GB1560699A - 2-or 3-thienyl-polyenes - Google Patents

Abstract

The compounds of the formula I <IMAGE> in which one of the groups R1 or R2 is <IMAGE> and the other of the groups R1 or R2 and R3 and R4 are hydrogen, lower alkoxy-lower alkyl, hydroxymethyl, halogen, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)amino-lower alkyl, di(lower alkyl)amino-lower alkyl, hydroxyl, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoylamido or a nitrogen-containing heterocycle, and R5 is formyl, lower alkoxymethyl, lower alkanoyloxymethyl, carboxyl, lower alkoxycarbonyl, lower alkenoxycarbonyl, lower alkynoxycarbonyl, di(lower alkyl)carbamoyl or N-heterocyclylcarbonyl, and their pharmaceutically acceptable salts inhibit the growth of tumours. They are prepared by assembling the polyene side chain from an aliphatic component and from a thienyl component by the principle of the Wittig reaction.

Description

(54) 2- OR 3-THIENYL-POLYENES (71) We, F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT, a Swiss Company of 124--184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following state ment:- The present invention relates to 2- or 3thienyl - polyenes, a process for the manufacture thereof, and certain pharmaceutical preparations containing same.

The polyene compounds provided by the present invention are compounds of the general formula

wherein one of Rl and R, represents the group

and the other of R1 and R2 and R, and R4 represent a hydrogen or halogen atom or a (lower alkoxy) - (lower alkyl), hydroxymethyl, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono(lower alkyl) - amino, di (lower alkyl)amino, mono(lower alkyl) amino-(lower alkyl), di(lower alkyl)amino - (lower alkyl), hydroxy, lower alkenyl, lower alkenoxy, lower all:anoyl, lower alkanoyloxy, nitro, lower alkoxy carbonyl, lower alkanoylamido or nitro gen - containing heterocyclic group and R; represents a formyl, hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carb oxyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, carbamoyl, mono (lower alkyl) - carbamoyl, di(lower alkyl)carbamoyl, N - heterocyclyl carbonyl or aroyloxymethyl group, and pharmaceutically acceptable salts thereof, as herein defined.

As used in this specification, the term "lower alkyl" means alkyl groups which contain up to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl and 2 - methyl - propyl), the term "lower alkoxy" means alkoxy groups which contain up to 6 carbon atoms (e.g.

methoxy, ethoxy and isopropoxy), the term "halogen" means fluorine, chlorine, bromine or iodine with bromine and chlorine being preferred, the term "lower alkenyl" means alkenyl groups which contain u pto 6 carbon atoms (eg. vinyl, allyl and butenyl, the term "lower alkenoxy" means alkenoxy groups which contain up to 6 carbon atoms (e.g.

vinyloxy and allyloxy) and the term "lower alkanoyloxy" means alkanoyloxy groups which contain up to 6 carbon atoms (e.g.

acetoxy, propionyloxy and butyryloxy). The alkanoyl portion of the lower alkanoylamido groups and the lower alkanoyl groups is derived from an alkanecarboxylic acid which contains up to 6 carbon atoms (e.g. acetic acid, propionic acid and pivalic acid). The term "aroyloxymethyl" means aroyloxymethyl groups in which the aroyl moiety is derived from an aromatic carboxylic acid which contains from 7 to 11 carbon atoms (e.g. benzoic acid, toluic acid and xylylic acid).

The preferred aroyloxymethyl groups are the benzoyloxymethyl and tolyloxymethyl groups.

The alkoxy groups present in the alkoxymethyl and alkoxycarbonyl groups are straight-chain and branched-chain alkoxy groups which contain up to 20 carbon atoms (e.g. methoxy, ethoxy, isopropoxy and cetyloxy). Preferred, however, are those alkoxy groups which contain up to 6 carbon atoms. The said alkoxy groups can be unsubstituted or substituted by nitrogen-containing groups, for instance an unsubstituted or alkyl-substituted amino or morpholino group or a piperidyl or pyridyl group. The alkenoxy and alkynoxy groups present in the alkenoxycarbonyl and alkynoxycarbonyl groups are alkenoxy and alkynoxy groups which contain up to 6 carbon atoms (e.g. allyloxy and propargyloxy). The alkanoyloxy groups present in the alkanoyloxymethyl groups are derived from alkanecarboxylic acids which contain from 1 to 20 carbon atoms (e.g.

acetic acid, propionic acid, pivalic acid, palmitic acid and stearic acid) with the alkanecarboxylic acids which contain from 1 to 6 carbon atoms being preferred. The lower alkyl groups present in the mono(lower alkyl)carbamoyl and di(lower alkyl)carbamoyl groups straight - chain or - branched - chain lower alkyl groups (e.g. methyl, ethyl or isopropyl).

Examples of mono(lower alkyl)carbamoyl and di(lower aIllyl)carbamoyl groups are the methylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl groups. The terms "N-heterocyclyl" and "nitrogen-containing heterocyclic group" mean 5-membered and 6-membered saturated heterocyclic rings which, in addition to the nitrogen atom, may contain a second nitrogen atom or an oxygen or sulphur atom. Of the heterocyclic rings, the piperidino, morpholino, thiomorpholino and pyrrolidino rings are preferred.

Preferred polyene compounds provided by this invention are compounds of the general formula

wherein one of Rl and R2 represents the group

and the other of R1 and R2 and R, and R4 represent a hydrogen or halo gen atom or a lower alkyl group and R, represents a lower alkoxy-carbonyl, carboxyl or mono(lower alkyl)-carb amoyl group, and pharmaceutically acceptable salts thereof, as herein defined.

Examples of polyene compounds provided by this invention are: 3,7 - Dimethyl - 9 - (3 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (3 - methyl - 2 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (5 - methyl - 2 - thienyl) 2,4,6,8 - nonatetrfaenoic acid ethyl ester, 3,7 - dimethyl - 9 - (3 - methyl - 5 - methoxy 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (3 - methyl - 5 - nitro 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl -9 - (2,5 - dimethyl -3 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl -9 - (2,4 - dimethyl - 3 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4 - dimethyl - 5 methoxy - 3 - thienyl) - 2,4,6,8 - nona tetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4 - dimethyl - 5 methoxymethyl - 3 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - [2,4 - dimethyl - 5-(1- methoxyethyl) - 3 - thienyl] - 2,4,6,8 nonatetraenoic acid ethyl ester, 3,7 - dimethyl -9 - (2,4 - dimethyl - 5 methylthio - 3 - thienyl) - 2,4,6,8 - nona tetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4- dimethyl - 5 - acetyl 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4 - dimethyl - 5 dimethylamino - 3 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - [2,4 - dimethyl - 5 - (l- methoxyethyl) - 3 - thienyl] - 2,4,6,8 acid ethyl ester, 3,7 - dimethyl - 9 - (2,4 - diethyl - 5 methyl - 3 - thienyl) - 2,4,6,8 - nona tetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4 - diethoxycarbonyl 5 - acetylamino - 3 - thienyl) . 2,4,6,8 nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (3,4,5 - trimethyl - 2 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraenoic acid, 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraen - 1 - ol, 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 1 - methoxy- 2,4,6,8 - nona tetraene, 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraen - 1 - al, 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraenamide, 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraene - N ethylamide, 3,7 - dimethyl - 9 - (2,5 - dichloro - 3 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,5 - dichloro - 4 methyl - 3 - thienyl) - 2,4,6,8 - nonatetra enoic acid ethyl ester, 3,7 - dimethyl - 9 - (2,4 - dichloro - 5 methyl - 3 - thienyl) - 2,4,6,8 - nonatetra enoic acid ethyl ester, 3,7 - dimethyl - 9 - (5 - bromo - 2 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (3,4 - dibromo - 2 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester, 3,7 - dimethyl - 9 - (3,4 - dibromo - 5 methyl - 2 - thienyl) - 2,4,6,8 - nonatetra enoic acid ethyl ester, and 3,7 - dimethyl - 9 - (3,4,5 - tribromo 2- thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

The polyene compounds provided by this invention are pharmacodynamically valuable.

They are effective in regressing the growth of tumours such as papillomae.

The toxicity of the polyene compounds provided by this invention is slight. For example, when all - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester is administered intraperitoneally to mice weighing 30 g in a daily dosage of 100 mg/kg, then no indication of a hypervitaminosis-A becomes evident after 14 days (total of 10 administration days).

The first indications of hypervitaminosis-A in mice appears at a daily dosage of 200 kg after 14 days (total of 10 administration days). This manifests itself in a weight decrease, a moderate hair loss and slight flaking of the skin.

The tumour-inhibiting activity of the polyene compounds provided by this invention is significant. In the papilloma test, tumours induced with dimethylbenzanthracene and croton oil regress. The diameter of the papillomae within two weeks after the intraperitoneal administration of all - trans - 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl)- 2,4,6,8 - nonatetraenoic acid ethyl ester decreases by 79% at a dosage of 400 mg/kg/ week and by 60% at a dosage of 100 mg/kg/ week.

The compounds of formula I and pharmaceutically acceptable salts thereof, as herein defined, can be used as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible carrier material.

Pharmaceutical preparations for systemic administration can be prepared, for example, by adding a compound of formula I or a pharmaceutically acceptable salt thereof, as herein defined, as the active ingredient to pharmaceutically acceptable, non-toxic, inert, solid or liquid carriers which are usual in such preparations. The pharmaceutical preparations can be administered topically, enterally or parenterally. Suitable preparations for enteral administration are, for example, tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. Suitable pharmaceutical preparations for parenteral administration are infusion solutions.

The dosages in which the compounds of formula I and pharmaceutically acceptable salts thereof, as herein defined, are administered can be varied according to the mode and route of administration and according to the requirements of the patient. For example, amounts of from 5 mg to 200 mg can be administered daily in a single dosage or in divided dosages. Capsules containing 10 mg to 100 mg of active ingredient are a preferred form of administration.

The pharmaceutical preparations can also contain pharmaceutically acceptable inert or pharmacodynamically active additives. Tablets or granules, for example, can contain a variety of pharmaceutically acceptable binders, fillers, carrier materials or diluents. Liquid preparations can, for example, take the form of sterile water-miscible solutions. Capsules can contain a pharmaceutically acceptable filler or thickener. Furthermore, pharmaceutically acceptable flavour-improving additives and pharmaceutically acceptable substances commonly used as preservatives, stabilisers, moisture-retainers or emulsifiers, salts for varying the osmotic pressure, buffers and other pharmaceutically acceptable additives can also be present in the pharmaceutical preparations.

The aforementioned pharmaceutically acceptable carrier materials and diluents are well-known in the pharmaceutical field and can be organic or inorganic substances such as water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic and polyalkyleneglycols. It is, of course, a prerequisite that all adjuvants used in the preparation of the pharmaceutical preparations are non-toxic and pharmaceutically acceptable.

For topical administration, the pharmaceutical preparations are expediently made up in the form of salves, tinctures, creams, solutions, lotions, sprays and suspensions. Ointments, creams and solutions are preferred.

These pharmaceutical preparations for topical administration can be prepared by mixing a compound of formula I or a pharmaceutically acceptable salt thereof, as herein defined, as the active ingredient with pharmaceutically acceptable non-toxic, inert, solid or liquid carriers which are customary in such preparations and which are suitable for topical administration.

Compositions for topical administration preferably contain, on a weight basis, the following amount of active ingredient: 0.01% to 03 n more preferably 0.02% to 0.1%, in solutions, and 0.05% to 5%, more preferably 0.1% to 2%, in ointments or creams.

A conventional pharmaceutically acceptable antioxidant (e.g. tocopherol, N - methyl tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene) can also be incorporated into the present pharmaceutical preparations.

The pharmaceutically acceptable salts referred to in the present description and claims are salts of carboxylic acids of formula I with pharmaceutically acceptable bases and salts of amines of formula I with pharmaceutically acceptable adds. The salts can be prepared by reacting a carboxylic acid of formula I by-conventional means with a base (e.g. an alkali metal hydroxide such as sodium or potassium hydroxide), or by reacting an amine of formula I with an organic or inorganic acid (e.g. a hydrohalic acid such as hydrochloric acid or hydrobromic acid, or benzoic acid, acetic acid, citric acid and Iactic acid).

