FI57254B - ANALOGIFICANT FARAMENT FRAMSTAELLNING AV ANTIARYTMISKT AKTIVA PRIMAERA AMINOACYLANILIDER - Google Patents

Description

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Patent · och r * Fift «ratyrala * nv 'AihMcm uthfd och utUkrlfcM puMIcmd 31.03.80 (32) (33) (31) h7« l *** y «υ« ΙΙι · υ · —Begird prlortuc 08,01.73 USA ( US) 321800 (71) Astra Pharmaceutical Products, Inc., Neponset Street, Worcester,

Mass. 0l606, USA (72) Robert Nichol Boyes, Worcester, Mass., Benjamin Randall Duce, Worcester,

Mass., Emil Richard Smith, Worcester, Mass.-, Eugene William Byrnes ,. Worcester, Mass., USA (7k) Berggren Qy Ab (5 ^) Analog method for the preparation of primary aminoacylanilides for the prevention of cardiac arrhythmias - Analogiförfarande för framställning av antiarhytmiskt aktiva primary primary aminoacylanilider (6l) Addition to the patent the invention relates to an analogous process for the preparation of new primary aminoacylanilides which have been shown to be effective agents for preventing pulse irregularities.

A number of anilides are known which are structurally distinct from those disclosed herein. Some of them have been shown to have therapeutic use in the literature: Swedish patents 147,308, 147,309 and 153,705; Swiss patents 318,077, 336,815 and k6k 882; German Patent 967,642; French Patent 1 struck 363; British Patents 705,460, 726,080, 754,413 and 809,286; 42 Chemical Abstracts 7871 d (1948); 47 Chemical Abstracts 1055 g (1958) and U.S. Patent 3,542,850.

Since the introduction of intensive treatment for coronary heart disease, emphasis has been placed on the treatment of additional ventricular impulses and other cardiac arrhythmias. No conventional drug is completely satisfactory to combat such arrhythmias. Drugs such as guinidine, procainamide, · propranolol, and diphenylhydantoin (phenytoin (Brit. Pharm.)) Have been used, but have unwanted side effects. Certain phenoxy derivatives of aminopropane have also been studied, but their effect on the central nervous system is 2 57254 similar to phenytoin. Proceedings of the British Pharmacological Society, Vol. 39, pp. 183 (1970).

In addition to the above-mentioned compounds, other pharmaceutical preparations have anti-pulse irregularity properties. For example, the local anesthetic xylocaine (lidocaine), whose chemical name is 2-diethylamino-2 *, 6'-acetoxylide, is an antiarrhythmic drug suitable for intravenous or intramuscular use. Parkinson, P.I., et al.,

Brit. Med. J., Vol. 2, pp. 29-30, (1970) and The Merck Index, 8th Ed., (Merck & Company, Inc., Rahway, New Jersey, 1968), pp. 618, but is not effective orally due to low blood levels of the drug. . Eisinger and Hellier, Lancet, 1969, II, 1303 and Boyes et al., F; Clin. Pharmacol. Therap. 12, No. 1, pp. 105-116 (1971). When lidocaine is administered orally, there is a clear loss of drug, probably due to hepatic function, through which most of the drug must pass through immediately after it has been absorbed from the intestinal tract. The duration of blood levels achieved with lidocaine is also quite short, which prevents protection from lasting for a long time.

It is also known that certain 2-aminotetralins have anti-pulse irregularity properties. D.M. Graeff et al., Journal of Medicinal Chemistry, Vol. 14, pp. 60-62 (1971). This invention relates in particular to an analogous process for the preparation of primary aminoacylanilides of the general formula r3Wr2 r9 R4 - (/ - N - CO - C - ( C) - NHp (I) H, vj · 1 «v or optically active isomers thereof, except for the racemic form of 2-amino-2 ', 6'-propionoxylilide, in which R1 represents hydrogen, methyl or ethyl, R2 represents methyl or ethyl, R 7 represents hydrogen or methyl, R 7 represents hydrogen, methyl or an alkoxy group having 1 to 4 carbon atoms, R 8 represents methyl, ethyl or chlorine, R 7 represents hydrogen, methyl or ethyl, R 8 represents hydrogen, R 4 represents hydrogen , methyl or ethyl, R 10 represents hydrogen, and n is 0 or .1, provided that when n is 0 and R 1, R 5, R 7 and R 8 all represent hydrogen and R 2 and R 6 are each methyl, R 1 is not methoxy, n-butoxy , hydrogen or me- Λ * 3 57254 style when n = O, and R 1, R 1, R 2 *, R 2 and R 10 mean hydrogen and R 3 is methyl, not r 6 is chlorine; and for the preparation of their therapeutically acceptable salts, characterized in that a) ammonia is reacted with a compound of the general formula R 1 / r 2 r 7 f

R 1 * -V - CO - 0 - (C) n - X

i1 Is> 10

\ r6 R R

wherein R 1 -R 4 5 6 and R 1 -R 10 and n are as defined above and wherein X represents chlorine, bromine, iodine or p-toluenesulfonyloxy; "or b) a compound of formula * 3W r2 r7 r * R4-vy-n - co - c - (c)" - x le J10 wherein R1-R1 * and R1-R "^ and n have the same meaning as above and wherein X represents chlorine, bromine or iodine, is reacted with potassium phthalimide, after which the n-substituted phthalimide formed is reacted with »hydrazine hydrate and then the formed intermediate is heated in the presence of an acid; or c) for the preparation of compounds of general formula I in which n is 1, ammonia is reacted with a compound of general formula R 3 / R 2

R * -ff N - CO - C = CH

\ == / I I

X R6 R A B

li. g 2 wherein R -R and R are as defined above and A and B are selected from the group consisting of and R 1 and R 1 and R 1, respectively; or 4 d) for the preparation of compounds of general formula I in which R 1 and R 2 each represent hydrogen and R is 1, a compound of general formula 4 is obtained.

R4-V \ S-n -CO-C-C = N

r 8 wherein R 1 -R 2 and R 2 -R 10 are as defined above, to react with a reducing agent or hydrogen; or e) a compound of formula r \ r2 R °. wherein R-1-R and R are as defined above are reacted with a compound of formula f f9 XCO - C - (c) n - NHP R8 R10 7 10 wherein R'-R and n are as defined above above, X is chlorine or bromine and P is an amine protecting group, to form an intermediate which is then reacted with a suitable agent to remove the amine protecting groups, followed by reacting the compound obtained according to any one of methods a) to e) to the optical isomer and / or therapeutically acceptable. salt.

The new compounds are particularly useful when administered orally.

It will be appreciated that with certain combinations of the groups Ry, Rg, Rg and R1Q and the number n, the compounds of formula I exist in different stereoisomeric forms. Such forms may be obtained by conventional methods, for example, the d- and 1-optical isomers may be prepared by treating the starting materials with 1- and d-tartaric acid.

The following novel compounds are preferred embodiments of this invention: 5 57254 H3C \ / CH3 ((7-NHCOCHpNHp (2-amino-2 ', 31,6'-trimethylacetyl- / anilide)), ((y-N - COCH- NH 2 (2-amino-N-ethyl-2 ', 6'-propion-c 2 H 5 (5h 3 2 oxylide) TH, (γ * NHCOCH-NH 3 (2-amino-2', 6'-propionoxide): / [(+) - or (-) form) (CH3 nch3 ^ ^ CH3 ((% * - NHCO (^ H-NH2 (2-amino-2 ', 6'-butyroxylidide)) CH3 (phN NHCOCH-NH2 (2-amino-2'-ethyl-6'-methyl-1H-propionanil))

Nc2H5 3 ^ CH3 \ / NCOCHp-NH5 (2-amino-N-methyl-2 ', 6'-acetoxyl-

\ = / I «MD

XCH3 ^ 6 57254 ^ ch / 1 / NCOCHNHg (2-amino-N-methyl-2 *, 6'-propionoxylide) CH3 CH3_ / CH3 ^ y-NCOCH3N2 (2-amino-N-ethyl-2 ' , 6'- (COHc acetoxylidide) ch3 2 5 -XCH3 \ / "NHCOCH ^ CH2Nt ^ (3-amino-2 ', 6 * -propionoxylide) ch3 _ / CH3 fx ~ \ / NHCOCH2-CH-NH2 (3-amino- 2 ', 6'-butyroxylidide) CH CH 3 / CH 3 K γ-NHCOCH 2 CH 2 NH 2 (3 * amino-2, -ethyl-6, -methyl-n-propionanilide) c2h5 / * h3 H2C-tert-NHCOCH2CH2NH2 amino-2 ', * 1', 6'-propionomesidide) N ch3 CH3 C3H70-trans-NHCOCH2 CH2 NH2 (3-amino-2 ', 6'-dimethyl-4N-propoxypropionanilide) xch3 57254

CjHjO-P \ NHCOCHNHp (2-amino-yl'-butoxy-2 ', 6'-dimethyl-γ- [1-propionanilide) N: h3 ch3_ ^ CH3 c jj g P -NHCOCHNH2 (2-amino- 2 1,6'-dimethyl-N, N-propoxy (N, N-propionanilide) X CH 2

The term "therapeutically acceptable salt" as used herein is understood to mean an acid addition salt which is physiologically innocuous when administered at a dose and at intervals (e.g., as a frequency of treatment) that are effective in the stated therapeutic use of the parent compound. acceptable acid addition salts include, but are not limited to, salts of mineral acids such as hydrochloric, phosphoric, or sulfuric acid and salts of organic acids such as succinic and tartaric acid and sulfonic acids such as methanesulfonic acid.

In clinical practice, the derivatives of the invention are normally administered orally or by injection in the form of pharmaceutical preparations consisting of the active ingredient in free base form or one generally therapeutically acceptable salt such as hydrochloride in association with a pharmaceutically acceptable carrier which may be solid, semi-solid or liquid diluent. or as an ingestible capsule. Usually the active substance is 0.1 to 10% by weight. co. preparation, e.g. in aqueous solution, in the form of its soluble acid salt, although in the form of solid preparations such as tablets or capsules, the compounds of the claimed invention may have a concentration of up to 100% by weight. tablet or capsule.

Pharmaceutical preparations, all in the form of dosage units of at least 100 mg for oral use, may be formulated by mixing either the base or acid salt form with a solid, powdered carrier. Examples are lactose, sucrose, sorbitol, mannitol and starches such as potato starch, corn starch or amylopectin, cellulose derivatives and gelatin. The carrier can also be a lubricant, such as magnesium or calcium stearate, Carbowax or other polyethylene glycol wax compressed into tablets or cores, which can then be coated with either a concentrated sugar solution which may contain gum arabic, gelatin or talc. titanium dioxide, or which may alternatively be coated with a varnish dissolved in a readily soluble organic solvent or mixture of organic solvents. Dyes can also be added to these coatings. Sustained-release tablets can be prepared using multiple layers of active drug separated by slowly dissolving layers. Another way to prepare sustained release tablets is to divide the dose of active drug into granules with different thicknesses of coatings and to compress the granules into tablets together with a carrier. The active agent may also be incorporated into slowly dissolving tablets made from fats and waxes, or it may be uniformly distributed in a tablet or insoluble material, such as a physiologically inert plastic material, as disclosed in U.S. Patent No. 3,317,394.

