CH616155A5 - Process for the preparation of novel cycloalkanoquinolone- carboxylic acid esters - Google Patents

Description

The present invention accordingly relates to a process for the preparation of new cycloalkanoquinolone carboxylic acid esters of the formula I.

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61 «155

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COOR

wherein

R is an alkyl group having 1 to 5, preferably 1 to 3, carbon atoms;

X is an alkyl group with 1 to 5 carbon atoms, which is optionally substituted by halogen, preferably chlorine, a hydroxy, alkoxy, acyloxy or alkyl mercapto group, or an alkenyl group with up to 5 carbon atoms; and n is one of the numbers 3 to 5.

The compounds of formula I can be used for the production of medicaments with an antimicrobial effect.

The compounds of formula I are prepared according to the invention by reacting in compounds of formula II

0

wherein X 'has the same meaning as X and can also be hydrogen, esterified by introducing the group R and, if one started from a compound of formula II, wherein X' is hydrogen, in the compound of formula I obtained Introduces substituents X according to the N-alkylation.

The process according to the invention can advantageously be applied to compounds of the formula II such as are obtained by cyclization of a compound of the formula III

0

R

X

wherein Ri represents a corresponding w-haloalkyl or co-alkenyl group.

The esterification of the compounds of the formula II can be carried out under dehydrating conditions with an excess of the alcohol in question. The dehydration of the reaction mixture can be carried out either by azeotropic distillation with a tractor solvent, e.g. Methylene chloride or benzene, or by the addition of dehydrating substances, e.g. concentrated sulfuric acid, hydrogen chloride or boron trifluoride etherate can be achieved. In some cases, the compounds of formula I can also be esterified with diazoalkanes.

If compounds of the formula I in which X is hydrogen are initially obtained, as is the case when starting compounds of the formula II in which X 'is hydrogen, the alkyl group X can advantageously be reacted with alkyl halides, sulfates or -toosylates are introduced; these are expediently reacted in a higher-boiling inert solvent, such as dimethyl sulfoxide or dimethylformamide.

A number of substituents of the N-alkyl group can be subsequently converted particularly inexpensively. For example, a hydroxy substituent can be acylated with a reactive acid derivative. Suitable reactive derivatives for this purpose are in particular the anhydrides and halides, which are preferably reacted with the hydroxy compound in inert solvents with the addition of a weak base. By reacting with hydrogen halide gas, the hydroxyl group can further be converted into the corresponding halogen derivative, the water formed preferably being separated off by azeotropic distillation. Stronger alkylating agents, e.g. Alkyl halides or alkyl sulfonates, convert the hydroxy or mercapto substituents into the alkoxy or alkyl mercapto substituents. On the other hand, an alkoxy or aralkoxy substituent can be split off by boiling with hydrohalic acid without the remaining molecular structure being appreciably attacked. Furthermore, the haloalkyl group can be converted into an alkyl or arylmercaptoalkyl radical by reaction with the alkali salt of a corresponding mercapane.

N-allylquinolones can preferably be mixed with aqueous alkali, e.g. rearrange aqueous sodium hydroxide solution or strong organic bases, optionally with the addition of solubilizers such as alcohols, cyclic ethers or dimethyl sulfoxide in N-vinylquinolones. If the N-allylquinolones are made from quinolones and allyl esters of strong acids with the addition of acid-binding agents (weak alkali or tertiary amine), the rearrangement can then be carried out directly in the same vessel without intermediate isolation of the allylquinolones by adding stronger bases. Allylquinolones that are difficult to rearrange can be rearranged in alcohol or dimethyl sulfoxide to accelerate the reaction with sodium alcoholate.

If the starting compounds of the formula II are prepared by cyclization of compounds of the formula III, the reaction is advantageously carried out under the conditions of a Friedel-Crafts reaction in an anhydrous medium with metal halides, e.g. Aluminum chloride, boron trifluoride, zinc chloride or strong mineral acids e.g. concentrated sulfuric acid or polyphosphoric acid, or their anhydrides, e.g. Phosphorus pentoxide.

The compounds of the formula I can be applied enterally and parenterally in solution, suspension or in solid form. They are preferably administered in the form of tablets or dragees with an active ingredient content of 100 to 500 mg per tablet. The tablets can contain other solid carriers, such as starch, lactose, methyl cellulose, talc, highly disperse silicic acid, higher molecular fatty acids, maize.

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contain magnesium stearate, gelatin, solid high molecular weight polymers such as polyethylene glycol and optionally flavorings and colorants.

Suspensions are preferably applied with an active ingredient content of 20-100 mg / ml and water as a solvent. To stabilize the suspension, high molecular weight, water-soluble substances such as cellulose ether or polyethylene oxide are added. Sweeteners, flavors, flavors and colors can also be added.

