KR790001067B1 - Process for preparing heteroarylbenzoxepin-aceticacids - Google Patents

Abstract

Title compd., useful as analgesics and inflammation inhibitors(no data), was prepd. Thus, lower alkylester reacted with the lower alkylester of (hydroxy-phenyl) acetic acid to give Ia(X = pentagonal or hexagonal heteroaryl ring contg. 1 or 2 O, N, or S with C, R1 = H or methyl, R2 = H or methyl, n = 1,2,3) and II or III (Y=Br, Cl) was cyclized followed by hydrolysis to give Ib(R = H or C1-5 straighted or branched alkyl).

Description

Method for producing heteroarylbenzooxepin-acetinic acid

The present invention relates to a method for producing heteroarylbenzoxepin-acetinic acids having anti-inflammatory and analgesic action.

Japanese Patent Publication No. 7200425, published January 7, 1972, describes that sulfa compounds and derivatives of the following structural formula have analgesic, antipyretic and anti-inflammatory effects.

U.S. Patent Application Serial No. 459,774, filed April 10, 1974, discloses 6,11-dihydrodibenz- [b, e] oxepin-acetinic acid and its derivatives for anti-inflammatory and analgesic activity. It is demonstrated. The tricyclic compounds of the present invention have significant structural differences and unexpectedly excellent action.

The compound of the present invention has the following structure, wherein X has the structure of 5 or 6 heteroaryl ring containing 1 or 2 oxygen, nitrogen or sulfur atom together with the carbon atom to which it is bonded, and R is hydrogen Or C ₁ -C ₅ straight or branched alkyl, R ¹ is hydrogen or lower alkyl of C ₁ -C ₄ , R ² is hydrogen or methyl, n is a number of 1,2 or 3;

One variation of the invention includes dicarboxylic acids and tricyclic compounds, and also carboxylic acids (R is hydrogen) and their esters (R is alkyl). Preferred compounds are those in which the heteroaryl ring is unsubstituted. Especially those in which the heteroallyl ring is furan or thiopene are preferable. The compound of the present invention can be prepared by one of the following methods.

How (a)

1. X, R ¹ and n are as described above and Y is halogen, lower alkyl ester of the following structural formula, ester having 1-4 carbons in alcohol unit

Acid removers such as potassium carbonate or sodium ethoxide and solvents such as acetone, butanone, ethanol or dimethylformamide in the presence or absence of the initiator upon reaction at temperatures between ambient temperature and boiling point of the solvent for 2-3 minutes to 72 hours Reacted with a lower alkyl ester of acetinic acid in the presence of (hydroxyphenyl) to give a diester for the corresponding

2. The diester is saponified with the corresponding dicarboxylic acid by known suitable methods. Preferably, a base such as potassium hydroxide or sodium is used in a solvent such as ethanol or water for 15 minutes to 24 hours at a temperature between ambient temperature and the boiling point of the solvent.

3. ring closure by treatment with a dehydrating agent such as polyphosphoric acid, ethanol phosphorus pentoxide or sulfuric acid in the presence or absence of a solvent such as tetramerylenesulfone or acetinic acid at a temperature of 50-120 ° C. for 5 minutes to 15 hours. The heteroaryl benzoxepin which is a compound of the present invention of the following structural formula is obtained.

Method (me)

1, Method (b) The dicarboxylic acid prepared in step (2) is subjected to 15 minutes to 6 hours, such as thionyl halide or phosphorus pentahalide, in the presence or absence of solvent at a temperature between ambient temperature and reflux temperature of the reaction mixture. React with a sufficient amount of preparation to produce a dihalide halide.

2. The diacid halide is ring closed under pretelcraft conditions and hydrolyzed by known methods to afford the compound of the invention as described in process (a) step (3). A preferred ring closure method is to use Lewis acids, such as stannin chloride, at ambient temperature. In addition, the divalent halide is heated to a temperature of 80-125 ° C. for 10 minutes to 24 hours, closed and hydrolyzed to produce the inventive compound.

