WO2001012608A1

WO2001012608A1 - Quinoline compounds and process for producing the same

Info

Publication number: WO2001012608A1
Application number: PCT/JP2000/005497
Authority: WO
Inventors: Nobuhiro Umeda; Kunihito Ito; Seiichi Uchida; Yasuyuki Shiinoki
Original assignee: Nippon Soda Co., Ltd.
Priority date: 1999-08-18
Filing date: 2000-08-17
Publication date: 2001-02-22
Also published as: AU6593700A

Abstract

Novel quinoline compounds which are useful as cGMP-specific phosphodiesterase (PDE) inhibitors and salts thereof. More particulary, quinoline compounds represented by general formula (1) and pharmaceutically acceptable salts thereof wherein R1 represents nitro, cyano, halogeno, etc.; m is 0or an integer of from 1 to 4; R?2 and R3¿ represent each hydrogene etc.; R4 represents hydrogen, C¿1-6? alkyl, optionnally substituted phenyl, an optionally substituted saturated or unsaturated heterocycle, etc.; and R?5¿ represents an optionally substituted saturated or unsaturated heterocycle bonded to the quinoline ring via a carbon atom in the cycle.

Description

Specification

Quinoline compound and method for producing the same

Technical field :

The present invention relates to a novel quinoline compound useful as a cGMP-specific phosphodiesterase (PDE) inhibitor, a salt thereof, and a method for producing the same.

Background art:

c GMP is a substance that plays an important role as a second messenger in the signal transduction pathway in the living body, and its degrading enzyme, c GMP-specific phosphodiesterase (PDE) inhibitor, inhibits intracellular c GMP Increases concentration, for example, hypertension, heart failure, myocardial infarction, angina, arteriosclerosis, restenosis after PTCA, cardiac edema, pulmonary hypertension, renal failure, renal edema, liver edema, asthma, bronchitis, dementia It is useful for prevention and Z or treatment of immunodeficiency, glaucoma or impotence.

Examples of the 4-benzylamino quinoline derivative similar to the compound of the present invention include Ukrainskii K himicheskii Z hurnal, 37 (3), 26 3-26 5 (1 97 l); Kimiia G eterotsiklicheskikn S oedinenii, (7), 976-978 (1975); U krainskii K himicheskii Zhurnal, 4 2 (1 0), 1 1 0 8-1 1 0 9 (1 9 7 6) ; K himiia G eterotsiklicheskikn S oedinenii, (2), 22 1 — 22 3 (199 0); WO 93/0721 24 Compounds having a group are described. Further, W093 / 07124 discloses that it has a cGMP PDE inhibitory effect. However, as in the compound of the present invention, a compound in which the substituent at the 2-position of the quinoline ring is a heterocyclic group and is bonded to a carbon atom constituting the heterocycle, and a compound at the 2-position of the quinoline ring Is not known. Disclosure of the invention:

An object of the present invention is to provide a novel quinoline compound useful as a medicament, a pharmaceutically acceptable salt thereof, and a method for producing the same.

The present invention provides: (a) a compound represented by the general formula (1):

(In the formula, R ^1, the double Bok port group, Shiano group, a halogen atom, - ₆ alkyl group, C ₆ alkoxy group, C ₁ -! ₆ haloalkyl group, C _ ₆ haloalkoxy group, C ₆ alkylthio group, - ₆ alkyl sulphates enyl groups, C i alkylsulfonyl groups, C i ₆ alkylcarbonyl group, hydroxycarboxylic carbonyl groups, C alkoxycarbonyl group or C ₆ properly even mono alkyl group may be disubstituted force, Represents a rubamoyl group.

m represents 0 or an integer of 1 to 4. When m represents an integer of 2 or more, R ¹ may be the same or different.

R ^2, R ³ are each independently a hydrogen atom, arsenic Dorokishi group, a halogen atom, C ^ ₆ § alkyl group, - ₆ alkoxy groups, C - 6 haloalkoxy group or an optionally substituted phenylene le radical Represents

R ⁴ is a hydrogen atom, C ₆ alkyl group, C _{3 8} cycloalkyl group, an optionally substituted off Eniru group, base may be substituted Njiru group or an optionally substituted N, 0 is also properly S, Represents a saturated or unsaturated heterocyclic group containing 1 to 4 atoms.

R ⁵ is a saturated or unsaturated heterocyclic group containing 1 to 4 optionally substituted N, 0 or S atoms, which is bonded to a quinoline ring at a ring carbon atom; Or

Expression

A: C (= 0) r ¹ , B: CH = CH CO r ^] , C: (CH ₂ ) _n C 0 r ¹

Wherein, r ¹ is a hydrogen atom, arsenic Dorokishi group, - ₆ alkoxy groups, optionally substituted off enoxy group, which may be substituted base Njiruokishi group, C ₃ _ ₈ cycloalkyl group, optionally substituted good phenyl group, also can properly be N, 0 substituted heterocyclic group of saturated or unsaturated containing one to four S atoms or wherein N r ² r ³

(Gamma ² is a hydrogen atom or a C E -s alkyl group, r ³ is a hydrogen atom, C IS alkyl group properly is Yoi § Mi amino group may be mono- also Shikuwaji substituted with formyl, C — S alkoxy group, C

₃ - ₈ cycloalkyl group, C ^ ₆ alkoxycarbonyl which may be substituted with a group C ₆ alkyl group, a substituted or unsubstituted phenyl group, base may be substituted Njiru group, an optionally substituted N,

Represents a saturated or unsaturated heterocyclic group containing 1 to 4 0 or S atoms, or r ² And r ³ together form one CH ₂ CH ₂ YCH ₂ CH _{2 —} (Y is 0 CH ₂ or N r ⁴ <r ⁴ is a hydrogen atom, ₆ alkyl group, phenyl group which may be substituted or Represents a benzyl group which may be substituted.> Represents a group represented by the following formula: )

n represents 1, 2 or 3. Represents a group selected from

However, when R ² = R ³ = H and R ⁴ are phenyl groups, m = 0. }

And a pharmaceutically acceptable salt thereof,

(b) General formula (2)

(Wherein, R i, R ⁵ and m represent the same meaning as described above, and X represents a halogen atom.) And a compound represented by the general formula (3):

(Wherein, R ² R 3 and R ⁴ have the same meanings as described above). A process for producing a compound represented by the general formula (1), characterized by reacting , and

(c) General formula (l a)

(Wherein R i R2, R3, R ⁴ and m represent the same meaning as described above) and a compound represented by the general formula (5):

H-N, 5)

(Wherein, r ² r ³ represents the same meaning as described above).

