NO179948B - New isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides and their use - Google Patents

Abstract

Novel isobutyl-substituted methanesulfonylquinolylmethoxy-phenyl-cycloalkyl-acetic acid amides can be prepared by reacting corresponding racemic or enantiomeric acids with methanesulfonamide, whereby the racemic end products can be separated by conventional methods into the enantiomers. In isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides can be used as active ingredients in medicinal products. R stands for cyclohexyl,.

Description

The invention relates to new isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides and their use.

Substituted 4-(quinolin-2-yl-methoxy)phenylacetic acid derivatives and α-substituted 4-(quinolin-2-yl-methoxy)phenylacetic acid derivatives are known from EP 344 519 (US 4 970 215) and EP 339 416.

The present invention relates to new isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides of general formula I:

there

R<1> stands for cyclohexyl,

in the form of racemates and enantiomers,

as well as both of the enantiomeric compounds of formula I where R<1> stands for cyclopentyl or cycloheptyl,

and their salts.

Within the scope of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Especially preferred are e.g. salts with hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Within the scope of the present invention, in addition to metal salts, monovalent metals and ammonium salts are preferred. Particularly preferred are alkali salts such as e.g. sodium, potassium and ammonium salts.

The compounds according to the invention with general formula I are prepared in a manner known per se by reacting the carboxylic acid with general formula II:

there

R<*> has the above meaning,

optionally during pre-coupled activation, with methanesulfonamide of formula III.

in inert solvents, in the presence of a base and/or catalyst,

and in the case of enantiomers, either directly use the enantiomerically pure acids II or separate the racemates I by usual methods.

Separation of the enantiomers preferably takes place by column chromatography.

The procedure can e.g. is explained in more detail with the following formula:

The sulphoamidation generally takes place in inert solvents in the presence of a base and a dehydrating agent.

Suitable solvents are inert organic solvents that do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzol, xylol, toluene, hexane, cyclohexane and petroleum fractions, nitromethane, dimethylformamide, acetonitrile or hexamethylphosphoric acid triamide . Likewise, it is possible to use mixtures of the solvents. Particularly preferred is dichloromethane.

Usual basic compounds are suitable as bases for the sulphoamidation. These preferably include alkali and alkaline earth hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali hydrides such as sodium hydride, alkali and alkaline earth carbonates such as sodium carbonate, potassium carbonate or alkali alcoholates such as e.g. sodium methanolate or -ethanolate, potassium methanolate or -ethanolate or potassium tert-butylate or mixtures of amines such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, dimethylaminopyridine, pyridine, triethylamine or N-methylpiperidine.

As dehydration reagents, carbodiimides such as e.g. 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 propanephosphonic anhydride or isobutylchloro -format or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or phosphonic acid diphenylesteramide or methanesulfonic acid chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

When carrying out the sulphoamidation, the base is generally used in an amount of from 1 to 3 mol, preferably from 1 to 1.5 mol, with respect to 1 mol of carboxylic acid (II).

In the event that the reaction takes place over the mixed anhydride, dimethylaminopyridine is preferably used as catalyst.

The catalyst is generally used in catalytic to equimolar amounts, preferably equimolar amounts.

The sulfoamidation is generally carried out in a temperature range from 0°C to 150°C, preferably at 25°C to 40°C. The sulfoamidation is generally carried out at normal pressure. However, it is also possible to carry out the process at negative pressure or at positive pressure (e.g. . in a range from 0.5 to 5 bar).

The carboxylic acids with general formula II are, with the exception of the case that R<1> - cycloheptyl as specific substance representatives, especially in enantiomeric form, new and can e.g. be produced by that one

either transfer compounds of general formula IV or I Va:

there

r<1> has the above meaning,

T and T' are the same or different and stand for a hydroxy protecting group such as benzyl or tert.butyl,

and

R<2> and R<2,> are the same or different and mean C₁-C₂alkyl, after removal of the protecting group with 2-halo-methylquinoline of formula V

there

V stands for halogen, preferably chlorine or bromine,

in inert solvents by etherification of the compound of general formula VI or Via:

there

R1, R2 and R<2Æ> have the above meaning,

and in that case the compound of general formula Via

reacts these in a second step in an alkylation with a compound of general formula VII:

there

R<1> has the meaning indicated above, and

W stands for chlorine, bromine or iodine,

in inert solvents,

and then saponify the ester by usual methods,

and in the case of enantiomers, column chromatographically separate the racemic acids by the usual methods of chiral acids.

