WO1993016071A1

WO1993016071A1 - Heterocyclic derivatives as angiotensin ii antagonists

Info

Publication number: WO1993016071A1
Application number: PCT/JP1993/000133
Authority: WO
Inventors: Teruo Oku; Hiroyuki Setoi; Hiroshi Kayakiri; Shigeki Satoh; Takayuki Inoue; Yuki Sawada; Akio Kuroda; Hirokazu Tanaka
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1992-02-07
Filing date: 1993-02-03
Publication date: 1993-08-19
Also published as: JPH07508502A; GB9202633D0

Abstract

The object compound of formula (I) wherein R is quinolyl or naphthyridinyl which may have suitable substituent(s), R1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R?2, R3 and R4¿ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R?2 and R3¿ are linked together to form 1,3-butadienylene; R5 is hydrogen or imino-protective group; A is lower alkylene; Q is CH or N; X is N or CH; Y is NH, O or S; and n is 0 or 1; and pharmaceutically acceptable salts thereof which are useful as a medicament.

Description

DESCRIPTION

Heterocycl i c deri vati ves as angiotensi n II antagoni sts

TECHNICAL FIELD

The present invention relates to novel heterocyclic derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to novel quinol ine or naphthyridine derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as angiotensin I I antagonism and the like, to process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.

Accordingly, one object of the present invention is to provide novel quinoline or naphthyridine derivatives and a pharmaceutically acceptable salt thereof, which are useful as a potent and selective antagonist of angiotensin I I receptor.

Another object of the present invention is to provide process for preparation of said quinoline or naphthyridine derivatives or a salt thereof. A further ob j ect of the present invent ion is to provide a pharmaceutical composition comprising, as an active ingredient, said quinoline or naphthyridine derivatives or a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a use of said quinoline or naphthyridine derivatives or a pharmaceutically acceptable salt thereof as a medicament such as angiotensin I I antagonist useful for treating or preventing angiotensin I I mediated diseases, for example, hypertension (e. g. essential hypertension, renal hypertension, etc. ), heart failure, and the like in human being or animals.

DISCLOSURE OF INVENTION

The heterocyclic derivatives of the present invention are novel and can be represented by the formula (I) :

wherein R is quinolyl or naphthyridinyl which may have suitable substituent(s), R is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, ammo or acylamino, R^, R^ and R⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form 1, 3-butadienylene, R"³ is hydrogen or imino-protective group,

A is lower alkylene, Q is CH or N, X is N or CH, Y is NH, 0 or S, and n is 0 or 1.

According to the present invention, the object compound (I) can be prepared by the following processes.

Process 1

(ID

or a salt thereof

Process 2

or a salt thereof

or a salt thereof

Process 3

or

or a salt thereof

Process 4

Removal of the imino — protective group

(I - d) or a salt thereof

or a salt thereof Wherein R, R¹ R², R³, R⁴, R⁵, A, Q, X, Y and n are each as defined above, is oxo(lower)alkyl or halogen, R k is hydroxy(lower)alkyl or hydrogen, R ^ is i ino-protective group, and

R" is acid residue.

Suitable salts of the compound (I) are conventional non-toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e. g. sodium salt, potassium salt, cesium salt, etc.), an alkali earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e. g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N^!- dibenzylethylenediamine salt, etc. ), etc. ; an inorganic acid addition salt (e. g. hydrochloride, hydrobromide, sulfate, phosphate, etc. ) ; an organic carboxylic or sulfonic acid addition salt (e. g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. ); a salt with a basic or acidic amino acid (e. g. arginine, aspartic acid, glutamic acid, etc. );and the like, and the preferable example thereof is an acid addition salt.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.

The term "lower" is .intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" and lower alkyl group in the term "lower alkylthio" may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, preferably one having 1 to 5 carbon atoms, and the like. Suitable "lower alkenyl" may include vinyl, 1-propenyl, allyl, 1- butenyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms, in which the most preferred one is vinyl. Suitable "lower alkylene" is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, hexamethylene, and the like, in which the preferred one is methylene. Suitable "halogen" means fluoro, chloro, bromo and iodo.

Suitable "lower alkoxy" may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferable one is Ci -C _* alkoxy. Suitable acyl group in the term "acylamino" may include carbamoyl, thiocarbamoyl, sulfamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, in which the preferable one is aliphatic acyl such as lower alkanoyl (e. g. formyl, acetyl, propionyl, butyryl, hexanoyl, etc. ).

Suitable "mono or di or trihalo (lower) alkyl " may include chl oromethyl, f luoromethy l, d if luoromethyl , dichl oromethyl , trifluoromethyl, trifluoromethylpropyl, and the like.

Suitable " hydroxy (lower)alkyl " may include hydroxymethyl, hydroxyethyl, and the like.

Suitable "oxo (lower)alkyl " may include formyl, formylmethyl, formylethyl, and the like.

Suitable "esterified carboxy" may include lower alkoxycarbonyl (e. g. methoxycarbonyl, ethoxycarbonyl, etc. ), and the like.

Suitable "imino-protective group" may include conventional one, and the preferable example thereof is ar( lower) alkyl such as mono-(or di- or tri-)phenyl(lower)alkyl (e. g. benzyl, benzhydryl, trityl, etc. ), acyl such as lower alkoxycarbonyl (e. g. tert-butoxycarbonyl, etc. ), lower alkanesulfonyl (e. g. mesyl, etc. ), arenesulfonyl (e. g. tosyl, etc. ), oxo ; and the like, in^~which the most preferred one is trityl.

Suitable substituent in the term "quinolyl or naphthyridinyl which may have suitable substituent (s) " is conventional one used in a pharmaceutical field and may include lower alkyl, halogen, lower alkoxy, hydroxy (lower)alkyl as mentioned above, respectively ; optionally esteri f ied carboxy such as carboxy, lower alkoxycarbonyl (e. g. ethoxycarbonyl, etc. ) ; oxo, and the like. Suitable "acid residue" may include halogen (e. g. fluoro, chloro, bromo, iodo), acyloxy (e. g. acetoxy, tosyloxy, mesyloxy, etc.) and the like.

Par t i cu l ar ly , t he pref erred embod i men t of " qu i nol y l o r naphthyridinyl which may have suitable substituents" is as follows.

4-quinolyl, 4-(2-lower alkyDquinolyl, 2-(4-lower alkyDquinolyl, 1 -(2-oxo-4-lower alkyDquinolyl, 2-lower alkyl-1, 5-naphthyridin-4-yl.

The processes for preparing the object compound (I ) of the present invention are explained in detail in the following.

Process 1 :

The object compound (I) or a salt thereof can be prepared by subjecting the compound (II) to the formation reaction of a tetrazole group. The agent to be used in the present reaction may include conventional ones which is capable of converting a cyano group to a tetrazolyl group such as metal azide, for examle, alkali metal azide(e. g. , potassium azide, sodium azide etc.), tri(lower)alkyltin azide(e. g. trimethyltin azide, etc.), triaryltin azide (e. g. triphenyltin azide, etc.), or the like.

The present reaction is usually carried out in the presence of a base such as tri(lower)alkylamine(e. g. triethylamine, etc.), and the like, or 1, 3-dimethyl-2-imidazolidinone, and the like.

