SK86693A3 - New isobutylsubstituted amids metansulfonyl-quinolylmeto- xyphenylcycloalkylacetic acid - Google Patents

Abstract

Isobutyl-substituted methanesulphonylquinolylmethoxyphenylcycloalkylacetamides of the formula <IMAGE> in which R<1> stands for cyclohexyl in the form of the racemate and of the enantiomers and also the enantiomers when R<1> stands for cyclopentyl or cycloheptyl and their salts. The isobutyl-substituted methanesulphonylquinolylmethoxyphenylcycloalkylacetamides can be prepared by reaction of the corresponding racemic or enantiomeric acids with methanesulphonamide, it being possible to separate the racemic final products into the enantiomers by customary methods. The N-methanesulphonyl-2-[3-isobutyl-3-(quinolin-2-yl-methoxy)phenyl]-2-ay eloalkylacetamides can be employed as active compounds in pharmaceuticals. The substances can act as inhibitors of enzymatic reactions in arachidonic acid metabolism, in particular of lipoxygenase.

Description

Technical field

The present invention relates to novel isobutyl substituted amides of methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid, a process for their preparation and their use in medicaments.

BACKGROUND OF THE INVENTION

Substituted 4- (quinolin-2-ylmethoxy) phenylacetic acid derivatives and α-substituted 4- (quinolin-2-ylmethoxy) phenylacetic acid derivatives are known from EP 344519 (US 4 970 215) and EP 339 416.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides novel isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic amides of formula

in which

R ³ represents a cyclohexyl group, in the form of the racemate and the enantiomers, as well as both enantiomers of the compounds of formula I, in which R ^{1 represents a} cyclopentyl or cycloheptyl group, and salts thereof.

Physiologically acceptable salts are preferred within the scope of the present invention. Physiologically acceptable salts of the compounds of the present invention can be salts of the compounds of the present invention with mineral acids, sulfonic acids or carboxylic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propidic acid, lactic acid, tartaric acid, citric acid aric acid, maleic acid or benzoic acid.

Physiologically acceptable salts also include metal salts, preferably monovalent metal salts or ammonium salts of the compounds of the present invention. Particularly preferred are, for example, alkali metal salts such as sodium and potassium salts as well as ammonium salts.

The compounds of the formula I according to the invention are prepared by the formation of carboxylic acids of the formula II

(II) co ₂ h wherein R ^{1 is} as defined above,

leave after possibly upstream with methanesulfonamide of formula III activation react H ₂ N - SO ₂ - CH ₃ (III)

in inert solvents and in the presence of a base and / or a catalyst, and in the case of enantiomers either the enantiomeric acids of formula II are used directly or the racemate of formula I is separated by conventional methods.

The separation of enantiomers is preferably carried out by column chromatography.

The method of the present invention can be explained, for example, by the following equation:

CO ₂ H

1) Mesyl chloride

2) H ₂ N-SO ₂ CH ₃

--►

Triethylarnin DMAP

CO-NH-SO ₂ -CH ₃

Sulfonamidation is generally carried out in inert solvents in the presence of a base and a dehydrating agent.

Suitable solvents here are the customary organic solvents which do not change under the reaction conditions. These preferably include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, carbon tetrachloride, 1,2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum. fractions, or also nitromethane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents mentioned. Dichloromethane is particularly preferred.

Suitable bases for sulfonamination are the customary basic compounds. These include in particular alkali or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrides such as sodium hydride, alkali metal or alkaline earth metal carbonates such as sodium carbonate or potassium carbonate or alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide or organic amines such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, dimethylaminopyridine, pyridine, triethylamine or N-methylpiperidine.

Suitable dehydrating agents are carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or

1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfonate or further propanephosphoric anhydride, isobutyl chloroformate, benzotriazolyloxy-trist (dimethylamino) phosphonium hexafluorophosphate, diphenyl ester phosphoric acid or phosphonic acid chloride methanephosphonic acid, optionally in the presence of a base such as triethylamine, N-ethylmorpholine, N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

In carrying out the sulfonamidation, the bases are generally used in an amount of 1 mol to 3 mol, preferably 1 mol to 1.5 mol, based on 1 mol of the corresponding carboxylic acid of the formula II.

