CA1074798A

CA1074798A - Vinyl derivatives and process for preparing them

Info

Publication number: CA1074798A
Application number: CA218,932A
Authority: CA
Inventors: Shinsaku Minami; Shinichi Nakamura; Yoshiyuki Takase; Masanao Shimizu; Minoru Sugita; Jun-Ichi Matsumoto
Original assignee: Dainippon Pharmaceutical Co Ltd
Current assignee: Sumitomo Pharma Co Ltd
Priority date: 1974-01-04
Filing date: 1975-01-29
Publication date: 1980-04-01

Abstract

ABSTRACT

Piperazine derivatives of the formula

Description

g~

This invention relates to new and useful vinyl derivatives having antibacterial activities, a process for preparing them, and also to their use.
In the course of our studies on antibacterial agents of the 1,4-dillydro_4_o~o_1,8_naphthyridine (or 1,4-dihydro-4-oxo quinoline)-3-carboxylic acid type, ~e found that compounds resulting from the introduction of a vinyl group into the l-position of 1,8-naphthyridine nucleus (or quinoline nucleus) and a l-piperazinyl group or 4-allcyl-1-piperazinyl group into its 7-position are useful as antibacterial agen~s, especially against Pseudomonas aeruginosa.
l~ This invention provides compounds of the following formula ,COOH (I) C~C~12 ,.

wherein A is a ~CH-group or nitrogen atom, and Rl is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and salts thereof.
Compounds of the above formula in which Rl is a hydrogen atom, metlyl group or ethyl groupj and their salts are especially preferred.
Especially suitable compounds are: 1,4-dihydro-7-(1-piperazinyl)-4-o~o-1-vinyl-1,8-naphthyridine-3-carboxylic acid, 1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-1-vinylquinoline-3-carboxylic acid, and 1,4-dihydro-7-(4-ethyl-1-piperazinyl)-4-oxo-1-villylquinoline-3-carboxylic acid, and ~O phar~aceutically acceptable acid addition salts, preferably hydrochloride and methanesulfonate.

The compounds of formula (I) are synthesized by: (i~ reacting a compound of fo~mlla (a) ~ (a) Y Z

.

7~18 wherein X is a halogen atom, R3 is hydrogen or an alkyl group o-f 1 to 6 carbon atoms and Y and Z are different from each other and one of Y and Z
represents a hydrogen atom ~hile the other represents a halogen atom, a lower alkoxy group, a benzyloxy group, an alcoholic hydroxy group, an acyloxy group, an arylsulfonylo~y group, a lower alkylsulfonyloxy group~ an S-aryldithio-oarbonyloxy group, a lo~er s-alkyldithiocarbonyloxy group, a lower dialkyl-amino group, a cyclic amino group or a group that can form a tertiary amine N-oxide or a quaternary ammonium salt or a quaternary ammonium hydroxide by bonding to the -CH-CH2 or CH-CH2 moiety of the 1,H-CH2 group, with a compound Y Z Y Z
10 ot` ~ellcral formula (b) Rl - N~ H (b) wherein Rl is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an acyl group, to fo~l a compound of the general formula I-A
O ~:

Rl - N N COOR3 I-A
IH-lcH2 Y Z

and subjecting the compound of formula I-A to heat to elimina~e Y and Z and, if Rl is acyl or R3 is alkyl subjecting the product to hydrolysis to convert R' or R to ~ydrogen; (ii) heating a compound of fo R' /--~N /
1 \ I

Y Z
wherein ~ and R3, Y and Z are as defined above except that when A is nitro-~ 3 75~

gen and Ri is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms neither Y nor Z is halogen to eliminate Y and Z and, if Rl is acyl or R3 is alkyl subjecting the product to hydrolysis to replace Rl or R3 by hydro-gen, (iii) hydrolysing a compound of formula _ N N ~ COOR3 C}~CH2 ~herein A and R3 are as defined above and Rl is an alkyl group having 1 to 6 carbon atoms or an acyl group other than an acetyl group, provided that t~hen ~ is a nitrogen atom Rl is an acyl group other than an acetyl group;
~iv) reacting a compound of formula tO ~ ~~3 wherein X and R3 are as defined above, with a compound of formula Rl" - N\__~H

~hcrein Rl" is an alkyl group of 1 to 6 carbon atoms and, if R3 is other than a hydrogen atom, hydrolysing the product to obtain a compound of formula I in which Rl is alkyl of 1 to 6 carbon atoms.
If required the products of formula I can be converted into pharmaceutically acceptable salts.
Specific examples of the acyl group represented by Rl are acid residues generally used as a protective group, such as formyl, acetyl, trifluoroacetyl, benzoyl, benzyloxycarbonyl, ethoxycarbonyl, or tert.-~ _ 4 _ 7~l~