The present reaction is usually carried out in a solvent such as xylene, dioxane, chloroform, methylene chloride, 1, 2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which does not adversely affect the reaction.

The reaction^"temperature is not critical and the reaction is usually carried out under warming or heating, preferably under heating. Further, the compound (I) wherein R is amino can be prepared by reducing the corresponding nitro compound in a conventional manner, and the compound (I) wherein R is acylamino can be prepared by acylating the amino compound obtained above in a conventional manner.

^■ And further, the present reaction includes, within its scope, the case that the dihalo(lower)alkyl group on R , R"^ or R⁴ is transformed to the oxo(lower)alkyl group during the reaction or at the post-treating step of the present process.

Process 2 : The obj ect compound ( I -b) or a salt thereof can be prepared by subjecting the compound (I -a) or a salt thereof to reduction.

The reduction may include, for example, chemical reduction with an alkali metal borohydride (e. g. sodium borohydride, etc. ) , and catalytic reduction with palladium catalysts (e. g. palladium on carbon, etc. ), and the like.

This reaction is usually carried out in a conventional solvent which does not adversely inf luence the reaction such as alcohol [e. g. methanol, ethanol, propanol , etc. ] , tetrahydrofuran, dioxane, dimethylsulfoxide, N, N-dimethylf ormamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 3 :

The object compound (I-c) or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with the compound (IV) or a salt thereof.

The present reaction is usually carried out in the presence of a base such as alkyl lithium (e. . n-butyl lithium, etc.), alkali metal hydride (e. g. sodium hydride, potassium hydride, etc.), di(lower)alkylamine (e.g. diisopropylamine, etc. ), tri (lower)alkylamine (e. g. trimethylamine, triethylamine, etc.), pyridine or its derivative (e.g. picoline, lutidine, 4-dimethylaminopyridine, etc. ), or the like.

The present reaction is usually carried out in a solvent such as dioxane, dimethyl sulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran, or any other solvent which does not adversely affect the reaction. In case that the base to be used is liquid, it can also be used as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating. Process 4 :

The object compound (I-e) or a salt thereof can be prepared by- subjecting the compound (I-d) or a salt thereof to removal reaction of the imino-protective group. Suitable method for this removal may include conventional one which is capable of removing an imino-protective group on a tetrazolyl group such as hydrolysis, reduction, or the like. The hydrolysis is preferably- carried out in the presence of the base or an acid.

Suitable base may include, for example, an inorganic base such as alkali metal hydride (e. g. sodium hydroxide, potassium hydroxide, etc. ), alkaline earth metal hydroxide, (e. g. magnesium hydroxide, calcium hydroxide, etc. ), alkali metal carbonate, (e. g. sodium carbonate, potassium carbonate, etc. ), alkaline earth metal carbonate (e. g. magnesium carbonate, calcium carbonate, etc. ), alkali metal bicarbonate (e. g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate

(e. g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e. g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e. g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc. ), or the like, and an organic base such as trialkylamine (e. g. trimethylamine, triethylamine, etc.), picoline, N- methylpyrrolidine, N-methylmorpholine, 1, 5-diazabicyclo- [4, 3, 0]non-5- one, 1, 4-diazabicyclo[2, 2, 2]octane, 1, 5-diazabicyclo[5, 4, 0]-ucdecene-5 or the like. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof. Suitable acid may include an organic acid (e. g. formic acid, acetic acid, propionic acid, etc. ) and an inorganic acid (e. . hydrochloric acid, hydrobromic acid, sulfuric acid, etc. ).

The present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature orunder warming or heating.

The starting compounds (II), (III) and (IV) are new and can be prepared by the methods of Preparations mentioned below or a similar manner thereto or a conventional manner. The object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction precipitation, fractional crystallization, recrystallization, chro atography, and the like.

The object compound (I) thus obtained can be converted to its salt by a conventional method.

The object compound (I) of the present invention exhibits angiotensin antagonism such as vasodilating activity and is useful as an angiotensin II antagonist and effective to various angiotensin II mediated diseases such as hypertension (e. g. essential hypertension, renal hypertension, etc. ), heart failure, and the like.

Further, the object compounds of the present invention are useful as therapeutical and/or preventive agents for cardiopathy (e. g. angina pectoris, arrhythmia, myocardial infarction, etc. ), hyperaldosteronism, cerebral vascular diseases, senile dementia, ophtahlimic diseases (e. g. glaucoma, etc.), and the like; and diagnostic agents to test the renin angiotensin system.

For therapeutic or preventive administration, the object compound(I) of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral, external and inhalant administration. The pharmaceutical preparation may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.

If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.

While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases.

The following Preparations and Examples are given for the purpose of illustrating the present invention.

Preparation 1

Sodium hydride (125.6mg) was added to 4-hydroxy-2-methylquinoline

(500mg) in 10ml of dimethylformamide at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 30 minites.

Then l~(4-bromomethylphenyl)-4- chloropyrrole-2-carbonitrile (928.4mg) was added to the solution at room temperature, and the reaction mixture was stirred at room temperature for 30 minites. Ethyl acetate and water was added to the mixture, and filtered in vacuo. The filtrate was separated, and the organic layer was washed with water (twice)and brine, and dried over magnesium sulfate , evaporation. The solid was washed with ether to give 4-[4-(4-chloro-2-cyano-l-pyrrolyl)benzyloxy]-2- methylquinoline (761mg) as a white solid. mp : 214-216°C NMR (DMSO-dg, <5) : 2.60 (3H, s), 5.48 (2H, s), 7.11 (1H, s),

7.4K1H, d, J=1.0Hz), 7.50 (1H, t, J=7.5Hz), 7.61-7.92 (7H, m), 8.15 (1H, d, J=7.5Hz)

Praparation 2 Sodium hydride (69mg) was added to the 2-ethyl-4-hydroxyquinoline

(299mg) in 6ml of dimethylformamide at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. Then l-(4-bromomethylphenyl)-4-chloropyrrole-2-carbonitrile (510mg) was added to the solution at room temperatuer, and the reaction mixture was stirred at room temperature for one hour. Ethyl acetate and water was added to the mixture, and filtered in vacuo to give 4-[4^~(4-chloro-2- cyano-l-pyrrolyl)benzyloxy]-2-ethylquinoline (396.6mg). The filtrate was separated, and the organic layer was washed with water (twice) and brine, and dried over magnesium sulfate, evaporation. The solid was washed with diisopropyl ether to recover the same compound (183.5mg) as a white solid, mp : 184-188. 5°C

NMR (DMS0-d₆, όD : 1. 32 (3H, t, J=7. 5Hz), 2. 90 (2H, q, J=7. 5Hz), 5. 49

(2H, s), 7. 10 (1H, s), 7. 40 (1H, d, J=l. 0Hz), 7. 50C1H, dt, J=l. 0Hz & 7.

