force Ruponiru, C ₆ _ ₁₄ Ariru Ichiriki Ruponiru, C ₇ _ ₁₆ Araruki Lou force Ruponiru, C ₆ _ ₁₄ Ariruokishi - power Ruponiru , C ₇ - ₁₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atom, a sulfur atom 1, which is selected from the group consisting of and oxygen atom To 3 containing heteroatoms of 5 or 6 membered heterocyclic force Ruponiru, mono- C _ ₆ alkyl - force Rubamoiru, di _ C _i-6 alkyl - force Rubamoiru, C ₆ one ₁₄ Ariru - force Rubamoiru, carbon atoms Besides, a 5- or 6-membered heterocyclic compound having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, rubamoyl, _ ₆ alkyl monothiocarbonyl, C ₃ _ ₆ cycloalkyl-thiocarbonyl, an alkoxy - Chiokaruponiru, c ₆ _ ₁₄ Ariru - Chio carbonyl, c ₇ _ ₁₆ Ararukiru - Chi Sairyoku Ruponiru, C ₆ _ ₁₄ Ariruokishi one Chiokaruponiru, C ₇ ^ ₆ Ararukiruoki Sich Sairyoku Ruponiru, nitrogen atom in addition to carbon atoms, 5- or 6-membered heterocyclic thiocarbonyl containing 1 to 3 heteroatoms selected from sulfur and oxygen, Bruno - C _i-6 alkyl one Chiokarubamoiru, di - C doctor ₆ alkyl one Chiokarubamoiru, (: ₆ _ ₁₄ Ariru one Chiokarubamoiru, nitrogen atom in addition to carbon atoms, 3 to 1 selected from sulfur and oxygen atoms 5- or 6-membered heterocyclic thiocarbamoyl, sulfamoyl, mono-alkylsulfamoyl, di--6-alkylsulfamoyl, C ₆ _ ₁₄ arylsulfamoyl, (: to _6- alkylsulfonyl, C ₆ _ ₁₄ § Li one Rusuruhoniru, (^ _ ₆ alkylsulfinyl Finiru, C ₆ - ₁₄ § Li one Rusurufiniru, C ₆ alkoxysulfinyl sulfinyl, c ₆ _ _{1 4} § Li one Ruo alkoxy sulfinyl, CL_ ₆ alkoxysulfonyl Oyobi C ₆ _ ₁₄ § Li one Ruo alkoxy sulfo Ashiru group selected from alkylsulfonyl or (ϊν ') wherein, 1 to substituents selected from the substituent group A 5 Yes A 5- to 14-membered heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may be substituted) R ⁹ is (i) a hydrogen atom, (ii) a cyano group, (iii) said, 1 to substituents selected from the substituent group A may have five each C - ₆ alkyl group, C ₂ - ₆ alkenyl group, C ₂ - ₆ alkynyl group, C ₃ _ ₆ Shikuroa alkyl group, C ₃ - ₆ cycloalkenyl group, C ₆ _ ₁₄ Ariru group or C ₇ _ ₁₆ Araruki group, (iv) said, 1 to substituents selected from the substituent group A may have five, formyl, force Rupokishi, Karupamoiru, C ^ ₆ alkyl Ichiriki Ruponiru, C ₃ _ ₆ Shikuroa alkyl - Power Ruponiru , Alkoxy one-pot Ronil, C ₆ _ ₁₄ aryl-carboni Le, ₍₇ _ ₁₆ Ararukiru one carbonyl, C ₆ _ ₁₄ 7 Riruokishi Ichiriki Ruponiru, C ₇ _ 1 ₆ Ararukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atoms, to 1 selected from sulfur atom and oxygen radicals 3 pieces containing heteroatoms of 5 or 6 membered heterocyclic force Ruponiru, mono- - 6 alkyl Ichiriki Rubamoiru, di - C i _ ₆ alkyl - force Rubamo i le, C ₆ _ ₁₄ Ariru - force Rubamoiru, other than carbon atoms nitrogen atom, a sulfur atom Oyo to 1 selected from beauty oxygen atom containing heteroatoms three of the 5 or 6-membered heterocyclic ring force Rubamoiru, C i_ ₆ alkyl chromatography Chio carbonyl, C ₃ _ ₆ cycloalkyl over Chio in power Ruponiru, d-6 alkoxy - Chio force Ruponiru, C ₆ _ ₁₄ Ariru - Chiokarupo two Le, C ₇ _ ₁₆ Ararukiru - Chiokaruponiru, C ₆ _ ₁₄ § Li one Ruokishichi Sairyoku Lupo two Le, c ₇ _ ₁₆ Rarukiruokishi - Chio carbonyl, nitrogen atom in addition to carbon atom, a sulfur atom and 1 to 5 or 6-membered heterocyclic ring Chio carbonyl containing heteroatoms three of the selected oxygen ll child, Chiokarubamoiru, mono one ₍₆ alkylene Ruchiokaru Bamoiru, di - - 6 