DK165554B - Quinolizin-4-one compounds, a process for preparing them, preparations which comprise the compounds, a process for producing the preparations, and the use of the compounds - Google Patents

Abstract

4H-Quinolixin-4-onecarboxylic acids and derivs. of formula (I) and their salts are new. In (I), R1 = COOH, opt. substd. CONH2, CN, CSNH2 or tetrazolyl; R7 = H or aryl; R2 = H, OH, 1-6C alkyl or 1-6C alkoxy; R3 = H, OH, 1-6C alkyl, 1-6C alkoxy, opt. protected COOH, 2-6C alkenyloxy, opt. substd. aryl, arylthio, aroyl, aryl-(1-6C)alkyl, arenesulphonyl, arylamino opt. monosubstd. or aryloxy; or R2 + R3 = (CH2)3, CH=CH or CH=CH-CH=CH at any ring positions. Specifically claimed are N-(5-(1H-Tetrazolyl))-4H-quinol-izin-4-one-3-carboxamide (Ia) and the corresp. 1-Ph, 1-PhO and 1-PhCO cpds. and their Na salts, are specifically claimed.

Description

DK 165554 B

The present invention relates to novel quinolizin-4-one compounds and pharmaceutically acceptable salts thereof which have inhibitory effects on allergy and ulcer, a process for the preparation of the compounds, a pharmaceutical composition comprising the compounds, a process for preparation of such preparations and use of the compounds in the manufacture of a medicament for use in the treatment of allergic and ulcer diseases in humans and animals; *

Accordingly, an object of the present invention is to provide the novel and useful quinolizinone compounds and pharmaceutically acceptable salts thereof.

Another object of the invention is to provide a process for preparing the quinolizinone compounds or salts thereof, which process is characterized by:

1) a compound of general formula II

2 R7 R3 wherein r7, r2 and R.3 are each as defined below and R4 represents protected carboxy or a salt thereof subjected to an elimination reaction of the carboxy protecting group to form a compound of general formula Ia R2 R7 R3

ζ ^ ί-COOH

ISLAND

2

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and each is as defined below, or a salt thereof; or 2) a compound of the general formula Ia * 2 Z'm- co ° H ia 5 wherein R 1, R 2 and R 2 are each as defined below, or its reactive derivative at the carboxy group or a salt thereof is reacted with H wherein R 1 is as defined below to form a compound of the general formula Ib R 2 R 7 R 3 CONHR 10 Ib 0 10 wherein R 1, R 2 -O, R 2 and each are as defined below, or a salt thereof; or 3) a compound of the general formula Id R2 R7 R3 TV "0

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Wherein R7 and R3 are each as defined below, or a salt thereof is reacted with hydrogen sulfide to form a compound of the general formula le R2 S7 R3 η us 5 where R7, R4 and R3 are each as defined below, or a salt thereof; or 4) a compound of the general formula Id R 2 R 7 R 30 where R 7 and R 3 are each as defined below, or a salt thereof, is subjected to a reaction to form a tetrazole group using an agent comprising a combination of a alkali metal azide and an ammonium halide to form a compound of the general formula If R2 R7 R3 W

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wherein k7 and each are as defined below, or a salt thereof, or 5) a compound of the general formula Ig

R2 R7, RI

0 5 where R 1 and R 2 are each as defined below and R 1 represents lower alkoxycarbonyl, or a salt thereof, is subjected to an elimination reaction of the carboxy protecting lower alkyl group to form a compound of general formula Ih

2 7 COOH

Wherein R 1, R 2 and R 2 are each as defined below, or a salt thereof.

It is a further object of the invention to provide a pharmaceutical composition which contains as active ingredient said quinolizinone compounds or pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable and substantially non-toxic carrier or excipient.

A further object of the invention is to provide a process for the preparation of a pharmaceutical composition which is characterized in that a compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient is mixed with an inert carrier.

The quinolizinone compounds of the invention have the general formula I

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5 R2 R? R 3 wherein R 1 represents carboxy, thiocarbamoyl, tetrazolyl or a group 5 -CONHR 3, wherein is hydrogen, pyrimidinyl, pyrimidinyl substituted with lower alkyl, pyrazinyl, triazolyl, pyridazinyl substituted with halogen, or tetrazolyl; R 2 represents hydrogen or aryl; R 2 represents hydrogen, hydroxy, lower alkyl or lower alkoxy;

ISLAND

RJ represents hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, aryl, aryl substituted by halogen or lower alkoxy, arylthio or aryloxy;

ISLAND ISLAND

R and R are positioned at any position on the quinolizine ring; and pharmaceutically acceptable salts thereof.

According to the present invention, the compounds of general formula I can be prepared by the process variants illustrated in the following reaction schemes.

20 Method variant 1 2 fp -i Elimination of carboxy- 2 „7 3

R R R K

\ \ / the protection group /

ISLAND

IIa or a salt thereof or a salt thereof

Method variant 2 6

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"2 P7 R3 d2" 7 _3 \ \ / h2n-r! 0 r. R r iCO * ™ Η C0MR1 ° 5a Ib or its reactive derivative or a salt thereof at the carboxy group or a salt thereof

Process variant 3 10

Rx l / 3 <r7 R3 ^ M-oohh2 DehydrateU8rt "8 c." 0 o

Ic Id or a salt thereof or a salt thereof 15 Procedure variant 4 rwwr3 r2 e? r3

Hydrogen sulfide m ^ V - t v ~ ΐ2 o o s

Id le 20 or a salt thereof or a salt thereof

Method variant 5 7

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9 7 o Alkali metal azide „2„ 7 p3

R R R R. Rv R

Ammonium Halide N-N

1 Cy-- —- o Oh

Id If or a salt thereof or a salt thereof

Method variant 6

2 R7 _3 p2 R? COOH

10 R \ Elimination of the lower R alkyl alkyl group R.

Ig 1h or a salt thereof or a salt thereof wherein, lp, r7 and r10 are each as defined above, denotes protected carboxy, and R | represents lower alkoxycarbonyl.

Among the starting compounds of the present invention, the compound of general formula II can be prepared by the processes shown in the following 20 reaction schemes.

8

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Process A- (1):

R4 H

rL r <Hr5 eL

r ^ i R R ff <Y c

([1 µl HS

Il <L iv '

6 T

CH2R ° 4 I

* VS5 R4

III V

or a salt thereof. or a salt thereof Process A- (2): R2 R6 (in J _6 r2 f I Closure reaction V * -> $ C * v R4 0 V Ila 10 or a salt thereof or a salt thereof

Process B: \ 6 r6

Introduction of the hydroxy- \, ίτ jl protecting group r? X P ||

i5 HO

Fire Ile or a salt thereof or a salt thereof 9

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Process C: α Introduction of hydroxy-

the protection group L II

CH2OH -> It ^ H2OR8

Illd Ille or a salt thereof or a salt thereof

Process D:

OR8 ° .H

Elimination of the hydroxy-1 protecting group I R> IIh Ili or a salt thereof or a salt thereof 15 Process E: <? S S02

^ A. Oxidation ^ JL

- * 0 &.

Island Island

Ll Hk 20 or a salt thereof or a salt thereof where and each is as defined above, R 1 represents lower alkoxy,

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10 rA represents hydrogen, protected hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkenyloxy, aryl, which can carry halogen, lower alkyl or lower alkoxy, arylthio, aroyl, ar-lower alkyl, arensulfony1, N-lower alkylanilino or aryloxy, represents a hydroxy protecting group, r9 represents protected hydroxy, and N is 1 or 2.

Suitable pharmaceutically acceptable salts of the compounds of general formula I are conventional non-toxic salts and include acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluene sulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.) or a salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.) or a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc. ) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, Ν, Ν'-dibenzylethylenediamine salt, etc.).

Suitable examples and illustrations of the various definitions encompassed by the present invention which are used in the above and below are explained in detail below.

The terms "lower" denote 1-6 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" and "lower alkyl" moieties in "lower alkyl" may be straight or branched with 1-6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl or the like. .

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, pentyloxy, tert.pentyloxy, hexyloxy and the like, preferably with 1-4 carbon atoms.

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H

Suitable "lower alkoxycarbonyl" may include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tertiary pentyloxy-carbonyl, hexoxyloxycarbonyl and 1-cyclopropyl.

Examples of triazolyl are 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl and 2H-1,2,3-triazolyl. Examples of tetrazolyl are 1H-tetrazolyl and 2H-tetrazolyl. Examples of triazinyl are 1,2,3-, 1,2,4- and 1,3,5-triazinyl.

Suitable "halogen" may include chlorine, bromine, iodine or fluorine.

Suitable "protected hydroxy" may include a hydroxy group protected with a conventional hydroxy protecting group, e.g. lower alkyl (e.g., methyl, ethyl, propyl, n-butyl, etc.), lower alkenyl (e.g., vinyl, allyl, etc.), ar-lower alkyl such as mono- or di- or triphenyl-lower alkyl (e.g., benzyl, benzhydryl, trityl, etc.), etc., trisubstituted silyl such as tri-lower alkylsilyl (e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert.butyldimethylsilyl, diisopropylmethylsilyl) , etc.), triarylsilyl (e.g., triphenylsilyl, etc.), triar lower alkylsilyl (e.g., tribenzylsilyl, etc.), etc., and the like.

Suitable "aryl" may include phenyl, tolyl, xylyl, cumenyl, naphthyl biphenylyl and the like, which groups may have one or more substituents selected from halogen, (e.g., fluoro, chloro, bromo, iodo, etc.) and lower alkoxy. as exemplified above.

As to suitable "aryl" moieties in the terms "arylthio" and "arlavere alkyl", reference is made to those exemplified above.

Suitable "aryloxy" may include phenoxy, tolyloxy and the like.

With respect to suitable "hydroxy protecting groups", reference is made to those exemplified above.

The process variants for preparing the compounds of general formula I according to the invention are explained in detail below:

Freeware mode variant 1 12

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The compound of the general formula Ia or a salt thereof can be prepared by subjecting the compound of the general formula II or a salt thereof to an elimination reaction of the carboxy protecting group.

With respect to a suitable salt of the compound of general formula II, reference is made to the acid addition salts exemplified for the compound of general formula I, and with respect to suitable salts of the compound of general formula Ia, reference is made to the salts exemplified for the compound of the general formula I.

In the present elimination reaction, all conventional methods used in the elimination reactions of carboxy protecting groups can be used, e.g., hydrolysis, reduction, elimination using a Lewis acid, etc. If the carboxy protecting group is an ester, it can be eliminated by hydrolysis or elimination using a Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases may include, for example, inorganic bases such as alkali metal hydroxide (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.). e.g., magnesium carbonate, calcium carbonate, etc.), alkaline number hydrogen bicarbonate (e.g., sodium bicarbonate, potassium hydrogen carbonate, 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] undecen-5 or the like. Hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

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Suitable acids may include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrochloric acid, sulfuric acid, etc.).

The present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.

The temperature of the reaction is not critical and it may conveniently be selected depending on the nature of the carboxy protecting group and the elimination method.

Elimination using a Lewis acid is preferred for the elimination of substituted or unsubstituted lower alkyl esters and is carried out by reacting the compound of the general formula II or a salt thereof with a Lewis acid such as a boron trihalide (e.g. trichloride, boron trifluoride, etc.), a titanium tetrahalide (e.g., titanium tetrachloride, titanium tetrabromide, etc.), a tintetrahalide (e.g., tintetrachloride, tintetrabromide, etc.), an aluminum halide (e.g., aluminum chloride, aluminum bromide, etc.) e.g., trichloroacetic acid, trifluoroacetic acid, etc.) or the like. The elimination reaction is usually carried out in the presence of cation-absorbing agents (e.g., anisole, phenol, etc.) and usually carried out in a solvent such as a nitroalkane (nitromethane, nitroethane, etc.), an alkylene halide (e.g., methylene chloride, ethylene chloride, etc.). diethyl ether, carbon disulfide or any other solvent that does not adversely affect the reaction. These solvents can be used as mixtures thereof.

The reduction elimination can preferably be used to eliminate protecting groups such as a halogen-lower alkyl ester (e.g., 2-iodoethyl, 2,2,2-trichloroethyl, etc.), an ar-lower alkyl ester (e.g., benzyl, etc.) or the like.

For example, a reduction method applicable to the elimination reaction may comprise reduction using a combination of a metal (e.g., zinc, zinc amalgam, etc.) or a salt of a chromium compound (e.g., chromochloride, chromoacetate, etc.) and an organic or an inorganic acid ( e.g., acetic acid, propionic acid, hydrochloric acid, etc.); and a conventional 14

DK 165554B

catalytic reduction in the presence of a conventional metallic catalyst (e.g., palladium carbon, Raney nickel, etc.).

The reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or warming up.

The present elimination reaction of the carboxy protecting group comprises the case where another protected carboxy is converted to free carboxy during the reaction or post-treatment step of this process variant.

Method variant 2

The final compound of the general formula Ib or a salt thereof can be prepared by reacting the compound of the general formula Ia or its reactive derivative at the carboxy group or a salt thereof with 15 H 2 N-R 10.

For suitable salts of the compound of general formula Ib, reference is made to the salts exemplified for the compound of general formula I.

Suitable reactive derivatives at the carboxy group of the compound of general formula Ia may include acid halides, acid anhydrides, activated esters and the like. Suitable examples may be an acid chloride; an acidic acid; a mixed acid anhydride with an acid such as a substituted phosphoric acid (e.g., a dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, a halogenated phosphoric acid, etc.), a dialkylphosphoric acid, sulfuric acid, sulfuric acid, -linic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or an aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [[CH3) 2] = 011 -] ester, vinyl ester, propar gylester, p-nitrophenyl ester,

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2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, or ester, or piperidyl ester, N-hydroxy compound (e.g., N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H * benzotriazole, etc.) and the like.

If the compound of general formula Ia is used in free acid form or in salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-di-cyclohexylcarbodiimide, N-cyclohexyl-N '-morpholinoethylcarbodiimide, N-ethyl N '- (3-dimethylaminopropyl) carbodiimide, 1,1'-carbonyldiimidazole, thionyl chloride, oxalyl chloride, a lower alkoxycarbonyl halide (e.g. ethyl chloroformate, isobutyl chloroformate, etc.), 1- (p-chlorobenzene sulfonloxy) -6 -H-benzotriazole or the like.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction. Of these solvents, hydrophilic solvents can be used in admixture with water.

The reaction in the presence of a condensing agent is usually carried out under anhydrous conditions, which is not critical.

The reaction may be carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate, etc.), a tri-lower alkylamine (e.g., trimethylamine, triethylamine, etc.), pyridine or derivatives thereof (e.g., picoline, lutidine, 4-dimethylaminopyridine, etc.) or the like. In the event that the base or condensing agent used is a liquid, this may also be used as a solvent.

