DE2224596C3 - 2-cyanoalkyl-6,7-benzomorphane compounds - Google Patents

Description

CH-CH-C ₁₁ H ^ -CN

(IV)

II
CH = C-CN

IO

15th

in which R is a hydrogen atom, a hydroxyl group, a C ₁ - ^ - AlkOXy or an alkanoyl © xy radical with 1 to 8 carbon atoms, H _{1 is} a hydrogen atom, an unsubstituted or halogen atom, C, _ ₃ -alkyl, - alkoxy or alkylthio substituted phenyl group, a Trifluormethylpheiiylgruppe, a C ₁ _ ₅ alkyl group © of the radical (C _m H _{2m + p. 1)} - (R ₉₎ ,, represents j in which i is an integer? from 1 to 6, ρ denotes the number 1 or 2 and R ₉ denotes a C 1-6 alkoxy radical. R ₂ is a hydrogen atom or a C ₁ _ ₃ -AlkyIrest, R _3, unsubstituted or ₁ _ ₃ alkoxy substituted phenyl or C by a C ₁ _ ₃ alkyl radical, R represents a hydrogen atom ₄ represents a hydrogen atom or a hydroxyl or together with R ₃ an oxygen atom or a C ₁ _ ₃ alkylidene group, R ₅ represents a hydrogen atom or a C ₁ _, - representing alkyl. R ₆ denotes a hydrogen atom or a methyl group, R ₇ and R ₈ independently of one another represent hydrogen atoms or C ₁ _ ₂ -alkyl radicals and / 1 is an integer from 0 to 2, as well as their salts with acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that a 6,7-benzomorphan of the general formula II

40

R ₁

45

(II)

in which the radicals R to R _{h have} the meaning given in claim 1, either

a | in a manner known per se with a Nilril of the general formula III

Λ Cl I ₁ ,, CN

(III)

in which η has the Hedeu- f> o tunu mentioned in claim I and A has the resl of the general formula lilac

KR _s
X CH (Il

(111 al in which R ₇ and R _{8 have} the meaning given in claim 1, optionally in the presence of a solvent and a catalyst, at temperatures from room temperature to the boiling point of the solvent and the compound obtained is optionally converted into its salt with an acid.

3. Medicinal products with analgesic effects, containing a 2-cyanoalkyl-6,7-benzomorphane compound according to claim 1.

The invention relates to that in the claims
featured item.

Preference is given to 2-cyanoalkyl-6,7-benzomorphane compounds of the general formula I a

30th

35 C _x H _2x -CN

-N

(la)

wherein R is a hydrogen atom, a hydroxyl group, a C ₁ -. alkoxy or alkanoyloxy with up to 8 carbon atoms, R ₁ represents a hydrogen atom, a phenyl group or a C, _ ₅ represents -AlkyI-rest. R ₂ denotes a hydrogen atom or a C _{1-6 alkyl radical and χ represents an integer from 1} to 3, as well as their salts with acids.
The ones used as starting compounds

6,7-benzomorphanes of the general formula II are known and are obtained by demethylating the corresponding 2 - methyl - 6,7 - benzomorphane compounds. In US-PS 3138 603 is z. B. describes a process that proceeds according to the following scheme A:

R '

(Il BrCN
(2) HCI

Il

IK)

CH ₁

represents, in which K, and R _H in An where R 'denotes a melhoxy or acetoxy group.

The reaction of the 6,7-benzomorphane of the general formula 11 with the nitrile of the general formula UI is carried out in an inert solvent, L. B. in η-hexane, benzene, toluene, xylene, chloroform, dimethylformamide, methanol, ethanol 5 or isopropanol. The reaction is preferably carried out in the presence of a basic compound, e.g. B. in the presence of sodium or potassium carbonate, sodium or potassium bicarbonate. Sodium or potassium hydroxide, sodium amide, sodium unhydride, pyridine or triethylamine. The reaction temperature is from 20 to 200 ° C., preferably from 50 to 150 ° C. The reaction product can be separated off from the reaction mixture in a customary manner. z. B. by filtration or precipitation.

The reaction of the 6,7-benzomorphane of the general formula 11 with a nitrile of the general Formula IV is a new process and corresponds to eii> .er modified Michael addition. This is easy to do Process variant yields the 2-cyanoalkyliV-benzomorphane compounds of general formula 1 in excellent yields and high purity. The implementation is possibly in Presence of a suitable solvent. / B. of methanol, ethanol, ether, chloroform. Methylene chloride. Benzene. Toluene. Xylene or dimethylformamide. Furthermore, a catalyst be used, e.g. B. sodium methoxide. Sodium amide or potassium hydroxide. The reaction proceeds at temperatures from room temperature to the boiling point d;: s solvent.

