DE2530412A1 - CHINOLINCARBONIC ACID DERIVATIVES II - Google Patents

Description

The invention relates to new quinoline carboxylic acid derivatives and processes for the preparation of these compounds which KIs urinary antiseptics have valuable pharmacological effects to have.

The invention relates to quinoline carboxylic acid derivatives of the general formula I.

COOR,

(D,

wherein R. is an unsaturated, straight-chain or branched one Alkyl group with 1 - 6 carbon atoms and

Rp denotes hydrogen or a saturated or unsaturated straight-chain or branched alkyl radical with 1-6 C atoms and, if R ₂ denotes hydrogen, the physiologically acceptable salts with inorganic or organic bases.

Among the straight-chain or branched un-

609883/1235 - · -

Board of Directors: Dr. Christian Brunn Hins-Jürgen Hamann Dr. Heinz Hannse Postal address: SCHERING AG D-I Berlin 65 PO Box 65 0311

Karl Otto Mittelstenscheid Dr. Horst Witzel Postscheck account: Berlin-West 11 75-101, bank code 10010010

SIeIIv .: Dr. Herbert Asmls Berliner Commorzbank AG, BBrIIn, account no. 108 7006 00, bank code 100 400

Chairman of the Supervisory Board: Dr. Eduard V. Schwartzkoppen Berliner Disconto-Bank AG, Berlin, Konlo-Nr. 241/6008, bank code! 100 700

Company headquarters: Berlin and Bergkamen

ΑΛ Vimnn

Berliner I .andels-Cesellschaft - Frankfurter Bank -, Berlin,

SCHERING AG

Intellectual Property

saturated alkyl groups with 1-6 carbon atoms such as vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, Pentenyl, hexenyl, propadienyl, butadienyl, hexadienyl, isopropenyl, 1-methylpropenyl> 2-methylpropenyl, 2-methylallyl, isopentenyl, 3.j5-dimethyiallyl, a'thynyl, Propargyl, butynyl, hexynyl, 1-methyl-2-propynyl, 2-methyl-3-pentynyl, 2-penten-4-ynyl, 1-methyl-2-penten-4-ynyl and 2-methyl-10-butadienyl are understood, such groups with 1-4 carbon atoms are preferred.

Among the straight-chain or branched saturated alkyl groups mentioned, groups such as methyl, ethyl, Propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, neopentyl, hexyl understood groups with 1-4 carbon atoms are preferred.

If R _{2 is} hydrogen, the new compounds can be used in the form of their physiologically acceptable salts with inorganic or organic bases.

Inorganic and organic bases, as used in the usual way by the person skilled in the art, are used for salt formation, in question.

Bases that are known to be preferred for salt formation include, for example: Potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, Magnesium hydroxide, glucamine, N-methylglucamine,. N. N-Dime thy iglucamine, ethanolamine, diethanolamine, morpholine,

609883/1235 - 3 -

Board of Directors: Dr. Christian Bruhn · Hans-Jürgen Hamann · Dr. Heinz Hannse Postal address: SCHERING AG · D-I Berlin 65 ■ Postfach 65 0311 Karl Otto Mittelstenscheid ■ Dr. Horst Witzel Postscheck account: Berlin-West 11 75-101, bank number 10010010 Deputy: Dr. Herbert Asmis Berliner Commerzbank AG, Berlin, account no. 108 7006 00. Bank code 100 400 OQ Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Dlsconto-Bank AG, Berlin, account no. 241/5008. Bank code 100 700

c ». j-. n "." ii "" h "". narHn unH Rornkampn Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin,

SCHERINGAG

Intellectual Property

ft-methylmorpholine, tris (hydroxymethyl) methylamine, etc.

From patent application P 20 30 899.0 it is known that 2,3-dihydrofuro // 2,3-g / quinoline-7-carboxylic acids have good inhibitory values show against gram-positive and gram-negative bacteria and are therefore suitable as urinary tract therapeutics. links for this indication, sufficient excretion in the urine must show, because the Dosage depends. Only with an increase in the urine level can the administration of an active ingredient in a lower dose take place.

It has now been found that the new compounds of general formula I have a good inhibitory action against gram-positive and gram negative bacteria against e.g. B. 5-Ethyl-2,3,5,8-tetrahydro-8-oxo-furo / 2,3-g7-quinoline-7-carboxylic acid (from P 20 ^ O 899 · 0) show an increased urine excretion, like the following table using the example of the compounds according to Example 3 and Example 4 in comparison with 5-ethyl-2.3.5.8-tetrahydro-S-oxo-furo /^.^- g / quinoline-T-carboxylic acid identifies. The numerical values indicate the percentage of an administered dose which is found in the urine of rats within 6 ^ hours is excreted at a dose of 100 mg / kg per os.

link

5-Ethy1-2.3.5.8- tetrahydro-8-οχο-fur0 / 2.3-g7quinoline-7-carboxylic acid

8-oxo-5- (1-propenyl) -2.3.
5.8-tetrahydro-

furo / 2.3-g / quinoline-7-carboxylic acid
(Example 3)

8-0x0-2.3.5.8-tetrahydro-5-vinyl-furo / 2.3 ~ s7 quinoline-7-carboxylic acid

(Example 4)

Excretion (%)

0.48 %

609883/1235

3.4

- • 4 -

Board of Directors: Dr. Christian Brunn · Hans-Jürgen Hamann - Dr. Heinz Hannse Karl Otto Mittelstenscheid Dr. Horst Witzel Deputy: Dr. Herbert Asmis · · Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Company headquarters: Berlin and Bergkamen Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen HRB 0061 Postal address: SCHERING AG ■ D-1 Berlin 65 · P.O. Box 650311 Postal check account: Berlin-West 11 75-101, bank code 10010010 Berliner Commerzbank AG, Berlin, account no. 108 7006 00, bank code 100400 Berliner Dlsconto-Bank AG .. Berlin, account no. 241/5008, BankleiUahl 10070000 Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, Account no. 14-362, bank code 10020200

SCHEPJNG AG.