butoxycarbonyl.
The deriva~ives of the alcoholic hydroxy groups as Y and Z include, for examRle, acyloxy groups such as acetyloxy or ethoxycarbonyloxy; aryl-sulfonyloxy groups such as tosyloxy or benzenesulfonyloxy, or lower alkyl-sulfonylo.Yy groups such as methanesulfo~yloxy or ethanesulfonyloxy; or S-aryldithiocarbonyloxy groups such as S-tolyldithiocarbonyloxy or . ~ j - 4a -~7~7~
S-phenyldithiocarbonyloxy~ or lower S-alkyldithiocarbonyloxy such as S--metllyldithiocarbonyloxy or S-ethyldithiocarbonyloxy groups.
Specific examples of ~leaving amino group" as Y and Z are -N(CH3)2,-N(C~H5)2, - N ~ (CH3)3I , - ~ (C2H5)3O ~ , and -~(CH3)2 Pre~erred groups represented by -CH-CH2 are those in which Y is a hydrogen atom, and Z is a halogen atom ~especially, a chlorine or bromine atom), arylsulfonyloxy group, lower alkylsulfonyloxy group or "leaving amino group`' .
This reaction is performed by reacting the compounds (a) with (b), if desired, in a solvent. Preferably, the reaction is carried out in the presence of a base, as a dehydrohalogenating agent, such as sodium bicarbonate, sodium carbonate, potassium carbonate or triethylamine. The compounds ~a) and ~b) are used in stoichiometric c~nounts. However, generally, the compound (b) is used in excess, and may be made serve also as the dehydrohalogenating agent. The compound (b) may be used in the form of hydrate or acid addition salt o~, for example, hydrochloric acid.
The reaction temperature is about 20 to 270C., preferably about 50 to 200C., especially preferably about 70 to 130C.
The solvent used in this reaction should be selected depending upon the properties of the starting materials to be used. Examples of the solvent are alcohols such as ethanol or propanol, aromatic hydrocarbons such as ben-zene or toluene, halogenoalkanes such as dichloroethane or chloroform, ethers such as tetrahydrofuran, dioxane or diphenyl ether, acetonitrile, dimethyl sul-foxide, dimethylformamide, and water. They may be used either alone or in a~l~ixture.
Wl~en Rl' of the compound [I-~ obtained by this reaction is an acyl group or when R3 of this con~ound is an alkyl group having 1 to ~ carbon atoms, the compound, with or withou~ isolation and purification, is subjected to a hydrolysis reaction by an usual method to form a compound[~ in which Rl or R3 is a hydrogen atom. When R2 f the compound ~-~ is a group represented by -~H-ÇH2 the compound, with or without isolation and purification, is subjected t~ an elimination reaction by heating it to form a compound ~I~ in which R2 --5~

, ~7~79~3 is a vinyl group.
The hydrolysis reaction is carried out by contacting the compound LI-~ (Rl' = acyl group or R3 = alkyl group) with water. Generally, the reaction is carried out in ~he presenee o~ a catalyst such as an acid or base in order to promote the reaction. Examples of the acid are inorganic acids such as hydro~lloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosplloric acid, and organic acids such as acetic acid, oxalic acid or tol-uenesulfonic acid. Examples of the base are alkali metal hydroxides such as sodium hydroxide or barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate9 and sodi~n acetate.
l`his reaction can also be performed by directly hPating the material ln the presence of the above acid, and then adding water. The solvent is usually water, but depending upon the properties of the material, an inert solvent such ~s ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid can also be used together with water. The reaction temperature may be from room temperature to about 200C., preferably 70 to 120C.
The elimination reaction is carried out by simply heating the com-pound ~ R2 = ~ ~ ~~ 2)~ or heating it in the presence of an appropriate catalyst such as an acidic substance, an acid anhydride or a base. Examples o the catalyst are ordinary acids such as hydrochloric acid, sulfuric acid, polyphosphoric acid, phosphoric anhydride, formic acid, acetic acid, toluene-sulfonic acid, or potassium bicarbonate, Lewis acids such as thionyl chloride, phosphorus oxychloride, boron trifluoride or zinc chloride, alkali hydroxides alkali carbonates, metal hydrides such as sodium hydride, alkali metal alkoxldes such as sodium ethoxide, sodium methoxide or potassium tert.-butoxide, pyridine, collidine, benzyltrimethylammonium hydroxide, acetic anhydrida, phthalic anhydride, silver oxide, iodine, and tert.-butyl lithi~n.
The reaction temperature is ~usuaLly about 50 ~o about 270C. The reaction proceeds without a solvent, but preferably, an inert solven* is usedO
Ex~mples of the s~lvent are wate~ alcohols, acetic acid, dimethylformamide, dimethyi sulfoxide, ether, benzene, dioxane, tetrahydrofuran and pyridine.

In this reaction, Rl' and/or R3 of the compound [-A~ may be replaced by a hydrogen atom depending upon the nature of Rl' and/or R3, and the react-ion conditions applied.
The starting compound of the general formula (a) can be obtained as follows: For example, by alkylating a known compound of the general formula ~ ~ COOR3 wherein X, R3 and A are the same as defined above, with CH2Z-CHY--halogen ~Z and Y are the same as defined above ), a starting compound (a) in which R2 is -CH-IH2 group ~z and Y~are the same as defined above) is ob~ained. By sù~jeZcting this compound to a similar elimination reaction to lQ tllo abova, a starting compound (a) in which R2 is a vinyl group can be obtaill~d .
The compounds prepared by the above procedure of the present invent-ion can be isolated and purified by ordinary methods. The compounds rI~ can be obtained in the free state or in the form of a salt depending upon the selection of the starting compounds and the reaction conditions. Furthermore, the compounds rI~ can be converted to their pharmaceutically acceptable acid addition or alkali metal salts by treatment with acids or alkalies. ~ `
Th~ acids may be a variety of organic and inorganic acids, examples of which are hydrochloric acid, acetic acid, lactic acid, succinic acid, oxalic acid and methanesulfonic acid. The alkalies may be potassium and sodium hydroxides and carbonates.
A clinical dosage of the compound LI] depends on the body weight, age and administration route but it is generally in the range of 100 mg - 5 g/day, preferably of 20Q mg -3`g/day.
The compounds ~I~ may be used as medicinss, for example, in the form of pharmaceutical preparations containing the compound in admixture with an organic or inorganic, solid or liquid pharmaceutical adjuvant suitable for peroral~ parsnteral9 enteral or local administration. Pharmaceutically accept-able adjuvants are substances that do not react with the compounds, and in-clude, for example3 water gelatin, lactose, starch~ cellulose, preerably .- . .. . . , ,,........ ., ~, , .

