DE1518959B1 - Process for the preparation of basic substituted cyclohexenes - Google Patents

Description

The present invention relates to a new process for the preparation of basic substituted Cyclohexenes of the general formula Formation of the surprisingly stable adducts of general formula III:

Ki iV>

wherein R ₁ and R ₂ , which can be the same or different, a lower alkyl radical or two alkylene radicals linked to one another to form a heterocyclic ring and R ₃ denotes a methyl, ethyl, n-propyl and n-butyl group, which consists of that at room temperature or slightly elevated temperatures butadiene- (1,3) of the general formula

QH ₅ COOR ₃

Il +

CH ₂

CH

CH CH

CH ₂ II

/ ^N

- CH = CH - CH = CH ₂

.QH ₅

COOR,

with an atropic acid ester of the general formula

QH ₅ \ COOR ₃ C.
H Il
CH ₂ : one Solvent

be reacted in the absence of a solvent.

The preparation according to the invention of these substituted cyclohexenes takes place after a reaction which in principle follows the diene synthesis according to D i e 1 s and Aider, but according to the previous one State of the art can neither be assumed nor interpreted.

With atropic acid esters of the general formula I as the ene component, no diene synthesis has yet been possible be carried out with success. According to current knowledge of the mechanism of the Diene synthesis, this negative result is in line with expectations, since this mode of reaction of all activating groups, the carboxylic acid esters have proven to be the most inactive (See, for example, "Organic Reactions, Vol. IV [1948], p. 71" and "Chem. Ber., Vol. 97 [1964], p. 3183"). In addition, 1,1-disubstituted ethylenes are known per se to be poor dienophilic reactants (See, for example, "Chem. Reviews, Vol. 61 [1961], p. 540"). By the meeting of these two The fact that atropic acid esters in Diels-Alder reactions has been explained so far as unfavorable properties fail.

Therefore, it is completely unexpected within a few hours at room temperature in high Yield progressing addition of atropic acid esters of the general formula I to the unstable ones 1-Amino-butadienes of the general formula II under To keep the reaction under control, it is necessary to cool at the beginning of the implementation. The.

The reaction takes place without a solvent. If one dissolves the components in the solvents customary for carrying out a diene synthesis, such as benzene, toluene or ether, then - quite in contrast to the normal diene reactions - the polymerization of the aminobutadienes of the general formula II comes to the fore, and the Yields of the compounds of the general formula III decrease. The compounds obtained according to the invention are strong analgesics of comparatively low toxicity. The compound 3 t-dimethylamino-4-phenyl-4t-carbethoxy-zl ¹ -cyclohexene hydrochloride is free of intestinal and respiratory paralyzing side effects in contrast to all commercially available strong analgesics.

The following examples illustrate the invention.

example 1

S-Dimethylamino ^ -phenyM-carbethoxy-J ^ cyclohexene

In a 1-1 round bottom flask, 194 g (2 mol) of freshly distilled 1-dimethylamino-butadiene- (1.3) are combined with 352 g (2 mol) of atropic acid ethyl ester at room temperature. After stirring for about 10 minutes, the reaction mixture begins to warm increasingly. By cooling with ice water, the temperature of the flask contents at 40 is maintained to 6O ⁰ C. After the reaction has subsided, the mixture is allowed to stand overnight at room temperature.

The next day the viscous product is dissolved in 101 ether and with ethereal hydrogen chloride precipitated as hydrochloride. The yield of the crude product is practically quantitative. Through fractional crystallization from ethyl acetate — methyl ethyl ketone (10: 1) is an almost complete separation in two cis / trans isomeric products 1A and 1B are achieved. The separation is particularly good due to the low solubility of the 172 hydrate of IA through-

manageable. In the course of the separation, the _{amount of water necessary for the formation of the IV 2} hydrate of IA is therefore added to the solvent mixture. 1A: 3c-dimethylamino-4-phenyl-4c-carbäthoxyj'-cyclohexene hydrochloride l '/ ₂ H ₂ O, mp = 84 ° C, Kp.o.oi (the base) = "97.5 to 98 ° C, yield 64.4%.

Analysis for C ₁₇ H ₂₇ ClNO ₃₅ .

