FI95911C - Process for the preparation of therapeutically useful N-alkenylbenzo / b / thieno / 3,2-b / oxazine-2,4-dione - Google Patents

Description

95911

This invention relates to a process for the preparation of certain prodrugs of 3-hydroxybenzothiophenes having a 2-enamido side chain. More particularly, it is directed to the preparation of cyclic prodrugs of N-alkenyl-3-hydroxybenzo [b] thiophene-3-carboxamides having cyclo-10 oxygenase and 5-lipoxygenase inhibitory activity.

U.S. Patent 4,760,086, issued July 26, 1988, discloses numerous N-alkenyl-3-hydroxybenzo [b] thiophene-3-carboxamides of formula (I), xi

15 jL

XvX-X -OR 1. .

». ; \

20 R

wherein each of Χχ-Χ4, H and Rx-R4 is generally defined as hydrogen, lower alkyl, aryl, heteroaryl, lower cycloalkyl, benzyl, lower alkenyl or lower alkynyl, each of which may be substituted with various substituents.

Said compounds are shown to be effective inhibitors of cyclooxygenase and 5-lipoxygenase and therefore valuable in the treatment of inflammation, pain, fever and other diseases mediated by prostaglandin and / or jaw-30 trienes.

U.S. Patent 4,656,265, issued April 7, 1987, discloses cyclic prodrugs of non-steroidal, anti-inflammatory oxicams. In said prodrugs, the parent oxocams are chemically modified to form a condensed 1,3-oxazine-2 95911 gas system which decomposes in vivo to restore the parent compound.

This invention relates to a process for the preparation of therapeutically useful N-alkenylbenzo-5 [b] thieno [3,2-b] oxazine-2,4-diones of formula (II) which are as defined above. cyclic prodrugs of the compounds of formula (I) wherein each of R, R 1 and R 4 is hydrogen.

The substituents phenyl and thienyl in the double bond may be of the type syn, anti or a mixture of both. Thus, formula (II) shows the substituents attached to the double bond by wavy lines. The purpose of this disclosure is to describe all isomeric forms of the compounds of formula (II). Individual isomers of the compounds of formula (II) may be prepared starting from the appropriate isomer of the required reactant of formula (I). Alternatively, the isomers can be separated from their mixtures by known methods, such as chromatography.

The compounds of formula (II), in contrast to the parent compounds of formula (I), are not enolic acids and therefore cause less gastric irritation than the parent compounds. After administration to a mammal, including a human, the compounds of formula (II) release the parent compound by some metabolic process.

The compounds of formula II prepared by the process of the invention differ in their structure from the starting compounds of formula I known from EP-A-160 408 and also from the compounds known from U.S. Pat. No. 4,656,265 and FI-89. 208, based on the structure of these prior art compounds, it could not be taken for granted that the compounds of formula II would also have the same type of therapeutic properties.

The compounds of this invention may be used in pharmaceutical compositions suitable for administration to a mammal, including a human, said compositions comprising a pharmaceutically acceptable carrier and a cyclooxygenase and / or 5-lipoxygenase inhibiting amount of a compound of formula (II); and in a method of treating diseases arising from biological mediators formed by cyclooxygenase and / or 5-lipoxygenase-catalyzed reactions in a mammalian body, the method comprising administering to the mammal in need of such treatment cyclooxygenase and / or 5- 20 lipoxygenase inhibiting amount of a compound of formula (II).

Compounds of formula (II) are prepared by reacting a compound of formula (I) wherein each of R, R 1 and R 4 is hydrogen with phosgene used as a cyclizing agent in a reaction inert solvent in the presence of an acid scavenger at a temperature between -70 ° C - + 50 ° C.

Suitable reaction-inert solvents, i. solvents which do not react with the reactants or products in such a way as to reduce the yield of the desired product include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachlorides and 1,2-dichloroethane; ethers such as ethyl or isopropyl ether, dioxane and tetrahydrofuran; acyclic hydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbons, 4,959,111 such as benzene, toluene and xylene; cyclic hydrocarbons such as cyclopentane and cyclohexane; ethyl acetate, dimethylformamide, acetonitrile and dimethyl sulfoxide. Preferred solvents are methylene chloride, ethyl ether, tetrahydrofuran and ethyl acetate.