~C~747~38 microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, sor-bitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propy-lene glycol, polyalkylene glycols, methylparaben and other known medicinal adjuvants. The pharmaceutical preparations may be, for example, powder, tab-lets ointments, suppositories, creams or capsules, or in liquid ~orm as solutions, suspensions or emulsions. They may be s~erilized and/or contain ass.istants such as preserving, stabilizing, we~ting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may further con-tain other therapeutically ~aluable substances. The preparations are ~ormed by conventional methods.
The antibacterial activities of the ~ypical compounds of this in-vent.ion are shown in Tables I-III together with some of the known compounds.
In the Tables II and III, the ED50 and LD50 values were calculated in accordance with the Bcherns-Kaerber method. ~Arch. Exp. Path, Pharm., 62, 480 ~193]~ .
The numbers of the tested compounds are those described in the Example.
The known compounds, N~ and compound No. A are as follows:
NA: l-Ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (Nalidixic acid), which is disclos~d in ~nited States Patent No. 3,149,104.
No.A: l-Ethyl-7-dimethylamino 4-oxo-1,8-naphthyridine-3-carboxylic acid, which is disclosed in United States Patent No. 3,149,104.

~747~ill~il 1) In vitro antibacterial activity against 3 strains of bacteria - ~ MIC ~u~7m ~ _ . Escherichia Shigella Pseudomonas coli flexneri aeruginosa No. Compound K-12 ~ .. Tsuchijima 1* ~ ~ ~ ~ 1 3 10 ~ H=CH2 _

2 ~~A-CH2 1 1 3 _ _ ~15~ ~
___ ,-4 H3- ~ ~N ~ L 1 3 lO

5* _ Cl=CI~_ _ __ 1 3 .

D ~l~ ~

COOH I I >

. .~ .... .. . .......... .. ,.... , ... ..
NA O ____________ ~

~ I ~,COUI I 1 3 ~ 100 * Hydrochloride - ,, -, . - ~ . .. .

79~3 The minimum inhibitory concentration (MIC) was determined by the well known serial dilution method.
Experimental conditions:
Mcduum: nutrient broth, pH 7.0 ~5 m~/tube) Inoculum: one drop of 1:105 dilution of an overnight broth culture per tube Incubation temperature and time: 37C, 48 hours -9a-~7~7g~

2) In vivo efficacy against systemic infection with Pseudomonas aeruginosa and Salmonella typhimurium in mice.
Table II
Pseudomonas aeruginoSa**Salmonella typhimurium***

ED50 (mg/kg) ED50 ~mg/kg) Compound ip ~ o 1* 3~9 86.6 19.3 22.9 2 17.8 50 3.4 8.8

3 19.3 66.7 - 11.5

4 38.6 192.0 < 12.5 ~ 50

5* 1.4 135.0 5.5 51.5 _____________________________________________________________ ______ No A > 100 > 200 > 50 > 100 NA > 100 ~ 200 18.9 18.9 *hydrochloride **Experimental conditions:
Organism: Pseudomonas aeruginosa No. 12 Mice: male mice ~ddY-S) weighing 20 g approximately.

Infection: intraperitoneal infection with 50 ~o 100 LD50 ~about 5 x 103 cells/mouse) of a bacterial suspension in 4%

gastric mucin.
Medication: t~ice, about 5 minutes and 6 hours after infec~ion.
Drug: an alkaline solution ~pH 8-9) for intraperitoneal adminstra-tion.
Observation: 7 days.
ip: intraperitoneal administration.
po: oral administration.

***Exper~mental conditions:
Organism Salmonella typhimurium S 9 Mice: male mice ~ddY-S) weighing 20 g approximately Infection: Intraperitoneal infection with 50 to 100 LD50 ~abou~ 105 cells/mouse) of a bacterial suspension in a nutrient broth.

-10- , .. .

~7479~3 Medication: twice a day for 4 days from the day of infection.
Drug: an alkaline solution ~ph 8-9) for intraperitoneal administration and suspension in 0.2% carboxymethyl cellulose for oral administration.
Observation: 14 days.
ip: intraperitoneal administration.
po: oral administration.
3) Acute toxicity in mice Table III
**LDso (mg/kg) Compound Po l* >2000 2 >2000 3 >2000 5* >2000 _____________________.____________________ *hydrochloride **Experimental conditions:
' Mice: female mice ~ddY-S~ weighing 20 g approximately.
Drug: Suspension in 0.2% carboxymethyl cellulose for oral administration.
The follouing Examples further illustrate the present invention.
Example 1 1~4-Dihydro-4-oxo-7-~l-pipera2inyl)-l vinyl-1~8-naphthyridine-3 carboxylic àcid ~ydrochloride. CCompound_l) .
To a solution of 2.5 g of 7-chloro-1,4-dihydro-4-oxo-1-vinyl-1, 8-naphthyridine-3-carboxylic acid in 80 m~ of ethanol was added 5.8 g of piper-azine hexahydrate. The mixture was heated to reflux for 2 hours and concent-rated to dryness under reduced pressure. To the resulting resid~e~ was added lO m~ of lN-HC~. The crystal that separa~ed on cooling was collec~ed and dissolved in 40 ml of hot water. The solution with 0.5 g of charcoal was warmed for several minutes and filtered. The filtrate, aftGr addition of 7~7~8

