A procedure for the preparation of an arilisopropenilic anti-inflammatory compound. (Machine-translation by Google Translate, not legally binding)

DESCRIPTIVE MEMORY corresponding to the grant application of a.

PATENT OF INVENTION

APPLICANT: ELI ... LILLY. AND .. COMPANY

HOME-^{East Μο0 & ΓΪ}Υ Street, INDIANAPOLIS,

INDIANA, USA

• STATEMENT: A PROCEDURE FOR PREPARATION

OF AN ARILISOPROPENILIC COMPOUND

ANTIINELAMATORY.

Priority: Patent .e.state.a.idense.3i.^c>... 91.559 ...... del.20.-11 — .7.0

129.237 29-5-71

pp

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4-1-

<td></td><td>l</td>

<td> 1</td><td>This invention relates to a method of preparation of new aralkyl compounds of formula I ArfR '</td>

<td> 5</td><td>where, Ar represents 3-phenoxyphenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 4-cyclohexylphenyl, 4-isobutylphenyl, 4-cyclohexyl-3-chlorophenyl, 4-phenoxy-3-methylphenyl, 4-phenoxy-3-methoxyphenyl, 4 ' -flu.orbiphenyl, 3-chloro-4-allyloxyphenyl, 4-n-</td>

<td>i, '' ι.</td><td>butylphenyl, or 4-sec-butylphenyl and R is iso-propenyl. Symptomatic relief of inflammation is achieved</td>

<td> 10</td><td>tion and swelling, softness, reduced mobility, pain</td>

<td> 15</td><td>and consequent fever when administered to humans · and animals suffering from an inflammatory state, for orally or parenterally, from 1 to 100 mg daily of a compound aralkyl per kg body weight. Among these compounds useful in the practice of this invention, the following are found:</td>

<td> 20</td><td>3- phenoxy-u-methylstyrene 4- i so but il-α-methyl tyrene 3- phenylthio-a-methylstyrene 4- phenylthio-a-methylstyrene 4-cyclohexyl-a-methylstyrene 3-eloro-4-cyclohexyl-a-methylstyrene</td>

<td> 25</td><td>3- methyl-4-f enoxi-a-metiles t go eno 4- (4-f luorf enyl / í-methylstyrene 4-n-butyl-a-methylstyrene 4-sec-butyl-a-methylstyrene 3-methoxy-4-phenoxy-a-methylstyrene</td>

<td> 30</td><td>3-Chloro-4-allyloxy-u-methylstyrene The compounds used in the practice of this invention are excellent anti-inflammatory agents and generates] mind are exempt from the usual gastric effects</td>

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Secondary observed with other agents of this type. The following table gives examples of anti-inflammatory activities. The DE ^ q values ​​by oral route, expressed in mg / kg of the compounds used in this invention, determined in the test for the blockage of erythema performed essentially by the method indicated by Winder, CV

<td colspan="3">et al. Archives Int. Pharmacodym, Vol. 116</td><td rowspan="2">P. 261</td>

<td colspan="3">(1958), are found in the following table:</td>

<td></td><td>TABLE I</td><td></td><td></td>

<td>Ar</td><td>R</td><td>^FROM50</td><td>oral (mg / kg)</td>

<td>5-phenoxyphenyl</td><td>isopropenyl</td><td></td><td> 5</td>

<td>4-isobutylphenyl</td><td>isopropenyl</td><td></td><td> 40</td>

<td>5-phenylthiophenyl</td><td>isopropenyl</td><td></td><td> 50</td>

<td>4-phenylthiophenyl</td><td>isopropenyl</td><td></td><td> 30</td>

<td>, 4-cyclohexyl enyl</td><td>isopropenyl</td><td></td><td> 35</td>

<td>5-methyl-4-phenoxyphenyl</td><td>isopropenyl</td><td></td><td> 50</td>

<td>4'-fluorbiphenyl</td><td>isopropenyl</td><td></td><td> 23</td>

<td>5-methoxy-4-phenoxyphenyl</td><td>isopropenyl</td><td></td><td> 22</td>

<td>5-chloro-4-allyloxyphenyl</td><td>isopropenyl</td><td></td><td> 50</td>

<td>4-n-butylphenyl</td><td>isopropenyl</td><td></td><td> &lt;50</td>

<td>4-sec-butylphenyl</td><td>isopropenyl</td><td></td><td> 25</td>

The compounds are prepared by heating at reflux from appropriate aryl-isopropanoles according to the following reaction schemes. In what follows Ar'es

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portion, aryl as defined in the generic formula:

OH .1 Ar-C-CK₃^hp^SWto W ...... Ar-C = CH₂

CIi₃ CH₃

A pharmaceutical preparation in the form of a dosage unit adapted for administration to obtain an anti-inflammatory effect, comprises per dosage unit an amount of effective and non-toxic anti-inflammatory agent, comprised approximately between 50 and 1000 mg of a compound of at least formula Ar-R as defined above and a pharmaceutical diluent. A preferred pharmaceutical formulation is adapted for oral administration and comprises administration of the compound in soft gelatin capsules, hard gelatin capsules and tablet formulations, illustrated below. A preferred compound for administration according to this aspect of the invention is 4-phenylcumene, but all or part of this 4-phenylcumene can be substituted by another compound of those mentioned above,

The following examples illustrate the methods that can be employed in the preparation of the compounds useful in the practice of this invention.

SJalviDLO 1

It is heated to reflux and a propanol suspension in 4 K sulfuric acid and ethanol is stirred vigorously for 1.5 hours. Ethanol is then added and the reaction mixture is heated to reflux with stirring for an additional 2.5 hours. After cooling to room temperature, the reaction mixture is poured onto ice water and extracted with ether, benzene and chloroform. The swe | Wbw · «T» n organic extracts are combined, washed with bi solution. sodium carbonate and water and dried over sodium sulfate. After evaporating the solvents in vacuo, the residue is crisp, carved into hexane.

The following compounds are prepared by the method of Example 1, using the corresponding propanol as the starting material:

4-Phenoxy-u-methylstyrene, eg 12U-126 ° / ü, 08 mm;

3- í'eniltio-a-methylstyrene, eg 113-115 ° / θ, θ5 mrn;

4- 1'εηί1ίΐο-β - ΐ'ΠΘϋΐΘ3ϋΓΘηο, eg 147-167 ° / 0.2 mm;

4-lsobutyl-a-methylstyrene, eg 75-100 ° / 0.4 mm;

4-sec-Butyl-methylstyrene, eg 52-53 ° / 0.07 mm;

3- mefcil-4-f enoxi-rt-metllestirenn, eg 125-1349¾, 08mm;

4- Cycloh.exil-a-methylstyrene, eg 122-142 / Ü, 1 ¡ñon;

3- methoxy-4-phenoxy-d-methylstyrene, eg 157-1 oO ° / C, p7mm;

4- (4-Pluorphenylj-a-methylstyrene, mp 127-128;

2-Isopropenyl-6-methoxynaphthalene, mp 93-95 °.

Preparation of 3-pheno ^ i-^g-methylstyrene

Methylmagnesium iodide is prepared by adding dropwise 228 g of methyl iodide to a stirred suspension of 36.4 g of magnesium in 1000 ml of ether. A solution of 148 g of 3-phenoxyacetophenone in 500 ml of ether is added dropwise and the reaction mixture is then stirred at room temperature overnight and decomposed by dropwise addition of 265 ml of saturated chloride solution. ammonium Water is then added and the reaction mixture is extracted with ether and ethyl acetate. The combined organic extracts are washed with water and dried over sodium sulfate. By evaporation of the solvents, an oily residue remains that is distilled twice giving 94.8 g of 3-phenoxy-ctmethylstyrene, eg 1O3-115 ° / O, O8 mm; - 1.5873.

Analysis for C ^ R ^ o:

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Calculated: C, 85.66; You, 6.71

Found: C, or 5.69; H, 6.90

3- Chloro-4-alliyoxy-a-methylstyrene, eg 99-105 ° /

0.07 mm;

4- n-Butyl-d-methylstyrene, eg 84-8b ° / O, O5 mm; In practice, one of the anti-inflammatory agents described herein is administered to a subject suffering from an inflammatory condition, in doses of the order of 1.0 to 100 mg / kg of body weight, daily, in a single dose or in doses. divided. If divided doses are used, the anti-inflammatory agent is generally administered every 4 or hours. Since some of the anti-inflammatory agents used in the practice of this invention do not possess analgesic analgesic activity, it may be preferable to administer the agent in combination. with an analgesic agent such as aspirin to d-propoxyphene, until swelling, tenderness, reduced mobility and the like have subsided. Although oral administration is the preferred route of administration, the anti-inflammatory agents described herein can also be administered ferally or as rectal suppositories.

As many of the compounds employed in Za practice are oils, they can be adsorbed first in an inert vehicle such as talc, silica gel or the like before being formulated in capsules, tablets, pills, powders or granules. These solid dosage forms for oral administration may also contain, as is the usual practice, additional substances other than inert diluents, eg lubricating agents, such as magnesium stearate, in the case of capsules, tablets and pills, the dosage forms may also contain regulatory agents

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Clel Pí. Tablets and pills can be additionally prepared with enteric coatings. These compounds can also be incorporated into soft gelatin capsules.

Liquid dosage forms for oral administration include pharmaceutically acceptable forms such as emulsions, solutions, suspensions, syrups and elixirs, containing inert diluents commonly used in the art, such as water or a suitable oil.

In the formulation of the compounds of this invention in liquid dosage forms for oral administration, it may be preferable to dilute the agent to be formulated with a suitable oil such as peanut oil, cotton oil, sesame oil, corn or the like This diluted mixture constitutes the internal phase of the emulsion. Flavoring agents, sweetening agents and the like are dissolved in water, acting as the external phase of the emulsion. In addition to inert diluents, these compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents and flavoring, edulising and perfuming agents.

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

The dose of active ingredient in the compositions of this invention can be varied; however, it is necessary that the amount of active ingredient be such that an adequate dosage level is obtained. The selected dose depends on the desired therapeutic effect, the route of administration and the duration of treatment. Generally

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They administer to the mammals dose levels between 1.0 and 100 mg / kg of body weight, daily, to obtain effective relief from inflammation, pain and, with some compounds, fever. However, the prescribed doses of one or more of these compounds in a suitable formulation will probably range between about 5θ mg and 1000 mg, 1 to 4 times a day, depending on the patient's body weight, the condition being treated and other factors To the patient's doctor.