DE2064825C - Enterally and parenterally applicable anti-inflammatory drugs - Google Patents

Description

The invention provides enterally and parenterally applicable anti-moguls available that one Aryi compound of the general formula

Ar-R ti)

contain, where Ar 3-PhenoxyphenyL 4-Phenoxyphenyl. ^ Phenylthiophenyl. ^^ rydohexylphenyU ^ Biphenylyl, 4-isobutylphenyl, 4-Cydohex> l-3-dilophenyl, 4- phenoxy-3-methylphenyl, 4-phenoxy-3-methoxyphenyl, 4-iso-propylphenyl, 4- (1-cydooctenylH phenyl 4-cydooctylphenyl, 4'-fluorobiphenylyl, ^ tert -butylphenyl, 6-methoxy-2-naphthyl, 4- {2-norbornylKphenyl or $ -indanyl and R is iso-propyl iso-propenyl. However, iso-butyl or η-butyl means with the restrictions that. when R is n-butyl is. Ar is 4-biphenylyl and when R is iso-butyl, Ar is 4-phenoxyphenyl. The invention also relates to an anti-inflammatory veterinary preparation, a suitable carrier and at least one aralkyhydrocarbon according to the above Definition includes According to the invention, a pharmaceutical preparation in the form of a prepared for use suitable dosage unit to achieve an anti-inflammatory effect are, with an anti-inflammatory, non-toxic amount per dosage unit within the range of from about 50 mg to about 500 mg of at least one aralkyl hydrocarbon compound according to the above definition as well as a pharmaceutical diluent contain sutd.

It is known that mammals, both human and animal, among numerous Suffering from disease states that include inflammation and their accompanying symptoms, such as swelling, tenderness, decreased mobility, pain and fever, belong. Although there are a number of anti-inflammatory drugs that are used for symptomatic treatment of inflammatory conditions, such as B. rheumatoid arthritis, rheumatoid spondylitis. Osteoarthritis, degenerative joint changes and the like, are effective, it has been found that such Means to have a number of undesirable side effects, which include irritation to the stomach. Therefore, the search for improved anti-inflammatory drugs continues.

The anti-inflammatory drugs of the invention seem from the serious gastric side effects caused by A number of commercially available anti-inflammatory drugs are caused to be free.

A number of compounds represented by the above formula I are known as fasting agents (US Pat. No. 2,768,040) or as cooling or damping agents for neutron reactors (US Pat. No. 2902425). The anti-inflammatory activity of these compounds is but completely unexpected.
The means according to the invention cause one

symptomatic relief of inflammation and swelling associated with ulceration, tenderness reduced mobility, as well as pain and fever, if 1 to 100 mg / kg body weight! daily from the aralkyl defined above

hydrocarbons to oral or inflammatory humans and animals administered parenterally.

The compounds suitable as active ingredients for the compositions according to the invention include

3-phenoxy-alpha-methylstyrene.

3- phenoxycumene,

4- phenoxy-alpha-methyl styrene,
4-phraoxycumene.

4-iso-buty! Diphenyl ether,

4-n-butyibiphenyl,

4-phenylcumene,

4-iso-butyl-a Ipha-methyl styrene.

4-isobutylcumene.

4-phenylthio-iilpha-methylstyrene.

4-cyclohexyl-alpha-methylstyrene,

+ -Cyclobexylcumene,

S-chloro ^ yclohexyl-alpha-methylstyrene. S-methyl ^ phenoxy-alpha-methylstyrene, S-methoxy - ^ - phenoxycutnol,

4-iso-propyl-alpha-methylstyrene,

4-iso-propylcumene,

1 - (4-cumenyl) -cycloocteia,

4-CyclooctylcumoL

4- (4- fluorophenyD-alphamethylstyrene,

4- (4-fluorophenyl) -cuniol,

H-methoxy-4-phenoxy-alpha-methylstyr oil,

2-iso-propenyl-6-metho j y naphthalene,

4-part-butyl-alpha-methylstyrene,

4- (2-norbonyl heumol,

5-iso-propenylindane.

Have the active ingredients of the claimed funds have excellent anti-inflammatory effects and are generally free from common gastritic

Side effects as seen with other such agents. The oral ED ₅₀ , expressed in ocig / kg, of the compounds used according to the invention, determined according to the erythema inhibition test, which is essentially based on that of Windet, CV. inter alia in Archives Lit. Pharmacodynl, VoL U6, p. 261 (1918), the method reported is given in the table below.

