LT3537B - Quinoline derivatives - Google Patents

Abstract

The present invention is related to new quinoline compounds that can be expressed in formula I:<IMAGE>The compounds suppress gastric acid secretion stimulated from outside and inside, and can therefore be used for prevention and treatment of gastric and intestine inflammatory diseases.

Description

The present invention relates to novel compounds and therapeutically acceptable salts thereof which inhibit externally and internally stimulated gastric acid secretion and can therefore be used for the prophylaxis and treatment of inflammatory diseases of the stomach. In other aspects, the present invention relates to the use of the compounds provided herein in therapy, to the preparation of these novel compounds, to pharmaceutical preparations containing one of the compounds of the present invention or therapeutically acceptable salts thereof as active ingredient, and to the use of these active compounds in production of the aforementioned therapeutic purposes.

Substituted quinoline derivatives which inhibit gastric acid secretion are known, for example, from EP-A1-259,174 and EP-Al-330,485.

It has been unexpectedly discovered that the compounds of formula I, which are 4-amino-3-acylquinoline derivatives and in which the quinoline is substituted at the 8-position by alkylthioethoxy, alkylthiopropoxy, alkylsulfinylethoxy, alkylsulfinylpropoxy, alkylsulfonylethoxy or alkylsulfonylpropoxy groups, results in their inhibition of gastrointestinal H ⁺ , K ⁺ -ATPase.

In one aspect, the present invention relates to compounds of formula I:

S (O) _n and pharmaceutically acceptable salts thereof, wherein R ¹ is (a) C 1 -C 6 alkyl, (b) C 3 -C 6 cycloalkyl, or (c) C 3 -C 6, C 1 -C 6 cycloalkylalkyl;

R ² is (a) H, (b) C 1 -C 6 alkyl, (c) C 1 -C 6 alkoxy, or (d) halogen;

R ³ is C 1 -C 6 alkyl;

R ⁴ is (a) H, (b) C 1 -C 4 alkyl, (c) halogen, or (d) OH;

m is an integer of 2 or 3, and n is an integer of 0.1 or 2.

In the present application and in the definition of the invention, the chemical formula or name of the compound encompasses all possible stereo and optical isomers and racemates, if any, and pharmaceutically acceptable acid addition salts and solvates, such as, for example, hydrates.

The terms used in this application and in the specification are defined as follows:

Unless otherwise stated, the term C 1 -C 6 alkyl refers to a straight or branched alkyl group having 1 to 6 carbon atoms. Examples of such lower alkyls include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and straight or branched chain pentyl and hexyl.

Unless otherwise stated, the term cycloalkyl means a cyclic alkyl group having from C3 to Cf a ring carbon atom which may in turn be substituted by a lower alkyl.

I

Examples of such cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, and cycloheptyl.

li

Unless otherwise stated, the term C 1 -C 6 alkoxy means a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples of such lower alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy and straight or branched chain pentoxy and hexoxy.

Unless otherwise stated, the term halogen means fluorine, chlorine, bromine or iodine.

The compounds of formula I may be obtained in the form of a neutral compound or a salt, depending on the conditions of preparation and starting materials. The present invention includes both neutral compounds and their salts.

The salts of the novel compounds which they form with acids may be converted into their free bases by known methods, using ion exchange or basic agents such as alkali. The resulting free bases, in turn, can form salts with organic and inorganic acids.

For the formation of salts with new acids, it is preferable to use acids which give the salts suitable for therapy. Examples of such acids are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxy ethanesulfonic acid, toluenesulfonic acid, toluic acid.

Suitable compounds of the formula I are those in which:

R ¹ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , cyclopropyl or cyclopropylmethyl;

R ² is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH (CH ₃ ) CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ , or halogen;

R ³ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , or CH ₂ CH ₂ CH ₃ ; and

R ⁴ is H, CH ₃ , CH ₂ CH ₃ , halogen or OH.

More preferred compounds of formula I are those wherein:

R ¹ is CH ₂ CH ₃ or CH ₂ CH ₂ CH ₃ ;

II

R ² is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OCH ₃ , or Cl;

R ³ is CH ₃ , CH ₂ CH ₃ , or CH ₂ CH ₂ CH ₃ ; and

R ⁴ is H, CH ₃ , F, Cl or OH.

A preferred compound of formula I according to the present invention is that wherein R ¹ is CH 2 CH 2 CH 3; R ² and R ³ are CH 3; R ⁴ is H; m = 2, on = 1, i.e., compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfylethoxy) quinoline.

Another aspect of the present invention is the use of compounds of formula I in therapy.

Receipt

The present invention also provides processes for the preparation of compounds of formula I. These compounds are obtained by the following processes:

(A) A compound of general formula II

wherein R ² and R ^{4 are as} defined above, reacting with a compound of general formula III

S (O) _n i;

wherein R ¹ , R ³ , m and n are as previously defined and X is a reaction leaving group such as halide, tosyloxy or mesyloxy.

The compounds of formula III are novel compounds and therefore relate to another aspect of the present invention.

The reaction is carried out with or without a solvent. When using a solvent, it is best to use a solvent such as acetonitrile, tetrahydrofuran, toluene or dimethylformamide.

When the reaction is carried out with a solvent, the reaction temperature is usually from 20 ° C to about the reflux temperature of the solvent, preferably from 20 ° C to about 110 ° C. The reaction time is usually from about 1 hour. up to about 24 hours

When the reaction is carried out without solvent, the reaction temperature is usually from 30 ° C to about 170 ° C. The reaction time is usually from about 15 minutes. up to about 2 hours

(B) Compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ and m are defined in (A), 1 or 2 may be obtained by oxidation of a compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ and m are defined above in (A), on is 0.

This oxidation can be carried out using oxidizing agents such as sodium hypochlorite, nitric acid, hydrogen peroxide (optionally in the presence of vanadium compounds), acid acids, peresters, ozone, dinitrogentetraoxide, iodosobenzene, Nhalogensuccinimide, 1-chlorobenzotriazole, t-butyl, 2,2-octane bromine complex, sodium metaperiodate, selenium peroxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine and sulfuryl chloride. The oxidation is carried out in a solvent such as a halogenated hydrocarbon, alcohol, ether or ketone.

The reaction can be carried out either enzymologically using the appropriate oxidizing enzyme or microbiologically using the appropriate microorganisms.

Compounds of formula II are commercially available or can be obtained by known methods.

Compounds of formula III can be obtained by known methods and by the following examples.

i:

Usage

Another aspect of the present invention relates to the use of compounds as defined above in the manufacture of a medicament for the inhibition of gastric acid secretion or for the treatment of inflammatory diseases of the stomach and intestines.

In general, the compounds of the present invention can be used in the treatment of mammals, including humans, inflammatory diseases of the stomach and intestines, and gastric acid mediated diseases, e.g.

In addition, these compounds can also be used to treat other gastrointestinal disorders that require inhibition of gastric secretion. Such diseases include, say, stomach tumors and acute upper gastrointestinal bleeding. They can also be used in patients during intensive care, before surgery and after surgery to prevent acid aspiration and stress ulceration.

Pharmaceutical preparations

Another aspect of the present invention is that it relates to pharmaceutical preparations containing as active ingredient at least one compound of the present invention or a therapeutically acceptable salt thereof.

The compounds of the present invention can be used in formulations in combination with other active ingredients, for example for the treatment or prophylaxis of human gastric mucositis caused by Helicobacter pylori. Such other active components may be antimicrobial agents, and in particular:

β-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefachlor or cefixime; or macrolides such as erythromycin or clarithromycin; or tetracyclines such as tetracycline or doxycycline; or aminoglycosides such as gentamicin, kanamycin or amikacin; or quinolones such as norfloxacin, ciprofloxacin or enoxacin; or other compounds such as metronidazole, nitrofurantoin or chloramphenicol;

I;

or preparations containing bismuth salts, such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgalate.

For clinical use, the compounds of this invention are formulated in pharmaceutical preparations for oral, rectal, parenteral or other administration. The pharmaceutical composition together with the compounds of the present invention contains one or more pharmaceutically acceptable ingredients. The carrier may be a solid, semi-solid, liquid solution, or a capsule. These pharmaceutical preparations are another aspect of the present invention. The amount of active compound in the formulations is usually from 0.1 to 95% by weight, preferably from 0.2 to 20% by weight in preparations for parenteral administration and from 1 to 50% by weight in formulations for oral use.

In preparing the pharmaceutical compositions of the compounds of this invention for oral administration in unit dosage form, the selected compound may be mixed with solid or powdered ingredients, e.g., lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or the like. with disintegrating agents or gelling agents such as magnesium stearate, calcium stearate, sterile sodium fumarate, and polyethylene glycol ointments. The mixture is then formed into granules or compressed tablets. Soft gelatine capsules may also be obtained by mixing the active compound of the present invention with a vegetable oil, fat or other suitable filler for soft gelatine capsules. The hard gelatine capsules may contain granules of the active compound. In addition, hard gelatine capsules may contain the active compound together with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, cereal starch, amylopectin, cellulose derivatives or gelatin.

Single doses for rectal administration may be prepared (i) in the form of a mixture of the active compound and a neutral fat excipient; (ii) gelatin capsules of the active compound and vegetable oil, paraffin oil or other suitable filler for administration to the rectum; (iii) in the form of finished micro-enema; (iv) in the form of dry micro-enema, which are dissolved in a suitable solvent just prior to acceptance.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, for example, syrups or suspensions containing from 0.2 to 20% by weight of the active ingredient and sugar or sugar alcohols and ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other excipients may be added to such liquid preparations. Liquid preparations for oral administration may also be prepared as a dry powder which is dissolved in a suitable vehicle prior to administration.

Solutions for parenteral administration may be prepared as solutions of the active compound of the invention in a pharmaceutically acceptable solvent. The preferred concentration is from 0.1 to 10% by weight. Stabilizing components and / or buffering ingredients may also be added to these solutions. The solutions can be dispensed as single doses into ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation which is dissolved in a suitable vehicle prior to administration.

The typical daily dose of the active compound varies over a very wide range depending on various factors, such as the individual needs of each patient, the route of administration or the disease. In general, oral and parenteral doses of the active ingredient are from 5 to 1000 mg per day.

EXAMPLES

1. Preparation of the compounds of the invention

An example

Preparation of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (0.67 g, 2.1 mmol) and o-toluidine (0.24 g, 2.3 mmol) is heated to 55 ° C and stirred 3.5 or. The solvent is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. The residue is quenched with diisopropyl ether. The precipitate is filtered off and washed with diisopropyl ether. 0.55 g (66%) of the title compound is obtained.

