DE2166503C3 - 2-Benzoyläthylbenzomorphane, process for their preparation and pharmaceuticals - Google Patents

Description

characterized in that a benzomorphane of the general formula II

N-H

(II)

in which R, Ri and R _{2 have} the meaning given in claim 1, with a compound of the general formula III

^ s— r - ph ri-r

in which R _{3 has} the meaning given in claim 1, X is a halogen atom and Y is an oxygen atom or an ethylenedioxy group, condensed and, if Y is the ethylenedioxy group, the resulting ethylene ketal of the general formula IV

_χ N-CH ₂ -CH ₂ -C ^ f Λ

> ^R >> / nSX

f ' ο ο

(IV)

CH ₂ CH ₂

in which R, Ri, R ₂ and R _{3 have} the meaning given in claim 1, hydrolytically cleaved and, if appropriate, the product obtained is converted into a salt by reaction with an inorganic or organic acid.

11. Medicament, characterized by a content of a compound according to claim 1 and customary carriers and / or diluents.

Analgesics of the benzomorphan group are known. The therapeutically most important representative of this class of compounds, Phenazocin has an extremely high analgesic potency in animal experiments, however, studies have shown that the "addictive capacity" of this compound is in line with the high analgesic intensity of action. The depressive effects of phenazocin on respiratory function is at least as great as that of an equianalgesic dose of morphine; see Ehrhart and Ruschig, "Medicines", Vol. 1, pages 342 to 348, Verlag Chemie, 1968, as well as z. B. Belgian patent specification 6 11 000.

The object of the invention is to provide new 2-BenzoyläthyI-Denzomorphane with analgesic properties to create the disadvantages of the known benzomorphans do not exhibit. This object is achieved by the invention.

The invention thus relates to 2-benzoylethylbenzomorphanes of the general formula I.

N-CH ₃ -CH ₂ -C - / ^ (I)

in which pure denotes a hydrogen atom or a hydroxyl group. Ri and R ₂ hydrogen atoms or Ci _ ₃ -alkyl

represent radicals, Rj is a halogen atom or a Ci -3-alkoxy radical means, and their salts with acids.

The invention also relates to a process for the preparation of the 2-Benzoy! ÄthyIbenzomorphane general formula I, which is characterized in that a benzomorphane of the general formula II

R.

in which R, Ri and R _{2 have} the above meaning, with a compound of the general formula III

C-CH ₂ -CH ₂ -X (III)

in which R _{3 has} the meaning given in claim 1, X is a halogen atom and Y is an oxygen atom or an ethylenedioxy group, condenses and, if Y is the ethylenedioxy group, the resulting ethylene ketal of the general formula IV

-N-CH ₂ -CH ₂ -C ^ f

(IV)

CH ₂

in which R, Ri, R2 and R _{3 have} the meaning given in claim 1, cleave hydrolytically and, if appropriate, convert the product obtained into a salt by reaction with an inorganic or organic acid

The reaction of the benzomorphane of the general formula II with the compound of the general formula III is usually carried out in an inert organic solvent such as η-hexane, benzene, toluene, xylene, chloroform, dimethylformamide, methanol, ethanol or isopropanol. The reaction is preferably carried out in the presence of a base such as sodium carbonate, potassium carbonate, NatriumbLarbonat, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, Nairiumhydrid, pyridine or triethylamine, performed The reaction can be carried out at temperatures of 20 to 200 ⁰ C, preferably 60 to 150 ⁰ C is performed. The The reaction product is isolated in the customary manner

If Y is the ethylene dioxy group, the corresponding ethylene ketal of 2-benzoylalkylbenzomorphans must be used of the general formula IV are cleaved hydrolytically. The hydrolysis takes place according to the usual Methods with an acid. The hydrolysis is preferably carried out in a solvent such as water, an alcohol such as methanol, ethanol, propanol, isopropanol or butanol, and preferably with Temperatures from room temperature to the boiling point of the solvent used carried out. Catalytic amounts of acid are necessary for hydrolysis. Examples of acids that can be used are Mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or organic acids such as acetic acid. The reaction is usually complete in about 30 minutes to 2 hours.