Method (C)

Compounds of the present invention prepared by process (A) or (B) are subjected to R as described above in the presence of an acid such as sulfuric acid, hydrochloric acid or P-toluenesulfonic acid at a temperature between 50 ° C. and the boiling point of alcohol for 15 minutes to 24 hours. It is esterified by reacting with an alcohol of the same structure ROH.

Those skilled in the art will know that the reaction time is short if the reaction temperature is high, so the relationship between the reaction time and the reaction temperature may be selected.

The tricycle compounds of the present invention are useful as systemic anti-inflammatory agents due to their ability to suppress inflammation in mammals. The activity of this compound can be determined by anti-inflammatory assay by carrageenan-induced rat plantar edema test [Proc. Scc. Exptl. Biol. Med. III 544 (1962). For example, 4,10-dihydro-10-oxochieno [3,2-c] [1] benzoxepin-8-acetinic acid 3.6 mg / kg, methyl 4,10-dihydro-10- Oxochieno [3,2-c] [1] -benzoxepin-8-acetate 4.2 mg / kg, 4,10-dihydro-10-oxofurano [3,2-c] [1] -benzo Oral administration of oxepin-8-acetic acid 24 mg / kg shows about 50% edema suppression.

The tricyclic compounds of the present invention are also useful as topical anti-inflammatory agents due to their ability to suppress mammalian dermatitis. The activity of representative compounds can be determined by croton-induced edema of mice. Endccrinolog 77, 625 (1965); Chin. Pharmacol. & Therap. 16, 900 (1974). For example, 4,10-dihydro-10-oxochieno [3,2-c] [1] benzoxepine-8-acetinic acid 2.5% and 4,10-dihydro-10-oxochi Furnace [3,2-c] [1] -benzox

2. The diester is saponified with the corresponding dicarboxylic acid by known suitable methods. Preferably, a base such as potassium hydroxide or sodium is used in a solvent such as ethanol or water for 15 minutes to 24 hours at a temperature between ambient temperature and the boiling point of the solvent.

3. Ring closure by treatment with a dehydrating agent such as polyphosphoric acid, ethanol phosphorus pentoxide or sulfuric acid in the presence or absence of a solvent such as tetramethylenesulfone or acetinic acid at a temperature of 50-125 ° C. for 5 minutes to 12 hours The heteroaryl benzoxepin which is a compound of the present invention of structural formula is obtained.

Method (me)

1. Method (b) The dicarboxylic acid prepared in step (2) is subjected to a process such as thionyl halide or phosphorus pentahalide in the presence or absence of a solvent at a temperature between 15 minutes and 6 hours at ambient temperature and the reflux temperature of the reaction mixture. React with a sufficient amount of preparation to produce a dihalide halide.

2. The diacid halide is ring closed under pretelcraft conditions and hydrolyzed by known methods to afford the compound of the invention as described in process (a) step (3). A preferred ring closure method is to use Lewis acids such as stannin chloride at ambient temperature. The divalent halide is also heated to a temperature of 80-125 [deg.] C. for 10 minutes to 24 hours to cyclize and hydrolyze to produce the compound of the present invention.

Method (C)

Compounds of the present invention prepared by process (A) or (B) are subjected to R as described above in the presence of an acid such as sulfuric acid, hydrochloric acid or P-toluenesulfonic acid at a temperature between 50 ° C. and the boiling point of alcohol for 15 minutes to 24 hours. It is esterified by reacting with an alcohol of the same structure ROH.

Those skilled in the art will know that the reaction time is short if the reaction temperature is high, so the relationship between the reaction time and the reaction temperature may be selected.

