CS256392B2 - Method of phenylnonatetronic acids' derivatives production - Google Patents

Abstract

1. Compounds of the formula see diagramm : EP0169571,P20,F2 wherein R1 signifies hydrogen, lower alkyl, chlorine, fluorine or trifluoromethyl ; R2 signifies hydrogen, lower alkoxy, trifluoromethyl-lower alkoxy, hydroxy, lower alkyl, chlorine, trifluoromethyl or fluorine ; R3 signifies hydrogen, lower alkyl, chlorine or fluorine ; R4 signifies alkyl with 4-10 C-atoms or -CH2 (CH2 )n CH2 OH ; X signifies -CH(R10 )O-, -CH(R10 )-, -O-, -C(R10 ) = CH- or -N(R10 )-; R5 signifies COOR9 ; n signifies 6 or 7 ; and R7 , R8 , R9 and R10 signify lower alkyl or hydrogen and salts thereof when R9 is hydrogen.

Description

The invention relates to compounds of formula I

in which

R 1 represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a chlorine atom, a fluorine atom or a trifluoromethyl group,

R ₂ represents a chlorine atom, a trifluoromethyl group, an alkyl group having 1 to carbon atoms, fluorine, hydroxyl, alkoxy having 1-7 carbon atoms, containing trifluormethylalkoxyskupinu alkoxycarbonyl 1-7 carbon atoms or hydrogen,

R ₃ is hydrogen, alkyl of 1-7 carbon atoms, chlorine or fluorine atom, ·

R ₄ represents a straight chain alkyl group having 4 to 10 carbon atoms or -CH ₂ (CH ₂ ) _n CH ₂ OH,

X is -CHO-, -CH-, -O-, -C = CH- or -N-,

II ^R 10 ^R 10 ^R 10 ^R 10

R 8 represents a COOR 6 group,

R 2, R _g , R _g and R 10 are each hydrogen or C 1 -C 7 alkyl and n is 6 or 7, and the pharmaceutically acceptable salts of the above compounds wherein R _g is hydrogen, process production of these substances and pharmaceutical compositions containing them.

Compounds of formula (I) above may be prepared according to the following Reaction Schemes 1, 2, 3, 4, 5, 6, and 7, which also describe the preparation of various starting materials and intermediates.

Scheme 2

(XIX)

(XXII)

(XXXI)

(XXXV)

м (*)

Scheme 4

(Ь ·) v

(LIV)

Scheme 5

F

F

Scheme 6

(LXI) (LXIII) (LXIII) (LXIV)

(LXV) (LXVI) (XI-A)

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, an alkyl group having 1 to 7 carbon atoms means an alkyl group having 1 to 7 carbon atoms having both

Scheme 7

з (LXXI) 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. . The term alkylidene refers to an aliphatic saturated hydrocarbon group in which the terminal carbon atom is divalent. If the term "lower" is used to describe some of the remainder, it will always be 1 to 7 carbon atoms.

The term 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 multinuclear aromatic groups which may be unsubstituted or substituted in in one or more positions by a C 1 -C 7 alkyl group such as naphthyl, phenanthryl or anthryl. A preferred aryl group is phenyl.

In accordance with one embodiment, compounds of formula I are prepared wherein X is -O- and R? and R _g are each C 1 -C 7 alkyl, preferably methyl. According to another preferred embodiment, R ₄ represents a group - (CH ₂ ) _y H, wherein δ has a value of 6 to 9, in particular Θ to 9 and most preferably 9. In this embodiment, R p is R ₂ and preferably hydrogen or R 6 and R 6 R ₂ are hydrogen and R ₂ is C 1 -C 7 alkoxy, such as methoxy or ethoxy. On the other hand, in this embodiment, R ₂ and R ₃ can be hydrogen and R _{3 are} chlorine or fluorine, or R _x and R ₂ can be hydrogen and R _{3 are} fluorine or chlorine.

According to yet another embodiment, compounds of formula I are prepared wherein R ₄ is -CH ₂ (CH ₂ ) _n CH ₂ OH. In this embodiment, in the compounds of formula (I), R ₁ , R ₂ and R ₃ are hydrogen or _{χ χ} is chlorine or fluorine and R ₂ and R ₃ are hydrogen. On the other hand, compounds of formula I are prepared in which R @ ₁ and R @ ₃ are hydrogen and R @ ₂ is C1 -C7 alkoxy, preferably methoxy or ethoxy. Also preferred in this embodiment are those compounds of formula I wherein R 1 and R ₂ are hydrogen and R ₃ is chlorine or fluorine.

The invention also includes salts of the compounds of formula (I) above with pharmaceutically acceptable non-toxic organic or inorganic bases, for example alkali metal or alkaline earth metal salts. Preferred salts are sodium, potassium, magnesium or calcium salts, as well as salts with ammonia or suitable non-toxic amines, such as lower alkylamines such as triethylamine, hydroxy (lower) alkylamines such as 2-hydroxyethylamine, bis (1-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, with cycloalkylamines such as dicyclohexylamine or benzylamines such as,, Ν'-dibenzylethylenediamine and dibenzylamine. These salts can be prepared by reacting compounds of formula I wherein R 8 is hydrogen with inorganic or organic bases according to conventional procedures known in the art.

The compounds of formula I as well as their salts are effective as disease modifiers in the treatment of rheumatoid arthritis and related diseases such as osteo-arthritis.

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 (E, E, E, E) -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 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 administering 0 at day 0 to the right hind paws of male rats (Charles River Lewis) weighing 120-140 g, which were kept separately and not obstructed in food and water intake by 0, 05 ml of adjuvant, 5% (w / v) 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 evolution of the inflammation 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 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 vehicle, at a dose of 0.25 ml / 100 g body weight. Arthritic control rats receive daily doses of vehicle only. On 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. . Plasma-induced decrease in fibrinogen levels is also used to quantitate anti-inflammatory activity. Fibrinogen is a protein found in increased amounts in the plasma of adjuvant-induced arthritis rats.

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

Table I

Substance Orally Volume reduction Change ( Growth filed paws in the bottom 23 content) physical dose right left fibrinogen weight [mu] mol / kg in plasma (%) (G)

indomethacin carrier medium

- - - 28-31 3 -66 -67 -30 + 46 60 -33 -49 -18 - 7

CO ₂ H

^OC 9 ^H 19

-43 -58

-55 +27

OC ₉ H ₁₉

co ₂ c ₂ h ₅ nhc ₈ h ₁₇ + 24

+ 35

CO ₂ H

O (CH ₂ ) ₈ OH + ₂₇ ° C ₂ h + 46 C ₉ h ₁₉

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, 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 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 succinate 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 0.5 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.

Those compounds of formula I wherein X is -O- may be prepared from compounds of formula III

in which

R, and R ₂ are as hereinbefore defined, by procedures described in SCHEME first

In the formulas shown in Reaction Scheme 1, n, Rf, R ₂ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R 6, and R 8 is as defined above, 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 VI 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 purpose 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 reactions 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 this hydroxyl group during the reduction of a compound of formula III and subsequent conversion to the compound of formula II-A.

К protecting the hydroxyl 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 by conventional ester hydrolysis after preparation of the Wittig salts of formulas XIII and XVI or ρσ to form 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 IV 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 can be used to effect this reaction.

In accordance with another embodiment, a compound of formula X in which R ₂ represents a hydroxyl group, this group is protected in the form of hydrolysable ester prepared from a compound of formula III by alkylation or etherification of a compound of formula V to give a compound of formula XI.

In the compound of formula (V), Z may be any conventional leaving group, such as mesyloxy, tosyloxy or halide ion. Any conventional hydroxyl etherification method may be used to carry out the reaction of step (f). by reacting it with a halide or leaving group.

In the reaction according to step (f), when R 6 represents a hydroxyalkyl group, the hydroxyl function of the radical R ₄ need not be protected. This is because under the conditions used in this reaction step, a compound of formula V reacts with a compound of formula III to form a compound of formula XI without the need to protect the hydroxyl function of the alkyl chain. The alkylation or etherification takes place directly on the hydroxyl function on the phenyl core of the compound of formula (III), with little or no reaction with the hydroxyl group in the alkyl chain of R ₄ . The compound of formula XI is converted to the compound of formula XII in reaction step (g) by reduction. The same conditions as described in connection with reaction step (a) can be used to convert the compound of formula XI to the compound of formula XII.

The compound of formula XII is converted by the reaction of step (h) to a compound of formula XIII by reacting a compound of formula XII with a triarylphosphine hydrohalide as described above for step (b). A compound of formula XIII is converted to a compound of formula X by reaction with a compound of formula VII

OHC

(VII) in the sense of reaction step (i). Any of the conditions commonly used in Wittig reactions can be used to perform reaction step (i).

In another embodiment, a compound of formula X is produced by first converting a compound of formula XI to a compound of formula XIV. Compound of formula

XI is converted to a compound of formula XIV by aldol condensation with a compound of formula XX. Any conventional aldol condensation method can be used to react the compound of formula XI with a compound of formula XX to form a compound of formula XIV. In the next step, the compound of formula XIV is condensed either by Grignard reaction with vinylmagnesium halide or by reaction with vinyllithium to form a compound of formula XV. The reaction of step (k) may be carried out using any of the conditions commonly used in the condensation with lithium compounds or Grignard reagents. The compound of formula XV is converted to the compound of formula XVI by reaction with a triarylphosphine hydrohalide as described above in connection with step (b). The compound of formula XVI is then converted to a compound of formula X in reaction step (m) by reaction with a compound of formula XVII. The reaction of step (m) is carried out using a standard Wittig reaction as described in connection with the reaction of step (i). The compound of formula (XVI) provides a compound of formula (X) by reaction with a compound of formula (XVII). A compound of formula (X) can be converted to the free acid, i.e., a compound of formula (I) wherein R 1 is carboxyl by hydrolysis of the ester moiety. Any conventional method of ester hydrolysis can be used to prepare a compound of formula I in which it is a carboxyl group.