(1 H-NMR, 500 MHz, CDCl 3, 1.05 (t, 3H), 1.84 (m, 2H), 2.25 (s, 3H), 2.35 (s, 3H),

3.10 (m, 4H), 4.34 (t, 2H), 6.89 (d, 1H), 6.95-7.15 (m, 5H), 7.27 (d, 1H), 9 , 26 (s, 1H), 11.84 (s, 1H).

r j

An example

Preparation of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Butyryl-4- (2-methylphenylamino) -8- (2-methylthioethoxy) quinoline (0.15 g, 0.38 mmol) was dissolved in methylene chloride (3 mL) and cooled to -20 ° C. Then, a solution of 71% m-CPBA (0.089 g, 0.36 mmol) in 1 mL of methylene chloride was added dropwise. Allow the mixture to warm to room temperature and stir for a further 15 minutes. at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. After chromatography, eluting with methylene chloride: methanol 10: 1, 0.064 g (41%) of the desired product is obtained.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.04 (t, 3H), 1.82 (m, 2H), 2.34 (s, 3H), 2.80 (s, 3H), 3, 08 (t, 2H), 3.21 (m, 1H), 3.44 (m, 1H), HHHH 4.62 (m, 2H), 6.89 (d, 1H), 6.94-7, 16 (m, 5H), 7.28 (d, 1H), 9.20 (s, 1H), 11.82 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfonylethoxy) quinoline

3-Butyryl-4- (2-methylphenylamino) -8- (2-methylthioethoxy) quinoline (0.037 g, 0.092 mmol) was dissolved in methylene chloride (1.5 mL) and cooled to -20 ° C. Then a solution of 71% mCPBA (0.047 g, 0.19 mmol) in 0.5 ml methylene chloride is added dropwise. Allow the mixture to warm to room temperature and then stir for a further 30 minutes. at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. The residue is quenched with diisopropyl ether and the product crystallized. Chromatography of the precipitated residue with eluent methylene chloride: ethyl acetate 1: 1 gives 0.022 g (56%) of the title compound.

(1 H-NMR, 500 MHz, CDCl ₃ ) 1.07 (t, 3H), 1.84 (m, 2H), 2.35 (s, 3H), 3.10 (t, 2H),

3.39 (s, 3H), 3.62 (t, 2H), HHHH 4.61 (t, 2H), 6.89 (d, 1H), 6.94-7.17 (m, 5H), 7.28 (m, 1H),

9.15 (s, 1H), 11.86 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-isopropylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (400 mg, 1.23 mmol) and 2-isopropylaniline was heated for 30 min. At 150 ° C. The mixture was diluted with CHCl ₃ and extracted with 2N HCl. The organic phase is washed with saturated sodium bicarbonate solution. The organic layer is dried over Na ₂ SO ₄ and evaporated. The residue is purified on a chromatography column (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5). 340 mg (80.5%) of the desired product are obtained.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.0 (t, 3H), 1.1 (d, 3H), 1.2 (d, 3H), 1.75 (m, 2H), 2, 15 (s, 3H), 3.1 (m, 3H), 3.2 (t, 2H), HHHH 4.3 (t, 2H), 6.8 (d, 1H), 7.0-7, 2 (m, 4H), 7.4 (m, 2H), 9.4 (d, 1H).

An example

Preparation of 3-butyryl-4- (2-isopropylphenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Butyryl-4- (2-isopropylphenylamino) -8- (2-methylthioethoxy) quinoline (0.22 g, 0.52 mmol) was dissolved in methylene chloride (15 mL) and added to 0.093 g of NaHCO ₃ in 15 mL of H ₂ O. A solution of 71% m-CPBA (0.12 g, 0.50 mmol) in 7 mL of methylene chloride is added dropwise to the mixture at 4 ° C. The mixture is stirred for one hour at room temperature. The mixture is then washed with saturated sodium bicarbonate solution. The organic layer is dried over Na ₂ SO ₄ and evaporated. Chromatography with methylene chloride: methanol 10: 1 as eluent gives 0.130 g (57%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.0 (t, 3H), 1.3 (m, 6H), 1.8 (m, 2H), 2.78 (s, 3H), 3, 08 (t, 2H), 3.2 (m, 6H), 3.35 (m, 1H), 3.45 (m, 1H), HHHH 4.6 (m, 2H), 6.82 (d, 1H), 6.86 t, 1H), 7.05 (m, 3H), 7.2 (t, 1H), 7.38 (d, 1H), 9.18 (s, 1H), 11.8 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-isopropylphenylamino) -8- (2-methylsulfonylethoxy) quinoline

Of a solution of 3-butyryl-4- (2-isopropylphenylamino) -8- (2-methylthioethoxy) quinoline (0.22 g, 0.52 mmol) in 15 mL of a solution of methylene chloride and NaHCO ₃ (0.186 g, 2.2 mmol). of H ₂ O cools to 4 ° C. A solution of 70% m-CPBA (0.24 g, 1.0 mmol) in 7 mL of methylene was added dropwise

Of chloride. The mixture is stirred for 1 hour at 4 ° C, then the organic layer is dried over Na ₂ SO ₄ and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 90:10) gives 16 mg (6.8%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.2 (m, 6H), 1.8 (m, 2H), 3.1 (t, 2H),

3.35 (s, 3H), 3.45 (m, 1H), 3.65 (m, 2H), HHHH 4.6 (m, 2H), 6.85 (d, 2H), 6.9-. 7.1 (m, 4H),

7.4 (d, 1H), 9.1 (s, 1H), 11.8 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-propanoyl-4-chloro-8- (2-methylthioethoxy) quinoline (0.60 g, 1.9 mmol) and o-toluidine (0.25 g, 2.3 mmol) was heated to 55 ° C in acetonitrile and stir for 3.5 hours. The solvent is evaporated and the residue is partitioned between methylene chloride and 10% sodium carbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : EtOAc 60:40) gives 0.45 g (61%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.26 (t, 3H), 2.21 (s, 3H), 2.33 (s, 3H), 3.06 (t, 2H),

3.10 (kv, 2H), HHHH 4.33 (t, 2H), 6.87 (d, 1H), 6.96-7.12 (m, 5H), 7.25 (d, 1H), 9.26 (s, 1H), 11.78 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Propanoyl-4- (2-methylphenylamino) -8- (2-methylthioethoxy) quinoline (0.10 g, 0.26 mmol) was dissolved in methylene chloride (5 mL). NaHCO3 (45 mg) in water (5 mL) is added to the solution. The mixture is cooled to 4 ° C. A solution of 71% m-CPBA (0.062 g, 0.25 mmol) in methylene chloride (5 mL) was added dropwise. The mixture is stirred for 1 hour at 2-4 ° C, then the organic layer is washed with saturated sodium bicarbonate solution. The organic layer is dried over Na ₂ SO ₄ and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : EtOH 90:10) gives 50 mg (48%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.26 (t, 3H), 2.33 (s, 3H), 2.78 (s, 3H), 3.10-3.50 (m, 4H) ), 4.61 (m, 2H), 6.85 (d, 1H), 6.92-7.11 (m, 5H), 7.28 (d, 1H), 9.18 (s, 1H) , 11.81 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (2-methylsulfonylethoxy) quinoline

3-Propanoyl-4- (2-methylphenylamino) -8- (2-methylthioethoxy) quinoline (0.12 g, 0.32 mmol) was dissolved in methylene chloride (5 mL). To the solution, added NaHCO3 (110 mg) in 10 mL H ₂ O. The mixture was cooled to 4 ° C. A solution of 71% m-CPBA (0.17 g, 0.69 mmol) in methylene chloride (5 mL) was added dropwise. The mixture is stirred for 1 hour at 2-4 ° C, then the organic layer is washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : EtOAc 50:50) gives 0.060 g (45%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.26 (t, 3H), 2.34 (d, 3H), 3.15 (s, 2H), 3.37 (s, 3H), 3, 61 (t, 2H), HHHH 4.58 (t, 2H), 6.86 (d, 1H), 6.95-7.11 (m, 5H), 7.26 (d, 1H), 9, 13 (s, 1H), 11.81 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-ethylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-propanoyl-4-chloro-8- (2-methylthioethoxy) quinoline (0.093 g, 0.34 mmol) and 2-ethaniline (0.048 g, 0.39 mmol) in acetonitrile (1 mL) was heated to 65 ° C and stirred for 4 h. or. The solvent is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; ethyl acetate) affords 40 mg (30%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.22-1.30 (m, 6H), 2.22 (s, 3H), 2.76 (s, 2H), 3.06 (t, 2H) ), 3.15 (kv, 2H), HHHH 4.34 (t, 2H), 6.82 (d, 1H), 6.91-7.06 (m, 2H), 7.14 (m, 1H) ), 7.28 (m, 1H), 9.21 (s, 1H), 11.83 (s, 1H).

and 12 Examples

3-Propanoyl-4- (2-ethylphenylamino) -8- (2-methylsulfinylethoxy) quinoline (Example 11); and

Preparation of 3-propanoyl-4- (2-ethylphenylamino) -8- (2-methylsulfonylethoxy) quinoline (Example 12)

3-Propanoyl-4- (2-ethylphenylamino) -8- (2-methylthioethoxy) quinoline (0.022 g, 0.056 mmol) was dissolved in methylene chloride (0.7 mL). NaHCO ₃ (12 mg,) H ₂ O (0.7 mL) was added to the solution. The mixture is cooled to 4 ° C. A solution of 71% m-CPBA (0.017 g, 0.07 mmol) in methylene chloride (0.5 mL) was added dropwise. The mixture is stirred for 1 hour at 2-4 ° C, then the organic layer is washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 90:10) gives 8 mg (35%) of the compound of Example 11 and 10 mg (42%) of the compound of Example 12.

Example: ( ¹ H-NMR, 300 MHz, CDCl ₃ ) 1.25 (m, 6H), 2.73-2.81 (m, 5H), 3.15 (kv, 2H), 3.22 (m , 1H), 3.41-3.49 (m, 1H), HHHH 4.62 (m, 2H), 6.84 (d, 1H), 6.93-7.19 (m, 5H), 7 , 31 (d, 1H), 9.19 (s, 1H), 11.88 (s, 1H).

Example: (1 H-NMR, 300 MHz, CDCl ₃ ) 1.29 (m, 6H), 2.77 (kv, 2H), 3.16 (kv, 2H), 3.37 (s, 3H), 3.61 (t, 2H), HHHH 4.60 (t, 2H), 6.85 (d, 1H), 6.94-7.20 (m, 5H), 7.31 (d, 1H), 9.14 (s, 1H), 11.90 (s, 1H).

An example

Preparation of 3-butyryl-4- (4-fluoro-2-methylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (2.75 g, 8.2 mmol) and 4-fluoro-2-methylaniline (1.34 g, 10.7 mmol) in acetonitrile (20 mL) annoying 8 or. with reflux. The solution is cooled and 1.52 g of crystallized product is filtered off. The filtrate was evaporated to give 0.4 g of the desired product after chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5). Overall yield 1.92 g (57%).

