FI83518C - FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT VAERDEFULLA KINOLIZINONFOERENINGAR. - Google Patents

Description

1 83518

The present invention relates to a process for the preparation of pharmacologically valuable quinolizinone compounds of the formula * 2 / N R1 where 0 R1 is carbidyl, carbamoyl, carbamoyl -nylcarbamoyl, pyrimidinylcarbamoyl substituted with alkyl, pyrazinylcarbamoyl, phenylcarbamoyl which may be substituted by hydroxy, thiazolylcarbamoylthioylamoylamoylamoyl, substituted with amino, pyridazinylcarbamoyl, R 2 is hydrogen, hydroxy, lower alkyl or lower alkoxy, and R 3 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkenyloxy, phenyl, naphthyl, biphenyl, phenyl substituted with lower alkyl, halogen or lower alkoxy, phenylthio, benzoyl, phenyl (former) alkyl, benzenesulfonyl, phenylamino substituted with lower alkyl on a nitrogen atom, or phenoxy; or a salt thereof.

These new quinolizinone compounds have anti-allergic and anti-ulcer activities.

According to the present invention, the target compound (I) can be prepared by the methods shown in the following schemes.

2,83518

Method 1: R2 R3 R2 r3

Removal of the carboxy group protecting / ^ jiνγί; Ί f »T I] group L N ji

^ VV ---- ^ V ^ COOH

0 ° '(II) (Ia) or a salt thereof, or a salt thereof

Method 2; R2 f r2 r3 C ^ COOH - 0¾

ö O

(Ia) (Ib) or a reactive derivative thereof or a salt thereof in a carboxy group or a salt thereof

Method 3: 2

il VA

COv Dehydration ^ X XCONH2 -9- 0 o (Ie) (Id) or a salt thereof or a salt thereof 3 83518

Method 4; 2 r3 _2 & 3 R I R 1

Hydrogen sulfide f N 1 -> ^ "YVnH.

O O II 2 s (Id) (Ie) or a salt thereof or a salt thereof

Method 5: 2 R 3 R 2 f - - ^ h-y

is

B

(Id) (If) or a salt thereof or a salt thereof

Method 6:

2 R3 COOH

R la P2 1

Carboxy group direct R

Q ^ NnJ \ χand group deletion χ

o R ^ o R

(Ig) (Ih) or a salt thereof, or a salt thereof ^ R 83518 2 3 7 wherein R, R and R are each as defined above, R 1 is amidated carboxy, and R 3 and R a are each protected carboxy.

From the starting compounds of this invention, compound (II) can be prepared by the methods illustrated in the following schemes.

Method A - (1): -: - 2

R4 H

R2 V- (, O

6 (IV) R4Y ^ r5

CH 2 R -14 R

(III) (V) or a salt thereof or a salt thereof

Method A - (2); ! r6 (Ί 'Ί 2 R ·

li J 6 I

R ° Tire chemical

Rs !!! ^ _, O / v R4 ° (V) (Ha) or a salt thereof or a salt thereof

Method B - (1): R4 H.

CH "CH-'CH r4 ^ r5 CHCy« * <1 6 _ ^ _ -CV * 6: N CH2R a5 n4

(11Ie) (Vc) R

or a salt thereof or a salt thereof 5 83518

Method B - (2):

CIL

c / K '\\ CC Tire closure- CH' p

A r6 reaction_ CH

r4Y ^ r5 8 1r4 p4 · R (Vc) (Uh) or a salt thereof, or a salt thereof

Method C - (1):

R4 H

} - (CC Oi1.

R4 R5 2 "00" = '. --1 ”, • 'τΝ R * (Ula) (Va) or a salt or salt thereof' Method C - (2): 11 (ch) f 1Δ 11 2 n Ring closure reaction C [] I4 (Va) (Hb) .. or a salt thereof or a salt thereof -Method D - (1): 4 * / = ^ N s 4

R R L 11 R

(Sarcasm). • Ν '^ γ ^ SA 4 - ^ HAd5

w CH-R * T R

1 1 4 (Illb) R (Vb) or a salt thereof, or a salt thereof 6 83518

Method D - (2):, ΥΎ r4 Γ Π 4,

^ Tire closing- JL

p4 I reaction f il I] Y ^ R5 -> o H.

(Vb) (Ile) or a salt thereof or a salt thereof

Method E: R6 R6

hydroxy group

HoAAA ''. ^ Attachment of a protecting group ^ ^ (Hd) (Ile) or a salt thereof or a salt thereof

Method F: 00kR4. Oxidation of R 4 o 0 (Ilf) dig) or a salt thereof or a salt thereof

Method G: Addition of a Hydroxy Group ^ CH 2 OH Protecting Group OR 2 (IIId) (IIId) or a salt thereof or a salt thereof 7,83518

Method H:

OR8 0H

Deprotection of the hydroxy group -> N 1 4

0 O

(uh) (ui) or a salt thereof, or a salt thereof

Method I: 9 9 1 S0 ~ S | *

Oxidation ^ C. N jL 4 ^ Ν ^ Λη4 TR ° (Iij) (Ilk) or a salt thereof or a salt thereof wherein R2 and R4 are each as defined above, R5 is lower alkoxy, R6 is hydrogen, protected hydroxy, lower alkyl, lower alkoxy, carboxy, protected carboxy, lower alkenyloxy, aryl.

8 83518 which may have a suitable substituent (s), arylthio, aroyl, ar (lower) alkyl, arenesulfonyl, arylamino which may have a suitable substituent, or aryloxy, R® is a hydroxy protecting group, R® is a protected hydroxy and n is 1 or 2.

Suitable pharmaceutically acceptable salts of the subject compounds (I) are conventional non-toxic salts, including an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.). e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g., archinine, aspartic acid, glutamic acid, etc.), or a metal salt such as an early metal salt (e.g., sodium salt, potassium salt, etc.). , and an alkaline earth metal salt (e.g., a calcium salt, a magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., a trimethylamine salt, a triethylamine salt, a pyridine salt, a picoline salt, a dicyclohexyl salt, etc.), N-N'-dibenzyl .

The following are detailed examples of the various definitions used in this publication that are within the scope of the invention.

The term "lower" means 1 to 6 carbon atoms, unless otherwise stated.

Methods for preparing the target compounds (I) of the present invention are described in detail below.

9 83518

Method 1:

The target compound (Ia) or a salt thereof can be prepared by deprotecting the carboxy group from the compound (II) or a salt thereof.

The suitable salt of the compound (II) may be the same as the acid addition salt exemplified in connection with compound (I), and the suitable salt of compound (Ia) may be the same as exemplified in connection with compound (I).

In this elimination reaction, all conventional methods used for deprotection of a carboxy group can be used, e.g., hydrolysis, reduction, removal by Lewis acid, etc. When the carboxy group protecting group is an ester, it can be removed by hydrolysis or using Lewis aid. The hydrolysis is best performed in the presence of a base or acid.

A suitable base may be, for example, an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), or an alkali metal carbonate (e.g., sodium carbonate, e.g., carbonate, etc.). alkali metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alpha metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate, alkaline earth metal phosphate , 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 -diazabicyclo [4.3.0] non-5-one, 1,5-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [5.4.0] undecene-5 or the like. The base hydrolysis is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

A suitable acid may be an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

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

The reaction temperature1a is not critical. It can be selected based on the nature of the carboxy group protecting group and the method of removal.

Elimination with a Lewis acid is preferably used to remove a substituted or unsubstituted ar (lower) alkyl ester. The reaction is carried out by reacting the compound (II) or a salt thereof with a Lewis acid such as chlorine trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetrachloride, titanium tetrabromide, etc.), tin tetrahalide (e.g. e.g., tin tetrachloride, tin tetrabromide, etc.), aluminum halide (e.g., aluminum chloride, aluminum bromide, etc.), trihaloacetic acid (e.g., trichloroacetic acid, trifluoroacetic acid, etc.), or the like. This elimination reaction is best performed in the presence of cation scavengers (e.g., anisole, phenol, etc.). It is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.), an alkylene halide (e.g. methylene chloride, ethylene chloride, etc.), diethyl ether, sulfuric acid or any other solution which does not adversely affect the reaction. These solvents can be used as a mixture.

Reductive elimination is best applied to the removal of a protecting group such as a halogen (a 1 empi) or a (e.g.

2-iodoethyl, 2,2,2-trichloroethyl, etc.) ester, ar (lower) alkyl (e.g. benzyl, etc.) ester or the like.

n 83518

The reduction method used in the elimination reaction may be, for example, reduction using a metal (e.g. zinc, zinc amalgam, etc.) or a salt of a chromium compound (e.g. chromium (2) chloride, chromium (2) acetate, etc.) and an organic or inorganic acid (e.g. acetic acid). -acetic acid, propionic acid, hydrochloric acid, etc.) combination; and conventional catalytic reduction in the presence of a conventional metal catalyst (e.g., palladium / carbon, Raney nickel, etc.).

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

This deprotection reaction of the carboxy group also includes the case where another protected carboxy is converted to the free carboxy during the reaction or post-treatment step of the present process.

Method 2:

The target compound (Ib) or a salt thereof can be prepared by amidating the compound (Ia) or a reactive derivative thereof in the carboxy group or a salt thereof.

| The suitable salt of the compound (Ib) may be the same as that exemplified in connection with the compound (I).

The amidating agent used in this amidation reaction may be an amine having a suitable substituent (s) such as a heterocycle group having a suitable substituent (s), or aryl which may have a suitable substituent (s) on a nitrogen atom.

Suitable reactive derivatives of the compound (Ia) at the carboxy groups include an acid halide, an acid anhydride, an activated ester and the like. A suitable example may be, for example, an acid chloride, an acid azide; mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, 8-acidic acid, aliphatic acid, aliphatic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or an aromatic carboxylic acid (e.g. benzoic acid, etc.) symmetrical acid anhydride; or an activated ester (e.g. cyanomethyl ester, methoxyethyl ester, dimethyliminomethyl / (CH 2) 2 O = CH - / ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl , mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, N-diethylene, 8-quinolylthioester, etc.), or ester N With 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.) and the like.

When the compound (Ia) is used in the reaction in its free acid form or in its salt form, the reaction is best carried out in the presence of a conventional condensing agent. These include, for example, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-ethyl-N '(3-dimethylaminopropyl) carbodiimide, 1,1'-carbonyldiimidazole , thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide (e.g., ethyl chloroformate, isobutyl chloroformate, etc.), 1- (p-chlorobenzenesulfonyloxy) -6-, chloro-1H-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, N1-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:. in anhydrous but not critical conditions.

The reaction can be carried out in the presence of an inorganic or organic base 13,835,8. These include, for example, alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), tri (lower) e.g., trimethylamine, triethylamine, etc.), pyridine or a derivative thereof (e.g., picoline, lutidine, 4-dimethylaminopyridine, etc.), or the like. In case the base or condensing agent used is liquid, it can also be used as a solvent.

The reaction temperature is not critical. The reaction is usually carried out under heating or heating, preferably under heating.

Method 3:

The target compound (Id) or a salt thereof can be prepared by dehydrating the compound (Ie) or a salt thereof.

The dehydrating agent used in this dehydration reaction may be phosphoryl chloride, thionyl chloride, phosphorus pentoxide, phosphorus. .pentachloride, phosphorus pentabromide and the like.

This reaction is usually carried out in a solvent such as dioxane 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. The reaction is usually carried out at ambient temperature with heating or heating.

Method 4:

The target compound (Ie) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof with hydrogen sulfide.

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

i4 8 3 51 8

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

Method 5:

The target compound (If) or a salt thereof can be prepared by forming a tetrazolyl group in the compound (Id) or a salt thereof.

A suitable salt of the compound (If) and (Id) may be an acid addition salt exemplified in connection with the compound (I).

The substance used in this reaction may be a conventional reagent such as a combination of an alkali metal azide (e.g., potassium azide, sodium azide, etc.) and an ammonium halide (e.g., ammonium chloride, or the like).

This reaction is usually carried out in a solvent 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. The reaction is usually carried out under heating or heating.

Method 6:

The compound (Ih) or a salt thereof can be prepared by deprotecting the carboxy group from the compound (Ig) or a salt thereof.

Suitable salts of compounds (Ig) and (Ih) may be the same as those exemplified for compound (I).

The present reaction can be carried out in the same manner as in Method 1 mentioned above. Therefore, with respect to the reaction methods and conditions (e.g., reaction temperature, solvent, etc.), reference is made to the corresponding data of Method 1.

Method A - (1);

Compound (V) or a salt thereof can be prepared by reacting compound (III) or a salt thereof with compound (IV).

Suitable salts of the compounds (III) and (V) may be the same as the acid addition salts exemplified in connection with the compound (I).

The present reaction is best carried out in the presence of alkyllithium (e.g., n-butyllithium), lithium diisopropylamide, alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.) and the like.

This reaction is usually carried out 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. The reaction is usually carried out under cooling, at ambient temperature or under heating.

Method A - (2):

Compound (IIa) or a salt thereof can be prepared by ring closure in compound (V) or a salt thereof.

A suitable salt of the compound (V) may be an acid addition salt exemplified in connection with the compound (I).

This reaction can best be carried out in the presence of a suitable substance such as a mixture of diphenyl and diphenyl ether used as a heating agent.

16 8351 8

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

Method B - (1):

Compound (Vc) or a salt thereof can be prepared by reacting compound (IIIc) or a salt thereof with compound (IV).

Suitable salts of the compounds (Vc) and (IIIc) may be the acid addition salts exemplified in connection with the compound (I).

This reaction can be carried out in the same manner as the reaction of the above-mentioned Method A to (1).

Method B - (2):

Compound (Uh) or a salt thereof can be prepared by ring closure in compound (Vc) or a salt thereof.

Suitable salts of the compound (Uh) and (Vc) may be the acid addition salts exemplified in connection with the compound (I).

This reaction can be carried out in the same manner as the above-mentioned reaction of Method A to (2).

Method C - (1):

Compound (Va) or a salt thereof can be prepared by reacting compound (IIIa) or a salt thereof with compound (IV).

Suitable salts of the compound (IIIa) and (Va) may be the acid addition salts exemplified in connection with the compound (I).

This reaction can be carried out in the same manner as the above-mentioned reaction of Method A to (1).

Method C - (2): 17 8351 8

Compound (lib) or a salt thereof can be prepared by ring closure in compound (Va) or a salt thereof.

Suitable salts of the compound (Hb) and (Va) may be the acid addition salts exemplified in connection with the compound (I).

This reaction can be carried out in the same manner as the above-mentioned reaction of Method A to (2).

Method D - (1): (Vb) or a salt thereof can be prepared by reacting the compound (IIIb) or a salt thereof with the compound (IVa).

Suitable salts of the compounds (IIIb) and (IIIb) may be the acid addition salts exemplified in connection with the compound (I).

This reaction can be carried out in the same manner as the above-mentioned reaction of Method A to (1).

Method D - (2):

Compound (Ile) or a salt thereof can be prepared by ring closure in compound (Vb) or a salt thereof.