Soft gelatin capsules (pearl-shaped sealed capsules) and other sealed capsules consist, for example, of a mixture of gelatin and glycerol and may contain mixtures of the active ingredient and vegetable oil. Hard gelatine capsules contain the active ingredient and solid, powdered carriers such as lactose, sucrose, sorbitol, mannitol or starches such as potato starch, corn starch or amylopectin or cellulose derivatives or gelatin and stearate or magnesium stearate or stearate or stearate. The dosage unit for each of these capsules may be at least 100 mg of either a base or an acid addition salt.

The compounds of the invention for parenteral administration by injection are most preferably composed of an aqueous solution of a water-soluble, pharmaceutically acceptable acid salt of the active ingredient and optionally also contain a stabilizer and / or a buffer. Solutions can be made isotonic by the addition of sodium chloride. The recommended dosage unit for these solutions is also at least 100 mg of the compounds listed above or their therapeutically acceptable salts.

The described methods a) to e) according to the invention are described in more detail below. All radical notations in the formulas are the same as set forth above unless otherwise indicated. The phrase "product" refers to the compounds of this invention.

a) Reaction between haloacylanilide and ammonia in alcohol or alcohol-water mixture; R3 \ _ / R2 Γ \ Ϊ7 | 9 3 R4 -Γ y-N - CO - C - (C) n - X + NH4 -► X = \ Al r8 rio

rfi

0 Product + HX

57254 9 (X is Cl, Br, I or a group known to react in the same way as these halogens, e.g. a p-toluenesulfonyloxy group, i.e. p-CH 2 -O-SO 2).

b) Gabriel reaction, i.e. reaction between chlorine, bromine or iodoacylanilide and potassium phthalimide to form N-substituted phthalimide, which is reacted with hydrazine hydrate to give an intermediate which decomposes on heating with acid:> C Ϊ 'r4 “\) - N - CO - C - (0) n - X ♦ l ^ j [N k - »\ r, Rl S8 R10 6 oo r9 r,> 9 i7

I N - (C) _ - C - CO - N - (N) -R. + KX

1 1 i 0 R10 R8 R1 r6 nh2 - nh2 Ψ f9 R7 m - (c) n - c - co - n— (V_Ri (+ h20 I I I) - 'Γ 1Γ \ _H R10 r8 ri r6 o Δ H + k

Co: · - 10 57254 c) Addition of ammonia to the anilide of an unsaturated carboxylic acid (n = 1): R-iv s R5 | 10 nh4 + -r y-N - CO - (j: = (j! + NH3 ---> Product X = \ R k R7 R9 r6 d), Reduction or hydrogenation of cyanoacylanilide R3 \ S R2 // γ. I reduction or

Rn V V-N -CO-C-C = N -> ^ \ / I I hydrogenation R1 R8 r6

Product (Rg and R ^ q = H and n = 1) e) Reaction of an aminoacyl halide having an amino protecting group (P) and aniline to form an intermediate compound from which the protecting group is separated to give the desired amine: R-iv m Ro / 2 R7 Rq

_ / T \ I I

R1, * {'y— NH + XCO - C - (C) n - NHP -> \ _ / I il

Ri r8 rio r6

R3 \ _ / t R R

y ~ i 1 1 R ^ - {fy — N - CO - C - (C) n “NHP + (substance suitable for removing the protecting group, VR ^ Rg R10 e.g. acid, HX) r6 __ iy Product

.1 "S

v * »· 11 57254

The analog method according to the invention is described in more detail below.

Example 1 Synthesis of 2-amino-2f, 61-propionoxide (intermediate) from 2-bromo-21,6 * -propionoxide The 2-amino-2 ', 61-propionoxide compound was synthesized by saturating with gaseous ammonia at room temperature a suspension of 50 g (0.195 μl). ) 2-Bromo-2 *, 6'-propionoxylide in a mixture of 500 ml of $ 95 alcohol and 400 ml of concentrated aqueous ammonia. Impregnation was performed with mechanical stirring. After 25 hours, the mixture was resaturated with ammonia gas. Stirring at room temperature was continued for a total of 116 hours, after which time a sample was taken. Gas chromatographic analysis showed that about 95% of the bromine compound had been converted to the desired product. The solvents were evaporated in vacuo and the residue was dissolved in 80 ml of 3 molar hydrochloric acid. After 220 ml of water was added to the mixture, the insoluble matter was filtered off, washed with 100 ml of water and then dried. The insoluble matter weighed 9.5 g and was essentially an unreacted bromine compound. The filtrate was reacted with 50 ml of 7-polar NaOH, extracted three times with methylene chloride (50 ml + 2 x 25 ml portions), dried over potassium carbonate and then evaporated. The yield of the residue was 26.8 g, which corresponds to 71.4% of the theoretical catch. This residue was a colorless solidifying oil and was dissolved in 200 ml of chloroform. Hydrogen chloride was blown into the solution until a sample of the solution was found to be acidic on wet pH indicator paper. A precipitate was obtained and collected by filtration. It was washed with chloroform and dried. Its melting point was determined to be 246-247.5 ° C. Gas chromatographic analysis of the substance showed the presence of only one component. Calculated values for 2-amino-2 ', 6'-propionoxylide hydrochloride (C 2 H 2 Cl 2 O 2, molecular weight = 228.5) are: C 57.8; H 7.49; N 12.2; Cl 15.5i and the values obtained by analysis were: C 57.7; H 7.69; N 12.2; Cl 15.5. Infrared analysis (KBr disc, hydrochloride) showed: v 2000-1850 (broad zone with shoulder, NH 4+), 1670 (amide I), 1540 (amide II), 1386, 1375 (symmetric methyls), 760 cm 1 (three adjacent hydrogen atoms in the phenyl ring).

Example 2 Synthesis of 2-amino-2 *, 61-propionoxylide (intermediate) from chloro-g * propionoxide In a one liter flask, 17.5 g of 2,6-xylidine and 123 ml of glacial acetic acid were mixed with a mixture of cooled to 10-15 ° C. An amount of 20 g of 2-chloropropionyl chloride was added and stirred rapidly, followed immediately by a cooled solution (<10 ° C) of 47.9 g of sodium acetate trihydrate in 200 ml of water. The contents were mixed immediately and stirred for 30 min with mechanical shaking. The solid component was filtered and washed very thoroughly with distilled water. After drying, 2-chloro-2 ', 6'-propionoxylide melted at 136.5-137.5 ° C. After recrystallization from 95 μl of alcohol, it melted at 137-138 ° C. Analysis: Calculating from the formula CUH14CrNO: C 62 »4> H 6> 6 ?; C1 16.7. Experimental: C, 62.3; H 6.74;

Cl 16.6.

A mixture of 24.7 g of 2-chloro-2 ', 6'-propionoxylide, 100 ml of 95 £ ethanol, 75 ml of concentrated ammonia and 0.12 g of potassium iodide was placed in a pressure vessel and saturated with gaseous ammonia at room temperature. The vessel was sealed and kept at 75 ° C for 96 hours. After cooling, the contents were purified as described in Example 1. The yield of 2-amino-2 ', 6'-propionoxylide was 89-97%.

Example 3. Synthesis of 2-amino-21,6 * -propionoxylide (intermediate) -jg - j'o di-2 * &. from propionoxide A solution of 8.0 g of sodium iodide dissolved in 50 ml of acetone was added to a warm solution of 9.5 g of 2-bromo-2 ', 61-propionoxide in 50 ml of acetone. After refluxing with stirring for one hour, the reaction mixture was cooled, filtered from precipitated sodium bromide (3.8 g) and the filtrate was diluted with 300 ml of water. The precipitate was filtered off, washed thoroughly and recrystallized from aqueous acetone and had a melting point of 198.5-199.5 ° C. The yield of 2-iodo-2 ', 6'-propionoxylide was almost quantitative. Calculated for C 12 H 18 N 2 O: C, 43.6; H 4.66; I 41.9; N 4.62. Experimental: C, 43.7; H 4.76; I 41.9; N 4.56.

A mixture of 11.4 g of 2-iodo-2 ', 6'-propionoxylide, 145 ml of 95% alcohol and 76 ml of concentrated ammonia was saturated with gaseous ammonia and stirred at room temperature until no 2-iodine -2 ', 6'-propionoxylide could not be shown to be present in the gas chromatographic analysis. The reaction mixture was then purified as described in Example 1. Yield of 2-amino-21,6'-propionoxylidide: 85-89% ·

Example 4. D- and 1-isomers of 2-amino-21,6'-propionoxylide The racemic compound of 2-amino-2 ', 6'-propionoxylide was resolved into the optical d- and 1-isomers by the following method: 2-amino-2 *, The racemate of 61-propionoxylide (51.9 g, 0.27 mol) dissolved in 95% ethanol (18¾ ml) was added to a hot, clear solution of di-p-toluoyl-d-tartaric acid (104.3 g, 0, 27 mol) in 95 St ethanol (300 ml). An almost colorless precipitate formed which was filtered off after cooling (4 ° C) for 48 hours and washed with a small amount of cold 95% ethanol and dried.

The precipitate was recrystallized from 95> 6 ethanol until a constant rotation angle (ö = -114 °) was reached. An aqueous solution of the resulting salt was treated with 7-M sodium hydroxide and the liberated base was extracted into methylene chloride. After drying (CH 2 Cl 2), the solvent was evaporated to leave a solidifying oil (17 g), which / 1x7 = -24.6 °.

The hydrochloride was prepared from a chloroform solution of the base and gaseous hydrogen chloride. After recrystallization from absolute ethanol and ether (6: 5), 17.7 g of salt were obtained, m.p. was 264-265 ° C (decomposes) and -44.1 °.

The mother liquors from the preparation of the diastereoisomeric salt and subsequent recrystallizations were combined, evaporated and mixed with water and 7-M sodium hydroxide to liberate the base. This was extracted to completion with methylene chloride and the combined extracts were dried (K 2 CO 3). After evaporation, a solidifying oil (30.5 g) was obtained.

The base was dissolved in 95% ethanol (108 mL). To this solution was added di-p-toluoyl-1-tartaric acid (6.1 L, 0.159 mol) dissolved in 95% ethanol (176.6 mL). The precipitate formed was isolated from the cooled solution and recrystallized from $ 95 ethanol to a constant rotation angle, ~ + 115 ° · Yield 34.9 g.

From the purified salt, a base and a hydrochloride were prepared in a manner similar to that described above for the (-) antipode. There was thus obtained 11.0 g of a base with +.0./ ^* ^ = + 24.9 ° and finally 13.1 g of hydrobromide 57254 chloride, melting at 264.5 ° C (decomposes) and = + 43.7 °.

