CS253447B1

CS253447B1 - 11- (2-alkoxycarbanHoyloxy) cyclo-hexylmethyl-1-methylammonium chloride and a process for their preparation

Info

Publication number: CS253447B1
Application number: CS863780A
Authority: CS
Inventors: Fridrich Gregan; Jan Durina; Ingrid Tumova; Alois Borovansky
Original assignee: Fridrich Gregan; Jan Durina; Ingrid Tumova; Alois Borovansky
Priority date: 1986-06-23
Filing date: 1986-06-23
Publication date: 1987-11-12
Also published as: CS378086A1

Abstract

Riešenie sa týká [l-(2-alkoxykarbaniloyl· oxy J cyklohexylmetyl ] dimetylamónlumchlo- ridov všeobecného vzorca I, kde R znamená 1 až 8 atómov uhlíka v lineárnom alky- lovom reťazci a spósobu přípravy týchto zlúčenín z l-(dimetylamínometylcyklohe- xyl)-2-alkoxykarbanilátov všeobecného vzorca II působením éterového roztoku chloro- vodíka pri teplote —5 až —2 °C. Finálně zlúčeniny majú výrazný lokálně anesetický účinok a sú iba velmi málo toxické. /-ζλ ) NH-CO-O O~R 253447 < K H PThe solution relates to [1-(2-alkoxycarbaniloyl·oxy J cyclohexylmethyl ] dimethylammonium chlorides of the general formula I, where R represents 1 to 8 carbon atoms in a linear alkyl chain and a method for preparing these compounds from 1-(dimethylaminomethylcyclohexyl)-2-alkoxycarbanilates of the general formula II by the action of an ethereal solution of hydrogen chloride at a temperature of -5 to -2 °C. The final compounds have a pronounced local anesthetic effect and are only very slightly toxic. /-ζλ ) NH-CO-O O~R 253447 < K H P

Description

No. 4,233,447

The present invention relates to [1- (2-alkoxycarbaniloyl-oxy-cyclohexylmethyl-dimethyl-ammonium chloride) of the general formula (I).

OR

(CH 3) z

H

Cl 1 wherein R is 1 to 8 carbon atoms in the linear alkyl chain and the process for preparing such salts. The carbanillates which contain an amino group in their molecule, but in particular with hydrochloric acid, have significant local anesthetic and, in some cases, antiarrhythmic activity. Of the carbanillates in which the tertiary carbon is bound by the oxygen of the carbanil group, only a few compounds are known to date in the chemical literature. All compounds that are within the scope of the invention are novel substances not previously described in the chemical literature, where they have found previously unknown locally anesthetic effects on the body. In the examples, selected compounds are disclosed which, as well as their method of preparation, are presented together with the characterization and indications of the locally anesthetic activity index of these compounds. The examples illustrate, but do not limit, the use of the method of preparing the compounds of the invention and characterize them. their properties.In addition to extracts, results. elemental element analysis, Rf values (Silufol, system: cyclohexane-benzene-diethylamine (45: 11: 3} detection under UF radiation, IR-spectral characteristics (chloroform γ in cnr1) and 1 H-NMR spectral characteristics Also, locally anesthetic activity indices found in superficial and infiltration applications as well as acute toxicity are used to determine locally anesthetic activity, using a method that is based on determining the efficacious concentration of the substance and the standard. the anesthetic activity of the topical application was detected on the cornea of the rabbit, the cocaininium chloride standard, c = 10-2 mole dm-3, and the index-anesthetic activity of the infiltration application was detected on the skin of the back of the moratum, the standard procainium chloride c = 2.10 The acute toxicity LD 50 in mg / kg was determined in mice by subcutaneous administration. 1- (2-alkoxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride consists in treating the ether solution of 1- (dimethylaminomethylcyclohexyl) -2-alkoxycarbanilate with an ethereal solution of hydrogen chloride at a temperature of -5 to -2 ° C. The starting materials are ours

of the present invention AO (PV of the present invention AO 253 446 with priority from 23 June 1986. Example 1 0.006 mole of 1- (dimethylaminomethylcyclohexyl-2-methoxycarbanilate is dissolved in 20 cm 3 of anhydrous ether and stirring at -40 ° C). A saturated solution of hydrogen chloride in ether is added to a solid of 5 DEG-2 DEG C. The traces of moisture are distilled off from the product and removed by azotropic distillation with benzene to give [1- (2-methoxycarbaniloyloxy) cyclohexylmethyl] -dimethylammonium chloride. from butanone Colorless crystals mp 176-178 ° C;

Rf = 0.39; Yield 53% of theory;

% H, 7.94; N, 8.17; Found: C, 58.95; H, 7.89; 23% N; IR spectral characteristics γ (N — H © 3 425, γ (N — Hj 2 570 to 2 430, γ (C = O 17175, γ (C = C) 1,605, S (C — N — H 1512; 1 H-NMR spectral characteristics © (CH 5) 2 N 2.91, 2.96, CH 2 N 3.74, 3.80, NH 11.8; Local Anesthetic Activity Index 4.1, 9.5, LD 50 = 100 Example 2