For injection solutions, the compounds of the formula I are preferably used in aqueous solution in amounts of 10-100 mg / dose. Such injection solutions also contain the usual additives such as stabilizers, solubilizers, buffers and mannitol or sodium chloride in the amount necessary to produce an isotonic solution.

The examples below serve to explain the method according to the invention.

example 1

l-ethyl-3-carbäthoxy-l, 4-dihydro-cyclopentano (h) - quinolone- (4)

A mixture of 2.57 g l-ethyl-3-carboxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 2.8 g potassium carbonate, 4.5 g ethyl iodide and 25 ml dimethylformamide becomes 2 Stirred at 100 ° C for hours. Then the inorganic material is suctioned off hot and the filtrate is diluted with 50 ml of water. 2 g of l-ethyl-3-carbethoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4) separate out. This is filtered off and dried. The recrystallization can be carried out from dioxane. The connection then has an mp at 143 to 145 ° C.

Example 2

l-ethyl-3-carbomethoxy-l, 4-dihydro-cyclopentano (h) - quinolone- (4)

A mixture of 1.3 g l-ethyl-3-carboxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 1.4 g potassium carbonate, 2.1 g methyl iodide and 13 ml dimethylformamide becomes 2 Stirred at 100 ° C for hours. Then the inorganic material is suctioned off hot and the filtrate is diluted with 25 ml of water. 1.13 g of pure l-ethyl-3-carbomethoxy-1,4-dihydro-cyclopentano (h) -quinolone- (4) separate from the mp. 135 to 137 ° C.

Example 3

l-ethyl-3-carbopropoxy-l, 4-dihydro-cyclopentano (h) - quinolone- (4)

A mixture of 1.3 g l-ethyl-3-carboxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 1.4 g potassium carbonate, 2.58 g n-propyl iodide and 13 ml dimethylformamide is stirred at 100 ° C for 2 hours. Then the inorganic material is suctioned off hot and the filtrate is diluted with 25 ml of water. 1.29 g of l-ethyl-3-carbopropoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4) of mp 150 to 154 ° C. separate out.

Example 4

] - [ß-chloroethyl] -l, 4-dihydro-3-carbäthoxy-cyclopentano (h) - quinolone- (4)

1.25 g of l- [ß-chloroethyI] -l, 4-dihydro-3-carboxy-cyclo-pentano (h) -quinolone- (4) are made absolute in 40 ml. Suspended ethanol and refluxed dry hydrochloric acid gas for about 20 hours. The progress of the reaction is followed by chromatography. It is then cooled and precipitated with cold water. To separate non-esterified material, boil it with about 60 ml of hot benzene, filter and evaporate the benzene filtrate, thereby precipitating 0.6 g of pure l- [ß-chloroethyl] -l, 4-dihydro-3-carb-ethoxy-cyclopentano ( h) -quinolone- (4) from mp. 181 ° C.

Example 5

l- [ß-hydroxyethyl] -3-carbäthoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

A mixture of 680 mg l- [ß-hydroxyethyl] -3-carb-oxy-l, 4-dihydro-cyclopentano (h) -chinoIon- (4), 700 mg potassium carbonate, 1.13 g ethyl iodide and 7 ml dimethylformamide Stirred at 100 ° C (bath temperature) for 2 h. The inorganic material is then suctioned off hot and the filtrate is diluted with about 15 ml of water. There are deposited 570 mg of 1 - [ß-hydroxyethyl] -3-carbäthoxy-1,4-dihydro-cyclopen-tano (h) -quinolone- (4) of mp. 198 to 203 ° C.

Example 6

l- [ß-methoxyethyl] -3-carbäthoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

A mixture of 770 mg l- [ß-methoxyethyl] -3-carb-oxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 740 mg potassium carbonate, 1.25 g ethyl iodide and 7.7 ml Dimethylformamide is stirred for 2 hours at 100 ° C (bath temperature). Then the inorganic material is suctioned off hot and the filtrate is diluted with 20 ml of water. This separates 710 mg of 1 - [ß-methoxyethyl] -3-carbäthoxy-1,4-dihydro-cyclopentano (h) -quinolone- (4) from mp. 169 to 170 ° C.

Example 7

1 - / $ -hydroxyethyl] -3-carbomethoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

A mixture of 2.73 g of l- [ß-hydroxyethyl] -3-carb-oxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 2.8 g of potassium carbonate, 4.2 g of methyl iodide and 14 ml of dimethylformamide is stirred at 100 ° C for 2 hours. Then the inorganic material is filtered off hot and the filtrate is diluted with about 40 ml of water. This separates 1.9 g of l- [ß-hydroxyethyl] -3-carbomethoxy-1,4-dihydrocyclopentano (h) - quinolone. After recrystallization twice from mixtures of dimethylformamide and dimethyl sulfoxide, the substance has a melting point at 233 ° C.

