JP2641686B2 - New quinoline derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel quinoline derivative having excellent pharmacological action, and a salt thereof. More specifically, the present invention relates to a novel quinoline derivative having an angiotensin II antagonistic action and a blood pressure lowering action, and useful as a therapeutic agent for circulatory diseases such as hypertension, and a salt thereof.

[0002]

2. Description of the Related Art The blood pressure of a living body is regulated by the sympathetic nervous system and the balance between the pressor system and the hypotensive system. The renin-angiotensin system is involved in the pressor system. Renin acts on angiotensinogen to produce angiotensin I. Angiotensin I is further converted to angiotensin II by an angiotensin converting enzyme. Angiotensin II has a strong vasoconstrictor action and acts on the adrenal cortex to promote aldosterone secretion, resulting in an increase in blood pressure. Since angiotensin II acts via the angiotensin II receptor on the cell membrane, its antagonists are similar to angiotensin converting enzyme inhibitors.
Can be used as a treatment for hypertension caused by II.

Hitherto, peptidic angiotensin II antagonists represented by salaracin have been known, but it is known that oral administration is not effective because of its peptidic nature. Recently, non-peptide angiotensin II antagonists have been reported (for example, see JP-A-56-7107).
No. 4, Japanese Patent Application Laid-Open No. 3-501020), and it has been confirmed that oral administration is effective.

[0004]

Means for Solving the Problems The present inventors diligently searched for a non-peptidic compound having an angiotensin II antagonistic effect and being effective by oral administration. As a result, they have found that the novel quinoline derivative represented by the following general formula (1) and a salt thereof are effective. The present invention is this novel quinoline derivative and a salt thereof.

[0005]

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[In the general formula (1), R ^{1 to} R ⁸ are as follows. R ¹ : lower alkyl group, halo-lower alkyl group, cyclo-lower alkyl group, alkenyl group, alkoxyl group, alkoxy-lower alkyl group, or alkylthio group. R ² , R ³ : both may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyclo-lower alkyl group, an alkenyl group, an alkoxyl group, a C _m F _{2m + 1} -,-(CH
_{2) n} R ⁹ _{or, - (CH 2) p COR} 10.

R ⁴ : hydrogen atom, halogen atom, lower alkyl group, alkoxyl group, or C _m F _{2m + 1-} . R ^5: a hydrogen atom, a halogen atom, -COOH, -COO
R ^11, -CONH ₂ or -CN,. ^{R 6: -COOH, -COOR 12,} -CONH 2, -C
N, -NHSO ₂ CF ₃ or C bond tetrazolyl group. R ⁷ and R ⁸ : both may be the same or different, and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group, or C _m F _{2m + 1-} . X and Y: both may be the same or different, and each is independently CH or a nitrogen atom.

However, the above R ^{9 to} R ¹² and m,
n and p show the following. R ⁹ : a hydroxyl group or an alkoxyl group. R ¹⁰ : a hydrogen atom, a hydroxyl group, a lower alkyl group, or an alkoxyl group. R ¹¹ and R ¹² : both may be the same or different, and each is independently a lower alkyl group, an alkenyl group, a cyclo lower alkyl group, an aryl group, or an aralkyl group.

M is an integer of 1 to 6. n is an integer of 1 to 4. p
Is an integer of 0 to 4. ]

The salt of the quinoline derivative represented by the general formula (1) includes an acid addition salt derived from the quinoline derivative and an inorganic acid or an organic acid. Such salts include, for example, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, p-toluenesulfonate,
Examples include oxalate, tartrate, citrate, maleate, fumarate, succinate, lactate, glutarate, acetate, trifluoroacetate, salts of various amino acids, and the like.

The salt of the quinoline derivative represented by the general formula (1) includes a salt formed from the quinoline derivative and a base. Such salts include, for example,
Alkali metals (eg, sodium, potassium), alkaline earth metals (eg, calcium, magnesium),
There are salts formed from ammonium and substituted ammonium (eg, dimethylammonium, triethylammonium) and the like.

In the above description and the following description, the term "lower" for an organic group means 1 to 6 carbon atoms. The “lower alkyl group” may be linear or branched, and suitable examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, Hexyl group and the like. “Halo lower alkyl group” is a lower alkyl group substituted with halogen, and suitable examples thereof include a chloromethyl group, a 2-chloroethyl group, a bromomethyl group,
2-bromoethyl group, 1,2-dichloroethyl group, 1,
Examples thereof include a 2-dibromoethyl group and a 3-trifluoromethylpropyl group. "Lower cycloalkyl group"
A cycloalkyl group having 3 to 6 carbon atoms constituting a ring is mentioned, and suitable examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.

The "alkenyl group" is preferably a lower alkenyl group, and more preferably has 2 to 4 carbon atoms.
And suitable examples thereof include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, and a 1-butenyl group. As the "alkoxyl group", a lower alkoxyl group is preferable, more preferably a straight-chain or branched alkoxyl group having 1 to 4 carbon atoms, and suitable examples thereof include a methoxy group, an ethoxy group, a propoxy group, Butoxy group and the like. As the “alkoxy lower alkyl group”, those in which the alkoxyl group portion is a lower alkoxyl group are preferable, and suitable examples thereof include:
Examples include a methoxyethyl group, a 3-methoxypropyl group, and a 2-ethoxyethyl group. The “alkylthio group” is preferably a lower alkylthio group, and suitable examples thereof include a methylthio group, an ethylthio group, a propylthio group, a butylthio group and the like. The “alkenyl group”, “alkoxy group”, and “alkylthio group” preferably have 1 to 4 carbon atoms.

Further, in the above description and the following description of the present specification, “halogen atom” means a fluorine atom,
It means chlorine atom, bromine atom and iodine atom. “Aryl group” refers to a monovalent aromatic hydrocarbon group, which may have a substituent (eg, a lower alkyl group, a halogen atom, a lower alkoxyl group, a lower alkylamino group, etc.), and is preferably phenyl. Groups and derivatives thereof, for example, phenyl group, tolyl group, p-halophenyl group (eg, p-chlorophenyl group, p-bromophenyl group, etc.), alkoxyphenyl group (eg, methoxyphenyl group, ethoxyphenyl group, etc.), And a dialkylaminophenyl group (for example, a dimethylaminophenyl group, a diethylaminophenyl group, and the like). Further, "aralkyl group" refers to an aryl group-substituted alkyl group,
Examples of the aryl group as the substituent include those described above, and the alkyl group preferably has 1 to 4 carbon atoms. Suitable examples include a benzyl group, a benzhydryl group, a trityl group, a phenethyl group and the like.

Among the quinoline derivatives represented by the general formula (1), R ¹ is preferably a lower alkyl group or an alkenyl group, and R ² and R ³ may be the same or different, and are each independently. a hydrogen atom, a halogen atom, a lower alkyl _{group, - (CH 2) n R} 9 or, - (CH
₂ ) _p COR ¹⁰ (where R ⁹ is a hydroxyl group or an alkoxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is an integer of 1 to 4, p is 0
To 4 of an integer), R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom, -COOH or -COOR ¹¹ (R ¹¹ is a lower alkyl group, an alkenyl group, a lower cycloalkyl group, an aryl group or an aralkyl group, in is), R ⁶ is -COO
H, —COOR ¹² (R ¹² is a lower alkyl group, an alkenyl group, a cyclo lower alkyl group, an aryl group, an aralkyl group), or a C-bonded tetrazolyl group, R ⁷ and R ⁸
May be the same or different and are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a lower alkyl group or an alkoxyl group, a compound in which X is a nitrogen atom and Y is CH.

