DE1932384A1 - Derivatives of 2-oxo-1,2-dihydroquinoline - Google Patents

Description

CASSELLA FARBWERKE MAINKUR SHARED COMPANY

6000 FRANKFURT (MAIN) -FECHENHEiM

Ref. 2842

Frankfurt (Main), June 2nd, 1969 Dr Ur / Cz

Derivatives of 2-oxo-1,2-dihydroquinoline

The present invention relates to valuable derivatives of 2-oxo-1,2-dihydro-quinoline of the general formula

(I)

where R is hydrogen or * low molecular weight alkyl,

R _{1 is} hydrogen, low molecular weight alkyl, alkenyl, aralkyl, aryl, dialkylaminoalkyl, where the ara N-atoms can be linked directly or via a heteroatom to form a five, six or seven-membered ring,

R ₀ hydrogen, low molecular weight alkyl or aryl,

R_ low molecular weight alkoxy,

X hydrogen, halogen or low molecular weight alkyl,

m the numbers 1, 2 or 3 _t

A and A _{2 are} straight-chain or branched alkylene radicals with 2 to ^ C atoms and

Y is hydrogen, a hydroxyl group or the remainder

0-CO

mean.

909883/1692

Ref. 2842

The new derivatives of 2-oxo-l, 2-dihydro-quinoline are obtained if

a) 2-Oxo-1,2-dihydroquinoline derivatives of the general formula

r- ^R i

(II)

X R

wherein Y is hydrogen or a hydroxyl group, with an alkoxybenzoic acid of the general formula

HOOC

(III)

or a functional derivative, optionally in the presence of an acid-binding agent, acylated, or if one

b) 2-oxo-1,2-dihydroquinoline derivatives of the general formula

R-,

(IV)

X R

with an alkoxybenzoic acid haloalkyl ester of the general formula

(V)

C ^R 3> m

where Hai stands for a halogen atom, optionally in the presence an acid-binding agent, condensed, or if one

909883/1692

- 3 - Ref. 2842

c) derivatives of 7-ΗγαΓοχγ-2-οχο-1,2-dihydroechinolins of the general formula

(VI)

with a piperazine derivative of the general formula

VcO-OA ₂ -N, NA ₁ -HaI (VII)

where Hai stands for a halogen atom, optionally in the presence of an acid-binding agent.

As low molecular weight alkyl radicals R, R,, R "and X and alkoxy radicals R ~ In particular, those with 1-4 carbon atoms come into consideration.

In the case of the use of starting materials in which the intermediate member A does not provide a hydroxyl group, the claimed process provides contains the corresponding monoesters and, in the case of the presence of a hydroxyl group, mono- or diesters. Im last said case provides process variant a) when using 1 mol of the alkoxybenzoic acid or the functional derivative the monoesters, if 2 moles are used, the corresponding diesters. In the case of the preparation of diesters, the esterification can also be carried out in stages, with one in the two stages

909883/1692

- 4 - Ref. 2842

also various alkoxybenzoic acids and their functional parts ■ Can use derivatives as acylating agents. In this way it is possible to produce mixed diesters, the two different ones Contain acyl residues, process variant cj also provides both the corresponding mono- and the corresponding diesters, which depends on the meaning of the substituent Y in the starting product used piperazine derivative depends. Process variant b) initially only leads to monoesters, which, however, if the intermediate member A 'contains an acylatable hydroxyl group, with one mole of an acylating agent according to process variant a) can also be converted into diesters.

The derivatives according to the invention of 2-oxo-l, 2-dihydro-

quinolines are valuable medicines; they have, for example, a specific, coronary vasodilator effect and are in this Superior to known substances of this type. Their salts are colorless, crystalline substances that are easily soluble in water.

909883/1692

-4Γ- -'ef. 2Ξ42

The pharmakoIogisehe T ^T L n i -rsuchung the eoronargefaßerue ternden effect u'unie of .Sauers to FFD Mokes basis of the change in blood roronarvenösen according to the method described by ¥ .KA Sthap ^ r uri employees tern method in dogs by ρ sr Liihi t (see WKA SCiIAFEn, II. ΧΙΗΝΕΝΈΙΙΧ and -Ϊ.Μ. R (WJAARD "About .1 ι e km» tinn ier-Ii before measurement of the acid pressure in the venous CnrnnarMut "(\ aunyn-Schmiedeberg ¹ S Arch. exp . Path. u. Pharmak. ii k 3, 3 ^ 3-3 ^ 9 (19 ^ 3)) . the anesthetized, spontaneously atnuincien animals received the l ^r ntersuchungspräparate in1 ravenös applied. In. this test arrangement executes by the sub siu'hui'gssubstanz liervorgerufene expansion of the coronary arteries and the associated increase of the Coronardttrclifl ow ^ \ ^ an increase in blood Sauerstnffdruckes in poronarvenüsen "the measurement of the Sauer to ff pressure was polarographiscli n \ t a platinum electrode according to Gleichnann-I.iibbers (see U. Π I.EICIIMANN u "DU LrERBKuS" Here measurement of the S oxygen pressure in gases and liquids with the platinum flexrode with special consideration of the measurement in the blood "Pflügers Arch. 22Jl * '» "ίΐ - + ?, 3 (1960)). The heart rate was continuously determined from the systemic maxima of the arterial blood pressure. The arterial blood pressure is known in the art. "" Ϋΐτ eiripiu Siratham — strain — gauge — El elct roiaaiioraeter in the types a femoral is measured.

