HU209300B - Method for producing quinolone-carboxylic acid derivatives and pharmaceutical preparatives containing these compounds - Google Patents

Abstract

The present invention also provides for the preparation of a pharmaceutical composition. x1 (CH2) i-j (CH2) n-Y (q) ^ N'CHCH2) m (CH2) r (c) HU 209 300 B Scope of the description: 24 pages (including 11 pages)

Description

Description: 24 pages (including 11 pages)

HU 209 300 B

The present invention relates to quinolone, carboxylic acid derivatives and pharmaceutical compositions containing them.

The new quinolone carboxylic acid derivatives are substituted at the 7-position by a cyclic amino group bearing a quaternary carbon atom. Pharmaceutical preparations are antibacterial agents.

In the general formula (I)

R ⁴ is a group of formula (a), (b) or (c), is 0,1 or 2, and m 1 or 2 and 1 + m together are 1,2 or 3 when R ⁴ (a) or ( b) and 1 and m are 1 when R ⁴ (c)

X ¹ OR - wherein R is hydrogen or C 1-3 alkyl or C 1-3 alkanoyl Y is C 1-3 alkoxy or NR 1 R - wherein

R 'and R are hydrogen or (C 1 -C 3) alkyl, or one (C 3 -C 5) cycloalkyl or (C 1 -C 6) alkoxycarbonyl and the other hydrogen may be taken together to form (CH ₂ ) _k - or -CH ₂ CH ₂ OCH ₂ CH ₂ - wherein k is 4

X ² and X ³ are oxygen

A is = CR ⁵ - wherein R ^{5 is} hydrogen or halogen, n is 1 or 2, except those compounds wherein R ⁴ is a and m is 1.1 and X ¹ is OR wherein R is hydrogen or (C 1 -C 3) alkanoyl and n is 1 or 2, Y is -NR'R where R 'and R are hydrogen or one (C 1 -C 3) alkyl, or a pharmaceutically acceptable hydrate of these compounds is prepared. and the acid addition salts thereof and the alkali, alkaline earth, silver and guanidium salts thereof. These compounds are very effective antibacterial agents, especially

Gram-positive range.

Thus, they can be used as active ingredients in human and veterinary medicine, and veterinary treatment also includes the treatment of fish to treat or prevent bacterial infections.

The novel compounds of formula I can be prepared by reacting a compound of formula II wherein Z is a fluorine or chlorine atom and

A is reacted with a compound of formula (ΠΙ) above, wherein R ⁴ is as defined above, optionally in the presence of acid scavengers.

For example, using 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 3-ethylaminomethyl-3-hydroxypyrrolidine as starting materials, the course of the reaction is illustrated in Scheme 1.

The compounds of formula (II) used as starting materials are known or may be prepared by known methods. Examples include:

7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (U. S. Patent 3,142,854), 1-Cyclopropyl-6,7-difluoro-1,4 -dihydro-4-oxo-3-quinolinecarboxylic acid (European Patent Application 113 091),

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,420,743),

-cyclopropyl-6,7-8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (German Patent Application 3,318,145).

The compounds of formula (III) used as starting materials are partly novel.

They are produced by various methods.

1. A nitrogen protected spirooxirane of formula (1) [J. Med. Chem. 30, 222 (1987); U.S. Pat. No. 4,508,724; European Patent No. 189,370] reacts with an amine of formula (2) to open the ring to form the hydroxyamines of formula (3). Cleavage of the protecting group affords the starting material of formula IIIa (see Scheme 2).

2. Cyclization of the succinic acid ester (4) (Tetrahedron Letters 46, 4561 (1973)) to benzylamine gives 1-benzyl-3-hydroxy-5-oxo-pyrrolidine-3-carboxylic acid alkyl ester (5) which is reacted with the amine (2) to give the amide (6). Subsequently, it is reduced with lithium aluminum hydride and the benzylic group is hydrogenolytically cleaved to give the starting compound (IHb) (see Scheme 3).

3. (1-Benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl) acetic acid (7) [Gazz. Chim. Drink. 24, 226 (1984)] to the amide (8) and then reduced with lithium aluminum hydride and cleaved the benzyl group to give the starting material (lile) (see Scheme 4).

4. Starting from a protected protected cyclic oxoamine on the nitrogen of formula (9), the starting material of formula (IIid) can be prepared (Acta Chem. Scand. B 34, 319 (1980)]. (See Scheme 5).

5. The hydroxy groups of formula (IIIa) - (IIIid) may be alkylated.

6. The cyclic oxoamines of formula (9) can be prepared from ketals [Helv. Chim. Acta 50, 1289 (1967)].

Examples of starting materials of formula (ΙΠ) include, but are not limited to, chiral compounds as well as racemates and enantiomeric pure materials:

3-aminomethyl-3-hydroxy-pyrrolidine,

3-tert-butoxy light yellow oil aminomethyl-3-hydroxy-pyrrolidine,

3-hydroxy-3-methylamino-pyrrolidine,

3-ethylamino-methyl-3-hydroxy-pyrrolidine,

3-hydroxy-3-propylamino-methylpyrrolidine,

-ethylaminomethyl-3-methoxypyrrolidine,

-ethoxy-3-ethylaminomethyl-pyrrolidine,

3-acetoxy-3-ethylamino-methylpyrrolidine,

3-dimethyl-aminomethyl-3-hydroxy-pyrrolidine,

3-hydroxy-3-pyrrolidino-methylpyrrolidine,

3-hydroxy-3-morpholinomethyl-pyrrolidine,

3-cyclopropyl-aminomethyl-3-hydroxy-pyrrolidine,

3-isopropyl-aminomethyl-3-hydroxy-pyrrolidine,

1,4-dioxa-7-azaspiro [4.4] nonane.

HU 209 300 B

The reaction of the compounds of the formulas II and III is preferably carried out in a diluent such as dimethylsulfoxide, Ν, Ν-dimethylformamide, hexamethylphosphoric trisamide, sulfolane, water or an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol. monomethyl ether, acetonitrile or pyridine. Mixtures of these solvents can likewise be used.

As the acid scavenger, conventional inorganic or organic scavengers are used. Preferred are alkali hydroxides, alkali carbonates, sodium hydride, organic amines and amidines. Particularly suitable are triethylamine, 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) or excess An amine of formula III,

The reaction temperature may be varied within a wide range, generally from 20 to 200 ° C, preferably from 80 to 180 ° C.

The reaction can be carried out at atmospheric pressure, but also at elevated pressure, generally between 1 and 100 bar, preferably between 1 and 10 bar.

The process generally comprises from 1 to 15 moles, preferably from 1 to 6 moles, of amine (II) per mole of carboxylic acid (II).