(Wherein, R i, R ² , R 3, R ⁴ , r 2, _r 3 and _m have the same meanings as described above).

Embodiment of the invention:

In the compound of the present invention, R ¹ represents a nitro group, a cyano group, a halogen atom such as fluorine, chlorine, bromine, etc .; ₆ alkyl group, main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, C _ ₆ alkoxy groups, such as t one-butoxy, chloromethyl, dichloromethyl, Bok Li click port Romechiru, Furuoromechiru, Jifuruoromechiru, Application Benefits Furuoromechiru, 1 one Furuo Roechiru , 1, 1 difluoroethyl, pentafluoroethyl, etc., C _1-6 haloalkyl group, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1 — Fluoroethoxy, 1, 1—difluoret Cix- ₆ haloalkoxy groups such as xyl, 1, 1, 1-trifluoroethoxy, Cj- ₆ alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, methylsulfenyl, E chill sulphates enyl, Bro Pils Ruff enyl, I isopropyl sulphates enyl, Petit Rusuru phenylalanine, C E, such as t one Puchirusurufue sulfonyl - ₆ § Rukirusurufue group, methylsulfonyl, Echirusuruhoniru, propylsulfonyl, I C alkyl sulfonyl groups such as isopropylsulfonyl, butylsulfonyl, and t-butylsulfonyl; and C i- ₆ alkylcarbonyl groups such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, and t-butylcarbonyl. , Hi Butyloxycarbonyl group, main butoxycarbonyl, ethoxycarbonyl, propoxy-carbonyl, Lee Seo propoxycarbonyl, butoxycarbonyl, C丄such t one butoxycarbonyl - ₆ alkoxycarbonyl group, methyl, Echiru, propyl, isopropyl, Petit Le, Isopuchiru, s —Indicates a carbamoyl group that may be mono- or di-substituted by Ci- ₆ alkyl groups such as butyl and t-butyl.

R ² and R ³ are each independently a hydrogen atom, a hydroxy group, fluorine, chlorine, bromine, etc. Halogen atom, Ci- ₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, etc., methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc. C i _ ₆ alkoxy group, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1 difluoroethoxy, 1,1,1-difluoroethoxy the ci- ₆ haloalkoxy group or a (any position, such as Application Benefits off Ruoroe butoxy, ci _ ₆ such as fluorine, chlorine, a halogen atom such as a bromine, methyl, C alkyl radical or main butoxy such Echiru, Etoki sheet Alkoxy group, chloromethyl, dichloromethyl, trichloromethyl, full Oromechiru, Jifuruoromechiru, may be substituted with ci _ ₆ haloalkyl group such as Application Benefits Furuoromechiru) represents a phenylene Le group.

R ^2, R ³ is a hydrogen atom or - ₆ alkyl group is preferable.

R ⁴ is a hydrogen atom, methyl, Echiru, propyl, i an isopropyl, heptyl, Isopuchiru, s - heptyl, C, such as t one-butyl i - ₆ alkyl group, cyclopropyl, cyclopentyl, C _3, such as cyclohexyl cyclo - ₈ cycloalkyl group, (in any position, fluorine, chlorine, a halogen atom such as bromine, methyl, C i _ ₆ alkyl group or main butoxy, C alkoxy group such as ethoxy, such Echiru, chloromethyl, dichloromethyl, DOO Phenyl group (which may be substituted with Ci- ₆ haloalkyl group such as chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.) (halogen atom such as fluorine, chlorine, bromine, etc., methyl, ethyl, etc. at any position) C i _ ₆ alkyl or main butoxy a, C i, such as ethoxy - ₆ alkoxy group, black Methyl, dichloromethyl, Application Benefits chloromethyl, Furuoromechiru, Jifuruoromechi Le, preparative may be substituted with C _ ₆ haloalkyl group such as Li Furuoromechiru) benzyl group, the or the (arbitrary position, fluorine, chlorine, such as bromine halogen atoms, such as methyl, Echiru C i -! ₆ alkyl group or main butoxy, C _ ₆ alkoxy group such as ethoxy, chloromethyl, di- chloromethyl, preparative Rikuroromechiru, Furuoromechiru, Jifuruoromechiru, etc. Application Benefits Furuorome chill C - ₆ (It may be substituted with a haloalkyl group.) It represents a saturated or unsaturated heterocyclic group containing 1 to 4 N, 0 or S atoms such as furyl, phenyl, pyrrolyl, pyridyl, 1,3-dioxindanyl and the like.