The following table summarizes the results of the phaiMiakol og i see investigations carried out. The preparations were each tested in the form of their dihydrocarbons:

9 09883/1692

ce ο co

preparation

Dosage Maximum; Change maximum

mg / kg of oxygen change

i.v. pressure in the (oronar- der Her / -

venous blood frequency

ti ^r -n

in Min, i η ^f i · in Min, in ^r '<

Maximum e Aiid < ¹ I-UDIi des Blutd rue! Es' VitK 1 worth sys to. . ii i: iw LuI. )

3-ß-DUithylaminoithy l-4-methy 1-7-

ethyl) piperazino / l. [_7 _ / - propoxy ] - 2-OXO-], 2-dihydroehino1 iti

3.-B-DiUtUyI aininoätüv l-'t-methy 1-7- \ jffk '~ ⁽ iT-3, ^ i, 5-trimeth <ixybenzoxv- 2. o prvjpyl) -piperazino / I ¹ J ,, -propoxyj 2-oxo-t, 2-dihydroehino ~ l in

3; - B-Di \ i thy larain ο M thy \ —h -me thy 1-7- lir /? ¹ "-φ-3» ^ »5-trimetlioxybenzoxy- 2. o isopropyl) -piperazino /"l'jj ^ -propoxy "* - 2-oxo-1,2-dihydroquinoline

ItTi ¹ I ' ~ (ß "3> ² I j 5-trime t ^ lioxybenzoxyntliy 1) - piperazino / i ^y jj - pro poxy | - 2-oxo-1,2-dihydrochixiu Hn

3-ß-Piperidinoäthyl- »H-: nethyi-7- ^c rßi '- (ϊΓ-3ι *, 5-trime Γ'

propyl j-piperazino ^ 'I ^ Jy-pro poxy ν _ 2-oxo-1,2-diliydroquinol χ η 2.0

2.ο

IiTi - ^ '- (^ - "» ^ »S-trimetlioxybenzoxyisopropyl) -piperazino / i' J? / - propoxyJ-2-oxo- 1,2-dihydroquinoline .ο

+ Rl + 10 '

+ 116 + 10 "+ 100

> 20

20th

> -20

-

-

-

• 12

-

20th

20th

- 1

20th

-

it) Μι π.

ro co cc

preparation

O CD CD OO

on to lsi

DOS i ^f ; f'n i .v. "axi.nule change maximum
of the oxygen change
pressure in the coronary - the cardiac venous skin frerjuenz
η ^r io in MIn. in 'O in

Maxima per change in blood pressure (>'-> t te! Value sys to 1 .--. Iiastol.) In ' f. in min

5-ß-P i pe rid inoa t hy 1 -4-niet hy I -7- k ir_ t ' -; d ^% -5, Ί, 3-t * ime ⁺ _!;. Ox> benzoxy- 2. ο but \ 1 -ρ ι IjP t az JLTiO / 1 "_ / j -propoxy'j- - 2-vXkj- L, 2-di hy dt uchinu 1 in

i-ß ^ Morphol i ηou ι hy 1-4-nif · thy l-7 ~ $ / 4 '~ (X ¹ - ^, ^l t , 5- ^: tf ime t hoxylenzoxy- 2. υ pröpyl) -piperazii .o £ I '_ / 7-propoxy', -, 2-oxo-l, 2-d ihydr; .chii. ·! in

3-ß-D iiithy 1 am i noii thy i —4-me t hy I -7— l &'D * ' - (ii — 3 ♦ -Ι, 5-1 rime ί ': .oxyl' fn / oxy- 2 «ο äthyi) -p iperaz ino / l ³ ^ / -fj-hydr oxy— propcxy -2-oxo-l., 2- (ij hyd roch itiol in

3-n-Ru ty 1 -4-me thy I -7- If ^ '- (Π-3, ^i, 3-tr lmethoxybenzoxyiithy 1) -ρ iperaz ino- _2.ο Α "Ί V / -SS- (3, ^z i, 5-trimetlioxybetizoxy) -propoxyi · -2-oxo-l., 2-dihydrochino 1 in