alkyl - Chiokarubamoiru, C ₆ _ ₁₄ Ariru - containing heteroatoms Chiokaruba moil, nitrogen atom in addition to carbon atoms, to 1 selected from sulfur and oxygen atoms to three of 5 or 6-membered heterocyclic ring Chiokarubamoiru, Surufamoi Le, mono- CI- ₆ alkylsulfamoyl, di-alkylsulfamoyl, c ₆ _ ₁₄ § reel sulfamoyl, ₆ alkylsulfonyl, c ₆ _ ₁₄ Arirusu Ruhoniru, alkylsulfinyl, C ₆ - ₁₄ § reel sulfide El, Surufi Roh, sulfo, C i _ ₆ Arukokishisuru Iniru, C ₆ _ ₁₄ § Li - Ruo alkoxy sulfinyl, alkoxysulfonyl and C ₆ one ₁₄ § Li one Ruo carboxymethyl sulfonyl from Ru selected Ashiru group or, (v) Equation 1〇R ⁹ , (R ⁹ 'is a ① hydrogen atom, ② The 1 a substituent selected from the substituent group A to 5 may have respective CI- 6 alkyl group, C ₂ _ ₆ alkenyl, C ₂ - ₆ alkynyl group, C ₃ _ ₆ cycloalkyl Le group , C ₃ - ₆ cycloalkenyl group, C ₆ - ₁₄ Ariru group or 〇 ₇ _ ₁₆ Ararukiru group or, ③ a substituent selected from the substituent group A may have 1-5 amino acids, formyl, force Rubamoiru, C丄- ₆ alkyl Ichiriki Ruponiru, C ₃ _ ₆ cycloalkyl Ichiriki Ruponiru, Ci- ₆ alkoxy - force Ruponiru, C ₆ - ₁₄ § Li one Roux force Ruponiru, 〇 ₇ __ ₁₆ Araruki Lou force Ruponiru, C ₆ _ ₁₄ Ariruokishi Ichiriki Ruponiru, C ₇ _i ₆ Ararukiruokishi one carbonyl, nitrogen in addition to carbon atoms atom, 1 selected from sulfur atom and an oxygen atom to 3 for containing heteroatoms 5 or 6-membered heterocyclic ring force Ruponiru, mono- alkyl Ichiriki Rubamoiru, di alkyl Ichiriki Rubamoiru, (: ₆ _ ₁₄ Ariru - power Rubamoiru, nitrogen atom in addition to carbon atoms, 1 selected from sulfur atom and an oxygen atom to 3 containing heteroatoms of 5 or 6 membered heterocyclic force Rubamoiru, Al kills over Chio carbonyl, C ₃ _ ₆ cycloalkyl over Chio carbonyl, alkoxy sea Chio carbonyl, C ₆ _ ₁₄ Ariru - Chio carbonyl, C ₇ _ ₁₆ Ararukiruchi Okaruponiru, c ₆ _ ₁₄ § Ruokishi one Chiokaruponiru, c ₇ - ₁₆ Ararukiruoki Sich Sairyoku Ruponiru, nitrogen atom in addition to carbon atom, a sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic ring Chiokaruponiru selected from oxygen atom, Ji old power Rubamoiru, mono - ^ - ₆ alkyl - Chiokarubamoiru, di - C Bok ₆ alkyl one Chiokarubamoiru, C ₆ - ₁₄ Ariru one Chiokarubamoiru, nitrogen atom in addition to carbon atoms, to 1 selected from sulfur atom and an oxygen atom 3 pieces of the containing hetero atoms 5 or 6-membered heterocyclic ring Chiokarubamoiru, sulfamoyl, mono- Arukirusu Rufamoiru, di - C doctor ₆ alkylsulfamoyl, C ₆ _ ₁₄ § reel sulfamoyl Le, (^ _ ₆ alkylsulphonyl, C ₆ _ ₁₄ § reel sulfonyl, CI- ₆ alkylsulfinyl Finiru, C ₆ _ ₁₄ § Li one Rusurufini , Alkoxysulfinyl sulfinyl, C ₆ _ _{x 4} § reel O carboxymethyl sulfide El, E alkoxysulfonyl and C ₆ - ₁₄ Ari Ruo carboxymethyl sulfonyl shows a Ashiru group selected from) a group represented by;  X is ①a methylene group which may have a substituent selected from the above-mentioned substituent group A or ②a carbonyl group;  4. The compound according to claim 3, wherein n represents 0 or 1. 5. The compound according to claim ^{3, wherein} R ² and R ³ each represent a —6 alkyl group. 6. The compound according to claim 3, wherein R ⁴ and R ⁵ each represent a hydrogen atom. 7. The compound according to claim 3, wherein R ⁶ and R ⁷ each represent a C i- ₆ alkyl group. 8. The compound according to claim 3, wherein R ⁹ represents a hydrogen atom. 9. The compound according to claim 3, wherein n represents 0. 10. R ¹ is the formula