Intellectual property law - l [ -

The new compounds can be used in the usual pharmaceutical application forms, such as tablets, coated tablets, Capsules, pills, solutions, etc. are administered.

The new compounds can be prepared by adding a compound of the general formula II, the ' can be in the tautomeric forms A or B,

OH

11 A

II B

wherein R _{2 has} the meaning given above with a compound R ¹¹ X, wherein

R "has the meaning given above for R- or a saturated, straight-chain or branched alkyl residue, with 1-6 carbon atoms, 1 or 2 halogen atoms, hydroxyl groups, acyioxy groups with 2-4 carbon atoms, benzoyloxy groupsi Alkanesulfonyloxy groups with 1-4 carbon atoms in the alkyl radical or benzenesulfonyloxy groups, which are on the. The nucleus can be substituted by halogen atoms or by alkyl groups containing 1-4 C atoms, contains, means, and X the meaning of a halogen

609883/123 5

Chair: Dr. Christian Bruhn · Hans-Jörgen Hamann · Dr. Heinz Hanns * Karl Olto MiUelstenscheld Dr. Gerhard Raspe Dr. Horst Wltzol Deputy: Dr. Herbert Asmls'

Chairman of the Supervisory Board: Dr. Eduard v. Sctiwarizkoppen Seat of the company: Berlin and Bergkamen n ,, «,« «« Commercial register: AG Charlottenbuig 93 HRB 283 and AG Kamen HUB 0061 Postal address: SCHERING AG D-1 Berlin 65 PO Box 650311 Poalschock-Konio: Borlln-Wesl 1175-101, bank code 10010010 Borllnor Commorzbank AG, Berlin, Konlo-Hr.'ioa700C00, number 10040000 Berliner DlscoMo-Dank AQ, Berlin, account no. 841/5000, ßankielt number 100 700 Borllnor Handols-Gosellscr.aft - FianklurterGank -, Berlin, Konlo no. 1Ί-302, OanklolUahl 1002U200

SCHERiNGAG

% ~ ¹ J) ~ Intellectual Property

adorns, an alkanesulfonyloxy group with 1-4 carbon atoms in the alkyl radical or a benzenesulfonyloxy group, which can be substituted by halogen atoms or by alkyl groups containing 1-4 carbon atoms, and then splitting off substituents present in R "in a manner known per se and then esterified a free carboxyl group in any order or saponified an esterified carboxyl group and / or _{rearranges the carbon-carbon multiple bond in R 1,} depending on the final product desired, in a manner known per se and, if desired, a free carboxylic acid with an inorganic or organic base in the water-soluble salt transferred.

When R "is a saturated straight-chain or branched alkyl radical with 1 or 2 substituents leading to the introduction are eliminated by multiple bonds, the alkyl radical has the above, for straight-chain or branched saturated alkyl groups given meaning. As a substituent come into consideration: the halogens fluorine, chlorine, bromine, iodine, fluorine, chlorine and bromine being particularly preferred, the hydroxyl group, the acyloxy radicals formyloxy, acetoxy, propionyloxy, Butyryloxy, pentanoyloxy, hexanoyloxy, where Residues with 1-4 carbon atoms are particularly preferred, alkanesulfonyloxy groups, such as methane or ethanesulphonyloxy, the methane radical being preferred, o-, m- or p-halobenzenesulphonyloxy groups, being the p-position and among the halogens

609883/1235

: Dr. Eduard v. Schwartzkoppen ^ trading company - Frankfurter Bank -. Berlin.

^ S ^ Account no. 14-362. Bank.e.U.h. 10020200 "3 ED, V .7CT

" Intellectual Property

SCHERING AG

hereditary law)

Fluorine, chlorine, bromine and iodine, the halogens chlorine and bromine are particularly preferred, and o-, m- or p-alkylbenzenesulfonyloxy groups, where the p-position is particularly preferred and among the alkyl groups Methyl, ethyl, propyl, butyl those with 1-2 carbon atoms have priority. As for the number of substituents 1 substituent on the alkyl of the radical R "is preferred.

The radical X in the compound R ¹¹ X can contain the halogen atoms fluorine, chlorine, bromine and iodine, fluorine, bromine and iodine being preferred, an alkanesulfonyloxy group with alkane as methane or ethane, methane being preferred, or an arylsulfonyloxy group with aryl as phenyl, o-, m- or p-alkyl phenyl (alkyl = methyl, ethyl), o-, m- or p-halophenyl, naphthyl, etc. mean.

The alkylation is carried out in an alkaline medium, preferably in water or in organic solvents, such as. ., Etc., alcohol, dimethyl sulfoxide, dioxane, tetrahydrofuran and mixtures thereof or with water at 0 to I5O ⁰ C, preferably at O -.. 100 ° C, with a reaction time of 0.5 hours to 5 days, performed. The alkaline medium used is, for. B. 1-10 equivalents of alkali, preferably NaOH or KOH, to the alkylating reagent used, in particular 2-6 equivalents in aqueous alcohol or dimethyl sulfoxide.

The N-alkylation can be carried out with an alkylation reagent R ¹¹ X,

609883/1235

Board of Directors: Dr. Christian Brunn · Hans-Jöraen Hamann · Dr. Heinz Hannse Postal address: SCHERING AG D-I Berlin 65 PO Box 65 0311 Karl Otto Mittelstenscheid Dr. Horst Witzel Postscheck account: Berlin-West 1175-101, bank code 10010010 Deputy: Dr, Herbert Asmls Berliner Commerzbank AG, Berlin, account no. 108 7006 00, bank code 10040000 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-Bank AG, Berlin, account no. 241/5008, bank code 100 700 Company headquarters: Berlin and Bergkamen Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin,

u- "w", i. ",";., _or . from nharinttcmburu 93 HRB 283 and AQ Kamen HRB ΟΟβΙ account no. 14-362, bank code 100 202 00

