DE2342061A1 - MEDICINAL PREPARATIONS WITH A CONTENT OF 2- (3,5-DI-TERT.-BUTYLPHENYL) -INDANE-1,3-DIONE - Google Patents

Description

¹¹ medicinal products containing 2 - (3,5-di-tert-butylphenyl) indane-1,3-dione "

Priority: August 21, 1972, Great Britain, No. 38 939/72

The invention relates to medicinal preparations with a content of 2- (3 »5-di-tert-buty! Phenyl) -indan-1,3-dione.

Numerous 2- (alkylphenyl) indan-1,3-diones are known. For example are in GB-PS 1 172 696 2- (o-alkylphenyl) -indan ~ 1,3-diones with anticoagulant and anti-inflammatory effects described. The same compounds and several other 2- (alky! Phenyl) indan-1,3-diones were obtained from CA. Bruynes in his submitted to the Free University of Amsterdam in 1968 Dissertation, which examined a number of them for their anticoagulant properties and found that the 2- (o-alkylphenyl) indan-1 »3-diones described in the British patent have the greatest activity.

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There are also various 2-phenylindanediones with anti-inflammatory properties Known effect. The anti-inflammatory activity of the known compounds is common for therapeutic purposes sufficient, but the compounds known to have anti-inflammatory activity cannot be used clinically to control inflammation because they are also anticoagulant Have properties. This trait is undesirable, and it seems difficult to find the two

the Vcrbinriun'j'ji ".

Properties to be separated by structural modification /.

Fontaine, L. et al., Med. Pharmacol. Exp. 17 (1967) pp 497-507 and J. G. Lombardino and E. H. Wiseman, J. tfed. Chem. 11: 3 ^ 2 to 3 ^ 7 (1968) have different phenyl indandione derivatives examined for their anti-inflammatory and anti-coagulant effects. Confirm in these publications these researchers that anti-inflammatory activity in general is accompanied by anticoagulant activity in the 2-phenylindane-1,3-diones. Lombardino and Wiseman however, found some compounds within this group that had no measurable anticoagulant in their experiments with rats Effect, but still showed anti-inflammatory activity. Typical of these compounds is a substituent in the m-position of the phenyl group and in the 5-position of the indanedione radical. According to the findings of Lorabardino and Wiseman, 2-m-tolyl-5- (trifluoroniethyl) indan-1,3-dione, below referred to as compound B, the strongest anti-inflammatory effect.

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The present invention is based on the finding that a 2-phenylindane-1,3-dione has a much simpler structure has a higher anti-inflammatory effect than compound B and also has no undesirable anticoagulant properties having. This connection is the 2- (3,5 ~ Di-tert-buty! Phenyl) indan-1,3-dione, hereinafter referred to as a compound A denotes the formula

O ^, C (CI-I ₃ )

Although this connection is described in Bruynes' dissertation, however, it was not known whether this compound possessed pharmacological properties.

The pharmacological properties of compound A were compared with those of compound B. The prothrombin time was determined by the ^rt thrombotest ⁿ method (Owren PA, Arch. Int. Med. III, 248 (1963) and Parmacoterapi, vol. 25 (1969), p. 1). The coagulation was determined with the "Dedex" coagulometer instead of manual shaking. In this experiment, none of the compounds showed an anticoagulant effect in non-lethal doses. The anti-inflammatory effect was demonstrated on the experimental carrageenin edema in the rat paw by the method of CA. Winter et al., Proc. Soc. Exp. Biol. Med. 111: 544 (1962). The results are summarized in Table I.

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Table I.

Test connection Dose,
mg / kg po Paw volume
(100 units
= 1 ml) LD ₅₀
mg / kg po Control attempt 117 - Indomethacin 2
6th
18th 79.5
56.6
51.9 r
25th
- Connection Λ 9
27 70.7
45.7
43.0 194 Connection B 9
27 125
107
74.5 -

From Table I it can be seen that the anti-inflammatory activity of compound A is of the same order of magnitude as that of indomethacin, a well-known anti-inflammatory drug, and that compound B is much less active. Compound A has a significantly lower toxicity than indomethacin.

The concentration of compound A in comparison to indomethacin arthritis induced by the sodium salt of uric acid in dogs was determined by the method of D.J.C. Mc. Carthy et al., J.Exp. Med., Vol. 124 (1966) p.99, modified by Euchi Fujihira, Chem. Pharm. Bull., 19 (1971), pages 1506 to 1508. With this method, the weight is registered which is carried by the leg affected by the sodium salt of uric acid on a Ua agc burdens. The results are summarized in Table II.

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BATH ORIGINAL

Table II

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§Nungo exercised by the injected paw? ·. tr-G-./ichi- xr.% ' es durchoclinittl. Weight per dor. χ π group vo.v

der Νη-Γ .Γ Πί.ίηΙρ ¹ ; ·: ·! ^ '.

■ before the urat- [ hours D a ch the ■ • Ta-uratlpehan cn.iir. ϊtreatment ι

i control

■ 102.7 97.3 i 64.7 0.0 0.0 19.0 31.2

■
Connection Λ
(mg / kp; im) ^; 102.8 I 97.4
100.4! 99.7
84.6 j 115.2 76.4 70.9
82.7; 89.7
86.4: 100.0 Indomethacin ■ j *
(mp / kß im) '\ 92.3
97.4
102.3 107.7
102.4
97.4 80.9
119.9
104.0 37.6
45.7
96.9 83.8 82.6 82.6
101.1 96.8 95.6
99.9 99.2 104.4 1
3
9 1
3
9 25.2: 58.9 68.8
26.7 j 69.1 104.0
107.6 1110.4, 106.2
1 ·

Ha-urats From Table II it can be seen that the effect of / by 3 mg / kg of compound A and by 9 mg / kg indomethacin completely will be annulled. This means that in this experiment the compound A has a three times higher activity than Indomethacin.

As non-steroidal anti-inflammatory drugs often have an ulcerogenic effect show was the formation of gastric ulcer after administration investigated therapeutically effective doses of compound A and known anti-inflammatory drugs. Fasting male rats in Wire-bottomed cages were given water ad for 24 hours libitum. Then they were given a suspension of the 2 ' Compound administered orally. 6 hours later the

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BATH ORIGINAL

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Animals killed and laparotomized. It was examined the number and represents extent of ulcer formation. The ulcerative effect was expressed as the ulcer index using the following formula:

Ί Π

Ulcer Index - 10. log, / XNumber. Extent of ulcer formation) (- 1 /.

The extent of ulcer formation is assessed as follows: "; skala

expressed:

1 means a just visible ulcer formation in the stomach * ":! η d and 4 means perforation.

The results of a typical series of tests are shown in Table-;

III summarized.

Table III

Test connection

Dose, rag / kg

Connection A

27 9 3

; indomethacin

■ 27 9 3

jO-acetylsalicylic acid

300

100

33

Ulcer index

0.4 0.0 0.0

10.4 6.8 0.8

2.8

1.9 0.8

'Control attempt 1 Control attempt 2

0.0 0.0

From Table III it can be seen that Compound A when followed in therapeutically effective doses has a substantial ge

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BAO ORIGINAL

Has less ulcerogenic effect than indomethacin and O-acetylr alicylic acid c.

The acute toxicity (LDj-q) in rats, calculated on the basis of mortality within 8 days after oral administration, is 194 rag / kg for compound A and 25 mg / kg for indomethacin. Compound A is also significantly less toxic than indomethacin when administered orally to rats for h days. Three out of six animals that received 5 mg / kg indomethacin daily and all six animals that received 25 mg / kg indomethacin daily died. All animals (two groups of six animals each), before receiving the same doses of Compound A, survived the experiment.

The lack of an anticoagulant activity in the compound A is surprising, since this activity is found in structurally closely related 2- ( 3 j5-dialkylphenyl) -indan-1,3-diones, rats were given the compound A _t the 2nd orally for 2 days - (3,5-Diethylphenyl) -indan-1,3-dione (Compound C) and the 2- (3,5-Diisopropylphenyl) -indan-1,3-dione (Compound D) were administered. 100 mg / kg of the compound to be examined was administered four times, namely at 5:00 p.m. and on the following day at 9:00 a.m., 5:00 p.m. and 9:00 a.m. The prothrombin time was determined at 3:00 p.m. on the last day of the experiment. The results are summarized in Table IV.

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Table IV

Test connection Prothrombin time, see * A.
C.
D.
Control attempt 31
49-39-159-44
125-161-116-118
30th

■ *) If the fourth obtained with different animals are only small Show differences, the mean is given; the individual values are listed if they are within a Dose group varied considerably.

The compound A shows not only anti-inflammatory effects but also analgesic effects when applied to rats after Method of M.V. Caroll et al., Archiv, int. Pharmacodyn., Vol. 125 (1960), p. 383 is examined. Compound B has no analgesic effect.

Compound A can be prepared by known methods for preparing analogous compounds. There is a procedure in the condensation of phthalide with 3,5-di-tert-butylbenzate aldehyde in the presence of sodium methylate. The reaction is preferably carried out with excess sodium methylate and in the presence a water-binding substance, preferably an organic ester such as ethyl acetate, carried out. In a different procedure 3,5-di-tert-butylbenzylidene phthalide is reacted with sodium methylate in methanol and the alkali metal salt obtained is reacted treated with dilute acid. The reaction is preferably carried out by refluxing the phthalide

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with an equivalent amount of sodium methylate in methanol performed. The methanol is distilled off and the residue in dissolved in cold water. The product precipitates on acidification. Examples of suitable acids are non-oxidizing inorganic acids such as hydrochloric acid or organic acids such as acetic acid.

Another process is the conversion of a dialkyl phthalate of the general formula II.

.COOR

(II)

COOR

with an alkyl phenylacetate of the general formula

¹¹¹

ROC-CH ₂ γ) (III)

In the formulas, R denotes a lower alkyl radical. The reaction is carried out in the presence of an alkali metal alcoholate such as sodium methylate and preferably under reflux in an inert organic solvent such as toluene. After cooling, the reaction mixture is decomposed with water / water and isolate the product.

The compound A can be used both in veterinary medicine and in human medicine as an anti-inflammatory agent. For the treatment of humans, the daily dose can be 10 to 100 mg when administered orally or parenterally. For thera- _j

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The compound can be used for therapeutic purposes in the form of conventional medicinal products can be used. Accordingly, the invention also relates to medicaments which the compound A together with a customary carrier and / or diluent and / or adjuvant. Medicinal preparations with a content from about 10 to 100 mg of compound A is preferred.

Medicinal preparations for oral administration, especially tablets, including sustained release tablets, Pills and capsules are preferred. The tablets and pills can be used in a conventional manner with one or more pharmacological compatible diluents or excipients. Examples of these diluents are Lactose, starch, calcium sulfate, dicalcium phosphate, microcrystalline cellulose and formaldehyde casein. The tablets and pills can still contain disintegrants, such as starch, sodium alginate, highly disperse silicic acid, methylene acid, dioctyl sodium sulfosuccinate or potassium bicarbonate, lubricants such as calcium or magnesium stearate, a mixture of glycerol palmitate and stearate, stearic acid, talc or polyethylene glycol, binders such as gelatin or polyvinylpyrrolidone, or cellulose derivatives, such as methyl cellulose. Capsules made from absorbable Substances such as gelatin can use the drug alone or in admixture with a solid or liquid diluent contain.

Liquid medicinal preparations can be in the form of suspensions, emulsions, syrups or elixirs, the medicinal substance in one conventional liquid carriers for orally administrable preparations

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" ¹¹ " 7342061

contain. Examples of such liquid carriers are vegetable oils, such as olive oil, peanut oil or sesame oil, polysorbic acid esters, Propylene glycol, polyethylene glycol, glycerin or a syrup or an elixir base.

The medicinal substance can also be used in medicinal preparations which can be administered parenterally packaged, e.g. as a suspension or emulsion in a conventional one used for injection preparations organic liquid, e.g. a vegetable oil such as olive oil.

The examples explain the production of medicinal preparations.

example 1

Tablets are made from the following ingredients: 2- (3,5-Di-tert-butylphenyl) -indan-1,3-dione '100 g Lactose 50 g

Potato starch 50 g.

The ingredients are mixed together and granulated with a 5% by weight solution of starch in water / water. The granulate is dried. The granules become 1000 tablets each weighing 200 mg.

Example 2 Tablets made from the following ingredients:

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2- (3,5-Di-tert-butylphenyl) -indan-1,3-dione <25 g

Lactose 20 g

Dicalcium phosphate "20 g

Potato starch 25 g

Polyvinylpyrrolidone 5 g

Magnesium stearate 1 g

Talc 4 g.

The drug, the lactose, the dicalcium phosphate and the starch are mixed together and with a 5 weight percent Granulated solution of polyvinylpyrrolidone in water. The granules are dried and covered with magnesium stearate and talc mixed. Tablets weighing 100 mg each are made from the granules.

Example 3

Tablets are made from the following components:

2- (3,5-Di-tert-butylphenyl) -indan-1,3-dione 50 g

microcrystalline cellulose 50 g

Sodium alginate 25 g of highly dispersed silica 2.5 g

Methyl cellulose 5g

Stearic acid 7.5 g

The drug, the microcrystalline cellulose and the sodium alginate are mixed together and granulated with a 5% by weight solution of methyl cellulose in water. The granules are dried and mixed with the highly disperse silica and stearic acid. From the mixture

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tablets with a weight of 140 mg each are produced.

Example 4

Tablets are made from the following components:

2- (3,5-Di-tert-butylphenyl) -indan-1,3-dione 50 g

Lactose 22 g

Potato starch 22 g

Talc 5 g

Magnesium stearate 1g

The drug, the lactose and the starch are mixed together mixed and granulated with a 5 percent strength by weight solution of starch in water. The granulate is dried and mixed with talc and magnesium stearate. Tablets weighing 100 mg each are produced from the mixture.

Example 5 illustrates the preparation of 2- (3,5-di-tert-butylphenyl) indan-1,3-dione.

Example 5

17.3 g of sodium metal are dissolved in 200 ml of methanol. The received Solution of the sodium methylate becomes a solution of 56.5 g of 3,5-di-tert-butylbenzaldehyde and 33.5 g of phthalide are added to 150 ml of anhydrous ethyl acetate. The mixture will boiled under reflux for 4 hours under nitrogen as a protective gas. The methanol is then distilled off / and after cooling the residue is dissolved in about 1 liter of cold water. The aqueous solution is three times with 100 ml of di-

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extracted ethyl ether and then with 4 η sulfuric acid acidified. The precipitate formed is filtered off and recrystallized from ethanol. The 2- (3t5-di-tert-butylphenyl) indane-1,3-dione is obtained from 134 to 135 ° C.

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Claims (1)

- 15 claim Medicinal preparations, characterized by a content of 2- (3 »5-di-tert.-butylphenyl) indane-1,3-dione. 409810/1176