Compounds of formula I in which X is -N- are prepared from a compound of formula XXII R 6

in which

Rp R ₂ and R are as defined above, the method according to the above reaction scheme the second

In the formula of the Reaction Scheme 2 are R, R _2, R _3, R _4, R ?, R _g, R ', Z * and Y are as defined above. The symbol R ₁₃ in Scheme 2 has the same meaning as R ₄ but contains one carbon less in the alkyl group corresponding to the R ₄ alkyl group. Thus, R ₁₃ represents an alkyl group having 3 to 9 carbon atoms or the radical -CH ₂ (CH ₂ ) CH ₂ OH, wherein m is an integer less than n. This means that m is an integer of 5 to 6. In Scheme 2, R R g represents a hydrogen atom or a lower alkyl group having 1 to 7 carbon atoms and R ^ _Q represents a lower alkyl group having 1 to 7 carbon atoms. In this embodiment, a lower alkyl group containing one carbon atom is less than the alkyl group designated R < q >.

In Scheme 2, a compound of formula XXII is reacted with an acid chloride of formula XIX in which Z 'is halogen to give a compound of formula XXIII, which is then converted either to a compound of formula XXVI or to a compound of formula XXXI. If R ₃ in a compound of formula XIX is a radical _{-CH2- (CH2)} ,, ^ Η ΟΗ in which m is an integer of 5-6 does not affect the presence of hydroxyl groups in the substituent R @ ₃ reaction leading к to form a compound of formula XXVI or a compound of formula XXXI. This hydroxyl group was found to remain intact during the series of reactions described in Reaction Scheme 2.

This hydroxyl group can, of course, also be protected by providing a hydrolysable ether functionality which protects the hydroxyl group during the above-mentioned reactions. Any conventional ether protecting group may be used to protect the hydroxyl group during these reactions. Preferred ether protecting groups include tetrahdropyranyloxy, tert-butoxy, tri (lower) alkylsilyloxy, such as trimethylsilyloxy, and the like. Any conventional ether protecting group may be used to protect the terminal hydroxyl group that may be present in R ₁₃ . On the other hand, the reactions described in Reaction Scheme 2 can be carried out without any protection of the terminal hydroxyl group.

In the first step of this process, a compound of formula XXII is reacted with a compound of formula XIX to form a compound of formula XXIII. Any method of coupling an amine with an acid halide can be used to effect this reaction. In the next reaction step, a compound of formula XXIII is converted to a compound of formula XXIV (see reaction step (η)) by treating the compound of formula XXIII with a reducing agent. Any conventional alkali metal aluminum hydride reducing agent may be used in the reaction, with lithium aluminum hydride being the preferred reducing agent. This reaction can be carried out under any of the conditions commonly used in the reduction with an alkali metal aluminum hydride reducing agent.

The compound of formula XXIV can then be converted to a compound of formula XXVI via an intermediate of formula XXV. In the first step of this process (step (o)), a compound of formula (XXIV) is converted to a phosphonium salt of formula (XXV) by reaction with a triarylphosphine hydrohalide using the procedure described above for step (b). The compound of formula XXV is then converted to the compound of formula XXVI in reaction step (p) by reaction with an aldehyde of formula VII (see Scheme 1). Reaction step (p) to produce the compound of formula XXVI consists in a Wittig reaction carried out in the same manner as described above for reaction step (i). Optionally, the compound of formula XXVI wherein R 8 is lower alkyl may be converted to the corresponding free acid by conventional basic hydrolysis. Any conventional base ester hydrolysis method can be used to convert the compound of Formula XXVI to the free acid. The compound of formula XXVI in which it contains a terminal hydroxyl group etherified with a conventional ether protecting group can in turn be converted to the free alcohol by acid hydrolysis. Any conventional method of hydrolysis of ethers can be used to effect this reaction. The hydrolysis of the ether derivative of formula (XXVI) may be carried out either before or after acid hydrolysis for the hydrolytic cleavage of the ester protecting group Rg. If the radical R1 in the compound of formula X in Reaction Scheme 1 contains an etherified hydroxyl group, the compound of formula X can be hydrolyzed in the same manner as the compound of formula XXVI.

Alternatively, the compound of formula XXIV can be converted to a tertiary amine of formula XXXI. In this conversion, a compound of formula XXIV in reaction step (q) is reacted with an acid halide of formula XIX-A to form a compound of formula XXVII. This reaction is carried out in the same manner as described above for the reaction of a compound of formula XXII to a compound of formula XXIII.

The compound of formula XXVII is reacted in reaction step (r) to the compound of formula XXIX by reaction with lithium aluminum hydride as a reducing agent as described above in connection with reaction step (n).

In the next step of this reaction scheme, a compound of formula XXIX is converted to a compound of formula XXX (see reaction step (s)) by reaction with a triarylphosphine hydrohalide. This reaction is carried out in the same manner as described above in connection with reaction step (b). The compound of formula XXX is converted to the compound of formula XXXI in reaction step (t) by reaction with a compound of formula VII (see Reaction Scheme 1). The reaction in the sense of reaction step (t) consists in a Wittig reaction. Reaction step (t) may be carried out in the same manner as described above in connection with reaction step (i). Optionally, the compound of formula XXXI in which R8 is lower alkyl may be converted to the corresponding compound of formula XXXI containing a free acid group by basic hydrolysis. If the radical contains a terminal hydroxyl group protected in the form of a hydrolyzable ether, such a compound of formula XXXI can be converted to the corresponding compound having a free hydroxyl group in the radical R _{4 by} conventional hydrolysis of the ether moiety. The hydrolysis of the ether moiety can be carried out before or after the hydrolysis of the ester group R @ 8.

When in Scheme 2, R _{2 is a} hydroxyl group, it is preferred to protect the hydroxyl group with an ester protecting group. This ester protecting group can be cleaved again after formation of the Wittig salt of formula XXX.

Those compounds of formula (I) wherein X is - (1 H-) are prepared from a compound of formula (XXXV) R 6

in which

Z represents an ether radical, a bromine atom or an iodine atom,

R 8, R ₃ and R 8 are as defined above and

R 8 Q represents a hydrogen atom or a lower alkyl group according to Reaction Scheme 3.

In the formula of the Reaction Scheme 3 are Rg, R _2, Rg, R, R y, R _g, R ', RgQ, RGG, Y, Z' and Z are as defined above.

According to Reaction Scheme 3, a compound of formula XXXV is first reacted with a compound of formula XXXIV in reaction step (u) to form a compound of formula XXXVI. This procedure consists of a Wittig reaction. In the compound of formula XXXVI, Rgg may optionally be -CH ₂ - (CH ₂ ) 4 -OH, in which the free hydroxyl group may optionally be protected by conversion to any of the aforementioned conventional ether groups. However, it has been found that in the present case it is not necessary to protect this free hydroxyl group by conversion to ether. In carrying out the reactions of Scheme 3, this free hydroxyl group is not attacked in the reactions by which a compound of Formula XXXVI is converted to a compound of Formula XXXXI. However, in order to obtain the best yields, it is generally preferred to protect this hydroxyl group by forming a hydrolyzable ether moiety.

The reaction according to reaction step (u) consists in a Wittig reaction between a compound of formula XXXV and a compound of formula XXXIV using the same reaction conditions as described above in relation to reaction step (i).

The compound of formula XXXVI can be converted into the compound of formula XXXVII by hydrogenation in step (v). This reaction can be carried out using any of the hydrogenation methods. Conventional hydrogenation methods include treating a compound of formula XXXVI in an inert organic solvent with hydrogen in the presence of a catalyst. Any conventional hydrogenation catalyst can be used in this reaction, one of the preferred catalysts being palladium. This reaction may be carried out using any conventional inert organic solvent. Further, any reaction conditions customary for catalytic hydrogenations can be used in the reaction of step (v).

In the next step of the process, a compound of formula XXXVII is converted to a compound of formula XXXIX (see reaction step (w)) by reacting a compound of formula XXXVII with formaldehyde or a formaldehyde-releasing compound. In carrying out this reaction, a compound of formula XXXVII is first converted to a metal derivative by treatment with an alkali metal alkali derivative such as n-butyllithium. Generally, this reaction is carried out in an inert organic solvent, such as an ether solvent. Preferred solvents are diethyl 256392 ether and tetrahydrofuran. Temperature and pressure are not critical to the reaction. The reaction can be carried out at room temperature and at atmospheric pressure. If desired, higher and lower temperatures can be used. After reaction of the compound of formula XXXVIII with an alkali metal alkyl derivative, formaldehyde or formaldehyde-releasing compound is added to the reaction medium. Any conventional formaldehyde-releasing compound, such as paraformaldehyde, may be used for this purpose. This reaction is carried out in the same reaction medium and under the same conditions as the metallation of the compound of formula XXXVIII.

The compound of formula XXXIX is converted to the compound of formula XXXX in reaction step (x) by reacting the compound of formula XXXIX with a triarylphosphine hydrohalide. This reaction is carried out in the same manner as described above in connection with reaction step (b). The compound of formula XXXX is converted to the compound of formula XXXXI in reaction step (s) by reaction with a compound of formula VII [see Scheme 1]. This reaction in the sense of step (y) consists of a Wittig reaction carried out under the same conditions as described in relation to reaction step (i). The compound of formula XXXXI can be converted to the corresponding compound containing a free carboxyl group instead of the radical R '. This reaction is a conventional ester hydrolysis by the method described above, but any conventional ester hydrolysis method may be used. If the residue contains a terminal hydroxyl group protected with an ether protecting group, this ether group can be hydrolytically cleaved to form a free hydroxyl group using conventional hydrolysis of ethers such as aqueous inorganic acid. Any conventional method of hydrolysis of ethers can be used for this purpose. The ether-protected hydroxyl group can be hydrolyzed either before or after hydrolysis of the ester group to give the compound of formula XXXXI as the free acid.

In order to obtain compounds of formula I in which X is -C CHCH-, the compound of formula XXXV in Scheme 1 is reacted in reaction step (u) with a compound of formula XXXIV, where R ^ is, form compounds of formula XXXVI wherein R ₁₃ represents a radical the compound of formula XXXVI, wherein R ₃ represents a radical R₁, is then subjected to the same series of reactions as the compound of formula XXXVII, i. reaction steps (w), ( x) and (y) to form compounds of formula I wherein

X is a residue

-C = CH1

When R ₂ of compound of formula XXXV in Scheme 3 is a hydroxyl group, it is preferable to protect this hydroxyl group esterification of a lower alkanoic acid. This ester protecting group can be cleaved to form the Wittig salt of formula XXXX. '

Compounds of formula I above and important intermediates of formula II

in which the formulas are as defined, X is a residue and the remaining formulas are to be prepared from the compound of formula L above ^R 10 above.

in which

R p R ₂ , R 4 and Z are as defined above, according to the process of Flow Diagram 4.