Suitable salts of the compounds (Ile) and (Vb) may be the acid addition salts exemplified in connection with the compound (I).

This reaction can be carried out in the same manner as the above-mentioned reaction of Method A to (2).

Method E:

The target compound (Ile) or a salt thereof can be prepared by attaching a hydroxy protecting group to the compound (Ild) or a salt thereof.

Suitable salts of the compounds (Ild) and (Ile) may be the acid addition salts exemplified in connection with the compound (I).

18 8351 8

In the case where the protecting group to be attached is lower alkyl or lower alkenyl, the reaction can be carried out by reacting compound (IId) with a lower alkylating agent or lower alkenylthianene.

The lower alkylating agent or lower alkenylating agent used in this reaction may be a conventional agent such as mono (or di) lower alkyl sulfate (e.g., dimethyl sulfate, etc.), lower alkyl (lower) alkanesulfonate (e.g., methyl methanesulfonate, etc.), halogen (lower) alkane. e.g., bromomethane, iodomethane, iodoethane, iodobutane, etc.), halogen (lower) alkene (e.g., iodopropene, etc.) or the like.

When a lower alkyl ester of an acid is used as the lower alkylating agent, 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.

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

The reaction temperature is not critical. The reaction is usually carried out under cooling - heating close to the boiling point of the solvent.

Method F;

Compound (Iig) or a salt thereof can be prepared by oxidizing compound (IIf) or a salt thereof.

A suitable salt of the compound (IIf) may be an acid addition salt exemplified in connection with the compound (I).

A suitable oxidant to be used in this oxidation reaction may be a conventional one such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

This oxidation is carried out in a solvent such as benzene, toluene, chloroform, methylene chloride, carbon tetrachloride, diethyl ether, dimethylformamide or any other solvent which does not adversely affect the reaction. The solvent can be selected based on the quality of the oxidant used.

The reaction temperature of the oxidation reaction of this method is not critical. The reaction is carried out under cooling, at ambient temperature, heating or heating. The reaction temperature is selected based on the quality of the oxidant used.

Method G;

Compound (Ile) or a salt thereof can be prepared by attaching a hydroxy protecting group to compound (Ild) or a salt thereof.

This reaction is carried out in a conventional manner.

In the case where the protecting group to be attached is a silyl group, this reaction is carried out by reacting a compound (Ilg) or a salt thereof with a compound of the formula (VI).

Ra - X (VI) wherein Ra is trisubstituted silyl and X is an acid residue.

A suitable acid residue may be halogen (e.g. chlorine, bromine, etc.) or the like.

This reaction is best performed in the presence of imidazole, 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, Ν, Ν-dimethylformamide, pyridine, or any other organic solvent. .

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

Method H:

Compound (lii) or a salt thereof can be prepared by removing a hydroxy group from a protecting group compound (Uh) or a salt thereof.

This elimination reaction is carried out by a conventional method such as Method 1.

The present reaction is best 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, Ν, Ν-dimethylformamide, pyridine or any other organic solvent.

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

Method I;

The target compound (IIk) or a salt thereof can be prepared by oxidizing the compound (IIj) or a salt thereof.

The oxidant used in this reaction may be an inorganic peracid or a salt thereof (e.g., periodic acid, sulfuric acid or its sodium or potassium salt, etc.), an organic peracid or a salt thereof (e.g., perbenzoic acid, m-chloroperbenzoic acid, perforic acid, peracetic acid). , chloroperacetic acid, trifluoroperacetic acid or its sodium or potassium salt), ozone, hydrogen peroxide, urea hydrogen peroxide, N-halide succinimide (e.g. N-bromosuccin-2i 8351 8 imide, N-chlorosuccinimide, etc.) * hypochlorite compound tert-butyl hypochlorite, etc.), permanganate (e.g., potassium permanganate, etc.), or any other conventional oxidant that can oxidize a sulfinyl group to a sulfonyl group.

The present reaction can also be carried out in the presence of a compound containing a metal of groups Vb and Vbb of the Periodic Table of the Elements, e.g., tungstic acid, molybdenic acid, vanadium acid, etc., or an alkali or alkaline earth metal salt thereof.

This 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.

Reaction 1 is not critical. The reaction is best carried out under cooling - at ambient temperature.

The compound (I) having the most potent antimicrobial activity can be represented by the following formula: R 7 R 3 "Y 2 R 10 wherein

R 1, R 2, R 3 and R 7 are each as defined above, and in particular R 1 is tetrazolylamino, R 2 and R 7 are each hydrogen, and R 3 is aryloxy or aroyl.

22 8351 8

To demonstrate the pharmaceutical utility of the quinoquinone compound (I), the results of pharmaceutical experiments are given below.

(1) Test compounds: (A) N- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one-3-carboxamide (B) N-C5- (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-Quinolizin-4-one-3-carboxylic acid (Q) 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 (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 23 8351 8 (L) N- [5- (1H-tetrazole-1-yl) '] - 1-phenoxy-4H-quinolizine Sodium salt of 4-one-3-carboxamide (2) Experiment: (A) Inhibition of stress ulcer 1. Experimental method: Spraque Dawley rats. Each animal was immobilized in a small cage and allowed to breathe in a water bath. The temperature of the water bath was maintained at 22 ° C. Test compounds were administered orally just prior to immobilization. After seven hours, the animals were sacrificed and their stomachs removed. The stomach was then fixed with 2% formalin. The area of the ulcers was measured in each animal. The average area of the experimental animals (4 mm) was compared with the area of the control animals.

2. Test results:

Test Compound Dose Inhibition No. __ (mg / kg) ____ (A) 32 83.6 (B) 32 89.2 (D) 32 89.2 (E) 32 88.6 (F) 32 63.2 (J) 32 67 .0 (L) 0.01 57.3 (B) PCA effect (passive cutaneous anaphylaxis) 24 8351 8 1. Experimental method: The animals used in the PCA reaction were 7-week-old female Spraque-Daw1ey rats weighing 180-200 g (Nihon Kurea). Each experiment contained five observations.

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

Seven-week-old female BDF1 mice11 e (Nihon Kurea) were given a primary injection (left foot, s.c.) of 100 micrograms of 0VA in 0.05 ml of saline, and after 20 days a booster injection by the same route. Blood was collected 28 days after primary injection and sera were stored at -80 ° C.

The animals were pre-run on an electric machine and prepared for the PCA test (Passive Cutaneous Anaphylaxis) by injecting 0.05 ml of mouse antiserum dilutions (1/16, 1/32) into each side of the dorsal skin.

After 48 hours, the animals were challenged by intravenous injection of 1 ml of 0.5% Evans Blue dye containing 5 mg OVA. After 50 minutes, the animals were sacrificed and the injuries were measured (diameter).

The smallest skin reaction was a blue spot 5 mm or larger in diameter on the dermal side of the inverted skin. Drug activity was assessed using the following formula: treated with drug (diameter)% inhibition = (1 -------------------------------- ---) χ 100 treated with saline (dia. mm) 25 8 3 51 8 The drugs were suspended in 0/1% methylene / saline and administered intravenously with antigen.

2. Test results

Test compound Dose Antiserum Inhibition No._ (mg / kg) concentration _ (%) (A) 10 1/16 94.5 (B) 10 1/16 100 (C) 10 1/16 100 (G) 10 1/16 94.7 (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 this invention can be used as a pharmaceutical preparation, e.g. in solid, semi-solid or liquid form containing the active ingredient of this invention in admixture with an organic or inorganic carrier or excipient suitable for external, oral or parenteral application. The active ingredient may be mixed with, for example, conventional non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and other suitable uses. Useful carriers include water, glucose, lactose, acacia, chelate, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and other carriers which may be used in the preparation of solid or semi-solid preparations. liquid preparations, and in addition, excipients, stabilizers, thickeners and colorants and perfumes can be used. The pharmaceutical compositions may also contain preservatives or bacteriostatic agents which retain the activity of the active ingredient in the desired preparations. The active target compound is incorporated into the pharmaceutical composition in such an amount that it produces the desired therapeutic effect on the course or condition of the disease.

When this mixture is administered to humans, it is best administered intravenously, intramuscularly or orally. Although the dosage or therapeutically effective amount of a target compound of this invention will vary and will also depend on the age and condition of each individual patient being treated, a daily dose will generally be about 0.05-5 mg of active ingredient / kg body weight (human or animal). The average single dose is usually about 2.5 mg, 25 mg and 250 mg.

The following Preparation Examples and Examples are provided to illustrate the invention.

Preparation Example 1: To a solution of 2-methylpyridine (7 ml) in tetrahydrofuran (140 ml) was added dropwise a solution of n-butyllithium (49 ml of a 1.59 mol solution in hexane) under ice-cooling. The resulting dark red solution was allowed to warm to ambient temperature and stirred for 1 hour. After cooling to -78 ° C, diethyl ethoxymethylene malonate (15.68 ml) in tetrahydrofuran (50 ml) was added over 30 minutes. The reaction mixture was allowed to warm to -20 ° C and stirred for 30 minutes at -20 ° C. Acetic acid (4.48 ml) was added. The solvent was distilled off, the residue was dissolved in ethyl acetate and washed with 10% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated to give an oil (27 g). The residue was chromatographed on silica gel (Merck 70-230 mesh, 270 g) eluting with chloroform to give ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl butyrate (19 g) as an oil.

IR (film): 1730, 1590, 1470, 1440, 1370 cm -1 NMR (CDCl 3) δ: 0.97 (t, 3H, J = 8Hz), 1.26 (t, 6H, J = 8Hz), δ , 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);

Preparation Example 2

A mixture of ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) butyrate (18.9 g), diphenyl (48.85 g) and diphenyl ether (135.8 g) was heated to 250 ° C for 40 minutes. The reaction mixture was cooled to ambient temperature and chromatographed on silica gel (Merck 70-230 mesh, 620 g) eluting with hexane followed by a mixture of ethanol and chloroform (1:49). The resulting crude oil was crystallized from a mixture of ether and hexane (1: 1) to give 3-ethoxycarbonyl-4H-quinolizin-4-one (11.48 g) as yellow crystals.

IR (Nujol): 1670, 1625, 1490 cm -1 NMR (CDCl 3) δ: 1.42 (t, 3H, J = 7Hz), 4.42 (g, 2H, J = 7Hz), 6.62 (d , 1H, J = 8Hz), 7.02-7.38 (3m, 1H), 7.53-7.68 (m, 2H), 8.33 (d, 1H, J = 8Hz), 9.23 -9.47 (m, 1 H)

Preparation Example 3

The following compounds were obtained in the same manner as the compound of Preparative Example 1.

(1) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (5-ethylpyridyl) / butyrate.

IR (film): 1750, 1730 cm-1 (2) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-quinolyl) butyrate.

IR (film): 1750 (shoulder), 1730 cm -1 (3) Ethyl 4-phenyl-3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) butyrate.

28 8351 8 IR (membrane): 1750 (shoulder), 1730 cm-1 (4) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (5-hydroxypyridyl) / butyrate.

IR (film): 2550, 1730, 1490, 1270, 1160, 1090, 1025 cm -1 NMR (CDCl 3) δ: 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) (5) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (1-isoquinolyl) butyrate.

IR (film): 1750, 1730 cm -1 (6) Ethyl 3-ethoxy-2-ethoxycarbonyl-3- [8- (5,6,7,8-tetrahydroquinolyl)] propionate.

IR (film): 1750, 1730 cm -1 (7) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (3-methylpyridyl) / butyrate.

IR (Nujol): 1750, 1735, 1575, 1440, 860, 790 cm -1 NMR (CDCl 3) δ: 0.92 (t, 3H, J = 5Hz), 1.27 (t, 6H, J = 5Hz) , 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 = 6Hz and 3Hz), 7.45 (d, 1H, J = 6Hz), δ , 42 (d, 1H, J = 3Hz): (8) Ethyl 3-ethoxy-2-carboethoxy-4- [2- (4-methylpyridyl) / butyrate.

IR (film): 1750, 1730, 1600, 1240, 1150, 1020 cm -1 NMR (CDCl 3) δ: 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) (9) Ethyl 3-ethoxy-2-ethoxycarbonyl -4- [2- (6-methylpyridyl) / butyrate.

IR (film): 1650, 1630, 1590, 1580, 1270, 1150, 1090 cm -1 NMR (CDCl 3) δ: 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 29 8351 8 (m, 1H), 4.18 (q, 4H, J = 7Hz), 4.33-4.67 6.85-7.15 (m, 2H), 7.33-7.66 (m, 1H) ) (10) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl) pentanoate.

IR (film): 1750, 1730, 1590, 1300, 1090, 1020 cm -1 NMR (CDCl 3) δ: 1.00 (t, 3H, J = 7Hz), / 1.35 (t, J = 7Hz), 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) (11) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- [2- (5-methylpyridyl) / butyrate .

IR (film): 1740, 1730, 1600, 1480, 1150, 1090, 1025 cm -1 NMR (CDCl 3) δ: 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), 8.37 (m, 1H) (12) Ethyl 3-ethoxy-2-ethoxycarbonyl-3- [7- (6,7-dihydro-5H-cyclo lopenta (b / pyridyl) / propionate.

IR (film): 1750 (shoulder), 1730, 1590, 1580 cm -1 NMR (CDCl 3) δ: 0.80 (t, 3H, J = 7Hz), 1.30 (t, 6H, J = 7Hz), 2.00-2.40 (m, 2H), 2.80-3.70 (m, 4H), 4.0 (q, 2H, J = 7Hz), 4.20 (q, 4H, J = 7Hz) ), 4.80 (dd, 1H, J = 8 Hz and 2 Hz), 7.00-7.60: (m, 2H), 8.3-8.50 (m, 1H); (13) Ethyl 3-ethoxy-4-methoxy-4- (2-pyridyl) -2-ethoxycarbonyl butyrate.

IR (film): 1750, 1730, 1590, 1365, 1090, 1025, 760 cm -1 NMR (CDCl 3) δ: 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) (14) Ethyl 3-ethoxy-4-ethoxycarbonyl-4- (2-pyridyl) butyrate. Preparation Example 4

The following compounds were obtained in the same manner as the compound of Preparative Example 2.

30 8351 8 (1) 2-Ethoxycarbonyl-1H-pyrido [1,2-a] quinolin-1-one.

Sp. 104-105 ° C.

IR (Nujol): 1730, 1660, 1530 cm -1 NMR (CDCl 3) δ: 1.43 (t, 3H, J = 7Hz), 4.43 (q, 2H, J = 7Hz), 6.40 (d , 1H, J = 8Hz), 7.0 and 7.45 (ABq, 2H, J = 10Hz), 7.50-7.70 (m, 4H), 8.20 (d, 1H, J = 8Hz) , 9.70-10.0 (m, 1H) (2) 7-Ethyl-3-ethoxycarbonyl-4H-quinolizin-4-one. Sp.81-83 ° C.

IR (Nujol): 1720, 1630 cm -1 NMR (CDCl 3) δ: 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) (3) 1-Phenyl-3-ethoxycarbonyl-4H-quinolizin-4-one. Sp.120-123 ° C.