In addition to the compounds listed in the examples, the following compounds were prepared:

Compound R ⁴ THE 1 A group of formula (2) = CH 15 A group of formula (4) = CF 18 A group of formula (6) = CH 20 A group of formula (6) CC1 = 22 (7) = CH 23 (7) = CF 24 (7) CC1 = 36 A group of formula (11) eeCF 37 A group of formula (11) CC1 39 Is a group of formula (12) = CH 40 Is a group of formula (12) = CF 41 Is a group of formula (12) CC1 = 42 Is a group of formula (13) = CH 43 Is a group of formula (13) = CF

The compounds of the present invention exhibit a broad spectrum of antibacterial activity against Gram-positive and Gram-negative germs, especially against enterobacteria, especially against various antibiotics such as penicillin, cephalosporin, aminoglycoside, sulfonamide, tetracycline, with very low toxicity.

These valuable properties allow the compounds to be used in medicine as a chemotherapeutic agent, and are suitable for preserving inorganic and organic materials, in particular all kinds of organic substances such as polymers, lubricants, dyes, fibers, leather, paper, wood, food and water.

The compounds are active against a broad spectrum of microorganisms and are useful in the control, prevention and / or amelioration of Gram-negative and Gram-positive bacteria and bacterial microorganisms and diseases caused by such pathogens.

The compounds are particularly effective against bacteria and bacterial-like microorganisms, making them particularly suitable for the prevention and treatment of local and systemic infections caused by such pathogens in human and veterinary medicine.

For example, local and / or systemic diseases can be treated and / or prevented by the following pathogens or a mixture of pathogens: Gram-positive cocci, such as Staphylococci (Staph, aureus, Staph. Epidermidis) and Streptococci (Strept. Agalactiae, Strept. Faecalis). pneumoniae, Strept. pyogenes); Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rods such as Enterobacteriaceae, such as Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. Freundii, Citrob. Divernis), Salmonella and Shigella; and Klebsiella (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (E. aerogenes, E. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettger, Pr. vulgaris), Providencia, Yersinia , and the genus Acinetobacter. In addition, the antibacterial spectrum extends to the genus Pseudomonas (Ps. Aeruginosa, Ps. Maltophilia) as well as to strictly anaerobic bacteria such as Bacteroides fragilis, Peptococcus and Peptostreptococcus genus, and Clostridium pneumoniae and mycoplasma M. , M. hominis, M. urealyticum) and mycobacteria such as Mycobacterium tuberculosis.

The above list of pathogens is exemplary only and is not limiting. Diseases caused by the named pathogens or mixed infections can be prevented, ameliorated or cured by the compounds. Examples of such diseases are infectious diseases in humans, such as ear infections, pharyngitis, pneumonia, peritonitis, renal pelvic inflammation, bronchitis (acute or chronic), inflammation of the bladder, endocarditis, systemic infections, septicemia, upper respiratory tract infections, septicemia, enteritis, liver abscesses, húgycsőcsulladás, prostatitis, epididymitis, gastrointestinal infections, bone and limb infections, cystic fibrosis, skin infections, postoperative wound infections, abscesses, fibrositis, wound infections, infected burns, foot infections, post-dental surgery, infections, osteomyelitis, septic arthritis, cholecystitis, peritonitis with inflammation of the appendix, inflammation of the bile ducts, abscesses of the abdomen, pancreatitis, sinusitis, mastoiditis, mammary inflammation, m andulitis, typhoid fibrosis and meningitis

HU 209 300 B nervous system infections, pleural effusion, endometrial inflammation, genital infections, pelvic peritonitis and ocular infections.

In addition to bacterial infections in humans, other species, such as swine: coli diarrhea, engero blood poisoning, sepsis, dysentery, salmonella infection, uterine inflammation, agalactia syndrome, mammary inflammation may be treated;

ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonella, pastorella, mycoplasmosis, genital infections;

horse: bronchopneumonia, foal paralysis, infant and cot infections, salmonella, dog and cat: bronchopneumonia, diarrhea, dermatitis, ocular inflammation, urinary tract infection, prostatitis;

poultry (hens, guinea fowl, quail, pigeon, ornamental bird, etc.): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonella, pastorella, parrot.

For use in breeding and in bacterial diseases of utility and ornamental fish, they are equally applicable to the above pathogens, and their antibacterial spectrum is extended to other pathogens, e.g. .

In addition to the non-toxic inert, pharmaceutically acceptable carriers, the invention also provides pharmaceutical compositions comprising one or more compounds of the invention, which compositions may contain one or more active ingredients.

The pharmaceutical compositions are prepared in dosage units. That is, the active ingredients provided according to the invention are converted into tablets, dragees, capsules, pills, suppositories and ampoules, each containing a fraction or multiplicity of the active ingredient. Dosage units, for example, contain one, two, three or four simple doses or one-half, one-third, or one-fourth of a single dose. Preferably, a single dose comprises the amount of the active ingredient which can be administered to a patient in a single administration, and usually corresponds to a daily dose or half or one third or one quarter thereof. Non-toxic inert pharmaceutically acceptable carriers include solid, semi-solid, or liquid diluents, fillers, or formulation aids.

Preferred pharmaceutical compositions are tablets, dragees, pills, granules, suppositories, solutions, suspensions, emulsions, pastes, ointments, gels, creams, emulsions, powders and sprays.

The tablets, dragees, capsules, pills and granules may be mixed with conventional carriers such as (a) a filler such as starch, lactose, cane sugar, glucose, mannitol and silica, (b) a binder such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, (c) a humectant such as gbcerin, (d) a disintegrant such as agar, calcium carbonate, sodium carbonate, (e) a dissolution delay agent such as paraffin and (f) a absorption accelerator. such as quaternary ammonium compounds, (g) a wetting agent such as cetyl alcohol, glycerol monostearate, (h) an adiposive agent such as kaolin and bentonite, (i) a glidant such as talc, calcium and magnesium stearate, and solid polyethylene -glycols or mixtures of the substances listed in (a) to (i).

The tablets, dragees, capsules, pills and granules may be coated with the usual opacifying agents, and the compositions may be formulated so that the active ingredient (s) are / are released exclusively or predominantly in a designated part of the intestinal tract, optionally masses such as polymeric material and wax may be used. The active ingredient (s) may optionally be formulated in microencapsulated form with one or more specified carriers.

The suppositories may be mixed with the active ingredient (s) or with water-soluble or water-insoluble carriers, such as polyethylene glycol or an ester of a fat such as cocoa fat and a higher ester such as a C14 alcoholic C16 fatty acid.

Creams, ointments and pastes, as well as gels, may contain, in addition to the active compounds, customary carriers such as animal and vegetable fats, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc or zinc. mixture of materials.

Powders and sprays may contain, in addition to the active ingredient or ingredients, customary carriers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or a mixture of these materials. The sprays may also contain conventional propellants, such as chlorofluorocarbons.

The solutions and emulsions contain, in addition to the active compounds, conventional carriers such as solvents, solvent carriers or emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, , 3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, glycerol forms, tetrahydrofurfuryl alcohol, polyethylene glycol, these substances may contain sorbitol.

For parenteral administration, solutions and emulsions may also be in sterile or blood-tonic form.

The suspensions may contain the active ingredient, or active ingredients, and customary vehicles, such as liquid diluents, e.g. bentonite, agar-agar and tragacanth, or a mixture thereof.