R ⁵ is a saturated or unsaturated heterocyclic group containing 1 to 4 optionally substituted N, 0 or S atoms bonded at a ring carbon atom, or a formula

^{A: C 0 r 1, B} : CH = CHCO r, C:! (CH ¾) n C 0 r 1 [Wherein, r ¹ represents a hydrogen atom, a hydroxy group, a C ₆ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc., (fluorine, chlorine, bromine And C ₆ alkyl groups such as methyl and ethyl or C ₆ -alkoxy groups such as methoxy and ethoxy, and C haloalkyl groups such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, and trifluoromethyl. which may be) phenoxy group, base may be substituted Njiruokishi group, cyclopropyl, cyclopentyl, C ₃ of heptyl and the like cyclohexyl, the cycloheteroalkyl - _s cycloalkyl group, (in any position, fluorine, chlorine, bromine Such as halogen atoms, C alkyl groups such as methyl and ethyl, or ! Main butoxy, C, such as e butoxy - ₆ alkoxy group, chloromethyl, dichloromethyl, Application Benefits chloromethyl, Furuoromechiru, Jifuruoromechiru, C i _ ₆ Roh etc. Application Benefits Furuoromechiru may be substituted with a mouth alkyl) phenyl group, also is properly good N, 0 substituted heterocyclic group, saturated or unsaturated containing one to four S atoms or wherein N r ² r ³

(Gamma ² is a hydrogen atom or a methyl, a C alkyl group such Echiru, r ³ is a hydrogen atom, methyl, mono also is properly in C i-e alkyl group may properly formyl groups such Echiru disubstituted Moyoi § Mi amino group, main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, C i _ ₆ alkoxy groups, such as t-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, to cyclo hexyl, cyclohexane heptyl, Shikurookuchiru etc. C ₃ _ ₈ cycloalkyl group, main butoxycarbonyl, optionally substituted with C _i-6 alkoxycarbonyl groups such as ethoxycarbonyl C - s alkyl group, (in any position, fluorine, chlorine, such as bromine ₆ alkyl group or main butoxy, C丄such ethoxy - _- halogen atom, methyl, C ₁ such Echiru ₆ alkoxy group, click port b It may be substituted by a C-6 haloalkyl group such as methyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.) A phenyl group, a benzyl group, or an optionally substituted N, 0 or Represents a saturated or unsaturated heterocyclic group containing 1 to 4 S atoms, or r ² and r ³ together form one CH ₂ CH ₂ YCH ₂ CH ₂ —

(Y is 0, CH ₂ or N r ⁴ <r ⁴ is a hydrogen atom, methyl, ethyl, propyl, isopyl, butyl, t-butyl, etc., a C- ₆ alkyl group or (fluorine at any position chlorine, a halogen atom such as bromine, methyl, C ^ such Echiru - ₆ alkyl group or main butoxy, C, such as ethoxy carboxymethyl - ₆ alkoxy group, chloromethyl, dichloromethyl, Application Benefits chloromethyl, full Ruoromechiru, Jifuruoromechiru , Trifluoromethyl, etc. may be substituted with a Ci- ₆ haloalkyl group.) Represents a phenyl group or a benzyl group.>). You may. )

n represents 1, 2 or 3. Represents a group selected from

Is a heterocyclic group in the definition of R ^5, furyl group, thienyl group, pyrosulfate Lil group, Te preparative La arsenide Dorofu Lil group, Te Torahi Dorocheniru group, pyrrolidone Jiniru group, Lee Mi Dazoriru group, Okisazo Lil group, thiazolyl Group, pyrazolyl group, isooxazolyl group, isothiazolyl group, oxadiazolyl group, thiadiazolyl group, pyridyl group, piperidyl group, viranyl group, thiavinylil group, pyrimidinyl group, pyridazinyl group, virazinyl group, piperazinyl group, It represents a morpholyl group, a benzimidazolyl group, a quinolyl group, a benzisocylyl group, a methylenedioxyphenyl group, etc., and these heterocyclic groups can be substituted at any position by a cyano group, a nitro group, an amino group, Chill, ethyl, propyl, isopropyl, butyl, isoptyl, s-butyl Le, C _i-6 alkyl group such as a t one-butyl, main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, C _i-s alkoxy group such as t one-butoxy, chloromethyl, dichloromethyl, Application Benefits chloromethane chill, Furuoromechiru, C _ ₆ haloalkyl groups such as difluoromethyl, trifluoromethyl, and the formula C (= 0) 0 r ⁴ or C (= 〇) N r ⁵ r 6 (where r ⁴ , r ⁵ , and r ⁶ are hydrogen atoms Or a Ci- ₆ alkyl group such as methyl, ethyl, propyl, isopropyl, isobutyl, isobutyl, s-butyl, t-butyl, etc.). Examples of the pharmaceutically acceptable salts include salts of compounds represented by the general formula (1) with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and acetic acid, propionic acid, lactic acid, succinic acid, and the like. Salts of organic acids such as tartaric acid, cunic acid, benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid can be mentioned.

The method for producing the compound of the present invention will be described below.

Manufacturing method 1

(Wherein, R 1, R 2, R 3, R 4, R 5, _m and X have the same meanings as described above.) The target compound (1) is prepared by compound (2) and compound (2) in a solvent. 3) and the reaction temperature 10

It can be obtained by reacting at 00 ° C. The solvent is not particularly limited as long as it is an inert solvent for the reaction. Examples of the solvent include alcohols such as methanol, ethanol and n-butanol, ethers such as dioxane, and benzene, toluene and xylene. Aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like can be used.

Also, by adding a tertiary amine such as triethylamine, favorable results may be obtained.

Production method 2 Production of compounds in which R ⁵ is a carboxylic acid derivative

The compound (la) is reacted in a solvent such as water, alcohols such as methanol and ethanol, in the presence of an inorganic base such as sodium hydroxide, at a reaction temperature of 10 to 100 ° C. Thus, the compound (lb) is produced.

Compound (1c) can be produced by subjecting compound (lb) and compound (5) to dehydration condensation by a conventional method.

This dehydration condensation reaction is performed in the presence of a suitable condensing agent. In this case, as the condensing agent, for example, 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminobutyryl) -13-ethylcarbodiimide hydrochloride, 2-ethoxy-11-ethoxycarbodium Two-way 1,2-dihydroquinoline.

In addition, N-hydroxysuccinic acid imid, 1-hydroxybenzotriazole, 3,4-dihydroxy 3-hydroxy-4,1-oxo-1,2,3-benzotriazine were added to this reaction system. By coexisting the above, the reaction can proceed more quickly. The reaction solvent is not particularly limited as long as it is an inert solvent for the reaction. Examples thereof include ethers such as methyl ether, tetrahydrofuran (THF), 1,4-dioxane, benzene, and toluene. And aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, DMSO, pyridine, etc.