3-ß7Di; ithyl argi noa thy 1 ~ kr \ e thy 1 -7-ί ^ / 4 '- (/ - 3,4, 5-tri ine tli oxy ben ζ oxypropy 1) -pipe razino / l' _y / '—Π— (5, 4, 3-' ^Ί ·· °

tr ime f lioxybenzoxy) -propoxv | -2-oxo-1 , 2-d iliyd smelled ino 1 in

> 20

- 30

TOO

+ GG

+20

-J

-1.2 .so -3;

OO

3-ß-Diethylaminoethyl-4-methy 1-7- \ ^ /. ^ '- (0-3,4,5-1 r imethoxybenzoxyisopropyl) -piperazino ^' l '_ // -H- (I, ¹ * , 3-tr imethoxybenzoxy) propoxy -2-oxo-1, 2-dihydroehino 1. in

15th

5 -50

CD CO ΓΟ CaD OO

- 8 - Ref. 28-2

In the production of coated tablets and Taljletten with the inventive 2-oxo-1,2-dihydro-quinoline derivatives as active ingredients These substances can be proportioned with the usual tablet additives such as starch, lactose, talc and similar to be mixed. All common in pharmacy Tnbl etti οrungs- and. Drajriematerinlien can be used will. For the production of injection solutions, e.g. the hydrochlorides of 2-0xo-1,2-dihydroquinol inderivate particularly suitable as these are mostly readily water-soluble. Of course, injection solutions cannot either water-soluble products using known suspending agents, emulsifiers and / or solubilizers can be produced in a known manner.

909883/1692

Ref. 2842

Example 1 ;

-N N-CH ₉ -CH ₂ -CH ₃ -0

40.1 g (0.1 mol) 3-n-butyl-4-methyl-7-H "- / 4 ~ '- (β-hydroxyethyl) -piperazino / 1! YW-propoxyr-2-oxo-1, 2-dihydro-quinoline are suspended in 500 ml of dry benzene. After adding 10.1 g (0.1 mol) of triethylamine, a solution of 23 g (0.1 mol) of 3,4,5-trimethoxybenzoyl chloride in 100 ml of dry benzene are added, the mixture is stirred for 1-2 hours at room temperature and then for 3-4 hours under reflux, the precipitated triethylamine hydrochloride is then filtered off with suction while the filtrate is washed with water, dilute aqueous sodium bicarbonate solution and again with water. The benzene solution purified in this way is dried over calcined sodium sulfate and concentrated in a water jet vacuum at 50. This gives 3-n-butyl-4-methyl-7-JY- [4 ¹ - (β-3,4,5-trimethoxybenzoxyethyl) ) -piperazino / 1 '__ 7 / -p ^ opoxy j-2-oxo-1,2-dihydro-quinoline in colorless crystals with a melting point of 12.9. The dihydrochloride has a decomposition point of 120 °.

Yield: 54 g = 81% of theory based on the dihydrochloride.

The 3-n-butyl-4-methyl-7-iT-14 * used as the starting product - (ß-hydroxyethyl) -piperazino / 1 '_ // - propoxy | -2-oxo-1,2-dihydroquinoline can be made as follows:

9098 83/1692

-χC _

Ref. 2842

a) 23.1 g (0.1 mol) of 3-n-butyl-4-methyl-7-hydroxy-2-oxo-1,2-dihydroquinoline are dissolved in 150 ml of methyl sulfoxide with stirring, and 11.2 g (0.1 mol) of potassium tert-butoxide are added. This solution is stirred for 15 minutes at 30. 17.3 g (0.11 mol) of 1,3-bromochloropropane are then added dropwise with stirring. Then stir 12 hours at room temperature and then pour the reaction mixture in water. The crude product, which separates out in crystalline form, is filtered off with suction, washed with water and removed for further purification Dioxane recrystallized.

This gives 3-n-butyl-4-methyl- ^{7- '^:} -chloropropoxy-2-oxo-1 _/ 2-dihydroquinoline in the form of colorless needles with a melting point of 205-207 °.

Yield: 21 g = 68.4% of theory.

The following compounds of the general formula '

Cl-CH ₂ -CH ₂ -CH ₂ -0

90 9 583/1692

-II-

Ref. 2842

Fp:

^C 2 ^H 5

CH ₂ = CH-CH ₂ -

N-CH, -CH ₂ -

N-CH ₂ -CH ₀ -

ⁿ ~ ^C 3 ^H 7

^C 6 ^H 5

CH ₃

CH ₃

CH

CH

C ₃ H ₇

CH

(C ₂ H _{5) 2} N-CH ₂ -CH ₂ - CH.