SCHERINGAG

Commercial reditc protection

in which R ″ already has the ultimately desired meaning for R ₁ , or - which may be useful or necessary for experimental reasons (e.g. R ₁ meaning a vinyl group) - with an alkylating agent R ¹¹ X can be carried out in which R "represents a saturated alkyl radical which is substituted by a radical which can easily be eliminated with the formation of the ultimately desired unsaturated C — C bond in R ^. Assuming such substituted R ″ X alkylating reagents, the eliminations usually proceed spontaneously under the alkylation conditions to give the desired end products of the general formula I. If substituents present in R ″ are not split off simultaneously under the alkylation conditions, the subsequent EliminieruTg with basic reagents such as NaOH, KOH, K-tert-butylate, NaH, kgCO ,, pyridine, amines in solvents such as water, alcohol, dimethylformamide or dimethyl sulfoxide at temperatures between 0 and I5O ⁰ C, preferably between 20 and 100 ° C, carried out in 0.5-10 hours, preferably in 0.5-5 hours.

Contains the primary product of the process according to the invention the unsaturated C-C bond in the radical R- is not yet in the ultimately desired position, it is shifted according to methods such as those known to those skilled in the art for solohe rearrangement reactions are generally known.

609883/1235

i! S ^^^^^^^^ S ^ ^. 0-tBer.ln 65. Postfa * 650311

Deputy HerbertAsml's postal check account: Berlln-West11 75-101, bank code 10010010 Preacher of the Supervisor Dr. Eduardv.Schwartzkoppen ^^^ SS ^^^^^^^ S ^^

SCHERING AG

" " Intellectual Property

The reaction can take place under alkaline or acidic reaction conditions. As basic rearrangement catalysts come z. B. alkalis such as NaOH, KOH or K-tert.-butoxide in question and as an acidic catalyst e.g. trifluoroacetic acid, -

Basic rearrangement is preferred. It takes place e.g. at temperatures between 0 and 180 ° C, preferably at 0 150 ° C, in 0.5 - 24 hours, preferably in 2 - 4 hours, with 5 - 7 π NaOH or KOH in solvents such as water, Ethylene glycol, dimethylformamide or the like.

The 7-position -COQRg group in the process product can be a free or esterified carboxyl group. Is Rg In the starting product a Η atom, under the alkylation conditions, an esterification of the free Carboxyl group take place, especially when R "is in the alkylating agent is equal to R.

If -COOR _{2 is} an esterified carboxyl group in the starting product, is. the stability of this ester group depends on the conditions of the alkyl: <^ ungs- and / or elimination reaction. If these reactions are carried out at, in particular, a higher reaction temperature, the ester group is wholly or at least partially saponified as well. Depending on the ultimately desired meaning of Rg, a free carboxyl group is esterified or post-esterified and an esterified carboxyl group is saponified by methods known per se.

609883/1235 * ■

Board of Directors- Dr Christian Bruhn · Hans-Jürgen Hamann · Dr. Heinz Hannse Postal address: SCHERING AQ · D-1 Berlin 65 · Pesttacti «6 0311 KarlOttoMIttelstenscheid · Dr HorstWltzel Postscheck account: Berlin-West 1175-101. Bank number 10010010. Deputy: Dr. Herbert Asrrrf * Berlin Commerzbank AQ. Berlin. Account no. 108 7006 00, BankleltzaW 100 «0 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Dlsconto-Bank AQ. Berlin, account no. 241/5008, bank loan number 100 700

ft- Berlin and Berokamen Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin,

^^^ Account no. 14-362, BankleltzahM0020200. _mtoumH

SCHERING AG

Intellectual Property

• The salt formation is carried out in a manner known per se, z. B. with 1 normal solution of the appropriate inorganic or organic bases; being the received Solution is evaporated and the remainder ζ. · Β. the end Alcohol / water mixtures (5-9 * 5-1) is recrystallized.

The reaction products are usually obtained due to the multiple bonds in R ₁ and optionally also in Rp in the form of their cis / trans isomer mixtures / which can be separated into the cis and trans form in the usual way, e.g. 3. by fractional crystallization or chromatography.

The new compounds can be used in the usual pharmaceutical application forms such as tablets, coated tablets, Capsules, pills, solutions, suspensions, etc. can be administered.

The new compounds should be used in conjunction with the additives customary in galenic pharmacy, for example are used in the manufacture of agents against urinary tract infections.

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609883/1235

Board of Directors · Dr Christian Bruhn ■ Hans-Jürgen Hamann · Dr Heinz Hannse Postal address: SCHERING AG D-1 Berlin 65 PO Box 65 0311 KarlOtto'Mit'telstenscheid · Dr Horst Witzel Postscheck account: Berlin-West 1175-101, bank number 10010010 StellV · Dr Herbert Asmis Berliner Commerzbank AG ₁ Berlin, account no. 108 7006 00, bank code 100 «0 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-Bank AG. Berlin, account no. 241/5008. Bank code! 100 700 00 _

ft- Berlin and Bergkamen Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin,

SSSZSuSSa HRB 283 U. AG Kamen HRB 0061 KoMo-Nr. 14-362. Bank code 100 202 00 - ^ ^ _{| y} ^

SCHERING AG

•Intellectual Property

The application can be in the pharmaceutically usual Application forms take place. The compounds according to the invention are particularly for oral administration suitable e.g. B. in tablets, coated tablets, capsules, pills and suspensions. Tablets contain for example 0.1 to 1 g of active ingredient and 0.1 to 5 g of a pharmacologically inert excipient. As auxiliary materials are used for tablets, for example: lactose, starch, talc, gelatin, magnesium stearate etc.

The compounds according to the invention are both in the human as well as in the veterinary field.

The new active ingredients should be in amounts between 0.1 and 4.0 g per patient and per day are used.

The following examples are intended to explain the process according to the invention in more detail.