6 m( of lN-HC-(, was cooled to give 2.7 g of the product as colorless neQdles, m.p. 285-287C. ~decomp.) Example 2 1,4-Dihydro-7-~4-methyl-1-piperazinyl)-4~oxo-1-vinylquinoline-3-carboxylic acid (Compound ?) and its hydrochloride. (Comp~und 10) A mixture containing 5.0 g of 7-chloro-1,4-dihydro-4-oxo-1-vinyl-~uinoline-3-carboxylic acid, 75 m~ of dimethyl sulfoxide and 15 ml of 1-methylpiperazine was heated to 110C for 3 hours with stirring and then con-centrated to dryness under reduced pressure~ The residue was triturated with methanol to give crystals, which were collected and recrys~allized from dime-thylforma~ide--water ~1:1) to afford 2.85 g of the hydrochloride, m.p ~ 300C~
The hydrochloride ~1:5 g~ was dissolved in 200 m~ of hot water and ncutralized with lN-NaOH solution. The crystals that separated on cool-ing were collected and recrystallized from acetonitrile to give 1.2 g~of the compound 2 as slightly hygroscopic pale yellow needles, m.p. 224-225C.
Example 3

7-~4-Ethyl-l-piperazinyl)-1,4-dihydro-4-:oxo-1-vinylquinoline-3-car~ox~lic acid, m~p., 211-213CJ CCompound 3) was prepared in the same manner as in Example 2 using l-ethyl-piperazine in place of l-methylpip~razine.
ExamPle 4 1~4-Dihydro-7-~4-methyl-1-piperazinyl~4-oxo-1-vinyl~1,8-naphthyridine -3-carboxylic acid ~Compound 4).
To a solution of ~1.4 g of 7-chloro-1,4-dihydro-4-oxo-1-vinyl-1>

8-napllthyridine-3-carboxylic acid in 50 m~ of ethanol was added 1.5 g of 1-methylpiperazine. The mixture was heated to reflux for 1.5 hour and concent-rated to dryness under reduced pressure. The resulting solid was was~hed with cold ethanol and recrystallized from ethanol to give 1.2 ~ of the product as pale yellow needles, m. p. 238-239C.
Example 5 1,4-Dihydro-4-oxo-7-~1-piperazinyl)-1-vinylqui.noline-3-carboxylic acid hydrochloride, m.p. 283-287C, ~decomp.) ~Compound 5) was prepared in the same manner as in Example 2 using piperazine in place of l-methylpiperazine.

' , ' ' .

~i~7~791~
Example 6 1,4-Dihydro-4-oxo-7-~l-piper-aziny~ viny~ 8-naphthyridine-3 carboxylic acid hydrochloride ~Compound 1~.
To a solution of 4.0 g ~f ethy. 7-chloro~ 2-chloroethyl)-1,4-~ihydro-4-oxo-1,8-naphthyridine-3-carboxylate in 40 m~ of ethanol was added 6.0 g of l-ethoxycarbonylpipera~ine. The mixture was heated to reflux for 1.5 hour and concentrated to dryness ~mder reduced pressure. To the residue were added 50 m~ of ethanol and 50 m~of 10% XO~I solution, and the mixture was heated again to reflux for 1.5 hour. After removal of the e~hanol by distillation, the resulting aqueous solution was acidified with concentrated hydrochloric acid to give 2.9 g of the product, m.p. 285-287C (decomp.).
r~ lple 7 1,4-Dihydro-7-t4-methyl-1-piperazinyl)-4-oxo-1-vinyl-1,8-naphthy-ridine-3-carboxylic acid ~Compound 4).
To a solution of 2.2 g of ethyl 7-~chloro-1-~2-chloroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate in 30 m~ of e~hanol was added 2.0 g of l-methylpiperazine. The mixture was heated to reflux for 1.5 hours, then concentrated to dryness under reduced pressure and the residue was ex-tracted with chloroform. The extract NaS dried over anhydrous sodium sulfa~e ~md the chloroform was evaporated to leave 3.3 g of crude crystals~ which were dissolved in a mixture of 30 m~ of 10% NaOH and 30 m~ of ethanol. The resulting mixture was heated to reflux fo~ 2 hours. After removal of the ethanol, the mixture was acidified with acetic acid, then neutraliæed with 7%
NaHC03 solution and extracted with chloroform. The chloroform was evaporated to leave the crystalline residue, which was recrystallized from ethanol to give 1.22 g of the product as pale yellow needles, m.p. 238-239G.
Example 8 Ethyl 1-~2-chloroethyl)-7-~4-ethoxycarbonyl-1-piPerazinyl)-1,4-dihydro-4-oxo-1;8-naphthyridine-3-carboxylate ~Com~eound 7); Intermediate.
To a solution of 16.5 g of ethyl 7-chloro-1-~2-chloroethyl)~
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate in 170 m~ of ethanol was added 24.0 g of l-ethoxycarbonyl-piperazine and the mixture was heated to reflux for ` ~7~9~

