DE2362553A1 - NEW PIPERAZINE DERIVATIVES - Google Patents

Description

ΜΤΕΝΤΓΝΥνΠΤΕ

DR. E. WIEGAND DIPL-iNG. W. NIEMANN

DR. M. KOHLER DIPL.-ING. C. GERNHARDT y ο p. J c C. *

MDNCHEN HAMBURG ^ - 0 D Z 0 O ^

TELEPHONE: 55547.5 8000 MONKS 2,

ICLEGIfAMMEs CARPATENT. MATHILDENSTRASSE 12

W. 41877/73 - Ko / Ne _{17 #} December 1973

Dainippon Pharmaceutical Co., Ltd. Osaka (Japan)

"New Piperazine Derivatives

The invention 'deals with new and valuable Piperazine derivatives with antibacterial activities, processes with their manufacture and with their "use"

The invention is concerned with compounds of the following l ^? oriae]

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A and B are a carbon atom or a nitrogen atom, excluding the case where the two radicals A and B are nitrogen atoms,

IL is a hydrogen atom, an alkyl group with 1 "to 4 carbon atoms, a benzyl group or an acetyl group,

Ep a water to ff atom, an alkyl group with 1 to 4 carbon atoms, a benzyl group or a vinyl group,

B _{7 denotes} a hydrogen atom or an alkyl group having 1 "to 6 carbon atoms,

and their salts.

Ira following are preferred groupings of compounds in Bohemia of formula (I) as antibacterial

Means indicated:

Hydrogen, ethyl, hydrogen

Methyl vinyl

Particularly suitable compounds are given below.

1,4-dihydro-1-ethyl-7- (4-sethyl-1-piperazinyl) -4-oxoquinoline-3-carboxylic acid

1,4-Dihydro-1-ethyl-7- (i-piperazinyl) -4-oxoquinoline-3-carboxylic acid

oxo-1,6-naphthyri din-3-carbonss.ure

1,4-Dihydro-1-ethyl-7- (i-piperazinyl) -4-oxo-1,6-naphthyridin- ^ -carboxylic acid

1,4-Oi: ^ dro-1-ethyl-7- (i-piperasinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid

1,4-Dihyd3? O-7-C ^z t-ieth.yl-1 -pipe razir ^ yl) -4-oxc- A- vinyl-1,8-napiithyridine-3-carboron: acid

A09825 / 1183

1,4-Dihydro-? - ^ - methyl-1-piperazinyl) -4 ~ oxo-1-vinyl-1,6-naphthyri din-3-carbonic acid

1,4-Dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1-vinylquinoline-3-carboxylic acid

1-, 4-Dihydro-7- (i-piperazinyl) -4-oxo-1-vinyl-'1,8-naphthyridine-3-carboxylic acid

1,4 "-Dihydro-7- (i-piperazinyl) -4-oxo-1-vinyl-1,6-naphthyridine-3-carboxylic acid

1,4 ~ Dihydro ~ 7 - ('1-piperazinyl) - ^ - oxo-i-vinylquinoline-3-carboxylic acid
as well as pharmaceutically acceptable fermentation addition salts or

Alkali salts of such compounds.

The compounds of the formula (I) can by one of the following processes a). to d) established v / earth.

Method a): Arai n ierunp;

The compounds of the formula (I) are obtained by reacting compounds (a) of the following formula

?, COOE.

(a)

v / orin

X is a halogen atom and

Ep, E. ,, A and B have the same meaning as above,
with compounds (b) of the following formula

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OO

where R ^ has the same meaning as above, obtain.

This implementation is done by heating the compounds : (a) and (b) together with a solvent, optionally carried out in a closed reaction vessel. It it is preferred to carry out the reaction in the presence of a base as a dehydrohalogenation agent, for example sodium bicarbonate, Sodium carbonate, potassium carbonate or triethylamine. Usually the connections Ca) and (b) used in stoichiometric amounts the compounds (b) can be used in excess, so that they can also be used as dehyc.rohalogenating agents works. The compound (b) can be in the form of a hydrate or an acid addition salt, for example with hydrochloric acid. The preferred reaction temperature lies in the range from 60 to 200 ° 0.

The solvent used in this reaction must correspond to the properties of the starting materials used selected v / earth. Examples of solvents are alcohols such as ethanol or propanol, aromatic '' Hydrocarbons such as benzene or toluene, haloalkanes, such as dichloroethane or chloroform, ethers such as tetrahydrofuran, dicxane or diphenyl ether, acetonitrile, Dimethyl sulfoxide, dimethylformamide and water. These can be used both individually and in geroic.