For the preparation of the 2-cyanoalkyl-6.7-ben / oirorphan compounds of the general formula I. in which R is an alkanoyloxyresl, acylieri the corresponding I-cyanoalkyl-OJ-benzomorphane compounds. in which R represents a hydroxyl group, in a known manner. /. B. by Treat with an acid anhydride or an acid halide.

If R _{2 represents} an alkyl radical, the 2-cyanoalkyl-6-benzene / omorphane compounds of the general formula 1 are obtained in two stereoisomers. namely as a cis isomer (with R ₂ in the ./ configuration) and as a trans isomer (with R ₂ in the / «configuration).

These isomers can be separated in a known manner, e.g. B. by fractional crystallization, fractional distillation or column chromatography. Besides that, they can also do this be prepared that the corresponding cis or trans isomers of 6,7-benzomorphane of the general Formula II is reacted with a nitrile of the general formula III or IV. Each of the isomers also has asymmetric carbon atoms, so that four by conventional optical separation processes various optically active isomers are obtained. namely the (+) - cis-, (-) - cis-, (+ (-trans- and (- i-trans-lsomerc.

The 2-cyanoalkyl-6,7-benzomorphane compounds of the general formula 1 have a basic nitrogen atom in the molecular structure. and therefore form salts with acids. Such salts are obtained from Reaction with organic or inorganic acids such as formic acid, acetic acid. Propionic acid. Butyric acid. Malonic acid, fumaric acid. Succinic acid. Glutamic acid. Tartaric acid, oxalic acid. C'ilric acid c. Lactic acid. Maleic acid. Hydroxymaleic acid, glycolic acid, gluconic acid, glucuronic acid. S; icrh: irins; iure. Ascorbic acid. Phenylacetic acid. Benzoic acid, p-aminobenzoic acid, phthalic acid, salicylic acid. Anthranilic acid, p-hydroxybenzoic acid, p-aminosalicylic acid. Picolinic acid, 3-hydroxy-2-naphtholic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid. Quinic acid, tropic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. Hydroxyethanesulfonic acid, hydrofluoric acid. Hydrochloric acid. Hydrobromic acid, hydroiodic acid. Perchloric acid, nitric acid, sulfuric acid or phosphoric acid.

Benzomorphane compounds such as Phcnazocin and Pentazocin or that known from US Pat. No. 3,138,603 2'-hydroxy-2,5,9-trimelhyl-6,7-benzomorphine. are known to be effective analgesics. However, such benzomorphans are mostly addicting or cause narcotic symptoms at the usual dosage, e.g. B. Inability to move or Stupor, so that their uses are limited.

In contrast, the compounds according to the invention surprisingly have analgesic and analgesic effect. but without causing addiction.

Experimental results are given below.

A. Experimental procedure

1. Chronic administration of test compounds on rats

(viii. Folia Pharmacoloeica Japonica. Vol. 54 [1958] p. 120)

The Tesl connections are given to groups of twice a day for four consecutive weeks administered subcutaneously in each case to 20 male rats of the Wistar Slammes with a body weight of 150 g. The day after the F.nt / ug the test connection is the change in body weight definitely.

+ = slight weight loss. - = no weight loss.

2. Analgesic effects in mice

(cf. Folia Pharmacologica Japonica, Vol. 56 [I960], p. 83)

The test compounds are administered subcutaneously to a group of 100 mice from the ICR slam with a body weight of 20 to 25 g. These animals are then injected intrapcriloneally with 0.6% aqueous acetic acid. The pain / feeling expressed by bending and twisting of the abdomen is observed. At the same time, the behavior of control tables to which only 0.6% acetic acid was administered is observed. To evaluate the analgesic effect, the number of curvatures of the abdomen is determined within 12 minutes after the administration of acetic acid. The animals in the control group bend about 30 times. The test compounds are considered to be effective when the number of ^{writhes of the mice is decreased to 1} ', or even lower! can be. The KD ₅ ,, is calculated according to Litchfield-W i 1 c ο χ ο η.

3. Akulc toxicity in mice

The test compounds are administered subcutaneously to groups of 10 mice each from the ICR strain with a body weight of 20 to 25 g. The number of animals received is determined after 7 days. The LD _5n values are calculated according to L itchfi c 1 d - W i I c ο χ ο η.

B. Results

The results are summarized in the following table:

Table I.