In the formulas shown in Reaction Scheme 4, the symbols r 1, R ₂ , R g, r ₂ , R g, r ',

Y and Z are as hereinbefore defined and R is a radical R _4, wherein the hydroxyl group contained in the radical R @ j is protected in the form of a hydrolyzable ether group, a tetrahydropyranyl group, as well as any other ether groups mentioned above.

The compound of formula L is converted to the compound of formula LI by treatment with an alkali metal alkoxide of formula L-A. This reaction is carried out by treating a compound of formula L with a compound of formula L-A under conditions commonly used in the reaction of an alkali metal alkoxide with a halide.

In the next step, the compound of formula LI is converted to a compound of formula LII by first treating the compound of formula LI with an alkyl lithium such as n-butyllithium, thereby metallating the compound of formula LI. The metallized compound of formula LI is then reacted with formaldehyde or a formaldehyde-releasing compound. When converting a compound of formula LI to a compound of formula LII, the same reaction conditions as described for reaction step (w) are used. The compound of formula LII is converted to the compound of formula LIII by reaction with triarylphosphine hydrohalide as described in reaction step (b) above. The phosphonium salt of formula IIIa is subjected to a Wittig reaction with a compound of formula VII (see Scheme 1) to give a compound of formula LIV. This reaction, resulting in the formation of the compound of formula LIV, is carried out in the same manner as described above in connection with reaction step (i).

When R ₁₅ in the compound of formula (LIV) contains a protected hydroxyl group, it can be subjected to hydrolysis by conventional methods of hydrolyzing readily cleavable ether groups to give a compound with a free hydroxyl group. Any conventional method of hydrolyzing ether protecting groups can be used for this purpose. The conditions commonly used to hydrolyze ether protecting groups do not affect the other ether group contained in the compound of formula LIV. The compound of formula LIV can be converted to the corresponding free acid by conventional ester hydrolysis.

If the symbol R ₂ in the compounds of formulas L, LI, LII and LIII is hydroxy, it is preferable to protect this hydroxyl group with hydrolyzable ester groups, such as lower alkanoyloxy. The hydrolyzable ester protecting group may be cleaved after formation of the Wittig salt of formula (III).

The double bonds at positions 2, 3, 4, 5, 6, 7 and 8, 9 in the compound of formula I may, if desired, be either of the cis- or trans-configuration. However, the compounds may also exist in the form of a mixture of different cis and trans isomers. In the compound of formula VII, the double bonds may be present either in the cis- or trans-configuration, depending on the desired arrangement of the double bonds in the compounds of formula I. In the Wittig reaction carried out in the preparation of the compounds of formulas I and II (i) and the like, a double bond is formed at the 8, 9 position as a mixture of 8,9-cis- and -trans-isomers. These cis and trans isomers may be separated by conventional means, such as fractional crystallization and the like.

Further, when the compounds of formula I contain a double bond in the trans-configuration at position 2,3, this isomer can be converted to the corresponding cis-double-bonded compound by conventional isomerization techniques known in the art. These techniques include the action of iodine in an inert organic solvent on the corresponding compound of formula (I) by isomerization with iodine to give a compound of formula (I) with a double bond in position

2.3 with cis configuration.

The compounds of formula I include all geometric isomers including mixtures of these geometric isomers.

The compound of formula XI in which R1 is a fluorine atom is a novel compound and can be prepared from a compound of formula LV

in which

And R ₂ have the above meanings.

Reaction Scheme 5 wherein R² _2, R and R as defined above.

According to Reaction Scheme 5, a compound of formula LV is alkylated by reaction with allyl bromide. When a compound is desired in which R ₂ represents a hydroxyl group is used as starting material a compound of formula LV, where the hydroxyl group represented by R ₂ is protected by esterification, i.e. a compound of formula LV, where R ₂ is a protected hydroxyl group. Any suitable method of alkylating a hydroxyl group with an allyl bromide can be used to effect the reaction of converting a compound of formula LV to a compound of formula LVI. The compound of formula LVI is then switched to a compound of formula LVII by heating to a temperature of 190 ° C to 230 ° C. This rearrangement may occur without the use of a solvent or in the presence of a higher boiling hydrocarbon solvent. When R ^ represents a hydrogen atom, a compound of formula LVII is obtained as a mixture with an isomeric compound corresponding to formula LVII in which the allyl group is in para-position to the fluorine atom on the benzene ring. This isomer may be separated or subjected to the following reactions and separated from the reaction mixture at a later stage.

The compound of formula LVII is then converted to the compound of formula LVIII by reaction with a compound of formula V. (Scheme 1) as described in step (f). In the next step of the reaction scheme, compound LVIII is converted to compound LIX by isomerization with a strong base such as an alkali metal alkoxide in the presence of an inert organic solvent, preferably potassium tert-butoxide in dimethylsulfoxide. The compound of formula LIX is converted to the compound of formula LX by ozone treatment. The reaction is carried out at a temperature of from -70 ° C to -20 ° C while operating in an inert organic solvent. Any conventional inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, may be used for this purpose.

The compound of formula (LX) is a compound of formula (XI) wherein R 1 is fluorine. This compound can be converted to compound X in accordance with Reaction Scheme 1.

When R ₂ is a hydroxyl group are in the compound of formula III presence of two hydroxyl groups. It is therefore generally preferred to prepare a compound of formula XI wherein R ₂ is a protected hydroxyl group, the compounds of formula LXI procedure according to reaction scheme 6. In this way, compounds of formula I wherein X is -0-, R ₂ represents a hydroxyl group and R1 and R2 are as defined above. In Reaction Scheme 6, R 6 and R 6 together with the attached oxygen atom represent a hydroxyl group protected by a conventional hydrolysable protecting group, preferably a lower alkanoyl group.

According to Reaction Scheme 6, a compound of Formula LXI is converted to a compound of Formula LXII using the same reaction described for the conversion of a compound of Formula LV to a compound of Formula LVI (Reaction Scheme 5). The compound of formula LXII is then converted to a compound of formula LXIII using the same procedure as described for the conversion of a compound of formula LVI to a compound of formula LVII. In the following steps, the compound of formula LXIII is converted to the compound of formula LXIV in the same manner as described for step (д ') in Reaction Scheme 5, and then to the compound of formula LXV as described for step (h ") in The conversion of a bromobenzene derivative of formula LXV to a phenolic compound of formula LXVI is carried out by procedures well known in the art, such as that described by Kidwell and Darling, Tetrahedron Letters, (1966), pp. 531-535.

The next step in preparing the intermediate of the formula XI wherein R ₂ is a protected hydroxyl group, i.e. compounds of general formula XI-A, the hydroxyl group in the compound of formula LXVI protected by esterification by any conventional hydrolyzable ester group to give a compound of formula LXVII in wherein R ₂ together with the bound oxygen atom form a hydrolyzable ester group. Any conventional method of esterifying hydroxyl groups with organic acids, such as lower alkanoic acids containing 1 to 7 carbon atoms, can be used to prepare the compound of Formula LXVII. The compound of formula XI-A is prepared from a compound of formula LXVII by the reaction described above in connection with the conversion of a compound of formula LIX to a compound of formula LX (see Scheme 5). .

When converting a compound of Formula XI-A to a compound of Formula XVII as described in Reaction Scheme 1, it is generally preferred to hydrolyze the ester substituent forming the R ₂ moiety to form the Wittig salt of Formula XIII or XVI.

In accordance with another embodiment of the invention, a compound of formula XI wherein the trifluoromethyl group (i.e., a compound of formula XI-B) can be prepared by reaction of Scheme 7 from a compound of formula LXX. In the first reaction step of this process, the compound of formula LXX is converted to a compound of formula LXXI using the same procedure described above for the reaction of step (f) wherein the compound of formula III is reacted with a compound of formula V to give a compound of formula XI in this reaction, in case that R ₂ represents a hydroxy group, alkylation takes place on the hydroxyl group in the ortho position к CF ^ very slowly. Thus, this group does not necessarily need to be protected, as the alkylation takes place preferably at the hydroxyl group in the meta-position. Mixtures of alkylated products resulting from this reaction can be separated by conventional separation techniques. The compound of formula LXXI is converted to the compound of formula XI-B by conventional formylation of the benzene ring, such as by treatment with alkyl lithium and dimethylformamide.

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 (VII)

OHC - (- C = CH-CH = CH-) - C = CH-C-OR 'g (VII') is reacted with a compound of formula XVI

(XVI ') where man / have a value of 0 or 1, with the sum of m + n' always equal to 1, and if m has a value of 0, X is -O-,

R ^, Rg, R ^, R ^, R?, Rq and X are as defined above,

R 'represents an alkyl group having 1 to 7 carbon atoms,

Y represents an aryl radical such as a phenyl radical and

Z 'is a halide ion, whereupon the optionally alkyl ester group -COOR' in the resulting product is converted to a free carboxyl group, and the product of formula I in which it is a free carboxyl group is optionally converted to a pharmaceutically acceptable salt thereof.

The invention is illustrated by the following non-limiting examples. The term ether in these examples refers to diethyl ether and the solvents are evaporated under vacuum.

Example 1 / [2- (nonyloxy) phenyl] methyl / triphenylphosphonium bromide

110 g of 2-hydroxybenzaldehyde are alkylated by mixing with 180 g of 1-bromononane, anhydrous potassium carbonate and 800 ml of dimethylformamide. The mixture was heated at 80 ° C for 14 h. Hexane and water were added, the hexane extract was concentrated and the residue was distilled. 210 g of 2-nonyloxybenzaldehyde having a boiling point of 121 DEG C./40 mbar are obtained.

A solution of 100 g of the above-prepared 2-nonyloxybenzaldehyde in 1000 ml of ethanol at 10 ° C is reduced by adding 6 g of sodium borohydride (excess). The mixture was stirred at room temperature for 15-20 minutes, and the resulting 2-nonyloxybenzyl alcohol was isolated by extraction with hexane. Evaporation of the hexane in vacuo gave 98 g of crude 2-nonyloxybenzyl alcohol. The resulting 2-nonyloxybenzyl alcohol was added to a mixture of 144 g of triphenylphosphine hydrobromide and 500 ml of acetonitrile, and the solution was heated under reflux for 14 hours. The solvent was evaporated in vacuo and the residue was crystallized from a mixture of tetrahydrofuran and ethyl ether. 208 g of pure [2- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide are obtained.

