DE1568252A1 - 1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene - Google Patents

Description

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

P t5 68 252.7 Oase 5641 / 1-3 / A

Germany

1,2-diphenyl ~ 2-propionyloxy ~ 3- (dimethylamine) - ·

The invention; relates to 1,2-di-phenyl-2-prQpiQ-nyloxy-3- (dimethylaminoniethyl) -3-yuan the formula

109826/1830

Documents. (Art.7 ^! .Al ». 2 No. 1 Set 3 dea ÄnJtrunoee-s. <. 4.8.

The new compound has valuable pharmacological properties Properties, especially an analgesic effect, as found in animal experiments, e.g. on the mouse. It is also effective as a morphine antagonist. The Ver- . binding can accordingly be used as an analgesic. Furthermore, it has an antitussive effect, so it can also be used as a corresponding in this regard Find remedies.

In addition, the new compound can be more valuable as a starting or intermediate product for the manufacture of others Connections serve.

The new connection is established by methods known per se.

The preferred procedure is to use the 1,2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol propionylationfc.

The propionylation can nstt by reaction a propionylating agent such as propionic acid is preferred in the form of their functional derivatives, such as halides, especially chlorides, reactive amides such as Imid & Zollde or anhydrides, e.g. internal anhydrides such as ketenes or

■. . : ''i:>: -, "■ \ ■ ■■■ '■

Enol esters such as isopropenyl propionate or in the presence of a condensing agent such as dicyclohexylcarbodiiraide and the like Connections are made.

Depending on the process conditions and starting materials, the end product is obtained in free form or in the Form of its salts. The salts of the end product can in itself

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known way, e.g. with alkalis or ion exchangers be converted into the free base. From the latter can be reacted with organic or inorganic acids, which can be used for the formation of therapeutically Salts are suitable for obtaining salts. As such acids may be mentioned: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, Glycol, milk, apple, wine, lemon, ascorbic, maleic, Hydroxymaleic, pyruvic or levulinic acid; Phenyl acetic, benzoin, p-aminobenzoic, anthranil, p-hydroxybenzoic, Salicylic or ρ-aminosalicic acid, methanesulfonic, Ethanesulfonic, hydroxyethanesulfonic, ethylene sulfonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid; Methionine, tryptophan, lysine or arginine.

These or other salts of the new compound, such as the picrates, can also be used to purify the obtained The free base is used by converting the free base into salts, separating them and, in turn, the base from the salts clears. As a result of the close relationships between the new compound in free form and in the form of its salts are im Previously and subsequently under the free base, appropriately and appropriately, optionally also the corresponding salts to understand.

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It is also possible to start from a compound obtainable as an intermediate product at any stage in the process and carry out the missing process steps, or form the starting materials under the reaction conditions, or, if appropriate, use the reaction components in the form of their salts. For example, 1,2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol in the form of its O-salts, such as the O-metal salts, e.g. the O-alkali metal salts such as Sodium or potassium salts, or the O-magnesium halide salts, such as magnesium bromide salts, as they are formed in the Grignard reaction, i.e. it can be used directly by the the complex resulting from the Grignard reaction is reacted with the acylating agent.

The 1,2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol used as starting material can be obtained by treating deoxybenzoin with the compound of formula

BrMg — C — CH ₂ —N

CH ₂ ^0-3

converts, and, if desired, decomposes the complex obtained.

The compounds mentioned are reacted in a manner known per se, primarily in the presence of a Solvent or diluent, e.g. of an ether such as tetrahydrofuran. The decomposition of the complex obtained

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. 5

is carried out in the usual way, e.g. by hydrolysis. Depending on the choice of starting materials, the new compounds are obtained in the form of the optical antipodes or the racemate. Obtained racemates can be according to known Break down methods into the optical antipodes. It is advantageous to isolate the more effective of the two antipodes.

The new compound can be used, for example, in the form of pharmaceutical preparations, which they can be used in free Form or in the form of their salts in a mixture with a suitable for enteral, parenteral or topical application ' pharmaceutical organic or inorganic, solid or liquid carrier material. For the formation of the same such substances are possible that do not react with the new compounds, such as water, gelatine * lactose, Starch, stearyl alcohol, magnesium stearate, talc, vegetable Oils, benzyl alcohol, gum, propylene glycols, petroleum jelly or other known excipients. The pharmaceutical Preparations can e.g. as tablets, coated tablets, capsules, ointments, creams, or in liquid form as solutions, suspensions or emulsions are present. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, Stabilizing, wetting or emulsifying agents, solubilizers or salts to change the osmotic pressure or buffers. You can also use other therapeutically valuable Contain substances. The pharmaceutical preparations will be

109826/1830 bad original

obtained by conventional methods.

The 1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene hydrochloride (I) and the d - (+) - 1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3 Butene maleate (II) was tested for its analgesic effect in the Writhing syndrome test on mice with the well-known commercial product ad-4-dimethylamino-1 _J 2'-diphenyl-3-methyl-2-propionoxy hydrochloride (Darvon ^ ') compared.

Method:

Phenylparachinone injected into the abdominal cavity causes writhing syndrome (intermittent contractions) in mice of the abdomen, twisting and twisting the trunk, stretching of the rear extremities). Analgesics prevent this sundrome from developing.

White mice o * receive the substance to be tested for the analgesic effect orally 55 minutes before application of phenylparachinone (2.5 mg / kg ip). 60 minutes after its administration, the frequency of the extension of the hind limbs is observed for 10 minutes. The determined ED, - _n is the

50

low dose, which is the same as in the untreated control group

holding value depreciates by $ 50. The result is the following Image:

BATH ORIGINAL

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link toxicity analgesia 45
32
45 More therapeutic
index "> 50 ^ED 50 ^L V ^ED 50 on the mouse mg / kg p.o. I.
It
Comparative
product ojjO
1200
230 i4, o
37.5
5.1

It can be seen that the compound of the present invention is superior to the commercial product Darvon ^.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified. .

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Example 1 :

2β, 7 g l, 2-diphenyl-3- (dimethylaminomethyl) -5-buten-

2-ol are heated to 50 for 5 hours in 100 ml of propionic anhydride. The excess propionic anhydride is evaporated in vacuo, the residue is mixed with sodium hydrogen carbonate solution while cooling well until an alkaline reaction occurs, extracted 2 times with ether and washed the ethereal solution with water. By drying this solution and evaporating the In the ether one receives 1,2-diphenyl-2-propionyloxy-3-feimethylaminomethy]) - 2-butene the formula

Il
C-C-CH ₂ -CH _{3 OH} ^

—C — CH ,, - IT

Il ^ά CH ₂ CH ₂

By converting this compound in ethyl acetate with ethanolic hydrochloric acid, 1,2-diphenyl-2-propionyloxy-3- <d.imethylaminomethy]) -5-butene hydrochloride is obtained, f. 188 °.

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The 1,2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol used as the starting material can be obtained as follows:

By introducing 2 molar equivalents of dimethylamine in a benzene solution of 2,3-dibromopropene under ice-cooling and subsequent heating to 50 there is obtained the N, N-dimethyl-2-bromallylaminy Kp. ₇ g_ ₇ g 63-64 °. j

7.2 g of magnesium (0.3 Mol) etched with a little iodine and treated with 20 ml of absolute tetrahydrofuran and 0.8 ml of ethyl bromide. By easy Heating the reaction starts and takes place within 15-20 Minutes ^ 9.2 g (0.3 mole) of N, N-dimethyl-2-bromoallylamine in 50 ml of absolute tetrahydrofuran added dropwise in such a way that the solution remains constantly boiling. Heat more while stirring 30 minutes to simmer until the magnesium is down to small Remains is dissolved. Now, without cooling, 39.3 g (0.2 mol) of deoxybenzoin in 125 ml of absolute tetrahydrofuran are added dropwise in such a way that that the reaction solution remains boiling continuously. The mixture is then refluxed for 6 hours. One pours up 60 g of ammonium chloride in 500 ml of water, extracted the precipitated oil with ether, washed the ether with water and extract it several times with 2-n. Acetic acid (total with 500 ml). The acetic acid solution is 10-n. Caustic soda (125 ml) made alkaline and the precipitated oil was taken up in ether. The ethereal solution is dried and the

10 9826/1830

Aether evaporated. The 1,2-diphenyl-3- (dimethyl

aminomethyl) -3-buten-2-ol as residue. This crystallizes when standing, P. 56 - 58 °.

Example 2:

7.2 g of magnesium (0.3 mol) are etched with a little iodine in a stirred flask, and 0.8 ml of ethyl bromide is added to 20 ml of absolute tetrahydrofuran. The reaction is started by gentle heating and 49.2 g (0.3 mol) of N, N-dimethyl-2-bromoallylamine in 50 ml of absolute tetrahydrofuran are added dropwise within 15 to 20 minutes so that the solution remains boiling all the time. The mixture is heated to boiling for a further 30 minutes, while stirring, until the magnesium has dissolved apart from small residues. Now, without cooling, 39.3 g (0.2 mol) of deoxybenzoin in 125 ml of absolute tetrahydrofuran are added dropwise in such a way that the reaction solution remains constantly boiling. The mixture is then refluxed for 6 hours. Then one drips into this solution, which the magnesium bromide salt of the formula

OMgBr

ORIGINAL BATHROOM 109826/1830

contains, at about 30 °, a solution of 97.8 g (0.75 mol) of propionic anhydride in 50 ml of tetrahydrofuran. The mixture is then heated to 50 ° for 5 hours. The solution is concentrated to approximately 50-100 ml and then poured into 500 ml of water. · The cloudy aqueous solution is extracted with ether (ethereal solution A). A basic residue is obtained from the aqueous phase by adding 50 ml of saturated sodium carbonate solution, etherifying and evaporating the ether. ^:

The essential solution A is with 250 ml 2-n. ice-cold hydrochloric acid extracted. By treating the extract with 300 ml of ice-cold 2-n. Ammonium hydroxide solution, shake out with ether and evaporation of the ether, a basic residue is obtained. This one and the basic one mentioned above The residue is combined, dissolved in 100 ml of ethyl acetate and treated with 2.5 n. ethanolic hydrochloric acid to weak acidic reaction. The 1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene hydrochloride crystallizes, .F, 188 °, off. '■

The same reaction product is obtained if 60.0 g of propionyl chloride are used instead of propionic anhydride (0.75 mol) in 50 ml of tetrahydrofuran.

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Example 3 ^:

30 g of d-1,2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol are heated to 70 ° (bath temperature) with 200 ml of propionic anhydride for 5 hours. The excess propionic anhydride is evaporated in vacuo. The residue is dissolved in ethyl acetate and a solution of about 10 % more than the calculated amount of maleic acid in acetone is added. Then the d-1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-buten-maleate is precipitated in crystalline form by successive addition of ether, P. 127 131 °, [a] ^ ⁰ = + 35 ° * 0.5 ° (in water, c = 2.05 #).

The dl, 2-diphenyl-3- (dimethy ¹ aminomethyl) -3-buten-2-ol used as output material can be prepared as follows:

56.28 g (0.2 mole) 1,2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol are dissolved in 200 ml of acetone and with a solution of 15.0 g (0.1 mol) of D (+) tartaric acid in ml of acetone are added. Rub in and leave to stand for 4 hours at room temperature. The precipitated crystals will be sucked off and washed with acetone. (From this mother liquor, as described in the following example, the £ - Form). By recrystallizing the crystals obtained from a mixture of 250 ml of acetone and 285 ml absolute ethanol one obtains the d-1,2-diphenyl-3- (di-

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BATH ORIGINAL

methylaminomethyl) -3-buten-2-ol-D-tartrate, m.p. 142-145 °, [α] ^ ° = + 86 ° ± 1 ° (in water, c = 1 %).

50 g of dl / 2-diphenyl-3- (di ^me fc ^h ylarainomethyl) -3-buten-2-ol-D-tartrate are dissolved in 300 ml of water and mixed with 200 ml of 2-n. Sodium hydroxide solution is added and the mixture is extracted with ether. The ethereal solution is washed twice with water, dried and evaporated to dryness in a vacuum. The residue obtained is d-1,2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol from P. 79 - 84 °, [a] ^ ° = + 195 ° t 0.5 ° ( in chloroform, c = 2 %).

Example 4:

30 g of £ -l, 2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol are heated to 70 (bath temperature) for 5 hours with 200 ml of propionic anhydride. The excess propionic anhydride is evaporated in vacuo. The residue is dissolved in ethyl acetate and a solution of about 10 $ more than the calculated amount of maleic acid in acetone is added. Then the 2-1 * 2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene-maleate is precipitated in crystalline form by successive addition of ether. (128) I30-I32 ⁰ , La] ^ ⁰ = -32 ° ± 1 ° (in water, c = 2.05 ^).

The ^ -1,2-diphenyl-3- (dimethylaminomethyl) -3-butene-2-oil used as the starting material can be obtained e.g. as follows:

The acetone mother liquor from Example 3 is with a Solution of 15.0 g (0.1 mol) of D (+) tartaric acid in 400 ml of acetone. Rub in and leave to stand for 4 hours. the

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obtained crystals are suction filtered and treated with acetone

Wash 20 °. This gives a tartrate with an [a] _D of -26

to -36 (in water).

