DE1770447A1 - 1,4-Dihydro-6,7-methylenedioxy-4-oxo-quinoline-3-carboxylic acid derivatives substituted in the 1-position - Google Patents

Description

Warner-Lambert i'na ^ pißqiiOiicälUfiomßsiny * "ι /. FWM Ι3δ§

Morris Plains, N.J., USA

1,4-Dihydro ~ 6,7-methylenedioxy-4-oxo-quinoline - ^ - carbonic acid derivative substituted in the 1-position.

The invention relates to antibacterial preparations containing 1,4-dihydro-1-R-6,7 ~ methylenedioxy-4-oxo-quinoline-3-carboxylic acid derivatives of

Formula |

contain, in which R is lower alkyl, substituted lower alkyl, preferably hydroxy or carboxy lower alkyl, lower alkenyl or cycloalkyl and

R ₁ either O-alkyl, O-mono- or O-dialkylaminoalkyl, NH-lower alkyl, NH-aralkyl, NH-aryl, -N <^ | , -NH (CH ₂ ) _n -N ^ J | where η is 1 to 4 or -NHCOOR ₂ , in which each R _{2 is} lower alkyl or aralkyl and R is lower alkyl or R ₂ and R, together with the nitrogen atom, can form a cyclic radical, such as morpholino, piperidino, piperazino or the like , or R _{1 is} also an easily hydrolyzable group, such as thioster, nitrile or the like group.

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• ι-

In the definitions given above and below for R, R ₁ , R ₂ and R ₃ , “alkyl” is an alkyl group having 1 to 12 carbon atoms in a straight or branched chain, for example methyl, ethyl, propyl or isopropyl, “cycloalkyl” is a A group comprising 5 to 8 carbon atoms, for example cyclopropyl, cyclobutyl or cyclohexyl, and "aralkyl" both a monoisocylic ring system, such as benzyl, and a heteroaromatic ring system, such as pyridyl, furyl or the like, to be understood.

The preparations according to the invention show strong antibacterial effectiveness, in particular against gram-negative bacteria, for example the Escherichia or Proteus group. Consequently they are useful bactericidal agents for treating mammals such as dogs, guinea pigs, Cats, monkeys and the like, which are attacked by bacteria responsive to these preparations. Purpose of application the above compounds with known pharmaceutical carriers, such as lactose, starch, dicalcium phosphate, Syrup and the like, forming various dosage forms such as tablets, suspensions and the like, combined, wherein the active ingredient is present in amounts of about 100-500 mg per dosage unit. You can also with sterile carriers, e.g. sterile water or sterile isotonic saline solution, for parenteral use suitable dosage forms are combined to their

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Manufacture of pharmaceutical St <.uida.rd process applicable are. Generally, a dose administered orally or by injection three or four times a day is im Range between about 100 and 1500 mg and preferably of about 250 mg for the treatment of those gram negative Recommended for bacteria caused bacterial infections. A surprising property of these preparations consists in the finding that they are metabolically slower in the mammalian organism and consequently are longer effective than other quinoline compounds, e.g. those according to US Pat. No. 3,287,458. Because of this prolonged effectiveness, the dose necessary to be administered to the patient can be substantial be reduced.

The compounds according to the invention can also be mixed with animal foods, for example in one 1 to 25% by weight of the food in the form of cornmeal, water and the like.

The compounds according to the invention can also be used in a form suitable for topical application, with Preparations of this type about 1 to 20 wt .- # of selected active ingredient as well as pharmaceutical standard commonly used for the production of local preparations « May contain thinners, e.g. talc, petroleum jelly

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or other hydrophobic or hydrophilic ointment bases. These preparations are applied to the inflammation sites.

The preparations according to the invention can also use other, known ones to increase their range of antibacterial activity contain antibacterial ingredients, for example tetracyclines, nitrofurans, sulfa drugs or the like.

The active ingredients according to the invention are produced by four different processes:

According to method A, a compound of the formula

, COCl

with an alcohol, for example methanol, diethylaminoethanol. Cyclohexanol or the like, with formation of a formula! «- Compound with R ₁ equal to O-lower alkyl, O-dialkylaminoalkyl, O« cycloalkyl or O-lower kenyl.

