CS256398B2 - Method of phenylnona tetronic acids' derivatives production - Google Patents

Abstract

A method for producing phenylnonatetraene derivatives acids of formula I, v wherein R 1 is hydrogen, C 1 -C 7 -alkyl, chlorine, fluorine or trifluoromethyl, P2 represents, chloro, trifluoromethyl, C1-C6-alkyl, fluorine (McJ-Cy-alkoxy, trifluoromethyl- -C 1 -C 7 -alkoxy or hydrogen, R 3 represents hydrogen, Cy-Cy-alkyl, chloro or fluoro, R4 is straight chain alkyl containing from 4 to 10 carbon atoms or. \ t the group -CH 2 (CH 2) n CH 2 OH, r 5 represents the group COOR 8, R 7, R 8 and R 8 are each is hydrogen or IR-C-alkyl and n is 6 or 7, and salts thereof compounds wherein Rg is an atom hydrogen, consisting of the reaction of the compound of formula VIII with a compound of formula V wherein R 9 is C 1 -C 7 -alkyl and Z is a leaving group, optionally subsequent ester hydrolysis and in converting the free acid to salt. The compounds produced are pharmacologically effective and can be used as antirheumatic and immunosuppressive agents.

Description

In the compounds of the invention, halogen means all four halogens, i.e. chlorine, bromine, iodine and fluorine, with chlorine and bromine being preferred halogens. As used herein, a C 1 -C 7 alkyl group refers to a C 1 -C 7 alkyl group having both a straight and branched chain. Preferred alkyl groups of this type include methyl, ethyl, isopropyl, n-butyl and the like, with methyl and ethyl being particularly preferred. The term C 1 -C 7 alkoxy refers to C 1 -C 7 alkoxy groups such as methoxy, ethoxy, isopropoxy, isobutoxy and the like. "C 1 -C 7 alkyl" refers to an alkoxy group as defined above substituted with a trifluoromethyl group. The term "alkylidene group" refers to an aliphatic saturated hydrocarbon group in which the terminal carbon atom is divalent.

Aryl refers to mononuclear aromatic hydrocarbon groups which may be unsubstituted or substituted at one or more positions by C 1 -C 7 alkyl groups such as phenyl, tolyl and the like, and multinucleated aromatic groups which may be unsubstituted or substituted in in one or more positions by an alkyl group of up to 7 carbon atoms such as naphthyl, phenanthryl or anthryl. A preferred aryl group is phenyl.

In accordance with one embodiment, compounds of formula (I) are prepared wherein R? and R 8 are each C 1 -C 7 alkyl, preferably methyl.

In another preferred embodiment, R 8 is a group wherein y has a value of 6 to 9, especially 8 to 9, and most preferably 9. In this embodiment, R 8, R 8 and R 8 are preferably hydrogen or R 8 and R 8 are hydrogen and R 8 is alkoxy. 1 to 7 carbon atoms, such as methoxy or ethoxy. On the other hand, in this embodiment, R g and R g may be hydrogen and R g may be chlorine or fluorine, or R g and R g may be hydrogen and R g may be fluorine or chlorine.

In accordance with yet another embodiment, compounds of Formula I are prepared wherein R 8 is -CHg (CHg) _n CHgOH. In this embodiment, in the compounds of formula (I), R8, R8 and R8 are hydrogen or R8 is chlorine or fluorine, and R8 and R8 are hydrogen. On the other hand, compounds of formula (I) are prepared in which R8 and R8 are hydrogen and R8 is C1-C7alkoxy, preferably methoxy or ethoxy. Also preferred in this embodiment are those compounds of formula I wherein R 8 and R 8 are hydrogen and R 8 is chlorine or fluorine.

The invention also includes salts of the compounds of formula (I) with pharmaceutically acceptable non-toxic organic or inorganic bases, for example alkali or alkaline earth metal salts. Preferred salts are sodium, potassium, magnesium or calcium salts, as well as salts with ammonia or with suitable non-toxic amines, such as C 1 -C 7 alkylamines, e.g. triethylamine, C 1 -C 7 hydroxyalkylamines, e.g.

2-hydroxyethylamine, bis (1-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, with cycloalkylamines such as dicyclohexylamine or benzylamines such as N, N'-dibenzylethylenediamine and dibenzylamine. These salts may be prepared by reacting compounds of formula I wherein:

R 8 represents a hydrogen atom, with inorganic or organic bases, carried out according to conventional procedures known in the art.