BAD OBiGlNAL

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Process "b): Intermolecular Cyclization ■ Of the compounds of the formula (I), those of the following formula

■ IT

it I. COOR R ¹ I.
2 - 0
it

wherein R'ο εί ^{η is a} hydrogen atom, an alkyl group having 1 ^: to 4 carbon atoms and R ^ ,,, R ^, .A and B have the same meaning as above,,. . . by heating compounds of formula (e); .. "■ -.-

Ri- ¹ V

wherein EV _{7 is} an alkyl group with 1 to 6 carbon atoms. represents and R, -R'ρ, A and B the. same meaning as. own above, ■ ... "- ■

to initiate the intermolecular cyclization ei> halter · ,. "

Dier.o kcaktion v.drd .by "heating the \ ^{r orbirutungen:} (c) DIRA kt · or a hoehaiedendea LösürKU '-, i; tr- 1, V RLC iJipiierv /" * · τ · ü.the >. ο-.Dichlorobenzene, üi-pht-ii ^ l? ^^ kl d. _y iiibu r-yl ~. ■ iititha] at i "-i! Iti · mixtures of these auiign; ^f uiLi-i.,»; - _: in. = :. · -. Rf c-if :; t: c ^ - ''

BAD O £ J:>"- ■ - & / - - * t τ ίΤ 3: · ■■"".;'"

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Hot temperature is 14Q / up to 260 ° G.:, λ ■

It is also possible to use the cyclization series Presence of a common cyclizing agent, such as poly- phosphoric acid, a polyphosphoric acid alkyl ester, concentrated sulfuric acid or phosphorus pentoxide. If polyphosphoric acid, a polyphosphoric acid alkyl ester or Fliospliorpent oxide used as a cyclizing agent the pLeaction is generally carried out in a solvent, such as benzene, dioxane or dimethylformamide. If concentrated sulfuric acid is used, the reaction generally in a solvent such as acetic anhydride or acetic acid. Of course, depending on the properties of the Cyclisicrungsmittel this also serve as a solution. If a cyclizing agent is used, the reaction will take place at relatively low temperatures, for example at a temperature of 100 to 16Q ^ C carried out.

When this reaction is carried out in the presence of a coloring agent is carried out, the carboxylic acid ester portion suffers sometimes hydrolysis and is converted into the free carboxylic acid.

Process c) : alkylation

Of the compounds of the formula (I), there are those of the following formula

L Q - I Ί Π 3

wherein R "- an alkyl group having 1 to 4 carbon atoms or represents a Benzyj group and the radicals R *, R-, ", A and B are as defined above by reacting a compound (d) represented by the following formula CD)

(egg)

wherein R-, R ₇ , A and B have the same meaning as above

own, ' :

obtained with an alkylating agent corresponding to R "ο.

Known alkyl solvents can be used v / earth. Specific examples include alkyl halides, such as methyl iodide, ethyl iodide, benzyl chloride and lower Alkyl esters such as dimethyl sulfate, diethyl sulfate, methyl p-toluenesulfona.t or Triäthylphosj) has »

In general, this reaction is carried out by reacting the compound (d) kit in a stb'chioiuetxaschen amount of the Alkylierangsmitrcl in an inert solvent increased x "temperature, for example from 25 to 150 G, The alkylating agent can, if necessary, be carried out can be used in excess. The solvent can be either pure or watery. Examples for solvents are ethanol, diocene, dimethylformamide, Dimethyl sulfoxide and water, the reaction is carried out by adding an acid acceptor, for example a base, such as Alkali carbonate, alkali hydroxide, alkali alkoxide, sodium

4 0 S 8 2 S / 1 1 8 3

hydride, triethylamine, benzyl trim thy lammonium hydroxide and Like., promoted. If this reaction is carried out in a water-containing solvent, the carboxylic acid ester portion suffers sometimes hydrolysis depending on the reaction conditions and becomes the free one Carboxylic acid transferred. If, furthermore, compounds of the formula (d) in which R. is a hydrogen atom are alkylated can be in the ^ - position N-alkylated products of the piperazine nucleus sometimes together with in the 1-position of the quinoline or naphthyridine nucleus substituted " N-Alkyliex'ten products are obtained.

As a result, the desired products can be obtained through, appropriate selection of starting material, solvent and alkylating agent can be obtained.

Method d): hydrolysis

Of the compounds (I), there can be those represented by the following formula

⁰ COOII

R ^, Rp, A and B have the same meaning as above

own,

by hydrolysis of a compound (s)

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COOR '

R ₁ -KN BN

(e)

., Rp and R ¹ -ζ have the same meaning as above be

sit,

get v / earth.

This reaction is carried out by contacting the compound (e) with water. Will be very general to favor the implementation of this in the presence of a catalyst, for example an acid or a base, executed.

Examples of an acid are inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, Sulfuric acid or phosphoric acid and organic acids such as acetic acid, oxalic acid or toluenesulfonic acid.

Examples of a base are alkali hydroxides, such as sodium hydroxide or barium hydroxide, alkali carbonates, such as sodium carbonate or potassium carbonate as well as llatriunacetat.

The reaction can also be carried out by directly heating the materials in the presence of one of the above acids carried out with the subsequent addition of water. The solvent used is usually water, however, depending on the properties of the material, a solvent such as ethanol, dioxane, Ethylene glycol diraethyl ether, benzene or acetic acid together to be used with V / ater. The reaction temperature

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can be room temperature, but it is usually 50 to 200 ° C, preferably 70 to 120 ° C.

If the compound in which R 1 is _an acetyl group is hydrolyzed under more severe reaction conditions, the acetyl group and the group H 'are split off by hydrolysis.