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16

The reaction temperature is not critical and the reaction is usually carried out under weak or vigorous heating, preferably under vigorous heating.

Method variant 3 ___

The final compound of the general formula Ie or a salt thereof can be prepared by reacting the compound of the general formula Id or a salt thereof with hydrogen sulfide.

The present reaction is usually carried out in a solvent 10 such as 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 at ambient temperature under weak or vigorous heating.

Method variant 4

The final compound of the general formula If or a salt thereof can be prepared by subjecting the compound of the general formula Id or a salt thereof to a reaction to form a tetrazole group.

As to suitable salts of the compound of general formulas If and Id, reference is made to the acid addition salts exemplified from the compound of general formula I.

The agent used in the reaction comprises a combination of an alkali metal azide (e.g. potassium azide, sodium azide, etc.) and an ammonium halide (e.g. ammonium chloride).

The reaction is usually carried out in a solvent such as dioxane, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran,

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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 weak or vigorous heating.

Method variant 5

The compound of general formula Ih or a salt thereof may be prepared by subjecting the compound of general formula Ig or a salt thereof to an elimination reaction of the lower alkyl group.

As to suitable salts of the compounds of the general formulas Ig and Ih, reference is made to the salts exemplified for the compound of the general formula I.

The reaction can be carried out in a manner similar to process variant 1 described above, and therefore reference is made to process variant 1, 15 regarding reaction methods and conditions (e.g. reaction temperature, solvent, etc.).

Process A- (1):

The compound of the general formula V or a salt thereof can be prepared by reacting the compound of the general formula III or a salt thereof with the compound of the general formula IV.

As to suitable salts of the compounds of general formulas III and V, reference is made to the acid addition salts exemplified for the compound of general formula I.

The reaction can preferably be carried out in the presence of an alkyl lithium (e.g. n-butyllithium), lithium diisopropylamide, an alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, etc.) and the like.

18

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The reaction is usually conducted in a solvent such as acetone, dioxane, acetonitrile, dimethylformamide, benzene, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate or any other solvent which does not adversely affect the reaction.

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

Process A- (2): 10 _

The compound of general formula IIa or a salt thereof may be prepared by subjecting the compound of general formula V or a salt thereof to a cyclization reaction.

As to suitable salts of the compound of general formula V, 15, reference is made to the acid addition salts exemplified for the compound of general formula I.

The reaction may preferably be carried out in the presence of a suitable agent such as a mixture of diphenyl and diphenyl ether used as a heating medium.

The reaction temperature is not critical and the reaction is usually carried out under heating.

Process B:

The final compound of the general formula Ile or a salt thereof can be prepared by subjecting the compound of the general formula Ile or a salt thereof to a reaction for introducing the hydroxy protecting group.

19

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For suitable salts of the compounds of the general formulas Ild and Ile, reference is made to the acid addition salts exemplified for the compound of the general formula I.

If the protecting group to be introduced is lower alkyl or lower alkenyl, the reaction may be carried out by reacting the compound of the general formula Ild with a lower alkylating agent or lower alkenylating agent.

The lower alkylating agent or lower alkenylating agent used in the present reaction may comprise conventional agents such as a mono (or di-) lower alkyl sulfate (e.g., dimethyl sulfate, etc.), a lower alkyl lower alkanesulfonate (e.g., methyl methanesulfate). phonate, etc.), a halogen-lower alkane (e.g., bromomethane, iodomethane, iodethane, iodobutane, etc.), a halogen-lower alkene (e.g., iodine propene, etc.) or the like.

If a lower alkylating agent is used as a lower alkyl ester of an acid, the reaction is usually carried out in a solvent such as water, acetone, tetrahydrofuran, ethanol, ether, dimethylformamide or any other solvent which does not adversely affect the reaction.

The reaction is preferably carried out in the presence of a conventional base such as an inorganic or organic base.

The reaction temperature is not critical and the reaction is usually carried out under temperature conditions varying from cooling to heating at the solvent boiling point.

Process C:

The compound of the general formula IIle or a salt thereof can be prepared by subjecting the compound of the general formula Uld or a salt thereof to a reaction for introducing the hydroxy protecting group.

20

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The reaction may be carried out in a conventional manner.

If the protecting group to be introduced is a silyl group, the reaction is carried out by reacting the compound of the general formula Wool or a salt thereof with a compound of the general formula 5 VI

Ra - X VI

where Ra represents trisubstituted silyl and X represents an acid residue.

Suitable acid residues may include halogen (e.g., chlorine, bromine, etc.) or the like.

The reaction is preferably carried out in the presence of imidazole, a 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent. adversely affects the reaction.

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

Process D:

The compound of general formula II or a salt thereof may be prepared by subjecting the compound of general formula Uh or a salt thereof to an elimination reaction of the hydroxy protecting group.

The elimination reaction is carried out according to conventional methods such as method variant 1.

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21

The reaction is preferably carried out in the presence of a mild reagent such as tetra-n-butylammonium fluoride.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction. .

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

Process E:

The final compound of the general formula Hk or a salt thereof can be prepared by oxidizing the compound of the general formula IIj or a salt thereof.

The oxidizing agent used in this reaction may contain an inorganic peracid or a salt thereof (e.g., periodic acid, persulfuric acid, or its sodium or potassium salts, etc.), an organic peracidic acid or a salt thereof (e.g., perbenzoic acid, m-chloroperbenzoic acid, acid, peracetic acid, chloroperacetic acid, trifluoroacetic acid or its sodium or potassium salts, etc.), ozone, hydrogen peroxide, urea / hydrogen peroxide, an N-halogeno succinimide (e.g. N-bromosuccinimide, N-chlorosuccinimide, etc.), a hypochlorite compound butyl hypochlorite, etc.), a permanganate (e.g., potassium permanganate, etc.) or any other conventional oxidizing agent capable of oxidizing a sulfinyl group to a sulfonyl group.

The reaction may also be carried out in the presence of a compound comprising a group of Vb or VIb metal in the periodic system, e.g. tungsten, molybdenic acid, vanadic acid, etc. or an alkali or alkaline earth metal salt thereof.

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The oxidation reaction is usually carried out in a conventional solvent which does not adversely affect the reaction, such as water, acetic acid, chloroform, methylene chloride, acetone, methanol, ethanol or a mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out by semen under temperature conditions varying from cooling to ambient temperature.

More specifically, those compounds of general formula I having the most potent antimicrobial activity may be represented by the following general formula R 30 where R 1, R 2, and R 2 are each as defined above, and preferably R Represents tetrazolylamido, R 1 and R 2 each represent hydrogen and R 1 represents aryloxy or aroyl.

Therefore, in order to demonstrate the pharmaceutical utility of the quinolizinone compound of general formula I, pharmaceutical test data are illustrated below.

1. Test compounds: (A) N- [5- (1H-Tetrazolyl)] - 4H-quinolizin-4-one-3-carboxamide (B) N- [5- (1H-Tetrazolyl)] - 7-ethyl 4H-quinolizin-4-one-3-carboxamide (C) N- [5- (1H-Tetrazolyl)] - 7-methoxy-4H-quinolizin-4-one-3-carboxamide (D) N- [5- ( 1H-Tetrazolyl) -1-phenyl-4H-quinolizin-4-one-3-carboxamide (E) N- (2-Pyrimidinyl) -4H-quinolizin-4-one-3-carboxamide (F) 4H-Quinolizine -4-one-3-carboxylic acid (G) -3- [5- (1H-Tetrazolyl)] - 4H-quinolizin-4-one (H) N- [5- (1H-Tetrazolyl)] -7-hydroxy 4H-quinolizin-4-one-3-carboxamide (I) N- [5- (1H-Tetrazolyl)] -9-methyl-4H-quinolizin-4-one-3-carboxamide 23

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(J) 7- (n-Butoxy) -1-phenyl-N- [5- (1H-tetrazolyl)] -4H-quinolizin-4-one-3-carboxamide (K) N- [5- (1H-Tetrazolyl) )] -1-Methyl-4H-quinolizin-4-one-3-carboxamide (L) N- [5- (1H-Tetrazolyl)] -1-phenoxy-4H-quinolizin-4-one-3-carboxamide Mid-sodium salt.

2. Test: (A) Inhibition of stress pulses 1) Test method:

Sprague-Dawley rats were used which weighed approx. 200 g. Every 10 animals were immobilized in a small cage and placed in a water bath, allowed to breathe. The temperature of the water bath was maintained at 22 ° C. The test compounds were administered orally immediately prior to immobilization. 7 hours later, the animals were sacrificed and their stomachs removed. The stomach was then fixed with 2% formalin. The ulceration fs 15 areas were measured for each animal. The mean area (Mr) in the test animals was compared to the area in the control animals and the inhibition relative to controls was calculated.

2) Test Results: 20 Test Compound Dose Inhibition No. (mg / kg) (%) (A) 32 83.6 (B) 32 89.2 25 (D) 32 89.2 (E) 32 88.6 (F) 32 63.2 (J) 32 67.0 (L) 0.01 57.3

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24 (B) Effect on passive cutaneous anaphylaxis (PCA) 1)

Recipient animals for PCA reactions were Sprague-Dawley female rats, 7 weeks old, 180-200 g (Nihon Kurea). Each experiment included 5 observations - 5 observations.

Five times crystallized ovalbumin (OVA) (Sigma, Lot 31F-8061) was used as antigen.

BDF1 female mice, 7 weeks old (Nihon Kurea), were given a primary injection (left footpad, subcutaneously) of 100 µg OVA in 0.05 ml of salt-10 water and after 20 days a booster injection by the same route. Blood was withdrawn 28 days after the primary injection and the sera were stored at -80 ° C.

The animals were pre-cut with an electric mower and prepared for passive cutan anaphylaxis (PCA) by injection of 0.05 ml of 15 antiserum dilutions (1/16, 1/32) on each side of the dorsal skin.

They were then stimulated 48 hours later with an intravenous injection of 1 ml of 0.5% Evans-Blue containing 5 mg of OVA. 50 minutes later they were sacrificed and the lesions measured (diameter).

A minimal skin response was with a 5 mm or larger blue spot measured on the 20 dermal side of reflected skin. Substance activity was calculated using the following formula: Substance-treated (dia; mm)% Inhibition 1-x 100 saline-treated (dia; mm) Drugs were suspended in 0.1% methylcellulose / saline and administered intravenously with the antigen.

DK 165554 B

25 2) Test results

Test Composition Dose Antiserum Concentration Inhibition No. (mg / kg) Tration (%) 5 ___ (A) 10 1/16 94.5 (B) 10 1/16 100 (C) 10 1/16 100 (G) 10 1 / 16 94.7 10 (H) 10 1/16 100 (I) 10 1/16 86.5 (K) 10 1/16 82.5 (L) 0.1 1/32 100 The pharmaceutical composition of the invention can may be used in the form of a pharmaceutical composition, for example in solid, semi-solid or liquid form containing an active substance of the invention in admixture with an organic or inorganic carrier or excipient suitable for external, oral or parenteral use. For example, the active ingredient may be formulated with the usual nontoxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. Suitable carriers are water, glucose, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in solid form preparations. semi-solid or liquid form, and auxiliaries, stabilizers, thickeners, dyes and perfumes can also be used. The 30 pharmaceutical compositions may also contain preservatives or bacteriostatic agents to keep the active ingredient in the desired compositions stable in activity. The active compound is included in the pharmaceutical composition in an amount sufficient to provide the desired therapeutic effect on the disease process or condition.

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DK 165554B

When using the preparation in humans, it is preferred to use it by intravenous, intramuscular or oral administration. Although the dose or therapeutically effective amount of the compound of the invention varies with respect to and also depends on the age and condition of each patient to be treated, a daily dose of approx. 0.05-5 mg of the active ingredient per kg for humans or animals, and on average, single doses of approx. 2.5 mg, 25 mg and 250 mg.

The invention is illustrated by the following preparations and examples.

PREPARATION 1

To a solution of 7 ml of 2-methylpyridine in 140 ml of tetrahydrofuran was added dropwise 49 ml of a 1.59 M n-butyllithium solution in hexane under ice-cooling. The resulting dark red solution was allowed to warm to ambient temperature and stirred for 1 hour. After 15 cooling to -78 ° C, a solution of 15.68 ml of diethylethoxymethylene malonate in 50 ml of tetrahydrofuran was added over 30 minutes. The reaction mixture was allowed to warm to -20 ° C and stirred for 30 minutes at -20 ° C. 4.48 ml of acetic acid was added. The solvent was distilled off and the residue was dissolved in ethyl acetate and washed with a 10% aqueous solution of sodium hydrogen carbonate, water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated to give 27 g of an oil. The residue was chromatographed on silica gel (Merck 0.21-0.063 mm, 270 g) eluted with chloroform to give 19 g of ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) butyrate as an oil.

IR Spectrum (film): v = 1730, 1590, 1470, 1440 and 1370 cm -1.

NMR Spectrum (CDCl3): δ (ppm) - 0.97 (t, 3H, J = 8Hz), 1.26 (t, 6H, J = 8Hz), 3.12 (d, 1H, J = 8Hz) , 3.2-3.6 (m, 2H), 3.62 (d, 1H, J = 8Hz), 4.21 (q, 4H, J = 8Hz), 4.47 (q, 2H, J = 8Hz), 6.97-7.80 (m, 3H), 8.42-8.67 (m, 1H).

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DK 165554B

PREPARATION 2

A mixture of 18.9 g of ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) butyrate, 48.85 g of diphenyl and 135.8 g of diphenyl ether was heated to 250 ° C for 40 minutes. The reaction mixture was cooled to ambient temperature and chromatographed on silica gel (Merck 0.21-0.063 mm, 620 g) eluted with hexane and then with a mixture of ethanol and chloroform (1:49) to give a crude oil which was recrystallized from a mixture of ether and hexane (1: 1) to give 11.48 g of 3-ethoxycarbonyl-4H-quinolizin-4-one as yellow crystals.

IR Spectrum (Nujol): ν max = 1670, 1625 and 1490 cm

NMR Spectrum (CDCl3): δ (ppm) - 1.42 (t, 3H, J ~ 7Hz), 4.42 (q, 2H, J-7Hz), 6.62 (d, 1H, J «8Hz) , 7.02-7.38 (m, 1H), 7.53-7.68 (m, 2H), 8.33 (d, 1H, J-8Hz), 9.23-9.47 (m, I H).

PREPARATION 3 The following compounds were prepared in a manner similar to Preparation 1: 1) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (5-ethylpyridyl)] butyrate.

IR Spectrum (film): i / χ »1750 and 1730 cm -1.