HU 209 300 B

The listed formulations may also contain a coloring agent, a preservative, and seed and flavor enhancers such as marjoram oil, eucalyptus oil, a sweetener such as saccharin.

The therapeutic compounds are used in the above pharmaceutical compositions, preferably in a concentration of 1.2 to 99.5%, preferably 0.5 to 95% by weight, based on the total weight. The pharmaceutical compositions may contain, in addition to the active compounds of the present invention, additional pharmaceutical active ingredients.

The pharmaceutical compositions are prepared in a known manner, for example, by mixing the active ingredient (s) with the carrier (s) in a known manner.

The above compositions may be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally or locally (powder, ointment, drops) and used to treat infections of the body cavities and cavities. Suitable formulations include solutions for injection, solutions, suspensions, gels for oral administration, molded formulations, emulsions, ointments or drops. For topical application, ophthalmic and dermatological preparations may be formulated with silver and other salts, nasal drops, eye ointments, powders or solutions. The animals may also be ingested in food or drinking water in an appropriate form.

Gels, powders, powders, pills, prolonged-release tablets, premixes, concentrates, granules, pellets, boluses, capsules, aerosols, sprays, inhalants for humans and animals can also be used. The compounds of the invention may also be incorporated into other carriers such as plastics, plastic chains for topical therapy, collagen or bone cement. In general, it has been found advantageous in both human and veterinary medicine to use the active compounds in a total amount of 0.5 to 500, preferably 5100 mg / kg body weight, every 24 hours, optionally in multiple single administrations, to achieve the desired result. A single dose contains the active ingredient in an amount of from 1 to 80, preferably from 3 to 30 mg per kg body weight. It may be necessary to deviate from the above dosages, depending on the species or body weight of the individual being treated, the type and severity of the disease, the type of formulation, the mode of administration of the drug, and the interval or duration of administration.

In some cases less than the amount of active ingredient indicated above is sufficient, but in other cases this amount of active ingredient must be exceeded. The optimum dosage and mode of administration of the active ingredient will be apparent to one skilled in the art.

The novel compounds can be used in the usual concentrations with food or nutritional formulations or with drinking water. Thereby, infection or cure of Gram-negative or Gram-positive bacteria can be prevented and cured, thereby improving nutrient delivery and increasing growth.

Minimum Inhibitory Concentrations (MICs) were tested on isosensitizer agar (oxoid) by serial dilution. For each test substance, a series of agar plates containing the concentrations of the active compound at double dilution are prepared. The agar plates were inoculated with a multipoint inoculator (Denley). Overnight cultures of pathogens were used for the inoculation, which were first diluted so that each inoculation point was ca. 10 contains ⁴ colony forming particles. The inoculated agar plates are evaporated at 37 ° C and the germ growth is counted after 20 hours. The MIC value (pg / ml) represents the lowest drug concentration at which no visible germination was observed in the naked eye.

The following table shows the MIC values of some of the substances according to the invention in comparison with Ciprofloxacin and Norfloxacin:

Minimum inhibitory concentration values (mg / l) determined by the agar dilution method (Denley multipoint inoculator, iso-sensitizer agar, oxoid)

Example 1 2 3 4 5 11 14 15 Cipro- ciprofloxacin Norflo- xacin Staphylococcus aureus FK422 0.5 0,125 0.5 0.062 0.25 0.062 0,125 0.031 0.25 0.5 1756 0.5 0,125 0.5 0.062 0,125 0.062 0,125 0.031 0.25 0.5 133 0.5 0,125 0.5 0.031 0,125 0.062 0,125 0.031 0.25 0.5 Streptococcus faecalis (Enterococcus) 27101 1 0.25 0.5 0,125 0.25 0.25 0,125 0.062 0.25 0.5 9790 1 0.25 0.5 0,125 0.25 0.25 0,125 0.062 0.25 0.5

HU 209 300 B

Preparation of intermediates of formula (III):

Example A

3- (ethylamino) -3-hydroxypyrrolidine

a) Ethyl 5-Aza-1-oxa-spiro [2,4,] heptane-5-carboxylic acid

Trimethylsulfoxonium iodide (23.5g, 107mmol) and sodium hydride (3.3g, 80% in paraffin oil) were mixed and 80ml anhydrous dimethylsulfoxide was added at 10 ° C. After stirring for 1 hour at room temperature, 15.7 g (100 mmol) of 3-oxo-pyrrolidine-1-carboxylic acid ethyl ester [J. Med Pharm. Chem. 5, 752 (1962)] dissolved in 20 ml of absolute dimethylsulfoxide. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-saturated NaCl solution and extracted with diethyl ether. The ethereal solution was washed with brine, dried over sodium sulfate, evaporated and distilled.

Yield: 6 g

MP: 80 ° C / 0.15 mbar

b) 3- (Ethylaminomethyl) -3-hydroxypyrrolidine-1-carboxylic acid ethyl ester g (46.7 mmol) of 5-aza-1-oxaspiro [3,4] heptane-5-carboxylic acid; ethyl ester was added dropwise to 50 ml of a 50% aqueous solution of ethylamine and stirred overnight at room temperature. The mixture is evaporated and the residue is distilled off.

Yield: 8 g

Mp .: 130 ° C / 0.05 mbar

c) 3- (Ethylaminomethyl) -3-hydroxypyrrolidine

7.7 g (35.6 mmol) of 3-ethylaminomethyl-3-hydroxypyrrolidine-1-carboxylic acid ethyl ester are 22 g of barium hydroxide. A solution of 8 H ₂ O in 220 ml of water was heated under reflux overnight. The barium carbonate is filtered off with suction and concentrated. The residue was boiled with dioxane (5 x 100 mL) and the dioxane solution was evaporated and distilled.

Yield: 4.2 g

MP: 70-75 'C / 0.1 lbar

Example B.

3- (Aminomethyl) -3-hydroxypyrrolidine

a) 3- (aminomethyl) -1-benzyl-3-hydroxypyrrolidine

9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro [2,4] heptane (U.S. Patent 4,508,724) are added dropwise to 50 ml of ammonia solution (25%). and stir overnight at room temperature. The mixture was evaporated and the residue was distilled.

Yield: 4.4 g

Mp .: 135 'C / 0.4mbar

b) 3- (aminomethyl) -3-hydroxypyrrolidine

A solution of 3- (aminomethyl) -1-benzyl-3-hydroxypyrrolidine (3.9 g, 18.9 mmol) in methanol (25 mL) was hydrogenated over 1 g of 10% palladium on carbon at 90 ° C and 95 bar. . The catalyst was filtered off, the filtrate was evaporated and the residue was distilled.

Yield: 1.2 g

Mp .: 80 ° C / 0.14 mbar

Example C

3- (ethylamino) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (ethylaminomethyl) -3-hydroxypyrrolidine

5-Benzyl-5-aza-1-oxaspiro [2,4] heptane (10.2 g, 53.9 mmol) was added dropwise to 60 ml of a 50% aqueous solution of ethylamine and stirred overnight at room temperature. Evaporate and distill.