According to method B, using analogous reaction conditions the aforementioned compound II with a suitable amine to form a formula! compound where R * is the same

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17704A7

-R ₂

NH-alkyl, NH-aryl, NH-aralkyl, -NH (CH ₂ ) _n N ^ jJ ² or -B2

implemented.

According to Method C, compound II is made with hydroxylamine or substituted hydroxylamines to form a formula I compound with Rj equal to -NHOH or -NHOR reacted,

According to method D, compound II is reacted with a carbamic acid ester, such as ethyl carbamate, to form a formula I compound _{where R 1} is -NHCOOR.

The starting compound II is obtained by treating a quinolene compound of the formula

COOH

with thionyl chloride, oxalyl chloride or any other known acid-converting reagent obtain. Compound III is described in US Pat. No. 5,287,458.

The following examples serve to further explain the invention »

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Method a

Example 1: 1-Ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-3-carboxylic acid chloride.

Thionyl chloride was added to a slurry of 26.1 g (0.1 mol) of pure 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-3-carboxylic acid in 100 ml of dry benzene. 2 g (0.11 mol) were added and the mixture was refluxed for 12 hours. After the subsequent addition of 250 ml of petroleum ether, the mixture was filtered, 29 g of crude product in the form of a yellow-brown plague, melting point 235-256 ° (decomp.) T being obtained. By refluxing the crude product with 500 ml of methylene chloride and hot filtration, 24.3 g (& 7%) of 1-ethyl-1,4-dihydro-6, T-methylenedioxy ^ -oxo-quinoline-I-carboxylic acid chloride were obtained as a light brown solid with a melting point of 245 ° (decomp.) Obtained.
Analysis (C ₁₅ H ₁₀ ClNO ₄ )

Calculated: C 55.83 H 3.60 N 5 * 01 Cl 12.68 found: C 56.03 H 3> 8? N 4.94 Cl 12.87

Example 2: 1-Ethyl-1,4-dihydro-6,7-methylene-iioxy-4-oxo-quinoline-3-carboxylic acid cyclohexyl ester.

A mixture of 14 g (0.05 mol) of 1-ethyl-1,4-dihydro-6,7-n »ethylenedioxy ^ -oxo-quinoline ^ -carboxylic acid chloride, 6 g (0.06 mol) of freshly distilled cyclohexanol and 30 g of pyridine were heated on the steam bath for 2 hours. Then the volatile constituents removed in vacuo and the residue

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rubbed several times with water and filtered. The crude product was recrystallized from a Gemisoh of carbon tetrachloride and Shellysolve B (3: 1), whereby 15.4 g (90 #) 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-jü -carboxylic acid cyclohexyl ester with a melting point of 204-206 °.
Analysis (C ₁₉ H ₂₁ NO ₅ )

Calculated: C 66.46 H 6.16 N 4, o8 Found: C 66.46 H 6.24 N 3 * 91

Example 3: 1-Ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid ethyl ester.

This compound was obtained according to the procedure given in Example 2 using analogous reaction conditions and replacing the cyclohexanol with ethanol. M.p. 177-178 ⁰
Analysis (C ₁₅ H ₁₅ NO ₅ )

Calculated: C 62.28 H 5.2J N 4.48 found: C 61.99 H 5 * 07 N 4.71

Example 4: 1-Ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-

quinoline-3-carboxylic acid propyl ester.

This compound was obtained by the process given in Example 2 using analogous reaction conditions and replacing the cyclohexanol with n-propanol. 159-160 °.
Analysis (C ₁₆ H ₁₇ NO ,.)

calculated: 0 6j_, j6 H:., 56 N 4.62 found: C 6. ^, 1 J Ii - \ 7 £ H ^l ~, ~ i

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Example 5s 1-Ethyl-1,4-dihydro-6,7-niethylenedioxy-4-oxoquinoline-3-carboxylic acid butyl ester.

This compound was obtained according to the procedure given in Example 2 using analogous reaction conditions and replacing the cyclohexanol with n-butanol. M.p. 1 ^ 1-155 °.
Analysis (C., 7H ₁ QNO ₅ )

Calculated: C 64.35 H 6.04 N 4.41 Found: C 64.23 H 5.9 * N 4.23

Example 6: 1-Ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid tert-amyl ester.