The compounds of formula (T), as well as their salts, are effective as disease modifiers in the treatment of rheuraatoid arthritis and related diseases such as osteoarthritis.

The compounds of formula I may be used to treat patients suffering from rheumatoid arthritis and related diseases. In these cases, the disclosed compounds treat the consequences of these diseases in a beneficial manner by reducing the joint destruction caused by the disease and suppressing inflammation, temperature and joint pain caused by rheumatoid arthritis and related diseases. The compounds of formula (I) and salts thereof are also useful for treating diseases resulting from immune system hyperactivity, such as transplant autoimmunity, autoimmune diseases, and graft-responsive reactions to recipients.

The unexpected absence of toxicity of the compounds of the invention is evident from the fact that (Ε, Ε, Ε, Ε) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid has an LD _{50 of} greater than 1000 mg / kg when administered to mice both intraperitoneally and orally.

The compounds of the invention are potent antiarthritic agents from the results obtained in testing these compounds in rats with chronic adjuvant-induced arthritis. This experimental system has been described by Billingham and Davies in the Handbook of Experimental Pharmaoology (ed. J. R. Vane and S. H. Ferreira), Vol. 50/11, pp. 108-144, Springer-Verlag, Berlin, 1979.

In this test, arthritis is induced by administering 0 on day 0 to the right council paws of male rats (Charles River Lewis) weighing 120-140 g, which were kept separately and not obstructed in food and water intake by subplantar injection of 0, 05 ml of adjuvant 0.5% (hippot / volume) suspension of heat-killed Mycobacterium butyricum organisms in heavy mineral oil containing 0.2% digitonin]. Immediately after injection of the adjuvant, paw volumes (both hind paws) are measured. To monitor the development of the inflammatory process in the arthritis paws, paw volumes are then measured at intervals of 3 to 7 days by dipping the paw up to the mark on the outer ankle in a rhythmic plethysmograph.

Test substances are administered once daily (starting on the day of injection of the adjuvant) by gavage using polyoxyethylene sorbitan monooleate (Tween 80) as vehicle, at a dose of 0.25 ml / 100 g body weight. Arthritic control rats receive daily doses of vehicle only. At day 23-25, rats are sacrificed, their plasma collected and turbidimetric using ammonium sulfate as described by Exner et al. Amer. J.

Clin Path, 71, 521-527 (1979), is used to determine plasma fibrinogen levels. The anti-inflammatory activity of the test compounds is determined by comparing the swelling range (paw volume at the respective day, i.e., day 4 to day 25, minus paw volume at day 0) in arthritic rats treated with the test substance with swelling range in arthritic rats given vehicle only. . A test substance caused by a decrease in plasma fibrinogen levels is also used to quantitate the anti-inflammatory activity. Fibrinogen is a protein found in increased amounts in the plasma of adjuvant-induced arthritis rats.

The results obtained when comparing the various compounds of the invention with indomethacin and 13-cis-vitamin A-derived acid are shown in the following. Table I:

Oral Decrease (%) Volume Change (Decrease in ingestion of paws at day 23) Content body dose of fibrinogen weight (Umol / kg right left in plasma (%) (g)

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In Table I above, the reduction in paw volume as a percentage demonstrates the efficacy of the compounds of the invention in controlling arthritis induced by adjuvant.

As can be seen from the results in this table, the compounds of the invention effectively suppress swelling due to the application of an adjuvant. Furthermore, the compounds of the invention effectively reduce the plasma fibrinogen content associated with rheumatoid arthritis in general. Furthermore, as can be seen from the weight gains, the compounds of the invention * do not significantly reduce the weight gains of the test animals at the doses tested, suggesting that the compounds of the invention are not toxic.

The compounds of formula I and their pharmaceutically acceptable salts can be used in a wide variety of dosage forms. The disclosed compounds can be administered in unit dosage forms such as tablets, pills, powders, and capsules, as well as in the form of injectables, solutions, suppositories, emulsions, dispersions and other suitable forms. The pharmaceutical preparations containing the compounds of the formula I are conveniently prepared by mixing the active ingredient with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical pharmaceutically acceptable carriers are, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, natural petrolatum, and other commonly used pharmaceutically acceptable carriers. The pharmaceutical compositions may also contain non-toxic excipients such as emulsifiers, preservatives and wetting agents, and the like, such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan, dioctyl sodium sucoinate and the like.