Br

143-144 234-233 172-173 160-162

218-220

209 '

175

208 ° dec,

142-143

b) 31.7 g (0.1 mol) of B-n-1,2-dihydro-quinoline and 13 g (0.1 mol) of N- (ß-hydroxyethyl) piperazine are dissolved in 150 ml of chlorobenzene and, after the addition of 10.6 g (0.1 mol) of anhydrous soda for 12 hours at 120 stirred. After it has cooled down, suction off the precipitated table salt and concentrate the filtrate in a vacuum. The remaining crude product can be recrystallized from ethyl acetate for further purification.

909883/1692

-12 - Ref. 2842

This gives 3-n-butyl-4-methyl-7- | 2p · [ ^{4 <} - (β-hydroxyethyl) - \. _; piperazino £ l '^ / 7-propoxyji-2-oxb-l, 2-dihydro-quinoline in the form
colorless needles of m.p. 145-147., ^: '· .. · "■ -: - i ....'

Yield x 34 g "= 85% of theory.

The following general Preparing the corresponding intermediate products

ΓΛ

HO-A - N N-CH ₀ -CILr-CH ₀ -CK 2 \ / 2 2 2

^X ' X

^R 2 ^A 2

C ₆ H ₅ -CH ₂ -CH ₂ -H 156 °

¹¹ 172 °

1 & 2 °: ■> ■ -CH ^ -CH ₂ -CH ₂ -CH ₂ ^ - "170 °

12 5-12

167 ° _. ¹¹ ■■■■ '; ■ - 125-126 °

"C ₃ Ii ₇ -" .. "' -CH ₂ -CH (CH ₃ ) -" 123 °

CH ₂ = CH-CH ₂ - CH ₃ -CH ₂ -CH ₂ - "100 °

¹¹ "- CH - CH - CH -" TX7

"-CH ₂ -CH (CH ₃ ) -" 120 °

9098 83/16 9 2- V-

C ₄ H ₉ CH ₃ -CH ₂ -CH ₂ -CH ₂ - Ü rt -CH ₂ -CH (CH ₃ ) - "ir it -CH ₂ -CH ₂ -CH ₂ -CH ₂ -

-13 - Ref. 2842

R ₁ , R ₉ A ₂ X Fp:

H 149-150 °

1 50 °

-CH ₂ -CH (CH ₃ ) - "166 °

-CH ₂ -CH ₉ -CH ₂ -CH ₂ - "13 3 °

-CH ₂ -CH ₂ - Br 124 °

-CH ₂ -CH ₂ -CH ₂ - "12 5 °

-CH ₂ -CH (CH ₃ ) - "125 °

W N-CH ₀ -CH ₀ - "-CH ₀ -CH ₀ -H 178 °

¹ * s Δ Δ '. Δ Δ

-CH ₂ -CH ₂ -CH ₂ - "175-177 °

-CH ₂ -CPl (CH ₃ ) - "194 °

-CH ₂ -CH ₉ -CH ₂ -CH ₂ - "165 °

-CH ₂ -CH ₂ - "" -CH ₂ -CH ₉ - "194 °

ti Γ * Ζ1 Γ * Η Γ * 11 "1 Qc;

-CH ₂ -CH ₂ CH ₂ iyb

) - "212 °

-CH ₂ -CH ₂ -CH ₂ -CH ₂ - "192 °

N-CH ₉ -CH - "-CH ₉ -CH-" 197 °

\ / ^{Ζ Ζ Ζ} -

2 ~ " ²⁰⁴ °

) - "" 188 °

2 ^CH 2 ^CH 2 ^CH 2 ^iyJ

9 0 9 8 83/16 92

-Ah-

Ref. 2842

R-,

Fp:

-CH ₂ -CH (CH ₃ ) -

-CH ₂ -CH ₂ -CH ₂ - "

-CH ₂ -CH ₂ -CH ₂ -CH ₂ - "

13 7

132

124 '

In a manner analogous to that described in paragraph 1 of this example, the following can be obtained from the abovementioned intermediates Compounds according to the invention are prepared:

-CO-OA ₂ -N

R-

A.

Fp:

C ₂ H ₅ C ₄ H ₉

^C 6 ^H 5

CH,

C ₃ H ₇

-CH _n -CH _n - H

-CH ₂ -CH (CH ₃ ) -

-CH ₀ -CH ₀ -CH ₀ - "
^ 2 2 2

■ "CHrt ™" Cfi \ Cri-j j ■ "

-CH ₂ -CH ₂ -CH ₂ -CH ₂ - "

-CH ₂ -CH (CH ₃ ) -

231-233 (2 HCl)

246-248 °

233 ° \ ⁱ

230-232 °

230-233 °

225-22 7 °

237 °

150 ° (decomp.) "

909883/1692

Ref. 2842

X Fp ϊ

CH ₂ -CH = CH ₂

(C ₂ II ₅

CH ₂ -CH ₂ -

—CH -— CH "

CII ₂ -CH (CH ₃ )

H 149 ° (dec.) (2 HCl

139 (decomp.) "

127 ° (decomp.)