Of the starting compounds (a), those in which Sp is a hydrogen atom or an alkyl group having 1 to M carbon atoms are obtained in the same manner as in process b), and those in which Rg is a benzyl group are obtained in in the same manner as in process c). Of the initial compounds (a), those in which Ep is a vinyl group are obtained by reacting compounds (d) and a 1,2-di-analogue bitane, for example 1,2 -Diehlorethane, 1,2-dibronethane, in the same way as in process c) with formation of haloalkylated compounds and then heating the compounds to 50 to 2? 0 ° C in the presence of a base, for example potassium carbonate, sodium hydride or pyridine, obtain.

The starting compounds (c) can be obtained according to the method of British Patent 1,129,558 will.

This reaction is shown schematically below:

B ^ - NH

'ü ° ■

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worm

R., R'ov ^ Vx »- ^ - ^and d 3- have the same meaning as above

own.

The starting compounds (d) and (e) are obtained in the same manner as in the process a) or b).

The compounds according to the present invention, which were prepared by the above process, can be isolated and purified by conventional methods. The compounds (I) can be in the free state or obtained in the form of a salt depending on the selection of the starting compounds and the reaction conditions will. Furthermore, the compounds (I) can be converted into pharmaceutically acceptable Amine salts or carboxylic acid salts by treatment with an acid or an alkali or conversely can be obtained. The acid can consist of a variety of organic or inorganic acids, and examples thereof are hydrochloric acid, acetic acid .. lactic acid, succinic acid, oxalic acid and methanesulfonic acid.

The clinical dosage of the compound (I) depends on body weight, age and route of administration, however, is generally within the range of 100 mg to 5 g / day, preferably 200 mg to 3 g / day.

The compounds (I) can be used as medical preparations, for example in the form of pharmaceutical preparations, which the compound in admixture with an inorganic or organic, solid or liquid pharmaceutical Aids that are suitable for oral, parenteral, enteral or local administration, included. Pharmaceutically acceptable Aids are substances that do not react with the compounds and include, for example, water, gelatin, Lactose, starch, cellulose, preferably microcrystalline cellulose, carboxymethyl cellulose, methyl

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cellulose, sorbitol, magnesium stearate, talc, vegetable oils, Benzyl alcohol, gum, propylene glycol, polyalkylene glycols, methyl paraben, and other known medical supplies. The pharmaceutical preparations can "for example in powder, tablet, ointment, suppository, cream or Capsule form or in liquid form as a solution, suspension or emulsion. They can be sterilized and / or auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, Contain salts to regulate osuiotischen pressures or buffers. They can also contain other therapeutically useful substances. The preparations are made according to the usual Process made.

The antibacterial activities of typical compounds according to the invention are shown in Tables I to III together with some "known compounds. In Tables II and III the values for EDj-Q and LDtq according to the Bcherns-Kaerber method (Arch. Exp. Path, Pharm., 162, 480 (19.31)).

The number of tested connections is in the example specified.

The known compounds PA, NA and AT-1249 were the following:
PA: 5j8-dihydro-8-ethyl-2-pyrrolidino-5-oxopyrido-

/ 2,3- <17 pyrimidine-6-carboxylic acid, which is the most valuable Compound according to British Patent 1,129,358.

ΉΑ: 7-methyl-4-oxo-1-ethyl-1,8-naphthylidin-3-

carboxylic acid (NaIidixic acid), which is found in the U.S. Patent 3,149,104 is indicated.

AT-1249: 7-Dimethylanlino-4-oxo-1-ethyl-1,8-naphthylidine-3-carboxylic acid, which is disclosed in U.S. Patent 3,149,104.

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Anti-bacterial activity in vitro against three strains of bacteria

Table I.

IS -3Sr ο connection

2 COOH

Staphylococcus aureus, Tarajjima

Escherichia
coli K-12

Pseudomonas

aeruginosa

Tsuchijima

10

1090

CH, N N

S CCOH

1162

10

cn cn co

Table I (continued)

114?

CH-Ji

.0 ν

μ COCH

\ 100

10

ο to oo

1214

CCCH

GCOH

100

.

ro co

CD

cn cn co

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hO

• Ρ Q)

ω • ρ

H α> rH ι-!

■ s

O O

O ■ ζ-

ο ο

tr.

10

IN

αϊ ν ~

It O .- O Ii O O Ii O - ν * II A. II II. O - ι II It Il Il
II Il I. Il Il Il II V " II II 1! II Il Il Il II Il " Il Il Il Il Ii Il II O π O Il ν ~ Ii Il Il Il II II Il Il II - Il Ii II II Il ir Il Il -. LP II II / ^Ν Ol a (S-O I! \. Il II I! π Ii \ Il \ Il ι - <- II Il / \ II
Ii
II KN rc H Ι-Μ t M II O O II Il Ii U
Ii II Il Il Il π Il II : ι (^ η CVJ Ii ν- η Il Il Il
If II
Ii Il

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Ο O

ω ω • ρ

O O

O O f

building

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The minimal Hemmfconzentratipn (HIG) was after known serial dilution method determined.