In the case of the mixed anhydride reaction, dimethylaminopyridine is preferably used as the catalyst.

The catalyst is generally used in a catalytic to equimolar amount, preferably in an equimolar amount.

Sulfonamidation is generally carried out at a temperature in the range of 0'C to 150C, preferably 25'C to 40'C.

Sulfonamidation is generally carried out under normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

The carboxylic acids of formula II is other than where R ¹ is cycloheptyl, As actual substance representatives, particularly the enantiomeric form, new and can be prepared, for example, it is either converted compound of the formula IV or IVa

(IV)

(IVa) wherein R 1 is as defined above and

T and T 'are the same or different and represent a hydroxy protecting group such as benzyl or tert-butyl; and

R ² and R ² are the same or different and are alkyl having 1 to 4 carbon atoms, the removal of the protective groups by the 2-halomethylquinoline of formula V

r (IN) ^ n ^ ch ₂ -v in which

V is a halogen atom, preferably chlorine or bromine, in inert solvents by etherification to compounds of formulas VI or VIa

(VI)

(VIa)

CO ₂ R ₂ 'in which r 1, R 1 and R 1' are as defined above, and in the case of the compounds of the formula VIa, in a second step, these are subjected in alkylation to alkylation with the compounds of the formula VII

R ¹ - W (VII) wherein R ¹ has the abovementioned meaning and

W represents a chlorine, bromine or iodine atom, and then the ester is saponified by conventional methods, and in the case of enantiomers, racemic acids are separated into chiral acids by conventional methods by column chromatography.

The cleavage of the protecting groups from the corresponding ethers IV and IVa is carried out by customary methods, for example by hydrogenolytic cleavage of benzyl ether in the above inert solvent in the presence of a catalyst with hydrogen gas.

The etherification can be carried out in inert organic solvents, optionally in the presence of a base. Solvents for etherification include inert organic solvents which do not change under the reaction conditions. These include, in particular, ethers such as dioxane, tetrahydrofuran or diethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane or trichlorethylene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions and further nitromethane, dimethylformamide, acetonitrile, acetone or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents mentioned.

As bases for etherification, inorganic or organic bases can be used. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as carbonate calcium or organic amines (trialkyl / C ₁ -C / amines) such as triethylamine, or heterocycles such as pyridine, methylpiperidine, piperidine or morpholine.

It is also possible to use alkali metals such as sodium or their hydrides such as sodium hydride as bases.

The etherification is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably in the range of 10 ° C to 100 ° C.

The etherification is generally carried out under normal pressure, but it is also possible to work under reduced or elevated pressure, for example in the range of 0.05 to 0.5 MPa.

In general, 0.5 to 5 moles, preferably 1 to 2 moles, of a halide of the formula (III), based on 1 mol of the reaction partner, are used. The base is generally used in an amount of 0.5 to 5 moles, preferably 1 to 3 moles, based on the halide.

The compounds of the formulas IV and IVa are known or can be prepared by customary methods.

The compounds of formula V and their preparation are also known.

Suitable solvents for the process of the present invention and for the alkylation are inert organic solvents which do not change under the reaction conditions. These include, in particular, ethers such as dioxane, glycol dimethyl ether, tetrahydrofuran or diethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene, hydrocarbons such as benzene, toluene, hexylene, xylene petroleum fractions, and also nitromethane, dimethylformamide, acetonitrile, acetone, hexamethylphosphoric triamide, ethyl acetate, triethylamine, pyridine or dimethylsulfoxide. Mixtures of the solvents mentioned may also be used. Dichloromethane is preferred.

The alkylation is carried out in the abovementioned solvents at a temperature in the range of 0 ° C to 150 ° C, preferably at room temperature up to 100 ° C and under normal pressure.

The compounds of formula III are known.

The compounds of formula (VI) are novel as specific agents and can be prepared as described above.

Separation of the racemates is carried out by column chromatography generally on chiral HPLC columns using a solvent mixture such as n-heptane / 2-propanol or via diastereomeric esters.