Of course, the daily dose of active ingredients administered will vary depending upon the novel compound employed, the route of administration selected and the weight of the patient. The dosages administered are not limited by any definitive limits, since they are generally effective amounts in which the compounds of the invention exert their pharmacological function. A representative typical method of administration of the compounds of the invention and their salts is oral administration. In this route of administration, the compounds of formula (I) and their salts can be administered orally at a daily dose of from 0.6 mg / kg to 100 mg / kg. Preferably, the compounds may be administered daily in unit dosage forms for oral administration, with a daily dosage of from 1 to 30 mg / kg body weight, particularly preferably from 1 to 10 mg / kg.

Compounds of formula I may be prepared from compounds of formula III

in which

R ^, R £ and R-are as defined above, according to Reaction Scheme 1 above.

In the formulas shown in Reaction Scheme 1, n, R 1, R ₂ , R _g , R 4 and R _{g have the} above meanings, R 8 represents an alkyl group having 1 to 7 carbon atoms, Z represents a leaving group, Y represents an aryl group preferably a phenyl group and Z 'represents a halogen atom.

The compound of formula III is converted to the compound of formula IV in reaction step (a) by reducing the aldehyde group to an alcohol group. This reaction is carried out using conventional reducing agents converting aldehydes to alcohols. Any conventional reducing agent may be used for the reaction of step (a). In carrying out this reaction, it is generally preferred to use an alkali metal borohydride such as sodium borohydride as a reducing agent. The reaction of step (a) may be carried out using any of the conditions commonly known for carrying out such reduction reactions. When R ₂ represents a hydroxyl group it is generally preferred to protect the hydroxyl group in this · during the reduction of a compound of formula III and subsequent conversion. To protect the hydroxy function represented by R ₂ may be any conventional hydrolyzable hydroxy-protecting group such as a lower alkanoyl group. This ester protecting group can be cleaved after conventional Wittig salts of formula (VI) or ether (X) by conventional ester hydrolysis.

The compound of formula IV is converted to the compound of formula VI in reaction step (b) by reacting the compound of formula IB with a triarylphosphine hydrohalide. In this way, the phosphonium salt of formula VI is formed. Any suitable method of reacting an allyl type alcohol with a triaryl phosphine hydrohalide may be used to effect this reaction. The phosphonium salt of formula VI is subjected to a Wittig reaction with a compound of formula VII in reaction step (c) to give a compound of formula VIII. Any of the conditions commonly used in Wittig reactions may be used to carry out the reaction of step (c).

Alternatively, the compound of formula III can be converted to the compound of formula VIII directly by reaction with a phosphonium salt of formula IX according to step (e). The reaction of the phosphonium salt of formula IX with a compound of formula III to give a compound of formula VIII is carried out under the same conditions as described in connection with reaction step (c).

Compound (VIII) is converted to compound (X) by etherification or alkylation with compound (V) according to step (d). In the compound of formula (V), Z may be any conventional leaving group, such as mesyloxy, tosyloxy or halide ion. Any conventional method of etherifying a hydroxyl group by reacting it with a halide or leaving group can be used to carry out the reaction of step (d).

It is an object of the present invention to provide a process for the preparation of the compounds of formula (I) and salts thereof, characterized in that the compound of formula (VIII)

is reacted with a compound of formula r ₄ z wherein in the above formulas

R ', R', R, R., 5. and R 'are as defined above,

R represents an alkyl group having 1 to 7 carbon atoms and

Z is a leaving group such as a mesyloxy group, whereupon the optionally present alkyl ester moiety of the formula -COORg is converted to a free carboxyl group and the product of formula I wherein Rg is a free carboxyl group is optionally converted to a pharmaceutically acceptable salt.

The invention is illustrated by the following non-limiting examples. The term ether in these examples refers to diethyl ether and the evaporation of solvents is carried out in vacuo.

