AU598446B2 - Quinolizinone compound, processes for preparation thereof and pharmaceutical composition comprising the same - Google Patents

Description

C0 M M 0 N W E A L T H OF A U S T RAL I A PATENTS ACT 1952 COMPLETE SPECIFICATION (Original) FOR OFFICE USE Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: This document contains the amendments made under Section 49 and is correct for printing.

4- 7 5+ Q 9- *..ame of Applicant: *0 0* 0 0. Address of Applicant: *oo Oo. O o*: Actual Inventor(s): Address for Service: 1 0* Address for Service: 06 S FUJISAWA PHARMEACEUTICAL CO., LTD.

No. 3,4-chome, Doshomachi, Higashi-ku, Osaka,

JAPAN

YOSHIHIKO KITAURA TERUO OKU HIDEO HIRAI TOSIYUKI YAMAMOTO MASASHI HASHIMOTO DAVIES COLLISON, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

Complete specification for the invention entitled: "QUINJLIZINONE COMPOUND, PROCESSES FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME" The rollowing statement is a full description of this invention, including the best method of performing it known to us -1- 1 C rCC QUINOLIZINONE COMPOUND, PROCESSES FOR \c PREPARATION THEREOF AND PHARMACEUTICAL C r c cnc COMPOSITION COMPRISING THE SAME This invention relates to quinolizinone compound and a salt thereof. More particularly, it relates to a new quinolizinone compound and a pharmaceutically acceptable salt thereof which have inhibitory activities on allergy and ulcer, to processes for preparation c thereof, and to a pharmaceutical composition comprising the same.

Accordingly, one object of this invention is to provide the new and useful quinolizinone compound and a pharmaceutically acceptable salt thereof.

Another object of this invention is to provide processes for preparation of said quinolizinone compound and the salt thereof.

A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said quinolizinone compound or the pharmaceutically acceptable salt thereof.

i c i r -2- Still further object of this invention is to provide a therapeutical method for treatment of allergic disease and ulcer in huzan being and animals.

The quinolizinone compou nd of this invention can be represented by the following formula (I) R2 7

R

3 wherein Rl is carbo; 100

CONHR

1 0 wherein R 1 0 is hydrogen; so#:pyridyl; pyriniidinyl; pyrimidinyl we*: substituted with lower alkyl; pyrazinyl; *4 so phenyl; phenyl substituted with hydroxy; ot* 1 haoy;tizny;tizll raoy 0:90 substituted with amino; pyridazinyl; *moo pyridazinyl substitued with halogen; or tetrazolyl; 9* 20 cyano, thiocarbamoyl, or tetrazolyl stood.

R

7 is hydrogen or aryl;

R

2 is hydrogen, hydroxy, lower alkyl or lower alkoxy; and

R

3 is hydrogen; hydroxy; lower alkyl; lower alkoxy; carboxy; lower alkoxycarbonyl; to. lower alkenyloxy; aryl optionally substituted with halogen, lower alkyl or lower alkoxy; arylthio, aroyl, ar(lower)alkyl, arenesulfonyl, N-lower alkylanilino; or Accotding to this invention, the object compound (I) can be prepared by the processes as illustrated by the following schemes.

900329. Dx59PE.OO1,dbfuJ apse, 2 ~723 Process 1 R R 7 R3 0 Elimination of the carboxy protective grOMap

COOH

C t It (11) or a salt thereof (I a) or a salt thereof Process 2: 2 7 R R.

H

2

N-R

1 0

COOH

ri 5 C t 0 (lb) or a salt thereof (I a) or its teactive derivative at the carboxy group or a salt thereof Process 3: .7 R3 t7 R3 Dehydration CMN4

CONH

2 (I c) (1d) or a salt thereof or a salt thereof -4- Process 4 Hydrogen sulfide CS-N 'Y C -NH 2 0 I

S

or a salt thereof (I d) or a salt thereof

P

Process 5

CI~N

(Id) or a salt thereof (if) or a salt thereof

A

0 0 Process 6 Elimination of lower alkyl group

COOH

(I g) or a salt thereof wherein R 2

R

3

R

7 and R 10are each e

~'R

4 is Protected carboxy, and

R

3 is lower alkyoxycarbonyl.

a (1h) Dr a salt thereof as defined above, Among the starting compounds in the present invention, the compound (NI) can be prepared by the processes which are illustrated in the following schemes.

Process A R 2 N CH 2

R

R 4 H.

a4>K- R

(IV)

t c~t t~.

I

r' C a et *t' C I 1~

I

L~.

I

I

(III)

or a salt thereof Process A

MV

or a salt thereof 1%

R

6 Ring closure reaction t 4 k AUO (Ila) or a salt thereof 11* 11* or a salt thereof Process B: *1 Introduction of

R

the hydroxy protectAVd group 9F R 0 Mle) if or a salt thereof (Ild) or a galt therec

K

6 Process C: Introduction of the hydroxy p~ 0 ~rotective group (II Id) (IIIe) or a salt thereof or a salt thereof Process D: 0 0 *0*~e 0e @0 00 4 o OO~ .ooo 00:30 Elimination of the hydroxy protective group (IIh) or a salt thereof (Iii) #0S0

I

0000 0000 0 .0.0 0 *000 eq a or a salt thereof Process E: Oxidation (Ii or a salt thereof (IM) or a salt thereof (to be continued to the next page.) i 7 wherein R 2

R

4 and R 7 are each as defined above,

R

5 is lower alkoxy,

R

6 is hydrogen; protected hydroxy; lower alkyl; lower alkoxy; carboxy; lower alkoxycarbonyl; lower alkenyloxy; aryl optionally substitued with halogen, lower alkyl or lower alkoxy; arylthio; aroyl; ar (lower)alkyl; arenesulfonyl; arylamino optionally substituted with N-lower alkylanilino; or aryloxy,

R

8 is hydroxy protective group,

R

9 is protected hydroxy and n is 1 or 2.

Suitable pharmaceutically acceptable salts ',of the object compounds are conventional non-toxic salt and include and acid addition salt such as an organic acid salt acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate), an inorganic acid salt (e.g.

hydrochloride, hydrobromide, hydriodide, sulfate, nitrate, phosphate), or a salt with an amino acid (e.g.

arginine, aspartic acid, glutamic acid), or a metal salt S 25 such as an alkali metal salt sodium salt, potassium salt) an an alkaline earth metal salt calcium salt, magnesium salt), an ammonium salt or an organic base salt 4 trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'dibenzylethylenediamine salt.

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

0- 0 l.dbP 0.bt ;c 00403.DABSPE.OO1dbfuji.spec.7 To -8- The termi "lower" is intended to mean 1 to 6 carbon atoms, u~nless otherwise indicated.

Suitabl~e "lower alkyl" and "lower alkyl" moiety in "ar(lower)alkyl" includes straight or branched, having 1 to 6 carbon atom(s), such as methyl, ethyl, prop3,,l, isopropyl, butyl, t-butyl, pentyl or hexyl.

Suitable "lower alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertbutoxy, pentyloxy, tert-pentyloxy and hexyloxy, preferably one having i to 4 carbon atom(s).

Suitable "lower alkenyloxy" includes vinyloxy, 1-propenyloxy, allyloxy, 1-butenyloxy, 2butenyloxy and 2-pentenyloxy, preferably ones having 2 to 4 atoms.

Suitable "lower alkoxycarbonyl" includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, lot tert-butoxycarbonyl, pentyloxycarbonyl, tert- 25 pentyloxycarbonyl, hexyloxycarbonyl and 1cyclopropylethoxycarbonyl.

Suitable "1triazolyl"' includes 4H-1,2,4triazolyl, lH-l, 2,3-triazolyl and 2H-1, 2,3-triazolyl.

Suitable "tetrazolyl" includes lHtetrazolyl and 2H-tetrazolyl.

Suitable "triazinyl" includes 1,2,3triazinyl, 1, 2,4-triazinyl and 1,3, T 00329.DABSPZ.OO1.dbfuji.vpec,8 I 1, 11- -9- Suitable "halogen" includes chlorine, bromine, iodine and fluorine.

Suitable "protected hydroxy" includes a hydroxy group protected by a conventional hydroxyprotective group, for example, lower alkyl methyl, ethyl, propyl, n-butyl), lower alkenyl vinyl, allyl), ar(lower)alkyl such as mono- or di- or triphenyl (lower)alkyl benzyl, benzhydryl, trityl, trisubstituted silyl such as tri(lower)alkylsilyl (e.g.

trirmethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, diisopropylethylsilyl), triarylsilyl triphenylsilyl) and tttv 15 triar(lower)alkylsilyl tribenzylsilyl).

t4 I I tt Suitable "aryl" includes phenyl, tolyl, 4 It t xylyl, cumenyl, naphthyl and biphenylyl which may have one or more suitable substituent(s) such as halogen (e.g.

fluorine, chlorine, bromine, iodine), lower alkyl or lower alkoxy.

Suitable "aryl" moiety in the tErms "arylthio" and "ar(lower)alkyl" can be referred to the w 25 ones as exemplified above.

o 44 Suitable "aroyl" includes benzoyl, toluoyl e and naphthoyl.

Suitable "arenesulfonyl" includes benzenesulfonyl and p-toluenesulfonyl.

Suitable "aryloxy" includes phenoxy and tolyloxy.

Suitable "hydroxy protective group" can be referred to the ones as exemplified above.

o 3. DARSP.O1.01,dbfuji..p.c.9

IL

i 10 The processes for preparing the object compounds of the present invention are explained in detail in the following.

Process 1: The object compound (la) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to elimination reaction of the carboxy protective group.

Suitable salt of the compound (II) can be referred to the acid addition salt exemplified for the compound and suitable salt of the compound (Ia) can t t S 15 be referred to the ones as exemplified for the compound t C iV In the present elimination raction, all conventional methods used in the elimination reaction of the carboxy protective group, for example, hydrolysis, reduction, elimination using Lewis acid are applicable.

When the carboxy protective group is an ester, it can be eliminated by hydrolysis or elimination using Lewis acid.

SThe hydrolysis is preferably carried out in the presence r 25 of a base or an acid.

Suitable base includes, for example, an 1 inorganic base such as alkali metal hydroxide (e.g.

a C sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxide magnesium hydroxide, calcium hydroxide), alkali metal carbonate sodium carbonate, potassium carbonate), alkaline earth metal carbonate magnesium carbonate, calcium carbonate), alkali metal bicarbonate sodium bicarbonate, potassium bicarbonate), alkali metal acetate sodium acetate, S29 DABSPZ. 001,dbui. I uj';T

P

tj 1. II~t l~t L IC I I

II

IIC

r CRI

I

111±

(CII

T 4 It I .1 t I

I

I~+

II It.

Ip I I I 7.1 potassium acetate), alkaline earth metal phosphate (e.g.

magnesium phosphate, calcium phosphate) or alkali metal hydrogen phosphate disodium hydrogen phosphate, dipotassium hydrogen phosphate), and an organic base such as trialkylamine trimethylamine, triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, diazabicyclo non-5-one, 1,4-diazabicyclo [2,2,2]octane or 1,5-diazabicyclo[5,4,0]undecene-5. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Suitable acid may include an organic acid (e.g.

formic acid, acetic acid, propionic acid) and an inorganic acid hydrochloric acid, hydrobromic acid, sulfuric acid).

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

The reaction temperature is not critical, and it may 20 suitably selected in accordance with the kind of the carboxy protective group and the elimination method.

The elimination using Lewis acid is preferable to eliminate substituted or unsubstituted ar(lower)alkyl ester and carried out by reacting the compound (II) or a 25 salt thereof with Lewis acid such as boron trihalide boron trichloride, boron trifluoride), titanium tetrahalide titanium tetrachloride, titanium tetrabromide), tin tetrahalide tin tetrachloride, tin tetrabromide), aluminium halide aluminum chloride, aluminum bromide) or trihaloacetic acid (e.g.

trichloroacetic acid, trifluoroacetic acid). This elimination reaction is preferably carried out in the presence of cation trapping agents anisole, phenol) and is usually carried out in a solvent such as nitroalkane nitromethane, nitroethane), alkylene halide methylene chloride, 900403. DABSPE.001, dbfuj upec.11 12 ethylene chloride, diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof.

The reduction elimination can be applied preferably for elimination of the protective group such as halo(lower)alkyl 2-iodoethyl, 2,2,2-trichloroethyl) ester or ar(lower)alkyl benzyl) ester.

The reduction method applicable for the elimination reaction may include, for example, reduction by using a combination of a metal zinc, zinc amalgam) or a salt of chromium compound chromous chloride, 15 chromous acetate) and an organic or an inorganic acid o a acetic acid, propionic acid, hydrochloric acid); and conventional catalytic reduction in the presence of a conventional metallic catalyst palladium carbon, Raney nickel).

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

The present elimination reaction of the carboxy protective group includes, within its scope, the case 25 that another protected carboxy are converted into free carboxy during the reaction or the post-treating step of the present process.

Process 2 This objection compound (Ib) or a salt thereof can be prepared by reacting the compound (Ia) or its reactive derivative at the carboxy group or a salt thereof with

H

2

N-R

10 3 Suitable salt of the compound (Ib) can be referred to the salt exemplified for the compound f 900329DABSP.001dbu2 i 900329,DABSPE.001,dbfujl.upc.12 13 Suitable reactive derivative at the carboxy group of the compound (Ia) may include and acid halide, an acid anhydride, and an activated ester. The suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid dialklyphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid), dialkylphosphorous acid, sulforous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g.

pivalic acid, pentanoic acid, isopentanoic acid, 2ethylbutyric acid or trichloroacetic acid) or a aromatic carboxylic acid benzoic acid); a symmetrical acid anhydride; or an activated ester cyanomethyl ester, S 15 methoxymethyl ester, dimethyliminomethyl [(CH 3 2

N=CH-]

ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, Sphenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl s thioester), or an ester with a N-hydroxy compound (e.g.

N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, Nt hydroxysuccinimide, N-hydroxyphthalimide and l-hydroxy-6rtt( 25 chloro-lH-benzotriazole.

tco When the compound (Ia) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexyJ.carbodiimide, N-cyclohexyl-N' -morpholinoethyl carbodimide, N-ethyl-N'- (3-dimethylaminopropyl)carbodiimide, 1,1'carbonyldiimidazole, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide ethyl chloroformate, isobutyl chlorofomate or 1-(p-chlorobenzenesulfonyloxy)- A. 6-chloro- 1H-benzotriazole.

900329 DABSPE. 001, dbfuji.spec.13 14 The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuan, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents may be used in a mixture with water.

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

t, The reaction may be carried out in the presence of S 15 an inorganic or an organic base such as an alkali metal hydroxide sodium hydroxide, potassium hydroxide), an alkali metal carbonate sodium carbonate, potassium carbonate), an alkali metal bicarbonate (e.g.

t t sodium bicarbonate, potassium bicarbonate), tri(lower)alkylamine trimethylamine, triethylamine) or pyridine or its derivative picoline, lutidine, 4-dimethylaminopyridine). In case that the base or the Zt condensing agent to be used is in liquid, it can be used also as a solvent.

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

L

Process 3 The object compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof 900403,DABSPE.001.dbfuji ,pec.14 15 to dehydration reaction.

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

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

The reaction temperature is not critical and the 1,5 reaction is usually carried out at ambient temperature, a under warming or heating.

Process 4 The object compound (Ie) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof Es with hydrogen sulfide.

