Untitled record

The present invention relates to a process for the preparation of aralkyl compounds with anti-inflammatory properties of general formula I:

CH₃

I (I)

Ar-C = CH, wherein Ar represents a radical selected from the group consisting of 3-phenoxyphenyl, 3, phenylthiophenyl, 4-phenylthiophenyl, 4-isobutylphenyl, 4-cyclohexyl-3-chlorophenyl, 4-phenoxy-3-methylphenyl, 4-Phenoxy-3-methoxy-enyl, 4'-fluorobiphenyl, 3-chloro-4-allyloxyphenyl, 4-n-butylphenyl, 4-sec-butylphenyl.

A process for the preparation of 4-phenyl-2-methyl-1-butene-1-carboxylic acid is known in which the unsaturated double bond is obtained following the activation of the ketone. ₂₀and dimethoxyphosphinylethylnitrile in the presence of sodium hydride and in absolute benzene medium at room temperature, then treating the reaction mixture with dimethylformamide. 25

This process has the disadvantage that it consists of difficult reaction phases and requires expensive raw materials.

The process according to the present invention eliminates the disadvantages mentioned by the fact that in order to obtain the aralkyl hydrocarbons of said formula I, isopropanol of formula II is refluxed: CH₃

I

Ar_C — OH (II)

I

CH_of wherein Ar has the meanings mentioned in the presence of sulfuric acid and ethanol as an organic solvent.

The following are 11 examples of embodiments of the invention.

Example 1. 4-Phenyl-alpha-methylstyrene

A 42.4 g suspension of 2- (4-biphenylyl) 2-propanol in 100 ml of 4 N sulfuric acid and 50 ml of ethanol was boiled for recirculation and stirred vigorously for 1.5 h. ml of ethanol, and the reaction was again boiled and stirred for 2.5 h. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with ether, benzene and chloroform. The organic extracts were combined, washed with sodium bicarbonate solution and water and dried over sodium sulfate.

After evaporation of the solvent in vacuo, the residue is recrystallized from hexane, 23.4 g is obtained with the melting point 116. . . 118 ° C.

LEI PRICE 2.20

Analysis for: C₁₅H₁₄:

- calculated: 0 = 92.74%; H = 7.26%;

- Found: C, 92.45%; H = 6.98%.

Examples 2 ... 11. The following compounds are prepared according to the method of Example 1, using the appropriate alcohol as the starting material.

3- Phenylthio-alpha-methylstyrene, boiling point 113 ... 115 ° C / 0.05 mm, n³⁵ = 4.6248 containing 10% carbinol measured as Nmr of 2- (3-phenylthiophenyl) -2-propanol.

4- phenylthio-alpha-methylstyrene boiling point 147 ... 167 ° C / 0.2 mm n £³ = 1.6373 din

2- (4-phenylthiophenyl) -2-propanol.

Analysis for C₁₅H₁₄S:

- calculated: Ο = ·, 79.62 · θ /₀; H = 6.24%.

- Found: C, f79.49%; H = 6.64%.

4-iso-butyl-alpha-methylstyrene boiling point 147, 167 ° C / 0, 2 mm; n³⁶ = 1.6374, from 2 - (4-phenylthiophenyl) -2-pr opanol.

Analysis for C_J6H₁₄S:

- calculated: C = 79.62%; H = 6.24%;

- found: 0 = 79.49%; H = 6.64%.

4-iso-butyl-alju-methylstyrene, boiling point 75-100 ° G / 0.4 mm; ng⁵ = 1.5182, from 2- (4-iso-butylphenyl) -2-propanol.

Analysis for Ο₄₃Η_Ι8:

- calculated: 0 = 89.59%; H = 10.41%.

- · found: 0 = 89.52%; H = 40.49%.

4-sec-butyl-alpha-methylstyrene boiling point 52-53 ° C / 0.03 mm; n³⁵ = 1.5188, from 2- (4-sec-butylphenyl) -2-propanol.

Analysis for C₁₃H_1S:

- calculated: 0 = 89.59%; H = 10.41%.

- found: 0 = 89.36%; H = 10.43%.

4-cyclohexyl-alpha-methylstyrene boiling point 122-114 ° C / 0.15 mm, n = = 5484, from 2- (4-eichlohexylphenyl) -2-propanol.

Analysis for C₁₅H₂₀:

- calculated: 0 = 89.94%; H? = Il0,06%.

- - found: 0 = 90.15%; H = 10.33%.

3- methoxy-4-phenoxy-alpha-methylstyrene, boiling point 157. . . 160 ° G / 0.07 mm, = = 1.5914, from 2- (3-methoxy-4-phenoxyphenyl-2propanol.

Analysis for Cieîî_ieA:

- calculated: 0 = 79.97%; H = 6.71%.

- found: 0 = 79.75%; H = 6.24%;

4- (4-fluorophenyl) -alpha-methylstyrene melting point 127. 128 ° C, from 2- (4'-fluorobiphenyl) -2-propanol.

Analysis for C₁₃H₁₃F:

- calculated: 0 = 84.87%; H, 6.17%.

- found: 0 = 84.68%; H = 6.45%.