217

(3 HCi;

22 7

CH ₂ -CH (CH ₃ )

211

218 ° >. '2O4 ° (zer-ö'.) '

-CH ₂ -CH ₂ - "

-CH ₂ -CH ₂ -CH ₂ -

-CH :( CH ₃ ) -

160 ° (decomp.) 200 ° (decomp.) 100 ° (decomp.): (3 HCl 112 ° ■ '- "

-CH ₂ -CB (CH ₃ ) -

88 ° "

115 ° "

--CH -

-CH _<2 -CH (CH ₃ ) - -CH - CH - CH., - CH _v

218

242

212

215 ^l

909883/1 632., .-,

Ref. 2842

J \.

O N-CH ₀ -CH ₀

R,

-CH,

A,

J-CH ₂ -CH ₂ -

-CH-CR (CTL) -

-CH ₀ -CH - QH-> -

C * £ λ £

-CH ₂ -CH ₂ -

-CH ₀ -CH (CH -.) -

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -

X Fp:

H 148 ° (Zeirs;) "(3> HCl)

138

120 ^u

118 ^V

120

example 2 •
• -CO-O-CH ₂ -C CH ₃ O _n CH ₃ O < J CH ₃ O '

N-CH ^ -CH-CH _n , -O '

² I.

43.1g (0.1 mol) 3-n-butyl-4-methyl-7-ίr-4'-C 1-4 -hydroxypropyl) -piperazino / 1 '// - ß-hydroxypropoxyf-2-oxo-1,2 -dihydro-quinoline are dissolved in 300 ml of dimethylformamide and mixed with 10.1 g (.0.1 mol) Triethylamine. Offset. Now, add dropwise with stirring 23 g (0.1 mol) 3,4,5-Trimethoxybenzpyl.chloride, dissolved in 100 ml of anhydrous Benzene, within 2 hours. After the exothermic reaction has subsided, stirring is continued for 15 hours at room temperature. then the reaction mixture is concentrated in vacuo. The residue

9 0 9883/169 2

the mixture is stirred with dilute hydrochloric acid, the dilute in the Hydrochloric acid insoluble components are separated by shaking with ethyl acetate. The aqueous hydrochloric acid solution is provided with Potash is alkaline and takes up the oily crude product in ethyl acetate. The ethyl acetate solution is ignited over Dried sodium sulfate and then freed from the solvent in vacuo. In this way 3-n-butyl-4-methyl-7- ^ jp-Γ4 · - (^ - 3 " , 4 ", 5" -trimethoxybenzoxypropyl) -piperazino / I'7 / -β-hydroxypropoxyf-2-oxo-1,2-dihydro-quinoline in the form of colorless crystals, melting point: 115 °.

Yield: 32 g = 51.3% of theory.

The 3-n-butyl-4-methyl-7- XT- I 4 '- (V-hydroxypropyl) -piperazino / l] 7 / -β-hydroxypropoxy> -2-oxo-1,2-dihydro required as the starting product -quinoline can be made as follows:

a) 23.1 g (0.1 mol) of 3-n-butyl-4-methyl-7-hydroxy-2-oxo-1,2-dihydro-quinoline are suspended in 200 ml of isopropanol and after adding 30 g of epichlorohydrin and 0.5 g of piperidine as Catalyst heated to 100 ° and stirred for 6 hours at this temperature. The reaction mixture is then concentrated in vacuo and the remaining crude product dissolved in methylene chloride. The methylene chloride solution is shaken a few times with dilute Caustic soda and then with water. After drying over calcined sodium sulfate, the solution is concentrated in vacuo to dryness. This gives 3-n-butyl-4-methyl-7- (2 ', 3'-epoxyproppxy} -2-oxo-1, 2-dihydro-quinoline in the form of colorless needles with a melting point of 147 °.

Yield: 22 g = 76.6% of theory.

909883/1692

- 16 - Ref. 2842

The following connections can be established in an analogous manner:

3-ethyl-4-phenyl-7- (2 ', 3'-epoxy-propoxy) -2-oxo-1,2-dihydro-quinoline

Mp: 228-229 °

3-n-Butyl-4-n-propyl-7- (2 ', 3'-epoxy-propoxyJ-2-oxo-1,2-dihydroquinoline M.p .: 144-147 ° 3-Allyl-4-methyl-7- (2 ', 3'-epoxy-propoxy) -2-oxo-1,2-dihydro-quinoline

M.p .: 145-146 °

The 7- (2 ', 3'-epoxy-propoxy) -2-oxo-1,2-dihydro-quinolines which are basically substituted in the 3-position can be produced more advantageously by the following method:

