MXPA99012076A - Procedure and intermediate compounds for preparing 5-lipoxigen inhibitors - Google Patents

Abstract

The present invention relates to a process for preparing a compound of the formula (See Formula) wherein A is Cl-C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, CI alkyl -C3 or benzyl, in the preferred compound A is CH3; IOS inhibitors of 5-lipoxygenase which are prepared according to the present invention with selective inhibitors of the action of the enzyme lipoxygenase and are useful in the treatment or in the relief of inflammatory diseases , allergies and cardiovascular diseases in mammals

Description

PROCEDURE AND INTERMEDIATE COMPOUNDS FOR PREPARING 5-LIPOXYGENASE INHIBITORS BACKGROUND OF THE INVENTION This invention relates to the process and intermediate compounds for preparing 5-lipoxygenase inhibitors. The 5-lipoxygenase inhibitors that are prepared according to the present invention have been described in the patent application of the United States of America under serial No. 09 / 020,0140, which is a continuation of the application 08 / 809,901 filed on June 13, 1997, now abandoned. This pending application is entitled "5-lipoxygenase inhibitors" and is incorporated by reference in its entirety. The 5-lipoxygenase inhibitors, which are prepared according to the present invention, are selective inhibitors of the action of the enzyme lipoxygenase, and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing a compound of the formula wherein A is C 1-6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 Cs alkyl or benzyl, which comprises reacting a compound of the formula wherein A is C 1 -C 4 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 -C 3 alkyl or benzyl, with a sulfonic acid within an alkyl alcohol C 1 - C5; and precipitating the compound of formula i by the addition of an organic solvent that is less polar than alcohol. The acid is methane sulphonic acid and the organic solvent is diisopropyl ether or ethyl acetate.

In a further aspect of the present invention, the compound of formula II is prepared by reacting a compound of formula wherein A is CrC6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, with a hydroxide in a solvent of the type of an alcohol. The hydroxide is potassium hydroxide and the alcohol is tertiary butyl alcohol.

In a further aspect of the present invention, the compound of formula III is prepared by reacting a compound of formula wherein A is C 1 -C 4 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 -C 3 alkyl or benzyl, with an organic or mineral acid. The acid is acetic acid, sulfuric acid, formic acid or p-toluene sulfonic acid. The preferred acid is formic acid. In a further aspect of the present invention, the compound of formula IV is prepared by reacting the compound of formula wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, and wherein X is Cl, Br, I or OCH3 , with an excess of an acetaldetaldehyde acetal. The amino acetaldehyde acetal is the amino acetaldehyde dimethyl acetal or the amino acetaldehyde diethyl acetal. In a further aspect of the present invention, the compound of formula V, wherein X is Cl, Br or I, is prepared by reacting a compound of formula wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, with a phosphorus pentahalide in an inert solvent . The compound of formula V can also be prepared by reacting a compound of formula VI with (CH3) 3? + BF "to form an intermediate compound in which X is OCH3. The pentahalogenide is phosphorus pentachloride, phosphorus pentaiodide or pentabromide. of phosphorus and the solvent is toluene The preferred A is In a further aspect of the present invention, the compound of formula VI is prepared by the reaction of a compound of the formula VIII wherein X is Cl, Br or I with an excess of 4-amino-thiophenol and with a base in an inert solvent, to give a compound of formula and further treating a compound of formula VII by acylation with a halide or acid anhydride. Another more preferable way of preparing a compound of formula VI is to react a compound of the formula VIII O -: V 1 1 in which X is Cl, Br or I, with an excess of 4-amido-thiophenol and with a base in an inert solvent. The 4-amido-thiophenol is 4-acetamido-thiophenol. The solvent is NMP or DMSO. 0 The base is a mixture of sodium carbonate and cesium carbonate.

In a further aspect of the present invention, the compound of formula VIII can be prepared by reacting a compound of formula IX 0 wherein X is Br, Cl or I with bis- (2-chloro-ethyl) -ether, an alkaline base and a phase transfer catalyst in an inert solvent. The phase transfer catalyst is tetrabutyl ammonium hydrogen sulfate. The base is sodium hydroxide.