The 2-Benzoyläthylbenzomorphane are used to prepare the salts of the general formula I by customary methods with an organic or inorganic Acid, such as formic acid, acetic acid, butyric acid, malic acid, fumaric acid, succinic acid, glutamic acid, Tartaric acid, oxalic acid, citric acid, lactic acid, glycolic acid, gluconic acid, glucuronic acid, saccharic acid, Ascorbic acid, benzoic acid, phthalic acid, salicylic acid, glyceric acid, anthranilic acid, cholic acid, picolinic acid, Picric acid, tropic acid, indole acetic acid, barbituric acid

re, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, Benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid

The 2-Benzoyläthylbenzomorphane of the general formula I, in which R _{2 represents} a Ci-3-Alkylrest, come in the cis configuration (R ₂ = Λ form) and in the trans configuration (R ₂ = j5 form) . These two diastereoisomers can be separated from one another and purified by customary fractional crystallization, fractional distillation or column chromatography.

Each of these diastereoisomers can also be obtained by condensation of the corresponding cis- or trans-benzomorphane of the general formula II prepared with the compound of the general formula III will.

Each of these diastereoisomers has asymmetric carbon atoms, so that there are four different ones optically active 2-Benzoyläthylbenzomorphane of the general formula I by customary methods for cleavage of optical isomers, namely the (+) -cis-, (-) -cis-, (+) -trans- and (-) -trans-forms.

The benzomorphanes of the general formula II used in the process according to the invention are selected from the corresponding 2-methyl-6,7-benzomorphane derivatives prepared by demethylation.

The 2-benzoylethylbenzomorphanes which can be prepared according to the invention and their salts with acids are Valuable analgesics with a calming effect which, surprisingly, showed no tendency in animal experiments Show addiction.

Known 6,7-benzomorphans such as 2'-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (see US Pat. No. 3,138,603) have a strong analgesic effect, however, tendency towards addiction. Therefore, these compounds are limited in their applicability. at the subcutaneous administration of compounds of the invention to 150 g male rats from Wistar strain (20 animals per group) no dependence on test compounds was observed.

The 2-Benzoyläthylbenzomorphane of the general formula I have a mild to strong analgesic Effect on curvature syndrome test. Some of them are more analgesic than pentazocine. At the

55

60

65

Curvature syndrome test is given intraperitoneally to mice Injected 0.6 percent aqueous acetic acid. The syndrome is due to intermittent contraction of the Abdomen, torsion and curvature of the trunk and stretching of the hind legs marked for each Dose a group of 5 mice was used. the

Table I.

Compounds were made 20 minutes before the injection Acetic acid injected subcutaneously. The number of mice that showed no pain response was recorded. the EDm was calculated using the Litchfield and Wilcoxon method. In Table I are the results compiled.

Test connection Curvature syn dromtest ED50, mg / kg, s. c. mouse ff-2'-hydroxy-2 - [/? - (p-fluoro- 15.0 benzoyl) ethyl] -5,9-dimethyl- 6,7-benzomorphan 2'-hydroxy-2 - [/? - (p-fluorobenzoyl) - 7.0 ethyl] -6,7-benzomorphane ff-2'-hydroxy-2 - [/? - (p-methoxy- 7.0 ben7oyI) ethyl] -5,9-dimethyI- 6,7-benzomine nphap 2- [HP-Fl ^uo rt> ^enz oyl) -n-propyl] - 6.0 5-methyl-6,7-denzomorphan Pentazocine [2'-hydroxy-2- 17.5 (3 ", 3" -dimethylallyl) -5,9-dimethyl- 6,7-benzomorphane]

Comparative experiment

The 2-benzoylalkylbenzomorphanes according to the invention are with the from J. Org. Chem., 24, 116 (1959), known comparable compounds with regard to toxicity, addiction and analgesic effectiveness compared in the curvature syndrome test. The results are summarized in Table II below As can be seen from Table II, the compounds of the invention, in comparison with the known test compounds, only slightly improved toxicity and addiction values. Against it there is a greatly improved analgesic effectiveness compared to the comparison substances. as Experimental animals in the abstinence syndrome test were used Wistar rats; likewise with the determination the LDso values. To determine the analgesic effect in the curvature syndrome test, as in used in the experiment summarized in Table I, mice.