1.5 hour. After concentration to dryness under reduced pressure the residue was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and concentrated to give a crude product which was recrystalli~ed from ethyl acetate to give 20.0 g of the product as colorless needles, m.p. 174-175C.
I`x~mylc 9 Ethyl 1-~2-chloro thyl)-1,4-dihydro-7-~4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carbo~ylate ~Com~ound 8); Intermediate.
A mixture containing 2.2 g of ethyl 7-chloro-1-~2-chloroethyl)-1, 4-dihydro-4-oxo-1~8-naphthyridine-3-carboxylate, 2.0 g of l-methylpiperazine ~d 30 m~ of ethanol was heated to reflux for 1.5 hour. After concentration to ~ryness under reduced pressure the residue was extracted with chloroform. -~
Thc extract ~as dried and distilled to remove the chloroform ~o give crude crystals, which were recrystallized from a mixture o n-hexane and acetone to yield 2.1 g of the product as pale yellow needles, m.p. 125-127C.
Example 10 1,4-Dihydro-4-oxo-7-~l~pipera2inyl)-l-vinyl-1,8-naphthyridine-3-carboxylic acid hydrochloride. ~Compound 1).
~ Ethyl 1-~2-chloroethyl~-1,4-dihydro-7-C4-ethoxycarbonyl-1-pipera-zinyl)~4-oxo-1,8-n~phthy~dine-3-carboxylate (3.36 g) was dissolved in 55 m~
of ethanol by heating to reflux. To the solution was added 55 mY of 10~ NaOH
solution. The mixture was heated on a steam bath for 1 hour, concentrated to about 40 m~, heated again for 2.5 hours, then acidified with IN-HC~, and cooled to give a precipitate which was collected and dissolved in 50 m~ of hot water. The solution was treated with charcoal and filtered. The filtrate, after addition of 5 m~ of IN-MC,~, was allowed to stand at room ~emperature to give 2.19 g of product as colorless needles, m.p 285-2S7C ~decomp.).
~B~ Ethyl 7-C4-acetyl-1-piperazinyl)-1-~2-bromoethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate C2.25 g~ was worked up as in Example 10 CA) to give 1.36 g of the product, m.p. 285-287C. (decomp.).
Exam~e_ll 1,4-Dihydro-4-oxo-7-Cl-p perazinyl~ inyl-1,8-naphthy~id~ne-3--1~-carboxylic acid hydrochloride ~Compound l)_ To a mixture of 5 m~ of ethanol and 10% KOH was added 1.0 g of ethyl l-(2-chloroethyl)-1,4-dillydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine -3-carboxylate. ll~e mixture was heated to reflux for 1 hour and, after concentratioll to llalf of the original volume, heated for an additional 45 minutes. Tlle reaction mixture was acidified with acetic acid and filtered.
'll~c 11trate was acidified witl- 10% HC~ and allowed to stand at room tem~erature overnight to give a precipitate, which was collected and waslled with ethanol to give 0.76 g of the product as colorless needles m.p. 285-287C ~decomp.~.
Exanlplc 1 ~ Dihydro-4-oxo-7-~4=methyl-l-piperazinyl)-l-vinyl-l~8-naph tl~yridino-3-carbo~ylic acid ~Compound 4) To 0.80 g of ethyl 1-(2-chloroethyl)- 1,4 -dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylate was added 10 mQ
of a 10% aqueous solution of sodium hydroxide. The mixture was heated at 90-95C for 30 minutes and neutralized with acetic acid while cooling.
The resulting mixture was extracted with chloroform. The extract was washed with water and concentrated to leave a yellow solid which was collected alld recrystallized from ethanol to give 0.56 g of the product as pale yellow cedles, m.p. 238-239C.
Example 13 1,4-Dihydro-4-oxo-7-(l-piperazinyl~-l-vinyl-1~8~naphthyr-dine-3 carboxylic acid (Co_pound 9) and its methanesulfonate (C_mpound ~
A suspension of 2.0 g of ethyl, 1,4-dihydro-4-oxo-7-(1-piperazinyl) -I-vinyl-1,8-naphthyridine-3-carboxylate in 20 m~ of 5% NaOH solution was heated to 85C for 15 minutes. The clear solution was acidified with ace~ic acid and then neutralized wi~h 7% NallC03 solu-tion. The crystals that se-parated on cooling were collected by filtration and recrystallized from ethanol 30 to give 1.68 g of the product (compound 9) as pale yellow needles~ m.p.
261-263C (decomp.).
To a suspension of 1.0 g of the compound 9 in 15 m~ of water were ~:
,- . . - , ' ~::

7~

added 0.5 m-(of methanesulfonic acid and then 100 m4 of ethanol. The yellow solution was cooled to 0 to give a precipita~e, which was collected and washed with ethanol. The precipitate was dissolved in 10 m~ of water and filtered to remove insoluble materials. To the ~iltrate was added ethanol to form 1.1 g of the methanesulfonate as yellow needles, m.p. 299-301C
~decomp ?
Iixample 14 1,4-Dihydro-7-~4-methyl-1-piperazinyl~-4-oxo-l-vinylquinoline -3-carboxylic acid (Com~ound 2~
A suspension of 2.5 g of ethyl 1,4-dihydro-7-(4-methyl-1-piperazinyl) -4-oxo-1-vinylquinoline-3-carboxylate in 20 m~ of 5% NaOH solution was heated to 85C for 30 minutes. The clear solution was acidified with acetic acid atl~l subseqllently neutralized with 7% Na}lC03 solution to give a precipitateJ
which was collected by filtration and recrystallized from acetonitrile to yield 1.83 g of the product as pale yellow needles, m.p. 224-2~5C.
Example 15 1,4-Dihydro-7-~4-methyl-1-piperazinyl)-4-oxo-1-vinyl-1,8-naphthyri-dine-3-carboxylic acidl m.p. 238-239C, ~Compound 4) ~as prepared in the same manner as in Example 13 using ethyl 1,4-dihydro-7-~4-methyl-1-pipera~
2n zinyl)-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate as a starting material.
F.xample 16 7-~4-Ethyl-l-piperazinyl)-1,4-dihytrG-4-oxo-1-vinylquinoline-3-carboxylic acid, m.p. 211-213C, ~Compound 3) was prepared in the same manner as in Example 14 using ethyl 7-(4-ethyl-1-piperazinyl~-1,4-dihydro-4-oxo-l-vinylquinoline-3-carboxyla~e as a starting material.
Example 17 1,4-Dihydro-4-oxo-?-(1-~iperazinyl)-1-vinyl-1 8-naphthyridin~
-3-carboxylic acid ~Compound 9) and its hydrochloride ~Compound 1) A mixture containing 5.0 g of ethyl 7-~4-ethoxycarbonyl-1-pipera-zinyl)-1~4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxyla~e, 50 m-~ of ethanol and 50 m~

.. . . . .