5 0Hz), 7. 67 (2H, d, J=9. 0Hz), 7. 71 (1H, dt, J=l. 0Hz & 7. 0Hz), 7. 80 (2H, d,

J=9. OHz), 7. 83 (1H, d, J=1. 0Hz), 7. 90 (1H, dd, J=7. OHz & 1. 0Hz), 8. 16

(1H, dd, J=7. OHz & 1. OHz)

Preparation 3

10 4-hydroxy-2-propylquinol ine (600mg) was dissolued in 12ml of dimethylformamide under nitrogen atmosphere and sodium hydride (128. 8mg) was added to the solution. The mixture was stirred at room temperature for 30 minutes, and l-(4-bromomethylphenyl)-4-chloropyrrole- 2-carbonitrile (947. 2mg) was added to the solution. The mixture was

15 stirred at room temperature for 1. 5 hours and poured into water. The solution was extracted with ethyl acetate , and the organic layer was washed with water and brine, and dri ed over magnesi um sulfate, evaporation. The solid was washed with ether to give 4- [4-(4-chloro-2- cyano-l-pyrrolyl)benzyloxy]-2-propylquinoline (894. Omg) as a white solid.

20 mp : 149-153 °C

NMR (DMS0-d₆, <5 ) : 0. 94 (3H, t, J=7. 5Hz), 1. 69-1. 90 (2H, m), 2. 84C2H, t, J=7. 5Hz), 5. 50 (2H, s), 7. 10 (1H, s), 7. 39 (1H, d, J=1. 5Hz), 7. 50 (1H, t, J=7. 5Hz), 7. 66 (2H, d, J=9. OHz), 7. 62-7. 93 (2H, m), 7. 79 (2H, d, J=9. 0Hz), 7. 82 (1H, d, J=1. 5Hz), 8. 15 (1H, d, J=7. 5Hz)

25

Preparation 4

To a stirred solution of l-(4-bromomethylphenyl)-4-chloropyrrole- 2- carbonitrile (1.50g) in N, N-dimethylformamide (15ml) was added potassium acetate (996mg) in one portion under nitrogen atmosphere and the

* 30 resulting mixture was stirred at ambient temparature for 2 hours. The mixture was diluted with ethyl acetate and washed with water (three times) and saturated sodium chloride. The organic phase was added over magnesium sulfate, filtered, and concentrated in vacuo to give l-(4- acetoxymethylphenyl)-4-chloropyrrole-2-carbonitrile(l.41g) as a

35 ^' colorless oil. NMR (CDClg, c5 ) : 2. 15 (3H, s), 5. 16 (2H, s), 6. 91 (1H, d, J=l. 5Hz), 7. 04 (1H, d, J=1. 5Hz), 7. 41 (2H, d, J=9. OHz), 7. 52 (2H, d, J=9. OHz)

Preparation 5 To a stirred solution of l-(4-acetoxyphenyl)-4-chloropyrrole-2- carbonitrile (1.40g) in ethanol (14ml) was added potassium carbonate (1.

06g) at room temperature and the heterogeneous mixture was stirred at the same temperature for one and half hours. The mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The organic phase was washed with water and then saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to afford 4-chloro-l-(4

-hydroxymenthylphenyDpyrrole -2-carbonitrile (823mg) as a white solid. mp : 89-92 °C

NMR (CDClg, δ ) : 1.87 (1H, t, J=5. OHz), 4.78 (2H, d, J=5. OHz), 6.90 (1H, d, J=1.5Hz), 7.04 (1H, d, J=1.5Hz), 7.42 (2H, d, J=9. OHx),

7.53 (2H, d, J=9.0Hz)

Preparation 6

To a stirred of solution 4-chloro-l-(4-hydroxymethylphenyl)-pyrrole- 2-carbonitrile (569mg) in N, N-dimethylformamide (11ml) was added sodium hydride (98mg;60% oil dispersion) at room temperature and the resulting mixture was stirred at the same temperature for half an hour. Then 4- chloroquinoline was added to the mixture, and the mixture was stirred for an hour. The mixture was diluted with ethyl acetate and water and the precipitated solid was filtered and washed with ethyl acetate, to give

4-[4-(4-chloro-2-cyano-l-pyrrolyl)benzyloxy]quinoline as a while solid. mp : 199-203°C

NMR (DMS0-d₆, δ ) : 5.51 (2H, s), 7.17 (1H, d, J=5. OHz), 7.40 (1H, d, J=l.5Hz), 7.59 (1H, t, J=8.0Hz), 7.66 (2H, d, J=9. OHz), 7.77 (1H, t, J=8. OHz), 7.79 (2H, d, J=9.0Hz), 7.83 (1H, d, J=l.5Hz), 7.98 (1H, d, J=8.0Hz), 8.23 (1H, d, J=8. OHz), 8.76 (1H, d, J=5. OHz)

Preparation 7

Sod i um hyd r i de ( 1 25. 6mg) wa s added to t he 4 - hydro xy - 2 - ' methylquinoline(500mg) in 10ml of dimethylformamide at room temperature under nitrogen atmosphere. The mixture was stierrd at room temperature _* for 1.5 hours. Then 2-(4-methanesulfonyloxymethyl)-l.5-dimethylpyrrole-

3-carbonitrile (956mg) was added to the solution at room temperature, and the reaction mixture was stirred at room temperature for 2 hours, and 5 poured into water . The solution was diluted with ethyl acetate . The resulting solid was collected by filtration to give 4-[4-[3-cyano-l.5- dimethyl-2-pyrrolyl)benzyloxy]-2-methylquinoline (314. O g). The filtrate was separated, and the aqueous layer was extracted with ethyl acetate . The combined organic layer was was hed with water (three times) and 10 brine, and dried over magnesium sulfate evaporation, and the solid was washed with ether to recover the same compound (632.8mg) mp : 148.5-150.5 °C

NMR (DMS0-d₆, <5) : 2.27 (3H, s), 2.63 (3H, s), 3.50 (3H, s), 5.46 (2H, s), 6.36 (1H, s), 7.12 (1H, s), 7.5K1H, dt, J=l. OHz & 7.0Hz), 15 7.57 (2H, d, J=9. OHz), 7.71 (1H, dt, J=l. OHz & 7. OHz), 7.73 (2H, d, J=9. OHz), 7.88 (1H, dd, J=7. OHz & 1. OHz), 8.17 (1H, dd, J=7. OHz & 1. OHz)

Preparation 8 20 Sodium hydride (125.6mg) was added to 4-hydroxy-2-methylquinoline

(500mg)in 10ml of dimethylformamide at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 1.5 hours.

Then 2-(4-methanesulfonyloxymethyl)-l-ethyl-5-methylquinoline (1. Og) was added to the solution at room temperature, and the reaction mixture was

25 stirred at room temperature for 2 hours, and poured into water . The solution was extracted with ethyl acetate (twice), and the extracts were washed with water (three times) and brine, and dried over magnesium sulfate, evaporation. The residue was subjected on silica gel. The fraction eluted with a mixture of ethyl acetate and dichloromethane (1:2)

* 30 was collected and the solvent was removed in vacuo. The residue was washed with isopropylether to give 4-[4-(3-cyano-l-ethyl-5-methyl-2-

* pyrrolyl)benzyloxy]-2- methylquinoline (l.Olg) as a white solid, mp : 139-142 °C

NMR (CDClg, <5) : 1.22 (3H, t, J=7.0Hz), 2.31 (3H, s), 2.71 (3H, s), 35 3.90 (2H, q, J=7.0Hz), 5.31 (2H, s), 6.23 (1H, s), 6.73 (1H, s), 7.47 (1H, dt, J=l. OHz & 7.0Hz), 7.49 (2H, d, J=9. OHz),