The novel N-methanesulfonyl-2- [3-isobutyl-3- (quinolin-2-ylmethoxy) phenyl] -2-cycloalkylacetic acid amides of the present invention can be used as active ingredients in medicaments. These substances may act as inhibitors of enzymatic reactions in the metabolism of arachidonic acid, in particular 5-lipoxygenase.

They are therefore advantageous for the treatment and prevention of respiratory diseases such as allergic asthma, bronchitis, empphysema, shock lung, pulmonary hypertonia, inflammatory rheumatism and edema, gout, thrombosis and thromboembolism, ischemia (peripheral, cardiac and cerebral disorders) and cerebral infarctions, heart rhythm disorders, angina pectoris, arteriosclerosis, tissue transplants, dermatoses such as psoriasis, inflammatory dermatoses such as eczema, dermatophyte infections of the skin by bacteria, metastases, and also for cytoprotection in the gastrointestinal tract.

The phenyl-substituted quinolines of the present invention can be used in both human and veterinary medicine.

The pharmacological effect values of the substances according to the invention are determined by the following method:

As a measure for 5-lipoxygenase inhibition, the release of leukotriene B ₄ (LTB ₄ ) on polymorphically granular human leukocytes (PMN) upon addition of substance and Ca-Ionophor A 23187 was determined by reverse phase HPLC according to P. Borgeata et al., Proc. Nat. Acad. Sci. 76, 2148-2152 (1979). The results are shown in the following table.

table

Inhibition of lipoxygenase (human PMNL)

Example ^IC 50 (Mol / 1) 1 5.2 x 10 ^-8 6 5.8 x 10 ⁸ 7 7.0 x 10 “ ⁸

The present invention relates to pharmaceutical compositions which, in addition to inert, non-toxic and pharmaceutically acceptable carriers or excipients, contain one or more compounds of the formula I or consist of one or more active compounds of the formula I. Furthermore, the present invention also relates to a process for the manufacture of such formulations.

The therapeutically active compounds of formula I are to be present in these preparations in a concentration of about 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight of the total mixture.

In addition to the active compounds of the formula I, these pharmaceutical preparations can also contain other pharmaceutical active compounds.

The above pharmaceutical preparations can be prepared by conventional methods according to known methods, for example with a carrier or carriers or excipients or excipients.

In general, it has proven advantageous to administer the active compound (s) of the formula I in an amount of about 0.01 to about 100 mg / kg, preferably about 1 to 50 mg / kg of body weight per 24 hours, optionally in the form of several individual doses.

However, it may be necessary to dispense with the abovementioned amounts, depending on the body weight, optionally on the type of application, but also on the individual tolerance to the medicament, the type and type of formulation and the time or interval at which the application is administered.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example I

2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -, methyl ester -

2-cyclohexyl-acetic acid

CO ₂ CH ₃

12 g (0.033 mol) of methyl 2- [3-isobutyl-4- (quinolin-2-ylmethoxy) phenyl] acetic acid and 6.52 g (0.04 mol) = 4.9 are dissolved under an argon atmosphere. ml of cyclohexyl bromide in 36 ml. dimethylformamide and the solution is cooled to 0 C. C. 4.88 g (0.04 mol) of potassium tert-butylate, dissolved in 80 ml of dimethylformamide, were added dropwise with stirring. After about 2 hours of reaction time, the temperature is allowed to rise to room temperature, acidified with 2N hydrochloric acid and concentrated to dryness in vacuo. The residue is taken up in 100 ml of dichloromethane and 50 ml of water, the organic phase is separated, dried in vacuo to a small volume and the residue is separated by column chromatography (silica gel 60, eluent: dichloromethane / ethyl acetate = 100/2).

Yield: 13 g (88.4% of theory) of a slightly yellowish oily substance.

Example II

2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cyclohexyl-acetic acid

C0 ₂ H

10.2 g (0.0236 mol) of the compound of Example I are taken up in 70 ml of 2-propanol and heated to boiling overnight with 50 ml of 1 N sodium hydroxide. After cooling, the reaction mixture was neutralized with 50 ml of 1 N hydrochloric acid. The precipitate is filtered off with suction, washed and dried and then recrystallized from diisopropyl ether.