Example 5. Synthesis of 2-amino-N-methyl-2 ', 6 * -acetoxylide A concentrated aqueous ammonia solution (30 ml, 0.459 mol) was added to a solution of 2-chloro-N-methyl-2', 6'-acetoxylide ( 10.0 g, 0.0474 mol) in 95 / S alcohol (20 ml) in a pressure vessel and the mixture was kept at 75 ° C for six hours. The reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in water (50 mL) and the pH was adjusted to> 10 with 7 M NaOH, after which the base was extracted with methylene chloride. The combined extracts were dried (KgCO 3) and the solvent was evaporated. From the residue (8.2 g, 90% yield), d-tartrate was prepared by dissolving the residue in absolute ether and adding it to a solution of an equivalent amount of d-tartaric acid dissolved in absolute ethanol. The precipitate formed was filtered off, washed with absolute ether, and recrystallized from 95 5S alcohol. Sp. 173-176 ° C (decomposes). Calculated for C 15 H 22 N 2 O 7: C 52.6; H 6.48; N 8.18. Experimental: C 52.5; H 6.25; N 8.15.

Example 6. Synthesis of 3-amino-2,6,6-propionoxylide

A mixture of 3-bromo-2 ', 6T-propionoxylide (25.6 g, 0.3D mol), potassium phthalimide (20.3 g, 0.10 mol) and dimethylformamide (85 ml) was refluxed for two hours. After cooling, a solution of 30 ml of glacial acetic acid in 75 ml of water was added, and the mixture was stirred for one hour. The solid was filtered off and dried, then suspended in 95% alcohol (200 ml) and 85% aqueous hydrazine hydrate (9 ml, 0.28 mol) was added. The mixture was stirred and refluxed for two hours. Concentrated hydrochloric acid (11 ml) was added and stirring was continued at room temperature for several hours. The solid was filtered off and washed with 95% alcohol. The filtrate was evaporated to about 200 ml, cooled in an ice bath and diluted to 1000 ml with ether. The precipitated hydrochloride was filtered off, redissolved in 150 ml of absolute alcohol, filtered hot and the cooled filtrate was diluted with 550 ml of ether. After cooling to 0 ° C, the hydrochloride was filtered off, washed with a small amount of ether and dried. Yield: 18.2 g (80%). Sp. 2l8-221 ° C. Calculated for C 11 H 17 ClN 2 O: C 57.8; H 7.49; Cl 15.5; N 12.2.

Experimental: C 57.7; H 7.48; Cl 15.7; N 12.1.

Example 7 Synthesis of> 3-amino-2 *, 6'-butyryloxylide

One gram of ammonium chloride was added to a solution of 21,6'-crotonoxide (11.8 g, 0.062 mol) in $ 95 alcohol (150 mL) and the mixture was saturated with gaseous ammonia at 0 ° C.

The mixture thus prepared was placed in a pressure vessel and kept at 80 ° C for 15 hours. The contents were transferred to a distillation unit and the solvents were evaporated in vacuo to leave a solidifying oil. This was dissolved in 1 M HCl (75 mL) and extracted with ether. The ether was discarded. The acidic solution was made alkaline with sodium hydroxide to pH 11. The liberated oily base was extracted to completion with methylene chloride. The combined extracts were dried (CH 2 Cl 2), filtered and concentrated in vacuo. An ethereal hydrogen chloride solution was added and the formed hydrochloride precipitate (10.0 g) was collected and recrystallized from a mixture of alcohol and ether. The colorless crystals, dried for two hours at 0.1 mm Hg and 100 ° C, melted at 171-173 ° C. Calculated for C 12 H 19 N 2 O 2: C, 59.4; H 7.89; Cl 14.6; N 11.5. Experimental: C, 59.3; H 8.01;

Cl 14.4; N 11.4.

Example 8. Synthesis of 2-amino-N-methyl-2H-propionoxylide

A solution of N-methyl-2,6-xylidine (19.4 g, 0.143 mol) in glacial acetic acid (123 mL) was cooled to 13 ° C, 2-bromopropionyl bromide (34.3 g, 0.160 mol) was added. , stirred and then a solution of sodium acetate trihydrate (47.8 g) in water (200 ml) pre-cooled to 3 ° C was added. The ingredients were mixed together and stirred for 30 min. After addition of water (1000 ml), a precipitate formed which was filtered off and washed thoroughly with water and dried. Yield of 2-bromo-N-methyl-2 ', 6'-propionoxylide: 10.5 g, m.p. 78.5-80 ° C.

The 2-bromo-N-methyl-2 ', 6'-propionoxide (10.0 g, 0.037 mol) thus prepared was suspended in alcohol (50 ml) and concentrated aqueous ammonia (40 ml) was added. The mixture was saturated with ammonia at 25 ° C and then heated to 50 ° C under pressure.

During this process, the disappearance of 2-bromo-N-methyl-2 ', 6'-propionoxylide was monitored by gas chromatography. After virtually all of this starting material had reacted (48 hours), the solvents were evaporated in vacuo. The residue was dissolved in water (25 ml) by adding enough 1M hydrochloric acid to acidify the solution. The acidic solution was extracted three times with ether. The ether was discarded and the acidic solution was basified with 7-M sodium hydroxide and saturated with potassium carbonate. The liberated base was extracted into methylene chloride and the combined extracts were dried (CO 2), filtered and the solution saturated with hydrogen chloride gas. The solution was concentrated by evaporation to a volume of about 45 ml and ether ether (50 ml) was added. A crystalline precipitate formed which was filtered off; yield 8.68 g (97%), m.p. 212-214 ° C (decomposes). Calculated from the formula is 57254 C12H19ClN2O: C 59 »4i H 7, 89ί Cl 14.6; N 11.5. Experimental C 59.2; H 7.73; Cl 14.5; N 11.5.

Example 9 Synthesis of 2-amino-4'-butoxy-2 ', 6 * -dimethylpropionanilide A. Synthesis of 4-butoxy-2,6-dimethylazobenzene

To a solution of sodium (2.0 g, 0.09 mol) in absolute ethanol (119 mL) was added 2,6-dimethyl-4-hydroxyazobenzene (18.3 g, 0.08 mol) prepared according to the method proposed by BC Saunders and G.H.R. Watson, Biochem. J. 46: 629-233 (1950). To the resulting red-orange solution was added 1-bromobutane (22.3 g, 0.162 mol) slowly from a separatory funnel and the mixture was refluxed for five hours. After cooling, the precipitated sodium bromide was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ether and the ether solution was extracted, first with 0.5 M sodium hydroxide and then once with water. The ether phase was dried (Na 2 SO 4), filtered and evaporated to dryness. The catch was over 90%. This substance is completely sufficient for the next step. After recrystallization from 95 nocturnal ethanol, it melted at 47-47.5 ° C. Calculated for c 18 H 22 N 2 O: c 76.6; H 7.85; N 9.92. Experimental: C 76.7; H 7.84; N 9.86.

B. Synthesis of 4-butoxy-2,6-dimethylaniline

To a flask equipped with a reflux condenser and stirred 4-butoxy-2,6-dimethylazobenzene (53.4 g, 0.189 mol) was added an aqueous solution of ethanol (480 mL) (480 mL). The mixture was heated to near boiling point with stirring and sodium hydrosulfite (Na 2 S 2 O 2, 121.4 g, 0.697 mol) was added in small portions over 30 minutes. The mixture was refluxed for 75 min. Most of the alcohol was distilled off and the oily amine layer formed at this stage was dissolved in ether. The aqueous phase was made alkaline with sodium hydroxide and extracted with ether. All combined ether extracts were dried (Na 2 SO 4), filtered and all low boiling components evaporated under reduced pressure (solvent and aniline), after which the residue was partitioned in vacuo. The fraction boiling at 25 ° C-10 ° C (0.1 mm Hg) was collected. Yield: (63%); ηβ = 1.5337 · (Cf. E. Honkanen, Am. Acad. Sci. Pennical. Ser. A II. 99 (I960)).

C. Synthesis of 2-bromo-4'-butoxy-2 ', 6'-dimethylpropionanilide In a 2-liter flask, 4-butoxy-2,6-dimethylaniline (50.7 g, 0.263 mol) and glacial acetic acid (224 ml) were mixed and the mixture was cooled to about 10 ° C. To this was added and rapidly stirred 2-17.57254 bromopropionyl bromide (62 μg, 0.289 mol), immediately followed by a precooled (5 ° C) solution of sodium acetate trihydrate (87.2 g) in water (362 mL). The whole mixture was shaken vigorously to ensure thorough mixing of the components. After 30 minutes of mechanical shaking, the precipitate was filtered off and washed thoroughly with distilled water. It was then dried. The yield was 68.9 g (72%). Recrystallized from 95% ethanol, it melted at 135.5-136 ° C. Calculated for c 15 H 22 BrCl 2: c 54.9; H 6.75; Br 24.3. Experimental: C 55.1; H 6.22; Br 24.7.

D. Synthesis of 2-amino-4'-butoxy-2 ', 6'-dimethylpropionanilide - A mixture of 2-bromo-4'-butoxy-2', 6T-dimethylpropionanilide (14.0 g, 0.0426 mol), 95 of alcohol (109 ml) and concentrated aqueous ammonia (87 ml) were saturated with gaseous ammonia at room temperature with constant stirring. The disappearance of the bromine compound was monitored by gas chromatography. After completion of the reaction, the solvents were evaporated and the residue was stirred for two hours at room temperature in a mixture of 3-M hydrochloric acid (50 ml) and water (400 ml). The insoluble matter was filtered off and the filtrate was extracted with ether. The ether was discarded and the aqueous solution was basified with pH 11 7-M NaOH and extracted to completion with methylene chloride. The combined extracts were dried (CO 2), filtered and the solvent evaporated to give a tan oil (9.3 g, 82%). This was converted to the hydrochloride with gaseous hydrogen chloride in ether. After recrystallization from a mixture of alcohol and ether (1: 1), it melted at 225-226 ° C. Vacuum drying at elevated temperature (2 mm Hg, 100 ° C) caused a decrease in the weight of the hydrochloride monohydrate obtained. Calculation of the hydrochloride monohydrate C 2 H 2 Cl 2 O 2 • H 2 O 5.65 · Experimentally: H 2 O 5.90.

Calculated from the anhydrous hydrochloride c 15 H 25 ClN 2 O 2: C 59.9; H 8.33; Cl 11.8; N 9.31. Experimental: C, 59.7; H 8.48; Cl 11.8; N 9.52. Example 10. Synthesis of 2-amino-2,6,6-butyryloxylide

A mixture of 35.0 g of 2-bromo-2 ', 6'-butyryloxylide, 300 ml of 95 J alcohol and 300 ml of concentrated ammonia was saturated with gaseous ammonia, placed in a pressure vessel and kept at 60-65 ° C for 24 hours. hours. The solvents were evaporated in vacuo and the residue was dissolved in 200 mL of 1.5 M HCl. After filtration, the solution was made alkaline to pH 11 with 7 M NaOH and extracted with ether three times. The combined ether extracts were dried (K 2 CO 4) and the solvent evaporated in vacuo. The yield was 21.5 g (80%). The residue was dissolved in a mixture of ether and chloroform (2: 1) and the hydrochloride was prepared by adding ethereal hydrogen chloride solution. After recrystallization from ethanol-butanol (1: 1), it melted at 213.5-214.5 ° C. Calculated for C 12 H 19 ClN 2 O: C, 59.4; H 7.89; Cl 14.6; N 11.5. Experimental: C, 59.3; H 7.83; Cl 14.5; N 11.4.