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

t C The reaction temperature is not critical and the 30 reaction is usually carried out at ambient temperature, under warming or heating.

Process 5 The object compound (If) or a salt thereof can be prepared by subjecting the compound (Id) or a salt thereof R ^.7 16 tt,~ f. t z i Ir t It

III.

i t i i 2 II It to the formation reaction of a tetrazole group.

Suitable salt of the compound (If) and (Id) can be referred to the acid addition salt exemplified for the compound The agent to be used in the present reaction may include conventional ones such as combination of alkali metal azide potassium azide, sodium azide) and ammonium halide ammonium chloride) The present 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 and the reaction is usually carried out under warming or heating.

Process 6 s The compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to elimination reaction of the carboxy protective group.

Suitable salts of the compounds (Ig) and (Ih) can be referred to the salts exemplified for the compound The present reaction can be carried out in a similar manner to that of Process 1 as mentioned above, and therefore the reaction modes and conditions reaction temperature, solvent) are referrred to those of Process 1.

Process A (1) The compound or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with the compound (IV).

Suitable salts of the compounds(III) and can be referred to the acid addition salts exemplified for the compound The present reaction can be preferably carried out in the presence of alkyl lithium n-butyl lithium), lithium diisopropylamide and alkalimetal alkoxide sodium methoxide, sodium ethoxide).

*V

-17- The present reaction is usually carried out in a solvent such as acetone, dioxane, acetonitrile, dimethylformamide, benzene, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ;thyl acetate, or any other solvent which does not adversely affect the reaction.

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

Process A c t The compound (IIa) or a salt thereof can be tz, prepared by subjecting the compound or a salt thereof to ring closure reaction.

rt Zno Suitable salt of the compound can be referred ?t*t to the acid addition salt exemplified for the compound The present reaction may preferably be carried out n"S in the presence of a suitable agent such as the mixture c i of diphenyl and diphenylether, which is used as heating t e medium.

The reaction temperature is not critical and the reaction is usually carried out under heating; 4t V Process B The cbject compound (lie) or a salt thereof can be prepared by subjecting the compound (lid) or a salt thereof to introduction reaction of the hydroxy protective group.

Suitable salt of the compounds (lid) and (lie) can be referred to the acid addition salts as exemplified for the compound 18 In case the protective group to be introduced are lower alkyl or lower alkenyl, the reaction can be carried out by reacting the compound (IId) with lower alkylating agent or lower alkenylating agent.

The lower alkylating agent or lower alkenylating agent to be used in the present reaction may include conventional one such as mono(or di)lower alkyl sulfate dimethyl sulfate), lower alkyl(lower) alkanesulfonate methyl methanesulfonate), halo(lower)alkane bromomethane, iodomethane, iodoethane, iodobutane) or halo(lower)alkene (e.g.

iodopropene).

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

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

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

Process C S* The compound (IIIe) or a salt thereof can be prepared by subjecting the compound (IIId) or a salt thereof to introduction reaction of the hydroxy protective group.

The present reaction can be carried out in a conventional manner.

-d 322o ,D SP,01.dbtAj.epec.11 -19- In case that the protective group to be introduced is a silyl group, the present reaction is carried out by reacting the compound (IIId) or a salt thereof with the compound of the formula Ra X (VI) wherein Ra is a trisubstituted silyl and X is an acid residue.

Suitable acid residue may include halogen chlorine or bromine).

The present reaction is preferably carried out 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, t tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, T pyridine or any other organic solvent which does not adversely influence the reaction.

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

Ct Process D i The compound (IIi) or a salt thereof can be prepared by subjecting the compound (IIh) or a salt thereof to elimination reaction.of the hydroxy protective group.

The present elimination reaction is carried out in accordance with a conventional method such as Process E, The present reaction is preferably carried out in the presence of a mild reagent such as tetra-n-butylammonium fluoride.

;1; 20 The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.

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

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

me.b The oxidizing agent to be used in this reaction may include an inorganic peracid or a salt thereof periodic acid, persulfuric acid, or sodium or r potassium salt thereof), an organic peracid or a salt thereof perbenzoic acid, m-chloro- Sperbenzoic acid, performic acid, perccetic acid, chloroperacetic acid, trifluoroperacetic acid, or sodium or potassium salt thereof), ozone, hydrogen peroxide, urea-hydrogen peroxide, Nhalosuccinimide N-bromosuccinimide, N-chlorosuccinimide), hypochlorite compound tert-butyl hypochlorite), permanganate potassium .permanganate), or any other conventional oxidizing agent which can oxidide a sulfinyl group to a sulfonyl group.

Tie present reaction can also be carried out in the presence of a compound comprising Group Vb or VIb Se metal in the Periodic Table of elements, for examplt tungstic acid, molybdic acid, vanadic acid, etc., or an alkali or an alkaline earth metal salt threof.

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

h o p 21 The reaction temperature is not critical and the reaction is preferably carried out under cooling to' at ambient temperature.

Particularly, the compounds possessing the most potent antimicrobial activity can be represented by the following formula:

R

7 3 R R R2(N

YLR

1 0 wherein R, R 2 R and R 7 are each as defined above, and more particularly, R is tetrazolylamido, t

R

2 and R 7 are each hydrogen, and t R 3 is aryloxy or aroyl.

(to be continued to the next page.) (to be continued to the next page.) f t :,crI 21-1 For the purpose of showing pharmaceutical utility of the quinolizinone compound pharmaceutical test data thereof are illustrated in the following.

Test compound M-[5-(lH-Tetrazolyl)]-4H-quinolizin-4-one-3carboxamide (hereinafter referred to as compound N-[5-(1H-Tetrazolyl) ]-1-phenyl-4H-quinolizin- 4-one-3-carboxamide (hereinafter referred to as compound \rc, Test 15 Inhibition on stress ulcer S) Test Method I 'e Sprague-Dawley rats weighing about 200 g were used.

ce Each animal was immobilized in a small cage and put in a water bath allowing to rzspire. The temperature of the water bath kept at 22°C. The test compound ®and G were administered orally just before the immobilization.

tft Seven hours later, the animals were sacrificed and (t their stomachs were removed. The stomach was then fixed with 2% formalin. The area of ulcers was measured S, 25 for each animal. The mean area (mm 2 in the test animals was compared with that in the control animals.

k 22 Test Result

C

C C C v C C C C C

CIS

1 t tI C Ulcer index Treatment No. MantSE Inh.% 1 19 2 26 Control 3 12 19.2 2.8- 4 14 1 18 Compound0 2 32 mg/kg 3 3 6.2 3.0 67.7 4 4 51 Ulcer index Treatment No. ~.Inh.% MM2 Mean ±S.E.

1 2 52 Control 3 .58 j48.4 *8.3- 4 17 1 Compound 2 11 32 mg/kg 3 3 8.4 ±1.9 83.7 23 Effect on passive cutaneous anaphylaxis (PCA).

O Test Method Recipient animals for PCA reactions were female Sprague-Dawley rats, 7 weeks old, 180g-200g (Nihon Kurea).

Each experiment included 5 observations.

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

Female BDF1 mice, 7 weeks old (Nihon Kurea), were given a primary injection (left foot pad, of 100 mcg OVA in 0.05ml saline and after 20 days a booster injection by the same route. Blood ,as collected 28 days after the primary injection and the sera were stored at The animals were shared with an electric clipper in advance and prepared for Passive Cutaneous Anaphylaxis (PCA) by injecting 0.05ml of mouse antiserum dilutions (1/16, 1/32) in each side of the dorsal skin.

They were then challenged 48 hours later with an intravenous injection of 1ml of 0.5% Evans Blue containing 5 mg OVA. Fifty minutes later, they were killed and the lesions (diameter) measured.

A minimal skin response was one with a 5 mm or greater diameter blue spot measured on the dermal side of reflected skin. Drug activity was estimated using the following formula; S( inhibition drug treated (dia;mm) Sinhibition aline treated (dia;mm) x 100 Drugs were suspended in 0.1% methyl cellulose/saline and given intravenously with the antigen.

S

I: A4/ A O Ii i/ 0 24 0 Test Result: i a,

U,

a *1

S

pa, *9 Dose Inhibition

M%

mg/kg Antiserum. concentration 1/16 1/32 1 97.2 100 Compound0 1010 94.5 100 The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains an active substance of this invention in admixture with an organic or inorganic carrier or excipient suitable for external, oral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, 7115 talc, corn starch, keratin, collidal silica, potato starcto urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The pharmaceutical compositions can also contain preservative or bacteriostatic agents to keep the active ingredient in the desired preparations stable in activity. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired tlierapeutic effect upon the eq. 5 a 25 process or condition of diseases.

For applying this composition to humans, it is preferably to apply it by intravenous, intramuscular or oral administration. While the dosage or therapeutically effective amount of the object compound of this invention varies from and also depends upon the age and condition of each individual patient to be treated, a daily doses of about 0.05-5 mg of the active ingredient/kg of a human being or an animal in generally give for treating diseases, and an average, single dose of about 2.5 mg, 25 mg and 250 mg in generally administered.

e "i'S The following preparations and examples are given t< for purpose of illustrating this invention.

c C t Preparation 1 To a solution of 2-methylpyridine (7 ml) in tetrahydrofuran (140 ml) was added dropwise a solution of n-butyl lithium (49 ml of 1.59 mol solution in hexane) with ice-cooling. The resulting dark red solution was allowed to warm to ambient temperature and stirred for an hour. After cooling to -78°C, a solution of diethyl ethoxymethylenemalonate (15.68 ml) in tetrahydrofuran (50 ml) was added over a period of 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) Swas added. The solvent was distilled off, the residue 30 was dissolved in ethyl acetate and washed with aqueous solution of sodium bicarbonate, water and saturated aqueous sodium chloride, After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated to give an oil (27 The residue was chromatographed on silica gel (Merck 70 230 mesh, 270 g) -26 eluting with chloroform to give ethyl 3-ethoxy-2ethoxycarbonyl-4-(2-pyridyl)butyrate (19 g) as an oil.

IR (film) :1730, 1590, 1470, 1440, 1370 cm- NMR (CDC1 3 0.97 (to 3H, J=8Hz), 1.26 6H, J=BHz), 3.12 1H, J=8Hz), 3.2-3.6 2H), 3.62 1H, J=8Hz) 4.21 4H, J=8Ez) 4.47 2H, J=8Hz), 6.97-7.80 (in, 3H), 8.42-8.67 (mn, 1H) Preparation 2 A mixture of ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl)butyrate (18.9 diphenyl (48.85 g) and diphenyl ether (135.8 g) was heated to 250 0 C for t minutes. The reaction mixture was cooled to ambient temperature and chromatographed on silica gel (Merck 7020ms,620 g) eluting with hexane and then a 7 -20meh mixture of ethanol and chloroform.(l:49) to give a crude oil, which was crystallized from a mixture of ether and hexane to give 3-ethoxycarbonyl-4H.quinolizin-4-one (11.48 g) as yellow crystal.

ZR (Nujo01) :1670, 1625, 1490 cm- I4MR (CDCl 3 6 :1.42 3H, J=7Hz) 4.*42 2H, J=7Hz), 6.62 1H, J=8Hz), 7.02-7.38 Cm, 1H), 7.53-7.68 Cm, 2H), 8.33 Cd, 1H, J=8Hz), 9.23-9.47 Cm, 1H) Preparation 3 t~ The ,following compounds were obtained according to a similar manner to that of Preparation 1.

Ethyl 3-ethoxy-2-ethoxycarbonyl 4 -2(CSethylpyridylflbutyrate.

ZR (film) :1750, 1730 cm 27 Ethyl 4-phenyl-3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl)butyrate.

IR (film) 1750 (sh) 1730 cm Ethyl 3-ethoxy-2-ethoxycrboriyl-4-(2-(5hydroxypyridyl) butyrate.

IR (film) 2550, 1730, 1490, 1270, 1160, 1090, 1025 cm 1 NMR (CODC1) 6 0.97 3H, J=7Hz), 1.25 6H, J-7Hz), 3.07 2H, J=5Hz), 3.20-4.77 8H), 6.47 1H), 7.07-7.37 2H), 8.17 1H) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (3methylpyridyl)]butyrate.

IR (Nujol) 1750, 1735, 1575, 1440, 860, 790 cm 1 NMR (CDC1) 6 0.92 3H, 3.5Hz), 1.27 6H, 3 2.37 3H), 3.08-3.60 4H), tcc r 3.70 1H, J=5Hz), 4.18 2H, -SHz), I 4.22 2H, J=5Hz) 4.52 1H) 7.05 (dd, 1H,'J=6Hz ard 3Hz), 7.45 1H, 3=6Hz), 8.42 1H, J=3Hz) t Ethyl 3-ethoxy-2-carboethoxy-4-(2-(4methylpyridylflbutyrate.

IR (film) 1750, 1730, 1600, 1240, 1150, 1020 cm NMR (CD 3 l 6 0.97 3 H, J=7Hz), 1.27 6H, J 3=7Hz), 2.32 31) 3.10 2H, 3=5.5Hz) 3.26-3.58 2H), 4.20 3H, J7Hz), 4.23 3H, J=7Hz), 6.87-7.13 2H), 8.40 1H, 3.6Hz) 28 Ethyl 3-ethoxy-2-ethoxycarbonyl-4-(2-(6methylpyridy~lbutyrate.

ZR (film) 1650, 1630, 1590, 1580, 1270, 1150, 1090 cm 1 NMR (CDC1 6 0.97 t, 3H, 3=7Hz), 1.25 6H, 3=7Hz), 2.48 Cs, 3H), 3.07 2H, 3.60 2H, J7Hz), 3.23-3.57 1H), 4.18 4H, 3=7Hz), 4.33-4.67 1H), 6.85-7.15 2H), 7.33-7.66 IH) Ethyl 3-ethcxy-2-ethoxycarbony1-4-(2-pyridyl)pentanoate.

ZR (film)': 1750, 1730, 1590, 1300, 1090, 1020 cm 1 NMR (CDCl 3 6 1.00 3H, J7Hz) [1.35 J=7Hz), 1.25 J-7Hz), 1.25 913), 3.00-3.75 4H), 3.93-4.58 Cm, 5H), 6.98-7.60 2H), 7.65 1H), 8.58 1H) r Ethyl 3-ethoxy-2-ethoxycarbonyl-4-(2-(5methylpyridyl)]butyrate.

ZR (film) 1740, 1730, 1600, 1480, 1150, 1090, 1025 cmC 1 NMR (CDC1) 6 1.00 Ct, 3H, 3=7Hz), 1.27 6H, 1.C 2.32 3H), 3.00-3.77 4H), 4.22 3H, J-7Hz), 4.25 3H, J=7Hz), 7.03-7.50 Cm, 2H), 8.37 Cm, 1H) Ethyl 3-ethoxy-4-methoxy-4-(2-pyridyl)-2e thoxycarborylbutyr ate.

ZR (film) 1750, 1730, 1590, 1365, 1090, 1025, 760 cm 1 NMR (CDCl 3 6 0.78 Ct, 3H, 3=7Hz), 1.25 Ct, 31, J-7Hz) 1.28 Ct, 3H, J7Hz), 3.33 2H, J-4Hz), 3.60-4.60 7.07-7.90 3H), 8.62 1H) 29 Preparation 4 The following compounds were obtained according to a similar manner to that of Preparation 2.

7 -Ethyl- 3-ethoxycarbonyl- 4H-quinol izin- 4-one.

mp. 81-830C.