The tricycle compounds of the present invention are useful as systemic anti-inflammatory agents due to their ability to suppress inflammation in mammals. The activity of this compound can be determined by anti-inflammatory assay by carrageenan-induced rat plantar edema test [Proc. Scc. Exptl. Biol. Med. III 544 (1962). For example, 4,10-dihydro-10-oxochieno [3,2-c] [1] benzoxepin-8-acetinic acid 3.6 mg / kg, methyl 4,10-dihydro-10- Oxochieno [3,2-c] [1] -benzoxepin-8-acetate 4.2 mg / kg, 4,10-dihydro-10-oxofurano [3,2-c] [1] -benzo Oral administration of oxepin-8-acetic acid 24 mg / kg shows about 50% edema suppression.

The tricyclic compounds of the present invention are also useful as topical anti-inflammatory agents due to their ability to suppress mammalian dermatitis. The activity of representative compounds can be determined by croton-induced edema of mice. Endccrinolog 77, 625 (1965); Chin. Pharmacol. & Therap. 16, 900 (1974). For example, 4,10-dihydro-10-oxochieno [3,2-c] [1] benzoxepine-8-acetinic acid 2.5% and 4,10-dihydro-10-oxochi 5% of no [3,2-c] [1] -benzoxepin-8-acetate showed edema inhibition of 65% and 24%, respectively.

The tricyclic compounds of the present invention are also useful as analgesics because of their ability to relieve pain in mammals. Representative compounds of the present invention can be seen in the activity of the 2-phenyl-1,4-benzoquinone induced mouse torsion test, an analgesic canon test method.

These data indicate that the compounds of the present invention exhibit systemic anti-inflammatory and / or analgesic activity at 0.1-50 mg / kg and local anti-inflammatory action at concentrations of 0.1-20%.

Examples of the compounds of the present invention include the following: 4,10-dihydro-10-oxofurano [3,2-c] [1] benzooxepin-7-acetinic acid

Ethyl 4,10-dihydro-10-oxofurano [3,2-c] [1] benzoxepin-8-acetate

Amyl 4,10-dihydro-1,2,3-trimethyl-10-oxopyrrolo- [3,2-c] [1] benzooxepin-8-acetinic acid

5,11-dihydro-11-oxopyrazino [2,3-c] [1] benzoxepin-8-acetinic acid

5,11-dihydro-11-oxopyrimido [4,5-c] [1] benzoxepin-9-acetinic acid

n-propyl 4,10-dihydro-10-oxooxazolo [4,5-c] [1] benzoxepin-8-acetate

4,10-dihydro-10-oxothiazolo [4,5-c] [1] benzoxepin-8-acetinic acid

n-butyl 4,10-dihydro-10-oxoimidazo [4,5-c] [1] benzoxepine acetate

4,10-dihydro-10-oxochieno [2,3-c] [1] benzoxepin-8-acetinic acid

4,10-dihydro-α-methyl-10-oxochieno [3,2-c] [1] benzoxepin-8-acetic acid

4,10-dihydro-αmethyl-10-oxofurano [2,3-c] [1] benzoxepin-7-acetic acid

4,10-dihydro-10-oxoisoxazolo [4,5-c] [1] benzoxepin-8-acetic acid

An effective amount of the tricyclic compound of the present invention may be administered orally to a patient by capsule or tablet or topically as an ointment, solution, or plaster, or parenterally as a sterile solution or suspension. In some cases, it may be administered intravenously as a sterile solution. have. The final product, the free acid itself is effective, but may be prepared and administered as a pharmaceutically acceptable addition salt in consideration of stability, convenience of crystallization, and solubility increase. Such salts include natrium, potassium, calcium, magnesium, ammonium salts and the like.

The active substance of the present invention is administered together with an inert diluent, an edible carrier, or the like and contained in a gelatin capsule or as a tablet. For oral administration, the active ingredient of the present invention is used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, etc. in combination with excipients. These formulations should contain at least 0.5% of active ingredient but are dependent on the formulation and contain 4-70% weight ratio of a single formulation. Good compositions and formulations are oral formulations containing 1.0-500 mg of active ingredient.