The reaction temperature ranges from 115 ° C to the boiling point of the solvent, preferably from 0 to 80 ° C.

Production Method 3 Production of a compound in which R ⁵ is a heterocycle.

If 3- 1 R ⁵ is 1, 2, 4 one Okisajiazo one rule 5 I le group.

Compound (Id) can be obtained by reacting compound (la) with 1- (hydroxyimino) alkylamine in a solvent at a reaction temperature of 10 to 150 ° C in the presence of a base.

Examples of the solvent include ethers such as diethyl ether, THF, 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, 1,2-dichloroethane, and the like. Halogenated hydrocarbons, acetate nitrile, DMF, DMSO and the like can be used.

Examples of the base include alkali metal alkoxides such as sodium methoxide and potassium t-butoxide, triethylamine, N, N-dimethylylaniline, pyridine, 1,8-diazabicyclo [5.4.0 Organic bases such as ndenecene-17 (DBU), metal hydrides such as sodium hydride, and inorganic bases such as potassium carbonate and sodium hydroxide are used.

In addition, more favorable results may be obtained by adding a molecular sieve.

3-2 When R 5 is 1,3,4-oxodiazo-2-yl group

Compound (le) is produced by reacting compound (la) with hydrazine monohydrate in a solvent at a reaction temperature of 10 to 150 ° C.

Examples of the solvent include alcohols such as methanol, ethanol, and n-butanol; ethers such as getyl ether, THF, 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane; Halogenated hydrocarbons such as form and 1,2-dichloroethane, acetonitril, DMF, DMSO and the like can be used.

Next, the compound (le) is reacted with trimethyl orthoformate at a reaction temperature of 10 to 150 ° C in the presence of an organic acid such as acetic acid or P-toluenesulfonic acid to form the compound (1 （). ) To manufacture.

3—3 If R 5 is a 5-year-old

Compound (la) is reacted with diisobutylaluminum hydride in a solvent such as ether such as getyl ether, THF, and 1,4-dioxane at a reaction temperature of 80 to 20 ° C to obtain a compound ( lg).

Next, compound (Ih) can be produced by reacting compound (lg) with p-toluenesulfonylmethyl isocyanide in a solvent in the presence of a base at a reaction temperature of 10 to 150 ° C. Monkey

As the solvent, alcohols such as methanol, ethanol, and n-butanol, acetonitril, DMF, DMSO, and the like can be used.

Examples of the base include alkali metal alkoxides such as sodium methoxide and potassium t-butoxide. Organic bases such as cooxide, triethylamine, N, N-dimethylaniline, pyridine and DBU, metal hydrides such as sodium hydride, and inorganic bases such as potassium carbonate and sodium hydroxide can be used.

Production method 4 R ⁵ is CHC

Preparation of compounds that are Oll r ¹ .

Compound (lh) was reacted with a base in a solvent such as ethers such as getyl ether, THF, and 1,4-dioxane, alcohols such as methanol, ethanol, and n-butanol, and solvents such as DMF and DMSO. The compound (lg) can be produced by reacting a phosphonoacetic acid ester or a Wittig reagent with a compound (lg) at a reaction temperature of 80 to 20 ° C.

As the base, metal hydrides such as sodium hydride, and inorganic bases such as potassium carbonate and sodium hydroxide can be used. The compounds (2) and (4), which are the starting compounds for producing the compound of the present invention, can be produced, for example, by the method shown in the following reaction formula.

(i)

(ii)

(R

(In the formula, R ¹ R ⁵ , r ¹ , X and m represent the same meaning as described above, r represents a lower alkyl group, and M represents a metal such as sodium and potassium.)

The compound (1) of the present invention may have optical isomers, which are included in the scope of the present invention.

In the present invention, after completion of the reaction, the desired product can be obtained by performing ordinary post-treatment.

The structure of the compound of the present invention was determined from IR, NMR, MS and the like. BEST MODE FOR CARRYING OUT THE INVENTION:

Next, the present invention will be described more specifically with reference to Reference Examples and Examples. Reference example 1

Manufacture of ethyl 3- (4-phenyl phenyl) amino 3- (4-pyridyl) acrylate

4.6.5 g of 4-chloroaniline, 3-ethyl-3- (4-pyridyl) probionate 7.05 gp-0.73 g of toluenesulfonic acid monohydrate, 60 ml of toluene Was refluxed for 3 hours in a flask equipped with a Dean Stark. The reaction solution was cooled and precipitated The crystals are separated by filtration and the crude product obtained by depressurizingly distilling the solvent of the filtrate is purified by silica gel column chromatography (form: methanol = 100: 1) to obtain the target compound. 4.8 1 g was obtained. Reference example 2

Preparation of 2- (4-Pyridyl) -1-6-chloro-1-H-quinolin-4-one

4.8 g of ethyl 3- (4-phenylphenyl) amino 3- (4-pyridyl) acrylate and 30 ml of diphenyl ether were stirred at 250 ° C. for 30 minutes. The reaction solution was cooled, poured into 200 ml of hexane, and the crystals were collected by filtration. It was washed with hexane and air-dried to obtain 3.83 g of the desired product. Reference example 3

Production of 2- (4-pyridyl) -1,4,6-dichroquinoline hydrochloride

2-((4-pyridyl) -16-chloro-1H-quinolin-141-one (1.0 g), diisopropylethylamine (0.8 ml), and oxychlorine (10 ml) were heated to reflux for 1 hour. The phosphorus oxychloride was distilled off under reduced pressure, water was added to the obtained crystals, and the crystals were collected by filtration. It was washed with ether and air-dried to obtain 0.78 g of the desired product. Example 1

2- (4-pyridyl) 4- (3-chloro-4-methoxybenzylamino) 6-chloro Manufacture of mouth quinoline (Compound No. 1)