Example 2 f (2-Hydroxyphenyl) methyl] triphenylphosphonium bromide

The 2-hydroxybenzyl alcohol was treated as described in Example 1 with triphenylphosphine hydrobromide in acetonitrile to give β (2-hydroxyphenyl) methyl] triphenylphosphonium bromide.

Example 3

(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 at -35 ° C was treated with a solution of n-butyllithium in hexane (2.1 mol equivalents) to the ylide which was reacted with 1 mol of 7-formyl- ethyl ester. 3-methyl-2,4,6-octatrienoic acid. The reaction mixture was stirred at -70 ° C for 15 min. The organic products were isolated using hexane / ethyl acetate (4: 1) and treated with dilute mineral acid (2M aqueous hydrochloric acid) after crystallization from the mixture. of dichloromethane and hexane gives, in 90% yield, pure (E, E, E, E) -9- (2-hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester.

Example 4

(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 for 30 minutes. to reflux, 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 to give (E, E, E, E) -9- (2-hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester at 38% yield. mp 143-145 ° C.

Example 5 '(E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

A solution of 150 g of [[2- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide in 1100 mL of tetrahyrofuran is cooled to -50 ° C to give a fine suspension of the solid salt, to which 180 mL of a 1.6 M n-butyllithium in hexane solution is added. forming a ylide solution. The mixture was stirred at -40 ° C for 15 minutes, then cooled to -70 ° C and 65 g of 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester dissolved in 250 mL of tetrahydrofuran was added. . Hexane and 40% aqueous methanol were added to the reaction mixture, and the hexane extract was concentrated. 64 g (58% yield) of (E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester of melting point are obtained. 52-53 ° C.

This ester is subjected to hydrolysis 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 to the solution and mixing the mixture. Heat to reflux 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 6 (E, E, E, E) -3,7-dimethyl-9- [2 - [(2,2-dimethyloctyl) oxy] phenyl] -2,4,6,8-nonatetraenoic acid

In an analogous manner to Example 1, 2-hydroxybenzaldehyde is condensed with 2,2-dimethyl-1-iodooctane to give 2- (2,2-dimethyloctyloxy) benzaldehyde, which is reduced to 2- (2,2-dimethyloctyloxy) benzyl alcohol, which is then converted to [2- (2,2-dimethyloctyloxy) phenyl] methyl] triphenylphosphonium bromide. Condensation of this phosphonium bromide with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 followed by hydrolysis as in Example 5 affords (Ε, Ε, Ε, E) -3,7-dimethyl -9- [2 - [(2,2-dimethyloctyl) oxy] phenyl] -2,4,6,8-nonatetraenoic acid melting after crystallization from a mixture of dichloromethane and hexane at 113-117 ° C.

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

Lithium octanoate, prepared from octanol and n-butyllithium, is condensed with 2-bromobenzyl bromide in a mixture of tetrahydrofuran, hexane and dimethylformamide to give 2- (octyloxy) methylbromobenzene. This material was first treated with n-butyllithium in a mixture of ether and hexane, and then paraformaldehyde to give 2- (octyloxy) methylbenzyl alcohol. This intermediate is reacted with triphenylphosphonium bromide to convert to? - 2- (octyloxy) methyl] phenyl] methyl] triphenylphosphonium bromide. Condensation of this material with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as in Example 3 followed by hydrolysis as in Example 5 affords (E, E, E, E) -3,7-dimethyl- 9- [2- (octyloxy) methyl] phenyl] -2,4,6,8-nonatetraenoic acid melting after crystallization from a mixture of dichloromethane and hexane at 120-121 ° C.

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

2-Chloro-6-hydroxybenzaldehyde is alkylated with 1-bromnonanane according to the procedure of Example 1 to give 2-chloro-6-nonyloxybenzaldehyde. Reduction of this material with sodium borohydride as in Example 1 afforded 2-chloro-6-nonyloxybenzyl alcohol, which, by treatment with triphenylphosphine hydrobromide in acetonitrile as in Example 1, afforded 2-chloro-6- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide. This intermediate was condensed with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 to give (E, E, E, E) -9-? 2-chloro-6- ethyl ester (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. This ester was converted to (E, E, E, E) -9- (2-chloro-6- (nonyloxy) phenyl) -3,7-dimethyl-2,4,6,8-nonatetraene by hydrolysis as in Example 5. an acid melting after crystallization from a mixture of ethyl acetate and hexane at 129-131 ° C.

Example 9 (E, E, E, E) -9- (5-methoxy-2-nonyloxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

The 5-methoxy-2-hydroxybenzaldehyde is alkylated with nonyl bromide and reduced with sodium borohydride as in Example 1 to give 5-methoxy-2-nonyloxybenzyl alcohol which, by treatment with triphenylphosphine hydrobromide, yields β (5-methoxy-2-nonyloxyphenyl) methyl] triphenylphosphonium bromide. Condensation of this material with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as in Example 3 followed by hydrolysis as in Example 5 affords (E, E, E, E) -9- (5-methoxy -2-nonyloxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid melting after crystallization from methanol at 125-126 ° C.

Example 10.

(E, E) -? - 5- (2-nonyloxyphenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium bromide g 2- (nonyloxy) benzaldehyde, dissolved in 500 ml acetone, was reacted with 100 ml of acetone at room temperature for 18 hours ml of 1M aqueous sodium hydroxide solution. A mixture of sodium chloride solution and a mixture of equal volumes of ethyl acetate and hexane was added to the reaction mixture, the organic phase was concentrated and the residue was crystallized from hexane. 53 g of 4- (2-nonyloxyphenyl) -3-buten-2-one are obtained.

A solution of 58 g of 4- (2-nonyloxyphenyl) -3-buten-2-one in 200 ml of tetrahydrofuran at temperature

-30 ° C was added to 200 mL of a 1.6 M solution of vinylmagnesium bromide in tetrahydrofuran diluted with additional tetrahydrofuran to 1000 mL. After the addition was complete, the mixture was stirred at 0 ° C for 30 minutes, then 100 mL of saturated aqueous ammonium chloride solution and 2 L of ether were added and the resulting mixture was filtered to remove solids. Concentration of the organic extract and purification of the residue by silica gel chromatography gave 40 g of oily (E) -5- (2-nonyloxyphenyl) -3-hydroxy-3-methyl-1,4-pentadiene.

A solution of 66 g of (E) -5- (2-nonyloxyphenyl) -3-hydroxy-3-methyl-1,4-pentadiene in 250 ml of acetonitrile is added to a suspension of 66 g of triphenylphosphine hydrobromide in 300 ml of acetonitrile at 10 ° C. . After warming to room temperature, the mixture was stirred at this temperature for 2 hours, then the solution became a solution. This solution is extracted twice with 250 ml of hexane each, the acetonitrile layer is concentrated to a volume of about 400 ml and cooled to -10 ° C. The solid product was filtered off and washed with acetonitrile and hexane to give 21 g of pure (E, E) [5- (2-nonyloxyphenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium bromide.

Example 11

The procedure of Example 5 was followed using (E, E) - [5- (2-nonyloxyphenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium bromide as the starting material. The Ylide was reacted with 3-formyl-2-butenoic acid ethyl ester and purified by chromatography on silica gel and hydrolyzed with aqueous ethanolic potassium hydroxide solution as in Example 5 to give (E, E, E, E) -9- (2-nonyloxyphenyl) 13,7-dimethyl-2,4,6,8-nonatetraenoic acid.

Example 12 (Z, E, E, E) -9- [2- (nonyloxy) phenyl-] 3,7-dimethyl-2,4,6,8-nonatetraenoic acid g ethyl ester (E, E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid is dissolved in 200 ml of hexane containing 0.5 g of iodine and the resulting solution is stirred at room temperature for 30 minutes. rooms. The hexane is freed from iodine by washing with 10% (w / w) aqueous sodium thiosulfate solution, dried and concentrated. A mixture of isomeric compounds differing in the double bond configuration is obtained. Separation by silica gel chromatography gave 1.5 g of (Z, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester in net condition. This product provides pure (Z, Ε, Ε, Ε) -9- (η 2- (nonyloxy) phenyl) -3,7-dimethyl-2,4,6,8 by refluxing under refluxing aqueous ethanolic potassium hydroxide solution. -nonatetraenoic acid, m.p. 135-136 ° C.

Example 13 (E, E, E, Z) -9- [12- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

The material from the mother liquors resulting from the crystallization of (E, Ε, Ε, Ε) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester in Example 5 consists of: mixtures containing different isomers. After purification by chromatography, an ethyl ester of 80% purity is obtained which, after hydrolysis carried out as in Example 5, yields pure (Ε, Ε, Ε, Z) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2. 4,6,8-nonatetraenoic acid, m.p. 105-109 ° C.

Example 14

2-Decyl-1-bromobenzene

0.1 mole of nonylmethyl-triphenylphosphonium bromide in 200 ml of tetrahydrofuran was converted to the ylide at -10 ° C by treatment with 0.1 mole equivalent of n-butyllithium (1.6M hexane).

To the mixture was added 2-bromobenzaldehyde (0.09 mol) in tetrahydrofuran (25 ml) and after stirring at 0 ° C for another 30 minutes, hexane and aqueous methanol (40:60) were added. The hexane extract is concentrated and the residue is distilled to give 2- (1-decenyl) -1-bromobenzene in 90% yield.

This material was dissolved in the hexane contents. 10% palladium on carbon catalyst and hydrogenated at room temperature to normal; n pressure until saturation of the olefinic bond. The solids were filtered off, the hexane was evaporated and the residue distilled. Yield: 80% pure 2-decyl-1-bromobenzene, b.p. 120 DEG C./0.1 mbar.

Example 15

2-decyl-l-hydroxymethylbenzene _t

To 0.1 mol of 2-decyl-1-bromobenzene dissolved in 150 ml of ether was added 0.11 equivalents of n-butyllithium (1.6M in hexane) and the mixture was stirred at room temperature for 2 hours.

After addition of 0.2 mole equivalent of dry paraformaldehyde, the mixture was stirred at room temperature for an additional 18 hours, water was added and the reaction mixture was extracted with ether. The ether extracts were dried, concentrated and the residue chromatographed. Pure 2-decyl-1-hydroxymethylbenzene is obtained in 75% yield.