Example 8

l - [{i-hydroxyethyl] -3-carbobutoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

A mixture of 2.73 g of 1- [ß-hydroxyethyl] -3-carb-oxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 2.8 g of potassium carbonate, 5.5 g of n- Butyl iodide and 13.6 ml of dimethylformamide is stirred at 100 ° C for 2 hours. Then the inorganic material is suctioned off hot and the filtrate is diluted with about 40 ml of water. 2.15 g of l- [β-hydroxyethyl] -3-carbobutoxy-l, 4-dihydro-cyclopentano (h) -quinolone - (4) are deposited. After recrystallization twice from aqueous dimethylformamide, the substance has a melting point at 149 ° C.

Example 9

l - ["{- hydroxypropyl] -3-carbäthoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

A mixture of 1.43 g of 1 - [y-hydroxypropyl] -3-carb-oxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 1.4 g of potassium carbonate, 2.35 g of ethyl iodide and 14.3 ml of dimethylformamide

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are stirred for 2 hours at 100 ° C (bath temperature). Then the inorganic material is suctioned off hot and the filtrate is diluted with about 40 to 50 ml of water. 0.9 g of l- [Y-hydroxypropyl] -3-carbethoxy-1,4-dihydro-cyclopentano (h) -quinolone- (4) are deposited. After recrystallization from ethanol or dioxane, the substance has a melting point at 184 ° C.

Example 10

l- [propene (1 ') -yl- (1')] -3-carbäthoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

A mixture of 538 mg l- [propene- (l ') - yl- (l')] - 3-carboxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 560 mg potassium carbonate, 936 mg of ethyl iodide and 2.8 ml of dimethylformamide are stirred for 2 hours at 100 ° C (bath temperature). The inorganic material is then filtered off hot, washed with a little hot dimethylformamide and the filtrate is diluted with about 10 ml of water. 500 mg of l- [propene (r) -yl- (r)] - 3-carbäthoxy-l, 4-dihydro - cyclopentano (h) -quinolone- (4) are separated from the melting point 156 to 159 ° C.

Example 11

l-propyl-3-carbäthoxy-l, 4-dihydro-cyclopentano (h) - quinolone- (4)

A mixture of 1.5 g l-propyl-3-carboxy-l, 4-dihy-dro-cyclopentano (h) -quinolone- (4), 1.53 g potassium carbonate, 2.59 g ethyl iodide and 7.5 ml Dimethylformamide are stirred at 100 ° C for 2 hours. It is filtered off from the inorganic material and the filtrate is mixed with 40 ml of water, thereby separating pure l-propyl-3-carbethoxy-1,4-dihydro-cyclopentano (h) -quinolone- (4), which is suctioned off and dried becomes. Mp 131-133 ° C. Yield: 1.56 g.

Example 12

l- [ß-acetoxyethyl] -3-carbäthoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

1.3 g of l- [ß-hydroxyethyl] -3-carbäthoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4) are refluxed with 13 ml of acetic anhydride for 1 hour. After cooling, the l- [ß-acetoxy-ethyl] -3-carbäthoxy-l, 4-dihydro - cyclopentano (h) -quinolone crystallizes when rubbed with a glass rod. It is filtered off, washed with ether and dried.

Yield: 1.11 g. The recrystallization can

616155

thylformamide. The compound then has a melting point at 196 to 198 ° C.

Example 13

l- [ß-Methylmercapto-ethyl] -3-carbomethoxy-l, 4-dihydro - cyclopentano (h) -quinolone- (4)

A mixture of 100 mg of l- [ß-methylmercapto-ethyl] - 3-carboxy-l, 4-dihydrocyclopentano (h) -quinolone- (4), 1 ml of dimethylformamide, 141 mg of methyl iodide and 91 mg of potassium carbonate are added for 1 hour 100 ° C stirred. Subsequently, hot is suctioned off from the inorganic material and the filtrate is mixed with a little water, pure l- [ß-methylmercapto-ethyl] -3-carbomethoxy-l, 4-dihydro - cyclopentano (h) -quinolone- (4) separates. from. This is filtered off, washed with water and dried. Yield: 70 mg. Mp .: 163 to 166.5 ° C.

Example 14

l- [ß-Methylmercapto-ethyl] -3-carbomethoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

20 mg of l- [ß-methylmercaptoethyl] -3-carboxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4) are mixed in 1 ml of a methanol / methylene chloride mixture saturated with diazomethane (mixing ratio 1: 1) Allow to stand for 30 minutes at room temperature. Then 1 ml of the above diazomethane solution is added and the mixture is left to stand at 50 ° C. for a further 30 minutes. It is then evaporated, triturated with a little methanol and filtered off. Yield: 10 mg. Mp .: 163 to 166 ° C.