Table 11

Test connection Curvature syn LD ₅₀ , dose Abstinence- dromtest, EDj ₀ , mg / kg, s. c. (mg / kg, s. c. syndrome mg / kg, s. c, mouse meets while 4 weeks)

> 270 20th > 27O 20th > 270 20th > 250 20th

ff-2'-Hydroxy-2 - [/ Hp-fluorobenzoyl) ethyl] - 15.0

5,9-dimethyl-6,7-benzomorphane

2'-hydroxy-2-fjo- (p-fluorobenzoyl) ethyl] - 7.0

6,7-benzomorphan

ff-2'-hydroxy-2-fj? - (p-methoxybenzoyl) ethyl] - 7.0

5,9-dimethyl-6,7-benzomorphane

2- (3-Oxo-3-phenylpropyl) -5,9-dimethyl-> 40

6,7-benzomorphan (J.Org. Chem., Vol. 24 (1959),
P. 116; Verb. Lic)

2'-hydroxy-5,9-dimethyl-2- (3-oxo-3-phenyl-> 40

propyl) -6,7-benzomorphane (J. Org. Chem., Vol. 24
(1959), p. 116; Verb. Lld)

± = ambiguous result that lies between the evaluation + and -.

Some compounds of the invention have a strong 65 hotplate test and Hoffner's method. the

analgesic effect not only in the curvature syn- Compounds du · invention also have a mild one

dromtest, but also in other experiments with a calming effect, sometimes the analgesic

Determination of the ardgesic effect, as potentiated the effect in the anti-apomorphine test.

> 25O

The connections of the finding / own in the Gcgcn-Siil / to iinderen morphine and b.7-Hen / oiiiorplu; i! Derivatives do not have any unfavorable side effects, such as rigor. Ahme. Cramps, nausea and respiratory depression.

In contrast, the connections of the noise a strong local anesthetic effect in relation to morphine and its well-known bacteria.

The valuable properties of the 2-en / oylalkylhyn- / omorphane the general I ormel I are based on the 2-benzoylethyl rope chain. These properties are neither with morphine nor with other b.7Ben / omorphancn to find.

The compounds of the invention can be prepared in the form of their salts in sterile water or an equivalent amount in a pharmacologically acceptable sense, if the free rabbit is used, or in a physiologically acceptable aqueous medium, such as physiological saline. dissolved, and filled into ampoules oxv-1 chloropropane is added and the mixture is increased to 30 to 150 hours and stirred. The precipitate formed is filtered off. The filtrate is evaporated and water is added to the residue. Diethyl ether is added to the mixture extracted and the combined ether extracts evaporated to dryness, leaving the stated product as an oil.

2.2 2'-llydroxy-2 [/i-(p-fluorobenzene/oyl) ethyl] -b.7-ben/omorphane

Line solution of 1.05 g of the obtained according to 2.1 Compound in 5 ml of methanol. 2.5 ml of water and 0.5 ml of concentrated hydrochloric acid are heated to 82 to 97 ( heated / l and stirred, then with 0.03 g of decolorizing charcoal treated and filtered. The l'illral is evaporated that The residue was made alkaline with aqueous ammonia solution and extracted with diethyl ether. The unite th ether extracts are evaporated, and the

in dosage units from 1 to 15 mg / in total mil other common excipients. how (Aleium carbonate. Strong. Milk / sugar, lalkiim. Magnesium stearal or (iiimmiarabictim, to! derive or Capsules / processed for oral administration