Example 16 (E, E, E, E) -9- (decylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

Following the procedure of Example 1, 2-decyl-1-hydroxymethylbenzene was converted to the phosphonium salt by treatment with triphenylphosphonium bromide in acetonitrile. This salt is treated as above with n-butyllithium in tetrahydrofuran and then, as above, reacted with 7-formyl-3-methyl-2,4,6-heptatrinic acid methyl ester.

The crude condensation product is purified by silica gel chromatography and then subjected to basic hydrolysis to give pure (Ε, Ε, Ε, Ε) -9- (decylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraene acid melting after crystallization from a mixture of hexane and ether at 107-108 ° C.

Example 17

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

To 1 mol of 2-aminobenzyl alcohol at 0 ° C was added 2.2 mol of octanoyl chloride in a mixture of dichloromethane and triethylamine. After reaction for 30 minutes at 10 ° C, the mixture was washed with water and the ether was distilled off. The crude residue was dissolved in 2000 mL of tetrahydrofuran, 1500 mL of 1N aqueous sodium hydroxide was added to the solution, and the mixture was stirred at room temperature for 3 hours. After addition of water and ether, the crude work-up gives crude hydroxymethyl-octylamide which, after purification by chromatography, yields 85% pure octylamide.

100 g of this material was dissolved in 500 ml of tetrahydrofuran and added to a suspension of 2 mol equivalents of lithium aluminum hydride in 1000 ml of tetrahydrofuran. The mixture was heated at reflux for 8 hours, then cooled to 0 ° C and 100 ml of aqueous sodium sulfate solution were added.

The solids were filtered off, the solvents were evaporated in vacuo and the residue was purified by silica gel chromatography to give 75 g of pure 2-hydroxymethyl-N-octylaniline.

This material was dissolved in 300 ml of acetonitrile containing 1.1 equivalents of triphenylphosphine hydrobromide, heated at reflux for 24 hours, and then concentrated. The residue was digested with ether to give the desired phosphonium salt as a white solid.

This salt is converted to the corresponding ylide by adding 1.5 mol equivalents of n-butyllithium and stirring at 0 ° C for 1 hour, to which 1.6 mol equivalents of 7-formyl-3-methyl-2,4,6-heptatrienoic acid ethyl ester is added. in tetrahydrofuran and the mixture was stirred at 10 ° C for 1 hour.

Addition of hexane and aqueous methanol (2: 3) and removal of hexane in vacuo gave a crude condensation product which, after purification by chromatography on silica gel and crystallization from hexane, afforded 25% pure ethyl ester (E, E, E, E). 1-9- (2-octylaminophenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, m.p. 38-40 ° C.

Example 18

2-fluoro-6-nonyloxybenzyl alcohol

To a solution of 100 g of 3-fluorophenol in 1000 ml of dimethylformamide containing 165 g of potassium carbonate was added 115 g of allyl bromide and the mixture was heated at 80 ° C for 18 hours.

After addition of water and hexane, the hexane extracts are washed with 5% aqueous sodium hydroxide solution, saturated sodium chloride solution and concentrated to give 155 g of the desired allyl ether. 134 g of this material was heated at 220 ° C for 16 hours to give a mixture of 3-fluoro-2- (2-butenyl) phenol and 5-fluoro-2- (2-butenyl) phenol. Směs This mixture was dissolved in 2000 ml of dimethylformamide containing 170 g of 1-bromononane and 150 g of potassium carbonate and the solution was heated to 80 ° C for 16 hours. Dilution with water, extraction with hexane and concentration of the extracts gave a mixture of products which, by distillation, yielded 186 g of a mixture of 3- (2-fluoro-6-nonyloxy) phenyl] butene and 3- (3-fluoro-2-nonyloxy) phenyl] butene boiling at 120 to 125 ° C / 13 Pa.

185 g of this mixture of isomers are left at room temperature for 6 hours in 1000 ml of dimethylsulfoxide containing 1.5 g of potassium tert-butoxide. Addition of water and extraction with hexane gave a mixture of 1- [(2-fluoro-6-nonyloxy) phenyl] butene and 1- [3-fluoro-2-nonyloxy) phenyl] butene.

175 g of this mixture of isomers is dissolved in 2000 ml of a 9: 1 mixture of dichloromethane and methanol and a stream of ozone is introduced into the solution at -40 DEG C. for 8 hours. After this time, the reaction mixture was poured into a mixture of water, hexane and dimethylsulfoxide (100 mL) and stirred at room temperature for 1 hour.

The hexane extract was washed with water, dried over magnesium sulfate, an additional 50 mL of dimethylsulfide was added and the mixture was allowed to stand at room temperature for 16 hours. After evaporation of the solvents, 155 g of a mixture of aldehydes, i.e. 2-fluoro-6-nonyloxybenzaldehyde and 4-fluoro-2-nonyloxybenzaldehyde, are obtained.

To 150 g of this mixture of aldehydes in 2000 ml of ethanol, 15 g of sodium borohydride was added at 5 ° C, and the resulting mixture was stirred at room temperature for 30 minutes. Water (500 ml) and brine (500 ml) were added to the reaction mixture, and the alcohol mixture was extracted with hexane. Evaporation of the solvents and chromatography of the residue on silica gel using hexane with 5% ethyl acetate as eluent gave 76 g of pure 2-fluoro-6-nonyloxybenzyl alcohol.

Example 19 (E, E, E, E) -9- [2-fluoro-6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

A mixture of 2-fluoro-6-nonylbenzyl alcohol (19 g) and triphenylphosphine hydrobromide (26 g) was refluxed in acetonitrile (250 ml) for 14 hours and then concentrated to dryness to give 42 g of 2-fluoro-6-nonyloxy. (phenyl) methyl] triphenylphosphonium bromide. This phosphonium salt was dissolved in 600 mL of tetrahydrofuran, cooled to -50 ° C, and 45 mL of 1.6 M n-butyllithium in hexane was added. After stirring for 15 minutes at -50 ° C, it is added

8.4 g of 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester, warm the reaction mixture to room temperature and stir for an additional 15 minutes. After addition of hexane, the mixture was washed with water and 40% aqueous methanol, dried over magnesium sulfate, the hexane extract was concentrated and the residue purified by chromatography using 5% ether in hexane as eluent. 11 g of pure trans-isomer are obtained.

After crystallization from a mixture of hexane and ethyl acetate, 9.5 g of (E, E, E, E) -9- [2-fluoro-6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6-ethyl ester are obtained. , 8-nonatetraenoic acid.

To a solution of 6.5 g of this ester in 150 ml of ethanol was added a solution of 7 g of potassium hydroxide in 40 ml of water, and the mixture was heated under reflux for 1 hour. The cooled reaction mixture was poured into cold aqueous hydrochloric acid and the acidic mixture was extracted with chloroform. Evaporation of the solvents and recrystallization of the residue from hexane-ethyl acetate gave pure (Ε, Ε, Ε, Ε) -9- (2-fluoro-6- (nonyloxy) phenyl) -3,7-dimethyl-2,4,6 8-nonatetraenoic acid, m.p. 107-109 ° C.

Example 20 '

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-nonatetraenoic 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 capsule filling weight 300 mg 300 mg 300 mg

Method:

1) mixing components 1 to 3 in a suitable mixer

2) Add talc and magnesium stearate and mix briefly

3) the capsules are filled using a suitable device.

Example ₍ ad 21

Similar capsules are prepared according to the procedure of Example 20 except that (Ε, Ε, Ε, Ε) -9- (2-fluoro-6- (nonyloxy) phenyl) -3 is used as the active ingredient (Component No. 1). 7-dimethyl-2,4,6,8-nonatetraenoic acid.

Example 22 ’.

This example describes the preparation and composition of the composition in the form of tablets (wet granulation).

No. Ingredient mg / tablet mg / tablet mg / tablet

1 (E, E, E, E) -9-f2- - (nonyloxy) phenyl] - -3,7-dimethyl-2,4,6,8-nonatetraenoic acid 100 ALIGN! 250 500 2 lactose 98.5 147.5 170 3 polyvinylpyrrolidone 15 Dec 30 40

continued table

C. Component mg / tablet mg / tablet mg / tablet 4 modified starch 15 Dec 30 40 5 cornstarch 15 Dec 30 40 6 magnesium stearate 1.5 2.5 5 tablet weight 45 mg 4 90 mg 79 5 mg

Method:

1) The components 1, 2, 4 and 5 are mixed in a suitable mixer, the mixture is granulated using polyvinylpyrrolidone dissolved in aqueous alcohol, the granulate is dried and ground in a suitable mill.

2) Magnesium stearate is added and tablets are compressed from the mixture on a suitable press.

Example 23

Similar tablets were prepared in an analogous manner to Example 22 except that (E, E, E, E) -9- (2-fluoro-6- (nonyloxy) phenyl) -3 was used as the active ingredient (component 1). 7-dimethyl-2,4,6,8-nonatetraenoic acid.

Example 24

This example describes the preparation and composition of the composition in the form of tablets (direct compression).

Ingredients;

C. Component mg / tablet mg / tablet mg / tablet 1 (E, E, E, E) -9- - (nonyloxy) phenyl] - -3,7-dimethyl-2,4,6,8-nonatetraenoic acid 15 Dec 30 60 2 lactose 207 192 162 3 avicel 45 45 45 4 starch for direct pressing 30 30 30 5 magnesium stearate 3 3 tablet weight 300 mg 300 i 300 mg

Method:

1) Component 1 is mixed with an equal amount of lactose and mixed thoroughly.

2) Add components 3 and 4 and the remaining amount of component 2. Mix thoroughly.

3) Add magnesium stearate and mix for 3 minutes.

4) Tablets are compressed from the mixture using a suitable punch.

Example 25

This example describes the composition and preparation of capsules.

Ingredients:

C. Component mg / capsule mg / capsule mg / capsule 1 (E, E, E, E) - (3,7-Dimethyl) -9- [2- [(8-hydroxyoctyl) oxy] phenyl] -2,4,6,8-nonatetraenoic 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 capsule filling weight 300 mg 300 mg 300 mg

Method:

1) Mix components 1 to 3 in a suitable mixer.

2) Add talc and magnesium stearate and mix briefly.

3) The capsules are filled using a suitable device.

Example 26

This example describes the composition and preparation of tablets (wet granulation).