Naturally, cyclizing agents other than phosgene can be used. Typical such substances are those of the formula Y-COCl, where Y is (C 1-4) alkoxy, phenoxy, benzyloxy or trichloromethoxy. However, phosgene is the preferred cyclizing agent.

Suitable acid scavengers for use in the process of the invention include those basic compounds which scavenge the hydrogen chloride formed in the reaction but do not form an undesired by-product under the conditions used with the Y-COCl-rea-Gent or the compounds of formula (I). Examples of suitable acid scavengers are tertiary amines such as trialkylamines having 3 to 30 carbon atoms, dialkylarylamines and alkyldiarylamines having 8 to 30 carbon atoms, aralkyldialkylamines having 9 to 30 carbon atoms, N- alkyl heterocyclic amines having from 6 to 25 carbon atoms; alkali metal or alkaline earth metal carbonates or bicarbonates, and alkaline earth metal oxides or hydrochlorides. Particularly preferred acid-binding agents are sodium bicarbonate, calcium carbonate, calcium oxide, N, N-dimethylaniline, N-methylmorpholine and N-methylpiperidine. Most preferred is triethylamine.

In theory, a cyclizing agent Y-COCl and 30 starting compounds of formula (I) are required in equimolar amounts to form the desired compounds of formula (II). In practice, however, an excess of cyclizing agent is generally used in order to ensure that the reaction takes place completely and to minimize the formation of inactive by-products. Typically, a molar excess of about 1-10 times is used with good results.

The reaction can be carried out at a temperature between about -70 ° C and + 50 ° C. The recommended temperature range is -30 ° C to 30 ° C. The preferred temperature range is -10 ° C to -25 ° C, with a range of 0 ° C to 25 ° C being a particularly preferred range.

The reaction is generally complete in less than 4 hours and the products are separated and purified by standard methods known to those skilled in the art.

The starting materials of formula (I) are obtainable by the methods disclosed in U.S. Patent 4,706,086. Cyclizing agents are commercially available as well as acid scavengers.

The cyclic prodrugs of this invention are evaluated for their anti-inflammatory activity according to known methods by oral administration of multiple doses in model experiments, e.g. in U.S. Patent 4,760,086 and other literature: see, e.g., CA. Winter's publication "Progress in Drug Research", edited by. 25 E. Jucker, Birkhauser Verlag, Basel, vol. 10, 1966, pages • · 139 - 192.

Compared with the parent compounds of formula (I), the new prodrugs of formula (II) were found to have a markedly reduced ability to inhibit prostaglandin synthesis from arachidonic acid in experiments which. was performed by T.J. Using a method modification by Carty et al., Prostaglandins, 19, 51-59 (1980). The modified method uses cultures of rat basophilic leukemic cells (RBL-1) prepared by the method of Jakschik 35 et al., Ibid, 16, 733 (1978), mouse ««. · · 6 95911 instead of connective tissue cell cultures (MC5-5) and rabbit synovial cell cultures. In this case, the compounds according to the invention themselves are relatively inactive as anti-inflammatory agents, but they provide an active anti-inflammatory compound due to in vivo hydrolysis. Since compound (II) is not enolic acid and it is known that hydrolysis occurs after the prodrug leaves the stomach, it significantly reduces the gastric irritation caused by oral administration of the carriers, enol oxicams.

Calculated on a molar basis, these prodrugs are generally administered in the same amount and frequency as the parent compounds from which they are derived. The non-enol nature of these compounds generally allows for higher tolerable doses if such a higher dosage is required to control inflammation.

The compounds of the invention will generally be administered either orally, parenterally or topically in doses ranging from about 0.01 mg to 150 mg per kilogram of body weight, although variations may occur depending on the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.5 mg to about 7.5 g per patient per day is desirably the most widely used amount. However, variations may occur depending on the species of animal being treated and its individual response to said drug, as well as the type of pharmaceutical preparation and the period and time interval within which such drug is administered.

