DE2065070C3 - 3r N monomethylamine © 4c phenyl 4t athoxycarbonyl cyclohexene (1) and their salts with pharmacologically acceptable acids excretion from 2007215 - Google Patents

Description

wherein R is hydrogen, an ethyl, phenethyl, morpholinoethyl or allyl radical, and their Salts with pharmacologically acceptable acids.

The compounds of general formula I according to the invention show strong analgesic and anti, phlogistic activity on pharmacological investigations commonly used mammals such as mice, rats, dogs and the like Use is indicated for all kinds of painful conditions. The one necessary to eliminate pain The dose is between 5 and 50 mg / kg body weight.

For pharmaceutical use, the products according to the invention can be mixed with the usual galenic Provide additives to medically useful application forms, such as tablets. Capsules, Ampoules, etc., can be processed.

The compounds according to the invention in which R is not hydrogen are derived from the compound of the general formula Ia produced. This can be done Sr-N.N-Dimethylamino ^ c-phenyl ^ t-ethoxycarbonyl-cyclohexen- (l) (II) can be produced. The preparation of the compounds of formula 11 is in the German U.S. Patents 1,518,959, 1,618,476, 1,618,482, and 1,668,156.

3r - N - monomethylamino - 4c - phenyl - 4t - ethoxycarbonyl-cyclohexen- (1) (Ia), a compound which, because of its strong analgesic activity, is of pharmaceutical interest per se and which is known as Starting product used for the preparation of the other substances of general formula I can be used on simplest way by bromination of II in a chlorinated hydrocarbon, preferably in chloroform, at -15 to OC. but preferably made at -10 C. and subsequent treatment with water will.

CH ₃
j
CHj-N H COOCH ₅

Ii l
ν 'Q ₁ H ₅

(ID
CH ₃
—NH COOCH,

Bi
H, O

I ix

C ₁₁ H ₅

(Ia)

The compound of the formula I a can also be obtained from the compound of the formula II in low yield by oxidation using Hg (II) acetate in aqueous acetic acid at an elevated temperature, preferably the boiling point of 10% acetic acid, by oxidation using gaseous oxygen in the presence of precious metal analyzers, preferably PtO ₂ . in an inert solvent, preferably benzene.

The compound la can with ethyl. Phenethyl. Morpholinoäthyl- or allyl halides according to the following Reaction scheme implemented:

CH

H-N

R = ethyl. Phenethyl-, morpholinoethyl-. Allyl

halides,
X = halogen.

These reactions of a secondary amine, which are known per se, require on the one hand because of the low basicity and the enormous steric hindrance of the N atom, on the other hand because of the sensitivity of the Connection I a cine special work technique. In the alkylation reactions it consists in that one the reaction by using at least an equimolar amount of N-ethyldiisopropylamine as Forces condensing agent in the presence or absence of a solvent and a temperature range from 70 to 130 "C. As suitable

Solvents have aromatic hydrocarbons, especially toluene.

The following examples are intended to illustrate the invention.

example 1

. "ir-N-Monomethylamino- ^ c-phenyMt-ethoxycarbonyl-cyclohexen- ( I) (I a)

al To a stirred solution of 273.3 g (1 mol) II in 0.5 l of chloroform, 159.8 g (1 mol) of bromine, dissolved in 250 ecm of chloroform, are added dropwise at - IOC over the course of 1.5 hours. The mixture is stirred at -10 ° C. for a further 30 minutes. The reaction solution is introduced into 4 l of water and the phases are stirred for 5 hours at room temperature. It is made alkaline with aqueous ammonia, the organic phase is washed twice with water, dried over MgSO ₄ and concentrated; the residue is taken up in allyl acetate and the hydrochloride of 1 (R = H) is precipitated with a solution of gaseous hydrogen chloride in ethyl acetate. The product is pa m.p. 218 to 219 ° C; recrystallisable from ethyl acetate-isopropanol mixture. The free base with a melting point of 39.5 to 40.5 ° C. is produced by alkalizing with aqueous NaQH. Yield: 320 g (62% as hydrochloride).

C ₁₆ H ₂₂ ClNO ₂ (molecular weight 295.9):

Calculated:

C 64.94. H 7.50. N 4.73. Cl 11.98%: found:
"C 64.74. H 7.36. N 4.82, Cl 12.34%.

b) 10 g (0.4 mol) II in 1 1 10% acetic acid dissolved, a solution of 505 g (1.6 mol) of Hg (II) acetate in 2 1 of 10% acetic acid and the mixture is heated to boiling for 2 hours. The precipitated Hg (II) salt is separated off and the filtrate alkalized with 2 η sodium hydroxide solution. The oily part is taken up in ether; the ether phase is concentrated and the residue extracted with petroleum ether. After the solvent has evaporated, the The residue was taken up in ethyl acetate and converted into the hydrochloride as above. Yield: 24.0 g (23.5% of theory) m.p. 212 to 213 "C.

c) 13.6 g (0.05 mol) II are dissolved in 100 ml benzene, _{mixed with 2 g PtO 2} and shaken for 8 days in an O ₂ atmosphere without pressure. It is filtered, the benzene phase extracted with 2η-acetic acid and the aqueous layer made alkaline with 2N NaOH. The separated oil is taken up in ethyl acetate and converted into the hydrochloride as under b). M.p. 212 to 213 C. Yield: 0.6 g (4.7%).