IR (Nujol) :1720, 1630 cm NMR (CCcl 3 6 32 3H, J=7H z) 1. 44 3H, 3=7Hz), 2.76 2H, 3=7Hz), 4.40 C(q, 2H, 3=7Hz) 6.60 Cd, 1H, 3=8Hz) 7.52 2H) 8.32 1H, 3=8Hz) 9.20 Cs, 1H) 1-Phenyl1 3 ethoxycarbonyl4Hquilo li zin 4 -one.

mp. 120-1230C. v~rt R (Nujol) 1730, 1620 cm 4NMR (CDC1 3 6 :1.36 Ct, 3H, 3=7Hz), 4.38 2H, 3=7Hz) 7.04-7.76 Cm, 7H) 8.32 lE), 9.48 Cd, 1H, 3=8Hz) 8-Hydroxy-3-ethoxycarbofylY14Hquifolizifl 4 -one.

mp. 2420C. (dec.) IR (Nujol) :3300, 3200, 1680, 1660, 1620, 1300, NMR CDMSO-d 6 6: 2.27 Ct, 3H, 3=7Hz) 4.23 2H, 3=8Hz), 6.13 1H, 3=8Hz) 7.58 (dd, 1H, 3=2Hz, 8Hz), 7.90 Cd, 1H, 3=8Hz), 8.07 Cd, 1Hi, 3=8Hz) 8.82 IH, 3=2Hz) 4~ 4Anal. Calcd for C 12

H

11

NO

4 C, 61.80; H, 4.75 ~Found C, 62.18; H, 5.05 mp. 125-126*C.

IXRA~

v I

'/VTO

r li L*ii- 30 IR (Nujol) 3090, 1725, 1645, 1590, 1125, 1100 cm 1 NMR (CDC1 3 6 1.40 3H, J-7Hz), 2.50 3H), 4.42 2H, J-7Hz), 6.63 1i, J39Hz), 7.07 1H, J-7Hz) 7.47 i, Ji7Hz) 8.35 Cd, 1H, J-9Hz),.9.32 Cd, J37Hz, 1E) Anal. Calcd for C 13

H

13 N0 3 C; 67.52, H; 5.67 Found C; 67.51, E; 5.83 8-Methyl-3-ethoxycarbonyl-4H-quinolizin-4one. mp. 146-148 0

C.

IR (Nujol) 3060, 1720, 1660, 1640, 1245, 1155, 790 -m 1 t CCt c t t r It, C NMR (CDC1 3 6 1.40 (t, 4.38 2H, JI7HZ), 7.00 (dd, 1H, J-7Hz, J-2Hz), 8.32 1H, J=7Hz) 3H, J7Hz), 2.50 3H), 6.50 IH, Ji9Hz), 2Hz), 7.30 1H, j=9Hz), 9.28 1H, C I

IIC

I

Anal. Calcd for C, 3

H

13 N0 3 C; 67.52, H; 5.67 Found C; 67.38, H; 5.65 3-Ethoxycarbonyl-6-methyl-4H-quinolizin-4one. mnp. 90-930C.

ZR (Nujol) 1720, 1650, 1620, 1590, 1265, 1120, 1100, 795 cm- 1 NMR (CDC1 3 6 1.35 3H, 3.05 3H), 4.38 (qj 2H, J-7Hz), 6.38 1H, J=8Hz), 6.67 1H), 7.25 1H, 8.18 1H, J38Hz) Anal. Calcd for C 1 3

H

13 N0 3 C; 67.52, H; 5.67, N; 6.07 Found C; 67.28, H? 5.63, N; 6.03 1-Methyl-3-ethoxycarbonyl-4H-quinolizin-4one. mp. 142-143*C.

rq~ trrs f '4

VII

111* 31 IR (Nujol) 1720, 1650, 1620, 1595, 1300, 1230, 1160, 1120, 775 cm 1 NMR (CDC1 3 6 1.42 3H, J-7Hz), 2.40 3H), 4.43 2H, J-7Hz), 7.20 1H), 7.62-7.80 2H), 8.25 1H), 9.47 1H) Anal. Calcd for C 13

H

13 N0 3 C; 67.52, H; 5.67, N; 6.06 Found C; 67.49, 1; 5.94, N; 6.06 7-Methyl-3-ethoxycarbonyl-4H-quinolizif- 4 one. mp. 146-149 0

C.

ZR (Nujol) 1720, 1620, 1145, 1110 cm 1 NMR (CDCl 3 6 1.42 3H, J-7Hz), 2.45 3H), 4.43 2H, J-7Hz), 6.62 1H, JinHz), 7.47-7.57 2H1), 8.33 1H, J-8Hz), 9.23 1H1) Anal. Calcd for C 13

H

13 N0 3 C; 67.52, H; 5.62, N; 6.06 Found C; 67.44, H; 5.85, N; 6.00 1-Methoxy-3-ethoxycrbonyl-.-uinolizin-4one. mp. 132-1330C.

IR (Nujol) 1680, 1670, 1620, 1595, 1360, 1120, 1020, 770 cm- 1 NMR (CDC1 3 6 1.43 311 J-7Hz), 3.93 (s, 3H), 4.45 2H,, J-7Hz), 7.25 Cm, 1H), 7.67 1H), 7.97-8.20 2H), 9.47 (d, '1H, Anal. Calcd for C 13

H

1 3 N0 4 C; 63.15, H; 5.30, N; 5.66 Found C; 62.80, H; 5.33, N; 5.63

A

A

A 2

S

u~-:1 i 32 Preparation To a stirred solution of 3-ethoxycarbonyl-7-hydroxy- 4H-quinolizin-4-one (4.5 g) in dry N,N-dimethylformamide ml) was added sodium hydride (60% in mineral oil, 0.93 g) at room temperature and the resulting solution was kept for 30 minutes at 506C. The reacticas mixture was treated with methyl iodide (4.13 g) and stirred for 30 minute 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 give an oil (12.3 g) which was applied to a silica gel column. Elution with chloroform-methanol t (99:1) gave 3-ethoxycarbonyl-7-methoxy-4H-quinolizin- 4-one (3.75 mp, 156-1580C. t tZR (Nujo1) :1720, 1620, 1500, 1140, 1100 cm N4MR (C~D 3 5 1.43 3H, J-7Hz), 3.93 3H), 0 4.43 2H, J=7Hz), 6.63 1H, 7.23-7.70 2H), 7.28 1H, 9.00 111) Anal. Calcd for C 13

H

1 3N0 4 C; 63.15, H; 5.30 Found C; 62.62, H; 5.52 VI Preoaration( 6) The following compounds were obtained according to a similar manner to that of Prenaration t 3-Ethoxycarbonyl-7-n-butoxy-4H-quinolizin-4-one.

mp. 132-1330C.

ZR (Nujol) :1710, 1620, 1540, 1280, 1240, 1140, 845, 780 cm 1 NMR (CoD 3 -S 1.0 0(t 3H j J-6H z) 1. 43 3H, J-7.5Hz), 1.50-2.33 (in, 4H), 4.10 2Ht J-6Hz), 4.43 2HO 3-7.5Hz), 6.63 Cd, Me, J'm8Hz), 7.23-7.67 2H), 8.28 lH, J-8Hz), 8.97 Cd, lH, J-2Hz) '1 4 4 t t 9 33 Anal. Calcd for C 16

H

19

NO

4 C; 66.42, H; 6.62, N; 4.84 Found 66.54, H; 6.52, N; 4.82 3-Ethoxycarbonyl-7-isopropoxy-4H-quinolizil- 4-one. mp. 132-1340C IR (Nujol) :1725, 1625, 1240, 1140, 1100, 970# 840 cm- 1 NMR (CDC1 3 6 :1.42 6H, J-6Hz), 1.43 3H, 4.43 1H, J=7.5Hz), 4.65 2H), 6.62 1H, J-8.5Hz), 7.20-7.68 (in, 2H), 8.27 Cd, 1H, J-8.5Hz), 9.00 1H, J=2Hz) Anal. Calcd for C 15

H

17 N0 4 C; 65.44, H; 6.22, N; 5.09 Found 65.66, H; 6.15, N; 5.10 ii Itt 4

I

I

a, #0&4

I

I

0oTs 43 Preparation 7 The following compounds were obtained according to a similar manner to that of Preparation 1.

5(1) Ethyl. 4-phenyl-4-(2-quinolyl)-3-ethoxy-2ethoxycarbonylbutyrate.

ZR (Film) :1750, 1730, 1590, 1500, 1150, 1090, 1030 NMR (CDC1 3 ,6 0.82 (3H, t, J=7Ez) 1.20 (3H, t, J=7Hz), 1.28 (3H, t, J=7Hz), 3.12 (1H, in), 3.42-4.47 (6H, in), 4.67 (1H, in), 5.25 (lB, m), 7.12-8.27 (11H, m) 4; et,(2) Ethyl 4-(2-pyridyl) -4-(l-naphthyl)-3-ethoxy- 2-ethoxycarbonylbutyrate.

ZR (Film) :1750, 1720, 1580, 780, 750 cm 1 NMR(CC1316) :0.60 (3H, t, J-7Hz), 1.20 (6H, t, J=7Hz), 2.20-4.53 (811, in), 5.33 (1H, mn), 6.95-8.10 (10Hf, mn) 8.58 (111, m) Ethyl 4-(2-pyridyl)-4-(4-biphenylyl)-3ethoxy-2-ethoxycarbonylbutyrate.

ZR (Film) :1750# 1730, 1590, 1485, 1300, 1150, 760 c (CDC1 3 1 6) :0.83 (3H, t, Jin7Hz), 1.33 (6H, to Jin7Hz) 3.28 (1ff, mn), 3.63 (2H, q, J-7Hz) 4.25 (4ff, q# J-7ffz), 4.50-5.30 (2H, in), 7.02-7.83 (2ff, in), 8.65 (1H, mn) Ethyl 4-phenoxy-4-(2-pyridyl)-3-ethoxy-2ethoxycarbonylbutyrati.

IR (Film) :1750, 1730, 1590, 1490, 12110, 1060, 750cm NMR (CDC1 3 0.80 (3ff, t, J".7Hz), 1.03 (3H, to J-7Hz), 1.28 (3ff, t, J=7Hz), 2.73 (1H, mn), 3.17-3.70 (2H, m, 3.80-4.40 (4H, n), 4.60 5.55 (1H, 6.80-7.03 (3H, m), 7.10-7.40 (3H, 7.42-7.80 (2H, m) 8.65 (1K, n) Ethyl 4- (3-tolyl) (2-pyridyl) -3-ethoxy-2ethoxycarbonylbutyrate.

IR (Film) 1750, 1730, 1600, 1590, 1100, 700 cm 1 NMR (CCl 4 6) 0.72 t, J=7Hz), 1.07-1.45 (6H, m) 2.33 s) 3.12-3.73 (3H, m) 3.87-4.48 (SH, 4.95 6.85-7.72 H(7, m) 8.58 (1K, m) Ethyl 4-(2-pyridyl)-4-(4-chlorophenyl)-3ethoxy-2-ethoxycarbonyIlbutyrate.

Il (Film) 1750, 1730, 1590, 1490, 1090, -1 750 cm MR (CDC1, 6) 0.63-0.97 (3H, 1.05-1.50 m) 3.03-3.82 (3H, m) 3.93-4.58 (SH, in), 4.93 (1H, 6.90-7.72 (7H, 8.53

M)

t 9 Ethyl-4- (2-pyridyl) -4-(3-methoxyphenyl) -3- 0 25 ethoxi-2-ethoxycarbonybutyrate.

IR (Film) 1750, 1730, 1590, 1470, 1440, 1370, 1160, 1100, 1040, 760, 700 cm 4 NMR (CCd 4 6) 0.73 t, J-7Hz), 1.07-1.48 (6H, 2.85-4.53 (8H, 3.72 (3H, s), 4.93 (1K, m) 6.50-7.70 (7H, 8.60 (1K, Mn) Ethyl 4-(2-tolyl)-4-(2-pyridyl)-3-ethoxy-2ethoxycarbonylbutyrate.

IR (Film) 3060, 1740, 1720, 1590, 1440, 1090, 11 860, 750 cm 1 TC

J

1Y-

II___

36 ITY (CC 4 6) 0.70 3H, t, J-7Hz) 1.03-1.48 (6H, 2.4 (3H, 2.80-4.93 (9H, m), 6.90-7.60 (7H, 8.47 (1E, m) Ethyl 4-(2-pyridyl) -4-t-butyldimethylsiloxy- 3-ethoxy-2-ethoxycarbonybutyrate.

-1 IR (Film) 1750, 1730, 1590, 1580 cl Preparation 8 The following compounds were obtained according to a similar manner to that of Preparation 2.

r 4 *r 4 *4* 9., #4 4 9r~ (1) 4-one.

1- (l-Nahthyl) -3-ethoxycarbonyl-4H-quinolizinmp 161-163*C IR (Nujol) 1690, 1665, 1590, 1270, 1240, 780, 770 cm NMR (CDC1 3 6) 1.38 (3H, t, J-7Hz), 4.43 (2H, q, J=7Hz), 7.05-7.77 (8H, 7.80-8.10 (2H, ml, 8.43 (1H, 9.58 (1H, m) Anal. Calcd for C 2 2

H

1 7 NO C; 76.95, H; 4.99, N; 4.08 Found C; 77.14, H; 5.27, N; 3.89 4 4* 4 a, a a~ i-: 37 1- (4-Biphenylyl) -3-et-hoxycarbonyl-4Hquinolizin-4-one.

mp :183-184.5*C IR (Nujol) :1690, 1680, 1625, 1590, 1260, 770, 740=_1 21 K NMR (CDC1 3 1.40 (3H, t, J-7Hz), 4.50 (2H, q, J-7Hz), 7.08-8.02 (12H, mn), 8.43 (1H, s) 9.55 U2., Mn), Anal. Calcd for C 2 4

H

1 9 NO0 3 4H 2 0 C; 77.09, H; 5.27, N; 3.75 Found C; 77.04, H; 5.49, N; 3.60 o(3) 1-Phenoxy-3-ethoxycarbonyl-4H-quinolizin-4- .1~5mp :108-109*C IR (Nujol) :1680, 1670, 1620, 1590, 1225, 1200, 1000 i NMR(CC1316) 1.40 (3H, t, J-7Hz), 4.42 (2H, q, J=7Hz), 6.78-7.48 MS, mn), 7.57-7.98 (2H, mn), 8.23 (1H, s) 9.45 (Ili, mn) Anal. Calcd for C 18

H

15

NO

Fond 69.89, H; 4.89, N; 4.53 round C; 70.18, H; 5.03, N; 4.51

J,

1- (3-Tolyl) -3-ethoxycarbonyl-4H-quinolizin- 4-one.

mp :109-111C ZR (Nujol) ;1725, 1645, 1620, 1595, 1240, 770 NM (CDC 1 3 1.42 (3H, t, J=7Hz), 2.45 (3H, s), 4.45 (2H, q, J-7Hz) 7.08-7.48 (SlH, m) 7.53-7.95 (2H, 8.42 (lH, 9.55 (1H, mn) Anal. Calcd for C 19

H

17 N0 3 1/5H 2 0: C; 73.39, H; 5.64, N; 4.50 Found C; 73.58, H; 5.62, 4.49 BA4A r 38 1-(4-Chlorophenyl)-3-ethoxycarbonyl-4Hquinolizin-4-one.

np 159-160*C ZR (Nujol) 1680, 1670, 1490, 1295, 1260, 1240, 1130, 1020, 765 cm 1 NMR (CDC1 3 5) 1.40 (3H, t, Ji7Hz), 4.43 (2H, q, J=7Hz),6.97-7.87 (7H, 8.32 s), 9.48 m) Anal. Calcd for C 18 H 1 C; 65.96, H; 4.31, N; 4.27 Found C; 65.81, H; 4.49, N; 4.19 1- (3-Methoxyphenyl) -3-ethoxycarbonyl-4Hquinolizin-4-one.