7~

of 10% KOH was heated to reflux for 1.5 hours and, after removal of the ethanol by distillation, heated for an additional 30 minutes. The mixture ~as acidifed with acetic acid and filtered to remove insoluble materials.
The filtrate was acidified with concentrated HC~ to give a precipitate, wllicll was collected M d washed with e~hc~nol to give 3.8 g of tl~e pro~uct as hydrochloride. m.p. 285-287C ~decomp.).
A suspension of the hydrochloride (3.0 g) in 30 m~ of water was made alkaline ~Yith 10% KOH and filtered. The filtrate was adjusted to pH 7-8 with acetic acid to glve a precipitate, which was collected and re-ln crystallized from eth M ol to give 3.2 g of the product as pale yellow needles, m.p. 261-263C (decomp.).
`.x~lmplc 18 1,4-Dillydro-4-oxo-7-(1-piperazinyl)-1-vinylquinoline-3- carboxy-lic acid hydrocllloride ~Compound 5) and its methanesulfonate ~Compound 11).
A mixture containing 5.0 g of 1,4-dihydro-7-~4-ethoxycarbonyl-1-piperazinyl)-4-oxo-1-vinylquinoline-3-carboxylic acid, 80 m~ of 10% NaOH
solution M d 35 m~ of ethanol was heated to reflux for 1.5 hours. After evaporation of ethanol under reduced pressure the mixture was treated with charcoal and filtered. The filtrate was adjusted to pH 1 with hydrochloric ~cid to give a precipitate, which was collected and recrystallized from 50% eth M ol to yield 3.95 g of the hydrochloride as yellow crystals, m.p.
283-287C ~decomp~).
To a suspension of 2.3 g of the hydrochloride in 10 m~ of water was added 6 m~ of methanesulfonic acid. The resulting solution was filtered ~nd 250 m~ of eth M ol was added to the filtrate to give a precipitate, which was collected and washed with ethanol. The precipitate was dissol~ed in 15 m~ of water. Ethanol was added to the solution to form 1.7 g of ~he methanesulfonate as yellow needles, m.p. 305C (decomp.).
Example 19 1,4-Dihydro-4-oxo-7-~1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid hydrochloride ~Compou~d 1).
Ethyl 7-C4-acetyl-1-pipera~inyl~-1,4-;dihydro-4-oxo-1-vinyl-1, : : . . , . , :

:~97~7~3 8-naphthyridine-3-carboxylate ~1.6 g) ~as dissolved in 30 mi of 10% NaO~I
solution by heating at 90C for 1 hour. The solution was filtered to remove insolublf~ materials and the filtrate was acidified with concentrated hydrochloric acid to give 1.0 g of the product, m.p. 285-287C ~decomp.).
Example 20 1,4-Dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine -3-carboxylic acid hydrochloride ~Col~o~d 1).
A suspension of 3.0 g of ethyl 1,4-dihydro-4-oxo-7-~4-trifluoro-acetyl-l-piperazinyl)-l-vinyl-1,8-naph~hyridine-3-carboxylate in 20 m-~
10 of 70% K2C03 solution was heated to 80C for 30 minutes. The solution was acidified with concentra~ed hydrochloric acid to give 2.2 g of the pro;luct, m.p. 285-287C ~decomp.).
Ex~lmpl~ 21 1,4-Dihydro-4-oxo-7-~1-piperazinyl~-1-vinylquinoline-3-carboxylic acid hydrochloride ~Compound 5~.
A mixture containing 3.0 g of 7-C4-formyl-1-piperazinyl)-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid and 40 m~ of 10% aqueous hydrochloric acid was heated to 90C for 1 hour and then concentrated to dryness under reduced pressure. Addition of ethanol to the residue 20 gave a solid, I~hich was collected and recryst.allized from 50% e~hanol to yield 2.6 g of the product, m.p. 283-287C Cdecomp.).
The following Examples 22 *o 25 illustrate the preparation of .intermediates.

~ .
Ethyl 7-chloro-1-(2-chloroethyl)-1,4-dihydro-4-oxo-13,8-naphthri-dine-3- arboxylate To suspension of 20.2 g of ethyl 7-chloro-1,4-dihydro-'1-oxo-1,8-naphthyridine-3-carboxylate in 500 m~ of dimethylformamide was added a solution of 16.5 g of pot:assium carbonate in 25 me of water. To the mixture kept at 75C was added 57.5 g of 1-bromo-2-chloroethane with stir-ring, then the resulting mixture was maintained at 75C for 3.5 hours and filtered to remove insoluble materials. Ille filtrate was concentrated to dryness under reduced pressure. The residue was extracted with chloroform.
The extract was washed with water and dried. The chloroform was evaporated to leave crystals, which were recrystalli~ed from ether to give 22 g of the product as colorless needles, m.p. 14S-149C.
Bxalllple 23 7-Cllloro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid A mixture containing 5.0 g of ethyl 7-chloro-1-(2-chloroethyl) -1,4-dihydro-4-oxo-1,8-naph-thyridine-3-carboxylate, 4.3 g of sodium methoxide and 30 miof methanol was heated to reflux for 1 hour, and con-centrated to about 10 m~and water (20 m~) was added. The resulting solu-tion was heate~ again to 90C for 5 hours, cooled, and acidified ~ith acetic ~cid to give a precipitate, which was collected ~Id washed with methanol.
Ti~e precipitate l~as added to 20 m4 of phosphorus oxychloride and the mix-ture l~as heated to 90C for 45 minutes. After removal of an excess of phosphorlls oxychloride by distillation under reduced pressure, the residue t~as poured into ice-water. The mixture was extracted with chloroform.
The extract was washed with water, dried, and concentrated to dryness to give a crude solid, which was recrystalli~ed from ethanol to give 2~ 2.9 g of the product, m.p. 235-238C.
~xample 24 Ethyl 7-chloro-l-(2-chloroe-t-hyl)-l~z~-dihydro-4-oxoquinoline-3 carboxylate.
To a mixture containing 23.4 g of e-thyl 7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate and 6.9 g of 65% sodium hydride was added 90 g of 2-tosyloxyethyl chloride. The resulting mixture was heated to 100C for 4 hours. After concentration to dryness, the residue was extracted with chloroform. The extract was washed with water and dried over ~nhydrous sod-ium sulfate. The solvent was removed by the distillation to leave a solid ~0 which was recrystallized from ethanol to give the product, m.p. 207.5-209.5C.
Example 25 7-Chloro-1~4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid.