Calculated ... C 60.61, Ή 8.18, N 4.16, Cl 10.53%; Found ... C 60.85, H 7.97, N 4.44, Cl 10.27%.

IB. 3t- dimethylamino - 4 - phenyl - 4t - carbäthoxyl'-cyclohexen-hydrochloride, mp = 159 ° C, bp _{o Ol} (the base) = 95.5 to 96 ° C, yield .22,2%.

Analysis for C ₁₇ H ₂₄ ClNO ₂ .

Calculated ... C65.89, H7.81, N4.52, Cl 11.45%; ' ⁵ found .... C 65.65, H 7.65, N 4.38, Cl 11.52%.

Total yield of analytically pure product (1A + 1 B): 86.6% of theory.

20th

Example 2

3-diethylamino-4-phenyl-4-carbethoxyl'-cyclohexene

250 g (2 MqI) freshly distilled 1-diethylaminobutadiene (l, 3) are reacted analogously to Example 1 with 352 g (2 mol) of ethyl atropate. Yield: 70% of theory.

2A: 3c-diethylamino-4-phenyl-4c-carbäthoxyj'-cyclohexene hydrochloride, F. = 147 ° C (from ethyl acetate / isopropanol).

Analysis for C ₁₉ H ₂₈ ClNO ₂ .

Calculated ... C 67.53, H 8.34, N 4.15, Cl 10.50%; found .... C 67.13, H 8.15, N 4.37, Cl 10.52%.

Isolation of 2 B was omitted because of its low content (<10%) in the reaction product.

35

40 Example 3

3-N-piperidino-4-phenyl-4-carbethoxy-J ^ cyclohexene

274 g (2 mol) of l-N-piperidino-butadiene (2,3) are analogous with 352 g (2 mol) of ethyl atropate Example 1 implemented. Yield: 72% of theory.

3 A: 3 c - N - piperidino - 4 - phenyl - 4c - carbäthoxy-J ^ cyclohexene hydrochloride, F. (from acetone) = 168 ° C (decomposition).

Analysis for C ₂₀ H ₂₈ ClNO ₂ .

Calculated ... C 68.65, H 8.06, N 4.00, Cl 10.13%; found .... C 68.60, H 7.76, N 4.10, Cl 9.82%.

The isolation of 3 B was due to its very low content (< 5%) omitted in the reaction product.

Example 4

SN-Pyrrolidino ^ -phenyM-carbethoxy-J ^l -cyclohexene

246.4 g (2 mol) of l-N-pyrrolidino-butadiene- (l, 3) are mixed with 352 g (2 mol) of atropic acid ethyl ester according to Example 1 implemented. Yield: 75% of theory.

4 A: S-cis-N-pyrrolidino ^ -phenyl ^ -cis-carbäthoxy- ^ -cyclohexene hydrochloride, m.p. = 170 to 172 ° C (Dioxane).

60

65 Analysis for C ₁₉ H ₂₆ ClNO ₂
(Molecular weight = 335.86).

Calculated ... C 67.94, H 7.80, N 4.17, Cl 10.55%; found ..:. C 67.70, H 7.67, N 4.18, Cl 10.16%.

4 B: 3-trans-N-pyrrolidino ^ -phenyl ^ -trans-carbethoxy-J ^ cyclohexene hydrochloride. M.p. = 177 to 179 ° C (dioxane).

Analysis for C ₁₉ H ₂₆ ClNO ₂
(Molecular weight = 335.86).

Calculated
found .

C 67.94, H 7.80, N 4.17, Cl 10.55%; C 67.74, H 7.90, N 4.06, Cl 10.21%.

The two isomers were separated by chromatographic enrichment of the stereoisomeric bases in acidic activated Al ₂ O ₃ (Woelm) - mobile phase: benzene - and subsequent fractional crystallization from anhydrous dioxane with an addition of 0.5 to 1% hydrogen chloride gas. The isomer distribution corresponds to 4A: 4B = 4: 1.