The inert solvent is a mixture of tetrahydrofuran and water. The invention also relates to a new compound of the formula.

The invention also relates to a new compound of the formula.

SAW wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl. The invention also relates to a new compound of the formula wherein A is C 1 -C 6 alkyl, an aryl, which is mono- or di substituted with F, Cl, Br, OCH 3, C 1 Cs alkyl or benzyl, and wherein X is I, Br, Cl or OCH 3. The invention also relates to a new compound of the formula wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, and wherein R is C-? -C6 alkyl.

The invention also relates to a new compound of the formula wherein A is C 1 -C 6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 -C 3 alkyl benzyl. A preferred compound is form2 / pag11 These new compounds are useful in the preparation of 5-lipoxygenase inhibitors and their pharmaceutical composition is useful in the treatment or alleviation of inflammatory diseases, allergies and cardiovascular diseases in mammals.

DETAILED DESCRIPTION OF THE INVENTION The new synthesis procedure is shown in scheme 1 following actions SCHEME 1 continuation IV The 3-bromo-phenyl-acetonitrile in tetrahydrofuran is treated with aqueous NaOH, tetrabutylammonium hydrogen sulfate and bis- (2-chloroethyl ether) to give the aryl bromide compound of the formula VIII. The aryl bromide compound VIII is treated either with 4-amino-thiophenol to give the aniline compound VII, followed by acylation, or with the 4-amido-thiophenol to give the amide compound VI. The imidazole function is incorporated with transformation of the amido group in formula VI by heating compound VI with a phosphorus penthalogenide to give compound V, which is treated with an amino-acetaldehyde alkyl acetal to provide the amidine compound IV. The amidine IV compound occurs as a mixture of tautomers that are not isolated and are immediately subjected to an acid-induced cyclization to provide the midazole compound III. Subsequent hydrolysis of the nitrile function in the imidazole compound III provides compound 5 inhibitor of lipoxygenase. The preferred form of salt is achieved by treating the compound II with methanesulphonic acid to give the compound I. The novel process of the present invention eliminates the two costly palladium (O) coupling reactions above, to introduce a sulfide bond in the molecule as described in the US Patent Application 09 / 020.0140 incorporated by reference in its entirety. In addition, the above preferred sulfur atom was introduced beforehand by means of a TIPS-thiol reagent (TIPS ES TRIISOPROPIL- SILYL) which is prepared from the toxic hydrogen sulfide and the expensive TIPS chloride. Compound I wherein A is CH3 constitutes the preferred salt form of a 5-lipoxygenase inhibitor, which is useful in the treatment or alleviation of inflammatory diseases, allergies and cardiovascular diseases in mammals. In particular, compound I is useful in the treatment or alleviation of inflammatory diseases. These useful 5-lipoxygenase inhibitors can be administered in a wide variety of dosage forms. For the treatment of the various conditions described above, the compounds and their pharmaceutically acceptable salts can be administered to a human individual either alone, or preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition in accordance with normal pharmaceutical practice. The compounds can be administered orally or parenterally in a conventional manner. When the compounds are administered to a human individual for the prevention or treatment of an inflammatory disease, the oral dose range will be from about 0.1 to 10 mg / kg, per body weight of the individual to be treated per day, preferably from about 0.1 to 4 mg / kg per day, in single or divided doses. If parenteral administration is desired, then an effective dose will be that of about 0.05 to 5 mg / kg per body weight of the individual to be treated per day. In some cases, it may be necessary to use dosages located outside these limits, since dosages will necessarily vary according to the age, weight and response of the individual patient as well as the severity of the patient's symptoms and the potency of the particular compound. that is being administered. For oral administration, the compounds of the invention and their pharmaceutically acceptable salts can be administered, for example in the form of tablets, powders, rhombic tablets, syrups or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, vehicles that are commonly used include lactose and corn starch. In addition, lubricating agents such as magnesium stearate are commonly added. In the case of capsules, useful diluents are lactose and dried corn starch, when aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For use by the intramuscular, intraperitoneal, subcutaneous and intravenous routes, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be appropriately adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the preparation isotonic. In addition, particularly for the treatment of asthma, the compounds of formula I of this invention can be administered to a human subject by inhalation. For this purpose, they are administered as an aerosol or nebulization, according to classical practice. The present invention is illustrated by the following examples, but is not limited to the details thereof.