Example 11. Synthesis of 3-amino-2'-ethyl-6 * -methylpropionanilide A. Synthesis of 3-bromo-2'-ethyl-6'-methylpropionanilide In a glass stoppered flask, a solution of 2-ethyl-6-methylaniline (15, 0 g, 0.111 mol) in glacial acetic acid (95 nil), cooled to 13 ° C and 3-bromopropionyl chloride (21.1 g, 0.122 mol) was added. The mixture was stirred and immediately combined with a cooled (3 ° C) solution of sodium acetate trihydrate (36.9 g) in water (150 ml). The mixture was shaken vigorously for 30 min. The white product formed was filtered off, washed thoroughly with water and dried. This product, i.e. 3-Bromo-2'-ethyl-6'-methyl-propionanilide (27.4 g, 91%) melted at 149-150 ° C and was sufficiently pure for the next step.

B. Synthesis of 3-amino-2'-ethyl-6'-methylpropionanilide The 3-bromo-2'-ethyl-6'-methylpropionanilide described above (13.5 g, 0.0500 mol), potassium phthalimide (10.2 g, 0.0551 mol) and dimethylformamide (50 ml) were stirred at reflux for two hours. A mixture of glacial acetic acid (20 ml) and water (50 ml) was added with constant stirring until the mixture reached room temperature. The solid phthalimide derivative was filtered off, washed with water and dried. Yield: 13.8 g (82.1%), m.p. 208 to 209.5 ° C. This product (13.8 g, 0.041 mol) was suspended in 250 mL of alcohol and 85 of hydrazine hydrate (4.0 mL) was added. The mixture was refluxed with stirring for two hours. Concentrated hydrochloric acid (8 ml) was added and stirring was continued until the mixture reached room temperature. The solid was filtered off, washed with a small amount of 95% ethanol and discarded. The solvents were evaporated from the filtrate and the residue was dissolved in water, filtered, basified with 7-M sodium hydroxide and extracted to completion with methylene chloride. The extracts were dried (K 2 CO 4) filtered and gaseous hydrogen chloride was introduced into the solution. The resulting salt was filtered off, washed with methylene chloride and dried (9.5 g) and recrystallized from alcohol-ether. Yield of 3-amino-2'-ethyl-6'-methylpropionanilide: 7.35 g, m.p. 215,5-2l6 ° C. Calculated for C 12 H 19 ClN 2 O: C, 59.4; H 7.89; Cl 14.6; N 11.5. Experimental: C, 59.3; H 7.80;

Cl 14.6; N 11.7.

14 57254

Example 12. Synthesis of 2-amino-2 ', 6'-dimethyl-4 * -propoxypropionanilide A. Synthesis of 2,6-dimethyl-4-propoxyazobenzene

To a solution of sodium (2.0 g) in absolute alcohol (120 ml) were added 2,6-dimethyl-4-hydroxyazobenzene (18.3 g) and 1-bromopropane (20 g). The mixture was refluxed for three hours and left at room temperature overnight. The precipitate of sodium bromide was filtered off, washed with a small amount of cold absolute ethanol and discarded. The alcohol was removed from the filtrate by distillation, the residue was dissolved in ether (200 ml) and extracted with 2N sodium hydroxide solution (4 x 50 ml) and once with water. After drying (Na 2 SO 4) and filtration, the ether solution was evaporated to dryness to leave an oily substance (20.2 g) which was sufficiently pure for the next reaction step.

B. Synthesis of 2,6-dimethyl-4-propoxyaniline

The 2,6-dimethyl-4-propoxyazobenzene salt from the previous step (20.2 g) was dissolved in 95 # alcohol (175 mL). Water (160 mL) was added and the mixture was heated to reflux. Sodium hydrosulfite (Na 2 S 2 O 4) (44.8 g) was added to the boiling solution in small portions. At the end of this addition, reflux was continued for 30-60 min. The alcohol was removed by distillation under reduced pressure. The remaining heterogeneous residue was made alkaline and extracted with ether. The ether extract was dried (Na 2 SO 4), filtered and evaporated. The residual oil was fractionally distilled in vacuo. After the aniline pre-distillate, the desired product was distilled at 101 ° C (0.7 mm Hg); 2 ζ n ^ = 1.5393. The yield of 2,6-dimethyl-4-propoxyaniline was 6.86 g (51%) · Calculated from the formula C 1 H 3 NO: C 73.7; H 9.56; 0 8.93. Experimental: C 73.3; H 9.82; 0 8.76.

C. Synthesis of 2-bromo-2 ', 6'-dimethyl-4'-propoxypropionanilide This compound was prepared analogously to the corresponding C-p-butoxy homologue of Example 9. An 88% yield of crude compound was obtained. After recrystallization from methanol, it melted at 147.5-148 ° C. Calculated from C 53.5; H 6.41; Br 25.4.

Experimental: C, 53.6; H 6.32; Br 25.4.

D. Synthesis of 2-amino-2 ', 6'-dimethyl-4'-propoxypropionanilide This compound was prepared in the same manner as in Example 9 D.

2-amino-4'-butoxy-2 ', 6'-dimetyylipropionanilidi. The yield of the crude base was 94%, which was converted to the hydrochloride and recrystallized from a mixture of absolute alcohol and ether; mp. 226-227 ° C. Calcd for C 18 H 12 N 2 O 2 O 2: C, 58.6; H S, 08; 0 11.2. Experimental: C, 58.5; H 8.08; 0 11.2.

so 57254

Example 13 «A. Synthesis of 2-bromo-2'-ethyl-6'-methylpropionanilide In a two-phase system containing aqueous sodium hydroxide solution (20 g of sodium hydroxide in 200 ml of water) and a mixture of 13.5 g of 2-ethyl-6-methylaniline and 75 ml of toluene (cooled to 8 ° C) were added dropwise with stirring 25 g of 2-bromopropionyl bromide. After this addition, stirring was continued for 15 min and the formed crystals were filtered off. (Addition of petroleum ether to the filtrate precipitates more product which can be added to the first crop). Total yield: 22.8 g (8 **%). After recrystallization from a mixture of ether and petroleum ether, it melted at 181-182 ° C.

B. Synthesis of 2-amino-2'-ethyl-6 * -methylpropionanilide

A slurry of 20.9 g of 2-bromo-2'-ethyl-6'-methylpropionane-Lid, 125 ml of 95 ° alcohol and 75 ml of concentrated ammonia was saturated with gaseous ammonia and kept at 55 ° C for 30 hours. a pressure vessel. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 2-M hydrochloric acid and extracted with ethyl acetate. The acidic phase was made alkaline to pH 9 and extracted with methylene chloride to give 15.5 S of a crystallizing oil. Recrystallized from a mixture of ether and petroleum ether. the compound (2-amino-2'-ethyl-6'-methylpropionanilide) melted at 68.5-70 ° C. Calculated for C 12 H 18 N 2 O: C 9 9.3; H B, 79> N 13.6.

Experimental: C, 69.7; H 8.72; N 13.5 ·

Example 14. Synthesis of 2-amino-N-ethyl-21,6'-acetoxylide

A mixture of 34.6 g of crude 2-chloro-N-ethyl-2 ', 6'-acetoxylide (prepared in the same manner as in Example 13A from chloroacetyl chloride and N-ethyl-2,6-xylidine), ** 50 ml of ethanol and 65Ο ml of concentrated aqueous ammonia were treated in the same manner as in Example 13B. The hydrochloride was prepared from an ethereal solution of the obtained crude yellowish oily base and hydrogen chloride. The salt was recrystallized from a mixture of methylene chloride and ethyl acetate and melted at 173.5-176 ° C. Yield of pure 2-amino-N-ethyl-2 ', 6'-acetoxylide: 29.2 g. Calculation of C 18 H 19 ClN 6 O 2: 50 59.3; H 7.88; N 11.6. Experimental: C, 59.5; H 8.03; N 11.5.

Example 15 Synthesis of 3'-ηηίηο-2 *, 4'6'-propionomesidide This compound was prepared in the same manner as in Example 11B for 3-amino-2'-ethyl-6'-methylpropionanilide starting from 13.5 g of 3- bromo-2 ', 4', 61-propionomesidide and 10.2 g of potassium phthalimide dissolved in 50 ml of dimethylformamide and refluxing the mixture for 3 hours. The phthalimide derivative forming the intermediate weighed 14.5 g (90% yield). This derivative 21 57254 was decomposed as described in Example 11B to give the desired base, which was converted to the hydrochloride by introducing anhydrous hydrogen chloride into a chloroform solution of the base. After recrystallization from alcohol to which a small amount of water had been added, it melted at 272.5-273.5 ° C. Its pKaf ^ value was found to be about 8.7-8.8.

a

Calculated for C 12 H 19 ClN 2 O: C 59, H 7.89i Cl 14.6; N 11.5-Experimental: C 59.2; H 7.78; Cl 14.5; N 11.6.

Example 16. Synthesis of 3-amino-21,61-dimethyl-4 '-propoxypropionanilide

A. Synthesis of 3-7 bromo-2 ', 6'-dimethyl-4'-propoxypropionanilide This compound was prepared in the same manner as in Example 11A

3-Bromo-2'-ethyl-6'-methylpropionanilide from 20 g of 4-propoxy-2,6-xylidine, 95 ml of glacial acetic acid, 37 g of sodium acetate trihydrate, 150 ml of water and 21.2 g 3-bromopropionyl bromide. The yield was 93% recrystallized (methanol-water) melting at 121.5-122.5 ° C.

B. Synthesis of 3-amino-2 ', 6'-dimethyl-4'-propoxypropionanilide This compound was prepared in the same manner as in Example 11 B.

3-Amino-2'-ethyl-6 * -methylpropionanilide 15.7 g of 3-bromo-2 ', 6'-dimethyl-41-propoxypropionanilide and 10.2 g of potassium phthalimide in 50 ml of dimethylformamide. The phthalimide derivative forming the intermediate was obtained in 88% yield. It was decomposed by suspending in 250 ml of 95 # alcohol, adding 4 ml of 64-55 hydrazine and refluxing for 90 min. From the obtained base was prepared the hydrochloride, m.p. 208-210.5 ° C. Calculated from C 53.6; H 3.08; Cl 12.4; N 9.77. Experimental: C, 58.8; H 8.20;

Cl 12.3; N 9.96.

Example 17. 2-Amino-2 ', 3', 6'-trimethylacetanilide A. 2-Chloro-2 ', 3', 6'-trimethylacetanilide

A mixture of 7.8 g of 2,3,6-trimethylaniline (RA Scherrer and HR Beatty, J.Org.Chem., 37, 1681 (1972)) and 50 ml of glacial acetic acid was cooled to 10 ° C in a glass stoppered flask. , 7.23 g of chloroacetyl chloride were added, stirred rapidly, and then a cooled solution of 19.3 g of sodium acetate trihydrate in 80 ml of water was added immediately. The mixture was shaken for 30 min and the solid was filtered off and washed thoroughly with water. After drying, a yield of 9.94 g (81%) was obtained. It melted at 145-146 ° C. Analysis: Calculated for C 18 H 18 ClNO: C, 62.4; H 6.67; Cl 16.8. Experimental: C 62.4; H 6.73; Cl 16.8.