2) Ethyl 4-phenyl-3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) butyrate.

20 IR Spectrum (film): χ - 1750 (shoulder) and 1730 cm- ·.

3) Ethyl 3-ethoxy-2-ethoxycarbonyl 1-4 - [2- (5-hydroxypyridyl 1)] butyrate.

IR Spectrum (film): v - 2550, 1730, 1490, 1270, 1160, 1090 and max 1025 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = 0.97 (t, 3H, J = 7Hz), 1.25 (t, 6H, J = 7Hz), 3.07 (d, 2H, J-5Hz) , 3.20-4.77 (m, 8H), 6.47 (m, 1H), 7.07-7.37 (m, 2H), 8.17 (m, 1H).

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DK 165554B

4) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (3-methylpyridyl)] butyrate.

IR spectrum (Nujol): v - 1750, 1735, 1575, 1440, 860 and 790 cm

QåX

NMR Spectrum (CDCl3): δ (ppm) = 0.92 (t, 3H, J = 5Hz), 1.27 (t, 6H, J5Hz), 2.37 (s, 3H), 3.08 -3.60 (m, 4H), 3.70 (d, 1H, J-5Hz), 4.18 (q, 2H, J = 5Hz), 4.22 (q, 2H, J = 5Hz), 4 , 52 (m, 1H), 7.05 (dd, 1H, J = 6 and 3Hz), 7.45 (d, 1H, J-6Hz), 8.42 (d, 1H, J = 3Hz).

5) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (4-methylpyridyl)] butyrate.

IR Spectrum (film): v = 1750, 1730, 1600, 1240, 1150 and 1020 cm cm “.

max. NMR Spectrum (CDCl 3): δ (ppm) - 0.97 (t, 3H, J = 7Hz), 1.27 (t, 6H, J = 7Hz), 2.32 (s, 3H), 3 , 10 (d, 2H, J = 5.5Hz), 3.28-3.58 (m, 2H), 4.20 (q, 3H, J = 7Hz), 4.23 (q, 3H, J = 7Hz), 6.87-7.13 (m, 2H), 8.40 (d, 1H, J = 6Hz).

6) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (6-methylpyridyl)] butyrate. IR Spectrum (film): u - 1650, 1630, 1590, 1580, 1270, 1150 and ΟΙβΛ 1090 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) - 0.97 (t, 3H, J = 7Hz), 1.25 (t, 6H, J = 7Hz), 2.48 (s, 3H), 3, 07 (d, 2H, J = 5.5Hz), 3.60 (q, 2H, J = 7Hz), 3.23-3.57 (m, 1H), 4.18 (q, 4H, J = 7Hz) ), 4.33-4.67 (m, 1H), 6.85-7.15 (m, 2H), 7.33-7.66 (m, 1H).

7) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) pentanoate.

IR Spectrum (film): - 1750, 1730, 1590, 1300, 1090 and 1020 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) - 1.00 (t, 3H, J-7Hz), [1.35 (t, J = 7H- z), 1.25 (t, J = 7Hz), 1.25 (s) 9H], 3.00-3.75 (m, 4H), 3.93-4.58 (m, 5H), 6.98-7.60 (m, 2H), 7, 65 (m, 1H), 8.58 (m, 1H).

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DK 165554B

8) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (5-methylpyridyl)] butyrate.

IR spectrum (film): u - 1740, 1730, 1600, 1480, 1150, 1090 and nineax 1025 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) - 1.00 (t, 3H, J = 7Hz), 1.27 (t, 6H, J-7Hz), 2.32 (s, 3H), 3.00 -3.77 (m, 4H), 4.22 (q, 3H, J-7Hz), 4.25 (q, 3H, J = 7Hz), 7.03-7.50 (m, 2H), δ , 37 (m, 1H).

9) Ethyl 3-ethoxy-4-methoxy-4- (2-pyridyl) -2-ethoxycarbonylbutyrate.

IR Spectrum (film): +/- 1750, 1730, 1590, 1365, 1090, 1025 and

IQflX

760 cm -1.

NMR Spectrum (CDCl3): δ (ppm) - 0.78 (t, 3H, J = 7Hz), 1.25 (t, 3H, J-7Hz), 1.28 (t, 3H, J-7Hz) , 3.33 (d, 2H, J-4Hz), 3.60-4.60 (m, 9H), 7.07-7.90 (m, 3H), 8.62 (m, 1H).

PREPARATION 4 The following compounds were obtained in a manner similar to Preparation 2.

1) 7-Ethyl-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 81-83 ° C.

IR Spectrum (Nujol): 1 / - 1720 and 1630 cm -1 NMR Spectrum (CDCl 3): δ (ppm) - 1.32 (t, 3H, J-7Hz), 1.44 (t, 3H, J -7Hz), 2.76 (q, 2H, J-7Hz), 4.40 (q, 2H, J-7Hz), 6.60 (d, 1H, J «8Hz), 7.52 (s, 2H ), 8.32 (d, 1H, J = 8Hz), 9.20 (s, 1H).

2) 1-Phenyl-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 120-123 ° C.

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DK 165554B

IR Spectrum (Nujol): t / + = 1730 and 1620 cm

NMR Spectrum (GDC13): δ (ppm) - 1.36 (t, 3H, J = 7Hz), 4.38 (q, 2H, J = 7Hz), 7.04-7.76 (m, 7H) , 8.32 (s, 1H), 9.48 (d, 1H, J = 8Hz).

3) 8-Hydroxy-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 242 ° C (decomp.).

IR Spectrum (Nujol): u - = 3300, 3200, 1680, 1660, 1620, 1300, 1140, msx 960 and 900 cm -1.

NMR Spectrum (dimethylsulfoxide -dg): S (ppm) = 2.27 (t, 3H, J = 7Hz), 4.23 (q, 2H, J = 8Hz), 6.13 (d, 1H, J = 8Hz), 7.58 (dd, 1H, J = 2 and 8Hz), 7.90 (d, 1H, J »8Hz), 8.07 (d, 1H, J = 8Hz), 8.82 (d , 1H, J = 2Hz).

Analysis:

Calculated for ΟΟΟΟΗ: C 61.80 H 4.75.

Found: C, 62.18; H, 5.05.

4) 9-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one, m.p. 125-126 ° C.

IR Spectrum (Nujol): v = 3090, 1725, 1645, 1590, 1125 and

ITlfiX

1100 cm'1.

NMR Spectrum (CDCl 3): δ (ppm) = 1.40 (t, 3H, J = 7Hz), 2.50 (s, 3H), 4.42 (q, 2H, J = 7Hz), 6.63 (d, 1H, J = 9Hz), 7.07 (t, 1H, J = 7Hz), 7.47 (d, 1H, J = 7Hz), 8.35 (d, 1H, J = 9Hz), 9.32 (d, J = 7Hz, 1H).

Analysis:

Calculated for C, 67.52; H, 5.67.

Found: C, 67.51; H, 5.83.

5) 8-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 146-148 ° C.

IR Spectrum (Nujol): = 3060, 1720, 1660, 1640, 1245, 1155 and 790 cm

DK 165554 B

31 NMR Spectrum (CDCl3): δ (ppm) = 1.40 (t, 3H, J = 7Hz), 2.50 (s, 3H), 4.38 (q, 2H, J = 7Hz), 6.50 ( d, 1H, J-9Hz), 7.00 (dd, 1H, J = 7 and 2Hz), 7.30 (d, 1H, J = 2Hz), 8.32 (d, 1H, J-9Hz), 9.28 (d, 1H, J = 7Hz).

Analysis: δ Calculated for 33 ^3 ^ () 3: C 67.52 ′ H 5.67.

Found: C, 67.38; H, 5.65.

6) 3-Ethoxycarbonyl-6-methyl-4H-quinolizin-4-one, m.p. 90-93 ° C.

IR Spectrum (Nujol): - 1720, 1650, 1620, 1590, 1265, 1120, 1100 inex and 795 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = 1.35 (t, 3H, J-7Hz), 3.05 (s, 3H), 4.38 (q, 2H, J-7Hz), 6.38 ( d, 1H, J-8Hz), 6.67 (m, 1H), 7.25 (d, 1H, J-4.5Hz), 8.18 (d, 1H, J-8Hz).

Analysis:

Calcd for ^ 3 ^ 3 ^ 03: C 67.52 H 5.67 N 6.07.

Found: C, 67.28; H, 5.63; N, 6.03.

7) 1-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 142-143 ° C.

IR Spectrum (Nujol): v - 1720, 1650, 1620, 1595, 1300, 1230, 1160, Π13.Χ 1120 and 775 cm cm ".

NMR Spectrum (CDCl 3): δ (ppm) = 1.42 (t, 3H, J-7Hz), 2.40 (s, 3H), 4.43 (q, 2H, J-7Hz), 7, 20 (m, 1H), 7.62-7.80 (m, 2H), 8.25 (s, 1H), 9.47 (m, 1H).

Analysis:

Calcd. For C ^ 3H₂O: C 67.52 H 5.67 N 6.06.

Found: C, 67.49; H, 5.94; N, 6.06.

8) 7-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 146-149 ° C.

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DK 165554B

IR Spectrum (Nujol): v ** 1720, 1620, 1145 and 1110 cm

max NMR Spectrum (CDCl3): δ (ppm) - 1.42 (t, 3H, J = 7Hz), 2.45 (s, 3H), 4.43 (q, 2H, J = 7Hz), 6, 62 (d, 1H, J = 8Hz), 7.47-7.57 (m, 2H), 8.33 (d, 1H, J = 8Hz), 9.23 (m, 1H).

Analysis:

Calculated for ΟΟΟΗΙϊΟΙϊΟ: C 67.52 H 5.62 N 6.06.

Found: C 67.44 H 5.85 N 6.00.

9) 1-Methoxy-3-ethoxycarbonyl-4H-quinolizin-4-one, m.p. 132-133 ° C.

IR spectrum (Nujol): v - 1680, 1670, 1620, 1595, 1360, 1120, 1020 max and 770 cm cm ".

NMR Spectrum (CDCl 3): δ (ppm) = 1.43 (t, 3H, J = * 7Hz), 3.93 (s, 3H), 4.45 (q, 2H, J-7Hz), 7, (M, 1H), 7.67 (m, 1H), 7.97-8.20 (m, 2H), 9.47 (d, 1H, J-7.5Hz).

Analysis:

Calcd for O 2% 3Ν04: C 63.15 H 5.30 N 5.66.

Found: C, 62.80; H, 5.33; N, 5.63.

PREPARATION 5

To a stirred solution of 4.5 g of 3-ethoxycarbonyl-7-hydroxy-4H-20 quinolizin-4-one in 90 ml of dry N, N-dimethylformamide was added sodium hydride (60% in mineral oil, 0.93 g, at room temperature). ) and the resulting solution was kept for 30 minutes at 50 ° C. The reaction mixture was treated with 4.13 g of methyl iodide and stirred for 30 minutes at the same temperature. The reaction mixture was poured into dilute hydrochloric acid solution and extracted with chloroform. The organic phase was washed with water, dried over anhydrous magnesium sulfate and evaporated to give 12.3 g of an oil which was put on a silica gel column. Elution with chloroform / methanol (99: 1) gave 3.75 g of 3-ethoxycarbonyl-7-methoxy-4H-quinolizin-4-one, mp 156-158 ° C.

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DK 165554B

IR Spectrum (Nujol): 1 / = 1720, 1620, 1500, 1140 and 1100 cm -1.

ΠΙβΧ NMR Spectrum (CDCl3): δ (ppm) - 1.43 (t, 3H, J «7Hz), 3.93 (s, 3H), 4.43 (q, 2H, J-7Hz), δ, 63 (d, 1H, J = 8.5Hz), 7.23-7.70 (m, 2H), 7.28 (d, 1H, J-8.5Hz), 9.00 (m, 1H).

Analysis:

Calcd for C CjH₂jNO4: C, 63.15; H, 5.30.

Found: C, 62.62; H, 5.52.

PREPARATION 6 The following compounds were prepared in a manner similar to Preparation 5.

1) 3-Ethoxycarbonyl-7-n-butoxy-4H-quinolizin-4-one, mp 132-133 ° C.

IR Spectrum (Nujol): v - 1710, 1620, 1540, 1280, 1240, 1140, 845

ClflX

and 780 cm "· * ·.

NMR Spectrum (CDCl3): δ (ppm) = 1.00 (t, 3H, J = 6Hz), 1.43 (t, 3H, J-7.5Hz), 1.50-2.33 (m , 4H), 4.10 (t, 2H, J = 6Hz), 4.43 (q, 2H, J = 7.5Hz), 6.63 (d, 1H, J = 8Hz), 7.23-7 , 67 (m, 2H), 8.28 (d, 1H, J = 8Hz), 8.97 (d, 1H, J = 2Hz).

Calcd. For C 16 H 19 NO 4: C 66.42 H 6.62 N 4.84.

Found: C, 66.54; H, 6.52; N, 4.82.

2) 3-Ethoxycarbonyl-7-isopropoxy-4H-quinolizin-4-one, mp 132-134 ° C.

IR Spectrum (Nujol): ν = 1725, 1625, 1240, 1140, 1100, 970 and 2540 cm40 ".

MMR Spectrum (CDCl3): S (ppm) * 1.42 (d, 6H, J = 6Hz), 1.43 (t, 3H, J = 7.5Hz), 4.43 (q, 1H, J * = 7.5Hz), 4.65 (m, 2H), 6.62 (d, 1H, J = 8.5Hz), 7.20-7.68 (m, 2H), 8.27 (d, 1H) , J = 8.5Hz), 9.00 (d, 1H, J = 2Hz).

DK 165554 B

34

Calcd for C 15 H 17 NO 4: C 65.44 H 6.22 N 5.09.

Found: C, 65.66. H 6.15 N 5.10.

PREPARATION 7 The following compounds were prepared in a manner similar to Preparation 1.

1) Ethyl 4-phenyl-4- (2-quinolyl) -3-ethoxy-2-ethoxycarbonylbutyrate.

IR Spectrum (film): “1750, 1730, 1590, 1500, 1150, 1090 and 1030 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) - 0.82 (3H, t, J = 7Hz), 1.20 (3H, t, J = 7Hz), 1.28 (3H, t, J = 7Hz) ), 3.12 (1H, m), 3.42-4.47 (6H, m), 4.67 (1H, m), 5-, 25 (1H, m), 7.12-8, 27 (11H, m).

2) Ethyl 4- (2-pyridyl) -4- (1-naphthyl) -3-ethoxy-2-ethoxycarbonylbutyrate.