Yield: 9.5 g (96.3% of theory) of colorless crystals.

Melting point: 130 C.

Examples III and IV

(+) -2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cyclohexyl acetic acid (Example III)

(-) -2- (3-isobutyl-4- (quinolin-2-ylmethoxy) phenyl) -2-cyclohexyl acetic acid (Example IV)

The title compound is obtained by resolution of the racemate (Example II) by chiral column chromatography.

(+) - enantiomer: spec. rotation: 17.96 (CHCl 3) (Ex III) mol. rotation: 77/41 (-) - enantiomer: spec. rotation: -18.86 (I want ₃ ) mol. rotation: -81.28 (Ex. IV).

Example V

2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] 2-cycloheptyl-acetic acid methyl ester

g (0.0275 mol) of 2- [3-isobutyl-4- (quinolin-2-yl-methoxy) phenyl] -acetic acid methyl ester was reacted analogously to Example I with 10.04 g (0.055 mol) of cycloheptyl bromide and 6.17 g (0.055 mol) of potassium tert-butylate to give the title compound.

yield: quantitative, yellow-brown oil.

EXAMPLE VI

2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cycloheptyl-acetic acid

COOH

Analogously to Example II, the title compound was prepared from the compound of Example V and 30 mL of 1 N sodium hydroxide followed by acidification.

Yield: 11.3 g (92.3% of theory) of colorless crystals. Melting point: 112 C. C.

Examples VII and VIII

(+) - 2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cycloheptyl-acetic acid (Example VII)

(-) - 2- (3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl) -2-cycloheptyl acetic acid (Example VIII)

co ₂ h

The title compounds are prepared from the racemate (Example VI) by chromatographic separation on HPLC-H 1050-Chiralpak AS in a solvent mixture of 96% n-heptane and 4% 2-propanol containing

1% water and 0.2% trifluoroacetic acid. (+) - enantiomer: spec. Rotation: 15.72 (CHC1 ₃₎ mol. Rotation: 69,96 (Ex. VII) (-) - enantiomer: spec. rotation: -18.7 (CHC1 ₃₎ mol. rotation: -86.19 (Ex. VIII).

Example IX

2- [3-Isobutyl-4- (quinolin-2-yl-methoxy) phenyl] -2-cyclopentyl-acetic acid methyl ester

CO ₂ CH ₃

Analogously to Examples I and V, the title compound is prepared from 10 g (0.0275 mol) of 2- [3-isobutyl-4- (quinolin-2-ylmethoxy) phenyl] acetic acid methyl ester. 2 g (0.055 mol) of cyclopentyl bromide and 6.17 g (0.055 mol) of potassium tert-butylate.

Yield: quantitative, yellow-brown oil.

PríkladX

2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cyclopentyl-acetic acid

CO ₂ H

Analogously to Examples II and VI, the title compound is prepared from the compound of Example IX by saponification with 30 ml of sodium hydroxide followed by acidification. Yield: 10.5 g (91.5% of theory) of slightly yellow crystals. Melting point: 120 ° C.

Examples XI and XII

(+) -2- [3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cyclopentyl acetic acid (Example XI)

(-) - 2- (3-Isobutyl-4- (quinolin-2-ylmethoxy) phenyl) -2-cyclopentyl acetic acid (Example XII)

The title compounds are obtained analogously to Examples VII and VIII by chromatographic separation of the compound of Example X.

(+) - enantiomer: spec. rotation: 44.56 (THF) mol. rotation: 185.84 (Ex. XI) (-) - enantiomer: spec. rotation: -41.07 (THF) mol. rotation: -171.28 (Ex. XII). Example XIII

N-Methanesulfonyl-2- [3-isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cycloheptylacetic acid amide

Under an argon atmosphere, 2 g (0.0045 mol) of the compound of Example VI are stirred in 20 ml of dried tetrahydrofuran and treated with 1.82 g (0.018 mol) of triethylamine (d = 0.73). A clear solution is formed. While cooling with an ice bath, 1.14 g (0.01 mol) of mesyl chloride (d = 1.48) is added dropwise to this solution, and the reaction mixture is stirred for 15 minutes at this temperature and then 1.52 g are added dropwise with stirring. (0.016 mol of methanesulfonamide and 1.1 g (0.009 mol) of dimethylaminopyridine, dissolved in 10 ml of dried tetrahydrofuran. The reaction mixture was allowed to come to room temperature overnight, then poured into toluene and extracted with water and dilute acid. The organic phase is separated, dried over anhydrous sodium sulphate, concentrated to a small volume in vacuo and the pale brown residue (2.42 g) is separated by column chromatography (silica gel 60, eluent: toluene / ethyl acetate / ice. acetic acid). 1.75 g (74.6% of theory) of a colorless product (amorphous) are obtained.