"V,

table

ZQM4BZB '

Ar & © Jak ED ,, 3-PhenGxyahenyi jso-propenyl 5 3-phenoxyphenyl iso-Piopyl 25th 4-phenoxyphenyl iso-propenyl 15th 4-phenoxyphenyl iso-propyi 6th 4-phenoxyphenyi iso-butyl 20th 4-biphenyl n-butyl 10 4-biphenylyI iso-propyi 4th 4-iso-butylphenyl iso-propeny! 40 4-iso-butylphenyl iso-propyi 8th . 4-phenykhiophenyl iso-propenyl 30th 4-CyclohexyJpheiiy] iso-propenyl 35 4-cyclohexylphenyl iso-propyi 15th S-methyl - ^ - phenoxy- phenyl iso-propenyte 50 3-methoxy-4-phenoxy- - phenyl iso-propyi 15th 4-iso-propylene phenyl iso-propenyl 25th 4-iso-propylphenyl iso-propyl 0.8

Ar λ -. .. · ■; tniEtE) 5 4 <! - Cydooctenyl) - phenyl iso-ftapyi .25- 4-Cycfootiy ^ ii) Btsii iso-PropyJ 4'-fluorobiphenyIyI iso-piopenyl ^ J ^; , ■ -23 ' _i0 4 * -p | uorb ^ henyt ^ BO-PlJOpjd m S-methoxy - ^ - phenoxy- phenyl iso-PBopenyl. = 22nd 6-methoxy-2-naphthyl iso-propenyl 25th 4-tert-butylphenyi iso-? ropenfl 20th ^t5 4H (2-norbornyI) -pheay iso-Propjä .m. 5-indanyl iso-propenyl 50 "

I. Ar-COOH

R ¹ OH The active ingredients of the claimed agents are prepared by methods known per se for producing aralkyl hydrocarbons. The compounds used here can be prepared from a suitable arycarboxyl compound, Ar being a compound defined according to the general form and R ^{1 being} lower alkyl.

Ar-COOR

CH,

/
CH

CH,

H ₂ ZPd CH ₃ Mg _x
Diethyl ether

Ethyl acetate "Η® OH

Ax-C-CH ₃
CH ₃

H _2A SO ₄ (4N)

Ar-C = CH ₂
CH ₁

II. Ar-C

CH,

(Grignard)

CH ₃ MgCl OH

Ar-C-CH ₃
CH ₃

H, / Pd _> Ar-CH

Ethyl acetate \ ~

H * CH ₃

III. Ar-C

CH ₃

Φ, Ρ®—

NaH Wütig - Ar-C = CH ₂
CH ₃

! Υ. Ar-C-CH ₂ CH ₂ CH ₃

"Ethyl acetate 'Ar-CH ₂ CH ₂ CH ₂ CH ₃

004 825

H ₂ N-NH,

KOH

According to the invention, a pharmaceutical preparation in Fiona one suitable for use iihi to achieve antiphlogistibi d bi jd di

g g pg

With a specific effect, each dosage unit contains an anti-inflammatory, non-toxic amount within the range of about 50 to 500 nag of at least one aryl compound of the general formula Ar-R (I) as defined above and a pharmaceutical diluent. A preferred pharmaceutical preparation is one those that are suitable for oral administration, and such a preparation includes the dosage forms of the compounds in soft gelatin capsules, hard gelatmekapseln and tablet formulations, as is explained below the other compounds listed above can also partially or completely replace 4-phenylcumene.

The above compounds can be prepared by methods known per se. Below processes are illustrated which are used for the preparation of suitable compounds according to the invention can be.

Production of 2- (4-biphenylyl) -2-propano!

A solution of 98 g of 4-acetylbiphenyl, in 500 ml Ether and SOOmI benzene were dissolved dropwise with stirring 500 ml of a ZI5moiaren solution of Methyl magnesium chloride diluted with an equal volume of ether with a added at such a rate that the reaction was kept at moderate reflux overnight.

The reaction mixture was then allowed to cool to room temperature, and excess Grignard reagents became more saturated by adding dropwise 178 ml Ammonium chloride solution decomposes. The organic layer was derived from the resulting inorganic Decanted off residue and poured into ice water. The organic layer was then separated, washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. After evaporation of the solvents in vacuo, a white solid residue remained, which disappeared Hexane was recrystallized and 85 g of 2- (4-biphenyl) -2-propanol from melting point 88.5 to 90.5 ° C.