Ingredients:

C. Ingredient mg / tablet mg / tablet mg / tablet

-dimethyl 1-9- (η 2 - [(octyloxy) methyl] phenyl] -2,4,6,8-nonatetraenoic acid

250

500

2 lactose 98.5 147.5 170 3 polyvinylpyrrolidone 15 Dec 30 40 4 modified starch 15 Dec 30 40 5 cornstarch 15 Dec 30 40

continued table

No. Composition mg / tablet mg / tablet mg / tablet magnesium stearate 1.5 2.5 5 tablet weight 245 mg 490 mg 795 mg

Method:

1) Components 1, 2, 4 and 5 are mixed in a suitable mixer and the mixture is granulated using polyvinylpyrrolidone dissolved in aqueous alcohol. The granulate is dried and the dry granulate is ground in a suitable mill.

2) Magnesium stearate is added and tablets are compressed from the mixture on a suitable press.

Example 27

CL.2-Trifluromethyl-6- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide

A mixture of 51 g of alpha, alpha, alpha-trifluoro-m-cresol, 70 g of 1-bromononane and 100 g of potassium carbonate is heated at 85 DEG C. in dimethylformamide for 48 hours. After addition of water and hexane and usual work-up, 89 g of pure (3-trifluoromethyl) phenyl-nonyl ether are obtained, boiling at 115 ° C / 13 Pa.

g of this product was treated with 233 ml of 1.5M n-butyllithium in hexane in 1.5 L of ether at -20 ° C, stirred at room temperature for 2 hours, then cooled to -40 ° C and added to the reaction mixture. excess dry dimethylformamide (40 mL) in 100 mL ether, warmed to 0 ° C and water was added. Extraction with hexane and silica gel chromatography using 5% ether in hexane as eluent gave 35 g of (2-trifluoromethyl-6-nonyloxy) benzaldehyde which, after reduction with sodium borohydride in ethanol using the procedure described in Example 1, and chromatography on silica gel to give 32 g of (2-trifluoromethyl-6-nonyloxy) benzenemethanol. 31 g of this material was converted to ([2- (2-trifluoromethyl-6- (nonyloxy) phenyl) methyl) triphenylphosphonium bromide) by treatment with triphenylphosphine hydrobromide using the procedure described in Example 1.

Example 28 (E, E, E, E) -9- [2- (trifluoromethyl) -6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid mmol cc 2-trifluoromethyl- 6- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide in 600 ml of tetrahydrofuran was converted to ethyl ester (Ε, Ε, Ε, Ε) by reaction with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester. 1-9 2- (Trifluoromethyl) -6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. Purification by chromatography and crystallization from hexane gave pure ethyl ester in 41% yield. 5.2 g of this ester gave 3 g of pure (E, E, E, E) -9- [2- (trifluoromethyl) -6- (nonyloxy) phenyl] -3,7-dimethyl- 2,4,6,8-nonatetraenoic acid melting after crystallization from a mixture of ethyl acetate and hexane at 135-136 ° C.

Example 29 (E, E, E, E) -9-Q- (hexyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid [N - (hexyloxy) phenyl] methyl] triphenylphosphonium bromide, prepared according to Example 1 by reaction of 2-hydroxybenzaldehyde and 1-bromohexane, as described in Example 3, converted to (E, E, E, E) -9- [2- (hexyloxy) phenyl] -1,7-dimethyl-2,4 6,8-nonatetraenoic acid melting after crystallization from ethanol at 137-138 ° C.

Example 30 [[2- (pentoxy) -5- (hydroxy) phenyl] methyl] triphenylphosphonium bromide

A solution of 1 mol of 4-bromophenol in 500 ml of tetrahydrofuran was added to a suspension of 1.17 mol of sodium hydride in 1.2 liters of dimethylformamide at 25 ° C. After the addition was complete, 1.32 mol of allyl chloride was added, the mixture was stirred at 45 ° C for a further 3 hours, and after addition of water and hexane, the product was isolated in the usual manner. By distillation, an allyl- (4-bromophenyl) ether of b.p. This material was heated with dimethylaniline at 195 ° C for 4 hours and then subjected to distillation. 0.81 mol

2-allyl-4-bromophenol.

A solution of 0.81 mol of this material in 200 ml of tetrahydrofuran was added to a mixture of 0.8 mol of 1-bromnonanane, sodium hydride (0.92 mol) and 1 g of potassium iodide in 1 liter of dimethylformamide at 25 ° C. After the evolution of hydrogen ceased, the mixture was heated at 50 ° C for 14 h, then cooled, added to excess water and extracted with hexane. Distillation yielded 256 g of nonyl- (2-allyl-4-bromophenyl) ether, b.p. 147-156 ° C / 13 Pa. 255 g of this material are heated with 2 g of potassium tert-butoxide at 35-40 ° C in 1 liter of dimethylsulfoxide and 0.5 liter of tetrahydrofuran for 2 hours. 5 ml of acetic acid and water are then added to the reaction mixture. The reaction product is isolated with hexane to give 234 g of pure 1- [2- (nonyloxy) -5- (bromo) phenyl] propene, bp 145-155 [deg.] C./13 Pa:

A solution of 0.56 mol of the above material in 600 ml of tetrahydrofuran was converted to Grignard reagent at 55 ° C for 3 hours with 1 mol of magnesium. After completion of the reaction, the mixture was cooled to 0 ° C and 0.75 mol of trimethylborate in 200 ml of ether was added. After stirring for 30 minutes at 25 ° C, the mixture was cooled to 0 ° C, poured into a mixture of 10% ammonium chloride and 500 ml of 10% hydrogen peroxide, and the resulting mixture was stirred at 25 ° C for 1 hour. Addition of water and hexane followed by evaporation of the hexane phase gave pure p- [2- (1-propenyl) -4- (nonyloxy) phenyl] phenol by chromatography of the crude product over a short column of silica gel. Yield 73 g.

Acetylation of 0.8 g of this material with acetyl chloride and triethylamine in dichloromethane gave 89- (2- (1-propenyl) -4- (nonyloxy) -1- (acetoxy) benzene) in 89% yield). 99 g of this material is dissolved in a mixture of 150 ml of methanol and 1.5 liters of dichloromethane and ozone is introduced into the solution at -40 DEG C. until all the starting material is consumed. 50 ml of dimethylsulfide and 500 ml of water are added, the mixture is stirred vigorously for 30 minutes at 25 ° C, then the organic phase is dried over magnesium sulphate and concentrated. 83 g of 2- (nonyloxy) -5- (acetoxy)] benzaldehyde are obtained.

g of this material was reduced to 6 g of sodium borohydride in 1 liter of ethanol at 20 DEG C. for 2 hours. Crude [2- (nonyloxy) -5- (acetoxy)] benzenemethanol was obtained, which was immediately treated for 30 minutes at 60 ° C with 300 mL of 40% aqueous potassium hydroxide in 1 liter of ethanol. The reaction mixture was acidified with 6M aqueous hydrochloric acid and extracted with chloroform. After concentration of the chloroform extract, a crude product is obtained which, by trituration with hexane, gives 63 g of pure solid .beta.-4- (hydroxymethyl) -4- (nonyloxy)] phenol. A solution of 62 g of this material in a mixture of 0.5 L of acetonitrile and 86 g of triphenylphosphine hydrobromide was refluxed for 14 hours and then concentrated to dryness at 50 ° C to give glassy [[2- (nonyloxy)]. -5- (hydroxy) phenyl] methyl] triphenylphosphonium bromide.

Example 31 (E, E, E, E) -9- [5-hydroxy-2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

To 0.23 mol of 2- (nonyloxy) -5- (hydroxy) phenyl] methyl] triphenylphosphonium bromide in 1.5 liters of tetrahydrofuran at -70 ° C was added 315 ml of 1.6M n-butyllithium in hexane, and then 59 ml. g of ethyl 8-formyl-3,7-dimethyl-2,4,7-octatrienoate in tetrahydrofuran. The mixture was warmed to -15 ° C, acidified with acetic acid and extracted with ether and 40% aqueous methanol.

Purification by silica gel chromatography yields pure (E, E, E, E) -9- [5-hydroxy-2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester . 6 g of this ester gave nyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, melting after crystallization from ethyl acetate at 170-173 ° C.

Example 32 (E, E, E, E) -9- [2- (nonyloxy) -5- (2,2,2-trifluoroethoxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraene acid

4.4 g of (E, E, E, E) -9- [5-hydroxy-2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester together with 7 g of potassium carbonate and 6 g of 2,2,2-trifluoroethyl p-toluenesulfonate in 200 ml of dimethylformamide are heated at 90 DEG C. for 72 hours. Water and hexane were added to the reaction mixture, and after usual work-up and purification by silica gel chromatography, 0.75 g of pure ethyl ester was obtained. Hydrolysis of this ester (0.9 g) using the procedure of Example 5 gave 0.6 g of pure (E, E, E, E) -9- [2- (nonyloxy) -5- (2,2,2- trifluoroethoxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid melting after crystallization from tetrahydrofuran / hexane at 121 ° C.

Example 33 (Z) - [C2- (1-Decenyl) phenyl] methyl] triphenylphosphonium bromide and (E) 1-decenyl) phenyl] methyl] triphenylphosphonium bromide

The mixture of E- and Z-isomers of 2- (1-decenyl) -1-bromobenzene prepared in Example 16 (1: 4) was converted to the mixture of E- and Z-isomers of 2- (1-decenyl) -1 by the procedure of Example 15. -hydroxymethylbenzene. This mixture was separated by chromatography on silica gel to give pure E- and Z-alcohol. Reaction of each of these isomers with triphenylphosphine hydrobromide as in Example 1 affords the corresponding phosphonium salts, i.e. (Z) - (1-decenyl) phenyl] methyl] triphenylphosphonium bromide and (E) - (2- (1-decenyl) phenyl)] methyl] triphenylphosphonium bromide.

Example 34 (E, E, E, E, Z) -9- (2- (1-decenyl) phenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

The title compound was prepared in an analogous manner to Example 33 using (Z) -1-decenyl) phenyl] methyl] triphenylphosphonium bromide. After hydrolysis of the ethyl ester and crystallization of the crude acid from ether, pure (Ε, Ε, Ε, Ε, Z) -9- [2- (1-decenyl) phenyl] -3,7-dimethyl-2,4,6 is obtained, 8-Nonatetraenoic acid, m.p. 103-105 ° C.

In the following examples, (E, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid is used as compound A. In these examples, Compound A is tested for its anti-inflammatory activity in animal models of inflammation and in animal models of adjuvant-induced chronic arthritis.

