CS256398B2 - Process for the production of derivatives of phylnonatetraenoic acids - Google Patents

Abstract

A process for the preparation of phenylnonatetraenoic acid derivatives of the general formula I, in which Ri represents hydrogen, C1-C7-alkyl, chlorine, fluorine or trifluoromethyl, P2 represents chlorine, trifluoromethyl, C1-C7-alkyl, fluoro(Mc1-C7-alkoxy, trifluoromethyl- -C1-C7-alkoxy or hydrogen, R3 represents hydrogen, C1-C7-alkyl, chlorine or fluorine, R4 represents a straight-chain alkyl containing 4 to 10 carbon atoms or the group -CH2 (CH2)nCH2OH, R5 represents a COORg group, R7, Rg and Rg each represent a hydrogen atom or C1-C7-alkyl and n has the value 6 or 7, and salts of those compounds mentioned above, in which Rg represents a hydrogen atom, consisting in the reaction of a compound of the general formula VIII with a compound of the general formula V, where R9 is C1-C7-alkyl and Z represents a leaving group, in the optional subsequent hydrolysis of the ester group and in the conversion free acids to salt. The compounds produced are pharmacologically active and can be used as antirheumatic and immunosuppressive agents.

Description

In the compounds of the invention, halogen refers to all four halogens, i.e. chlorine, bromine, iodine and fluorine, with chlorine and bromine being preferred. The term C1-7 alkyl as used herein refers to C1-7 alkyl groups having both straight and branched chains. Preferred alkyl groups of this type include methyl, ethyl, isopropyl, n-butyl and the like, with methyl and ethyl being particularly preferred. The term C1-7 alkoxy refers to alkoxy groups containing 1 to 7 carbon atoms, such as methoxy, ethoxy, isopropoxy, isobutoxy and the like. The term trifluoromethylalkoxy includes 1 to 7 carbon atoms. "C1-C7 alkyl" means an alkoxy group as defined above substituted with a trifluoromethyl group. "C1-C7 alkylidene" means an aliphatic saturated hydrocarbon group in which the terminal carbon atom is divalent.

The term aryl refers to mononuclear aromatic hydrocarbon groups which may be unsubstituted or substituted at one or more positions by alkyl groups having 1 to 7 carbon atoms, such as phenyl, tolyl, etc., and polynuclear aromatic groups which may be unsubstituted or substituted at one or more positions by alkyl groups having 1 to 7 carbon atoms, such as naphthyl, phenanthryl or anthryl. A preferred aryl group is phenyl.

According to one embodiment, compounds of general formula I are prepared in which R 1 and R 2 each represent an alkyl group having 1 to 7 carbon atoms, preferably a methyl group.

In another preferred embodiment, Rg represents a group where y has a value of 6 to 9, in particular 8 to 9 and most preferably 9. In this embodiment of the invention, Rg, Rg and Rg preferably represent hydrogen atoms or Rg and Rg represent hydrogen atoms and Rg represents an alkoxy group having 1 to 7 carbon atoms, such as methoxy or ethoxy. On the other hand, in this embodiment, Rg and Rg may represent hydrogen atoms and Rg a chlorine or fluorine atom, or Rg and Rg may represent hydrogen atoms and Rg a fluorine or chlorine atom.

In accordance with yet another embodiment, compounds of formula I are prepared in which Rg represents the group -CHg (CHg) _n CHgOH. In this embodiment, in compounds of formula I, Rg, Rg and Rg represent hydrogen atoms or Rg represents a chlorine or fluorine atom and Rg and Rg are hydrogen atoms. On the other hand, in this embodiment, compounds of formula I are prepared in which Rg and Rg represent hydrogen atoms and Rg represents an alkoxy group with 1 to 7 carbon atoms, preferably a methoxy group or an ethoxy group. In this embodiment, compounds of formula I in which Rg and Rg represent hydrogen atoms and Rg represents a chlorine or fluorine atom are also preferred.

The invention also includes salts of the compounds of the above general formula I with pharmaceutically acceptable non-toxic organic or inorganic bases, for example salts with alkali metals or alkaline earth metals. Preferred salts are sodium, potassium, magnesium or calcium salts, as well as salts with ammonia or with suitable non-toxic amines, such as alkylamines with 1 to 7 carbon atoms, for example triethylamine, hydroxyalkylamines with 1 to 7 carbon atoms, for example

2-hydroxyethylamine, bis(1-hydroxyethyl)amine or tris(2-hydroxyethyl)amine, with cycloalkylamines, for example dicyclohexylamine or with benzylamines, for example N,Ν'-dibenzylethylenediamine and dibenzylamine. These salts can be prepared by reacting compounds of general formula I, in which

R 1 represents a hydrogen atom, with inorganic or organic bases, carried out by conventional procedures known in the art.

Compounds of formula T, as well as their salts, are effective as disease modifiers in the treatment of rheumatoid arthritis and related diseases such as osteoarthritis.

The compounds of formula I can be used to treat patients suffering from rheumatoid arthritis and related diseases. In such cases, the compounds described beneficially modify the consequences of these diseases by reducing the destruction of joints caused by this disease and suppressing the inflammation, temperature and pain of the joints caused by rheumatoid arthritis and related diseases. The compounds of formula I and their salts are also useful for the treatment of diseases resulting from hyperactivity of the immune system, such as transplant autoimmunity, autoimmune diseases and graft-versus-host disease.

The unexpected lack 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 _LD50 value of greater than 1000 mg/kg both intraperitoneally and orally in mice.

That the compounds of the invention are effective antiarthritic agents is evident from the results obtained when these compounds are tested in rats with chronic arthritis induced by the excipient. This experimental system is described by Billingham and Davies in Handbook of Experimental Pharmacology (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 subplantar injection of 0.05 ml of adjuvant [a 5% (vol/vol) suspension of heat-killed Mycobacterium butyricum in heavy mineral oil containing 0.2% digitonin] into the right hind paws of male rats (Charles River Lewis) weighing 120 to 140 g, which were housed separately and were not restricted in food or water intake. Immediately after injection of the adjuvant, paw volumes (both hind paws) are measured. To monitor the development of swelling caused by the inflammatory process in the arthritic paws, paw volumes are then measured at intervals of 3 to 7 days by immersing the paw up to the mark on the external ankle in a mercury 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 the vehicle, at a dose of 0.25 ml/100 g body weight. Arthritic control rats receive daily doses of vehicle only. On days 23-25, the rats are sacrificed, their plasma collected, and turbidimetrically assayed using ammonium sulfate as described by Exner et al. Amer. J.

Clin Path, 71, 521-527 (1979), plasma fibrinogen levels are determined. The anti-inflammatory activity of the test compounds is determined by comparing the extent of swelling (paw volume on the relevant day, i.e. day 4 to day 25, minus paw volume on day 0) in arthritic rats treated with the test substance with the extent of swelling in arthritic rats treated with vehicle alone. The reduction in plasma fibrinogen levels caused by the test substance is also used to quantitatively evaluate anti-inflammatory activity. Fibrinogen is a protein found in increased amounts in the plasma of rats with adjuvant-induced arthritis.

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

Oral Decrease (%) in volume Change (decrease) in body weight (Umol/kg right left plasma volume (%) (g)

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In Table I above, the percentage reduction in paw volume demonstrates the efficacy of the compounds of the invention in suppressing swelling caused by adjuvant-induced arthritis.

As is evident from the results shown in this table, the compounds of the invention are effective in suppressing the swelling caused by the application of the adjuvant. Furthermore, the compounds of the invention are effective in reducing the plasma fibrinogen content, which is generally associated with rheumatoid arthritis. Furthermore, as is evident from the weight gains, the compounds of the invention* at the tested doses do not significantly reduce the weight gains of the experimental animals, indicating 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 compounds described can be administered in unit dosage forms such as tablets, pills, powders and capsules, as well as in the form of injectable preparations, solutions, suppositories, emulsions, dispersions and other suitable forms. Pharmaceutical preparations containing the compounds of 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, etc., such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan, dioctyl sodium succinate, etc.

The daily dose of the active ingredients administered will of course vary depending on the novel compound used, the route of administration chosen and the weight of the patient. The doses administered are not limited by any definite limits, as they are generally effective amounts in which the compounds of the invention exhibit their pharmacological function. A representative typical method of administration of the compounds of the invention and their salts is oral administration. By this route of administration, the compounds of formula I and their salts can be administered orally in a daily dose of from 0.6 mg/kg to 100 mg/kg. These compounds can preferably be administered daily in unit dosage forms for oral administration, the daily dose being from 1 to 30 mg/kg of body weight, particularly preferably from 1 to 10 mg/kg.

Compounds of general formula I can be prepared from compounds of general formula III

in which

R^, R£ and R-j have the above meaning, by proceeding according to the above reaction scheme 1.

In the formulas shown in Reaction Scheme 1, the symbols n, R1, _R2 , _Rg , R2 and _Rg have the above-mentioned meanings, Rg represents an alkyl group with 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 general formula III is converted to the compound of general formula IV in reaction step (a) by reduction of the aldehyde group to an alcohol group. This reaction is carried out using conventional reducing agents for converting aldehydes to alcohols. Any conventional reducing agent can be used for the reaction in step (a). In carrying out this reaction, it is generally preferred to use an alkali metal borohydride, such as sodium borohydride, as the reducing agent. The reaction in step (a) can be carried out using any conditions commonly known for carrying out such reduction reactions. If R ₂ represents a hydroxyl group, it is generally advantageous to protect this hydroxyl group during the reduction of the compound of general formula III and the subsequent conversion. Any conventional hydrolyzable protecting group for the hydroxyl function, such as a lower alkanoyl group, can be used to protect the hydroxyl function in the meaning of the symbol R ₂ . This ester protecting group can be cleaved by conventional ester hydrolysis after the preparation of Wittig salts of formula VI or after the formation of the ether of formula X.

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. This produces a phosphonium salt of formula VI. Any suitable method for reacting an allyl alcohol with a triarylphosphine hydrohalide can be used to carry out 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 form a compound of formula VIII. Any conditions commonly used in Wittig reactions can be used to carry out the reaction according to step (c).

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

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

The actual subject of the invention is a process for the production of compounds of the above-mentioned general formula I and their salts, characterized in that the compound of the general formula VIII

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

R,, R„, R, R., S. and R_ have the meanings given above,

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

Z represents a leaving group, such as a mesyloxy group, whereupon the alkyl ester residue of the general formula -COORg present in the reaction product is optionally converted into a free carboxyl group and the obtained product of the general formula I, in which Rg represents a free carboxyl group, is optionally converted into a pharmaceutically acceptable salt.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way. In these examples, the term ether means diethyl ether and the evaporation of the 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 mol of [^(2“hydroxyphenyl)methyl]triphenylphosphonium bromide in tetrahydrofuran is converted to the ylide at -35 ^° C by the action of a solution of n-butyllithium in hexane (2.1 mol equivalent) which is reacted with 1 mol of ethyl 7-formyl-3-methyl-2,4,6-octatrienoic acid. The reaction mixture is stirred for another 15 minutes at -70 °C, after which the organic products are isolated using a mixture of hexane and ethyl acetate (4:1) and treated with dilute mineral acid (2M aqueous hydrochloric acid) to give pure ethyl (E,E,E,E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid in a yield of 90% after chromatography and crystallization from a mixture of dichloromethane and hexane.

Example 2

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

A mixture of 0.5 mol of 2-hydroxybenzaldehyde, 0.6 mol of (7-carboxy-2,6-dimethyl-2,4,6-heptatrien-1-yl)triphenylphosphonium bromide and 750 ml of 1,2-epoxybutane is heated to reflux for 30 minutes, then cooled, poured into a mixture of equal volumes of ether and hexane and, after filtration, the filtrate is concentrated. The residue gives, after crystallization from a mixture of ether and hexane, a 38% yield of ethyl ester. (Ε,Ε,Ε,E)-9-(2-hydroxyphenyl)-3,7-di.methyl-2,4,6,8-nonatetraenoic acid with a melting point of 143 to 145 °C. ,·

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

To a mixture of sodium hydride (24 g, 50% [wt] dispersion in mineral oil) and 1000 ml of dimethylformamide at 10 °C was added 0.4 equivalents of (E,E,E,E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester and the resulting mixture was stirred at room temperature until the evolution of hydrogen ceased, thereby forming the sodium salt of (E,E,E,E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. To this salt solution was added a solution of 0.5 equivalents 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 chromatography on silica gel. After crystallization from hexane, pure ethyl (E,E,E,E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid is obtained.

This ester is subjected to hydrolysis, which is carried out 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 heating the mixture to reflux for 1 hour. After adding 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 (Ε,Ε,E,E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid are obtained, melting point 102-103 °C.

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

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

Hydrolysis of this ester, carried out according to the procedure of Example 3, yields (E,E,E,E)-9256398

- _[ ><( ₈ -hydroxyoctyl)oxy] _phenyl ]-3,7- _aminomethyl - _{2-4,6,8 - nonatetetraenoic} acid melting after crystallization from ethyl acetate at 122 to 123 °C.

Example 5

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

Composition:

No. Folder mg/capsule mg/capsule mg/capsule 1 (Ε,Ε,Ε,Ε)-9-f2-(nonyloxy)phenyl]-3,7-dimethyl- -2,4,6,8-nonatetra- enoic acid 15 30 60 2 lactose 239 224 194 3 starch 30 30 30 4 talc 15 15 15 5 magnesium stearate _1 _1 1 mass! iost of capsule filling 300 mg 300 mg 300 mg

Procedure:

1) ingredients no. 1 to 3 are mixed in a suitable mixer2) talc and magnesium stearate are added and the mixture is mixed for a short time

3) The mixture is filled into capsules using suitable equipment.

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.