28.8 g (0.1 mol) of 3-β-piperidinoethyl-4-methyl-7-hydroxy-2-oxo-1,2-dihydroquinoline are dissolved in 150 ml of Dimethy1sulfoxyd and after adding 11.2 g (0.1 mol) of potassium tert-butoxide for 30 minutes stirred at room temperature. Then 46.3 g (0.5 mol) of epichlorohydrin are added in one portion with stirring. After 3 hours Stirring at room temperature is the reaction mixture in water poured. The crude product, which separates out as an oily, is taken up in ethyl acetate. The ethyl acetate layer is then thinned with Washed sodium hydroxide solution, dried over potash, and in vacuo constricted. The remaining reaction product is recrystallized from dioxane for purification. One receives on this Way 3-ß-piperidinoethyl-4-methyl-7- (2 ', 3'-epoxy-propoxy) 2-oxo-1,2-dihydroquinoline of m.p. 193-195 °.

Yield: 18 g = 52.7% of theory.

909883/1692

"^ V -; ^ - 1} _ Ref. 2842

^ i-- ■ · - ■ - ■: --- ν 19323 ^ 4 .-.

The following compounds are obtained in an analogous manner:

3-ß-diethylaminoethyl 4-methyl-7- (2 ', 3'-epuxy-propoxy) -2-oxo-1,2-dihydroquinoline M.p .: 158-159 °

3 -T- dimethyl amino ß methyl propyl-4-methyl-7 (2 ', 3'-epoxy-propoxy) 2-oxo-1,2-dihydroquinoline mp: 190 °

3-ß-piperidine-ethyl-4-n-propyl-7- (2 ', 3'-epoxypropoxy) -2-oxo-1,2-dihydroquinoline Mp: 144-148 °

3-ß-Morpholinoethyl-4-methyl-7- (2 ', 3'-epoxy-propoxy) -2-oxo-1,2-dihydroquinoline Mp: 171-173 °.

b) 28.7 g (0.1 mol) of 3η butyl-4-methyl-7- (2 ', 3'-epoxy-propoxy) -2-oxo-1,2-dihydroquinoline are dissolved in 150 ml of alcohol and after the addition of 43.2 g (0.3 mol) of N- (T-hydroxypropyl) piperazine Boiled under reflux for 12 hours. The reaction mixture is then concentrated in a water jet vacuum and the remaining Excess of N- (ΤΓ-hydroxypropyl) piperazine on the oil pump distilled off. The residue is stirred with ethyl acetate. This gives 3-n-butyl-4-methyl-7-jT-14 '- (TT-hydroxypropyl) -piperazino / 1 '^ / y -ß -hy dr oxy -propoxy ί -2-oxo-1,2-dihydro-quinoline of m.p. 158-159 °.

Yield:., 34 g -. = 79% of theory. , .-.,;.

In an analogous manner, see the following general.

Prepare intermediate products according to formula:

■ · '' - ^r '' - ■■ - "'- ■ ■ R"

) -A _o -N .NC

HO-A ₀ -N .N-CH ₀ -CH-CH ₀ -O

² N / ² y ²

OH

9 0 9 8 8 3/1692 0ra _Q , _{NAL lNSPEeTm}

- 20 - Ref. 2842

R ₁ R ₂ A ₂ Fp:

HN CH ₂ -CH ₂ -

CH ₃ -CH ₂ -CH ₂ - 15 7-160 Il -CH ₂ -CH (CH ₃ ) - 176 ° Il -CH ₂ -CH ₂ -CH ₂ -CH ₂ - 136 ° ^C 6 ^H 5 -CH ₂ -CH ₂ - 187 ° Il -CH ₂ -CH (CH ₃ ) - 169 ° Tl-C ₃ H ₇ -CH ₂ -CH ₂ - 176 ° Il -CH ₂ -CH (CH ₃ ) - _97A o (Tue
²³⁶ ch CH ₃ -CH ₂ -CH ₂ - 160 ° ir -CH ₂ -CH ₂ -CH ₂ - 145 ° 11th -CH ₂ -CH (CH ₃ ) - 153 ° 11th -CH ₂ -CH ₂ - 158 ° Il -CH ₂ -CH ₂ -CH ₂ - 156 ° Il -CH ₂ -CH (CH ₃ ) - 168 ° 11th —CHn —CH «-H ^ ~" CHn ^-
£ L - C * cL 12 5 ° ) -CH- ₂ - CH-CHp-CH (CH ₃ ) - 157 ° CH ₃ -CH ₂ -CH ₂ - 206 ° Il -CH ₂ -CH ₂ -CEi ₂ - 206 ° It -CH ₂ -CH (CH ₃ ) - 228 °

y _chloride)

9 0 9J 8 3/1 6 9 2

Ref. 2842

O N-CH ₀ -CH ₀ - \ / ^{2 2}

CH.