Yield: 10.7 g

MP: 120 ° C / 0.18 mbar.

b) A mixture of 3- (ethylaminomethyl) -3-hydroxypyrrolidine g (42.7 mmol) in 1-benzyl-3- (ethylaminomethyl) -3-hydroxypyrrolidine in 60 mL of methanol was treated with 2 g of 10% methanol. hydrogenated at a temperature of 97 ° C and a pressure of 107 bar. The catalyst was filtered off, the filtrate was evaporated and the residue was distilled.

Yield: 4.8 g

MP: 74 ° C / 0.08 mbar

Example D

3-Hydroxy-3- (methylamino) pyrrolidine dihydrochloride

a) 1-Benzyl-3-hydroxy-3- (methylaminomethyl) pyrrolidine dihydrochloride

5-Benzyl-5-aza-1-oxaspiro [2,4] heptane (10.2 g, 58.3 mmol) was added dropwise to 70 ml of a 30% aqueous methylamine solution and stirred overnight at room temperature. The mixture was evaporated and the residue was distilled.

Yield: 8.8 g

Mp: 145 ° C / 0.35 mbar

The distillate was dissolved in dilute hydrochloric acid and the solution was evaporated. The crystalline residue is triturated with isopropanol, filtered off with suction and dried.

Yield: 7.3 g

M.p. 202 'C

b) 3-Hydroxy-3- (methylaminomethyl) pyrrolidine dihydrochloride

1-Benzyl-3-hydroxy-3- (methylaminomethyl) -pyrrolidine dihydrochloride (6.9 g, 23.5 mmol) was hydrogenated in 2 g of 10% palladium on carbon in 100 ml of methanol. at 100 bar. The catalyst is suctioned off, the solution is evaporated and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.

Yield: 4 g

Mp: 231-232 'C.

Example E

3- (Cyclopropyl) aminomethyl-3-hydroxy-pirrolidindihidro chloride

a) 1-Benzyl-3- (cyclopropylaminomethyl) -3-hydroxypyrrolidine dihydrochloride

9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro [2,4] heptane are added dropwise to a mixture of 9.7 g (0.17 mol) of cyclopropylamine in 40 ml of water, and stir overnight at room temperature. The mixture was evaporated and the residue was distilled.

Yield: 8 g

MP: 130 'C / 0.08 mbar

HU 209 300 B

The distillate was dissolved in dilute hydrochloric acid and the solution was concentrated. The crystallization residue is triturated with acetone, filtered off with suction and dried.

Yield: 8.3 g

M.p. 182-184 'C

b) 3- (Cyclopropylaminomethyl) -3-hydroxypyrrolidine dihydrochloride

A mixture of 7.9 g (24.7 mmol) of 1-benzyl-3- (cyclopropylaminomethyl) -3-hydroxypyrrolidine dihydrochloride in 100 ml of methanol was treated with 2 g of 10% palladium on carbon at 50 ° C. and hydrogenated at 100 bar. Suction, evaporate and triturate with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.

Yield: 3.4 g

Example F.

3- (aminomethyl) -3-hydroxy-piperidine

a) 5-Aza-1-oxaspiro [2,5] octane-5-carboxylic acid methyl ester

Trimethylsulfoxonium iodide (23.5 g, 107 mmol) and sodium hydride in 80% paraffin oil (3.4 g, 100 mmol) were added dropwise at 80C with anhydrous dimethyl sulfoxide (10 mL). After stirring for 1 hour at room temperature, 15.8 g (100 mmol) of 3-piperidone-1-carboxylic acid methyl ester (Acta Chem. Scand. B 30, 1976, p. 884]. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice and saturated brine and extracted with diethyl ether. The ethereal solution was washed with brine, dried over sodium sulfate, evaporated and distilled.

Yield: 8 g

MP: 68 'C / 0.15 mbar

b) 3- (Aminomethyl) -3-hydroxy-piperidine-1-carboxylic acid methyl ester

9.1 g (53.2 mmol) of 5-aza-1-oxaspiro [2,5] octane-5-carboxylic acid methyl ester was added dropwise to 50 ml of 25% ammonia solution and stirred overnight at room temperature. Evaporate and distill the residue.

Yield: 5.6 g

MP: 103 'C / 0.1 lbar

c) 3- (aminomethyl) -3-hydroxypiperidine

Methyl 3- (aminomethyl) -3-hydroxypiperidine-1-carboxylate (5.1 g, 27.1 mmol) was treated with barium hydroxide (15.8 g). Heat with 8H ₂ O in 150 mL of water at reflux overnight. The barium carbonate is filtered off with suction and concentrated. The residue is boiled with five times 70 ml of dioxane, the dioxane solutions are concentrated and distilled.

Yield: 1.8 g

Mp: 63 ° C / 0.05 mbar

Example G

3-Hydroxy-3- (methylaminomethyl) piperidine (a) Methyl 3-hydroxy-3- (methylaminomethyl) piperidine-1-carboxylic acid

Methyl 5-aza-1-oxaspiro [2,5] octane-5-carboxylic acid (9.3 g, 54.3 mmol) was added dropwise to 50 ml of a 25% aqueous solution of methylamine and stirred overnight at room temperature. The reaction mixture was concentrated and the residue was distilled.

Yield: 9.2 g

MP: 83-95 'C / 0.1 mbar b) 3-Hydroxy-3- (methylaminomethyl) piperidine

Methyl 3-hydroxy-3- (methylaminomethyl) piperidine-1-carboxylic acid (8.7 g, 43 mmol) was treated with 24 g of barium hydroxide. 8H ₂ O in 240 ml of water was heated under reflux overnight. The barium carbonate is filtered off with suction and concentrated. The residue was boiled with dioxane (5 x 100 mL) and the dioxane solution was evaporated and then distilled.

Yield: 4.2 g

MP: 56 ° C / 0.05 mbar

Example H.

3- (ethylaminomethyl) -3-hydroxypiperidine

a) Methyl 3- (ethylaminomethyl) -3-hydroxypiperidine-1-carboxylic acid

Methyl 5-aza-1-oxaspiro [3,5] octane-5-carboxylic acid (9.3 g, 54.3 mmol) was added dropwise to 50 ml of a 50% aqueous solution of ethylamine and stirred overnight at room temperature. The reaction mixture was concentrated and the residue was distilled.

Yield: 11.2 g

MP: 104-108 'C / 0.2 mbar

b) 3- (Ethylaminomethyl) -3-hydroxypiperidine g (46.2 mmol) 3- (ethylaminomethyl) -3-hydroxypiperidine-1-carboxylic acid methyl ester 28.5 g of barium -hydroxide. A mixture of 8H ₂ O in 280 ml of water was heated under reflux overnight. The barium carbonate was filtered off with suction, evaporated, the residue was boiled with dioxane (5 x 120 mL), and the dioxane solution was concentrated and distilled.