Test conditions:

Medium: nutrient liquid, pH 7.0 (5 ml / tube)

Inoculate: 1 drop of a 1:10 dilution of a culture broth left on top per tube

Inocubation temperature and time:

37 ° C for 48 hours.

2) In vivo efficacy against systemic infection with Pseudomonas aeruginosa and Salmonella typhimurium in mice

Table IΓ

Compound Pseudomonas aeruginose * Salmonella typhimurim (AT-Kr.) ED ₃₀ (mg / kg) ED ^ ₀ (mg / kg)

ip IP 9.6 po 1090 91.4 15.5 13.6 1091 6.3 18.7 = 109 1214 9.2 54.5 H 43.8 1367 H 12.5 14.9 70.7 1317 50.0 - 23.9 1249 > 100 1S, 9 - N / A '> 100 43.5 18.9 PA > 100 46.7

* Test conditions:

Organism: Pseudomonas aeruginosa Ir. 12th

Mice: Male mice (ddY-S) with a weight of about 2Qg

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Infection: Intraperitoneal infection at 50

100 LD ₅₀ (approx. 5 χ 1θ3 cells / mouse)

a bacterial suspension in 4%
gastric chicken

Medication: twice, about 5 minutes and
6 hours after infection

Hedikanentation: alkaline solution (pH 8 to 9) for intraperitoneal administration

Observation: 7 days

ip: Intraperitoneal Ve rab. tracking
** Test conditions:

Organism: Salmonella typhimuriuci S-9

Mice: Male home (ddY-S) weighing about 20 g

Infection: Inta ^ aperitoneal infection with ^ 0 to 100 LDr ₀ (about 105 cells / house) one

bacterial suspension in an I nutrient broth

Medication ": twice a day for 4 days from the day of infection

Medication: Alkaline solution (pH 8 to 9) for intraperitoneal administration and suspension in C, 2% carboxymethyl cellulose for oral administration

Observation: 14 days

ip: intraperitoneal administration

po: oral administration.

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3) Acute toxicity in mice

Table III link
(AT No.) LD ₅₀ (mg / kg) 1090
IO91
1214-
1317 iv po N / A
PA >500> 2000
>500> 2000
> 500 268 15I6
26.79 / ^ 4000

Test conditions:

Mice: Male mice (ddY-S) weighing
about 20 g

Medication: Alkaline solution (pH 8 to 9) for
intravenous administration and suspension in
0.2 % carboxymethyl cellulose for oral administration

Observation: 7 days iv: intervenous administration po: oral administration

Example 1

1,4-Kihy dro-i-ethyl-A-oxo-7- (1-pi "D eraziny 1) -quinoline-3-carboiic acid (AT-1i95) and hydrochloride thereof (AT-1091)

A mixture with a content of-1,5 S 7-chloro-1,4-dihydiO-i-ethyl - ^ - oxoquinoline-J-carboxylic acid, 5) 0 g of piperazine hexahydrate and 8 ral water was in a closed

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senen tube heated to 170 ° C for 18 hours. That The reaction mixture was washed with chloroform to remove materials soluble in the organic solvent shaken. The obtained aqueous layer was treated with decolorizing activated carbon and hydrochloric acid acidified to form a precipitate, which is collected and made from a mixture of ethanol and water was recrystallized, 1.55 g of the hydrochloride, Melting point above 300 ° C. '

The hydrochloride was dissolved in hot water and the solution was adjusted to pH 7.5 "to 8.0 with 10% aqueous Sodium hydroxide solution adjusted. The resulting free carboxylic acid was collected and made from a mixture of Dimethylformamide and water recrystallized, melting point 272 Ms 275 ° C.

Example 2

1,4-Dihydro-1-ethyl-7- (4- methyl-1-piperazinyl) -4-oxoquinoline-3-carboxylic acid (AT-1174)

A mixture with a content of 0.95 g of 7-chloro-1-ethyl-1, ^ - dihydro - ^ - oxoquinoline-3-carboxylic acid, 0.85 S 1-methyl- piperazine and 6 ml of water were heated in a sealed tube to 170 ° C. for 15 hours. The reaction mixture was washed with chloroform to remove the organic solvent-soluble material shaken. The obtained aqueous layer was neutralized with acetic acid and gave a solid, which was collected, washed with water and taken from a mixture of dimethylformamide and water was recrystallized to give 0.81 g of the product with a melting point of 220.5 to 225.5 ° C.

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Example 5

1,6-naphthyridine-3-carboxylic acid (AT-I317)

To a suspension of 1.27 g of 7-chloro-1,4-dihydro-1-ethyl-4-oxo-1,6-naphthyridine-3-carboxylic acid 1.25 g of 1-diethylpiperazine were added in 35 ml of ethanol .und the mixture was heated to reflux for 15 hours. The resulting precipitate was collected and extracted from ethanol recrystallized and gave 1.49 g of the product in the form yellow needles, melting point 238 to. 240 ° C.