7.62 (2H, d, J=9. OHz), 7.69 (1H, dt, J=l. OHz & 7. OHz),

7.98 (1H, dd, J=7. OHz & 1.0Hz), 8.24 (1H, dd, J=7. OHz & 1. OHz)

Preparation 9

Sodium hydride(46.2mg) was added to the 2-ethyl-4-hydroxyquinoline (200mg) in 4ml of dimethyl sulfoxide at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. Then 2-(4-methanesulfonyloxymethylphenyl)-l-ethyl-5-methylpyrrole-3- carbonitrile (367.6mg) was added to the solution at room temperature and the reaction mixture was stirred at room temperature for 12 hours, and poured into water . The solution was extracted, with ethyl acetate (twice). The combined extracts were washed with water (twice) and brine, and dried over magnesium sulfate, evaporation. The residue was purified by silica gel column chromatography eluted by a mixture of ethyl acetate and n-hexane (1:2)to give 4-[4-(3-cyano-l-ethyl-5-methyl-2-pyrrolyl)- benzyloxy]-2-ethylquinoline (444. lmg) as an amorphous oil. NMR (CDClg, (5) : 1.22 (3H, t, J=7. OHz), 1.39 (3H, t, J=7.5Hz), 2.31 (3H, s), 2.97 (2H, q, J=7.5Hz), 3.91 (2H, q, J=7. OHz), 5.34 (2H, s), 6.25 (1H, s), 6.74 (1H, s), 7.47 (1H, dt, J=l. OHz & 7.0Hz), 7.49 (2H, d, J=9. OHz), 7.62 (2H, d, J=9. OHz), 7.69 (1H, dt, J=l. OHz & 7.0Hz), 7.98 (1H, dd, J=7. OHz & 1. OHz),

8.25 (1H, dd, J=7. OHz & 1. OHz)

Preparation 10

The following compound was obtained according to a similar manner to that of Preparation 3.

4-[4-(2-chloro-4-cyano-l-methyl-3-pyrrolyl)benzyloxy]-2- ethylquinoline mp : 198-202 °C

NMR (CDClg, δ ) : 1.32 (3H, t, J=7.5Hz), 2.89 (2H, q, J=7.5Hz), 3.70 (3H, s), 5.43 (2H, s), 7.11 (1H, s), 7.42-7.62 (3H, m), 7.62-7.75 (3H, m), 7. 82-7.93 (2H, m), 8.14 (1H, d, J=9. OHz)

Preparation 11 A mixture of 4-chloro-l-(4-methylphenyl)pyrrole-2- carbonitrile (10.8g), sodium azide(12.9g) triethylamine hydrochloride(34.2g) and 1, 3- dimethyl-2-imidazolidinone(100ml) were stirred at 135 °C for 15 hours under nitrogen atomosphere. The mixture was washed with ice-water and hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic phase was combined and washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue preparative thin layer chromatography (dichloromethane-methanol=9:l) to afford 4-chloro -l-(4-methylphenyl)-2-(lH-tetrazol-5-yl)pyrrole (9.42g). NMR (DMSO-dg, <5) : 2.37 (3H, s), 6.92 (1H, d, J=1.5Hz), 7.17 (2H, d, J= 8.0Hz), 7.26 (2H, d, J=8. OHz), 7.47 (1H, d, J=l.5Hz)

Preparation 12

4-chloro-l-(4-methylphenyl)-2-(lH-tetrazol-5-yl)pyrrole (5.24g), triphenylmethyl chloride(5.91g), triethylamine(3. Oml), dichloromethane (50ml) were combined under nitrogen atomosphere. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diisopropyl ether to give 4-chloro-l-(4-methylphenyl)-2 -(l-trityl-lH-tetrazol-5-yl)pyrrole(10.05g) as an amorphous solid. NMR (CDClg, δ : 2.32 (3H, s), 6.82-7.39 (21H, m)

Preparation 13

A mixture of 4-chloro-l-(4-methylphenyl)-2-(l-trityl-lH-tetrazol-5 -yl)pyrrole (5.35g), N-bromosuccinimide(3.98g) and 2, 2 ^' -azobis(4-methoxy

-2, 4-dimethylvaleronitrile(345mg) in dichloromethane(54ml) was refluxed for 3 hours, cooled to room temperature, and filtered. The filtrate was washed with aqueous sodium hydrogencarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 5-bromo-l-(4-bromomethylphenyl)-4-chloro-2-(l- trityl-lH-ltetrazol-yl)pyrrole(5.24g). mp : 180-182 °C

NMR (CDClg, δ ) : 4.39 (2H, s), 6.82-7.42 (21H, m)

Preparation 14 The following two compounds were obtained as mixture according to a similar manner to that of Preparation 1 by reacting 2^~hydroxy-4- ethylquinoline with l-(4-bromomethylphenyl)-4-chloropyrrole-2- carbonitrile. (l)2-[4-(4-chloro-2-cyano-l-pyrrolyl)benzyloxy]-4-methylquinoline. mp : 159-160.5 °C

NMR (CDClg, δ ) 2.64 (3H, s), 5.60 (2H, s), 6.83 (1H, s), 6.91 (1H, d, J=0.5Hz), 7.03 (1H, d, J=0.5Hz), 7.38-7.49 (lH,m), 7.43 (2H, d, J=9. OHz), 7.58-7.72 (1H, m), 7.67 (2H, d, J=9. OHz), 7.85 (1H, dd, J=6.0, 0.5Hz), 7. 90C1H, dd, 6.0,0.5Hz)

(2)l-[4-(4-chloro-2-cyano-l-pyrrolyl)benzyl]-4-methyl-2-quinolone. mp : 186-187.5 °C

NMR (CDClg, <5) : 2.53 (3H, s), 5-61 (2H, bs), 6.70 (1H, s), 6.88 (1H, d, J=0.5Hz), 6.98 (1H, d, J=0.5Hz), 7.19-7.31 (2H, m), 7.35 (4H, s), 7.48 (1H, dt, J=0.5, 7. OHz), 7.77 (1H, dd, J=7.0, 0.5Hz)

Example 1

4-[4-(4-Chloro-2-cyano-l-pyrrolyl)benzyloxy]-2-methylquinoline (992.3mg), trimethyltin azide (1.64)g and xylene (10ml) were combined under nitrogen atmosphere, and stirred at 125 °C for 18 hours. After cooled to room temperature, methanol (15ml) and cone, sulfuric acid (0. 5ml) were added to the mixture and stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo, and methanol was added to the residue. IN sodium hydroxide was added to the solution until pH4, and concentrated in vacuo. The solid was washed with water and ethanol. The solid triphenylmethyl chloride (515.8mg) and pyridine (5ml) were combined under nitrogen atmosphere. The mixture was stirred at room temperature for 15 hours. The mixture was diluted in ethyl acetate, and washed with water (twice) and brine, and dried over magnesium sulfate, evaporation. The residue was washed with ether to give 4-[4-[4-chloro-2- (l-trityl-lH-tetrazol-5-yl)-l-pyrrolyl]-benzyloxy]-2-methylquinoline (543.6mg) as a white solid, mp : 191-193 °C (dec. ) NMR (DMS0-d₆, <5) : 2.60 (3H, s), 5.36 (2H, s), 6.78-6.91 (6H, m), 6.97 (lH, ^' d, J=1. 0Hz), 7. 10 (1H, s), 7. 19-7. 37 (12H, m),