Yield: 4.5 g

MP: 70 ° C / 0.09 mbar

Example I

4- (aminomethyl) -4-hydroxypiperidine dihydrochloride

a) Ethyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate

13.4 g (72.3 mmol) of 6-aza-1-oxaspiro [2,5] octane-6-carboxylic acid ethyl ester (EP 189 370) are added dropwise to 60 ml of 25% ammonia solution and overnight. stirring at room temperature. It is then concentrated and distilled.

Yield: 8.1 g

MP: 110-130 'C / 0.04mbar

b) 4- (Aminomethyl) -4-hydroxypiperidine dihydrochloride g (4.9 mmol) of ethyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate was concentrated in 10 ml. hydrochloric acid was refluxed overnight, then concentrated and the crystals were triturated with acetone. It is aspirated and dried in a vacuum dryer over phosphorus pentoxide.

Yield: 1 g

M.p. 230-233 'C

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Example J.

4-Hydroxy-4- (methylamino) piperidine dihydrochloride

a) Ethyl 4-hydroxy-4- (methylaminomethyl) piperidine-1-carboxylic acid

Ethyl 6-aza-1-oxaspiro [2.5] octane-6-carboxylic acid (5.2 g, 28 mmol) was added dropwise to 30 ml of a 25% aqueous solution of methylamine and stirred overnight at room temperature and evaporated. and recrystallized from wash gas (hygroscopic crystals).

Yield: 3.3 g

b) 4-Hydroxy-4- (methylaminomethyl) piperidine dihydrochloride g (13.9 mmol) 4-hydroxy-4- (methylaminomethyl) piperidine-1-carboxylic acid ethyl ester. Concentrated hydrochloric acid was heated at reflux overnight, evaporated, the crystals were triturated with acetone, filtered off with suction and dried in a vacuum dryer over phosphorus pentoxide.

Yield: 2.7 g

M.p. 236-238 ° C

Example K.

4- (Dimethylamino) -4-hydroxypiperidine dihydrochloride

a) Ethyl 4- (dimethylaminomethyl) -4-hydroxypiperidine-1-carboxylic acid

Ethyl 6-aza-1-oxaspiro [2.5] octane-6-carboxylic acid (5.2 g, 20 mmol) was added dropwise to a solution of dimethylamine (30 mL), a 40% aqueous solution, and stirred overnight. at room temperature. It is then concentrated and distilled.

Yield: 5.2 g

MP: 150-155 ”C / 3 mbar

b) 4- (Dimethylaminomethyl) -4-hydroxypiperidine dihydrochloride

Ethyl 4- (dimethylaminomethyl) -4-hydroxy-piperidine-1-carboxylic acid (4.5 g, 19.4 mmol) was heated to reflux overnight with 35 mL of concentrated hydrochloric acid and the crystals were triturated with acetone. . It is aspirated and dried in a vacuum dryer over phosphorus pentoxide.

Yield: 4.1 g

Mp 224-227 ° C

Example L.

4- (ethylamino) -4-hydroxypiperidine dihydrochloride

a) Ethyl 4- (ethylaminomethyl) -4-hydroxypiperidine-1-carboxylic acid

Ethyl ester of 6-aza-1-oxaspiro [2,5] octane-6-carboxylic acid (5.7 g, 30.8 mmol) was added dropwise to a 50% aqueous solution of ethylamine (30 mL), stirred overnight at room temperature and evaporated. and distill.

Yield: 5.5 g

MP: 100-104 ° C / 0.01 bar

b) 4- (Ethylaminomethyl) -4-hydroxypiperidine dihydrochloride

Ethyl 4- (ethylaminomethyl) -4-hydroxypiperidine-1-carboxylic acid ethyl ester (4.6 g, 20 mmol) was heated under reflux overnight with 35 mL concentrated hydrochloric acid.

After evaporation, the crystals are triturated with acetone, filtered off with suction and dried in a vacuum dryer over phosphorus pentoxide.

Yield: 4.2 g

Mp 225-229 ° C

Example M.

3-Hydroxy-3-methylpyrrolidine (78.4 mmol) 1-benzyl-3-hydroxy-3-methylpyrrolidine (EP 132 845) was dissolved in 150 ml ethanol and 2 g 10% palladium hydrogenated at 100 bar and 90 ° C. The catalyst is suctioned off, the filtrate is evaporated and the residue is distilled.

Yield: 4.6 g

MP: 60-64 ° C / 0.08 mbar

Example N.

3- (Dimethylamino) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (dimethylaminomethyl) -3-hydroxypyrrolidine

9.6 g (50 mmol) of 5-benzyl-5-aza-1-oxaspiro [3,4] heptane was added dropwise to 50 ml of 50% dimethylamine solution and stirred overnight at room temperature. The mixture was evaporated and the residue was distilled.

Yield: 10.3 g

MP: 94 'C / 0.05 mbar.

b) 3- (Dimethylaminomethyl) -3-hydroxypyrrolidine

9.4 g (39 mmol) of 1-benzyl-3- (dimethylaminomethyl) 3-hydroxypyrrolidine are hydrogenated in 60 ml of methanol in the presence of 2 g of 5% palladium on carbon at 100 ° C at 90 bar. The catalyst was filtered off, the filtrate was evaporated and the residue was distilled.

Yield: 4.3 g

Mp .: 51 ° C / 0.06 mbar.

Example O

3-Hydroxy-3- (methoxymethyl) -pyrrolidine

a) 1-Benzyl-3-hydroxy-3- (methoxymethyl) pyrrolidine

26.8 g (0.14 mol) of 5-benzyl-1-oxa-5-azaspiro [2,4] heptane were treated with 2.6 ml (14 mmol) of a 30% sodium methylate solution in 200 ml of absolute methanol. heat under reflux at night. Evaporate and distill.

Yield: 25.6 g (83%)

MP: 107-112 ° C / 0.15 mbar

b) 3-Hydroxy-3- (methoxymethyl) pyrrolidine g (45 mmol) 1-benzyl-3-hydroxy-3- (methoxymethyl) pyrrolidine in the presence of 3 g 10% palladium on carbon in 200 ml hydrogenated in methanol at 100 ° C and 100 bar. The catalyst is suctioned off, the filtrate is evaporated and the residue is distilled.

Yield: 4.7 g (80%)

Mp .: 65 ° C / 0.4 mbar

Example P.

3- (tert-butoxycarbonyl-aminomethyl) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (tert-butoxycarbonylaminomethyl) -3-hydroxypyrrolidine

HU 209 300 B

3.2 g (80 mmol) of sodium hydroxide are dissolved in 40 ml of water, 15.6 g (75 mmol) of 3- (aminomethyl) -1-benzyl-3-hydroxypyrrolidine and 50 ml of tert-butanol are added dropwise at room temperature.

17.7 g (79 mmol) of di-tert-butyl ester of disic acid. After stirring overnight at room temperature, the mixture is filtered off with suction and the crystals are washed with dichloromethane and the filtrate is extracted with dichloromethane. The extracts were dried over potassium carbonate, evaporated and the residue was recrystallized from diisopropyl ether.

Yield: 19.1 g (83%).