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.85 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 3.05 (m, 4H), 4.35 (t, 2H), 6.75-6.90 (m, 2H), 7.00 (m, 4H), 9.20 (s, 1H), 11.80 ( s, 1H).

Ii and 15 Examples

3-Butyryl-4- (4-fluoro-2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline (Example 14) and 3-Butyryl-4- (4-fluoro-2-methylphenylamino) -8- (2- methylsulfionyl-ethoxy) -quinoline (Example 15)

3-Butyryl-4- (4-fluoro-2-methylphenylamino) -8- (2-methylthioethoxy) quinoline (1.6 g, 3.88 mmol) was dissolved in methylene chloride (35 mL). 0.3 M NaHCO ₃ solution (36 mL) is added to the solution. The mixture is cooled to 4 ° C. 70% m-CPBA (1.22 g, 5.04 mmol) in methylene chloride (16 mL) was added dropwise. The mixture is stirred for 1 hour at 2-4 ° C, then the organic layer is washed with 0.3 M NaHCO ₃ solution. The organic layer was dried over Na ₂ SO 4 and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) yields 1.55 g (93%) of the compound of Example 14 and 0.31 g (18%) of the compound of Example 15.

example: (1 H-NMR, 300 MHz, CDCl ₃ ) 0.95 (t, 3H), 1.75 (m, 2H), 2.20 (s, 3H),

2.70 (s, 3H), 3.00 (t, 2H), 3.10 (m, 1H), 3.30-3.40 (m, 1H), HHHH 4.50 (m, 2H), 6.70 (m, 1H), 6.75 (m, 1H), 6.85-6.95 (m, 3H), 7.00 (m, 1H), 9.10 (s, 1H), 11 , 85 (s, 1H).

Example ^(J H-NMR 300 MHz, CDC1 ₃₎ 1.05 (t, 3H), 1.80 (m, 2H), 2.30 (s, 3H);

3.10 (t, 2H), 3.40 (s, 3H), 3.60 (t, 2H), HHHH 4.60 (t, 2H), 6.75-6.80 (m, 1H), 6.85-6.90 (m, 1H), 6.95-7.05 (m, 4H), 9.15 (s, 1H), 11.85 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-isopropylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-propanoyl-4-chloro-8- (2-methylthioethoxy) quinoline (305 mg, 1 mmol) and 2-isopropylaniline (1 mL) was heated to 25 mL of acetonitrile overnight under reflux. The solution is evaporated and the residue partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. After residue chromatography, 30 mg (8%) of the desired product is obtained via prep-thin layer chromatography (TLC) (methylene chloride: ethyl acetate 1: 1).

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.3 (m, 9H), 2.25 (s, 3H), 3.05 (t, 2H), 3.15 (s, 2H),

3.4 (m, 1H), 4.3 (t, 2H), 6.8 (d, 1H), 7.00 (m, 4H), 7.2 (t, 1H), 7.4 (d) , 1H), 9.20 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-ethylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (3.69 g, 9.84 mmol) and 2-ethylaniline (1.55 g, 12.8 mmol) in acetonitrile (20 mL) was heated to or. with reflux. The solution is evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 97: 3) gives 2.79 g (69%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.00 (t, 3H), 1.25 (t, 3H), 1.80 (m, 2H), 2.20 (s, 3H), 2, 80 (m, 2H), 3.10 (m, 4H), 4.35 (t, 2H), 6.85 (m, 1H), 6.90-7.10 (m, 4H), 7.15 (t, 1H), 7.30 (m, 1H), 9.20 (s, 1H).

and 19 Examples

3-Butyryl-4- (2-ethylphenylamino) -8- (2-methylsulfinylethoxy) quinoline (Example 18); and

Preparation of 3-butyryl-4- (2-ethylphenylamino) -8- (2-methylsulfonylethoxy) -quinoline (Example 19)

3-Butyryl-4- (2-ethylphenylamino) -8- (2-methylthioethoxy) quinoline (1.98 g, 4.85 mmol) was dissolved in methylene chloride (40 mL). To the solution was added 0.3 M NaHCO ₃ solution (45 mL). The mixture is cooled to 4 ° C. 70% m-CPBA (1.54 g, 6.31 mmol) in methylene chloride (20 mL) was added dropwise. The mixture is stirred for 1 hour at 2-4 ° C, then the organic layer is washed with 0.3 M NaHCO ₃ solution. The organic layer was dried over Na ₂ SO 4 and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 97: 3) yields 0.62 g (30%) of Example 18 and 0.39 g (18%) of Example 19.

Example: (1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.30 (t, 3H), 1.85 (m, 2H),

2.75 (m, 2H), 2.85 (s, 3H), 3.05 (t, 2H), 3.20-3.30 (m, 1H), 3.40-3.50 (m, 1H), HHHH 4.65 (m, 2H), 6.85 (m, 1H), 6.90-7.00 (m, 1H), 7.05-7.10 (m, 3H), 7, 15 (t, 1H), 7.30 (m, 1H),

9.20 (s, 1H), 11.95 (s, 1H).

Example: (1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.30 (t, 3H), 1.85 (m, 2H),

2.75 (m, 2H), 3.10 (t, 2H), 3.40 (s, 3H), 3.65 (m, 2H), HHHH 4.60 (m, 2H), 6.85 ( d, 1H), 6.95-7.10 (m, 4H), 7.20 (t, 1H), 7.30 (m, 1H), 9.10 (s, 1H).

l:

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (2-propylthioethoxy) quinoline

A mixture of 3-propanoyl-4-chloro-8- (2-propylthioethoxy) quinoline (2.5 g, 7.4 mmol) and o-toluidine (0.94 g, 8.86 mmol) in acetonitrile (10 mL) was heated to or. with reflux. The solvent is evaporated and the residue is partitioned between methylene chloride and 10% NajCCh solution. The organic layer was dried over Na2SO4 and evaporated. The product was purified by column chromatography (methylene chloride: ethyl acetate 80:20). 1.8 g (60%) of the title compound are obtained.

(1 H-NMR, 300 MHz, CDCl 3) 1.00 (t, 3H), 1.28 (t, 3H), 1.66 (m, 2H), 2.35 (s, 3H), 2.62 (t, 2H), 3.09 (t, 2H), 3.14 (s, 2H), 4.32 (t, 2H), 6.80-7.25 (m, 7H), 9.22 ( s, 1H), 11.76 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (2-propylsulfinylethoxy) quinoline

3-Propanoyl-4- (2-methylphenylamino) -8- (2-propylthioethoxy) quinoline (0.5 g, 1.22 mmol) is dissolved in 10 mL of methylene chloride. To the resulting solution is added a solution of sodium bicarbonate (250 mg, 3.0 mmol) in 10 mL of water. The mixture is cooled to 2-4 ° C. Within 10 minutes. dropwise a solution of 70% mCPBA (295 mg, 1.20 mmol) in 10 mL of methylene chloride. The temperature of the mixture is allowed to rise to room temperature and then stirred at this temperature for 30 minutes. The organic layer was dried over Na2S ₄ and evaporated. Purify the residue on a chromatography column (methylene chloride: ethanol 90:10). Obtain 380 mg (73%) of the title compound.

(1 H-NMR, 300 MHz, CDCl 3) 1.11 (t, 3H), 1.28 (t, 3H), 1.87 (m, 2H), 2.35 (s, 3H),

2.89 (m, 2H), 3.10-3.20 (m, 3H), 3.40 (m, 1H), HHHH 4.63 (kv, 2H), 6.90-7.40 (m , 7H),

9.19 (s, 1H), 11.85 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (2-propylsulfonylethoxy) quinoline

3-Propanoyl-4- (2-methylphenylamino) -8- (2-propylthioethoxy) quinoline (500 mg, 1.22 mmol) was dissolved in 10 mL of methylene chloride. To the resulting solution is added a solution of sodium bicarbonate (500 mg, 5.95 mmol) in 10 mL of water. The mixture is cooled to 2-4 ° C. A solution of 70% m-CPBA (600 mg, 2.43 mmol) in 10 mL of methylene chloride is added dropwise. The temperature of the mixture is allowed to rise to room temperature and then stirred at this temperature for 30 minutes. The methylene chloride layer is separated and washed with water. The organic layer is then dried over Na ₂ SO 4 and evaporated. The crude product is purified by chromatography on a column (methylene chloride: ethanol 50:50). Obtained 340 mg (63%) of the title compound.

(1 H-NMR, 300 MHz, CDCl 3) 1.13 (t, 3H), 1.27 (t, 3H), 1.96 (m, 2H), 2.35 (s, 3H),

3.16 (kv, 2H), 3.47 (t, 2H), HHHH 4.58 (t, 2H), 6.85-7.25 (m, 7H), 9.12 (s, 1H), 11.81 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (3-propylthiopropoxy) quinoline

A mixture of 3-propanoyl-4-chloro-8- (8-propylthiopropoxy) quinoline (2.0 g, 5.7 mmol) and o-toluidine (0.7 g, 6.5 mmol) in acetonitrile (10 mL) was heated to or. with reflux. The solvent is evaporated and the residue is partitioned between methylene chloride and 10% sodium carbonate solution. The organic layer is dried over sodium sulfate and evaporated. The residue was purified by chromatography on a column (methylene chloride: ethyl acetate 70:30). Obtain 1.3 g (54%) of the title compound.