The removal of the protective group of corresponding ethers IV and IVa takes place according to usual methods, e.g. by hydrogenolytic cleavage of benzyl ether in the above-mentioned inert solvents in the presence of a catalyst with hydrogen gas.

The esterification can be carried out in inert organic solvents, possibly in the presence of a base. The solvents for etherification can be inert organic solvents, which do not change under the reaction conditions. These preferably include ethers such as e.g. dioxane, tetrahydrofuran or diethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzol, xylol, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetonitrile, acetone or hexamethylphosphoric acid triamide. Likewise, it is possible to use mixtures of solvents.

Inorganic or organic bases can be used as bases for etherification. These preferably include alkali hydroxide sites such as e.g. sodium hydroxide or potassium hydroxide, alkaline earth hydroxides such as barium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate, alkaline earth carbonates such as calcium carbonate or organic amines (trialkyl(C^-C^)amine) such as triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or morpholine.

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

The etherification generally takes place in a temperature range of 0°C to +150°C, preferably from +1°C to +100°C.

The etherification is generally carried out at normal pressure. However, it is also possible to carry out the method under negative or positive pressure (e.g. in a range from 0.5 to 5 bar).

In general, 0.5 to 5 mol, preferably 1 to 2 mol of halide (V, with respect to 1 mol of reaction partner) are added. The base is generally added in an amount of from 0.5 to 5 mol, preferably from 1 to 3 mol, with respect to the halide.

The compounds of general formula IV and IVa are known in and of themselves or can be prepared by conventional methods.

Likewise, the compounds of general formula V and their preparation are known.

Suitable solvents for the method according to the invention and for alkylation are ordinary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as benzene, toluene, xylol, hexane, cyclohexane or petroleum fractions or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or acetic ester or triethylamine, pyridine, dimethylsulfoxide , dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Likewise, it is possible to use mixtures of the mentioned solvents. It is preferred with dichloromethane.

The alkylation is carried out in the above-mentioned solvents at temperatures from 0°C to +150°C, preferably at room temperature to +100°C at normal pressure.

The compounds of general formula III are known per se.

The compounds with general formula VI are partly new as specific substance representatives and can be prepared as described above.

Separation of the racemates generally takes place by column chromatography on chiral HPLC columns with solvent mixtures such as e.g. n-heptane/2-propanol or above diastereomeric esters.

The new N-methanesulfonyl-2-[3-isobutyl-3-(quinolin-2-yl-methoxy)phenyl]-2-cycloalkylacetic acid amides according to the invention can be used as active ingredients in pharmaceuticals. The substances can act as inhibitors of enzymatic reactions within the framework of arachidonic acid metabolism, in particular of hypooxygenase.

It is therefore preferred for the treatment and prevention of diseases in the respiratory tract such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammation/rheumatism and oedemas, thrombosis and thromboembolism, ischemia (peripheral, cardiac, cerebral blood flow disorders), heart and cerebral infarctions , angina pectoris, arteriosclerosis, in tissue transplants, dermatoses such as psoriasis, inflammatory dermatoses and for cytoprotection in the gastrointestinal tract.

The phenyl-substituted quinolines according to the invention can be used both in human medicine and also in veterinary medicine.

The pharmacological effects of the substances in the invention are determined in the following method: As a measure of lipoxygenase inhibition, the release of leukotriene B4 (LTB4) in polymorphonuclear human leukocytes (PMN) was determined after the addition of substances and Ca-ionophore using reverse phase HPLC according to Borgeat , P. et al., Proe. Nat. Acad. Sci., 76, 2148-2152 (1979).