0.78 g of 2- (4-pyridyl) -1,4,6-dichloroquinoline hydrochloride, 0.73 g of 3-chloro-41-methoxybenzylamine, and 0.1 ml of DMS for 4 hours The mixture was stirred at 100 ° C. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 100: 3) to obtain 0.39 g of the desired compound. Obtained. m.p. 2 3 8 ° C Reference example 4

Manufacture of ethyl 3- (4-chlorophenyl) amino-3-ethoxycarbonyl acrylate

C t

6.4 g of 4-chloroaniline, 6.8 g of sodium salt of getyloxal acetate and 24 ml of acetic acid were stirred at 50 ° C. for 4 hours. The reaction solution was cooled to room temperature, and stirred at room temperature for one hour. The reaction solution was poured into ice water, made basic with an aqueous sodium hydroxide solution, and extracted with chloroform. After washing with 1 N hydrochloric acid, 1 N sodium hydroxide, and saturated saline, it was dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform) to obtain 5.79 g of the desired product. Reference example 5

Production of 2-ethoxycarbonyl-2-6-chloro-1H-quinoline-141 C00Et

5.79 g of ethyl 3- (4-chlorophenyl) amino-3-ethoxycarbonyl acrylate and 40 ml of diphenyl ether were stirred at 250 ° C. for 30 minutes. The reaction solution was cooled, poured into 200 ml of hexane, and the crystals were collected by filtration. The solid was washed with hexane and air-dried to obtain 3.36 g of the desired product. Reference example 6

Production of 2-ethoxyethoxycarbonyl 4, 6-dichroquinoline

2.36 g of 2-ethoxycarbonyl-6-chloro-1H-quinolin-4-one, 3.36 g of diisoprop-pyruethylamine, 2.69 m1, and 35 m1 of oxychlorine were heated under reflux for 1 hour. . The oxine chloride was distilled off under reduced pressure, and the obtained crystals were dissolved in chloroform and poured into warm water. The extract was extracted with a black form, washed with 1 N aqueous sodium hydrogen carbonate, 1 N hydrochloric acid, and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.66 g of the desired product. Example 2

Production of 2-ethoxycarbonyl-41- (3-chloro-4-methoxybenzylamino) -1-6-mouth quinoline (Compound No. 61)

COOEt 3.66 g of 2-ethoxycarbonyl-1,4,6-dichroquinoline, 3.43 g of 3-chloro-4-methoxybenzylamine, and 40 ml of DMSO were stirred at 100 ° C for 6 hours. . The reaction solution was poured into ice water, extracted with ethyl acetate, washed three times with water and once with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (black-mouthed form) to obtain 1.06 g of the desired compound.

m. p. 1 39. C Example 3

Production of 2-carboxyl-41- (3-chloro-4-methoxybenzylamino) -6-chloroquinoline (Compound No. 64)

2-Ethoxycarbonyl 4- (3-chloro-1--4-methoxybenzylamino) -16-chloroquinoline 1.06 g, ethanol 20 ml, sodium hydroxide dissolved in water 3 ml 0 .2 g were refluxed for 3 hours. The solvent was distilled off under reduced pressure, the obtained crystals were dissolved in water, 1N hydrochloric acid was added, and the obtained crystals were collected by filtration. After washing with water and air-drying, 0.52 _{g of the} desired compound was obtained. 250 ° C dec.Example 4

Preparation of 4- (3-chloro-4-benzyloxyamino) -1-6-quinoline-2-N-phenylcarboxamide (Compound No. 68)

2-Carboxy-4-1 (3-chloro-4-methoxybenzylamino) -1-6-Chloroquinoline 0.2 g, aniline 0.05 g, 1- (3-dimethylaminopropyl) -13 —Ethylcarbodimid hydrochloride 0.1 1 g, 1-hydroxybenzotriazole 0.08 g, triethylamine 0.06 g, DMF 5 m1 are stirred at 100 ° C for 2 hours. did. The reaction solution was poured into ice water, and the obtained crystals were washed with water and ether and air-dried to obtain 0.22 _g of the desired compound.

m.p.83-85 ° C Example 5

Production of 4- (3-chloro-4-methoxybenzylamino) -6-chloro-2- (4-pyridyl) quinoline hydrochloride

4- (3-Chloro-4-methoxybenzylamino) -6-chloro-2- (4-pyridyl) quinoline 0.5 g, 20 ml of chloroform, and 5 ml of methanol are stirred at 0 ° C and chlorided. Hydrogen was blown for 20 minutes. After the reaction solution was brought to room temperature, nitrogen gas was blown therein for 10 minutes to remove hydrogen chloride. The solvent was distilled off under reduced pressure, and the obtained crude product was dissolved in 10 ml of chloroform and 2 ml of methanol, stirred at 0 ° C., poured into 10 ml of ether, and the crystals were filtered. The extract was washed with ether and air-dried to obtain 0.5 g of the desired product. m.p. 188-190 ° C Example 6

Production of 4- (3-chloro-1--4-methoxybenzylamino) -1-6-cyano-2- (3-methyl-1,2,4-oxoxazol-1-5-yl) quinoline

4- (3-chloro-1-4-methoxybenzylamino) -1 6-cyano-2-ethoxycarbonylquinoline 0.5g, 11- (hydroxyminino) ethylamine 0.13g, 4A 0.1 lg, 0.07 g of 60% sodium hydride and THFlOml were heated under reflux for 4 hours. The reaction solution was poured into ice water, neutralized with 1 N hydrochloric acid, and then filtered through celite. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain 0.23 g of the desired product. mp266t; Example 7

Manufacture of N-amino (4- (3-chloro-4-methoxybenzylamino) -1 6-cyanoquinoline-1.yl) carboxamide

4- (3-Chloro-4-methoxybenzylamino) -6-cyano-2-ethoxycarbonylquinoline (1.0 g), hydrazine monohydrate (1.38 g), and ethanol (20 ml) were heated to reflux for 6 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with chloroform and dried in air to obtain 0.93 g of the desired product. m.p.272-274 ° C Example 8