IR Spectrum (film): 1750, 1720, 1580, 780 and 750 cm

NMR Spectrum (CDCl 3): δ (ppm) - 0.60 (3H, t, J = 7Hz), 1.20 (6H, t, 20 J = 7Hz), 2.20-4.53 (8H, m ), 5.33 (1H, m), 6.95-8.10 (10H, m), 8.58 (1H, m).

3) Ethyl 4- (2-pyridyl) -4- (4-biphenylyl) -3-ethoxy-2-ethoxycarbonylbutyrate.

IR Spectrum (film): v - 1750, 1730, 1590, 1485, 1300, 1150 and max 25 760 cm -1.

DK 165554 B

NMR Spectrum (CDCl 3): δ (ppm) δ 0.83 (3H, t, J »7Hz), 1.33 (6H, t, J« 7Hz), 3.28 (1H, m), δ , 63 (2H, q, J-7Hz), 4.25 (4H, q, J-7Hz), 4.50-5.30 (2H, m), 7.02-7.83 (2H, m) , 8.65 (1H, m).

4) Ethyl 4-phenoxy-4- (2-pyridyl) -3-ethoxy-2-ethoxycarbonylbutyrate.

IR spectrum (film): v - 1750, 1730, 1590, 1490, 1220, 1060 and max 750 cm -1.

NMR Spectra (CDCl 3): δ (ppm) δ = 0.80 (3H, t, J-7Hz), 1.03 (3H, t, J-7Hz), 1.28 (3H, t, J-7Hz) ), 2.73 (1H, m), 3.17-3.70 (2H, m), 3.80-4.40 (4H, m), 4.60 (1H, m), 5.55 ( 1H, m), 6.80-7.03 (3H, m), 7.10-7.40 (3H, m), 7.42-7.80 (2H, m), 8.65 (1H) , m).

5) Ethyl 4- (3-tolyl) -4- (2-pyridyl) -3-ethoxy-2-ethoxycarbonylbutyrate.

IR Spectrum (film): 1 / - 1750, 1730, 1600, 1590, 1100 and 700 cm cm ".

NMR Spectrum (CCl4): δ (ppm) - 0.72 (3H, t, J = 7Hz), 1.07-1.45 (6H, m), 2.33 (3H, s), 3.12 -3.73 (3H, m), 3.87-4.48 (5H, m), 4.95 (1H, m), 6.85-7.72 (7H, m), 8.58 ( IH, m).

6) Ethyl 4- (2-pyridyl) -4- (4-chlorophenyl) -3-ethoxy-2-ethoxycarbonyl-butyrate.

IR Spectrum (film): 1 / - 1750, 1730, 1590, 1490, 1090 and 750 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = O; 63-0.97 (3H, m), 1.05-1.50 (6H, m), 3.03-3.82 (3H, m) ), 3.93-4.58 (5H, m), 4.93 (1H, m), 6.90-7.72 (7H, m), 8.53 (1H, m).

7) Ethyl 4- (2-pyridyl) -4- (3-methoxyphenyl) -3-ethoxy-2-ethoxycarbonyl butyrate.

IR Spectrum (film): v - 1750, 1730, 1590, 1470, 1440, 1370, 1160, ΛαΛ 1100, 1040, 760 and 700 cm -1.

36

DK 165554B

NMR Spectrum (CCl4): δ (ppm) = 0.73 (3H, t, J = 7Hz), 1.07-1.48 (6H, m), 2.85-4.53 (8H, m) , 3.72 (3H, s), 4.93 (1H, m), 6.50-7.70 (7H, m), 8.60 (1H, m).

8) Ethyl 4- (2-tolyl) -4- (2-pyridyl) -3-ethoxy-2-ethoxycarbonylbutyrate.

IR Spectrum (film): "3060, 1740, 1720, 1590, 1440, 1090, 860 and 750 cm -1 NMR Spectrum (CCl , 1.03-1.48 (6H, m), 2.4 (3H, m), 2.80-4.93 (9H, m), 6.80-7.60 (7H, m), δ , 47 (1H, m).

9) Ethyl 4- (2-pyridyl) -4-tert.butyldimethylsiloxy-3-ethoxy-2-ethoxy-carbonylbutyrate.

IR Spectrum (film): = 1750, 1730, 1590 and 1580 cm cm '.

PREPARATION 8 The following compounds were prepared in a manner similar to Preparation 2.

1) 1- (1-Naphthyl) -3-ethoxycarbonyl-4H-quinolizin-4-one, mp 161-163 ° C.

IR Spectrum (Nujol): u - 1690, 1665, 1590, 1270, 1240, 780 and 770 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) - 1.38 (3H, t, J = 7Hz), 4.43 (2H, q, 20 J = 7Hz), 7.05-7.77 (8H, m ), 7.80-8.10 (2H, m), 8.43 (1H, s), 9.58 (1H, m).

Analysis:

Calculated for C 22 H 17 NO 3: C 76.95 H 4.99 N 4.08.

Found: C 77.14 H 5.27 N 3.89.

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DK 165554B

2) 1- (4-Biphenylyl) -3-ethoxycarbonyl-4H-quinolizin-4-one, mp 183-184.5 ° C.

IR Spectrum (Nujol): v - 1690, 1680, 1625, 1590, 1260 770 ° max. & 740 cm -1 NMR Spectrum (CDCl3): δ (ppm) = 1.40 (3H, t, J = 7Hz), 4.50 (2H, q, J-7Hz), 7.08-8.02 (12H, m), 8.43 (1H, s), 9.55 (1H, m).

Analysis:

Calculated for C24 H19 NO3.1 / 4H2 O: C 77.09 H 5.27 N 3.75.

Found: C 77.04 H 5.49 N 3.60.

3) 1-Phenoxy-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 108-110 ° C.

IR Spectrum (Nujol): 1 / - 1680, 1670, 1620, 1590, 1225, 1200 and 1000 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) - 1.40 (3H, t, J-7Hz), 4.42 (2H, q, J 7Hz), 6.78-7.48 (6H, m ), 7.57-7.98 (2H, m), 8.23 (1H, s), 9.45 (1H, m).

Analysis:

Calculated for C C ^H ^NO ^: C, 69.89; H, 4.89; N, 4.53.

Found: C, 70.18; H, 5.03; N, 4.51.

4) 1- (3-Tolyl) -3-ethoxycarbonyl-4H-quinolizin-4-one, mp 109-111 ° C.

IR Spectrum (Nujol): v - 1725, 1645, 1620, 1595, 1240 and 770 cm -1.

nuax NMR Spectrum (CDCl 3): δ (ppm) - 1.42 (3H, t, J-7Hz), 2.45 (3H, s), 4.45 (2H, q, J = 7Hz), 7, 08-7.48 (5H, m), 7.53-7.95 (2H, m), 8.42 (1H, 25 s), 9.55 (1H, m).

Analysis:

Calculated for C19 H17 NO3.1 / 5H2 O: C, 73.39; H, 5.64; N, 4.50.

Found: C, 73.58; H, 5.62; N, 4.49.

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5) 1- (4-Chlorophenyl) -3-ethoxycarbonyl-4H-quinolizin-4-one, m.p. 159-160 ° C.

IR Spectrum (Nujol): v - 1680, 1670, 1490, 1295, 1260, 1240, 1130,

IudX

1020 and 765 cm -1 NMR Spectrum (CDCl3): δ (ppm) - 1.40 (3H, t, J = 7Hz), 4.43 (2H, q, J = 7Hz), 6.97-7.87 (7H, m), 8.32 (1H, s), 9.48 (1H, m).

Analysis:

Calculated for Ο ^ π ^ ΟΙΝΟβ: G 65.96 H 4.31 N 4.27.

Found: C, 65.81; H, 4.49; N, 4.19.

6) 1- (3-Methoxyphenyl) -3-ethoxycarbonyl-4H-quinolizin-4-one, mp 155-157 ° C.

IR Spectrum (Nujol): 1 / = 3070, 1730, 1650, 1625, 1595, 1130, 1100 max and 780 cm cm ·.

NMR Spectrum (CDCl 3): δ (ppm) - 1.42 (3H, t, J = 7Hz), 3.80 (3H, s), 4.40 (2H, q, J-7Hz), 6.85 -7.93 (7H, m), 8.35 (1H, s), 9.47 (1H, m).

Calcd. For C ^ gHH NONO 1/4 ^O: C 69.61 H 5.38 N 4.27.

Found: C, 69.62; H, 5.29; N, 4.19.

7) 1- (2-Tolyl) -3-ethoxycarbonyl-4H-quinolizin-4-one, mp 97-98 ° C.

IR Spectrum (Nujol): v = 1730, 1680, 1620, 1480, 1230, 1100 and max 25 785 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) * 1.45 (3H, t, J J 7Hz), 2.10 (3H, s), 4.48 (2H, q, J = 7Hz), 7.18 -7.83 (7H, m), 8.42 (1H, s), 9.68 (1H, m).

Analysis:

Calcd for C 74.25 H 5.57 N 4.56.

Found: C, 74.50; H, 5.66; N, 4.50.

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8) 1- tart. Butyldimethyls in loxy-3-ethoxycarbonyl 1-4H-quinol iz in- 4 -one, 5 m.p. 80eC.

IR Spectrum (Nujol): 16 1695, 1675, 1620 and 1590 cm "·.

NMR Spectrum (CDCl3): δ (ppm) - 0.2 (6H, s), 1.10 (9H, s), 1.45 (3H, t, J-7Hz), 4.45 (2H, q , J-7Hz), 7.10-8.0 (3H, m), 8.10 (1H, s), 9.15 (1H, d, J-8Hz).

Analysis:

Calcd for C 18 H 25 NO 4 Si: C 62.22 H 7.25 N 4.03.

Found: C, 61.97; H, 7.04; N, 4.08.

PREPARATION 9

A mixture of 19.3 ml of 2-hydroxymethylpyridine, 36.2 g of tert.butyldimethylsilyl chloride and 27.2 g of imidazole in 190 ml of dime thyl formamide was stirred for 2 hours at room temperature. Water was added to the reaction mixture and extracted with n-hexane. The organic phase was washed with water, dried over magnesium sulfate and then evaporated. The residue was distilled to give 42.30 g of 2-tert.butyldimethylsiloxy-methylpyridine.

IR Spectrum (film):> - - 1595, 1585, 1260, 1160 and 1140 cm -1

NMR Spectrum (CDCl 3): δ (ppm) - 1.0 (6H, s), 1.83 (9H, s), 4.70 (2H, s), 6.85-7.20 (1H, m) ), 7.25-7.70 (2H, m), 8.20-8.30 (1H, m).

PREPARATION 10 To a solution of 3.32 g of 1-tert.butyldimethylsiloxy-3-ethoxycarbonyl-4H-quinolizin-4-one in 100 ml of tetrahydrofuran was added at 0 DEG C.

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11.47 ml of a 1M solution of tetra-n-butylammonium fluoride. The mixture was stirred for 1 hour and the solvent was distilled off. The residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was filtered and evaporated. The residue was chromatographed on silica gel eluted with chloroform to give 1.13 g of 1-hydroxy-3-ethoxycarbonyl-4H-quinolizin-4-one, mp> 250 ° C.

IR Spectrum (Nujol): γ - 3100, 1690, 1650 and 1620 cm - ^.

NMR Spectrum (Dimethylsulfoxide -dg): δ (ppm) = 1.30 (3H, t, J = 7Hz), 4.25 (2H, q, J = 7Hz), 7.20-7.60 (1H , m), 7.90-8.10 (2H, m), 9.20-9.30 (1H, m), 9.60 (1H, s).

Analysis:

Calculated for C 61.80 H 4.75 N 6.01.

Found: C, 61.11; H, 4.58; N, 5.91.

PREPARATION 11 The following compounds were prepared in a manner similar to Preparation 1.

1) Ethyl 4-phenyl-3-ethoxy-2-ethoxycarbonyl-4- (5-hydroxy-2-pyridyl) -butyrate.

NMR Spectrum (CDCl3): δ (ppm) = 0.90 (3H, t, J = 7.2Hz), 1.14 (3H, t, J = 7.2Hz), 1.30 (3H, t , J = 7.2Hz), 3.03 (3H, s), 3.20-4.50 (7H, m), 5.00-5.60 (2H, m), 6.50-7.80 (8H, m), 8.57 (1H, d, J = 4.4Hz).

2) Ethyl 3-ethoxy-2-thoxycarbonyl -4-benzoyl -4- (2-pyridyl) butyrate.

3) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) -4-benzylbutyrate.

IR Spectrum (film): v = 1750, 1730, 1635, 1585, 1365, 1290, 1245,

IHflX

1185, 1140, 1090, 1025, 745 and 700 cm -1.

41

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NMR Spectrum (CDCl3): δ (ppm) = 0.98-1.50 (9H, m), 2.93-4.67 (11H, m), 6.73-7.63 (8H, m) , 8.48-8.63 (1H, m).

4) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) -4-phenylthiobutyrate.

IR Spectrum (film): v - 1750, 1730, 1590, 1440, 1300, 1150, 1090, 5 1025 and 760 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = 0.83-1.40 (9H, m), 3.07-4.43 (7H, m), 4.53-4.92 (2H, m) , 7.0-7.73 (8H, m), 8.53 (1H, m).

PREPARATION 12 The following compounds were prepared in a manner similar to Preparation 2.

1) Ethoxycarbonyl-7-hydroxy-1-phenyl-4H-quinolizin-4-one.

IR Spectrum (Nujol): t / y = 1720, 1620, 1490 and 1450 cm

NMR Spectrum (dimethylsulfoxide -dg): S (ppm) = 1.30 (3H, t, J-7Hz), 4.26 (2H, q, J-7Hz), 7.46 (5H, m), δ , 60-7.70 (2H, m), 7.97 (1H, s), 8.98 (1H, d, J = 2Hz).

Analysis:

Calcd for C 18 H 15 NO 4: C 69.89 H 4.89 N 4.53.

Found: C, 69.20; H, 5.30; N, 4.14.

2) 3-Ethoxycarbonyl-1-benzoyl-4H-quinolizin-4-one, m.p. 176-178 ° C.

IR Spectrum (Nujol): v 1750, 1630, 1580, 1485, 1220, 1110 and

QlåX

785 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = 1.37 (3H, t, J = 7Hz), 4.38 (2H, q, J = 7Hz), 7.20-8.07 (7H, m) , 8.62 (1H, s), 8.82-9.10 (1H, m), 9.42-9.67 (1H, m).

Analysis:

Calculated for C C ^H₂ NCN ^: C, 71.02; H, 4.70; N, 4.36.

Found: C, 70.76; H, 4.96; N, 4.33.

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3) 3-Ethoxycarbonyl-1-benzyl-4H-quinolizin-4-one, m.p. 102-105 ° C.

IR Spectrum (Nujol): v - 1690, 1670, 1625, 1595, 1320, 1235, 765 max and 725 cm -1.

NMR Spectrum (CDCl3): δ (ppm) = 1.43 (3H, t, J = 7Hz), 4.23 (2H, s), 4.48 (2H, q, J = 7Hz), 7.02 -7.42 (6H, m), 7.52-7.78 (2H, m), 8.28 (1H, 10 s), 9.45 (1H, m).

Analysis:

Calcd. For C 215: C 74.25 H 5.57 N 4.56.

Found: C, 73.97; H, 5.72; N, 4.42.

4) 3-Ethoxycarbonyl-1-phenylthio-4H-quinolizin-4-one, m.p. 171-173 ° C: IR Spectrum (Nujol): 1 / = 1740, 1660, 1625, 1575, 1280, 1220, 1140, max 1120, 780 and 750 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = 1.40 (3H, t, J = 7Hz), 4.42 (2H, q, J = 7Hz), 6.68-7.47 (5H, m) , 7.73 (1H, m), 8.33 (1H, m), 8.72 (1H, s), 9.52 (1H, m).

Analysis:

Calculated for C 66.44 H 4.65 N 4.30.

Found: C, 66.17; H, 4.69; N, 4.28.

PREPARATION 13 25 To a solution of 9.31 g of 2-methylpyridine in 200 ml of tetrahydrofuran was added at -20 ° C 73.3 ml of a 1.5M hexane solution of n-butyl lithium. The resulting solution was stirred for 30 minutes

DK 165554 B

At room temperature and added to a solution of 15.02 g of ethyl benzoate in 100 ml of tetrahydrofuran at -60 ° C. After stirring for 2 hours at -60 ° C, 15 ml of acetic acid was added and the resulting mixture was allowed to warm to room temperature and concentrated in vacuo.

The residue was dissolved in ethyl acetate and washed with water. The aqueous phase was re-extracted with ethyl acetate and the combined extracts were washed with water, a 10% aqueous solution of sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extracts were filtered and evaporated. The residue (20.5 g) was chromatographed on silica gel (Merck 0.21-0.063 mm, 308 g) and eluted with chloroform to give 10.86 g of 2-pyridylmethylphenyl ketone as an oil.

IR Spectrum (Nujol): * - 1680, 1630, 1600, 1545, 1270, 1200, 1145, nidx 1060, 800, 775 and 690 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) -4.43 (1.5H, s), 6.02 (0.5H, s), 6.83-8.65 (9H, m).

PREPARATION 14 1) To a solution of 10.66 g of 5-hydroxy-2-methylpyridine in 426 ml of tetrahydrofuran was added 143 ml of a 20 1.5M solution of n-butyllithium at -30 ° C to -10 ° C. in hexane. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature. After cooling to -78 ° C, 11.14 ml of cyclohexane was added dropwise and the mixture was allowed to warm to 0 ° C and stirred for 30 minutes at 0 ° C. After addition of 24.6 ml of acetic acid, the solvent was distilled off and the residue was diluted with ethyl acetate and washed successively with water, 10% aqueous sodium hydrogen carbonate and aqueous saturated sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated.

The residue was washed with ethyl acetate to give 11.96 g of 5-hydroxy-2- [(1-hydroxycyclohexyl) methyl] pyridine.

IR Spectrum (Nujol): max max "1615, 1575, 1500 and 1460 cm '^.

DK 165554 B

44 NMR Spectrum (CD 3 OD): δ (ppm) - 1.20-2.00 (10H, m), 2.90 (1H, s), 4.95 (2H, s), 7.20 (2H, m), 8.05 (1H, d, J = 2.0Hz).

2) A solution of 1 g. Of 5-hydroxy-2- [(1-hydroxycyclohexyl) methyl] pyridine in 15 ml of acetic acid containing 5 ml of sulfuric acid was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into ice, made basic with 102 aqueous sodium hydrogen carbonate and extracted with ether. The combined ether extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was washed with isopropyl alcohol to give 409 mg of 2-benzyl-5-hydroxy-pyridine.

IR Spectrum (Nujol): νmayi = 1560, 1450, 1370 and 1280 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = 4.07 (2H, s), 6.85-7.43 (7H, m), 8.08 (1H, d, J = 3.0Hz), , 30 (1H, broad s).

PREPARATION 15

To a solution of 1.0 g of 1-phenylthio-3-ethoxycarbonyl-4H-quinolizin-4-one in 20 ml of acetic acid and 7.5 ml of chloroform was added 583 mg of potassium permanganate at 0 ° C. After stirring for 2 hours at the same temperature, the reaction mixture was allowed to warm to room temperature and 20 stirred for an additional 1 hour. 194 mg of permanganate was added and stirred overnight. To the resulting reaction mixture was added saturated aqueous sodium thiosulfate solution under ice-cooling and the mixture was extracted with chloroform. After drying over magnesium sulfate, the chloroform extract was filtered and evaporated. The residue was washed with diisopropyl ether to give 583 mg of 1-phenylsulfonyl-3-ethoxycarbonyl-4H-quinolizin-4-one, m.p.

IR Spectrum (Nujol): v = 1710, 1680, 1640, 1580, 1200 and 1 Hcl 2 C '1150 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) = 1.45 (3H, t, J = 7Hz), 4.45 (2H, q, 45

DK 165554B

J 7Hz), 7.20-8.10 (7H, m), 8.60 (1H, d, J-8Hz), 9.18 (1H, s), 9.50 (1H, d, J 8Hz).

Analysis:

Calculated for C C ^Hj ^N₂S: C, 60.50; H, 4.23; N, 3.92.

Found: C, 60.44; H, 4.51; N, 3.88.

PREPARATION 16

To a solution of 5 g of 3-ethoxycarbonyl-7-hydroxy-1-phenyl-4H-quinolizin-4-one in 100 ml of N, N-dimethylformamide was added sodium hydride at 50 ° C (63.6% in mineral oil, 732 mg). . After stirring for 30 minutes at 50 ° C, 2.77 ml of n-butyl iodide was added. After stirring for 1 hour at 50 ° C, the mixture was cooled to room temperature and added to a mixture of aqueous hydrogen chloride and ice. The mixture was extracted with chloroform and the chloroform extract was washed with 10% aqueous sodium bicarbonate and aqueous saturated sodium chloride. After drying over magnesium sulfate, the chloroform extract was filtered and concentrated in vacuo. The residue was chromatographed on silica gel (Merck 0.21-0.063 mm, 100 g) eluted with chloroform and then 10% methanol in chloroform to give 2.37 g of 3-ethoxy-carbonyl-7- (n-butoxy) - 1-phenyl-4H-quinolizin-4-one, m.p. 94-95 ° C.

IR Spectrum (Nujol): δ 1730, 1690, 1655, 1630 and 1480 cm cm-.

NMR Spectrum (CDCl 3): δ (ppm) - 0.95 (3H, t, J = 5Hz), 1.42 (3H, t, J-5Hz), 1.30-2.10 (4H, m) , 4.13 (2H, t, J-5Hz), 4.45 (2H, q, J = 5Hz), 7.30 (1H, d, J = 7Hz), 7.42 (5H, m), 7 , 67 (1H, d, J-7Hz), 8.27 (1H, s), 9.08 (1H, d, J-2Hz).

Analysis:

Calcd for ^ 2 ^ 3 ^ 4- C 72.31 H 6.34 N 3.83.

Found: C 71.74 H 6.39 N 3.80.

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PREPARATION 17 The following compound was prepared in a manner similar to Preparation 5.

1-Allyloxy-3-ethoxycarbonyl-4H-quinolizin-4-one, mp 82-84 ° C.

IR spectrum (Nujol): v = 1690, 1680, 1660, 1620, 1580, 1320, 1235, nonx 1100, 1015 and 770 cm -1.

NMR Spectrum (CDCl3): δ (PF®) (3H, t, J = 7Hz), 4.42 (2H, q, J = 7Hz), 4.50-4.75 (2H, m), δ, 15-5.67 (2H, m), 5.78-6.47 (1H, m), 6.97-8.32 (4H, m), 9.47 (1H, d, J = 7.5Hz ).

Analysis:

Calculated for C 15 H 15 NO 4: C 65.93 · H 5.53 N 5.13

Found: C, 66.11; H, 5.36; N, 4.94.

PREPARATION 18 The following compound was prepared in a manner similar to Preparation 13.

(5-hydroxy-pyridin-2-yl) methylphenylketon.

NMR Spectrum (CDCl 3): δ (ppm) δ 4.44 (2H, broad s), 6.85-7.70 (5H, m), 7.70-8.30 (3H, m), 9, 34 (2H, s).

PREPARATION 19 20 The following compound was prepared in a manner similar to Preparation 1.

Ethyl 4-benzoyl-3-ethoxy-2-thoxycarbonyl-4- (5-hydroxypyridin-2-yl) butyrate.

47

DK 165554B

IR Spectrum (Nujol): 1/1730, 1720, 1675 and 1595 cm cm ".

PREPARATION 20 The following compound was prepared in a manner similar to Preparation 2.

5 1 - Benzoyl - 3 - thoxy carbonyl - 7 - hydroxy - 4H - quino 1 iz in- 4 - one.

IR Spectrum (Nujol): ymav * 1740, 1630, 1570 and 1490 cm

NMR Spectrum (dimethylsulfoxide -dg): δ (ppm) - 1.22 (3H, t, J + = 7Hz), 4.27 (2H, q, J-7Hz), 7.43-7.97 (6H , m), 8.22 (1H, s), 8.87 (1H, d, J-10Hz), 8.95 (1H, d, J-2Hz).

PREPARATION 21 The following compound was prepared in a manner similar to Preparation 5.

1-Benzoyl-3-ethoxycarbonyl-7-n-butoxy-4H-quinolizin-4-one, mp 158-159 ° C.

IR Spectrum (Nujol): 1 / - 1740, 1680, 1630, 1580 and 1510 cm -1.

NMR Spectrum (CDCl 3): δ (ppm) - 0.98 (3H, t, J = 5Hz), 1.23 (3H, t, J-7Hz), 1.30-2.10 (4H, m) , 4.02-4.48 (4H, m), 7.37-8.18 (6H, m), 8.33 (1H, s), 8.88 (1H, d, J-10Hz), 9 , 03 (1H, d, J = 2Hz).

PREPARATION 22 20 To a solution of sodium ethoxide (151 mg sodium) in 20 ml of ethanol was added at room temperature 1 ml of ethyl pyrid-2-yl acetate and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 1.33 ml of diethylethoxymethylene malonate at room temperature and 48

DK 165554B

the mixture was stirred at room temperature overnight. To the mixture was added 0.75 ml of acetic acid at room temperature and the precipitate was filtered off and washed with water to give 896 mg of 1,3-dieth-oxycarbonyl-4H-quinolizin-4-one, mp 130-131 ° C.

IR Spectrum (Nujol): 1680, 1625 and 1585 cm

NMR Spectrum (CDCl 3): δ (ppm) = 1.40 (6H, t), 4.20-4.55 (4H, m), 7.20-7.46 (1H, m), 7.72 -8.00 (1H, m), 9.15 (1H, s), 9.27-9.64 (2H, m).

EXAMPLE 1 To a solution of 2.17 g of 3-ethoxycarbonyl-4H-quinolizin-4-one in 65.2 ml of methanol was added dropwise at room temperature 6.5 ml of 6N aqueous sodium hydroxide. After stirring for 20 minutes, 10 ml of water was added. After stirring for 20 minutes, 30 ml of water was further added. After stirring for 1 hour, the reaction mixture was made acidic to a pH of 3 by means of 4N aqueous hydrochloric acid. The precipitate was filtered off and washed with water to give 1.75 g of 4H-quino-lizin-4-one-3-carboxylic acid as pale yellow crystals, mp 233 ° C.

IR Spectrum (Nujol): t / = 1730, .1610, 1585 and 1320 cm

NMR Spectrum (Dimethylsulfoxide -dg): δ (ppm) = 7.26 (d, 1H, J = 9Hz), 7.50-7.95 (m, 1H), 8.00-8.20 (m , 2H), 8.41 (d, 1H, J = 9Hz), 9.20-9.40 (m, 1H).

EXAMPLE 2

To a suspension of 1.69 g of 4H-quinolizin-4-one-3-carboxylic acid in 16.9 25 ml of N, N-dime thylformamide was added at ambient temperature 2.17 g of 1,1'-carbonyl diimidazole. The resulting suspension was heated to 100 ° C for 30 minutes and 1.06 g of 5-amino-1H-tetrazole was added at 100 ° C. After stirring for 20 minutes at 100 ° C, the reaction was 49

DK 165554B

the mixture cooled to 0 * C. The precipitate was filtered and washed with precooled N, N-dimethylformamide and then ether to give 2.0 g of N- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one-3-carboxamide as a yellow solid , melting point> 260 ° C.

IR Spectrum (Nujol): - 3200, 1660, 1620, 1500 and 1310 cm cm ".

NMR Spectrum (CF 3 COOH): δ (ppm) - 7.42 (d, 1H, J-8Hz), 7.68-7.88 (m, 1H), 7.98-8.29 (m, 2H) , 8.72 (d, 1H, J = 8Hz), 9.48 (d, 1H, J = 8Hz).

Analysis:

Calcd. For C11H802N6: C, 51.56; H, 3.15;

Found: C, 51.70; H, 3.22; N, 32.99.

EXAMPLE 3 The following compounds were prepared in a manner similar to Example 1.

1) 7-Ethyl-4H-quinolizin-4-one-3-carboxylic acid, mp 193-195 ° C.

IR Spectrum (Nujol): γ = 3100, 1725, 1700 and 1605 cm cm ".

NMR Spectrum (CF 3 COOH): δ (ppm) - 1.52 (t, 3H, J-8Hz), 3.12 (q, 2H, J-8Hz), 7.92 (d, 1H, J-9Hz) , 8.32 (s, 2H), 8.73 (d, 1H, J-9Hz), 9.30 (m, 1H).

Calcd. For C 21 O 3: C, 66.35. H 5.10, N 6.45.

Found: C 66.40 H 5.14 N 6.46.

2) 1-Phenyl-4H-quinolizin-4-one-3-carboxylic acid, mp 198 ° C.

IR Spectrum (Nujol): max max 33 3315, 1740 and 1620 cm ** ·.

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DK 165554B

NMR Spectrum (CF 3 COOH): δ (ppm) = 7.32-7.82 (m, 5H), 7.92-8.23 (m, 1H), 8.25-8.52 (m, 2H) , 8.70 (s, 1H), 9.48-9.72 (m, 1H).

Analysis:

Calc'd for 6 6 6 03-5-5-5-5-5 /: C 66.78 H 4.64 N 4.87.

Found: C, 66.89; H, 4.22;

3) 7-Hydroxy-4H-quinolizin-4-one-3-carboxylic acid, m.p.> 270 ° C.

IR Spectrum (Nujol): δ = 3120, 2690, 1690 and 1590 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) = 7.87 (d, 1H, J = 8.5Hz), 8.07-8.42 (m, 2H), 8.58 (d, 1H, J = 8.5Hz), 9.07 (m, 1H).

Analysis:

Calculated for C 10 H 7 NO 4.1 / 4H 2 O: C 57.28 H 3.61 N 6.68.

Found: C 57.51 H 3.60 N 6.75.

4) 7-Methoxy-4H-quinolizin-4-one-3-carboxylic acid, mp 215-216 ° C *.

IR Spectrum (Nujol): v = 3150, 3100, 1700, 1610 and 1590 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) = 4.18 (s, 3H), 7.88 (d, 1H, J = 8.5Hz), 8.10-8.47 (m, 2H), δ , 67 (d, 1H, J = 8.5Hz), 8.88 (m, 1H).

Analysis:

Calculated for C C ^HjjNO ^: C, 60.27; H, 4.14; N, 6.39.

Found: C, 59.90; H, 4.38; 6.48.

5) 9-Methyl-4H-quinolizin-4-one-3-carboxylic acid, mp 259-260 ° C.

IR Spectrum (Nujol): v = 3100, 3020, 1740, 1610, 1590, 1120 and

IQS.X

780 cm -1.

51

DK 165554B

NMR Spectrum (dime thylsulfoxide -dg): δ (ppm) - 2.92 (s, 3H), 7.90 (d, 1H, J »7.5Hz), 8.07 (d, 1H, J , 5Hz), 8.05-8.38 (m, 1H), 8.82 (d, 1H, J + 9.5Hz), 9.42 (d, 1H, J-7.5Hz).

Analysis: δ Calculated for ΟΟΝΟΝΟβ: C 65.02 H 4.46 N 6.89.

Found: C, 64.92; H, 4.76; N, 6.89.

6) 8-Methyl-4H-quinolizin-4-one-3-carboxylic acid, mp 228-230 ° C.

IR Spectrum (Nujol): v 3090, 3030, 2700, 1630, 1620, 1580 and m &apos; 785 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) = 2.82 (s, 3H), 7.82 (d, 1H, J-9Hz), 7.92 (dd, 1H, J-7 and 2Hz), 8.17 (d, 1H, J-2Hz), 8.68 (d, 1H, J-9Hz), 9.37 (d, 1H, J-7Hz).

Analysis:

Calc'd for ΟΟΟΝΟβ: C 65.02 H 4.46 N 6.89.

Found: C, 64.88; H, 4.79; N, 6.85.

7) 6-Methyl-4H-quinolizin-4-one-3-carboxylic acid, m.p. 185-187 ° C.

IR Spectrum (Nujol): 1 / - 3100, 2700, 1720, 1615, 1595, 1295, 1040

IQdX

and 800 cm * 1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 3.45 (s, 3H), 7.82 (d, 1H, J «9Hz), 7.58-7.97 (m, 1H), δ 10-8.30 (m, 2H), 8.68 (d, 1H, J = 9Hz).

Analysis:

Calcd. For C ^ 9H₂O: C 65.02 H 4.46 N 6.89.

Found: C, 64.60; H, 4.52; N, 6.91.

8) 1-Methyl-4H-quinolizin-4-one-3-carboxylic acid, mp 258-260 ° C.

IR Spectrum (Nujol): v - 1740, 1610, 1450 and 780 cm cm 1.

max 52 °

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NMR Spectrum (CF 3 COOH): δ (ppm) = 2.87 (s, 3H), 8.15 (m, 1H), 8.35-8.77 (m, 3H), 9.66 (m, 1H) ).

Analysis:

Calculated for C C HHgNClN: C, 65.02; H, 4.46; N, 6.89.

Found: C, 64.70; H, 4.56; N, 6.86. (9) 7-Methyl-4H-quinolizin-4-one-3-carboxylic acid, mp 222-222 ° C.

IR Spectrum (Nujol): v = 1720, 1600, 1590, 1320, 1125, 1110 and 840 ntsx cm

NMR Spectrum (CF 3 COOH): δ (ppm) = 2.77 (s, 3H), 7.93 (d, 1H, J = 9Hz), 8.22-8.38 (m, 2H), δ 73 (d, 1H, J = 9Hz), 9.32 (s, 1H).

Analysis:

Calculated for (+9 9 ^ 3: C, 65.02; H, 4.46; N, 6.89.

Found: C, 65.04; H, 4.31; N, 6.91.

10) 7-n-Butoxy-4H-quinolizin-4-one-3-carboxylic acid, mp 120-122 ° G.

IR Spectrum (Nujol): 1 / = 1725, 1600, 1590, 1320, 1070 and max 1000 cm -1 NMR Spectrum (CF3 COOH): δ (ppm) = 1.07 (t, 3H, J = 6Hz), 1 , 30-2.20 (m, 4H), 4.40 (t, 2H, J = 6Hz), 7.90 (d, 1H, J = 9.5Hz), 8.13-8.43 (m , 2H), 8.67 (d, 1H, J = 9.5Hz), 8.93 (d, 1H, J = 2Hz).

Analysis:

Calculated for C, 64.36; H, 5.79; N, 5.36.

Found: C, 64.46; H, 5.80; N, 5.31.

11) 7-Isopropoxy-4H-quinolizin-4-one-3-carboxylic acid, mp 218-219 ° C.

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DK 165554B

IR Spectrum (Nujol): 1 / = 3140, 3090, 1720, 1620, 1120, 1060, 1000

utclX

and 780 cnT ^ ·.

NMR Spectrum (CF 3 COOH): δ (ppm) - 1.67 (d, 6H, J = 6Hz), 4.97 (1H, J-6Hz), 7.88 (d, 1H, J = 9Hz), δ , 10-8.43 (m, 4H), 8.63 (d, 1H, J = 9Hz), 5.90 (d, 1H, J = 2Hz),

Analysis:

Calculated for Ο ^ Η ^ ΝΟή, *. C 63.15 H 5.30 N 5.66.

Found: C, 63.28; H, 5.18; N, 5.65.

12) 1-Methoxy-4H-quinolizin-4-one-3-carboxylic acid, mp 259-10 261 ° C.

IR Spectrum (Nujol): 1 / fflax = 3100, 1630, 1620, 1580, 1100, 1070 and 780 cnT

NMR Spectrum (CF 3 COOH): δ (ppm) = 4.27 (s, 3H), 8.00-8.67 (m, 3H), 8.90 (m, 1H), 9.52 (d, 1H) , J «7.5Hz).

Analysis:

Calculated for c 60.28 · H 4.14 N 6.39.

Found: C 59.64 H 4.15 N 6.30.

Example 4 The following compounds were prepared in a manner similar to Example 2.

1) N- [3- (4H-1,2,4-Triazolyl)] - 4H-quinolizin-4-one-3-carboxamide, m.p.> 250 ° C.

IR Spectrum (Nujol): v = 3400, 3300, 1700, 1660, 1650 and

QlåX

1620 cm "* ·.

NMR Spectrum (CF 3 COOH): δ (ppm) = 7.90-9.60 (m, 7H).

Analysis:

Calculated for C C HHgNgigi: C 56.47 H 3.55 N 27.44.

Found: C, 56.83; H, 3.79; N, 27.50.

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2) N- [5- (1H-Tetrazolyl)] -9-methyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v - 3200, 3100, 3080, 1660, 1620, 1590 and

UlflX

790 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) = 2.80 (s, 3H), 7.50-7.87 (m, 2H), 8.08 (d, 1H, J 7Hz), 8.78 (d, 1H, J = 9Hz), 9.43 (d, 1H, J = 7Hz).

Analysis:

Calculated for C CH ^NgCC: C, 53.33; H, 3.73; N, 35.10.

Found: C, 55.28; H, 3.88; N, 31.35.

3) N- [5- (1H-Tetrazolyl)] -7-ethyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 250 ° C.

IR Spectrum (Nujol): v - 3200, 1660, 1640, 1620, 1590 and

ULflX

1490 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 1.50 (t, 3H, J = 7Hz), 3.05 (q, 2H, J = 7.5Hz), 7.45 (d, 1H, J 9Hz), 8.08 (s, 2H), 8.68 (d, 1H, J = 9Hz), 9.33 (m, 1H).

Analysis:

Calculated for C C ^HHN₂O₂O * C 54.93 H 4.25 N 29.56.

Found: C, 55.32; H, 4.32; N, 29.72.

4) N- [5- (1H-Tetrazolyl)] -1-phenyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): 1 / - 3180, 3100, 1680, 1620 and 1490 cm

NMR Spectrum (CF 3 COOH): δ (ppm) = 7.27-8.02 (m, 6H), 8.05-8.35 (m, 2H), 8.70 (s, 1H), 9, 48-9.75 (m, 1H).

Analysis:

Calculated for C 17 H 12 N 6 ° 2: C, 61.44; H, 3.64; N, 25.29.

Found: C, 61.21; H, 3.80; N, 24.83.

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5) N- [5- (1H-Tetrazolyl)] -7-hydroxy-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v - 3120, 3090, 2530, 1670, 1640, 1540 and mdx 980 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 7.73-7.70 (m, 2H), 8.03 (m, 1H), 8.67 (m, 1H), 9.15 (m, 1H) ).

Calcd. For CUH8N603: C 49.06 H 3.32 N 32.11.

Found: C, 48.56; H, 3.47; N, 32.66.

6) N- [5- (1H-Tetrazolyl)] -7-methoxy-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): 1 / - 3200, 3100, 1680, 1650 and 1610 cm cm *.

NMR Spectrum (CF 3 COOH): δ (ppm) - 4.13 (s, 3H), 7.42 (d, 1H, J-9Hz), 7.73-8.17 (m, 2H), 8.58 (d, 1H, J = 9Hz), 8.92 (m, 1H).

Analysis:

Calcd for C 213 O3: C, 50.35; H, 3.52; N, 29.36.

Found: C, 50.54; H, 3.55; N, 29.63.

7) N- (2-Pyrimidinyl) -4H-quinolizin-4-one-3-carboxamide, mp 218 ° C.

IR Spectrum (Nujol): = 1690, 1650 and 1620 cm -1.

NMR Spectrum (Dimethylsulfoxide-dg): δ (ppm) - 7.10-8.20 (m, 5H), 8.50-8.80 (m, 3H), 9.20-9.40 (m , I H).

Analysis:

Calculated for: C, 63.15; H, 3.79; N, 21.04.

Found: C, 61.20; H, 4.19; N, 20.76.

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8) N- [5- (1H-Tetrazolyl)] - 8-methyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v = 3200, 3150, 1660, 1635, 1590 and 780 cm

x NMR Spectrum (CF 3 COH): S (ppm) = 2.73 (s, 3H), 7.35 (d, 1H, J = 9Hz), 7.65 (dd, 1H, J = 7 and 2Hz), 7.88 (d, 1H, J = 2Hz), 8.65 (d, 1H, J = 9Hz), 9.38 (d, 1H, J = 7Hz).

Analysis:

Calculated for C 12 H 10 N 6 O 2: C, 53.33; H, 3.73; N, 31.10.

Found: C, 54.03; H, 3.84; N, 30.38.

9) N- [5- (1H-Tetrazolyl)] -6-methyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v = 3200, 1660, 1620, 1590, 1030, 820 and

Q & X

790 cm "NM NMR Spectrum (CFCOCOOH): δ (ppm) = 3.33 (s, 3H), 7.37 (d, 1H, J = 9Hz), 7.37-7.62 (m, 1H), 7.87-8.07 (m, 2H), 8.60 (d, 1H, J = 9Hz).

Analysis: Calculated for C ^ hH NN ^: C, 53.33; H, 3.73; N, 31.10.

Found: C, 53.63; H, 3.92; N, 31.42.

10) N- [5- (1H-Tetrazolyl)] -1-methyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): +/- 3180, 1665, 1640, 1620, 1595, 1500, 1040, ΧαΧ 1020 and 770 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) = 2.77 (s, 3H), 7.83-8.10 (m, 1H), 8.38 (d, 2H, J = 3Hz), 8.72 (s , 1H), 9.65 (d, 1H, J = 6Hz).

Analysis:

Calculated for ΟΟΟΗΗΝΝ: C 53.55 H 3.73 N 31.10.

Found: C, 53.71; H, 4.04; N, 31.03.

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11) N- [5- (1H-Tetrazolyl)] - 7-methyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): u - 3200, 1670, 1610, 1580, 1500, 1310, 1060, max 1040 and 840 cm -1 NMR Spectrum (CF3 COOH): , 7.47 (d, 1H, J-9Hz), 8.03-8.50 (m, 2H), 8.70 (d, 1H, J = 9Hz), 9.33 (s, 1H).

Analysis:

Calcd for c12 H10 N6 O2: C, 53.33; H, 3.73; N, 31.10.

Found: C, 53.61; H, 3.69; N, 31.34.

12) N-Pyrazinyl-4H-quinolizin-4-one-3-carboxamide, m.p.> 250 ° C.

IR Spectrum (Nujol): v - 3400, 1675, 1620, 1580, 1520, 1500, 1400,

Q13X

15 1320 and 780 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 7.43 (d, 1H, J + 9.5Hz), 7.78 (m, 1H), 8.00-8.23 (m, 2H), δ , 77 (d, J-9.5Hz), 8.83 (d, J-7.5Hz), 8.78-8.98 (m, 3H), 9.55 (d, 1H, J = 7, 5Hz), 9.82 (s, 1H).

Analysis: 20 Calcd. For H2 O: C 59.15 H 4.25 N 19.71.

Found: C 59.58 H 4.03 N 19.99.

13) N- [6- (3-Chloropyridazinyl)] - 4H-quinolizin-4-one-3-carboxamide, m.p.> 250 ° C.

IR Spectrum (Nujol): 1 / - 3100, 1680, 1620, 1580, 1510, 1070 and

MDX

25 780 cm -1.

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NMR Spectrum (CF 3 COOH): δ (ppm) - 7.38 (d, 1H, J = 9Hz), 7.63-8.50 (m, 5H), 8.77 (d, 1H, J = 9Hz) , 9.48 (m, 1H).

Analysis:

Calculated for ΟΟΗΗΙΝή: C, 55.92; H, 3.02; N, 18.63.

Found: C, 55.65; H, 3.15; N, 19.14.

14) N- [5- (1H-Tetrazolyl)] - 1-methoxy-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): 1 / - 3200, 1660, 1650, 1620, 1290, 1015 and 775 max cm -1 NMR Spectrum (CF 3 COOH): δ (ppm) = 4.33 (s, 3H), 13 (m, 1H), 8.33 (s, 1H), 8.33-9.02 (m, 2H), 9.62 (d, 1H, J = 7.5Hz).

Analysis:

Calcd. For C12 H20 O6: C, 50.35; H, 3.52; N, 29.36.

Found: C, 50.46; H, 3.45; N, 29.39.

15) N- [2- (4,6-Dimethylpyrimidinyl)] -4H-quinolizin-4-one-3-carboxamide, mp 217-218 ° C.

IR Spectrum (Nujol): v = 3460, 3120, 1690, 1650, 1620, 1060 and

IQ3X

790 cm 2

NMR Spectrum (CF 3 COOH): δ (ppm) = 2.87 (s, 6H), 7.38 (d, 1H, J = 9Hz), 7.47-8.32 (m, 4H), δ 75 (d, 1H, J = 9Hz), 9.63 (d, 1H, J = 7.5Hz).

Analysis:

Calculated for C C ^HjjN40O2.1 / 3 ^O: C 63.99 H 4.92 N 19.04.

Found: C, 63.99; H, 4.92; N, 18.66.

16) N- [5- (1H-Tetrazolyl)] - 7-n-butoxy-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v = 3200, 1665, 1640, 1625, 1590, 1000, 850

1D3X

and 780 cm -1.

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NMR Spectrum (CF 3 COOH): δ (ppm) -1.10 (t, 3H, J = 6.5Hz), 1.37-2.3 (m, 4H), 4.38 (t, 2H, J 6.5Hz), 7.53 (d, 1H, J-8.5Hz), 7.97- 8.28 (m, 2H), 8.67 (d, 1H, J-8.5Hz), 9, 03 (s, 1H).

For C 54.88 H 4.91 N 26.00.

Found: C, 55.14; H, 4.89; N, 25.83.

17) N- [5- (1H-Tetrazolyl)] - 7-isopropoxy-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v - 3200, 1680, 1650, 1620, 1500, 1310 and 0) βΧ 10 780 cm * 1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 1.77 (d, 6H, J + = 6Hz), 5.12 (sept, 1H, J-6Hz), 7.67 (d, 1H, J ~ 8 , 5Hz), 8.02-8.37 (m, 2H), 8.80 (d, 1H, J-8.5Hz), 9.20 (s, 1H).

Analysis: Calculated for 44.44. 503: C, 53.50; H, 4.49; N, 26.74.

Found: C, 53.73; H, 4.41; N, 27.04.

EXAMPLE 5 1) To a suspension of 2.27 g of 4H-quinolizin-4-one-3-carboxylic acid in 22.7 ml of dry Ν, Ν-dimethylformamide was added 2.92 g of 1,1'-carbon-20-yldiimidazole. The resulting suspension was heated to 100 ° C and held there for 30 minutes. After cooling to room temperature, the resulting solution was treated with dry ammonia and stirred for 20 minutes. The precipitated crystals were collected by filtration and washed with water to give 1.94 g of 4H-quinolizin-4-one-3-carboxamide, mp 230-232 ° C.

IR Spectrum (Nujol): v - 3350, 3120, 1660 and 1630 cm -1.

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60 NMR Spectrum (CF 3 COOH): δ (ppm) = 7.58 (d, 1H, J = 9Hz), 7.75- 8.07 (m, 1H), 8.12 (m, 2H), 8, 60 (d, 1H, J = 9Hz) and 9.52 (d, 1H, J = 7Hz).

Analysis:

Calcd. For C ^ 3H₂O: C 63.83 H 4.28 N 14.89.

Found: C, 63.96; H, 4.43; N, 14.90.

2) To a solution of 1.20 g of 3-cyano-4H-quinolizin-4-one in a mixture of 50 ml of pyridine and 30 ml of triethylamine, hydrogen sulfide gas was bubbled over 30 minutes at room temperature. The resulting mixture was allowed to stand at ambient temperature for 3 days.

The solvent was distilled off and the residue was washed with a warm mixture of chloroform and methanol (1: 1) and filtered. The filtrate was concentrated and the residue was washed again with a warm mixture of chloroform and methanol (9: 1) and filtered. The filtered cake was washed thoroughly with a mixture of chloroform and methanol 15 (9: 1) to give 0.76 g of 4H-quinolizin-4-one-3-thiocarboxamide, m.p. 220-230 ° 0.

IR Spectrum (Nujol): i / = 3300, 3100, 1650, 1620 and 1500 cm · 1.

NMR Spectrum (dimethylsulfoxide-dg): δ (ppm) = 7.07 (d, 1H, J = 8Hz), 7.36-7.67 (m, 1H), 7.80-8.10 (m, 2H), 9.13 (d, 1H, J = 8Hz), 9.26 (d, 20H, J = 8Hz), 9.80 (broad s, 1H).

3) 4.21 g of 3-cyano-4H-quinolizin-4-one, 1.77 g of sodium azide and 1.45 g of ammonium chloride were dissolved in 42 ml of N, N-dimethylformamide and the resulting mixture was heated at 120 ° C. for 2 days. The reaction mixture was evaporated and the residue was dissolved in aqueous.

25 triium hydrogen solution and filtered. The filtrate was acidified to a pH of 1-2 with dilute hydrochloric acid. The precipitate was filtered, washed with water and then with cold N, N-dime thylphoramide.

The filtered solid was dissolved in hot N, N-dimethylformamide and filtered. The filtrate was treated with ether and kept at 0 ° C. The 30 precipitated crystals were filtered and recrystallized from a mixture of ether and N, N-dimethylformamide to give 1.1 g of 3- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one, m.p.> 250 ° C.

DK 165554 B

61 IR Spectrum (Nujol): v 3200, 3100, 3050, 1660, 1620 and

l & CLX

1590 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 7.40 (d, 1H, J-8Hz), 7.60-8.30 (m, 3H), 8.60 (d, 1H, J-8Hz) , 8.90 (s, 1H), 9.40-9.60 (m, 1H).

Analysis:

Calculated for C 10 H 70 N 5: C 56.34 H 3.31 N 32.85.

Found: C, 56.55; H, 3.87; N, 33.02.

EXAMPLE 6 1) A suspension of 196.7 mg of 4H-quinolizin-4-one-3-carboxylic acid in 9.9 ml of 0.1N aqueous sodium hydroxide solution was stirred for 1 hour at room temperature. The resulting reaction mixture was filtered and the filtrate lyophilized to give 201 mg of sodium 4H-quinolizin-4-one-3-carboxylate.

IR Spectrum (Nujol): +/- 1660 cm -1.

NMR Spectrum (D 2 O): δ (ppm) δ 6.80 (d, 1H, J-8Hz), 7.00-7.30 (m, 1H), 7.40-7.60 (m, 2H ), 8.05 (d, 1H, J-8Hz), 8.96 (d, 1H, J-8Hz).

2) The following compound was prepared in a manner similar to Example 6-1).

N- [5- (lH-tetrazolyl)] - 4H-quinolizine-4-one-3-carboxamide sodium salt.

IR Spectrum (Nujol): 1 / - 1670 cm -1

NMR Spectrum (D 2 O -dimethylsulfoxide-d 6): δ (ppm) - 6.80 (d, 1H, J «8Hz), 7.20-7.40 (m, 1H), 7.40-7.60 ( m, 2H), 8.10 (d, 1H, J-8Hz), 8.88 (d, 1H, J »8Hz).

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EXAMPLE 7 The following compounds were prepared in a manner similar to Example 1.

1) 1- (1-Naphthyl) -4H-quinolizin-4-one-3-carboxylic acid, m.p.> 270 ° C.

IR Spectrum (Nujol): i / may = 1730, 1720, 1610 and 770 cm

NMR Spectrum (CF 3 COOH): δ (ppm) - 7.10-8.37 (10H, m), 8.82 (1H, s), 9.62 (1H, m).

Calcd. For C20 H13 NO3.1 / 2H2O: C 74.07 H 4.35 N 4.32.

Found: C, 74.12; H, 4.13; N, 4.22.

2) 1- (4-Biphenylyl) -4H-quinolizin-4-one-3-carboxylic acid, mp 261-263 ° C.

IR Spectrum (Nujol): u - 3100, 1720, 1660, 1610, 1580, 1290, 890

TUflX

15 and 775 cm

NMR Spectrum (CF 3 COOH): δ (ppm) δ 7.20-8.47 (12H, m), 8.70 (1H, s), 9.53 (1H, m).

Analysis:

Calcd. For C22 H15 NO3.1 / 4H2 O: C, 76.40; H, 4.52; N, 4.05.

Found: C 76.41 Η 4.57 N 3.93.

3) 1-Phenoxy-4H-quinolizin-4-one-3-carboxylic acid, mp 224-226 ° C.

IR Spectrum (Nujol): v - 3100, 2650, 1725, 1640, 1620, 1580, 1210 ΠΙαΛ and 910 cm - ^.

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NMR Spectrum (CF 3 COOH): δ (ppm) - 7.20-7.37 (2H, m), 7.43-7.73 (3H, m), 8.78 (1H, s), 8.27 (1H, d, J-7.5Hz), 8.60 (1H, t, J-7.5Hz), 9.05 (1H, d, J-8.5Hz), 9.63 (1H, d, J-7.5Hz).

Analysis: 5 Calculated for C Hj HjH₂ ^NO C C 68.33 H 3.94 N 4.98.

Found: C, 68.45; H, 3.96; N, 4.96.

4) 1- (3-Tolyl) -4H-quinolizin-4-one-3-carboxylic acid, mp 176-178 ° C.

IR Spectrum (Nujol): v = 3130, 1740, 1620, 1590, 1220, 770 and max 10 705 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 2.52 (3H, s), 7.17-7.67 (4H, m), 7.90-8.50 (3H, m), δ 70 (1H, s), 9.58 (1H, m).

Analysis:

Calcd. For C 17 H 13 NO 3: C, 73.11; H, 4.69; N, 5.02.

Found: C, 73.11; H, 4.85; N, 5.13.

5) 1- (4-Chlorophenyl) -4H-quinolizin-4-one-3-carboxylic acid, mp 269-271 ° C.

IR Spectrum (Nujol): 1 / - 3140, 1740, 1620, 1490, 1320, 1290, 1090, max 890, 825 and 775 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) - 7.35-7.78 (4H, m), 7.92-8.47 (3H, m), 8.73 (1H, s), 9, 62 (1H, m).

Analysis:

Calculated for C 16 H 10 ClNO 3: C, 64.12; H, 3.36; N, 4.67.

Found: C, 63.95; H, 3.33; N, 4.58.

6) 1- (2-Tolyl) -4H-quinolizin-4-one-3-carboxylic acid, m.p. 168-170 ° C.

IR Spectrum (Nujol): ν 3400, 1720, 1610, 1290, 1070 and 780 cm -1.

max NMR Spectrum (CF 3 COOH): S (ppm) = 2.17 (3H, s), 7.25-7.75 (4H, m), 7.98-8.63 (3H, m), 80 (1H, s), 9.72 (1H, m).

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Analysis:

Calculated for C 17 H 13 NO 3: C 73.11 H 4.69 N 5.02.

Found: C, 72.95; H, 4.91; N, 5.01.

7) 1- (3-Methoxyphenyl) -4H-quinolizin-4-one-3-carboxylic acid, mp 222-224 ° C.

IR Spectrum (Nujol): v = 3100, 1725, 1600, 1490, 1220, 1030 and

mflX

780 cm "10 NMR Spectrum (CF3COOH): δ (ppm) = 4.10 (3H, s), 7.15-8.62 (7H, m), 8.77 (1H, s), 9.62 (IH, m).

Analysis:

Calculated for C cjHj 3NO4: C, 69.15; H, 4.44; N, 4.74.

Found: C, 69.67; H, 4.70; N, 4.67.

8) 1-Hydroxy-4H-quinolizin-4-one-3-carboxylic acid.

IR Spectrum (Nuiol): u = 3200, 3100, 1690 and 1620 cm @ -1.

max NMR Spectrum (CF 3 COOH): S (ppm) = 8.00-9.50 (5H, m).

Analysis:

Calculated for C C ^HyNO ^: C, 58.54; H, 3.44; N, 6.83.

Found: C, 57.93; H, 3.56; N, 6.77.

EXAMPLE 8 The following compounds were prepared in a manner similar to Example 2.

N- [5- (1H-Tetrazolyl)] - (1-naphthyl) -4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

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IR Spectrum (Nuiol): u * 3280, 1665, 1640, 1620, 1290, 780 and max 770 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) δ 7.27-8.25 (10H, m), 8.77 (1H, s), 9.68 (1H, m).

Analysis:

Calcd. For 212H144.66: C, 65.96; H, 3.69; N, 21.98.

Found: C, 60.51; H, 3.75; N, 21.91.

2) N- [5- (1H-Tetrazolyl)] - 1- (4-biphenylyl) -4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR spectrum (Nujol): +/- 3180, 1670, 1625, 1590, 1100, 1035, 780 max, and 730 cm -1.

Analysis:

Calcd. For 233 ° C * 2 · C 67.64 H 3.95 N 20.58.

Found: C, 68.04; H, 4.31; N, 20.39.

3) N- [5- (1H-Tetrazolyl)] - 1-phenoxy-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v 3200, 3150, 1660, 1620, 1590, 1010, 780 max and 750 cnT 2.

NMR Spectrum (CF 3 COOH): δ (ppm) - 7.08-7.67 (5H, m), 7.97 (1H, m), 8.22-8.47 (2H, m), δ 70 (1H, m), 9.67 (1H, m).

Analysis:

Calcd. For δ7.2d03 C 58.62 H 3.47 N 24.13.

Found: C, 59.39; H, 3.54; N, 24.06.

4) N- [5- (1H-Tetrazolyl)] - 1- (3-tolyl) -4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v - 3160, 1670, 1640, 1620, 1600 and max. NMR Spectrum (CF 3 COOH): δ (ppm) δ = 2.52 (2H, s), 7.17-7.62 ( m, 4H), 7.70-8.40 (3H, m), 8.73 (1H, s), 9.63 (1H, m).

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1585 cm -1.

Calcd. For C 18 H 14 N 6 ° 2: C 62.42 H 4.07 N 24.26.

Found: C, 63.03; H, 4.16; N, 24.56.

5) N- [5- (1H-Tetrazolyl) -1- (4-chlorophenyl) -4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v - 3220, 1675, 1640, 1600, 1480, 1290, 1040 ΙΏ5Χ 10 and 770 cm -1.

Analysis:

Calculated for C C 7HH ClClNgO₂: C, 55.67; H, 3.02; N, 22.91.

Found: C 57.45 H 3.26 N 21.47.

6) N- [5- (1H-Tetrazolyl)] - 1- (3-methoxyphenyl) -4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR spectrum (Nujol): v = 3150, 1680, 1640, 1620, 1590, 1490, 1300,

IQEX

1210, 1030, 790 and 780 cm -1.

NMR Spectrum (CF 3 COOH): δ (ppm) = 4.13 (3H, s), 7.17-7.52 (3H, m), 7.55-8.15 (2H, m), 8.18 -8.43 (2H, m), 8.80 (1H, s), 9.67 (1H, m).

Analysis:

Calculated for C 0 0H₂O: C 59.67 H 3.89 N 23.19.

Found: C, 59.81; H, 4.19; N, 23.35.

7) N- [5- (1H-Tetrazolyl)] -1- (2-tolyl) -4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): +/- 3200, 3120, 1680, 1620, 1490, 1290, 1030

IIlclX

and 780 cm -1.

DK 165554 B

NMR Spectrum (CF 3 COOH): δ (ppm) = 2.15 (3H, s), 7.25-7.70 (4H, m), 7.77-8.43 (3H, m), 8.77 (1H, s), 9.77 (1H, s).

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Analysis:

Calcd for C C gH ^N0O₂: C 62.42 H 4.07 N 24.26.

Found: C, 62.75; H, 4.06; N, 24.35.

8) N- [5- (1H-Tetrazolyl)] -1-hydroxy-4H-quinolizin-4-one-3-carboxamide, m.p.> 250 ° C.

IR Spectrum (Nujol): v = 3200 (shoulder), 1660, 1620 and 1580 cm -1.

IQEX

Analysis: 10 Calcd. For 0.63. 03.1 / 2.0: C, 46.97; H, 3.22; N, 29.85.

Found: C, 46.48; H, 3.31; N, 29.57.

EXAMPLE 9 The following compounds were prepared in a manner similar to Example 1.

1) 7- (n-Butoxy) -1-phenyl-4H-quinolizin-4-one-3-carboxylic acid, mp 155-157 ° 0.

IR Spectrum (Nujol): i / 1720, 1610, 1495 and 1425 cm -1.

NMR Spectrum (dimethyl sulfoxide δ 5): δ (ppm) = 0.95 (3H, t, J-5Hz), 1.3-2.0 (4H, m), 4.20 (2H, t, J 5Hz), 7.3-7.7 (5H, m), 7.80 (2H, s), 8.10 (1H, s), 8.80 (1H, s), 14.1 (1H, wide s).

2) 1-Phenylthio-4H-quinolizin-4-one-3-carboxylic acid, mp 195-197 * 0.

IR Spectrum (Nujol): v - 3350, 1720, 1620, 1400, 1285, 1065, 885, max 780 and 740 cm -1.

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Analysis:

Calculated for C C ^HH jNO3S: C, 64.63; H, 3.73; N, 4.71.

Found: C, 65.04; H, 3.90; N, 4.73.

EXAMPLE 10 The following compounds were prepared in a manner similar to Example 2.

1) 7- (n-Butoxy) -1-phenyl-N- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one-3-carboxamide, m.p.> 205 ° C (dec.).

IR Spectrum (Nujol): i / m = 1670, 1635, 1580 and 1370 cnT

NMR Spectrum (dimethylsulfoxide -dg): δ (ppm) = 1.00 (3H, t, J = 5.6Hz), 1.02-2.10 (4H, m), 4.18 (2H, t , J-6Hz), 6.80-7.25 (2H, m), 7.30-7.65 (3H, m), 7.68-8.00 (2H, m), 8.20 (1H) , s), 8.87 (1H, broad s).

2) N- [5- (1H-Tetrazolyl)] -1-phenylthio-4H-quinolizin-4-one-3-carboxamide, m.p.> 270 ° C.

IR Spectrum (Nujol): v = 3180, 1660, 1640, 1620, 1285, 1035, 780 gauge and 730 cm cm ".

Analysis:

Calculated for εΐ7Η12Ν6 ° 2δ: C 56.04 H 3.32 N 23.06.

Found: C, 56.61; H, 3.53; N, 23.48.

EXAMPLE 11 The following compounds were prepared in a manner similar to Example 6-1).

1) N- [5- (1H-Tetrazolyl)] - 1-phenyl-4H-quinolizin-4-one-3-carboxamide sodium salt, m.p.> 250 ° C.

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IR Spectrum (Nujol): v = 3150 (wide), 1660 (shoulder), 1650, 1640 msx and 1620 cm cm ".

NMR Spectrum (Dimethylsulfoxide-dg): δ (ppm) - 7.40-8.00 (9H, m), 8.50 (1H, s), 9.30-9.60 (1H, m).

2) N- [5- (1H-Tetrazolyl)] -1-phenoxy-4H-quinolizin-4-one-3-carboxamide sodium salt, m.p.> 250 ° C.

IR Spectrum (Nujol): i / = 1660 cm

NMR Spectrum (Dimethylsulfoxide-dg): δ (ppm) - 6.9-7.8 (6H, m), 8.01 (2H, d, J ~ 4Hz), 8.32 (1H, s), 9 , 42 (1H, d, J = 7Hz), 12.30 (1H, s).

Analysis:

Calcd for C 17 H 11 N 9 Na 3 O: C 55.14 H 2.99 N 22.70.

Found: C, 54.78; H, 3.63; N, 20.44.

EXAMPLE 12 The following compound was prepared in a manner similar to Example 2.

1) 1-Ethoxycarbonyl-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-carboxamide, m.p.> 250 ° C.

IR Spectrum (Nujol): - 1665, 1640, 1610, 1595 and 1580 cm -1.

Mass spectrum: m / e 328 (M4-).

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EXAMPLE 13 The following compounds were prepared in a manner similar to Example 6-1).

1) 7-n-Butoxy-1-phenyl-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-5 carboxamide sodium salt.

IR Spectrum (Nujol): t / a α = 1680, 1640, 1620 and 1585 cm cm *.

NMR Spectrum (dimethylsulfoxide-dg): δ (ppm) = 0.80-1.20 (3H, m), 1.30-2.10 (4H, m), 4.00-4.48 (2H, m), 7.43-7.68 (5H, m), 7.70-7.90 (2H, m), 8.40 (1H, s), 9.00 (1H, d, J 2Hz) .

EXAMPLE 14

To a solution of 1 g of 1,3-diethoxycarbonyl-4H-quinolizin-4-one in 20 ml of chloroform was added at room temperature 0.49 ml of trimethylsilyl iodide and the mixture was stirred for 4 hours and heated at reflux for 4 hours. After cooling to room temperature, the mixture was washed with water, aqueous sodium thiosulfate and brine. Drying over magnesium sulfate and evaporation gave a crystalline residue which was washed with isopropyl alcohol to give 794 mg of 1-ethoxycarbonyl-4H-quinolizin-4-one-3-carboxylic acid, m.p. 189 ° C.

IR Spectrum (Nujol): 17 1735, 1710, 1635 and 1620 cm '·.

NMR Spectrum (Dimethylsulfoxide-dg): S (ppm) δ 1.34 (3H, t, J J 7Hz), 4.33 (2H, q, J J 7Hz), 7.45-7.95 (1H , m), 8.00-8.45 (1H, m), 8.90 (1H, s), 9.05-9.60 (2H, m).

Mass spectrum: m / e 261 (M +).

Analysis: Calculated for ^³ 3 05 05: C 59.77 H 4.24 N 5.36.

Found: C, 59.12; H, 4.59; N, 5.33.

EXAMPLE 15 71

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To a solution of 896 mg of 1,3-diethoxycarbonyl-4H-quinolizin-4-one in 9 ml of methanol was added at room temperature 2.58 ml of 6N aqueous sodium hydroxide and the mixture was heated at reflux for 5 hours. After cooling to 0 ° C, the reaction mixture was acidified to pH 2 with 6N hydrochloric acid and the precipitate was filtered and washed with water to give 202 mg of 4H-quinolizin-4-one-1,3-dicarboxylic acid , melting point> 250 ° C.

IR Spectrum (Nujol): δ mav 16 1675, 1655 and 1635 cm "·.

NMR Spectrum (D 2 O, NaOD): δ (ppm) - 7.30-8.10, 8.65 (1H, s), 8.70-9.00 (1H, m), 9.30 (1H) , d, J «7Hz).

EXAMPLE 16

To a solution of 500 mg of 1-ethoxycarbonyl-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-carboxamide in 5 ml of N, N-dimethylformamide * 6 ml was added at room temperature. In aqueous sodium hydroxide and the mixture was heated at 100 ° C for 1 hour. After cooling at 0 ° C, the mixture was acidified to a pH of 2 by 6N hydrochloric acid and the precipitate was filtered and washed with water to give 280 mg of 1-carboxy-N- (1H-tetrazol-5-yl). ) -4H-quinolizin-4-one-3-carboxamide, m.p.> 250 ° C.

IR Spectrum (Nujol): 16 1670, 1640, 1615 and 1590 cm "·.

NMR Spectrum (D 2 O-NaOD): δ (ppm) - 7.24-7.60 (1H, m), 7.60-8.07 (1H, m), 8.68-9.05 (1H, ra), 8.84 (1H, s), 9.30 (1H, d, J-8Hz).

Mass spectrum: m / e 272 (M +).

Analysis:

Calcd for C12 H8 N6 ° 4-H2 O: C, 45.29; H, 3.16; N, 26.41.

Found: C, 45.29; H, 3.62; N, 26.56.

Claims (8)

IR Spectrum (Nujol): i / = 1690, 1605, 1370 and 1300 cm -1 max NMR Spectrum (dimethylsulfoxide -dg): 6 (ppm) - 6.75 (1H, s), 7.15-7, 45 (1H, m), 7.76 (2H, d), 8.90 (1H, d, J = 6Hz). Mass Spectrum: m / e 205 (M +). Calcd. For C ^ qH ^ NONO .:: C, 58.54; H, 3.44; N, 6.83. Found: C, 58.49; H, 3.17; N, 6.86. 1. Quinolizin-4-one derivatives of the general formula I wherein RA represents carboxy, thiocarbamoyl, tetrazolyl or a group -CONHrAO wherein hydrogen, pyrimidinyl, pyrimidinyl is substituted with lower alkyl, pyrazinyl, triazolyl, pyridazinyl substituted with halogen, or tetrazolyl; I? 7 represents hydrogen or aryl; R 2 represents hydrogen, hydroxy, lower alkyl or lower alkoxy; represents hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, aryl, aryl substituted by halogen or lower alkoxy, arylthio or aryloxy; R 1 and R 2 are positioned at any position on the quinoline ring; and pharmaceutically acceptable salts thereof. Compounds according to claim 1, characterized in that hydrogen or phenyl, r 2 represents hydrogen, hydroxy, lower alkyl or lower alkoxy, represents hydrogen, lower alkyl, lower alkoxycarbonyl, carboxy, phenyl, naphthyl, biphenylyl, tolyl, phenyl, which carries halogen, phenyl, which carries lower alkoxy, phenylthio or phenoxy. Compounds according to claim 2, characterized in that r! represents carboxy, carbamoyl, 4,6-dimethylpyrimidin-2-ylcarbamoyl, pyrazinylcarbamoyl, pyrimidin * 2-ylcarbamoyl, 1H-tetrazol-5-ylcarbamoyl, 3-chloropyridazin-6-ylcarbamoyl, thiocarbamoyl, thiocarbamoyl represents hydrogen, hydroxy, methyl, ethyl or methoxy, R 4 represents hydrogen, methyl, ethoxycarbonyl, carboxy, phenyl, naphthyl, biphenylyl, 3-methylphenyl, phenoxy, 4-chlorophenyl, 2-methylphenyl, 3-methoxyphenyl or phenylthio. A compound according to claim 3, characterized in that it is N- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one-3-carboxamide or its sodium salt, N- [5- (1H-tetrazolyl)] - 1-phenyl-4H-quinolizin-4-one-3-carboxamide or its sodium salt, N- [5- (1H-tetrazolyl)] - 1-phenoxy-4H-quinolizin-4-one 3-carboxamide or its sodium salt, or A process for the preparation of compounds of the general formula I R 2 <R 3 10 wherein R , pyridazinyl substituted with halogen, or tetrazolyl; represents hydrogen or aryl; R 2 represents hydrogen, hydroxy, lower alkyl or lower alkoxy; Represents hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, aryl, aryl substituted by halogen or lower alkoxy, arylthio or aryloxy; or pharmaceutically acceptable salts thereof, characterized in that 1) a compound of the general formula II wherein R 7, R 2 and R 3 are each as defined above and R 2 represents protected carboxy or a salt thereof is subjected to an elimination reaction of the carboxy protecting group to form a compound of the general formula Ia R 2 R 7 R 3 COOH 1 O wherein R 7, R 2 and R 3 are each as defined above, or a salt thereof; or 2. a compound of the general formula la R 2 R 7 COOH 1a wherein R 7, R 2 and R 3 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof is reacted with ^ NR 2 · ®, where R 1 is as defined above to form a compound of the general formula Ib R 2 R 7 R 3 15 76 wherein R 7, R 1, O, R 2 and R 2 are each as defined above, or a salt thereof; or 3. a compound of the general formula Id s2 R7 R3 co - ** 0 5 wherein R7, R4 and R4 are each as defined above, or a salt thereof is reacted with hydrogen sulfide to form a compound of the general formula le ΟζΗ ** wherein R 7, R 2 and each are as defined above, 10 or a salt thereof; or 4. a compound of the general formula Id R2 rTr3 09- ° 0 where R7, R4 and R4 are each as defined above, or a salt thereof is subjected to a reaction to form a tetrazole group using a agent comprising a combination of an alkali metal azide and an ammonium halide to form a compound of the general formula If R2 R7 R3 And H is as defined above, 5 or a salt thereof, or 5. a compound of the general formula Ig R 2, R 7, R 3 o wherein R 2, R 2 and each are as defined above, and r | represents lower alkoxycarbonyl, or a salt thereof, is subjected to an elimination reaction of the carboxy-protecting lower alkyl group to form a compound of the general formula Ih₂O CO COOH -R-Rl wherein R ^, R ^ and R ^ are each as defined above, or a salt thereof. DK 165554 B 78 N- [5- (1H-tetrazolyl)] -1-benzoyl-4H-quinolizin-4-one-3-carboxamide or its sodium salt. Pharmaceutical composition, characterized in that it comprises an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable and substantially non-toxic carrier or excipient. Process for the preparation of a pharmaceutical composition, characterized in that a compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient is admixed with an inert carrier. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of allergic and ulcer diseases in humans and animals.