According to the process provided by the present invention, the polyene compounds of formula I hereinbefore and pharmaceutically acceptable salts thereof, as herein defined, are manufactured by reacting a compound of the general formula

wherein one of RG and R7 represents a group of the formula

and the other of R , and R; and R, and R4 represent a hydrogen or halogen atom or a (lower alkoxy)-(lower alkyl), hydroxymethyl, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono(lower alkyl)amino, di (lower alkyl)amino, mono(lower alkyl)amino-(lower alkyl), di(lower alkyl)amino-(lower alkyl), hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoylamido or nitrogen-containing heterocyclic group, m stands for zero or 1, A represents an oxo, P[Xj3Y or

group, X represents an aryl group, Z represents a lower alkoxy group and Y; represents the anion of an organic acid or an inorganic acid, with a compound of the general formula

wherein B represents an oxo group when A in the compound of formula II represents a --P[X]sYB or

group or B represents a -P[X],eye or

group when A in the compound of formula II represents an oxo group, n stands for zero or 1, X, Y and Z have the significance given earlier, and R', represents a formyl, carboxyl, alkoxy carbon, alkenoxycarbonyl, alkynoxycarbonyl, di(lower alkyl)-carbamoyl or N - heterocyclylcarbonyl group when B represents a --P[X],Ye .or

group, or R', represents a carboxyl, alkoxymetayl, alkanoyloxymethyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl or N - heterocyclyl carbonyl group when B represents an oxo group.

In formulae II and III, the sum of m and n is always 1.

The "aryl" group denoted by X hereinbefore includes all generally known aryl groups, but preferably mononuclear aryl groups such as phenyl, (lower alkyl)-phenyl or (lower alkoxy) - phenyl (e.g. xylyl, mesityl and p - methoxyphenyl). The inorganic acid anions denoted by Y are preferably the chloride, bromide, iodide and hydrosulphate anions.

The preferred organic acid anion denoted by Y is the tosyloxy anion.

The products of the reaction between compounds of formula II and compounds of formula III which contain a carboxyl group at R's can be esterified or amidated at the carboxyl group. When R' represents an ester group, the reaction product can be saponified or amidated at the ester group. When R', represents a carboxyl group or an ester group, the reaction product can be reduced to the corresponding alcohol, a hydroxymethyl group (-CH2OH) being formed. The hydroxymethyl group at R's can be esterified or etherified. The resulting alcohol ester can be saponified if desired. Where R' represents a free hydroxymethyl group or an ester thereof, such groups can be oxidised to give a corresponding aldehyde or carboxylic acid, i.e. to form the corresponding compound in which R's represents a formyl or carboxyl group.

An acid or amine obtained by the present process can be converted, if desired, into a pharmaceutically acceptable salt, as herein defined.

The compounds of formula II in which or or R, represents a -CH2-P[X),Ye or

group can be prepared by treating a corresponding substituted thiophene with formaldehyde in the presence of a hydrohalic acid (e.g. concentrated hydrochloric acid) in a solvent (e.g. glacial acetic acid) if desired to form the halide. The halide is then reacted in a conventional manner with a triarviphos- phine in a solvent, preferably triphenvl phosphine in toluene or benzene, or with a tri alkvlphosphite (e.g. triethylphosphite).

The compounds of formula II in which RG or R7 represents the group

can be prepared by first formylating the corresponding thiophene (e.g. in the presence of a Lewis acid). As the formylating agent there can be used an orthoformic acid ester, formyl chloride, dimethylformamide and Nmethyl formanilide. Especially suitable Lewis acids are the halides of zinc, aluminium, titanium, tin and iron (e.g. zinc chloride, aluminium trichloride, titanium tetrachloride, tin tetrachloride and iron trichloride) as well as the halides of inorganic and organic acids such as phosphorus oxychloride and methane- sulphonyl chloride.

If the formylating agent is present in excess, the formylation may be carried out without the addition of a further solvent. In general, however, the formylation should be carried out in an inert solvent (e.g. nitrobenzene or a chlorinated hydrocarbon such as methylene chloride). The formylation can be carried out at a temperature between 0 C and the boiling point of the mixture.

A resulting substituted thiophenecarboxaldehyde can subsequently be chain4engthened in a conventional manner by condensation with acetone in the cold (i.e. at about 0 C to 30 C) in the presence of alkali (e.g. dilute aqueous sodium hydroxide) to give a substituted thienyl - but - 3 - en - 2 - one which can be converted into the corresponding substituted thienyl - 3 - methyl - 3 - hydroxypenta - 4 - en - 1 - yne by conventional means (e.g. by means of a Grignard reaction by the addition of acetylene). The resulting acetylenic carbinol can subsequently be partially hydrogenated in a conventional manner using a partially deactivated noble metal catalyst (e.g.

a Lindlar catalyst). The resulting tertiary ethylenic carbinol can alternatively be prepared by the addition of a vinylmagnesium halide to the substituted thienyl - but - 3en - 2 - one.

The thus-formed tertiary ethylenic carbinol can subsequently be converted, under allyl rearrangement, into the desired phosphonium salt.

The compounds of formula II in which Re or R7 represents the group

can be prepared by treating the tertiary ethylenic carbinol with a triarylphosphine, preferably triphenylphosphine, in the presence of a hydrohalide (e.g. hydrogen chloride or hydrogen bromide) in a solvent (e.g. benzene). The tertiary ethylenic carbinol can, moreover, be halogenated to give a halide corresponding to formula II in which m stands for 1 and A represents a halogen atom.

This halide can be reacted with a trialkylphos- phite !e.g triethylphosphite) to yield a corresponding phosphonate of formula II in which or or R7 represents the group

Compounds of formula II in which m stands for zero and A represents an oxo group can be prepared, for example, by formylating a substituted thiophene as described earlier to form the corresponding thiophene carboxaldehyde.

Compounds of formula II in which tr.

stands for 1 and A represents an oxo group can be prepared, for example, by submitting a substituted thienyl - but - 3 - en - 2 - one, described earlier, to a Wittig reaction with ethoxycarbonyimethylene - triphenylphosphorane or with diethylphosphonoacetic acid ethyl ester. The resulting substituted thienyl - 3methyl - penta - 2,4 - dien - 1 - oic acid ethyl ester is subsequently reduced in the cold with a mixed metal hydride (e.g. lithium aluminium hydride) in an organic solvent (eg. diethyl ether or tetrahydrofuran) to yield a substituted thienyl - 3 - methyl - penta - 2,4 - dien - 1ol. The dienol is then oxidised with an oxidising agent such as manganese dioxide in an organic solvent (e.g. acetone or methylene chloride) at a temperature between 0 C and the boiling point of the mixture to give the corresponding substituted thienyl - 3 - methylpenta - 2,4 - dien - 1 - aL The compounds of formula III are prepared as follows: Compounds of formula III in which n stands for zero and B represents a triarylphosphonium or dialkoxyphosphinyl group aforesaid can be readily prepared by reacting an optionally esterified 3 - halomethyl - crotonic acid or an etherified 3 - halo - methyl - crotyl alcohol with a triarylphosphine in a solvent, preferably triphenylphosphine in toluene or benzene, or with a trialkylphosphite such as triethylphosphite.

Compounds of formula III in which n stands for 1 and B represents a triarylphosphonium or dialkoxyphosphinyl group aforesaid can be prepared, for example, by reducing the formyl group of the corresponding aldehyde in which n stands for 1 to the hydroxymethyl group using a metal hydride such as sodium borohydride in an alkanol (e.g.

ethanol or isopropanol).

The resulting alcohol can be halogenated using a conventional halogenating agent (e.g.

phosphorus oxychloride) and the resulting 8halo - 3,7 - dimethyl - octa - 2,4,6 - triene1 - carboxylic acid ester, a halide corresponding to formula III in which n stands for 1 and B represents a halogen atom or a derivative thereof, can be reacted either with a triarylphosphine in a solvent, preferably triphenylphosphine in toluene or benzene, to give a phosphonium salt or with a trialkylphosphite, preferably triethyiphosphite, to give the corresponding phosphonate.

Compounds of formula III in which n stands for zero and B represents an oxo group can be prepared, for example, by oxidatively cleaving an optionally esterified tartaric acid; for example, using lead tetraacetate at room temperature in an organic solvent such as benzene. The resulting glyoxalic acid derivative is subsequently condensed in a conventional manner (e.g. conveniently in the presence of an amine) with propionaldehyde at an elevated temperature (e.g. at a temperature between 60"C and llO"C) with water cleavage to yield the corresponding 3 - formylcrotonic acid derivative.

Compounds of formula III in which n stands for 1 and B represents an oxo group can be prepared, for example, by reacting 4,4 - dimethoxy - 3 - methyl - but - 1 - en - 3ol with phosgene in the cold, preferably at --10"C to -200C, in the presence of a tertiary amine such as pyridine and condensing the resulting 2 - formyl - 4 - chloro - but2 - ene, a halide corresponding to formula III in which B represents a halogen atom and n stands for zero, under conditions of a Wittig reaction with an optionally esterified 3 - formyl - crotonic acid or to an optionally esterified or etherified 3 - formyl - crotyl alcohol to yield the corresponding aldehyde of formula III.

The reaction of an aldehyde of formula II with a phosphonium salt or phosphorane of formula III or the reaction of an aldehyde of formula III with a phosphonium salt or phosphorane of formula II to produce a polyene compound of formula I can be carried out by, for example, either the Wittig or Horner techniques.

According to the Wittig procedure, the reaction components are reacted with one another in the presence of an acid-binding agent (e.g. in the presence of an alkali metal alcoholate such as sodium methylate, or in the presence of sodium hydride, or in the presence of an optionally alkyl-substituted alkylene oxide, preferably in the presence of ethylene oxide or 1,2-butylene oxide). If desired, an inert organic solvent (e.g. a chlorinated hydrocarbon such as methylene chloride or dimethylformamide) can be used. The reaction is carried out at a temperature between room temperature and the boiling point of the reaction mixture.

According to the Horner procedure, the reaction components are reacted with one another with the aid of a base in the presence of an inert organic solvent; for example, with the aid- of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxan or 1,2 - dimethoxy - ethane or with the aid of an alkali metal alcoholate in an alkanol (e.g. sodium methylate in methanol) at a temperature between 0 C and the boiling point of the reaction mixture.

For convenience, the reactions described hereinbefore can, in some cases, be carried out without isolating the phosphonium salt or phosphonate from the medium in which it is prepared.

A carboxylic acid of formula I can be converted by conventional means (e.g. by treatment with thionyl chloride, preferably in pyridine) into an acid chloride which can be converted by treatment with ammonia or with an amine into an amide or by reaction with an alkanol into an ester.

A carboxylic acid ester of formula I can be hydrolysed by conventional means (e.g. by treatment with an alkali, preferably aqueousalcoholic sodium hydroxide or potassium hydroxide) at a temperature between room temperature and the boiling point of the mixture and then amidated either via an acid halide or as described hereinafter.

A carboxylic acid ester of formula I can be converted directly into the corresponding amide (e.g. by treatment with lithium amide).

The ester is advantageously treated with lithium amide at room temperature.

A carboxylic acid or carboxylic acid ester of formula I can be reduced by conventional means to give the corresponding alcohol of formula -I. The reduction is advantageously carried out. using a metal hydride or alkyl metal hydride in an inert solvent. The preferred hydrides are the mixed metal hydrides such as lithium aluminium hydride and bis (methoxyethylenoxy) - sodium aluminium hydride. Suitable solvents are, inter alia, ether, tetrahydrofuran and dioxan when lithium aluminium hydride is used and ether, hexane, benzene and toluene when diisobutylaluminium hydride or bis(methoxyethylenoxy)-sodium aluminium hydride is used.

An alcohol of formula I can be etherified with an alkyl halide (e.g. ethyl iodide) in the presence of a base, preferably sodium hydride, in an organic solvent such as dioxan, tetrahydrofuran, 1,2 - dimethoxyethane or dimethylformamide at a temperature between 0 C and room temperature.

An alcohol of formula I can be esterified by treatment with an alkanoyl halide or anhydride, expediently triphenyl - phosphonium chloride of melting point 2360-2370C.

Example 2 3,7 - Dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester 1.9 g of 2,4,5 - trimethyl - thiophene - 3carboxaldehyde and 6.75 g of (7 - ethoxycarbonyl - 2,6 - dimethyl - 2,4,6 - heptatrienyl)triphenylphosphonium bromide were dissolved in 50 ml of dry dimethylformamide. The solution was treated dropwise at 10 C with a solution of 0.29 g of sodium in 8 ml of ethanol.

The mixture was subsequently stirred for 4 hours at room temperature, then introduced into 100 ml of methanol/water (60:40 parts byy volume) and thoroughly extracted with hexane. The hexane extract was washed with methanol/water (60:40 parts by volume) and then with water, dried over sodium sulphate and evaporated. There was obtained 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 - thienyl)2,4,6,8 - nonatetraenoic acid ethyl ester which melted at 880-890C after recrystallisation from hexane.