Lipoxygenase inhibition (human PMNL):

TJtgang connections

Example I

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

Under an argon atmosphere, 12 g (0.033 mol) of 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenylacetic acid methyl ester and 6.52 g (0.04 mol) = 4.9 ml of cyclohexyl bromide 1 36 ml of DMF are dissolved and cooled to 0°C. While stirring, 4.88 g (0.04 mol) of potassium tertiary butylate, dissolved in 80 ml of DMF, are added dropwise to this. After approx. After a reaction time of 2 hours, the temperature is allowed to rise to RT, acidified with 2 N hydrochloric acid and evaporated in vacuo to dryness. The remaining residue is stirred with 100 ml of dichloromethane and 50 ml of water, the organic phase is separated off, dried with Na£SO 4 , evaporated in vacuo to a small volume and the remaining residue is separated by column chromatography (silica gel 60, eluent: dichloromethane/acetic ester = 100/2). Yield: 13 g (88.456 of theory), light yellow oil.

Example II

2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexyl-acetic acid

10.2 g (0.0236 mol) of the compound from example I is taken up in 70 ml of 2-propanol and heated with 50 ml of sodium hydroxide solution overnight until boiling. After it has cooled, it is neutralized with 50 ml of 1 N hydrochloric acid. Precipitated precipitate is sucked off, washed and dried and then recrystallized from diisopropyl ether.

Yield: 9.5 g (96.356 of theoretical), colorless crystals Freezing point: 130°C.

Example III and Example IV

(+) 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexylacetic acid (Example III)

(-) 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexylacetic acid (Example IV)

The title compound is obtained by separation of racemates (Example II) by chromatographic purification on chiral columns.

(+)-enantiomer: specific rotation: 17.96 (CHC13)

(Example III)

mole rotation: 77.41

(-)-enantiomer: specific rotation: -18.86 (CHC13)

(example IV)

mole rotation: -81.28

Example V

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

10 g (0.0275 mol) of 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)-phenylacetic acid methyl ester is reacted analogously to the procedure in example I with 10.04 g (0.055 mol) of cycloheptyl bromide and 6.17 g (0.055 mol) of potassium tertiary butylate to the title compound.

Yield: quantitative, yellow-brown oil.

Example VI

2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptyl-acetic acid

Analogously to the procedure in example II, the title compound is prepared from the compound in example V and 30 ml of 1 N caustic soda with subsequent acidification.

Yield: 11.3 g (92.356 of theoretical), colorless crystals Freezing point: 112<*>C

Example VII and Example VIII

(+) 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptylacetic acid (Example VII)

(-) 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptylacetic acid (Example VIII)

The title compound is prepared from the racemate (Example VI) by column chromatographic separation on HPLC-H 1050-Chiralpak AS in a solvent mixture of 9656 of n-heptane and 456 of a mixture of 2-propanol, containing 156 of water and 0.256 of trifluoroacetic acid.

(+)-enantiomers: specific rotation: 15.72,

solvent CHCl3,

example VII

mol rotation: 69.96 (-)-enantiomer: specific rotation: -18.7, solvent CHCl3,

example VIII

mole rotation: -86.19

Example IX

2-[3-isobuty1-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptyl-acetic acid methyl ester

Analogous to the procedure in examples I and V, the title compound is prepared from 10 g (0.0275 mol) of 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-acetic acid methyl ester, 8.2 g ( 0.055 mol) of cyclopentyl bromide and 6.17 g (0.055 mol) of potassium tertiary butylate.

Yield: quantitative, yellow-brown oil.

Example X

2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl-acetic acid

Analogous to the procedure in examples II and VI, the title compound is prepared from the compounds in example IX by saponification with 30 ml of caustic soda and subsequent acidification.

yield: 10.5 g (91.556 of theoretical), slightly yellow-like crystals

Freezing point: 120<*>C

Examples XI and XII

(+) 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentylacetic acid (Example XI)

(-) 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentylacetic acid (Example XII)

The title compound is obtained analogously to the procedure in examples VII and VIII by chromatographic purification of the compounds from example X.

