SK270791A3 - Substituted aminoalkylester phenylcarbame acid and method of their preparation - Google Patents

Abstract

Compounds of formula I wherein R 1 and R 2 are as defined above hydrogen, methyl, chloro or alkoxy having 1 to 8 carbon atoms, R 3, R 4, R 3 and R 6 are hydrogen or methyl; can be prepared by reacting an isocyanate with a phthalimide derivative in an inert solvent at reflux for 5 to 24 hours. Said compounds having antiarrhythmic and local anesthetic effect is possible use in the chemical and pharmaceutical industries.

Description

Technical field

The invention relates to substituted aminoalkyl esters of phenylcarbamic acid of the formula I

R ³ R ⁵

C ⁴ -N ⁶ , I, R ⁴ R ⁶ (I), wherein R and R, which may be the same or different, represent H, methyl, chlorine or C 1 -C 8 alkoxy, R ³ , R ^{3 4} ,

R ³ and R ³ are hydrogen or methyl, their salts with inorganic and organic acids as well as their preparation,

BACKGROUND OF THE INVENTION

The substituted aminoalkyl esters of the phenylcarbamic acid of the formula I are original, not yet described compounds.

SUMMARY OF THE INVENTION

According to the invention, substituted amino-alkyl esters of phenylcarbamic acid of the formula I nh ₂ (I), or differently, represent H,. . . carbon atoms, R ³ , R ⁴ ,

6

R ³ and R ³ are hydrogen or methyl as well as salts with inorganic or organic acids.

The compounds of formula I may be prepared by

R ³ R ⁵

R ⁶

2 wherein R and R, which may be the same methyl. chlorine or alkoxy of 1 to 8, according to the process of the invention, by reacting an isocyanate of the formula II wherein R ¹ and R ^{2 of the} formula III

(II), with phthalimide general

(III), wherein R ¹ , R ⁴ , and R 4 are as previously defined, in an inert organic solvent, preferably anhydrous, at the boiling point of the solvent for 5 to 24 hours. As inert anhydrous organic solvent, toluene is preferred.

After completion of the reaction, the reaction mixture is shaken with water, the organic solvent layer is filtered and the solvent is distilled off. The residue which is substituted phthalimide is dissolved in an alcohol, preferably ethanol, heated to a temperature slightly below the boiling point of the mixture. (75 ° C) and the hydrazine hydrate liberates the final product compound of Formula I.

Release of the final substance is accomplished by addition of hydrochloric acid, filtering off the phthalyl hydrazide precipitate, distilling off the organic solvent and dissolving the residue in water. The alkaline base released is shaken into ether. From this solution, the basic ester can be converted directly to the desired salt and further purified by crystallization from an organic solvent or from a mixture of organic solvents. For example, hydrochloride, sulfate, oxalate, fumarate are suitable salts of organic and inorganic acids. Further details are given in the examples.

The starting materials are commercially available compounds such as o-aminophenol, aminoalcohols, phthalimide, or novel substances prepared analogously to the methods described in the letter '

- 3 hikes, such as the original compounds of formula III.

The evaluation of the compounds according to the invention shows that they have a marked antiarrhythmic and also local-anesthetic effect. Antiarrhythmic act approximately the same as standard mexiletine e.g. 2,6-dimethylcarbanilic acid (PA-2) 1-methyl-2-aminoethyl ester hydrochloride is approximately 2 times more antiarrhythmic than mexiletine in adrenaline-induced arrhythmias. Anti-arrhythmic as effective as mexiletine is 1-methyl-2-aminoethyl ester of 2-methoxycarbanilic acid (PA-4) fumarate in aconitin-induced arrhythmias and expressed in its consumption. At concentrations expressed in ouabain consumption, the antiarrhythmic effect is somewhat stronger e.g. 1-methyl-2-aminoethyl ester of 2-chloro-6-methylcarbanilic acid (PA-3) hydrochloride. Tables 1.1 and 3 show the results of the anti-arymic activity of the compounds of the invention against the mexiletine standard and relative to the control.

Table 1

Antiarrhythmic effect of substances, expressed by the number of arrhythmias induced by a paired dose of adrenaline

substance number of ary darkness substance count arrhythmias inspection x WITH S. E. 11.40 4.84 1.14 PA-4 x WITH S.E. 6.33 * 4.68 1.91 mexiletine PA-5 x 2.86 * x 2.00 * WITH 2.79 WITH 1.41 5. E. 1.06 S · E. 0.53 PA-1 PA-6 x 6.17 * X 6.57 * WITH 3.25 WITH 4.16 S. E. 1.33 S. E. 1:57 PA-2 P A-7 7 1.75 * x 6.33 * with 1.58 WITH 4.46 S. E. 0.56 SoE. 1.82 PA-3 X 1.29 * WITH 1.89 S. E. 0.71

* statistically significant values

- 4 Table No · 2

Antiarrhythmic effect of substances, expressed by consumption of aconitine

substance Akonitin consumption (/Ug.kg ” ¹ ) extrasystoles fibrillation lethality inspection x 103.44 186,56 338.56 WITH 29.65 34.97 41.97 · S.E. 10.48 12.36 14.84 PA-1 x 86,87 223.60 423.04 WITH 36,84 53.28 106.45 S.E. 13.92 20.14 40,24 PA-2 x 89.63 222.83 319.21 WITH 29,09 49.19 34.76 · S.E. 10.99 18.59 13.13 PA-3 x 108.21 153.44 400.14 WITH 41.05 54,82 76.15 S.E. 14.51 19.38 26.93 PA-4 x 91.92 194.93 388.85 * WITH 5.15 67.90 22.68 S.E. 2.10 27.72 9.26 mexiletine x 54.10 143.33 323,88 WITH 10.99 46.06 52.75 S.E. 4.15 17.41 19.94

* statistically significant values of mexiletine = 1- (2,6-dimethylenphenase) -2-propanamine and akonitin = 1alpha, 3alpha, 6alpha, 14alpha, 15alpha, 16beta / -20-ethyl-1,6,16-trimethoxy-4- / methoxy »ethyl / aconitrates-3,8,13,

14,15-pentol-8-acetyl-14-benzoate

- 5 Table 3

Antiarrhythmic effect of substances, expressed as ouabaine consumption

substance ---- ouabaine consumption (/Ug.kg) extrasystoles fibrillation lethality inspection x 335.3 439.2 587.9 WITH 62.16 12.19 27.77 S.E. 27.80 5.45 12.42 PA-1 x 323.5 367.3 495.1 WITH 60.81 44.10 48.11 S. E. 21.50 15.59 17.01 PA-2 x 278.4 367.1 478.3 WITH 21.26 56,57 83.99 S. E. 7.09 18.86 28.00 P A-3 x 286.4 373.5 503.9 WITH 36.42 37.41 32.75 S · E. 14.87 15.27 13.37 P A-4 x 372.5 470.2 606.8 WITH 36.70 31.21 26.39 S · E. 13.89 11.79 9.98 mexiletine X 392.6 486.2 639.5 WITH 75.46 77.22 51,95 S.E. 28.52 29.19 19.63

ouabain = 1beta, 3beta, 5,11alpha, 14,19-hexahydroxy-5beta-card-20/22 / enolid-3-L-Tamnopyranoside

An advantage of the compounds of the invention is their low acute toxicity. In all cases of subcutaneous administration to white mice, strain H is acute toxicity, expressed as an estimate of LD (jg »greater than 100 mg.kg ^-1) .

Examples of embodiments of the invention

Example 1

2-Chloro-6-methylcarbanilic acid 2-amino-1-methyl ester j

0.01 mol (1.67 g) of 2-chloro-6-methylphenylisocyanate dissolved in 10 ml of anhydrous toluene is added portionwise to 0.11 mol (2.25 g) of 2-hydroxypropylphthalimide in 10 ml of anhydrous toluene and heated for 6 hours. hours to boil. The crude product was recrystallized from acetone-ether. Substituted phthalimide (0.01 mol, 3.72 g) was dissolved in ethanol (25 ml), and 80% hydrazine hydrate (0.015 mol) was added with stirring over 5 minutes. 25 ml of ethanol are again added to the resulting precipitate and the mixture is heated at 75 ° C for 1.5 h. To the mixture was added 2.15 mL of conc. HCl and heated with stirring at 60 ° C for 1 h.

After cooling the reaction mixture in an ice bath, the phthalyl hydrazide precipitate is filtered off and ethanol is distilled off under reduced pressure. The crude product was dissolved in water, basified with NaOH and the liberated base was taken up in ether. After drying with KgCO ^, the liberated base is recrystallized from ethyl acetate. The hydrochloride is prepared from the ether dissolved in ether with ethereal dry hydrochloric acid and recrystallized from 2-propanol (m.p. 99-102 ° C).

Example 2

2-Amino-2-methyl-1-propyl 3-propyloxyphenylcarbamate j

To the reaction mixture of 0.05 mol (10.8 g) of substituted phthalimide dissolved in 10 ml of anhydrous toluene is added portionwise 0.05 mol (8.8 g) of 2-propoxyphenyl isocyanate in 10 ml of anhydrous toluene. The crude product was dissolved in 25 ml of ethanol and 0.015 mol of 80% hydrazine hydrate was added with stirring over 5 minutes. E resulting precipitate was again added 25 ml 7 e-butanol and the mixture was heated for 1.5 hours at 75 DEG C. _The mixture was added to 2.15 ml conc. HCl and heated at 60 ° C for 1 hour with stirring. After cooling the reaction mixture in an ice bath, the phthalyl hydrazide precipitate is filtered off and ethanol is distilled off under reduced pressure. The crude product was shaken into ether after alkalization with NaOH. The solution is shaken with water, the ether layer is dried over KgCO3 and the hydrochloride is released with ethereal dry hydrochloric acid. The liberated hydrochloride was recrystallized from acetone-ether (mp 156-159 ° C).

Using the above procedures, the following compounds have not been previously described in the literature:

2-Methylphenylcarbamic acid 1/2-amino-1-methyl ester (PA-1), hydrochloride, m.p. 167-169 ° C (2-propanol) anal. C 53.98 / 53.68

H, 7.00 / 6.92; N, 11.45 / 11.35

IR (cm ^"1, KBr) V (N_H) 3315, V (C_q) ^1700, ν (θ = ο) ^1:" -59O UV (nm, H ₂ 0) 270, 230, 210

2,6-dimethylphenylcarbamic acid 2/2-amino-1-methyl ester (PA-2), hydrochloride, m.p. 93-95 [deg.] C. (2-propanol) anal. with C ^ HH NgNgO vyp calc. C 55.70 / 54.05

H, 7.40 / 7.35; N, 10.38 / 9.99

IC (cm, KBr) ν max = 3 299, λ (c = o) ¹ V (c = c) = 590

UV (nm, H ₂ O) 265, 208

3/2-Amino-1-methylethyl 2-chloro-6-methylphenylcarbamate (PA-3), hydrochloride, m.p. 99-102 ° C (acetone-ether) anal .: C ₁ H 2 N 3 O 5 ClCl calc. C 47.32 / 47.12

H, 5.78 / 5.12; N, 10.04 / 9.96

IC (cm, KBr) ν (σ_jj) 3260, δ q_qj ^ 710, λ (q-q) ^ 595

UV (nm, H ₂ 0) 265, -, 210 (nm, EtOH) 290, 238, 214

2-methoxyphenylcarbamic acid 4/2-amino-1-methyl ethyl ester (PA-4), fumarate, mp 169-174 ° C (methanol) anal.: ^C 15 ^H 20 ^N 2 ° 7 calc. C 52.93 / 52.81

H, 5.92 / 5.76; N, 8.23 / 8.11

IR (cm, KBr) V ({jj_f) 5360,? (0 = 0) 5 ^^^, ^ the q_c) 1úO5 UV (nm, H ₂ 0) 279, 232, 213

2-Propoxyphenylcarbamic acid 5/2-amino-1-methylethyl ester (PA-5), hydrochloride, m.p. 133-135 ° C anal .: C, H, N, .0.01 confirmed by GC-Mass

Ij 4 1 c. j

IR ^(cm-1, CHC13) to (n._h) 3OO5, V (C = 0) ^1700, v (C = C) H90 UV (nm, EtOH) 292, 288, 278, 236

6/2-amino-2-methyl-1-propyl 2-propoxyphenylcarbamic acid ester (PA-6), hydrochloride, 1.1. 156-160 ° C (acetone-ether) anal .: C ^^^ NgO ^ Cl confirmed by GC-Mass

IC (cm, CHCl3) V (n_h) ² θ ^ θ, ν (0 = 0) ^ θ ^ θ '^ (0 = 0) ^ ⁴ ^ θ

7/2-Amino-2-methyl-1-propyl 2-chloro-6-methylphenylcarbamate (PA-7), hydrochloride, m.p. 99-102 ° C (acetone-ether) anal .: ^C 12 ^H 18 ^N 2 ° 2 ^C1 2 confirmed by GC-Mass

IC (cm, CHCl3) 3000, [nu] C-V (q ₌ q) ^ 590

UV (nm, ethanol) 290, 234, 214

Industrial usability

The invention can be used in the chemical, pharmaceutical and medical industries.

Claims (3)

PATENT CLAIMS Substituted aminoalkyl esters of phenylcarbamic acid of general formula I Where R and R, which are the same or different, are hydrogen, methyl, chlorine or alkoxy of 1 to 8 carbon atoms, R, R ⁴ , Ir and lt are hydrogen or methyl, and salts thereof with inorganic or organic acids · 2. A process for the preparation of substituted aminoalkyl esters of phenylcarbamic acid of the formula I according to claim 1, characterized in that the isocyanate of the formula II is reacted. NCO 'Ό - R ² 1 2 which R and R already have this meaning, phthalimide general of formula III 0 R ⁵ R ³ N - G - C - OH 'Ŕ ⁶ 0 3 w 6 y h wherein R 1 to R 2 are as defined above (II), (III), 10 in an inert solvent at the boiling point of the solvent for 5 to 24 hours. 3. The process according to claim 2, wherein the reaction is carried out in an inert anhydrous solvent.