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609883/1235

Board of Directors: Dr. Christian Brunn · Hans-Jürgen Hamann · Dr. Heinz Hannse Postal address: SCHERING AG D-I Berlin 65 PO Box 65 0311

Karl Otto Mittelstenscheid Dr. Horst Witzel Poslschfk account: Berlin-West 11 75-101, bank code 10010010

Deputy: Dr. Herbert Asmls Berliner Commerzbank AG, Beilln, account no. 108 7006 00, bank code 100 400

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Dlsconto-Bank AG, Berlin, account no. 241/5008, bank code 103 7OQ

Seat of the company - Berlin and Bergkamen Berliner Handels-Gesellschaft - Frankfurter Bank -. Berlin,

SCHERING AQ

Commercial advertising

- li -

example 1

5-AlIyI-S-oxo-2.3.5.8-tetrahydro-furo [2.3-g] quinoline-7-carboxylic acid

a) 5-AlIyI-S-OXO ^ .3.5.8-tetrahydro-furo [2.3-g] quinoline-7-carboxylic acid allyl ester '.

5.8 g of powdered sodium hydroxide are suspended in 27 ml of dimethyl sulfoxide, then. J5, lg 8 ~ hydroxy-2,3-dihydro-furo [2,3-g3quinoline-7-carboxylic acid added and stirred for 10 min. At room temperature. Then 5 * 67 ml of allyl bromide are added, stirred for 2 hours at room temperature, then poured into water. The Festp o'dukt _r is filtered and recrystallized from ethanol. Melting point 100 ° C. Yield 2.5g.

b) 5-AlIyI-S-OXO ^ .3.5.8-tetrahydro-furo [2.3-g] quinoline-7- ^! carboxylic acid

1.0 g of 5-allyl-8-oxo-2.3.5 »8-tetrahydro-furo ^ .5-s7 quinoline-7-carboxylic acid allyl ester are refluxed with 10 ml of 2N NaOH for 10 minutes. The solution is filtered and acidified.! / The precipitated product is recrystallized from DMP. Melting point 264-279 ⁰ C. Yield 0.55 g.

609883/1235

Chairman: Dr. Chrljttan Bruhn · Hans-Jürgen Htminn · Dr. He'm H «nnt« Po »Un» chritI: SCHERINQ AO · D-1 Btflln 65 · P.O. Box 65 0311 Kail OltoMmelsInnJCtieid - Dr. Gerhard Hasp * Dr. Horst WtUeI Pc »<s * ccfc-KoMo: toim-Wcsl 11 T5-101, OankleiMarsl loa 10010 StOlIv .: Dr. Herbert Asmis B «rt <n <r Commei / tjnK AG. berlin, Konlo no. ic8 700600. Bank number IMiOOM Vortlt2 # n <ler of the Aubkhisrat: Dr Eduard v. $ * Wartzkopp «n ft« rlin »r Diseonto-e * niiAG, Berlin. Account number 241/5006. BanklaiUahl 10070000 Site of the company · fcerlin and Bernkamen. p. * »! iner H.m <j. 'sGosell ^ iiinH - Frankfurter Bank -, Berlin, H ^ lit ^ «eoto no. Μ * 2. e.oM «u ·« 100Z _V 200 ......

SCHERiNGAG

Intellectual Property

- 12 -

Example 2

8-0x0-5- (1-propenyl) -2.J5.5.8-tetrahydro-furo [2 .3-g] quinoline-7-carboxylic acid

500 mg 5-allyl-8-oxo-2.3.5.8-tetrahydro-furo [2 "3-g] quinoline-7-carboxylic acid are dissolved in 5 ml of 5N NaOH and 2.5 ml Ethylene glycol heated to 130 ° for 3 hours. Water and concentrated hydrochloric acid are added to the precipitated material recrystallized from dimethylformamide. Melting point C. Yield 0.30g.

Example 3

8-0xo-5- (l-propenyl) -2.3.5.8-tetrahydro-furo [2.3-g} quinoline-7-carboxylic acid, sodium salt

0.30 g of 8-0xo-5- (1-propenyl) -2.3.5.8-tetrahydro-furo [2.3-g] quinoline-7-carboxylic acid are dissolved in 1.1 ml of NaOH. It is evaporated and the residue is recrystallized from isopropanol / water 8: 2. Melting point 235 ^° C. Yield 0.20 g.

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609883/1235

Board of Directors: Dr. Christian Bruhn ■ Harm-Jürgen Hamann · Dr. Heinz Hanns · Postal address: SCHERING AQ · D-I Berlin 65 · Postfach 650311 Karl Otto Mittelstenscheid Dr. Gerhard fiaspe Dr. Herat Witzel Postscheck account: Berlin-West 1175-101, bank code 10010010 Deputy: Dr. Herbert Asmls Berliner Commerzbank AQ, Berlin, account no. 108 7006 00, bank code 100 «0 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-Bank AG, Berlin, account no. 241/5006, bank code 100 700 00 ' Company headquarters: Berlin and Bergkamen Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, Commercial register: AG Charlottenburg93 HRB283 and AG Kamen HRB0061 account no. 14-362, bank code 10020200

SCHERING AG

Intellectual Property Example 4

8-0x0-2.3.5-8-tetrahydro-5-vinyl-furo [2.3-g] quinoline-7-carboxylic acid

a) 6.0 g of powdered sodium hydroxide are in 45 ml Suspended dimethyl sulfoxide, 5 * 0 g of 8-hydroxy-2,3-dihydrofuro [2.3-g] quinoline-7-carboxylic acid entered and stirred for 10 min. at room temperature. There are 8.2 g of 1-bromo-2-fluoroethane added, then stirred for 2 hours. It is poured into water, acidified with concentrated hydrochloric acid. The solid product obtained is chromatographed over 200 g of silica gel with dioxane / conc. NH ^ OH / water 8: 1: 2, the pure substance recrystallized from dimethylformamide. Melting point 300-304 ° C (dec.). Yield 0.3g.

b) 2.8 g of powdered sodium hydroxide are suspended in 20 ml of dimethyl sulfoxide, 2.3 g of 8-hydroxy-2,3-dihydrofuro [2.3-g] quinoline-7-carboxylic acid are added and the mixture is stirred at room temperature for 10 minutes. 2.6 ml of 1,2-dibromoethane are added and the mixture is stirred for 24 hours at room temperature. It is poured into water, acidified with concentrated hydrochloric acid. The solid product obtained is over silica gel with dioxane / conc. NH ^ OH / water 8: 1: 2 chromatographed, the pure substance recrystallized from dimethylformamide. Melting point 300-304 ⁰ C (dec.). Yield 0.04g.