(+)-enantiomer: specific rotation: 44.56 (THF).

example XI

mole spin: 185.84

(-)-enantiomer: specific rotation: -41.07 (THF), Example XII

mole rotation: -171.28

Example XIII

N-methanesulfonyl-2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptylacetic acid amide

Under argon, 2 g (0.0045 mol) of the compound from Example VI is slurried in 20 ml of dry THF and mixed with 1.82 g (0.018 mol) of triethylamine (d = 0.73). This results in a clear resolution. When cooling in an ice bath, 1.14 g (0.01 mol) mesyl chloride (d = 1.48) is added dropwise, stirred at this temperature for a further 15 min and then allowed to add dropwise while stirring 1.52 g (0.016 mol) methanesulfonamide and 1 .1 g (0.009 mol) of dimethylaminopyridine, dissolved in 10 ml of dry THF. It is left to react overnight, whereby the temperature rises to RT. The mixture is poured into toluene and extracted with water and dilute acetic acid. The organic phase is separated, dried with Na2SC>4, evaporated in vacuo to a small volume and the remaining light brown oil (2.42 g) is treated by column chromatography (silica gel 60, eluent: toluene/acetic ester/glacial acetic acid = 8/2/1) .

1.75 g (74.656 of theoretical) of a colorless product (amorphous) is obtained.

Progress examples

Example 1

N-methanesulfony1-2-[3-1isobutyl-4-(quinolin-2-yl-methoxy)phenyl]-2-cyclohexylacetic acid amide

The title compound is prepared analogously to the description in Example XIII from 3.5 g (0.08 mol) of the compound from Example II, 1 g (0.008 mol) mesyl chloride, 0.912 g methanesulfonamide, 1.62 g (0.016 mol) triethylamine and 0. 98 g (0.008 mol) of dimethylaminopyridine.

Yield: 3.48 g (84 .956 of theoretical), colorless amorphous powder Freezing point: 163-170"C

Example 2 and Example 3

(+) N-methanesulfonyl-2-[3-isobutyl-4-(quinolin-2-yl-methoxy)-phenyl]-2-cyclohexylacetic acid amide (Example 2)

(-) N-methanesulfonyl-2-[3-isobutyl-4-(quinolin-2-yl-methoxy)-phenyl]-2-cyclohexylacetic acid amide (Example 3)

Both enantiomers are obtained by column chromatographic separation of the compound from example 1 on HPLC-HP 1050 Chiralcel OD in an eluent mixture of 8656 n-heptane and 1456 of a 2-propanol mixture containing 156 water + 0.256 trifluoroacetic acid.

(+)-enantiomers: specific rotation: +32.15° (CHC13),

example 2

mol rotation: +163.32° (-)-enantiomer: specific rotation: -28.96° (CHC13), example 3

mole rotation: -147.12°

The pure enantiomers listed in Table 1 can either be prepared analogously to the description in examples 2 and 3 via separation of the racemate or by using corresponding enantiomerically pure carboxylic acids.

Claims (7)

1. New isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides, characterized by formula: there R<1> stands for cyclohexyl, in the form of racemates and enantiomers, as well as the enantiomers, when R<1> stands for cyclopentyl or cycloheptyl, and their salts. 2. Racemate, (+)-enantiomers and (-)-enantiomers of the compound, characterized by formula: and their salts. 3. Racemate, (+)-enantiomers and (-)-enantiomers of the compound, characterized by formula: and their salts. 4. Racemate, (+)-enantiomers and (-)-enantiomers of the compound, characterized by formula: and their salts. 5. Medicine, characterized in that it contains at least one isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amide according to claim 1. 6. Use of isobutyl-substituted methanesulfonyl-quinolylmethoxyphenyl-cycloalkylacetic acid amides according to claim 1 for the production of pharmaceuticals. 7. Use according to claim 6 for the production of lipoxygenase-inhibiting drugs.