Example .4

Ethyl-1, "4-dihydro-1-ethyl-4-oxo-7- (i-piperazinyl) ⁱ -1,6-naphthydidine-3-carboxylate (AT-1388)

A mixture containing 1.40 g of ethyl 7-chloro-1,4-dihydro-1-ethyl-4-oxo-1,6-naphthyridine-3-carboxylate, 2.0 g of piperazine hexahydrate and 50 ml of ethanol was used for Heated to reflux for 12 hours. The reaction mixture was concentrated and cooled to give a pesticide which was collected and recrystallized from ethyl acetate where 1.53% of the product was obtained as a yellow powder with a melting point of 169 to 170 ° C.

Example 5

1,4-dihydro-1-ethyl-4-oxo-7- (i-piperazinyl.) -1,8-naphthyridine-3-carboxylic acid (AT-1214)

To a suspension of 1.53 B 7- ^c klor-1-ethyl-1,4-

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dihydro-4-oxo-1, e-naphthyridin ^ -carboxylic acid in 90 ml Acetonitrile 5> 82 g of piperazine hexahydrate were added. The mixture was stirred "at room temperature for. Left to stand for 3 hours and then evaporated to dryness in vacuo. The remaining solid obtained was dissolved in 15 ml of a 10% strength aqueous solution of potassium hydroxide recorded. The solution was adjusted to pH. 8 to 9 adjusted by adding acetic acid and resulted on cooling a solid, collected from it, washed with water and was uckristaliisiert from water, with 2.3 g of the product in the form of colorless ITalden nit a Melting point of 271 to 272 ° C were obtained.

Example 6

^/ 1,4-Dihydro-4-oxo-7 -. (I-pipera2inyl) -1-vinylquinoline-3-carboxylic acid hydrochloride (AT-1412)

A mixture containing 1.0 g of 7-chloro-1,4-dihydro- ^! 4-oxo-1-vinylquinoline-3-carboxylic acid, 6.2 g of piperazine hexahydrate and 30 ml of dimethylformamide were heated to 110 ° C. for 4 hours while stirring. The Eeaktions mixture was concentrated to dryness in vacuo and to the residue obtained successively 50 ml of water and 5 ^m l of acetic acid course Sets. The acidic mixture was heated on a steam bath for 3 to 5 minutes and filtered to remove the insoluble material. After the filtrate had been concentrated to dryness, the residue obtained was taken up in 40 ml of water. About 5 ^ 1 of 20% hydrochloric acid was added to the aqueous solution, and then the solution was cooled to separate out the solid. The collected solid

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was made from a mixture of methanol and water, which containing a drop of 20% hydrochloric acid, recrystallized and gave 0.55 g of the product, melting point 283 Ms 287 ° C with decomposition.

Example 7

Ethyl 1,4-dihydro-7- (4-methvl "1-piperazinyl) -4-oxo-1,8-naphthyridine-5-carboxylate tAT-1227)

A suspension of 1.6 g of diethyl 6- (4-methyl-1-piperazinyl) -2-pyridylaminomethylene malonate in 12 ml of diphenyl ether was heated to 250 to 255 ° C for 15 minutes heated and then left to cool down to room temperature. To the reaction mixture, 12 ml of n-hexane was added. The resulting precipitate was collected and recrystallized from ethanol, 1.21 g of the product as yellow, fine needles, melting point 248.5 250 ° G with decomposition, were obtained »

Example 8

Ethyl-15 4-dihydro-1 ~ ethyl-7- (4 ~ methyl-1-piperazinyl) 4-oxo-1, e-naphthyridine-J-carboxylate

A mixture containing 1.0 g of diethyl-N-ethyl-N- / 2- (4-methyl-1-piperazinyl) -6-pyridyl-7-aminomethylene alonate and 6.0 g of polyphosphoric acid was heated to 140 ° C for 15 minutes and then in ice-water poured. The mixture obtained is mixed with 28%, aqueous ammonia mixed alkaline and with chloroform exti-ated. The extract was washed with water and dried over anhydrous sodium sulfate. Then it became

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The solvent was removed by distillation and a crude product remained, which was recrystallized from η-hexane and gave 0.69 g of the product as pale yellow needles, melting point 130 to 130.5 ° ^C. ».

Example 9

7- (4-Acetyl-1-piperazinyl) -1,4-dihydro-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (AT-125O)

A mixture containing 1.58 g of 7- (4-acetyl-1-piperazinyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 10 ml of a 12% aqueous solution of sodium hydroxide, 5 ml of ethyl iodide and 130 ml of dimethylformamide was heated to 90 ° C for 2 hours. The reaction mixture was evaporated to dryness in vacuo and the residue obtained is dissolved in about 10 ml v / water. The aqueous solution was neutralized with acetic acid and deposited a solid which was taken up in chloroform. The chloroform solution was up filtered to remove the insoluble material and the solvent was distilled off, leaving a solid, which was recrystallized from ethanol and 1> 53 S of the product as colorless, fine needles, melting point above 300 ° C.