Example 1

(E, E, E, E) -9- (2-Hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester

A solution of 1 mole of [N- (2 'hydroxyphenyl) methyl] triphenylphosphonium bromide in tetrahydrofuran at -35 C ^U with a solution of n-butyllithium in hexane (2.1 molar equivalent) was converted to the ylide reacted with 1 mol of 7-formyl -3-methyl-2,4,6-octatrienoic acid. The reaction mixture was stirred at -70 ° C for 15 minutes, then the organic products were isolated using hexane / ethyl acetate (4: 1) and treated with dilute mineral acid (2M aqueous hydrochloric acid) after chromatography and crystallization from the mixture. of dichloromethane and hexane yielded in 90% pure (E, E, E, E) -9- (2-hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester.

Example 2

(E, E, E, E) -9- (2-Hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester

A mixture of 2-hydroxybenzaldehyde (0.5 mol), (7-carboxy-2,6-dimethyl-2,4,6-heptatrien-1-yl) triphenylphosphonium bromide (0.6 mol) and 1,2-epoxybutane (750 ml) was heated at room temperature for 30 minutes. The mixture is refluxed, then cooled, poured into a mixture of equal volumes of ether and hexane and, after filtration, the filtrate is concentrated. The residue was crystallized from ether / hexane in 38% yield. (E, E, E, E) -9- (2-hydroxyphenyl) -3,7-dimethylmethyl-2,4,6,8-nonatetraenoic acid, m.p. 143-145 ° C. , ·

Example 3 (E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,4,6,8-nonatetraenoic acid

To a mixture of sodium hydride (24 g, 50% dispersion in mineral oil) and 1000 ml dimethylformamide at 10 ° C was added 0.4 equivalents of (E, E, E, E) -9- (2-hydroxyphenyl) ethyl ester. -3,7-dimethyl-2,4,6,8-nonatetraenoic acid and the resulting mixture was stirred at room temperature until the evolution of hydrogen ceased to give the sodium salt of the ethyl ester (Ε, Ε, Ε, E) -9- ( 2-hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. To this salt solution was added a solution of 0.5 equivalent of 1-nonyl tosylate in 200 mL of dimethylformamide, and the reaction mixture was stirred at 45 ° C for 14 hours. After addition of hexane and water, the hexane extract is concentrated and the residue is purified by silica gel chromatography. After crystallization from hexane, pure (E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester is obtained.

The ester is hydrolyzed by dissolving 70 g of the ester in 1000 ml of ethanol, adding a solution of 80 g of potassium hydroxide in 400 ml of water, and refluxing for 1 hour. After addition of water and aqueous mineral acid, the solids are extracted with chloroform, the organic extract is concentrated and the residue is crystallized from a mixture of ethyl acetate and hexane. 38 g of (E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid of melting point 102 DEG-103 DEG C. are obtained. .

Example 4 (E, E, E, E) -9- [2- (8-hydroxyoctyl) oxy] phenyl-3,7-dimethyl-2,4,6,8-nonatetraenoic acid

The sodium salt of (E, E, E, E) -9- (2-hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester in dimethylformamide, prepared as described in Example 3, was prepared in an analogous manner. as in Example 3, treated with 1,8-dihydroxyoctane monotosylate to give (E, E, E, E) -9- [2- (8-hydroxyoctyl) oxy] phenyl-3,7-dimethyl-2,4-ethyl ester 6,8-nonatetraenoic acid, which is isolated by silica gel chromatography.

Hydrolysis of this ester by the procedure of Example 3 afforded (E, E, E, E) -9256398

- [><(8-hydroxyoctyl) oxy] phenyl _N-yl] -3,7-ai _m 2 _of ethyl 4,6,8- _n o _n e _{n r} Atet acid The melting point after crystallisation of ethyl acetate at from 122 to Mp 123 ° C.

Example 5

This example describes the composition and preparation of a capsule composition.

Ingredients:

C. Component mg / capsule mg / capsule mg / capsule 1 (E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl- -2,4,6,8-nonatetra- enoic acid 15 Dec 30 60 2 lactose 239 224 194 3 starch 30 30 30 4 talc 15 Dec 15 Dec 15 Dec 5 magnesium stearate _1 _1 1 hm! capsule filling 300 mg 300 mg 300 mg

Method:

1) components 1 to 3 are mixed in a suitable mixer2) talc and magnesium stearate are added and the mixture is mixed briefly

3) the capsules are filled using a suitable device.