I! e i s ρ i e I I

\ -2 I l \ dro \ v-2 - [, f- (p-fliiorben / osl) aihvl)
5.4 (Iimeths 1-6,7-ben / omorphati

Line solution of 4.0 g \ 2 I Kdrow 5.4dimelhvl -h.7-ben / omorphan in 4 ¹ dimethylformamide is JMI nut 2:52 g Natriiimbicarbonal and a solution son 4.h / g of 3- (p I luorphenyl) 3.3 älhvlendioxv 1 - chloropropane in 20 ml of dimethylformamide was added and the mixture was refluxed and stirred for 7 hours. Film off the formed lalliing and the filtrate evaporated to dryness. Is left behind \ 2 I lydmxv -2- [3 (p-fluoiphcnvl) 3 ".3" -ätlnlcndioxy-n propyl] -5.4 dimelhvl b.7 hcn / omorphan as a brown oil.

In a mixture of 8.5 g of the compound obtained in KO ml of methanol. 40 ml of water and 15 ml of kou / cnl of hydrochloric acid are refluxed for 1 hour. The reaction mixture is then evaporated under reduced pressure and the residue The solution is extracted with dietary ether, the combined ether extracts are washed with water, dried over sodium sulfate and evaporated. A crude oil is added, i.e. the dietary ether and ethyl acetate are replaced after standing In the refrigerator a crystalline Läili ¹ ";:. is formed which is recrystallized from Aihvlacelal. The specified product of I".

IR absorption ri ··· ■ !! «

2650, 2580, 1685, 1620. IhOO. 1 183

Example 2

2-1 hydroxy-2 - [, i- (p-fluorobenzene / oyl) ethyl]
b.7-ben / oniorphan

2.1 2 -If \ drox \ -2- [3 (p-fluorophenvl)
3.3 "-al hy lendioxy al hy lbinyl] -b.7-ben / omorphan

[■ in Ciemiseh from 0.45 g of 2'-hydroxy-b.7 hen / omorphan. 0.3 g sodium bicarbonate and 10 ml dimetiu llormamid becomes with O.b4 g 3- (p-F "kiorphenyl) -3.3-äth \ lendidas specified product from I. 155 to I 54 C.

IR absorption ri "',, n ...

2675, 2540, 1685, 1618, 1546, 1448.

H e i s ρ i e I 3

2-Uip I luorben / oyl) ethylJ-5-methvl-6.7-henzomorphan

3.1 2 (3 - (p-Lluorophenvl) 3 ".3" -äthylendio \ v n-prop \ l] -5-methyl-b.7 benzoniorphane

A mixture of 1.87 g of 5-methylb.7-benzomorphane. 1.0g sodium bicarbonate. 2.45g 3 (p-l luorphenvl) 3.3 äthvlendioxvl chlorpropane and 20 ml of dimethylformamide is eihilzt for 4 hours at 110 to 145 C and touched. The mixture is then strongly concentrated under reduced pressure, and water is added. That (The mixture is extracted several times with benzene, the combined Hen / olexlrakle are washed with water see, dried over sodium sulfate and evaporated under reduced pressure. You get that specified product as a viscous liquid wedge.

IR absorption v '··

154 3. 1500.830. 753. 71b.

3.2 2- [,! - (p-l'luorben / oy I) -Ut hyl Jo-met hy I-h.7 ben / omorphan

I in (iemisch from 3.b g of the compound obtained according to 3.1. 40 ml of methanol and 15 ml of water i rd with 5 ml of concentrated hydrochloric acid are added. Heated under reflux for 1 hour, then treated with I ntfärbiingskohle and filtered. The lillrate is evaporated under reduced pressure, the residue with aqueous Ammonia solution made alkaline and made with diehlormcthan extracted. The extract is washed with water, dried over sodium sulfate and evaporated. The residue is distilled under reduced pressure.