22 57254 B. 2-Amino-2 *, 3 ', 6'-trimethylacetanilide

A mixture of 9.74 g of 2-chloro-2 ', 3'-6'-trimethylacetanilide, 9.45 g of potassium phthalimide and 41 ml of dimethylformamide was refluxed with mechanical stirring for two hours. To the mixture was added 16.4 ml of glacial acetic acid diluted with 4 ml of water, and the whole mixture was heated and stirred for 30 minutes. The solid was filtered off and dried, yielding 13.9 g (94%) of an adduct with a melting point of 270-271 ° C. The adduct was suspended in 75 g of 95 east alcohol and 3.7 ml of 85 5 g of aqueous hydrazine hydrate was added. The mixture was heated with vigorous stirring, 40 ml of 95% alcohol was added and reflux was continued for one hour. To the mixture were added 5.6 ml of concentrated hydrochloric acid and 40 ml of 95 S6 alcohol, and stirring was continued while cooling the mixture for 30 minutes. The solids were filtered off and the filter cake was slurried in water and filtered off. This procedure was repeated once. The combined filtrates (if necessary re-filtered) were evaporated, leaving 9.5 g of material which was recrystallized from alcohol to which some water had been added. The crystals melted at 283.5-284.5 ° C (decomposed): Analysis: Calculated for c11h17ClN2O: C, 57.8; H 7.49; Cl 15.5; N 12.2. Experimental: C 57.7; H 7.50; Cl 15.4; N 12.4.

Example 18. 3-Amino, 2 ', 6'-propionoxylide 5 g (0.026 mol) of 2-cyano-21,6'-acetoxylide (N. Löfgren and C. Tegner, Acta Chem. Scand. 9, 293-496, 1955) in 50 ml of 10% ethanolic ammonia was hydrogenated on a Parr shaker at 25-40 ° C and 2.5 atmospheric pressure in the presence of 1 g of rhodium / alumina. At the end of the hydrogenation, the catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in ethanol, and the hydrochloride salt was prepared by adding hydrogen chloride gas. The salt was completely precipitated by the addition of ether. After filtration, the hydrochloride salt was recrystallized from ethanol / ether. The product melted at 218-221 ° C and was completely identical to the product described in Example 6.

Example 19 · (+) - 2-amino-2 ', 61-propionoxylide

Carbobenzoxy-L-alanine (4.50 g, 0.020 mol) and 2,6-xylidide (2.72 g, 0.0224 mol) were dissolved in 50 ml of methylene chloride. Dicyclohexylcarbodiimide (4.6 g, 0.0223 mol) dissolved in .20 ml of methylene chloride was added. The mixture was heated to boiling point and then allowed to cool to room temperature in a water bath. After standing for another hour at room temperature, the precipitate was removed by filtration, washed with a smaller portion of methylene chloride and dried, yielding 4.38 g (97%) of the by-product diphenyl urea, m.p. 228.5-230.5 ° C. The filtrate was evaporated to dryness with a colorless solid residue which, after drying, weighed 6.69 g (102%) and had a melting point of 167-169.5 ° C.

(3.25 g, 0.010 mol) of the product thus obtained, N- (carbobenzoxy-L-alanyl) -2,6-xylidine, was mixed with 25 ml of absolute ethanol and 25 ml of methylene chloride. Palladium / charcoal catalyst (1.0 g) was added and the mixture was hydrogenated on a Parr shaker at 3.4 atmospheric pressure. After about an hour, the catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in 1M hydrochloric acid (25 ml) and filtered. The filtrate was basified with 7-M sodium hydroxide. The base was extracted with methylene chloride to facilitate extraction by saturating the aqueous phase with potassium carbonate. The combined extracts (15 ml) were dried over anhydrous potassium carbonate and diluted with 30 ml of anhydrous ether. Hydrogen chloride was passed through the solution and the precipitated hydrochloride was removed by filtration and recrystallized from ethanol / ether. 1.89 g of colorless crystals were obtained. Repeated recrystallization gave the product, m.p. 264.5-265.5 ° C. 0.2640 g was dissolved in 10.0 ml of methanol to give a specific rotation of + 41.7 °, indicating a purity of at least 95%. The resulting L-2-amino-2 ', 6'-propionoxylide was identical to the product described in Example 4. The mixture of the product obtained and the (-) enantiomer of Example 1 melted at 234-251 ° C, which marked a significant reduction in the melting point.

The following examples illustrate the therapeutic utility of the compounds described herein:

Example 20

The antiarrhythmic activity of several compounds of this invention was demonstrated by observing the protection they afforded against chloroform-induced vibration in mice. The experiments in mice were performed according to a modification of the method proposed by J.W. Lawson, “Antiarhythmic activity of some isoquino-line derivatives determined by a rapid screening procedure in the mouse,” J. Pharm. Exp. Therap., Vol. 160, pp. 22-31 (1968) .This method is based on the finding that when an anesthetized, untreated mouse is exposed to chloroform vapor, it soon ceases to breathe and at that time both electrocardiographic and visual examination reveals that the ventricles are trembling. using a standard time for each test run and using four different doses of the same drug, from which values a dose-response curve was constructed and the ED 2 Q value thus obtained was compared with the ED 2 Q value obtained with standard lidocaine.The relative potency is the ED 1 Q / lidocaine ED, -0 The treatment was subcutaneous:

Test compound Relative potency * 2-amino-2 ', 6 * -propionic oxide / [-) form? 0.45 (0.26-0.78) 2-amino-2 ', 6'-propionoxylide (1 +) form? 0.11 (0.06-0.21) 2-amino-2 ', 6'-dimethyl-4'-propoxypropionanilide 0.6l (0.40-1.1) 2-amino-4'-butoxy-2 ', 6'-dimethylpropionanilide 0.84 (0.48-1.5) 3-amino-2'-ethyl-6'-methylpropionanilide 0.29 (0.09-0.81) 2-amino -2 * -ethyl-6'-methylpropionanilide »0.7 3-amino-2T-4, -6t-propionomeside 0.30 (0.2-0.6) 2-amino-N-ethyl-2 ' , 6'-acetoxylide 1.02 (0.5-2.4) 3-amino-2'.6'-dimethyl-41-n-propoxypropionanilide 0.20 (0.12-0.34) 2- amino-2 ', 6'-butyroxylide 0.35 (0.21-0.56) 2-amino-N-methyl-2 *, 6'-propionoxide 0.36 (0.24-0.52) 2- Amine <DN-ethyl-2,6'-propionoxylide 0.73 (0.44-1.0) 2-amino-2'-ethyl-6'-methylacetanilide 0.27 (0.14-0.40) 2-Amino-2'-6'-diethylpropionanilide 0.48 (0.27-0.73) 2-Amino-N-methyl-2 ', 6'-acetoxylide 0.51 (0.19 “1» 3) 2-Amino-2 ', 6'-diethylacetanilide 0.22 (0.13 - 0.36) 3-Amino-2', 6'-propionoxylide 0.4 (0.2-0.8) 3-Amino- 2 ', 6'-butyroxylide 0.99 (0.60 - 1.9) xValue outside parentheses indicates statistic average.

Figures within parentheses are safety margins.

Example 21

Several compounds of this invention were tested to measure the protection they provide against chloroform-induced vibration in guinea pigs. The guinea pigs (250-350 g) were placed separately in a series of 4000 ml beakers containing cotton wool and 100 ml chloroform. Upon cessation of respiration, the animal was removed from the beaker, the chest was opened, and the heart was examined for the presence or absence of ventricular fibrillation. The nature of the heartbeat was confirmed by electro-cardiographic recordings. If the vibration was not obvious, the heart was touched with forceps. Vibration was considered to occur if weak oscillating movements were visible on the surface of the ventricle and if they lasted for at least 5 seconds after thoracic opening or mechanical irritation. Ventricular fibrillation was considered to be absent in those animals in which smooth ventricular function was evident after these procedures.

A single dose (ca. 1-5 ml) of each test compound was administered intraperitoneally with a 25 gauge needle twenty minutes before the animals were placed on chloroform vapor.

The table shows the observed protection with different doses of test compounds.

Percent protection

Test compound Dose (mg / kg) in the test group 2-amino-N-methyl-2'-6'-acetoxylide 328 100% 165 90% 3-amino-2 ', 6'-butyryloxycylide 326 100% 2-amino-N-methyl -2'-6'-propionoxylide 200 87% 2-amino-26'-butyryloxycylide 63 50% 3-amino-2 ', 6'-dimethyl-4 * -propoxypropionanilide 200 33% Surprisingly, the compounds of this invention show antiarrhythmic effects. They have a weak local anesthetic effect compared to lidocaine, a known drug for the prevention of anesthesia and arrhythmias.

Despite the generally well-known prior art teaching that antiarrhythmic activity and local anesthetic activity are closely related and that primary amines are much weaker local anesthetics than the corresponding secondary amines, the weak local anesthetics of this invention have potent antiarrhythmic properties. A.P.

26 57254

Truant and B. Takman, "Local Anesthetics", Drills, Pharmacology and Medicine, J.R. DiPalma, ed. McGraw Hill Book Co. New York, (1965) and P.F. Doerge, "Local Anesthetic Agents," Textbook of Organic Medicine and Pharmaceutical Chemistry, 5th Ed. C/O. Wilson et al. Lippincott, Philadelphia, Pa. pp. 597-598 (1966).

When administered to mammals, the compounds of this invention do not produce methaemoglobin in the bloodstream of the animal. This is due to the type of substituents in these compounds in the ortho position of the benzene ring.

The use of analogous compounds for the preparation of these primary aminoacylanilides can be carried out with effective antiarrhythmics.

That stort antal anilider lively structured avviker frän de nuri beskrivna är kända. Vissa av dessa har i litteraturen beskrivits ha therapeutikarbarbarhet: Swedish Patent Nos. 147,308, 147,309 and 153,705, Swiss Patent Nos. 318,077, 336,815 and 464,882, German Patent No. 967,642, French Patent No. 1,161,363, British Patent No. No. 705,460, 726,080, 75-413 and 809,286; 42 Chemical Abstracts 7871 d (1948); 47 Chemical Abstracts 1055 g (1958) and U.S. Patent 3,542,850.

In particular, the intense heat exchanger is limited to the use of extrasystoles and ventricular ventricles. Inget conventionally used in full swinging, there is no effect on the controller. Sädana läkemedel som quinidine, procainamide, propranolol and diphenylhydantoin (phenytoin (Brit. Pharm.)) Are used in combination with other active ingredients. All phenoxy derivatives of aminopropane are studied in the central nervous system and include phenytoin. Proceedings of the British Pharmacological Society, Vol. 39, pp. 183, (1970).

The use of an over-the-counter pharmaceutical form is an antiarrhythmic agent. See ex. Xylocaine (lidocaine), a chemically named 2-diethylamino-2 ', 6 • -acetoxylide, which inhibits antiarrhythmics for intravenous or intramuscular use Bruk, Parkinson, P.I., et al.

