NO751753L - - Google Patents

Description

The present invention relates to methods for the production of new aralkyl hydrocarbons with the following formula:

where Ar represents 3-phenoxyphenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 4-cyclohexylphenyl, 4-iso-butylphenyl, 4-cyclohexyl-3-chloro-phenyl, 4-phenoxy-3-methylphenyl, 4-phenoxy-3-methoxyphenyl , 4'-fluorobiphenyl, 3-chloro-4-allyloxyphenyl, 4-n-butylphenyl or 4-sec-butylphenyl, characterized by dehydrolysing an isopropanol compound with the formula Ar - C (CH^)20H', where Ar is as defined above.

Symptomatic relief of inflammation of the following swelling, soreness and tenderness as well as reduced mobility, pain and fever is provided when one adds from 1 to 100 mg/kg body weight daily of an aralkyl compound as defined above,

to humans and animals suffering from inflammatory conditions, and this administration can be either oral or parenteral.

Among compounds that can be used in the present invention are the following:

3-phenoxy-α-methylstyrene

4-sib-butyl-a-methylstyrene

3-phenylthio-α-methylstyrene

4- phenylthio-α-methylstyrene

4-cyclohexyl-α-methylstyrene

3- methyl-4-phenoxy-α-methylstyrene

4-n-butyl-a-methylstyrene

4-sec-butyl-α-methylstyrene

1-(4-cumenyl)cycloethene

4-(4-fluorophenyl)-α-methylstyrene

3-Methoxy-4-phenoxy-α-methylstyrene

3-chloro-4-allyloxy-α-methylstyrene

The compounds used in practice in connection with the present invention are excellent anti-inflammatory agents and are usually free of the side effects that occur in the intestinal tract that are often seen in connection with other known agents. Examples of such anti-inflammatory activity are given in the following table. Oral ED^q expressed as ten mg/kg of the compounds according to the present invention is determined by an erythema-inducing test carried out essentially as described by Winder, CV. et al. Archives Int. Pharmacodym, vol. 116, page 261

(1958). The results are shown in the following table.

In general, it is the case that compounds used in the present invention can be prepared by methods which are known in themselves for the production of aralkyl hydrocarbons. The compounds used can be prepared from a suitable arylcarboxylic acid or acetophenone.

Another aspect according to the present invention relates to pharmaceutical preparations in dosage units which are adapted for oral or parenteral administration. This results in an anti-inflammatory effect. An anti-inflammatory effective and non-toxic amount will be in the range from approx. 50 to approx. 1000 milligrams of a compound of the formula

as defined above, as well as a pharmaceutical diluent. A preferred pharmaceutical preparation is one which is suitable for oral administration and which could be soft gelatin capsules, hard gelatin capsules or tablets as illustrated below. A preferred compound for delivery according to this aspect is 4-phenylcumene, but one can also use other compounds of the type indicated above as a substitute for all or part of said 4-phenylcumene.

The above-mentioned compounds can, as said, be produced by methods which are known per se. The following examples illustrate methods that can be used for the preparation of compounds that can be used in the present invention.

Example 1.

Preparation of 2-(4-biphenylyl)-2-propane.

A solution of 98 g of 4-acetylbiphenyl dissolved in 500 ml of ether and 500 ml of benzene was added dropwise with stirring to 500 ml of a 2.15 molar solution of methylmagnesium chloride which had been diluted with corresponding volumes, and at such a rate that the reaction boiled gently under reflux. After the addition was complete, the mixture was refluxed overnight.

The mixture was then cooled to room temperature and the excess of said Grignard reagent was decomposed by the dropwise addition of 178 ml of a saturated ammonium chloride solution. The organic layer was decanted from the resulting inorganic residue and poured into ice water. The organic layer was separated, washed with dilute sodium bicarbonate solution and water and then dried over sodium sulfate. Evaporation of the solvents in vacuum gave a white solid residue which was crystallized from hexane, whereby 85 g of 2-(4-biphenylyl)-2-propanol were obtained, melting point 88.5 - 90.5°C. Analysis, calculated for C.-H--O: C, 84.87; H, 7.60.

lb lb

Found: C, 85.01; H, 7.54.

This compound can be used to prepare 4-phenyl-a-methylstyrene by the method indicated in example 10. Examples 2-9.

The following compounds were prepared as indicated in Example 1, from the corresponding acetophenone or substituted benzoate ester, using appropriate amounts of methylmagnesium halide solution: 2-(3-phenylthiophenyl)-2-propanol, b.p. 154-156°/ 0.05 ram;

23

nD = 1.6132, from 3-phenylthioacetophenone.

Analysis, calculated for C15H160S; C, 73.72; H, 6.60; S, 13,12.

Found: C, 73.46; H, 6.63; S, 13.35.

2-(4-phenylthiophenyl)-2-propanol, bp, 144-153°C/0.09 mm;

25

nD =1.6154, from 4-phenylthioacetophenone.

Analysis, calcd for C 2 H 2 O 2 : C, 73.72; H, 6.60; S, 13,12.

Found: C, 73.99; H, 6.89! S, 12.91. 2-(4-iso-butylphenyl)-2-propanol, bp, 77-85°/0.16 mm;

25

nD = 1.5050, from 4-iso-butylacetophenone.

Analysis, calculated for C13H20<0:>C, 81.20; H, 10.48

Found: C, 80.97; H, 1052.

2-(4-sec-butylphenyl)-2-propanol, boiling point 73-80°/0.05 mm,

nD<23>=1.5094, from 4-sec-butylacetophenone.

Analysis, calcd for C13H2()0: C, 81.20; H,, 1048.

Found: C, 81.09; H, 10.71. 2-(4-cyclohexylphenyl)-2-propanol, melting point: 71-74 C,

from 4-cyclohexylacetophenone.

Analysis, calcd for C 2 H 2 O: C, 82.51; H, 10,16.

Found: C, 82.49; H, 10.04. 2-(3-Methoxy-4-phenoxyphenyl)-2-propanol, bp, 170-177 /0.07mmnD<25>=1.5762 from 3-methoxy-4-phenoxy-acetophenone.

Analysis, calculated for C 16 HlgO 3 : C,<74.39>; H, 7.02.

Found: C, 74.58; H, 7.29. 2-(3-Methyl-4-phenoxyphenyl)-2-propanol, bp, 145-146°/0.08 mm, n d 25=1.5705, from 3-methyl-4-phenoxy-acetophenone. 2-(4'-fluorobiphenylyl)-2-propanol, m.p., 110-111 , from 4'-fluoro-4-acetylbiphenyl.

Analysis, calculated for C15H15<F>O: C 78.24; H, 6.57

Found: C, 77.95; H, 6.79.

These alcohols were converted into α-methylstyrenes by the method indicated in example 10.

Example 10.

Production of 4-phenyl-a-methylstyrene.

A suspension of 42.4 g of 2-(4-biphenylyl)-2-propanol in 100 ml of 4N sulfuric acid and 50 ml of ethanol was boiled under reflux and vigorous stirring for 1.1/2 hours. Then 50 ml of ethanol was added and the mixture was refluxed for a further 2.1/2 hours. After cooling to room temperature, the mixture was poured into ice water and extracted with ether, benzene and chloroform. The organic extracts were combined, and washed with sodium bicarbonate solution and water, and then dried over sodium sulfate. After evaporation of the solvents in vacuo, the residue was crystallized from hexane, whereby 23.4 g of 4-phenyl-a-methylstyrene was obtained, melting point 116-118°C.

Analysis, calculated for C. _H, .: C, 92.74: H, 7.26

lb 14

Found: C, 92.45; H, 6.98.

Example 11-21.

The following compounds were prepared as indicated in Example 10 using an appropriate propanol as starting material. 3-phenylthio-a-methylstyrene, boiling point 113-115°/0.05 mm; =

1.6248 which contains 10% of the starting carbinol, as this could be measured by Nmr, from 2-(3-phenylthio-phenyl)-2-propanol.

4-phenylthio-o-methylstyrene, boiling point 147-167/0.2 mm; n^ 25 = 1.6374, from 2-(4-phenylthiophenyl)-2-propanol.

Analysis, calculated for C, cH1ylS: C, 79.62; H, 6.24.

laughed 14

Found: C, 79.49; H,. 6.64.

4-iso-butyl-a-methylstyrene, boiling point, 75-100°/0.4 mm; nD 25 = 1.5182, from 2-(4-iso-butylphenyl)-2-propanol.

Analysis, calcd for C 2 H 2 : C, 89.59; H, 10.41

Found: C, 89.52; H, 10.49

4-sec-butyl-α-methylstyrene, bp, 52-53°/0.07 mm; nD<24>= 1.5188, from 2-(4-sec-butylphenyl)-2-propanol.

Analysis, calcd for C13Hlg: C, 89.59; H, 10.41.

Found: C, 89.36; H, 10.43.

4-cyclohexyl-α-methylstyrene, boiling point 122-14 2°/

25

0.15mm; nD = 1.5484, from 2-(4-cyclohexylphenyl)-2-propanol. Analysis, calculated for C.,-H0rt: C, 89.94; H, 10.06.

laughed 2U

Found: C, 90.15; H, 10.33.

3-methyl-4-phenoxy-α-methylstyrene, bp 125-134°/0.08 mm, nD<25>= 1.5856, from 2-(3-methyl-4-phenoxyphenyl)-2-propanol.

Analysis, calculated for C,, E., 0: C, 85.68; H, 7.19.

lb lb

Found: C, 85.44; H, 7.06

3-methoxy-4-phenoxy-α-methylstyrene, boiling point 157-160°/0.07 mm; nD<25>= 1.5914, from 2-(3-methoxy-4-phenoxyphenyl)-2-propanol.

Analysis, calcd for C.,H 1 CO_: C, 79.97; H, 6.71

lb lbZ

Found: C, 79.75; H, 6.76. . 4-(4-fluorophenyl)-α-methylstyrene, m.p., 127-128°, from 2-(4'-fluorobiphenylyl)-^2-propanol.

Analysis, calculated for C, 84.87; H, 6.17.

Found: C, 84.68; H, 6.45.

3-phenoxy-ct-methylstyrene, bp, 103-115°/0.08 mm;

25

nD = 1.5873, from 2-(3-phenoxyphenyl)-2-propanol.

Analysis, calculated for 15H14°» c'85.68; H, .6.71.

Found: C, 85.69; H, 6.90. 3-chloro-4-allyloxy-a-methylstyrene, bp, 99-105°/0.07 mm; nD<24>= 1.5623, from 2-(3-chloro-4-allyloxyphenyl)-2-propanol.

Analysis, calculated for c12Hi3C10: C'69'14'H' 6'29*' P» 7.68. . Found: C, 69.23: H, 6.20; 0, 7.85* 4- n-butyl-a-methylstyrene, bp, 84-88°/0.05 mm; nD 21 = 1.5182, from 2-(4-n-butylphenyl)-2-propanol.

Analysis, calcd for C--.H10: e, 89.48; H, 10.48.

1 j lo

Claims (3)

1. Process for the production of new aralkyl hydrocarbons with the formula: where Ar represents 3-phenoxyphenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 4-cyclohexylphenyl, 4-iso-butylphenyl, 4-cyclohexyl-3-chlorophenyl, 4-phenoxy-3-methylphenyl, 4-phenoxy-3-methoxy-phenyl , 4<1->fluorobiphenyl, 3-chloro-4-allyloxyphenyl, 4-n-butylphenyl or 4-sec-butylphenyl, characterized by dehydrolyzing an iso-propanol compound with the formula Ar - C ( CE^) ^ OB. where Ar is as defined above. 2. Method according to claim 1, characterized in that Ar is 3-phenylthiophenyl, 3-chloro-4-allyloxy-phenyl, 4-n-butylphenyl or 4-sec-butylphenyl and R<1> is iso-propenyl. 3. Method according to claim 1, characterized in that Ar is 4-phenoxy-3-methoxyphenyl or 4.<1->fluorobiphenyl.