Manufacture of 4- (3-chloro-4-methoxybenzylamino) -1 6-cyano 1-2- (1,3,4-oxadiazo-lu-2-yl) quinoline

2-N-aminoacetamide 4- (3-chloro-4-13-methoxybenzylamino) -1-6-cyanoquinoline 0.9 g, P-toluenesulfonic acid monohydrate 0 · lg, orthogi 20 ml of trimethyl acid was stirred at 50 ° C for 4 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give an intermediate, N- (1-aza-12-methoxybile). 1- (4- (3-Chloro-4-methoxybenzilamino) -16-cyanoquinolin-12-yl) carboxamide (mp134-136 ° C) was obtained. After heating this intermediate, 0.1 _{g of} p-toluenesulfonate monohydrate and 20 ml of trimethyl orthoformate under reflux for 8 hours, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column. Purification by chromatography (chromatography form: ethyl acetate = 5: 3) gave the desired product O. lg. mp235- 237 ° C

Example 9

6-Cyanol 4- (3-chloro-1-4-methoxybenzylamino) -1- 2-formylquinoline

Under an argon atmosphere, 6.24 g of 6-cyano-4- (3-chloro-4-methoxybenzylamino) -12-ethoxycarbonylquinoline and 160 ml of THF were stirred at 110 ° C, and then 1 M hydrogen was added. 17.2 ml of a diisobutylaluminum fluoride toluene solution was added and the mixture was stirred for 2 hours. The reaction solution was brought to room temperature, poured into ice water, neutralized with 1 N hydrochloric acid, and filtered through celite. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3.23 g of the desired product. mp257 ° C

Example 10

Production of 6-cyano 4- (3-chloro-4--3-methoxybenzylamino) -2- (1,3-oxazolyl-5-yl) quinoline

6-Cyan-4- (3-chloro-4-methoxybenzylamino) -1-formylquinoline 0.5 g, P-toluenesulfonylmethylisosocyanide 0.3 g, lithium carbonate 0.23 g, methanol 15 ml The mixture was refluxed for 7 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with water and air-dried to obtain 0.5 g of the desired product. m.p.272—274 ° C

Example 1 1

Production of (4- (3—chloro-1--4-methoxybenzylamino) -1-6-cyanoquinoline) -2-ethyl ethyl acrylate

Under an argon atmosphere, 0.12 g of 60% sodium hydride and THFlOml were stirred at 0 ° C, 0.64 g of ethylphosphonoacetate dissolved in THFlOml was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, the reaction solution was brought to 0 ° C., 6-cyano 4- (3-chloro-4-methoxybenzylamino) -12-formylquinoline lg dissolved in 40 ml of THF was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed with 1N hydrochloric acid. The obtained crystals were washed with water and air-dried to obtain 1.12 g of the desired product. mp165-167 ° C Example 1 2

(4 -— (3-chloro-1--4-methoxybenzylamino) -1-6-cyanoquinoline) -2-production of 2-ylacrylic acid

(4- (3-Chloro-4-methoxybenzylamino) -16-cyanoquinoline) -12-ethyl acrylate 1.10 g, sodium hydroxide dissolved in 15 ml of ethanol and 7.5 ml of water 0.19 g was added and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were dissolved in water and washed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer, and the obtained crystals were washed with water and air-dried to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (chromatography: methanol = 5: 1) to obtain 0.45 g of the desired product as a low-polarity compound. m.p.270 ° C Example 13

Production of (4- (3-chloro-4-methoxybenzylamino) -1-6-carboxyquinoline) -1-ylacrylic acid

Example 12 (4- (3-chloro-4-methoxybenzylamino) -16-cyanoquinoline) Obtained as a highly polar compound by the same reaction as in the production of 2-ylacrylic acid. 0.02 g mp 255 ° C Representative examples of the compounds of the present invention including the above Examples are shown in Tables 1 and 2.

Abbreviations and symbols used in the table have the following meanings.

M e: methyl, Et: ethyl, P r: propyl, He x: hexyl

n: normal, i: iso, t: tertiary, c: cyclo

P h: phenyl, B n: benzyl, P y: pyridyl, Th: phenyl

F u: furyl, T z: thiazolyl, 0 z: oxazolyl, Q u: quinolyl Table 1

C

N I a:

t

鹦 0 ¾: c.

Compound physical constant

(RRR ⁵

No. C]: Melting point

149 6 -CI CH ₂ -Ph- 3-C1-4- 0CH ₃ CH ₂ C0NH ₂

150 6-CI CH ₂ -Ph-3-Cl-4-0CH ₃ COPh

151 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ C0-Ph-4-Cl

152 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ CO-Ph-4-0CH ₃

153 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ CO- 4-Py

154 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ C0-3-Py

155 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ C0-2-Py

156 6 — CI CH ₂ -Ph-3-Cl-4-0CH ₃ CO-2-Τζ

157 6 — CI CH ₂ -Ph-3-Cl-4-0CH ₃ CO-2-Οζ

158 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ CO-cPr

159 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ CO-cHex

160 6 — CI Ci —Ph—d—L—4—L

161 6-CI CH, -Ph-3-Cl-4-0CH ₃

162 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃

H

163 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃

H ₃ C

164 6-CI CH ₂ -Ph-3-Cl-4-0CH ₃

N one ^N, CH ₃

165 6 — CI CH „-Ph-3-Cl-4-0CH ₃

, N

_{166 6 - CI CH 2 -Ph-} 3-Cl-4-0CH 3 "lb I and Shi Y ₂ one - 3 and i one 4 one UH ₃

168 6 -CI CH ₂ -Ph-3-Cl-4-0CH ₃ -x

^S CH ₃

169 6 -CI CH ₉ -Ph-3-Cl-4-0CH,

H

170 6 — CI CH _o -Ph-3-Cl-4-0CH ₃

U 6S0 d〇zw

Compound physical constant

(R _m RR

No. []: Melting point

302 6-N0 ₂ CH ₂ -Ph-3-Cl-4-0CH ₃

303 6-N0 CH „-Ph-3-Cl-4-0CH)