In all these tests, Compound A and the other co-test substances were administered in peanut oil containing 0.05% propyl gallate as an antioxidant. Rats were given a volume of 5 ml / kg and mice a volume of 10 ml / kg. Control animals are given an appropriate volume of peanut oil as a vehicle.

Example 35

Effect of Compound A on Delayed Hypersensitivity to Methylated Sera from Cattle

Experimental animals:

Male and female MFI mice (E33 sub-strain). Starting weight approx. 25 g.

Materials:

Methylated sera from bovine sera (Sigma). Freund's complete Difco adjuvant

Method:

Groups of 10 mice were sensitized at day 0 at two sites on the abdomen by intradermal injections of methylated sera from bovine serum and Freund's complete adjuvant in a water-in-oil emulsion. These preparations are administered in a volume of 0.05 ml. On day 9, mice are injected with 20 µl of a 1% methylated serum bovine albumin solution into one paw and 20 µl of water into the opposite paw. Paw volumes are measured after 24 hours using a mercury displacement plethysmograph. For each group of experimental animals, the average percentage increase in the volume of paw treated with bovine serum albumin compared to water treated paw alone is calculated. The vehicle and test substance administration starts on day 0 and ends on day 9.

Results:

The results obtained are shown in Table II below. Each group of experimental animals consists of 4 male (M) and 6 female (F) mice, the male and female being housed in separate cages. Test substances are administered orally in a volume of 10 ml / kg (10 doses).

Table II

Effects of Compound A on Delayed Hypersensitivity to Methylated Sera from Cattle

Test substance

Dose increase in volume (mg / kg) of paw (%)

% Reduction compared to control (peanut oil)

Average change in body weight (g)

peanut oil 109 - 11 M F 3.8 0.2 etretinate 10 59 í 9 ^XX 46 M -0.8 F -2.0 compound AND 10 102 - 12 ^ns 6 M 3.3 F -0.2 compound AND 30 50 ± 7 ^XXX 54 M 2.8 F 0.5 compound AND 100 ALIGN! 40 t 5 ^XXX 63 M 3.3

F -0.2

Legend:

ns - insignificant xx p <0.01 xxx p <0.001 when compared to the control experiment (vehicle application) using a paired Student's t-test

Example 36

Effect of Compound A on the development of rat-induced arthritis with an adjuvant

Experimental animals:

AHH / R female rats with an initial weight range of 110 to 140 g.

Materials:

Auxiliary agent for injection. Homogenized suspension of heat-killed M. tuberculosis organisms (human strains C, DT and PN) at a concentration of 5 mg / ml in liquid paraffin.

Method:

The rats are randomized into groups of five animals and arthritis is induced in each rat by subplantar injection of 0.1 ml of the adjuvant suspension into the right hind paw. Test compounds are gutted by gavage every morning, starting on the day of adjuvant injection. For comparative purposes, only two vehicle groups are administered to two groups of control rats and a group of three normal rats is followed. The administered substances are administered daily until the end of the test (day 15) except on the first weekend (days 5 and 6). The treatment of the individual groups is shown in Table III, with entretinate being used as the standard comparator.

The right hind paw volume measurement is performed first on days 2 and 4 after injection of the adjuvant (primary phase). Then, the volume of the right and left hind paws is measured first at day 8 and then every two or three days until the end of the experiment at day 15 (secondary phase). At this time, the mobility of each ankle, as well as the incidence and extent of secondary forests on the nose, ears, right paws, left hind paw and tail, are assessed according to the degree of possible flexion and using an agreed assessment system.

Evaluation of results:

The paw swelling curves with the injected injected agent are integrated from day 0 to day 4 to restore the primary swelling, and from day 8 to day 15 to detect the secondary swelling. Similarly, from day 8 to day 15, the secondary swelling of the paw that has not been injected with the excipient is integrated. Calculations are performed using a specific computer program to calculate the mean - standard deviation for each area. The statistical significance of the differences from the control values is determined by the Student's t-test (pair test) and the percent reductions compared to the control areas are calculated.

Percentage improvements in joint mobility and percentage reductions in forests are also identified. In the latter case, the Wolcoxon pair test is used to express the deviation from the control value.

Results:

The test results are shown in Table III below.

254 392

1-H M M d

Rί r-i □

л rtl

ιη rH 'Φ 00 Д 0 » what > 1 Φ tí r4 - / 4 > ф Ρ Ρ (Л 0 in d д rH д Ρ 1 and t O Ν > 4 Д Ό

X X X cn m! —I + m

J

LO o

AND

X <N

-ΙO in

AND

CM N * O

СЧ U ~> r4 + 4 +

Effect of Compound A and Ertretinate on the Arthritis Induced in the Rat by the Adjuvant

u г M c *>

СЧ Q> ЧЧ g «к к p Ф ω H op

M Й Й Ό vd Д > OP 0 Φ , X rH > Ф —- WITH ω M í + Д d Й ми H vtí > P Ό d Д й д 0 tx .X Λ4 - 0 Φ P (Л 0 M ЧЧ tí vd Д Й > Φ * d d > N P M • i4 04 / Д Й no Λ

d tr (Л X X 0 > «D P Q Her Φ 04 /

d d> x o + P ЧС m r-4

Ф b

X

X LO LO

X <N ГX X

X

Ν '

LO LO

O tn

X 1 LO

X LO 10

X r ^ ·

P Ul Ф P <3S Г · LO

O

C0

O ř * l

LO LO OL

L0 10 40

Ф

M P Й 0 Й d Д P 'd d Д d 04 / •> 4 Д r4 rH rH Д Ή O 4ti 0 'Ф Ф P 0 WITH Й Д > o Φ P Й P U1 0 Й Д O Д O O P O Д O Д rH Й / X ω Φ

'> 4> O

4 «β P ω o P i P

hh <β N '> <

children d

H P d p <л statistical analysis according to Wilcoxon test (pair test)

P <0.05

гЧ СЧ X X X X X d Ό Д Ф ty Ф Й X

Example 37

Effect of compound A on developed type 2 collagen-induced arthritis

Experimental animals:

Male and female rats (Alderley Park Strain 1).

Materials:

Collagen type 2 (prepared from cattle nasal septum). Freund's Incomplete Adjuvant (Difco).

Method:

Rats are sensitized to type 2 collagen by intradermally injecting them with a ml of water-in-oil emulsion containing equal parts of a solution of collagen type 2 in 0.45 M sodium chloride, 1 mg / ml, 0.02 M tris buffer, pH 7 , 4 and Freund's incomplete adjuvant. Rats that develop arthritis are assigned to control group receiving peanut oil (6 males, 4 females) or Compound A (6 males, 5 females) on day 15 after sensitization. To ensure an even distribution of rats between these groups, the hind paw volume is measured. On the night of day 15-16, the urine of the test animals is collected and dosing is started on day 16. These urine samples are analyzed for glycosaminoglycan (GAG) content. Compound A is administered orally at a dose of 100 mg / kg. A second urine collection is performed overnight between days 19 and 20. These urine samples are also analyzed for glycosaminoglycan content. At day 20, a second hindpaw volume measurement is made. The rats are then anesthetized with sodium pentobarbitone, blood is collected, sacrificed and their hind and forepaws are x-rayed. The test substance is administered to rats on days 16-19 inclusive (4 doses).

Results:

The results obtained are shown in Table IV below.

Table IV

Effect of Compound A in the Type 2 Collagen Induced Arthritis Test

Day Paw Volume Compound A administered at a dose of 100 mg / kg Control group

GAG (jig) weight (g) paw volume (peanut oil)

GAG (ug) weight (g)

16 2.44 - 0.08 1 586 - 307 247 + 14 2.48 í 0.07 1 538 i 192 249 + 19 Dec 20 May 2.66 - 0.06 634 - 72 229 + 10 2.46 í 0.07 729 í 134 258 + 19 Dec

Note: both male and female rats lost weight during Compound A treatment

Example 38

Effect of compound A on non-immune inflammation

Experimental animals:

Female rats (Alderley Park Strain 1) weighing 170 to 170 at the start of the test

205 g.

Materials:

Lambda-carrageenin, prepared as a saline solution and autoclaved.

Method:

• Groups of 8 rats each receive 10, 30 and 100 mg / kg of Compound A orally for 10 days per day. Control animals receive only the vehicle. 1 hour after the last administration, the animals are anesthetized with methohexitone (Brietal, 50 mg / kg) and injected into their pleural cavity with 0.2 ml of 1% lamga-carrageenin. Four hours later, the animals are sacrificed by an overdose of pentobarbitone (SagataL), the pleural exudate is collected and the pleural cavity is rinsed with 2 ml phosphate buffered saline (PBS-A, Oxoid). Exudate volume is recorded and the cell count is determined using an automatic cell counter (Coulter). For separate determination of polymorphonuclear leukocyte (PMN) and mononuclear cell (MN) counts, cell counts were performed on Giems stained exudate stains.

Immediately after isolation of the pleural exudates, the tibias of the animals are removed and the force required to break them is determined.

Animal body weights are recorded daily. Statistical analyzes are performed using a paired Student's t-test.

Results:

The results obtained are given in Table V below. Doses of the administered substances are given in mg / kg daily.

'256392 H • H • H 4->

Ή a

0) ε o H

N

D4 d r4 S4 ω

c> Φ e

N со

I ш со гЧ о

4- I

Effect of Compound A on Four-Hour Development of Carrageenin-Induced Pleural Inflammation

tn

Г со

О + 1

ωω

Zz оо сог- гч

О40 О

4-1 + 1

ТЗ 3 4-> ω о дз o> о и 'd

CL,

> 14 о Cl,

tip 4Φ • ' > □ d 0 С CL, z > ф with β Рч> 0 Λί N гЧ 40 φ О no X

М

0)> О

О о.