Production examples

Example 1

N-Methanesulfonyl-2- [3-isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cyclohexylacetic acid amide

The title compound was prepared analogously to Example XIII from 3.5 g (0.008 mol) of the compound of Example II, 1 g (0.008 mol) mesyl chloride, 0.912 g methanesulfonamide, 1.62 g (0.016 mol) triethylamine, 98 g (0.008 mol) of dimethylaminopyridine.

Yield: 3.48 g (84.9% of theory) of a colorless amorphous powder. Melting point: 163-170 ° C.

Príklad2a3

(+) - N-Methanesulfonyl-2- (3-isobutyl-4- (quinolin-2-ylmethoxy) phenyl) -2-cyclohexylacetic acid amide (Example 2) (-) - N-Methanesulfonyl-2- [3] amide -isobutyl-4- (quinolin-2-ylmethoxy) phenyl] -2-cyclohexylacetic acid (Example 3)

Both enantiomers are obtained by separating the compound of Example 1 by column chromatography on HPLC-HP 1050 Chiracel OD in a solvent mixture of 86% n-heptane and 14% 2-propanol containing 1% water and 0.2% trifluoroacetic acid.

(+) - enantiomer: spec. Rotation: 32.15 (CHC1 ₃₎ mol. Rotation: 163.32 (Ex. 2) (-) - enantiomer: spec. Rotation: -28.96 (CHC1 ₃₎ mol. rotation: -147.12 (Ex. 3).

The pure enantiomers listed in Table 1 below may be used

produced analogously to is described in Examples 2a and 3 by separation

racemate or by using the corresponding enantiomerically pure carboxylic acids.

Table 1

6> (+) about + 147.99 ° (€ HCl ₃ ) + 28.35 ’ (CHCl3) 7 Cv (-) -169.91 ° (CHCl ₃ ) -32.55 ° (CHCl3)

? l ^of S <oG-3>

Claims (10)

PATENT CLAIMS 1. New isobutyl-substituted methanesulfonylquinolylmethoxyphenyl-cycloalkylacetic acid amides of the general formula I in which: R ¹ represents a cyclohexyl group, in the form of the racemate and the enantiomers, as well as the two enantiomers of the compounds of formula I, in which R ^{1 represents a} cyclopentyl group or a cycloheptyl group and salts thereof. 2. The racemate, the (+) - enantiomer and the (-) - enantiomer of the compound of formula · and salts thereof. 3. The (+) - enantiomer and the (-) - enantiomer of a compound of formula 4. The (+) - enantiomer and the (-) - enantiomer of the compound of formula and salts thereof. The novel isobutyl-substituted methanesulfonylquinolylmethoxyphenyl-cycloalkylacetic acid amides of the formula I according to claim 1 for therapeutic use. 6. Preparation of novel amides of izobutylsubstituovaných methanesulfonyl-chinolylmetoxyfenyl cycloalkylacetamides of formula I according to claim 1, characterized in that the carboxylic acid of formula II is optionally upstream of the methanesulfonamide the formula III _H2 N - _SO2 - _CH3 activation interested (III) in inert solvents and in the presence of a base and / or a catalyst, and in the case of ^; enantiomers are either directly used enantiomeric acids of formula II or the racemate of formula I is separated by conventional methods. A process according to claim 6, characterized in that the enantiomers are separated by column chromatography. A medicament comprising at least one isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amide of the formula I according to claim 1. Use of isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides of the formula I according to claim 1 for the manufacture of medicaments. Use of isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides of the formula I for the manufacture of medicaments inhibiting lipoxygenase.