609883/1235 - 14 -

Board of Directors: Dr. Christian Bruhn · Hans-Jürgen Hamann · Or. Heinz Hannse Postal address: SCHERING AQ · D-1 Berlin 65 ■ P.O. Box 650311

Karl Otto Millelstenscheld Dr. Gerhard Raspe Dr. Horst Witzel Postscheck account: Berlin-West 11 75-101, bank code 10010010

Deputy: Dr. Herbert Asmis Berliner Commerzbank AG, Berlin, account no. 108 7006 00, bank code 10040000

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-BankAG, Berlin, account no. 241/5008, bank code 10070000

Seat of the company: Berlin and Bergkamen Berliner Haiidels-Gesellschaft - Frankfurter Bank -, Berlin,

Commercial register: AG Charlottenburg S3 HRB 2S3 and AG Kamen HRB 0061 account no. 14-362, bank code 100 20200

SCHERING AG

Intellectual Property

c) 2.3 g e-

carboxylic acid are in a mixture of 2.04 g of potassium hydroxide, 14.8 ml of water, 46 ml of ethanol and 7 * 5 g of 1,2-bromofluoroethane given and refluxed for 5 days. The solid product obtained is filtered off and poured over 200 g of silica gel with dioxane / conc. NH ^ OH / water 8: 1: 2 chromatograph! Ert, then recrystallized from ethanol. It will be 0.36 g 5- (2-fluoroethyl) -8-0x0-2.3.5.8-tetrahydrofuro / 2 \ 2-g / quinoline-7-carboxylic acid obtained with the decomposition point 3 ° 8-314 ° C. 0.36 g of 5- (2-fluoroethyl) -8-0x0-2.3.5.8-tetrahydro-fur0 / 2.3-g7-quinoline-7-carboxylic acid are added to a mixture of 4.8 g of NaOH and 3.5 ml of dimethyl sulfoxide and 2 hours at 25 ° C touched. It is poured into water, acidified with concentrated hydrochloric acid and the solid product obtained over silica gel with dioxane / conc. NH ^ OH / water 8: 1: 2 chromatographed. There are 0.20 g of e-Oxo ^ O ^ .S-tetrahydro-S-viny quinoline-7-carboxylic acid with a melting point of 300 - 304 ° C (decomposition) obtain.

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609883/1235

Board of Directors: Dr. Christian Bruhn · Hans-Jürgen Hamann · Dr. Heinz Hannse Postal address: SCHERING AG D-1 Berlin 65 Postfach 65 03 Y.

Karl Otto Mittelstenscheid Dr. Horst WiUeI postal check account: Berlin-West 11 75-101, bank code 10010010

Deputy: Dr. Herbert Asmls Berliner Commerzbank AG, Berlin, account no. 103 7Q06 00, bank code 100 400

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-Bank AG, Berlin, account no. 241/5003, bank code! 100 700

Company headquarters: Berlin and Bergkamen Berliner Handeis-Gesellschaft - Frankfurter Bank -, Berlin,

Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen HRB 0061 account no. 14-362, Bankleitzshl 100 202 00

'- H3 ED IV 17094

SCHERING AG

Intellectual Property Example 5

8-oxo-5-propargyl-2.3.5.8-tetrahydro-furo [2. j5-g] quinoline-7 - c art) ons aur e

2.21 g of 8-hydroxy-2,3-dihydro-furo [2.3-g] quinoline-7-carboxylic acid and 4.7 ml of 3-bromopropine are taken in a solution of 1 * 96 g of KOH in 14.2 ml of water and 4o ml of ethanol for 5 days Refluxed. The product that crystallizes out after cooling is recrystallized from acetic acid. Melting point 308-31O ° C. Yield 1.7g.

Example 6

8-Oxo-5-pr opadieny 1-2. J5.5.8-th trahydro-furo [2. j5-g] quinoline-7-carboxylic acid

a) 0.54 g of 8-0xo-5-propargyl-2. ^. 5.8-tetrahydro-furo [2. ^ - g] quinoline-7-carboxylic acid are dissolved in a suspension of 0.56 g of powdered potassium hydroxide and 11 ml of dimethylformamide entered at 0 ⁰ C. It is stirred for 2 hr. At 0 ⁰ C, poured into water, acidified with hydrochloric acid and recrystallized from dimethylformamide the Pestprodukt obtained. Melting point 257-26l ° C. Yield 0.16g.

• ■ 16 - '

609883/1235

Board of Directors: Dr. Christian ßruhn - Hans-Jürgen HamannDr. Heinz Hannse Postal address: SCHERING AG · D-1 Berlin 65 · P.O. Box 650311

Kart Otto MittelstenscMfli · Dr. Gerhard Raspe ■ Dr. Horst Wltzel Postscheck account: Berlin-West 1175-101. Bank code 10010010

Place: Dr. Herbert Asm »· Commerzbank AG from Berlin. Berlin. Account no. 108 7006 00, bank code 100 400

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-Bank AG, Berlin. Account no. 241/5008. Bank code 10070000

Seat of the company: Berlin and Bergkamen Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, -

Commercial register: AG Chafloltenburg 93 HRB283 and AG Kamen HRB0061 account no. 14-362, bank guide number 10020200

-.16 -

SCHERiNG AQ

Intellectual Property

b) 0.20 g of 8-0xo-5-propargyl-2.3.5.8-tetrahydro-furo [2.3-g] c hi no lin-7-carboxylic acid are dissolved in 10 ml of trifluoroacetic acid Stirred for 20 hours at room temperature, it is poured into water and the pest product obtained from dimethylformamide recrystallized. Melting point 257-26l ° C. Yield 0.10g.