Example 2

3r- (N-methyl-N-ethyl-amino) -4c-phenyl-4t-ethoxycarbonyl-cyclohexene ( 1)

51.8 g (0.2 mol) of 3r-N-monomethylamino-4c-phenyl -4t- ethoxycarbonyl -cyelohexene - (I) (I; R = H) are mixed with 35 g of diethyl sulfate and 45 g of N-ethyl within one hour -diisopropylamine at 100 ⁰ C combined. Is then heated for 2 hours at 125 to 13O ⁰ C. After cooling, it is stirred with a solution of 0.3 mol of KOH in 30 cc of water and extracted the separated aqueous phase extracted with ether. The combined organic phases are dried and freed from ether and amine. The residue is taken up in ethyl acetate. Unreacted starting product is precipitated by adding 20 ml of a saturated ethereal oxalic acid solution.

3r- (N-methyl-N-ethylamino) -4c-phenyl-4t-ethoxycarbonyl-cyclohexene (1) is precipitated from the filtral as naphthalene-1,5-disulfonate. Yield: 40.0 g (47%) from isopropanol, mp 171 to 173 C. ^J.

C ₄₆ Hs ₈ N ₂ O ₁₀ S, (molecular weight 863.12): Calculated:

, o C 64.01, H 6.77, N 3.25. S 7.44%:

found:

C 6431, H 6.68. N 3.18. S 7.15%.

Example 3

3r- (N-methyl-N-al! Yl-amino) -4c-pheny l-4t-ethoxycarbonyl-cyclohexene (l)

25.9 g (0.1 mol) Ia (R = H) are heated to 90 ° C. for 1 hour with 16 g of AUyI bromide and 22 g of ethyldiisopropylamine. The cooled product is taken up with ether, the insolubles are filtered off and the ethereal phase is washed with water and dried over potassium carbonate. The residue of the ether phase (at 12 Torr, 100 ³ C) is dissolved in isopropanol and an isopropanolic naphthalene-1,5-disulfonic acid solution is added. The naphthalene-1,5-disulfonate of the base separated out. Yield: 26.2 g (30%) from isopropanol. Mp. 182-185 ⁰ C.

_o C ₄₈ H ₅₈ N ₁ O ₁₀ S ₂ (molecular weight 887.1): Calculated ... C 64.98, H 6.60. N 3.16, S 7.22%; found .... C 65.20, H 6.55. N 3.24, S 7.13%.

Example 4

3r- (N-methyl-N-phenäthylamino) -4c-phenyl-4t-ethoxycarbonylcyclohexen- ( 1)

51.8 g (0.2 mol) of la (R = - H) and 45 g / i-Phenäthylbromid be with 55 g of N-Älhyldiisopropylamin in 300 cc of dimethyl sulphoxide for 3 hours at 100 ^c C heated. The reaction solution is introduced into 1 l of water; it is then extracted with toluene and the organic phase is brought to dryness in vacuo. The residue is taken up in ethyl acetate and freed from the starting material as in Example 2. The base is released by evaporation and alkalization with 2N NaOH. It is precipitated in isopropanolic solution analogously to Example 3 as naphthalene-1,5-disulfonate. Yield: 15 g (31%) from ethanol isopropanol. Mp. 172-173 ⁰ C.

C ₅₈ H ₆₆ N ₂ O ₁₀ S ₂ (molecular weight 1015.32i:

Calculated ... C 68.61. H 6.55, N 2.76. S 6.31%; found .... C 68.44. H 6.65. N 2.70. S 6.43%. 55

Example 5

3r- (N-methyl-N- / i-morpholinoethyl-amino) -4c-pheny l ^ t-ethoxycarbonyl-cyclohexene-f 1)

25.9 g (0.1 mol) Ia (R = H) and 0.1 mol of freshly prepared N- (2-chloroethyl) morpholine are dissolved in 100 ecm of dimethyl sulfoxide and together with 35 g of N-ethyldiisopropylamine for 6 hours to 100 ^c C heated. The product is taken up in toluene; the organic phase is washed thoroughly with water, _{dried over K 2} CO ₃ and concentrated. The title product is obtained as oxalate after the addition of ethyl acetate / oxalic acid to the solution of the residue in ethyl acetate.

Yield: 9 g (18%) from acetonitrile. Mp. 173 to

C ₂₄ H ^ N ₂ O-, (molecular weight 462.55):

Calculated ... Γ 62.32. H 7.41. N 6.05%;

found .... C 62.14, H 7.30. N 5.87%.

Pharmacological results / u Examples 1 to

Connection as required
Example no.

j analgesia

Tuxiziiäl j ii-Dji, in mg kg

Ds ,, in mg kg '. Phenyl

i p-quinone-Tesi

I mouse); (Mouse)

550 i.e.

7.5 i. sx.

-WOu-. ! 4.5 s.c.

453 i.g. I 8.0 i.g. 1600 i.g. j 37.5 i.g. 1600Lg. ί 53.0 i.g.

Connection according to
Example no

3-cyclohexen- (l) -yl-

amine salicylate (LJSA.-
_{| 0} Patent 3 459 865 |

(Comparison)

3-C'yclohexen-l 1) -ylamine hydrochloride
(U.S. Patent
3 459 865) (comparison)

Toxiciiäi LD ₅₀ in mg.kg

(Mouse)

Analgesia ED ₅₀ in me / kg

Phenyl

p-cbinon-TesI

(Mouse)

300 sc ^] 5.0 s. (

87 p. O.

1195 p.o. ': 35 p.c.

The superiority over the compounds known from US Pat. No. 3,459,865 is obviously.

Claims (1)

Sponsorship: 3! ■ -N-Monomethylamino-4c-phenyl-4i-aih <r .._ \ carbon) l-c \ clohexene- (l) the general formula CH, RN H COOC ₂ H, in which R is hydrogen, an ethyl. Phenäthyk Morpholinoäthyl- or Allylrest means, and their salts with pharmacologically acceptable Acids. The present invention relates to 3r-N-Monomethylamino ^ c-pheuyMt-ethoxycarbonyl-cyclohexene- (l) (I) of the general formula CH ₃ R-N H COOCH,