117-119 ° C

b) 3- (tert-Butoxycarbonylaminomethyl) -3-hydroxypyrrolidine

1-Benzyl-3- (tert-butoxycarbonylaminomethyl) -3-hydroxypyrrolidine (18.7 g, 61 mmol) was dissolved in methanol (120 mL) and in the presence of 3 g of 5% palladium on carbon in 90 ° C. The catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from ethyl acetate.

Yield: 9.2 g (70%).

124-127 ° C

Example Q.

3-Methoxy-3- (methylamino) pyrrolidin

a) 1-Benzyl-3- (benzylmethylaminomethyl) -3-hydroxypyrrolidine

A solution of benzylmethylamine (15.6 mL, 0.115 mol) in water (300 mL) was added dropwise to 5-benzyl-1-oxa-5-azaspiro [2,4] heptane (18.2 g, 95 mmol) and at room temperature for 15 hours. agitated. It was extracted with dichloromethane and the extracts were dried over potassium carbonate, evaporated and distilled at 160 'C (oil bath temperature).

Crude yield: 27.1 g

Content by gas chromatography: 100%

b) 1-Benzyl-3- (benzylmethylaminomethyl) -3-methoxypyrrolidine g (83 mmol) crude 1-benzyl-3- (benzylmethylaminomethyl) -3-hydroxypyrrolidine 50 ml A solution of absolute tetrahydrofuran in water is added dropwise to a solution of 4 g of 80% sodium hydride in 100 ml of anhydrous tetrahydrofuran, while heating under reflux. After the evolution of hydrogen had ceased, 12.4 g (87 mmol) of methyl iodide was slowly added dropwise, followed by heating overnight under reflux. The mixture was poured into ice-water, extracted with toluene, dried over potassium carbonate, evaporated and distilled.

Yield: 16.5 h

Melting range: 140-173 ° C / 0.1-0.23 mbar

Yield: 9.1 g (26%) after further distillation.

Gas chromatography content: 80%

Mp: 141 ° C / 0.07 mbar

c) 3-Methoxy-3- (methylaminomethyl) pyrrolidine

A solution of 80% 1-benzyl-3- (benzylmethylaminomethyl) -3-methoxypyrrolidine (8.4 g, 20 mmol) in methanol (100 mL) was treated with concentrated hydrochloric acid (4.4 mL) and

Hydrogenated on 10% palladium on charcoal at 80 ° C and 120 bar. The catalyst was filtered off, evaporated and a solution of potassium hydroxide (3 g) in methanol (50 ml) was added. The potassium chloride was filtered off and evaporated. The residue was taken up in chloroform again, filtered, concentrated and distilled.

Yield: 1.7 g (59%)

Mp: 33 ° C / 0.08 mbar

Example 1 Compound 14

1.4 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.1 g (10 mmol) of 1,4-diazabicyclo [2.2. 2] octane and 0.8 g (5.5 mmol) of 3- (ethylaminomethyl) -3-hydroxypyrrolidine in 10 ml of acetonitrile and 5 ml of dimethylformamide are heated at reflux for 1 hour. The suspension is concentrated in vacuo, the residue is well mixed with water, and the resulting precipitate is filtered off with suction, washed with water, dried and recrystallized from glycol monomethyl ether.

Yield: 1.2 g (58%) of 1-cyclopropyl-7- (3-ethylaminomethyl) -3-hydroxy-1-pyrrolidinyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline. carboxylic acid.

230-232 ° C (dec.)

Example 2 Compound 15

1.5 g (5 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 5 ml of dimethylformamide 1.1 g (10 mmol)

1.4-diazabicyclo [2.2.2] octane and 0.8 g (5.5 mmol) of 3-ethylaminomethyl-3-hydroxypyrrolidine are added and the mixture is heated under reflux for 1 hour. The suspension is evaporated, the residue is filtered off with suction, washed with water and dissolved in a little semi-concentrated hydrochloric acid. Upon addition of ethanol, the hydrochloride precipitates. It is suctioned off, washed with ethanol and dried at 100 ° C in vacuo.

Yield: 1.3 g (56.5%) of 8-chloro-1-cyclopropyl-7- (3- (ethylaminomethyl) -3-hydroxy-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4 oxo-3-quinolinecarboxylic acid hydrochloride.

222-223 ° C (dec.)

Example 3 Compound 16

By analogy to Example 1, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1-cyclopropyl-7- (3- (ethylaminomethyl) -3- hydroxy-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Mp 202-207 ° C

Example 4 Compound 17

8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.5 g, 5 mmol) in acetonitrile (10 mL) and dimethylformamide (5 mL) mmol)

With 1,4-diazabicyclo [2.2.2] octane and 1.12 g (5.5 mmol) of 3-hydroxy-3- (methylaminomethyl) -pyrrolidine dihydro

The mixture was heated under reflux for 1 hour. The suspension is evaporated, mixed with water and the insoluble product is suctioned off, washed with water and dried. The crude product (1.97 g) was recrystallized from dimethylformamide.

Yield: 1.55 g (75.7%) of 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-6- (3-hydroxy-3- [methylaminomethyl] -1-pyrrolidinyl) -4 oxo-3-quinolinecarboxylic acid.

255-268 ° C (dec.)

Example 5 Compound 18

By analogy to Example 4, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was reacted and the resulting crude product (1.75 g) was dissolved in 10 ml of semi-concentrated hydrochloric acid, the hydrochloride being ethanol precipitate, suction, wash with ethanol, dry at 100 ° C under vacuum.

Yield: 1.2 g (56%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-hydroxy-3- [methylaminomethyl] -1-pyrrolidinyl) -4-oxo-3- quinolinecarboxylic acid hydrochloride.

274-276 'C (dec.)

Example 6 Compound 19

2.65 g (10 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 20 ml of acetonitrile and 10 ml of dimethylformamide are 3.3 g (30 mmol) ) With 1,4-diazabicyclo [2.2.2] octane and 2.5 mg (11 mmol) of 4- (ethylaminomethyl) -5-hydroxypiperidine dihydrochloride and refluxed for 1 hour. . The suspension is evaporated and the residue is mixed with water to give a pH of 7, the precipitate is filtered off with suction, washed with water, dried and recrystallized from dimethylformamide.

Yield: 3.0 g (75.2%) of 1-cyclopropyl-7- (4- [ethylaminomethyl] -4-hydroxy-1-piperidinyl) -6-fluoro-1,4-dihydro-4-oxo 3-quinolinecarboxylic acid.

M.p. 258-259 'C (dec.)

Example 7 Compound 20

By analogy to Example 6, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was reacted with 1-cyclopropyl-7- (4- [ethylaminomethyl] - 4-Hydroxy-1-piperidinyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained.

270-280 'C (dec.)

Example 8 Compound 21

According to Example 6, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 4-hydroxy-4- (methylaminomethyl) piperidine dihydrochloride was treated with 1-cyclopropyl. -6-Fluoro-1,4-dihydro-7- (4-hydroxy-4- (methylaminomethyl) -1-piperidinyl) -4-oxo-3-quinolinecarboxylic acid.