Boiling point 3-chloro-4-ylloxy-alpha-methylstyrene 49. .. 105 ° C / 0.07 mm; n "= 4,5623 of 2- (3-chloro-4-allyloxyphenyl) 2-propanol.

Analysis for C_[ZH₁₃G1O:

- calculated: 0 = 69.14%; 14 = 6.29%, 0 = = 7.68.

- found: 0 = 69.23%; H 6,2Oo /₀; O = = 7.85%.

4-n-butyl-alpha-methylstyrene, boiling point 84 ... 88 ° C / 0.5 mm; n £⁵ = 1.5182 of 2- (4-n-butylphenyl) -2-propanol.

Analysis for C₁₃H₁₈:

- calculated: 0 = 89.59%; H = 10.41%.

- found: 0 = 89.48%; H '= 10.48%.

The raw materials used in obtaining ποθεί or aralkyl compounds are obtained as follows:

a) 2- {4-biphenylyl) -2-propanol.

A 98 g solution of 4-acetylbiphenyl dissolved in 500 ml of ether and 500 ml of benzene was added dropwise under stirring, to 500 ml of a 2.15 M solution, of methyl magnesium chloride which was diluted with a equal volume of ether and then boil slowly with re-circulation. Then the reaction is allowed to cool to room temperature and the excess of the Grignard reagent is decomposed by dropwise adding 178 ml of a saturated ammonium chloride solution.

The organic deposit is decentered by the resulting inorganic residue and poured into ice water. The organic product is then washed with water and dilute sodium bicarbonate solution and dried over sodium support. Evaporation in vacuo gives a crystalline residue of product by weight of 85 g with a melting point 88.5 ... 90.5 ° C.

Analysis for C₁₅H₁₆:

- calculated: 0 = 84.87%; H = 7.60%.

- found: 0 = 85.01%; 14 = .7,54%.

This compound is used to prepare 4-phenylmethylstyrene by the method of Example 1.

The following compounds are prepared in. according to the method above (1) from the corresponding acetophenone or dc to the substituted benzoate ester, using appropriate amounts of methylmagnesium halide solution.

2- (3-phenylthiophenyl) -2-propanol, boiling point 154 ... 158 ° C / 0.05 mm, n³/ = = 1.6132 of 2-phenylthioacetophenone.

Analysis for C_I5H_ieBONE:

- calculated: 73.72%; H = 6.60%; S = = 43.12%.

- found: O = i73.46%; H = 6.63%; S = = 43.35%.

2- (4-Phenolthiophenyl) -2-propanol, boiling point 144 ... 153 ° C / 0.09 mm, n³⁵= 1.6154 from phenylthioacetophenone.

Analysis for C₁₅H₁₆BONE:

- - calculated: 0 = 73.72%; H = 6.60%; S = = 13.12%.

- found: 0 = 73.99%; H = 6.89%; S = = 42.91%.

2- (4-iso-butylphenyl) -2-propanol boiling point 77. . . 85 ° C / 0.16 mm, n '; = 1,5050 of 4-iso-butylacetophenone.

Analysis for C_I3H_9eA:

- calculated: 0 = 81.20%; 41 = 40.48%.

- found: 0 = 80.97%; H = 10.52%.

2- (4-sec-butylphenyl) -2-propanol, boiling point 73 ... 80 ° C / 0.03 mm, n "^s = 1,5094 of 4-sec-butylacetophenone.

Analysis for C₁₃H₂A:

- calculated: 0 = 81.20%; H = 10.48%.

- found: 0 = 81.09%; H il0,71%.

2- {4-cyclohexylphenyl) -2-propanol m.p.

Analysis for C₁₅H_2IA:

- calculated: 0 = 82.51%; Η = αθ, 16 # /_Ο.

- found: 0 = 82.49%; H = 10.04%.

, 2- (3-methoxy-4-phenoxyphenyl) -2-propanol boiling point 170 ... 177 ° C / 0.07 mm, 1¾⁵ = 1.5762 from 3-methoxy-4-phenoxyacetophenone.

Analysis for C₁₆H₁₈A₃·.

- calculated: 0 = 74.39%; H, 7.02%.

- found: 0 = 74.58%; H = 7.29%. 2- (3-methyl-4-phenoxyphenyl) -2-propanol, boiling point 145 ... 146 ° C / 0.08 mm, n®⁵ = 1.5705 from 3-ethyl-4-phenoxyacetophenone.

Analysis for C₁₆H₁₈A₂:

- calculated: 0 = 79.31%; H .7,49%.

- found: 0 = 79.47%; H = 7.63%.

2- (4'-fluorobiphenyl) -2-propanol, melting point 110. 111 ° C from 4'-fluoro-4-acetylbiphenyl.

Analysis for C₁₅H_J5FO:

- calculated: 0 = 78.24%; H = 6.57%.

- found: 0 = 77.95%; H = 6.790 /₀.

A sensitive relief of inflammation and accompanying phenomena, swelling, sensitivity, low mobility, pain and fever is caused if it is administered to people or people suffering from an inflammatory condition 1 up to 100 mg / kg body weight of an aralkyl compound so as defined above, by oral or parental route.

They are included in the compounds used in practicing this invention: 3-phenyl-alpha-methylstyrene, 4-iso-butyl-alpha-methylstyrene, 3-phenylthio-alpha-methylstyrene, 4-phenylthio-alpha-methylstyrene, 4-cellhexyl-alpha- methylstyrene, 3-chloro-4-cyclohexyl-alpha a-methylstyrene, 4-n-butylalfa-methylstyrene, 4-sec-butyl-alpha-methylstyrene, 1- (4-cumenyl) -cyclohextene, 4- (4-fluorophenyl) -alpha-methylstyrene, 3-methoxy-4-phenoxyalkyl-methylstyrene, 3-chloro-4-allyloxy-alpha-methylstyrene.

The compounds used in practicing this invention are excellent anti-inflammatory agents generally do not produce the usual gastric side effects that are observed with other such agents. Examples of such anti-inflammatory activities are given in the following table. ED₅₀ orals expressed in mg / kg for the compounds used in this invention as determined by erythema blockade, according to the method reported in CV, Winter and others are shown in the following table:

<td>It</td><td>K</td><td>Oral ED_sr(Mg / kg)</td>

<td>3-phenoxyphenyl</td><td>iso-propenyl</td><td> 5</td>

<td>4-iso-butylphenyl</td><td>iso-propenyl</td><td> 40</td>

<td>4-feniÎtiofenil</td><td>iso-propenyl</td><td> 30</td>

<td>4-cyclohexylphenyl</td><td>iso-propenyl</td><td> 35</td>

<td>3-methyl-4-phenoxy enoxy</td><td>iso-propenyl</td><td> 50</td>

<td>4'-fluorobifenilil</td><td>iso-propenyl</td><td> 23</td>

<td>3-chloro-4-aliloxifeniI</td><td>iso-propenyl</td><td> 50</td>

<td>4-n-butylphenyl</td><td>iso-propenyl</td><td> 50</td>

<td>4-see-Butyl</td><td>iso-propenyl</td><td> 25</td>

Another aspect of this invention is to propose and procure a pharmaceutical preparation as a dosage unit for anti-inflammatory administration and administration of an anti-inflammatory effect within a range of about 50 to about 1,000 mg of at least one compound. of formula:

/ CH₃Ar — C ζ ^XCH₂ As defined above as well as a pharmaceutical diluent, A preferred pharmaceutical formulation is one adopted for oral administration and will include administration of the compound in soft gelatin capsules, hard gelatin capsules and tablets. A preferred compound for administration according to this aspect of the invention is 4-phenylcumen, since the other compounds shown above may be substituted in whole or in part for 4-phenylcumen.

In practicing this invention one of the anti-inflammatory agents shown above is administered to the subject suffering from an inflammatory condition in dosages from about 1.0 to about 100 mg / kg of body weight, daily, either in a single dose or in divided doses. .

If divided doses are used the anti-inflammatory agent is given every 4 or 6 h. Since some of the anti-inflammatory substances used in practice do not possess analgesic activity, it is preferable to administer this agent in combination with another analgesic agent, such as aspirin or d -propixifene for ϊ

when the swelling, the sensitivity, the low mobility begins to give back. Although oral administration is most preferable, the route of administration nonetheless, anti-inflammatory agents may also be administered parenterally or rectally in the form of suppositories.

Because most of the compounds used are in an oily state, they can be absorbed into an inert carrier such as lacquer, silica gel, or the like before being capsulated or transformed into tablets, pills, powders or granules. Those that are made for oral administration may also comprise other inert substances or diluents such as magnesium stearate. Tablets and pills can also be prepared with enteric coatings. These compounds can also be incorporated into soft gelatin capsules.

Liquid doses for oral administration may comprise pharmaceutically acceptable forms such as emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used such as water or a suitable oil, in this form it is preferable to dilute the agent which it had to be formulated with a suitable oil such as walnut oil, cottonseed oil, sesame oil or the like. These diluted mixtures comprise the internal phase of the emulsion. Sweetening and other sweetening agents or the like are also dissolved in water which acts as an external phase of the emulsion. In addition to inert diluents, these mixtures may also comprise other agents for moisturizing, emulsifying and suspending, odorizing, sweetening and other agents.

Compositions for rectal administration or suppositories should contain in addition to the active substance and an excipient, such as butter, cocoa or a suppository wax.

The dosages of the active ingredient according to the invention may be varied, however, it is necessary that the amount of the active ingredient be such as to give an appropriate dosage. The dosage chosen depends on the desired tera68010 effect, the route of administration and the duration of treatment. Generally the dosage levels are between 1 and 100 mg / kg of body weight, daily, in mammals, in order to obtain an effective withdrawal of inflammation, pain and with some compounds of fever. However, the doses to be prescribed from one or more of these compounds in a convenient formulation, are 10 probably taken between 50 to 1,000 mg, up to 4 times daily, depending on the body weight of the patient, the treatment conditions or other factors that the doctor must take into account.

The present invention has the advantage that it allows to obtain new compounds with anti-inflammatory activity, in economic conditions and with higher yields.