Brit. Med. J., Vol. 2, pp. 29-30, (1970) and the Merck Index, 8 Ed., (Merck & Company, Inc., Rahway, New Jersey, 1968), p. 618, which contains an oral excipient for oral administration. concentration 27 5 7 2 5 4 av medlet i blodet. Eisinger and Hellier, Lancet, 19β9> II »1303 and Boyes et al., Clin. Pharmacol. Therap. 12, No. 1, pp. 105-116 (1971). In the case of an orally adapted drug, it may be used as a medical device, for which the medical device may be used for medical purposes. In the event of an interference with the airplane, the airplane shall not be subject to this card, the headlamp and the power supply.

The 2-aminotetraliner is used as an anti-arrhythmic agent. D.M. Graeff et al., Journal of Medicinal Chemistry, Vol. 14, pp. 60-62 (1971).

For this purpose, it is possible in particular to carry out an analysis of the amino acid content of the primary aminoacylanilide of the formula R \ / R7 R * „) r \ f 1 (I) R- (f ') - N - CO - C - (C) - NH ~

\ = / li 1 s liS

\, RR ° R ± and n6 or optically active isomeric derivatives, with the corresponding racemic forms of the 2-amino-2 ', 6'-propionic oxides, in the form of formula 1 2 R is ethyl, ethyl or ethyl eller etyl, ·? 4 R is methyl or methyl, R is methyl, methyl or alkoxy of 1-4 cholatomers, R is methyl, ethyl or chloro, methyl, methyl or ethyl, R® is hydrogen, methyl or ethyl, R ^ ® betecknar väte, och n är O eller 1, förutsatt att när n = O och r \ R · ^, R ^ och R® alla är väte och R ^ 6 4 och R bäda är methyl, sä är R inte methoxy, n-butoxy, a derivative and methyl, then n = O and R 2, R 2, R 2, R 2 and R® down to a derivative and R 1 or methyl; (a) ammonia in the form of an ammonia with the formulation "3 r2 \ _ / R7 R9

R11 —ft 'V — N - CO - C - (C) „- X

k · 1 «\ R0 1 vilken R ^ -R ^ och R ^ -R10 samt n har ovan angivna betydelser, och 28 5 7 2 5 4 i vilken X betecknar chloro, Bromo, iodine ell p-toluenesulfonloxy; or b) a mixture with a form R3 R2 _ w f f

R4 - \ - N - CO - C - (C) - X

mJ i.> i “i vilken R ^ -R ^ och R ^ -R ^ ° samt n har ovan angivna betydelser, och i vilken X betecknar chloro, Brom eller iod, med potassiumphthalimide, var-efter man omsätter den bildade n- substituents on phthalimides with hydrazine hydrates and därpä. uprvärmer den bildade mellanprodukten i närvaro av en syra; or (c) for the production of a compound of formula I and n = 1, the ammonia content of the formula of the formula, 5 R ^ R ^

r ^ _—] / \ S_ N - CO - C = CH

\ = / Il I I

- \ 6 R AB

1 ii 6 l vilken R -R and R har ovan angivna betydelser och A samt B är 7 O q -I rv Valda ur Gruppen bestäende av Rf samt R respektive R ~ och R;

(d) for the purposes of the application of Form I

Q Ί Π i vilken R och R b & da är väte och n = 1, omsätter en förening med den allmänna formuleln f 7 Y / R '

N - CO - C - C ϊ N

and R 1 -R 1 * and R 2 -R® are selected from the group consisting of reducing agents and reducing compounds; or (e) in the case of a formulation χΕ 29 57254 in which R1-Rlt and R ^ har ovan angivna betydelser, med en förening med formeIn R7 R9

I I

XCO - C - (C) „- NHP

4 «1». 7 10 liters of R-R and a branch of an amine group, X of chlorine or Bromine and P of an amine group, for which the product is derived from a dehydrated group with a mixture of the group of amines man (s) of the method of treatment of the optical isomer and / or the therapeutically acceptable site.

However, it is possible to administer oral administration.

. . 7 8 9

It is possible to use a combination of R, R, R, R10 and the same commercial form: with the formula I and the former stereoisomer. Sddana former kan framställas via conventional method, sd kan t.ex. d- and 1-optical isomeric framställas medelst behandling med 1--hh d-vinsyra.

The following alternatives are used for the formation of the following: H ^ C CH ^ u 7 — NHCOCHpNH? (2-amino-2 ', 3', 6 • -trimethyl-N-acetanilide) -CH3 CH, N-COCHNHp (2-amino-N-ethyl-21,6'-pro-1-pionoxylide) CH3C2H5 CH3_ / CH3 // NHCOCH-NH3 (2-amino-2 ', 6'-propionoxy- [4-ylide: (+) - or (-) - form) \ h3 3 _ / H3 v 7-NHCOCH -NHo (2-amino-2 *, 6'-butyroxylidide) 30 57254 cn3 C \ NHCOCH-NHp (2-amino-2'-ethyl-6'-methyl- [1-propionanilide) 'C2H5 CH3 ch3 ff \ —NCOCH2-NH2 (2-amino-N-methyl-2 ', 6'-acetoxylidide) \ CH7 nch3 3 CH3 (/ NCOCHNHp (2-amino-N-methyl-2', 6 '- \') propionoxylide) ^ ch3 3ch3 ch3 ff \ —NCOCHpNHp (2-amino-N-ethyl-2 ', 6'- \ __ / I acetoxylide) CH3 2 5 ch3 ({\ —NHCOCHpCHpNHp (3-amino-2', 6 ' -propionoxy- (d'-lidide) CH3 CH3 (N-NHCOCHO-CH-NH5 (3-amino-2 ', 6'-butyroxy- (2-lidide)) CH3 CH3 P \ -NHCOCHpCHpNHp (3- amino-2'-ethyl-6'-methyl- [ddd propionanilide) C2h5 31 57254 Λ H-, C —— ν 7-NHCOCH5CH5NH5 (3-amino-2 '*, 6'-propiono-5'-mesides ) ch3 ch3 C, H70- ^ 'S-NHCOCHpCHpNHp (3-amino-2', 6'-dimethyl-4'--5 '- [* propoxypropionanilide) ^ cHj / ¾ c H O-f \ —NHCOCHNHp (2-amino-4'-butoxy-2 ', 6'-dimethylpropionanilide) CH, nCH3 3 ch3 C, H70-7-NHCOCHNHp (2-amino-2', 6'-dimethyl- 4 3 '- (I propoxypropionanilide) \ CH3 ch3 d

The use of "therapeutic therapies" is described in terms of the ability of the technicians to use the physiologically effective method in which the dosage and the interval (e.g. Representative therapeutically active compounds in the form of a mixture of these and other organic compounds, in the form of phosphorus or hydrogen sulfide and in the form of organic syrup, in the form of a mixture of hydrogen and vinyl, in the presence of sulfone.

For clinical use, the active ingredient may be orally formulated orally or parenterally in the form of a pharmaceutical formulation with the best and most active ingredients in the form of an active ingredient or in the form of a therapeutically active ingredient, e.g. hydrochlorides, which are medically and pharmaceutically acceptable in the form of a fast, cheap or fastening medium or a capsule which is fastened. The active balance of the active substance is preferably 0.1% and 10% of the yield, e.g. i vattenlösning i form av sitt lösliga syraadditionssalt. In addition, the active substance in the form of a compound or a capsule is used, the concentration of which is in the form of a tablet or a capsule, the concentration of which is up to 100% of the tablet or capsule.

The pharmaceutical preparation is in the form of a dosage form of at least 100 mg of the oral dosage form for a single genome or a single addition to a fast powder form. Exempel does not contain lactose, sackaros, sorbitol, mannitol, och starch, starch or amylopectin, cellulose and gelatin. Bäraren kan ocksä reserve et smörjmedel säsom magnesium or calcium stearate, carbarbax preparations or polyethylene glycol preparations in the same manner as tablets or tablets, which can be used as a carrier in the presence of a concentrate, a separate talk och / eller titandioxid, eller som alternativt kan täckas med ett lack som har lösts i ett lätt-flyktigt organicisk lösningsmedel eller i en blandning av organiciska lösningsmedel. The first instance of this Regulation was amended accordingly. The tablets with the same name are used in the genome to form an active substance in the form of an active substance. That is provided in the form of a tablet of the same type of active substance and a mixture of active substances and a mixture of tablets of the same type. The active substance may be incorporated into a tablet with the same or even the same properties as the active substance or tablet, or the substance may be incorporated into a tablet or other substance, in addition to the physiological optics of the plastics substance. 39 ^ (Fryklöf et al.).

Mjuka gelatin capsule (pearl capsule capsule) and andra capsule capsule bestär av t.ex. and bleaching with gelatin and glycerol and with the aid of active bleaching agents with the aid of oily tablets. The gelatin capsule contains granules of the active substance in the form of a powder, lactose in the form of lactose, sackose, sorbitol, mannitol or starch or amylopectin, cellulose or other cellulose. Doseringsenheten när det gäller alla dessa kapslar kan rezervat ätminstone 100 mg för säväl basen som syraadditionssaltet.

In particular, the use of injectable formulations of the parenteral formulation by injection of the active ingredient in the form of water, in the form of a pharmaceutical formulation, in addition to the active ingredient and in the case of a single active substance, may be performed. . Lös-ningarna kan kraas isotoniska genom tillsats av sodium sodium chloride. The preferred dosage form for the administration is 100 mg of this formulation or a therapeutically acceptable salt.

However, it is possible to specify a) to e) in which the details are not included. Alla beteckningar pä radicaler i formlerna är desamma som angivits ovan sävit inte annorlunda angivlts. The term "product" is meant to be used in the preparation.

a) Reaction with haloacylanilide and ammonia with alcohol or with the addition of alcohol and water: R3 R2, a \ / R7 R9

4 I I

R— <'> - N - CO - C - (C) „- X + NH, A8 A *

Product + HX

(X is Cl, Br, I or a group which is preferably treated with a halogen, e.g. p-toluenesulfonyloxy, twice p-CH 2 -O-SO 2) · b) Gabrieleactionen, dvs. reaction with chlorine, bromine or iodacylanilides and potassium phthalimides to give the N-substituted phthalimides in the form of hydrazine hydrates in different colors and to the product with the addition of a hydrogen sulfide: R3 R2 7 9 8

v / R 'Ry H

- 00 - | - <C) n - X + l ^ iTioc * --- * W.6A1 A8 A «o 0 R2 B3

1 f R7 W

1 1 / V-r11 * kx A10 I, 8 A1 o NH2 - NH2 3¾ 57254 f f Ry / 5 NH- (C) - C-CO-N - / Λ-R + Hp ° M i “s * Δ H + Ψ

O

I il + Produkt kXJ »c) Addition of ammonia to anilides av en omättad carboxyl-syra (n = 1): R3 R2 10„ y - (_ i R "λ ΓΊ - C ° - C =? + NH3 nh / s. Product l1 R7 ft9 d) Reduction or hydration with en cyanoacylanilides R3 R2 r7 R3 - // Λ — N -CO-CC = N reduction or \ / ^ | I ---> ^ = - ('1 18 hydration \ c π n R6

The product (R 1 and R 10 = H and n = 1) 35 57254 (e) The addition of aminoacyl halides, the amino group of which is a group (P) and the anhydrous product of the same group of products, in which case the following groups are present: R3 R2 79 \ _ / R 'Ry 4) / Yv I 1 RM) - NH + XCO - C - (C) - NHP ->' “Y R1 R8 R10 R3 R2 \ _ / R7 R9 i, r \ li R- —T -N - CO - C - (C) - NHP + (medium heated for \ / I] _ | k ”avlägsnande av skydds- \ 6 R Rö R10 grupp, t.ex. en syra, R HX) - ^ Produkt

Analogs of the present invention are not illustrated in detail.