Example 7

5- (2-butenyl) -8-oxo-2.3.5.8-tetrahydro-furo [2.3 ~ g] quinoline-7-carboxylic acid

a) 5- (2-butenyl) -8-oxo-2.5.5.8-tetrahydro-furo [2.3-g] quinoline-7-carboxylic acid 2-butenyl ester

2.5 g of 8-hydroxy-2,3-dihydro-furo [2.3-g] quinoline-7-carboxylic acid are at room temperature in a suspension of j5.0 g Sodium hydroxide added to 21.8 ml of dimethyl sulfoxide, then 4.4 g of crotyl bromide are added. It is stirred for 2 hours at room temperature, poured into water and the resulting Solid product recrystallized from ethanol. Melting point 111 ° C. Yield 0.85g.

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609883/1235

Board of Directors: Dr. Christian Bruhn · Hans-Jürgen Hamann · Dr. Heinz Hannse Postal address: SCHERING AG · D-1 Berlin 65 · P.O. Box 650311 Karl Otto Mittelstenscheid Dr. Gerhard Raspe Dr. Hörnt Witzel Postscheck account: Berlin-West 1175-101, bank number 10010010 Deputy: Dr. Herbert Asmls Berliner Commerzbank AG, Berlin, account no. 108 7006 00, bank code 100 400 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-Bank AG. Berlin, account no. 241/5008, bank number 100 70000 Company headquarters: Berlin and Bergkamen Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, Commercial register: AG Charlottenburg 93 HRB 283 U. AG Kamen HRB 0061 account no. 14-362, bank number 100 20200 ^

SGHERiNGAi

Intellectual Property

b) 5 -. (2-butenyl) -8-oxo-2.3.5.8-tetrahydro-furo [2.3-g] ch ± nolin-7-carboxylic acid

0.75 g of 5- (2-butenyl) -8-oxo-2.3.5.8 ~ tetrahydro-furo [2.3-g], quinoline-7-carboxylic acid 2-butenyl ester in 10 ml of 2n NaOH refluxed for 10 min. It is filtered, acidified with hydrochloric acid and the pest product obtained recrystallized from dimethylformamide. Melting point 276-286 ° C. Yield 0.4-3g.

Example 8 '■

5- (1-butenyl) -8-.OXO-2.3.5.8-tetrahydro-f urο [2.3-g] quinoline-7-carboxylic acid '..-'

0.30 g of 5- (2-butenyl) -8-oxo-2.3.5.8-tetrahydro-furo [2 _i 3-g] quinoline-7-carboxylic acid are dissolved in 3 ml of 5N NaOH and 1.5 ml of ethylene glycol for 4 hours. heated to 130 ° c. It is diluted with a little water, acidified with hydrochloric acid and the pest product obtained is recrystallized from dimethyl sulfoxide / water. Melting point 270-271 ⁰ C. Yield 0.11 g.

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6 0988 3. / 1235

d: Or. Christian Bruhn. Han _S .JOrq _e n H _a rr. _B nn · Or. Heini H.nn ,. Pom.ns ^ rM: SCMER-NG AG - D- 'B.rlln 65 · PoMlach 65 0311

Karl Olio Millelslensctioid · Dr. Gernard Haspö ■ Or. Horsl Wiuol Pojis ^ fcv-Kcnio: POrPn-WCSt 1175-101. tijnklcil ^ ar.l 10010010 S'ollv - Dr ΗργβπγΙ Asmis ßoil.nor Ccmtr.vribank AG. Berlin. Kon'.o no. 1C8 7005 00. Bünkleitz number 1M4M0Q

iorsiüonder de »Board of Supervisors: Dr Eduard V. Schw ^ kopp.r, BT.mer Ο ,, οοΓ., ο-Β ^ ηΚ AG. Uerlm. Kon.c no. 241 / M08. B _a nk. _e , üahl too JM

.n EcTlinci H.inii. 's-Gf 5ell'.criBtt - FianMuiter Bank -, Borlln,

SCHERING AG

Intellectual Property

Example 9

5- (2-methyl-2-p: ropenyl) -8 ~ oxp-2.3.5.8 ~ tetrahydro-furo [2.3-g] quinoline-7-car bons acid e

a) 5- (2-Methyl-2-propenyl) -8-oxo ~ 2.3.5.8-tetrahydro ~ furo [2.3-g] quinoline-7-carboxylic acid (2-methyl-2-propenyl) ester

2.3 g of 8-hydroxy-2,3-dihydrofuro [2.3-g] quinoline-7-carboxylic acid are in a suspension of 3.0 g of sodium hydroxide and entered 20 ml of dimethyl sulfoxide, then 6.0 g Methallyl bromiu. It is stirred for 2 hours at room temperature, Poured into water and the resulting plague product recrystallized from ethanol. Melting point 169-172 ° C. yield 0.80 g. '

b) 5- (2-Methyl-2-propenyl) -8-oxo-2.3.5.8-tetrahydro-furo- [2.3-g] quinoline-7-carboxylic acid '

0.75 g of 5- (2-methyl-2-propenyl) -8-oxo-2.3.5.8-tetrahydrofuro [2.3 ~ g] quinoline-7-carboxylic acid (2-methyl-2-propenyl) ester. are suspended in 10 ml of 2N NaOH and refluxed for 10 min. It is filtered, mixed with hydrochloric acid. acidified and the solid product obtained from dimethylformamide recrystallized. Melting point 265-272 ° C, yield 0.30 g.