Analysis for C ₁₅ H ₁₆ O:

Calculated ... C 84.87, H 7.60;
Found .... C 85.01, H 7.54.

The following compounds were prepared from the appropriate using the procedure described above Acetophenone or substituted benzoate esters using suitable amounts of Methyl magnesium halide solution prepared:

2-f, 4-phenoxypheny]) - 2-propanoL boiling point: 148 to L52 ° C / 0.2mmHg, n $ = 1.5760, from 4-phenoxyacetophenone.

Analysis for Q ₅ H ₁₆ O ₂ :

Calculated ... C 78.92, H 7.06;
found .... C 78.91, H 7.09.

Ar-CH ₂ -CH (CH ₃ ^

2- (4-pbenyltbiophe3yl) -2. propaiioL boiling point: 144bisl53 ° CAi »09mniHs, n? = 1.61S4 _{s from} 4-phenylthioacetophenone.

Analysis for Q ₅ Hi ₆ OS:
Calculated .... C 73.72, H 6.60, S 13.12; found .... C 73.99, H 6, 9, S 12 £ L 2- <4-iso-butylphenyl) -2-propanoL Boiling point: 77

up to 85 ° C / 0.16mmHg, nf = 1.5050, from 4-iso-bulylacetophenone.

Analysis for C ₁₃ H ₂₀ O: Calculated ... C 8UO, H 10.48;

Found C 80.97, H 10.51

2- {4-Cyclohexy] phenyl-2-propanol, melting point: 71 to 74 ° C, from Vcycfohexylacetophenone.

Analysis for C ₁₅ H ₂₂ O: Calculated ... C 82.51, H 10.16;

found .... C 82.49, H 10.04.

2 - (3 - methoxy - 4 - phenoxyphenyl) - 2 - propanol, boiling point: 170 to 177C / 0.07 mm Hg, n? = 1.5762, from S-methoxy- ^ phenoxyacetophenone.

Analysis for C ₁₆ H ₁₈ O ₃ : Calculated ... C 74.39, H 7.02;

found .... C "74.58, H 7.29.

2- (3-Methyl-4-phenoxyphenyl) -2-propanol, boiling point: 145 to 146 ° C 0.08 mm Hg, ηϊ = 1.5705, from S-methyl- ^ phenoxyacetophenone.

Analysis for C ₁₆ H ₁₈ O ₂ :

Calculated ... C 79.31, H 7.49; found .... C 79.47, H 7.63.

"2- (4-tert-butylphenyl) -2-propanol, melting point: 75 to 76.5 ° C, from 4-tert-butylbenzoic acid ethyl ester.

Analysis for C ₁₃ H ₂₀ O:

Calculated ... C 81.20, H 10.48; found .... C 80.98, H 10.58.

2- (4'-Fluorobiphenyiyl) -2-propanol, melting point: 110 to 11 FC, from 4'-fluoro-4-acetylbiphenyl.

Analysis for C ₁₅ H ₁₅ FO:

Calculated ... C 78.24, H 6.57; found .... C 77.95, H 6.79.

2 - (6 - methoxy- 2 - naphthy 1) - 2 - propanol, melting point: 83 to 86 ° C, from i-acetyl-o-methoxynaphthalene.

Analysis for C ₁₄ H ₁₆ O ₂ :

Calculated ... C 77.75, H 7.46, O 14.79: found .... C 77.54, H 7.22, O 14.96;

Production of 4-phenyl-alpha-methylstyrene

A suspension of 42.4 g of 2- (4-biphenylyl) -2-propanol in 100 ml of 4 η-sulfuric acid and 50 ml of ethanol was refluxed and heated for 1.5 hours strongly stirred. Then 50 ml of ethanol were added, and the reaction mixture was further stirred Held at reflux for 2.5 hours. After the reaction mixture has cooled to room temperature the reaction mixture was poured into ice water and treated with ether, benzene and chloro-

form extracted 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 crystallized from hexane and there were 23.4 g. "- receive phenyl-alpha-methylstyrene having a melting point 116-118 ⁰ C.

C 92.74, H 7.26; C 92.45, H 6.98.

Analysis for Q ₃ ] Ii ₈ :

Calculated ... C 89.59, H 10.41; found C 89 ^ 3, H 10.20.