The (7 - ethoxyycarbonyl - 2,6 - dimethyl- 2,4,6 - heptatrienyl) - triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: a) 8 - Hydroxy - 3,7 - dimethyl - 2,4,6- octatrien - 1 - oic acid ethyl ester 36 g of 7 - formyl - 3 - methyl - 2,4,6octatrien - 1 - oic add ethyl ester were dissolved in 600 ml of absolute ethanol. The solution was treated portionwise with 1.8 g of sodium borohydride. The mixture was stirred for 2 hours at 10 C, then poured on to ice-water and 3 - N aqueous hydrochloric acid and extracted with ether. The ether extract was washed successively with water, a saturated aqueous sodium bicarbonate solution and once more with water, dried over sodium sulphate and evaporated. There was obtained 8 - hydroxy - 3,7 - dimethyl - 2,4,6 octatrien - 1 - oic acid ethyl ester.

b) 8 - Bromo - 3,7 - dimethyl - 2,4,6 - octa trien - 1 - oic acid ethyl ester 36.5 g of 8 - hydroxy - 3,7 - dimethyl2,4,6 - octatrien - 1 - oic acid ethyl ester were dissolved in 380 ml of ether. The solution was cooled to 0 C and, after the addition of 3 drops of pyridine, treated dropwise with 28.6 g of phosphorus tribromide in 120 ml of hexane. The mixture was stirred for 20 minutes at 0 C, then poured on to ice-water and extracted with ether. The ether extract was washed successively with water, a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulphate and evaporated. There was obtained 8 bromo - 3,7 - dimethyl - 2,4,6 - octatrien - 1 oic acid ethyl ester.

c) 1 - Ethoxycarbonyl - 2,6 - dimethyl 1,3,5 - heptatrien - 7 - yl) - triphenyl phosphonium bromide 43.7 g of 8 - bromo - 3,7 - dimethyl - 2,4,6octatrien - 1 - oic acid ethyl ester were dissolved in 500 ml of benzene and treated with 42.0 g of triphenylphosphine. The mixture was stirred for 12 hours at room temperature and then cooled at 0 C. The precipitated (1ethoxycarbonyl - 2,6 - dimethyl - 1,3,5heptatrien - 7 - yl)triphenylphosphonium bromide melted at 193"--194"C.

Example 3 3,7 - Dimethyl - 9 - (2,4,5 - trimethyl - 3 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester 1.7 g of 8 - (diethoxyphosphinyl) - 3,7 - dimethyl - 2,4,6 - octatrienoic acid ethyl ester were introduced into 8.0 ml of tetrahydrofuran. The solution was cooled to 0 C after the addition of 0.27 g of sodium hydride (5060%), then stirred for 30 minutes at 0 C and thereafter treated dropwise over a period of 15 minutes with a solution of 1.0 g of 2,4,5 - trimethyl - thiophene - 3 - carboxaldehyde in 5 ml of tetrahydrofuran. The mixture was stirred for 7 hours at room temperature, then poured into ice and, after the addition of 2-N hydrochloric acid, extracted with ether. The ether extract was washed neutral with water, dried over sodium sulphate and evaporated under reduced pressure. The residual 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl)- 2,4,6,8 - nonatetraenoic acid ethyl ester was recrystallised from hexane and had a melting point of 88 89"C. Instead of the 0.27 g of sodium hydride used hereinbefore, there can also be used as the condensation agent an alkali metal alcoholate [e.g. sodium ethylate (0.125 g of sodium in 5 ml of ethanol)].

The 8 - (diethoxyphosphinyl) - 3,7 - dimethyl - 2,4,6 - octatrienoic acid ethyl ester used as the starting material can be prepared, for example, as follows: A) 3 - Formyl-crotonic acid butyl ester Aa) Glyoxalic acid butyl ester 1775 g of lead tetraacetate (90%) were gradually introduced within 30 minutes at 250-300C into a solution of 1000 g of L(+)tartaric acid dibutyl ester in 3850 ml of benzene. The mixture was subsequently stirred for 1 hour at room temperature. The sediment was filtered off and extracted with 500 ml of benzene. The benzene extract was evaporated under reduced pressure. The residual glyoxalic acid butyl ester boiled, after rectification, at 50"--65"C/12 Torr.

Ab) 3 - Formyl - crotonic acid butyl ester 836 g of the foregoing glyoxalic acid butyl ester were introduced into 376 g of propion aldehyde. The mixture was treated drop wise at 60"C with 40.8 g of di-n-butylamine.

In so doing, the temperature should not rise higher than 105"C. The mixture was then stirred for 2 hours at 1160-1110C, cooled and taken up in ether. The ether extract was washed successively with 500 ml of 1-N sulphuric acid, 700 ml of water, 1000 ml of 501 by weight aqueous sodium bicarbonate solution and subsequently with 1000 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residual 3 - formyl - crotonic acid butyl ester boiled, after rectification, at 930-1050C/14 Torr.

B) (2-Formyl-but-2-en-4-yl)triphenyl- phosphonium chloride Ba) 4,4 - Dimethoxyy - 3 - methyl - but - 1 yn-3-ol After the addition of a small amount of iron (III) nitrate, 2700 ml of liquid ammonia were treated portionwise while stirring and cooling with 169.5 g of potassium. As soon as the initially blue colouration had disappeared (i.e. after about 30--45 minutes), acetylene gas in a stream of 3 litres/minutes was led in until the dark colouration of the mixture became lighter. Then, the gas stream was reduced to 2 litres/minutes and the mixture treated dropwise with a solution of 500 g of methylglyoxal dimethylacetal in 425 ml of absolute ether. The introduction of acetylene was continued for 1 hour while stirring. The mixture was subsequently treated portionwise with 425 g of ammonium chloride, gradually warmed to 30"C within 12 hours with evaporation of the ammonia and extracted with 1600 ml of ether. The ether extract was dried over sodium sulphate and evaporated under reduced pressure. The residual 4,4 - dimethoxy3 - methyl - but - 1 - yn - 3 - ol boiled, after rectification, at 33"C/0.03 Torr; nuj= 1.4480.

Bb) 4,4 - Dimethoxy - 3 - methyl - but - 1 en - 3 - ol 198 g of 4,4 - dimethoxy - 3 - methyl - but- 1 - yn - 3 - ol were dissolved in 960 ml of high-boiling petroleum ether and, after the addition of 19.3 g of 5% palladium catalyst and 19.3 g of quinoline, hydrogenated under normal conditions. After the uptake of 33.5 litres of hydrogen, the hydrogenation was stopped. The catalyst was filtered off. The filtrate was evaporated under reduced pressure. The residual 4,4 - dimethoxy - 3methyl - but - 1 - en - 3 - ol boiled, after rectification, at 70"--72"C/18 mm Hg.

Bc) 2 - Formyl - 4 - chloro - but - 2 - ene 195 ml of phosgene were led into 1570 ml of carbon tetrachloride at - 100C. After the addition of 213 g of pyridine, the solution was treated dropwise at a temperature of --10"C to -200C with 327 g of 4,4-dimethoxy - 3 - methyl - but - 1 - en - 3 - ol. The mixture was slowly warmed to 259C while stirring, stirred for a further 3 hours at room temperature, cooled to 15"C and treated with 895 ml of water. The aqueous phase was separated and rejected. After standing for 12 hours in the cold, the organic phase was treated, with 448 ml of 5% by weight aqueous sulphuric acid, stirred for 5 hours, then washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residual 2 - formyl - 4 - chloro - but - 2 - ene boiled, after rectification, at 37 A03C/1.S Torr; nu2=1.4895.

Bd) (2 - Formyl - but - 2 - ene - 4 - yl)tri- phenylphosphonium chloride 165.7 g of 2 - formyl - 4 - chloro - but - 2ene were dissolved in 840 ml of benzene and treated with 367 g of triphenylphosphine.

The mixture was heated to boiling under reflux for 12 hours in a nitrogen atmosphere and then cooled to 20"C. The precipitated '2formyl - but - 2 - ene - 4 - yl)triphenylphosphonium chloride melted, after washing with benzene and drying, at 2500-2520C.

C) 8 - (Diethoxyphosphinyl) - 3,7 - di methyl - 2,4,6 - octatrien - 1 - oic acid ethyl ester Ca) 7 - Formyl - 3 - methyl - 2,4,6 - octatrien 1 - oic acid butyl ester 212.6 g of (2 - formyl - but - 2 - ene - 4 yl)triphenylphosphonium chloride and 95 g of 3 - formyl - crotonic acid butyl ester were introduced into 1100 ml of butanol and treated at 5"C with a solution of 57 g of triethylamine in 60 ml of butanol. The mixture was subsequently stirred for 6 hours at 25"C, then cooled, introduced into water and thoroughly extracted with hexane. The hexane phase was washed repeatedly with methanol/water (6:4 parts by volume) and then with water, dried over sodium sulphate and filtered. The filtrate was isomerised for 12 hours by shaking with iodine. The iodine was removed by the addition of sodium thiosulphate. The filtrate was washed with water, dried and evaporated under reduced pressure. The residual 7 formyl - 3 - methyl - 2,4,6 - octatrien - 1 - oic acid butyl ester boiled, after rectification, at l020-1050C/0.09 Torr.

Cb) 8 - (Diethoxyphosphinyl) - 3,7 - di methyl - 2,4,6 - octatrien - 1 - oic acid ethyl ester 3.03 g of 8 - bromo - 3,7 - dimethyl - 2,4,6octatrien - 1 - oic acid ethyl ester were slowly heated to 125"C with 1.66 g of triethylphosphite. The surplus bromo ester was distilled off. The residue was cooled, poured into ice, extracted with ether and an aqueous sodium bicarbonate solution, dried and evaporated under reduced pressure. The residual 8 - (di ethoxyphosphinyl) - 3,7 - dimethyl - 2,4,6octatrien - 1 - oic acid ethyl ester was immedi ately reacted with 2,4,5 - trimethyl - thiophene - 3 - carboxaldehyde as described in the first paragraph of this Example.

Example 4 All - trans - 3,7 - dimethyl - 9 - (3,4,5 - tri methyl - 2 - thienyl) - 2,4,6,8 - nonatetra enoic acid ethyl ester 3.2 g of (3,4,5 - trimethyl - 2 - thenyl)triphenylphosphonium bromide were suspended in 80 ml of 1,2 - butylene oxide and 1.5 g of 3 - methyl - 7 - formyl - 2,4,6 - octatrienoic acid ethyl ester were added. The resulting mixture was refluxed under argon for 1 hour, after which time the solvent was evaporated. The residue which formed was diluted with methanol/water (6:4) and extracted four times with hexane. The combined hexane solutions were washed once with methanol/water (6:4) and twice with pure water, dried over sodium sulphate, filtered and evaporated. The resulting crude product was purified by column chromatography on silica gel and elution with hexane/ether (95:5). Recrystallisation of the thus-obtained all - trans - 3,7 - dimethyl - 9 - (3,4,5 - trimethyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester from hexane/ethyl acetate (99:1) gave yellow crystals of melting point 96 98 C.

The (3,4,5 - trimethyl - 2 - thenyl)triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: a) 2 - Hydroxymethyl - 3,4,5 - trimethyl thiophene 1.9 g of 3,4,5 - trimethyl - thiophene - 2carboxaldehyde were dissolved in 20 ml of ethanol. The resulting solution was cooled to 0"--5"C and 125 mg of sodium borohydride were added in small portions. The resulting mixture was stirred at room temperature for 3 hours, poured into ice-water, extracted with ethyl acetate, dried over sodium sulphate, filtered and evaporated. The resulting crystalline 2 - hydroxymethyl - 3,4,5 - trimethylthiophene melted at 45"48"C.

b) (3,4,5 - Trimethyl - 2 - thenyl)triphenyl phosphonium bromide 2.2 g of 2 - hydroxymethyl - 3,4,5 - trimethyl - thiophene were dissolved in 25 ml of acetonitrile and 4.6 g of triphenylphosphonium bromide were added. The resulting mixture was heated to 50"C for 3 hours. After evaporation of the solvent, the residue which formed was diluted with ethyl acetate, heated briefly and filtered. The crystalline (3,4,5 - trimethyl - 2 - thenyl)triphenylphosphonium bromide obtained was dried at 50"C under a high vacuum and melted at 208"--215"C.

Example 5 All - trans - 3,7 - dimethyl - 9 - (3 - methyl 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester 1.16 g of a 50 so suspension of sodium hydride in mineral oil were washed three times with pentane, dried and suspended in 50 ml of dimethylformamide. A suspension of 7.5 g of (3 - methyl - 2 - thenyl)triphenylphosphonium bromide in 25 ml of dimethylformamide was added dropwise at 0OC. After stirring for 15 minutes, a solution of 3.74 g of 3methyl - 7 - formyl - 2,4,6 - octatrienoic acid ethyl ester in 40 ml of dimethylformamide was added dropwise. After stirring for 2.5 hours at room temperature, the mixture was poured into methanol/water (6:4) and extracted several times with hexane. The combined organic phases were washed once with methanol/water (6:4), dried over sodium sulphate, filtered and evaporated. The crude product was purified by recrystallisation from hexane to give all - trans - 3,7 - dimethyl - 9 (3 - metyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 86"- 87 C.