304 6-N0 ₂ CH ₂ -Ph-3-Cl-4-0CH ₃

H

305 6-N0 ₂ CH ₂ -Ph-3-Cl-4-0CH ₃

H ₃ C

o

306 6-N0 ₂

― N_N, CH ₃

N n ₃

307 6-N0 ₂ CH ₂ -Ph-3-CI- 4- 0CH ₃

N

308 6-N0 ₂ CH ₂ -Ph-3-Cl-4-0CH ₃ ''

0

309 6-N0 ₂ CH ₂ -Ph-3-Cl-4-0CH ₃

310 6-N0 ₂

311 6-N0 ₂ CH ₂ -Ph-3-Cl-4-0CH ₃

H

312 6-N0 ₂ CH ₂ -Ph-3-Cl-4-0CH ₃

N, CH ₃

313 H CH ₂ -Ph-3-Cl-4-0CH, 4-Py [207-209]

314 6-F CH ₂ -Ph-3-Cl-4-0CH, 4-Py

315 6-Br CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py

316 6- CF ₃ CH ₂ -Ph-3- C to 4-0CH. 4-Py (243-245)

317 6-COCH3 CH. -Ph-3-C 4-0CH. 4-Py (240-242)

318 6-C00Et CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py [223-225]

319 6-C00H CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py [250-252]

320 6-SCH3 CH ₂ -Ph-3-Cl-4-0CH, 4-Py [235-237]

321 6-S0 ₂ CH ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py [199-201]

322 6-C0NH ₂ CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py (264-266)

323 6-C0NMe ₂ CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py [114-116] Compound (R 1) RR 5 Physical constant number []: Melting point

324 6-OCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py

325 6-OCF3 CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py (210-212)

326 6- CH ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py

327 6-Et CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py

328 6- ⁿ Pr CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py

329 6-iPr CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py

330 H CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

331 6-F CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

332 6-Br CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

333 6-CF ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

334 6-COCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

335 6-C00Et CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

336 6-C00H CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

337 6-SCH ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

338 6-S0 ₂ CH ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

339 6-C0NH ₂ CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

340 6-C0NMe ₂ CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

341 6-OCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

342 6-OCF3 CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

343 6-CH3 CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

344 6-Et CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

345 6- ⁿ Pr CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

346 6-iPr CH ₂ -Ph-3-Cl-4-0CH ₃ 3-Py

347 H CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

348 6-F CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

349 6-Br CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

350 6-CF3 CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

351 6-COCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

352 6-C00Et CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

353 6-C00H CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

354 6-SCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ 2-Py

Compound physical constant

RR ⁵

No. []: Melting point

386 6-C00Et CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

387 6-COOH CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

388 6-SCH ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

389 6-S0 ₂ CH ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

390 6-C0NH ₂ CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

D L / U ll iu c bll 2 11 0 U Ππ 1 n t y

392 6-OCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

393 6-OCF3 CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

394 6-CH3 CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

395 6-Et CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

396 6- ⁿ Pr CH ₂ -Ph-3- Cl-4- 0CH ₃ C0NH-4-Py

397 6-iPr CH ₂ -Ph-3-Cl-4-0CH ₃ C0NH-4-Py

398 H CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

399 6-F CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

400 6-Br CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

401 6-CF ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

402 6-COCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

403 6-C00Et CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

404 6-COOH CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

405 6-SCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

406 6-S0 ₂ CH ₃ CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

407 6-CONHn CH-Ph-3-CI-4-0CH ₃ C0NH-2-Tz

408 6-C0NMe ₂ CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

409 6-OCH3 CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

410 6-OCF3 CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

411 6-CH3 CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

412 6-Et CH ₂ -Ph-3-Cl-4-0CH ₃ CONH-2-Τζ

413 6- ⁿ Pr CH ₂ -Ph- 3- C1-4-0CH, CONH-2-Τζ

414 6-iPr CH ₂ -Ph-3-C to 4-OCH CONH-Z-Tz

415 6-COOH CH ₂ -Ph-3-Cl-4-0CH ₃ CH = CHC00H [255]

416 6-Cl CH ₂ -Ph 4-Py

4 ^ ^ ^ ^

oo σ¾ σ¾ σ> σ> cn n σ¾

1 1 σ:

1 1 1 1 1 1 1 1 1 t—

ο ο o o o o o o o

— Ο o

o — — o — o ο

— O ■, o in 't o., O

a t

1 1 1 1 1 1

'-a 1 1 1 3 1 -o oo

1 1 1 1 1 1

■ "0 -σ

1

, 6 io

Compound physical constant

RR ⁵

No. []: Melting point

591 6, 7-C12 CH ₂ -Ph-3-Cl-4-0CH ₃ 4-Py [275-277] Table 2

Industrial applicability:

Next, the pharmacological activity of the compound of the present invention is shown.

Pharmacological test example 1 Inhibitory effect of phosphodiesterase

Cyclic nucleotide phosphodiesterases from human platelets and dog heart and kidney were obtained from Thompson et al. (Thompson W.J., eta 1., A dvancesin Cyclic Nucleotide Research 10, 6). According to the method of 9-92, 19779), on D EAE-cellulose column chromatography (Whatman, DE-52, 03.2 x 13 cm), 70 to 100 mM ammonium acetate It was eluted by the concentration gradient method of tritium and separated into each isozyme. From platelets, PDE 5 (c GMP specific PDE), PDE 3 (c GMP inhibited PDE) and PDE 2 (c GMP stimu 1ated PDE), and from the heart, PDE 1 (Ca-calmodulin dependent PDE) PDE 4 (cAMP specific PDE) was isolated from the kidney. Phosphodiesterase activity was measured by partially modifying the method of Thompson et al. That is, 1 M [3H] -cAMP or [3H] -cGMP is degraded by phosphodiesterase, and the resulting 5'-AMP or 5'-GMP is converted to snake venom (Sigma V 7 0 0) to decompose it into adenosine or guanosine. This reaction solution was added to an anion exchange resin (Bio-Rad, AG 1 -X8), and unadsorbed adenosine or guanosine was measured by a liquid scintillation counter. From the concentration inhibition curve, the concentration (IC 50) at which the enzyme activity was inhibited by 50% was determined. Table 3 shows the results. Table 3