7. 38-7. 53(3H, m), 7. 68 (1H, t, J=7. 5Hz), 7. 86 (1H, d, J=7. 5Hz),

8. 02C1H, d, J=7. 5Hz)

Example 2

4- [4- [4-chloro-2- (l-trityl-lH-tetrazol-5-yl) -l-pyrrolyl] - benzyloxy]-2-methylquinoline (524mg), 4N-hydrochloric acid/1, 4-dioxane

(5ml) and water (0.4ml) were combined under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, and concentrated in vacuo. The residue was washed with methanol. The residue, IN sodium hydroxide (710.4ml) and methanol (10ml) were combined, and dissolved at

70 °C. The mixture was concentrated in vacuo, and the residue was washed with water. The residue, IN sodium hydroxide (787ml) and water

(2ml) were combined , and dissolved at 70 °C. The mixture was filtered through a millipore filter and lyophilized to afford sodium salt of 4-[4

-[4-chloro-2-(l-trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]-2- methylquinoline. (275. lmg) as a solid.

NMR (DMSO-dg, <5) : 2.62 (3H, s), 5.36 (2H, s), 6.39 (1H, d, J=1.0Hz), 7.09 (1H, s), 7.19 (1H, d, J=l. OHz), 7.24 (2H, d, J=9.0Hz), 7.48C1H. dt, J=l. OHz & 7.5Hz), 7.5K2H, d, J=9.0Hz), 7.69C1H, dt, J=1.0Hz & 7.5Hz), 7.85 (1H, dd, J=7.5, 1. OHz), 8.120H, dd, J=7.5, 1. OHz)

Example 3

4-[4-(4-Chloro-2-cyano-l-pyrrolyl)benzyloxy]-2-ethylquinoline (578.

2mg), trimethyltin azide (920.5ιg) and toluene (6ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 120°C for 14 hours. After cooled to room temperature, methanol and con. sulfuric acid (0.3ml) were added to the mixture, and stirred at room temperature for one hour. The organic solvent was evaporated in vacuo, and the residue was dissolved in methanol. IN sodium hydroxide was added to the solution until pH4. The reaction mixture was concentrated in vacuo. The residue was subjected to silica gel column chromatography, and eluted with a mixture of methanol and dichloromethane (1:6). The solid was washed with methyl cyanide, and the solid was washed with hot ethanol to give 4-[4- [(4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]-2- ethylquinoline. mp : 198-201 °C

NMR (DMSO-dg, δ) : 1.33 (3H, t, J=7.5Hz), 2.90 (2H, q, J=7.5Hz), 5.44 (2H, s), 6.82 (1H, d, J=l. OHz), 7.13 (1H, s), 7.35C2H, d, J=9. OHz), 7.47 (1H, d, J=1.0Hz), 7.51 (1H, dt, J=l. OHz & 7. OHz), 7.61 (2H, d, J=9. OHz), 7.71 (1H, dt, J=l. OHz & 7.0Hz) , 7.89 (1H, dd, J=7. OHz & 1. OHz), 8.13 (1H, dd, J=7. OHz & 1. OHz)

Example 4

4-C4-C4-Chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]-2- ethylquinoline (326.5mg), IN sodium hydroxide (757.2ml) and water (1ml) were combined, and stirred at 80°C (water bath) for 3 minutes. The mixture was filtered through millipore, and lyophilized to give sodium salt of 4- [4- [4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy] -2- ethylquinoline.

NMR (D₂0, δ : 1.02 (3H, t, J=7.5Hz), 2.50 (2H, q, J=7.5Hz), 4.35 (2H,s), 6.03 (1H, s), 6.10 (1H, d, J=1.0Hz), 6.43-6.57 (3H, m), 6.59 (1H, t, J=7.0Hz), 6.72 (2H, d, J=9.0Hz), 7.01 (1H, t, J=7.0Hz), 7.26 (1H, d, J=7.0Hz), 7.41 (1H, d, J=7. OHz)

Example 5

4-[4-(4-Chloro-2-cyano-l-pyrrolyl)benzyloxy]-2-propylquinoline (859.4mg), trimethyltin azide (1.32g) and xylene (16ml) were combined under nitrogen atmosphere. The mixture was stirred at 120 °Cfor 20 hours. After cooled to room temperature, methanol and cone, hydrochloric acid were added to the mixture, and stirred at room temperature for one hour. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. IN sodium hydroxide was added to the solution until pH4, and concentrated in vacuo. The residue was purified by silica gel column chromatography with a mixture of methanol and dichloromethane (1:9) as eluent to afford 4-[4-[4-chloro-2-(lH-tetrazol-

5-yl)-l-pyrrolyl]benzyloxy]-2-propylquinoline (489.4mg) as off-white solid which was solidified by treating with acetonitrile. mp : 151.5-156 °C NMR (DMS0-d₆, δ) : 0.96 (3H, t, J=7.5Hz), 1.70-1.93 (2H, m), 2.88 (2H, t, J=7.5Hz), 5.46 (2H, s), 6.89 (1H, d, J=1.5Hz), 7.16 (1H, s), 7.36 (2H, d, J=9. OHz), 7.48 (1H, d, J=1.5Hz), 7.53 (1H, t, J=8.0Hz), 7.62 (2H, d, J=9. OHz), 7.73 (1H, t, J=8.0Hz), 7.92 5 (1H, d, J=8. OHz), 8.14 (1H, d, J=8. OHz)

Example 6

4-[4-[4-Chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]-2- propylquinoline (489.8mg), IN sodium hydroxide (1.1ml) and water (3ml)

10 were combined, and dissolved at 80°C. The mixture was filtered, and the filtrate was stood at room temperature for 2 hours. The solid was collected by filltration to give sodium salt of 4-[4-[4-chloro-2-QH- tetrazol-5-yl)-l-pyrrolyl]benzyloxy]-2-propylquinoline (189.9mg) as a white solid.

15 mp : 172-178 °C

NMR (DMS0-d₆, δ) : 0.97 (3H, t, J=7.5Hz), 1.70-1.92 (2H, m),

2.85 (2H, t, J=7.5Hz), 5.39 (2H, s), 6.39 (1H, d, J=l.5Hz),

7.09 (1H, s), 7.18 (1H, d, J=l.5Hz), 7.25 (2H, d, J=9. OHz),

7.42-7.59 (3H, m), 7.70 (1H, t, J=8. OHz), 7.87 (1H, d, J=8. OHz), 8.11

20 (1H, d, 8.0Hz)

Example 7

4- [4-(4-Chloro-2-cyano-l-pyrrolyl)benzyloxy]quinoline (568.7mg), trimethyltin azide (975.9mg) and xylene (10ml) were combined under

25 nitrogen atmosphere. The mixture was stirred at 120°C for 17 hours after cooled to room temperature, methanol and cone, hydrochloric acid were added to the mixture, and stirred at room temperature for one hour. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. IN sodium hydroxide was added to the solution until pH~4, and 30 concentrated in vacuo, and the residue was purified by silica gel column chromatography (elution by methanol/dichloromethane=l/5) to afford 4- [4

-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]quinoline (80.3mg) as a amorphaus solid which was solidified by treating with acetonitrile.