More preferably, among the quinoline derivatives represented by the general formula (1), R ¹ is a lower alkyl group, R ²
And R ³ may be the same or different, and each independently represents a hydrogen atom, a lower alkyl group,-(CH ₂ ) _n
R ⁹ , or — (CH ₂ ) _p COR ¹⁰ (wherein
R ⁹ is a hydroxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is 1 and p is 0 to 1), R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom or a chlorine atom, R ⁶ Is -COOH, -COOR ¹² (where,
R ¹² is a lower alkyl group, an alkenyl group, a cyclo-lower alkyl group, an aryl group, or an aralkyl group), or a C-bonded tetrazolyl group, and R ⁷ and R ⁸ may be the same or different and each independently represents a hydrogen atom , Fluorine atom,
A compound in which a chlorine atom or a lower alkyl group, X is a nitrogen atom, and Y is CH.

Most preferred for antihypertensive activity are the following quinoline derivatives, and salts thereof.

2- {6-[(2-butyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoic acid, 2- {6-[(7- methyl-2-propyl -3H- imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoic acid, 2- {6 - [(2-ethyl-5, 7-dimethyl - 3H-
Imidazo [4,5-b] pyridin-3-yl) methyl
Quinolin-2-ylbenzoic acid, or a salt thereof.

Methyl 2- {6-[(2-butyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoate, 2- {6-[(7 -Methyl-2-propyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoate methyl or 2- {6-[(2-ethyl-5 , 7-dimethyl-3H-
Imidazo [4,5-b] pyridin-3-yl) methyl
Quinolin-2-yl methyl benzoate.

2-butyl-3- {2- [2- (1H-
Tetrazol-5-yl) phenyl] quinolin-6-yl {methyl} -3H-imidazo [4,5-b] pyridine, 7-methyl-2-propyl-3- {2- [2- (1H
-Tetrazol-5-yl) phenyl] quinoline-6
Yl} methyl}-3H-imidazo [4,5-b] pyridine, 2-ethyl-5, 7-dimethyl-3 - {{2- [2-
(1H-tetrazol-5-yl) phenyl] quinolin-6-yl {methyl} -3H-imidazo [4,5-b]
Pyridine, 2-ethyl-5, 7-dimethyl-3 - {{4-chloro -
2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl {methyl} -3H-imidazo [4,5-b] pyridine or a salt thereof.

The quinoline derivative represented by the general formula (1) can be produced, for example, by the following method.

The first method is a method (A) for converting the compounds represented by the general formula (1) into each other. The second method is
This is a method (B) of converting a compound similar to the general formula (1) having a different substituent or the like into a compound represented by the general formula (1).
This similar compound refers to a compound having the same skeleton as the compound represented by the general formula (1). The third method is a method (C) for synthesizing a compound represented by the general formula (1) or a compound similar thereto by the reaction of two or more intermediate compounds, and the latter similar compound is then converted to a method (B). To convert to the compound represented by the general formula (1). This method (C)
Means a method related to a reaction for forming a skeleton.

As an example of the method (A), there is the following method, for example. In the general formula (1), R ⁵ is —COOH, R
^When R ⁶ is —COOR ¹² (R ¹² is a lower alkyl group, an alkenyl group, a cyclo-lower alkyl group, an aralkyl group, or an aryl group), R ⁵ is —COOR ¹¹ (R ¹¹
A lower alkyl group, an alkenyl group, a lower cycloalkyl group, an aralkyl group or aryl which group) in which one of one equivalent of an alkali such as sodium hydroxide, by hydrolysis with potassium hydroxide, the R ⁶ −
COOR ¹² (R ¹² is a lower alkyl group, an alkenyl group, a cyclo-lower alkyl group, or an aryl group).

In the general formula (1), when R ⁵ is hydrogen, R ⁵ is —COOH and R ⁶ is —COOR ¹² (R
Wherein ¹² is a lower alkyl group, an alkenyl group, a cyclo-lower alkyl group, or an aryl group), in a solvent having a high boiling point, such as diphenyl ether, at a temperature near the boiling point of the solvent under reflux.

In the general formula (1), when R ⁶ is —COOH, R ⁶ is —COOR ¹² (R ¹² is a lower alkyl group,
Which is an alkenyl group, a cyclo-lower alkyl group, an aralkyl group, or an aryl group).

In the general formula (1), one method for obtaining a compound in which R ⁶ is a C-bonded tetrazolyl group is to convert R ⁶ to —CN to sodium azide or ammonium azide (preferably sodium azide and ammonium chloride). Or a suitable azide compound such as tributyltin azide (preferably prepared in situ from sodium azide and tributyltin chloride) and an anhydrous solvent such as toluene, xylene, dimethoxyethane, tetrahydrofuran In which the reaction is carried out at the reflux temperature of the solvent or at a temperature close to the reflux temperature. When tributyltin azide is used, it is treated with a basic aqueous solution or an acidic aqueous solution after the reaction to remove the tributyltin group.

Another method for obtaining a compound of the formula (1) wherein R ⁶ is a C-bonded tetrazolyl group is according to the method of JV Duncia et al. [J. Org. Chem., 56, 2395 (1991)].
After the R ⁶ is converted to -COOH compound is -COOH into an acid chloride or an active ester is reacted with 2-aminopropionitrile, further triphenyl phosphine, in a method of reacting with diethyl azodicarboxylate, and trimethylsilyl azide is there.

As a typical example of the method (B), there is a method of converting a functional group or a substituent. For example, by converting a functional group or a substituent from a similar compound having the same skeleton as the compound represented by the general formula (1) and having no functional group or substituent outside the general formula (1), the general formula (1 ) Is available. As a typical example of functional group conversion, there is an example in which a functional group protected by a protecting group is deprotected. Also, R
^The compound represented by the general formula (1) can be synthesized by converting the protected functional group of ⁶ into R ⁶ . An example of such a method (B) is, for example, the following method.

In the general formula (1), when R ⁶ is a C-bonded tetrazolyl group, a compound similar to the general formula (1) having a C-bonded tetrazolyl group protected by a suitable protecting group at the position corresponding to R ⁶ By subjecting it to a deprotection operation. Examples of the protecting group in this case include a triphenylmethyl group and a cyanoethyl group. Deprotection operations are described, for example, in TW Greene, “Protective Groups
in Organic Synthesis ”(John Wiley and Sons. Inc.,
1981).

In the general formula (1), R ⁶ is —NHSO ₂
CF ₃ can be obtained from a compound similar to the general formula (1) having an amino group at the position corresponding to R ⁶ by using anhydrous trifluoromethane in a suitable solvent such as dichloromethane in the presence of a suitable base such as triethylamine. It can be obtained by reacting with methanesulfonic acid.