3-Mediyl-4-phenoxy-alpha-metfayistyroL Siede-125 Ins iWCjßst mm Hg, nf = 1 ^ 856, from jd ^) 2A

Analysis for Q ₆ Hi ₆ O: Calculated ... € 85.68, 117.19; C 85.44, H 7.06.

3-methoxy74-phenoxy-älpha-methylstyrene, _i boiling point: 157 to 160 ° C / 0.07mm Hg ,, n? = 1.5914, from 2- (3-methoxy-4-phenoxyphenyl) -2-propanol.,

Analysis for G H O Analysis lur

Calculated
found .

The following compounds were prepared according to the procedure described above for the preparation of 4-phenyl-alpha-methylstyrene using the corresponding propanol produced as starting material:

4-phenoxy-alpha-methylstyrene, boiling point: 120 to 126 ° C / 0.08 mm Hg, n? = 1.5934, from 2- (4-Pfaenoxyphenyl ^ -propanol.

Analysis for C ₁₅ H ₁₄ O:

Calculated ... C 85.68, H 6.71; found C 85.44, H 6.87.

4-phenylthio-alpha-methylstyrene boiling point: 147 up to 167 ° C / 0.2 mm Hg, n? = 1.6374, from 2- {4-phenylthiophenyl) -2-propanol.

A 1 ti- r μ <! ·
Analysis for Ms "» »·

Calculated ... C 79.62, H 6.24; found C 79.49, H 6.64.

4-iso-butyl-alpha-methylstyrene boiling point: 75 to 100 ° C / 0.4mmHg, ni? = 1.5182, from 2- (4-iso-butylphenyl) -2-propanol.

Ai for r H
Analysis mr Ms "« ·

Calculated ... C 89.59, H 10.41;

Found C 89.52, H 10.4V.

4-Cyclohexyl-alpha-methylstyrene Boiling point: 122 up to 142 ° C / 0.15mmHg, n? = 1.5484, from 2- <4-cyclohexylphenyl) -2-propanol.

Analysis for C ₁₅ H ₂₀ :

Calculated ... C 89.94, H 10.06; found .... C 90.15, H 1033.

5-iiso-propenylhandane, boiling point: 148 to 151 ^C C / SmTHiTn? = - l & sCward purified by preparative vapor phase chromatography, from 2- (5-indanyl) -2-propanol.

Analysis for QaH ₁₄ :

Calculated ... C 9LJÖ8, U &92; found C 90, SQ, H 8.84.

4-tert-ButyI'alpha-MeÖrylstyrol _> Boiling point: Ϊ05 to iI5 ° C / 5nnni% nf = 8
hl2L

... ^ ^ to ", -. Do you regret ... L. V? I, H o, / 1, found .... C 79.75, H 6.76.

4 - (4 - fluorophenyl) - alpha - methylstyrene, melting _kt . _{127 to 128} o _C ; from 2- (4'-fluorobiphenyl ^ 2-prop-

^{y 1S} "" _UA17 .

Calculated ... C 84.87, H 6.17,

gaunden .... c B4, & 8, M ö, 4D.

2 - iso - propenyl - 6 - methoxynaphthalene, melting point: 93 to 95 ° C, from 2- (6-methoxy-2-naphthyl) -2-propanol

Analysis for C ₁₄ H ₁₄ O- Calculated ... C 84.81, H 7.12, O 8.07; found .... C 84.61, H 7.10, O 8.13.

Manufacture of 3-phenoxy-alpha-methylstyrene Methyl magnesium iodide was added by dropwise

Addition of 228 g of methyl iodide with stirring to a solution of 36.4 g of magnesium in 1000 ml of ether. A solution of 148 g of 3-phenoxy-acetophenone in 500 ml of ether was added dropwise, _{υηά & because} reaction mixture was then stirred overnight at room temperature and by dropwise addition of a VOA 265 ml saturated ammonium chloride solution decomposes. After adding water, the reaction mixture was extracted with ether and ethyl acetate. The combined organic extracts were washed with water and over sodium _sulphate ggtrociuiet After evaporation of the solvent _{an oily} j _{BUEB center} back _uc R k _stan d, which was distilled twice and 94.8 g of 3-PheBOxy-alpha-methylstyrene having a boiling point of 103 to 115 ° C / 0.08 mm Hg, n? = 1.5873.

Analysis for C ₁₅ H ₁₄ O:

Calculated ... C 85.68, H 6.71; found .... C 85.69, H 6.90.

Manufacture of l ^ umenylKycloocten

A solution of 4-cumenylmagnesium bromide was prepared by adding dropwise a solution of 70 g of 4-bromocumene in about 250 ml of ether with stirring to a suspension of 8.75 g of magnesium shavings in SOmI ether, 2x1 with a few drops of ethene bromide had been inflicted, and at a slower rate, that moderate reflux was maintained. The reaction mixture was stirred for 3 hours at room temperature A solution of 38 g of cyclooctanone in 250 ml of Ääia was added dropwise and the reaction mixture wake up overnight on the reflux After the reaction mixture has been brought to room temperature

temperature had abgekSfaJt, it was quenched by careful addition of 60 ml of saturated Ammomttfflchlorid <Solution zersetzL The ether layer was au ¹ thus deposited inorganic mate rial separated from the by decanting The inorganic

Precipitate was washed with ether and benzene. The combined organic solutions were mixed then washed the diluted sorbent with water and dried over sodium sulfate After ver

2 O 6 # 815

steaming the solvent in vacuum, the residue was distilled üöd of 25.1 g of l- {4 ^ cumenyl) -cyclboCteniäit gave a yield a boiling point of 128 to l40 ^b C / D, l inmHg, and nl "of 1.5459 .

Analysis for C ₁₇ H ₂₄ :
Calculated ^> C 89 * 41 * H10-59; found .... C $ 89.4 H 10.77 *

Production of 2-hydroxy-2- (4-cumenyl) norbornane

2-hydroxy-2- (4-cumenyl) norbornane, boiling point: 137 to 145 ° C / 0.1 mm Hg, which contained a trace of 2- {4-cumenyl) -2-norbornene, was after above-described process for the preparation of 1- (4-cumenyl) -cyclooclene using suitable Amounts of 4-BromcumoL Magnesium and Norkampfer manufactured

Production of 4-phenylcumene

A mixture of 21.2 g of 2- (4-biphenyl) -2-propanol, 4 g of 5% Pd / C, 20 drops of H ₂ SO ₄ and 200 ml of ethyl acetate was hydrogenated until the calculated amount of hydrogen had been absorbed. After the catalyst had been separated off by filtration, the reaction mixture was washed successively with water, 5% NaHCO 3 solution and water and dried over sodium sulfate. After evaporation of the solvents in vacuo, an oily residue was obtained, which was distilled and gave a yield of 163 g of 4-phenylcumene with a boiling point of 100 to 112 ° CAM »mm Hg and an ni" of 1.5849.

Analysis for Q _S H ₁₆ :

Calculated ... C 91.78, H 8.22; found .... C 92.06, H 7.97.

The following compounds were prepared using the procedure described above to prepare 4-Phenylcumene using the corresponding Propanolbenzylalkohok or styrene as starting material manufactured:

4 - Phenoxycumene, Skdpunkt ^ JO4 to U0 ° C 0.05 mm Hg, η? = 1.5591, from 2- {4-phenoxyphenyl) -2-propanol.

Analysis for C ₁₅ H ₁₆ O:

Calculated ... C 84.87, H 7.60; tired .... € 84.3% Ή7.38 »

^ PhenyJthiocumoi, Sieäepuakt: 135 to 141 ⁰ C / 0.97 mm Hg ₃ Ii? = i, etX) Q, ans2 <4-Phenytfliiophen5i ^ 2-propanoL
Analysis for Q ₅ H ₁₆ S:

Calculated ... € 78.89, H?, Q6; found .... € 78 * 81 »» 7.16. · 4-iso-BotylcBm ^, boiling point: 52 to 69 ° C / lSlfe serf = 1 ^ 862, aas Z ^ st ^ atsifireiiSiJ

Analysis for Q ₅ H ₂₂ !
Calculated ... C 89.04, H 10.96;
found .... C 89.27, H 10.66.

^ Cyclooctylcttmol, boiling point 126 to 134 ⁰ C / 0.1 mm Hg, η'ό = 1.5230, from l ^ CumenylJ-eycloocten.

Analysis for Q ₇ H ₂₆ :

Calculated ... C 88.62, H 11.38;
found .... C 88.38, H 11.52.

4- (2-norbornyl) cumene, boiling point: 150 to 156 ° C / 5 mm Hg, «S * = 1.5333, from 2-hydroxy-2- (4-cumenyl) norbornane.

»5 Analysis for C ₁₆ H ₂₂ :

Calculated ... C 89.65, H 10.35;
found .... C 89.38, H 10.20.

4- (4-fluorophenyl) cumene, melting point: 91 to 94 ° C, from 2- (4'-fluorobisphenylyl) -2-propanol.

Analysis for C ₁₅ H ₁₅ F:

Calculated ... C 84.08, H 7.06. F 8.86;
found .... C 84.02, H 6.92, F 849.

Manufacture of 3-phenoxycumene

A mixture of 21 g of 3-phenoxy-alpha-methylstyrene. 1 g of platinum oxide and 200 m! Ethanol was hydrogenated until the calculated amount of hydrogen was absorbed had been. The catalyst was filtered off and the filtrate was evaporated in vacuo. The Residual oil was distilled to yield 17.1 g of boiling 3-phenoxycumene 140 to 150 ° C / 5 mm Hg and a n? of 1.5574.

Analysis for Q ₅ H ₁₅ O:

Calculated ... C 84.87, H 7.60;
found .... C 84.82, H 7.51.

Analysis for Cj ₀ H ₂ ^
Calculated ... C88.56, H 11.44; .... C 88.8S, H iU4-

Production of 4-isobutyldiphenyl ether

A mixture of 48 g of 4-phenoxy-iso-butyrophenone. 24 g of 85% Hydryzinhydrat, 26.4 g of 85% potassium hydroxide and 150 ml Diäthylengjykol was stirred and heated for 1 hour at 12O ⁰ C. The tempe-

temperature of the reaction mixture was then raised for 1 hour at 200 ⁰ C, so that the volatile materials could abdestilberen from the mixture. The reaction mixture was then allowed to cool slightly, then 20 ml of water were added, and the reaction

^ Gas mixture as previously for a further hour at 200 ⁰ C. The heated reaction mixture was cooled and exöahiert with ether The Aiherextrakt was gewaschea twice mil water, dried over Natriunisnffiit aod evaporated in vacuo. The

The residual oil was distilled and yielded twice a yield of 29.2 g of 4-iso-biliary dihydrate ether from boiling point 121 to 130 ° C / 9.1 mm Hg and one n? of 1.5461.

Analysis for Q ₃ H ₁₈ O:

Calculated ... C84j9i, H8.02;
■ * ... C84 ^ 5, H7.97.

4-CyClOeA ^ COL Boiling point: IQS to IiO ⁰ Q 0 £ mm. fife «f - I *» i73, ans ~ ....-.,.-.-_. ».

Person administered who is suffering from an inflammatory condition suffered, although i »doses -roa about 1.0 up to about 100 mg / kg body weight daily as a single Dosage or ia Posffii oBteteflter Dosea. WeäQ

teteflter Dosea. WeäQ divided doses were used, that became

12;

Anti-inflammatory drug generally every 4 to 6 hours administered because some of the anti-inflammatory drugs according to the Ecfinduög ke & eaniilgetischet effectiveness atiu zen, it may be unfair to use the means in vet with an analgesic; Medium, e.g. B. aspirin or d-propoxypheni; to be used for as long as: | to i Shll l ^ dhki; d

acting condition and other factors of interest ypn to the patient’s physician. .... ,. _r

example 1
Capsule preparation

4-phenylcumene
"ÜSSl ''"'"'

g% g _; ^ pi5 |> Oo r

Administration is the preferred form of application, The anti-inflammatory drugs described here can also be used parenterally or in the form of rectal suppositories be applied.

Many of the compounds used according to the invention are oils, and these can initially be from an inert carrier, such as. B. talc, silica gel or the like. Adsorbed and then processed into capsules, tablets, pills, powders or grains. Such solid dosage forms for oral use can also, as is generally customary, in addition to inert diluents, other substances, z. B. lubricants such. B. magnesium stearate. In the case of capsules, tablets and pills, the dosage forms can further contain buffering agents. Tablets and pills can can also be made with coatings that are insoluble in gastric juices. These connections can also be incorporated into soft gelatin capsules.

To liquid & Dosienmg iörmen for oral Anwenchm _g include such pharmaceutically acceptable forms such as emulsions, solutions, suspensions, syrups and elixirs containing inert diluent used in general such. B. water or a suitable oil.

When formulating the anti-inflammatory effects Compounds according to the invention can be made into liquid dosage forms for oral use it may be advantageous to mix the agent to be formulated with a suitable oil such as peanut oil, Cottonseed oil, sesame oil or corn oil or the like to be diluted. Such a dilute mixture represents Flavors, sweeteners and the like are dissolved in water, which is used as a outer emulsion phase acts. In addition to inert diluents such preparations can also include adjuvants, such as. B. wetting agents, tmuigier- una suspending agents, Sweeteners, flavors and fragrances, contain.

Means for rectal use or suppositories can, in addition to the active compounds, excipientia or binders, such as. B. cocoa butter or a wax for suppositories.

The dosages of the active ingredient can be varied in the preparations according to the invention will; however, it is necessary that the amount of the active ingredient is such that i ^

g ^

nete dosage form is achieved. The chosen dosage depends on the desired therapeutic effect, also on the type of application and the duration of the treatment. In general, when using seeds, doses between 1.0 and 100 mg / kg body weight are used daily to achieve an effective reduction in inflammation, pain and, in some cases, fever. The prescribed doses of one or more of our compounds ia a gee% ktten Pormaüeraag are, however, likely to be SQ d 500 di bi il

g j

SQ and 500 mg, sometimes up to four times a day, depending on the patient's body weight, de, za be-The 4-phenylcumene is mixed with the silica gel in a suitable mixer to form a homogeneous powder. The powder is placed in appropriately sized empty gelatin capsules for drug administration. For example, a # 00 gelatin capsule has been found to contain 0.55 g of powder, which corresponds to 330 g of the drug. Other ingredients can be added in the usual manner to improve the performance of the processing machines, to aid in the disintegration of the drug quantity, to improve the tolerability and so on. Other materials, of which silica gel is only an example, can be used either individually or together in order to adsorb the compounds according to the invention, if they are of an oily nature, and to process them further to a dry powder.

Example 2

Preparation of soft elastic capsules
30th

4-Phenylcumene can be found in a soft gelatin film, either neat or with a suitable liquid diluents, such as. B. a vegetable oil, are encapsulated. Other components can be added if necessary, in order to e.g. B. to improve the divisibility, the absorption to promote, etc. The encapsulation can be accomplished by means of a suitable device, such as z. B. by means of the shear circulation injection device that in "Remington's Pharmaceutical Sciences", 13th edition, is described and known as such

Example 3

Emulsion preparation
45

4-phenylcumene 133 g

Soybean oil 26.7 g Sorbitan monostearate 2 ^ 7 g Polyoxyalkylene derivative from Sorbitan Moaostearate 0.40 g Cane sugar 333 g Methyl paraben 0.1g Propyiparaben 0.1 g Peppermint oil 0, OS g Water q.s. 100 ad

Dose: 15 mL equivalent to 200 mg of medicinal substances.

Sorbitan moaostearate and soybean oil are mixed and ^{heated to 70 0} C. The polyoxyalkylene defivai from the sorbitam monostearate and the parabens WSdea are distributed in approximately 100 ml of water at 70 ⁰ C, and the cane sugar is added. The oil phase is added to the aqueous phase using a suitable mixer z. B: in a "Waring BJea-6s der", and throw the phases to form a tired product. After cooling, 4-Phenylcamol and Pfetfermmzöl are added and the mixture is stirred again.

M3

Example 4
Soup preparation us

Weight percent

4-phenylcumene 15.5

White wax, USP 4.0

Cocoa Butter / USP,;. 80.5

white WSii (s is in dom 4-Pn5enylcutupl dissolved with the help of moderate heat. The cocoa butter is scraped up and slowly added to the mixture After the cocoa butter is completely melted, the mixture is made, if necessary with additional Heating, poured into suppository molds of suitable size for the desired dosage; z. B. a 2.58 g suppository of the above mixture gives a 400 mg dose of 4-phenylcumene.

Example 5
Tablet preparation

4-phenylcumene 15.0%

Silica gel 10.0%

Cellulose in microcrystalline

Form (see Merck Index,

8th edition, p. 220) 66.0%

Flowable starch 7.5%

Stearic acid 1.5%

4-Phenylcumene is mixed with silica gel to form a dry powder which is compatible with the other, previously mixed ingredients is mixed. The preparation can then by means of a suitable tablet machine for the formation of tablets with the desired weight for example of 667 mg, corresponding to 100 mg 4-phenylcumene, are pressed together.

825

from a Hanoyia lamp (Kromayer model 10), placed in contact with the skin on the back of the guinea pigs. The unexposed Areas under the cover provided an S area of contrast, ^ m to classify the erythema may, the animals were randomly distributed and 'in

■ transparent divided plastic containers with a size of 10 χ 20 cm and a height of

'' ■ "'■■' • 3Ü5 .em accommodated, starting with one hour

ίο after exposure and then at half-hour intervals within a further I ^1/2 hours, the degree of the resulting erythema by means of an arbitrary point system based on the degree of contrast and redness formed rated antiphlogistics delay the development of erythema and therefore a great impact on the initial evaluation periods. Therefore, the results have been given a factor of 4.3.2 and 1 for the evaluation times of 1.0, 1.5, 2.0 and 2.5 hours.

The erythema was scored as follows:

Erythema assessment system

evaluation

Appearance of the punished areas

Ver: -chsbericht

Anti-inflammatory effects of 4-phenylcumene on those caused by ultraviolet radiation Erythema in guinea pigs

40 no blush and no contrast

slight blush with a weak »»
Outline of the cover

light to moderate blush with a
characteristic outline

considerable blush with a characteristic regular outline

The overall evaluations from each experimental group of four guinea pigs were compared with the Compare control treatment and the percent inhibition was calculated as follows:

The Effects of Different Formulations of 4-Phenylcumene on the Development of a Through Ultraviolet radiation induced erythema on the skin of albino guinea pigs has been identified. The preparations were administered orally, rectally and subcutaneously.

Control — treatment
control

=% Inhibition.

The preparations from the compound 65268 were tested as follows:

Methods

A modification of the Mediode by Wieder et al., (1958?) Used winde to measure the anti-phiogistic effect of this remedy. AHwnomeerse & wemchea of each sex, who weighed 225 to 309 g • shaved on the back oad with a diemiscfaea HreetiMingsmitteä enöiaart, üoä ssvss IS stands before the guinea pigs were caressed by ultraviolet light. The animals were tied up overnight. Immediately after the guinea pigs were treated with a test compound, the dose was stopped

on the skirt of the liquid methyl cellulose-SBSpenSfOB .....

2. SospeasioB (S0icage3 |

3. Emulsion

4. 15% cocoa buoys

results

Appearance type

g pp

Mhea aagebracäil, and this became then 7 Sekondea tang emem very new oltiavioleaen light aasgesetat IMe ülttavioleöliditqaeae consisted oral and

subcutaneous
orally

orally
rectate

The "OTaIe dose of 4-Phefl.ylcomoU which gives a 5Q% H nHug der ErySiembilduiig (ED50) iB est Mediyisa ^ oiosesuspension Tsewirk", was "eE 4.0 mg / kg determined.

Cutaneous administration of this formulation was not very different.

- Pie compound when adsorbed on ^ licagel and in the form of an aqueous suspension nut one Dosage of 50mgyfcg had been administered produced a 92 %% e inhibition of the ErjSheanbfldüqg!

Emulsion; The imulsion produced when administered orally at a dose of approximately 38 mg / kg 79% inhibition of erythema formation.

When administered rectally and at a dose of approximately 35 mg / kg 231, the cocoa butter suppositories resulted in a 50% inhibition of the formation of eryüiem.

Conclusions ;

4-Phenylcumene was found to be hmsie & t-3ich the Henuaung of the ejjythema formation in relation to Brythema induced by mtraviolet thesi radiation in guinea pigs in all forms of preparation examined is effective

IO

¹ I Winder, CV, Was, J, "err, V, Bc" n, M. and Posiere, CE, "A Standard of Phannacological Influeuceson IHtraviQlet Erythema in Guinea Figs", Arch. Int. Phaimacodyn, JId,

Miim

Claims (1)

ygg ■ j containsea _J where Ar3-Pheaioxyplieayf, 4-Kienox5'- XtAenyl, ^ Phenylthiophenyl, 4-Cycio & exy | pfeaijL, - ^ H-biphenylyl, 4-iso-BBtyiphenyl, 4-Qyck> hexyl 3 - chloiphenyl, 4 - phenoxy - 3 - sjeäiylpijsnyl, to 4- phenoxy - 3 - methaxypheayi, 4-iso - propyi- © dear S-Indasgi means md R iso-ftopyij iso-Propenst Iso-butyl or n-Bntyl means with the ISnsc & räntaingea, however, that when R is o-butyl fet, Ar is 4-Biphenyiyi and when R is iso-Bntyl, Ar 4-phenoxyphenyl isL