Example 10

1, ^/ ) -Dihydro-1-ethyl-4-oxo-7- (i-piperazinyl) -quinoline-3-carboxylic acid (AT-1195)

To 2.0 g of ethyl 1,4-dihydro-1-ethyl-4-oxo-7- (ipiperazinyl) -quinoline-3-carboxylate 10 ml of a 5% aqueous solution of potassium hydroxide was added.

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- 23 -

The mixture was heated to 90 ° C for 30 minutes with stirring heated and neutralized with acetic acid while cooling, so that a solid separated out, which collected and was recrystallized from a mixture of ethanol and water, yielding 1.85 g of the product having a melting point from 272 to 275 ° C.

Example 11

1,4-Dihydro-1-ethyl-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid (AT-1214)

To 1.6 g of ethyl 7- (4-acetyl-1-piperazinyl) -1,4-dihydro-1-ethy1-4-oxo-1,8-naphthyridine-3-carboxylate were added 15 ^ l of a 10% strength , aqueous solution of sodium hydroxide was added. The mixture was heated to 95 ° C. for 1.5 hours and neutralized with acetic acid while cooling, and a precipitate was obtained, which was collected and crystallized from water, ¹ giving 1.0 g of the product in the form of colorless needles, melting point 272 to 273 ° ^c > were obtained.

Example 12

1,4-Dihydro-1 ⁱ -ethyl-7- (4-methyl-1-piperazinvl) -4-oxoquinoline-3-carboxylic acid hydrochloride (AT-IO90J

To a mixture containing 2.0 g of ethyl 1,4-

carboxylate, vmrden 20 ml of dimethylformamide and 0.50 g of 65% sodium hydride and 5 ^m% Äthyl3οdid added.

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The resulting mixture was ^{heated to 90 ° G} for 2 hours and then evaporated to dryness in vacuo. 10 ml of a 5% iS ^en > aqueous potassium hydroxide solution were added to the residue obtained. The alkaline mixture was then heated to 90 ° G for 50 minutes and, after cooling, shaken with chloroform to remove the material soluble in the organic solvent. The aqueous solution was adjusted to pH 2 to 3 with hydrochloric acid and gave a precipitate, which was collected from a mixture of ethanol and water and recrystallized, whereby 1.76 g of the product with a melting point above 300 G were obtained,

Example 13

1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -1-vinyl-1 , ß-naphthyridine ^ -carboxylic acid (AT-1276)

G to 0.80 Ethyl 1- (2-chloräth7l) -1 _J ^ ~ dihydro-7- (4-methyl-1-piperazinyl) naphthyl--4-0X0-1,8? Idin-3-carboxylate 10 xol of an 10% strength aqueous solution of sodium hydroxide was added. The mixture was heated to 90 to 95 ° C. 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, leaving a yellow solid which was collected and recrystallized from ethanol and 0.56 g of the product in the form of pale yellow ca de in with a melting point of 238 to 239 ° G.

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example

Following the procedure of Example -1 was 1,4-I) ihy dro-i-ethyl-7- (4-methy1-1-piperazinyl) -4-oxoquinoline-3-carboxylic acid hydrochloride obtained with a melting point above 300 ° C (AT-1090).

Example 13

The following compounds were prepared in the same way as in Example 2 »

R ₀ melting point

² ( ⁰ G)

213.5-214.5

AT- _

■ // \\ ~, - 277 - 279

AT-

1162 H 288-289

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Example 16

Following the procedure of Example 3 was 1, ^ - Dihydro-i-ethyl-l · -oxo-7- (i ~ piperazinyl) -1,6-naphthyridine-3-carboxylic acid obtained with a melting point of 294 to 296 ° C with decomposition (AT-1367).

Example 17

Following the procedure of Example 4, the ethyl 1,4-di! Bydro-1-ethyl-7- (4-methyl-1-pipe: razinyl) -4-oxo-1, ö-naphthyridine-J-carboxylate with a melting point of 176 Ms 177 ° C (AT-1J87) and the ethyl-7- (4-benzyl-1-piperazinyl) -1,4-dihydro-1-ethyl-4-oxo-1,6-naphthyridine J-carboxylate with a melting point of 172 to 173 ° C (AT-1410).

Example 18

The following connections are made in the same Prepared as in Example 5: (AT-1239): 7- (4 "-Benzyl-1- piperazinyl) -1,4-dihydro-ethy1-4-oxo-1,8-naphthyridine-3-carboxylic acid , ϊρ 205.5 up to 206.5 ° E (AT-1225): 1,4-dihydro-1-ethyl-7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, Bp 233 to 235 ° C,

ethyl 1,4-dihydro-1-ethyl-7- (4-methyl ~ 1-piperazinyl) -4-0x0-1,8-naphthyridine-3-carboxylate, ϊρ 13Ο to 130.5 ° C,

Example 19 Following the procedure of Example 6 was

409825/1 183

1 ^ -Dihydro-? - (i-piperazinyl) -4-oxo-1-vinyl-1, G-naphthyridine-J-carboxylic acid hydrochloride obtain.

Example 20

According to that. The method according to Example 7 was ethyl 1,4-dihydro-1-ethyl-7- (4-methyl-1-piperazinyl) -4-0X0-1,6-naphthyridine-3-carhoxylate ₎ melting point 176 to 177 ° C (AOJ-1387).