The (3 - methyl - 2 - thenyl)triphenyl- phosphonium bromide used as the starting material can be prepared, for example, as follows: 4.5 g of 2 - hydroxymethyl - 3 - methylthiophene were dissolved in 90 ml of acetonitrile and 12.3 g of triphenylphosphonium bromide. were added. The mixture was heated to 70"C for 3 hours. After cooling, the resulting precipitate was filtered off, washed with benzene and dried at 80"C under a high vacuum. The resulting (3 - methyl - 2thenyl)triphenylphosphonium bromide melted at 2660-2690C.

Example 6 All - trans - 3,7 - dimethyl - 9 - (5 - methyl 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester 1.45 g of a 50 suspension of sodium hydride in mineral oil was washed three times with pentane, dried and suspended in 75 ml of dimethylformamide. A suspension of 10.3 g of (5 - methyl - 2 - thenyl)triphenylphosphonium bromide in 50 ml of dimethylformamide was added dropwise at 0 0C. After stirring for 15 minutes, a solution of 6.25 of 3 - methyl - 7 - formyl - 2,4,6 - octatri enoic acid ethyl ester in 50 ml of dimethylformamide was added dropwise. After stirring for 1 hour at room temperature, the mixture was poured into methanol/water (6:4) and extracted several times with hexane. The combined organic phases were washed once with methanol/water (6:4), dried over sodium sulphate, filtered and evaporated. The crude product was purified by recrystallisation from hexane to give all - trans - 3,7 - dimethyl 9 - (5 - methyl - 2 - thienyl) - 2,4,6,8 - nona tetraenoic acid ethyl ester of melting point 920-930C.

The (5 - methyl - 2 - thenyl)triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: 4.6 g of 2 - hydroxymethyl - 5 - methylthiophene were dissolved in 100 ml of acetonitrile and 12.2 g of triphenylphosphonium bromide were added. The mixture was heated to 75"C for 2.5 hours. After cooling, the resulting precipitate was filtered off, washed with benzene and dried at 80"C under a high vacuum. The resulting (5 - methyl - 2thenyl)triphenylphosphonium bromide melted at 2620-2660C.

Example 7 All - trans - 3,7 - dimethyl - 9 - (2,5 - di- methyl - 3 - thienyl) - 2,4,6,8 - nona teuaenoic acid ethyl ester 7.0 g of (2,5 - dimethyl - 3 - thenyl)triphenylphosphonium chloride were suspended in 200 ml of 1,2 - butylene oxide and 3.4 g of 3 - methyl - 7 - formyl - 2,4,6 - octatrienoic acid ethyl ester were added. The mixture was refluxed under argon for 5.5 hours. The resulting solution was poured into 500 ml of methanol/water (6: 4), extracted four times with hexane, washed with methanol/water, dried over sodium sulphate, filtered and evaporated. The crude product was purified by recrystallisation from hexane to give alltrans - 3,7 - dimethyl - 9 - (2,5 - dimethyl3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethvl ester of melting point 1190-1210C.

The (2,5 - dimethyl - 3 - thenyl(triphenylphosphonium chloride used as the starting material can be prepared, for example, as follows: 11.8 g of triphenylphosphine and 7.0 g of 2,5 - dimethyl - 3 - chloromethyl - thiophene were dissolved in 100 ml of toluene. The mixture was refluxed overnight under argon, cooled to room temperature and the precipitated white phosphonium salt was collected by filtration, washed several times with cold benzene and dried at 80"C under a high vacuum. The resulting (2,5 - dimethyl - 3 thenvl)triphenvlphosphonium chloride melted at 2460-2500C.

Example 8 All - trans - and 2,4,6 - trans - 8 - cis - 3,7 dimethyl - 9 - (2,4- dimethyl - 5 - chloro 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester According to the procedure described in Example 9, (2,4, - dimethyl - 5 - chloro - 3thenyl)triphenylphosphonium chloride was condensed with 7 - formyl - 3 - methyl - 2,4,6octatrienoic acid ethyl ester to form all - trans3,7 - dimethyl - 9 - (2,4 - dimethyl - 5chloro - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester which was recrystallised from hexane and had a melting point of 109"-- llO"C.

Preparative layer chromatography of the filytrate yielded, after recrystallisation from hexane, a mixture of 80 " of 2,4,6 - trans 8 - cis - 3,7 - dimethyl - 9 - (3,4 - dibromo 5 - methyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester and 20% of the alltrans isomer of melting point 73"--76"C.

The (2,4- dimethyl - 5 - chloro - 3 - thenvl)triphenylphosphonium chloride used as the starting material can be prepared, for example, as follows: a) 2,4 - Dimethyl - 5 - chloro - thiophene 2.5 g of 2,4 - dimethyl - thiophene were dissolved in 45 ml of methylene dichloride and 3.3 g of sulphuryl chloride were added dropwise. The mixture was kept at room temperature for 0.5 hour and then refluxed for 2 hours. The mixture was poured into water, extracted with hexane, washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. Distillation gave 2,4 - dimethyl - 5 - chlorothiophene of boiling point 730-750C/l8 mm.

b) 2,4 - Dimethyl - 3 - chloromethyl - 5 chloro thiophene 3.04 g of 2,4 - dimethyl - 5 - chloro - thiophene were dissolved in 60 ml of acetic acid and 2.1 g of formalin and 32 ml of concentrated hydrochloric acid were added. The mixture was stirred at room temperature for 2 hours, then poured into ice-water and extracted with hexane. The organic solution was washed with 5% sodium bicarbonate solution, dried, filtered and evaporated to yield 2,4 dimethyl - 3 - chloromethyl - 5 - chloro - thio phene.

c) (2,4 - Dimethyl- 5 - chloro- 3 - thenyl) triphenylphosphonium chloride (2,4- Dimethyl- 5 - chloro - 3 - thenyl)triphenylphosphonium chloride can be prepared in a manner analogous to that described in Example 13 by reacting 2,4 - dimethyl - 3chloromethyl - 5 - chloro - thiophene with triphenylphosphine; melting point 2460-2510C.

Example 9 All - trans - 3,7 - dimethyl - 9 - (2,5 - di chloro - 3 - thienyl) - 2,4,6,8 - nonatetra enoic acid ethyl ester To a cold (- 100C) suspension of 1.02 g (2 mmoles) of crude (2,5 - dichloro - 3thenyl)triphenylphosphonium bromide in 20 ml of dry ether was added slowly via a syringe 0.82 ml (2 mmoles) of a 2.45-M solution of n-butyl lithium in hexane. After completion of the addition, the mixture was allowed to stir at --10"C for 10 minutes. Then, a solution of 416 mg (2 mmoles) of 3,7 - dimethyl7 - formyl - 2,4,6 - octatrienoic acid ethyl ester was added at 0"--2"C. The mixture was allowed to warm to room temperature for 1.5 hours and poured into 25 ml of sodium chloride solution. Some brown solid was filtered off and the organic layer of the filtrate was separated, washed with two 50 ml portions of sodium chloride solution and then dried over sodium sulphate. Evaporation of the solvent gave a yellow solid which was extracted with several 25 ml portions of hexane. The hexane extracts were combined and concentrated to yield a yellow solid which was purified by chromatography on 45 g of silica gel packed in hexane containing 2% ether. Elution with this solvent mixture gave all - trans - 3,7 - dimethyl - 9 - (2,5 - dichloro3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

The (2,5 - dichloro - 3 - thenyl)triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: 22 g (90 mmoles) of 2,5 - dichloro - 3bromomethyl - thiophene were mixed with 26 g (99 mmoles) of triphenylphosphine and 150 ml of benzene. The mixture was heated to reflux for 2.5 hours, cooled and filtered to give (2,5 - dichloro - 3 - thenyl) - triphenylphosphonium bromide of melting point 208"--215"C.

Example 10 All - trans - 3,7 - dimethyl - 9 - (3,4 - di bromo - 5 - methyl - 2 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester According to the procedure described in Example 7, (3,4 - dibromo - 5 - methyl - 2 thenyl)triphenylphosphonium chloride was condensed with 7 - formyl - 3 - methyl2,4,6 - octatrienoic acid ethyl ester to form all - trans - 3,7 - dimethyl - 9 - (3,4 - dibromo 5 - methyl - 2 - thienyl) - 2,4,6,8 - nonatetra enoic acid ethyl ester which was recrystallised from hexane/ethyl acetate (1:1), melting point 1500-1S30C.

The (3,4 dibromo - 5 - methyl - 2 - thenyl) triphenylphosphonium chloride used as the starting material can be prepared, for ex ample, as follows: a) 2 - Chloromethyl - 3,4 - dibromo - 5 methyl - thiophene A solution of 11.7 g of 2 - methyl - 3,4 dibromo - thiophene in 30 ml of acetic acid was added to 60 ml of concentrated hydrochloric acid. After the dropwise addition of 4.1 g of a 37% aqueous solution of formaldehyde, the mixture was heated to 70"C for 1 hour. The mixture was cooled, diluted with water and extracted with ether. The combined organic phases were washed with water, sodium bicarbonate solution and water, dried over sodium sulphate, filtered and evaporated to give 2 - chloromethyl - 3,4 - dibromo - 5methyl - thiophene.

b) (3.4 - Dibromo - 5 - methyl - 2 - thenyl)- triphenvlphosphonium chloride 3,4 - Dibromo - S - methyl - 2 - thenyl)triphenylphosphonium chloride can be prepared in a manner analogous to that described in Example 7 by reacting 2 - chloromethvl3,4 - dibromo - 5 - methyl - thiophene with triphenylphosphine; melting point 215"-- 216"C.

Example 11 All - trans - 3,7 - dimethyl - 9 - (3,4,5 - di bromo - 2 - thienyl) - 2,4,6,8 - nonatetra enoic acid ethyl ester According to the procedure described in Example 5, (3,4,5 - tribromo - 2 - thenyl)triphenylphosphonium chloride was condensed with 7 - formyl - 3 - methyl - 2,4,6 - octatrienoic acid ethyl ester to form all - trans3,7 - dimethyl - 9 - (3,4,5 - tribromo - 2thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester which was recrystallised from hexane/ ethyl acetate (95 : 5); melting point 84"- 86"C.

The (3,4,5 - tribromo - 2 - thenyl)triphenylphosphonium chloride used as the starting material can be prepared, for example, as follows: 9.0 g of triphenylphosphine and 10.4 g of 3,4,5 - tribromo - 2 - chloromethyl - thiophene were dissolved in 200 ml of toluene.

The mixture was refluxed overnight under argon, cooled to room temperature and the precipitated phosphonium salt was collected by filtration, washed several times with cold benzene and dried at 80"C under a high vacuum. The resulting (3,4,5 - tribromo - 2thenyl)triphenylphosphonium chloride melted at 2480-2490C.

Example 12 All - trans - 3,7 - dimethyl - 9 - (2,4 - di chloro - 5 - methyl - 3 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester A suspension of 10.83 g (22.6 mmol) of (2,4 - dichloro - 5 - methyl - 3 - thenyl)tri- phenylphosphonium chloride and 5.15 g (24.8 mmol) of 7 - formyl - 3 - methyl - 2,4,6octatrienoic acid ethyl ester in 350 ml of 1,2butylene oxide was heated to 70"C for 4.5 hours. The resulting clear solution was cooled, poured into 500 ml of methanol/water !6:4) and extracted with hexane. The combined hexane extracts were washed with methanol water (6: 4), dried and evaporated. The resulting crude material was purified by chromatography [silica gel; hexane/ethyl acetate (4: 1)] to yield, after recrystallisauon from hexane, all - trans - 3,7 - dimethyl - 9 (2,4 - dichloro - 5 - methyl - 3 - thienyl)2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 990-1000C.

The (2,4 - dichloro - 5 - methyl - 3thenyl)triphenylphosphonium chloride used as the starting material can be prepared, for cx- ample, as follows: a) 3 - Chloro - 2,4 - dichloro 5 - methyl thiophene 8.6 g (0.107 mol) of formalin and 90 ml of concentrated hydrochloric acid were added to a solution of 10.87 g (0.065 mol) of 2methyl - 3,5 - dichloro - thiophene in 45 ml of acetic acid. The resulting mixture was heated to 70"C for 18 hours, cooled, poured into ice-water and extracted with ether. The organic solution was washed with water, sodium bicarbonate solution and water, dried and evaporated to yield 3 - chloro - methyl2,4 - dichloro - 5 - methyl - thiophene as a crude oil.

b) 2,4 Dichloro - 5 - methyl - 3 - thenyl) triphenylphosphonium chloride A mixture of 13.1 g (ca 0.061 mol) of crude 3 - chloro - methyl - 2,4 - dichloro - 5methyl - thiophene, 26.2 g (0.10 mol) of triphenylphosphine and 200 ml of toluene was warmed to 100"C for 20 hours and then cooled to room temperature. The resulting precipitate was collected by filtration, washed with cold benzene and dried at 80"C under a high vacuum to yield (2,4 - dichloro - 5methyl - 3 - thenyl)triphenylphosphonium chloride of melting point 2110-2140C.