Unicrsuchie connection

Chronic
Administration! of rough

(mi: ku Taul
while
4 weeks

Abslinence Syndrome

Analytical effect in M; iuscn

ED ₅₁ ,

(mg / kg)

Therapeutic Indes

2'-Hydroxy-2 - (/ f-cyanoethyl) -6,7-benzomorphane 2'-Hydroxy-2 - (/ i-cyanoethyl) -5-methyl- <fr, 7-benzomorphane

l'-Hydroxy-I-i / i-cyanäthyli-S ^ -dimclhyl- (, 7-benzomorphan

J'-Hydroxy-2 - (/ i-cyanoethyl) -5,9-diethyI-6,7-benzomorphane

6.7-benzomorphane

J'-Hydroxy-2- (γ-cyanopropyl) -5,9-dimethyl-6.7-benzomorphane

2'-Hydroxy-2 - (; - cyanopropyl) -5-methyl-9-ethyl-6,7-benzomorphane

2'-Hydroxy-2 - (- / - cyanopropyl) -5,9-diethyl-6,7-benzomorphane

6,7-benzomorphan

S-G'-cyanoethyU-S-methyl-oJ-benzomorphane i'-Hydroxy-2- (A-cyanobutyl) -5,9-dimethyl-6,7-ben / omorphane

2'-Hydroxy-3'-methyl-2 - (/; - eyanethyl) -5,9-dimethyl-6.7-benzomorphane

2'-Hydroxy-2 - (/; - cyanoethyl) -5-phenyl-6,7-benzomorphane

2'-Hydroxy-2 - (; - cyanopropyl) -5-phenyl-6,7-benzomorphane

2'-methoxy-2 - (; - cyanopropyl) -5,9-diethyl-6,7-ben / omorphane

2'-Hydroxy-2 - (,; - methyl- / i'-cyanoethyl) -5,9-dimethyl-6,7-ben / omorphane

2'-Hydroxy-2-methyl-5- (p-chloropiii: nyl) -6,7-benzomorphane (DT-AS 14 45 845) pentazocine

3.1 530 171.0 2.9 510 175.9 0.9 520 577.S 1.4 530 378.6 0.3 520 1 733.3 3.0 670 223.3 0.85 670 7SS.2 0.3 650 2 166.7 0.19 650 3 421.1 29.4 500 17.0 25.1 630 25.1 3.5 520 148.6 35.0 540 15.4 36.8 586 15.8 1.9 610 321.1 5.5 530 96.4 51.3 275 5.36 17.5 183 10.46

This table shows that 2'-Hydroxy-2-methyl-5- (p-chlorophynyl) -6,7-benzornorphan (geiTuiß DT-AS 14 45 845) causes absenteeism and physical dependence. Opposite occurs no absence syndrome in the compounds of the invention on.

In addition, the compounds of the invention consistently have higher analgesic activity and activity a lower acute toxicity than the comparative compound according to Dl-AS 14 45 845. The therapeutic Index entrusted this connection 5.36.

while the corresponding values of the compounds the invention are much higher. 60 The following examples explain the invention.

example 1

₆ 2'-hydroxy-2 - (/; - cyanoethyl) -5,9-dimethyl-

6,7-bcnzomorphan

A mixture of 1.1 g of 2'-hydroxy-5.9-dimethyl-6.7-ben7omorphan. 0.5 g sodium bicarbonal. 0.42 g

/ i'-Chlorpropionilril and 20 ml of dimethylformamide is stirred at 120 to 160 ° C. for 4 hours. The precipitate obtained is filtered off, the fillral is concentrated under reduced pressure to remove dimethylformamide / u, and then water is added. The precipitate obtained in this way is converted from methanol to 2'-hydroxy-2- (,; - cyanatliyl) -5.9-dimethyl-6.7-ben / omorphane. F. 165.5 C. recrystallized.

IR

2640, 2240, 1610, 15S0. 1495. 1240.

Analysis C ₁ -H ₂₂ N ₂ O:

Calculated ... C 75.52.
found .... ("75.40.

Il 8.20.
H 8.13.

N 10.36:
N 10.31.

IS

B c i s ρ i e 1 2

2'-Hydroxy-2 - (; - cyanopropyl) -5,9-dimethyl-6.7-bcn / omorphane

A mixture of 1.1 g of 2'-hydroxy-5.9-dimethyl-6,7-benzomorphane. 0.5g sodium bicarbonate and 20ml Dimethylformamide is mixed with 0.52 g of chlorobutyronitrile added and then stirred at 120 to 160 ° C. for 4.5 hours. Then the solvent distilled off under reduced pressure and water is added to the residue. The resulting mixture is extracted with ether, the extract is washed, dried over sodium sulfate and filtered. When the filtrate is concentrated to dryness, 2'-hydroxy - 2 - (; · - cyanopropyl) - 5,9 - dimethyl - 6.7 - benzomorphane obtained as a viscous liquid wedge.