(Note) Control: Sildenafil Pharmacological test example 2 Vasodilator effect

The vasodilator effect is based on the method described by Kenichi Hirata and Mitsuhiro Yokoyama (Arteriosclerosis + Hyperlipidemia Research Strategy, Shujunsha, pp. 275-27, 1996). The procedure was as follows. Sprague—Dawley male rat (body weight 180-360 g) Remove the thoracic aorta, remove excess connective tissue, cut blood vessels every 5 mm, and use ring specimens It was evaluated by the Magnus method (37 ° C). The nutrient solution used was a Kleps-Henseleit nutrient solution aerated with 5% carbon dioxide gas and 95% oxygen gas. The sample was equilibrated for about 60 minutes, and then contracted by adding 1 M phenylephrine. At the second contraction of phenylephrine, acetylcholine was added, and an endothelial cell-dependent relaxation reaction was confirmed. During the third contraction of phenylephrine, the test drug was added cumulatively, and its relaxation effect was observed. All test substances were dissolved in DMSO and used for the experiment. The test drug was evaluated using the 50% relaxation rate (EC50) obtained from the vascular relaxation rate (maximum relaxation was obtained by adding 100 ^ M papaverine) for each concentration. I got it. Table 4 shows the results.

Table 4

(Note) Control drug: Sildenafil As described above, the compound of the present invention has a strong inhibitory activity and a highly selective cGMP-specific PDE inhibitory action and vasodilatory action, for example, hypertension, heart failure, myocardial infarction , Angina, arteriosclerosis, restenosis after PT CA, cardiac edema, pulmonary hypertension, renal failure, renal edema, hepatic edema, asthma, bronchitis, dementia, immunodeficiency, glaucoma or impotence Or it is useful for treatment.

Claims

The scope of the claims

1. General formula (1)

{In the formula, R ^1, nitro group, Shiano group, a halogen atom, C s alkyl group, - ₆ alkoxy group, - ₆ haloalkyl groups, C haloalkoxy group, - ₆ alkylthio groups, C - ₆ Arukirusurufu Lubamoyl which may be mono- or di-substituted with an enyl group, a C ₆ alkylsulfonyl group, a C i _ ₆ alkylcarbonyl group, a hydroxycarbonyl group, a C ₆ alkoxycarbonyl group, or a C i-6 alkyl group Represents a group.

m represents 0 or an integer of 1 to 4. When m represents an integer of 2 or more, R 1 may be the same or different.

R ² and R ³ each independently represent a hydrogen atom, a hydroxy group, a halogen atom, a C i -e alkyl group, a C i -e alkoxy group, a C ₆ haloalkoxy group or a substituted Represents a hydroxyl group.

R ⁴ is a hydrogen atom, an alkyl group, C _{3 8} cycloalkyl group, substituted with good off Eniru group, a substituted base may Njiru group or an optionally substituted N, 0 also properly the S atom, Represents a saturated or unsaturated heterocyclic group containing 1 to 4

R ⁵ is a saturated or unsaturated heterocyclic group containing 1 to 4 optionally substituted N, 0 or S atoms bonded to a quinoline ring at a ring carbon atom, or

Expression

A: C (= 0) r ¹ , B: CH = CHCO r ¹ , C: (CH ₂ ) _n C 0 r ¹

Wherein, r ¹ is a hydrogen atom, arsenic Dorokishi group, 〇] - ₆ alkoxy group, optionally substituted off enoxy group, which may be substituted base Njiruokishi group, C _{3 8} cycloalkyl group, optionally substituted A phenyl group, a saturated or unsaturated heterocyclic group containing 1 to 4 optionally substituted N, 0 or S atoms, or a compound represented by the formula N r ² r ³ (where r ² is a hydrogen atom or C alkyl the group, r ³ is a hydrogen atom, C -! 6 alkyl group mono also is properly in properly formyl di substituted or unsubstituted amino group, C ₆ alkoxy group, C _{3 8} cycloalkyl group, C ₆ A C; _s alkyl group which may be substituted with an alkoxycarbonyl group, a phenyl group which may be substituted, A benzyl group, a saturated or unsaturated heterocyclic group containing 1 to 4 optionally substituted N, 0 or S atoms, or r ² and r ³ together one _{_{_{CH 2 CH 2 YC H 2 CH}}} 2 _ (Y is 0, C Eta ₂ or N r ⁴ rather r ⁴ are hydrogen atom, C ^ - 6 alkyl group, also is good phenyl group or substituted substituted Represents a benzyl group which may be represented by>).). n represents 1, 2 or 3. Represents a group selected from

However, when R ² = R ³ = H and R ⁴ is a phenyl group, m = 0. )

And a pharmaceutically acceptable salt thereof,

2. General formula (2)

(Wherein, R ¹ , R ⁵ and m have the same meaning as in claim 1, and X represents a halogen atom.) And a compound represented by the general formula (3)

(Wherein, R 2, R ³ and R ⁴ have the same meanings as in claim 1). The compound represented by the general formula (1) Manufacturing method.

3. General formula (l a)

(Wherein R ¹ , R ² , R ³ , R ⁴ and m have the same meaning as in claim 1), and a compound represented by the general formula (5):

Two

H- < ⁽⁵⁾

(Wherein, r ² and r ³ represent the same meaning as in claim 1). General formula (lb)

^{^{(Wherein, R 1, R 2, R}} 3, R 4, r 2 3 and m represents. As defined above) preparation of a compound table with.