The residue was purified by preparative thin layer chromatography on

35 silica gel developed by a mixtune of ammonia, methanol and chloroform (4: 25:65) to recover the same solid (43- 7mg) which was washed with ether, mp : 213-216 °C

NMR (DMS0-d₆, <5) : 5.47 (2H, s), 6.94 (1H, d, J= 5Hz), 7.19 (1H, d, J=5. OHz), 7.36 (2H, d, J=9. OHz), 7.49 (1H, d, J= 5Hz), 7.59 (1H, t, J=8. OHz), 7.61 (2H, d, J=9. OHz), 7.77 (1H, t, J=8. OHz), 7.98 (1H, d, J=8.0Hz), 8.22 (1H, d, J=8.0Hz), 8.78 (1H, d, J=5. OHz)

Example 8

4-[4-[4-Chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]quinoline (37.7mg), IN sodium hydroxide (93.8ml) and water(lml) were combined, and dissolved at 80 °C. The mixture was filtered through a millipore filter, and the filtrate was lyophilized to afford sodium salt of 4-[4-[4

-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]quinoline (41.6mg) as a pale yellow solid. NMR (DMSO-dg, δ ) : 5.40 (2H, s), 6.38 (1H, d, J=l.5Hz),

7.15 (1H, d, J=5.0Hz), 7.17 (1H, d, J=1.5Hz), 7.24 (2H, d, J=9.0Hz), 7. 51 (2H, d, J=9. OHz), 7.56 (1H, t, J=8.0Hz), 7.76 (1H, t, J=8. OHz), 7.96 (1H, d, J=8.0Hz), 8.21 (1H, d, J=8-0Hz), 8.76 (1H, d, J=5. OHz)

Example 9

4- [4-(3-Cyano-1, 5-dimethy1-2-pyrrolyl)benzyloxy] -2- methylquinoline(900m g), trimethyltin azide (1.51g) and xylene (9ml) were combined under nitrogen atmosphere. The mixture was stirred at 120 °C for 46 hours. After cooled to room temperature, and methanol and cone, hydrochloric acid (0.5ml ) were added to the solution at room temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was suspended in methanol. IN sodium hydroxide was added to the mixture until pH5, and concentrated in vacuo. The residue was subjected to column chromatography on silica gel. The fraction eluted with a mixture of methanol and chloroform (1:10 then 1:5) was collected and the solvent was evaporated in vacuo. The residue was washed with acetonitrile to give 4-[4-[l, 5-dimethyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyloxy]-2- methylquinoline (713. Omg) as an off-white solid. mp : 189-194 °C NMR (DMSO-dg, δ ) : 2.30 (3H, s), 2.79 (3H, s), 3.36 (3H, s), 5.57 (2H,s), 6.43 (1H, s), 7.44 (1H, s), 7.46 (2H, d, J=9. OHz), 7.68 (2H, d, J=9. OHz), 7.70 (1H, dt, J=l. OHz & 7.5Hz), 7.91 (1H, dt, J=l. OHz & 7.5Hz), 8.10 (1H, dd, J=7.5Hz & 1. OHz), 8.28 (1H, dd, J=7.5Hz & 1. OHz)

Example 10

4-C4-C1, 5-Dimethyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyloxy]-2- methylquinoline (704.3mg), IN-sodium hydroxide (1.72ml), water (5ml) and ethanol 5 ml were combined, and dissolved at 90 °C. The mixture was filtered through a millipore filter, and the filtrate was concentrated in vacuo. The residue was dissolved in 10ml of water, and filtered through a millipore filter. The filtrate was lyophilized to afford sodium salt of 4-[4-[1.5-dimethyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyloxy]-2- methylquinoline (6.29mg) as off white powder.

NMR (DMS0-d₆, δ ) : 2.27 (3H, s), 2.63 (3H, s), 3.37 (3H, s), 5.37 (2H, s), 6.17 (1H, s), 7.12 (1H, s), 7.48 (1H, dt, J=l. OHz & 7.0Hz), 7.49 (2H, d, J=9. OHz), 7.53 (2H, d, J=9. OHz), 7.69 (1H, dt, J=l. OHz & 7.0Hz), 7.86 (1H, dd, J=7. OHz & 1.0Hz), 8.14 (1H, dd, J=7. OHz & 1. OHz)

Example 11

4- [4-(3-Cyano-l-ethyl-5-methyl-2-pyrrolyl)benzyloxy]-2- methylquinoline (990mg), trimethyltin azide (1. 6g) and xylene ( 10ml) were combined under nitrogen atmosphere. The mixture was stirred at 120°C for 46 hours. After cooled to room temperature, methanol and cone. hydrochloric acid(0. 5ml) were added to the solution at room temperature, and stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was dissolved in methanol. IN sodium hydroxide was added dropwise to the solution until pH5, and concentrated in vacuo. The residue was subjected on silica gel. The fraction eluted with chloroform and the mixture of methanol and dichloromethane (1 : 10) was collected, and the solvent was evaporated in vacuo. The residue was solidified with acetonitrile to give 4- [4- [l- ^' ethyl- 5-methyl- 3- ( l H- tet razol- 5-y l) - 2-pyrroly l] benzyloxy] -2 - methylquinoline (989. Omg) as an off-white solid, mp : 192-201 °C

NMR (DMSO-dg, δ ) : 1.09 (3H, t, J=7. OHz), 2.33 (3H, s), 2.66 (3H, s), 3.82 (2H, q, J=7. OHz), 5.47 (2H, s), 6.39 (1H, s), 7.14 (1H, s), 7.44 (2H, d, J=9. OHz), 7.53 (1H, dt, J=l. OHz & 7.0Hz), 7.67 (2H, d, J=9. OHz), 7.73 (1H, dt, J=l. OHz & 7.0Hz), 7.89 (1H, dd, J=7. OHz & 1. OHz), 8.19 (1H, dd, J=7. OHz & 1. OHz)

Example 12 4-[4-[l-Ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]- benzyloxy]-2-methylquinoline (970mg), IN- sodium hydroxide (2.29ml), water (5ml) and ethanol 5ml were combined, and dissolved at 90°C The mixture was filtered through a millipore filter, and the filtrate was concentrated in vacuo. The residue was dissolved in 10ml of water and lyophilized to give sodium salt of 4-[4-[l-ethyl-5-methyl-3-(lH-tetrazol

-5-yl)-2-pyrrolyl]benzyloxy]-2-methylquinoline (955.2mg) as off white powder.

NMR (D₂0, <5) : 0.32 (3H, bt), 1.88 (3H, s), 2.25 (3H, s),

2.97 (2H, bm), 4.32 (2H, s), 5.93 (1H, s), 6.27 (1H, s), 6.54 (1H, t, J=7.0Hz), 6.79 (2H, d, J=9.0Hz), 6.89 (2H, d, J=9. OHz), 6.94 (1H, t, J=7.