Tartrates obtained from various experiments with [α] from -26 to -36 are combined, dissolved in water, with 2-n. Sodium hydroxide solution precipitated the base and isolated it with ether. 79.4 g (0.282 mol) of the 1,2-diphenyl-3-

20 °

(dimethylaminomethyl) -3-buten-2-ol, which has an [α] ~ of approximately -92 (in chloroform) are dissolved in 300 ml of acetone and a solution of 21.0 g (0.14l mol) of D-tartaric acid in 400 ml of hot acetone is added. After 5 hours it is sucked off. 54 g of a product from P. 138-141 ° and [a] ^ are obtained -42 (in water) (the mother liquor, again mixed with 21.0 g of D-tartaric acid in 400 ml of acetone, gives a further 57 g of melting point 130-137 ° and [a] 2 °° = -i4 °).

The D-tartrate with [a] _D = -42 is made from a mixture

recrystalline from 250 ml acetone and 285 ml absolute ethanol

o Siert and provides a crystalline product melting at 139-145 ° and [a] _D =

-49 ° (in water).

Another recrystallization from a mixture of 250 ml of acetone and 200 ml of ethanol gives a product with a temperature of Ι4γ_ΐ49 ° and [a] S ° = -67 ° (in. Water). This tartrate is dissolved in water - with 2-n. Sodium hydroxide solution precipitates the base and this isolated using ether. The ethereal solution is washed twice with water, dried and the ether evaporated. This gives 6-1, 2-diphenyl-3- (dimethylaminomethyl) -3-buten-2-ol with a melting point of 79-80 °, [a] ^ ° = -201 ° + 0.5 ° (in chloroform , c = 2 %). 109826/1830 ORIGINAL BATHROOM

Example 5:

Tablets containing 30 mg of 1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene hydrochloride can, for example
can be produced in the following composition:

per tablet

1,2-Diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -J-butene hydrochloride

Colloidal silica Lactose sugar Wheat starch Cellulose powder Maranta starch Talk

Magnesium stearate

30.0 mg 3.0 mg 20.0 mg 10.0 mg 20.0 mg ΙΌ, Ο mg 6.0 mg 1.0 mg 100.0 mg

Manufacturing:

1,2-Diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene-hydrochloride, lactose, wheat starch and cellulose powder are mixed and this mixture with ethyl alcohol
well moistened. The colloidal silica is then added in small portions and kneaded until a plastic mass has formed. This mass is driven through a sieve with a mesh size of 4 - 5 mm and dried at 45. The dried granulate is passed through a sieve of 0.8 - 1.0 mm mesh

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beaten wide and mixed homogeneously with the explosives, lubricants and lubricants. The tablet mixture is on The usual way is compressed into tablets with a diameter of 6 mm and a gross weight of 100 mg.

Example 6:

Hard gelatine capsules containing 50 mg 1,2-diphenyl-2-propionyloxy-5- (dimethylaminomethyl) -J-butene hydrochloride can e.g. be produced in the following composition:

per capsule

1,2-diphenyl-2-propionyloxy -J5- (dimethylaminomethyl) -3-butene hydrochloride

Lactose Talc Colloidal Silica

30.0 mg 7 ^, 5 mg 5.0 mg 0.5 mg 110.0 mg

Manufacturing:

1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene hydrochloride is mixed homogeneously with the milk sugar, the talc and the colloidal silica. With With the help of a suitable capsule filling and sealing machine this capsule mixture is filled into size 4 hard gelatine capsules. The mean filling weight per capsule should be 110 mg be.

ORIGINAL BATHROOM 109826/1830

Claims (3)

Claims ": 1. A compound of the formula 0 -C CH ^ -CH- CH C CH ₂ N ^ CH and their salts. 2. d - (+) - 1,2-Diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene , l - (-) - l, 2-diphenyl-2-propionyloxy-j5- (dimethylaminomethyl) -3-butene and their salts. 3. Process for the preparation of 1,2-diphenyl-2-propionyloxy-3- (dimethylaminomethyl) -3-butene and its salts, characterized in that in 1,2-diphenyl-3- (dimethylamlnomethyl-3-buten-2-ol or introduces the propionic acid residue into a salt thereof in a manner known per se, and, if desired, optionally the resulting racemates are separated into the optical antipodes and / or converting obtained salts into the free base or converting the obtained free base into their salts. BAD ORIGIWt 109826/1830