Wherein, R ¹⁶ is a hydrogen atom, which may have a substituent C ₆ - ₁₄ Ariru group, an optionally substituted amino group, heterocyclic group which may have a substituent R ² and R ³ each represent an alkyl group, R ⁴ and R ⁵ each represent a hydrogen atom, and R ⁶ and R ⁷ each represent (a ₆ alkyl group; and R ⁸ represents a halogen atom). 4. The hydrogen atom or —〇R ^1Q (R ^1Q represents a hydrogen atom, an alkyl group or an acyl group which may have a substituent), R ⁹ represents a hydrogen atom, and n represents 0. Compounds. 11. R ^1Q represents (1) a hydrogen atom, (2) an alkyl group optionally substituted with pyridyl, or (3) an halogen atom-substituted 6-alkylsulfonyl, R ¹⁶ represents (1) hydrogen atom, (2) phenyl substituted with Asechiruamino group, ωω · ^ - ₆ Arukirusu Ruhoniru group, (ii) pyridinium Zirka Lupo cycloalkenyl or (iii) sulfamoyl - optionally mono- or di-substituted with a substituent selected from ₆ alkyl Le group 11. The compound according to claim 10, wherein the compound represents (4) a pyridyl or (5) an octagen atom. 12. A prodrug of the compound of claim 3. 13. Expression