-CH ₂ -CH ₂ -CH ₂ -

-CH ₂ -CH ₂ -

-CH ₂ -CH (CH ₃ )

Fp:

133

146 '

208 '

223

212

Example 3 ;

CH ₃ O

CH ₃ O CH ₃ O

-CO-O-CH ₂ - CH ₂ - CH ₂ -N. ^N " ^CH ₂ -CH-CH ₂ -O-

C = O

CH ₃ O

OCH-

OCH,

43.1 g (0.1 mole) of 3-n-butyl-4-methyl-7-jj- [V - (^ hydroxypropyl) -piperazino ^ / l ^ / y-β-hydroxypropoxy r-2-oxo-1,2-dihydro-quinoline are dissolved in 500 ml of anhydrous chloroform and 20.2 g (0.2 mol) triethylamine added. Now 46 g (0.2 mol) of 3,4,5-trimethoxybenzoyl chloride, dissolved in 200 ml, are added dropwise with stirring anhydrous chloroform, within 2 hours. After the exothermic reaction has subsided, the mixture is stirred for a further 2 hours at 40-50 after. After cooling, water is added and the mixture is separated

09883/1692

- 22 - Ref. 2842

off the chloroform layer and wash it with water, 5% strength Sodium bicarbonate solution and again with water. After drying over calcined sodium sulfate, the solvent is distilled in a vacuum at 50 °. The residue is diluted in aqueous

> ■

Dissolved hydrochloric acid and extracted the hydrochloric acid solution with ethyl acetate for cleaning. It is now made alkaline (pH 9) with potash and the reaction product separated out as an oil is extracted with ethyl acetate. The Essigesterlösung is annealed sodium sulfate f dried. The dihydrochloride of 3-n-butyl-4-methyl-7-l V "- 14 '- (Tp-3, 4, 5-tr imethoxybenzoxypropyl) piperazino / 11_7 / - ß- (3, 4, 5-trimethoxybenzoxy) -propoxy / -2-oxo-l, 2-dihydro-quinoline in colorless crystals from decomp. P. 150.

Yield: 55 g = 78% of theory.

The diester described above is also obtained if the monoester obtained according to Example 2 is in chloroform with 3,4,5-trimethoxybenzoyl chloride with the addition of triethylamine implements.

903883/169 2

Ref. 2842

4 ;

-CO-O-CH ₁ -CH _n -N λ 2

r ~ \

N-CH _n -CH-CH- 2 j Z

OH

44.6 g (0.1 mol) of 3-n-butyl-4-methyl-7- (T "-piperazino / T '_ / -β-hydroxypropoxy) -2-oxo-1,2-dihydro-quinoline dihydrochloride suspended in 250 ml of anhydrous chlorobenzene and after adding 41.4 g (0.3 mol) of potash at 50-60 ° with stirring a solution of 2 7.5 g (0.1 mol) of 3,4,5-trimethoxybenzoic acid β-chloroethyl ester in 50 ml of anhydrous chlorobenzene is added dropwise over the course of one hour. The mixture is then stirred under reflux for 12 hours. Undissolved material is then filtered off while still hot and the filtrate is freed from the solvent in a water-jet vacuum. After further work-up as in Example 2 given, the dihydrochloride of 3-n-butyl-4-methyl-7-i ') T- | 4 ¹ - (ß-3, 4, 5-trimethoxybenzoxyethyl) -piperazino / l | J ^ / - ß- hydroxypropoxy / -2-oxo-1,2-dihydro-quinolines in the form of colorless needles from decomp. P. 180.

Yield: 48 g = 70% of theory.

The same product is obtained if 1- (ß-3,4,5-trimethoxybenzoxyethyl) -4- (T-chloro-ß-oxypropyl) piperazine vom Zers.P. 155 (dihydrochloride) with 3-n-butyl-4-methyl-7-hydroxy-2-oxo-1,2-dihydro-quinoline from Fp. 22 6 implements.

909883/1692

Ref. 2842

The 3-n-butyl-4-methyl-7- (Γ-piperazino / l ^ J ⁷ - ß-hydroxy propoxy) - 2-oxo-1,2-dihydroquinoline used as a starting product in the above example can can be produced as follows:

86 g (1 mol) of anhydrous., Distilled piperazine are dissolved in 150 ml of chlorobenzene and heated to 120 °. A solution of 32 g (0.1 mol) of 3-n-butyl-4-methyl-7- (I-chloro-β-hydroxy-propoxy) -2-oxo-1,2-dihydro-quinoline in 100 ml is added to this solution Chlorobenzene was slowly added dropwise with stirring. The mixture is then stirred at 120 for 12 hours. After cooling, the reaction mixture is filtered off with suction from the precipitated piperazine and the filtrate is concentrated in vacuo. Small amounts of the excess piperazine that are still present are distilled off at the oil pump. The residue is taken up in methylene chloride, the solution is washed with water, dried and concentrated somewhat. When mixed with ethereal hydrochloric acid, the dihydrochloride of 3-n-butyl-4-methyl-7- (JSF-piperazino / 1 [_ / - ß-hydroxy-propoxy) -2-oxo-1,2-dihydro-quinoline crystallizes in Form of colorless needles from decomposition P. 140

Yield: 22 g = 49.3% of theory.