Claims (11)

SUBJECT OF THE INVENTION A process for the preparation of phenylnonatetraenoic acid derivatives of the general formula I in which H represents a C 1 -C 7 alkyl group, a chlorine atom, a fluorine atom or a trifluoromethyl group, a chlorine atom, a trifluoromethyl group, an alkyl group having 1 to 7 carbon atoms, a fluorine atom, a C 1 -C 7 alkoxy group, a C 1 -C 7 trifluoromethylalkoxy group or a hydrogen atom means a hydrogen atom, a C 1 -C 7 alkyl group, a chlorine or fluorine atom, a straight chain alkyl group containing 4-10 carbon atoms or -CH 2 ^CH ^ _n ^0IÍ ' R 8 represents a group COOR _g , R _? , Rg and Rg are hydrogen or alkyl having 1-7 carbon atoms and n is 6 or 7 and pharmaceutically acceptable salts of such compounds in which R _g represents a hydrogen atom, characterized in that a compound of formula VIII is reacted with a compound of formula wherein in the above formulas R 1, R 2, R 6, R 6, R 6, R 6, R 6 and R 8 are as defined above, R _g represents an alkyl group having 1-7 carbon atoms and Z is a leaving group such as a mesyloxy group, whereupon the optionally present alkyl ester moiety of the formula -COOR _{g is} converted to a free carboxyl group and the product of formula I in which Rg is a free carboxyl group is optionally converted to a pharmaceutically acceptable salt . 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R 8 represents a hydrogen, chlorine or fluorine atom, R 8 is hydrogen, C 1 -C 7 alkoxy, chloro or fluoro, R 8 represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a chlorine atom or a fluorine atom, R 8 represents a C 8 -C 10 alkyl group having a straight chain of 8 or 9 carbon atoms, Rg represents a group -C00R _g n, R ?, Rg and _Rg are as defined in claim 1 and salts of such compounds in which R _g is hydrogen. 3. A process according to claim 2, wherein the corresponding starting materials are used to form compounds of formula I wherein R1 is an alkyl group as defined in item 2, and the remaining general symbols are as in item 2. 4. A process according to claim 3, to form compounds of formula I wherein the general symbols are as in point 3. that the corresponding starting materials are used, R 6 represents a chlorine or fluorine atom, and remains 5. A process according to claim 3, wherein the compounds of formula (I) are those corresponding to (I) in which they are alkoxy with carbon and the remainder of the general formulas are as in (3). starting materials having 1 to 7 atoms 6. A process according to claim 2, wherein the corresponding starting materials are used to form 9 - {(2-chloro-6- (nonyloxy) phenyl) -3,7-dimethyl-2,4,6,8-nonatetraene. acid. 7. A process according to claim 2, wherein the corresponding starting materials are used to form (E, E, E, E) -9- (2-fluoro-6- (nonyloxy) phenyl) -3,7-dimethyl- 2,4,6,8-nonatetraenoic acid. 8. The process of claim 2, wherein the corresponding starting materials are used to give 3,7-dimethyl-9- (5-methoxy-2-nonyloxyphenyl) -2,4,6,8-nonatetraenoic acid. 9. A process according to claim 2, wherein the corresponding starting materials are used to form 9 - [[2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. Process according to claim 2, characterized in that the corresponding starting materials are used to give (Ε, Ε, Ε, E) -3,7-dimethyl-9- [2- (8-hydroxyoctyl) oxy] phenyl 3. ~ 2,4,6,8-nonatetraenoic acid. 11. The method of claim 1, wherein the corresponding starting materials are used to form (E, E, E, E) -8- 2- (trifluoromethyl) -6- (nonyloxy) phenyl. dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9- [2- (octyloxy) phenyl] -2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9- (2-dimethyloctyl) oxy] phenyl] -2,4,6,8-nonatetraenoic acid, 9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6 ethyl ester, 8-nonatetraenoic acid, (E, E, E, E) -9- [2- (hexyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, (E, E, E, (E) -9- (5-hydroxy-2- (nonyloxy) phenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, (E, E, E, E) -9- ^ 2- (nonyloxy) -5- (2,2,2-trifluoromethoxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid; and 3,7-dimethyl-9- [1 H - (octyloxy (methyl) phenyl) -2,4,6,8-nonatetraenoic acid.