EXAMPLE I 4- (3-Bromo-phenyl) -tetrahydro-pyrano-4-carbonitrile 3-Bromo-phenyl-acetonitrile (51 g) in THF (300 ml) was treated with 40% aqueous NaOH (470 ml), tetrabutylammonium hydrogen sulfate (9 g) and dropwise addition of bis- ( 2-chloro-ethyl) -ether (32 ml). The reaction mixture was heated to reflux for 4 hours and then cooled. The mixture was diluted with EtOAc (400 mL), washed with 5% HCl (200 mL), with water (200 mL) and saturated NaHCO3. After drying over MgSO, the solvent was removed to give crude compound CP-399.554 as a waxy solid (75.4 g). the solid was suspended in a 1: 1 mixture of diisopropyl ether and hexanes (100 ml) to give 4- (3-bromo-phenyl) -tetrahydro-pyran-4-carbonitrile (55.3 g, 80% yield).

EXAMPLE II 4-r3- (4-Amino-phenyl-sulfanyl) -pheniH-tetrahydro-pyran-4-carbonitrile 4- (3-Bromo-phenyl) -tetrahydro-pyran-4-carbonitrile (133.4 g), Na 2 CO 3 (363.6 g), Cs 2 CO 3 (223.1 g) and aminothiophenol (62.8 g) were heated in N-methyl-pyrrolidinone (2.3 I) at 130 ° C for 24 hours. Additional amino-thiophenol (35.6 g) was added and heating continued for another 8 hours. The mixture was cooled to room temperature, poured into a mixture of ice and water (6.8 I) and separated by filtration. The product was suspended in water (2.5 L), filtered again and washed with water (1.5 L). The product was then suspended in EtOH (0.5 L), separated by filtration and dried at 40 ° C / 20 mbar, to give 4- [3- (4-amino-phenyl-sulfanyl) -phenyl] -tetrahydro- pyrano-4-carbonitrile (134.3 g, 86%).

EXAMPLE III N-f4-r3- (4-Cyano-tetrahydro-pyran-4-yl) -phenyl-sulfan-phenyl > -acetamide The 4- (3-bromo-phenyl) -tetrahydro-pyrano-4-carbonitrile (1.33 g) was mixed with Na 2 C 3 (1.59 g), Cs 2 CO 3 (0.651 g) and 4-acetamido-thiophenol (1 g) in N -methyl-pyrrolidinone (15 ml). The reaction mixture was heated at 130 ° C overnight. After cooling, the mixture was poured into ice water. The product was filtered off as a solid, and collected by suction filtration. The solid was recrystallized from a mixture of EtOAc and hexanes to provide the N-. { 4- [3- (4-cyano-tetrahydro-pyran-4-yl) -phenyl-sulfanyl-phenyl} -acetamide (1.4 g, 80% yield).