This compound was according to the procedure given in Example 2 using analogous reaction conditions and replacing the cyclohexanol with tert. Obtained amyl alcohol. M.p. 172 - 173 ° analysis (C ₁ QH ₂₁ NO ₅ )

Calculated: C 65.24 H 6.39 N 4.23 Found: C 65.16 H 6.36 N 4.46

Example 7: 1-Ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid hexyl ester.

This compound was obtained by the process given in Example 2 using analogous reaction conditions and replacing the cyclohexanol with n-hexyl alcohol. M.p. 90-92 °.
Analysis (C ₁₉ H ₂₅ NO ₅ )

calculated: C 66.07 H 6.71 N 4.06 found: C 65.90 H 6.81 N 4.19 209812/1714 '

\ i / υ 4 4

Example 8: 1-Ethyl-1, ^ - dihydro-ejT-methylenedioxy - ^ - oxoquinoline-3-carbdic acid decyl ester.

This compound was obtained according to the procedure given in Example 2 using analogous reaction conditions and replacing the cyclohexanol with n-decyl alcohol. M.p. 99-101 °.
Analysis (C ₂₅ H ₅₁ NO ₅ )

Calculated: C 68.80 H 7.78 N 3, ^ 9 ■ Found: C 69.07 H 7.89 N 5.70

Example 9: 1-Ethyl-1,4-dihydro-6,7 ~ methylenedioxy-4-oxo-

quinoline-3-carboxylic acid ^ {2-diethylamino-ethyl ester).

This compound was obtained according to the procedure given in Example 2 using analogous Reaktlonsbediggungen and replacing the cyclohexanol with diethylaminoethanol. M.p. 108-109 °.
Analysis (C ₁₉ H ₂₄ N ₂ O ₅ )

Calculated: C 63.52 H 6.71 N 7.77 Found: C 63.52 H 6.75 N 7.48

Example 10: Ethyl 1-methyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-carboxylate.

The acid chloride was first prepared from the free acid according to Method A, Example 1 with thionyl chloride, without isolation by reaction with ethanol in the

ο ethyl ester has been converted. 202-203 analysis (C ₁₄ H ₁₅ NO ₅ )

calculated ι C 61.09 H 4.76 N 5.09

Found i C 61.26 H 4.99 N 5.08 209812 / 17U

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i: · ^ ^: -, - : Hi 1 -Propel-1,4-dihydrous 6,7- "ii} ethylenedioxy-4-oxoquinoline-3-carboxylic acid ethyl ester.

The acid chloride was first prepared from the free acid according to method A, Example 1 with thionyl chloride, which was converted into the ethyl ester by reaction with ethanol without isolation. 147-149 °. Analysis (C ₁₆ H ₁₇ NO ₅ )

Calculated: C 63.56 H 5.65 N 4.26 Found: C 63.34 H 5.80 N 4.44

Example 12: f-Butyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3 "" carboxylic acid ethyl ester.

The acid chloride was first prepared from the free acid according to method A, Example 1 with thionyl chloride, which was converted into the ethyl ester by reaction with ethanol without isolation. Mp 117 -. 119 · Analysis (C ₁₇ H ₁ Q ₅

Calculated: C, 64.35, H, 6.04, N, 4.41 found: C, 64.51, H, 6.23, N, 4.50

Method B.

Example 1: 1-Ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-3-carboxylic acid (2-diethylaminoethyl) aanide.

A mixture of 8.4 g (0.03 mol) 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-3-carboxylic acid chloride, 4.6 g (0.04 mol) Ν , Ν-diethyl ethylenediamine and 150 ml of benzene were refluxed for 8 hours. The volatile components

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j. / U 4- M- #

were then im. Saugpumpenyvakuiur * removed, the residue was triturated with 5 # sodium hydroxide solution and recrystallized from aqueous isopropyl alcohol. In this way, 10.2 g (94 %) of 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid (2-diethylaminoethyl) amide with a melting point of 199 ° -201 ° were obtained .

analysis

Calculated: C 6-49, H 7.01, N 11.69 Found: C 65.57 H 7.05 N 11.76

Example 2: 1-Ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid (m-methoxypheny1) amide

This compound was obtained according to method B, example 1 using m-anisidine. M.p. 240-241 °. Analysis (C ₂₀ H ₁₈ N ₂ O ₅ )

Calculated: C 65.56 H 4.95 N 7.65 Found: C 65.50 H 5.02 N 7.41

Method c

1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline -? - hydroxamic acid.