(1 H-NMR, 300 MHz, CDCl 3) 0.94 (t, 3H), 1.26 (t, 3H), 1.57 (m, 2H), 2.25 (m, 2H),

2.34 (s, 3H), 2.49 (t, 2H), 2.75 (t, 2H), 3.15 (s, 2H), HHHH 4.27 (t, 2H), 6.83- 7.23 (m, 7H), 9.22 (s, 1H), 11.73 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (3-propylsulfinylpropoxy) quinoline

3-Propanoyl-4- (2-methylphenylamino) -8- (3-propylthiopropoxy) quinoline (200 mg, 0.47 mmol) was dissolved in 5 mL of methylene chloride. To the resulting solution is added a solution of sodium bicarbonate (80 mg, 0.95 mmol) in 5 mL of water. The mixture is cooled to 2-4 ° C. Within 10 minutes. A solution of 70% mCPBA (115 mg, 0.47 mmol) in 5 mL of methylene chloride was added dropwise. The temperature of the mixture is allowed to rise to room temperature and then stirred at this temperature for 30 minutes. The methylene chloride layer is separated and washed with water. The organic layer is then dried over Na ₂ SO 4 and evaporated. The crude product is purified on a chromatography column (methylene chloride: ethanol 95: 5). 160 mg (77%) of the title compound are obtained.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.06 (t, 3H), 1.27 (t, 3H), 1.79 (m, 2H), 2.33 (s, 3H),

2.49 (m, 2H), 2.60-2.80 (m, 3H), 2.93 (m, 1H), 3.17 (kv, 2H), HHHH 4.34 (m, 2H), 6.857.30 (m, 7H), 9.26 (s, 1H), 12.01 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (3-propylsulfonylpropoxy) quinoline

3-Propanoyl-4- (2-methylphenylamino) -8- (3-propylthiopropoxy) quinoline (200 mg, 0.47 mmol) was dissolved in 5 mL of methylene chloride. To the resulting solution is added sodium bicarbonate (160 mg,

1.90 mmol) in 5 mL of water. The mixture is cooled to 2-4 ° C. A solution of 70% m-CPBA (230 mg, 0.94 mmol) in 5 mL of methylene chloride is added dropwise. The temperature of the mixture is allowed to rise to room temperature and then stirred at this temperature for 30 minutes. The methylene chloride layer is separated and washed with water. The organic layer is then dried over Na ₂ SO 4 and evaporated, the crude product is purified on a chromatographic column (methylene chloride: ethyl acetate 50:50). 110 mg (51%) of the title compound are obtained.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.06 (t, 3H), 1.28 (t, 3H), 1.88 (m, 2H), 2.35 (s, 3H),

2.50 (m, 2H), 2.97 (t, 2H), 3.16 (kv, 2H), 3.32 (t, 2H), HHHH 4.35 (t, 2H), 6.85- 7.30 (m, 7H), 9.19 (s, 1H), 11.78 (s, 1H).

i:

An example

Preparation of 3-butyryl-4- (4-hydroxy-2-methylphenylamethio) -8- (2-me (thioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (2.48 g, 6.63 mmol) and 4-hydroxy-2-methylaniline (1.06 g, 8.62 mmol) in acetonitrile (20 mL) annoying 8 or. with reflux. The reaction mixture is evaporated. Chromatography of the residue (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) yields 1.22 g (45%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.80 (m, 2H), 2.20 (s, 6H), 3.00-3.10 (m, 4H) ), 4.30 (m, 2H), 6.55 (m, 1H), 6.75-6.85 (m, 2H), 6.95 (m, 2H), 7.00-7.10 ( m, 1H), 9.15 (s, 1H).

and 28 Examples

3-Butyryl-4- (4-hydroxy-2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline (Example 27) and 3-Butyryl-4- (4-hydroxy-2-methylphenylamino) -8- (2- of methylsulfonylethoxy) -quinoline (Example 28)

3-Butyryl-4- (4-hydroxy-2-methylphenylamino) -8- (2-methylthioethoxy) quinoline (1.06 g, 2.59 mmol) was dissolved in methylene chloride (25 mL). 0.3 M NaHCO ₃ solution (24 mL) is added to the solution. The mixture is cooled to 4 C. 70% m-CPBA (0.82 g, 3.37 mmol) in methylene chloride (15 mL) is added dropwise. The mixture was stirred for 1.5 hours at 2-4 ° C, then the organic layer was washed with 0.3 M NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ and evaporated. Chromatography on silica gel with EtOAc: CH ₂ Cl ₂ 1: 1 as eluent gives 0.4 g (35%) of the title compound, and after chromatography on CH ₂ Cl ₂ : MeOH 9: 1 gives 0.52 g ( 47%) of the compound of Example 28.

Example: (1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.80 (m, 2H), 2.20 (s, 3H),

2.75 (s, 3H), 3.05 (m, 2H), 3.10-3.20 (m, 1H), 3.40-3.50 (m, 1H), HHHH 4.55 (m , 2H), 6.55-6.60 (m, 1H), 6.75-6.80 (m, 2H), 6.90-6.95 (m, 1H), 7.00-7.10 (m, 2H), 9.15 (s, 1H).

Example: (1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.80 (m, 2H), 2.25 (s, 3H), 3.05 (t, 2H), 3.35 (s, 3H), 3.60 (m, 2H), HHHH 4.55 (m, 2H), 6.55-6.60 (m, 1H), 6.75 (m, 1H), 6.80-6.85 (m, 1H), 6.95-7.05 (m, 2H), 7.10 (m, 1H), 9.10 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-chlorophenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (0.8 g, 2.5 mmol) and 2-chloroaniline (0.47 g, 3.7 mmol) in toluene (12 mL) is heated to 90 ° C is stirred at 3.0 or. Adds methylene chloride and water when cooled to room temperature. The solution is neutralized with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. It is then quenched with isopropyl ether to give 0.84 g (81%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.80-1.90 (m, 2H), 2.25 (s, 3H), 3.10-3.15 (m, 4H), HHHH 4.35-4.40 (m, 2H), 6.80-6.90 (m, 1H), 7.05-7.15 (m, 5H), 7.45-. 7.50 (m, 1H), 9.30 (s, 1H), 11.55 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-chlorophenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Butyryl-4- (2-chlorophenylamino) -8- (2-methylthioethoxy) quinoline (0.34 g, 0.82 mmol) was dissolved in methylene chloride (4 mL). Water (2 ml) and sodium hypochlorite (5% in water) (1.37 ml) are added to the solution and the mixture is stirred for 2 hours. Then add another portion of sodium hypochlorite (0.5 mL) and stir for a further 2 hours. The organic layer is dried over sodium sulfate and evaporated. The residue is recrystallized from a mixture of ethyl acetate and isopropyl ether. Yield: 0.25 g (71%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.85 (s, 3H), 3.10 (t, 2H) ), 3.20-3.30 (m, 1H), 3.45-3.55 (m, 1H), HHHH 4.60-4.70 (m, 2H), 6.80-6.90 ( m, 1H), 7.00-7.20 (m, 5H), 7.40-7.50 (m, 1H), 9.30 (s, 1H), 11.60 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-chlorophenylamino) -8- (2-methylsulfonylethoxy) quinoline

A solution of 3-butyryl-4- (2-chlorophenylamino) -8- (2-methylthioethoxy) quinoline (0.4 g, 0.96 mmol) in methylene chloride (5 mL) and saturated sodium bicarbonate solution (5 mL) was cooled to 4 ° C. A solution of 70% m-CPBA (0.48 g, 1.97 mmol) in 5 mL of methylene chloride is added dropwise. The mixture was stirred at 4 ° C for 1 h, then the organic layer was washed with sodium bicarbonate solution, then dried over Na ₂ SO ₄ and evaporated. It is then quenched with isopropyl ether to give 0.28 g (65%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.75-1.90 (m, 2H), 3.10 (t, 2H), 3.40 (s, 3H) ), 3.60-3.70 (m, 2H), HHHH 4.60-4.70 (m, 2H), 6.85-6.90 (m, 1H), 7.00-7.20 ( m, 5H), 7.45-7.50 (m, 1H), 9.20 (s, 1H), 11.65 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methoxyphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (0.8 g, 2.5 mmol) and 2-methoxyaniline (0.45 g, 3.7 mmol) in toluene (12 mL) is heated to 90 ° C is stirred at 3.0 or. Adds methylene chloride and water when cooled to room temperature. The solution is neutralized with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. It is then quenched with isopropyl ether to give 0.80 g (77%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.30 (s, 3H), 3.05-3.15 (m, 4H), 3.85 (s, 3H), HHHH 4.35-4.40 (m, 2H), 6.75-6.85 (m, 1H), 6.90-7.15 ( m, 5H), 7.257.30 (m, 1H), 9.25 (s, 1H), 11.55 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methoxyphenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Butyryl-4- (2-methoxyphenylamino) -8- (2-methylthioethoxy) quinoline (0.35 g, 0.85 mmol) was dissolved in methylene chloride (4 mL). Water (2 ml) and sodium hypochlorite (5% in water) (1.42 ml) are added to the solution and the mixture is stirred for 2 hours. Then add another portion of sodium hypochlorite (0.5 mL) and stir for a further 2 hours. The organic layer is dried over sodium sulfate and evaporated. The residue is recrystallized from a mixture of ethyl acetate and isopropyl ether. Obtained 0.32 g (88%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.80 (s, 3H), 3.05-3.10 (m, 2H), 3.20-3.30 (m, 1H), 3.45-3.55 (m, 1H), 3.80 (s, 3H), HHHH 4.60-4.70 ( m, 2H), 6.806.85 (m, 1H), 6.90-7.20 (m, 5H), 7.30-7.35 (m, 1H), 9.20 (s, 1H), 11 , 60 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methoxyphenylamino) -8- (2-methylsulfonylethoxy) quinoline

A solution of 3-butyryl-4- (2-methoxyphenylamino) -8- (2-methylthioethoxy) quinoline (0.35 g, 0.85 mmol) in methylene chloride (5 mL) and saturated sodium bicarbonate solution (5 mL) was cooled to 4 ° C. A solution of 70% m-CPBA (0.43 g, 1.74 mmol) in 5 mL of methylene chloride is added dropwise. The mixture is stirred at 4 ° C for 1 h, then the organic layer is washed with saturated sodium bicarbonate solution and then dried over sodium sulfate and evaporated. It is then quenched with isopropyl ether to give 0.28 g (65%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.90 (m, 2H), 3.05-3.10 (m, 2H),

3.40 (s, 3H), 3.60-3.70 (m, 2H), 3.85 (s, 3H), HHHH 4.60-4.65 (m, 2H), 6.80-6 , 85 (m, 1H), 6.90-7.20 (m, 5H), 7.30-7.35 (m, 1H), 9.15 (s, 1H), 11.60 (s, 1H) ).

An example

Preparation of 3-butyryl-4- (2,4-dimethylphenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (0.8 g, 2.5 mmol) and 2,4-dimethylaniline (0.45 g, 3.7 mmol) in toluene (12 mL) heat to 90 ° C and stir for 3.0 hours. Adds methylene chloride and water when cooled to room temperature. The solution is neutralized with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. It is then quenched with isopropyl ether to give 0.77 g (75%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.25 (s, 3H), 2.30 (s, 3H), 2.35 (s, 3H), 3.05-3.15 (m, 4H), 4.30-4.40 (m, 2H), 6.80-6.85 (m, 1H). , 6.90-7.10 (m, 5H), 9.20 (s, 1H), 11.85 (s, 1H).

An example

Preparation of 3-butyryl-4- (2,4-dimethylphenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Butyryl-4- (2,4-dimethylphenylamino) -8- (2-methylthioethoxy) quinoline (0.34 g, 0.83 mmol) was dissolved in methylene chloride (4 mL). Water (2 ml) and sodium hypochlorite (5% in water) (1.39 ml) are added to the solution and the mixture is stirred for 2 hours. Then add another portion of sodium hypochlorite (0.5 mL) and stir for a further 2 hours. The organic layer is dried over sodium sulfate and evaporated. Purification with isopropyl ether gives 0.32 g (91%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.30 (s, 3H), 2.35 (s, 3H), 2.80 (s, 3H), 3.05-3.15 (m, 2H), 3.20-3.30 (m, 1H), 3.40-3.55 (m, 1H) , 4.60-4.65 (m, 2H), 6.80-6.85 (m, 1H), 6.90-7.15 (m, 5H), 9.15 (s, 1H), 11 , 85 (s, 1H).