• .- 19 -

609883/1235. ·

Board of Directors · Dr Christian Bruhn · Hans-JGrqen Ham.nr, · Dr. Helmet Hanni. Post.nsct> r, fi: SCHEBING AG D-I Berlin $ 5 Postta * 650311 Karl Suo Mmeistens ^ oath · Dr. GmrTard Haspe Dr. Horst W.uol Postv ^ -ck-Kcnio: Pert.n-WeM 11 7S-101. DanWe.Wänl 10010010 StOlIv -Dr Horbnrl Asmis Borl.nor CommcriSanK AG. iiorlin. Account no. 108 7006 00.BanklelUahl 100 ^ 00 V ^^ rde. ^ B. * «Ral,: Or.Edu.rd..8 * w.rlli« PP.n ^ tm.r D.sconto-Ban. AG. Βο,., Η.Κοη, ο-Ν,. ^ Ι / ^ ΒαηΚ.β, ^. 100.00

tSc'lmcr Μ.ιπι: · ° i-GMntKctt.i <i - Ftnnkluiter Bank -, Borlin.

SCHERING AG

Intellectual Property

- 19 -

Example 10

5- (2-methyl-1-propenyl) -δ-οχο-2 .3 . 5.8- tetrahydr o- f uro [2. 3-g] quinoline-7-carboxylic acid

0.25 g of 5- (2-methyl-2-propenyl) -8-0x0-2.3.5.8-tetrahydrofuro [2.3-g] quinoline-7-carboxylic acid are dissolved in 3 nil 5N NaOH and 1.5 ml of ethylene glycol for 3 hours. heated to 130 ⁰ C. It is diluted with a little water, acidified with hydrochloric acid and the pest product obtained is recrystallized from dimethylformamide. Melting point 293-295 ° C. Yield 0.16 g, ■

Example 11 · · "

δ-Οχο-2.3 «5» 8-tetrahydro-5-vinyl-furoZ2.3- £ 7quinoline-7-. carboxylic acid, sodium salt

0.23 g S-

7-carboxylic acid are dissolved in 0.9 ml Γ η NaOH. It is concentrated in vacuo and the residue is recrystallized from isopropanol / water 8: 2. Melting point 253 - 257 g ⁰ C. Yield 0.13.

■ - ■ - ■ "- 20 ~

609883 / 1Z3 5

Vorland: Dr. Christian Bruhn · Hans-Jürqen Hamann · Or. Heinz Hanni »PoiUnjdind: SCHERING AG -D-I Berlin 65 · P.O. Box 65 0311 Karl OUo Mitielslensctioid · Dr. Gerhard Kaspu Dr. Horit Wiuel Posts J- «rk-Kcnlo: Pe'im-Wes! It 7S-101. Bank control 73hl 10010010 Stollv .; Dr Herber: Asmis Beil.nm Ccmir.encanii Au. iicrlin. Account no. 1C3700000. Bank leltiaht 100 <COOO Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berlin D-sconto-Biηκ AG. eerl.n. Konlo no. 2-ti / iOOe. BanKleiüahl lOO 7oo SiIz def Gesellschalt · Berlin and Borgkamen ßni-n «M.md, • s-Gcjoll'.cfia't - Tranklurter Bank -. Berlin. Commercial register: AG Charlollonbure S3 HHB 283 U. AG Kernen HRB OCiI Kor.ia-NT. HJc2. Bankloi ^ aM 1D0IV2C0

Claims (1)