The free base, dissolved in diethyl ether, is with brought anhydrous hydrogen chloride gas to the reaction. The Hydrochloric) is made from a mixture of Recrystallized acetone and methanol: L. 177 to 178 C.

2430. 167b. 1545. 1221. 1052.801.762.717.

I! c i s ρ ι e I 4

\ 2 I hydroxy-2 [ _t S (p-melhoxyben / oyl) -alhyi] - ">, 4-dimethyl b.7 ben / omorphan

4.1 \ l '- \ lyilrcixy-2 [3 "(p-melho \\ phenyl) -

) ". J" äthylendiow -n-pr <ip> I) - 5,4-dime thy I-

fij-benzomorphan

liin mixture of 2.17 j; 2'-I lydnny -5.4-dimethyl -b.7-benzomorphane, 0.5 g sodium bicarbonate. 2.b7 g of 3 (p-methoxyphenyl) -i.3 ailylenedioxy1 -ehliirpropane and \ ^r > ml of dimethylformamide becomes J ¹ /. 'Stunili'ii on 1 30 to 15 ¹ JC eihii / t and gcriihrl. The lallung formed is filtered off and the l-'ilirai evaporated under reduced pressure. The residue is mixed with water and extracted with diethyl ether. The combined Älherxtraktc are dried over sodium sulfate and evaporated. Ils! Does not include the specified rrotiuki from the r. i65 to ib'- 't C.

IK absorption ri · "'. Η ,,,

2W0. IhO 3. 1578. I IHO. 7 ^ 5.

4.2 \ -2'-Hydroxy-2 [, / - (p-meihoxyben / oyl) -iitliyl] -i.'i-diniethyl-b. / Ben / omorphan

i-in (iemisch from 1.7 g of the compound prepared according to 4.1. 8 ml of methanol. 4 ml of water and 0.8 ml of concentrated hydrochloric acid is heated to 79 to 81 ° C for 1 hour and stirred. Then the (iemisch with 0.0 " The filtrate is evaporated under reduced pressure, the residue is made alkaline with aqueous ammonia solution and extracted with dietary ether. The combined ether extracts are evaporated to dryness. The residue is obtained from a mixture of methanol and Allyl acetate recrystallized. The product melts at 172 to 17 ° C.

I R- absorption i »I **". Riim

Claims (10)

Claims: 1. 2-Benzoylethylbenzomorphane of the general formula I. in which R denotes a hydrogen atom or a hydroxyl group, Ri and R2 _{denote hydrogen atoms or Ci _ 3} -alkyl radicals, R ₃ denotes a halogen atom or a Ci-3-alkoxy radical, and their salts with acids. 2.2'-Hydroxy-2- [b- (p-fluorobenzoyl) ethyl] -5,9-dimethyl-6,7-benzomorphane. 3.2'-Hydroxy-2-rjJ- (p-fluorobenzoyl) ethyl] -6,7-benzomorphane. 4.2'-Hydroxy-2-rjJ- (p-methoxybenzoyl) -ethyI] -S ^ -dimethyl-6J-benzornorphane. 5.2'-Hydroxy-2-fJ? - (p-fluorobenzoyl) ethyl] -5-methyl-6,7-benzomorphane. 6.2'-Hydroxy-2-rjJ- (p-methoxybenzoyl) ethyl] -5-methyl-6,7-benzomorphane. 7.2'-Hydroxy-2 - [^ - (p-methoxybenzoyl) ethyl] -6,7-benzomorphane. 8.2 'Hydroxy-2- [0- (p-fluorobenzoyI) -ethyl] -9-methyl-6,7-benzomorphane. 9.2'-Hydroxy-2-fJJ- (p-methoxybenzoyl) ethyl] -9-methyl-6,7-benzomorphane. 10. Process for the preparation of 2-Benzoyläthylbenzomorphane according to claim 1 and its salts, (D