The following pharmacological investigations were carried out with the compound referred to above as 1B (3t-dimethylamino-4-phenyl-4t-carbethoxy-J ^{1 -cydohexene hydrochloride):}

1. Determination of acute toxicity

(Litchfield, JT, and Wilcoxon, F.,
J. Pharmacol. Exp. Therap., Vol. 96 [1949], p. 99)

The toxicity of the substance was initially determined on male mice (animal strain NMRI mice, experimental animal breeding E. Jautz, Kissleg, Allgäu; conventional breeding and husbandry; Altromin standard diet, Drinking water; Keeping in macroion cages, type III; for sobering the animals keeping on wire floors) tested in weights from 18 to 22 g for intragastric and subcutaneous administration. All in all 360 mice were used for these experiments. The 24-hour and 7-day values were used in each case certainly. For comparison, »Dolantin®« (1-methyl-4-carbethoxy-4-phenyl-piperidine hydrochloride) tested. The following values resulted:

substance Application type LD ₅₀ m (
24 hours 7 days IB intragastric
.intragastric
subcutaneous
subcutaneous 362
231
475
187 344
231
475
187 "Dolantin"
IB "Dolantin"

The toxicity was then determined in rats, also with intragastric and subcutaneous administration. The test animals were male animals (Wistar strain) weighing 80 to 100 g. in the all were for that. Studies 100 rats used. The toxicity of "Dolantin" was again co-determined. The following values resulted:

substance

IB

"Dolantin"

IB.

"Dolantin"

Application type

intragastrically, intragastrically, subcutaneously, subcutaneously

LD ₅₀

24 hours

650 275 600 275

7 days

537 275 300 194

The third animal species used for the toxicity studies was male guinea pigs weighing between 240 and 370 g. The substance was administered intragastrically and subcutaneously. Again the toxicity of "Dolantin" was determined at the same time. The following values resulted:

substance Application type Lp ₁
24 hours B.
7 days IB intragastric
intragastric
subcutaneous
subcutaneous 900
650
525
181 900
610
462
150 »Dolantin« ...
IB »Dolantin« ...

2. Determination of the analgesic effect

a) Phenyl-p-quinone method

(Siegmund, E., Cadmus, R., and Lu, G. Proc. Soc. exp. Biol. N.Y., Vol. 95 [1957], p. 729)

The experimental animals were male mice (animal strain NMRI mice, experimental animal breeding E. Jautz, Kissleg,

ίο Allgäu; conventional breeding and husbandry; Altromin standard diet, Drinking water; Keeping in Makrolon cages, type III; for sobering the animals Keeping on wire floors), weighing 18 to 22 g. The animals received 30 minutes after the intra-

is gastric administration of the substance to be examined or the control solution phenyl - ρ - quinone (0.25 ml / 20 g of the 0.02% solution) intraperitoneally . administered. The observation time was 20 minutes after phenyl-p-quinone. Belonged to each group 10 animals. As an analgesic effect, the suppression or reduction in the number of Pain reactions scored per group. The results of these tests are shown in the following table emerged:

Pretreatment

NaCl solution

IB, 25 mg / kg

"Dolantin", 25 mg / kg.

IB, 30 mg / kg

"Dolantin", 30 mg / kg.

1B, 35 mg / kg

"Dolantin", 35 mg, kg.

Application type

intragastric
intragastric
intragastric
intragastric
intragastric
intragastric
intragastric

Animal number Number of animals
with positive
Seed pain reaction 12th 12th 12th 7, 12th 7th 12th 3 12th 5 12th 1 12th 3

These experiments show that compound 1B has a stronger analgesic effect than "Dolantin". That becomes even clearer when one takes into account that the toxicity ratios with intragastric administration cheaper for connection 1B than for »Dolantin«.

b) Hot plate tests

(Eddy Nathan, B., Touch berry, CT., And Lieber man, J. E., J. Pharmacol., Vol. 98 [1950], p. 121, Eddy Nathan, B., And Lcimbach. Dorothy, J. Pharmacol., Vol. 107 [1953]. P. 385)

Test animals were also mice from the same strain, weighing from 18 to 23 g. The animals were placed on a heating plate kept constant at 60 C with the help of a thermostat and the reaction time, d. H. the time to licking the front paws, measured. After this initial measurement, the to be examined Substances or control solutions administered and at intervals of 30, 60, 90 and 120 minutes further measurements carried out. The results of some of these studies are shown in the table below nervor:

Pretreatment ApplikattOBMTt

Initial value in 7 ₀

Increase in values in% after minutes

30th

90

120

NaCl solution
"Dolantin" ..