The compound having an amino group at the position corresponding to R ⁶ is similar to the compound represented by the general formula (1), and the compound having the general formula (1) wherein R ⁶ is —COOH may be substituted with another functional group, if necessary. After protecting with a suitable protecting group, carbamate is obtained by carrying out Curtius rearrangement using diphenylphosphoryl azide using an alcohol such as t-butyl alcohol as a solvent in the presence of a base such as triethylamine, followed by ethanol and the like. The compound can be synthesized by subjecting hydrochloric acid to action in the above-mentioned solvent to perform acid hydrolysis.

The method (C) is a method involving a skeleton formation reaction, whereby a compound represented by the general formula (1) or a compound similar thereto is obtained. A typical skeleton forming reaction is a method of reacting a compound represented by the general formula (2) with a compound represented by the general formula (3).

The skeleton of the quinoline derivative represented by the general formula (1) comprises a compound represented by the following general formula (2) and an imidazopyridine represented by the following general formula (3), and a base such as hydrogen. An aprotic solvent such as N, N-dimethylformamide in the presence of sodium chloride, sodium carbonate, potassium carbonate, sodium methoxide, etc.
N, N-dimethylacetamide, tetrahydrofuran,
It is formed by reacting in a solvent such as dioxane at 0 ° C. to the reflux temperature of the solvent.

[0034]

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L in the general formula (2) represents a leaving group, for example, a halogen atom such as chlorine, bromine or iodine or a group such as methanesulfonyloxy or p-toluenesulfonyloxy. R ²⁴ , R ²⁵ , R ²⁶ ,
R ²⁷ and R ²⁸ each represent a corresponding R ⁴ ,
R ⁵ , R ⁶ , R ⁷ , and R ⁸ are the same as or convertible to corresponding R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ . ]

For example, R ²⁶ is not limited to R ⁶ ,
There are groups that can be converted to R ⁶ , such as groups that differ from R ⁶ only in that the functional group is protected with a protecting group. R which can be converted to other R ⁶
Examples of ²⁶ include an amino group and a protected amino group as described above.

[0037]

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[In the general formula (3), R ²¹ , R ²² and R ²³ have the same meanings as the corresponding R ¹ , R ² and R ^{3 in} the general formula (1), or the corresponding R ¹ , R 2 ^2, is a group that can be converted into R ^3. ]

In synthesizing the quinoline derivative represented by the general formula (1), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ do not always remain the same from the starting material to the final product. Frequently, it is necessary to perform transformations as exemplified below to lead to the final product. As an example of the following method (C), this method will be described using an example in which R ^{21 to} R ²⁸ other than R ²⁶ are the same as the corresponding intermediate compounds of R ^{1 to} R ^{8 in the} general formula (1). .

The quinoline derivative represented by the general formula (1) in which R ⁶ is a C-bonded tetrazolyl group is obtained by converting the compound represented by the general formula (2) in which R ²⁶ is a protected C-bonded tetrazolyl group into a compound represented by the general formula (1). (3) In the presence of an imidazopyridine and a base such as sodium hydride, sodium carbonate, potassium carbonate, and sodium methoxide, an aprotic solvent such as N, N-dimethylformamide;
N, N-dimethylacetamide, tetrahydrofuran,
It is obtained by reacting in a solvent such as dioxane at 0 ° C. to the reflux temperature of the solvent.

Alternatively, the compound represented by the general formula (2) in which R ²⁶ is a protected C-bonded tetrazolyl group can be converted to an imidazopyridine represented by the general formula (3) by phase transfer such as tetraalkylammonium salt. Catalysts such as "Al
iquat 336 "and other basic aqueous solutions, for example,
In a mixed solvent of an aqueous solution of sodium hydroxide or potassium hydroxide and a suitable organic solvent, for example, methylene chloride,
It can also be obtained by reacting at a temperature of from 0 ° C to the reflux temperature of the solvent.

The intermediate compound represented by the general formula (2) is obtained, for example, by converting the 6-position methyl group of the compound represented by the following general formula (4) into -CH ₂ L (L is a leaving group). Can be manufactured. The substituents in the general formula (4) are the same as the substituents in the general formula (2) (that is, R ²⁴ , R
²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are the same), but the substituent is not limited thereto as long as it can be converted. In the following general formulas (5) and (6), the same description will be given assuming that the substituents are the same as those in the general formula (2).

[0043]

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For example, when L is chlorine, bromine or iodine, the compound represented by the general formula (4) is reacted with N-chlorosuccinate in the presence of a radical initiator such as azobisisobutyronitrile or dibenzoyl peroxide. Acid imide, N
The compound can be converted to a compound represented by the general formula (2) by reacting with -bromosuccinimide or N-iodosuccinimide. A similar reaction can be performed by light irradiation instead of using the above radical initiator.

Of the compounds represented by the general formula (4), R ²⁵
Is -COOH, by adding a compound represented by the following general formula (6) to a compound represented by the following general formula (5) and adding the compound in a suitable alkali aqueous solution such as sodium hydroxide or potassium hydroxide. It is obtained by heating to reflux.

[0046]

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The compound represented by the general formula (4) wherein R ²⁵ is a hydrogen atom is synthesized from the compound represented by the general formula (4) wherein R ²⁵ is --COOH by converting a substituent thereof. be able to. For example, it can be obtained by heating and refluxing a solvent having a high boiling point such as diphenyl ether at a temperature near the boiling point of the solvent.

R ²⁵ and R ²⁶ are each -COOR ¹¹ , -C
The compound represented by the OOR ¹² a is Formula (4),
The compound can be synthesized from the compound represented by the general formula (4) in which R ²⁵ and R ²⁶ are —COOH by converting the substituent. For example, a compound in which R ¹¹ and R ¹² are methyl groups can be obtained by reacting thionyl chloride in methanol.

The compound represented by the general formula (4) in which R ²⁵ is —COOH and R ²⁶ is —COOR ¹² is a compound represented by the general formula (4) in which R ²⁵ and R ²⁶ are —COOR ¹¹ and —COOR ¹² , respectively.
Can be obtained by converting only the substituent of R ^{25 in} the compound represented by the formula: For example, it can be obtained by hydrolysis by adding one equivalent of an alkali such as sodium hydroxide or potassium hydroxide in a methanol-water mixed solvent.

[0050] The compounds represented by the general formula R ²⁶ is C bonded tetrazolyl group marked with suitable protecting groups such as triphenylmethyl group and a cyanoethyl group (4), R ²⁶ is -CN general It can be synthesized from the compound represented by the formula (4) by a method of converting the substituent.

For example, a compound represented by the general formula (4) wherein R ²⁶ is --CN is prepared by sodium azide, ammonium azide (preferably prepared in situ from sodium azide and ammonium chloride), or A suitable azide compound such as tributyltin azide (preferably prepared in situ from sodium azide and tributyltin chloride) and an anhydrous solvent such as toluene, xylene, dimethoxyethane, tetrahydrofuran, or the solvent reflux temperature or After the reaction at a temperature in the vicinity of the reaction (in the case of using tributyltin azide, the reaction is treated with a basic aqueous solution or an acidic aqueous solution to remove the tributyltin group), and then a protective group is added.

Still another method for obtaining a compound represented by the general formula (4) wherein R ²⁶ is a C-bonded tetrazolyl group having a suitable protecting group such as a triphenylmethyl group or a cyanoethyl group is described in JV Duncia et al. [J. Org. Chem.,
56, 2395 (1991)], -COOH of the compound represented by the general formula (4) in which R ²⁶ is -COOH is converted into acid chloride or active ester, and then reacted with 2-aminopropionitrile. And triphenylphosphine, diethyl azodicarboxylate, and trimethylsilyl azide.