Example 21

The following compounds were prepared in the same manner as in Example 9.

(At-1410): ethyl 7- (4-benzyl-1-piperazinyl) -1,4-dihydro-4-oxo-1, e-naphthyridine ^ -carboxylate, pp 172-173 ° C * (AT-1225 ): 1 _! 4-Dihydro-1-ethyl-7- (4-methyl-1-piperazinyl) -4-0X0-1, S-naphthyridine-3-carboxylic acid, pp 233-235 ° C. ■

Example 22

The following compounds were prepared in the same manner as in Example 10.

A09825 / 1183

R ₁ -NM "^ B

CCCH

1367

CH CH CH

CH

C)

220.5 - 222.5 294 - 296 (dec,

1406 CH Ή H 1225 CH N CH,

C ₂ H ₅

241 - 243 (dec.

233-235

1239

CM,,

205.5-206.5

example

Follow the procedure of Example 13 1,4-Dihydro-7- (i-piperazinyl) -4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid hydrochloride, Sohmelzpunkt 285 Obtained 287 ° C with decomposition (AT-1424).

The preparation of the intermediate compound of formula (a) is described in Examples 24 to 26 below

409825/1183

Example 24-

Ethyl 7-chloro-i, ^ - dihydro - ^ - oxo-1,6-naphthyridine-3-carboxylate

A mixture of 3.0 g of 4-amino-2-chloropyridine and 5.6 s diethyl ethoxymethylene malonate was at 95 C during Heated for 2 hours, during this period the ethanol formed in the course of the reaction by distillation removed under reduced pressure. Then n-hexane was added to the mixture. The solid obtained became collected and recrystallized from η-hexane and diethyl 2-chloro-4-pyridylaminomethylene malonate, Melting point 60 to 62 ° C.

To 30 ml of boiling diphenyl ether became the diester added and the resulting mixture at 253 to 255 ° C held for 6 minutes and then cooled to room temperature. When 20 ml of η-hexane was added, the precipitation of a solid, which was separated off and washed with chloroform. The recrystallization of the solid from dimethylformamide resulted in the specified compound, Melting point 300 ° C with decomposition.

Example 25

Ethyl 7-chloro-1,4-dihydro-1-ethyl ~ 4-oxo-1,6-naphthyridine-3-carboxylate and the free carboxylic acid

To a solution of 1.28 g of ethyl 7-chloro-1,4-dihydro-4-OXO-1,6-naphthyridine-r3-carboxylate in 100 ml of ethanol was a solution of 1.05 g of potassium carbonate in 10 ml Water and then added 2.4 g of ethyl iodide

409825/1183

adds. The resulting mixture was heated to reflux for 1.5 hours and then to dryness in vacuo concentrated. The residue was taken up in chloroform and the chloroform solution was washed with water and dried. Removal of the solvent gave a solid which was recrystallized from ethanol and yielded the ester, melting point 187.5-188.5 ° C.

This ester was converted to the free carboxylic acid by a conventional process, namely 7-chloro-1,4-dihydro-1-ethyl-4-oxo-1,6-naphthyridine-3-carboxylic acid, Melting point 260 to 262 ° C, hydrolyzed.

Example 26
7-chloro-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid

To a mixture of 23.4 g of ethyl 7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate and 6.9 g of 65% sodium hydride 90 S 2-tosylo: xyethyl chloride were added. The received Mixture was heated to 100 ° C for 4 hours. After concentration to dryness, the residue was washed off with chloroform extracted. The extract was dissolved with water and dried over anhydrous sodium sulfate. That Solvent was removed by distillation and a solid remained, which was recrystallized from ethanol was and ethyl 7-chloro-1 ~ (2-chloroethyl) ~ 1, 4-dihydro-4-oxoquinoline-3-carboxylate, Melting point 207.5 "to 209.5 ° C.

To 15 g of the ester obtained above, 240 ml added to a 10% aqueous solution of sodium hydroxide and 100 ml of ethanol. The resulting mixture became during Heated at reflux for 1 hour and filtered with decolorizing charcoal.

4098 2 5/1183

The pH of the filtrate was adjusted to 1 with hydrochloric acid and cooled so that a precipitate was obtained which was collected, washed with water and recrystallized from dimethylformamide, the indicated Compound, melting point 269 to J6915 ° C »obtained became.

Further compounds of the formula (a) can be used in the same manner as in Examples 24 to 26 using the appropriate starting materials in place of the 4-amino-2-chloropyridine in Example 24 of the alkyl ester of ethoxymethylene malonic acid instead of Ethyl ester in Example 24 using the alkylating agent, e.g. benzyl bromide, in place of Ethyl iodide in Example 25 or using the appropriate Starting materials instead of the quinoline derivative according to Example 26 can be obtained.

Two of the compounds of the formula (a) are known compounds, namely 7-chloro-i, 4-dihydro-i-ethyl-4-oxoquinoline-3-carboxylic acid and 7-chloro-1,4-dihydro-i-ethyl-4-0X0-1,8-naphthyri din-3-carboxylic acid.