Tablets, pills, capsules, troches, and the like may contain the following components: binders such as microcrystallized cerose, tragaganth, gelatin; Excipients such as starch or lactose, disintegrants such as alginic acid, primogel, corn starch, glidants such as magnesium stearate, sterotex, glidants such as colloidal silicon dioxide; You can add sweeteners such as sucrose or saccharin, or you can add flavorings such as peppermint, methyl salicylate, and orange flavor. When the single dosage form is a capsule, it may contain a liquid carrier such as fatty acid in addition to the above materials. Other formulations may contain other substances such as coatings. Thus tablets or pills can be avoided with sugar, shellac or other internal coatings. Syrups may contain, as well as active ingredients, sucrose and preservatives, dyes, colorants, flavors and the like. The materials used to make these various compositions should be pharmaceutically pure and nontoxic in their use.

For parenteral administration, the active ingredients of the invention are prepared in solution or suspension. These formulations should contain at least 0.5-30% by weight of active ingredient. Good compositions and formulations are parenteral units containing 0.5-100 mg of active ingredient. Solutions or suspensions may contain the following components; Water for injection, saline, nonvolatile oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; Fungicides such as benzyl alcohol and methylparaben; Antioxidants such as ascorbic acid or sodium hydrogen sulfite, chelating agents such as ethylene diaminetetraacetinic acid; Buffers such as acetates, citrate, phosphates; Osmotic pressure regulators such as sodium chloride or glucose. Parenteral preparations are sealed in glass or plastic ampoules, disposable syringes, or vials.

For topical administration, the active ingredients of the present invention are prepared as solutions, suspensions, ointments, creams and plasters. These formulations should contain at least 0.01% of active compound but only 0.05-20% by weight. The amount of active compound in such formulations depends on the appropriate dose. Good topical formulations contain 0.1-10% of active compound.

Topical formulations may also contain the following ingredients. : Water, nonvolatile oil, polyethylene glycol, glycerol, petroleum, stearic acid, containment, other synthetic solvents or mixtures thereof; Fungicides such as benzyl alcohol and methylparaben; antioxidants such as α-tocopherol acetate; Chelating agents such as ethylenediamineretraacetic acid; Buffers such as acetate, citrate, and phosphates; Emulsification aids such as polyoxyethylene monooleate; Colorants and immersion agents such as iron oxide or talc. Topical agents are placed in tubes, bottles, or jars of metal, glass, or plastic.

The present invention is explained in more detail by the following examples.

Example 1

A) a mixture of 25.0 g 3-bromomethyl-2-carboethoxythiophene, 18.2 g ethyl 4-hydroxyphenylacetate, 55.2 potassium carbonate, 1.0 g sodium iodide, and 500 ml butanone Reflux for time. The salt is filtered off and washed with ether to concentrate the filtrate in vacuo to give an amber oil. This oil is dissolved in ether and the ether solution is washed with 5% sodium hydroxide and water, filtered and the ether removed to give a yellow oil. 50 ml of water and 80.0 g of potassium hydroxide were added to an oil solution of 400 ml of ethanol, and the reaction mixture was refluxed for 16 hours and concentrated in vacuo. The aqueous solution was cooled, acidified with ice-cold concentrated hydrochloric acid to obtain a solid, dried, recrystallized from isopropanol and washed to give crystalline 4- (2-carboxy-3-chienylmethoxy) phenylacetinic acid having a melting point of 222 占 폚. To obtain.

B) Carefully immerse 5.80 g of phosphorus pentaoxide in 3.5 ml of anhydrous ethanol and keep the temperature below 80 ℃. The white viscose mixture is heated to 110 ° C. for 1 hour and 25 ml of tetramethylenesulfone are added. The reaction temperature is adjusted to 81-83 ° C. and 2.70 g of 4- (2-carboxy-3-chienylmethoxy) phenylacetinic acid is introduced. The temperature of the reaction mixture is maintained for 3 hours, the mixture is carefully poured into water, made basic and extracted with toluene. The aqueous layer is acidified with ice-cold concentrated hydrochloric acid to give a brown solid which is exported to chloroform, filtered and concentrated in vacuo to give a yellow solid. The solid triturated with ether is light yellow crystals, 4,10-dihydro-10-oxochieno [3,2-c] [1] benzsenoxin-8-acetinic acid, having a melting point of 162-164 ° C. .

Assay C ₁₄ H ₁₀ SO ₄

Calculated C 61.30% H 3.68 S 11.69%

Found C 61.47% H 3.73% S 11.58%

Example 2

0.70 g of 4,10-dihydro-10-oxochieno- [3,2-c] [1] benzoxepin-8-acetinic acid (Example 1), 8 ml of concentrated sulfuric acid and 150 ml of methanol The mixture is refluxed for 16 h. The reaction mixture is concentrated in vacuo, diluted with water and extracted with benzene. The combined benzene extract is washed with 5% sodium hydroxide, washed again with water, dried, filtered and concentrated in vacuo to give an oil to solidify it. The solid was recrystallized with methanol to obtain light yellow crystals, which were methyl-4,10-dihydro-10-oxochieno [3,2-c] [1] benzo having a melting point of 80-81 ° C. Oxepin-8-acetate.

Assay C ₁₅ H ₁₂ SO ₄

Calculated C 62.48% H 4.19% S 11.12%

Found C 62.49% H 4.28% S 11.27%

Example 3

1.0 g of 4,10-dihydro-10-oxochieno- [3,2-c] [1] benzoxepin-8-acetinic acid (Example 1), 50 ml of isopropanol and 8 ml The solution of concentrated sulfuric acid is refluxed for 16 hours and then concentrated in vacuo to give a dark brown oil. The oil is dissolved in chloroform, washed with water, saturated with sodium bicarbonate solution and water, dried, filtered and concentrated in vacuo to yield an amber oil which is left to solidify. The solid was recrystallized from isopropanol to give a colorless crystal and a melting point of 92-94 ° C., isopurophil 4,10-dihydro-10-oxochieno [3,2-c] [1] benzooxepin- 8-acetate is obtained.

Assay C ₁₇ H ₁₆ SO ₄

Calculated C 64.54% H 5.10%

Found C 64.42% H 5.17%

Example 4

A) A solution of 20.0 g of methyl 3-bromomethyl-2-fluoroate, 15.1 g of methyl 4-hydroxyphenylacetate, 52.0 g of potassium carbonate, 1.0 g of sodium iodide, and 360 ml of butanone 1 (A) to give a tan precipitate, which is recrystallized with acetonitrile to give 4- (2-carboxy-3-furylmethoxy) phenylacetinic acid having white crystals and a melting point of 204-205 占 폚. do.

B) 14.4 g of phosphorus pentachloride is added to a mixture of 9.6 g of 4- (2-carboxy-3-furylmethoxy) phenylacetinic acid and 140 ml of anhydrous benzene, and the suspension is stirred at ambient temperature for 4 hours. Benzene is removed at 85 ° C. under reduced pressure to give a dihalide halide. This solid is dissolved in anhydrous methylene chloride and 17.9 g of stannin chloride is added dropwise for 5 minutes. The reaction mixture is stirred at ambient temperature for 24 hours, followed by addition of 140 ml of 1N hydrochloric acid for 24 hours. The reaction mixture was basified and filtered, the organic layer was separated, the aqueous layer was washed with ether and acidified to give a brown solid which was filtered, washed with water and dried and recrystallized from acetonitrile to give a solid having a melting point of 177-178 ° C. 4,10 -Dihydro-10-oxoprano [3,2-c] [1] benzooxepin-8-acetinic acid is obtained.