Is mp 155-157*C ZR (Nujol) 3070, 1730, 1650, 1625, 1595, 1130, 1100, 780 cm 1 NMR (CDC1 3 6) 1.42 (3H, t, J-7Hz), 3.80 (3H, s), 4.40 (2H, q, J=7Hz), 6.85-7.93 (7H, m), 8,35 (ll, s) 9.47 (lE, m) Anal. Calcd for C 19

H

17 N0 4 *1/4H 2 0 C; 69.61, H; 5.38, N; 4.27 Found C; 69.62, H; 5.29, N; 4.19 1- (2-Tolyl) -3-ethoxycarbonyl-4H-quinolizin- 4-one.

mp 97-98*C ZR (Nujol) 1730, 1680, 1620, 1480, 1230., 1100, 785 cm 1 NMR (CDC1 3 6) 1.45 (3H, t, J=7Hz), 2.10 (3H, 4.48 (2H, q, J=7Hz), 7.18-7.83 (7H, n), 8.42 (iR, 9.68 in) Anal. Calcd for C 19

H

17 N0 3

O

C; 74.25, H; 5.57, N; 4.56 Found C; 74.50, H; 5.66, N; 4.50 t' i a ;a7B

J

-39 1-t-Butyldimethylsiloxy- 3-e thoxycarbonyl- 43-quinolizin-4-one.

mp BO*C IR (Nujol) :1695, 1675, 1620, 1590 cm NMR (CDC 3 ,t 6) 0.2 (6H, 1.10 (9H, s), 1.45 (3H, t, J=7Hz) 4.45 (2H, q, J=7Hz) 7.10-8.0 (3H, in), 8.10 (lB, s) 9.15 (il, d, J=8HZ) Anal. Calcd for C is H 25 NO 4 Si C; 62.22, H; 7.25, N; 4.03 Found C; 61.97, H; 7.04, N; 4.08 Preparation 9.

A mixture of 2-hydroxymethylpyridine (19.3 ml) t-butyldiznethylsilyl chloride (36.2 g) and imidazole (27.2 g) in dimethylformamide (190 ml) was stirred for two 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 d istilled to give 2 -t-butyl dime thyl s iloxymethylpyridine (42.30 g).

IR (Film) :1595, 1585, 1260, 1160, 1140 c- N14R (CJDCl 3 6 1. 0 (6H, s) 1. 83 (9H, s) 4.70 (2H, 6.85-7.20 (111, in), 7.25-7.70 (2H, mn), 8.20-8.30 (1H1, mn) Preparation To a solution of 1-t-butyldimethylsiloxy-3-

A

1 30 ethoxycarbonyl-4H-quinolizin-4 -one (3.32 g) in tetrahydrofuran (100 ml) was added a solution of tetran-butylammoniun fluoride (1M, 11.47 ml) at O9C.

The mixture was stirred for one hour and the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with water and saturated sodium c6iloride solution. Af ter drying over magnesium sulfate, t-he solvent was filtered and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give l-hydroxy-3-ethoxycarbonyl-4Hquinolizin-4-one (1.13 g).

my 250*C ZR (Nujol) :3 100, 1690, 1650, 1620 c- NMR (DMA SO-d 6 6) 30 (3H, t, J=7Hz) 4.25 (2H, q, J=7Hz) 7.20-7.60 (1H, mn), 7.90-8.10 (2H1, mn), 9.20-9.30 (111, m) 9.60 (11, s) 1. Anal. Calcd for C 12 H1 1

NO

C; 61.80, H; 4.75, N; 6.01 Found 61.11, H; 4.58, N; 5.91

'LS

C <24 r c- ~U ret* r r C9 tC

C

4 t 41 Freparation 11 The following compounds were obtained according to a similar manner to that of Preparation 1.

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

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

NMR (CDC1 3 6) 0.90 (3H, t, J=7.2Hz) 1.14 (3H, t, J=7.2Hz), 1.30 (3H, t, J-7.2Hz), 3.03 (3H, 3.20-4.50 (7i, m), 5.00-5.60 (2H, 6.50-7.80 (eli, m), 8.5.7 (1H, d, J-4.4Hz) Ethyl 3-ethoxy-2-ethoxycarbonyl-4-benzoyl-4- (2-pyridyl)butyrate.

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

IR (film) 1750, 1730, 1635, 1585, 1365, 1290, 1245, 1185, 1140, 1090, 1025, 745, 700 cm' NMR (CDC1 3 6) 0.98-1.50 (9H, 2.93-4.67 (iH, 6.73-7.63 (8H, 8.48-8.63 (1H, m) Ethyl 3-ethoxy-2-ethoxycarbonyl-4- (2-pyridyl)-4phenylthiobutyrate.

IR (film) 1750, 1730, 1590, 1440, 1300, 1150, 1090, 1025, 760 cm1 NMR (CDC1 3 6) 0.83-1.40 (9H, 3.07-4.43 (7H, i)W, 4.53-4.92 (2H, 7.0-7.73 (Sli, m), 8.53 (1H, m) o -42 Preparation 12 The following compounds were obtained according to a similar manner to that of Preparation 2.

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

IR (Nujol) :1720, 1520, 1490, 1450 cm 1 l NMR (DMSO-d 6 6) 1.30 O3H, t, J-7Hz), 4.26 (2H, q, J-7Hz) 7.46 (5E, m) 7.60-7.70 (2H, m) 7.97 (1H, s) 8.98 d, J-2Hz) Anal. Calcd forCiRisN4 C, 69.89; H, 4.89; N, 4.53 Found C, 69.20; H, 5.30; N, 4.14 3 -Ethoxycarbonyl-1- (N-methylanilino) -4H-quinolizin- C 4-one.

IR (Nujol) :1690, 1680, 1600, 1510, 1380, 1235 cm- 1 NMR (DMSO-d 6 6) 1.30 (3H, t, J=7Hz) 3.30 (3H, 4.28 (2H1, q, J=7Hz), 6.50-8.10 (8H, mn), 8.15 (1H, 9.40 (1H, d, .7=7Hz) 'Anal. Calcd for C 19

H

1 N 0 3 C, 70.79; H, 5.63; N, 8.69 9425Found 71.00; H, 5.40; N, 9.56 mp :129-1321C 3-Ethoxycarbonyl- 1-ben zoy 1-4 H-quinoli zin- 4-one.

mp :176-1781C IR (Nujol) :1750, 1630, 1580, 1485, 1220, 111,0, 785 cm 1 l NZ4R (CDC1, 1.37 (3H, t, .7=7Hz), 4.38 (2H, q, .7-7Hz), 7.20-8.07 (7H, m, 8.62 (111, s), 82-9.10 (li, m, 9.42-9.67 (1Hi, m) 43 Anal. Calcd for C 19 1

H

5 NO4 C, 71.02; H, 4.70; N, 4.36 Found C, 70.76; H, 4.96; N, 4.33 3-Ethoxycarbon-1-benzyl-4H-quinolizin-4-one.

mp 102-105°C IR (Nujol) 1690, 1670, 1625, 1595, 1320, 1235, -1 765, 725 cm 1 NMR (CDC1 3 6) 1.43 (3H, t, J=7Hz), 4.23 (2H, 4.48 (2H, q, J=7Hz), 7.02-7.42 (6H, m), 7.52-7.78 (2H, 8.28 (1H, 9.45 (1H, m) Anal. Calcd for C 1 9 1 7

NO

3 C, 74.25; H, 5.57; N, 4.56 Found C, 73.97; H, 5.72; N, 4.42 3-Ethoxycarbonyl-l-phenylthio-4H-quinolizin-4-one.

mp 171-173°C IR (Nujol) 1740, 1660, 1625, 1575, 1280, 1220, 1140, 1120, 780, 750 cm 20 NMR (CDC1 3 6) 1.40 (3H, t, J=7Hz), 4.42 (2H, q, J=7Hz), 6.68-7.47 (5H, 7.73 (1H, m), 8.33 (1H, 8.72 (1H, 9.52 (1H, m) Anal. Calcd for CI 8

H

1 5

NO

3 S C, 66.44; H, 4.65; N, 4.30 '5 Found C, 66.17; H, 4.69; N, 4.28 Preparation 13 A nixture of 2-chloromethylpyridine (50 g), N-methylaniline (42 and potassium carbonate (120 g) S 30 in N,N-dimethylformamide (200 ml) was stirred for 4 hours at 1200C. The reaction mixture was cooled to room temperature, added to water (1 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

I

and concentrated. The residue was crystallized from isopropyl alcohol to give N-methyl-N-(2-pyridylmethyl)aniline (39 g).

mp 600C IR (Nujol) 1610, 1590, 1570, 1510, 1470, -1 1440, 1360 cm Preparation 14 To a solution of 2-rethylpyridine (9.31 g) in tetrahydrofuran (200 ml) was added a 1.5M hexane solution of n-butyllithium (73.3 ml) at -20°C. The resulting solution was stirred for 30 minutes at room temperature and added to a solution of ethyl benzoate (15.02 g) in tetrahydrofuran (100 ml) at -60°C. After stirring for 2 hours at -60°C, acetic acid (15 ml) was added and tc the resulting mixture was allowed to warm to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water.

The aqueous layer was reextracted with ethyl acetate and the combined extracts were washed with water, aqueous solution of sodium hydrogen carbonate, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extracts were filtered and evaporated. The residue (20.5 g) was chromatographed on silica gel (Merck 70-230 mesh, 308 g) eluting with chloroform to give 2-pyridylmethyl phenyl ketone (10.86 g) as an oil.

IR (Nujol) 1680, 1630, 1600, 1545, 1270, C, 1200, 1145, 1060, 800, 775, 690 cm" 30 NMR (CDCI 3 6) 4.43 (1.5H, 6.02 (0.5H, s), 6.83-8.65 (9H, m) Preparation To a solution of 5-hydroxy-2-methylpyridine (10.66 g) in tetrahydrofuran (426 ml) was added 45 a solution of n-butyllithium (1.5M in hexane, 143 ml) at -30°-.-10 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature. After cooling to -780C, cyclohexane (11.14 ml) was added dropwise and allowed to warm to 0 C and stirred for 30 minutes at 0°C. After addition of acetic acid (24.6 ml), the solvent was distilled off and the residue was diluted with ethyl acetate, and washed successively with water, 10% aqueous sodium hydrogen carbonate and aqueous saturated sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated.

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

IR (Nujol) 1615, 1575, 1500, 1460 cm-

I

NMR (CD 3 OD, 6) 1.20-2.00 (10H, m), 2.90 (1H, 4.95 (2H, 7.20 (2H, m), c 8.05 (1H, d, A solution of 5-hydroxy-2-[(1-hydroxycyclohexyl)methyl]pyridine (1 g) in acetic acid (15 ml) containing sulfuric acid (5 ml) was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured on an ice, basified with mi' 10% aqueous sodium hydrogen carbonate, and extracted with ether. The combined ether extracts were washed with aqueous saturated sodium chloride, dried over ,iK magnesium sulfate, filtered, and concentrated. The 30 residue was washed with isopropylalcohol to give 2- (409 mg).

IR (Nujol) 1560, 1450, 1370, 1280 cm 1 NMR (CDCl 3 6 4.07 (2H, 6.85-7.43 (7H, m), 8.08 (lH, d, J-3.0Hz), 10.30 (IH, broad s) pp~ 46 Vc L Preparation 16 To a solution of l-phenylthio--et1oxycarbonyl-4Equinolizin-4-one (1.0 g) in acetic acid (20 ml) and chloroform (7.5 ml) was added potassium permanganate (583 mg) at OOC. After stirring for two hours at the same temperature, the reaction mixture was allowed to warm to room temperature and stirred further for- one hour. Potassium permanganate (194 mg) was added and stirred overnight. To the resulting reaction mihxture was adcded. Saturated aqueous sodium thiosulfate solution with ice-cooling and the mixture was extracted with chloroform. After drying over magnesium sulfate, th-e chloroform extract was filtered and evaporated. The residue was washed with diisopropyl ether to give 1-phenylsul fonyl- 3-ethoxycarbonyl-4H-quinolizin-4-one (583 mg), mp 182*C.

ZR (Nujol) :1710, 1680, 1640, 1580, 1200, 1150 cm- 1 NMR (CDCl 3 6) 1.45 (3H, t, J-7Hz), 4.45 (2H, q, J=7Hz) 7.20-8.10 (7H, in), 8.60 (1H, d, J=8Hz) 9.18 (1H, s) 9.50 (1H, d, J-$Hz) Anal. Calcd for C isH 15 C, 60.50; H, 4.23; N, 3.92 Found 60.44; H, 4.51; N, 3.88 Preparation 17 To a solution of 3-ethoxycarbonyl-7-hydroxyv-lphenyl-4H-quinolizin-4 -one (5 g) in N,N-dimethylformamide (100 ml) was added sodium hydride (63.61 ini mineral oil, 732 mg) at 506C. After stirring for minutes at 50*C, n-butyliodide (2.77 ml) was added.

After stirring for 1 hour at SOOCI the mixture was cooled to room temperature and added to a mixture of aqueous hydrogen chloride and an ice.

47 The mixture was extracted with chloroform and the chloro form extract was washed with 10% aqueous sodiuz= hyd'rogen carbonate and aqueous saturated sodium -hIoride. After drying over magnesium sulf ate, the (.zIloroform extract was filtered and concentrated in vacuo. The residue was chromatographed on silica gel (Merck 70-230 mesh, 100 q) eluting with chloroform and then 10% methanol in chloroform to give 3-ethoxy,carbonyl-7- (n-butoxy) -1-)..heny-4H-quinolizin-4 -one (2.37 g) mp 94-950C IR (Nujol) 1730, 1690, 1655, 1630, 1480 cm NMR (CDCl 3 6) 0.95 (3H, t, J=5Hz),, 1.42 (3Mr t, Jw$gz), 1.30-2.10 (4H1, mn), 4.13 (2H, t, J=5Hz) 4.45 (2H1, q, Jin5Hz) 7.30 (11, d, J-7Hz), 7.42 (511, in), 7.67 (1H1, d, J=7Hz), 8.27 (111, s) 9.08 (11, d, 3=2Hz) Anal. Calcd for CH NO

C

22 23 4 C, 72.31; H, 6.34; N, 3.83 Found 71.74; E1, 6.39; N, 3.80 Preparation 18 The following compound was obtained according to a similar manner to that of Preparation 5 1-Allyloxy- 3-ethoxycarbonyl- 41-quinoli zin- 4-one.

mp :82-846C ZR (Nujol) :1690, 1680, 1660, 1620, 1580, 1320, 1235, 1100, 1015, 770 cm 1 l NMR (CDC1 3 0 6) 43 (3H I t, 3 =7Hz) 4 .4 2 (2H1 q, Jin7Hz), 4.50-4.75 (2H1, in), 5.15r5.67 (2H1, 5.78-6.47 (111, mn), 6.97-8.32 (411, 9.47 (1H1, d, Anal. Calcd for C isH 15 N0 4 C, 65.93; H, 5.53; M1, 5.13 Found 66,11; H, 5.36; N, 4.94 47-1 Preparation 19 The following compound was obtained according to a similar manner to that of Preparation 14.