IR (Nujol): 1730, 1620 cm -1 NMR (CDCl 3) δ: 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) (4) 8-Hydroxy-3-ethoxycarbonyl-4H-quinolizin-4-one. mp 242 ° C (dec.) IR (Nujol): 3300.3200, 1680, 1660, 1620, 1300, 1140, 960, 900 cff. 1 NMR (DMSO-d6) δ: 2.27 (t, 3H, J = 7Hz), 4.23 (q, 2H, J = 8Hz), 6.13 (d, 1H, J = 8Hz), 7.58 (dd, 1H, J = 2Hz, 8Hz), 7.90 (d, 1H, J = 8Hz), 8.07 (d, 1H, J = 8Hz), 8.82 (d, 1H, J = 2Hz): Anal. Calcd for C 18 H 18 NO 3: C, 61.80; H, 4.75 Found: C, 61.18; H, 5.05 (5) 3-Ethoxycarbonyl-4H-pyrido [2,1-a] isoquinolin-4-one. Sp. 155 ° C.

IR (Nujol): 3100, 1740, 1650, 1640 cm -1 NMR (CDCl 3) δ: 1.46 (t, 3H, J = 7Hz), 4.46 (q, 2H, J = 7Hz), 7.23 (d, 1H, J = 8Hz), 7.35 (d, 1H, J = 8Hz), 7.50-7.83 (m, 3H), 8.20-8.50 (m, 1H) , 8.46 (d, 1H, J = 8Hz), 9.10 (d, 1H, J = 8Hz)

Anal. Calcd for C16H13NO3: C; 71.90, H; 4.90, N; 5.24 Found: C; 71.40, H; 5.06, N; 5.17 (6) 9-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one. Mp 125-126 ° C.

IR (Nujol): 3090, 1725, 1645, 1590, 1125, 1100 cm -1 NMR (CDCl 3) δ: 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), δ .35 (d, 1H, J = 9Hz), 9.32 (d, J = 7Hz, 1H)

Anal. Calcd for C13H13NO3: C; 67.52, H; 5.67 Found: C; 67.51, H; 5.83 3i 8351 8 (7) 8-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one M.p. 146-148 ° C.

IR (Nujol): 3060, 1720, 1660, 1640, 1245, 1155, 790 cm -1 NMR (CDCl 3) δ: 1.40 (t, 3H, J = 7Hz), 2.50 (s, 3H), δ .38 (q, 2H, J = 7Hz), 6.50 (d, 1H, J = 9Hz), 7.00 (dd, 1H, J = 7Hz, 2Hz), 7.30 (d, 1H, J = 2Hz), 8.32 (d, 1H, J = 9Hz), 9.28 (d, 1H, J = 7Hz) Anal. calculated: Cl 3 H 13 NO 3: C; 67.52, H; 5.67 Found: C; 67.38, H; 5.65 (8) 3-Ethoxycarbonyl-6-methyl-4H-quinolizin-4-one. Mp 90-9 3 ° C.

IR (Nujol): 1720, 1650.1620, 1590.1265, 1120, 1100, 795 cm -1 NMR (CDCl 3) δ: 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)

Anal. calculated for C 13 H 13 NO 3: C; 67.52, H; 5.67, N; 6.07 Found: C; 67.28, H; 5.63, N; 6.03 (9) 1-Methyl-3-ethoxycarvonyl-4H-quinolizin-4-one M.p. 142-14 ° C.

JR (Nujol): 1720, 1650, 1620, 1595, 1300, 1230, 160.1 120, 775 cm -1 NMR (CDCl 3) δ: 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, 1 H)

Anal. calculated c- | 3H-] 3NO3: C; 67.52, H; 5.67, N; 6.06 Found: C; 67.49, H; 5.94, N; 6.06 (10) 7-Methyl-3-ethoxycarbonyl-4H-quinolizin-4-one. M.p. 1 46-149 ° C.

IR (Nujol): 1720, 1620, 1145, 1110 cm -1 NMR (CDCl 3) δ: 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, 1 H)

Anal. calculated C- ^ H ^ NC ^: C? 67.52, H; 5.62, N; 6.06 Found: C; 67.44, H; 5.85, N; 6.00 (11) 2-Ethoxycarbonyl-8,9-dihydrocyclopenta [b] -3H-quinolizin-3-one. Sp. 149 ° C.

32 83 51 δ IR (Nujol): 3100, 1720, 1640.1620, 1600.1550, 1210.1150 cm -1 NMR (CDCl 3) δ: 1.43 (t, 3H, J = 7Hz), 3.30 ( broad s, 4H), 4.30 (q, 2H, J = 7Hz), 7.0-7.30 (m, 2H), 8.30 (s, 1H), 8.86 (d, 1H, J = 6Hz)

Anal. Calcd. 69.12, H; 5.39, N; 5.76 Found: C; 68.16, H; 5.47, N; 5.69 (12) 2-Ethoxycarbonyl-9,10-dihydro-8H-benzo [b] -3H-quinolizin-3-one. Sp. 118 ° C.

IR (Nujol): 1680, 1620, 1600, 1220 cm -1 NMR (CDCl 3) δ: 1.40 (t, 3H, J = 7Hz), 1.85-2.20 (m, 2H), 2.80 -3.20 (m, 4H), 4.40 (q, 2H, J = 7Hz), 6.85-7.30 (m, 2H), 8.13 (s, 1H), 9.20 (d , 1H, J = 7Hz)

Anal. Calcd for C 15 H 15 NO 3: C; 70.02, H; 5.88, N; 5.44 Found: C; 69.78, H; 5.95, N? 5.38 (13) 1-Methoxy-3-ethoxycarbonyl-4H-quinolizin-4-one M.p. 132-133 ° C.

IR (Nujol): 1680, 1670, 1620, 1595, 1360, 1120, 1020, 770 cm -1 NMR (CDCl 3) δ: 1.43 (t, 3H, J = 7Hz), 3.93 (s, 3H) , 4.45 (q, 2H, J = 7Hz), 7.25 (m, 1H), 7.67 (m, 1H), 7.97-8.20 (m, 2H, 9.47 (d, 1H, J = 7.5 Hz)

Anal. Calcd for C13H13NO4 *. C; 63.15, H; 5.30, N; 5.66 Found: C; 62.80, H; 5.33, N; 5.63 (14) 1-Ethoxycarbonyl-4H-quinolizin-4-one. Sp. 114 ° C.

: IR (Nujol): 1725, 1680, 1630 cm-1

Anal, calculated for C 18 H 18 N 2 O 2: C; 66.35, H; 5.10, N; 10.45 Found: C; 66.19, H; 4.81, N; 6.42

Preparation Example 5 A solution of 2-ethoxycarbonyl-8,9-dihydrocyclopenta [b] -3H-quinolizin-3-one (2.2 g) and dichlorodicyanobenzoquinone (2.26 g) in benzene (110 ml) was refluxed for 2 hours. The reaction mixture was cooled to 0 ° C and the precipitate was filtered. The filtrate was concentrated and the residue was chromatographed. was chromatographed on a silica gel column (44 g) eluting with chloroform-methanol (100: 1-10: 1). Evaporation of the corresponding fractions gave crude crystals which were washed with a mixture of ether and hexane 33 83 51 8. There was thus obtained 2-ethoxycarbonylcyclopenta [b] -3H-quinolizin-3-one (1.82 g), m.p. 127 ° C.

IR (Nujol): 3100, 1680-1700 (broad), 1620, 1570, 1230, 1210 cm -1 NMR (CDCl 3) δ: 1.46 (t, 3H, J = 7Hz), 4.46 (q, 2H , J = 7Hz), 6.80-7.60 (m, 3H), 8.13 (d, 1H, J = 8Hz), 8.70 (s, 1H), 9.20 (d, 1H, J = 8Hz)

Anal. Calcd for C14H11NO3: C; 69.70, H; 4.60, N; 5.81 Found: C; 69.34, H; 4.80, N; 5.78

Preparation Example 6 To a stirred solution of 3-ethoxycarbonyl-7-hydroxy-4H-quinolizin-4-one (4.5 g) in dry N, Ν-dimethylformamide (90 ml) was added sodium hydride (60% in mineral oil, 0.93 g) at room temperature and the resulting the solution was kept at 50 ° C for 30 minutes. The reaction mixture was treated with methyl iodide (4.13 g) 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 layer was washed with water, dried over anhydrous magnesium sulfate and evaporated to an oil (12.3 g) which was applied to a silica gel column. Elution with chloroform-methanol (99: 1) gave 3-ethoxycarbonyl-7-methoxy-4H-quinolizin-4-one (3.75 g), m.p. 156-158 ° C.

IR (Nujol): 1720, 1620, 1500, 1140, 1100 cm -1 NMR (CDCl 3) δ: 1.43 (t, 3H, J = 7Hz), 3.93 (s, 3H), 4.43 (q , 2H, J = 7Hz), 6.63 (d, 1H, J = 8.5Hz), 7.23-7.70 (m, 2H), 7.28 (d, 1H, J = 8Hz), 9 .00 (m, 1 H)

Anal. calculated for C 12 H 12 NO 3: C; 63.15, H; 5.30 Found: C; 62.62, H; 5.52

Preparation Example 7

The following compounds were obtained in the same manner as in the compound of Preparative Example 6.

3-ethoxycarbonyl-7-n-butoxy-4H-quinolizin-4-oni.Sp.132-133 ° C.

IR (Nujol): 1710, 1620, 1540, 1280, 1240, 1140, 845, 780 cm -1 NMR (CDCl 3) δ: 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, 348351 J = 8Hz), 8.97 (d, 1H, J = 2Hz)

Anal. Calcd. 66 / ^ 2, H; 6.62, N; 4.84 Found: C; 66.54, H; 6.52, H; 4.82 (2) 3-Ethoxycarbonyl-7-isopropoxy-4H-quinolizin-4-one. Sp.

132-134 ° C.

IR (Nujol): 1725, 1625, 1240, 1140, 1100, 970, 840 cm -1 NMR (CDCl 3) δ: 1.42 (d, 6H, J = 6Hz), 1.43 (t, 3H, J = 7.5Hz), 4.43 (q, 1H, J = 7Hz), 4.65 (m, 2H), 6.62 (d, 1H, J = 8Hz), 7.20-7.68 (m, 2H), 8.27 (d, 1H, J = 8.5Hz), 9.00 (d, 1H, J = 2Hz) Anal. calculated for C 12 H 12 NO 3: C; 65.44, H; 6.22, N; 5.09 Found: C; 65.66, H; 6.15, N; 5.10

Preparation Example 8

A solution of ethyl 2-pyridyl acetate (6.10 ml) in ethanol (120 ml) containing sodium methoxide (3.25 g) was refluxed for 1 hour. The resulting reaction mixture was treated with ethyl ethoxyacrylate (7.06 ml) and then refluxed for 3 days. Acetic acid (4.6 ml) was added to the reaction mixture, and the solvent was evaporated to dryness, the oily residue was dissolved in ethyl acetate and washed with water and aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and then evaporated. The obtained oily residue was chromatographed on a silica gel column. Elution with benzene-ethyl acetate (10: 1) gave ethyl 3-ethoxy-4-ethoxy-. carbonyl 4- (2-pyridyl) butyrate (9.80 g) as an oil.

Preparation Example 9

The following compounds were obtained in the same manner as the compound of Preparation Example 1.

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

IR (film): 1750, 1730, 1590, 1500, 1150, 1090, 1030 cm -1 NMR (CDCl 3, δ): 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) 35 8351 8 (2) Ethyl 4- (2-pyridyl) -4- (1-naphthyl) -3-ethoxy-2-ethoxycarboxylate. bonyylibutyraatti.

IR (film): 1750, 1720, 1580.780, 750 cm -1 NMR (CDCl 3, δ): 0.60 (3H, t, J = 7Hz), 1.20 (6H, t, 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-etoksikar-bonyylibutyraatti.

IR (membrane): 1750, 1730, 1590, 1485, 1300, 1150, 760 δ NMR (CDCl 3, δ): 0.83 (3H, t, J = 7Hz), 1.33 (6H, t, J = 7Hz) ), 3.28 (1H, m), 3.63 (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, ra) (4) Ethyl 4-phenoxy-4- (2-pyridyl) -3-ethoxy-2-ethoxycarbonyl butyrate.

IR (film): 1750, 1730, 1590, 1490, 1220, 1060, 750 cm -1 NMR (CDCl 3, 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-ethoxycarbonyl libutyrate: TR (film ): 1750, 1730, 1600, 1590, 1100, 700 cm -1 NMR (CCl 4, δ): 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 (1H, m) (6) Ethyl 4- (2-pyridyl) -4- (4-chlorophenyl) -3-ethoxy-2-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1490, 1090, 750 cm -1 NMR (CDCl 3, δ): 0.63-0.97 (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-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1470, 1440, 1370, 1160, 1100, 36 83 51 8 1040/760, 700 cm -1 NMR (CCl 4, δ): 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-ethoxycarbonyl libutyrate.

IR (membrane): 3060, 1740, 1720, 1590, 1440, 1090, 860, 750 cm -1 NMR (CCl 4, δ): 0.70 (3H, t, J = 7Hz), 1.03-1.48 <6H, m), 2.4 (3H, m), 2.80-4.93 (9H, m), 6.80-7.60 (7H, m), 8.47 (1H, m) ( 9) Ethyl 4- (2-pyridyl) -4-t-butyldimethylsiloxy-3-ethoxy-2-ethoxycarbonylbutyrate.

IR (film): 1750, 1730, 1590, 1580 cm-1

Preparation Example 10

The following compounds were obtained in the same manner as the compound of Preparative Example 2.

(1) 2-Ethoxycarbonyl-4-phenyl-1H-pyrido [1,2-a] quinolin-1-one.

Sp. 158-159 ° C.

IR (Nujol): 1690, 1670, 1625, 1580, 1230, 1130, 1000 cm -1 NMR (CDCl 3, δ): 1.40 (3H, t, J = 7Hz), 4.42 (2H, q, J = 7Hz), 7.10-7.70 (10H, m), 8.23 (1H, s), 9.68 (1H, m)

Anal Calcd for C22H17NO3: C; 76.95, H? 4.99, N; 4.08 Found: C; 76.76, H; 5.05, N; 4.00 (2) 1- (1-Naphthyl) -3-ethoxycarbonyl-4H-quinolizin-4-one. Mp 161-153 ° C.

IR (Nujol): 1690, 1665, 1590, 1270, 1240, 780, 770 cm -1 NMR (CDCl 3, δ): 1.38 (3H, t, J = 7Hz), 4.43 (2H, q, J = 7Hz), 7.05-7.77 (8H, m), 7.80-8.10 (2H, m), 8.43 (1H, s), 9.58 (1H, m) Anal. C22H17NO3: C, 76.95, H, 4.99, N, 4.08 Found: C, 77.14, H, 5.27, N, 3.89 (3) 1- (4-Biphenylyl) -3-ethoxycarbonyl-4H-quinolizin-4-one.

Sp. 183 to 184.5 ° C.