Assay C ₁₄ H ₁₀ O ₅

Calculated C 65.11% H 3.90%

Found C 65.29% H 3.96%

Example 5

(A) A mixture of 3.6 g (50% product) of ethyl 2-bromomethylnicotinate, 2.7 g of ethyl 4-hydroxyphenylacetate, 8.3 g of potassium carbonate, and 0.2 g of sodium iodide was mixed in 60 ml of butanone; Treated according to the method described in a) to obtain a beige solid, recrystallized with methanol and washed with a mixture of acetonitrile: ether = 1:10 to 4- (3-carboxy-2-pyridylmethoxy at a melting point of 185-187 ° C. ) White crystals of phenylacetinic acid are obtained.

B) Treating 5- (3-carboxy-2-pyridylmethoxy) -phenylacetinic acid according to the method of Example 1 (b), 5,11-dihydro-11-oxopyrido [2,3 -c] [1] benzoxepin-9-acetinic acid is obtained.

Example 6

1) To a suspension of 10.9 g of ethyl 4-formyl-1,2,5-trimethyl pyrrole-3-carboxylate in 40 ml of methanol, 5.6 g of sodium brohydride in methanol is added dropwise under nitrogen stream, and the reaction temperature is maintained at 50 캜 or lower. Let's do it. After completion of the dropwise addition, the mixture was stirred for 4 hours at ambient temperature, water 90 was added, the reaction solution was saturated with potassium carbonate and extracted with ether. The ether extracts were combined, dried and concentrated in vacuo to afford a yellow solid which was recrystallized with cyclohexane to give ethyl 4- (hydroxymethyl) -1,2,5-trimethylpyrrole-3-carboxylate at 184-186 ° C.

B) Dissolve 1.0 g of ethyl 4- (hydroxymethyl) -1,2,5-trimethylpyrrole-3-carboxylate in 15 ml of benzene, add 0.6 g of thionyl chloride dropwise, and then add 3.5 g of ambient product at ambient temperature for 3.5 hours. Stir. Benzene is removed in vacuo to yield a gray solid of ethyl 4- (chloromethyl) -1,2,5-trimethylpyrrole-3-carboxylate.

C) A mixture of 1.1 g of ethyl 4- (chloromethyl) -1,2,5-trimethylpyrrole-3-carboxylate, 30 g of methylol, 0.9 g of methyl 4-hydroxyphenyl acetate, and 0.29 g of sodium methoxide in an ice bath was added. Stir for hours and again for 19 hours at ambient temperature. The mixture is filtered and the filtrate is concentrated in vacuo to give an oil. This oil is dissolved in ether, washed with 5% sodium hydroxide solution and water, and dried to remove ether and yellow oil is obtained. 5 ml of water and 8 g of potassium hydroxide were added to a solution in 40 ml of ethanol of this oil, refluxed for 16 hours, and concentrated in vacuo. The aqueous solution is cooled and acid treated with ice-cold concentrated hydrochloric acid to obtain 4- (4-carboxy-1,2,5-trimethyl-3-pyrylmethoxy) phenylacetinic acid.

C) 4- (3-carboxy-1,2,5-trimethylpyrylmethoxy) phenylacetinic acid is converted to 4,10-dihydro-1,2,3-trimethyl- according to the method of Example 1 (b). Obtain 10-oxopyrrolo [3,4-c] [1] benzoxepin-8-acetinic acid.

Claims (1)

As detailed in the text The following compound of formula (A) is reacted with a lower alkyl ester of (hydroxyphenyl) acetinic acid to prepare a compound of formula (Ia) or to cyclic and hydrolyze the compound of formula (B) or (C) Next, a method of preparing the compound of formula (Ib) and esterifying the compound to prepare the compound of formula (Ib).

In the above structural formula X has a structure of 5 or 6 heteroaryl rings containing 1 or 2 oxygen, nitrogen or sulfur atoms together with the carbon atoms to which they are attached, R is hydrogen or C ₁ -C ₅ straight or branched alkyl, R ¹ is hydrogen or methyl, n is 1,2 or 3 numbers Y is cancel or chlorine.