The preparation of the intermediate compound of formula (c) is explained below.

Example 2? " ^a

Diethyl 6- (4-methyl- = 1-piperazinyl) -2-pyridylaminomethyl enmalonate

A mixture of 2.5 g of 6-amino-2- (4-methyl-i-piperazinyl) pyridine and 3.1 g of diethyl ethoxymethylene malonate was added 90 ° C heated for 2 hours and then cooled. Of the ■ obtained solid was recrystallized from benzene ande gave the product with a melting point of 114 to 115 ° C. ^

409825/1183

The other compounds of the formula (c) can be prepared in the same manner as in Example 27

Example 28

1, ^ - yy?
(_1-piperazinyl) -quinoline-3-carboxylic acid hydrochloride x 250 g

Starch 54 g

Calcium carboxymethyl cellulose 40 g

Microcrystalline cellulose 50 S

Magnesium stearate 6 g

The above ingredients were mixed, granulated and formed into tablets in a manner known per se. 1000 tablets each weighing 400 mg received.

Example 29

1v4-Dihydro-1-ethyl-4-oxo-7- (2-piperazinyl) -1,6-naphthyridine-3 ~
carbonic acid 250 g

Starch 50 g

Lactose. 55 p

Talc 15 g

The above ingredients were mixed and granulated and put into 1000 capsules according to conventional ones Procedure filled.

409825/1183

Example 3P_

1,4-dihydro-1-ethyl-A-oxo-7- (ipip erazinyl) -1,8-naphtiiyri din-J-

carboxylic acid 5 S

Sorbitol 30 g

Sugar 40 g

Methyl paraben small amount

Sodium carboxymethyl cellulose small amount

Flavors small amount

100 ml of water

A09825 / 1 1 83

Claims (1)

Patent claims 1. Compounds of the formula 2 COOR fir ir. A and B are a carbon atom or a nitrogen atom, excluding the case where the two residues A and B are nitrogen atoms, E. a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a benzyl group or an acetyl group, E _{2 is} a hydrogen atom, an alkyl group with Λ to 4 Carbon atoms, a benzyl group, or a vinyl group and E ^ is a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, mean and salts thereof. 2. Compounds of the formula 2 COOH 409825/1183 in which - " A and B have the same meaning as in claim 1, E, a hydrogen atom or a methyl group and E _{2a is} an ethyl or vinyl group, as well as the line of this. 3 * Ve E ¹ Mn fertilize the formula ° COOH β -K ^1Λ in which E ,. andxE ^ have the same meaning as in claim 2 ■.
4. Compounds of the formula 9, COOH where E " _a and E ^ _{a have} the same meaning as in claim" and their salts " *? «Connections del? formula 40982S / 1183 - 258 - where IL _a and E ^ have the same meaning vde in claim ₄ and their salts « 6. Compounds of the formula ? t COOH wherein A and B have the same meaning as in claim 1. 7 * compounds of the formula COOH wherein A and B have the same meaning as in claim 1. 8. Pharmaceutical composition containing as active ingredient 5/1183 constituent a connection after. Claim 2 mixed with pharmaceutically acceptable auxiliaries. 9- A method for producing a composition which contains a compound according to claim 2 as an active ingredient in the mixture with pharmaceutically acceptable auxiliaries, characterized in that they are in a manner known per se will be produced. 10. Process for the preparation of compounds of following formula where .-'._ ■ A and B are a carbon atom or a nitrogen atom, except for the pail, where the two radicals A and B are nitrogen atoms are, . B.,. a hydrogen atom, an alkyl group with "1 to 4 carbon atoms, a benzyl group or an acetyl group, Sp is a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a benzyl group or a vinyl group, and E, a hydrogen atom or an alkyl group of 1 to 6 Carbon atoms mean and their salts, characterized in that (a) a compound of the formula 409825/1183 wherein X is a halogen atom and the radicals Ep, R ^, A and B have the same meaning as above ", with a compound of the formula wherein R ^ has the same meaning as above, is reacted or
(b) a connection of the lOrrael ⁿ l " I «ι COOR ! K ₁ J S ₇ wherein R ¹ ^ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ¹ ^ is an alkyl group ii 6 KA with Λ to 6 carbon atoms and R ^ ,, have the same meaning as above, A and 409825/1183 to initiate the intermolecular cyclization with formation a compound of the formula S COOE ₇ wherein E ^, E'p, H- ,, A and B have the same meaning as above, is heated, or (c) a compound of the formula S CCX) R- where E., E ^, A and B have the same meanings as above possess, with an alkylating agent to form a compound of the formula COOE, 409825/1183 wherein IL ₁ E ,, A and B have the same meanings as above and E " _{o means} an alkyl group having 1 to 4 carbon atoms or a benzyl group, or (d) a compound of the formula "COOR'j wherein B., Rp, E ¹ , A and B have the same meanings as above, to form a compound of the formula COOII where E ^, E2, A and B have the same meaning as above own is hydrolyzed and optionally converting the compound obtained into a pharmaceutically acceptable one Acid addition salt or alkali salt is convicted of this. 0 9 8 2 5/1183