(5-Eydroxypyridin-2-yl) methyl phenyl ketone NMR (CDCl1 3 6) 4.44 (2H, broad 6.85-7.70 m) 7.70-8.30 (3H# m) 9.34 (2H, s) Preparation The following compound was obtained according to a similar manner to that of Preparation 1.

Ethyl 4 -ben zoyl- 3-e thoxy- 2-ethoxycarbonyl-4- hydroxypyridin-2-yl) butyrate IR (Nujol) :1730, 1720, 1675, 1595 cm Preparation 21 The following compound was obtained according to similar manner to that of Preparation 2.

1-Benzoyl- 3-ethoxycarbony1-7-hydroxy-4H-quinolizin- 4-one.

IR (Nujol) :1740, 1630, 1570, 1490 cm 1 NMR (DMSO-d 6 6) :1.22 (3H, t, J=7Hz) 4.27 (2H, qo J=7Hz), 7.43-7.97 (6H, in) 8.22 (1H, a) 8.87 (1H, d. .7=10Hz), 8.95 (1H# d, .7=2Hz) Preparation 22 r The following compound was obtained according to a similar manner to that of Preparation 1-Ben zoyl- 3-ethoxycarbonyl-7-n-butoxy-4Hquinolizin-4-one.

mp 158-1590C IR (Nujol) :1740, 1680, 1630, 1580v 1510 cm-1 -0 47-2- 1*iR (CDC1 3 6) :0.98 (3H, t, J5SHz), 1.23 (3H, t, J=7Hz), 1.30-2.10 (4H, in), 4.02-4.48 (4H, in), 7.37-8.18 M6, in), 8.33 UlI, 8.88 (lH, d, J-lOHz), 9.03 (lB, d, J-2Hz) Preparation?23 To a solution of sodium ethoxide (sodium, 151 mng) in ethanol (20 ml) was added ethyl pyrid-2-ylacetate (1 ml) at room temperature and the mixture was stirred for 1 hour at tie same temperature. To the mixture was added diethyl ethoxymethyleneinalonate (1.33 ml) &t room temperature and the mixture was stirred at room temperature overnight. To the mixture was added acetic acid (0.75 ml) at room temperature and the precipitate It6 was filtered and washed with water to give 1,3diethoxycarbonyl-4H-quinolizin-4-one (896 mg).

IR (Nujol) :1680, 1625, 1585 cm 1 20NMR (CDC1 3 1 t) :1.40 (6H, 4.20-4.55 (4H, in), &go 207.20-7.46 (1H, in), 7.72-8.00 (1H, mn), 9.15 (1H, 9.27-9.64 (2H, in).

0 NT

O

rX -48 Example 1 To a solution of 3-ethoxycarbonyl-4H-quinolizin-4..

one (2.17 g) in methanol (65.2 ml) was added dropwise 6N aqueous sodium hydroxide (6.5 ml) at room temperature.

After stirring for 20 minutes, water (10 ml) was added.

Af ter iitirring for 20 minutes, water (30 ml) was also added. After stirring for an hour, the reaction 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 crystal. mp 233*C.

IR (Nujol) :1730, 1610, 1585, 1320 m1 .NMR (DMSO-d 6 6 :7.26 1H, Jin9Hz), 7.50-7.95 (in, lH) 8.00-8.20 2H) 8.41 1H, is J-9Hz) 9.20-9.40 (in, 1H) Example 2 To a suspension of 4H-quinolizin-4-one-3carboxylic acid (1.69 g) in N,N-dimethylformamide (16.9 ml) was added 1,l'-carbonyldiimidazole (2.-17 g) at ambient temperature. The resulting suspension was heated to 1001C for 30 minutes and 5-ainino-111-tetrazole (1.06 g) was added at 1000C. After stirring for 4 Tt C20 minutes at 1004C, the reaction mixture was cooled to 0OC. The precipitate was filtered and washed with Cott 4- ~t 4 fr Is 30 49 pre-cooled N,N-dimethylformamide and then ether to give N- (lE-tetrazolyl) I -4H-quinolizin-4-one-3-carboxamide g) as yellow sol.,-d. mp 260*C.

IR (Nujol) 3200, 1660, 1620, 1500, 1310 cm 1 NWA (CIF 3 COOH) 6 7.42 1H, J-8Hz) 7.68-7.88 (in, 19) 7.98-8.29 2H), 8.72 1R, J=8Hz) 9.48 1H, J=8Hz) Ana.lysi~s Calcd. for C 1 1

H

8 0 2 N 6 C; 51.56, H; 3.15, N; 32.80 Found C; 51.70, H; 3.22, N; 32.99 Example 3 The following compounds were obtained according to a similar manner to that of Example_1.

7 -Ethy1-4H -quinli z in- 4-one- 3-carboxyl ic acid.

mp. 193-1950C.

IR (Nujol) :3100, 1725, 1700, 1605 cm NMR (C 3 COOH) 6 1.52 Ct, 35, J=8Hz) 3.12 2H, J=8Hz) 7.92 1H, J=9Hz) 8.32 2H) 8.73 1H, J=9Hz) 9.30 (in. 1H).

Analysis Calcd. for C 12

H

11 N0 3 C; 66.35, H; 5.10, N; 6.45 Found C; 66.40, H; 5.14, N; 6.46 1-Phenyl-4H-quin~1i zin- 4-one- 3-carboxylic acid.

mp. 1980C.

IR (Nujol) :3315, 1740, 1620 cm- 1

NMR'CF

3 COOH) 6 7.32-7.82 5H) 7.92-8.23 1Hi), 8.25-8.52 (in, 2H) 8.70 1H) 9.48-9.72 (mn, 1H) Analysis Calcd. for C1 6 H 11NO 3 /4 C; 66.78, H; 4.64, N; 4.87 Found C; 66.89, H; 4.22, N; 4.59 50 7-Hydroxy-4H-quinolizin-4-one-3-carboxylic acid. mp. 270C ZR (Nujol) 3120, 2690, 1690, 1590 cm- NMR (CF 3 COOH) 6 7.87 1li, 8.07-8.42 (no 2E)l 8.58 Cd, 1H, 9.07 (mn, 1H) Anal. Cilcd for C 1 H 7 N0 4 1/4H 2 0 C; 57.28, H; 3.61, N; 6.68 Found 57.51, H; 3.60, N; 6.75 7-Methoxy- 4H-quinoli zin-4 -one- 3-carboxylic acid.

mp. 215-216*C. ZR (Nujol) :3150, 3100, 1.700, 1610, 1590 CM NMR (CF 3 cOH) 6 4.18 Cs, 3H) 7.88 1E, J=8.SHz) 8.10-8.47 (in, 2H), 8.67 Cd, 1E, J-8SZ), 8.88 (Mi, iH) Anal. Calcd for C 1 1 a 9

NO

C; 60.27, H; 4.14, N; 6.39 Found 59.90, H; 4.38, N; 6.48 9-Methyl- 4H -quinolizin-4-one-3-carboxylic acid.

mp. 259-260*C.

IR (Nujol) :3100, 3020, 1740, 1610, 1590, 1120, 780 cm- 1 NMR CDMSO-d) 6 :2.92 Cs, 3H), 7.90 Cd, 1H, 6 8.07 Cd, i1H, J=9,SHz) 8.05-8.38 1H), 8.82 1H, 9.42 lH, Anal. Calcd for C 1 H 9

NO

3 C; 65.02, H; 4.46, N; 6.89 Found 64.92, H; 4.76, N; 6.89 8-methyl- 4H-quinol izin-4 -one- 3-carboxylic acid.- mp. 228-230*C ZR (Nujol) :3090, 3030, 2700, 1630, 1620, 1580, 785 cm' *NMR (CF 3 COOH) 6 :2.82 Cs, 3H), 7.82 1H, J-9Hz), e-I S A /17.92 (dds 1H. J-7Hz, 2Hz), 8.17 1H, J-2Hz), 8.68 We, 1H, J-9Hz) 9.37 1Hi, 7=7Hz) 51 51 Anal. Calcd for C 11

H

9

NO

3 C; 65.02, H; 4.46, N;6.89 Found C; 64.88, H; 4.79, N; 6.85 6-Methyl-4H-quinolizin-4-one-3-carboxylic acid.

mp. 185-187*C.

IR (Nujol) 3100, 2700, 1720, 1615, 1595, 1295, 1040, 800 cm NMR (CF 3 COOH) 6 3.45 3H), 7.82 1H, J=9Hz), 7.58-7.97 1H), 8.10-8.30 2H), 8.68 LE, J=9Hz) Anal. Calcd for C11H 9 N0 3 C; 65.02, H; 4.46, N; 6.89 Found C; 64.60, H; 4.52, N; 6.91 1-Methyl-4H-quinolizin-4-one-3-carboxylic acid.

mp. 258-260*C.

-1 IR (Nujol) 1740, 1610, 1450, 780 cm NMR (CF 3 COOH) 6 2.87 3H), 8.15 1H), 8.35-8.77 3H), 9.66 1H) Anal. Calcd for C, 1 HgNO 3 C; 65.02, H; 4.46, N; 6.89 Found C; 64.70, H; 4.56, N; 6.86 7-Methyl-4H-quinolizin-4-one-3-carboxylic acid. mp. 222-2240C IR (Nujol) 1720, 1600, 1590, 1320, 1125, 1110, 840 cm 1 NMR (CF COOH) 6 2.77 3H), 7.93 1H, J=9Hz), 8.22-8.38 2H), 8.73 1H, J=9Hz), 9.32 1H) Anal. Calcd for C 11

H

9

NO

3 C; 65.02, H; 4.46, N; 6.89 Found C; 65.04, H; 4.31, N; 6.91 t+ t

'A

1 52- 1-Methoxy-4E-quinolizin-4-one-3-carboxylic acid.

mp. 259-261 0

C.

ZR (Nujol) :3100, 1630, 1620, 1580, 1100, 1070, 780 c- NMR (CF 3 COOH) 6 :4.27 3H), 8.00-8.67 (in, 3H), 8.90 Cm, 1H), 9.52 1H, Anal. Calcd for C 11 H 9 N0 4 C; 60.28, H; 4.14, N; .6.39 Found 59.64, H; 4.15, N; 6:30 (11) 7-n-Butoxy-4H-quinolizin-4-one-3-carboxylic acid. mp. 120-1226C.

ZR (Nujol) 1725, 1600, 1590, 1320, 1070, 1000 cml NMR (CF 3 COH) 6 1.07 3H, J=6Hz), 1.30-2.20 4H) 4.40 Ct, 2H, J=6Hz) 7.90 1H, 8.13-8.43 Cm, 2H), 8.67 in, J=9.SHz), 8.93 iH, J-2Hz) Anal. Calcd for C 14

H

15 NO: C; 64.36, H; 5.79, N; 5.36 Found C; 64.46, H; 5.80, N; 5.31 (12) 7-Isopropoxy-4H-guinolizin-4-one-3-carboxylic acid. mp. 218-2190C.

ZR CNu~o1) :3140, 3090, 1720, 1620, 1120, 1060, 1000, 780 cm 1 NMR (CF 3 COOH) 6 :1.67 6H, J=6Hz) 4.97 C1H, J=6Hz) 7.88 Cd, iH, J=9Hz) 8.10-8.43 (in, 4H) 8.63 1H, J=9Hz) 8.90 1H, J=2Hz) 1 53 Anal. Calcd for C 13

H

13 N0 4 C; 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 according to a similar manner to'that of Example 2.

N-[3-(4H-1,2,4-Triazolyl)]-4H-quinolizin-4-one 3-carboxamide. mp. 2500C.

-1 IR (Nujol) 3400, 3300, 1700, 1660, 1650, 1620 cm NMR (CF 3 COOH) 6 7.90-9.60 7H) Anal. Calcd for C 1 2

H

9

N

5 0 2 C; 56.47, H; 3.55, N; 27.44 Found C; 56.83, H; 3.79, N; 27.50 N-[5-(1H-Tetrazolyl)]-9-methyl-4H-quinolizin-4one-3-carboxamide. mp. 2700C.

IR (Nujol) 3200, 3100, 3080, 1660, 1620, 1590, 790 cm 1 NMR (CF 3 COOH) 6 2.80 3H), 7.50-7.87 2H), 8.08 1H, J=7Hz), 8.78 1H, J=9Hz), 9.43 1H, J=7Hz) Anal. Calcd for C 1 2

H

1 0

N

6 0 2 C; 53.33, H; 3.73, N; 35.10 Found C; 55.28, H; 3.88, N; 31.35 N-(5-(1H-Tetrazolyl)]-7-ethyl-4H-quinolizin- 4-one-3-carboxamide. mp. 2500C.

IR (Nujol) 3200, 1660, 1640, 1620, 1590, 1490 cm- 1 NMR (CF 3 COOH) 6 1.50 3H, J=7Hz), 3.05 2H, J-7.5Hz), 7.45 1H, J=9Hz), 8.08 2H), 8.68 1H, J=9Hz), 9.33 1H) Anal. Calcd for C 1 3

H

1 2

N

6 0 2 C; 54.93, H; 4.25, N; 29.56 Found C; 55.32; H; 4.32, N; 29.72 A 54 N-(S-(1H-Tetrazolyl)]-l-phenyl-4H-quinolizin-4one-3-carboxamide. mp. 270*C.

IR (Nujol) 3180, 3100, 1680, 1620, 1490 cm NMR (CF 3 COOH) 6 7.27-8.02 Cm, 6E), 8.05-8.35 Cm, 2H), 9.70 1H), 9.48-9.75 Cm, 1H) Anal. Calcd for C 1

H

12

N

6 2 C; 61.44, H; 3.64, N; 25.29 Found C; 61.21, H; 3.80, N; 24.83 -(5-(1H-Tetrazolyl) -7-hydroxy-4H-quinolizin- 4-one-3-carboxamide. mp. 2700C.

IR (Nujol) 3120, 3090, 2530, 1670, 1640, 1540, 11 980 cm- NMR (CF COOH) 6 7.73-7.70 Cm, 2H), 8.03 1H), 8.67 Cm, 1H), 9.15 Cm, 1H) Anal. Calcd for C 11 H N 6 0 3 C; 49.06, H; 3.32, N; 32.11 Found C; 48.56, H; 3.47, N; 32.66 N-(5-C1H-Tetrazolyl)3-7-methoxy-4H-quilolizin- 4-one-3-carboxamide. mp. >270*C.

V -1 IR (Nujol) 3200, 3100, 1680, 1650, 1610 cm NMR (CF 3 COOH) 6 4.13 Cs, 3H), 7.42 Cd, 1H, J-9Hz), 7.73-8.17 Cm, 2H), 8.58 Cd, 1H, J-9Hz), 8.92 Cm, J.H) Anal. Calcd for C 12

H

1

N

6 0 3 C; 50.35, H; 3.52, N; 29.36 Found C; 50.54, H; 3,55, N; 29.63 N-(2-Thiazolyl)-4H-quinoliin-4 one-3carboxamide. mp. 240*C.

IR (Nujol) 3100, 1665, 1620, 1490, 1320 cm NMR (CF 3 COOH) 6 7.30-7.90 4H) y 8.03-8.47 Cm, 2H), 8.75 1H, J-9Hz) 9.42 Cd, 1H, J-7Hz) Anal. Calcd for C 1

H

9 N OS BA4/ C; 57.56, H; 3.34, N; 15.49 Found C; 57.25, H; 3.77, N; 15.24 0' INT r, N-(2-Hydroxyphenyl) -4H-quinolizin-4-one-3carboxamide. mp. 247*C.

IR (Nujol) 1650, 1630, 1600 cm NMR (CDC1 3 6 6.80-7.50 511), 7.70 2H, J=7Hz), 8.76 1H, J=8Hz), 9.40 1H, J-8Hz), 10.10 Cs, 1H) Anal. Calcd for C 16 H1 2

N

2 0 3 C; 68.57, H; 4.32, N; 9.99 Found C; 68.04, H; 4.48, N; 10.11 N-(2-Pyrimidinyl)-4H-quinoizin-4-one- 3 carboxamide. mp. 2180C.

-1 IR (Nujol) 1690, 1650, 1620 cm NMR (DM.SO-d 6 6 7.10-8.20 SH), 8.50-8.80 3H), 9.20-9.40 I) Anal. Calcd for C 14

R

10

N

4 0 2 C; 63.15, H; 3.79, N; 21.04 Found C; 61.20, H; 4.19, N; 20.76 *6O4 g(10) N-!5-(1H-Tetrazolyl)J-8-methyl-4H-quinolizin- 4-one-3-carboxamide. mp. 2700C -1 IR (Nujol) 3200, 3150, 1660, 1635, 1590, 780 cm NMR (CF 3 COOH) 6 2.73 3H), 7.35 1E, J=9Hz), 7.65 (dd, iE, J=7Hz, 2Hz), 7.88 (d, 1 J=2Hz), 8.65 1H, J=9Hz), 9.38 1H, Anal. Calcd for C 12

H

10

N

6 0 2 C; 53.33, H; 3.73, N; 31.10 Found C; 54.03, H; 3.84; N; 30.38 CS OC rr- 15- (lH-Tetrazolyl) -6-methyl-4H-quinolizin- 4-one-3-caroxamide. mp. 2700C.

IR (Nujol) 3200, 1660, 1620, 1590, 1030, 820, 790 cm NMR (CF 3 COOH) 6 3.33 Cs, 3H), 7.37 1H, J-9Hz), 7.37-7.62 Cm, 1H), 7.87-8.07 Cm, 2H), 8.60 li, J-9Hz) RAO~ -I 56 Anal. Calcd for C 12

H

10

N

6 0 2 C; 53.33, H; 3.73, N; 31.10 Found C; 53.63, H; 3.92, N; 31.42 (12) N-[5-(1H-Tetrazolyl)]-1-methyl-4--quinolizin-4one-3-carboxamide. mp. 270 0

C.

IR (Nujol) 3180, 1665, 1640, 1620, 1595, 1500, -l 1040, 1020, 770 cm NbiR (CF 3 COOH) 6 2.77 3H), 7.83-8.10 1E), 8.38 2H, J=3Hz), 8.72 IH), 9.65 (d, 1H, J=6Hz) Anal. Calcd for C 12

H

10

N

6 0 2 C; 53.55, H; 3.73, N; 31.10 Found C; 53.71, H; 4.04, N; 31.03 (13) N-(5-(1H-Tetrazolyl) 1-7-methyl-4H-quinolizin- 4-one-3-carboxamide. mp. 270*C.

IR (Nujol) 3200, 1670, 1610, 1580, 1500, 1310, 1060, 1040, 840 cm NMR (CF COOH) 6 2.73 3H), 7.47 1H, J=9Hz), 8.03-8.50 2H), 8.70 1H, J=9Hz), 9.33 H) Anal. Calcd for C 1 2

H

1 0 14Nu0 C; 53.33, H; 3.73, N; 31.10 Found C; 53.61, H; 3.69, N; 31.34 (14) 4-Triazinyl) -4H-quinolizin-4-one-3carboxamide. mp. 2630C (dec.) IR (Nujol) 3100, 1690, 1620, 1580, 1520, 1500, 1040 cm- 1 NMR (CF 3 COOH) 6 7.33 1H, J=9Hz), 7.60-8.23 3H), 8.72 1H, J=9Hz), 9.10-9.17 1H), *0 9.27-9.68 2H) Anal. Calcd for C 1 H N 5 0 2 *1/4H 2 0 C; 57.51, H; 3.59, N; 25.97 Found C; 57.51, H; 3.52, NI- 25.77 -57- N-pyrazinyl-4H-quinolizin-4-Ofle-3-carboxamide.

nip. 250 0

C.

IR (Nujol) :3400, 1675, 1620, 1580, 1520, 1500, 1400, 1320, 780 cm- NMR (F 3 COOH) 6 7.43 1H, J=9.5Hz) 7.78 (mn, 1H), 8.00-8.23 (mn, 2H), 8.77 8.83 J-7.5Hz), 8.78-8.98 (in, 3H), 9.55 1H, J=7.SHz), 9.82 1E) Anal. Calcd for C 14

H

10 4 0 2 *H 2 0 C; 59.15, H; 4.25, N; 19.71 Found C; 59.58, H; 4.03, N; 19.99 (16) N-(2-Pyridyl) -4H-quinolizin-4-ori-2carboxamide. nip. 228-2300c.

(17) N-16-(3-Chloropyridazinyl) ]-4H-cquinolizin- 4-one-3-carboxamide. nip. 2500C.

000000 0 #06IR (Nujol) 3100, 1680, 1620, 1580, 1510, 1070, 780cm1 NMR (CF 3 COOH) 6 :7.38 1H,J=9Hz),7.63-8.50 (in, 5H), 8.77 1H, J=9Hz) 9.48 (mn, 1H) iL1 58 Anal. Calcd for C 14

H

9 C1N 4 0 2 C; 55.92, H; 3.02, N; 18.63 Found C; 55.65, H; 3.15, N; 19.14 (18) N-[S-(1H-Tetrazolyl)]-l-methoxy-4H-quinolizin- 4-one-3-carboxamide. mp. 270*C.

IR (Nujol) 3200, 1660, 1650, 1620, 1290, 1015, 775 cm NMR (CF 3 COO) 6 4.33 3H), 8.13 IS), 8.33 Cs, IS), 8.43-9.02 2H), 9.62 (d, .0 1H, J=7.IAz) Anal. Calcd for C 12

H

1 0 6 0 3 C; 50.35, H; 3.52, N; 29.36 Found C; 50.46, H; 3.45, N; 29.39 2 3 fti 2 2 20 *fee L S...2 30 (19) 2 6 -Dime thypyrimidinyl) ]-4H-q -zin- 4-one-3-carboxamide. mp. 217-218*C.

ZR (Nujol) 3460, 3120, 1690, 1650, 1620, 1060, -1 790 cm NMR (CF 3 COOH) a 2.87 Cs, 6H), 7.38 Cd, 1H, J=9Hz), 7.47-8.32 Cm, 4H), 8.75 1H, J=9Hz), 9.63 1H, Anal. Calcd for C 16

H

1

N

4 0 2 41/3H C; 63.99, H# 4.92, N; 19.04 Found C; 63.99, H; 4.52, N; 18.66 (20) N- Cs-(1H-Tetrazolyl) -7-n-butoxy-4H-quinolizin- 4-one-3-carboxamide. mp. 2700C.

ZR (Nujol) 3200, 1665, 1640, 1625, 1590, 1000, 850, 780 cm 1 NMR (CF 3 COOH) 1.10 Ct, 3H, J6.Hz), 1.37-2.3 4H), 4.38 2H,, J=6.5Hz), 7.53 1H, J=8.SHz), 7.97-8.28 Cm, 2H), 8.67 li, 9.03 Cs, 1H) Anal. Calcd for C 1 sH 16

N

6 0 3 t C; 54.88, H; 4.91, N; 26.00 Found C; 55.14, H; 4.89, N; 25.83 v -59 (21) N- (lH-Tetrazolyl) I -7-isopropoxy-4H-quinolizin- 4-orie-3-carboxanide. mot 2700C.

IR (Nujol) :3200,. 1680, 1650, 1620, 1500, 1310, 780 cmJ 1 NMR (CF COOS) 6 :1.77 6S, J-6Hz) 5.12 (sept, IS, J-6Hz) 7.67 1E, J-S.5Ez) 8.02-8.37 2H), 8.80 1H, J-8.5Ez) 9.20 IS) Anal. Calcd for C 14

H

14 N 6 0 3 C; 53.50, H; 4.49, N; 25.74 Found 53.73, V1!; 4.41, N; 27.04 Example To a suspension of 4H-quinolizin-4-one-3carboxylic acid (2.27 g) in dry N,N-dimethylformamide (22.7 ml) was added l,l'-carbonyldimi'dazole (2.92 g) The resulting suspension was heated to 1006C and kept for minutes. After cooling to room temperature the resulting solution was, treated with dry ammonia and stirred for 20 minutes. The crystals separated was 2 a collected by filtration and washed with water to give *91*4H-quinolizin-4-one-3-carboxamide (1.94 g) mp. 230-2320C.

IR (Nujol) :3350, 3120, 1660, 1630 cml NMR (CF 3 COOH) 6 :7.58 Cd, 1H, J-9Hz) 7.75-8.07 (in, 1H), 8.12 2H) 8.60 1H, J=9Hz) and 9.52 Cd, 1H, J-7Hz).

Anal. Calcd for C 10

H

8 N 0 2 C; 63.83, H; 4.28, N; 14.89 Found 63.96, H, 4.43, 14.90 *3 0 A mixture of 4H-quinolizin-4-one-3-carboxamide g) and phosphorus oxychioride (50 ml) was refluxed for one hour. The reaction mixture was concentrAted under reduced pressure and the residue was dissolved in aqueous sodium bicarbonate solution and chloroform.

F "i:i:ii- -i I i

I:

fy,..

Ii 60 The chloroform extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was chromatographed on silica gel (30 g) eluting with chloroform-methanol (50:1) to give 3-cyano-4Hquinolizin-4-one, which on recrystallization from ether gave crystals (800 mg), mp. 198-200°C.

IR (Nujol) 2420, 1680, 1620 cm 1 NMR (DMSO-d 6 6 6.93 1E, J=8Hz), 7.30-7.60 7.86-8.20 3H), 9.13 1H, 0 J=8Hz) C C d C C C" C fI T

I:

Oi 4 1 I ItI6 11116 To a solution of 3-cyano-4H-quinolizin-4-one (1.20 g) in a mixture of pyridine (50 ml) and triethylamine ml) was bubbled hydrogen sulfide gas; over a period of 30 minutes at room temperature. The resulting mixture was allowed to stand at ambient temperature for 3 days.

The solvent was distilled off and the residue was washed with a hot mixture of chloroform and methanol 1) and filtered. The filtrate was concentrated and the residue was washed again with a hot mixture of chloroform and methanol and filtered. The filtered cake was washed well with a mixture of chloroform and methanol to give 4H-quinolizin-4-one-3thiocarboxamide (0.76 g).

mp. 220-2300C.

IR (Nujol) 3300, 3100, 165C, 1620, 1500 cm- 1 NMR (DMSO-d 6 6 7.07 1H, J=8Hz), 7.36-7.67 1H), 7.80-8.10 9.13 1H, J=8Hz), 9.26 1H, J=8Hz), 9.80 (broad s, 1H) i -tC 3-Cyano-4H-quinolizin-4-one (4.21 sodium azide (1.77 and ammonium chloride (1.45 g) was dissolved in N,N-dimethyl-formamide (42 ml) and the resulting mixture was heated at 120°C for two days. The reaction mixture was evaporated and the residue was dissolved in

A

61 aq'ueous sodium bicarboniate solution and filtered.

The filtrate was acidified with dilute hydrochloric acid to pH 1-2. The precipitates were filtered, washed with water and then cold N,N-dimethylformamide. The filtered solid was dissolved in hot N,N-dimethylformamide and filtered. The filtrate was treated with ether and kept at 0 0 C. The crystals separated were filtered and recrystallized from a mixture of ether and N,N-dimethylformamide to give 3- (5-(I..-tetrazolyl) ]-4H-quinolizin-4one (1.1 g).

mp. 250*C.

IR (Nujol) :3200, 3100, 3050, 1660, 1620, 1590 cm- NMR (C 3 COOH) 6 7.40 1H, J=811z), 7.60-8.30 (in, 3E), 8.60 1H, J=8Hz) 8.90 1H) 9.40-9.60 (in, lE) Anal. Calcd for C 0 H ON C; 56.34, H; 3.31, N; 32.85 Found IC; 56.55, H, 3.87, N; 33.02 r.3 4Lt Example 6 A suspension of 4H-quinolizin-4-one-3-carboxylic acid (196.7 mng) in 0.lN-agueous sodium hydroxide solution (9.9 ml) was stirred for one hour at room temperature.

The resulting reaction mixture was filtered and then the filtrate was lyophilized to give sodium 4H-quinolizin-4one-3-carboxylate (202. mg).

ZR (Nujol) :1660 cm1 NZ4R (D 2 0) 6 :6.80 1H, J=8Hz), 7.00-7.30 (mn, 1H), 7.40-7.60 (in, 2H) 8.05 1H, J=8Hz), 8.96 1H, J=8Hz) The following compound was obtained according to a similar manner to that of Example 6 N- IS- (lH-Tetrazolyl) 1-4H-'quinolizin-4-one-3- -62 carboxamide sodium salt.

ZR (Nujol) 1670 cm- WMR (D 0-DMSO-d 6 :6.80 1H, J-8Fz), 7.20-7.40 (in, 1H), 7.40-7.60 (mn, 2B), 8.10 1H, J-8Hz) 8.88 l1H, JinSEz)

"I

*%3 L3Stiq4/ -63- Example 7 The following compounds were obtained according to a similar manner to that of Example 1.

1- (1-Naphthyl) -4H-quinolizin-4-one-3carboxylic acid.

mp, >2706C ZR (Nujol) 1730, 1720, 1610, 770 cm' NMR (CF COOH, 6) :7.10-8.37 (10H, in), 8.82 (1H, s) 9.62 (il, m) Anal. Calcd for C 20

H

13

NO

3 *1/2H 2 O0 C; 74.07, H; 4.35, N; 4.32 Found C; 74.12, H; 4.13, N; 4.22 1 (4-Biphenylyl) -Hqioizn4-n-3 carboxylic acid.

mp :261-2631C ZR (Nujol) :3100, 1720, 1660, 1610, 1580, 1290, 890, 775 cm 1 NMR (CF 3 COOH, 6) :7.20-8.47 (12H1, in), 8.70 (11, 9.53 (iN, in) Anal. Calcd for C 22

H

15 N 3 1/4H 2 0: C; 76.40, H; 4.52, N; 4.05 C 0aFound C; 76.41, H; 4.57, N; 3.93 64 1-Phenoxy- 4H-quinoli zin-4-ore- 3-carboxylic acid.

mp 224-2260C ZR (Nujol) 3100, 2650, 1725, 1640, 1620, 1580, 1210, 910 cm 1 N31R (CF 3 COOK, 6) 7.20-7.37 (2H, 7.43-7.73 (3H, 8.78 (1H, 8.27 (111, d, J-7.5Hz) 8.60 (lR, t, J-7.5Hz), 9.05 (IS, d, 9.63 (IS, d, Anal. Calcd for C 16

E

11 NO0 4 C; 68.33, H; 3.94, N; 4.98 Found C; 68.45, H; 3.96, N; 4.96 1-(3-Tolyl)-4H-quinolizin-4-one-3-carboxylic acid.

t ttt: mp 176-178*C IR (Nujol) 3130, 1740, 1620, 1590, 1220, tttt -1 t t L 770, 705 cm NMR (CF 3 COOH, 6) 2.52 (3H, 7.17-7.67 (4H, 120 7.90-8.50 (3H, 8.70 (iN, a), tirt 9.58 (1H, m) Anal. Calcd for C 17

H

1 H3 3 C; 73.11, H; 4.69, N; 5.02 vt Found C; 73.11, H; 4.85, N; 5.13 1- (4-Chiorophenyl) -4H-quinolizin-4-one-3carboxylic dcid- Ite mp 269-2710C ZR (Nujol) 3140, 1740, 1620, 1490, 1320, 1290, ,NMR (CF COOH, 6) 7.35-7.78 (4H, 7.92-8.47 (3K, 8..73 (1H, 9.62 (1H, m) Anal. Calcd for C 1

H

1 C1N0 i C; 64.12, H; 3.36, N; 4.67 Found C; 63.95, H; 3.33, N; 4.58 iN 65 1- (2-Tolyl) -4H-quinolizin-4-one-3-carboxylic acid.

mp 168-170*C IR (Nujol) 3400, 1720, 1610, 1290, 1070, 780 cm 1 NMR (CF3COOB, 6) 2.17 (3H, 7.25-7.75 (4H, 7.98-8.63 (3E, 8.80 (Il, s), 9.72 m) Anal. Calcd for C 17

H

13

NO

3 C; 73.11, H; 4.69, N; 5.02 Found C; 72.95, H; 4.91, N; 5.01 1- (3-Methoxyphenyl) -4H-quinolizin-4-one-3carboxylic acid.

mp 222-2246C IR (Nujol) 3100, 1725, 1600, 1490, 1220, 1030, 780 cm 1 NMR (CF 3 COOH, 6) 4.10 (3H, 7.15-8.62 8.77 (1H, 9.62 (lE, 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 1-Hydroxy-4H-quinolizin-4-one-3-carboxylic acid.

cm-i IR (Nujol) 3200, 3100, 1690, 1620 cm NMR (CF COOH,, 6) 8.00-9.50 (5H, m), Anal. Calcd for C 10 H N0 4 C; 58.54, H; 3.44, N; 6.83 e 30 Found C; 57.93, H; 3.56, N; 6.77 Example 8 The following compounds were obtained according to a similar manner to that of Example 2.

-66- N-(5-(1H-Tetrazolyl)J-(1-naphthyl)-4Hquinolizin-4-one-3-carboxamide.

mp 270*C ZR (Nujol) 3280, 1665, 1640, 1620, 1290, 780, 770 cm77 NMR (CF 3 COOHi 6) 7.27-8.25 (10H, 8.77 (11, S) 9.68 (1H, M) Anal. Calcd for C 21 H 4

N

6 0 2 C; 65.96, H; 3.69, N; 21.98 Found C; 60.51, H; 3.75, N; 21.91 N-[5-(1H-Tetrazoyl) ]-1-(4-biphenylyl)-4Hquinolizin-4-one-3-carboxamide.

mp 270C ZR (Nujol) 3180, 1670, 1625, 1590, 1100, 1035, r tjl5 780, 730 cm 1 Anal. Calcd for C 3

H

1 6

N

6 0 2 C; 67.64, H; 3.95, N; 20.58 Found C; 68.04, H; 4.31, N; 20.39 ''It N- (5-(1H-Tetrazolyl)I -1-phenoxy-4H-quinolizin- 4-ore-3-carboxamide.

mp 270*C ZR (Nujol) 3200, 3150, 1660, 1620, 1590, 1010, -1 780, 750 cm NMR (CF COOH, 6) 7.08-7.67 (5H, 7.97 (11, m), I I 4 1 4 4 4 I r 67 8.22-8.47 (2H, 8.70 (Il, 9.67 (1H, m) Anal. Calcd for C 1 7

H

12

N

6 0 3 C; 58.62, H; 3.47, N; 24.13 Found C; 59.39, H; 3.54, N; 24.06 N-[5-(1H-Tetrazolyl) ]-1-(3-tolyl)-4Hquinolizin-4-one-3-carboxamide.

mp 2700C IR (Nujol) 3160, 1670, 1640, 1620, 1600, 1585 cm 1 NU4R (CF 3 COOH, 6) 2.52 (2H, 7.17-7.62 4H), 7.70-8.40 (3H, 8.73 (1H, s) 9.63 (1H, m) Anal. Calcd for C 1 8

H

1 4

N

6 0 2 C; 62.42, H; 4.07, N; 24.26 i1 Found C; 63.03, H; 4.16, N; 24.56 N-S- (1H-Tetrazolyl) ]-1-(4-chlorophenyl)-4Hquinolizin-4-one-3-carboxamide.

mp 270*C IR (Nujol) 3220, 1675, 1640, 1600, 1480, 1290, 1040, 770 cm Anal. Calcd for C 17 H 1 C1N 6 0 2 C; 55.67, H; 3.02, N; 22.91 Found C; 57.45, H; 3.26, N; 21.47 N- (2-Pyridyl) -1-phenyl-4H-quinolizin-4-one- 3-carboxamide.

mp 227-2290C IR (Nujol) 1680, 1620, 1550, 1480, 1300, 780, i 3.0J 770 cm NMR (CF 3 COOH, 6) 7.35-8.18 (1OH, 8.35-8.77 (2H, 9.60 (1H, m) Anal. Calcd for C 21

H

5

N

3 0 2 C; 73.89, H; 4.43, N; 12.31 Found C; 74.17, H; 4.61, N; 12.26

I~

,r 68

C

4r4V 441* 44 44 4* N-C5-(H-Tetrazolyl)-l-hydroxy-4Hquinolizin-4-one-3-carboxamide.

mp 250*C IR (Nujol) 3200 1660, 1620, 1580 Anal. Calcd for C 11

R

8

N

6 0 3 /2H 2 0 C; 46.97, H; 3.22, N; 29.85 Found C; 46,48, H; 3.31, N; 29.57 N- (IB-Tetrazolyl) (3-methoxyphnyl) quinolizin-4-on-3-carboxamide.

mp 2709C IR (Nujol) 3150, 1680, 1640, 1620, 1590, 1490, 1300, 1210, 1030, 790, 780 cm NMR (CF 3 COOH, 6) 4.13 (3H, 7.17-7.52 (3, 7.55-8.15 (2H, 8.18-8.43 (20, i), 8.80 9.67 (1H, m) Anal. Calcd for C 8

H

1 4

N

6 0 3 C; 59.67, H; 3.89, N; 23.19 Found C; 59.81, H; 4.19, N; 23.35 N-(5-(iH-Tetrazolyl)]-1-(2-tolyl)-4H-quinolizin- 4-one-3-carboxamide.

mp 2701C ZR (Nujol) 3200, 3120, 1680, 1620, 1490, 1290p 1030, 780 cmn 1 NMR (CF 3 COOH, 6) 2.15 (3H, 7.25-7.70 (4H, 7.77-8.43 (3H, 8.77 (10, s), 9.77 (10, a) Anal. Calcd for CieH 1 4

N

6 2 C; 62.42, H; 4.07, N; 24.26 Found C; 62.75, H; 4.06, N; 24.35 -69 Example 9 The following compounds were obtained according to a similar manner to that of Examvle 1.

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

mp :155-157 0

C

IR (Nujol) :1720, 1610, 1495, 1425 cm- NMR (DMSO-d 6 6) :0.95 (3H, t, J=5Hz) 1.3-2.0 O4H, mn), 4.20 (2H, t, J=SHz), 7.3-7.7 (5H, in) 7.80 (2H, s) 8.10 (lH, s) 8.80 (1H, s) 14.1 (1H, broad s) l-Allyloxy-4 H-quinol izin--4-one- 3-carboxylic acid.

is 1 mp :140-14 3 0

C

t4AIR (Nujol) 3100, 1730, 1720, 1610, 1580, 1420, It A ti Vitt NMR (CF 3 CO H, 6S) 4.90-5.13 (2H, mn), 5.35-5.78 (2H, mn), 5. 90-6 .57 (1H, mn), 7. 97 8. 67 (3H, m) 8.77-9.03 (1H, m) 9.39-9.67 (1H, m) q~t 1(3) 1- (N-Methylanilino) -4H-quinolizin-4-one-3tilt carboxylic acid.

At mp :185*C (dec.) t t 25 IR (Nujol) :1720, 1700 1620 cm 1 NMR (CF 3 COOH, 6) :3.58 (3H, 6.60-7.50 mn), 7.80-8.60 (3H, in), 8.64 (1H, s) (1H, d# J=7Hz) Anal. Calcd for C 1 7

H

1 4 N 0 69.38; H, 4.79; N, 9.52 Found,: C, 69.03; H, 4.76; N, 9.31 1-Benzyl-4H-quinolizin-4-one-3-carboxylic acid.

/1'mp :221-223*C IR (Nujol) :3380, 1720, 1620, 1410, 1320, 1070, 1020, 780 cm- Anal. Calcd for C 1 7 H 1 3 N0 3 C, 73.11; H, 4.69; N, 5.02 Found C, 73,72; H, 4.92; N, 5.04 l-Phenylthio-4H-quinolizin-4-one-3-carboxylic acid.

mp 195-1970C IR (Nujol) 3350, 1720, 1620, 1400, 1285, 1065, 885, 780, 740 cm1 Anal. Caled for C 1 6

H

11 N0 3

S'

C, 64.63; H, 3.73; N, 4.71 Found C, 65.04; H, 3.90; N, 4.73 1-Phenylsulfonyl-4H-quinolizin-4-one-3-carboxylic acid.

mp >250 0

C

IR (Nujol) 1730, 1640, 1620, 1580, 1160, -1.

1140 cm1 NZ4R (DMSO-d 6) 7.30-8.50 (7H, 8.60 (1H, d, J=8Hz), 9.00 (1H, 9.50 (1H, d, J=8Hz) Anal. Calcd for C 16

H

11 N0 5 S' C, 58.35; H, 3.37 Found C, 58.62; H, 3.31 Example so2S To a solution of 3-ethoxycarbonyl-l-benzoyl-4Hquinolizin-4-one (2.14 g) in chloroform (65 ml) was added dropwise trimethylsilyliodide (1.04 ml) at OOC.

0* After stirring for 30 minutes at 0 0 C, trimethylsilyliodide (1.04 ml) was added. After stirring for S 30 1 hour at room temperature, trimethylsilyliodide (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 a 1 71 cold chloroform to give l-benzoyl-4H-quinolizin-4-one- 3-carboxylic acid (1.252 g) as yellow crystals.

IR (Nujol) 1735, 1630, 1610, 1455, 1440, 1370 m-1 NMIR (CDC1 3 6) 6.70-8.30 (9H, 8.42-8.68 (18, d, J=3Hz) Anal. Calcd for C 17 E NO 4 17 11 4 C, 69.62; H, 3.78; N, 4.78 Found C, 62.89; H, 3.54; N, 3.70 Mass m/e 293 (M Example 11 The following compounds were obtained according to a similar manner to that of Example 2.

7-(n-Butoxy)-l-phenyl-N- 5- (lH-tetrazolyl) ]-48quinollzin-4-one-3-carboxamide.

mp >205 0 C (dec.) -1 IR (Nujol) 1670, 1635, 1580, 1370 cm NMR (DMSO-d 6 6) 1.00 (3H, t, J=5.6Hz), 1.02-2.10 (48, m) 4.18 (2H, t, J=6Hz), 4. t6.80-7.25 (2H, 7.30-7.65 (38, m), 14 7.68-8.00 (2H, m) 8.20 (18, s) 8.87 (18, broad s) N-[5-(1H-Tetrazolyl)]-l-phenylthio-4H-quinolizin- 4-one-3-carboxamide.

SV mp >2700C IR (Nujol) 3180, 1660, 1640, 1620, 1285, 1035, -1 7800 730 cm Anal. Calcd for C 17

H

12 N60 2

S

C, 56.04; H, 3.32; N, 23.06 Found C, 56.61; H, 3.53; N, 23.48 1-(N-Methylanilino)-N-(5-(1H-tetrazolyl)]-4H- -72 cuinolizin-4 -one- 3-carboxami=de.

mp >230 0

C

IR (Nujol) -3200, 1660, 1640, 1620, 1290, 1030 cm1 (CF 3 COOH, 6) 3.74 (3H, s) 6.80-7.60 mn), 7.62-8.08 (1H, mn), 8.15-8.40 (2H, m) 8.85 (1H, 9.65 (1H, d, J=7Hz) N- E5- (lE-Tetrazolyl) -1-allyloxy-4H-quinolizin-4one-3-carboxamide.

mp >270 0 C (dec.) IR (Nujol) :3200, 1660, 1620, 1580, 1500, 1220, 1100, 1040, 1020, 955, 770 cm 1 NMR (CF 3 COOH, 6) 4.90-5.17 (2H, mn), 5.37-5.80 q 15 (2H, mn), 5.90-6.55 (1H, mn), 8.93-9.02 (4H, m) 9.50-9.73 (1E, m) Anal. Calcd for C 14

H

12 N 6 0 3 C, 53.85; H, 3.87; N, 26.91 Found C, 54.20; H, 3.81; N, 26.93 N- (5-(1H-Tetrazolyl) I]-1-benzyl-4H-quinolizin-4v I gv I tone-3-carboxanide.

mp :>2700C.

IR (Nujol) :3140, 1660, 1620, 1595, 1490, 1295, COO, 251040f 1005, 775, 720, 690 cm' Anal. Calcd for Cie H 14

N

6 0 2 C, 62.42; H, 4.07; N, 24.26 $Found 62.88; H, 4.54; N, 24.52 N- (1H-Tetrazolyl) ]-1-phenylsulfonyl-4H-quinoli zin- 4-one-3-carboxamide.

mp :>250*C IR (Nujol) :1680, 1640, 1620, 1590 cmn Anal. Calcd for C 7

H

12 N 0 S C, 51.51; H, 3.05; N, 21.20 Found 51.71; H, 2.93; N, 21.83 Z4, ll -73 1-Benzoyl-N- (IH-tetrazolyl) )-4H-quinolizin- 4-one-3-carboxamide.

znp :>250*C ZR (Nujol) 1690, 1630, 1380, 1240, 1120 cm NMR (CF 3 COOH, 8) 7.40-8.25 (5H, mn), 8.22-8.51 (1E, in), 8.70 (1H, broad s) 8.93 (1H, 9.12 (1H, d, J=9Hz), 9.73 (lB, d, J=7Hz) Anal Calcd for C 1 8

H

1 2 N 6 0 3 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 according IS to a similar manner to that of Example 6- l-Benzoyl-N- (1H-tetrazolyl) ]-4H-quinolizi-n-4- One-3-carboxamide sodium salt.

mnp :248-250*C (dec.) ZR (Nujol) 1670, 1610, 1550, 1480, 1450 cm- 1 N- Oja-Tetrazolyl) I]-1-phenyl-4H-quinolizin-4one-3-carboxaxnide sodium salt.

mp :>250*C 215IR (Nujol) :3150 (broad), 1660 1650, 1640, 1620 cm 1 NNR (DMSO-d 6 a) :7.40-8.00 (9H, in), 8.50 (1H, s) 9.30-9.60 (l1H, m) N- (1H-Tetrazolyl) I]-1-phenoxy-4H-quinlizin-4one-3-carboxamnide sodium salt.

mp >2500C ZR (Nujol) :1660 cm'1 NMR (DMISO-d 6 ,8 6.9-7.8 (6H, mn), 8.01 (2H, d, 3=4kz) 8'.32 (1H, s) 9.42 (1Hi, d, J=7Hz) 12.30 (1H, 9) kNTOil -74- Anal. Calcd for C 1 7 H 1 1 N 6 NaO 3 Foud 55:14; H, 2.99; N, 22.70 Found C, 5.78;H, 3.63; 11, 20.44 c It 0A,1 0IV'O Example 13 The following compound was obtained according to a similar manner to that of Example 1.

l-Benzoyl- 7-n-buitoxy-4H-quinoliziri-4-ofle-3carboxylic acid rnp 155-156 0

C

IR (Nujol) :1720, 1620, 1580, 1495 cm 1 NMR (CDC1 3 1 6) :1.03 (3H, t, J=6Hz), 1.30-2.17 (4H, mn), 4.23 (2H, t, J=6Hz), 7.17-7.93 (6H, in), 8.70 (1H, 8.88 (1H, d, J=lO~z), 9.02 (1H, d, J=2Hz), 13.60 (1H, broad s) Example 14 The following compounds were obtained according to a similar manner to that of Examle-2.

1-Benzoyl- 7-n-butoxy-N- (1H- tetra zol- 5-yl) -4Hquinoli zin-4 -one- 3-carboxarnide mp :227*C IR (Nujol) 1680, 1660, 1625, 1585, 1550, 1495 cm- NMR (DMSO-d, 6) :1.2-2.0 (4H, mn), 4.23 (2H, t, J=GHz) 7.08 (2H. broad s) 7.37-8.17 (6H, m) 8.43 (1H, 8.75 (1H, d, J=lOHz), 7'25 8.93 (1H, d, J-2Hz) N- (4H-5-Ainno-l,2,4-triazol-3-yl) -7-n-butoxy-lphenyl-4H-quinolizin-4-one-3-carboxaiide mp :220 0

C

IR (Nujol) :1690, 1650, 1490, 1465, 1450 cm'- NMR (DMSO-d 6 ,6 0.80-1.10 (3H, 1.30-2.10 (4H, in), 4.18 (2H, t) 7. 03 (1H, s), 7.40-7.65 (5H, mn), 7.70 (lH, d, J=7Hz) 7.83 (1H, d, J=7Hz), 8.26 (1H, s) 8.87 (1H, s) Mass: r/e 387 (M4+)

NT

0 -76 1-Ethoxycarbonyl-N- (1H-tetrazol-5-yl) -4Hquinoli zin- 4-one-3 -cazboxamL-ide mp >250 0

C

IR (Nujol) 1665, 1640, 1610, 1595, 1580 cm- Mass: mn/e 328 (Mi) Example The following compounds were obtained according to a siM.iar manner to that of Example 6-M1.

l-Benzoyl-7-n-butoxy-N- (1H-tetrazol-5-yl) -4Hquinolizin-4-one-3-carboxamide sodium salt mp :200-203*C NMR (DMSO-d 6 I :0.98 (3H1, t, J-6Hz), 1.20-2.0 (4H, in), 4.25 (2H1, t, J=6Hz) 7.32-8.17 (6H1, mn), 8.57 (1H1, 8.75 (1H, d, J=lOHz) 9.02 (1H, d, J=-2Hz) 11.87 (1H1, broad s) 7-n-Butoxy-l-phenyl-N- (lH-tetrazol-5-yl) -4H1quinoli zin-4 -one- 3-carboxanide sodium salt IR (Nujol) 1680, 1640, 1620, 1585 cm' NMR (DMSO-d 6 ,6 0.80-1.20 (3H, in), 1.30-2.10 (4H, in), 4.00-4.48 (2H, mn), 7.43-7.68 in), 7.70-7.90 (211, mn), 8.40 (1H, s), 9. 00 (1H, d, J=2Hz) Examle 16 To a solution of 1, 3-diethoxycarbonyl-4Hquinolizin-4-one (1 g) in chloroform (20 ml) was added trimethylsilyl iodide (0.49 ml) at room temperature and the mixture was stirred for 4 hours and heated with 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 hr 77 is washed with isopropyl alcohol to give 1-ethoxycarbonyl- 4H-quinolizin-4 -one- 3-carboxylic acid (794 mg).

mp :189 0

C

IR (Nujol) 1735, 1710, 1635, 1620 cm- NI'S (DMSO-d 6 6) 1.34 M3, t, J=7Hz), 4.33 (2H, q, J=7Hz) 7.45-7.95 (1H, in), 8. 00-8. (1H, in), 8.90 (1H, 9.05-9.60 (2H, mn), mass W/e 261 Anal. Calcd. for C 13

H

11 NO C, 59.77; H, 4.24; N, 5.36 Found C, 59.12; H, 4.59; N, 5.33 Example 17 To a solution of 1,3-diethoxycarbonyl-4H-quinolizin- 4-one (896 mng) in methanol (9 ml) was added 6N aqueous sodium hydroxide (2.58 ml) at room temperature and themixtuxe was heated with reflux for an hour. After cooling to 0 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 4Hquinolizin-4-one-1,3-dicarboxylic acid (202 mg) mp >2500C IR (Nujol) 1675, 1655, 1635 cm NMR (D 2 0, NaOD, 6) :7.30-8.10 8.65 (1H1, s) 8.70-9.00 (1Hi, in), 9.30 (1H, d, J-7Hz) Example_18 To a solution of l-ethoxycarbonyl-N-(lH-tetrazol- 5-yl) 4H-quinoli zin-4 -one- 3-carboxanide (500 mng) in N,N-dimethylformamide (5 ml) was added 1N aqueous sodium hydroxide (6 ml) at room temperature and the mixture was heated at 1000C for an hour. After cooling to 0 0

C,

the mixture was acidified to pH 2 with 6N hydrochloric acid and the precipitate was filtered and washed with 78 water to give 1-carboxy-N-(1H-tetrazol-5-yl)-4Hquinolizin-4-one-3-carboxamide (280 mg).

mp >250 0

C

IR (Nujol) 1670, 1640, 1615, 1590 cm 1 NMR (D 2 0-NaOD, 6) 7.24-7.60 (1H, m), 7.60-8.07 (1H, 8.68-9.05 (1H, m), 8.84 (1H, 9.30 (1H, d, J=8Hz) Mass m/e 272 Anal. Calcd. for C 2H8 N604H2 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) was added N,N'-carbonyldiimidazole (934 mg) at room temperature and the mixture was heated at 60°C for minutes. To the mixture was added 2,2-dimethyl-1,3dioxane-4,6-dione(830 mg) at 60 0 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 and washed with water. The chloroform layer was extracted with aqueous sodium hydrogen carbonate and the aqueous layer was washed with chloroform j "F5 and acidified to pH 2 with 6N hydrochloric acid at 0OC and extracted with chloroform. ThI chloroform layer was washed with brine, dried over magnesium sulfate, and evaporated to give 2-hydroxy-4H-quinolizin-4-one-3carboxylic acid (220 mg).

30 mp 194-195°C SIR (Nujol) 1690, 1605, 1370, 1300 cm-1 NMR (DMSO-d 6 6) 6.75 (1H, 7.15-7.45 (1H, m), 7.76 (2H, 8.90 (1H, d, J=6Hz) Mass m/e 205 Anal.Calcd. for C 10

H

7

NO

4 C, 58,54; H, 3.44; N, 6.83 Found C; 58.49; H, 3.17; N, 6.86

Claims (6)

1. A compound of the formula: a 9feA4fe~ 9 15 a CAfe, cc Ac C 9

9. a tefefe 1. cccc wherein Rl is carboxy; qJK CONH R0wherein R 10 is hydrogen; pyridyl; pyrimidinyl; pyrimidinyl substituted with lower alkyl; pyrazinyl; phenyl; phenyl substituted with hydroxy; thiazolyl; triazinyl; triazolyl; triazolyl substituted witiz amino; pyridazinyl; pyridazinyl substituted with halogen; or tetrazolyl; cyano, thiocarbamoyl, or tetrazolyl; Ris hydrogen or aryl; R 2 is hydrogen, hydroxy, lower alkyl or lower alkoxy; and R 3 is hydrogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkenyloxy; aryl optionally substituted with halogen, lower alkyl or lower alkoxy; arylthio, aroyl, ar( lower)alkyl, arenesulfonyl, N-lower alkylanilino or aryloxy; and pharmaceutically acceptable salts thereof. Poo*c 690A *991. c*c9 a ce Ic c C 2. A compound of claim 1, wherein Rl is carboxy, carbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrimidinylcarbamoyl substituted with lower alkyl, pyrazinylcarbamoyl, phenylcarbamoyl, phenylcarbamoyl substituted with hydroxy, thiazolylcarbamoyl, triazinylcarbamoyl, triazolylcarbamoyl, triazolylcarbamoyl substituted with amino, 900403 *DAUSPE .001, dbtuj ±ispec, 79 1 pyridazinylcarbamoyl, pyridazinyicarbamoyl substituted with halogen, tetrazolylcarbamoyl, c "ano, tb,' zarbamoyl or tetrazolyl group, R 7 is hydrogen or phenyl, Ris hydrogen, hydroxy, lower alkyl, lower alkoxy, and Ris hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkenyloxy, phenyl, naphthyl, biphenyl, phenyl substituted with lower alkyl, phenyl substituted with halogen, phenyl substituted with lower a2.koxy, phenylthio, benzolyl, phenyl( lower)alkyl, benzenesulfonyl, N-lower alkylanilino, or phenoxy. 3. A compound of claim. 2, wherein R is carboxy, carbamoyl, pyrid-2-ylcarbamoyl, 4,6-dimethylpyrimidin-2-ylcarbamoyl# pyrazinyl- carbamoyl, phenylcarbanoyl, pyrimidin-2- ylcarbamoyl, 2-hydroxyphenylcarbamoyl, 4H-1, 2,4- triazol-3-ylcarbamoyl, 4H-5-aimino-l,2,4- *triazol-3-ylcarbamoyl, .l1H- tetra zo1- 5-yl- carbamoyl, *toothiazol-2-ylcarbanoyll l,2,4-triazin-6- ylcarbamoyl, pyrazinylcarbamoyl, 3-chioropyridazin- 6-ylcarbamoyl# cyano, thiocarbamoyl or tetrazolyl group# Ris hydrogen, hydroxy, methyl, ethyl or rnethoxy, R. 30 is hydrogen, hydroxy, methyl, methoxy, isopropoxy, n-butoxy, ethoxycarbonyl, carboxy, allyloxy, phenyl, naphthyl, biphenylyl, 3-niethyiphenyl, phenoxy, 4-chlorophenyl, 2-methylphenyl, 3-methoxyphenyl, benzyl, phenylthio# benzoyl, benzenesulfonyl or N-methylanilino. BA4 NT90o4o3,DABSPE.oo1.dtujL.upuc.80 F N- 81 4. A compound of claim, 3, which is N- (lH-tetrazolyl) I-4H-quinolizin-4-one-3- carboxamide or its sodiuni salt. 5. A compound of claim 3, which is N- [5-(lH-tetrazolyl) p henyl- 4H-quinol izin- 4- one-3-carboxamride or its sodium salt. 6. A compound of claim 3, which is (1H-tetrazolyl) I-l-phenoxy-4H-quinolizin-4- one-3-carboxaiide or its sodium salt. 7. A compound of claim 3, which is N- (lH-tetrazolyl)]I-l-benzoyl-4H- quinolizin-4-one-3-carboxamide .or its sodium salt. S. A process for preparing a compound of- the formula_- 2 7 3 0() wherein Rl is carboxy; CONH ROwherein P.10 is hydrogen; pyridyl; pyrimidinyl; pyrimidinyl substituted with lower alkyl; pyrazinyl; phenyl; phenyl substituted with hydroxy; thiazolyl; triazinyl; triazolyl; triazolyl substituted with amino; pyridazinyl; pyridazinyl substituted with halogen; or tetrazolyl; cyano, thiocarbamoyl, or tetrazolyl; R 7 is hydrogen or aryl; R 2 is hydrogen, hydroxy, lower alkyl or lower alkoxy; and Ris hydrogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkenyloxy; aryl optionally substituted with halogen, lower alkyl or lower alkoxy; aryithia, aroyl, ar( lower)alkyl, arenesulfonyl, N-lower. alkylenilino or aryloxy; kjH 1 82 arylthio, aroyl, ar(lower)alkyl, arenesulfonyl, N-lower alkylanilino or aryloxy; or a salt thereof which comprises subjecting a compound of the formula -2 R R 3 C ct wherein R R 2 and R 3 are each as defined above, and R 4 is protected carboxy, or a salt thereof, to elimination reaction of the carboxy protective group, to give a compound of the formula 7 2 3 wherein R R and R are each as defined above, or a salt thereof; or reacting a compound of the formula:' R2 7 3 COOH 0 wherein R 7 R 2 and R 3 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof, with H 2 N-R 10 wherein R 10 is as defined above, to give a compound of the formula: i u 4 7. 83 7 3 R R CONHR 1 0 wherein R 7 R 10 R 2 and R3 are each as defined above, or a salt thereof; or subjecting a compound of the formula 2 7 R CONH 2 wherein R, R 2 and R 3 are each as defined above, or a salt thereof, to dehydration reaction, to give a compound of the formula R 2 R 7 R 3 R CRN wherein R R and R are each as defined above, or a salt thereof; or reacting a compound of the formula C a n~ -rl- i u a I LI~II~ V ilX- j" I II 84 wherein R 7 F 2 and or a salt thereof, to give a compound t 7 'C N P3 are each as defined above, with hydrogen sulfide, of the formula R 3 -NH 2 R 3 are each as defined above, or ff Sfr ^F c wherein R R and or a salt thereof; SI subjecting a compound of the formula R2 R 7 R 3 RC wherein R 7 R 2 and R 3 are each as defined above,or a salt thereof, to the formation reaction of a tetrazole group, using a combination of alkali methal azide and ammonium halide, to give a compound of the formula 2 7 R 3 N NN i ":I r -Ill~- i 1111~- :1 85 7 2 3 wherein R R and R. are each as defined above, or a salt thereof, or subjecting a compound of the formula 2 R 7 3 a 1 1 wherein R R 2 and R 7 are each as defined above, and R 3 is lower alkoxycarbonyl, or a a salt thereof, to elimination reaction of lower alkyl, to give a compound of the formula 15 2 R 7 COOH 1 2 7 wherein R R and R are each as defined above, or a salt thereof. 9. A, pharmaceutical composition comprising an effective amount of a compound of claim 1 or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. F- al wt. 86 A method for the treatment of allergic and ulcer diseases which comprises administering to human beings and animals in need of such treatment a therapeutically effective amount of a compound of Claim 1.

11. A compound of Claim 1 substantially as hereinbefore described with reference to any one of the Examples.

12. A process for preparing a compound of Claim 1 substantially as hereinbefore described with reference to any one of the Examples.

13. A pharmaceutical composition containing a compound of Claim 1 substantially as hereinbefore described with reference to any one of the Examples. rr tt. t t S l DATED this day of 2nd April, 1990 FUJISAWA PHARMACEUTICAL CO., LTD By Its Patent Attorneys DAVIES COLLISON I tr 6

900402.DADSP.001,dbfuji. upc.86 i: