DE3019834C2 - Esters of 2- (4-isobutylphenyl) propanol-1, process for their preparation and pharmaceuticals containing these compounds - Google Patents

Description

CH-CH ₂

IO

CH-CH ₂ -OCR

ω, 5

in which R is an alkyl radical having 1 to 19 carbon atoms means.

2. Process for the preparation of the compounds according to claim 1, characterized in that one 2- {4-isobutylphenyl) -propanol-1 in a manner known per se of the formula II with a carboxylic acid derivative of the general formula ΠΙ

CH-CH ₂

x — c—

Il ο

(ΠΙ)

where X is a chlorine, an AlkoxylgniRpe or the Represents the radical R'COO, where R 'is different from R. and R has the same meaning as in claim 1

3. Medicinal products with anti-inflammatory and analgesic effects, containing as active ingredients at least one compound according to claim 1.

The invention relates to esters of 2- (4-isobutylphenyl) -propanol-1 of the general formula I.

(I)

in the pure alkyl radical with 1 to 19 carbon atoms 40 formula II with a carboxylic acid derivative of the general

means. NEN formula III according to the following reaction equation

The esters of the general formula I can be converted by adding 2- (4-isobutylphenyl) propanol-1 to the

CH ₃
\

CH ₃

CH-CH

CH-CH ₂ OH + X-C-R

(Π)

where X is a chlorine atom, an alkoxyl group or a radical R'COO that the compound of In general formula III represents a mixed anhydride, while R represents that given above Has meaning and R is different from R '

The compounds of general formula I have to at extremely low toxicity, a pronounced anti-inflammatory and analgesic effect. They are therefore valuable medicinal substances and are used in the fight against inflammation and painful conditions. The invention thus also relates to medicaments with anti-inflammatory and analgesic effects which contain at least one compound of general formula 1 as an active ingredient.

example 1

2- (4-Isobutylphenyl) propyl hexanoate
a) 2- (4-Isobutylphenyl) propanol-1

300 ml of tetrahydrofuran, 25 ml of water, 58 g of 2- (4-isobutyl) propanol and 1 g of NaOH are placed in a 1 liter three-necked cola equipped with a stirrer and a reflux condenser. 7.1 g of NaBH ₄ are then added in 1 g portions with stirring, the temperature being maintained at 40 to 45 ° C. After a reaction time of 2 hours at room temperature, the excess NaBH ₄ is decomposed by the slow addition of acetic acid, with stirring and cooling. Then you steam the

Most of the solvent is removed under reduced pressure, taken up again with water and extracted with Diethyl ether. The one after the diethyl ether has evaporated The oily residue obtained under reduced pressure is distilled. The at 145 to 150 ° C / l, 5 to 2 Torr passing fraction is won. The yield is «g (73.4 percent of theory).

IO

b) 2- (4-isobutylphenyl) propylic acid ester

500 ml of isopropyl ether, 42 g of pyridine and (slowly with stirring) 101 g (0.725 mol) of hexanoic acid chloride are placed in a 2 liter three-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel. After cooling to 0 ⁰ C is slowly added a solution of 95 g (0.5 mol) of 2- (4-isobutyl) -propanoI-l in 150 ml of isopropyl ether ziigesetzt The temperature rose to 40 ⁰ C. After 4 hours reaction time at ambient temperature the mixture is poured in 200 ml of water. The organic phase is separated off, washed with 0.1 η hydrochloric acid and dried over anhydrous sodium sulfate. The oily residue obtained after evaporation of the solvent under reduced pressure is distilled. The pure ester is distilled at 146 ° C./0.1 to 0.2 Torr above. The yield is 125.5 to 132.5 g (88 to 92 percent of theory). JO

B ice ρ i JI 2
Enanthic acid 2- (4-isobutylphMiyl) -i> topyl ester

r>

500 ml of isopropyl ether, 42.2 g of pyridine and (slowly with stirring) 107.4 g (0.725 mol) of oenanthic acid chloride are placed in a 2 liter three-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel. After cooling to 0 ⁰ C a solution of 95 g (0.5 mol) of 2- (4-isobutyl) propanol-l in 150 ml of isopropyl ether slowly. The temperature rises to 45 ° C. After a reaction time of 4 hours at room temperature, the mixture is poured into 200 ml of water. The organic phase is separated off, washed with 0.1 η hydrochloric acid and dried over anhydrous sodium sulfate. The after evaporation of the solvent The oily residue obtained under reduced pressure is distilled. The pure ester is distilled over at 150 ° C./0.1 to 0.2 Torr. The yield is 124 to 127 g (89.4 to 92 percent of theory). ,

Example 3
2- (4-isobutylphenyl) propylene octanoic acid ester

500 ml of isopropyl ether, 42.5 g of pyridine and (slowly with stirring) 122 g (0.725 mol) of octanoic acid chloride are placed in a 2 liter three-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel. After cooling to 0 ⁰ C a solution of 95 g (0,5MoI) 2- {4-Isobütyl) -propanoH in 150 ml of isopropyl ether is slowly zitgegeben-The temperature rose to 40 ⁰ C. After 4 hours reaction time at ambient temperature the mixture is poured in 200 ml Water. The organic phase is separated off, washed with 0.1 η hydrochloric acid and dried over anhydrous sodium sulfate. The oily residue obtained after evaporation of the solvent under reduced pressure is distilled. The pure ester is distilled at .155 ° 04 to 0.2 torr. The yield is 137 to 143.7 g (87 to 91 percent of theory).

Example 4
2- (4-isobufylphenyl) propyl decanoate

500 ml of isopropyl ether, 42 g of pyridine and (slowly with stirring) 140 g (0.725 mol) of decanoic acid chloride are placed in a three-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel. After cooling to 0 ⁰ C is slowly added a solution of 95 g (0.5 mol) of 2- (4-isobutyl) propanol-1 in 150 ml of isopropyl ether was added, the temperature rises to 40 ⁰ C. After 4 hours reaction at ambient temperature the mixture is poured in 200 ml of water. The organic phase is separated off, washed with 0.1 π hydrochloric acid and dried over anhydrous sodium sulfate. The oily residue obtained after evaporation of the solvent under reduced pressure is distilled. The pure ester is distilled over at 170 ° C./0.1 to 0.2 torr. The yield is 125.5 to 132.5 g (88 to 92 percent of theory).

Example 5
2- (4-isobutylphenyl) propyl acetate

500 ml of isopropyl ether, 42.5 g of pyridine and (slowly with a stirrer) 58.8 g (0.725 mol) of acetic acid chloride are placed in a three-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel. After cooling to 0 ⁰ C a solution of 95 g (0.5 mol) of 2- (4-isobutyl) propanol-1 in 150 ml of isopropyl ether is added slowly. The temperature rose to 40 ⁰ C. After 4 hours reaction at ambient temperature the mixture is poured into 200 ml of water. The organic phase is separated off, washed with 0.1 η hydrochloric acid and dried over anhydrous sodium sulfate. The oily residue obtained after evaporation of the solvent under reduced pressure is distilled. The pure ester distills over at 126 to 128 "C / 0.1 to 0.2 Torr. The yield is 1043 to 108.5 g (90 to 93 percent of theory) . Th.).

Further examples of the esters according to the invention are 2- (4-isobutylphenyl) propyl caproate and 2- (4-isobutylphenyl) propyl hexadecanoate.

Table I contains physical characteristics and analytical data for esters of the general formula I. specified.

Table I. 30th Boil 19 834 6th BerVgef. 5 R. Point, ⁰ C Elemental analysis, H 123-8 Torr 9v * / 9.38 -CH ₃ 130-4 C. 9.68 / 9.64 -CH ₂ -CH ₁ 135-8 76.9 / 76.8 9.9 / 9.78 - CH2 - Crlj OH3 140-2 0.1-0.2 77.4 / 773 10.1 / 9.9 -CH ₂ - (CHj) ₂ -CH ₃ 143-5 0.1-0 ^ 77.8 / 77.7 10 ^ / 10 -CH ₂ - (CHj) ₃ -CH ₃ 145-7 0.1-0 ^ 78.2 / 77.9 10.5 / 10.1 -CH ₂ - (CHj) ₄ -CH ₃ 150-1 0.1-0 ^ 78.6 / 78.4 10.7 / 10.5 Pu fCXX \ Γ * Μ
V-flT.2 < i * ^ "- 2JS v ^ nij 154-6 0.1-0.2 78 ^ / 78 ^ 10.8 / 10.6 -CH ₂ - (CHj) ₆ -CH ₃ 157-9 0.1-οα 79 ^ / 78.8 11.0 / 10.8 -CH ₂ - (CHj) ₇ -ICH ₃ 161-5 ο, ι-ο ^ 79 ^ / 79 ^ 1I; 1 / 1O ^ -CH ₂ - (CHj) ₈ -CH ₃ 165-9 0.1-0 ^ 79.7 / 79.5 IU / 11.1 -CH ₂ - (CHj) ₉ -CH ₃ 173-6 0.1-0 ^ 80.0 / 79.8 113 / 11.3 riij // "" ¹ UT \ f ~ * \ l
vJi2 V ^ - *** 2 / IO ^ ΊΊ.3 177-9 0.1-0.2 manss ir, 4 / lU4 -CH ₂ - (CHi) _n -CH ₃ 180-1 0.1-0 ^ 80.4 / 80.1 11 ^ / 11.4 -CH ₂ - (CHz) ₁₂ -CH ₃ 183-5 0.1-0 ^ 80.6 / 80.3 11.6 / 11.45 -CH ₂ - (CHj) ₁₃ -CH ₃ 185-8 0.1-0 ^ 80.7 / 80.5 11.7 / 11.5 -CH ₂ - (CHj) ₁₄ -CH ₃ 187-9 0.1-0 ^ 80.9 / 80.6 11.79 / 11.7 -CH ₂ - (CHj) ₁₅ -CH ₃ 181-3 0.1-0.2 81.0 / 80.8 11.86 / 11.8 -CHj- (CHj) ₁₆ -CH ₃ 0.1-0 ^ 81.2 / 80.9 ο, ι-ο ^ 81.3 / 81.1 0.1-0.2

The following are the toxicological and phnrmacological Properties of 2- (4-isobutylphenyl) propyl heptanoate (abbreviated to IPE).

acute toxicity

The acute toxicity was determined in Swiss mice and Wistar rats after oral and intraperitoneal administration examined. The administered volumes were 20 ml / kg body weight for the mouse and 5 ml / kg in the rat. For each dose, a group of 10 Animals (5 male and 5 female) are used. The DLäo values (mg / kg) were on the 7th day after the Administration determined according to the probit analysis. The results are shown in Table II.

Table II

Species route of administration DL

50

mouse orally 861 Mau: intraperitoneally 498 rat orally 1600 rat intraperitoneally 560

Anti-inflammatory effect

The rat paw edema test was used to determine the anti-inflammatory effect of IPE applied, with e'ne intraplantar injection of 0.1 ml of a carrageenin solution or suspension was made. IPE was administered orally 1/2 hour after the intraplantar injection of the inflammatory Substance administered. There were male Wistar rats with an average starting weight of 240 g used. The edema size was measured 4 hours after the injection with a mercury plethymograph For comparison, corresponding groups of rats were determined to be phenylbutazone and 2- (4-isobutylphenyl) propanoic acid (Ibuprofen) administered. The results of these tests are summarized in Table III.

Table III

Anti-inflammatory activity (carrageenin edema)

Treat mg / kg Appointment Percent inhibition lung consequential of carrageenin edema path compared to one untreated Control group IPE 10 orally 27 IPE 40 orally 56 Ibuprofen 10 orally 28 Ibuprofen 40 orally 52 Phenyl 10 orally 18th butazon Phenyl 40 orally 37 butazon

Analgesic effect

According to the methods of Hendershot and Forsaith (1959), the inhibition of phenylquinone

induced curvature investigated. IPE was obtained as an aqueous solution at time zero using a Gavage administered as male Swiss-Webster rats with a body weight of 18/2Og. 20th Minutes later, 0.25 ml of a> 0.02 percent solution of phenylquinone was injected intraperitoneally to to cause the curvatures. The animals were observed for the following 10 minutes. The phenylquinone solution was prepared by dissolving 4 mg of this compound in 0.5 ml of anhydrous ethanol. 19.5 ml of lukewarm water were added to this ethanol solution.

Table V

dose number Extent of mg / kg. the average orally animals Stomach damage control _ 16 0.4375 Phenylbutazone 100 16 6.0625 IPE 50 16 2.1875 *) IPE 100 16 3,250 *) ·) P pronounced significant in comparison to phenylbutazone.

Table IV

Analgesic effects of IPE (po) in comparison
with acetylsalicylic acid and the compound
(CH ₃₎ CH-CHj (l) CH (CH ₃₎ CQQH (4) C ₀ H ₄
(in the trade under the name »Ibuprofen«
available) in the rat curvature test

control 50 19/20 Acetyl 15/20 salicylic acid 150 Acetyl 9/20 salicylic acid 50 Ibuprofen 100 9/20 Ibuprofen 50 6/20 IPE 100 8/20 IPE 6/20

346
134

52

17.3
6.7

2.6

74 3.7 42 2.1 70 3.5 37 1.8

Because of its favorable properties, the compounds of the invention can be used as medicaments use anti-inflammatory and analgesic effects. Below are examples of such Medicinal indicated.

dose number of total Middle· mg / kg Animals with number value Curvature the the appearances / Krüm Krüm number of mings mung treated % animals

25th

Ulcerogenic effect

The compounds to be investigated were tested for their damaging effect on the stomach by '> » female Wistar rats examined. Animals with a transparent weight of 200 ± 20 g were used that were kept without food for 24 hours prior to treatment. The ones to be examined Compounds were given in doses of 50 and 100 mg / lcg administered. 2 hours later, the administration was repeated. The animals were 6 hours after the first Treatment after previous anesthesia with ether killed the stomachs were on the eventual Presence of a UIcus examined. 4 groups with 16 animals each were used:

1: control group

2: 100 mg / kg phenylbutazone

3: 50 mg / kg IPE

4: 100 mg / kg IPE.

The results are shown in Table V.

Example 6 300 mg
20 mg
300 mg Soft gelatin capsules Each capsule contains: Oenanthic acid 2- (4-isobutylphenyl) -
propyl ester
double-distilled glycerine
Polyethylene glycol Example 7 400 mg
30 mg
300 mg Soft gelatin capsules Each capsule contains: Oenanthic acid 2- (4-isobutylphenyl) -
propyl ester
double-distilled glycerine
Polyethylene glycol Examples 500 mg
40 mg
300 mg Soft gelatin capsule Each capsule contains: Oenanthic acid 2- (4-isobutylphenyl) -
propyl ester
double-distilled glycerine
Polyethylene glycol Example 9 600 mg
20 mg
45 mg
450 mg
ad 2.1g Suppositories Each suppository contains: Oenanthic acid 2- (4-isobutylphenyl) -
propyl ester
Lidocaine hydrochloride
ΜίεΙνοΙ
Wke "psoIE85
WitepsoIW35

Example 11 30 1 9 834 10 300 mg I. ZJ, 9 5 percent cream Example 13 10 mg P. Example 10 100 g cream contain: Vial (300 mg) 50 mg Ii Suppositories Oenanthic acid 2- (4-isobutylphenyl) - Each 2 ml vial contains: ad 3 ml r Each suppository contains: propyl ester i Oenanthic acid 2- (4-isobutylphenyl) - Cetostearyl alcohol -, Oenanthic acid 2- (4-isobutylphenyl) - I. propylesier Isopropyl myristate 800 mg propyl ester Lidocaine hydrochloride Petroleum jelly 20 mg Lidocaine (base) j * - Miglyol spermaceti 6 mg Benzyl alcohol 400 mg I. ■ Vitepsol E 85 Stearic acid 360 mg oleic acid ethyl ester 15 mg I. WitepsolW35 Polysorbitan monolaurate 60%
Triethanolamine-carboxyvinyl- ad 2.30 g in Example 14 50 mg polymer Vial (400 mg) ad 3 ml j Benzoic acid Each 2 ml vial contains: distilled water Ii Oenanthic acid 2- (4-isobutylphenyl) - ! propyl ester Example 12 5g Lidocaine (base) i 6.7 percent cream 4g Benzyl alcohol 100 g cream contain: ^fi g JIl oleic acid ethyl ester Oenarethic acid 2- (4-isibutylphenyl) - 6g 300 mg i propyl ester
Cetostearyl alcohol 6g Example 15 0.4 mg Isopropyl myristate 2g Vial (300 mg) 3.6 mg
1500 mg I. Vaseline oil 0.5 g > ■> Each 2 ml vial contains: 2 ml spermaceti ig 1 Stearic acid 2g Oenanthic acid 2- (4-isobutylphenyl) - I. Polysorbitan monolaurate 60% ad 100 g propyl ester I. Triethanolamine-carboxyvinyl- propyl p-hydroxybenzoate Ij polymer 1 (1 methyl p-hydroxybenzoate
Propylene glycol Benzoic acid pyrogen-free water 400 mg § distilled water Example 16 0.4 mv 1 Vial (400 mg) 3.6 mg I. 6.7 g
4g Each 2 ml vial contains: 1400 mg 1 6g 2 ml 1 6g Oenanthic acid 2- (4-isobutylphenyl) - 1 6g 40 propyl ester 2g propyl p-hydroxybenzoate 04 g methyl p-hydroxybenzoate Propylene glycol ig pyrogen-free water 2g 4-> ad 100 g

Claims (1)

:. Patent claims: L ester of 2- {4-isobutylphenyl) propanol-1 of CH ₃ general formula I 5 \ CH ₃
\ CH ₃ CH,