A mixture of 4.2 g (0.015 mol) of 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-5-carboxylic acid chloride and 25 ml of pyridine was mixed with 2.1 g (0.0J mol) of hydroxylamine hydrochloride added and, after stirring for 2 hours, heated on the steam bath for 3 hours. Pyridine was removed in a suction pump vacuum;

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and the residue was recrystallized from 90 # aqueous ethanol. 4.0 g (96%) of 1-ethyl-1,4-dihydro-δ ^ Hmethylendioxy ^ -oxo-quinoline ^ -hydroxamic acid were obtained in the form of pale yellow crystals with a melting point of 265-268 °.

An analytical sample obtained from 95 # ethanol melted

at 269 - 270 ⁰ . '·

Analysis (C ₁₅ H ₁₂ N ₂ O ₅ )

Calculated: C 56.52 H 4.38 N 10.14 Found: C 56.77 H 4.47 N 10.10

Method D

1-Ethyl-1,4-dihydro-6,7-π-ethylenedioxy-4-oxo-quinoline-j5-carboxylic acid (carbathoxy ^ amide).

A mixture of 8.4 g (0.03 mol) of 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-3-carboxylic acid chloride, 5 * 3 g (0.06 mol) of ethyl carbamate and 100 ml of pyridine were refluxed for 8 hours, the solvent was removed in vacuo, the residue was triturated with water and recrystallized from 90 # aqueous dimethylformamide. In this way, colorless, crystalline 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-quinoline-3-carboxylic acid (carbathoxy _w amide) was obtained in 76% yield. M.p. 273-275 ° (decomp.). The analysis sample melted at 276-277 ° (dec.). .. '··. Analysis (C ₁₆ H ₁₆ N ₂ O ₆ )

Calculated: C 57.83 H 4.85 N 8.43 Found: C 57.5 ^ H 4.94 N 8.25

The above detailed description serves only to explain the invention and is in no way intended to limit the scope of the invention.

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BATH ORIGINAL

Claims (1)

Claims . Antibacterial preparation, the active ingredient of which is a compound of the formula contains, in which R is lower alkyl, hydroxy or carboxy-lower alkyl, lower alkenyl or cycloalkyl and FL is either O-alkyl, 0-mono- or O-dialky! aminoalkyl, 0-cycloalkyl, NH-lower alkyl, NH-aralkyl, -NHOR, NH- aryl, -NH- (CH ₀₎ -N ^ ^R 2 or -NHCOOR _t represents ₀ in which R ₉ and R each are lower alkyl or form together with the nitrogen atom form a heterocyclic group. ?,. Compound according to Claim 1, characterized in that R is ethyl and R _{1 is} ethoxy. 3. A compound according to claim 1, characterized in that R is ethyl and R _{1 is} n-propyloxy. - 2 209812/1714 ^. Compound according to Claim 1, characterized in that R is ethyl and R _{1 is} n-butyloxy. 5. A compound according to claim 1, characterized in that R is ethyl and R _{1 is} tert-amyloxy. 6. A compound according to claim 1, characterized in that R is ethyl and R _{1 is} n-hexyloxy. 7. Compound according to Claim 1, characterized in that R is ethyl and R _{1 is} O-cyclohexyl. 8. A compound according to claim 1, characterized in that R is ethyl and R _{1 is} n-decyloxy. 9. A compound according to claim 1, characterized in that R is ethyl and R ₁ is NHOH. 10. A compound according to claim 1, characterized in that R is ethyl and R ₁ is -NHCOO ^ C ₂ H ₅ . 11. A compound according to claim 1, characterized in that R is ethyl and R ₁ is -NH-CgH ^ -OCH (m). 12. A compound according to claim 1, characterized in that R is ethyl and R ₁ is -NH (CH ₂ J ₂ N (C ₂ H ₅ J ₂₎ . - 3 209812/1714 13 · The compound of claim i., _{Characterized}} £ ate R ethyl and R ₁ is -OCHgCHgN (P ₂ H _{5) 2.} 14. A compound according to claim 1, characterized in that H is methyl and R ^ is ethoxy. 15. A compound according to claim 1, characterized in that R is n-propyl and R is A'thoxy. 16. A compound according to claim 1, characterized in that R η-butyl and R _{1 is} ethoxy. 209812/1714