EXAMPLES ll AND III combined N 4 -3- (4-Cyano-tetrahydro-pyran-4-yl) -phenyl-sulfanyl-1-phenol > -acetamide 4- [3- (4-Amino-phenyl-sulfanyl) -phenyl] -tetrahydro-pyran-4-carbonitrile (93.57 g) and Et3N (53.1 ml) were dissolved in EtOAc (1.23 I) and heated to 50- 60 ° C. To this solution was added acetyl chloride (27.7 ml) in EtOAc (73 ml) for 30 minutes. The obtained suspension was filtered and the filter cake was washed with EtOAc (3 x 150 ml). The combined EtOAc solutions were washed with water (0.5 I), with a semi-saturated aqueous solution of Na2CO3 (2 x 0.5 I) with water (0.5 I) and with a saturated aqueous solution of NaCl (0.25 I). The organic materials were dried with Na2SO and evaporated at 40 ° C. The crude product was recrystallized from EtOH at reflux (0.52 i) to give, after having cooled, filtered and dried 40 ° C / 20 mbar, the N-. { 4- [3- (4-cyano-tetrahydro-pyran-4-yl) -phene-sulfanyl] -phenyl} -acetamida (55.27 g, yield 52%). EXAMPLE IV 4-. { 3-r4- (2-Methyl-imidazol-1 -yl) -phenyl-sulfanin-phenyl > -tetrahydro-pyrano-4- carbonitrile The N-4- [3- (4-amino-phenyl-sulfanyl] -tetrahydro-pyran-4-carbonitrile (49.77 g) was dissolved in toluene (545 ml) and heated at 60 ° C as an azeotrope. In this solution, 20 ml of solvent were separated in the form of the azeotrope to remove the remaining water PCI5 (35.0 g) was added in several portions to the solution After stirring for 1 hour at 60 ° C, the solvent was separated by The residue was cooled to 10 ° C, and a mixture of Et 3 N (19. 8 ml) and amino acetaldehyde dimethyl acetal (15.2 ml) in EtOAc (500 ml) was added. for 30 minutes at 10 ° C and then more EtOAc (150 ml) was added.The mixture was washed with water (360 ml), followed by a saturated aqueous NaCl solution (150 ml). The organics were dried with Na2SO2 (52 g) and evaporated at 50 ° C. The residue was dissolved in formic acid (250 ml) and heated to reflux for 1 hour. The reaction mixture was concentrated at 50 ° C / 100 mbar to give an oil. The oil was dissolved in 10% aqueous citric acid (400 ml) and EtOAc (200 ml). The aqueous layer was extracted with EtOAc (350 mL). The pH of the aqueous layer was adjusted to 9-10 with a semi-saturated solution of K2CO3 (175 ml), and the solution was extracted with EtOAC (200 ml). The extract was dried with Na2SO (48 g) and evaporated at 50 ° C / 100 mbar to give, after filtration through a pad of silica using a mixture of CH2Cl2 and 10% MeOH as eluent, 4-. { 3- [4- (2-MethyI-imidazol-1-yl) -phenyl-sulfanyl] -phenyl} -tetrahydro-pyrano-4-carbonitrile (27.6 g, 55% overall yield).

EXAMPLE V 4- (3-r4- (2-Methyl-imidazol-1-iD-phenyl-sulfanip-phenyl) - tetrahydro-pyran-4-carboxylic acid amide The 4-. { 3- [4- (2-methyl-imidazol-1-yl) -phenyl-sulfanyl] -phenyl]} tetrahydro pyran-4-carbonitrile (27.35 g) was dissolved in t-BuOH (280 ml) at 50 ° C. To the solution was added KOH (12.28 g) and the mixture was stirred overnight. The suspension was cooled to room temperature and water (180 ml) was added. The suspension obtained was filtered and the filter cake was dried at 50 ° C to provide the acid amide 4-. { 3- [4- (2-metii-imidazol-1-yl) -phenyl-sulfanyl] -pheni !} -tetrahydro-pyrano-4-carboxylic acid (17.52 g, 55% yield).

JEMPLO VI 4-f3-β4- (2-methyl-imidazoi-1-i0-phenyl-su-fanm-phene-Hetrahydro-pyrano-4-carboxylic acid amide methyl ester-sulfonate) The acid amide 4-. { 3- [4- (2-methyl-imidazol-1-yl) -phenyl-suI-ynyl] -phenyl} -tetrahydro-pyran-4-carboxylic acid (5.05 g) was suspended in MeOH (39 ml) at room temperature. Methanesulfonic acid was added dropwise to the suspension until all the material had dissolved. The obtained solution was filtered, and the filter was washed with MeOH (20 ml). The combined solutions in MeOH were treated with diisopropyl ether (280 ml) at room temperature. After being stirred overnight, crystals were formed, which were collected by filtration and dried at 40 ° C / 19 mbar to provide the 4-amide methyl acid sulfonate. { 3- [4- (2-Methyl-imidazol-1-yl) -phenyl-sulfanyl] -phenyl} -tetrahydro-pyran-4-carboxylic acid (4.85 g, 77% yield).