37 83 5 18 IR (Nujol): 1690, 1680, 1625, 1590, 1260, 770, 740 cm -1 NMR (CDCl 3, δ): 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)

Anal. Calcd for C24H19NO3.1 / 4H2O: C; 77.09, H; 5.27, N; 3.75 Found: C; 77.04, H; 5.49, N; 3.60 (4) 1-Phenoxy-3-ethoxycarbonyl-4H-quinolizin-4-one M.p. 108-109 ° C.

IR (Nujol): 1680.1670, 1620, 1590, 1225.1200.1000 cm-1 NMR (CDCl 3, δ): 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) Anal. C18H15NO4: C; 69.89, H; 4.89; OF; 4.53 Found: C; 70.18, H; 5.03, N; 4.51 (5) 1- (3-Tolyl) -3-ethoxycarbonyl-4H-quinolizin-4-one. Mp 109-111 ° C.

IR (Nujol): 1725, 1645, 1620, 1595, 1240, 770 cm -1 NMR (CDCl 3, δ): 1.42 (3H, t, J = 7Hz), 2.45 (3H, s), 4, 45 (2H, q, J = 1 Hz), 7.08-7.48 (5H, m), 7.53-7.95 (2H, m), 8.42 (1H, s), 9.55 (1H, m)

Anal. Calcd. C 18 H 18 NO 3 / 5H 2 O: C; 73.39, H; 5.64, N; 4.50 Found: C; 73.58, H; 5.62, N; 4.49 (6) 1- (4-Chlorophenyl) -3-ethoxycarbonyl-4H-quinolizin-4-one.

Sp. 159-160 ° C.

IR (Nujol): 1680, 1670, 1490, 1295, 1260, 1240, 1130, 1020, 765 cm -1 NMR (CDCl 3, δ): 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)

Anal. calculated gH.j 4ClNO 3: C; 65.96, H; 4.31, N; 4.27 Found: C; 65.81, H; 4.49, N; 4.19 - (7) 1- (3-Methoxyphenyl) -3-ethoxycarbonyl-4H-quinolizin-4-one.

Sp. 155-157 ° C.

IR (Nujol): 3070.1730, 1650, 1625.1595, 1130, 1100, 780 cm -1 NMR (CDCl 3, δ): 1.42 (3H, t, J = 7Hz), 3.80 (3H, s ), 4.40 (2H, q, J = 7 Hz), 6.85-7.93 (7H, m), 8.35 (1H, s), 9.47 (1H, m)

Anal. Calcd for C 18 H 18 NO 4 / 4H 2 O: C; 69.61, H; 5.38, N; 4.27 Found: C; 69.62, H; 5.29, N; 4.19 38 8351 8 (8) 1- (2-Tolyl) -3-ethoxycarbonyl-4H-quinolizin-4-one. Mp 97-98 ° C.

IR (Nujol): 1730, 1680, 1620, 1480, 1230, 1100, 785 1 H NMR (CDCl 3, δ): 1.45 (3H, t, J = 7Hz), 2.10 (3H, s), 4.48 (2H, q, J = 7 Hz), 7.18-7.83 (7H, m), 8.42 (1H, s), 9.68 (1H, m)

Anal. Calcd for C19H11NO3: C; 74.25, H; 5.57, N; 4.56 Found: C; 74.50, H; 5.66, N; 4.50 (9) 1-t-Butyldimethylsiloxy-3-ethoxycarbonyl-4H-quinolizin-4-one. Sp. 80 ° C.

IR (Nujol): 1695, 1675, 1620, 1590 cm -1 NMR (CDCl 3, δ): 0.2 (6H, s), 1.10 (9Hz), 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)

Anal. calculated ciQH25N ° 4Si: C; 62.22, H; 7.25, N; 4.03 Found: C; 61.97, H; 7.04, N; 4.08

Preparation Example 11 A mixture of 2-hydroxymethylpyridine (19.3 ml), t-butyldimethylsilyl chloride (36.2 g) and imidazole (27.2 g) in dimethylformamide (190 ml) was stirred for 2 hours at room temperature. Water was added to the reaction mixture and extracted with n-hexane. The organic layer was washed with water, dried over magnesium sulfate and then evaporated. The residue was distilled to give 2-t-butyldimethylsiloxymethylpyridine (42.30 g).

IR (film): 1595, 1585, 1260, 1160, 1140 cm -1 NMR (CDCl 3, δ): 1.0 (6H, s), 1.83 (9H, z), 4.70 (2H, s) Δ 6.85-7.20 (1H, m), 7.25-7.70 (2H, m), 8.20-8.30 (1H, m)

Preparation Example 12 To a solution of 1-t-butyldimethylsiloxy-3-ethoxycarbonyl-4H-quinolizin-4-one (3.32 g) in tetrahydrofuran (100 ml) was added a solution of tetra-n-butylammonium fluoride (1 M, 11.47 ml) at 0 ° C. :in.

The mixture was stirred for 1 hour and the solvent was distilled off. The residue was soaked in ethyl acetate, washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was filtered off and evaporated. The residue was chromatographed on 39 8 3 51 8 silica gel eluting with chloroform to give 1-hydroxy-3-ethoxycarbonyl-4H-quinolizin-4-one (1.13 g). Mp.> 250 ° C.

IR (Nujol): 3100, 1690, 1650, 1620 cm -1 NMR (DMSO-d 6, δ): 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)

Anal. Calcd. 61-80, H; 4.75, N; 6.01 Found: C; 61.11, H; 4.58, N; 5.91

Preparation Example 13

The following compounds were obtained in the same manner as the compound of Preparative Example 1.

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

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

NMR (CDCl 3, δ): 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 = 4.4 Hz) (3) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-benzoyl-4- (2-pyridyl) butyrate.

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

IR (film): 1750, 1730, 1635, 1585, 1365, 1290, 1245, 1185, 1140, 1090, 1025, 745, 700 cm -1 NMR (CDCl 3, δ): 0.98-1.50 (9H, m), 2.93-4.67 (11H, m), 6.73-7.63 (8H, m), 8.48-8.63 (1H, m) (5) Ethyl 3-ethoxy-2 ethoxycarbonyl-4- (2-pryridyyli) -4-phenyl-cyclopropanethiocarboxylate.

IR (film): 1750, 1730, 1590, 1440, 1300, 1150, 1090, 1025, 760 cm-1 NMR (CDCl 3, δ): 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) 40 83 51 8

Preparation Example 14

The following compounds were obtained in the same manner as the compound of Preparative Example 2.

(1) 3-Ethoxycarbonyl-7-hydroxy-1-phenyl-4H-quinolizin-4-one.

IR (Nujol): 1720, 1620, 1490, 1450 cm -1 NMR (DMSO-d 6, δ): 1.30 (3H, t, J = 7Hz), 4.26 (2H, q, J = 7Hz), 7.46 (5H, m), 7.60-7.70 (2H, m), 7.97 (1H, s), 8.98 (1H, d, J = 2Hz)

Anal. 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- (N-methylanilino) -4H-quinolizin-4-one.

IR (Nujol): 1690, 1680, 1600, 1510, 1380, 1235 cm -1 NMR (DMSO-d 6, δ): 1.30 (3H, t, J = 7Hz), 3.30 (3H, s), 4.28 (2H, q, J = 7Hz), 6.50-8.10 (8H, m), 8.15 (1H, s), 9.40 (1H, d, J = 7Hz)

Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69 Found: C, 71.00; H, 5.40; N, 8.56

Sp. 129-132 ° C.

(3) 3-Ethoxycarbonyl-1-benzoyl-4H-quinolizin-4-one. Mp 176-178 ° C.

IR (Nujol): 1750, 1630, 1580, 1485, 1220, 1110, 785 cm -1 NMR (CDCl 3, δ): 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 )

Anal. Calcd for C19H15NO4: C, 71.02; H, 4.70; N, 4.36 Found: C, 70.76; H, 4.96; N, 4.33 (4) 3-Ethoxycarbonyl-1-benzyl-4H-quinolizin-4-one. Mp 102-105 ° C.

IR (Nujol): 1690.1670.1625, 1595.1320, 1235.765, 725 cm -1 NMR (CDCl 3, δ): 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, s), 9.45 (1 H, m)

Anal. Calcd for C 19 H 19 NO 3: C, 74.25; H, 5.57; N, 4.56 Found: C, 73.97; H, 5.72; N, 4.42 (5) 3-Ethoxycarbonyl-1-phenylthio-4H-quinolizin-4-one M.p. 171-173 ° C.

4i 8351 δ IR (Nujol): 1740, 1660, 1625, 1575, 1280, 1220, 1140, 1120, 780, 750 cm -1 NMR (CDCl 3, δ): 1.40 (3H, t, J = 7Hz), 4.42 (2H, q, J = 7 Hz), 6.68-7.47 (5H, m), 7.73 (1H, m), 8.33 (1H, m), 8.72 (1H, s) 9.52 (1 H, m)

Anal Calcd for C 18 H 18 NO 2 S: C, 66.44; H, 4.65; N, 4.30 Found: C, 66.17; H, 4.69; N, 4.28

Preparation Example 15 A mixture of 2-chloromethylpyridine (50 g), N-methylaniline (42 g) and potassium carbonate (120 g) in N, N-dimethylformamide (200 ml) was stirred for 4 hours at 120 ° C. The reaction mixture was cooled to room temperature, added to water (1 L) and extracted with ether. The ether extract was washed with water and then treated with activated carbon. After drying over magnesium sulfate, the ether extract was filtered and concentrated. The residue was crystallized from isopropyl alcohol to give N-methyl-N- (2-pyridylmethyl) aniline (39 g). Sp.60 ° C.

IR (Nujol): 1610, 1590, 1570, 1510, 1470, 1440, 1360 cm-1

Preparation Example 16 To a solution of 2-methylpyridine (9.31 g) in tetrahydrofuran (200 ml) was added a 1.5 M solution of n-butyllithium in hexane (73.3 ml) at -20 ° C. The resulting solution was stirred for 30 minutes at room temperature and ethyl benzoate ( 15.02 g) in tetrahydrofuran (100 ml) at -60 [deg.] C. Stirred for 2 hours at -60 [deg.] C., then acetic acid (15 ml) was added and the resulting mixture was allowed to warm to room temperature and concentrated in vacuo. The aqueous layer was re-extracted with ethyl acetate and the combined extracts were washed with water, 10% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride After drying over magnesium sulfate, the ethyl acetate extracts were filtered and evaporated. to give 2-pyridylmethylphenyl ketone (10.86 g) as an oil.

IR (Nujol): 1680.1630, 1600, 1545, 1270, 1200.1145, δ 83518 1060, 800, 775, 690 cm -1 NMR (CDCl 3, δ): 4.43 (1.5H, s), δ .02 (0.05H, s), 6.83-8.65 (9H, m) Preparation Example 17 (1) To a solution of 5-hydroxy-2-methylpyridine (10.66 g) in tetrahydrofuran (426 ml) was added n -butyllithium solution (1.5M in hexane, 143 mL) at -30 ° C / * -10 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature, cooled to -78 ° C, then cyclohexane was added dropwise. (11.14 ml) and allowed to warm to 0 [deg.] C. and stirred for 30 minutes at 0 [deg.] C. Acetic acid (24.6 ml) was added, after which 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, and the residue was washed with ethyl acetate to give 5-Hydroxy-2 - [(1-hydroxycyclohexyl) methyl] pyridine (11.96 g) was added.

IR (Nujol): 1615, 1575, 1500, 1460 cm -1 NMR (CD 3 OD, δ): 1.20-2.00 (10H, m), 2.90 (1H, s), 4.95 (2H, s), 7.20 (2H, m), 8.05 (1H, d, J = 2.0 Hz) (2) 5-Hydroxy-2 - [(1-hydroxycyclohexyl) methyl] pyridine (1g) in acetic acid ( 15 ml) containing sulfuric acid (5 ml) was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured onto ice, basified with 10% 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 2-benzyl-5-hydroxypyridine (409 mg).

IR (Nujol): 1560, 1450, 1370, 1280 cm -1 NMR (CDCl 3, δ): 4.07 (2H, s), 6.85-7.43 (7H, m), 8.08 (1H, d, J = 3.0Hz), 10.30 (1H, broad s)

Preparation Example 18 43 83518

Potassium permanganate (583 mg) was added at 0 ° C to a solution of 1-phenylthio-3-ethoxycarbonyl-4H-quinolizin-4-one (1.0 g) in acetic acid (20 ml). After stirring for 2 hours at the same temperature, the reaction mixture was allowed to warm to room temperature and stirred for another 1 hour. Potassium permanganate (194 mg) was added and stirred overnight. To the resulting reaction mixture was added a saturated aqueous solution of sodium thiosulfate 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 1-phenylsulfonyl-3-ethoxycarbonyl-4H-quinolizin-4-one (583 g), mp 182 ° C.

IR (Nujol): 1710.1680, 1640, 1580.1200, 1150 cm -1 NMR (CDCl 3, δ): 1.45 (3H, t, J = 7Hz), 4.45 (2H, q, J = 7Hz) ), 7.20-8.10 (7H, m), 8.60 (1H, d, J = 8Hz), 9.18 (1H, s), 9.50 (1H, d, J = 8Hz)

Anal Calcd for C 18 H 15 NO 5 S: C, 60.50; H, 4.23; N, 3.92 Found: C, 60.44; H, 4.51; N, 3.88

Preparation Example 19 To a solution of 3-ethoxycarbonyl-7-hydroxy-1-phenyl-4H-quinolizin-4-one (5 g) in N, N-dimethylformamide (100 ml) at 50 ° C was added sodium hydride (63.6% in mineral oil, 732 mg). After stirring for 30 minutes at 50 ° C, n-butyl iodide (2.77 ml) 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 hydrogencarbonate 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 (Merc 70-230 mesh, 100 g) eluting with chloroform followed by 10% methanol in chloroform to give 3-ethoxycarbonyl-7- (n-butoxy) -1-phenyl-4H-quinolizin-4 -one (2.37 g). Sp. 94-95 ° C.

IR (Nujol): 1730, 1690, 1655, 1630, 1480 cm -1 NMR (CDCl 3; δ): 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 44 8351 δ (1H, s), 9.08 (1H, d, J = 2Hz)

Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83 Found: C, 71.74; H, 6.39; N, 3.80

Preparation Example 20

The following compound was obtained in the same manner as the compound of Preparative Example 6.

1-allyloxy-3-ethoxycarbonyl-4H-quinolizin-4-oni.Sp.82-84 ° C.

IR (Nujol): 1690, 1680, 1660, 1620, 1580, 1320, 1235, 1100, 1015, 770 cm -1 NMR (CDCl 3, δ): 1.43 (3H, t, J = 7Hz), 4.42 (2H, g, J = 7Hz), 4.50-4.75 (2H, m), 5.15-5.67 (2H, m), 5.78-6.47 (1H, m), δ Δ 97-8.32f (4H, m), 9.47 (1H, d, J = 7.5Hz)

Anal Calcd 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 Example 21

The following compound was obtained in the same manner as the compound of Preparative Example 16.