According to the same working procedure or analogously to Example 14, l-propyl-3-carboxy-1,4-dihydro-cyclo-hexano (h) -quinolone- (4) 1-propyl-3-carbomethoxy-1,4- dihydro-cyclohexano (h) -quinolone- (4). (Mp .: 144 to 146 ° C).

Example 15

l- [ß-T osyloxy-ethyl] -3-carbäthoxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4)

A mixture of 500 mg of l- [ß-tosyloxy-ethyl] -3-carb-oxy-l, 4-dihydro-cyclopentano (h) -quinolone- (4), 5 ml of dimethylformamide, 750 mg of ethyl iodide and 375 mg of potassium carbonate Stirred for 2 hours at 50 ° C., then the inorganic material is filtered off, a little water is added and the separated substance is filtered off, washed with water and dried (350 mg). After recrystallization (e.g. from dioxane), 250 mg of pure l- [β-tosyloxy - ethyl] -3-carbethoxy-1,4-dihydro-cyclopentano (h) -quinolone- (4) of mp 189 ° C. are obtained.

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Claims (8)

616155 2. Process for the preparation of new cycloalkanoquinolone carboxylic acid esters of the formula I, in which R, X and n have the meaning given in claim 1, characterized in that a compound of the formula III 0 wherein Rj denotes a corresponding w-haloalkyl or w-alkenyl group, cyclizes and the compound of the formula II obtained in this way is further treated by the process according to claim 1. 2nd PATENT CLAIMS 1. Process for the preparation of new cycloalkanoquinolone carboxylic acid esters of the formula I 0 COOR wherein R is an alkyl group of 1 to 5 carbon atoms; X is an alkyl group with 1 to 5 carbon atoms, which is optionally substituted by halogen, a hydroxy, alkoxy, acyloxy or alkyl mercapto group, or an alkenyl group with up to 5 carbon atoms; and n is one of the numbers 3 to 5, characterized in that compounds of the formula II 0 COQH- wherein X 'has the same meaning as X and can also be hydrogen, esterified by introducing the group R and, if one started from a compound of formula II, wherein X' is hydrogen, in the compound of formula I obtained Introduces substituents X according to the N-alkylation. 3. The method according to claim 1, characterized in that in a compound of formula I obtained, in which the N-alkyl group carries a hydroxyl group as a substituent, the hydroxyl group is esterified by reaction with a reactive functional acid derivative. 4. The method according to claim 1, characterized in that in a compound of the formula I obtained, in which the N-alkylene group carries a hydroxyl group as a substituent, the hydroxyl group is replaced by chlorine by reaction with hydrogen chloride gas. 5. The method according to claim 1, characterized in that a compound of the formula I obtained, in which the N-alkyl group carries a hydroxyl group as a substituent, is converted into the corresponding N-alkoxyalkyl compound by treatment with an alkylating agent. 6. The method according to claim 1, characterized in that a compound of the formula I obtained, in which X is a haloalkyl group, is converted into the corresponding N-alkylmercaptoalkyl compound by treatment with an alkali salt of an alkyl mercaptan. 7. The method according to claim 1, characterized in that a compound of formula I obtained, wherein X is an N-alkoxyalkyl group, is converted into the corresponding N-hydroxyalkyl compound by hydrolysis. German Offenlegungsschriften Nos. 1 770 951, 1 912 944, 2 025 363, 2 043 817 and 2 011 885 describe cycloalkanoquinolonecarboxylic acids. Some of the lower alkyl esters of the quinolone carboxylic acids in question are described and claimed therein, but without their special significance being recognized. We have now found that a special group of these cycloalkanoquinolonecarboxylic esters in which the quinolone nitrogen is blocked by a substituent and the cycloalkanol bridge is the 7- and The 8-position of the quinolone combines surprisingly high antibacterial activity in vivo despite relatively little in vitro activity and the growth of many gram-negative and gram-positive microorganisms, e.g. Inhibit Staphylococcus aureus, Escherichia coli, Proteus vulgaris, Streptococcus pyogenes and Pseudomonas aeruginosa, which are known to cause infectious diseases. Because of the rapid excretion in the urine, these substances are particularly suitable for the treatment of urinary tract infections. It is obvious to the person skilled in the art that this difference between the in vitro and the in vivo action can only be brought about by metabolism of these substances by the human or animal organism. However, it is still unclear which molecular changes occur and why the well-known unesterified quinolonecarboxylic acids do not suffer this metabolism that enhances their effects in the organism.