The compound represented by the general formula (4) wherein R ²⁶ is a protected amino group is a compound represented by the general formula (4) wherein R ²⁶ is --COOH, for example, t-butyl. It is obtained by performing Curtius rearrangement using diphenylphosphoryl azide in the presence of a base such as triethylamine using an alcohol such as an alcohol as a solvent. In this case, the protecting group for the amino group is a carbamate such as t-butyl carbamate.

The imidazopyridine represented by the general formula (3) can be produced by the method described in JP-A-3-95181 or a method analogous thereto.

The compound (1) of the present invention can be isolated and purified by a conventional method, for example, by extraction, crystallization, fractional crystallization, recrystallization, chromatography and the like. The target compound (1) thus obtained can be converted into a salt thereof by a conventional method.

The objective compound [(1) and its salt] of the present invention is novel, exhibits excellent pharmacological actions such as angiotensin II antagonism, has low toxicity, and has excellent absorption, stability and immediate action. Etc. Therefore, it is useful as an angiotensin II antagonist for treating or preventing cardiovascular diseases such as angiotensin II-mediated diseases such as hypertension (eg, essential hypertension, renal hypertension, etc.) and heart failure. It is.

The objective compound of the present invention is a therapeutic agent for heart disorders (eg, angina, arrhythmia, myocardial infarction, etc.), aldosteronemia, cerebral circulation disease, senile dementia, eye diseases (eg, glaucoma). Or it is expected to be useful as a prophylactic agent and as a diagnostic agent for renin-angiotensin system tests.

For administration for treatment or prevention, the desired compound of the present invention is used as an active ingredient and is pharmaceutically acceptable such as an organic or inorganic solid or liquid excipient suitable for oral administration, parenteral administration or external use. It is used in the form of a conventional pharmaceutical preparation containing the compound as a mixture with a carrier. The pharmaceutical preparation may be in the form of solid such as tablets, granules, powders, capsules and the like, or may be in the form of liquids, suspensions, syrups, emulsions and liquids of lemonade. If necessary, add auxiliaries, stabilizers, wetting agents and other conventional additives to the above preparations, such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar. Pectin, peanut oil, olive oil, cocoa oil, ethylene glycol and the like.

The dose of the target compound of the present invention varies depending on the age of the patient, the condition of the disease, the type of the disease or the condition, the type of the target compound of the present invention to be applied, and the like, but is generally 0.01 mg to 500 mg per day. A dose in the range or even higher may be administered to the patient. In treating various diseases, the average dose of the compound of interest of the present invention was 0.05%.
mg, 0.1mg, 0.25mg, 0.5mg, 1m
g, 20 mg, 50 mg, 100 mg, etc.

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

[0061]

【Example】

 [Reference Example 1] Synthesis of 5-methylisatin

Water chloral 16.7 g (0.10 mol) of water (222 m
l) solution, sodium sulfate 243g, p-toluidine 10.0g
A solution of 9.56 g of concentrated hydrochloric acid (93.3 mmol) in water (56.0 ml) and a solution of hydroxylamine hydrochloride 20.5 g (0.29 mol) in water (242 ml) were mixed in this order, and the mixture was heated under reflux with stirring for 30 minutes. After cooling to room temperature, the tan precipitate was filtered off with suction. 1.5N
It was dissolved in 500 ml of sodium hydroxide solution and neutralized with 2M hydrochloric acid. This was filtered and the filtrate was acidified with 2M hydrochloric acid. The precipitated isonitroso compound was collected by filtration, washed with ice-cold water, and dried. This was added over 40 minutes to 62 g of concentrated sulfuric acid warmed to 60 ° C. Heat at 75 ° C. for another 10 minutes. After cooling to room temperature, the mixture was poured into 160 ml of ice-cold water, and the precipitate was collected by filtration.
10.0 g was obtained.

NMR (270 MHz, Acetone-d ₆ ) δ9.9 (bs, 1H);
6.9-7.5 (m, 3H); 2.3 (s, 3H)

Reference Example 2 Synthesis of 2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid

In 9.93 ml of water, 10.0 g (62.1 mmol) of 5-methylisatin obtained in Reference Example 1 and 4.96 g of sodium hydroxide (0.
12 mol), and then 10.2 g of 2-acetylbenzoic acid (6
2.1 mmol), and the mixture was heated to 90 ° C. and refluxed. After the reaction became mild, the mixture was further heated in a hot bath at 115 ° C. for 1 hour. After allowing to cool to room temperature, the mixture was poured into 200 g of ice-cold water. The aqueous layer was washed with ether and then acidified with 2M hydrochloric acid. The resulting precipitate is collected by filtration and 2- (2-carboxyphenyl) -6-methyl-
6.55 g of 4-quinolinecarboxylic acid was obtained.

NMR (270 MHz, Acetone-d ₆ ) δ 7.70-8.70 (m,
8H); 2.66 (s, 3H)

Reference Example 3 Synthesis of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate

2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid obtained in Reference Example 2 2.7
7 g (9.03 mmol) was suspended in 10 ml of methanol. While maintaining the temperature at -10 ° C, 1.3 ml (18 mmol) of thionyl chloride was added. After stirring overnight, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using chloroform to give 2- (2-methoxycarbonylphenyl) -6-
377 mg of methyl methyl-4-quinolinecarboxylate were obtained.

NMR (270 MHz, CDCl ₃ ) δ7.49-8.56 (m, 8H); 4.
04 (s, 3H); 3.62 (s, 3H); 2.60 (s, 3H)

Reference Example 4 Synthesis of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid

377 mg (1.23 mmol) of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate obtained in Reference Example 3 and 49 mg of sodium hydroxide
(1.2 mmol) was dissolved in 2 ml of methanol. 3 ml of water was added, followed by stirring overnight. After concentration under reduced pressure, water was added to the residue, the aqueous layer was acidified, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by flash chromatography on silica gel using a mixed solvent of chloroform / methanol (70/1) to give 2- (2-methoxycarbonylphenyl) -6-. 267 mg of methyl-4-quinolinecarboxylic acid were obtained.

NMR (270 MHz, CD ₃ OD) δ 7.70-8.58 (m, 8H); 3.
60 (s, 3H); 2.59 (s, 3H)

Reference Example 5 2- (6-methylquinoline-
Synthesis of 2-yl) methyl benzoate

267 mg (0.831 mmol) of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid obtained in Reference Example 4 was dissolved in 4.0 ml of diphenyl ether and heated at 225 ° C. for 10 minutes. After allowing to cool to room temperature, the residue was purified by flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (10/1) to obtain 154 mg of methyl 2- (6-methylquinolin-2-yl) benzoate.

NMR (270 MHz, CDCl ₃ ) δ7.47-8.13 (m, 9H); 3.
63 (s, 3H); 2.56 (s, 3H)

Reference Example 6 2- (6-methylquinoline-
Synthesis of 2-yl) benzoic acid

Methyl 2- (6-methylquinolin-2-yl) benzoate (7.08 g, 25.5 mmol) was suspended in methanol (75 ml), and sodium hydroxide (3.06 g, 76.6 mmol) was dissolved in water 35.
ml was added. Heated at 60 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, 200 ml of water was added to the residue, and the mixture was acidified with 2N hydrochloric acid. The precipitated solid is collected by filtration, washed with water and dried to give 2-
(6-Methylquinolin-2-yl) benzoic acid was obtained.