162 ° C (decomposed)

Example 9 Compound 22

In Example 2, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was reacted with 3-hydroxy-3- (methylaminomethyl) piperidine and 1-cyclopropyl. 6-Fluoro-1,4-dihydro-7- (3-hydroxy-3- (methylaminomethyl) -1-piperidinyl) -4-oxo-3-quinolinecarboxylic acid hydrochloride is obtained.

293-296 'C (dec.)

Example 10 Compound 23

In analogy to Example 1, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- (ethylaminomethyl) -3-hydroxypiperidine was treated with 1-cyclopropyl-7- ( 3-ethylaminomethyl-3-hydroxy-1-piperidinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

M.p .: 199-203 'C (dec.)

Example 77 (Reference) Compound 24

1.3 g (5 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 5 ml of dimethylformamide are 1.1 g (10 mmol). 1,4-Diazabicyclo [2.2.2] octane and 540 mg (5.4 mmol) of 3-hydroxy-3-methylpyrrolidine were heated at reflux for 1 hour. The suspension is evaporated, the residue is stirred with water and the precipitate is filtered off with suction, washed with water and recrystallized from dimethylformamide. Dry at 100 ° C in vacuo.

Yield: 1.4 g (81%) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (3-hydroxy-3-methyl-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid.

315-320 'C (dec.)

Example 72 Compound 25

All. 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1,4-dioxa-7-azaspiro [4,4] nonane 1-cyclopropyl-6- (1, 4-Dioxa-7-azaspiro [4,4] non-7-yl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Mp 229-230 ° C

Example 13 Compound 26 g 1-Cyclopropyl-7- (1,4-dioxa-7-azaspiro [4,4] non7-yl) -6-fluoro-1,4-dihydro-4-oxo The 3-quinolinecarboxylic acid was suspended in 100 mL of methanol and stirred with 100 L of semi-concentrated hydrochloric acid for 2 hours at room temperature. The suspension was evaporated and the residue was recrystallized from dimethylformamide.

Yield: 1 g (52%) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-oxo-1-pyrrolidinyl) -3-quinolinecarboxylic acid.

286-288 'C (dec.)

Example 14 Compound 27

According to Example 1, 3- (aminomethyl) -3-hydroxypyrrolidine 7- (3- (aminomethyl) -3-hydroxy-1-pyrrolidinyl) -1-cyclopropyl-6-8, difluoro-1,3 and -dihydro-4-oxo-3-quinolinecarboxylic acid.

HU 209 300 B

Mp 248 ° C (dec.)

Mass Spectrum: m / 3 379 (M ³ ), 361 (379-H ₂ O), 344 (361-F), 44 (CO ₂ ), 41 (C ₃ H ₅ ), 18 (H ₂ O).

Example 75 Compound 28

A14. Example 1A is reacted with 8-chloro-1-diclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. The product was purified by chromatography on silica gel using dichloromethane: methanol: 20% ammonia 2: 4: 1 as eluant and 7- (3- (aminomethyl) -3-hydroxy-1-pyrrolidinyl). 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained.

240-243 'C (dec.)

FAB Mass Spec: m / e 396 [(M + H) ⁺ ], 368 [(M + H-CO) ⁺ ].

Example 16 Compound 29

1.42 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroxy-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 5 ml of dimethylformamide and 0.8 g of 5.6 mmol)

3-hydroxy-3- (dimethylaminomethyl) pyrrolidine; and

A mixture of 1,1 g (10 mmol) of 1,4-diazabicyclo [2,2,2] octane was heated at reflux for 1 hour. The suspension is evaporated, the residue is mixed with water and acidified with dilute hydrochloric acid (1: 1). The crystallizing salt is filtered off with suction and recrystallized from dimethylformamide.

Yield: 1.1 g (50%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-hydroxy-3- [dimethylaminomethyl] -1-pyrrolidinyl) -4-oxo-3- quinolinecarboxylic acid hydrochloride.

292-295 'C (dec.)

Example 17 Compound 30

In Example 6, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was reacted with 3- (cyclopropylaminomethyl) -3-hydroxypyrrolidine dihydrochloride, and 1-Cyclopropyl-7- (3- [cyclopropylaminomethyl] -3-hydroxy-1-pyrrolidinyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained.

Mp: 161-162 'C (decomposed)

Example 18 Compound 31

a) R = (CH 2 -C-O-COb) R = H * .HCl

a) 6 g (20 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.5 g (22.7 mmol) of 1,4 diazabicyclo [2.2.2] octane and 4.2 g (20 mmol) of 3- (tert-butoxycarbonylaminomethyl) -3-hydroxypyrrolidine in 40 ml acetonitrile and 20 ml dimethylformamide heat under reflux. The solution is concentrated in vacuo, the residue is stirred with water, the undissolved precipitate is filtered off with suction and washed with water and dried.

Yield: 9.8 g (99%) of crude 7- (3- [tert-butoxycarbonylaminomethyl] -3-hydroxy-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro -4-oxo-3-quinolinecarboxylic acid.

192 DEG C. (decomposition) (after recrystallization from ethanol).

b) 9.5 g (19 mmol) of the product of Example 18 a) are stirred in 300 ml of semi-concentrated hydrochloric acid for 30 minutes at room temperature. The mixture was filtered and the filtrate was concentrated at 35 ° C and 12 mbar. The residue was recrystallized from glycol monomethyl ether.

Yield: 4.3 g (52%) of 7- (3- (aminomethyl) -3-hydroxy-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid hydrochloride.

M.p. 147-150 'C (dec.)

93% by high performance liquid chromatography

Example 19 Compound 32

Example 1 was reacted with 3-hydroxy-3- (methoxymethyl) pyrrolide and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-hydroxy-3- [methoxymethyl] -1 pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid is obtained.

M.p. 230-232 ° C (decomposition) recrystallized from dimethylformamide.

Example 20 Compound 33

In analogy to Example 1, 3-methoxy-3- (methylaminomethyl) pyrrolidine was reacted with 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-methoxy-3- [methylamino) Methyl 1-pyrrolidinyl) -4-oxo-3-quinolecarboxylic acid is obtained.

M.p. 245-247 DEG C. (decomposed) (recrystallized from dimethylformamide).

Example 27

By analogy to Example 18, the following compounds were obtained from 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid.

a) 7- (3- [tert-Butoxycarbonylaminomethyl] -3-hydroxy-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline -carboxylic acid m.p. 199-201 ° C (decomposed)

b) 7- (3- (Aminomethyl) -3-hydroxy-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, m.p. : 269-270 ° C (decomposed)

Example 22

Example 1 gave 3- (dimethylaminomethyl) -3-hydroxypyrrolidine to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3- [dimethylaminomethyl] -3 -hydroxy-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid.

M.p. 203-206 'C (dec.)

Example 23

Example 1 gave 3-diethylaminomethyl-3-hydroxypyrrolidine to give 1-cyclopropyl-7- (3- [diethylaminomethyl] -3-hydroxy-1-pyrrolidinyl) -6,8-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

202-203 'C (dec.)