An example

Preparation of 3-butyryl-4- (2,4-dimethylphenylamino) -8- (2-methylsulfonylethoxy) quinoline

A mixture of a solution of 3-butyryl-4- (2,4-dimethylphenylamino) -8- (2-methylthioethoxy) quinoline (0.33 g, 0.81 mmol) in methylene chloride (5 mL) and saturated sodium bicarbonate solution (5 mL) cools to 4 ° C. A solution of 70% m-CPBA (0.40 g, 1.66 mmol) in 5 mL of methylene chloride is added dropwise. The mixture is stirred at 4 ° C for 1 h, then the organic layer is washed with saturated sodium bicarbonate solution and then dried over sodium sulfate and evaporated. It is then quenched with isopropyl ether to give a crystalline product. Chromatography (S1O2; CH2Cl2: MeOH 90:10) gives 0.17 g (48%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.30 (s, 3H), 2.35 (s, 3H), 3.05-3.15 (m, 2H), 3.40 (s, 3H), 3.60-3.65 (m, 2H), 4.60-4.65 (m, 2H) , 6.80-6.85 (m, 1H), 6.90-7.15 (m, 5H), 9.10 (s, 1H), 11.90 (s, 1H).

An example

Preparation of 3-butyryl-4- (2,6-dimethylphenylamino) -8- (2'-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (0.8 g, 2.5 mmol) and 2,6-dimethylaniline (0.45 g, 3.7 mmol) in toluene (12 mL) heat to 90 ° C and stir for 3.0 hours. Adds methylene chloride and water when cooled to room temperature. The solution is neutralized with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (S1O2; EtOAc) gives 0.7 g (68%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.10 (s, 6H), 2.25 (s, 3H), 3.05-3.15 (m, 4H), 4.30-4.35 (m, 2H), 6.85-7.20 (m, 6H), 9.20 (s, 1H) , 12.25 (s, 1H).

An example

Preparation of 3-butyryl-4- (2,6-dimethylphenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Butyryl-4- (2,6-dimethylphenylamino) -8- (2-methylthioethoxy) quinoline (0.33 g, 0.81 mmol) was dissolved in methylene chloride (4 mL). Water (2 ml) and sodium hypochlorite (5% in water) (1.7 ml) are added to the solution and the mixture is stirred for 3 hours. The organic layer is dried over sodium sulfate and evaporated. Purification with isopropyl ether gives 0.20 g (58%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.90 (m, 2H), 2.10 (s, 3H), 2.15 (s, 3H), 2.80 (s, 3H), 3.10-3.15 (m, 2H), 3.20-3.30 (m, 1H), 3.40-3.55 (m, 1H) , 4.55-4.65 (m, 2H), 6.85-6.95 (m, 2H), 7.05-7.25 (m, 4H), 9.20 (s, 1H), 12 , 25 (s, 1H).

An example

Preparation of 3-butyryl-4- (2,6-dimethylphenylamino) -8- (2-methylsulfonylethoxy) quinoline

A mixture of a solution of 3-butyryl-4- (2,6-dimethylphenylamino) -8- (2-methylthioethoxy) quinoline (0.36 g, 0.88 mmol) in methylene chloride (5 mL) and saturated sodium bicarbonate solution (5 mL) cools to 4 ° C. A solution of 70% m-CPBA (0.42 g, 1.76 mmol) in 5 mL of methylene chloride is added dropwise. The mixture is stirred at 4 ° C for 1 h, then the organic layer is washed with saturated sodium bicarbonate solution and then dried over sodium sulfate and evaporated. The residue is removed with isopropyl ether to give a crystalline product. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 90:10) and final crystallization from ethyl acetate afforded 0.070 g (18%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.95 (m, 2H), 2.10 (s, 6H), 3.053.15 (m, 2H), 3.40 (s, 3H), 3.60-3.65 (m, 2H), 4.55-4.60 (m, 2H), 6.85-6.95 (m, 2H). , 7.007.25 (m, 4H), 9.10 (s, 1H), 12.30 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methyl, 6-chlorophenylamino) -8- (2-methylthioethoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline (0.8 g, 2.5 mmol) and 2-methyl, 6-chloroaniline (0.52 g, 3.7 mmol) in toluene (12 mL) heat to 90 ° C and stir for 3.0 hours.

Adds methylene chloride and water when cooled to room temperature. The solution is neutralized with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; EtOAc) gives 0.77 g (72%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.90 (m, 2H), 2.15 (s, 3H), 2.25 (s, 3H), 3.05-3.15 (m, 4H), 4.30-4.40 (m, 2H), 6.85-6.90 (1H), 6.90-7.05 (m, 2H), 7.15-7.35 (m, 3H), 9.20 (s, 1H), 12.15 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methyl, 6-chlorophenylamino) -8- (2-methylsulfinylethoxy) quinoline

3-Butyryl-4- (2-methyl, 6-chlorophenylamino) -8- (2-methylthioethoxy) quinoline (0.35 g, 0.82 mmol) was dissolved in methylene chloride (4 mL). Water (2 ml) and sodium hypochlorite (5% in water) (1.7 ml) are added to the solution and the mixture is stirred for 3 hours. The organic layer is dried over sodium sulfate and evaporated. The residue is recrystallized from ethyl acetate. Obtained 0.10 g (27%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.90 (m, 2H), 2.15 (m, 3H), 2.85 (m, 3H), 3.10-3.15 (m, 2H), 3.20-3.30 (m, 1H), 3.40-3.55 (m, 1H), 4.55-4.70 ( m, 2H), 6.85-7.00 (m, 2H), 7.05-7.10 (m, 1H), 7.15-7.35 (m, 3H), 9.20 (s, 1H), 12.20 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methyl, 6-chlorophenylamino) -8- (2-methylsulfonylethoxy) quinoline

A solution of 3-butyryl-4- (2-methyl, 6-chlorophenylamino) -8- (2-methylthioethoxy) quinoline (0.34 g, 0.79 mmol) in methylene chloride (5 mL) and saturated sodium bicarbonate solution (5 mL) ) cools to 4 ° C. A solution of 70% m-CPBA (0.38 g, 1.58 mmol) in 5 mL of methylene chloride is added dropwise. The mixture is stirred at 4 ° C for 1 h, then the organic layer is washed with saturated sodium bicarbonate solution and then dried over sodium sulfate and evaporated. After crystallization, 0.11 g (30%) of the desired compound is obtained from ethyl acetate.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.95 (m, 2H), 2.15 (s, 3H), 3.053.15 (m, 2H), 3.40 (s, 3H), 3.60-3.70 (m, 2H), 4.55-4.65 (m, 2H), 6.90-7.05 (m, 3H). , 7.157.25 (m, 2H), 7.30-7.35 (m, 1H), 9.15 (s, 1H), 12.20 (s, 1H).

An example

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (3-methylthiopropoxy) quinoline

A mixture of 3-propanoyl-4-chloro-8- (3-methylthiopropoxy) quinoline (1.2 g, 3.71 mmol) and otoluidine (0.795 g, 7.42 mmol) was heated in acetonitrile (18 mL) for 100 min. with reflux. The solvent is evaporated and the residue is purified on a chromatography column (methylene chloride: methanol 100: 3). 1.45 g (99%) of the title compound are obtained.

(1 H-NMR, 300 MHz, CDCl ₃ ) 1.3 (t, 3H), 2.15 (s, 3H), 2.2-2.3 (m, 2H), 2.33 (s, 3H) ),

2.75 (t, 2H), 3.15 (s, 2H), 4.28 (t, 2H), 6.83-6.92 (m, 1H), 6.95-7.18 (m, 5H), 7.25-7.33 (m, 1H), 9.25 (s, 1H) 11.75 (s, 1H).

and 46 Examples

3-Propanoyl-4- (2-methylphenylamino) -8- (2-methylsulfinylpropoxy) quinoline (Example 45); and

Preparation of 3-propanoyl-4- (2-methylphenylamino) -8- (3-methylsulfonylpropoxy) -quinoline (Example 46)

3-Propanoyl-4- (2-methylphenylamino) -8- (3-methylthiopropoxy) quinoline (1.03 g, 2.611 mmol) was dissolved in methylene chloride (30 mL). 0.3 M NaHCO3 solution (26 mL, 7.83 mmol) is added to the solution. The mixture is cooled to 4 ° C. Within 45 minutes dropwise a solution of 70% m-CPBA (0.895 g, 3.66 mmol) in methylene chloride (27 mL). The mixture is stirred for 30 min. At 4 ° C, the organic layer is then separated and washed with 0.3 M NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 100: 3 and 100: 6) affords 0.48 g (45%) of the compound of Example 45 and 0.50 g (45%) of the compound of Example 46.

Example: (1 H-NMR, 300 MHz, CDCl ₃ ) 1.3 (t, 3H), 2.38 (s, 3H), 2.44-2.55 (m, 2H), 2.65 (s) , 3H), 2.9-3.02 (m, 1H), 3.08-3.23 (m, 3H), 4.28-4.4 (m, 2H), HHHH 6.85-6, 92 (m, 1H), 6.95-7.18 (m, 5H), 7.25-7.34 (m, 1H), 9.25 (s, 1H), 11.8 (s, 1H) .

Example: (1 H-NMR, 300 MHz, CDCl ₃ ) 1.28 (t, 3H), 2.35 (s, 3H), 2.45-2.58 (m, 2H), 2.95 (s) , 3H), 3.18 (kv, 2H), 3.4 (t, 2H), HHHH 4.35 (t, 2H), 6.85-6.92 (m, 1H), 6.957.15 (m , 5H), 7.22-7.33 (m, 1H), 9.23 (s, 1H), 11.83 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-chlorophenylamino) -8- (3-methylthiopropoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (3-methylthiopropoxy) quinoline (0.95 g, 2.8 mmol) and 2-chloroaniline (1.51 g, 11.8 mmol) in toluene is heated to 55 ° C and stirred overnight. The solvent is evaporated and the residue is partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na ₂ SO 4 and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) gives 0.95 g (74%) of the desired product.

(1 H-NMR, 500 MHz, CDCl 3: 0.95-1.05 (t, 3H), 1.75-1.85 (m, 2H), 2.10 (s, 3H), 2.20- 2.30 (m, 2H), 2.70-2.80 (m, 2H), 3.0-3.10 (m, 2H), 4.20-4.30 (m, 2H), 6, 80 (d, 1H), 6.957.10 (m, 5H), 7.40 (d, 1H), 9.20 (s, 1H), 11.6 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-chlorophenylamino) -8- (3-methylsulfinylpropoxy) quinoline

3-Butyryl-4- (2-chlorophenylamino) -8- (3-methylthiopropoxy) cbinoline (0.31 g, 0.72 mmol) was dissolved in methylene chloride (10 mL). To the solution was added 5 mL of water followed by 1.5 mL (1.09 mmol) of 5% NaOCl in methylene chloride. The mixture is stirred at room temperature for 4 hours. The organic phase is separated off and evaporated. Chromatography on methylene chloride: methanol 95: 5 afforded 0.104 g (32%) of the title compound as eluent.

(1 H-NMR, 500 MHz, CDCl 3: 1.05 (t, 3H), 1.80-1.90 (m, 3H), 2.45-2.55 (m, 2H),

2.65 (s, 3H), 2.90-3.0 (m, 1H), 3.05-3.15 (m, 2H), 3.15-3.20 (m, 1H), 4, 30-4.40 (m, 2H), 6.85 (m, 1H), 7.05-7.15 (m, 5H), 7.45 (d, 1H), 9.25 (s, 1H) , 11.60 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-chlorophenylamino) -8- (3-methylsulfonylpropoxy) quinoline

A solution of 3-butyryl-4- (2-chlorophenylamino) -8- (3-methylthiopropoxy) quinoline (0.31 g, 0.72 mmol) in 5 mL of methylene chloride and sodium bicarbonate solution (0.27 g, 3.2 mmol) ) Cool 5 mL of H ₂ O to 4 C. Add 70% m-CPBA (0.4 g, 1.63 mmol) in 10 mL of methylene chloride. The mixture is stirred at 4 ° C for 1 hour, then the organic layer is washed

IUI saturated sodium bicarbonate solution and then dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) affords 69 mg (21%) of the title compound.

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.90 (m, 2H), 2.50-2.55 (m, 2H), 3, 00 (s, 3H), 3.05-3.10 (m, 2H), 3.40-3.45 (m, 2H), 4.35-4.45 (m, 2H), 6.80- 6.85 (m, 1H), 7.00-7.20 (m, 5H), 7.45-7.50 (m, 1H), 9.25 (s, 1H), 11.60 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methylphenylamino) -8- (3-methylthiopropoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (3-methylthiopropoxy) quinoline (0.95 g, 2.97 mmol) and 2-methylaniline (1.27 g, 11.8 mmol) in toluene is heated to 55 ° C and stirred overnight . The solvent is evaporated and the residue is partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na ₂ SO 4 and evaporated. Chromatography of the residue (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) gives 0.98 g (80.9%) of the desired product.

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.80 (m, 2H), 2.10 (s, 3H), 2.252.30 (m, 2H), 2.35 (s, 3H), 2.75-2.80 (m, 2H), 3.05-3.10 (m, 2H), 4.25-4.30 (m, 2H) , 7.857.90 (d, 1H), 6.95-7.15 (m, 5H), 7.25 (d, 1H), 9.20 (s, 1H), 11.75 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methylphenylamino) -8- (3-methylsulfinylpropoxy) quinoline

3-Butyryl-4- (2-methylphenylamino) -8- (3-methylthiopropoxy) quinoline (0.33 g, 0.8 mmol) was dissolved in methylene chloride (15 mL). To the solution is added 5 mL of water followed by 1.5 mL (1.09 mmol) of a 5% NaOCl solution in 10 mL of methylene chloride. The mixture is stirred for 4 hours. at room temperature. The organic phase is separated off and evaporated. Chromatography on methylene chloride: methanol 95: 5 afforded 0.18 g (53%) of the title compound as eluent.

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.85 (m, 2H), 2.30 (s, 3H), 2.40-2, 50 (m, 2H), 2.60 (s, 3H), 2.90-3.15 (m, 4H), 4.25-4.40 (m, 2H), 6.85-6.90 ( m, 1H), 6.95-7.15 (m, 5H), 7.25-7.30 (m, 1H), 9.20 (s, 1H), 11.90 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methylphenylamino) -8- (3-methylsulfonylpropoxy) quinoline

A solution of 3-butyryl-4- (2-methylphenylamino) -8- (3-methylthiopropoxy) quinoline (0.33 g, 0.81 mmol) in 5 mL of methylene chloride and sodium bicarbonate (0.27 g, 3.2 mmol) of the solution cools to 4 ° C with 5 ml of H ₂ O. A solution of 70% m-CPBA (0.4 g, 1.63 mmol) in 10 mL of methylene chloride is added dropwise. The mixture is stirred at 4 ° C for 1 h, then the organic layer is washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) affords 99 mg (28%) of the title compound.

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.90 (m, 2H), 2.35 (s, 3H), 2.502.55 (m, 2H), 3.00 (s, 3H), 3.10-3.15 (m, 2H), 3.35-3.45 (m, 2H), 4.35-4.40 (m, 2H). , 6.85-6.90 (m, 1H), 6.95-7.15 (m, 5H), 7.25-7.30 (m, 1H), 9.20 (s, 1H), 11 , 85 (s, 1H).

An example

Preparation of 3-butyryl-4- (2-methoxyphenylamino) -8- (3-methylthiopropoxy) quinoline

A mixture of 3-butyryl-4-chloro-8- (3-methylthiopropoxy) quinoline (0.95 g, 2.97 mmol) and 2-methoxyaniline (1.46 g, 11.8 mmol) in toluene is heated to 55 ° C and stirred at night. The solvent is evaporated and the residue is partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na ₂ SO 4 and evaporated. Chromatography of the residue (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) gives 0.90 g (71%) of the desired product.

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.10 (s, 3H), 2.252.35 (m, 2H), 2.75-2.80 (m, 2H), 3.05-3.10 (m, 2H), 3.80 (s, 3H), 4.25-4.35 (m, 2H) , 6.756.85 (m, 1H), 6.90-7.20 (m, 5H), 7.25-7.30 (m, 1H), 9.20 (s, 1H), 11.65 (s) , 1H).

An example

Preparation of 3-butyryl-4- (2-methoxyphenylamino) -8- (3-methylsulfinylpropoxy) quinoline

3-Butyryl-4- (2-methoxyphenylamino) -8- (3-methylthiopropoxy) quinoline (0.30 g, 0.70 mmol) was dissolved in methylene chloride (10 mL). To the solution is added 5 mL of water followed by 1.5 mL (1.09 mmol) of a 5% NaOCl solution in 10 mL of methylene chloride. The mixture is stirred for 4 hours. room

At a temperature of 11! The organic phase is separated off and evaporated. Chromatography on methylene chloride: methanol 95: 5 gives 0.14 g (4.6%) of the title compound as eluent.

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.0 (t, 3H), 1.75-1.85 (m, 2H), 2.45-2.55 (m, 2H), 2, 63 (s, 3H), 2.95 (m, 1H), 3.05-3.10 (m, 2H), 3.15 (m, 1H), 3.8 (s, 3H), 4.30 (m, 1H), 4.40 (m, 1H), 6.80-7.20 (m, 6H), 7.30 (m, 1H), 9.20 (s, 1H), 11.6 ( s, 1H).

An example

Preparation of 3-butyryl-4- (2-methoxyphenylamino) -8- (3-methylsulfonylpropoxy) quinoline

A solution of 3-butyryl-4- (2-methoxyphenylamino) -8- (3-methylthiopropoxy) quinoline (0.30 g, 0.71 mmol) in 5 mL of methylene chloride and sodium bicarbonate (0.27 g, 3.2 mmol) of a solution of 5 ml of H ₂ O is cooled to 4 ^W C. A solution of 70% m-CPBA (0.4 g, 1.63 mmol) in 10 ml of methylene chloride is added dropwise. The mixture is stirred at 4 ° C for 1 h, then the organic layer is washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH 95: 5) affords 41 mg (13%) of the title compound.

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.05 (t, 3H), 1.80-1.90 (m, 2H), 2.50-2.55 (m, 2H), 3, 00 (s, 3H), 3.05-3.10 (m, 2H), 3.40-3.45 (m, 2H), 3.80 (s, 3H), 4.35-4.40 ( m, 2H), 6.80-7.15 (m, 6H), 7.30-7.35 (m, 1H), 9.20 (s, 1H), 11.60 (s, 1H).

An example

Isolation of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline

A mixture of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline (9.3 g, 0.023 mmol) and D - (-) tartaric acid (3.45 g, 0.023 mmol) in methanol (180 ml) boil under reflux. Allow the solution to cool to room temperature and stir again for 60 hours. The precipitate is filtered off and washed with a total volume of 20 ml methanol. 6.1 g of tartaric acid salt are obtained (the filtrate is used in Example 57). The recrystallization from methanol is repeated 3 times to give 3.05 g, 1.30 g, and finally 1.05 g of the tartaric acid salt of Example 57. The salt is neutralized with a saturated solution of sodium bicarbonate in methylene chloride and water. The organic layer is dried over sodium sulfate and the solvent is evaporated. The residue is quenched with isopropyl ether to give 0.7 g of pure enantiomer.

I III

An example

Isolation of 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline in the sample evaporates the filtrate from the first crystallization. The salt is neutralized with a saturated solution of sodium bicarbonate in methylene chloride and water. The organic layer is dried over sodium sulfate and the solvent is evaporated. The solid residue (4.6 g, 0.011 mol) and L - (+) - tartaric acid (1.68 g, 0.011 mol) were dissolved in warm methanol (119 ml). After the solution has cooled to room temperature, it is stirred for 72 hours. The precipitate is filtered off and washed with a total volume of 11 ml of methanol. 1.5 g of tartaric acid salt are obtained. After recrystallization from methanol 1.05 g of Example 57 salt is obtained. The salt is neutralized with a saturated solution of sodium bicarbonate in methylene chloride and water. The organic layer is dried over sodium sulfate and evaporated. The residue is quenched with isopropyl ether to give 0.7 g of pure enantiomer.

Enantiomers are separated by a 250 x 4.6 mm internal diameter Chiralpak AD column (Daciel, Japan). Separation parameters:

n-hexane: 2-propanol: acetonitrile: diethylamine (82: 18: 2: 0.1); temperature: 35 ° C; flow rate 0.8 ml / min.

Enantiomer corresponding to Example 56: Retention time 14.5 min.

Enantiomer corresponding to Example 57: Retention time 18.4 min.

Table

Summary of the Examples Exemplified by the Invention

An example R ¹ R ² R ³ R ⁴ m n 1 CH2CH2CH3 ch ₃ ch ₃ H 2 0 2 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 2 1 3 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 2 2 4 ch ₂ ch ₂ ch ₃ CH (CH ₃ ) ₂ ch ₃ H 2 0 5 ch ₂ ch ₂ ch ₃ CH (CH ₃ ) ₂ ch ₃ H 2 1 6th ch ₂ ch ₂ ch ₃ CH (CH ₃ ) ₂ ch ₃ H 2 2 7th ch ₂ ch ₃ ch ₃ ch ₃ H 2 0

i UI

An example R ¹ R ² R ³ R ⁴ m n 8th CH ₂ CH ₃ ch ₃ ch ₃ H 2 1 9th CH2CH3 ch ₃ ch ₃ H 2 2 10th CH2CH3 CH2CH3 ch ₃ H 2 0 11th CH2CH3 CH2CH3 ch ₃ H 2 1 12th ch ₂ ch ₃ CH2CH3 ch ₃ H 2 2 13th CH2CH2CH3 ch ₃ ch ₃ 4-F 2 0 14th CH2CH2CH3 ch ₃ ch ₃ 4-F 2 1 15th CH2CH2CH3 ch ₃ ch ₃ 4-F 2 2 16th CH2CH3 CH (CH ₃ ) ₂ ch ₃ H 2 0 17th CH2CH2CH3 CH2CH3 ch ₃ H 2 0 18th ch ₂ ch ₂ ch ₃ CH2CH3 ch ₃ H 2 1 19th CH2CH2CH3 ch ₂ ch ₃ ch ₃ H 2 2 20th CH2CH3 ch ₃ ch ₂ ch ₂ ch ₃ H 2 0 21st CH ₂ CH ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 2 1 22nd CH2CH3 ch ₃ ch ₂ ch ₂ ch ₃ H 2 2 23rd CH2CH3 ch ₃ ch ₂ ch ₂ ch ₃ H 3 0 24th CH2CH3 ch ₃ ch ₂ ch ₂ ch ₃ H 3 1 25th CH ₂ CH ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 3 2 26th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-OH 2 0 27th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-OH 2 1 28th CH2CH2CH3 ch ₃ ch ₃ 4-OH 2 2 29th CH2CH2CH3 Cl ch ₃ H 2 0 30th ch ₂ ch ₂ ch ₃ Cl ch ₃ H 2 1 31st CH2CH2CH3 Cl ch ₃ H 2 2

T 3537 B

An example R ¹ R ² R ³ R ⁴ m n 32 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 2 0 33 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 2 1 34 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 2 2 35 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-CH ₃ 2 0 36 CH2CH2CH3 ch ₃ ch ₃ 4-CH ₃ 2 1 37 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-CH ₃ 2 2 38 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-CH3 2 0 39 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-CH3 2 1 40 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-CH3 2 2 41 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-C1 2 0 42 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-C1 2 1 43 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-C1 2 2 44 ch ₂ ch ₃ ch ₃ ch ₃ H 3 0 45 ch ₂ ch ₃ ch ₃ ch ₃ H 3 1 46th ch ₂ ch ₃ ch ₃ ch ₃ H 3 2 47 ch ₂ ch ₂ ch ₃ Cl ch ₃ H 3 0 48 ch ₂ ch ₂ ch ₃ Cl ch ₃ H 3 1 49 ch ₂ ch ₂ ch ₃ Cl ch ₃ H 3 2 50 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 3 0 51 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 3 1 52 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 3 2 53 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 3 0 54 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 3 1 55 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 3 2

2. Preparation of Intermediates

Example I

Preparation of 2- (2-methylthioethoxy) nitrobenzene

A mixture of 2-methylthioethyl chloride (18 g, 0.16 mol), o-nitrophenol (20.8 g, 0.15 mol) and potassium carbonate (24.7 g, 0.18 mol) was refluxed in acetonitrile for 24 hours. The reaction mixture was filtered and the solvent was evaporated. The residue is dissolved in methylene chloride and washed once with water and twice with saturated sodium carbonate solution. The organic layer is dried over sodium sulfate and the solvent is evaporated. As an oily residue is obtained

20.2 g (63%) of the title compound.

(1 H-NMR, 300 MHz, CDCl ₃ ): 2.21 (s, 3H), 3.00 (s, 3H), 2.90 (t, 2H), 4.27 (t, 2H), δ , 04 (m, 2H), 7.50 (m, 1H), 7.79 (m, 1H).

Example II

Preparation of 2- (2-methylthioethoxy) aniline

To a mixture of 2- (2-methylthioethoxy) nitrobenzene (18.1 g, 0.085 mol), concentrated HCl (72.4 mL) and ethyl alcohol is added tin chloride dihydrate (57.9 g, 0.26 mol) and ethyl alcohol ( 90 ml). The reaction mixture was stirred for 24 hours. at room temperature. Sodium hydroxide (6 M, 270 mL) is then added to the reaction mixture. The mixture is extracted with methylene chloride (3 x 400 mL), the organic layer is dried over sodium sulfate and the solvent is evaporated. 14.8 g (95%) of the title compound are obtained.

(1 H-NMR, 300 MHz, CDCl ₃ ): 2.28 (s, 3H), 2.90 (t, 2H), 4.18 (t, 2H), 4.83 (b, 2H), δ , 66-6.83 (m, 4H).

Example III

Preparation of 2-butyryl-3- [2- (2-methylthioethoxy) phenylamino] acrylate

A mixture of 2- (2-methylthioethoxy) aniline (1.6 g, 8.7 mmol), ethyl butyryl acetate (1.38 g, 8.7 mmol) and triethyl orthoformate (1.30 g, 8.8 mmol) is heated to . 120 ° C followed by distillation of ethyl alcohol. The reaction mixture is cooled to room temperature _and treated with methyl alcohol to give 1.08 g (35%) of the title compound as a solid.

(1 H-NMR, 300 MHz, CDCl ₃ ): 0.96 (t, 3H), 1.33 (t, 3H), 1.68 (m, 3H), 2.22 (s, 3H),

2.92 (t, 2H), 3.00 (t, 2H), 4.25 (m, 4H), 6.9-7.3 (m, 4H), 8.5 (d, 1H), 12 , 81 (pis, 1H).

Example IV

Preparation of 3-butyryl-8- (2-methylthioethoxy) -4 (1H) quinoline

Refluxed diphenyl ether was added ethyl 2-butyryl-4- [2- (2-methylthioethoxy) phenylamino] acrylate (1.07 g, 3.04 mmol). The mixture is heated under reflux for 50 minutes. The reaction mixture was then cooled to room temperature. Then add petroleum ether and stir for a further 90 min. Filtration of the precipitate afforded 0.8 g (85%) of the title compound.

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.02 (t, 3H), 1.75 (m, 2H), 2.22 (s, 3H), 3.00 (t, 2H),

3.25 (t, 2H), 4.36 (t, 2H), 7.15 (d, 1H), 7.35 (m, 1H), 8.06 (d, 1H), 8.58 (s) , 1H), 9.40 (pis, 1H).

Example V

Preparation of 3-butyryl-4-chloro-8- (2-methylthioethoxy) quinoline

3-Butyryl-8- (2-methylthioethoxy) -4 (1H) -quinoline (0.8 g, 2.8 mmol) and phosphorus oxychloride (10 mL) were stirred for 1 h. at room temperature. Evaporates phosphorus oxychloride. The residue is partitioned between water and methylene chloride. Sets the pH to 8 with sodium bicarbonate. Dry the organic layer over sodium sulfate and evaporate the solvent. 0.57 g (68%) of the desired compound is obtained.

(1 H-NMR, 300 MHz, CDCl ₃ ): 0.97 (t, 3H), 1.86 (m, 2H), 2.22 (s, 3H), 3.00 (t, 2H), 3 , 05 (t, 2H), 4.38 (t, 2H), 7.16 (d, 1H), 7.57 (m, 1H), 7.87 (d, 1H), 8.84 (s, 1H).

Example VI

Preparation of 3-propanoyl-4-chloro-8- (2-methylthioethoxy) quinoline

The title compound is obtained in the same manner as described in Example V. Yield: 0.6 g (75%).

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.26 (t, 3H), 2.26 (s, 3H), 3.01-3.07 (m, 4H), 4.39 (t, 2H), 7.15 (d, 1H), 7.55 (m, 1H), 7.85 (d, 1H), 8.84 (s, 1H).

Example VII

Preparation of 3-propanoyl-4-chloro-8- (2-propylthioethoxy) quinoline

3-Propanoyl-4-chloro-8- (2-propylthioethoxy) -quinoline is synthesized in the same manner as described in Example V. Yield: 2.5 g (88%).

(1 H-NMR, 300 MHz, CDCl ₃ ): 0.97 (t, 3H), 1.23 (t, 3H), 1.62 (m, 2H), 2.61 (t, 2H), 3 , 00-3.09 (m, 4H), 4.36 (t, 2H), 7.15 (d, 1H), 7.57 (t, 1H), 7.87 (d, 1H), δ, 85 (s, 1H).

Example VIII

Preparation of 3-propanoyl-4-chloro-8- (2-propylthiopropoxy) quinoline

3-Propanoyl-4-chloro-8- (2-propylthiopropoxy) quinoline is synthesized in the same manner as described in Example V. Yield 5.5 g (87%).

(1 H-NMR, 300 MHz, CDCl ₃ ): 0.90 (t, 3H), 1.20 (t, 3H), 1.54 (m, 2H), 2.22 (m, 2H), 2 , 44 (t, 2H), 2.72 (t, 2H), 3.00 (kv, 2H), 4.30 (t, 2H), 7.14 (d, 1H), 7.53 (t, 1H), 7.81 (d, 1H), 8.83 (s, 1H).

Example IX

Preparation of 3-butyryl-4-chloro-8- (3-methylthiopropoxy) quinoline

The title compound is synthesized in the same manner as described in Example V. Yield: 2.9 g (91%) (hydrochloride).

(1 H-NMR, 500 MHz, CDCl ₃ ): 1.02 (t, 3H), 1.8 (m, 2H), 2.30 (s,

2.90 (t, 2H), 3.10 (t, 2H), 4.50 (t, 2H), 7.52 (d, 1H), 7.90-7.95 (m, 1H), δ , 30-8.50 (m, 1H),

9.48 (s, 1H).

X Example

Preparation of 3-propanoyl-4-chloro-8- (3-methylthiopropoxy) quinoline

The title compound is synthesized in the same manner as described in Example V. Yield: 3.95 g (96%).

(1 H-NMR, 300 MHz, CDCl ₃ ): 1.28 (t, 3H), 2.1 (s, 3H), 2.3 (s, 2H), 2.8 (t, 2H), 3 , 08 (q, 2H), 4.38 (t, 2H), 7.23 (d, 1H), 7.6 (t, 1H), 7.9 (d, 1H), 8.9 (s, 1H).

3. Preparation of Pharmaceutical Preparations

The following examples illustrate the preparation of pharmaceutical preparations containing the compound of the present invention as an active ingredient.

Preparation A. Syrup

A syrup containing 1% by weight of the active substance is obtained from the following components:

The compound obtained in Example 2, 1.0 g

Sugar, powder 30.0 g

Saccharin 0.6 g

Glycerol 5.0 g

Odor agent 0.05 g

Ethanol 96% 5.0 g

Distilled water q.s. to a final volume of 100 ml

I

Dissolve sugar and saccharin in 60 g of warm water. After the solution has cooled, the acid salt of the active compound dissolved in the sugar solution and the glycerol and the flavoring agent dissolved in ethanol are added thereto. Dilute the mixture to a final volume of 100 ml.