NMR (270 MHz, CD ₃ OD) δ7.6-8.3 (m, 9H), 2.58
(s, 3H)

Reference Example 7 2- (6-methylquinoline-
Synthesis of 2-yl) benzamide

To 2.47 g (9.38 mmol) of 2- (6-methylquinolin-2-yl) benzoic acid obtained in Reference Example 6 was added 30 ml of toluene.
And 1.37 ml (18.76 mmol) of thionyl chloride and one drop of dimethylformamide were added. The mixture was heated under reflux for 3 hours, allowed to cool to room temperature, and the solid was collected by filtration. 10 ml of toluene
And dried three times. While vigorously stirring 30 ml of ice-cooled concentrated aqueous ammonia, the resulting solid was added so that the internal temperature did not exceed 15 ° C. The mixture was stirred overnight at room temperature, 30 ml of water was added, and the solid was collected by filtration. After washing three times with 20 ml of water, the filter cake was suspended in diethyl ether, collected by filtration and dried to obtain 2.05 g of 2- (6-methylquinolin-2-yl) benzamide.

NMR (270 MHz, CDCl ₃ ) δ 7.5-8.2 (m, 9H); 6.4
(bs, 1H); 5.6 (bs, 1H); 2.58 (s, 3H)

Reference Example 8 2- (6-methylquinoline-
Synthesis of 2-yl) benzonitrile

The pyridine was added to 2.05 g (7.82 mmol) of 2- (6-methylquinolin-2-yl) benzamide obtained in Reference Example 7.
15 ml was added and stirred, and p-toluenesulfonic acid chloride 1.4
9 g (7.82 mmol) were added. After stirring at room temperature for 2 hours,
The mixture was heated and stirred at 40 ° C. for a time. The reaction solution was poured into 30 ml of water, extracted with 50 ml of methylene chloride, and dried over magnesium sulfate. The filtrate was concentrated by filtration, and silica gel chromatography was performed using a mixed solvent of 7: 1 hexane / ethyl acetate to give 2- (6-methylquinoline-
0.86 g of 2-yl) benzonitrile was obtained.

NMR (270 MHz, CDCl ₃ ) δ 7.5-8.2 (m, 9H); 2.58
(s, 3H)

Reference Example 9 Synthesis of 5- [2- (6-methylquinolin-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole

To 855 mg (3.5 mmol) of 2- (6-methylquinolin-2-yl) benzonitrile obtained in Reference Example 8, toluene was added.
Add 3.5 ml, stir, and add sodium azide 0.24 g
(3.68 mmol) and 1 ml (3.83 mmol) of tributyltin chloride were added, and the mixture was heated under reflux for 45 hours. After cooling and diluting with 7 ml of toluene, 0.4 ml (4 mmo
l) and 1.01 g (3.61 mmol) of trityl chloride were added. After stirring at room temperature for 1.5 hours, 15 ml of hexane was added. The solid was collected by filtration and washed twice with 10 ml of water and three times with 5 ml of methanol. The cake was vacuum dried to give 1.36 g of 5- [2- (6-methylquinolin-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole.

NMR (270 MHz, CDCl ₃ ) δ 6.8-8.1 (m, 24H); 2.
54 (s, 3H)

Reference Example 10 Synthesis of 2- (4-chloro-6-methylquinolin-2-yl) benzonitrile

To 1.28 g (4.88 mmol) of 2- (6-methylquinolin-2-yl) benzamide obtained in Reference Example 7, 2.5 ml (34.2 mmol) of thionyl chloride was added, and the mixture was stirred and refluxed for 3 hours. The thionyl chloride is distilled off, and the residue is chloroform 100
Dissolved in ice water. The organic layer was separated, neutralized with 150 ml of an aqueous saturated sodium bicarbonate solution, washed with a saturated saline solution, and dried over magnesium sulfate. Filter and concentrate the filtrate, 10: 1
By performing silica gel chromatography using a mixed solvent of hexane / ethyl acetate, 2- (4)
150 mg of -chloro-6-methylquinolin-2-yl) benzonitrile were obtained.

NMR (270 MHz, CDCl ₃ ) δ 7.5-8.1 (m, 8H); 2.62
(s, 3H)

Reference Example 11 5- [2- (4-chloro-
Synthesis of 6-methylquinolin-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole

2- (4-chloro-6-methylquinolin-2-yl) benzonitrile 290 obtained by the method of Reference Example 10.
mg was subjected to the same method as in Reference Example 9 to give 5- [2- (4-chloro-6-methylquinolin-2-yl) phenyl] -2.
-(Triphenylmethyl) -2H-tetrazole 133mg
I got

NMR (270 MHz, CDCl ₃ ) δ 6.8-8.2 (m, 23H); 2.
6 (s, 3H)

Example 1 2- {6-[(2-ethyl-
Synthesis of 5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {methyl benzoate

To 154 mg (0.554 mmol) of methyl 2- (6-methylquinolin-2-yl) benzoate obtained in Reference Example 5, 2 ml of carbon tetrachloride was added, and 98.7 mg (0.554 mmol) of N-bromosuccinimide was further added. ) And azobisisobutyronitrile 4.
55 mg (0.0277 mmol) was added, and the mixture was heated under reflux for 1 hour. After concentration under reduced pressure, dichloromethane was added to the residue to dissolve and washed with water. After the organic layer was dried over magnesium sulfate, it was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1 ml of N, N-dimethylformamide. This is 2-ethyl-
71.1 mg (0.406 mmol) of 5,7-dimethyl-1H-imidazo [4,5-b] pyridine was dissolved in 1 ml of dimethylformamide, and 16.2 mg (0.406 mmol) of sodium hydride was added, followed by stirring for 30 minutes. The mixture was added to the solution and stirred overnight.

Thereafter, the residue obtained by concentration under reduced pressure was extracted with ethyl acetate, and washed twice with 20 ml of water. Magnesium sulfate was added to the organic layer, the mixture was allowed to stand for 30 minutes, and then filtered and concentrated. The residue was purified by flash chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (2/3) to give 2- {6-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5]. -B] pyridine-3-
Yl) methyl] quinolin-2-yl {methyl benzoate 1
48 mg were obtained.

NMR (270 MHz, CDCl ₃ ) δ6.94-8.08 (m, 10H);
5.66 (s, 2H); 3.63 (s, 3H); 2.83 (q, J = 7.5Hz, 2H); 2.70 (s, 3
H); 2.61 (s, 3H); 1.34 (t, J = 7.5Hz, 3H)

Example 2 2- {6-[(2-ethyl-
Synthesis of 5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {sodium benzoate

The 2- {6-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-
b] Pyridin-3-yl) methyl] quinolin-2-yl {benzoic acid methyl ester (116.9 mg, 0.260 mmol), sodium hydroxide (31.1 mg, 0.778 mmol), water (2 ml) and ethanol (2 ml) were added, and the mixture was stirred at room temperature for 24 hours.