HU 209 300 Β

Example 24

In Example 1, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 3- (diethylaminomethyl) -3-hydroxypyrrolidine are obtained from 1-cyclopropyl-7- (3 - [diethyl-amino-methyl] -3-hydroxy-lpir rolidinil) -6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as.

Mp 229-232 'C (decomposed)

Example 25

Example 1 gave 3- (isopropylaminomethyl) -3-hydroxypyrrolidine to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3- [isopropylaminomethyl] -3 -hydroxy-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid.

Mp: 213-214'C

Example 26

According to Example 1, 3- (N-ethyl-N-methylaminomethyl) -3-hydroxypyrrolidine gives 1-cyclopropyl-7- [3- (N-ethyl-N-methylaminomethyl) -3-hydroxy-l-pyrrolidinyl] -6,8-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

M.p .: 194-195 'C

Example 27

Example 1 provides 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 3- (1-pyrrolidinylmethyl) -3-hydroxypyrrolidine to give 1- cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-7- [3- (l-pyrrolidinylmethyl) -3-hydroxy-l-pyrrolidinyl] -3-quinolinecarboxylic acid.

Mp 229-234 'C (decomposed)

Example 28

Example 1 gives 3- (1-pyrrolidinylmethyl) -3-hydroxy-pyrrolidine to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [3- (1-pyrrolidinyl) -. methyl) -3-hydroxy-1-pyrrolidinyl] -3-quinolinecarboxylic acid.

Mp 210-215 ° C

Example 29

Example 1 gives 3- (4-morpholinylmethyl) -3-hydroxypyrrolidine to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [3- (4-morpholinylmethyl) -3 -hydroxy-1-pyrrolidinyl] -4-oxo-3-quinolinecarboxylic acid.

240-242 'C (dec.)

Example 30

2.2 g (5 mmol) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3- [dimethylaminomethyl] -3-hydroxy-1-pyrrolidinyl) -4-oxo A mixture of 3-quinolinecarboxylic acid and 250 mg of 4- (dimethylamino) pyridine in 80 ml of anhydrous pyridine was mixed with 2.5 ml of acetic anhydride and stirred for 15 hours at room temperature. The suspension is evaporated, the residue is mixed with ice water and the precipitate is filtered off with suction, washed with water and ethanol and dried.

Yield: 0.97 g (43%) of 7- (3-acetoxy-3- [dimethylaminomethyl] -1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid

215-216 'C (decomposed)

Example 37

According to Example 30, 1-cyclopropyl-7- (3- (dimethylaminomethyl) -3- [propionyloxy] -1-pyrrolidinyl) -6,8-difluoro-1,4-dihydro-4 with propionic anhydride. oxo-3-quinolinecarboxylic acid is obtained.

M.p .: 185-187 'C

Example 32

According to Example 30, 7- (3- (tert-butoxycarbonylaminomethyl) -3-hydroxy-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid is reacted with acetic anhydride and 7- (3-acetoxy-3- [tert-butoxycarbonylaminomethyl] -3-hydroxy-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1 4-Dihydro-4-oxo-3-quinolinecarboxylic acid is obtained.

Claims (3)

PATENT CLAIMS A process for the preparation of a compound of formula (I) wherein R ⁴ is a group of formula (a), (b) or (c), 1 is 0,1 or 2, and m 1 or 2 and 1 + m together are 1, 2 or 3 when R ^{4 is a} (a) or (b), and 1 and m is 1 when R ⁴ (c) is X ¹ -OR - wherein R is hydrogen or (C 1 -C 3) alkyl or (C 1 -C 3) alkanoyl, Y is C 1-3 alkoxy or NR'R where R 'and R are hydrogen or (C 1 -C 3) alkyl or one (C 3 -C 3) cycloalkyl or (C 1 -C 6) alkoxycarbonyl and the other hydrogen may be taken together to form - (CH ₂ ) _k - or -CH ₂ CH ₂ OCH ₂ CH ₂ - where k is 4, X ² and X ³ are oxygen, A is = CR ⁵ - wherein R ^{5 is} hydrogen or halogen, n is 1 or 2, except those compounds wherein R ⁴ is a and m is 1.1 and X ¹ is OR wherein R is hydrogen or (C 1 -C 3) alkanoyl and n is 1 or 2; and their alkali, alkaline earth, silver and guanidium salts, characterized in that a compound of formula (Π) - Z is fluorine or chlorine - with a compound of formula (ΙΠ) wherein R ⁴ is as defined above, optionally reacting in the presence of an acid scavenger and optionally treating a compound of formula R ⁴ (c) with an acidic treatment to form a compound of R ⁴ (b) wherein 1 and m are 1. or by acylating a hydroxy-containing compound in X ^{1 to a C} 1-3 alkanoyloxy compound or in Y in 1-6 The compound having a C 300 B alkoxycarbonylamino group is hydrolyzed in Y to a compound containing an amino group and / or a resulting compound of formula (I) into a pharmaceutically acceptable hydrate or an acid, alkali, alkaline earth, silver or guanidium salt thereof. Priority: 03/02/1989 2. A process for the preparation of compounds of formula I wherein R ⁴ is a group of formula (a), (b) or (c), 1 is 0, 1 or 2 and m 1 or 2 and 1 + m together are 1,2 or 3 when R ^{4 is} (a) or (b), and 1 and m are 1 when R ⁴ (c) is X ¹ -OR - wherein R is hydrogen or (C 1 -C 3) alkyl or (C 1 -C 3) alkanoyl, Y is C 1-3 alkoxy or NR 1 R - wherein R 'and R' are hydrogen or (C 1 -C 3) alkyl, or one (C 3 -C 5) cycloalkyl and the other hydrogen may be taken together to form - (CH ₂ ) _k - or - CH ₂ CH ₂ OCH ₂ CH ₂ - wherein k is ^ X ² and X ³ are oxygen, A is = CR ⁵ - wherein R ^{5 is} hydrogen or halogen, n is 1 or 2, except those compounds wherein R ⁴ (a) and m is 1.1 is 0 and X ¹ is OR - wherein R is hydrogen or (C 1 -C 3) alkanoyl and n is 1 or 2, Y is -NR'R where R 'and R are hydrogen or one (C 1 -C 3) alkyl and their pharmaceutically acceptable hydrates, acid addition for the preparation of their salts and their alkali, alkaline earth, silver and guanidium salts, characterized in that a compound of formula (Π) - Z is fluorine or chlorine - with a compound of formula (III) wherein R ⁴ is as defined above case of an acid-binding agent, and if desired, a compound containing an R ⁴ group report (c) R to a compound comprising (b) an acid treatment group ⁴ report and / or a Nucleus and converting the compound of formula (I) into a pharmaceutically acceptable hydrate or acid addition, alkaline, alkaline earth, silver or guanidium salt thereof. Priority: 05/02/1988 3. A process for preparing a pharmaceutical composition comprising mixing one or more compounds of formula (I) as defined in claim 1, wherein A, R ⁴ are as defined in claim 1, with pharmaceutically acceptable carriers.