1- (Dimethylaminomethylcyclohexyl) -2-heptyloxycarbanilate was used in the reaction, as described in Example 1. The (1- (2-heptyloxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride obtained was purified. crystallization of butanone: ethyl acetate (1: 1). Colorless crystals, mp 117-118 ° C;

Rf = 0.49; Yield 44% of theory;

Analysis for C 23 H 39 N 2 O 3 Cl (M + = 427.03); % H, 9.21; N, 6.56. Found: C, 64.69; Found:% C, 64.12;% H, 9.36;% N, 6.81; IR spectral characteristics γ (N-H) 33,425, γ (N-H) 2 570 to 2 430, γ (C = O) 1725, γ (C = C) 1 605, δ (C — N— H) 1512; @ 1 H-NMR spectral characteristics

(CH 3) 2 N, 2.91, 2.98, CH 2 N 3.74, 3.80, N-H n, 8;

Local Anesthetic Activity Index 4.1, 9.5; LD 50 = 600.

The same procedure was followed as follows: 3. [1- (2-Ethoxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride mp 171-173 ° C; R (0.43; Yield 55% of theory);

H, 8.19; N, 7.85. Found: C, 60.91; H, 8.46; 7.46% N; IR spectral characteristics γ (N-H) 3 425, γ (NH) 2 560 to 2 443, χ (C = O) 1725, γ (C-C) 1,605, i (C-N-H) 1512 ; Local Anesthetic Activity Index 6.3, 13.3; LD 50 = 300. 4. 1- (2-Protoxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride mp 169-171 ° C;

Rf = 0.44; Yield 52% of theory;

H, 8.42; N, 7.55. Found: C, 61.32; H, 8.32; 42% N; IC-spectral characteristics γ (N-H) β 3 427, γ (N-H) 2 560 to 2 544, γ (C = O) 1725, γ (C = C) 1 604, δ (C — N—- H) 1510;

Index of locally anesthetic activity 20,4,30,1; LD 50 = 400. [1- (2-butoxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride mp 164-165 ° C;

Rf = 0.45; Yield 54% of theory;

H, 8.64; N, 7.28; Found: C, 62.58; H, 8.78; 63% N; IR spectral characteristics γ (N-H) 33,425, γ (N-H) 1,560 to 2,543, γ (C OJ 1 724, γ (C = C) 1,605, δ (C-N-H) 1510 ;

Index of locally anesthetic activity 34,5,90,0; LD50 = 600. 6. [1- (2-Pentyloxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride mp 166-167 ° C;

Rf = 0.46; Yield 51% of theory;

Analysis calculated for C 21 H 35 N 2 O 3 Cl (M + = 398.98) calculated: C, 63.22; H, 8.84; N, 7.02 Found: C, 63.73; H, 8.59; 26% N; IR spectral characteristics γ (N-H) 4303 430, γ (N-H) 2 555 to 2 450, γ (C = O) 1725, γ (C = C) 1 605, δ (CNH) 1514;

Index of locally anesthetic activity 59,6,16,6; LD50 = 500. 7. [1- (2-Hexyloxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride, m.p.

Claims

253447 Rf = 0.48; Yield 50% of theory; Analysis C22 H37 N2 O3 Cl (M + = 413.00) Calculated: C, 63.98; H, 9.03; N, 6.78 Found: C, 64.43; 50% N; IR spectral characteristics γ (N-H) ©3 430, r (N-H) 2 555 to 2 460, γ (C = O) 1725, γ (C = C) 1,605, S (C-N—- H) 1514; Index of locally anesthetic activity 64,1,16,6; LD50 = 500. 8. [1- [2-octyloxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride mp 174-175 ° C; R 1 = 0.50; Yield 42% of theory; H, 9.37; N, 6.35; Found: C, 66.04; H, 9.19; 63% N; IR spectral characteristics χ (N-H) © 417, χ (N-H) 2 561 to 2 441, χ (C = O) 1724, χ (C =) 1 608, δ (C-N-H) 1515; NorLD 50 locally anesthetic activity index was not obtained due to lack of solubility of the drug in water. OBJECT OF THE INVENTION 1. The [1- (2-alkoxycarbaniloyloxy) cyclohexylmethyl] dimethylammonium chloride of the general formula I oyloxy) cyclohexylmethyl] dimethylammonium chloride of the general formula I according to claim 1, characterized in that 1- (dimethylaminomethylcyclohexyl) -2-alkoxycarbanilate of formula II

WH-CO-O O-R CHR

(QY-Ni-CO-OO-R II

wherein R represents a linear alkyl chain by the number of carbon atoms 1 to 8.

2. A process for the preparation of [1- (2-alkoxycarbenyl) wherein R is as defined above, with a saturated solution of hydrogen chloride in ether at -5 to -2 ° C. Severografia, n. P.