Then, the mixture was concentrated under reduced pressure, and partitioned between water and ether. The aqueous layer was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2- {6-[(2-ethyl-5,7-
Dimethyl-3H-imidazo [4,5-b] pyridine-3
-Yl) methyl] quinolin-2-yl {benzoic acid 46.0mg
I got 1 equivalent of water and 1N aqueous sodium hydroxide
(0.105 mmol), dissolved and freeze-dried to give 2- {6-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl). Methyl] quinolin-2-yl {sodium benzoate
43.6 mg were obtained.

NMR (270 MHz, D ₂ O) δ 6.89-8.00 (m, 10H); 5.5
0 (s, 2H); 2.79 (q, J = 7.6Hz, 2H); 2.49 (s, 3H); 2.41 (s, 3H);
1.17 (t, J = 7.6Hz, 3H)

Example 3 2-Ethyl-5,7-dimethyl-3-{[2- [2- (2- (triphenylmethyl)
-2H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl} -3H-imidazo [4,5-b]
Synthesis of pyridine

13 ml of carbon tetrachloride was added to 1.36 g (2.56 mmol) of 5- [2- (6-methylquinolin-2-yl) phenyl] -2- (triphenylmethyl) -2H-tetrazole obtained in Reference Example 9. Stir and add N-bromosuccinimide
0.46 g (2.46 mmol), azobisisobutyronitrile 21 mg
(0.128 mmol) and the mixture was heated under reflux for 3 hours. After allowing to cool, the mixture was concentrated, and the residue was partitioned between 40 ml of methylene chloride and 40 ml of water.
The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was 2-ethyl-5,7-dimethyl-1.
H-imidazo [4,5-b] pyridine 354 mg (2.02 mmol)
Of DMF in 11 ml of DMF was added to a solution obtained by adding 89 mg (2.22 mmol) of sodium hydride and stirring for 30 minutes. The mixture was stirred at room temperature for 15 hours, concentrated and then partitioned between ethyl acetate (20 ml) and water (20 ml), and the organic layer was dried over magnesium sulfate.

The filtrate was concentrated by filtration, and flash silica gel chromatography was performed using a 2: 3 mixed solution of hexane / ethyl acetate to give 2-ethyl-.
5,7-dimethyl-3-{[2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl} -3H-imidazo [4,5 -B] 0.86 g of pyridine was obtained.

NMR (270 MHz, CDCl ₃ ) δ 6.8-8.2 (m, 25H); 5.0
4 (s, 2H); 2.76 (q, J = 7.5Hz, 2H); 2.68 (s, 3H); 2.6 (s, 3H); 1.
28 (t, J = 7.5Hz, 3H)

Example 4 2-Ethyl-5,7-dimethyl-3-{[2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl} -3H-
Synthesis of imidazo [4,5-b] pyridine

The 2-ethyl-5,7-dimethyl-3-{[2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] quinoline-6 obtained in Example 3 -Yl] methyl} -3H-imidazo [4,5-
b] Pyridine (852 mg, 1.21 mmol) was suspended in methanol (12 ml), concentrated hydrochloric acid (12 ml) was added on an ice water bath, and the mixture was stirred at room temperature for 24 hours. The reaction solution was ice-cooled and made alkaline with a 10N aqueous sodium hydroxide solution. 10 ml of water was added and the mixture was filtered, and the cake was washed with 10 ml of a 1N aqueous sodium hydroxide solution. Concentrated hydrochloric acid was added dropwise to the filtrate with stirring to make it acidic. Ethyl acetate 1
The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 2-ethyl-5,7-dimethyl-.
3-{[2- [2- (1H-tetrazol-5-yl)]
518 mg of phenyl] quinolin-6-yl] methyl} -3H-imidazo [4,5-b] pyridine were obtained.

NMR (270 MHz, CD ₃ OD) δ 7.2-8.3 (m, 10H); 5.8
4 (s, 2H); 2.99 (q, J = 7.5Hz, 2H); 2.73 (s, 3H); 2.67 (s, 3H);
1.36 (t, J = 7.5Hz, 3H)

Example 5 2- {6-[(2-butyl-
Synthesis of 3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {methyl benzoate

Instead of 2-ethyl-5,7-dimethyl-1H-imidazo [4,5-b] pyridine, 2-butyl-
0.60 g (3.44 mmol) of 1H-imidazo [4,5-b] pyridine
The same operation as in Example 1 was performed using l) to obtain 2- ｛6-
0.68 g of [(2-butyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoate methyl was obtained.

NMR (270 MHz, CDCl ₃ ) δ 7.2-8.4 (m, 12H); 5.
7 (s, 2H); 3.62 (s, 3H); 2.85 (t, J = 7.6Hz, 2H); 1.83 (m, 2
H); 1.41 (m, 2H); 0.9 (t, J = 7.3Hz, 3H)

Example 6 2- {6-[(2-butyl-
Synthesis of 3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {sodium benzoate

2- {6-[(2-butyl-3H-imidazo [4,5-b] pyridin-3-yl) obtained in Example 5
Methyl] quinolin-2-yl methyl benzoate 0.68 g
(1.52 mmol) was subjected to the same operation as in Example 2 to give 2- {6
0.47 g of sodium [-[(2-butyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoate was obtained.

NMR (270 MHz, D ₂ O) δ 7.2-8.1 (m, 12H); 5.12
(s, 2H); 2.69 (t, J = 7.6Hz, 2H); 1.49 (m, 2H); 1.15 (m, 2
H); 0.68 (t, J = 7.3Hz, 3H)

Example 7 2- {6-[(2-propyl-3H-imidazo [4,5-b] pyridin-3-yl)
Synthesis of methyl] quinolin-2-yl {methyl benzoate

Instead of 2-ethyl-5,7-dimethyl-1H-imidazo [4,5-b] pyridine, 0.47 g of 2-propyl-1H-imidazo [4,5-b] pyridine (2.92 m
mol), the same operation as in Example 1 was carried out, and 2- ｛6
0.64 g of methyl [-[(2-propyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoate was obtained.

NMR (270 MHz, CDCl ₃ ) δ 7.2-8.4 (m, 12H); 5.
7 (s, 2H); 3.62 (s, 3H); 2.84 (t, J = 7.7Hz, 2H); 1.89 (m, 2
H); 1.0 (t, J = 7.3Hz, 3H)

Example 8 2- {6-[(2-propyl-3H-imidazo [4,5-b] pyridin-3-yl)
Synthesis of [methyl] quinolin-2-yl} sodium benzoate

Methyl 2- {6-[(2-propyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl} benzoate obtained in Example 7 0.6
4 g (1.46 mmol) was subjected to the same operation as in Example 2 to give 2-
{6-[(2-propyl-3H-imidazo [4,5-
b] pyridin-3-yl) methyl] quinolin-2-yl disodium benzoate (0.64 g) was obtained.