. - - ~ , . . : . . :
.

~7~7~3 To 15 g of ethyl 7-chloro~ 2-chloroe~hyl)-lj4-dihydro-4-oxo-quinoline-3-carboxylate were added 240 mQ of 10% aqueous solution of sodium hydroxide and 100 m~ of ethanol. The resulting mixture was refluxed for 1 hour and filtered with decolorizing charcoal. The pH of the filtrate W;IS adjusted to 1 witll hydrochloric acid and it was chilled to give a prec;pitate ~Y}IiC}l was collected, washed with water, and recrystallized from dimethylfo~namide to yield the product, m.p. 269-299.5C.
Ex~lple A
1,4-Dihydro-7-(1-piperazinyl)-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid llydrochloride .............................. 250 g Starch ~.~.~.. ~............ ~.... ~... ~..... O....... ~ 54 g Calcium carboxymethyl cellulose ................... 40 g Microcrystalline cellulose ........................ 50 g Magnesium stearate ................................ 6 g The above components were blended, granulated and made into tablets in a manner known per se. Thus, 1000 tablets each weighing 400 mg were formed.
Example B
1,4-Dihydro-7-C4-methyl-1-piperazinyl~-4-oxo-1-vinylquinoline-3-carboxylic acid ............................................. 250 g Starch ............................................ 50 g Lactose ........................................... 35 g Talc .............................................. 15 g The above components were blended and granulated and ~illed into 1,000 capsules in accordance with the conventional methods.
Example C
1,4-Dihydro-7-~4-ethyl l-piperazinyl)-4-oxo-1-vinylquinoline-3-carboxylic acid .............................................. 5 g Sorbitol .......................................... 30 g -2~-~8 Sugar ..................... ~ 40 g Methylparaben ............. .......................Smal l amount Sodium carboxymethyl cellulose .................... Small amount Flavour ........................................... Small amount l~ater to make .................................... 100 m~

-21 .

. .

; -

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of general formula I

wherein A is a =CH-group or nitrogen atom and R1 is hydrogen or an alkyl group having from 1 to 6 carbon atoms, and pharmaceutically acceptable salts thereof, which process comprises (i) reacting a compound of formula (a) (a) wherein X is a halogen atom, R3 is hydrogen or an alkyl group of 1 to 6 carbon atoms and Y and Z are different from each other and one of Y and Z represents a hydrogen atom while the other represents a halogen atom, a lower alkoxy group, a benzyloxy group, an alcoholic hydroxy group, an acyloxy group, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, an S-aryldithlocarbonyl-oxy group, a lower s-alkyldithiocarbonyloxy group, a lower dialkylamino group, a cyclic amino group or a group that can form a tertlary amino N-oxide or a quaternary ammonium salt or a quaternary ammonium hydroxide by bonding to the or moiety of the group, with a compound of general formula (b) (b) wherein R1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an acyl group, to form a compound of the general formula I-A

I - A

and subjecting the compound of formula I-A to heat to eliminate Y and Z and, if R1 is acyl or R3 is alkyl subjecting the product to hydrolysis to convert Ri or R3 to hydrogen;
(ii) heating a compound of formula wherein R1 and R3, Y and Z are as defined above except that when A is nitrogen and R1 is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms neither Y nor Z is halogen to eliminate Y and Z and, if R' is acyl or R3 is alkyl subjected the product to hydrolysis to replace R? or R3 by hydrogen, (iii) hydrolysing a compound of formula wherein A and R3 are as defined above and R1 is an alkyl group having 1 to 6 carbon atoms or an acyl group other than an acetyl group, provided that when A is a nitrogen atom R? is an acyl group other than an acetyl group (iv) reacting a compound of formula wherein X and R3 are as defined above, with a compound of formula wherein R?" is an alkyl group of 1 to 6 carbon atoms and, if R3 is other than a hydrogen atom, hydrolysing the product to obtain a compound of formula I
in which R1 is alkyl of 1 to 6 carbon atoms, and, if required, converting the product of formula I into a pharmaceutically acceptable salt.

2. A process according to claim 1 (ii) wherein the compound of formula is formed by reaction between a compound of formula and a compound of formula

3. A process according to claim 1(iii) wherein the compound of formula is formed by reaction between a compound of formula and a compound of formula

4. A process according to claim 1, 2 or 3 wherein X is a chlorine atom,

5. A process according to claim 1 wherein Z in the compound (a) is a chlorine or bromine atom.

6. A process according to claim 1 when process (i) or (iv) is used, 2 or 3 wherein the compounds are reacted in stoichiometric amounts in the pre-sence of a dehydrohalogenating agent at a temperature of about 20 to 270°C in a solvent which is inert under the reaction conditions.