Example 1. Synthesis of 2-amino-2 ', 6 * propionoxylides from 2-bromo-2', 6'-propionoxylides Synthesizes the genome from the rum temperature at a suspension of 50 g (0.195 mol) 2-Bromo-2 ', 6'-propionoxylides are obtained in a mixture of 500 ml of 95% alcohol and 400 ml of concentrated ammonia with ammonia gas. Mätningen utfördes under the mechanical omröring, After 25 timmar mättades blandningen äter med ammoniakgas. The total temperature at room temperature is approximately 116 timmar, varefter ett prov uttogs. Gas chromatographic analysis shows that 95% of the brominated products are present in their own products. The solution was stirred and stirred for up to 80 ml in 3 molar salts. After that, 220 ml of water are filtered through the filter material, then 100 ml of water are added and added afterwards. An essential material weight of 9.5 g is obtained and the starting material is brominated. The filtrate is stirred with 50 ml of 7 molar sodium hydroxide, extra three times with methylene chloride (50 ml + 2 x 25 ml portion), piercing with potassium carbonate and evaporating afterwards. At a distance of 26.8 g, a weight of 71.4% of the theoretical yield is observed. The mixture is then stirred in a clear oil, which is stirred rapidly and then in 200 ml of chloroform. Chlorine is bubbled into the aliquots and then reacted with pH pH indicator paper. En fällning 36 57254 erhölls vilken ätervanns genom filtrering. These include chloroform and throat. The temperature is preferably between 246 ° C and 247.5 ° C. Gas chromatographic analysis of the material can be performed on its own component. The starting material for 2-amino-21,6'-propionoxylides hydrochloride (C1-H1 ^ C1N2O with molecular weight 228.5) is: C 57.8; H 7.49; N 12.2; Cl 15.5; and analysis of the following color: C 57.7; H 7.69; N 12.2; Cl 15.5. Tnfraröd analysis (KBr plate, hydrochloride) visade: V2000-1850 (for Brett band med skuldra, NH 4+), 1670 (amide I), 1540 (amide IX), 1386, 1375 (symmetric methyl), 760 cm- 1 (three intentions).

Exempel 2. Synthesis of 2-amino-21,61-propionoxylides (side product) fr & n 2-chloro-2 ', 6'-propionoxylides I en enliters flask blandades 17.5 g of 2,6-xylidine and 123 ml of isethane and bleach mp 10-15 ° C. 20 g of 2-chloropropionyl chloride are added and the mixture is stirred at room temperature (<10 ° C) to give 47.9 g of sodium acetate trihydrate in 200 ml of water. Innehället blandades genast och omskakades under 30 min. pd mechanical force. These components are filtered and treated with distilled water. After this time, 2-chloro-2 ', 6'-propionoxylides were added at 136.5-137.5 °. After crystallization, 95% alcohol is melted at 137-138 °. Analysis: Calculated for C 11 H 14 ClNO: C 62 »4 H H 8.67; Cl 16.7. Punnet: C, 62.3; H 6.74; Cl 16.6.

24.7 g of 2-chloro-2 *, 6'-propionoxylides, 100 ml of 95% ethanol, 75 ml of concentrated ammonia and 0.12 g of potassium iodide are added to the mixture and triturated with ammonia at room temperature. Kärlet slöts och hölls at 75 ° C to 96 timmar. After the addition of up to 2% of the compounds in the exemptions 1. The content of 2-amino-2 ', 6'-propionoxylides is 89-97% ·

Exempel 3- Synthesis of 2-amino-2 ', 6'-propionoxylides (side product) with 2-iodo-2', 6'-propionoxylides

A solution of 8.0 g of sodium iodide in 50 ml of acetone is added and a solution of 9.5 g of 2-bromo-2 ', 6'-propionoxylide in 50 ml of acetone is added. After drying under 1 hour, the reaction mixture is stirred, sodium bromide (3.8 g) is added to the filtrate and the filtrate is taken up in 300 ml of water. The filtrate is filtered, saturated and crystallized with acetone. The temperature is 198.5-199.5 ° C.

2-iodo-2 ', 6'-propionoxylides can be quantified. Calcd for C 18 H 20 INO: C 43.6; H 4.66; 1 41.9; N 4.62. Punnet: C, 43.7; H 4.76; I 41.9; N 4.56.

11.4 g of 2-iodo-2 ', 6'-propionoxylides, 145 ml of 95% strength alcohol and 76 ml of concentrated ammonia are obtained, with 37 57254 of ammonia and the addition of 2-iodo-2', 6 ' -pro-pionoxyl oxide was used for all gas chromatographic analyzes. Reaction-blandningen upparbetades därefter sisorn beskrivits i exempel 1.

Excludes 2-amino-2f, 6'-propionoxylides: 85 “89% ·

Exempel 4. d- and 1-isomer of 2-amino-21,6'-propionoxylides

The racemic compounds of 2-amino-2 *, 6'-propionoxylide are prepared by d- and 1-optical isomeric preparations according to the following procedure:

The racemates of 2-amino-2 ', 6'-propionoxylides (51.9 g, 0.27 mol) were dissolved in 95% ethanol (18¾ ml) to give a pure solution of di-p-toluoyl. vinyl (104.3 g, 0.27 mol) in 95% ethanol (300 mL).

It is shown to be fused in pictures, to be followed by cooling (4 ° C) to 48 parts of the filter and to give a mixture of 95% ethanol and pellet.

The crystallization yields 95% ethanol to a constant optical flow rate of -114 °). The addition of 7-M sodium hydroxide and the base up to methylene chloride is used. After loading (KgCO 3), the evaporated solution was obtained as a white oil (L = <* 7v3.5 = -24.6 °).

Hydrochlorides in the form of chlorine and gas formate. After crystallization from absolute ethanol and ether (6: 5), a yield of 17.7 g is obtained, m.p. 264-265 ° (yield), sοςΐ ^ = -44.1 °.

Moderates are obtained in the form of crystals and in the subsequent crystallization of the diastereomeric salt after evaporation, and in the form of water and 7-M sodium hydroxide on the basis. Additional extracts are obtained with methylene chloride and combined extracts (KjCO2). After evaporation, oil (30.5 g) was added quickly.

The base was taken up in 95% ethanol (108 mL). The solution was taken up in di-p-toluoyl-1-vinyl (61.4 g, 0.159 mol) and treated with 95% ethanol (176.6 ml). The image is isolated in which the solution is crystallized and crystallized with 95% ethanol to give a constant optical yield, / ^.7^2.5 = + 115 °. Yield: 34.9 g.

For example, the base of the hydrochloride and the hydrochloride may be added to the (-) - antipode. The yield is 11.0 g of a base with - / '24r7p ^, ^ = + 24.9 ° and an amount of 13.1 g of the hydrochloride with a temperature of 264 ° C (soda ash) with / - «7g6 · 5 = - ^ 3.7 °.

38 57254

Example 5 · Synthesis of 2-amino-N-methyl-2 *, 6'-acetoxylide

Concentrated ammonia (30 mL, 0.459 mol) was added to give 2-chloro-N-methyl-2 ', 6'-acetoxylide (10.0 g, 0.0474 mol) in 95% alcohol (20 mL). i tryckkärl och upphettades till 75 ° C i sex timmar. The reaction mixture was stirred until the mixture was evacuated. The mixture was diluted with water (50 mL) and pH just over 10 with 7-M NaOH, and the base was extracted with methylene chloride.

The extracts were added to the throat (^ CO 2) and the solution was prepared ·. Fractions of Aterstoden (8.2 g, 90% yield) of the d-tartrate tet genome were added to the Aterstoden in absolute ether and adjusted to give an equivalent solution of d-vinyl in absolute ethanol. The filtrates are filtered off with absolute ethers and crystals of 95% alcohol. Melting point 173-176 ° C (sonication). Found for C 12 H 12 N 2 Cl 2 C 52.6 and H 6.48; N 8.18. Punnet: C 52.5; H 6.25; N 8.15.

Example 6. Synthesis of 3 "amino-21,6t-propionoxylides

The 3-bromo-2 ', 6'-propionoxylides (25.6 g, 0.10 mol), potassium phthalimide (20.2 g, 0.10 mol), and dimethylformamide (85 ml) were added. . These blends are added to a solution of 30 ml and 75 ml of water and blends are added. The paste was best filtered and filtered, and suspended in 95% alcohol (200 mL). 85% aqueous hydrazine hydrate (9 mL, 0.28 mol) was added dropwise. Blandningen omrördes ocvmdes till Aterlopp i tvA timmar. Concentrated salts (11 ml) are added to the mixture, and the mixture is stirred at room temperature under reflux. Pasta bestAndsdelar frAnfiltrerades och tvättades med 95% alcohol. The filtrate is taken up in 200 ml, cooled to 1000 ml and then dried to 1000 ml with ether. The hydrochloride is filtered off with a solution of 150 ml of absolute alcohol, which is filtered off with a solution of 550 ml of ether, after which the hydrochloride is filtered off at 0 ° C, filtered off with a mixture of ether and throat. Yield: 18.2 g (80%). Melting point 218-221 ° C. Cleaved for C1; 1H17ClN2O: C 57> 8 »H 7> 49; Cl 15.5; N 12.2. Funnet: C, 57.7; H 7.48; Cl 15.7; N 12.1.

Example 7 · Synthesis of 3-amino-2T, 6f-butyroxylide

To a solution of ammonium chloride in 2%, 6'-chronotonoxylides (11.8 g, 0.062 mol) in 95% alcohol (150 ml) was added dropwise with gas ammonia at 0 ° C. The base of the blanket is washed with a tricycle and up to 80 ° C at 48 ° C. This means that the distillations are removed and the solution is removed in vacuo, the color being Ater- 57254 39 times the oil is blast fast. The solution was taken up in 1 M HCl (75 nil) and extracted with ether. Etern dipping wine. The solution is dissolved in alkaline sodium hydroxide to pH 11. The oil is basically extracted with methylene chloride. The moss extract was added (K2CO3), filtered or concentrated in vacuo.

The reaction mixture was clarified with the hydrochloride (10.0 g) and the crystals and crystals were enriched with alcohol and ether. The crystal crystal is stirred at a temperature of 0.1 mm Hg and 100 ° C, at 171-173 ° C. Found for C12H19ClN2O: C, 59.4; H 7.89; Cl 14.6; N 11.5. Punnet: C, 59.3; H 8.01; Cl 14.4; N 11.4.