[Wherein, R ¹⁷ represents a vinyl group or an aryl group which may have a substituent] or a compound having a partial structure represented by the formula: R ¹ — CN [Wherein R ¹ has the same meaning as in claim 2] or a salt thereof.

[Wherein, R ¹ has the same meaning as described above] or a salt thereof.  1 4. Expression

 [Wherein each symbol is as defined in claim 3] or a salt thereof, and a compound represented by the formula R i — C N [Wherein, R ¹ has the same meaning as described in claim 3] or a salt thereof.  1 5 Expression

[Wherein, represents a single bond or a double bond]. A pharmaceutical composition comprising a compound having a partial structure represented by the following formula or a salt thereof. 1 6 Expression '

^{Wherein, R 2 ,, R 3 ',} R 6' and R ^7, each represents an alkyl group, R ¹⁶ 'is hydrogen atom, which may have a substituent C _{6 14} Ariru group, a substituent Which may have an amino group, a heterocyclic group which may have a substituent or a halogen atom], or a salt thereof.  17. A pharmaceutical composition comprising the compound according to claim 3, a salt thereof, or a prodrug thereof.  18. Expression

[Wherein represents a single bond or a double bond] a phosphodiesterase IV inhibitor _c comprising a compound having a partial structure represented by 19. Expression

[In the formula,-represents a single bond or a double bond.] Inflammatory disease, asthma, chronic obstructive pulmonary disease, chronic joint disease containing a compound having a partial structure represented by Prevention and treatment of rheumatism, autoimmune diseases, depression, Alzheimer's dementia, memory impairment, diabetes or arteriosclerosis.  20. The pharmaceutical composition according to claims 15 to 17, which is a phosphodiesterase IV inhibitor.  21. The preventive or therapeutic agent for inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis. Pharmaceutical composition.  22. Formula for mammals

 [Wherein, represents a single bond or a double bond]. A method for inhibiting phosphodiesterase IV, which comprises administering an effective amount of a compound having a partial structure represented by the formula or a salt thereof.  23. Formula for mammals  '

^{Wherein, R 2 ,, R 3 ',} 6' Oyobi 1 ^ ⁷ 'are each (: ₁₆ Arukiru group, R ^16' is hydrogen atom, which may have a substituent C ₆ _ ₁₄ 7 aryl group, an optionally substituted amino group, a compound having a partial structure represented by the substituted showing also heterocyclic group or a halogen atom] or effective salt thereof Characterized by administering an amount A method for inhibiting phosphodiesterase IV.  2 4. Formula for mammals

 [Wherein, represents a single bond or a double bond]. An inflammatory disease, asthma, chronic obstructive disease characterized by administering an effective amount of a compound having a partial structure represented by Prevention and treatment of lung disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory impairment, diabetes or arteriosclerosis.  2 5. Formula for mammals

[Wherein, R ² , R ³ , R ⁶ , and R ⁷ ′ are each a ₆ alkyl group, R ¹⁶ is a hydrogen atom, a C _{6 14} aryl group which may have a substituent, Represents an amino group which may have a substituent, a heterocyclic group which may have a substituent or a halogen atom), or an effective amount of a compound having a partial structure represented by or a salt thereof. Characteristic Prevention and treatment of inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory impairment, diabetes or arteriosclerosis. 26. Formula for producing phosphodiesterase IV inhibitors

 [Wherein, n ^ z represents a single bond or a double bond] or a salt thereof.  2 7. Formula for producing a preventive / therapeutic agent for inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory disorder, diabetes or arteriosclerosis.

 [Wherein, ZJ! Represents a single bond or a double bond] or a salt thereof.  2 8.

(Wherein, R ^2a and R ^3a each represent an aliphatic hydrocarbon group which may have a substituent, R ^4a and R ^5a each represent a hydrogen atom or a hydrocarbon group which may have a substituent, R ^{6 a} and R ^{7 a} represents a respectively hydrogen atom or an optionally substituted hydrocarbon group, R ^{6 a} and R ^{7 a} may have a substituent together with the adjacent carbon atoms 3 What May form an 8-membered ring, R ^8a represents (1) a hydrogen atom, (2) a hydrocarbon group optionally having a substituent, (3) an acyl group, (4) a heterocyclic group optionally having a substituent, ) A halogen atom, (6) -OR ^10a (R ^1Qa represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), (7) -SR ^lla (R ^lla represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent), (8) — S (0) R ^12a (R ^12a represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent), (9) one S (〇) ₂ R ^13a (R ^13a is have may have a substituent a hydrocarbon group or a substituent shown also heterocyclic group) or ^{(10) -NR 14a R 15a (} R 1 4 a and R ^15a has a hydrogen atom and a substituent, respectively. A hydrocarbon group, an acyl group or a heterocyclic group which may have a substituent). R ^9a represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxyl group which may have a substituent] or a salt thereof.