KR820000180B1 - Process for preparation of polyene compounds - Google Patents

Abstract

Title compds. (I ; R1,R2 = lower alkyl, R3 = H, Halogen, lower alkyl, lower alkeneoxy, lower alkanoylamido or N-heter-ocyclic; R4 = H, halogen,lower alkenyl, nitro, amino or N-heterocyclic; R6 = carbamoyl, monocarbamoyl or dicarbamoyl) were prepd. by the reaction of II with halogenizing agent and ammonia or mono- or di-loweralkylamine. I is useful for the treatment of tumors, skin diseases, and mucous membrane inflammation; the LD50 value of I is 700 or 1000 mg/kg in mice.

Description

Method for producing a polyene compound

The present invention relates to a method for producing a polyene compound having the following structural formula (I).

In the above structural formula

R ₁ and R ₂ are each lower alkyl group,

R ₃ is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkenoxy, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkanoylamido or N-heterocyclic group,

R ₄ is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkenoxy, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkinoylamido or N-heterocyclic group,

R ₅ is hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkenoxy, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkanoylamino or N-heterocyclic group ( Provided that at least one of R ₃ , R ₄ and R ₅ is not hydrogen, and when R ₃ or R ₅ is halogen R ₄ is not a lower alkoxy group and one of R ₃ , R ₄ and R ₅ is lower For alkyl the other two are not hydrogen simultaneously)

R ₆ represents a carbamoyl, mono (loweralkyl) carbamoyl, di (loweralkyl) carbamoyl group.

The lower alkyl and lower alkenyl groups mentioned above are preferably those containing up to 6 carbons such as methyl, ethyl, propyl, isopropyl or 2-methylpropyl groups and vinyl, allyl or butenyl groups, and lower alkoxy and lower alkenoxy The groups are also preferably those containing up to 6 carbons, such as methoxy, ethoxy, or isopropoxy groups and vinyloxy or allyloxyglob.

Of the halogen elements, fluorine and chlorine are preferable.

Amino groups may be mono- or di-substituted by straight or branched chain lower alkyl groups (eg methyl, ethyl, isopropyl, etc.).

Lower alkanoyl amido groups contain residues derived from lower alkane carboxylic acids containing up to 6 carbon atoms (e.g. acetic acid, propionic acid or pivalic acid).

The N-heterocyclic group is preferably a group consisting of 5 or 6 containing oxygen or sulfur or other nitrogen atoms in addition to nitrogen atoms, examples of which are pyrrolidino, piperidino, morpholino and thiomorpholino groups. Etc.

Carbamoyl groups may be mono- or substituted by branched or straight chain lower alkyl groups (eg methyl, ethyl or isopropyl). Examples of such substituted carbamoyl groups include methyl carbamoyl, dimethyl carbamoyl and diethyl carbamoyl groups.

Examples of the compound of formula (I) are as follows.

9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osanamide,

9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-pentane ethylamide,

The polyene compound according to the present invention is prepared as follows. In other words, the carboxyl group in the following compound of formula (II) is treated with a halogenating agent to form a carbonyl halide group, which is then amidated by reaction with ammonia or mono- or di-lower alkylamine.

R ₁ and R ₅ in the structural formula are as described above.

The present invention treats the compound of formula (II) by a known method [ie preferably treatment with thionyl chloride in pyridine] to give an acid chloride which is then treated with ammonia to give an amide.

The starting compound of formula (II) can be obtained as described in pending patent application 2008/74 (see also British Patent No. 1,468,401) in Korea.

The compounds of formula (I) can be separated into cis and trans components, if necessary, by cis / trans mixtures, or all can be isomerized to trans compounds.

Polyene derivatives obtained by the present invention are pharmacologically valuable. They are used as anti-inflammatory and allergic skin diseases as well as systemic and local therapies to treat malignant tumors and pathological changes before they become malignant. Moreover, they can be used to suppress wounds of the mucous membranes due to inflammation, altered or posterior changes.

The toxicity of the compounds of formula (I) is very low. For example, 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8 dissolved in new oil as can be clearly seen in the following table. The high toxicity [LD ₅₀ ] when administering -tetraene- 1-osan ethyl ester intraperitoneally of a mouse is 700 or 1000 mg / kg.

[table]

The present polyene derivatives have distinct oncolytic activity. In papilloma studies, tumors caused by dimethyl benz anthracene and soybean oil are regressed. The diameter of the papilloma decreases two weeks after intraperitoneal administration. In the case of the above-mentioned ethyl ether, 25% / kg dose of 4%, 50% / kg dose of 63% decreases.

The polyene derivatives of the present invention can also be used as a medicament. For example, it may be used in the form of a pharmaceutical preparation together with a suitable pharmaceutical carrier.

Pharmaceutical formulations suitable for systemic administration are prepared by adding the compound of formula (I) as an active ingredient to a non-toxic, inert, solid or liquid carrier conventionally used.

The pharmaceutical preparations may be enteral or parenteral. Pharmaceutical forms suitable for enteral administration include tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. Pharmaceutical forms suitable for parenteral administration include stagnant or injectable solutions.

The dosage of the polyene derivative depends on the extent of the lesion, the dosage form and the particular pharmaceutical dose.

The polyene derivative may be administered 5 to 200 mg once or several times a day. The dosage form is preferably a capsule containing about 10 to 100 mg of active ingredient.

Pharmaceutical formulations contain inerts and pharmacologically active additives. Tablets or granules contain a binder, filler, carrier, or diluent. The liquid preparation is in the form of a sterile solution which can be mixed with water. Capsules contain fillers or extenders in addition to the active ingredient. It may also contain flavor enhancers, preservatives, stabilizers, anti-humidifying agents or emulsifiers, salts, buffers and other additives to alter osmotic pressure.

The aforementioned carriers and diluents are natural organic or inorganic. Examples are water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. All auxiliaries used to make pharmaceutical preparations must be nontoxic.

For topical use, the pharmaceutical preparations are conveniently made from ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Double ointments, creams and solutions are preferred. Agents are made by mixing the polyene derivative with a nontoxic, inert, solid or liquid carrier suitable for topical use.

For topical administration, it is convenient to use a liquid formulation of about 0.01 to 0.3%, preferably about 0.02 to 0.1%, and an ointment or cream about 0.05 to 5%, preferably about 0.1 to 2.0%.

Pharmaceutical formulations include antioxidants such as tocopherol, N-ethyl-r-tocopheramine, butylated hydroxyanisole or butylated hydroxy toluene.

The following examples are intended to make the experimental process easier to understand.

Example 1

60 g of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan is dissolved in 1000 ml of acetone. After adding 128 g of methyl iodide and 128 g of potassium carbonate, the solution was stirred for 16 hours at 55 ° to 60 ° C. under nitrogen supply and evaporated under reduced pressure. The residue was dissolved in 1300 ml of petroleum ether (boiling point: 80 ° to 105 ° C.) and 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-, determined at -20 ° C. Nona-2, 4, 6, 8- tetraene- 1- pentane methyl ester (melting | fusing point: 98 degreeC-99 degreeC) is obtained.

In a manner similar to the above, from 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-ethyl iodide 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan ethyl ester having a melting point of 104 to 105 ° C. Was prepared, and 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan and isopropyl iodide 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-isopropyl isopropyl ester was prepared from From 9- (4-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1--acid and ethyl iodide 9- (4-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1- having a melting point of 105 to 106 ° C. Ethyl pentoxide A steer is produced and 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan and diethyl 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl- nona-2,4,6,8-tetraene-1-osan-2 of the pale yellow oily phase from aminoethyl chloride. -Diethylaminoethyl ester was produced and 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1- 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8- having a melting point of 113 to 114 ° C. from osan and beta-picolin chloride. Tetraene-l-oic acid (3-pyridyl) methyl ester is produced.

Example 2

28.6 g of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-oxane is added to 300 ml of benzene and nitrogen React with 12 g of phosphorus trichloride under feed. Subsequently, benzene was distilled off under reduced pressure, and 9- (4-methoxy-2,4,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan chloride was removed. Obtained and dissolved in 1200 ml of ether. The solution was added dropwise to 500 ml of liquid ammonia at −33 ° C. and stirred for 3 hours. The mixture is diluted with 500 ml of ether and stirred without cooling for 12 hours while ammonia is evaporating. The residue is dissolved in 10 l of methylene chloride and the solution is washed twice with 3 l of water, dehydrated over sodium sulfate and evaporated under reduced pressure. 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1 having a melting point of 207 to 209 ° C by recrystallization from ethanol -Acid amide is obtained.

In a similar manner to the above, 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan chloride and ethylamine 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-oate having a melting point of from 179 to 180 ° C. An amide was prepared and 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan chloride and diethyl 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1-osan having a melting point of 105 to 106 ° C from an amine. Diethylamide was prepared and 9- (4-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-1- 9- (4-methoxy-2,3,5,6-tetramethyl-phenyl) -3,7-dimethyl- having a melting point of 200 to 201 ° C from pentoxide chloride and ethylamine. Na-2,4,6,8-tetraene-1-pentane ethylamide is produced and 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6 from, 4,6,8-tetraene-1-oacid chloride and morpholine And 8-tetraene-1-osan morpholide.

In the following examples, pharmaceutical preparations containing the polyene derivatives prepared by the present invention are described.

Example A

A capsule filled with the following ingredients is prepared.

0.1 g of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene-l-oxoamide

51.4 g of wax mixture

103.0 g of vegetable oil

0.5 g of trisodium salt of ethylenediamine tetraacetic acid

150mg each capsule weight

10 mg of active substance in capsule

Example B

Water / fat emulsions containing 03% of the active ingredient are prepared with the following composition.

0.3 g of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-dimethyl-nona-2,4,6,8-tetraene- 1-oethylamide

Magnesium Stearate 2.0g

Fihydro Karen 13.0g

Example C

Solutions containing 0.1% active ingredient are prepared with the following composition.

0.1 g of 9- (4-methoxy-2,3,6-trimethyl-phenyl) -3,7-trimethyl-nona-2,4,6,8-tetraene- 1- pentate ethylamide

50 g propylene glycol

96% ethanol 100ml

Claims (1)

The carboxyl group in the compound of formula (II) is then treated with a halogenating agent to form a carbonyl halide group and amidated by reaction with ammonia or mono- or di-lower alkylamine to give the polyene compound of formula (I) How to manufacture.

In the above structural formula R ₁ and R ₂ are each lower alkyl group, R ₃ is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkenoxy, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkanoylamido or N-heterocyclic group, R ₄ is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkenoxy, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkanoylamido or N-heterocyclic group, R ₅ is hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkenoxy, nitro, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkanoylamido or N-heterocyclic group Provided that at least one of R ₃ , R ₄ and R ₅ is not hydrogen, and when R ₃ or R ₅ is halogen, R ₄ is not a lower alkoxy group and one of R ₃ , R ₄ and R ₅ is lower If alkyl, the other two are not simultaneous hydrogen) R ₆ represents a carbamoyl, mono (loweralkyl) carbamoyl, di (loweralkyl) carbamoyl group.