7. A process according to claim 1 wherein hydrolysis is carried out in the presence of an acid or basic catalyst at room temperature to about 200°C
in water or a solvent which is inert under the reaction conditions.

8. A compound of the formula I defined in claim 1 and pharmaceutically acceptable salts thereof whenever produced by the process of claim 1 or an obvious chemical equivalent thereof.

9. A process according to claim 1, 2 or 3 wherein the elimination renction is carried out in the presence of a catalyst which is an acid, anhy-dride or base at a temperature of about 50 to 270°C in a solvent which is inert under the reaction conditions.

10. A process according to claim 1 wherein in the starting materials A is nitrogen and R1' is hydrogen or an acyl group, which process includes a hydrolysis stop when R1' is an acyl group to replace the acyl group by a hydrogen atom.

11. A process according to claim 1(i) which comprises reacting ethyl 7-chloro-1-(2-chloroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate with 1-ethoxycarbonylpiperazine, subjecting the product to elimination and hydrolysing the product of the elimination to yield 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid and, if the hydro-chloride salt is required, reacting the product with hydrogen chloride.

12. A process according to claim 1(ii) which comprises subjecting ethyl 1-(2-chloroethyl)-1,4-dihydro-7-(4-ethoxycarbonyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylate to elimination and hydrolysis reactions to yield 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid, and, if the hydrochloride salt is required, reacting the product with hy-drogen chloride.

13. A process according to claim 1(ii) which comprises subjecting ethyl 7-(4-acetyl-1-piperazinyl)-1-(2-bromoethyl)-1,4 dihydro-4-oxo-1,8-naphthyri-dine-3-carboxylate to elimination and hydrolysis to yield 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid, and, if the hydrochloride is required, reacting the product with hydrogen chloride.

14. A process according to claim 1(iii) which comprises hydrolyzing ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-oxo-1-vinyl-1,8-naph-thyridine-3-carboxylate to yield 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid, and, if the hydrochloride is required, reacting the product with hydrogen chloride.

l5. A process according to claim 1(iii) which comprises hydrolyzing otl-yl 1,4-dihydro_4-oxo-7-(4-trifluoroacetyl-1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylate to yield 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid, and, if the hydrochloride is required, reacting the product with hydrogen chloride.

16. A process according to claim 1 wherein in the starting materials A
is a =CH-group and R1 is a methyl group.

17. A process according to claim 1(iv) which comprises reacting 7-chloro-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid with 1-methylpiperazine to yield 1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1-vinyl-quinoline-3-carboxylic acid and, if the hydrochloride is required, reacting the product with hydrogen chloride.

18. A process according to claim l(iii) which comprises hydrolyzing ethyl 1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1-vinylquinoline-3-carboxylate to yield 1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1-vinyl-quinoline-3-carboxylic acid.

19. A process according to claim 1 wherein in the starting materials A
is a =CH-group and R? is an ethyl group.

20. A process according to claim 1(iv) which comprises reacting 7-chloro-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid with 1-ethyl-piperazine to yield 1,4-dihyhro-7-(4-ethyl-1-piperazinyl)-4-oxo-1-vinylquinoline-3-car-boxylic acid.

21. A process according to claim 1(iii) which comprises hydrolyzing ethyl 1,4-dihydro-7-(4-ethyl-1-piperazinyl)-4-oxo-1-vinylquinoline-3-carboxy-late to yield 1,4-dihydro-7-(4-ethyl-1-piperazinyl)-4-oxo-1-vinylquinoline-3-carboxylic acid.

22. A process according to claim 1 wherein A is a nitrogen atom and R1 is an alkyl group of 1 to 6 carbon atoms.

23. A process according to claim 1(i) which comprises reacting ethyl 7-chloro-1-(2-chloroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate with 1-methylpiperazine and subjecting the product to heat and hydrolysis to yield 1,4-dihydro-7-(4-methyl-1 piperazinyl)-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid.

24. A process according to claim 1 wherein the starting materials are selected so that in the product of formula I A is a carbon atom and R1 is hy-drogen.

25. A process according to claim 1(iii) wherein in the starting material A is a =CH-group, R1" is an acyl group other than acetyl and R3 is alkyl of 1 to 6 carbon atoms.

26, A process according to claim 1(iii) which comprises hydrolyzing 1,4-dihydro-7-(4-ethoxycarbonyl-1-piperazinyl)-4-oxo-1-vinylquinoline 3-carboxylic to yield 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinylquinoline-3-carboxylic acid and, if the hydrochloride salt is required, reacting the product with hydrogen chloride and, if the methanesulfonate salt is required, reacting the product with methanesulfonic acid.

27. A process according to claim 1(iii) which comprises hydrolyzing 7-(4-formyl-1-piperazinyl)-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid to yield 1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinylquinoline-3-carboxylic acid,

28. A process according to claim 1(ii) wherein in the starting material R1' and R3 are both hydrogen and A is a nitrogen atom.

29. A process according to claim 1(iii) wherein in the starting material A is a nitrogen atom, R3 is hydrogen and R1" is an acyl group other than acetyl.

30. A process according to claim l(ii) wherein in the starting material A is a nitrogen atom, R1' is an alkyl group of 1 to 6 carbon atoms and R3 is hydrogen.

31. A process according to claim 1(iv) wherein in the starting materials R1''' is an alkyl group of 1 to 6 carbon atoms and R3 is hydrogen.

32. A process according to claim 1(iii) wherein in the starting materials A is a =CH-group, R1" is an alkyl group of 1 to 6 carbon atoms and R3 is an alkyl group.