IR

k.ip.l

: 2250, 1670 (weak). 1613, 15S5. 1500.

35

DSC (silica gel) R _f -Wcrt: 0.55 (acetone).

Example 3

2'-acetoxy-2 - (; - cyanpiOpyl) -5.9-dimethyl-

6, ⁷ -benzomorphan

A mixture of 1.2 g of 2'-hydroxy-2 - (; - cyanpropyll - 5.9 - dimethyl - 6.7 - benzomorphane hydrochloride. 0.31 g of anhydrous sodium acetate and 10 ml of acetic anhydride is stirred for 1 hour at 100 to 120 ° C., cooled and poured into ice water The mixture obtained is made alkaline with 50% aqueous potassium hydroxide solution while cooling with ice and the base released is quickly extracted with ether. The ether extract is washed, dried and filtered. 1.25 g of 2'-acetoxy-2- ( - / - cyanpropyl) -5.9-dimc- so thyI-6,7-benzomorphan obtained as a yellow liquid.

IR

kapiH

: 2240,1760,1637,1605,1 580. 1 495. 1 2 10.

Example 4

2'-Hydroxy-2 - (; - cyanopropyl) -5-methyl-9-ethyl-6,7-benzomorphane

A mixture of 0.58 g of 2'-hydroxy-5-methyl-9-ethyl-6,7-benzomorphane, 0.32 g of sodium bicarbonate and 15 ml of dimethylformamide are mixed with 0.28 g of chlorobutyronitrile and the mixture is refluxed for 4 hours cooked. The precipitate obtained is filtered off, the filtrate is concentrated under reduced pressure, to remove the solvent, and then treated with water. The resulting precipitate becomes 2'-Hydroxy-2 - (; <- cyanopropyl) - from ethyl acetate

5-methyl-9-ethyl-6.7-ben / omorphan. F. 154 to 157 "C, recrystallized.

IR

2640, 2230, 1611, 1573, 1496, 923, 790.

Analysis C _W H _{2 (} , N _: O:

Calculated ... C 76.47. H 8.78. N 9.39;
found .... C 76.73. H 8.96, N 9.19.

Example 5

2-hydroxy-2- ( ₁ cyanbutyl) -5.9-dimethyl-6,7-benzomorphane

A mixture of 1.0 g of 2'-hydroxy-5.9-dimethyl-6,7-benzomorphan. 0.58 g of sodium bicarbonal, 0.59 g of chlorovalcronitrile and 15 ml of dimethylformamide are refluxed for 4 hours. The precipitate obtained is filtered off, the filtrate is concentrated under reduced pressure and the residue obtained is mixed with water '-Hydroxy-2- (rVcyanbutyl) -5,9-dimethyl-6.7-benzomorphane, m.p. 158 to 16 IC, recrystallized.

IR η. ", ',,,,,,,. 2600, 2225, 1610, 1575, 1495, 1270, 860, 802.775.

Analysis C _1Q H ₂ "N ₂ O:

Calculated ... C 76.47, H 8.78, N 9.39:
found C, 76.31. H 8.79. N 9.21.

Example 6
2 - (,; - cyanoethyl) -5-methyl-6,7-benzomorphane

A solution of 1.0 g of S-methyl-o ^ -bcnz.omorphan 20 ml of acrylonitrile are added dropwise to 20 ml of anhydrous ether at room temperature. The received The mixture is refluxed for 20 minutes and concentrated to dryness, with a brown oil of 2- (/> '- cyanoethyl) -5-methyl-6,7-benzomorphan remains behind. The free base is obtained by treating with a solution of hydrochloric acid converted in methanol into the hydrochloride, which is converted from acetone-methanol to 2- (f »-Cyanathyl) -5-methyl-6,7-benzomorphan. F. 213.5 to 215.0 "C" is recrystallized.

IR ^, _Jtlln : 2420.2240.
Analysis C ₁₁₁ H ₂₁ N ₂ Cl:

Calculated ... C 69.42. H 7.64. N 10.12. Cl 12.81: found .... C 69.72. H 7.73. N 10.10. Cl 12.61.

Example 7
2 - (/ i-cyanoethyl) -5,9-dimethyl-6,7-benz.omorphan

A mixture of 2.01 g of S ^ -dimethyl-öJ-bcnzo- morphan. 40 ml of anhydrous ether and 0.55 g of acrylonitrile are refluxed for 1 hour and then concentrated to a yellow residue, which is distilled under reduced pressure. Here at 1.6 g of 2- (/ <- cyanoethyl) -5,9-dimethyl-6,7-bcn-zomnrphane. 150-155 ° /0.28 torr.

IR - Cp ₁₁₁ : 2230, 1490.

A solution of the compound obtained in ether

is treated with hydrogen chloride gas, whereby a solid forms, which abfiltricit and with ether is washed by recrystallization from Accton-

Mclhanol becomes 2- (/ i-cyanoethyl) -5,9-dimethyl-6,7-bcn-

/ omorphan hydrochloride. I- '. 23N to 24 (1 C "(under Decomposition).

IR ri ™; " _m : 2550, 2240, 965, 763, 750, 722.
Analysis C ₁₇ H ₂₁ N ₂ Cl:

Calculated ... C 70.20. H 7.97. N 9.63. Cl 12.19:
found .... C 70.32. H 7.95. N 9.84-Cl 12.34.

Example p

2 '-! Hydroxy-2 - (,; - cyanoether) -5-methyl-6.7-beri7omorphan

A solution of 1.02 g of 2'-hydroxy-5-methyl-6,7-benzomorphan in 20 ml of methanol is mixed with 10 ml Acrylonitrile added. The resulting mixture is stirred at room temperature for 2 hours and then concentrated to dryness. The crude product obtained is converted from ethyl acetate to 2'-hydroxy-2 - (, -, '- cyanälhyl) -5-methyl-6,7-benzomorphane. F. 161 to 163 C (prisms), recrystallized.

IR

2600.2240. 1610.15S0. 1500.

'Paraffin

Analysis C ₁₆ H ₂₀ N ₂ O:

Calculated ... C 74.96. H 7.86. N 10.93:
found .... C 74.66. H 7.95. N 10.98.

Example 9

2'-Acctoxy-2 - (,; - cyanoethyl) -5.9-dimethyl-6.7-benzomorphane

A mixture of 1.0 g of 2'-Hydro \ y-2 - (, -'-cyanoethyl) -5,9-dimethyl-6,7-benzomorphan and 10 ml of acetic anhydride is stirred for 1 hour at 100 to 110 C, then drained off and poured into ice water. Subsequently the mixture is made alkaline with 50 "oigcr aqueous potassium hydroxide solution while cooling with ice, and quickly with it Ether extracted. The elder extract is washed with saturated aqueous sodium chloride solution over sodium sulfate dried and filtered. The filiral obtained is concentrated to dryness, with 2'-aceloxy-2 - (,; - cyanoethyl) -5.9-dimethyl-6.7-benzomorphan as a yellow liquid wedge.

IR γ, '; _{γ | 1 |} : 225O. 1755, 1620, 1580, 1492, 1375, 1010, 942.

According to Example 1, the following compounds are made:

2 '- hydroxy - 2 - (; · - cyanopropyl) - 5 - phenyl-

6.7-ben / omorphan. J- ". 205 to 208 C:

2 - (■ · - Cyanopropyl) - 6.7 - benzomorphane - Imlro-

chlond. F.> 240 "C:

2 '- Hydroxy - 2 - (; · - cyanopropyl) - 5 - methyl-6,7-benzomorphane. F. I3S to 140 C:

2 '- Hydroxy - 3' - methyl - 2 - (,: - cyanäihyll-5.9-dimethyl-6.7-benzomorphan: F. 115 to 120 C and

2 '- Hydroxy - 2 - (/.' - cyanoethyl) - 5 - phenyl-6.7-benzomorphane. F. 108 to I 12 C.

According to Example 8, the following compounds are made:

2 '- Hydroxy - 2 - (, ·; - cyanoethyl) - 5 - niellnl-9-ethvi-6.7-bcnzomorphan. F. 124 to 130 C:
2 '- Hydroxy - 2 - (,; - cyanoethyl) - 5 - ethyl - 9 - mcthvl-6.7-bcnzoniorphan. F. 153 to 155 C and
2 '- Hydroxy - 2 - (,; - cyanoethyl) - 5.9 - diethyl-6.7-benzomorphane. F. 131 to 135 C.

Claims (1)

Patent claims: 1. 2-cyanoalkyl-6,7-benzomorphane compounds of the general formula I. Claim 1 have the meaning mentioned and X is a halogen atom, ^{reacts or at temperatures of 20 to 200 0} C in the presence of an inert solvent
b) with a nitrile of the general formula IV