'> 1> О

ε d G • и> о ϋΡ (0 Λί С> ф> ф з ε

О

X

СЧ СО

О О гч +1 · - <04 σ> сч г-н 4-1

СО гЧ

СО сч 4-1

О Ю Г «- <

«-Н о + 1 * 3 · ггЧ

I ω

00 ¹ 00 о

4-1 ω of 'З' гсч 40 г-н 4-1 ш

I ω

z со со о гсч 4-1 г-нΓόη5D счсч

II

X σ> g х

·. - 1П гЧ г- о

4-1 + 1 + 1

AND

С 40 и 1Л О 4-1

СО

СО с-Н

AND

СЧ 40

4-1 ω Z

--Н> -Н 4-1 г1П σ \ оо о 4-1

ОО 0404

СЧ 40СЧ со со’З ’

I II

X со

О о о + 1

X

СО 04 аз о о о + 1

гЧ СП сл СП ε ε ε ε ιη о ο о С0 о ^1-1 го Φ , —1 0 '> Ч > < 0 υ d d d • гЧ G G с d с • rl • Η • Η гЧ ε с , Χ а С 0 φ φ 0 ф Ф Η N > υ Ρ > č > □ 4J I.e 3 N 3 3 С 0 0 0 0 0 0 а г-Ч Í4 гЧ Λί ω ω ω

d тЗ с φ Сл

3 »3

Example 39

The effect of Compound A on the granule induced in rats by impregnated with a rag cloth

Experimental animals:

Female rats (AHH / R) having a body weight of 120 to 140 g at the start of the test.

Materials:

Pellets of 6.5 mm diameter are cut from cellulose rag (Wettex) and 0.1 ml of a suspension containing 0.5 mg / ml heat-killed M. tuberculosis organisms (human strains C, DT and PN) is applied to each of these pellets. ) in sterile saline. The pellets were dried, weighed and autoclaved.

Method:

The rats are randomized into groups of five animals and the daily administration of test substances is started. After the fifth dose, rats are anesthetized with sagatal (45 mg / kg intraperitoneally), their backs are shaved and two pellets (one on each side) are subcutaneously implanted into each rat by a small incision in the midline. The incision is closed and the rats are allowed to wake from anesthesia.

7 days after implantation, the rats are sacrificed, the pellets are removed, the adhering tissue is removed and their weight is determined. Place each pellet in 4 ml of distilled water, cut with small scissors and mix by ultrasound. After centrifugation, the supernatant was determined by flame photometry to determine the content of sodium and potassium ions. In addition, the adrenal gland and thymus are removed from each rat and weighed. Next, remove the lower part of both hind limbs to determine the force required to break the tibia. The body weight of the test animals is also recorded during the test.

Results:

The results obtained are shown in Table VI below.

Finding results:

For each parameter, the mean value - standard deviation is calculated and differences from the control values are determined using a paired Student's t-test. The decrease in granuloma weight is expressed as a percentage, the sodium and potassium ions content, and the percent changes in the adrenal and thymus weight and the force required to break the tibia.

Table VI

Effect of compound A, etretinate and dexamethasone on rat granuloma induced by the introduction of a rag pellet

Compound Dose Number Suppression of development granuloma . % Change Body change (mg / kg) rats in% hm- hm- forces weight (g) mass company company к zl- wet over- brz- changes Na ⁺ pellets K ⁴ ice- Líku tibia vinek control - 8 - - - - - - +9.6 or 1.3 Compound A 15 (p.oj i 5 -XX -. _c xx 15.1 14.5 -6,9 ^XX +17,6 ^XX -4.4 -4.0 +7.2 i 0.74 45 (p.o.) 1 5 10.8 11 0.8 +29,0 ^XX + 14.3 “1.12 +11.4 i 0.98

continuation of Table VI

Compound Dose Number Suppression development granuloma % Change Body change (mg / kg) rats in% hm- hm- forces weight (g) mass company company к zl- wet over- brz- changes pellets Na ⁺ K ⁺ . ice- Líku tibia vinek

etretinate 15 (p.o.) 4 2.7 5.9 3.9 +22.9 ^XX +15.2 -4.6 +13.3 - 2.6 dexamethasone 0.5 (s.c.) 1 5 65,5 ^XXX 51,2 ^XXX 75,2 ^XXX -49.5 ^XXX -79 ^XXX -11.5 ^{* X} +10.2 + 1.59

Legend:

after. - oral administration

sc = subcutaneous administration ^X P <0.05, ^XX p <0.02, ^XXX p <0.01 note: 2 control rats and 1 etretinate-treated rat died under anesthesia

Example 41

Effect on the course of already developed arthritis induced by the adjuvant

Experimental animals:

Male rats (Lewis, Charles River).

Materials: . ,

Heat-killed, dried Mycobacterium butyricum organisms.

Method: .

Arthritis is induced by injecting 0.1 ml of a suspension of heat-killed, dried Mycobacterium butyricum organisms in heavy mineral oil containing 0.2% digitonin (0.5% w / v)] at the base of the tail. Arthritis was allowed to develop for 21 days, and the volume of both hind paws was measured using a mercury plethysmograph. The rats are divided into groups of 8 animals having the same average paw volume and then administered for 7 days with Compound A, indomethacin (as a reference control) or vehicle. At the end of the treatment period, both hindpaw volumes are re-measured to determine the anti-inflammatory effect. Changes in body weight are also monitored and animal plasma collected for the determination of fibrinogen in plasma upon completion of the experiment (Exner et al., Amer. J. Clin. Path., 71, 521-527).

Results:

The results obtained are shown in Table VII below.

Table VII

Effect on the course already developed arthritis induced by adjuvant ^and?

Group Treatment Dose Paw volume change Fibrinogen in plasma Change in body weight (mg / kg) (ml) (mg / 100 ml) weight (g)

( ^d) arthritic vehicle medium Compound A 100 ALIGN! +0.53 - 0.08 1 773 i 30 7.5 5.2 + + 1,2 2.1 -0.96 - o, io ^x > 874 - 57 ^X (10) arthritická indomethacin 1 -1,22 - 0.15 ^X > 978 - 1OO ^X) 25.6 + 3.1

(10)

Legend:

^(a ) averages are given - the standard deviation of the compound is applied once daily for 7 days starting on day 22 after induction of arthritis; Tween 80 surfactant is used as the vehicle

(c) change in paw volume / body weight equal to paw volume / body weight at day 28 minus paw volume / body weight at day 22. since the adjuvant is injected into the root of the tail, the change in paw volume is considered to be the combined value for both hind paws the number of animals per group a value significantly different from that observed in vehicle-only arthritic animals (Student's t-test, p <0.05)

Claims (13)

OBJECT OF THE INVENTION A process for the preparation of phenylnonatetraenoic acid derivatives of the general formula I in which it represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a chlorine atom, a fluorine atom or a trifluoromethyl group, R2 represents a chlorine atom, a trifluoromethyl group, an alkyl group having 1 to ₂ carbon atoms; 7 carbon atoms, a fluorine atom, a hydroxyl group, an alkoxy group having 1 to 7 carbon atoms, a trifluoromethylalkoxy group having 1 to 7 carbon atoms in the alkoxy moiety, or a hydrogen atom, R1 is hydrogen, C1-C7alkyl, chlorine or fluorine, R ₄ represents a straight-chain alkyl group having 4 to 10 carbon atoms or -CH ₂ (CH ₂ ) _n CH ₂ OH, means -CHO-, -CH-, -O-, -? -N-, ^R 10 ^R 10 ^R 10 ^R 10 Rg represents a group COORg, R y, R _g , R _g and R ₁₀ each represent a hydrogen atom or a C 1 -C 7 alkyl group having a value of 6 or 1, a compound of formula VII 'and pharmaceutically acceptable salts of those compounds in which R _g represents an atom hydrogen, characterized in that it is reacted with a compound of the general formula XVI 'where man ^R 1' ^R 2 ' Z 'have a value of 0 or 1, provided that the sum of m + n' is always equal to 1 and if m has a value 0, X is -O-, R 8 and X are as defined above, means an alkyl group having 1 to an aryl radical such as a halide ion, If desired, it is converted into the free tg of the carboxylic acid by converting it into its pharmaceutically acceptable salt. thereafter optionally an alkyl ester group -COOR 'carboxyl group and the product of formula (I) wherein R ₍ 2. A process according to claim 1, wherein ^R @ 1 is hydrogen, chlorine or fluorine. ^R @ 2 is hydrogen, C1 -C6 alkoxy, 7 carbon atoms, chlorine atom ^R3 represents a hydrogen atom, an alkyl group having 1 to 2 or fluorine, 7 carbon atoms, chlorine ^R 4 represents an alkyl group of 8 to 10 atoms containing 8 or 9 carbon atoms, a carbon having a straight chain X represents -CH-Ο-, -CH-, -O- or -N-, ^R 10 ^R 10 ^R 10 ^R 5 represents -COORg and _# n, R y, R g, R g and R g are as defined in point 1, and salts of those 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, wherein the corresponding starting materials are used to produce compounds of formula I wherein X is -O-, and the remaining symbols are as in point 3. 5. A process according to claim 4, wherein the corresponding starting materials are used to form compounds of formula (I) wherein R @ 1 is chlorine or fluorine, and the remaining general symbols are as in point 4. 6. A method according to claim 4, characterized in that using the corresponding starting materials, to give compounds of formula I in which R ₂ is alkoxy having 1-7 carbon atoms and the other symbols are as defined in 4. 7. 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-nonatetraenoic acid. . 8. A process according to claim 2, wherein the corresponding starting materials are used to form (Ε, Ε, Ε, Ε) -9- (2-fluoro-6- (nonyloxy) phenyl) -1H-3,7-dimethyl. -2,4,6,8-nonatetraenoic acid. 9. 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. 10. The process of claim 2, wherein the corresponding starting materials are used to form 9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. 11. The process of claim 2, wherein the corresponding starting materials are used to give (E, Ε, Ε, Ε) -3,7-dimethyl-9- (2-octylaminophenyl) -2,4,6, Of 8-nonatetraenoic acid. 12. The method of claim 2, wherein the corresponding starting materials are used to form (Ε, Ε, Ε, Ε) -3,7-dimethyl-9- [2 - [(8-hydroxyoctyl) oxy] phenyl. -2,4,6,8-nonatetraenoic acid. 13. A process according to claim 1, wherein the corresponding starting materials are used to give (E, E, E, E) -8- (2- (trifluoromethyl) -6-nonyloxy) phenyl] -3,7- 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 - [(2,2-dimethyloctyl) oxy] phenyl] -2,4,6,8-nonatetraenoic acid, 9- [2- (nonyloxy) phenyl] -3,7-dimethyl ethyl ester -2,4,6,8-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, E) ) -9- [2- (nonyloxy) -5- (2,2,2-trifluoroethoxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9- [2 - [(octyloxy) methyl] phenyl] -2,4,6,8-nonatetraenoic acid, 9- (decylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, 3,7-dimethyl-9- (2-octylaminophenyl) -2,4,6,8-nonatetraenoic acid ethyl ester and ( E, E, E, E, E) -9- [2- (1-decenyl) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid.