FI84345B - FOERFARANDE FOER FRAMSTAELLNING AV ANTI-INFLAMMATORISKA OCH IMMUNOSUPPRESSIVA FENYLNONATETRAENSYRADERIVAT. - Google Patents

Description

1 84345

This invention relates to a process for the preparation of anti-inflammatory and immunosuppressive phenylnonatetraenoic acid derivatives of the formula R7 Hg I Is R. \ - CH = CH-C = CH CH-R, 10 ^ ΊΓ No. 5

Q 9 8 7 6 5 4 3 2 1 I

N 5 / As'x-r, 4 wherein R 1 is hydrogen, chlorine, fluorine or trifluoromethyl; R 15 is hydrogen, hydroxy, lower alkoxy or trifluoromethyl-lower alkoxy; is 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-; RK is C00Rn; and R ", R", Il I I 3 y / ö 20 R10 R10 R10 R10

Rg and R1q are hydrogen or lower alkyl; n is 6 or 7; and pharmaceutically acceptable salts thereof, when R 8 is hydrogen, characterized in that a) a compound of formula 25 ", R 2, I-X, X 4, 4 - is reacted with a compound of formula 35 RR 0

7 I8 II

OHC-C = CH-CH = CH-C = CH-C-OR / 9

VII

2 84345 or b) a compound of formula

R, R7 Y

5 Ro I 1 1 1 ^ 0H = CH-C = CH-CHo P-YZ 'xvi <OR ¥ 10 is reacted with a compound of formula R 0 XVI1 1 u 0HC-C = CH-C-OR'9 15 or c) a compound of formula R. R 7 Ro 0 20 .1 | Y 18 I! R? ^ CH ^ CH-C ^ CH-CH5 CH-C-CH-C-ORi, VI11%

OH

Is reacted with a compound of formula R 2 Z, wherein R 2, R 2, R 2 and R 8 are as defined above; Rg is lower alkyl; Y is aryl, Z is a leaving group and Z 'is a halide ion; and if desired, the carboxylalkyl ester group -COORg in the reaction product is converted to the free acid and further, if desired, the acid is converted to a pharmaceutically acceptable salt.

Figures 1, 2, 3, 4, 5, 6 and 7 schematically show process steps for the preparation of compounds of formula I above.

3,84345 As used herein, the term "halogen" includes all four halogens, i. chlorine, bromine, iodine and fluorine, with chlorine and bromine being preferred. The term "lower alkyl" denotes both straight-chain and branched lower alkyl groups having 1 to 7 carbon atoms. Preferred lower alkyl groups are methyl, ethyl, isopropyl, n-butyl, etc., with methyl and ethyl being particularly preferred. The term "lower alkoxy" means lower alkoxy groups having 1 to 7 carbon atoms, such as methoxy, ethoxy, isopropoxy, isobutoxy, etc. The term trifluoromethyl-lower alkoxy means a lower alkoxy substituent containing a trifluoromethyl substituent in which the lower alkoxy is defined above. The term alkylidene denotes an aliphatic saturated hydrocarbon group in which the terminal-15 carbon atom is divalent.

The term "aryl" denotes monocyclic aromatic hydrocarbon groups which may be unsubstituted or substituted at one or more positions by lower alkyl groups such as phenyl or tolyl, etc., and polycyclic aromatic groups which may be unsubstituted or substituted at one or more positions an alkyl group such as naphthyl, phenanthryl or anthryl. The primary aryl group is phenyl.

25 The term all-E means that all double bonds in the chain have an E-configuration.

In one group of compounds of formula I, X is -O- and R 7 and R 8 are lower alkyl, primarily methyl. In another preferred group of compounds, R 4 is - (CH 2) y H, wherein y is 6-9, more preferably 8-9, and most preferably 8-9. In this group of compounds, Rx and R2 are preferably hydrogen or R1 may be hydrogen and R2 may be lower alkoxy such as methoxy or ethoxy. On the other hand, in this group of compounds, R 2 may be hydrogen and R 1 is chlorine or fluorine.

In a further group of compounds of formula I 4 84345, R 4 is -CH 2 (CH 2) n CH 2 OH. In this group of compounds of formula I, R 1 and R 2 are hydrogen or R 1 is chlorine or fluorine and R 2 is hydrogen. On the other hand, in this group of compounds of formula I, R 1 is hydrogen and R 2 is lower alkoxy, preferably methoxy or ethoxy.

According to the present invention, salts of a compound of formula I above with pharmaceutically acceptable, non-toxic, inorganic or organic bases are also prepared, e.g. alkali metal and alkaline earth metal salts. Preferred salts are the sodium, potassium, magnesium or calcium salts, as well as the salts of ammonia or suitable non-toxic amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxy-ethylamine, bis (1-hydroxyethyl). ) amine or tris (2-hydroxyethyl) amine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N, N'-dibenzylethylenediamine and dibenzylamine. These salts can be prepared by treating compounds of formula I wherein R 9 is hydrogen with inorganic or organic bases by conventional methods well known in the art.

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

The compounds of formula I can be used to treat patients suffering from rheumatoid arthritis and related diseases. In such cases, the compounds alleviate the effects of these diseases by reducing the destruction of bone structure caused by this disease, as well as by reducing the inflammation, heat, and pain in the bone joints due to arthritis and related diseases. The compounds of formula I and their salts are also useful in the treatment of diseases due to immune hyperactivity, such as tissue transplant autoimmunity, autoimmune disease and Graff versus host disease. The unexpected absence of toxicity of the compounds of formula I can be seen from the fact that the (LD-E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4-6,8-nonatetraenoic acid LD50 in mice is greater than 1,000 mg / kg both intraperitoneally and orally.

The effectiveness of the compounds of this invention as anti-arthritic agents can be seen from the results obtained by administering the compounds to rats according to the chronic adjuvant arthritis test system presented by Billingham and Davies in the Handbook of Experimental Pharmacology ( suppliers JR Vane and SH Ferreira) Vol. 50/11, pp. 108-144, Springer-Verlag, Berlin, 1979).

In this method, the adjuvant arthritis was induced by injecting on day 0 0.05 ml of the excipient [a 20% (w / v) suspension of heat-killed, dried Mycobacterium butyricum in heavy mineral oil containing 0.2% digitonin] Charles River Lewis - on the underside of the right hind paw of male rats (120 - 140 g). Rats had been housed separately and given food and water 25 freely. Immediately after injection of the excipient, the paw volumes of both hind paws were measured. Paw volumes were also measured, to monitor the development of inflammatory swelling in the paws under arthritis, every 3 to 7 days by immersing the paw from the outer spindle 30 all the way into the mercury volume measuring device.

The drugs were administered once a day (from the date of injection of the excipient) by intubation using Tween 80 (polyoxyethylene sorbitan monooleate) as the vehicle at a dose of 0.25 ml per 100 g of body weight. 35 Arthritis control rats received daily doses of 6 84345 vehicle alone. On day 23-25, rats were sacrificed, plasma was collected, and plasma f ibi. inogen amounts were determined (ammonium sulfate turbidity measurement method) as described by Exner et al., Amer. J. Clin.

5 Path. 71 (1979) 521-527. The anti-inflammatory effect of the test compounds was determined by comparing the amount of paw swelling (paw volume on a given day, i.e. day four -> day 25, minus paw volume on day 0) with test compound-treated arthritis rats treated with vehicle-treated paw swelling. dusrotilla. Decreases in the amount of fibrinogen in the plasma of the acute phase protein, which is elevated in the plasma of rats with adjuvant arthritis, were also used to determine anti-inflammatory activity.

The results of the various compounds obtained according to the present invention compared with indomethacin and 13-cis-vitamin A acid are shown in the following table (Table I).

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Person © P © = - © © | 4i *! _l_j ____ j_1 _____ j -— i s 84345

In Table I above, the percentage reduction in paw volume demonstrates the efficacy of the compounds of formula I in reducing the swelling caused by adjuvant-induced arthritis. As can be seen from the results in this table, the compounds are effective in reducing adjuvant-induced edema. In addition, the compounds of this invention effectively reduced plasma fibrinogen, which is generally associated with rheumatoid arthritis. Furthermore, as can be seen from the weight gain of the animals, the compounds of formula I in the tested doses did not substantially reduce the weight gain of the animals. This indicates that the compounds are non-toxic.

The compounds of formula I and their pharmaceutically acceptable salts can be used in various pharmaceutical preparations. In these preparations, these compounds are administered in oral dosage unit forms, such as tablets, pills, powders, and capsules, as well as in such forms as injectable preparations, solutions, suppositories, emulsions, dispersions, and other suitable forms. Pharmaceutical preparations containing compounds of formula I are formed by mixing the compounds with a non-toxic organic pharmaceutical carrier or a non-toxic inorganic pharmaceutical carrier. Typical pharmaceutically acceptable carriers include, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, and other commonly used pharmaceutically acceptable carriers. The pharmaceutical preparations 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 sulfosuccinate and the like. 35 The daily dose of the compounds will vary, of course, depending on the particular 9,84345 new compound used, the route of administration chosen and the size of the recipient. The dose to be administered is not limited, but is usually the compounds obtained according to the present invention to the extent effective in terms of pharmacological activity. A typical route for the administration of the compounds of formula I or their salts is by oral administration. For administration by this route, the compounds of formula I or their salts may be administered at a dose of 0.5 mg / kg per day p.o. -> 100 mg / kg per day p.o. Preferably, these compounds can be administered in a daily dose of 1 to 30 mg per kilogram of body weight, particularly preferably in a dose of 1 to 10 mg / kg.

A compound of formula I wherein X is -O- can be prepared from compounds of formula 15 f

Ltd

N / ^ OH

20 wherein R 1 and R 2 are as defined above, according to the reaction scheme of Figure 1.

In the reaction scheme of Figure 1, n, R 1 # R 2, R 7 and R 8 are as defined above and R 19 is lower alkyl, Z is a leaving group; Y is aryl, preferably phenyl; Z 'is halogen.

The compound of formula III is converted to the compound of formula IV in reaction step (a) by reducing the aldehyde group to an alcohol. This reaction is carried out using a conventional reducing agent which converts aldehydes to alcohols. In reaction step (a), any conventional reducing agent may be used for this purpose. In carrying out this reaction, it is generally preferable to use an alkali metal borohydride such as sodium borohydride as a reducing agent. Any of the conditions conventional in such reduction reactions may be used to carry out reaction step (a). If R 2 is hydroxy, it is generally preferred to protect the hydroxy labeled with R 2 during the reduction of the compound of formula III and the subsequent conversion to the compound of formula I. When R 2 is hydroxy, any conventional hydrolyzable hydroxy protecting group, such as a lower alkanoyl group, can be used to protect the hydroxy group. This ester protecting group can be cleaved by conventional ester hydrolysis after formation of Wittig salts of formulas XIII and XVI or after formation of an ether of formula X.

A compound of formula IV is converted to a compound of formula VI in reaction step (b) by treating a compound of formula IV with a triarylphosphine hydrohalide. In this way, a phosphonium salt of formula VI is prepared. Any conventional reaction method between allyl alcohol and triarylphosphine hydrohalide can be used to carry out this reaction. The phosphonium salt of formula VI is reacted according to the Wittig reaction with a compound of formula VII in step (c) to form a compound of formula VIII. Any of the conditions commonly used in Wittig reactions can be used to carry out the reaction of step (c).

On the other hand, a compound of formula III can be directly converted to a compound of formula VIII by reacting it with a phosphonium salt of a compound of formula IX as in reaction step (e). The reaction of a phosphonium salt of formula IX with a compound of formula III to prepare a compound of formula VIII is carried out using the same conditions as described in reaction step (c).

A compound of formula VIII is converted to a compound of formula X by etherification or alkylation of a compound of formula 11 84345 VIII with a compound of formula V as in reaction step (d). In the compound of formula V, Z may be any conventional leaving group such as mesyloxy, tosyloxy or halide. Any conventional method of etherifying a hydroxy group in a reaction with a halide or a leaving group can be used to carry out reaction step (d).

According to another embodiment of this invention, a compound of formula X wherein R 2 is hydroxy protected by a hydrolyzable ester can be prepared from a compound of formula III by alkylation or etherification of a compound of formula III with a compound of formula V to give compound XI. . This reaction is performed by alkylation of a compound of formula III with a compound of formula V as in step (d). In reaction steps (f) and (d), wherein R 4 is a hydroxyalkyl group, the hydroxy in R 4 need not be protected. This is true because under the conditions used in this reaction step, a compound of formula V20 reacts with either a compound of formula III or a compound of formula VIII to form a compound of formula XI or a compound of formula X without protection of the hydroxy group in the alkyl chain. The alkylation or etherification takes place directly with either the phenylhydroxy moiety of the compound of formula III or the compound of formula VIII and the reaction with the hydroxy group in the alkyl chain labeled with R4 occurs little, if at all. The compound of formula XI is converted to the compound of formula XII by reduction in reaction step (g). To convert a compound of formula XI to a compound of formula XII, the same conditions as described in reaction step (a) can be used.

In reaction step (h), a compound of formula XII is converted to a compound of formula XIII by treating a compound of formula XII with a triarylosphine hydrohalide as described hereinabove in connection with step (b). A compound of formula XIII is converted to a compound of formula X by reacting a compound of formula XIII with a compound of formula VII in reaction step (i). This reaction step is carried out in the same manner as described hereinabove in connection with reaction step (c).

According to one embodiment of the present invention, 10 compounds of formula X are prepared by first converting a compound of formula XI to a compound of formula XIV. A 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 a 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 a Grignard reaction with a vinylmagnesium halide or by a lithium condensation reaction with vinyl lithium to give a compound of formula XV. Reaction step (k) can be carried out using any of the conditions conventional in lithium condensations or Grignard condensation reactions. A compound of formula XV is converted to a compound of formula XVI by reacting a compound of formula XV with a triarylphosphine hydrohalide as described hereinabove in connection with reaction step (b). The compound of formula XVI is then converted to the compound of formula X in reaction step (m) by reacting it with a compound of formula XVII. Reaction step (m) is carried out using the normal Wittig reaction shown in connection with reaction step (c). When a compound of formula XVI is reacted with a compound of formula XVII 35, a compound of formula X is formed. Formula X

The compound of i3 8 4 3 45 can be converted to the free acid, i. to a compound of formula I wherein R 5 is COOH by hydrolysis of the ester. Any conventional method of ester hydrolysis yields a compound of formula I wherein R 5 is COOH.

Compounds of formula I wherein X is -N- are prepared from compounds of formula R 10

10 R2> Y ^ vr ^ CII2OH

Wherein Rx and R2 are as defined above, according to the reaction scheme of Figure 2.

In Figure 2, R1 (R2, R4, R7, Re, R9 ', Z' and Y are as defined above. In Figure 2, R13 is the same as R4, but has one carbon less than the alkyl group in R4. Thus, R13 is an alkyl group having 3 to 9 carbon atoms, or -CH 2 (CH 2) m CH 2 OH, where m is one digit less than n, i.e., m is an integer of 5 or 6. In Figure 2, R 10 is hydrogen or lower alkyl of 1 to 7 carbon atoms. , and R10 is a lower alkyl group having 1 to 7 carbon atoms. In this embodiment, R10 "is a lower alkyl group having one carbon atom less than in the alkyl group denoted by R10 '.

In Figure 2, a compound of formula XXII is reacted with an acid chloride of formula XIX wherein Z 'is halogen to give a compound of formula XXIII which is subsequently converted to either a compound of formula XXVI or formula XXXI. When R13 in the compound of formula XIX is -CH2- (CH2) mCH2OH, where m is an integer of 5 or 6 carbon atoms, the hydroxy group present in the substituent 35 in R13 does not affect the reaction of 84 in the preparation of the compound of formula XXVI or formula XXXI. compound. It has been found that this hydroxy group remains intact throughout the reaction sequences shown in Figure 2.

On the other hand, this hydroxy group can be protected by forming a hydrolyzable ether functional group which protects the hydroxy group during all these reactions. Any conventional ether protecting group can be used to protect the hydroxy group for all of these reactions. Preferred ether protecting groups are: tetrahydropyranyloxy, t-butoxy, tri-former alkylsilyloxy, e.g. trimethylsilyloxy, etc. Any conventional ether protecting group may be used to protect the terminal hydroxy group optionally present as the R13 group. On the other hand, the reactions shown in Fig. 2 can be carried out without any protection of the terminal hydroxy group.

In the first step of the reaction, a compound of formula XXII is reacted with a compound of formula XIX to give a compound of formula XXIII. Any conventional method of condensing an amine with an acid halide can be used to carry out this reaction. In the next step, the compound of formula XXIII is converted to the compound of formula XXIV, in reaction step (n) by treating the compound of formula XXIII with a reducing agent. Any conventional alkali metal aluminum hydride reducing agent can be used to carry out this reaction, with lithium aluminum hydride being the primary reducing agent. To carry out this reaction, any of the conventional conditions used for reduction with an alkali metal aluminum hydride reducing agent can be used.

A compound of formula XXIV can be converted to a compound of formula XXVI via intermediate XXV. In the first step of this process, step (o), the compound of formula XXIV is converted to the sex phosphonium salt of formula XXV by reaction with a triarylphosphine hydrohalide as described hereinabove in connection with reaction step (b). The compound of formula XXV is converted to the compound of formula XXVI in reaction step (p) by reacting it with an aldehyde of formula VII. (See Figure 1.) Reaction step (p) to prepare a compound of formula XXVI is carried out according to the Wittig reaction in the same manner as in Reaction Step (c) above. The compound of formula XXVI wherein R 9 is lower alkyl may be converted to the free acid by conventional basic hydrolysis if desired. Any conventional alkaline hydrolysis method used to hydrolyze esters can be used to convert a compound of formula XXVI to the free acid. On the other hand, a compound of formula XXVI in which R4 has a terminal hydroxy group etherified with a common ether protecting group can be converted to the free alcohol by hydrolysis with an acid. Any of the conventional methods for hydrolyzing ethers can be used to perform this reaction. The ether hydrolysis of a compound of formula XXVI may be performed either before or after the acid hydrolysis with the acid used to hydrolyze the ester protecting group R9 '. On the other hand, if R4 in the compound of formula X has an etherified hydroxy group, the compound of formula X can be hydrolyzed in the same manner as the compound of formula XXVI.

On the other hand, a compound of formula XXIV can be converted to a tertiary amine compound of formula XXXI. In this reaction, a compound of formula XXIV 30 is reacted, in reaction step (q), with an acid halide of formula XIX-A to give a compound of formula XXVII in the same manner as described hereinabove for the conversion of a compound of formula XXII to a compound of formula XXIII. -35 to do.

84345 BC

The compound of formula XXVII is converted to the compound of formula XXIX in reaction step (r) by developing the compound of formula XXVII with a lithium aluminum hydride reducing agent as shown in connection with reaction step (n) 5.

In the next step of this reaction scheme, a compound of formula XXIX is converted to a compound of formula XXX in reaction step (s) by treatment with a triaryl-phosphine hydrohalide. This reaction is carried out in the same manner as in Reaction Step (b) described hereinabove. The compound of formula XXX is converted to the compound of formula XXXI in reaction step (t) by reacting it with a compound of formula VII (Figure 1).

In carrying out the reaction step (s), a Wittig reaction is used. Reaction step (t) may be carried out in the same manner as described hereinabove in connection with reaction step (c). A compound of formula XXXI wherein Rg 'is a lower alkyl group may be converted, if desired, to the corresponding compound of formula XXXI having a free acid group by hydrolysis with a base. On the other hand, if R 4 has a terminal hydroxy group protected by the formation of a hydrolyzable ether, the compound of formula XXXI can be converted to the corresponding compound in which R 4 is a free hydroxy group by conventional ether hydrolysis.

This ether hydrolysis can be performed before or after the hydrolysis of the ester group labeled with R9 '.

In the reaction scheme of Figure 2, when R 2 is hydroxy, it is recommended that this hydroxy group be protected to form a 30-mile ester protecting group. The ester protecting group can be removed after formation of the Wittig salts of formula XXX.

Compounds of formula I wherein X is -CH-

R 10 is prepared from a compound of the formula: wherein R "is either bromine or iodine; R 3 and R 2 are as defined above; and R 10 is hydrogen or lower alkyl as defined below. shown in Figure 3. In Figure 3, R 3, R 2, R 4, R 7, R 8, R 19, R 10, R 13, Y, Z 'and Z "are as defined above.

In Figure 3, a compound of formula XXXV is first reacted with a compound of formula XXXIV in reaction step (u) to give a compound of formula XXXVI. This reaction is carried out by the Wittig reaction. In the compound of formula XXXVI, R 13 may, if desired, be -CH 2 - (CH 2) m -OH, where the free hydroxy group may be protected, if desired, by forming any of the usual ether groups mentioned above. On the other hand, it has been found that this OH group may be a free hydroxy group and need not be protected by an ether protecting group. In carrying out the reactions of Figure 3, this free hydroxy group remains unchanged in reactions that convert a compound of formula XXXVI to a compound of formula XXXXI. However, in order to obtain the best yields in general, it is advisable to protect this hydroxy group by forming a hydrolyzable ether.

The reaction of step (u) is carried out by a Wittig reaction between compounds of formula XXXV and a compound of formula XXXIV using the same reaction conditions set forth below in connection with reaction step (c).

The compound of formula XXXVI can be converted to the compound of formula XXXVII by hydrogenation in reaction step (v). Any conventional hydrogenation method can be used to carry out this reaction. Conventional hydrogenation methods include treating a compound of formula XXXVI in an inert organic solvent medium with hydrogen gas in the presence of a catalyst. Any conventional hydrogenation catalyst can be used to carry out this reaction. The primary catalyst is palladium. Any conventional inert organic solvent can be used to carry out this reaction. In addition, any of the usual conditions used in catalytic hydrogenation can be used in reaction step (v).

In the next step of this reaction, a compound of formula XXXVII is converted to a compound of formula XXXIX in reaction step (w) by treating a compound of formula XXXVII with formaldehyde or a formaldehyde donating compound. In carrying out this reaction, a compound of formula XXXVII is first formed into a metal compound with an alkali metal alkyl, e.g. n-butyllithium. In general, this reaction is carried out in an inert organic solvent such as an ether solvent. Preferred solvents are diethyl ether and tetrahydrofuran. In carrying out this reaction, the reaction temperature and pressure are not critical. This reaction can be carried out at room temperature and atmospheric pressure. Higher and lower temperatures can be used if desired. After treating the compound of formula XXXVIII with an alkali metal alkyl, formaldehyde or a formaldehyde donating compound is added to the reaction medium. Any conventional compound capable of donating formaldehyde, such as paraformal dehyde, can be used in carrying out this reaction. This reaction is carried out in the same reaction medium and using the same conditions as in the formation of the metal compound 35 of the compound of formula XXXVIII.

The compound of formula XXXIX is converted to formula XXXX

i9 to 84345 in reaction step (x) by treating a compound of formula XXXIX with a triarylsphosphine halide. This reaction is carried out in the same manner as in Reaction Step (b) 5 above. In reaction step (y), a compound of formula XXXX is converted to a compound of formula XXXXI by reacting it with a compound of formula VII (see Figure 1). This reaction step (y) is carried out by the Wittig reaction using the same conditions as shown for LO in reaction step (c). The compound of formula XXXXi can be converted to the corresponding compound in which R9 'is replaced by a free carboxyl group. This reaction is performed by the usual ester hydrolysis described hereinabove. Any conventional ester hydrolysis method can be used. If R4 has a terminal hydroxy group protected using an ether protecting group, this ether group can be hydrolyzed to give a free hydroxy group by conventional ether hydrolysis, such as using an aqueous solution of an inorganic acid. Any conventional ether hydrolysis method can be used. The protected ether-hydroxy group can be hydrolyzed either before or after hydrolysis of the ester group to form the free acid of the compound of formula XXXXI.

If it is desired to prepare compounds of formula I wherein X is -C = CH-, the compound of formula XXXV of Figure 3 is reacted in reaction step (u) with a compound of formula XXXIV wherein R 13 is R 4 to give a compound of formula XXXVI wherein R13 is R4. This compound of formula XXXVI wherein R 4 is R 13 'is then treated in the same series of reactions as the compound of formula XXXVII, i. reaction steps (w), (x) and (y) to give compounds of formula I wherein X is 35 -C = CH-.

^ 10 2o 8 4 345

In the reaction scheme of Figure 3, when R 2 is a hydroxy group in the compound of formula XXXV, it is preferable to protect this hydroxy group by esterification with a lower alkanoic acid. This ester protecting group can be cleaved after formation of the Wittig salt of formula 5 XXXX.

A compound of formula I and II wherein X is -CH-O may be prepared from a compound of formula

Wherein R 1, R 2 and Z "are as defined above, according to the reaction scheme of Figure 4. In Figure 4, R 1, R 2, R 7, R a, R 10, R 8, Y and Z" are as defined above and R 15 is as defined above. is R4, wherein the hydroxy group in R15 is protected in the form of a hydrolyzable ether group such as tetrahydropyranyl, as well as the ether groups mentioned hereinabove.

The compound of formula L is converted to the compound of formula L1 by reacting it with an alkali metal alcoholate of formula L-A. This reaction is carried out by reacting a compound of formula L with a compound of formula L-A using standard reaction conditions between an alkali metal alcoholate and a halide.

At this stage, the compound of formula LI is converted to the compound of formula LII by first treating the compound of formula LI with an alkyllithium such as n-butyllithium to form a metal compound of the compound of formula LI. The metal compound of formula LI is then reacted with formaldehyde or a formaldehyde donating compound. When converting a compound of formula 2i 84345 LI to a compound of formula LII, the same reaction conditions as in reaction step (w) are used in this conversion. The compound of formula LII is converted to the phosphonium salt of formula LIU by treating the compound of formula LII with a triarylphosphine hydrohalide as described above in connection with reaction step (b). The phosphonium salt of formula LIU is reacted according to the Wittig reaction with a compound of formula VII (see Figure 1) to form a compound of formula LIV. This reaction to form a compound of formula LIV is carried out in the same manner as described above in connection with step (c).

When the R15 group in the compound of formula LIV 15 has a protected hydroxy substituent, said substituent can be hydrolyzed to form the free hydroxy compound by conventional methods of hydrolyzing easily removable ether groups. Any conventional method can be used to hydrolyze the ether protecting groups. The usual conditions used for the hydrolysis of ether protecting groups do not affect the other ether group in the compound of formula LIV. The compound of formula LIV can be converted to the free acid by standard ester hydrolysis.

If R2 in the compounds of formulas L, L1, LII and L1U is hydroxy, it is preferred that the hydroxy group be protected as a hydrolyzable ester group, such as by a lower alkanoyloxy group. The hydrolyzable ester protecting group can be cleaved after formation of the Wittig salt of formula LIU.

If desired, the double bonds in positions 2-3, 4-5, 6-7 and 8-9 in the compound of formula I may be in the cis or trans configuration. On the other hand, these compounds may be a mixture of different cis and trans isomers. In a compound of formula VII, the double bonds therein may be in either the cis or trans configuration depending on the desired stereoconfiguration of the double bonds in the compounds of formula I. In the Wittig reaction carried out in the preparation of compounds of formula I and II, as in steps (c), (e), (i), etc., a double bond is formed at the 8-9, 8-9-cis- and trans-position. as a mixture of isomers. These cis and trans isomers can be separated by conventional means such as fractional crystallization, etc.

In addition, when the double bond in the compounds of formula I is in the trans configuration at position 2-3, this isomer can be converted to the corresponding cis double bond by conventional isomerization methods known in the art. These methods include the treatment of each compound of formula I with iodine in an inert organic solvent. Isomerization with iodine yields a compound of formula I wherein the double bond 2-3 is in the cis position.

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

The compound of formula XI wherein R 1 is fluorine is a novel compound and can be prepared from a compound of formula wherein R 2 is as defined above according to the reaction scheme shown in Figure 5. In Figure 5, R2 and R4 are as defined above.

In Figure 5, a compound of formula LV is alkylated by reaction with allyl bromide. If a compound in which R2 is hydroxy is desired, the starting material used is a compound of formula LV in which the 23 84 345 hydroxy group denoted by R2 is protected by esterification, i. a compound of formula LV wherein R 2 is a protected hydroxy group. To carry out the reaction in which the compound of formula LVI is converted into the compound of formula LVI, any conventional method of alkylating a hydroxy group with allyl bromide can be used. The conversion of a compound of formula LVI to a compound of formula LVII is accomplished by heating the compound of formula LVI at a temperature of 190-120 ° C. This rearrangement 10 can occur without the use of any solvent or in the presence of a high boiling hydrocarbon solvent. A compound of formula LVII is formed in admixture with an isomer of a compound of formula LVII in which the allyl group is in the para position with respect to the fluoro substituent on the benzyl ring. This isomer can be separated or used in 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 reacting it with a compound of formula V (Figure 1) as described hereinabove in reaction step (d). In the next step of this reaction scheme, a compound of formula LVIII is converted to a compound of formula LIX by isomerization with a strong base such as an alkali metal alcoholate in the presence of an inert organic solvent, preferably potassium t-butylate in dimethyl sulfoxide. A compound of formula LIX is converted to a compound of formula LX by treating the compound of formula LIX with ozone gas. The temperatures used to carry out this reaction are -70 to -20 ° C. In addition, this reaction is carried out in an inert organic solvent. In this case, any customary inert organic solvent can be used, preferably halogenated hydrocarbons, such as methylene chloride.

A compound of formula LX is a compound of formula XI 24 8 4345 wherein R 1 is fluoro. This compound can be converted to a compound of formula X according to the reaction scheme shown in Figure 1.

When R 2 in the compound of formula III is hydroxy, it has two hydroxy groups. Therefore, it is generally preferred to prepare a compound of formula XI wherein R 2 is a protected hydroxy group from a compound of formula LXI, as shown in Figure 6. In this way, compounds of formula I in which X 10 is -O- can be prepared; R 2 is hydroxy and R 4 is as defined above. In Figure 6, Rx and R15 with their associated oxygen atom are hydroxy protected with a common hydrolyzable protecting group, preferably lower alkanoyl.

In Figure 6, a compound of formula LXI is converted to a compound of formula LXII using the same reaction shown for the conversion of a compound of formula LV to a compound of formula LVI (see Figure 5). The compound of formula LXII is then converted to the compound of formula LXIII using the same procedure as described for the conversion of a compound of formula LVI to formula LVI1. In the following steps, the compound of formula LXIII is converted to the compound of formula LXIV by the same method shown in Figure 5 in connection with step (g ') and then to the compound of formula LXV by the method shown in Figure 5 in connection with step (h'). The conversion of a bromobenzene compound of formula LXV to a compound of formula LXVI is accomplished by methods well known in the art, such as the method published by Kid-well * and Darling, Tetra-30 Hedron Letters, (1966), pp. 531-535.

In the next step, the preparation of an intermediate of formula XI wherein R 2 is a protected hydroxy group, i. a compound of formula XI-A, the hydroxy group in the compound of formula LXVI is protected by esterification with a standard hydrolyzable ester group of formula LXVII

25 84345, wherein R15 together with the oxygen bound thereto forms a hydrolyzable ester group. Any conventional method of esterifying hydroxy groups with an organic acid, such as a lower alkanoic acid having 1 to 7 carbon atoms, can be used to prepare a compound of formula LXVII. A compound of formula XI-A is formed from a compound of formula LXVII by the reaction set forth hereinabove to convert a compound of formula LIX to a compound of formula LX 10 (see Figure 5).

When performing the conversion of a compound of formula XI to a compound of formula XVII, as in Figure 1, it is generally preferred to hydrolyze the ester substituent which forms R 2 after formation of the Wittig salt of formula XIII or formula XVI.

According to one embodiment of the present invention, a compound of formula XI wherein R 3 is CF 3 (a compound of formula XI-B) may be formed by the reaction outlined in Figure 7 from a compound of formula LXX. In the first step of this reaction, a compound of formula LXX is converted to a compound of formula LXXI using the same procedure described hereinabove in step (d), wherein a compound of formula VIII is reacted with a compound of formula V to produce a compound of formula X. In this reaction, when R 2 is OH, the alkylation occurs very slowly with respect to the hydroxy group in the ortho position relative to the CF 3 group. Therefore, protection of this group may not be necessary because alkylation occurs primarily with the meta-hydroxy group. Any mixtures of alkylated products obtained in this reaction can be separated by conventional separation methods. The compound of formula LXXI is converted to the compound of formula XI-B by standard benzene ring formation methods, such as treatment with alkyl] lithium 26 8 4 3 4 5 and dimethylformamide.

In the following pharmacological test examples, Compound A is (all-E) -9- [2- (nonyloxy) phenyl] -3,2-dimethyl-2,4,6,8-nonatetraenoic acid. In the following examples, Compound A was tested in various experiments to determine its anti-inflammatory activity in animal models of inflammation and in some chronic models of adjuvant-induced arthritis.

In all experiments, Compound A and other retinoids tested in parallel were mixed with peanut oil containing 0.05% propyl gallate as an antioxidant. The dose volumes used were 5 ml / kg for rats and 10 ml / kg for mice. Control animals were given an appropriate volume of peanut oil vehicle.

15 Experimental Example 1

Effect of Compound A on Delayed Hypersensitivity to Methylated Bovine Serum Albumin (MBSA)

Animals

Subspecies E33 of male and female MFI mice. Initial weight 20 about 25 g.

ingredients

Methylated bovine serum albumin (MBSA) (Sigma) Freund's complete excipient (Difco).

Method 25 Groups of 10 mice were sensitized (day 0) by injecting intradermally into two gastric sites 0.05 ml of a water-in-oil emulsion containing MBSA and Freund's complete adjuvant. On day 9, mice were challenged by injecting 20 μΐ of a 1% MBSA solution into one paw and 30 20 μΐ of water into the opposite paw. After 24 hours, paw volumes were measured using the mercury displacement volume measurement method. For each treated group, the mean percentage increase in paw volume in the paw exposed to MBSA 35 was calculated compared to the increase in volume in the paw exposed to water 27 8 4 345. Dosing of vehicle and retinoid was started on day 0 and stopped on day 9.

Score

The results are shown in the following table (tau-5 lock II).

Table II

Effects of Compound A in the MBSA Delayed Hypersensitivity Test Treatment Dose Paw Volume- Reduction% Avg. 10 mg / kg% increase (change in weight of nut oil compared to control) (g)

Peanut 109 ± 11 M 3.8 crude oil F 0,2 15 Etretinate 10 59 ± 9 ** 46 M -0,8 F -2,0

Compound A 10 102 ± 12nS 6 M 3.3 F -0.2

Compound A 30 50 ± 7 *** 54 M 2.8 20 F 0.5

Compound A 100 40 ± 5 *** 63 M 3.3 F -0.2

There were four male and six female mice (kept in different cages) in each group. The drugs were administered orally at a dose of 10 ml / kg (10 doses).

the so-called. Not significant; ** p <0.01 *** p <0.001 compared to vehicle control using Student's "Two-tailed t test".

Experimental Example 2 Effect of Compound A on the development of adjuvant arthritis in the rat Animals Female AHH / R rats (PVG-derived with an initial weight of 110-140 g) were used.

35 28 84345

ingredients

Injection vehicle. A homogenized suspension of heat-killed M. tuberculosis (human strains C, DT and PN), 5 mg / ml, in liquid paraffin was prepared.

5 Method

The rats were randomly divided into five groups, and adjuvant arthritis was induced by injecting 0.1 ml of the excipient suspension into the right hind paw of each rat on the underside of the paw. Test compounds were administered by intubation of kun-10 in the morning from the day of vehicle injection. Two groups of control rats were given vehicle, as was the group of three normal rats used for control purposes. Dosages were performed daily until the end of the experiment 15, except for the first weekend (days 5 & 6) 15. The treatment groups are shown in Table III and contain Etretinate as the standard retinoid.

Right hindpaw volume measurements were taken at baseline and on days 2 and 4 after vehicle injection (primary phase). The volume of the right and left 20 hind paws was then measured on day 8 and every two or three days until the end of the experiment until day 15 (secondary phase). At this time point, the mobility of each ankle joint and the occurrence and severity of secondary lesions in the muzzle, ears, forefoot, left 25-mass hindpaw, and tail were also assessed as possible degrees of flexion and using a freely chosen grading system, respectively.

Evaluation of the results

For injected paws, time-30 series curves from days 0-4 were integrated to describe primary swelling and from days 8-15 (secondary swelling). Secondary swelling in the uninjected paw was integrated in a similar manner from days 8-15. The calculations were performed using a special computer program that calculated the average + it for each integrated field. The significance of differences from controls was determined using the Student's t-test 29 84 3 45 (2 tailed) and the percentage reductions from control areas were calculated. Percentage improvements in joint mobility and percentage reductions in the injury estimate were also determined. In the latter case, the Wilcoxon rank sum test (2 tailed) was used to express the difference from the control value using baseline data. For each group, the mean change in body weight was reported.

Results 10 The results are shown in the following table (Table III).

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Experimental Example 3

Effect of Compound A on certain type II collagen arthritis

Animals 5 Alderley Park Strain 1 male and female rats.

ingredients

Collagen type 2 (made from bovine nasal septal cartilage), Freund's incomplete excipient (Difco).

10 Method

Rats were sensitized to type 2 collagen by intradermal injection of 1 ml of an aqueous-oil emulsion containing equal parts of a 1 mg / ml solution of type 2 collagen in 0.45 M NaCl, 0.02 moles of Tris product, pH 7.4. and Freund, in an imperfect excipient. In rats, developing arthritis was determined on day 15 after sensitization for the peanut oil-treated control group (6 males, 4 females) or for the compound A-treated group (6 males, 5 females). 20 Precipitate volume measurements were performed to ensure even distribution of rats between groups. On days 15/16 overnight, urine samples were collected and dosing was started on day 16. Glucose aminoglycans (GAG) were analyzed from these urine samples. Compound A was administered at 100 mg / kg p.o. On days 19/20 during the night, a second urine collection was performed. Glycose aminoglycans (GAGs) were analyzed from these urine samples. On day 20, a second hindpaw measurement was performed. The rats were then anesthetized with sodium pentobarbitone, the vein was opened, sacrificed, and X-rays of the hind and forelegs were taken. Rats were given doses on days 16-19, inclusive (4 doses).

Score

The results are shown in the following table (tau-35 lock IV).

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33 84345

Test Example. 4

Effect of Compound A on non-immune inflammation

Animals

Alderley Park Strain 1 naaa-5 ras rats weighing 170-205 g at the beginning of the experiment were used in the experiment.

ingredients

Lambda-carrageenan. Prepared as saline and sterilized by autoclaving.

Method 10 Compound A was administered orally to groups of eight rats once daily for 10 days at doses of 10, 30 and 100 mg / kg. Control animals received vehicle. One hour after the last dose, the animals were anesthetized with methohexitone (Brietal, 50 mg / kg) and 0.2 ml of 1% lambda-carrageenan was injected into the alveolar cavity. Four hours later, the animals were sacrificed by administration of an overdose of pentobarbitone (Sagatal), the pleurisy fluid was collected, and the pleural cavity was rinsed with 2 ml of phosphate-buffered saline (PBS-A, Oxoid). The volume of inflammatory fluid was recorded and cell numbers were determined using an automatic cell counter (Coulter). Differential cell counts were performed on inflammatory fluid stains stained with Giemsa to determine the numbers of squamous leukocytes (PMN) and mononuclear cells (MN) separately.

Immediately after recovery of the pleurisy, the tibias of the animals were excised and their fracture stresses were determined.

The body weights of the animals were recorded for days-30. Statistical analyzes were performed using Student's two-tailed 't' test.

Score

The results are shown in the following table (Table V). In the following table, the dose is mg / kg / day.

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Experimental Example 5

Effect of Compound A on Impregnated Fungal Granules in a Rat Experiment

Animals 5 Female AHH / R rats (PVG derivatives) with an initial weight of between 120 and 140 g were used in the experiment.

ingredients

Sienipreparaatti. Round tablets (6.5 by 10 mm in diameter) were punched from cellulose sponge fabric ("Wettex") and 0.1 ml of a suspension of 0.5 mg / ml of heat-killed M. tuberculosis (human strains C, DT and PN) in sterile saline. The tablets were dried, weighed and autoclaved.

15 Method

Rats were randomly divided into five groups and given daily doses of test compounds. After the fifth dose, rats were anesthetized with Saga tallow (45 mg / kg i.p.), hair was shaved from the back, and two tablets were implanted subcutaneously (one on each side) in each rat through a small back centerline opening. The opening site was closed and the rats were allowed to recover from anesthesia.

Seven days after implantation, the rats were betrayed and the tablets were removed, the extraneous tissue was removed from them, and the tablets were weighed. Each tablet was then placed in a 4 ml sample of distilled water, digested with sharp scissors and disintegrated with high frequency sound waves. After centrifugation, the Na * and K * content of the surface layer was determined using flame photometry. In addition, the adrenal and thymus glands were removed from each rat and weighed and the lower hind limbs were removed to measure tibial fracture tension. Body weights throughout the experiment were also recorded.

35 36 84345

Score

The results are shown in the following table (Table VI).

Evaluation of the results

5 Mean ± SE was calculated for each parameter

and differences from control values were determined using the S udent ‘t’ test (2-tailed). Percent granuloma weight reductions, Na * and K * content and percentage adrenal and thymus changes, weight, and tibial fracture stress were determined.

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Animals Male Charles River-Lewis rats were used in these experiments.

Substances 5 Heat-killed, dried Mycobacterium butyricum.

Method

Excipient arthritis was induced by injecting 0.1 ml of excipient / suspension of 10 heat-killed, dried Mycobacterium butyricum (0.5% CW / V) in heavy mineral oil with 0.2% digitone / into the base of the tail. Arthritis was allowed to develop for 21 days and then the volume of both hind paws was measured using a mercury displacement volume meter. Rats 15 were divided into groups of eight animals with the same paw volumes, and then the rats were treated with Compound A, indomethacin (as a control drug), or vehicle for seven days, and at the end of the treatment period, the volumes of both hind paws were remeasured to evaluate anti-inflammatory effects. Changes in body weight were also monitored and, at the end of the experiment, plasma was collected to determine plasma fibrinogen (Exner et al., Amer. J. Clin. Path. 71: 521-527).

Results 25 The results are shown in the following table (Table VII).

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The following describes the invention without, however, limiting it. In the examples, the ether is diethyl ether and the solvents were removed in vacuo.

Example 1 5 [[(2-Nonyloxy) phenyl] methyl] triphenylphosphonium bromide 2-Hydroxybenzaldehyde (110 g) was alkylated by mixing this compound with 1-brominonane (180 g), dry potassium carbonate and dimethylformamide (800 ml). This mixture was heated at 80 ° C for 14 hours. Hexane and water were then added and the hexane extract was concentrated and the residue was distilled to give 2-nonyloxybenzaldehyde (210 g), b.p. 121 ° C (0.3 mmHg). Solutions of the 2-nonyloxybenzal-15 dehyde prepared above (100 g) in ethanol (1,000 mL) at 10 ° C were reduced by treatment with excess sodium borohydride (6 g) and after further stirring at 15 ° C. For 20 minutes at room temperature, the compound 2-nonyloxybenzyl alcohol was isolated with a new 20 ml of hexane. Removal of hexane in vacuo gave crude 2-nonyloxybenzyl alcohol (98 g). The resulting 2-nonyloxybenzyl alcohol was added to a mixture of triphenylphosphine hydrobromide (144 g) in acetonitrile (500 ml) and the resulting solution was refluxed for 14 hours. Removal of the solvents in vacuo and crystallization of the residue from tetrahydrofuran / ethyl ether gave pure [[2- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide (208 g).

Example 2 [(2-Hydroxyphenyl) methyl] triphenylphosphonium bromide 2-Hydroxybenzyl alcohol was treated with triphenylphosphine hydrobromide in acetonitrile as described in Example 1 to give [(2-hydroxy-35-phenyl) methyl] triphenylphosphonium bromide.

41 84345

Example 3 (All-E) -9- (2-Hydroxy-phenyl) -3,7-dimethyl-2,4.6.8-nonatetraenoic acid ethyl ester

A solution of [(2-hydroxyphenyl) methyl] tri-5-phenylphosphonium bromide (1 mol) in tetrahydrofuran was converted to the ylide at -35 ° C with a solution of n-butyllithium in hexane (2.1 molar equivalents) and then treated with 7- formyl-3-methyl-2,4,6-octa-trienoic acid ethyl ester (1 mol) and stirred at 10-70 ° C for a further 15 minutes. Isolation of the organic products with hexane / ethyl acetate (4: 1 v / v) and dilution with inorganic acid (2M aqueous HCl) gave pure (all-E) -9- (2-hydroxyphenyl) -3,7- dimethyl-2,4,6,8-nonatetraenoic acid ethyl 15 ester (90% yield) after chromatography and then crystallization from dichloromethane / hexane. Example 4 (All-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) in 1,2-epoxybutane (750 ml), refluxed for 30 minutes, cooled, poured into ether / hexane (ti-25 volumes 1: 1), filtered and evaporated to dryness. The residue was then crystallized from hexane / ether to give (all-E) 9- (2-hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester (yield 38%), m.p. . 143-145 ° C.

Example 5 (all-E) -9- [2- (Nonyloxy) phenyl] -3,7-dimethyl-2,4.6.8-nonatetraenoic acid

A solution of [[2- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide (150 g) in tetrahydrofuran (1100 mL) was cooled to -50 ° C to give 42 8 4 345 as a solid salt. fine suspension. To this mixture was added a solution of n-butyllithium in hexane (180 mL, 1.6 molar) to give a solution of the ylide. The mixture was then further stirred for 15 minutes at -40 ° C, cooled to -70 ° C and treated with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (65 g) dissolved in tetrahydrofuran (250 ml). ). Addition of hexane and aqueous methanol (40%) to the reaction mixture followed by evaporation of the hexane extract to dryness gave (all-E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6, 8-Nonatetraenoic acid ethyl ester (64 g, 58% yield), m.p. 52-53 ° C. This ester was then hydrolyzed to form a solution of this ester (70 g) in ethanol (1000 mL). This solution was treated with an aqueous solution of potassium hydroxide (80 g in 400 ml of water) and refluxed for one hour. Water and aqueous inorganic acid were then added, and the solids were extracted into chloroform. Evaporation of this organic extract to dryness and crystallization of the residue from ethyl acetate / hexane-20 gave (all-E) -9- [2-nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid (38 g). ), sp. 102-103 ° C.

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

A mixture of sodium hydride (24 g, 50% by weight in mineral oil) and dimethylformamide (1000 ml) at 10 ° C was treated with (all-E) -9- (2-hydroxyphenyl) -3,7-dimethyl With -2,4,6,8-nonatetraenoic acid ethyl ester (0.4 eq.). The resulting mixture was then stirred at room temperature until hydrogen evolution ceased, to give the sodium salt of (all-E) -9- (2-hydroxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. To this brine was then added a solution of 1-nonyl tosylate (0.5 eq.) In dimethyl-43 84345 liformamide (200 mL) and the reaction mixture was stirred for 14 hours at 45 ° C. The hexane / water mixture was then carefully added and the hexane extract was evaporated to dryness and the residue was purified by chromatography on silica gel.

Crystallization from hexane then gave pure (all-E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nona-tetraenoic acid ethyl ester. Hydrolysis of this ester as in Example 5 gave (all-E) -9- [2-nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid.

Example 7 (Al-E) -3,7-Dimethyl-9- [2 - [(2,2-dimethyloctyl) oxy] phenyl] -2,4,5,8-nonatetraenoic acid 2-Hydroxybenzaldehyde was condensed With 2,2-dimethyl-1-iodooctane to give 2- (2,2-di-15-methyloctyloxy) benzaldehyde, which was reduced to 2- (2,2-dimethyloctyloxy) benzyl alcohol and then converted to [[2- (2,2-dimethyloctyloxy) phenyl] methyl] triphenylphosphonium bromide as in Example 1. Condensing this phosphonium bromide with 7-formyl-3-methyl-20'-2,4,6-octatrienoic acid ethyl ester as described in Example 3 and then hydrolyzing , as in Example 5, gave (all-E) -3,7-dimethyl-9- [2 - [(2,2-dimethyloctyl) oxy] phenyl] -2,4,5,8-nonatetraenoic acid, m.p. 113-117 ° C from dichloromethane / hexane-25).

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

Lithium octanoate, prepared from octanol and n-30 butyllithium, was condensed in tetrahydrofuran / hexane-dimethylformamide with 2-bromobenzyl bromide to give 2- (octyloxy) methyl bromobenzene. This material was treated with n-butyllithium in ether / hexane and then treated with paraformaldehyde to give 2- (octyloxy) methylbenzyl alcohol. This material was then treated with triphenylphosphonine bromide to give t [2 - [(octyloxy) methyl] phenyl] methyl] triphenylphosphonium bromide. Condensation of this material with 7-formyl-3-methyl-2,4-octatrienoic acid ethyl ester as in Example 3 followed by hydrolysis as in Example 5 gave (all-E) -3,7-dimethyl- 9- [2 - [(octyloxy) methyl] phenyl] -2,4,6,8-nonatetraenoic acid, m.p. 120-121 ° C (from dichloromethane / hexane).

Example 9 (all-E) -9- [2-chloro-6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid 2-Chloro-6-hydroxy-benzaldehyde was alkylated 1 with brominonane as in Example 1 to give 2-chloro-6-nonyloxy-benzaldehyde. Reduction with sodium borohydroxide as in Example 1 gave 2-chloro-6-nonyloxy-benzyl alcohol, which was treated with triphenylphosphine hydrobromide in acetonitrile as in Example 1 to give [(2-chloro-6-nonyl-20-oxyphenyl) methyl] triphenyl] triphenyl] triphenyl] triphenyl . Condensation of the condenser with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 gave (all-E) -9- [2-chloro-6- (nonyloxy) phenyl] -3 , 7-dimethyl-2,4,6,8-style nonatetraeenihappo-ethyl ester. Ester 25 was hydrolyzed as in Example 5 to give (all-E) -9- [2-chloro-6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, m.p. . 129-131 ° C (from ethyl acetate / hexane).

Example 10 (All-E) -9- (5-methoxy-2-nonyloxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid 5-Methoxy-2-hydroxybenzaldehyde was alkylated with nonyl bromide. and reduced with sodium borohydride as in Example 1 to give 5-methoxy-2-35 nonyloxybenzyl alcohol, which was treated with tri-45,84345 with phenylphosphine hydrobromide to give [(5-methoxy-2-nonyloxyphenyl) methyl] phenyl] phenyl phosphonium bromide. Condensation of this material with 7-formyl-3-methyl-2,4,6-octa-trienoic acid ethyl ester as in Examples 3 and 5 followed by hydrolysis as in Example 5 gave (all-E) -9- (5-methoxy). -2-Nonyloxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, m.p. 125-126 ° C (without methanol).

Example 11 10 (all-E) -9- [2- (8-hydroxyoctyloxy) phenyl ],7,7-dimethyl-2,4,6,8-nonatetraenoic acid (all-E) -9- (2- hydroxyphenyl) -3,7-dimethyl-2,4.6.8-nonatetraenoic acid ethyl ester prepared as described in Example 6 was treated with dimethylformamide 1,8-dihydroxyoctane monotosylate as previously described in Example 6 to give All (E) -9- [2- (8-Hydroxy-octyl-oxy] -phenyl-3,7-diethyl-2,4,6,8-nonatetraenoic acid ethyl ester after chromatography on silica gel. Hydrolysis was carried out as in Example 5 (all-E ) -9 - [[2 - [(8-hydroxy-octyl-oxy] -phenyl] -3,7-dimethyl-phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, mp 122-123 ° C (from ethyl acetate).

Example 12 (all-E) - [5- (2-Nonyloxyphenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium bromide 2- (Nonyloxy) benzaldehyde (62 g) dissolved in acetone (500 ml) was treated with aqueous sodium hydroxide solution ( 100 ml, 1 mol) at room temperature for 18 hours, then brine and ethyl acetate / hexane (1: 1 by volume) were added, and the organic phase was concentrated and then crystallized from hexane to give 4- (2-nonyloxyphenyl). ) -3-buten-2-one (53 g).

A solution of 4- (2-nonyloxyphenyl) -3-buten-46 84345 2-one (58 g) in tetrahydrofuran (200 ml) was added to a solution of vinylmagnesium bromide in tetrahydrofuran (200 ml, 1.6 mol. diluted to 1 liter by addition of tetrahydrofuran) at -30 ° C. At the end of the addition, the mixture was stirred at 0 ° C for 30 minutes, quenched with saturated aqueous ammonium chloride (100 mL) and ether (2 L) and filtered free of solid. Concentration of the organic extract and purification by chromatography on silica gel gave 10 (E) -5- (2-nonyloxyphenyl) -3-hydroxy-3-methyl-1,4-pentadiene (40 g) as an oil.

A solution of (E) -5- (2-nonyloxyphenyl) -3-hydroxy-3-methyl-1,4-pentadiene (66 g) in acetonitrile (250 ml) was added to a slurry of triphenylphosphine. hydrobromide (66 g) in acetonitrile (300 ml) at 10 ° C. After warming to room temperature, the mixture was stirred at this temperature for two hours to give a solution. This solution was then extracted with hexane (2 x 250 mL) and the acetonitrile layer was concentrated to 20 (approximately 400 mL) and cooled to -10 ° C. The solids were filtered off, washed with acetonitrile, hexane and dried to give pure (all-E) - [5- (2-nonyloxyphenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium bromide (21 g).

Example 13 Starting from (all-E) - [5- (2-nonyloxyphenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium bromide and using the procedure of Example 5, the ylide was reacted with 3-formyl-2-butenoic acid ethyl ester. to give (all-E) -9- (2-nonyloxyphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid after chromatography on silica gel after hydrolysis and hydrolysis with aqueous ethanolic potassium hydroxide as in Example 5.

35 47 84 345

Example 14 (Z, E, E, E) -9- [2- (Nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid (all-E) -9- t2- (Nonyloxy) phenyl] -3,7-dimethyl-5,4,6,8-nonatetraenoic acid ethyl ester (10 g) was dissolved in hexane (200 ml) with iodine (0.5 g) and stirred. at room temperature for 30 minutes. The hexane was washed free of iodine with aqueous sodium thiosulfate (10% by weight), dried and evaporated to dryness to give a mixture of double bond isomers. Separation, chromatography on silica gel, gave pure (Z, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4.6.8-nonatetraenoic acid ethyl ester (1.5 g). Hydrolysis with aqueous ethanolic potassium hydroxide under reflux gave pure (Z, E, E, E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2.4.6.8-nonatetraenoic acid; mp. 135-136 ° C.

Example 15 (E, E, E, Z) -9- [2- (Nonyloxy) phenyl] -3,7-dimethyl-20'-2,4,6,8-nonatetraenoic acid

The mother liquor obtained by crystallization of (all-E) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nona-tetraenoic acid ethyl ester in Example 5 was a mixture of different isomers. Purification by chromatography gave 80% pure ethyl ester which, after hydrolysis as in Example 5, gave pure (E, E, E, Z) -9- [2- (nonyloxy) phenyl] -3,7-dimethyl - 2.4.6.8-nonatetraenoic acid; mp. 105-109 ° C.

Example 16 2-Decyl-1-bromobenzene

Nonylmethyltriphenylphosphonium bromide (0.1 mol) was converted to the ylide in tetrahydrofuran (200 ml) with n-butyllithium (0.1 molar equivalents; 1.6 mol in hexane) at -10 ° C.

2-Bromobenzaldehyde (0.09 mol) in 48 8 4 345 tetrahydrofuran (25 ml) was then added and, after stirring for a further 30 minutes at 0 ° C, hexane and aqueous methanol (40:60) were added. The hexane extract was concentrated and the residue was distilled to give 2-5 (1-decenyl) -1-bromobenzene (90%).

This material was dissolved in hexane with palladium-on-carbon catalyst (10%) and hydrogenated at room temperature and pressure until the olefin bond was saturated. The solids were filtered off and triturated with hexane and distillation of the residue to give pure 2-decyl-1-bromobenzene (80%); tr. 120 ° C (0.001 mmHg).

Example 17 2-Decyl-1-hydroxymethylbenzene 2-Decyl-1-bromobenzene (0.1 mol) dissolved in ether (150 ml) was treated with n-butyllithium (0.1 eq .; 1.6 mol in hexane) and the mixture was stirred at room temperature for two hours.

Dry paraformaldehyde (0.2 mol-20 flame equivalents) was then added and the mixture was further stirred for 18 hours at room temperature.

Water and more ether were then added and the ether extracts were dried and evaporated to dryness. The residue was chromatographed to give pure 2-decyl-25β-1-hydroxymethylbenzene (75% yield).

Example 18 (Al-E) -9- (2-Decylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid 2-Decyl-1-hydroxymethylbenzene was converted to the phosphonium salt with triphenylphosphonium hydrobromide in acetonitrile by the method of Example 1. This salt was then treated with n-butyllithium in tetrahydrofuran as above and then treated with 7-formyl-3-methyl-2,4,6-heptatrienoic acid methyl ester as above.

49 84 345

Purification of the crude condensation product by chromatography on silica gel followed by hydrolysis i a.a with base gave pure (all-E) -9- (2-decylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid; mp. 107-5108 ° C (from hexane-ether).

Example 19 (all-E) -9- (2-Octylamino-phenyl) -3,7-dimethyl-2,4,6,8-nonat-tetraenoic acid ethyl ester 2-Aminobenzyl alcohol (1 mol) was treated with oc-10-tanoyl chloride (2.2 mol). with dichloromethane-triethylamine at 0 ° C. After 30 minutes at 10 ° C, the mixture was washed with water and the ether was distilled off. The crude residue was dissolved in tetrahydrofuran (2,000 ml), treated with aqueous sodium hydroxide solution (1N, 1,500 ml) and stirred at room temperature for three hours.

Addition of water and ether gave crude hydroxymethyloctylamide. Purification by chromatography gave pure octylamide (85%).

This material (100 g) was dissolved in tetrahydrofuran (500 ml) and added to a slurry of lithium aluminum hydride (2 molar equivalents) in tetrahydrofuran (1,000 ml). The mixture was then heated at reflux for eight hours, cooled to 0 ° C and quenched with aqueous sodium sulfate (100 mL).

The solids were filtered off, the solvents removed in vacuo and the residue purified by chromatography on silica gel to give pure 2-hydroxymethyl-N-octylamine (75 g).

This material was dissolved in acetonitrile (300 ml) with triphenylphosphine hydrobromide (1.1 eq.) And the mixture was heated at reflux for 24 hours and then evaporated to dryness. The residue was extracted with heating with ether to give the phosphonium salt as a white solid.

mp 84,345 This material was converted to the corresponding ylide with n-butyllithium (1.5 molar equivalents) and stirred at 0 ° C for 1 h. Excess 7-formyl-3-methyl-2,4,6-heptatrienoic acid ethyl ester 5 (1.5 molar equivalents) in tetrahydrofuran was then added 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 the crude coupling product. Purification by chromatography on silica gel and crystallization from hexane gave pure (ali-E) -9- (2-octylaminophenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester (25%); mp. 38-40 ° C.

Example 20 2-Fluoro-6-nonyloxybenzyl alcohol A solution of 3-fluorophenol (100 g) in dimethylformamide (1000 ml) with potassium carbonate (165 g) was treated with allyl bromide (115 g) and heated to 80 ° C. at 18 hours.

Water and hexane were then added and the hexane extract was washed with aqueous sodium hydroxide (5%), brine and evaporated to dryness to give allyl ether (155 g). This material (134 g) 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. This mixture was dissolved in dimethylformamide (2,000 ml) containing 1-brominonane (170 g) and potassium carbonate (150 g) and heated at 80 ° C for 16 hours. Dilution with water and extraction with hexane gave a dry mixture of the products. Distillation gave a mixture of 3 - [(2-fluoro-6-nonyloxy) phenyl] butene and 3 - [(3-fluoro-2-nonyloxy) phenyl] butene (186 g), b.p. 120-125 ° C @ 0.1 mm.

This mixture of isomers (185 g) in dimethyl sulfoxide (1000 ml) with potassium tert-butyl 35 filtrate (1.5 g) was allowed to stand at room temperature si 84345 for six hours. 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.

This mixture of isomers (175 g) was dissolved in a mixture of dichloro-5 methane and methanol (9: 1, 2,000 ml) and ozone was bubbled into the mixture at -40 ° C for eight hours. After this time, the reaction mixture was poured into a mixture of water, hexane and dimethyl sulfide (100 ml), and stirred at room temperature for 1 hour.

The hexane extract was washed (with water), dried (MgSO 4), treated with dimethyl sulfide (50 mL) and allowed to stand at room temperature for 16 hours.

Removal of the solvents gave a mixture of aldehydes 2-fluoro-6-nonyloxybenzaldehyde and 4-fluoro-2-nonyloxy-15 benzaldehyde (155 g).

This mixture of aldehydes (150 g) was treated in ethanol (2000 ml) with sodium borohydride (15 g) at 5 ° C and then stirred at room temperature for 30 minutes. Water (1500 ml), brine (500 ml) were then added and the mixture of alcohols was extracted into hexane. Removal of the solvents and chromatography of the residue on silica gel (5% ethyl acetate-hexane) gave pure 2-fluoro-6-nonyloxy-benzyl alcohol (76 g).

Example 21 (all-E) -9- [2-Fluoro-6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid

A mixture of 2-fluoro-6-nonyloxybenzyl alcohol (19 g) and triphenylphosphine hydrobromide (26 g) in acetonitrile (250 ml) was heated at reflux for 14 hours and then evaporated to dryness to give [[(2-fluoro-6- nonyloxy) phenyl] methyl] triphenylphosphonium bromide (42 g). This phosphonium salt was dissolved in tetrahydrofuran (600 mL), cooled to -50 ° C, and treated with n-butyllithium (45 mL, 1.6 M in hexane). After further stirring for 15 minutes at -50 ° C, 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (8.4 g) was added and the reaction mixture was heated. to room temperature and stirred for a further 15 minutes. Hexane was then added and the mixture was washed with water, 40% aqueous methanol and dried (MgSO 4). Evaporation of the hexane extract to dryness and purification by chromatography (5% ether-hexane) gave the pure trans isomer (11 g).

Crystallization from hexane-ethyl acetate gave (all-E) -9- [2-fluoro-6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. ethyl ester (9.5 g).

A solution of the ester (6.5 g) in ethanol (150 ml) was treated with a solution of potassium hydroxide (7 g) in water (40 ml) and heated to reflux for 1 hour. The cooled reaction mixture was poured into cold aqueous hydrogen chloride solution, and the acid was extracted into chloroform. Removal of the solvents and crystallization from hexane-ethyl acetate gave pure (all-E) -9-20 [2-fluoro-6-nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid, m.p. . 107-109 ° C.

Example 22 Capsule recipes:

Lot Ingredients mg / kap- mg / kap- mg / capsule selenium 1. (all-E) -9- [2-nonyloxy.) - 15 30 60 phenyl] -3,7-dimethyl-2,4 , 6,8-nonatetraenoic acid 30 2. Lactose 239 224 194 3. Starch 30 30 30 4. Talc 15 15 15 5. Magnesium stearate __. L___ ____1___ ___1___

Capsule fill weight 300 mg 300 mg 300 mg 35 53 84345

Method: 1) Mix batches 1-3 in a suitable mixer.

2) Add talc and magnesium stearate and stir briefly.

5 3) Encapsulate with a suitable encapsulation machine.

Example 23

Capsules otherwise prepared by the method of Example 22, except that the active ingredient (batch 1) was (all-E) -9- [2-fluoro-6- (nonyloxy) phenyl] -3,7-dimethyl-10'-3,4, 6,8-nonatetraeenihappo.

Example 24

Tablet prescription (wet granulation)

Lot Ingredients mg / tab- mg / tab- mg / tablet counter 15 1. (all-E) -9- [2- (nonyloxy) -100,250,500 phenyl] -3,7-dimethyl-2,4 , 6,8-nonatetraenoic acid 2. Lactose 98.5 147.5 170 3. Polyvinylpyrrolidone (PVP) 15 30 40 20 4. Modified starch 15 30 40 5. Maize starch 15 30 40 6. Magnesium stearate 1.5 2.5 5

Tablet weight 245 mg 490 mg 795 mg

Method: 1) Mix batches 1, 2, 4 and 5 in a suitable mixer, granulate with PVP and dissolve in water / alcohol. Dry the granulate. Pour the dry granulate through a suitable roller.

2) Add magnesium stearate and squeeze in a suitable 30 press.

Example 25

The tablet was prepared otherwise in the same manner as in Example 24, except that the active ingredient (batch 1) was (all-E) -9- [2-fluoro-6- (nonyloxy) phenyl] -3,7-dimethyl-35-2, 4,6,8-nonatetraeenihappo.

54 84 345

Example 26

Tablet recipes (direct compression)

Lot Ingredient mg / tab- mg / tab- mg / tablet braill bra 5 1. (all-E) -9- [2- (nonoyl) -15-3060 phenyl] -3,7-dimethyl-2,4 , 6,8-nonatetraenoic acid 2. Lactose 207 192 162 3. Avicel 45 45 45 10 4. Direct compression starch 30 30 30 5. Magnesium stearate 3_____ _ 3 ...... 3____

Tablet weight 300 mg 300 mg 300 mg

Method: 1) Mix batch 1 with the corresponding amount of lactose-15 si. Mix well.

2) Mix with batch 3, 4 and the remaining batch 2. Mix well.

3) Add magnesium stearate and stir for three minutes.

20 4) Squeeze with a suitable punch.

Example 27 Capsule Recipe.it

Batch Ingredients mg / capsule mg / capsule mg / capsule cellulose 25 1. (all-E) - (3,7-dimethyl) -9-153060 [2 - [(8-hydroxyoctyl) oxy ] phenyl] -2,4,6,8-nonatetraenoic acid 2. Lactose 239 224 194 30 3. Starch 30 30 30 4. Talc 15 15 15 5. Magnesium stearate 1____ 1 1

Capsule fill weight 300 mg 300 mg 300 mg

Method: 35 1) Mix batches 1-3 in a suitable mixer.

55 84 345 2) Add talc and magnesium stearate and mix for a short time.

3) Encapsulate with a suitable encapsulation machine. Example 28 5 Tablet recipes (wet granulation)

Lot Ingredient mg / tab- mg / tab- mg / tablet braill bra 1. (all-E) -3,7-dimethyl-9-100 250 500 [2 - [(octyloxy) methyl] -10 phenyl] -2 , 4,6,8-nonatetraenoic acid 2. Lactose 98.5 147.5 170 3. Polyvinylpyrrolidone 15 30 40 4. Modified starch 15 30 40 15 5. Maize starch 15 30 40 6. Magnesium stearate 1.5 2.5 5

Tablet weight 245 mg 490 mg 795 mg

Method: 1) Mix batches 1, 2, 4 and 5 in a suitable mixer, granulate with PVP and dissolve in water / alcohol. Dry the granulate. Pour the dry granulate through a suitable roller.

2) Add magnesium stearate and squeeze with a suitable press.

Example 29 [[2-Trifluoromethyl-6- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide

A mixture of α, α, α-trifluoro-m-cresol (51 g), 1-brominonane (70 g), potassium carbonate (100 g) in dimethylformamide was heated at 85 ° C for 48 hours. Addition of water and hexane gave pure (3-trifluoromethyl) phenylnonyl ether (89 g); tr. 115 ° C / -0.1 mmHg. This product (89 g) in ether (1.5 L) at -20 ° C was stirred with n-butyllithium 35 (1.5 M in hexane; 233 mL) and then stirred twice. si hours at room temperature. This mixture was then cooled to -40 ° C, treated with excess dry dimethylformamide (40 ml) in ether (100 ml), warmed to 0 ° C and then treated with water. Extraction with hexane and chromatography on silica gel (5% ether-hexane) gave (2-trifluoromethyl-6-nonyloxy) benzaldehyde (35 g). Reduction of this product with sodium borohydride in ethanol according to the procedure described in Example 1 gave (2-trifluoromethyl-6-nonyl-10-oxy) benzenemethanol (32 g) after chromatography on silica. This material (31 g) was converted to [[2-trifluoromethyl-6- (nonyloxy) phenyl] methyl] triphenylphosphonium bromide by reacting it with triphenylphosphine hydrobromide according to Method 15 of Example 1.

Example 30 (all-E) -9- [2-Trifluoromethyl) -6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid [[2-trifluoromethyl-6- (nonyloxy) phenyl] methyl-20-yl] triphenylphosphonium bromide (97 mmol) in tetrahydrofuran (600 mL) was modified by reaction with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (all-E ) -9- [2- (trifluoromethyl) -6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester according to the procedure described in Example 3.

Purification by chromatography and crystallization from hexane gave pure ethyl ester (41%). Hydrolysis (5.2 g) as in Example 5 gave pure (all-E) -9- [2- (trifluoromethyl) -6- (nonyloxy) phenyl] -30,3,7-dimethyl-2,4,6 , 8-nonatetraenoic acid (3 g); mp.

135-136 ° C (from ethyl acetate-hexane).

Example 31 (all-E) -9- [2- (Hexyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid 35 [[2- (hexyloxy) phenyl] methyl] triphenylphospho-57 4,345 Nium bromide prepared by the method of Example 1 by reacting 2-hydroxybenzaldehyde with 1-bromohexane was converted to (all-E) -9- [2- (hexyloxy) phenyl] -3,7-diethyl-2, To 4,6,8-nonatetraenoic acid, m.p. 137-5138 ° C (from ethanol) by the method of Example 3.