30 In some cases, dosages below the lower limit of the above range may be more appropriate, while in other cases even higher doses may be used without adverse side effects, provided that such higher dosages are first divided into several smaller doses for administration throughout the day.

7 95911

These prodrugs are also formulated in the same manner and administered by the same methods as the parent compounds disclosed in U.S. Patent 4,760,086. The preferred route of administration is oral, with particular advantage over the non-enolimic nature of the compounds in question.

For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be used in combination with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates. such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; preferred substances in this connection would also be lactose and milk sugar as well as high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are desired for oral administration, various sweetening or flavoring agents, coloring agents or coloring agents and, if desired, emulsifying and / or suspending agents may be added to the essential active ingredient therein, together with such with diluents such as water, ethanol, propylene glycol, glycerol and various combinations thereof.

For parenteral administration, solutions in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water-soluble alkali metal or alkaline earth metal salts listed above. Aqueous solutions of 1 »·« 8 95911 should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These special solutions are particularly suitable for intravenous, intramuscular and subcutaneous administration. In addition, the above-mentioned compounds can also be administered topically, and this can be advantageously carried out using creams, ointments, jellies, ointments, creams and the like in accordance with standard pharmaceutical practice.

The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. On the contrary, it will be readily appreciated that various other embodiments, modifications, and equivalents of the invention may be practiced which will be readily apparent to those skilled in the art without departing from the spirit and / or scope of the present invention.

Example 1 N- [2-phenyl-2- (2-thienyl) ethenyl] -5-trifluoromethylbenzo [b] thieno [3,2-b] oxazine-2,4-dione 3-hydroxy-5- Trifluoromethyl-N- [2- (2-thienyl) -2-phenylethenyl] benzo [b] thiophene-2-carboxamide (0.2 g, 0.448 mmol) was dissolved in 30 mL of dry methylene chloride and cooled to 0 mL. ° C under nitrogen gas.

Triethylamine (0.156 mL, 1.12 mmol) was added and the reaction mixture was stirred at 0 ° C for several minutes. Excess phosgene gas was then bubbled into the mass. The reaction mixture was stirred at 0 ° C for about one hour, after which it was warmed to room temperature, at which time TLC analysis [CH 2 Cl 2 / hexane (2: 1)] showed almost complete consumption of starting material and formation of a single, more polar product. The reaction mixture was stirred at room temperature for an additional 2 hours, after which it was gently warmed to remove excess phosgene. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with 2N HCl (2 x 100 mL), water (1 x 100 mL), brine and dried (Na 2 SO 4). Concentration of the ethyl acetate extract in vacuo gave a total of 210 mg of a dark yellow-brown oil which was purified using a silica gel column (CH 2 Cl 2) to give 0.17 g of a light brown foamy solid. Recrystallization from toluene / hexane gave an orange-brown crystalline solid, m.p. 208-210 ° C, comprising a mixture of isomers: exact mass spectrum M + = 471.0225 calculated for C23H1203NS2F3 471.0212.

IR GKBr 1700 and 1780 cm-1.

Example 2

Isomeric Forms of the Product of Example 1 The procedure of Example 1 was repeated, but the individual isomers identified as isomers A and B of the starting material of Example 1 were used as reactants. Isomer A The product melted at 180-182 ° C; isomer B product between 219 and 221 ° C.

I I «·«

Claims (3)

A process for the preparation of therapeutically useful N-alkenylbenzo [b] thieno [3,2-b] oxazine-2,4-dione of formula II sS TD characterized in reacting a compound of formula (I) With a cyclizing agent of the formula Y-COC1, where Y is Cl, C1.4-alkoxy, phenoxy, benzyloxy or trichloromethoxy at a temperature of -70 - +50 ° C in the presence of an acid binding agent t < Process according to claim 1, characterized in that said cyclizing agent is phosgene. 3. A process according to claim 1, characterized in that said acid binding agent is triethylamine.