Claims (30)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing a compound of the formula wherein A is C 1 -C 4 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 -C 3 alkyl or benzyl, comprising; a) reacting a compound of the formula wherein A is C1-C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C-1-C3 alkyl or benzyl, with a sulfonic acid in an alkyl alcohol CrC5; and b) precipitating the compound of formula I by the addition of an organic solvent whose polarity is less than that of said alcohol.

2. The process according to claim 1, wherein the acid is methanol-sulphonic acid.

3. The process according to claim 1, wherein the organic solvent is diisopropyl ether or ethyl acetate.

4. The method of claim 1, wherein said compound of formula II is prepared by reacting a compound of formula wherein A is C1-C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, with a hydroxide in a solvent of the type of a alcohol.

5. The process according to claim 4, wherein the hydroxide is potassium hydroxide.

6. - The process according to claim 4, wherein the alcohol is tertiary butyl alcohol.

7. The method according to claim 4, wherein said compound of formula III is prepared by reacting a compound of formula wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, with a mineral acid.

8. The process according to claim 7, wherein the acid is acetic acid, sulfuric acid, formic acid or p-toluenesulfonic acid.

9. The process according to claim 8, wherein the preferred acid is formic acid.

10. The method according to claim 7, wherein said compound of formula IV is prepared by reacting a compound of formula V wherein A is C 1 -C 2 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 -C 3 alkyl or benzyl, and wherein X is Cl, Br, I or OCH 3, with an excess of an acetal of acetaldehyde.

11. The process according to claim 10, wherein the amino acetaldehyde acetal is the amino acetaldehyde dimethylacetal or the amino acetaldehyde diethyl acetal.

12. The process according to claim 10, wherein said compound of formula V wherein X is Cl, Br or I is prepared by reacting a compound of formula SAW wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, with a phosphorus pentahalide in an inert solvent; or wherein X is OCH3 in the formula V with (CH3) 3O + BF "to form an intermediate compound.

13. The process according to claim 12, wherein the pentahalogenide is phosphorus pentachloride, phosphorus pentaiodide or phosphorus pentabromide and the solvent is toluene.

14. - The process according to claim 12, wherein said compound of formula VI is prepared by reacting a compound of the formula VIII wherein X is Cl, Br or I with an excess of 4-amino-thiophenol and with a base in the sine of an inert solvent to give a compound of formula Vile and further treating a compound of formula VII by acylation with an acyl halide or anhydride.

15. The process according to claim 14, wherein the acylating agent is acetyl chloride.

16. The process according to claim 12, wherein said compound VI is prepared by reacting a compound of formula VIII VIII wherein X is Cl, Br or I with an excess of 4-amido-thiophenol and with a base in an inert solvent.

17. The method according to claim 16, wherein the 4-amido-thiophenol is 4-acetamido-thiophenol.

18. The method according to claim 16, wherein the base is NMP or DMSO.

19. The process according to claim 16, wherein the base is a mixture of sodium carbonate and cesium carbonate.

20. The process according to claim 14, wherein the base is a mixture of sodium carbonate and cesium carbonate.

21. The process according to claim 14, wherein said solvent is DMSO or NMP.

22. The process according to claim 16, wherein said compound of formula HIV can be prepared by reacting a compound of formula wherein X is Cl, Br or I, with bis- (2-chloro-ethyl) -ether, an alkaline base and a phase transfer catalyst in an inert solvent.

23. The process according to claim 22, wherein the inert solvent is a mixture of tetrahydrofuran and water, the base is sodium hydroxide and the phase transfer catalyst is tetrabutylammonium hydrogen sulfate. 24.- A compound of the formula Vile

25. - A compound of the formula SAW wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl. 26.- A compound of the formula wherein A is C 1 -C 4 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 -C 3 alkyl or benzyl and wherein X is Cl, Br, I or OCH3. 27.- A compound of the formula wherein A is C 1 -C 6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH 3, C 1 -C 3 alkyl or benzyl and wherein R is C 1 -C 6 alkyl. 28.- A compound of the formula wherein A is C? -C6 alkyl, an aryl, which is mono- or di-substituted with F, Cl, Br, OCH3, C1-C3 alkyl or benzyl, 29.- A compound of the formula

30. - A compound of the formula where Xes Bro Cl.