OHz), 7.22 (1H, d, J=7.0Hz), 7.39 (1H, d, J=7. OHz)

Example 13

4-[4-(3-Cyano-l-ethyl-5-methyl-2-pyrrolyl)benzyloxy]-2- ethylquinoline (432.8mg), trimethyltin azide (675.5mg) and xylene (5ml) were combined under nitrogen atmorphere. The mixture was stirred at

120 °C for 48 hours. After cooled to room temperature, methanol and cone, hydrochloric acid (0.5ml) were added to the solution at room temperature, and stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. IN sodium hydroxide was added dropwise to the solution until pH5, and concentrated in vacuo. The residue was subjected to column chromatography on silica gel. The fraction eluted with dichloromethane and then a mixture of methanol and dichloromethane (1:10) was collected, and the solvent was evaporated in vacuo. The residue was solidified with ethyl acetate to give 2-e:nyl-4-[4-.^r] -ethyl-5-methyl-3-(lH-tetrazol-5- yl)-2-pyrrolyl]-benzyloxy]quinoline (362.3mg) as an off-white solid, mp : 188.5-195 °C

NMR (DMSO-dg, δ ) : 1.09 (3H, t, J=7. OHz), 1.32 (3H, t, J=7.5Hz), 2.32 (3H, s), 2.92 (2H, q, J=7.5Hz), 3.81 (2H, q, J=7. OHz), 5.49(2H, s), 6.38

(1H, s), 7.16 (1H, s), 7.42 (2H, d, J=9. OHz), 7.53 (1H, dt, J=l. OHz & 7. OHz), 7.66 (2H, d, J=9. OHz), 7.73 (1H, dt. J=l. OHz & 7. OHz), 7.92 (1H, dd, J=7. OHz & 1. OHz), 8.20 (1H, dd, J=7. OHz & 1. OHz)

Example 14

4-[4-[l-Ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyloxy]- 2-methylquinoline (343.6mg), IN sodium hydroxide (0.785ml) and water were combined, and dissolved, and dissolved at 80 °C. The mixture was filtered through a millipore filter, and lyophilized to give sodium salt of 4-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]-benzyloxy]-2 -methylquinoline (331.9mg) as off-white powder. NMR (DMSO-dg, 5) : 1.03 (3H, t, J=7.0Hz), 1.34 (3H, t, J=7.5Hz), 2.28 (3H, s), 2.91 (2H, q, J=7.5Hz), 3.77 (2H, q, J=7.0Hz), 5.41 (2H, s), 6.15 (1H, s), 7.11 (1H, s), 7.44 (2H, d, J=9.0Hz), 7.52 (1H, dt, J=l. OHz & 7.0Hz), 7.54 (2H, d, J=9. OHz), 7.70 (1H, dt, J=l. OHz & 7.0Hz), 7.89 (1H, dd, J=7. OHz & 1. OHz), 8.18 (1H, dd, J=7. OHz & 1. OHz)

Example 15 The following compound was obtained according to a similar manner to that Example 3.

4-[4-(2-Chloro-l-methyl-4-(lH-tetrazol-5-yl)-3-pyrrolyl]benzyloxy]

-2-ethylquinoline ^~ mp : 133-137 °C NMR (DMSO-dg, δ) : 1.33 (3H, t, J=7.5Hz), 2.91 (2H, q, J=7.5Hz), 3.74

(3H, s), 5.41 (2H, s), 7.12 (1H, s), 7.35 (2H, d, J=9. OHz), 7.45-7.63

(4H, m), 7.70 (1H, dt, J=9. OHz & 1. OHz), 7.89 (1H, d, J=9. OHz), 8.14 (1H, d, J=9. OHz)

Example 16 The following compound was obtained according to a similar manner to that Example 4.

Sodium salt of 4-[4-[2-chloro-l-methyl-4-(lH-tetrazol-5-yl)-3- pyrrolyl]benzyloxy]-2-ethylquinoline. mp : 165-171 °C

NMR (D₂0, 5) : 1.02 (3H, t, J=7.5Hz), 2.47 (2H, q, J=7.5Hz), 2.94 (3H, s), 4.39 (2H, s), 6.07 (1H, s), 6.64 (1H, t, J=9. OHz), 6.73-6.88 (3H, ), 6.88-7.00 (2H, m), 7.08 (1H, t, J=9.0Hz), 7.33-7.53 (211, ^~ )

Example 17

Sodium hydride (115mg) was added to the 2-ethyl-4-hydroxy-l, 5- naphthyridine (500mg) in dimethylformamide (10ml) at room temperature under nitrogen atmosphere. The mixture was stirred at room tepmerature for 30 minutes, and 2-bromo-l-(4-bromomethylphenyl)-3-chloro-5-(l-trityl -lH-tetrazol-5-yl)pyrrole (1.67g) was added to the solution. The mixture was stirred at room temperature for 1.5 hours, and poured into water.

The aqueous solution was extracted with ethyl acetate (twice), and the organic layer was washed with water (twice) and brine, and dried over magnesium sulfate, evaporation. The residue was subjected to flash column chromatography on silica gel. The fraction eluted with ethyl acetate was collected, and the solvent was evaporated in vacuo. The residue was solidified with ether to give 4-[4-[2-bromo-3-chloro-5-(l- trityl-lH-tetrazol-5-yl)]-l-pyrrolyl]benzyloxy]-2-ethyl-l, 5-naphthyridine

(529.5mg) as off-white solid mp : 169-173 °C

NMR (CDClg, δ ) : 1.32 (3H, t, J=7.5Hz), 2.91 (2H, q, J=7.5Hz), 5.38 (2H, s), 6.80-7.37 (20H, m), 7.43 (2H, d, J=9. OHz), 7.63 (1H, dd, J=9. OHz & 5.0Hz), 8.31 (lH,-dd, J=9. OHz & 0.5Hz), 8.93 (1H, dd, J=5.0Hz& 0.5Hz)

Example 18

4-[4-[2-bromo-3-chloro-5-(l-trityl-lH-tetrazol-5-yl)-l-pyrrolyl]- benzyloxy]-2-ethyl-l, 5-naphthyridine(525.3mg), ethanol(5ml) and cone. hydrochloric acid (1.5ml) were combined, and stirred at 90°C(water bath) for^"10 minutes and at room tepmerature for 30 minutes. The mixture was filtered in vacuo to give the solid, the solid, methanol (15ml) and IN sodium hydroxide (655.3ml) were combined, and stirred at 90 °C(in water- bath) for 10 minutes and at 0 °C for one hour. The precipitate was collected by filtration to give 4-[4-[2-bromo-3-chloro-5-(lH-tetrazol-5- yl)-l-pyrrolyl]-benzyloxy]-2-ethyl-l, 5-naphthyridine(151.6mg) as a pale yellow solid. mp : 195-202 °C

NMR (DMSO-dg, <5) : 1.39 (3H, t, J=7.5Hz), 3.03 (2H, q, J=7.5Hz), 5.57 (2H, s), 7.18 (1H, s), 7.45 (2H, d, J=9.0Hz), 7.49 (1H, s), 7.72 (2H, d, J-9.0Hz), 7.85 (1H, dd, J=8.5Hz & 4. OHz), 8.39 (1H, d, J= 8.5Hz), 8.94 (1H, d, J=4. OHz)

Example 19

4-[4-[2-bromo-3-chloro-5-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]- 2-ethyl-l, 5-naphthyridine (144.8mg), IN sodium hydroxide (283.6ml), water ^• (2ml) and ethanol (2ml) were combined, and dissolved at 90 °C (in water bath). The mixture was filtrated through a millipore filter and the filtrate was concentrated in vacuo. The residue was dissolved in 4ml of water , and lyophilized to give sodium salt of 4-[4-[2-bromo-3-chloro-5