Example 13 All - trans - 3,7 - dimethyl - 9 - (2,4 - di ethoxycarbonyl - 5 - acetylamino - 3 thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester A suspension of 30.0 g (ca 47 mmol, containing 11% of succinimide) of (2,4 - diethoxycarbonyl - 5 - acetylamino - 3 - thenyl)triphenylphosphonium bromide and 9.75 g (47 mmol) of 7 - formyl - 3 - methyl - 2,4,6octatrienoic acid ethyl ester in a mixture of 500 ml of toluene and 100 ml of 1,2-butylene oxide was refiuxed for 3 hours until the solution became clear. The resulting solution was cooled and the solvent evaporated. The residue was suspended in 600 ml of methanol/water (6:4) and 1 litre of hexane and stirred for 0.5 hour. The insoluble material was filtered off and boiled with 3 litres of hexane. The insoluble material was filtered off from the cold solution, washed with hexane and purified by chromatography (silica gel; ethyl acetate).

Recrystallisation of the purer fractions from hexane/40 % ethyl acetate yielded all- trans- 3,7 - dimethyl- 9 - (2,4 - diethoxvcarbonyl 5 - acetylamino - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 1590-1610C.

The (2,4 - diethoxycarbonyl - 5 - acetylamino - 3 - thenyl)triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: a) 2,4 - Diethoxycarbonyl - 3 - methyl - 5 acetylamino - thiophene A solution of 23.0 g (0.09 mol) of 2,4 - di ethoxycarbonyl - 3 - methyl - 5 - amino - thiophene in 250 ml of acetic anhydride was heated to 100"C for 1.5 hours. The resulting mixture was cooled in an ice-bath and the precipitated crystals were filtered off to yield 2,4 - diethoxycarbonvl - 3 - methyl - 5acetylamino - thiophene of melting point 1300-1310C.

b) 2,4 - Diethoxycarbonyl - 3 - bromo methyl - 5 - acetylamino - thiophene 10.5 g (59 mmol) of N - bromosuccinimide and 20 mg of benzoyl peroxide were added to a solution of 17.5 g (59 mmol) of 2,4 - di ethoxycarbonyl - 3 - methyl - 5 - acetylaminothiophene in 250 ml of carbon tetrachloride.

The resulting mixture was refluxed for 24 hours until all solid material was floating on the surface. After 1 and 7 hours respectively there were added 20 mg of benzoyl peroxide.

Because a separation of the product, 2,4 - diethoxycarbonyl - 3 - bromomethyl - 5 - acetylamino - thiophene, and succinimide proved to be very difficult, the solvent was evaporated and the crystalline residue was used without further purification.

c) 2,4 - Diethexycarbonyl - 5 acetylamino 3 - thenyl)triphenyl - phosphonium bromide 22.2 g of crude 2,4 - diethoxycarbonyl - 3bromomethyl- 5 - acetylamino - thiophene, 19.7 g (75 mmol) of triphenylphosphine and 700 mi of toluene were refluxed for 3 hours.

The resulting precipitate was filtered from the hot solution and washed well with toluene to yield (2,4 - diethoxycarbonyl - 5 - acetylamino - 3 - thenyl)triphenylphosphonium bromide of melting point 1860-1950C. The nuclear magnetic resonance spectrum showed that the material contained 11% of succinimide.

Example 14 All - trans - 3,7 - dimethyl - 9 - (3 - methyl 5 - methoxy - 2 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester A suspension of 5.9 g (13.5 mmol) of (3methyl - 5 - methoxy - 2 - thenyl)triphenylphosphonium chloride and 2.81 g (13.5 mmol) of 7 - formyl - 3 - methyl - 2,4,6 - octatrienoic acid ethyl ester in 70 ml of 1,2 - butylene oxide and 200 ml of toluene was heated to 100"C for 14 hours. The resulting clear solution was cooled, poured into 500 ml of methanol/water (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude oily material was purified by chromatography (silica gel; hexane/ether; ratio 7: 3) to yield, after recrystallisation from hexane, all - trans - 3,7dimethyl - 9 - (3 - methyl - 5 - methoxy2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 660-720C.

The (3 - methyl - 5 - methoxy - 2 - thenyl)triphenylphosphonium chloride used as the starting material can be prepared, for example, as follows: a) 2 - Hydroxymethyl - 3 - methyl - 5 iodo - thiophene 6.58 g (33 mmol) of mercuric oxide and 7.62 g (30 mmol) of iodine were added alternately in small amounts to a vigorously stirred solution of 3.84 g (30 mmol) of 2 - hydroxymethyl - 3 - methyl - thiophene in 30 ml of benzene. The mixture was kept at room temperature by cooling with an ice-bath. The orange mercuric iodide which precipitated out was filtered off and washed well with benzene.

The combined organic solutions were washed with sodium thiosulphate solution and saturated sodium chloride solution, dried and evaporated to yield crude 2 - hydroxymethyl3 - methyl - 5 - iodo - thiophene as a colourless oil.

b) 2 Hydroxymethyl - 3 - methyl - 5 methoxy - thiophene 10.0 g (0.125 mol) of cupric oxide and 11.0 g (0.0433 mol) of 2 - hydroxymethyl - 3methyl - 5 - iodo - thiophene were added to a solution of 10.0 g (0.435 mol) of sodium in 90 ml of methanol. The resulting mixture was heated to 80"C for 18 hours while stirring vigorously. The cold solution was filtered, and the filtrate poured into ice-water and extracted with ether/hexane (ratio 4:1). The organic extracts were washed with 10% sodium thiosulphate solution and saturated sodium chloride solution, dried and evaporated to yield 2 - hydroxymethyl - 3 - methyl - 5methoxy - thiophene as a colourless oil.

c) (3 - Methyl - 5 - methoxy - 2 - thenyl) triphenylphosphonium chloride 21.0 g (80.2 mmol) of triphenylphosphine were added to a solution of 5.8 g (36.7 mmol) of 2 - hydroxymethyl - 3 - methyl - 5 - methoxy - thiophene in 60 ml of dry carbon tetrachloride and 80 ml of toluene. The temperature of the mixture was slowly raised to 80"C and heating was continued overnight. The resulting precipitate was filtered off from the cold solution, washed well with cold benzene and dried in a high vacuum to yield (3methyl - 5 - methoxy - 2 - thenyl)triphenylphosphonium chloride of melting point 180"-- 185"C.

Example 15 All - trans - 3,7 - dimethyl - 9 - (2,4 - di methyl - 5 - methoxy - 3 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester A suspension of 11.0 g (22.1 mmol) of (2,4dimethyl - 5 - methoxy - 3 - thenyl)triphenyl phosphonium bromide and 5.1 g (24.5 mmol) of 7 - formyl - 3 - methyl - 2,4,6 - octatrienoic acid ethyl ester in 450 ml of 1,2-butylene oxide was heated to 70"C until a clear solution resulted (about 12 hours). The resulting clear solution was cooled, poured into 500 ml of methanol/water (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude material was purified by column chromatography [silica gel; hexane/ether (10:3)] to yield, after recrystallisation from hexane, all - trans - 3,7 dimethyl - 9 - (2,4 - dimethyl - 5 - methoxy3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 81"--82"C.

The t2,4 - dimethyl - 5 - methoxy - 3- thenyl)triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: a) 2,4 - Dimethyl - thiophene - 3 - carbox aldehyde A solution of 15 g (79.0 mmol) of 2,4 - dimethyl - 3 - bromo - thiophene in 120 ml of dry ether was cooled to -700C and 36 ml of a hexane solution of n-butyl lithium (2.4-M; 86.4 mmol) were added dropwise.

The mixture was allowed to warm to --20"C for 10 minutes, again cooled to -700C and then quenched by the dropwise addition of 15 g (0.205 mol) of dimethylformamide. The mixture was stirred at room temperature overnight, poured into ice-water, stirred for 15 minutes and extracted four times with ether.

The ether phase was washed with saturated.

sodium chloride solution, dried and evaporated. The resulting oily residue was distilled to yield 2,4 - dimethyl - thiophene - 3 - carboxaldehyde of boiling point 50"--55"C/0.1 mm.

b) 2,4 - Dimethyl - 3 - hydroxymethyl thiophene 0.68 g (18 mmol) of sodium borohydride was added in three portions to a solution of 10.08 g (72 mmol) of 2,4 - dimethyl - thiophene - 3 - carboxaldehyde in 120 ml of ethanol. After 15 minutes, the mixture was poured into water, extracted with ether, dried and the solvent evaporated. The resulting residue was recrystallised from hexane to yield 2,4 - dimethyl 3 - hvdroxvmethyl - thiophene of melting point 80 08 10 C.

c) 2,4 - Dimethyl - 3 - hydroxymethyl - 5 iodo - thiophene 10.0 g (46 mmol) of mercuric oxide and 14.7 g (58 mmol) of iodine were added altern atelv over a period of 1.25 hours to a vigorously stirred solution of 8.2 g (57.7 mmol) of 2,4 - dimethyl - 3 - hydroxvmethyl - thiophene in 300 ml of benzene. The mixture was kept at room temperature by cooling with an ice-bath and stirring was continued for an additional hour. The mercuric iodide which precipitated out was filtered off and washed well with warm ether. The combined organic solutions were washed with 10% sodium thiosulphate solution and saturated sodium chloride solution, dried and evaporated. The resulting residue was dissolved in a minimum amount of hot ether, an equal amount of hexane was added and the solution cooled to 50 C. The crystals which precipitated out were filtered off and washed with cold hexane to yield, after drying, 2,4 - dimethyl - 3hydroxymethvl - 5 - iodo - thiophene of melting point 118.5"--120.5"C.

d) 2,4 - Dimethyl - 3 - hydroxymethyl - 5 methoxy - thiophene 12.0 g (0.151 mol) of cupric oxide and 12.5 g (0.0466 mol) of 2,4 - dim ethyl - 3 - hvdroxymethyl - 5 - iodo - thiophene were added to a solution of 12.5 g (0.543 mol) of sodium in 100 ml of dry methanol. The mixture was heated to 80"--82"C (internal temperature) for 20 hours while stirring vigorously and then cooled. The cold solution was diluted with 150 ml of methanol, filtered, poured into icewater and extracted with ether/hexane (ratio 4:1). The organic layers were washed with 5 XO sodium carbonate solution, dried and evaporated. The residue which resulted was recrystallised from hexane to yield 2,4 - dimethyl - 3 - hydroxymethyl 5 - methoxythiophene of melting point 550-600C. This product contained about 10% of 2,4 dimethyl - 3: hydroxy - methyl - thiophene which was formed in this reaction by reduction of the iodide. Fractional recrystallisation of a sample from hexane yielded pure 2,4dimethyl - 3 - hydroxymethyl - 5 - methoxythiophene of melting point 6405 0C.

e) (2,4 - Dimethyl - 5 - methoxy - 3 thenyl)triphenylphosphonium bromide 6.1 g (35.5 mmol) of 2,4 - dimethyl - 3hydroxymethyl - 5 - methoxy - thiophene were added at 35"C while stirring vigorously to a suspension of 13.4 g (39.0 mmol) of triphenylphosphonium bromide in 250 ml of acetonitrile. The deep purple colour which formed immediately disappeared after some minutes. The mixture was stirred for 3 hours.

The solvent was evaporated to a volume of about 25 ml and an excess of cold ether was added. The solvent then was decanted from the resulting oily precipitate which was dissolved in warm acetone and again precipitated by the addition of cold ether. The solvent was decanted and the resulting oily residue was dried in a high vacuum to yield (2,4 - dimethyl - 5 - methoxy - 3 - thenyl)triphenylphosphonium bromide.

Example 16 3,7 - Dimethyl - 9 - (2,4 - dimethvl - 5 - meth oxymethyl - 3 - thienyl) - 2,4,6,8 - nona tetraenoic acid ethyl ester 3.6 g of a 50 {, suspension of sodium hydride in mineral oil was washed once with pentane and suspended in 200 ml of dimethylformamide at 50C. 40.2 g of a solution of (7ethoxy - carbonyl - 2,6 - dimethyl 2,4,6- heptatrienyl)triphenylphosphonium bromide in 75 ml of dimethvlformamide were added slowly and stirred for 30 minutes. 12.6 g of a solution of 2,4 - dimethyl - 5 - methoxvmethyl - thiophene - 3 - carboxaldehyde in 50 ml of dimethylformamide were then added slowly. The resulting mixture was stirred at 5"C for 10 hours, poured into ice-water and extracted with hexane. The hexane extracts were combined and washed twice with methanol/water (6:4) and once with a saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The crude material was purified bv column chromatogranhy on silica gel and elution with ethyl ether/hexane (1: 3) to yield cis- and trans - 3,7- dimethyl - 9 - (2,4 - dimethyl- 5 methoxvmethvl - 3 thienyl) - -2,4,6,8 - nonatetraenoic acid ethvl ester.

The 2,4 - dimethyl - 5 - methoxvmethvlthiophene - 3 - carboxaldehyde used as the starting material can be prepared, for example, as follows: a) 4 - Bromo - 3,5 - dimethyl - thiophene 2 - carboxaldehyde 15.0 g of 2,4 - dibromo - 3,5 - dimethylthiophene were dissolved in 250 ml of anhydrous ether and cooled to -700C while stirring under argon. 24 ml of a 2.4-M solution of n-butyl lithium were slowly added to the solution, the mixture was warmed to --35"C for 10 minutes and then cooled again to -700C. 7.3 g of dimethylformamide were added slowly to the mixture and the resulting mixture was warmed to room temperature for 14 hours. The resulting solution was poured into icewater, stirred for 20 minutes and extracted with ether. The ether extracts were combined, washed with an aqueous solution of 5 % sodium carbonate and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated to yield 4 - bromo3,5 - dimethyl - thiophene - 2 - carboxaldehyde of melting point 44 45 C.

b) 4 - Bromo - 3,5 - dimethyl - 2 - hydroxy methyl - thiophene 11.8 g of 4 - bromo - 3,5 - dimethyl - thiophene - 2 - carboxaldehyde were dissolved in 250 ml of dry ethanol and stirred at 20go.

0.52 g of sodium borohydride was added, the resulting solution was stirred for 30 minutes, then poured into ice-water and extracted with ether. The combined ether extracts were washed with a solution of 5% sodium carbonate and a saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. Crystallisation from cold hexane yielded 4 - bromo - 3,5 - dimethyl - 2 - hydroxymethyl - thiophene of melting point 85"- 90"C.

c) 4 - Bromo - 3,5 - dimethyl - 2 - methoxy methyl - thiophene 2.9 g of a 50% suspension of sodium hydride in mineral oil was washed once with pentane and suspended in 100 ml of dimethylformamide at 5"C. 10.5 g of a solution of 4bromo - 3,5 - dimethyl 2 - hydroxymethylthiophene in 40 ml of dimethylformamide were added slowly to the suspension and the mixture was stirred for 30 minutes. 10 g of methyl iodide were added and the resulting mixture was stirred for 14 hours at 20"C.

The mixture was then poured into water and extracted with hexane. The hexane extracts were washed with a solution of 5% sodium carbonate and a saturated solution of sodium chloride, dried over sodium sulphate, filtered and evaporated to yield 4 - bromo - 3,5dimethyl - 2 - methoxymethyl - thiophene.

d) 2,4 - Dimethyl - 5 - methoxymethyl thiophene - 3 - carboxaldehyde 15.5 g of 4 - bromo - 3,5 - dimethyl - 2methoxymethyl - thiophene were dissolved in 200 ml of anhydrous ether under argon. The resulting solution was cooled to -700C and 22 ml of a 2.4-M solution of n-butyl lithium were slowly added. The mixture was warmed to -300C for 10 minutes and then cooled to -700C. 7.3 g of dimethylformamide were slowly added and the mixture was warmed to room temperature for 14 hours. The resulting mixture was poured into ice-water, stirred for 15 minutes and extracted with ether. The combined ether extracts were washed with a solution of 5% sodium carbonate and a saturated solution of sodium chloride, dried over sodium sulphate, filtered and evaporated to yield 2,4 - dimethyl - 5methoxymethyl - thiophene - 3 - carboxaldehyde.

Example 17 All - trans - 3,7 - dimethyl - 9 - (2,4 - di methyl - 3 - thienyl) - 2,4,6,8 - nona tetraenoic acid ethyl ester 1.35 g of a 50% suspension of sodium hydride in mineral oil was washed once with hexane and suspended in 120 ml of dimethylformamide. 12.0 g of a suspension of (2,4dimethyl - 3 - thenyl)triphenylphosphonium bromide in 20 ml of dimethylformamide was added dropwise at 0 0C and the mixture stirred for 30 minutes. 5.8 g of a solution of 3 - methyl - 7 - formyl - 2,4,6 - octatrienoic acid ethyl ester in 30 ml of dimethylformamide was then added dropwise. After stirring at 0 C for 2 hours, the mixture was poured into ice-water and extracted several times with hexane. The combined hexane extracts were washed twice with methanol/water (6:4) and once with a saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The resulting crude product was purified by column chromatography on silica gel and eluation with ether/hexane (1:4). Recrystallisation from hexane yielded all - trans - 3,7 - dimethyl - 9 - (2,4 - dimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acids ethyl ester of melting point 69 71 C.

The (2,4 - dimethyl - 3 - thenyl)triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: 4.4 g of 2,4 - dimethyl - 3 - hydroxymethylthiophene and 10.7 g of triphenylphosphonium bromide were dissolved in 40 ml of acetonitrile and stirred at 40"C for 1 hour. The resulting solution was cooled and 150 ml of ether were added. The white precipitate which formed was filtered off and washed with cold acetone to yield (2,4 - dimethyl - 3 - thenyl)triphenylphosphonium bromide of melting point 2620-2650C.

Example 18 All - trans - 3,7 - dimethyl - 9 - (2,4 - di- methyl - 5 - methylthio - 3 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester 1.40 g of a 50% suspension of sodium hydride in mineral oil were washed once with pentane and suspended in 120 ml of dimethylformamide. 14.5 g of a suspension of (2,4dimethyl - 5 - methylthio - 3 - thenyl)triphenylphosphonium bromide in 30 ml of dimethylformamide were added dropwise at 0 C and the mixture was stirred for 30 minutes. 6.5 g of a solution of 3 - methyl - 7formyl - 2,4,6 - octatrienoic acid ethyl ester in 30 ml of dimethylformamide was then added dropwise. After stirring at 0 0C for 2 hours, the mixture was poured into ice-water and extracted several times with hexane. The combined hexane extracts were washed twice with methanol/water .f6;4), once with a saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The resulting crude product was purified by column chromatography on silica gel and elution with ether/hexane (1: 4). Recrvstallisation from ether/hexane (1: 9) yielded all trans - 3,7 - dimethyl - 9 - (2,4 - dimethyl 5 - methylthio - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 760-780C.

The (2,4 - dimethyl - 5 - methylthio - 3thenyl)triphenylphosphonium bromide used as the starting material can be prepared, for example, as follows: a) 3 - Bromo - 2,4 - dimethyl - 5 - methyl thio - thiophene 20.0 g of 2,4 - dibromo - 3,5 - dimethylthiophene were dissolved in 300 ml of anhydrous ether. The resulting solution was cooled to -700C while stirring under argon.

32 ml of a 2.4-M solution of n-butyl lithium were added slowlv, the solution was warmed to --32"C for 10 minutes and then cooled again to -700C. 7.5 g of dimethyl disulphide were added slowly while the temperature was maintained at -700C. The resulting solution was warmed to room temperature, stirred for 2 hours, then poured into icewater, stirred for 15 minutes and extracted with ether. The combined ether extracts were washed with water, 5 % sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated to yield 3 - bromo - 2,4 - dimethyl 5 - methylthio - thiophene.

b) 2,4 - Dimethyl - 5 - methylthio - thio-' phene - 3 - carboxaldehyde 18.5 g of 3 - bromo - 2,4 - dimethyl - 5methylthio - thiophene were dissolved in 250 ml of anhydrous ether and cooled to -700C while stirring under argon. 34 ml of a 2.4-M solution of n-butyl lithium were added slowly and the solution was warmed to --25"C for 10 minutes. The mixture was again cooled to -700C and 7.3 g of dimethylformamide were added slowly. The mixture was stirred at room temperature for 2 hours, poured into ice-water, stirred for 15 minutes and extracted with ether. The combined ether extracts were washed with water, a 5% sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated to yield 2,4 - dimethyl - 5 - methylthio - thiophene- 3 - carboxaldehyde.

c) 2,4 - Dimethyl - 3 - hydroxymethyl - 5 methylthio - thiophene 15.0 g of 2,4 - dimethyl - 5 - methylthiothiophene - 3 - carboxaldehyde were dissolved in 150 ml of dry ethanol while stirring at 20"C. 0.8 g of sodium borohydride was added and the mixture was stirred for 30 minutes, then poured into ice-water and extracted with ether. The combined ether extracts were washed with a 50/n sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated to yield 2,4 - dimethyl - 3 - hydroxymethyl 5 - methylthio - thiophene.

d) (2,4 - Dimethyl - 5 - methylthio - 3 thenyl)triphenylphosphonium bromide 14.0 g of 2,4 - dimethyl - 3 - hydroxymethyl - 5 - methylthio - thiophene and 26.0 g of triphenylphosphonium bromide were dissolved in 75 ml of acetonitrile and stirred at 40"C for 1 hour. The resulting mixture was cooled, poured into 150 ml of ethyl acetate then treated with ether/hexane (5:1). The resulting solution was decanted from a gumlike residue. The residue was treated with hot acetone and the resulting white crystals were filtered off, washed with cold acetone and dried under a high vacuum at 80"C to yield (2,4 - dimethyl - 5 - methyl this 3 - thenyl)triphenylphosphonium bromide of melting point 245" 248"C.

Example 19 3,7 - Dimethyl - 9 - (3 - methyl - 5 - nitro 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester 3.7 g of a 50% suspension of sodium hydride in mineral oil were washed once with pentane and suspended in 450 ml of dimethylformamide. 42.8 g of a solution of (7 - ethoxycarbonyl - 2,6 - dimethyl - 2,4,6 - heptatrienyl)triphenylphosphonium bromide in 200 ml of dimethylformamide were added slowly at 0 0C and the mixture was stirred for 45 minutes. This mixture was added slowly to a cold (0 C) solution of 3 - methyl - 5 - nitrothiophene - 2 - carboxaldehyde in 350 ml of dimethylformamide under argon. The mixture was then stirred at 5"C for 2 hours, poured into ice-water and extracted with ether. The ether extracts were combined, washed twice with water, dried over sodium sulphate, filtered and evaporated. The resulting crude solid was dissolved in 600 ml of ethyl acetate and diluted with 4 litres of hexane. This solution was washed three times with water/methanol tax4:6) and the washings were extracted twice with hexane. All organic extracts were combined, washed once with water/methanol (4:6), once with a saturated sodium chloride solution, dried over sodium sulphate, filtered and 13.3 g of 3 - methyl - 7 - formyl - 2,4,6dimethyl - 9 - (3 - methyl - 5 - nitro - 2thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

Example 20 All - trans - 3,7 - dimethyl- 9 - (2,4- di- ethyl - 5 - methyl - 3 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester 27.0 g of (2,4 - diethyl- 5 - methyl - 3 thenyl)triphenylphosphonium chloride were suspended in 400 ml of 1,2 - butylene oxide and 13.3 g of 3 - methyl - 7 formyl - 2,4,6 octatrienoic acid ethyl ester were added. The resulting mixture was refluxed under argon for 3 hours and then the solvent was evapor ated. The residue was diluted with methanol/ water (6:4) and extracted several times with hexane. The combined organic phases were washed once with methanol/water (6 :4), dried over sodium sulphate, filtered and evaporated.

The resulting crude product was purified by column chromatography (hexane/5 % ethyl acetate). Two recrystallisations from hexane yielded all - trans - 3,7 - dimethyl - 9 - (2,4 diethyl - 5 - methyl - 3 thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester of melting point 790-800C.

The (2,4 - diethyl - collected. The mixture was then refluxed at 1600C for 2.5 hours and cooled to below 80"C. 50 g of potassium hydroxide were then added while stirring, the mixture was carefully warmed to 120"C, heated to reflux for 20 minutes and finally distilled until no further distillate was collected at 210 C. The resulting distillate was cooled and poured into 500 ml of ice-cold 2-N hydrochloric acid. The resulting product was extracted several times with ether. The combined organic phases were washed with water, sodium bicarbonate solution and water, dried over sodium sulphate, filtered and evaporated. The resulting crude product was purified by distillation to yield 2,4 - diethyl - 5 - methyl - thiophene of melting point 850-870C (20 mm).

b) 2,4 - Diethyl - 5 - methyl - 3 - chloro methyl - thiophene 15.0 g of 2,4 - diethyl - 5 - methyl - thiophene, 65 ml of acetic acid, 130 ml of 12-N hydrochloric acid and 8.9 g of formaldehyde (37% solution) were heated at 70"C for 2.5 hours. The mixture was cooled, poured into 600 ml of water and extracted several times with ether. The combined organic phases were washed with water, sodium bicarbonate solution and water, dried over sodium sulphate, filtered and evaporated to yield 2,4 - diethyl5 - methyl - 3 - chloromethyl - thiophene.

c) (2,4 - Diethyl - 5 - methyl - 3 - thenyl) triphenylphosphonium chloride 19.7 g of 2,4 - diethyl - 5 - methyl - 3chloromethyl - thiophene and 39.5 g of triphenylphosphine were dissolved in 400 ml of toluene. The solution was heated at 115"C overnight under argon and then cooled to room temperature. The white phosphonium salt which precipitated was collected by filtration, washed with toluene and dried at 100"C under a high vacuum to yield (2,4 - diethyl 5 - methyl - 3 - thenyl)triphenylphosphonium chloride of melting point 1920-1940C.

Example 21A 2,4,6 - Trans - 8 - cis - 3,7 - dimethyl - 9 (3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester 22.5 g of (3 - thenyl)triphenylphosphonium bromide were suspended in 200 ml of dimethylformamide and cooled to 00--50C.

2.4 g of a 50% suspension of sodium hydride in mineral oil were added in portions. After stirring for 30 minutes, a solution of 11.4 g of 3 - methyl - 7 - formyl - 2,4,6 - octatri enoic acid ethyl ester in 45 ml of dimethylformamide was added dropwise. After stirring for 3 hours at 0"--5"C, the mixture was poured into 1000 ml of water and extracted several times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulphate, filtered and evaporated. The resulting crude product was purified by column chromatography (hexane/ 10% ethyl acetate). Recrystallisations from hexane/15 /O ethyl acetate and hexane yielded 2,4,6 - trans - 8 - cis - 3,7 - dimethyl - 9 - (3thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 59.50-600C.

Example 21B All - trans - 3,7 - dimethyl - 9 - (3 - thienyl)- 2,4,6,8 - nonatetraenoic acid ethyl ester 26.6 g of (3 - thenyl)triphenylphosphonium bromide were suspended in 200 ml of dimethylformamide and the mixture was cooled to 0"--5"C. 2.90 g of a 50% suspension of sodium hydride in mineral oil were added in portions. After stirring for 1 hour, a solution of 13.7 g of 3 - methyl - 7 - formyl - 2,4,6octatrienoic acid ethyl ester in dimethyl formamide was added dropwise. After stirring for 2 hours at 0"--5"C, the mixture was poured into 1000 ml of water and extracted several times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulphate, filtered and evaporated.

The resulting crude product was purified by column chromatography (hexane/25 !, ethyl acetate). Recrystallisation once from hexane/ 25 % ethyl acetate, and repeated recrystallisation from hexane/ether, the latter having an isomerising effect, yielded all - trans - 3,7dimethyl - 9 - (3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester of melting point 99 101 C.

The (3 - thenyl)triphenylphosphonium bromide used as the starting material in Example 21A and in this Example can be prepared, for example, as follows: 34.3 g of 3 - bromomethyl - thiophene and 61.0 g of triphenyl - phosphine were dissolved in 500 ml of benzene. The mixture was refluxed overnight under argon and then cooled to room temperature. The tan phosphonium salt which precipitated was collected by filtration, washed several times with toluene and dried at 100"C under a high vacuum to yield (3 - thenyl)triphenyl - phosphonium bromide of melting point > 270 C.

Example 22 All - trans - 3,7 - dimethyl - 9 - (2,5 - di chloro - 4 - methyl - 3 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester 12.3 ml of n-butyl lithium (2.45-M in hexane) were added slowly to a cold (--10"C) suspension of 14.6 g (30.1 mmol) of (2,5 - di chloro - 4 - methyl - 3 - thenyl)triphenylphos phonium chloride in 200 ml of ether. The mixture was stirred for 10 minutes. A solu tion of 6.27 g (30.1 mmol) of 3 - methyl - 7 formyl - 2,4,6 - octatrienoic acid ethyl ester in 100 ml of ether was then added at - 10"C.

The mixture was allowed to warm slowly to room temperature over a period of 2 hours, then poured into ice-water and extracted with ether. The ether extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to yield a yellow oil which was triturated several times with hexane and filtered. The hexane extracts were concentrated and the residue was purified by chromatography on silica gel. Elution with hexane containing 1% ether yielded a yellow oil which crystallised. Repeated crystallisation from pentane yielded ethyl all - trans - 3,7dimethyl - 9 - (2,5 - dichloro - 4 - methyl3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester as yellow crystals of melting point 770-830C.

The (2,5 - dichloro - 4 - methyl - 3thenyl)triphenylphosphonium chloride used as the starting material can be prepared, for example, as follows: a) 3 - Chloromethyl - 2,5 - dichloro - 4 methyl - thiophene A mixture of 61.59 g (0.368 mol) of 2,5dichloro - 3 - methyl - thiophene, 13.1 g of paraformaldehyde and 3.1 g of zinc chloride was heated to 55"C. Hydrogen chloride gas was passed through the mixture for 7.25 hours.

The resulting mixture was cooled and poured into a mixture of ether and ice-water. The organic phase was separated and washed with sodium chloride solution, sodium bicarbonate solution and again with sodium chloride solution. Evaporation of the dried solvent gave a dark brown oil which was distilled under reduced pressure to yield 3 - chloromethyl2,5 - dichloro - 4 - methyl - thiophene as a pale yellow liquid of boiling point 87"- 92"C/0.75 mm.

b) (2,5 - Dichloro - 4 - methyl - 3 - thenyl) triphenylphosphonium chloride A mixture of 25.4 g (0.12 mol) of 3 - chloromethyl - 2,5 - dichloro - 4 - methyl - thiophene, 34.6 g (0.132 mol) of triphenylphosphine and 200 ml of benzene was heated to reflux overnight. The resulting beige solid was filtered off to yield (2,5 - dichloro - 4methyl - 3 - thenyl)triphenylphosphonium chloride of melting point 2380-2400C.

Example 23 All - trans - 3,7 - dimethyl - 9 - (2,4,5 - tri methyl - 3 - thienyl) - 2,4,6,8 - nonatetra en-1-ol 10.0 g of all - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester were dissolved in 200 ml of toluene and cooled to --78"C.

55.5 ml of a 25 ó solution of diisobutylaluminium hydride in hexane were added slowly to the resulting mixture. After stirring at --78"C for 30 minutes, the mixture was warmed to 0 C and 200 ml of 50S: aqueous methanol solution were added slowly. The mixture was filtered and the filter cake was washed with ether. The filtrate was extracted several times with ether. The combined organic phases were washed twice with water, dried over magnesium sulphate, filtered and evaporated to yield all - trans - 3,7 - dimethyl9 - (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,S- nonatetraen - 1 - ol.

Example 24 All - trans - 3,7 - dimethyl - 9 - (2,4,5 - tri methyl - 3 - thienyl) - 1 - methoxy 2,4,6,8 - nonatetraene 1.056 g of a 5004 suspension of sodium hydride in mineral oil were suspended in 100 ml of dimethylformamide. 5.76 g of all - trans3,7 - dimethyl - 9 - (2,4,5 - trimethyl 3thienyl) - 2,4,6,8 - nonatetraen - 1 - ol were then added. The resulting mixture was stirred for 5 minutes and then 3.75 ml of methyl iodide were added while cooling. After stirring at room temperature for about 20 hours, the mixture was poured into 200 ml of water and extracted several times with ethyl acetate.

The combined organic phases were washed with water, dried over magnesium sulphate, filtered and evaporated. The resulting crude product was purified by column chromatography xhexane/25 ,Ó ethyl acetate). Recrystallisation from methanol yielded alltrans - 3,7 - dimethyl - 9 - (2,4,5 - trimethyl3 - thienyl) - 1 - methoxy - 2,4,6,8 - nonatetraene of melting point 930-940C.

Example 25 All - trans - 3,7 - dimethyl - 9 - (2,4,5 - tri methyl - 3 - thienyl) - 2,4,6,8 - nona tetraen -1- al 5.1 g of all - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraen - 1 - ol were dissolved in 100 ml of methylene chloride (previously purified bv passage through a column of neutral alumina) and 26.1 g of manganese dioxide were added.

After stirring for 20 hours at room tempera ture, the mixture was filtered through Celite and evaporated. (The word "Celite" is a registered Trade Mark.) The resulting crude product was purified by column chromatography (hexane/25 % ethyl acetate). Two recrystallisations from hexane/25% ethyl acetate yielded all - trans - 3,7 - dimethyl - 9 - (2,4,5 trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraen 1 - al of melting point 1090-I100C.

Example 26 All - trans - 3,7 - dimethyl - 9 - (2,4,5 - tri methyl - 3 - thienyl) - 2,4,6,8 - nona tetraenoic acid 4.35 g of all - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester were dissolved in 30 nil of ethanol and a solution of 3 g of potassium hydroxide in 6 ml of water and 6 ml of ethanol was added. The mixture was stirred under argon for 2.5 hours at 50"C.

After cooling, the solution was poured on to ice-water, acidified with 3-N sulphuric acid and extracted several times with methylene chloride. The organic phase was washed twice with water, dried over sodium sulphate, filtered and evaporated. The resulting crude material was recrystallised from ethyl acetate to yield all - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid of melting point 208 212"C.

Example 27 All - trans 3,7 - dimethyl - 9 - (2,4,5 - tri methyl - 3 - thienyl) - 2,4,6,8 - nona tetraenamide 6.04 g of all - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid were suspended in 100 ml of toluene. 3.48 ml of phosphorus trichloride were added dropwise to the suspension at room temperature. After stirring for about 20 hours, the acid had dissolved and a red solution of the acid chloride resulted.

The toluene then was evaporated off and the acid chloride was dissolved in 150 ml of anhydrous liquid ammonia. The mixture was stirred at a low temperature for 3 hours and then at room temperature for 18 hours. The mixture was diluted with methylene chloride, poured into water and extracted several times with methylene chloride. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. Two recrystallisations from 95 % ethanol yielded all- trans - 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenamide of melting point 1980-2030C.

Example 28 All - trans - N - ethyl - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8 nonatetraenamide 1.78 g of all - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid were suspended in 20 ml of benzene. 563 mg of phosphorus trichloride were added dropwise to the suspension at room temperature. After stirring at 30"C for about 3 hours, the acid had dissolved and a red solution of the acid chloride resulted. The red solution was added dropwise to a mixture of 800 mg of ethylamine and 20 ml of methylene chloride - at 5"--10"C. After stirring for 1 hour at room temperature, the mixture was diluted with methylene chloride, poured into a saturated sodium chloride solution and extracted three times with methylene chloride. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. Recrystallisation from ethyl acetate gave all - trans - N - ethyl - 3,7 - dimethyl - 9 - (2,4,5 - trimethyl- 3 - thienyl)2,4,6,8 - nonatetraenamide of melting point 18"--187"C.

The following Examples illustrate typical pharmaceutical preparations provided by the present invention: Example A Wet Granulation Formulation (250 mg Tablets) Per Tablet All - trans - N - ethyl - 3,7 di methyl - 9 - (2,4,5 - trimethyl 3 - thienyl) - 2,4,6,8 - nona tetraenamide (2% excess) 255 mg Modified starch 25 mg Pregalatinised starch 25 mg Microcrystalline cellulose 35 mg Lactose (anhydrous) 30 mg Magnesium stearate 3 mg Talc 7 mg Total weight 380 mg Procedure: 1. Mix all ingredients, except magnesium stearate and talc, in a suitable mixer. Mill and mix.

2. Granulate with water to a uniform wet consistency. Mill and spread on trays.

3. Dry overnight in a suitable dryer.

4. Mill and prepare a premix with magnesium stearate and tale Mix for 5 minutes.

5. Compress on a suitable press.

Example B Direct Compression Formulation '25 mg Tablets) Per Tablet All - trans - N - ethyl - 3,7 - di- Tablet methyl - 9 - (2,4,5 - trimethyl 3 - thienyl) - 2,4,6,8 - nona tetraenamide (2% excess) 25.5 mg Lactose (anhydrous) 172.5 mg Microcrystalline cellulose (pH 101) 25 mg Starch 25 mg Magnesium stearate 2 mg Total weight 250 mg Procedure: 1. Mix all ingredients, except magnesium stearate, in a suitable mixer.

2. Make a premix with magnesium stearate and add to the mix of Step 1. Mix for 5 minutes.

3. Compress on a suitable press.

Example C Direct Compression Formulation (25 mg Tablets) Per Tablet All - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester '2% excess) 25.5 mg Lactose (anhydyrous) 172,5 mg Microcrystalline cellulose (pH 101) 25 mg Starch 25 mg Magnesium stearate 2 mg Total weight 250 mg Procedure: 1. Mix all ingredients, except magnesium stearate, in a suitable mixer.

2. Make a premix with magnesium stearate and add to the mix of Step 1. Mix for 5 minutes.

3. Compress on a suitable press.

Example D Wet Granulation Formulations (250 mg Tablets) Per Tablet All - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester (2% excess) 255 mg Modified starch 25 mg Pregelatinised starch 25 mg Microcrystalline cellulose 35 mg Lactose (anhydrous) 172.5 mg Magnesium stearate 3 mg Talc 7 mg Total weight 380 mg Procedure: 1. Mix all ingredients, except magnesium stearate and talc, in a suitable mixer. Mill and mix.

2. Granulate with water to a uniform wet consistency. Mill and spread on trays.

3. Drv overnight in a suitable dryer.

4. Mill and prepare a premix with mag nesium stearate and talc. Mix for 5 minutes.

5. Compress on a suitable press.

WHAT WE CLAIM IS:- 1. Polyene compounds of the general formula

wherein one of RX and R2 represents the group

and the other of R1 and R and R3 and R4 represent a hydrogen or halo gen atom or a (lower alkoxy) - (lower alkyl), hydroxymethyl, lower alkyl, lower alkoxy, lower alkylthio, carb oxvl, amino, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)amino - (lower alkyl), di(lower alkyly)amino - (lower alkyl), hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoyl amido or nitrogen containing hetero cyclic group and R, represents a formyl, hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxy carbonyl, alkenoxycarb onyl, alkynoxy carbonyl, carbamoyl, mono(lower alkyl) carbamoyl, di(lower alkyl)carbamoyl N - heterocyclylcarbonyl or aroyloxy methyl group, and pharmaceutically acceptable salts thereof, as herein defined.

* 2. All - trans - 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

3. All -trans - 3,7 - dimethyl - 9 - (3,4,5trimethyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

4. All - trans - 3,7 - dimethyl- 9 - (3- methyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

5. All - trans - 3,7 - dimethyl - 9 - (5methyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

6. All - trans - 3,7 - dimethyl - 9 - (2,5dimethyl - 3 - thienyl) - 2,4,5,8 - nonatetraenoic acid ethyl ester.

7. All - trans - 3,7 - dimethyl - 9 dimethyl - 5 - chloro - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

8. All - trans - 3,7 - dimethyl - 9 - (2,5dichloro - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

9. All - trans - 3,7 - dimethyl - 9 - (3,4dibromo - 5 - methyl - 2 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

10. All - trans - 3,7 - dimethyl - 9 - (3,4,5tribromo - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

11. All - trans - 3,7 - dimethyl - 9 - (2,4 dichloro - 5 - methyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

12. All - trans - 3,7 - dimethyl - 9 - (2,4 diethoxycarbonyl - 5 - acetylamino - 3thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

13. All - trans - 3,7 - dimethyl - 9 - (3methyl - 5 - methoxy - 2 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

14. All - trans - 3,7 - dimethyl - 9 - (2,4 dimethyl - 5 - methoxy - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

15. 3,7 - Dimethyl 9 - (2,4 - dimethyl-

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (47)

**WARNING** start of CLMS field may overlap end of DESC **. Example C Direct Compression Formulation (25 mg Tablets) Per Tablet All - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester '2% excess) 25.5 mg Lactose (anhydyrous) 172,5 mg Microcrystalline cellulose (pH 101) 25 mg Starch 25 mg Magnesium stearate 2 mg Total weight 250 mg Procedure: 1. Mix all ingredients, except magnesium stearate, in a suitable mixer. 2. Make a premix with magnesium stearate and add to the mix of Step 1. Mix for 5 minutes. 3. Compress on a suitable press. Example D Wet Granulation Formulations (250 mg Tablets) Per Tablet All - trans - 3,7 - dimethyl - 9 (2,4,5 - trimethyl - 3 - thienyl) 2,4,6,8 - nonatetraenoic acid ethyl ester (2% excess) 255 mg Modified starch 25 mg Pregelatinised starch 25 mg Microcrystalline cellulose 35 mg Lactose (anhydrous) 172.5 mg Magnesium stearate 3 mg Talc 7 mg Total weight 380 mg Procedure: 1. Mix all ingredients, except magnesium stearate and talc, in a suitable mixer. Mill and mix. 2. Granulate with water to a uniform wet consistency. Mill and spread on trays. 3. Drv overnight in a suitable dryer. 4. Mill and prepare a premix with mag nesium stearate and talc. Mix for 5 minutes. 5. Compress on a suitable press. WHAT WE CLAIM IS:-

1. Polyene compounds of the general formula

wherein one of RX and R2 represents the group

and the other of R1 and R and R3 and R4 represent a hydrogen or halo gen atom or a (lower alkoxy) - (lower alkyl), hydroxymethyl, lower alkyl, lower alkoxy, lower alkylthio, carb oxvl, amino, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)amino - (lower alkyl), di(lower alkyly)amino - (lower alkyl), hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoyl amido or nitrogen containing hetero cyclic group and R, represents a formyl, hydroxymethyl, alkoxymethyl, alkanoyloxymethyl, carboxyl, alkoxy carbonyl, alkenoxycarb onyl, alkynoxy carbonyl, carbamoyl, mono(lower alkyl) carbamoyl, di(lower alkyl)carbamoyl N - heterocyclylcarbonyl or aroyloxy methyl group, and pharmaceutically acceptable salts thereof, as herein defined.

2. All - trans - 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

3. All -trans - 3,7 - dimethyl - 9 - (3,4,5trimethyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

4. All - trans - 3,7 - dimethyl- 9 - (3- methyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

5. All - trans - 3,7 - dimethyl - 9 - (5methyl - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

6. All - trans - 3,7 - dimethyl - 9 - (2,5dimethyl - 3 - thienyl) - 2,4,5,8 - nonatetraenoic acid ethyl ester.

7. All - trans - 3,7 - dimethyl - 9 dimethyl - 5 - chloro - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

8. All - trans - 3,7 - dimethyl - 9 - (2,5dichloro - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

9. All - trans - 3,7 - dimethyl - 9 - (3,4dibromo - 5 - methyl - 2 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

10. All - trans - 3,7 - dimethyl - 9 - (3,4,5tribromo - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

11. All - trans - 3,7 - dimethyl - 9 - (2,4 dichloro - 5 - methyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

12. All - trans - 3,7 - dimethyl - 9 - (2,4 diethoxycarbonyl - 5 - acetylamino - 3thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

13. All - trans - 3,7 - dimethyl - 9 - (3methyl - 5 - methoxy - 2 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

14. All - trans - 3,7 - dimethyl - 9 - (2,4 dimethyl - 5 - methoxy - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

15. 3,7 - Dimethyl 9 - (2,4 - dimethyl-

5 - methoxymethyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

16. All - trans - 3,7 - dimethyl - 9 - (2,4dimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

17. All - tratrs- 3,7 - dimethyl - 9 - (2,4dimethyl - 5 - methylthio - 3 - thienyl)2,4,6,8 - nonatetraenoic acid ethyl ester.

18. 3,7 - Dimethyl - 9 - (3 - methyl - 5nitro - 2 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

19. All - trans - 3,7 dimethyl - 9 - (2,4 diethyl- 5 - methyl - 3 - thienyl) - 2,4,6,8 nonatetraenoic acid ethyl ester.

20. 2,4,6 - Trans - 8 - cis - 3,7 - dimethyl9 - (3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

21. All - trans - 3,7 - dimethyl - 9 - (3- thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

22. All - trans - 3,7 - dimethyl - 9 - (2,5 dichloro - 4 - methyl - 3 - thienyl) - 2,4,6,8nonatetraenoic acid ethyl ester.

23. All - trans - 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraen 1 - ol.

24. All - trans - 3,7 - dimethyl - 9 - (2,4,5 trimethyl - 3 - thienyl) - 1 - methoxy - 2,4,6,8nonatetraene.

25. All - trans - 3,7- dimethyl - 9 - (2,4,5 trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraen 1-al.

26. All - trans - 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid.

27. All - trans - 3,7 - dimethyl - 9 - (2,4,5 trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenamide.

28. All - trans - N - ethyl - 3,7 - dimethyl9 - (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8nonatetraenamide.

29. A process for the manufacture of the polyene compounds of formula I given in claim 1 and pharmaceutically acceptable salts thereof, as herein defined, which process comprises reacting a compound of the general formula

wherein one of R4 and R represents a group of the formula

and the other of Rs and R7 and R, and R4 represent a hydrogen or halogen atom or a (lower alkoxy)-(lower alkyl), hydroxy - methyl, lower alkyl, lower alkoxy, lower alkylthio, carboxyl, amino, mono(lower alkyl)amino, di (lower alkyl)amino, mono(lower alkyl)amino-(lower alkyl), di(lower alkyl)amino - (lower alkyl), hydroxy, lower alkenyl, lower alkenoxy, lower alkanoyl, lower alkanoyloxy, nitro, lower alkoxycarbonyl, lower alkanoylamido or nitrogen containing heterocyclic group, m stands for zero or 1, A represents an oxo, --p[X],ays or

group, X represents an aryl group, Z represents a lower alkoxy group and Y represents the anion of an organic acid or an inorganic acid, with a compound of the general formula

wherein B represents an oxo group when A in the compound of formula II repre sents a P[X],eYE or

group or B represents a P [X ] 3Gyd3 or

group when A in the compound of formula II represents an oxo group, n stands for zero or 1 and X, Y and Z have the significance given earlier in this claim, and R', represents a formyl, carboxyl, alkoxycarbonyl, alkenoxy carbon, alkynoxycarbonyl, di(lower alkyl)carbamoyl or N - heterocyclylcarbonyl group when B represents a P [X] 3OYE or

group, or R', represents a carboxyl, alkoxymethyl, alkanoyloxymethyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl or N - heterocyclyl carbonyl group when B represents an oxo group, and wherein in formulae II and III the sum of m and n is always 1, and, in optional sequence and if desired, esterifying or amidating a carboxylic acid obtained, or hydrolysing or amidating a carboxylic acid ester obtained, or reducing a carboxylic acid or carboxylic acid ester obtained to the corresponding alcohol and, if desired, etherifyying or esterifying said alcohol, or saponifying an alcohol ester, or oxidising an alcohol or alcohol ester obtained to a corresponding aldehyde or carboxylic acid, and, if desired, converting an acid or amine obtained into a pharmaceutically acceptable salt, as herein defined.

30. A process according to claim 29, wherein the reaction is carried out under the conditions of the Wittig reaction in the presence of an alkali metal alcoholate or in the presence of sodium hydride or in the presence of an alklene oxide which may be alkyl substituted.

31. A process according to claim 30, where in said alkali metal alcoholate is sodium methylate.

32. A process according to claim 30, wherein said alkylene oxide which may be alkylsubstituted is ethylene oxide or 1,2-butylene oxide.

33. A process according to claim 30, claim 31 or claim 32, wherein the reaction is carried out in an inert organic solvent.

34. A process according to claim 22, wherein said inert organic solvent is a chlorinated hydrocarbon.

35. A process according to claim 34, wherein said chlorinated hydrocarbon is methylene chloride.

36. A process according to claim 33, wherein said inert organic solvent is dimethylformamide.

37. A process according to claim 29, wherein the reaction is carried out under the conditions of the Horner reaction using a base in the presence of an inert organic solvent.

38. A process according to claim 37, wherein the reaction is carried out using sodium hydride in 1,2 - dimethoxyethane.

39. A process according to claim 37, wherein the reaction is carried out using an alkali metal alcoholate in an alI:anol.

40. A process according to any one of claims 29 to 39 inclusive, wherein 3 - methyl7 - formyl - 2,4,6 - octatrienoic acid ethyl ester is reacted with (2,4,5 - trimethyl - 3thenyl) - triphenylphosphonium chloride to give all - trans - 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

41. A process according to any one of claims 29 to 39 indusive, wherein 2,4,5 - trimethylthiophene - 3 - carboxaldehyde is reacted with (7 - ethoxycarbonyl - 2,6 - dimethyl2, 4, 6 - heptatrienyl)triphenylphosphonium bromide or with 8 - (diethoxyphosphinyl)- 3,7 - dimethyl - 2,4,6 - octatrienoic acid ethyl ester to give 3,7 - dimethyl - 9 - (2,4,5 - trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester.

42. A process according to claim 40, wherein all - trans - 3.7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester obtained is hydrolysed to give all - trans - 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid.

43. A process according to claim 42, wherein the all - trans - 3,7 - dimethyl - 9 - (2,4,5trimethyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid obtained is converted into the acid chloride and this acid chloride is reacted with ethylamine to give all - trans - N - ethyl - 3,7 dimethyl - 9 - (2,4,5 - trimethyl - 3 - thienyl)2,4,6,8 - nonatetraenamide.

44. A process according to claim 29 for the manufacture of the polyene compounds of formula I given in claim 1 and pharmaceutically acceptable salts thereof, as herein defined, substantially as hereinbefore described with reference to any one of Examples 1 to 28.

45. Polyene compounds of formula I given in claim 1 and pharmaceutically acceptable salts thereof, as herein defined, when manufactured by the process claimed in any one of claims 29 to 44 inclusive.

46. A pharmaceutical preparation containing a polyene compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof, as herein defined, in association with a compatible carrier material.

47. A pharmaceutical preparation according to claim 46, wherein said polyene compound is all - trans - 3,7 - dimethyl - 9 - (2,4,5 - tri methyl - 3 - thienyl) - 2,4,6,8 - nonatetraenoic acid ethyl ester or all - trans - N - ethyl - 3,7 dimethyl - 9 - (2,4,5 - trimethyl - 3 - thienyl)2,4,6,8 - nonatetraenamide.