Example 32 [[2- (Nonyloxy) -5- (hydroxy) phenyl] methyl] triphenylphosphonium bromide

A solution of 4-bromophenol (1 mol) in tetrahydro-10 furan (500 ml) was added to a slurry of sodium hydride (1.17 mol) in dimethylformamide (1.2 liters) at 25 ° C. After completion of the reaction, allyl chloride (1.32 mol) was added, and after stirring for a further three hours at 45 ° C, the product was isolated with water and hexane. Distillation gave allyl (4-bromophenyl) ether, b.p. 65-67 ° C / 0.1 mm (82%). This material was heated at 195 ° C with dimethylanaline for four hours and then distilled to give 2-allyl-4-bromophenol (0.81 mol). A solution of this material (0.81 mol) in tetrahydrofuran (200 ml) was added to a mixture of 1-brominonane (0.8 mol), sodium hydride (0.92 mol), potassium iodide (1 g) in dimethylformamide. (1 liter) at 25 ° C. After the evolution of hydrogen ceased, the mixture was heated at 50 ° C for 14 hours, cooled, added to excess water and extracted with hexane. Distillation gave nonyl (2-allyl-4-bromophenyl) ether (256 g); tr. 147-156 ° C / 0.1 mm. This material (255 g) in dimethyl sulfoxide (1 liter) and tetrahydrofuran (0.5 liters) was heated at 35-40 ° C with potassium tert-butylate (2 g) for two hours and then quenched with acetic acid. (5 ml) and water. Isolation of the reaction products with hexane gave pure 1- [2- (nonyloxy) -5- (bromo) phenyl) propene (234 g); tr. 145-155 ° C under a vacuum of 0.1 mm. A solution of the above substance (0.56 to 35 mol) in tetrahydrofuran (600 ml) was converted into Grig-58 84 345 nard reagent with magnesium (1 mol) at 55 ° C for three hours. After completion of the reaction, the mixture was cooled to 0 ° C and treated with trimethylborate (0.75 mol) in ether (200 ml). After stirring for a further 30 minutes at 25 ° C, the mixture was cooled to 0 ° C and treated with ammonium chloride (10%) and hydrogen peroxide (10%, 500 ml) and stirred for a further hour at 25 ° C. . Addition of water and hexane gave the crude product after removal of the hexane in vacuo. The crude product was passed through a pad of silica gel to give para- [2- (1-propenyl-4- (nonyloxy) phenyl] phenol (73 g). Acetylation of this material (0.8 g) with acetyl chloride and triethylamine in dichloromethane gave [2- (1-propenyl) -4- (nonyl-15-oxy) -1-acetoxy)] benzene (89%). This material (99 g) was dissolved in a mixture of methanol (150 mL) and dichloromethane (1.5 L aa) and treated with ozone at -40 ° C until all starting material was consumed. Dimethyl sulfide (50 ml) and water (500 ml) were then added, followed by vigorous stirring for 30 minutes at 25 ° C, the organic phase dried (MgSO 4) and evaporated to dryness to give [2- (nonyloxy) -5- (acetoxy)] benzaldehyde (83 g). Reduction of this material (80 g) with sodium borohydride (6 g) in ethanol (1 L) at 20 ° C for 25 hours gave crude [2- (nonyloxy) -5- (acetoxy)] benzenemethanol, which was treated immediately with with an aqueous solution of lumium hydroxide (300 ml, 40%) in ethanol (1 liter) for 30 minutes at 60 ° C. Acidification with aqueous acid (6 molar hydrochloric acid) and extraction with chloroform gave the crude product to dryness. Extraction of the residue with warm hexane gave pure [3- (hydroxymethyl) -4- (nonyloxy)] phenol (63 g) as a solid. A solution of this material (62 g) in acetonitrile (0.5 L) and tri-. 35 in phenylphosphine hydrobromide (86 g), heated to reflux for 14 hours and evaporated to dryness at 50 ° C to give [[2- (nonyloxy) 5- (hydroxy) phenyl] methyl] triphenylphosphonium bromide as a glass. .

Example 33 (all-E) -9- [5-hydroxy-2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid [[2- (nonyloxy) -5- ( hydroxy) phenyl] methyl] triphenylphosphonium bromide (0.23 mol) was treated in tetrahydrofuran (1.5 liters) at -70 ° C with n-butyllithium (1.6 mol in hexane; 315 ml) and then treated with ethyl 8-formyl-3,7-dimethyl-2,4,6-octatrienoate (59 g) in tetrahydrofuran. The mixture was then warmed to -15 ° C, acidified with vinegar and extracted with ether and aqueous methanol (40%). Purification by chromatography on silica gel gave pure (all-E) -9- [5-hydroxy-2- (nonyloxy) phenyl] -3,7 dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. Hydrolysis of this ester (6 g) by the method of Example 5 gave (all-E) -9- [5-hydroxy-2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraene -acid (3.5 g); mp. 170-173 ° C (from ethyl acetate).

Example 34 (all-E) -9- [2- (Nonyloxy) -5- (2,2,2-trifluoroethoxy-25) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ( All-E) -9- [5-hydroxy-2- (nonyloxy) phenyl] -3,7 dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester (4.4 g) was heated at 90 ° C for 72 hours. with potassium carbonate (7 g) and 2,2,2-trifluoroethyl p-toluenesulfonate (6 g) in dimethylformamide (200 ml). Work-up with water and hexane followed by purification with silica gave pure ethyl ester (0.75 g). Hydrolysis of this ester (0.9 g) by the method of Example 5 gave pure (all-E) -9- [2- (nonyloxy) -5-35 (2,2,2-trifluoroethoxy) phenyl] -3,7-dimethyl -2,4,6,8-nonatetraenoic acid (0.6 g) after filling with a mixture of tetrahydrofuran and hexane and 608 4 3 4 5; mp. 121 “C.

Example 35 (Z) - [[2- (1-decenyl) phenyl] methyl] triphenylphosphonium bromide and (E) - [[2- (1-decenyl) phenyl] methyl] -5-triphenylphosphonium bromide 2- (1-decenyl) The (E, Z) mixture of -1-bromobenzene prepared in Example 16 (1: 4) was converted to the (E, Z) mixture of 2- (1-decenyl) -1-hydroxymethylbenzene by the method of Example 17. This mixture was chromatographed on grapholine on silica gel to give pure (E1 and (Z) alcohols. Reaction of each of these isomers with triphenylphosphine hydrobromide as in Example 1 gave the corresponding phosphonium salts, i.

(Z) - [[2- (1-decenyl) phenyl] methyl] triphenylphosphonium bromide and (E) - [[2- (1-decenyl) phenyl] methyl] triphenylphosphonium bromide.

Example 36 (all-E) -9- [2- (1-Decenyl) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid 20 (E) - [[1- (1-Decenyl) phenyl] methyl] triphenylphosphonium bromide was converted to (Ali E) -9- [2- (decenyl) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester by the method described in Example 3. Hydrolysis with a base as in Example 5 and crystallization of crude acid-25 from acetonitrile gave (all-E) -9- [2- (1-decenyl) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid. , sp.

105 - 107 CC.

Example 37 (E, E, E, E, Z) -8- [2- (1-Decenyl) phenyl] -3,7-dimethyl-30-2,4,6,8-nonatetraenoic acid

The title compound was prepared in the same manner as in Example 36 using (Z) - [[2- (1-decenyl) phenyl] methyl] triphenylphosphonium bromide. Hydrolysis of the ethyl ester and crystallization of the crude acid from ether gave pure (E, E, E, E, Z) -9- [2- (1-decenyl) phenyl] -3,7 dimethyl-2,4,8,8-nonatetraenoic acid, m.p. 103 - 105 “C.

Claims (10)

1, A process for the preparation of α-ti-inflammatory and immunosuppressive phenylnonatetraenoic acid derivatives of the formula * 1 *, *. I7 lie B n ^ A ^ / CH = CH-C = CH-CH = CH-C = CH-R5 i | / -S. ΊΓ 9 8 7 6 5 4 3 2 ′ ′ -S · 1- 1- x-r 4 where hydrogen, chlorine, fiaor or trifluoromethyl; R 2 is hydrogen, hydroxy, lower alkoxy or trifluoromethyl-lower alkoxy; R 2 is a straight chain alkyl group, soin containing r A - 10 carbon atoms, or -CH 2 (CH 2) n CH 2 OH; X is -CHO-, -CH-, -O-, R10 R10 -C = CH- or -N-; R_ is the COOR; and R_, R0, Rn and i in 5 9 7 and 9 Is hydrogen or lower alkyl; n is 6 or 7; and for the preparation of the asi of iuLGu iidy ijul ci in noble cdi, where Rx is hydrogen, characterized in that a) a compound of the formula Rl TO) I Y 30 TCR. 4- is reacted with a compound of the formula or b) a compound of the formula 2. A process according to claim 1, characterized in that compounds of formula I are prepared in which R 2 is hydrogen, chlorine or fluorine; R 2 is hydrogen or lower alkoxy; R is an 8 to 10 carbon atoms containing 4 alkyl having a straight chain of 8 or 9 carbon atoms; X is 66 -CH-O-, -CH-, -O- or -N-; R 5 is COORg and n, R 2, RQ, R 10 R 10 R 10 R 9 and R 2 q are defined in claim 1; or their salts when R 9 is hydrogen. 5 Process according to claim 1, characterized in that a compound of the formula I is 9- [2-chloro-6- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraene acid produced. Process according to claim 1, characterized in that a compound of formula I (ali-E) -9- [2-fluoro-6 - (nonyloxy) phenyl] -3,7-dimethyl-2.4 .6.8- Nonatetraenoic acid is prepared. 5. A process according to claim 1, characterized in that a compound of formula I 3,7-dimethyl-9 - (5-methoxy-2-nonyloxy-phenyl) -2,4,6,8-non-atetraenoic acid is prepared. . 5. Yl 7 YY OR 10 is reacted with a compound of formula R0 I II xvii 15HC-C = CH-C-OR'9 or c) a compound of formula 20 ",? 7? 8? r 2 IT ch = ch-c = ch-ch = ch-c = ch-c-OR'9 viii OH is reacted with a compound of the formula R ^ Z, wherein R and Rg is as defined above; Rg is lower alkyl; Y is aryl, Z is a leaving group and Z * is a halide ion; and, if desired, the carboxyl alkyl ester group -COOR if desired, the acid is transformed into a pharmaceutically acceptable salt. Process according to claim 1, characterized in that a compound of formula I 9 - [2- (nonyloxy) phenyl] -3,7-dimethyl-2,4,6,8-nonatetraenoic acid is prepared. 7. A process according to claim 1, characterized in that a compound of formula I (all-E) -5,7,7-dimethyl-9- (2-octylaminophenyl) -2,4,6,8-nonatetraenoic acid is prepared. 25 Process according to claim 1, characterized in that a compound of formula I (all-E) -3,7-dimethyl-9- [2 - [(8-hydroxyoctyl) oxy] phenyl] - 2.4.6.8- nonatetraenoic acid is prepared. 9. A process according to claim 1, characterized in that a compound of formula I (all-E) -8- [2- (trifluoromethyl) -6-nonyloxy) phenyl] -3,7-dimethyl -2,4,6,8-nonatetraenoic acid is prepared. Process according to claim 1, characterized in that a compound of formula I 9- (2-decylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid is prepared.