-QH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]-2-ethyl-l, 5-naphthyridine (144. 9mg) as an off-white solid, mp : 195-202 °C

NMR (DMSO-dg) : 1.34 (3H, t, J=7.5Hz), 2.94 (2H, q, J=7.5Hz), 5.42 (2H, s), 6.60 (1H, s), 7.30 (2H, d, J=8. OHz), 7.32 (1H, s), 7.61 (2H, d, J=8. OHz), 7.72 (1H, dd, J=8. OHz & 4. OHz), 8.27 (1H, dd, J=8. OHz & 1.5Hz), 8.86 (1H, dd, J=4. OHz & 1.5Hz)

Example 20

The following compound was obtained according to a similar manner to that Example 1. 2-[4-[4-Chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyloxy]-4- methylquinoline. mp : 164-168.5 °C

NMR (DMSO-dg, δ ) : 2.62 (3H, s), 5.47 (2H, s), 6.39 (1H, d, J=0.5Hz), 7.

00 (1H, s), 7.16 (1H, d, J=0.5Hz), 7.19 (2H, d, J=9. OHz), 7.46 (2H, d, J =9. OHz), 7.39-7.52 (1H, m), 7.69 (1H, dt, J=0.5, 7. OHz), 7.81 (1H, dd, J= 7.0,0.5Hz), 7.98 (IH, dd, J=7.0, 0.5Hz).

Example 21

The following compound was obtained according to a similar manner to that Example 2.

Sodium salt of 2-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]- benzyloxy]-4-methylquinoline. mp : 122-128 °C

NMR (DMSO-dg, δ ) : 2.61 (3H, s), 5.47 (2H, s), 6.37 (IH, d, J=0.5Hz), 7. 00 (IH, s), 7.14 (IH, d, J=0.5Hz), 7.18 (2H, d, J=9. OHz), 7.40-7.51 (IH, m), 7.44 (2H, d, J=9. OHz), 7.67 (IH, dt, J=0.5, 7. OHz), 7.81 (IH, dd, J=7. 0,0.5Hz), 7.98 (IH, dd, J=7.0, 0.5Hz).

Example 22 The following compound was obtained according to a similar manner to that Example 1.

1-[4-[4-Chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-methyl-2- quinolone. mp : 230-236 °C NMR (DMSO-dg, <5) : 2.52 (3H, s), 5.55 (2H, bs), 6.65 (IH, s), 6.71 (IH, d, J=0.5Hz), 7.20 (4H, s), 7.29 (IH, dt, J=0.5, 7. OHz), 7.35 (IH, d, 0-

5Hz), 7.43 (IH, dd, J=7. OHz), 7.56 (IH, dt, J=0.5, 7. OHz), 7.83 (IH, dd,

J=7.0,0.5Hz).

Example 23

Sodium salt of l-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-4-methyl-2-quinolone. mp : 243-245 °C

NMR (DMSO-dg, <5) : 2.49 (311, s), 5.51 (2H, bs), 6.33 (IH, d, J=7.0Hz), 6. 64 (IH, s), 7.08 (IH, d, J=0.5Hz), 7.12 (4H, s), 7.27 (IH, t, J=7. OHz), 7.42 (IH, d, J=7.0Hz), 7.55 (IH, t, J=7. OHz), 7.81 (IH, d, J=7.0Hz).

Claims

C L A I M S

1. A compound of the formula :

wherein R is quinolyl or naphthyridinyl which may have suitable substituent(s),

R is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R , R^ and R⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R* are linked together to form 1, 3-butadienylene,

K³ is hydrogen or imino-protective group, A is lower alkylene, Q is CH or N,

X is N or CH, Y is NH, 0 or S, and n is 0 or 1, and pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein

R is quinolyl or naphthyridinyl, each of which may have lower alkyl, halogen, lower alkoxy, hydroxy(lower)alkyl, carboxy or lower alkoxycarbonyl. A compound of claim 2, wherein R is quinolyl or naphthyridinyl, each of which may have lower alkyl, halogen, lower alkoxy, hydroxy(lower)alkyl or lower alkoxycarbonyl, R-¹- is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or lower alkanoylamino, R , R^ and R⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono- or di- or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl, carboxy or lower alkoxycarbonyl, and K³ is hydrogen or mono- or di- or triphenyl(lower)alkyl.

4. A compound of claim 3, wherein

R and R⁴ are each hydrogen, and Q and X are each CH.

5. A compound of claim 4, which is represented by the formula:

6. A process for preparing a compound of the formula

wherein R is quinolyl or naphthyridinyl which may have suitable substituent(s), R is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,

0 9 Λ R^Δ, R° and K * are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form 1, 3-butadienylene, κ° is hydrogen or imino-protective group,

A is lower alkylene, Q is CH or N, X is N or CH, Y is NH, 0 or S, and n is 0 or 1, or a salt thereof, which comprises a) subjecting a compound of the formula :

wherein R, R¹, R², R³, R⁴, A, Q, X, Y and n are each as defined above, to formation reaction of a tetrazole group, to give a compound of the formula :

wherein R, R¹, R², R³, R⁴, R⁵, A, Q, X, Y and n are each as defined above, or a salt thereof, or subjecting a compound of the formula :

wherein R, R¹, R², R³, R⁵, A, Q, X, Y and n are each as defined above, and R⁴ _a is oxo(lower)alkyl or halogen, or a salt thereof, to reduction, to give a compound of the formula :

wherein R, R¹, R², R³, R⁵, A, Q, X, Y and n are each as defined above, and R⁴^ is hydroxy(lower)alkyl or hydrogen, or a salt thereof or reacting a compound of the formula :

R-0H wherein R is as defined above, and or a salt thereof, with a compound of the formula :

wherein R, R¹, R², R³, R⁴, R⁵, A, Q, X and Y are each as defined above, and R" is acid residue, or a salt thereof, to give a compound of the formula :

wherein R, R¹, R², R³, R⁴, R⁵, A, Q, X and Y are each as defined above, or a salt thereof, or subjecting a compound of the formula :

wherein R, R¹, R², R³, R⁴, A, Q, X, Y and n are each as defined above, and R _a is imino-protective group, or a salt thereof, to removal of the imino-pretective group, to give a compound of the formula :

wherein R, R¹, R², R³, R⁴, A, Q, X, Y and n are ^~ each as defined above, or a salt therof.

7. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

8. A method for treating or preventing angiotensin II mediated diseases, which comprises administering a compound of claim 1 or pharmaceutically acceptable salt thereof to human being or animals.

9. A method for treating or preventing hypertension or heart failure, which comprises administering a compound of claim 1 or pharmaceutically acceptable salt thereof to human being or animals.

10. A compound of claim 1 or pharmaceutically acceptable salt thereof for use as a medicament.

11. A compound of claim 1 or pharmaceutically acceptable salt thereof for use as an angiotensin II antagonist.

12. Use of a compound of claim 1 for manufacturing a medicament for treating or preventing angiotensin II mediated diseases.

13. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 with a pharmaceutically acceptable substantially non-toxic carrier or excipient.