NMR (270 MHz, D ₂ O) δ 7.2-8.2 (m, 12H); 5.5
(s, 2H); 2.76 (t, J = 7.8Hz, 2H); 1.63 (m, 2H); 0.83 (t, J =
(7.3Hz, 3H)

Example 9 2-Ethyl-5,7-dimethyl-3-{[4-chloro-2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] Synthesis of quinolin-6-yl] methyl} -3H-imidazo [4,5-b] pyridine

5- [2- (4-Chloro-6-methylquinolin-2-yl) phenyl] -2- obtained in Reference Example 11
133 mg of (triphenylmethyl) -2H-tetrazole (0.
236 mmol) in the same manner as in Example 3 to give 2
-Ethyl-5,7-dimethyl-3-{[4-chloro-2
57 mg of-[2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl} -3H-imidazo [4,5-b] pyridine were obtained.

NMR (270 MHz, CDCl ₃ ) δ 6.8-8.2 (m, 24H); 5.
7 (s, 2H); 2.8 (q, J = 8Hz, 2H); 2.7 (s, 3H); 2.6 (s, 3H); 1.
4 (t, J = 8HZ, 3H)

Example 10 2-ethyl-5,7-dimethyl-3-{[4-chloro-2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl} Synthesis of -3H-imidazo [4,5-b] pyridine

The 2-ethyl-5,7-dimethyl-3-{[4-chloro-2- [2- (2- (triphenylmethyl) -2H-tetrazol-5-yl) phenyl) obtained in Example 9 ] Quinolin-6-yl] methyl} -3H-imidazo [4,5-b] pyridine was subjected to the same operation as in Example 4 to give 2-ethyl-5,7-dimethyl-3-{[4-chloro 22 mg of -2- [2- (1H-tetrazol-5-yl) phenyl] quinolin-6-yl] methyl} -3H-imidazo [4,5-b] pyridine was obtained.

NMR (270 MHz, CDCl ₃ ) δ 7.2-8.0 (m, 8H); 6.9
(s, 1H); 5.6 (s, 2H); 2.8 (q, J = 8Hz, 4H); 2.6 (s, 3H); 2.5
(s, 3H); 1.3 (t, J = 8Hz, 3H)

Example 11 In the same manner as in the above Reference Examples and Examples, various compounds of the present invention shown in Tables 1 and 2 below were synthesized by changing the starting compounds. The table shows the substituents R ³¹ and R of the compound represented by the following general formula (7).
³² , R ³³ , R ³⁵ and R ³⁶ are shown. In the table, “tetrazolyl” means “1H-tetrazol-5-yl group”
And “Me” represents a methyl group. In addition, NMR data of the compounds [A] to [D] and the salts thereof shown in the remarks are shown below.

[0128]

Embedded image

[0129]

[Table 1]

[0130]

[Table 2]

Compound [A]: NMR (270 MHz, CD ₃ OD) δ 7.2
-8.3 (m, 9H); 5.6 (s, 2H); 2.9 (q, J = 8.1Hz, 2H); 2.6 (s, 3
H); 2.5 (s, 3H); 0.7 (t, J = 8.1 Hz, 3H) Compound [B]: NMR (270 MHz, Acetone -d ₆ ) δ 7.1-8.3
(m, 12H); 5.6 (s, 1H); 2.7 (t, J = 7.0Hz, 2H); 1.5 (m, 2H);
0.8 (t, J = 7.0 Hz, 3H) Na salt of compound [C]: NMR (270 MHz, D ₂ O) δ 7.2-8.2
(m, 11H); 5.5 (s, 2H); 4.0 (q, J = 7.0Hz, 2H); 2.5 (s, 3H);
1.4 (t, J = 7.0 Hz, 3H) Na salt of compound [D]: NMR (270 MHz, D ₂ O) δ 7.2-8.2
(m, 10H); 5.5 (s, 2H); 4.0 (t, J = 7.0Hz, 2H); 2.6 (s, 3H);
2.5 (s, 3H); 1.4 (t, J = 7.0 Hz, 3H) Na salt of compound [E]: NMR (270 MHz, D ₂ O) δ 7.2-8.2
(m, 12H); 5.5 (s, 2H); 4.0 (q, J = 7.1Hz, 2H); 2.5 (s, 3H);
2.2 (m, 1H); 1.4 (t, J = 7.1Hz, 3H); 1.1 (m, 4H)

[Activity Test Example 1] Inhibition experiment of binding of angiotensin II to rat smooth muscle cells

The compound of the present invention and ¹²⁵ I-Tyr ⁴ -angiotensin II (0.25 μCi,
150 μl: “NEX-105”, manufactured by NEX, hereinafter abbreviated as ¹²⁵ I-AII), and incubated at room temperature for 1 hour. After washing unbound ¹²⁵ I-AII with PBS (phosphate buffer), the radioactivity of the bound ¹²⁵ I-AII was measured, and the binding of the compound of the present invention synthesized in each Example to the angiotensin II receptor was measured. The inhibitory activity value (IC ₅₀ ) was determined. The results were as follows.

IC ₅₀ of the compound of Example 1: 4.4 × 10 ⁻⁷ M IC ₅₀ of the compound of Example 2: 6.4 × 10 ⁻⁹ M IC ₅₀ of the compound of Example 4: 9.4 × 10 ⁻¹⁰ M IC ₅₀ of compound 6: 1.1 × 10 ⁻⁸ M IC ₅₀ of compound of Example 10: 7.7 × 10 ⁻⁹ M

Formulation Example 1: Tablet 1) 10.0 mg of target compound of the present invention 2) Fine granules 209 (manufactured by Fuji Chemical Co., Ltd.) 46.6 mg sodium aluminate metasilicate 20 wt% corn starch 30 wt% lactose 50 wt% 3) crystalline cellulose 24.0 mg 4) carboxymethyl cellulose calcium 4.0 mg 5) magnesium stearate 0.4 mg

1), 3) and 4) are all
Pass through a 00 mesh sieve. After drying 1), 3), 4), and 2) to reduce the water content to a certain level, they are mixed at the above-mentioned weight ratio using a mixer. 5) is added to the mixed powder having uniform quality and mixed for a short time (30 seconds), and the mixed powder is tableted (punch: 6.3 mmφ, 6.0 mm).
R) to give a tablet of 8.5 mg per tablet.

The tablet may be coated, if necessary, with a commonly used gastrosoluble film coating agent (for example, polyvinyl acetal diethylaminoacetate) or an edible coloring agent.

Formulation Example 2: Capsule 1) 50 g of the target compound of the present invention 2) lactose 935 g 3) magnesium stearate 15 g After weighing each of the above components, they are mixed uniformly, and 200 mg of the mixed powder is filled in a hard gelatin capsule. did.

Formulation Example 3: Injection 1) 5 mg of the target compound of the present invention 2) 100 mg of sucrose 3) 10 ml of physiological saline The above mixture was filtered through a membrane filter, and then sterilized and filtered again. The solution was dispensed into vials, filled with nitrogen gas, and sealed to give an intravenous injection.

[0140]

As shown in the activity test examples, the quinoline derivative of the present invention has a high angiotensin II antagonistic activity and is useful as a therapeutic agent for cardiovascular diseases such as hypertension and heart failure due to its blood pressure lowering effect. Conceivable.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location C07D 471/04 107 C07D 471/04 107A 107E 107Z 473/00 473/00 473/02 473/02 473 / 28 473/28 473/40 473/40 (72) Inventor Yoshitomi Morisawa 1150 Hazawacho, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Asahi Glass Co., Ltd., Central Research Laboratory (72) Inventor Shin Arata Yasuda 1150 Hazawacho, Kanagawa-ku, Yokohama-shi, Kanagawa Address Asahi Glass Co., Ltd. Central Research Laboratory (72) Inventor Noriyoshi Nakamura 2- 25-1, Shodai Otani, Hirakata City, Osaka Midori Cross Co., Ltd. Central Research Laboratory (72) Inventor Yoshihisa Inoue 2-25, Shodai Otani, Hirakata City, Osaka Prefecture No. 1 Midori Cross Co., Ltd. Central Research Laboratory (72) Inventor Ebiichi 2-25-1, Odani Otani, Hirakata City, Osaka Midori Cross Co., Ltd. Inside the Central Research Laboratory (72) Inventor Takamichi Ishida 2-25-1, Shodai Otani, Hirakata-shi, Osaka Midori Cross Co., Ltd.

Claims (11)

(57) [Claims] 1. A quinoline derivative represented by the general formula (1) or a salt thereof. Embedded image [In the general formula (1), R ^{1 to} R ⁸ are as follows. R ¹ : lower alkyl group, halo-lower alkyl group, cyclo-lower alkyl group, alkenyl group, alkoxyl group, alkoxy-lower alkyl group, or alkylthio group. R ² , R ³ : both may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyclo-lower alkyl group, an alkenyl group, an alkoxyl group, a C _m F _{2m + 1} -,-(CH
_{2) n} R ⁹ _{or, - (CH 2) p COR} 10. R ^4: a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group or _{C m F 2m + 1, -} . R ^5: a hydrogen atom, a halogen atom, -COOH, -COO
R ^11, -CONH ₂ or -CN,. ^{R 6: -COOH, -COOR 12,} -CONH 2, -C
N, -NHSO ₂ CF ₃ or C bond tetrazolyl group. R ⁷ and R ⁸ : both may be the same or different, and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group, or C _m F _{2m + 1-} . X and Y: both may be the same or different;
CH or nitrogen atom. Here, the above R ^{9 to} R ¹² and m, n and p are as follows. R ⁹ : a hydroxyl group or an alkoxyl group. R ¹⁰ : a hydrogen atom, a hydroxyl group, a lower alkyl group, or an alkoxyl group. R ¹¹ and R ¹² : both may be the same or different, and each is independently a lower alkyl group, an alkenyl group, a cyclo lower alkyl group, an aryl group, or an aralkyl group. m is an integer of 1 to 6. n is an integer of 1 to 4. p is an integer of 0-4. ] 2. A quinoline derivative according to the general formula (1), wherein R ¹ is a lower alkyl group or an alkenyl group,
R ² and R ³ may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, — (CH ₂ ) _n R ⁹ , or — (CH ₂ ) _p COR.
¹⁰ (where R ⁹ is a hydroxyl group or an alkoxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is an integer of 1 to 4, and p is an integer of 0 to 4). 2. The compound of claim 1, wherein: 3. The quinoline derivative according to claim 1, wherein R ⁴ is a hydrogen atom and R ⁵ is a hydrogen atom, a chlorine atom, —COOH or —COOR ¹¹ in the general formula (1). Or 2 compounds. 4. The quinoline derivative according to claim 1, wherein R ⁶ is —COOH, —COOR ¹² or a C-bonded tetrazolyl group in the general formula (1).
A compound according to any one of claims 3 to 3. 5. The quinoline derivative in the general formula (1), wherein R ⁷ and R ⁸ may be the same or different and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a lower alkyl group, or an alkoxyl group. The compound according to any one of claims 1 to 4, which is a quinoline derivative which is a group. 6. The compound according to claim 1, wherein the quinoline derivative is a quinoline derivative in which X is a nitrogen atom and Y is CH in the general formula (1). 7. The quinoline derivative is a compound represented by the formula (1), wherein R ¹ is a lower alkyl group, R ² and R ³ may be the same or different, and each independently represents a hydrogen atom,
Lower _{alkyl, - (CH 2) n R} 9 or, - (CH
₂ ) _p COR ¹⁰ (where R ⁹ is a hydroxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group or an alkoxyl group, n is 1 and p is 0 to 1), R ⁴ is a hydrogen atom, and R ⁵ is Hydrogen or chlorine atom, R ⁶ is —COO
H, —COOR ¹² (where R ¹² is a lower alkyl group, an alkenyl group, a cyclo-lower alkyl group, an aryl group, or an aralkyl group), or a C-bonded tetrazolyl group, and R ⁷ and R ⁸ are the same or different. The compound according to claim 1, which is independently a hydrogen atom, a fluorine atom, a chlorine atom, or a lower alkyl group, a quinoline derivative in which X is a nitrogen atom and Y is CH. 8. 8- (6-butyl-3H-imida)
Zo [4,5-b] pyridin-3-yl) methyl] quinoli
2--2-ylbenzoic acid or a salt thereof, 2- {6-[(7-methyl-2-propyl-3H-imid)
Dazo [4,5-b] pyridin-3-yl) methyl] quino
Phosphorus-2-ylbenzoic acid or a salt thereof, 2- {6
-[(2-ethyl-5,7-dimethyl-3H-imidazo
[4,5-b] pyridin-3-yl) methyl] quinoline
-2-yl} benzoic acid or a salt thereof, 2- {6-[(2-butyl-3H-imidazo [4,5-
b] pyridin-3-yl) methyl] quinolin-2-i
Methyl methyl benzoate, 2- {6-[(7-methyl-2-propyl-3H-imi
Dazo [4,5-b] pyridin-3-yl) methyl] quino
Phosphorus-2-yl methyl benzoate, 2- {6-[(2-ethyl-5,7-dimethyl-3H-
Imidazo [4,5-b] pyridin-3-yl) methyl
Methyl quinolin-2-yl} benzoate, N- {2-} 6-[(2-ethyl-5,7-dimethyl-
3H-imidazo [4,5-b] pyridin-3-yl) me
Tyl] quinolin-2-yl {phenyl} trifluorome
Tansulfonamide, 2-butyl-3- {2- [2- (1H-tetrazole)
-5-yl) phenyl] quinolin-6-yl {methyl}
-3H-imidazo [4,5-b] pyridine, or
A salt of 7-methyl-2-propyl-3- {2- [2- (1H
-Tetrazol-5-yl) phenyl] quinoline-6
Ill {methyl} -3H-imidazo [4,5-b] pyridi
Or a salt thereof, 2-ethyl-5,7-dimethyl-3- {2- [2-
(1H-tetrazol-5-yl) phenyl] quinoline
-6-yl {methyl} -3H-imidazo [4,5-b]
Pyridine or a salt thereof, or 2-ethyl-5,7-dimethyl-3- {4-chloro-
2- [2- (1H-tetrazol-5-yl) phenyi
Le] quinolin-6-yl} methyl}-3H-Imi Dazo
[4,5-b] pyridine or a salt thereof. 9. An angiotensin II antagonist comprising the quinoline derivative or a salt thereof according to any one of claims 1 to 8 as an active ingredient. 10. A prophylactic or therapeutic agent for cardiovascular diseases, comprising the quinoline derivative according to any one of claims 1 to 8 or a salt thereof as an active ingredient. 11. A preventive or therapeutic agent for hypertension or heart failure comprising the quinoline derivative or a salt thereof according to any one of claims 1 to 8 as an active ingredient.