The active ingredient disclosed herein may be replaced by another pharmaceutically acceptable acid addition salt.

Preparation B. Pills

A tablet containing 50 mg of active compound is obtained from the following components:

I The compound obtained in Example 2 500 g Lactose 700g Methylcellulose 6g Polyvinylpyrrolidine with cross-links 50g Magnesium stearate 15g Sodium carbonate 6g distilled water q.s. II Hydroxypropylmethylcellulose 36g Polyethylene glycol 9g Pigment titanium dioxide 4g Purified water 313 g I. 2 the powder of the compound obtained in the example is mixed with lactose and granulate with

methyl cellulose and sodium carbonate in aqueous solution, squeeze the wet mass through a sieve, and dry the granulate in an oven. The dried granulate is mixed with polyvinylpyrrolidone and magnesium stearate. From a dry mix tablet making machine, a 7 mm diameter die is pressed into tablets (10,000 tablets). Each tablet contains 50 mg of active ingredient.

II. Prepare a solution of hydroxypropylmethylcellulose and polyethylene glycol in purified water. The solution disperses titanium dioxide and sprays the mixture on the I tablets in the Accela Cota® Manesty Coating Machine. The final weight of the tablet is 130 mg.

Preparation C. Intraventricular solution

A parenteral preparation for intravenous administration containing 4 mg of active compound per milliliter is obtained from the following components:

The compound obtained in Example 2 4 g

Polyethylene glycol 400 Injections 400 g

Disodium hydrogen phosphate q.s.

Sterile water Dissolve 400 g of the compound obtained in the sample in polyethylene glycol up to a final volume of 1000 ml and add 550 ml of water. The pH of the solution is adjusted to 7.4 by the addition of aqueous disodium hydrogen phosphate solution. Water is then added to a final volume of 1000 ml. The solution is filtered through a 0.22 µm filter and immediately blown into 10 ml sterile ampoules. The ampules melted.

4. Biological tests

A. The in vitro efficacy of inhibition of acid secretion in isolated rabbit gastric glands is determined by Berglindh et al. (1976) Acta Physiol. Scand., 97, 401-414. The IC50 values of the compounds obtained in Examples 1-12 range from 0.5 to 6.0 μΜ. The compounds of Examples 13-57 had IC50 values ranging from 0.75 to 14 μΜ.

B. The in vivo efficacy of inhibition of acid secretion in conscious rats is determined as follows:

Female Sprague-Dawly rats are used for testing. Artificial tubes are inserted to collect gastric secretion and to inject test substances into the stomach of the beast and the upper part of the duodenum. Investigations begin fourteen days after this operation for recovery.

Prior to secretion testing, the animals are deprived of food but water for 20 hours. Through the inserted tube, the stomach is repeatedly rinsed with tap water (37 ° C) and injected with 6 ml of Ringer glucose subcutaneously. Acid secretion for 3 hours. stimulated by infusion of pentagastrin and carbachol (20 and 110 nmol / kg h, respectively) (1.2 ml / h subcutaneously). At that time, half-hour samples of gastric secretion are collected. Test materials or inactive passes 60 min. n preparations are injected into the vein or into the duodenum (1.2 ml / h) after ou mm. from the onset of stimulation. Gastric secretion samples are titrated with 0.1 mol / L NaOH to pH = 7.0. Calculate the amount of acid liberated as the product of the volume and the concentration of the titrated solution.

Uses averages of tests performed on 4-5 rats for calculations. Acid release over a period of time after administration of test substances or inactive preparations is expressed as a fractional result, assuming acid release within 30 min. equals 1.0 before dosing. The percentage inhibition is calculated from the fractional results of the test compound and the inactive preparation. The ED50 values are calculated by graphically interpolating the log dose proportional curves of the dose-dependency curve or by estimating the single dose results, assuming that all curves have a similar inclination.

Claims (17)

DEFINITION OF INVENTION 1. A quinolone compound of the general formula I wherein R ¹ is (a) C] -Cfi alkyl, (b) C ₃ -Cfi cycloalkyl, or (c) the C ₃ -C _6, C-C ₆ cycloalkylalkyl; R ² is (a) H, (b) C 1 -C 6 alkyl, (c) C 1 -C 6 alkoxy, or (d) halogen; R ³ is C 1 -C 9 alkyl; R ⁴ is (a) H, (b) C 1 -C 4 alkyl, (c) halogen, or (d) OH; m is an integer of 2 or 3, and n is an integer of 0.1 or 2, or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R ¹ is CH ₃ , CH ₂ CH 3, CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , cyclopropyl or cyclopropylmethyl; R ² is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH (CH ₃ ) ₂ CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ or halogen; R ³ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or CH ₂ CH ₂ CH ₃ ; and R ⁴ is H, CH ₃ , CH ₂ CH ₃ , halogen or OH, or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, wherein R ¹ is CH ₂ CH ₃ or CH ₂ CH ₂ CH ₃ ; R ² is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , OCH ₃ or Cl; R ³ is CH ₃ , CH ₂ CH ₃ or CH ₂ CH ₂ CH ₃ ; and R ⁴ is H, CH ₃ , F, Cl or OH, or a pharmaceutically acceptable salt thereof. A compound according to claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that it is one of the compounds listed in the following table. An example R ¹ R ² R ³ R ⁴ m n 1 CH ₂ CH ₂ CH ₃ ch ₃ ch ₃ H 2 0 2 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 2 1 An example R ¹ R ² R ³ R ⁴ m n 3 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 2 2 4 ch ₂ ch ₂ ch ₃ CH (CH ₃ ) ₂ ch ₃ H 2 0 5 ch ₂ ch ₂ ch ₃ CH (CH ₃ ) ₂ ch ₃ H 2 1 6th ch ₂ ch ₂ ch ₃ CH (CH ₃ ) ₂ ch ₃ H 2 2 7th ch ₂ ch ₃ ch ₃ ch ₃ H 2 0 8th ch ₂ ch ₃ ch ₃ ch ₃ H 2 1 9th ch ₂ ch ₃ ch ₃ ch ₃ H 2 2 10th ch ₂ ch ₃ ch ₂ ch ₃ ch ₃ H 2 0 11th ch ₂ ch ₃ ch ₂ ch ₃ ch ₃ H 2 1 12th ch ₂ ch ₃ ch ₂ ch ₃ ch ₃ H 2 2 13th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-F 2 0 14th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-F 2 1 15th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-F 2 2 16th ch ₂ ch ₃ CH (CH ₃ ) ₂ ch ₃ H 2 0 17th ch ₂ ch ₂ ch ₃ ch ₂ ch ₃ ch ₃ H 2 0 18th ch ₂ ch ₂ ch ₃ ch ₂ ch ₃ ch ₃ H 2 1 19th ch ₂ ch ₂ ch ₃ CH2CH3 ch ₃ H 2 2 20th ch ₂ ch ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 2 0 21st ch ₂ ch ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 2 1 22nd ch ₂ ch ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 2 2 23rd ch ₂ ch ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 3 0 24th ch ₂ ch ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 3 1 25th ch ₂ ch ₃ ch ₃ ch ₂ ch ₂ ch ₃ H 3 2 26th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-OH 2 0 An example R ¹ R ² R ³ R ⁴ m n 27th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-OH 2 1 28th ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-OH 2 2 29th ch ₂ ch ₂ ch ₃ Cl ch ₃ H 2 0 30th ch ₂ ch ₂ ch ₃ Cl ch ₃ H 2 1 31st ch ₂ ch ₂ ch ₃ Cl ch ₃ H 2 2 32 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 2 0 33 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 2 1 34 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 2 2 35 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-CH ₃ 2 0 36 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-CH3 2 1 37 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 4-CH ₃ 2 2 38 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-CH ₃ 2 0 39 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-CH3 2 1 40 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-CH ₃ 2 2 41 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-C1 2 0 42 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-C1 2 1 43 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ 6-C1 2 2 44 ch ₂ ch ₃ ch ₃ ch ₃ H 3 0 45 ch ₂ ch ₃ ch ₃ ch ₃ H 3 1 46th ch ₂ ch ₃ ch ₃ ch ₃ H 3 2 47 ch ₂ ch ₂ ch ₃ Cl ch ₃ H 3 0 48 ch ₂ ch ₂ ch ₃ Cl ch ₃ H 3 1 49 ch ₂ ch ₂ ch ₃ Cl ch ₃ H 3 2 50 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 3 0 An example R ¹ R ² R ³ R ⁴ m n 51 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 3 1 52 ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ H 3 2 53 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 3 0 54 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 3 1 55 ch ₂ ch ₂ ch ₃ and ₃ ch ₃ H 3 2 A compound 3-butyryl-4- (2-methylphenylamino) -8- (2-methylsulfinylethoxy) quinoline or a pharmaceutically acceptable salt thereof. 6. A process for the preparation of a compound according to any one of claims 1 to 5, which comprises: (a) reacting a compound of general formula II wherein R ² and R ^{4 are as} defined in claim 1 with a compound of general formula III, S (O) _n Wherein R ¹ , R ³ , m and n are as defined in claim 1 and X is a reaction leaving group such as a halide, tosyloxy or mesyloxy group; or (b) the compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ and m are as defined in claim 1, on is 1 or 2, is obtained by oxidation of a compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ and m are defined in claim 1, on is 0. 7. The process of claim 6, wherein said oxidation step is carried out using an oxidizing agent (i) in a solvent such as a halogenated hydrocarbon, alcohol, ether or ketone; or (ii) is carried out enzymatically using an oxidizing enzyme; or (iii) performs microbiological oxidation using appropriate microorganisms. A compound according to any one of claims 1 to 5 for use in therapy. A compound according to any one of claims 1 to 5 for use in inhibiting gastric acid secretion and / or treating inflammatory diseases of the gastrointestinal tract. Pharmaceutical preparation, characterized in that it contains as active ingredient a compound as defined in any one of claims 1 to 5. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for inhibiting gastric acid secretion. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of inflammatory diseases of the stomach and intestines. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment or prophylaxis of Helicobacter pylori-induced inflammation of the gastric mucosa of a human being and related diseases in combination with another antimicrobial agent. 14. A pharmaceutical preparation for inhibiting gastric acid secretion, wherein the active ingredient is a compound according to any one of claims 1-5. 15. A pharmaceutical preparation for treating inflammatory diseases of the stomach and intestine, wherein the active component is a compound according to any one of claims 1 to 5. 16. A pharmaceutical preparation for the treatment or prophylaxis of Helicobacter pylori inflammation of the gastric mucosa of a human being and related diseases, wherein the active component is a compound according to any one of claims 1 to 5. A compound of the general formula III wherein R ¹ is C 1-6 alkyl; R ³ is C 1-6 alkyl; m is 2 or 3; n is 0, 1 or 2; and X is a reaction leaving group such as halide, tosyloxy or mesyloxy.