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

NMR (CDCl 3, δ): 4.44 (2H, broad s), 6.85-7.70 (5H, m), 7.70-8.30 (3H, m), 9.34 (2H, s) )

Preparation Example 22

The following compound was obtained in the same manner as the compound of Preparative Example 1.

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

JR (Nujoli): 1730, 1720, 1675, 1595 cm-1

Preparation Example 23

The following compound was obtained in the same manner as the compound of Preparative Example 2.

45,835 8 1-Benzoyl-3-ethoxycarbonyl-7-hydroxy-4H-quinolizin-4-one.

IR (Nujol): 1740, 1630, 1570, 1490 cm -1 NMR (DMSO-d 6 δ): 1.22 (3H, t, J = 7Hz), 4.27 (2H, q, J = 7Hz), δ , 43-7.97 (6H, m), 8.22 (1H, s), 8.87 (1H, d, J = 10Hz), 8.95 (1H, d, J = 2Hz)

Preparation Example 24

The following compound was obtained in the same manner as the compound of Preparative Example 6.

1-Benzoyl-3-ethoxycarbonyl-7-n-butoxy-4H-quinolizin-4-one.

Sp. 158-159 ° C.

IR (Nujol): 1740, 1680, 1630, 1580, 1510 cm -1 NMR (CDCl 3, δ): 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 Example 25

To a solution of sodium ethoxide (sodium, 151 mg) in ethanol (20 ml) was added ethyl pyrid-2-yl acetate (1 ml) at room temperature, and the mixture was stirred for 1 hour at the same temperature. Diethyl ethoxymethylene malonate (1.33 ml) was added to the mixture at room temperature, and the mixture was stirred at room temperature overnight. Acetic acid (0.75 ml) was added to the mixture at room temperature, then the precipitate was filtered and washed with water to give 1,3-diethoxycarbonyl-4H-quinolizin-4-one (896 mg). Sp.130-131 ° C.

IR (Nujol): 1680, 1625, 1585 cm -1 NMR (CDCl 3, δ): 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 <5N Aqueous sodium hydroxide (6.5 ml) was added dropwise at room temperature to a solution of 3-ethoxycarbonyl-4H-quinolizin-4-one (2.17g) in methanol (65.2 ml). After stirring for 20 minutes, water (10 ml) was added. After stirring for 20 minutes, water (30 ml) was added again. After stirring for 1 hour, the mixture was acidified to pH 3 with 4N aqueous hydrochloric acid. The precipitate was filtered and washed with water to give 4H-quinolizin-4-one-3-carboxylic acid (1.75 g) as pale yellow crystals. Sp. 233 ° C.

IR (Nujol): 1730, 1610, 1585, 1320 cm -1 NMR (DMSO-d 6) δ: 7.26 (d, 1H, J = 9Hz), 7.50-7.95 (m, 1H), 8.00-8.20 (m, 2 H), 8.41 (d, 1H, J = 9Hz), 9.20-9.40 (m, 1H)

Example 2 To a suspension of 4H-quinolizin-4-one-3-carboxylic acid (1.69 g) in N, N-dimethylformamide (16.9 ml) was added 1,1'-carbonyldiimidazole (2.17 g) at ambient temperature. . The resulting suspension was heated at 100 ° C for 30 minutes and 5-amino-1H-tetrazole (1.06 g) was added at 100 ° C. After stirring for 20 minutes at 100 ° C, the reaction mixture was cooled to 0 ° C. The precipitate was filtered and washed with precooled Ν, Ν-dimethylformamide followed by ether to give N- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one-3-carboxamide (2.0 g) as a yellow solid. Sp. > 260 ° C.

IR (Nujol): 3200, 1660, 1620, 1500, 1310 cm -1 NMR (CF 3 COOH) δ: 7.42 (d, 1H, J = 8Hz), 7.68-7.88 (m, 1H), δ , 98-8.29 (m, 2H), 8.72 (d, 1H, J = 8Hz), 9.48 (d, 1H, J = 8Hz)

Anal. calculated for C 18 H 9 Cl 2 N 2: C; 61.56, H; 3.15, N; 32.80 Found: C; 51.70, H; 3.22, N; 32.99

Example 3

The following compounds were obtained in the same manner as the compound of Example 1.

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

IR (Nujol): 3100, 1725, 1700, 1605 cm -1 NMR (CD 3 OH) δ: 1.52 (t, 3H, t, 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)

Anal. Calcd. 66.35, H; 5.10, N; 6.45 Found: C; 66.40, H; 5.14, N; 6.46 47 83 51 8 (2) 1-Phenyl-4H-quinolizin-4-one-3-carboxylic acid. M.p. 198 ° C.

IR (Nujol): 3315, 1740, 1620 cm -1 NMR (CF 3 COOH) δ: 7.32-7.82 (m, 5H), 7.92-8.23 (m, 1H), 8.25-8 , 52 (m, 2 H), 8.70 (s, 1 H), 9.48-9.72 (m, 1 H)

Anal. calculated in C. | .jNO ^. 5/4 ^ 0: C; 66.78, H; 4.64, N; 4.87 Found: C; 66.89, H; 4.22, N; 4.59 (3) 1H-Pyrido [1,2-a] quinolin-1-one-2-carboxylic acid M.p.258-260 ° C.

IR (Nujol): 2000, 1720 cm -1 NMR (CF 3 COOH) δ: 7.75-8.33 (m, 5H), 8.43 (d, 1H, J = 9Hz), 8.92 (d, 1H , J = 8.5 Hz), 9.73 (m, 1 H)

Anal. Calcd for C14H9NO3.1 / 10H2O: C; 69.76, H; 3.85, N; 5.81 Found: C; 69.87, H; 4.13, N; 5.94 (4) 7-Hydroxy-4H-quinolizin-4-one-3-carboxylic acid. M.p. > 270 ° C.

IR (Nujol): 3120, 2690, 1690, 1590 cm -1 NMR (CF 3 C 10 H) δ: 7.87 (d, 1H, J = 8.5 Hz), 8.07-8.42 (m, 2H), δ .58 (d, 1H, J = 8.5 Hz), 9.07 (m, 1H)

Anal. Calcd for C1QH7NO4.1 / 4H2O: C? 57.28, H; 3.61, N; 6.68 Found: C; 57.51, H; 3.60, N; 6.75 (5) 4H-Pyrido [2,1-a] isoquinolin-4-one-3-carboxylic acid. M.p. > 250 ° C.

IR (Nujol): 3100, 1730, 1640, 1620 cm -1 NMR (CF 3 COOH) δ: 8.0-8.40 (m, 4H), 8.80-9.30 (m, 4H)

Anal. Calcd for C 18 H 9 N 2 O 2: C; 70.29, H; 3.79, N; 5.85 Found: C; 70.43, H; 4.15, N; 5.89 (6) 9,10-Dihydro-8H-benzo [b] -3H-quinolizin-3-one-2-carboxylic acid. Sp. 254 ° C.

IR (Nujol): 3200, 1710, 1610, 1590 cm -1 N-NMR (DMSO-d 6) δ: 1.80-2.30 (m, 2H), 2.70-3.20 (m, 6H) , 7.30-7.85 (m, Ό 2H), 8.10 (s, 1H), 9.10 (d, 1H, J = 7Hz), 14.30 (s, 1H)

Anal. calculated for C 13 H 13 NO 3: C; 68.11, H; 4.84, N; 6.11 Found: C; 68.21, H; 5.12, N; 6.07 (7) 7-Methoxy-4H-quinolizin-4-one-3-carboxylic acid M.p.215-216 ° C.

IR (Nujol): 3150, 3100, 1700, 1610, 1590 cm-1 48 83 51 δ NMR (CF 3 COOH) δ: 4.18 (s, 3H), 7.88 (d, 1H, J = 8.5 Hz) Δ 8.10-8.47 (m, 2H), 8.67 (d, 1H, J = 8.5 Hz), 8.88 (m, 1H)

Anal. Calcd for C 11 H 9 NO 4: C; 60.27, H; 4.14, N; 6.39 Found: C; 59.90, H; 4.38, N; 6.48 (8) 9-Methyl-4H-quinolizin-4-one-3-carboxylic acid M.p.259-260 ° C.

IR (Nujol): 3100, 3020, 1740, 1610, 1590, 1120, 780 cm -1 NMR (DMSO-d 6) δ: 2.92 (s, 3H), 7.90 (d, 1H, J = 7, 5Hz), 8.07 (d, 1H, J = 9.5Hz), 8.05-8.38 (m, 1H), 8.82 (d, 1H, J = 9.5Hz), 9.42 ( d, 1H, j = 7.5 Hz)

Anal. Calcd. 65.02, H; 4.46, N; 6.89 Found: C; 64.92, H; 4.76, N; 6.89 (9) 8-Methyl-4H-quinolizin-4-one-3-carboxylic acid. Mp 228-230 ° C.

IR (Nujol): 3090, 3030, 2700, 1630, 1620, 1580, 785 cm -1 NMR (CF 3 COOH) δ: 2.82 (s, 3H), 7.82 (d, 1H, J = 9Hz), δ .92 (dd, 1H, J = 7Hz, 2Hz), 8.17 (d, 1H, J = 2Hz), 8.68 (d, 1H, J = 9Hz), 9.37 (d, 1H, J = 7 Hz)

Anal, calculated for C 65.02, H; 4.46, N; 6.89 Found: C; 64.88, H; 4.79, N; 6.85

(10) 6-Methyl-4H-quinolizin-4-one-3-carboxylic acid. Sp.185-187 ° C

IR (Nujol): 3100, 2700, 1720, 1615, 1595, 1295, 1040, 800 cm -1: NMR (CF 3 COOH) δ: 3.45 (s, 3H), 7.82 (d, 1H, J = 9Hz) ), 7.58-7.97 (m, 1H), 8.10-8.30 (m, 2H), 8.68 (d, 1H, J = 9Hz)

Anal. calculated for C 18 H 18 N 2 O 2: C; 65.02, H; 4.46, N; 6.89 Found: C; 64.60, H; 4.52, N; 6.91 (11) 1-Methyl-4H-quinolizin-4-one-3-carboxylic acid. Mp 258-260 ° C.

IR (Nujol): 1740, 1610, 1450, 780 cm -1 NMR (CF 3 COOH) δ: 2.87 (s, 3H), 8.15 (m, 1H), 8.35-8.77 (m, 3H), 9.66 (m, 1 H)

Anal. calculated for C 18 H 18 N 2 O 2: C; 65.02, H; 4.46, N; 6.89 Found: C; 64.70, H; 4.56, N; 6.86 (12) Cyclopenta [b] -3H-quinolizin-3-one-2-carboxylic acid.

Sp. > 250 ° C.

IR (Nujoli): 1730, 1620, 1590 cm-1 49 83 51 8

Anal. Calcd for C12H2NO3: C; 67.61, H; 3.31, N; 6.57 Found: C; 67.72, H; 3.37, N; 6.59

(13), 7-Methyl-4H-quinolizin-4-one-3-carboxylic acid. Mp 222-224 ° C

IR (Nujol): 1720, 1600, 1590, 1320.1125, 1110, 840 cm -1 NMR (CF 3 C 10 H) δ: 2.77 (s, 3H), 7.93 (d, 1H, J = 9Hz), δ , 22-8.38 (m, 2H), 8.73 (d, 1H, J = 9Hz), 9.32 (s, 1H)

Anal. calculated for C 18 H 18 N 2 O 2: C; 65.02, H; 4.46, N; 6.89 Found: C; 65.04, H; 4.31, N; 6.91 (14) 4H-Quinolizin-4-one-1-carboxylic acid. Sp. > 250 ° C.

IR (Nujol): 1695, 1650 cm -1 NMR (DMSO-d 6) δ: 6.46 (d, 1H, J = 10Hz), 7.30-8.20 (m, 2H), 8.41 (d, 1H, J = 10 Hz), 9.20-9.40 (m, 2H)

Anal. calculated for C 18 H 18 N 2 O 2: C; 63.49, H; 3.73, N; 7.40 Found: C; 63.50, H; 3.81, N; 7.53

(15) 1-Methoxy-4H-quinolizin-4-one-3-carboxylic acid. Mp 259-261 ° C

IR (Nujol): 3100, 1630.1620, 1580, 1100, 1070, 780 cm -1 NMR (CF 3 COOH) δ: 4.27 (s, 3H), 8.00-8.67 (m, 3H), δ .90 (m, 1H), 9.52 (d, 1H, J = 7.5 Hz)

Anal. Calculated Ο -, - ^ ΝΟ ^ C; 60.28, H; 4.14, N; 6.39 Found: C; 59.64, H; 4.15, N; 6.30 (16) 7-n-Butoxy-4H-quinolizin-4-one-3-carboxylic acid. Sp. 120-122 ° C.

IR (Nujol): 1725, 1600, 1590, 1320, 1070, 1000 cm -1 NMR (CF 3 COOH) δ: 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) Anal. Calcd for C14H15NO4: C; 64.36, H; 5.79, N; 5.36 Found: C; 64.46, H; 5.80, N; 5.31 (17) 7-Isopropoxy-4H-quinolizin-4-one-3-carboxylic acid. Sp. 218-219 ° C.

. IR (Nujol): 3140, 3090, 1720, 1620, 1120, 1060, 1000, 780 cm -1 NMR (CF 3 COOH) δ: 1.67 (d, 6H, J = 6Hz), 4.97 (1H, J = 6Hz), 7.88 (d, 1H, J = 9Hz), 8.10-8.43 (m, 4H), 8.63 (d, 1H, J = 9Hz), 8.90 (d, 1H, J = 2Hz) 50 8351 8

Anal. Calcd. 63.15, H; 5.30, N; 5.66 Found: C; 63.28, H; 5.18, N; 5.65

Example 4

The following compounds were obtained in the same manner as the compound of Example 2.

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

IR (Nujol): 3400, 3300, 1700, 1660, 1650, 1620 cm -1 NMR (CF 3 COOH) δ: 7.90-9.60 (m, 7H)

Anal. Calcd for C12H9N5O2: C; 56.47, H; 3.55, N; 27.44 Found: C; 56.83, H; 3.79, N; 27.50 (2) N- [5- (1H-Tetrazolyl)] - 9-methyl-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200, 3100, 3080, 1660, 1620.1590, 790 cm -1 NMR (CF 3 COOH) δ: 2.80 (s, 3H), 7.50-7.87 (m, 2H), δ .08 (d, 1H, j = 7Hz), 8.78 (d, 1H, j = 9Hz), 9.43 (d, 1H, J = 7Hz)

Anal. Calcd. 53.33, H; 3.73, N; 35.10 Found: C; 55.28, H; 3.88, N; 31.55 (3) N- [5- (1H-Tetrazolyl) -7-ethyl-4H-quinolizin-4-one-3-carboxamide. Sp. > 250 ° C.

IR (Nujol): 3200, 1660.1640, 1620, 1590, 1490 cm -1 NMR (CF 3 COOH) δ: 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)

Anal. Calcd. 54.93, H; 4.25, N; 29.56 L 12 6 2 Found: C; 55.32, H; 4.32, N; 29.72 (4) N- [5- (1H-Tetrazolyl) -1-phenyl-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3180, 3100, 1680, 1620, 1490 cm -1 NMR (CF 3 COOH) δ: 7.27 -8.02 (m, 6H), 8.05-8.35 (m, 2H), δ .70 (s, 1H), 9.48-9.75 (m, 1H)

Anal. calculated C .-, Η.-Ν, Ο-: C; 61.44, H; 3.64, N; 25.29 I / l z o z found: C; 61.21, H; 3.80, N; 24.83 51 8351 8 (5) N- [5- (1H-Tetrazolyl) -1H-pyrido [1,2-a] quinolin-1-one-2-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200, 1670, 1610, 1580, 1530, 1480 cm -1 NMR (CF 3 COOH) δ: 7.32 (d, 1H, J = 9Hz), 7.48-8.33 (m, 5H) Δ 8.83 (d, 1H, J = 8Hz), 9.63 (m, 1 H)

Anal. Calcd for C 15 H 10 N 6 O 2: C; 58/82, H; 3.29, N; 27.44 Found: C; 59.16, H; 3.42, N; 27.29 (6) N- [5- (1H-Tetrazolyl) -7-hydroxy-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3120, 3090, 2530, 1670, 1640, 1540, 980 cm -1 NMR (CF 2 COOH) δ: 7.73-7.70 (m, 2H), 8.03 (m, 1H) , 8.67 (m, 1H), 9.15 (m, 1H)

Anal Calcd for C 21 H 28 N 2 O 2: C; 49.06, H; 3.32, N; 32.11 Found: C; 48.56, H; 3.47, N; 32.66 (7) N- [5- (1H-Tetrazolyl) -4H-pyrido [2,1-a] isoquinolin-4-one-3-carboxamide. Sp. > 250 ° C.

IR (Nujol): 3200, 1660, 1640, 1620 cm -1

Anal. Calcd for C 18 H 15 N 2 O 2: C; 58.82, H; 3.29, N; 27.44 Found: C; 59.12, H; 3.57, N; 27.86 (8) N- [5- (1H-Tetrazolyl)] - 9,10-dihydro-8H-benzo [b] -3H-quinolizin-3-one-2-carboxamide. Sp. > 250 ° C.

IR (Nujol): 3200, 1660, 1640, 1620, 1600 cm -1 NMR (CF 2 COOH) δ: 2.00-2.50 (m, 2H), 3.00-3.60 (m, 4H), δ , 70-8.20 (m, 2H), 8.55 (s, 1H), 9.40 (d, 1H, J = 7Hz)

Anal, calculated c-j 4H- | 2N6 ° 2: C; 56-75, H '4.08, N; 28.36 Found: C; 56.86, H; 4.27, N; 28.58 (9) N- [5- (1H-Tetrazolyl)] - 7-methoxy-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200, 3100, 1680, 1650, 1610 cm -1 NMR (CF 2 COOH) δ: 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)

Anal. calculated ci2H10N6O3 '* C; H »3.52, N; 29.36 Found: C; 50.54, H; 3.55, N; 29.63 52 83 51 8 (10) N- (2-Thiazolyl) -4H-quinolizin-4-one-3-carboxamide. Mp 240 ° C.

IR (Nujol): 3100, 1665, 1620, 1490, 1320 cm -1 NMR (CF 3 COOH) δ: 7.30-7.90 (m, 4H), 8.03-8.47 (m, 2H), δ .75 (d, 1H, J = 9Hz), 9.42 (d, 1H, J = 7Hz)

Anal. Calcd for C13H9N3OS: C; 57.56, N; 3.34, N; 15.49 Found: C; 57.25, H; 3.77, N; 15.24 (11) N- (2-Hydroxyphenyl) -4H-quinolizin-4-one-3-carboxamide.

Sp.247 ° C.

IR (Nujol): 1650, 1630, 1600 cm -1 NMR (CDCl 3) δ: 6.80-7.50 (m, 5H), 7.70 (d, 2H; J = 7Hz), 8.76 (d , 1H, J = 8Hz), 9.40 (d, 1H, J = 8Hz), 10.10 (s, 1H)

Anal. Calcd for C16H12N2O3: C; 68.57, H; 4.32, N; 9.99 Found: C; 68.04, H; 4.48, N; 10.11 (12) N- (2-Pyrimidinyl) -4H-quinolizin-4-one-3-carboxamide.

Sp. 218 ° C.

IR (Nujol): 1690, 1650, 1620 cm -1 NMR (DMSO-d 6) δ: 7.10-8.20 (m, 5H), 8.50-8.80 (m, 3H), 9.20 -9.40 (m, 1H) Anal. Calcd for C 18 H 18 N 2 O 2 O 2: C; 63.15, H; 3.79, N; 21.04 Found: C; 61.20, H; , N, 20.76 (13) N- [5- (1H-Tetrazolyl)] - 8-methyl-4H-quinolizin-4-one-3-carboxamide, mp> 270 ° C.

IR (Nujol): 3200, 3150, 1660, 1635, 1590, 780 cm -1 NMR (CF 3 COOH) δ: 2.73 (s, 3H), 7.35 (d, 1H, J = 9Hz), 7.65 (dd, 1H, J = 7Hz, 2Hz), 7.88 (d, 1H, J = 2Hz), 8.65 (d, 1H, J = 9Hz), 9.38 (d, 1H, J = 7Hz)

Anal. Calcd. C. HinN, O: C; 53.33, H; 3.73, N? 31.10 L · 1 U O 6 obtained: C; 54.03, H; 3.84, N; 30.38 (14) N- [5- (1H-Tetrazolyl)] - 6-methyl-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200, 1660, 1620, 1590, 1030, 820, 790 cm -1 NMR (CF 3 COOH) δ: 3.33 (s, 3H), 7.37 (d, 1H, J = 9Hz), δ , 37-7.62 (m, 1H), 7.87-8.07 (m, 2H), 8.60 (d, 1H, J = 9Hz) Anal. ; 53.33, H; 3.73, N; 31.10 12 1 (J b 2 found: C; 53.63, H; 3.92, N; 31.42 53 8351 8 (15) N- / 5- (1H-Tetrazolyl) -1-methyl-4H-quinolizin-4-one-3-carboxamide, mp> 270 ° C.

IR (Nujol): 3180, 1665, 1640, 1620, 1595, 1500, 1040, 1020, 770 cm -1 NMR (CF 3 COOH) δ: 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)

Anal. calculated 2 ^ 10 ^ 6 ^ 2: ^ ^ ^ 3.55, H; 3.73, N; 31.10 Found: C; 53.71, H; 4.04, N; 31.03 (16) N- [5- (1H-Tetrazolyl) -7-methyl-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200.1670, 1610, 1580, 1500, 1310, 1060, 1040, 840 cm -1 NMR (CF 3 COOH) δ: 2.73 (s, 3H), 7.47 (d, 1H, J = 9Hz) ), 8.03-8.50 (m, 2H), 8.70 (d, 1H, J = 9Hz), 9.33 (s, 1H)

Anal. calculated for C 12 H 10 N 6 O 2: C; ^ 3.33, H; 3.73, N; 31.10 Found: C; 53.61, H; 3.69, N; 31,34 (17) N- [6- (1,2,4-Triazinyl) -4H-quinolizin-4-one-3-carboxamide. Sp. 263 ° C (decomposes).

IR (Nujol): 3100, 1690, 1620, 1580, 1520, 1500, 1040 cm -1 NMR (CF 3 COOH) δ: 7.33 (d, 1H, J = 9Hz), 7.60-8.23 ( m, 3H), 8.72 (d, 1H, J = 9Hz), 9.10-9.17 (m, 1H), 9.27-9.68 (m, 2H)

Anal. Calcd for C13H9N5O2.1 / 4H2O: C; 57.51, H; 3.59, N; 25.97 Found: C; 57.51, H; 3.52, N; 25.77 (18) N-pyrazinyl-4H-quinolizin-4-one-3-carboxamide. Mp> 250 ° C.

IR (Nujol): 3400, 1675, 1620, 1580, 1520, 1500, 1400, 1320, 780 cm -1 NMR (CF 3 COOH) δ: 7.43 (d, 1H, J = 9.5 Hz), 7.78 (m , 1H), 8.00-8.23 (m, 2H), 8.77 (d, 9.5Hz), 8.83 (d, J = 7.5Hz), 8.78-8.98 (m , 3H), 9.55 (d, 1H, J = 7.5 Hz), 9.82 (s, 1H)

Anal. calculated for C14H10N4O2.H2O: C; 59.15, H; 4.25, N; 19.71 Found: C; 59.58, H; 4.03, N; 19.99 (19) N- [5- (1H-Tetrazolyl) -cyclopenta [b] -3H-quinolizin-3-one-2-carboxamide. Sp. > 250 ° C.

: IR (Nujol): 3200, 3100, 1660, 1620, 1600 cm -1 NMR (CF 3 C 10 H) δ: 7.10-9.50 (m, 6H)

Anal. Calcd for 13HgNgO2: C; 55.72, H; 2.88, N; 29.99, so 8351 δ obtained: C; 55.95, H; 3.01, N; 29.64 (20) N- (2-Pyridyl) -4H-quinolizin-4-one-3-carboxamide. Mp 228-230 ° C.

(21) N- [5- (1H-Tetrazolyl) -4H-quinolizin-4-one-1-carboxamide.

Sp. > 250 ° C.

IR (Nujol): 1690 (sh), 1660, 1620 cm -1 NMR (CF 3 COOH) δ: 7.40-9.80 (m, 6H)

Anal. Calcd for C 18 H 9 N 2 O 2: C; 51.56, H; 3.15, N; 32.80 Found: C; 51.71, H; 3.43, N; 32.41 (22) N- [6- (3-Chloropyridazinyl)] - 4H-quinolizin-4-one-3-carboxamide. Sp. > 250 ° C.

IR (Nujol): 3100, 1680, 1620, 1580, 1510, 1070, 780 cm -1 NMR (CF 3 C 10 H) δ: 7.38 (d, 1H, J = 9Hz), 7.63-8.50 (m, 5H), 8.77 (d, 1H, J = 9Hz), 9.48 (m, 1H).

Anal Calcd for C 14 H 9 ClN 4 Cl 2: C; 55.92, H; 3.02, N; 18.63 Found: C; 55.65, H; 3.15, N; 19.14 (23) N- [5- (1H-Tetrazolyl) -1-methoxy-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200, 1660, 1650, 1620, 1290, 1015, 775 cm -1 NMR (CF 3 C 10 H) δ: 4.33 (s, 3H), 8.13 (m, 1H), 8.33 (s , 1H), 8.43-9.02 (m, 2H), 9.62 (d, 1H, J = 7.5 Hz)

Anal. calculated -j QNgC> 3: C; 50.35, H; 3.52, N; 29.36 Found: C; 50.46, H; 3.45, N; 29.39 (24) N- [2- (4,6-Dimethylpyrimidinyl)] - 4H-quinolizin-4-one-3-carboxamide. Sp. 217-218 ° C.

IR (Nujol): 3460, 3120, 1690, 1650, 1620.1060, 790 cm -1 NMR (CF 3 COOH) δ: 2.87 (s, 6H), 7.38 (d, 1H, J = 9Hz), 7.47-8.32 (m, 4H), 8.75 (d, 1H, J = 9Hz), 9.63 (d, 1H, J = 7.5Hz)

Anal. Calcd for C 9 H 14 N 4 O 2 .1 / 3H 2 O: C; 63.99, H; 4.92, N; 19.04 Found: C; 63.99, H; 4.92, N; 18.66 L N- [5- (1H-Tetrazolyl)] - 7-n-butoxy-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

55 8351 δ IR (Nujol): 3200, 1665, 1640, 1625, 1590, 1000.850.780 cm -1 NMR (CF 3 COOH) δ: 1.10 (t, 3H, J = 6.5Hz), 1.37-2 1.3 (m, 4H), 4.38 (t, 2H, J = 6.5Hz) r 7.53 (d, 1H, J = 8.5Hz), 7.97-8.28 (m, 2H) Δ 8.67 (d, 1H), J = 8.5 Hz), 9.03 (s, 1H)

Anal. calculated for C 18 H 19 N 2 O 2: C; 54.88, H; 4.91, N; 26.00 Found: C; 55.14, H; 4.89, N; 25.83 (26) N- [5- (1H-Tetrazolyl) -7-isopropoxy-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200, 1680, 1650, 1620, 1500, 1310, 780 cm -1 NMR (CF 3 COOH) δ: 1.77 (d, 6HmJ = 6Hz), 5.12 (sept, 1H, J = 6Hz) , 7.67 (d, 1H, J = 8.5 Hz), 8.02-8.37 (m, 2H), 8.80 (d, 1H, J = 8.5 Hz), 9.20 (s, 1H)

Anal. Calcd. 53.50, H; 4.49, N; 26.74 Found: C; 53.73, H; 4.41, N; 27.04

Example 5 (1) A suspension of 4H-quinolizin-4-one-3-carboxylic acid (2.27 g) in dry N, N-dimethylformamide (22.27 ml) was added 1,1'-carbonyldiimidazole (2.92 g). g). The resulting suspension was heated to 100 ° C and held for 30 minutes. After cooling to room temperature, the resulting solution was treated with dry ammonia and stirred for 20 minutes. The separated crystals were collected by filtration and washed with water to give 4H-quinolizin-4-one-3-carboxamide (1.94 g). Sp. 230-232 ° C.

IR (Nujol): 3350, 3120, 1660, 1630 cm -1 NMR (CF 3 COOH) δ: 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)

Anal. Calcd for C 18 H 9 N 2 O 2: C; 63.83, H; 4.28, N; 14.89 Found: C; 63.96, H; 4.43, N; 14.90 (2) A mixture of 4H-quinolizin-4-one-3-carboxamide (1.0 g) and phosphorus oxychloride (50 ml) was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in aqueous sodium bicarbonate solution and chloroform. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was chromatographed on silica gel (30 g) 56 8351 8 eluting with chloroform-methanol (50: 1) to give 3-cyano-4H-quinolizin-4-one, from which recrystallization from ether gave crystals (800 mg), m.p. 198-200 ° C.

IR (Nujol): 2420, 1680, 1620 cm -1 NMR (DMSO-cL ·) δ: 6.93 (d, 1H, J = 8Hz), 7.30-7.60 (m, 1H), δ, 98 to 8.20

O

(m, 3H), 9.13 (d, 1H, J = 8Hz) (3) To a solution of 3-cyano-4H-quinolizin-4-one (1.20 g) in pyridine (50 ml) and triethylamine (30 ml) sulfur-hydrogen gas was bubbled into the mixture for 30 minutes at room temperature. The resulting mixture was allowed to stand for 3 days at ambient temperature. The solvent was distilled off, and the residue was washed with a hot mixture of chloroform and methanol (1: 1) and filtered. The filtrate was concentrated and the residue was washed again with a hot mixture of chloroform and methanol (9: 1) and filtered. The filter cake was washed well with a mixture of chloroform and methanol (9: 1) to give 4H-quinolizin-4-one-3-thiocarboxamide (0.76 g). Sp. 220-230 ° C.

IR (Nujol): 3300, 3100, 1650, 1620, 1500 cm -1 NMR (DMSO-d 6) δ: 7.07 (d, 1H? J = 8Hz), 7.36-7.67 (m, 1H) , 7.80-8.10 (m,

O

2H) 9.13 (d, 1H, J = 8Hz), 9.26 (d, 1H, J = 8Hz), 9.80 (broad s, 1H) (4) 3-Cyano-4H-quinolizin-4- onion (4.21 g), sodium azide (1.77 g) and ammonium chloride (1.45 g) were dissolved in N, N-dimethylformamide (42 ml) and the resulting mixture was heated at 120 ° C for 2 days. The reaction mixture was evaporated and the residue was dissolved in aqueous sodium bicarbonate solution and filtered. The filtrate was acidified with dilute hydrochloric acid to pH 1-2. The precipitate was filtered, washed with water and then with cold N, Ν-dimethylformamide. The filtered solid was dissolved in hot N, N-dimethylformamide and filtered. The filtrate was treated with ether and kept at 0 ° C. The separated crystals were filtered and recrystallized from a mixture of ether and Ν, Ν-dimethylformamide to give 3- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one (1.1g). Sp. > 250 ° C.

IR (Nujol): 3200, 3100, 3050, 1660, 1620, 1590 cm-1. NMR (CF 3 COOH) δ: 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)

Anal. Calcd for C 18 H 19 N 2 O 2: C; 56.34, H; 3.31, N; 32.85 Found: C; 56.55, H; 3.87, N; 33.02 57 8351 8

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

IR (Nujol): 1660 cm -1 NMR (D 2 O) 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 obtained in the same manner as the compound of Example 6- (1).

N- / 5- (1H-tetrazolyl) / - 4H-quinolizin-4-one-3-carboxamide sodium salt.

IR (Nujol): 1670 cm -1 (NMR (D 2 O-DMSO-d 6) δ: 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).

. Example 7

The following compounds were obtained in the same manner as the compound of Example 1.

(1) 4-Phenyl-1H-pyrido [1,2-a] quinolin-1-one-2-carboxylic acid.

3p. 194-195 ° C.

IR (Nujol): 3150, 2650, 1740, 1725, 1590, 1440, 1115, 825 cm -1 NMR (CF 3 COOH, δ): 7.48-7.82 (5H, m), 7.93-8.48 (5H, m), 8.95 (1 H, s), 9.70 (1 H, m)

Anal. calculated for C20H13NO3: C; 76.18, H; 4.16, N; 4.44 Found: C; 76.32, H; 4.56, N; 4.32

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

IR (Nujol): 1730, 1720, 1610, 770 cm -1 NMR (CF 3 COOH, δ): 7.10-8.37 (10H, m), 8.82 (1H, s), 9.62 (1H, m): Anal. Calcd for C 20 H 13 NO 3 .1 / 2H 2 O: C; 74.07, H; 4.35, N; 4.32 Found: C; 74.12, H; 4.13, N; 4.22 se 8351 8 (3) 1- (4-Biphenylyl) -4H-quinolizin-4-one-3-carboxylic acid.

Sp. 261-263 ° C.

IR (Nujol): 3100, 1720, 1660, 1610, 1580, 1290, 890, 775 cm -1 NMR (CF 3 C 10 H, O): 7.20-8.47 (12H, m), 8.70 (1H, s ), 9.53 (1 H, m)

Anal. Calcd for C22H15NO3.1 / 4H2O: C; 76.40, H; 4.52, N; 4.05 Found: C; 76.41, H; 4.57, N; 3.93 (4) 1-Phenoxy-4H-quinolizin-4-one-3-carboxylic acid M.p.224-226 ° C.

IR (Nujol): 3100.2650, 1725, 1640, 1620, 1580, 1210, 910 cm -1 NMR (CF 3 COOH, δ): 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)

Anal. calculated for C 18 H 18 N 2 O 2: C; 68.33, H; 3.94, N; 4.98 Found: C; 68.45, H; 3.96, N; 4.96 (5) 1- (3-Tolyl) -4H-quinolizin-4-one-3-carboxylic acid mp 176-178 ° C.

IR (Nujol): 3130, 1740, 1620, 1590, 1220, 770, 705 cm -1 NMR (CF 3 C 10 H, δ): 2.52 (3H, s), 7.17-7.67 (4H, m), δ, 90-8.50 (3 H, m), 8.70 (1H, s), 9.58 (1H, m)

Anal. Calcd for C17H13NO3: C; 73.11, H; 4.69, N; 5.02 Found: C; 73.11, H; 4.85, N; 5.13 (6) 1- (4-Chlorophenyl) -4H-quinolizin-4-one-3-carboxylic acid.

Sp. 269-271 ° C.

IR (Nujol): 3140, 1740, 1620, 1490, 1320, 1290, 1090, 890, 825, 775 cm -1 NMR (CF 3 COOH, δ): 7.35-7.78 (4H, m), 7.92 -8.47 (3H, m), 8.73 (1H, S), 9.62 (1H, m)

Anal. calculated gH 2 qClNO 3: C; 64.12, H; 3.36, N; 4.67 Found: C; 63.95, H; 3.33, N; 4.58 (7) 1- (2-Tolyl) -4H-quinolizin-4-one-3-carboxylic acid. Sp. 168-. 170 ° C.

IR (Nujol): 3400, 1720, 1610, 1290, 1070, 780 cm -1. NMR (CF 3 C 10 H, δ): 2.17 (3H, s), 7.25-7.75 (4H, m), δ Δ 98-8.63 (3H, m), 8.80 (1H, s), 9.72 (1H, m)

Anal. Calcd for C17H13NO3: C; 73.11, H; 4.69, N; 5.02 Found: C; 72.95, H; 4.91, N; 5.01 59 8351 8 (8) 1- (3-Methoxyphenyl) -4H-quinolizin-4-one-3-carboxylic acid.

Sp. 222-224 ° C.

IR (Nujol): 3100, 1725, 1600, 1490, 1220, 1030, 780 cm -1 NMR (CF 3 COOH, δ): 4.10 (3H, s), 7.15-8.62 (7H, m), 8.77 (1 H, s); 9.62 (1 H, m)

Anal Calcd for C 17 H 13 NO 4: C; 69.15, H; 4.44, N; 4.74 Found: C; 69.67, H; 4.70, N; 4.67 (9) 1-Hydroxy-4H-quinolizin-4-one-3-carboxylic acid.

IR (Nujol): 3200, 3100, 1690, 1620 cm -1 NMR (CF 3 COOH, ο): 8.00-9.50 (5H, m)

Anal. Calcd for C 10 H 7 NO 4: 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 obtained in the same manner as the compound of Example 2.

(1) N- [5- (1H-Tetrazolyl) -4-phenyl-1H-pyrido [1,2-a] quinolin-1-one-2-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3250, 3150, 1675, 1640, 1610, 1580, 1115 cm -1

Anal Calcd for C 21 H 14 N 6 O 2: C; 65.96, H; 3.69, N; 21.98 Found: C; 66.43, H; 3.99, N; 22.15 (2) N- [5- (1H-Tetrazolyl) - (1-naphthyl) -4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3280, 1665, 1640, 1620, 1290.780, 770 cm -1 NMR (CF 3 COOH, δ): 7.27-8.25 (1 OH, m), 8.77 (1H, s) Δ 9.68 (1 H, m)

Anal. Calcd for C21H14N6O2: C; 65.96, H; 3.69, N; 21.98 Found: C; 60.51, H; 3.75, N; 21.91 (3) N- [4- (1H-Tetrazolyl)] - 1- (4-biphenylyl) -4H-quinolizin-4-one-3-carboxamide. Sp. Z 270 ° C.

IR (Nujol): δ 3180, 1670, 1625, 1590, 1100, 1035, 780, 730 cm-1

Anal. Calcd for C23H16N6O2: C; 67-64 'H' 3.95, N; 20.58 Found: C; 68.04, H; 4.31, N; 20.39 50 8351 8 (4) N- [5- (1H-Tetrazolyl] -1-phenoxy-4H-quinolizin-4-one-3-carboxamide, mp> 270 ° C.

IR (Nujol): 3200, 3150, 1660.1620, 1590, 1010, 780, 750 cm -1 NMR (CF 3 COOH, δ): 7.08-7.67 (5H, m), 7.97 (1H, m), 8.22-8.47 (2 H, m), 8.70 (1H, m), 9.67 (1H, m)

Anal. calculated C 18 H 18 N 2 O 2 · C 2; 58.62, H; 3.47, N; 24.13 Found: C; 59.39, H; 3.54, N; 24.06 (5) N- [5- (1H-Tetrazolyl) -1- (3-tolyl) -4H-quinolizin-4-one-3-carboxamide. Sp. Z 270 ° C.

IR (Nujol): 3160.1670, 1640.1620, 1600, 1585 cm -1 NMR (CF 3 COOH, δ): 2.52 (2H, s), 7.17-7.62 (m, 4H), δ, 70-8.40 (3 H, m), 8.73 (1H, s), 9.63 (1H, m)

Anal. Calcd for C 18 H 14 N 6 O 2: C; 62'42 'H? 4 ^ 07 / N? 24.26 Found: C; 63.03, H; 4.16, N; 24.56 (6) N- (5-1H-Tetrazolyl) -1- (4-chlorophenyl) -4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3220, 1675, 1640, 1600, 1480, 1290, 1040, 770 cm-1

Anal. calculated for C 18 H 18 ClN 2 O 2: C; 55.67, H; 3.02, N; 22.91 Found: C; 57.45, H; 3.26, N; 21.47 (7) N- (2-Pyridyl) -1-phenyl-4H-quinolizin-4-one-3-carboxamide. / Mp. 227-229 ° C.

IR (Nujol): 1680, 1620, 1550, 1480, 1300, 780, 770 cm -1 NMR (CF 3 COOH, δ): 7.35-8.18 (1 OH, m), 8.35-8.77 (2H, m), 9.60 (1H, m) Anal, calculated for C 11 H 11 CN 3 O: C, 73.89, H, 4.43, N, 12.31

Δ 1 1 D J Z

found: C; 74.17, H; 4.61, N; 12.26 (8) N- [5- (1H-Tetrazolyl) -1-hydroxy-4H-quinolizin-4-one-3-carboxamide. Sp. Mp 250 ° C.

IR (Nujol): 3200 (sh), 1660, 1620, 1580 cm -1

Anal. Calculated for C 18 H 28 N 2 O 2. 1 / 2H 2 O: C; 46.97, H; 3.22, N; 29.85 Found: C; 46.48, H; 3.31, N; 29.57 (9) N- [5- (1H-Tetrazolyl) -1- (3-methoxyphenyl) -4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

61 83 51 δ IR (Nujol): 3150, 1680, 1640, 1620, 1590, 1490, 1300, 1210, 1030, 790, 780 cm -1 NMR (CF 3 COOH, δ): 4.13 (3H, s), δ , 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)

Anal. calculated for C 18 H 14 N 6 O 3: C; 59.67, H; 3.89, N; 23.19 Found: C; 59.81, H; 4.19, N; 23.35 (10) N- [5- (1H-Tetrazolyl) -1- (2-tolyl) -4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

IR (Nujol): 3200, 3120, 1680, 1620, 1490, 1290, 1030, 780 cm -1 NMR (CF 3 COOH, δ): 2.15 (3H, s), 7.25-7.70 (4H, m ), 7.77-8.43 (3H, m), 8.77 (1H, s), 9.77 (1H, s)

Anal. Calcd for C 18 H 18 N 2 O 2: C; 62.42, H; 4.07, N; 24.26 Found: C; 62.75, H; 4.06, N; 24.35

Example 9

The following compounds were obtained in the same manner as the compound of Example 1.

(1) 7- (n-Butoxy) -1-phenyl-4H-quinolizin-4-one-3-carboxylic acid.

Sp. 155-157 ° C.

IR (Nujol): 1720, 1610, 1495, 1425 cm -1 NMR (DMSO-d 6, δ): 0.95 (3H, t, J = 5Hz), 1.3-2.0 (4H, m), 4.20 (2H, t, J = 5 Hz), 7.3-7.7 (5H, m), 7.80 (2H, s), 8.10 (1H, s), 8.80 (1H, s), 14.1 (1H, broad s) • (2) 1-Allyloxy-4H-quinolizin-4-one-3-carboxylic acid. Sp.

140-14 ° C.

IR (Nujol): 3100, 1730, 1720, 1610, 1580, 1420, 1095, 1065, 770 cm -1 NMR (CF 3 CO 2 H, δ): 4.90-5.1 δ (2H, xn), 5.35- 5.78 (2H, m), 5.90-6.57 (1H, m), 7.97-8.67 (3H, m), 8.77-9.03 (1H, m), 9.39 -9.67 (1H, m) (3) 1- (N-methylanilino) -4H-quinolizin-4-one-3-carboxylic acid.

Sp. 185 ° C (decomposes).

IR (Nujol): 1720, 1700 (sh), 1620 cm -1: NMR (CF 2 COOH, δ): 3.58 (3H, s), 6.60-7.50 (5H, m), 7.80- 8.60 (3H, m), 8.64 (1H, s), 9.50 (1H, d, J = 7Hz)

Anal Calcd for C 18 H 12 N 2 O 2: C; 69.38, H; 4.79, N; 9.52 Found: C; 69.03, H; 4.76, N; 9.31 (4) 1-Benzyl-4H-quinolizin-4-one-3-carboxylic acid. Sp.221-223 ° C.

IR (Nujol): 3380, 1720, 1620, 1410, 1320, 1070, 1020, 780 cm -1

Anal. Calcd for C 18 H 13 NO 3: C; 73.11, H; 4.69, N; 5.02 Found: C; 73.72, H; 4.92, N; 5.04 (5) 1-Phenylthio-4H-quinolizin-4-one-3-carboxylic acid. Sp. 195-197 ° C.

IR (Nujoli): 3350, 1720, 1620, 1400, 1285, 1065, 885, 780, 740 cm-1

Anal. Calcd for C 12 H 12 NO 3 S ': C; 64.63, H; 3.73, N; 4.71 stupid J

found: C; 65.04, N; 3.90, N; 4.73 (6) 1-Phenylsulfonyl-4H-quinolizin-4-one-3-carboxylic acid.

Sp. > 250 ° C.

IR (Nujol): 1730, 1640, 1620, 1580, 1160, 1140 cm -1 NMR (DMSO-d 6, δ): 7.30-8.50 (7H, m) 8.60 (1H, d, J = 8Hz), 9.00 (1H, s) 9.50 (1H, d, J = 8Hz). Anal. calculated C..N0CS ': C; 58.35, H; 3.37 1 b T I b obtained: C; 58.62, H; 3.31

Example 10 A solution of 3-ethoxycarbonyl-1-bentosyl-4H-quinolizin-4-one (2.14 g) in chloroform (65 ml) was added dropwise with trimethylsilyl iodide (1.04 ml) at 0 ° C. followed by the addition of trimethylsilyl iodide (1.04 mL). After stirring for 1 hour at room temperature, trimethylsilyl iodide (1.04 ml) was added. After stirring for 2 hours at room temperature, the reaction mixture was diluted with chloroform and washed with water. After drying over magnesium sulfate, the chloroform extract was filtered and concentrated. The precipitate was washed with cold chloroform to give 1-benzoyl-1H-quinolizin-4-one-3-carboxylic acid (1.252 g) as yellow crystals.

IR (Nujol): 1735, 1630, 1610, 1455, 1440, 1370 cm -1 NMR (CDCl 3, δ): 6.70-8.30 (9H, m), 8.42-8.68 (1H, d, J = 3Hz) 63 8351 8

Anal. Calcd. 69.62, H; 3.78, N; 4.78 Found: C; 62.89, H; 3.54, N; 3.70

Mass: m / e (M +)

Example 11

The following compounds were obtained in the same manner as the compound of Example 2.

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

IR (Nujol): 1670, 1635, 1580, 1370 cm -1 NMR (DMSO-d 6, δ): 1.00 (3H, t, J = 5.6 Hz), 1.02-2.10 (4H, m), 4.18 (2H, 6t, J = 6Hz), 6.80-7.25 (2H, m), 7.40-7.65 (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, mp> 270 ° C.

IR (Nujoli): 3180, 1660, 1640, 1620, 1285, 1035, 780, 730 cm-1

Anal. Calcd for C17H12N6O2S: C; 56.04, H; 3.32, N; 23.06 Found: C; 56.61, H; 3.53, N; 23.48 (3) 1- (N-Methylanilino) -N- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one-3-carboxamide. Sp. Z230 ° C.

IR (Nujol): 3200, 1660, 1640, 1620, 1290, 1030 cm -1 NMR (CF 3 COOH, δ): 3.74 (3H, s), 6.80-7.60 (5H, m), δ, 62-8.08 (1H, m), 8.15-8.40 (2H, m), 8.85 (1H, s), 9.65 (1H, d, J = 7Hz) (4) N- [5- (1H-Tetrazolyl)] - 1-allyloxy-4H-quinolizin-4-one-3-carboxamide, mp> 270 ° C (decomposes).

1 H (Nujol): 3200.1660, 1620, 1580, 1500, 1220, 1100, 1040, 1020, 955 770 cm -1 NMR (CF 3 COOH, δ): 4.90-5.17 (2H, m), δ , 37-5.80 (2H, m), 5.90-6.55 (1H, m), 8.93-9.02 (4H, m), 9.50-9.73 (1H, m)

Anal. Calcd for Cl4H12NgO3: C; 53.85, H; 3.87, N; 26.91 Found: C; 54.20, H; 3.81, N; 26.93 (5) N- [5- (1H-Tetrazolyl) -1-benzyl-4H-quinolizin-4-one-3-carboxamide. Sp. > 270 ° C.

64 83 51 8 IR (Nujoli): 3140, 1660, 1620, 1595, 1490, 1295, 1040, 1005, 775, 720, 690 cm-1

Anal. Calcd for C 18 H 14 N 6 O 2: C; 62.42, H; 4.07, N; 24.26 Found: C; 62.88, H; 4.54, N; 24.52 (6) N- [5- (1H-Tetrazolyl) -1-phenylsulfonyl-4H-quinolizin-4-one-3-carboxamide. Sp. > 250 ° C.

IE (Nujoli): 1680, 1640, 1620, 1590 cm-1

Anal. Calcd for C 18 H 18 N 2 O 2 S: C; 51.51, H; 3.05, N; 21.20 Found: C; 51.71, H; 2.93, N; 21.83 (7) 1-Benzoyl-N- [5- (1H-tetrazolyl) -4H-quinolizin-4-one-3-carboxamide. Sp. > 250 ° C.

IR (Nujol): 1690, 1630, 1380, 1240, 1120 cm -1 NMR (CF 2 COOH, δ): 7.40-8.25 (5H, m), 8.22-8.51 (1H, m), 8.70 (1H, broad s), 8.93 (1H, s), 9.12 (1H, d, J = 9Hz), 9.73 (1H, d, J = 7Hz)

Anal Calcd for C 18 H 18 N 2 O 9: C; 60.00, H; 3.36, N; 23.32 Found: C; 56.90, H; 3.80, N; 24.97

Example 12

The following compounds were obtained in the same manner as the compound of Example 6 to (1).

(1) 1-Benzoyl-N- [5- (1H-tetrazolyl)] - 4H-quinolizin-4-one-3-Carboxamide sodium salt. Sp. 248-250 ° C (decomposes).

IR (Nujol): 1670, 1610, 1550, 1480, 1450 cm -1 (2) N- [5- (1H-Tetrazolyl) -1-phenyl-4H-quinolizin-4-one-3-carboxamide- sodium salt, mp> 250 ° C.

IR (Nujol): 3150 (broad), 1660 (sh), 1650, 1640.1620 cm -1 NMR (DMSO-d 6, δ): 7.40-8.00 (9H, m), 8.50 (1H, s), 9.30-9.60 (1H, m) b (3) N- [5- (1H-Tetrazolyl) -1-phenoxy-4H-quinolizin-4-one-3-carboxylate; Boxamide sodium salt, mp 250 ° C.

IR (Nujol): 1660 cm -1 65 83 51 δ NMR (DMSO-d 6, δ): 6.9-7.8 (6H, m), 8.01 (2H, d, J = 4Hz), δ, 32 (1H, s), 9.42 (1H, d, J = 7Hz), 12.30 (1H, s)

Anal. Calcd. 55.14, H; 2.99, N; 22.70 Found: C; 54.78, H; 3.63, N; 20.44

Example 13

The following compound was obtained in the same manner as the compound of Example 1.

1-Benzoyl-7-n-butoxy-4H-quinolizin-4-one-3-carboxylic acid.

Sp. 155-156 ° C.

IR (Nujol): 1720, 1620, 1580, 1495 cm -1 NMR (CDCl 3> δ): 1.03 (3H, t, J = 6Hz), 1.30-2.17 (4H, m), 4, 23 (2H, t, J = 6Hz), 7.17-7.93 (6H, m), 8.70 (1H, s), 8.88 (1H, d, J = 10Hz), 9.02 ( 1H, d, J = 2 Hz), 13.60 (1H, broad s)

Example 14

The following compounds were obtained in the same manner as the compound of Example 2.

(1) 1-Benzoyl-6-n-butoxy-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-carboxamide. Sp. 227 ° C.

IR (Nujol): 1680, 1660, 1625, 1585, 1550, 1495 cm -1 NMR (DMSO-d 6, δ): 1.2-2.0 (4H, m), 4.23 (2H, t, J = 6Hz), 7.08 (2H, broad s), 7.37-8.17 (6H, m), 8.43 (1H, s), 8.75 (1H, d, J = 10Hz), δ .93 (1H, d, J = 2Hz) (2) N- (4H-5-Amino-1,2,4-triazol-3-yl) -7-n-butoxy-1-phenyl-4H-quinolizine 4-one-3-carboxamide. Sp. 220 ° C.

IR (Nujol): 1690, 1650, 1490, 1465, 1450 cm -1 - NMR (DMSO-dc, δ): 0.80-1.10 (3H, t), 1.30-2.10 (4H, m), 4.18 (2H, t), b 7.03 (1H, s), 7.83 (1H, d, J = 7Hz), 8.26 (1H, s), 8.87 (1H, s) Mass: m / e 387 (M +) * 3) 1-Ethoxycarbonyl-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-carboxamide. Sp. > 250 ° C.

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

Mass: m / e 328 (M +) 66 8 3 51 8

Example 15

The following compounds were obtained in the same manner as the compound of Example 6 to (1).

(1) 1-Benzoyl-7-n-butoxy-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-carboxamide sodium salt. Sp. 200-203 ° C.

NMR (DMSO-d 6, δ): 0.98 (3H, t, J = 6Hz), 1.20-2.0 (4H, m), 4.25 (2H, t, J = 6Hz), δ, 32-8.17 (6H, m), 8.57 (1H, s), 8.75 (1H, d, J = 10Hz), 9.02 (1H, d, J = 2Hz), 11.87 ( 1H, broad s) (2) 7-n-Butoxy-1-phenyl-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-carboxamide sodium salt.

IR (Nujol): 1680, 1640, 1620, 1585 cm -1 NMR (DMSO-d 6, δ): 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 16 To a solution of 1,3-diethoxycarbonyl-4H-quinolizin-4-one (1 g) in chloroform (20 ml) at room temperature was added trimethylsilyl iodide (0.49 ml) 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 1-ethoxycarbonyl-4H-quinolizin-4-one-3-carboxylic acid (794 mg). Sp. 189 ° C.

IR (Nujol): 1735, 1710, 1635, 1620 cm -1 NMR (DMSO-d 6, δ): 1.34 (3H, t, J = 7Hz), 4.33 (2H, q, J = 7Hz), 7.45-7.95

O

(1H, m), 8.00-8.4 δ (1H, m), 8.90 (1H, s), 9.05-9.60 (2H, m)

Mass: m / e 261 (M +)

Anal. calculated C ^ η -] NO5: C; 59.77, H; 4.24, N; 5.3 δ obtained: C; 59.12, H; 4.59, N; 5.33 67. 8351 8

Example 17 To a solution of 1,3-diethoxycarbonyl-4H-quinolizin-4-one (896 mg) in methanol (9 ml) at room temperature was added 6N sodium hydroxide (2.58 ml) and the mixture was heated at reflux for 1 hour. 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 4H-quinolizin-4-one-1,3-dicarboxylic acid (202 mg). Sp. > 250 ° C.

IR (Nujol): 1675, 1655, 1635 cm -1 NMR (D 2 O, NaOD, δ): 7.30-8.10, 8.65 (1H, s), 8.70-9.00 (1H, m ) 9.30 (1H, d, J = 7Hz)

Example 18 To a solution of 1-ethoxycarbonyl-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3-carboxamide (500 mg) in N, N-dimethylformamide (5 ml) at room temperature was added 1N aqueous sodium hydroxide (6 ml) and the mixture was heated at 100 ° C for 1 hour. After cooling to 0 ° C, the mixture was acidified to pH 26 with 6N hydrochloric acid and the precipitate was filtered and washed with water to give 1-carboxy-N- (1H-tetrazol-5-yl) -4H-quinolizin-4-one-3 -carboxamide (280 mg). Sp. > 250 ° C.

1R (Nujol): 1670, 1640, 1615, 1590 cm -1 NMR (D 2 O-NaOD, δ): 7.24-7.60 (1H, m), 7.60-8.07 (1H, m), 8.68-9.05 (1H, m), 8.84 (1H, s), 9.30 (1H, d, J = 8Hz)

Mass: m / e 272 (M +)

Anal. Calcd for C 18 H 9 N 2 O 2 • 2 <3: C; 45.29, H; 3.16, N; 26.41 Found: C; 45.29, H; 3.62, N; 26.56

Example 19

To a solution of pyridin-2-ylacetic acid hydrochloride (1 g) in N, N-dimethylformamide (10 ml) at room temperature was added N, N'-carbonyldiimidazole (934 mg) and the mixture was heated at 60 ° C for 20 minutes. :in. 2,2-Dimethyl-1,3-dioxane-4,6-dione (830 mg) was added to the mixture at 60 ° C, and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off, and the residue was diluted with chloroform at 68,83518 and washed with water. The chloroform layer was extracted with aqueous sodium hydrogencarbonate, and the aqueous layer was washed with chloroform and acidified to pH 26 with 6N hydrochloric acid at 0 ° C, and extracted with chloroform. The chloroform layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-hydroxy-4H-quinolizin-4-one-3-carboxylic acid (220 mg). Sp. 194-19 5 ° C.

IR (Nujol): 1690, 1605.1370, 1300 cm -1 NMR (DMSO-d 6.6): 6.75 (1H, s), 7.15-7.45 (1H, m), 7.76 ( 2H, d), 8.90 (1H, d, J = 6Hz)

Mass: m / e 205 (M &lt; + &gt;)

Anal. Calcd. 58.54, H; 3.44, N; 6.83 Found: C, 58.49, H; 3.17, N; 6.86

Claims (2)

69 83518 A process for the preparation of pharmacologically valuable quinolizone compounds of the formula R 2 R 30 wherein R 1 is carboxy, carbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrimidinylcarbamoyl substituted by alkyl, pyrazinylcarbamoyl, pyrazinylcarbamoyl hydroxy, thiazolylcarbamoyl which may be substituted by amino, pyridazinylcarbamoyl which may be substituted by halogen, tetrazolylcarbamoyl, cyano, thiocarbamoyl or tetrazolyl; R 2 is hydrogen, hydroxy, lower alkyl or lower alkoxy, and R 3 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkenyloxy, phenyl, naphthyl, biphenyl, phenyl substituted with lower alkyl, halogen or lower alkoxy, phenylthio, benzoyl, phenyl (lower), benzenesulfonyl, phenylamino substituted with lower alkyl on a nitrogen atom, or phenoxy; or a salt thereof, characterized in that (1) the carboxy group protecting group is removed from a compound of the formula "wherein R 2 and R 3 each have the same meaning as above, and R 4 is protected carboxy, or a salt thereof to give the compound , or a salt of COOH wherein R 2 and R 3 are each as defined above, or a salt thereof COOH wherein R 2 and R 3 are each as defined above, or a reactive derivative thereof in a carboxy group, or a salt thereof to give a compound of formula o wherein R 2 and R 3 are each as defined above and R 1 is amidated carboxy, or a salt thereof, or (3) dehydrating a compound of formula VI 8351 8 vA N CONH 2 O wherein R 2 and R 3 is each as defined above or a salt thereof to give a compound of the formula? R 30 wherein R 2 and R 3 are each as defined above or a salt thereof, or (4) a compound of the formula j * vS | 0 wherein R 2 and R 3 each have the same meaning as above, or a salt thereof, to react with hydrogen sulfide to give a compound of formula 2 R3> vS NAr "_NH2 o 72 8351 8 wherein R2 and R3 are each as defined above, or a salt thereof; or (5) forming a tetrazole group in a compound of formula 2 r3 VvS 0 wherein R2 and R3 are each as defined above, or a salt thereof to give a compound of the formula R2 R3 n- N τ II II NNr / 'U "Π H o wherein R2 and R3 are each as defined above, or a salt thereof, or (6) deprotecting the carboxy group from the compound , wherein R 1 and R 2 each have the same meaning as above, and R 1 is protected carboxy, or a salt thereof, to give a compound of formula 73 8351 8 COOH 2 nv ^ r 10 wherein R 1 and R 2 represent each the same as above, or a salt thereof. A process according to claim 1 for preparing a compound of the formula 'vA · 10 wherein R 1 and R 3 are as defined above and R 1 is tetrazolylcarbamoyl, or a salt thereof, characterized in that the compound of formula 2 is amidated. COOH o wherein R2 and R3 are as defined above, or a reactive derivative thereof in a carboxy group or a salt thereof. I 74 83 51 8 i! Patentkrav ί