IB

NaCl solution
"Dolantin" ..
IB

intragastric intragastric intragastric intragastric intragastric intragastric 50
50

75
75

100
100
100
100
100
100

12th
41
62

_2

18th

55

8th
12th
55
10
15th
64

25 45 21 18

47

40 22 20 5Q 69

"Dolantin" is not very effective in this test arrangement. This is based on the findings recorded above emerged. Compound IB, although less toxic, has a stronger effect on average than "Dolantin" in the same Cans *

c) Spot test c

(Gross, F., HcIv. Physiol. Acta 5 C 31 [1947], D'A m ο u r. F. E .. and Smith. D. L.,

J. Pharmacol, Vol., 72 [1941], p. 74)

Test animals were also mice from the same strain in the weights indicated. The root of the tail the animals were heated with the aid of a fume. After an initial measurement in which the average The time until the typical defense reaction was measured, the substance was administered intragastrically. Further measurements were made as with the hotplate method. carried out after 30, 60, 90 and 120 minutes.

Pretreatment

NaCl solution
"Dolantin" ..
IB

Application type

intragastric intragastric intragastric dose
mg kg

Initial value in '

100
HK)
100

Increase in values in ",, after minutes

30 60 9 «120

+ 6

42
48

60 9 « 0 -4 21 13th 24 20th

-8th

14th

An excellent method could also be achieved with this method Demonstrate analgesic effect for compound 1B, which exceeds that of "Dolantin".

3. Determination of the effect on breathing

Analgesics of the morphine type, and especially "Dolantin". have a pronounced respiratory depression Effect. Compound 1 B does not have a respiratory depressive effect in comparable doses. Since this finding is for the clinical use of the substance is of particular interest, special studies have been carried out in carried out in this direction:

Male and female cats weighing 2 to 4 kg were under numal anesthesia (50 to 60 mg kg intravenous) tracheostomized. With the help of a pisle recorder, a high-speed soot drum was recorded registers the volume of each individual breath. At the same time, the arterial Written down the pressure. An excerpt from one of these gives an overview of the registration technology Curves (see. Figs. I and 2). from which the effect the connection 1B and "Dolantin" can be seen. As can be seen from these records, will After administration of the compound 1 B, the breathing is more stimulated than depressed, influenced after administration from "Dolantin" there is a clear respiratory depression.

4. Determination of the effect on the smooth

Musculature

It is known that certain analgesics of the morphine type, especially "Dolantin". have a specific paralyzing effect on the intestines. However, 1 B has no inhibitory effect on peristalsis, such as the following typical experiment shows: A 2 cm piece of guinea pig **> thin intestine was suspended in Krebs solution between two Platinelektrodcn. With the aid of the platinum electrodes, the piece of intestine was electrically stimulated transmurally at regular intervals. The compound 1B and "Dolantin" were added to the bath liquid in increasing concentrations. The influence of both substances on the contraction of the intestine is based on the one shown in FIG. 3 curve recorded. It can be seen that 0.2 mg of "Dolantin" completely abolishes the ability of the intestine to contract, while 0.2 mg of compound 1B has no effect on the ability to contract. Even higher doses of compound 1 B did not affect the contractility of the piece of intestine.

Claims (1)

Claim: Process for the production of basic substituted Cyclohexenes of the general formula R ₁ R, CH ₅ COOR., wherein R, and R, which can be the same or different, a lower alkyl radical or two alkylene radicals linked to one another to form a heterocyclic ring and R ₃ denotes a methyl, ethyl, n-propyl and n-butyl group, characterized in that at Room temperature or slightly elevated temperatures butadiene- (1.3) of the general formula R ₁ . N - CH = CH - CH = CH, with an atropic acid ester of the general formula C ₁ , H ₅ COOR., CH, be reacted in the absence of a solvent. 1 sheet of drawings COPY 0ü9 5 * 1 197