In a manner analogous to that in Examples 2 and 3 and in this one As described in the example, the following compounds can be produced according to the invention:

^909883/1692 where

CO-O-A ^ -

J-CH-CH ₂ -O

Ref. 2842

= R

R-,

Fp. or Dec.P. of the dihydrochloride:

CH.

OH

-CH ₂ -CH (CH ₃ ) -

187 ¹

-CH ₂ -

207

^C 2 ^H 5

^C 6 ^H 5 169

-CH ₂ -CH (CH ₃ ) -

180

11-C ₃ H ₇ -CH ₂ -CH ₂ -

145 ¹

(C ₂ H ₅ ) ₂ N-CH ₂ -CH ₂ -

H N-CH ₉ -CH ₉ -

CH, -CH ₂ -CH (CH ₃ ) -

-CH ₂ -CH ₂ -

-CH ₂ -CH ₂ -

127

154

ο.trihydrochloride)

13 7 "

-CH ₂ -CH ₂ -CH ₂ -

128

CH ₂ = CfI-CH ₃ -

-CH ₂ -CH (CH ₃ ) -

OCH.

-0-CO

OCH-

-CH ₉ -CH ₉ -CH ₉ -

113 ^V

-CH ₂ -CH (CH ₃ ) - 129

0-988 3/1692

Ref. 2842

Fp. or Dec.P. of the dihydrochloride:

OCH.

(C ₂ H ₅ J ₂ N-CH ₂ -CH _{2 -CH 3} -0-CO

, - 130

ο (tri-

hydrochloride)

OCH,

-CH ₂ -CH (CH ₃ ) -

145

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -

125 ¹

. (CH ₃ J ₂ N-CH ₂ -CH (CH ₃ ) CH ₂ - "-CH ₂ -CH (CH ₃ ) -1O3 ^C

/ H N-CH ₂ -CH ₂ -

ⁿ " ^C 3 ^H 7 -CH ₂ -CH ₂ -

140

- 134

0 N-CH ₂ -CH ₂ -

CH. -CH ₂ -CH ₂ -

155 ¹

- 100

-CH ₂ -CH (CH ₃ ) - 133

909883/1692

Claims (3)

- 27 - Ref. 2842 Claims 1. Derivatives of 2-oxo-l, 2-dihydroquinoline of the general formula where II is hydrogen or low molecular weight alkyl, R. hydrogen, low molecular weight alkyl, alkenyl, aralkyl, aryl, dialkyl aminoalkyl, the am Alkyl groups standing directly or from the N atom a heteroatom can be colored to form a five, six or seven-membered ring, R _{0 is} hydrogen, low molecular weight alkyl or aryl, li "low molecular weight alkoxy, X hydrogen, halogen or low molecular weight alkyl, in the numbers 1, 2 or 3, A. and Ap a straight-chain or branched alkylene radical with 2 to k carbon atoms and Y is hydrogen, a hydroxyl group or the remainder mean. 2. Process for the preparation of the 2-oxo-l, 2-dihydroquinoline derivatives of the general formula (i) described in claim 1, characterized in that one a) 2-Oxo-1,2-dihydro-quinoline derivatives ^{1 of} the general formula ^l 2 ~~ ¹ (H) 909883/1692 Ref. 2842 wherein Y is hydrogen or a hydroxyl group, with one Alkoxybenzoic acid of the general formula HOOC (III) or a functional derivative, optionally acylated in the presence of an acid-binding agent, or that one b) 2-oxo-1,2-dihydro-quinoline derivatives of the general formula R, (IV) with an alkoxybenzoic acid haloalkyl ester of the general formula HaI-A 0OC (V) where Hai stands for a halogen atom, optionally in the presence an acid-binding agent, condensed, or that one c) derivatives of 7-hydroxy-2-oxo-l, 2-dihydroquinoline of the general formula (VI) 909883/16 92 - 29 - Ref. 2842 with a piperazine derivative of the general formula ( ^R 3 »m \ -CO-O-Pi ₂ -j / NA ₁ -HaI (VII) where Hai stands for a halogen atom, optionally in the presence of an acid-binding agent. 3. Pharmaceuticals, characterized in that they are used as active ingredients a 2-oxo-1,2-dihydroquinoline derivative of that recited in claim 1 general formula (i) included. 909883/1692