SCHERING AG Intellectual Property 20 - Patent claims ^ ΐΫ quinoline carboxylic acid derivatives of the general formula I. COOR, (D, wherein R _{1 is} an unsaturated, straight-chain or branched alkyl group with 1-6 carbon atoms and Rp is hydrogen or a saturated or unsaturated one straight-chain or branched alkyl radical with 1-6 C atoms and, if Rp is hydrogen, the physiologically compatible salts with inorganic or organic bases. 2) carboxylic acid allyl ester - 21 - 609883/123 Board of Directors: Dr. Christian Bruhn ■ Hans-Jürgen Hamann · Dr. Heinz Hannse Karl Otto Mittelstenscheid ■ Dr. Horst Witzel Deputy: Dr. Herbert Asmls'. Chairman of the Supervisory Board: Dr. Eduard v. BlackUkoppen SIU of society: Berlin and Bergkamen Commercial register: AG Charlottenburg 93 HRB 283 U. AG Kamen HRB 0061 Postal address: SCHERING AG ■ D-1 Berlin 65 · P.O. Box 650311 Postal check account: Berlin-West 1175-101. Bank number 10010010 Berliner Commerzbank AG, Berlin, account no. 108700600, bank number 10040000 Berliner Disconto-Bank AG, Berlin, account no. 241/6008, bank number 100700 Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, Account no. 14-362, bank number 10020200 ■ ·. ^. "" ,, ". SCHEPJNGAG Intellectual Property 5) 5-Allyl-8-oxo-2.3.5.8-tetrahydro-furo / 2 \> g7quinoline-7 • 'carboxylic acid. 4) 8-Oxo-5- (1-propenyl) -2.3.5.8-tetrahydro-furo / 2 .; 3-g7 quinoline-7-carboxylic acid. 5) 8-Oxo-5- (l-propenyl) -2.5.5.8-tetrahydro-furoZ2.5-g / . quinoline-7-carboxylic acid, sodium salt '.> 6) δ-Οχο-2 .3.5.8-tetrahydro-5-v ± nyl-furo ^ O-g7quinoline-7 ■ carboxylic acid. 7) e lin-7-carboxylic acid. 8) 8-0xo-5-propadienyl-2.3; 5.8-tetrahydro-furo / 2 \ 3-g7-quinoline-7-carboxylic acid. 9) 5- (2-butenyl) -8-0x0-2.3.5.8-tetrahydro-furo ^ 2.5-g7-quinoline-7-carboxylic acid 2-butenyl ester. 10) 5- (2-butenyl) -8-0x0-2.3.5.8-tetrahydro-furo ^ .3-g7-quinoline-7-carboxylic acid. 11) 5- (1-butenyl) -8-oxo-2.J.5.8-tetrahydro-furo / 2.> G7quinoline-7-carboxylic acid. 60988 3/1235 Board of Directors: Dr. Christian Brunn · Hans-Jürgen Hamann -Dr. Heinz Hannse Postal address: SCHERING AG · D-1 Berlin 65 ■ Postfach 65 0311 Karl Otto Mittellenscheid Dr. Horst Witzel Postscheck account: Berlin-West 11 75-101, bank code 10010010 Deputy: Dr. Herbert Asmis Berliner Commerzbank AG, Berlin, account no. 103 7006 OO, bank code 100 400 Chairman of the Supervisory Board: Dr. Eduard V. Schwartzkoppen Berliner Di3conto-Bank AG, Berlin, account no. 241/5008, bank code 100 700 Seat of the company: Berlin and Bergkamsn Berliner Handeis-Gesellschaft - Frankfurter Bank -, Berlin, Commercial register: AG Charlottenburfl 93 HRB 283 and AG Kamen HRB 0061 account no. 14-362, bank lot number 100 202 00 SCHERiNQAG Intellectual Property 12) 5 ~ (2-methyl-2-propenyl) -8-0x0-2.3.5.8-tetrahydro-. ftiroZ2.3-S? quinoline-7-carboxylic acid (2-methyl-2-prO-penyl) ester. 5- (2-methyl-2-propenyl) -8-0x0-2.3.5.8-tetrahydrofuro- -7-carboxylic acid 14) 5- (2-methyl-1-propenyl) -8-0x0-2.3.5.8-tetrahydro furo / 2 .jj-g / quinoline ^ -carboxylic acid. 15) 8-0x0-2.3.5. S- 7-carboxylic acid, sodium salt. 16) Medicinal products containing a compound as active ingredient according to claim 1. - 15 17) procedures for treating urinary tract infections, characterized in that a compound according to claim 1 is administered to living beings. 18) Process for the preparation of quinoline carboxylic acid derivatives of the general formula I, characterized by - 23 609883/1235 Board of Directors: Dr. Christian Brunn ■ Hcns-Jürgen Hamann · Dr. Heinz Hannse Postal address: SCHERING AG D-I Berlin 65 PO Box 65 0311 Karl Otto Mittelstenscheid Dr. Horst Witzel Postscheck account: Berlin-West 11 75-101, bank code 10010010 Deputy: Dr. Herbert Asmls Commerzbank AG from Berlin. Berlin, account no. 108 7006 00, bank number 100 400 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Dlscontc-Bank AG, Berlin, account no. 241/5008, Bönklelt number 100 700 CO Seat of the company 'Berlin and Bergkamen Berliner Hendels-Gesollschaft - Frankfurier Bank -, Berlin, Commercial register: AG Charlottenburg 93 HRB 283 U. AG Kamen HRB 0061 account no. 14-382, bank code 100 20200 ui cn iu itwj SCHERiNG AG Intellectual Property draws that a compound of the general formula II, which is in the tautomeric forms A or B may exist, II A COOR, II B wherein Rp has the meaning given above with a compound R ¹¹ X, wherein R "has the meaning given above for R- or a saturated, straight-chain or branched alkyl radical, with 1-6 carbon atoms, of 1 or 2 halogen atoms Hydroxy groups, acyloxy groups with 2-4 carbon atoms, benzoyloxy groups, alkanesulfonyloxy groups with 1-4 carbon atoms in the alkyl radical or benzenesulfonyloxy groups, substituted on the nucleus by halogen atoms or by 1-4 C atoms containing alkyl groups can be, contains, and X has the meaning of a halogen atom, an alkanesulfonyloxy group with 1-4 carbon atoms in the alkyl radical or a benzenesulfonyloxy group, which are replaced by halogen atoms or by 1-4 6 0 9883/1235 vorsiana: UH-IH »« ,. "." ....- n _alu , "", "_ Postal address: SCHERINQ AQ · D-1 Berlin 65 · Postfach 650311 Karl OUo Mittelstenscheid -. - ... "-,., _ ,, - _{u <m4nHI} Deputy: Dr. Herbert Asmls Chairman of the Supervisory Board: Dr. Eduard V. Schwartzkoppen Company headquarters: Berlin and Bergkamen Commercial register: AQ Charlottenburg 93 HRB 283 and AG Kamen HBB 0061 Board of Directors: Dr. Christian Brunn ■ Hans-Jürgen Hamann · Dr. Heinz Hannse Postal address: SCHERINQ AQ · D-1 Berlin 65 · Postfach 65 03 Il Karl Otto Mittelstenscheid Dr. Horst jokes! Postal check account: Berlin-West 11 75-101. Bank code 10010010 Deputy: Dr. Herbert Asmls. Berliner Commerzbank AG ₁ Berlin, account no. 108 700 500, bank number 100 400 - · - ■ * - · * - ·· ■ · - • »c.AwarMmnnen Berliner Disconlo-BankAG, Berlin, account number 241/8008, bank number 1007nO00 Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, Account no. 14-362, bank number 100 202 00 H3 EO IV I7W4 SCHERING AG Commercial security C-atom-containing alkyl groups can be substituted, has, converted and then splitting off substituents present in R ″ in a manner known per se and then esterifying a free carboxyl group or saponifying an esterified carboxyl group and / or the carbon-carbon multiple bond in R in any order ₁ depending on the final product desired, rearranged in a manner known per se and, if desired, a free carboxylic acid is converted into the water-soluble salt with an inorganic or organic base. Form number: 1439-1 ßü98ß3 / 19'3R Board of Directors: Dr. Christian Bruhn · Hans-Jürgen Hamann · Dr. HeinzTtennse Postinsairlft: SCHERING AG D-1 Berlin 65 Postfach 65 0311 Karl OttoMittelstenscheidDr. Horst Witzel Postscheck account: Berlin-West 11 75-101, bank code 10010010 Deputy: Dr. Herbert Asmis Commerzbank AG from Berlin. Berlin, account number, 100 7006 00, bank code 100 400 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconlo-Bank AG, Berlin, account no. 241/5008, bank code 100 700 Company headquarters: Berlin and Borgkamen Berliner Handols-Gcscllschaft - Frankfurter Bank -, Berlin, Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen HRB 0061 account no. 14-302, bank code 100 20200