Exempel 8. Synthetic acid 2-amino-N-methyl-2f, 6 * -propionoxylide

The solution was dissolved in N-methyl-2,6-xylidine (19.4 g, 0.143 mol) at 13 ° C, and 2-bromopropionyl bromide (34.3 g, 0.160 mol) was added dropwise. The mixture was stirred at room temperature with sodium acetate (47.8 g) in water (200 ml) and stirred at 3 ° C. The best results are obtained and measured for 30 minutes. Afterwards, add water (1000 ml) to the filtrate and filter through water, adding water to the water and throat.

Obtained from 2-bromo-N-methyl-21,6'-propionoxylide: 10.5 g; mp 78.5-80 ° C.

The 2-bromo-N-methyl-2 ', 61-propionoxylides (10.0 g, 0.037 mol) were suspended in alcohol (50 ml) and concentrated with ammonia (40 ml) to give a mixture of ammonia (25 ml). C varefter den upphettades to 50 ° C under tryck.

Under this procedure, 2-bromo-N-methyl-2T, 6'-propionoxylides were purified by gas chromatography. In practice, the starting material is then reacted (48 Tim.) With evaporation in a vacuum. The solution was diluted with water (25 ml) with brine to give 1-M salts as a solid solution, and the solution was further extracted with ether. The ether is dipped in wine and the residue is alkaline with 7-M sodium hydroxide and potassium carbonate. The mixture is basically extracted with methylene chloride and moss extracts with thoracic extracts (KgCO-j), filtered, and dissolved in chloroform. Concentration of the genome was carried out to a volume of 45 ml of ether (50 ml). The crystals are crystallized, filtered off, etc.: 8.68 g, (97 #), melting point 212-214 ° C (soda). Found for C12H19ClN2O: C, 59.4; H 7.89; Cl 14.6; N 11.5. Punnet: C, 59.2; H 7.73; Cl 14.5; N 11.5.

40 57254

Example 9 · Synthesis of 2-amino-4t-butoxy "2 ', 6T-dimethylpropionanilide A. Synthesis of 4-butoxy-2,6-dimethylazobenzene

Sodium (2.0 g, 0.09 mol) in absolute ethanol (119 ml) was added to 2,6-dimethyl-4-hydroxyazobenzene (18.3 g, 0.08 mol) from B.C. Saunders and G.H.H. Watson, Biochem. J.46: 629-233 (1950). The resulting orange solid was added as a slurry to 1-bromobutane (22.3 g, 0.162 mol) free of skiljetratt, och bland-ningen cooks under a solution at 5 timmar. In this case, sodium bromides and filtrates are added, which are filtered off. The mixture is added with ether and ether extraction, preferably with 0.5 M sodium hydroxide and a sedan with water. Eterfasen torkades (NagSOij), filtrerades och indunstades torr. Utbytet var över 90%. Deceive material is not expected to be steg. After crystallization, 95% ethanol was obtained at 47-47.5 ° C. Found for C 18 H 22 N 2 O: c 76 »7; H 7.85i N 9’92 · Funnet: c 76.7; H 7.84; N 9.86.

B. Synthesis of 4-butoxy-2,6-dimethylaniline

This flask was stirred with ethyl acetate and 4-butoxy-2,6-dimethylazobenzene (53.4 g, 0.189 mol) in 50% ethanol (480 mL). After stirring, the mixture was dried to dryness and sodium hydrosulfite (NagSgO 2, 121.4 g, 0.697 mol) was added to the smd portion over 30 minutes. Blandningen cooks under Aterlopp for 75 minutes. Det place of the alcohol-Hole avdestillerades och det oljiga aminskiktet som bildats under Opérationnelle were recorded in ether. Vatenfasen gjordes alkalisk med sodium sodium hydroxide and extraherades med ether. Samtliga sammanslagna ether extract (Na 2 SO 4) was added, filtered and reduced to a slurry component (10s-ningsmedel och Anilin), evaporated to a reduced trick. The residue is fractionated by distillation in vacuo. The fraction fraction is boiled at 105-108 ° (0.1 mm Hg). Yield: 63%> = 1.5337.

(jfr E. Honkanen, Ann, Acad, Sci. Fennicae, Ser All, 99 (i960)).

C. Synthesis of 2-bromo-4β-butoxy-2 ', 6'-dimethylpropionanilides in 4-butoxy-2,6-dimethylaniline (50.7 g, 0.263 mol) and isethylate (224 ml) the mixture was cooled to 10 ° C. 2-Bromopropionyl bromide (62.4 g, 0.289 mol) was added to the mixture as a mixture of sodium acetate trihydrate (87.2 g) and water (362 ml). The pet has been processed for the purpose of intimate blending with components. After 30 minutes of mechanical separation, filtering and filtration are carried out with distilled water. Pärefter stabbed in the den. Yield 68.9 g (72%). The crystals are 95% ethanol at 135.5-136 °. Found 4 to 57254 C 15 H 22 BrNO 2: C 54.9; H 6.75; Br 24.3. Punnet: C 55.1; H 6.22; Br 24.7.

D. Synthesis of 2-amino-4, -butoxy-2 ', 6'-dimethylpropionanilide

The mixture of 2-bromo-4'-butoxy-2 ', 6'-dimethylpropionanilide (14.0 g, 0.0426 mol), 95% alcohol (109 ml) and concentrated ammonia (87 ml) was stirred with water. gaseous ammonia at rum temperature and under constant temperature. Försvinnandet av Brom-föreningen újdes gaskromatogafiskt. The reaction mixture was stirred at room temperature and then stirred at room temperature for 2 minutes with 3 M salt (50 mL) and water (400 mL). The material was filtered off and filtered with extra ether. , filtered, and treated with colors and enriched oil (9> 3 g »82%). The mixture is converted to the hydrochloride with gas chloride in ether. After crystallization from alcohol-ether (1: 1) at 225-6 ° C. Vacuuming at room temperature (2 mm Hg, 100 ° C) was carried out to remove the hydrochloride monohydrate. Behavior of the hydrochloride monohydrate, C 1 H 2 Cl 2 O 2 O 2: H 2 O; 5.65 · Funnet: H2Q; 5.90. Water content of the hydrochloride O 2 O 2 O 2 O 2 O 2 O 2: C 59.9 »H 8.38; Cl 11.8; N 9.31- Funnet: C 59.7; H 8.48; Cl 11.8; N 9.52.

Example 10. Synthesis of 2-amino-2 ', 6'-butyroxylides 1 to 3 times with 35.0 g of 2-bromo-2', 6'-butyroxylides, 300 ml of 95% alcohol and 300 ml of concentrated ammonia gasform to ammonia and boiling point at 60-65 ° C for 24 hours. The solution was stirred and heated to 200 ml of 1.5 M HCl. After filtration, an alkaline solution was added to pH 11 with 7 M NaOH and extracts with ether were added. The extraction of ether extracts (KgCO 2) and solution were induced under vacuum. Yield 21.5 g (80%). The mixture was purified by ether and chloroform (2: 1), and the hydrochloride was then converted to chlorine in ether. After crystallization from ethanol-butanone (1: 1) the temperature is 213.5-214.5 ° C. Found for C 12 H 12 ClN 2 O: C, 59.4; H 7.89; Cl 14.6; N 11.5- Funnet: C 59.3; H 7.83; Cl 14.5; N 11.4.

Example 11. Synthesis of 3-amino-2'-ethyl-6'-methylpropionanilide A. Synthesis of 3-bromo-2, -ethyl-6'-methylpropionanilide I in a flask with glass solution during cooling with 2-ethyl-6- Methyl Aniline (15.0 g, 0.111 mol) was added dropwise (95 mL) at 13 ° C and 3-bromopropionyl chloride (21.1 g, 0.122 mol) was added dropwise. Ingredients 1.2 57254 were added dropwise to a cold (3 ° C) solution of sodium acetate trihydrate (36.9 g) in water (15 * 0 ml). Blandningen skakades kraftigt i 30 minuter. Den Vita product can be filtered, filtered and filled with water and sticks. Denna product, dvs.

3-Bromo-2'-ethyl-6'-methylpropionanilide (27.4 g, $ 91), m.p. 149-150 ° C and can be added dropwise.

B. Synthesis of 3-amino-2'-ethyl-6'-methylpropionanilide

The bromine-3'-bromo-2'-ethyl-6'-methylpropionanilides (13.5 g, 0.0500 mol), potassium phthalimide (10.2 g, 0.0551 mol) and dimethylformamide (50 ml) are added under Aterlopp i tvä timmar. The mixture is stirred at room temperature (20 ml) and water (50 ml) under a continuous mixture of water at room temperature, and the phthalimide derivatives are filtered off, then water and water are added.

Yield: 13 * 8 g ($ 82.1), m.p .: 208-209.5 ° C. The product (13.8 g, 0.04 L) was added to 250 mL of alcohol, followed by 4.0 mL of 85% hydrazine hydrate. Blandningen cooks under äterlopp med omröring i tvä timmar. Concentrated salts (8 ml) were added and the mixture was stirred at room temperature. Den fasta substansen avfiltrerades, tvättades med en liten mängd $ 95 alcohol och slängdes. The solution was evaporated from the filtrate and the other solution and water, filtered, basified with sodium hydroxide and extracted with methylene chloride. Extracts are added (1 CO 2), filtered, and the chloroform is dissolved in a solution. The salt was filtered off, filtered with methylene chloride and pierced (9.5 g) and crystallized with alcohol-ether. Yield: 3-amino-2 * -ethyl-6'-methylpropionanilide: 7.35 g, m.p .: 215-216 ° C. Found for C12H19ClN2Q: C, 59.4; H 7.89; Cl 14.6; N 11.5-Funnet: C 59.3; H 7.80; Cl 14.6; N 11.7.

Example 12. Synthesis of 2-amino-2 ', 6'-dimethyl-4'-propoxypropionanilide A. Synthesis of 2,6-dimethyl-4-propoxyazobenzene

Sodium (2.0 g) in absolute alcohol (120 ml) was added 2,6-dimethyl-4-hydroxyazobenzene (18.3 g) and 1-bromopropane (20 g). Blandningen cooks under the outside of the three-dimensional variety of the overcurrent temperature. In the case of sodium bromides, filtration is carried out on an absolute scale of absolute ethanol and slag. Alcohols fran the filtrate was separated by means of destillering, The residue was dissolved in ether (200 ml) and extracted with 2% sodium hydroxide solution (4 x 50 mL) and a Gäng, with water. After work-up (Ν3250 ^) and filtration, a solid color of the oily material (20.2 g) was added, which was added to give the reaction mixture as an oil.

1.3 57254 B. Synthesis of 2,6-dimethyl-4-propoxyaniline

The resulting mixture of 2,6-dimethyl-4-propoxyiazobenzene (20.2 g) was dissolved in 95% alcohol (175 ml). Water was added dropwise (160 mL) and the mixture was stirred at room temperature. Sodium hydrosulfite (Na 2 S 2 O 4) (44.8 g) was added dropwise to the mixture. The sedan can then be used for 30 to 60 minutes. Alcohols with destillering layer was removed at reduced pressure. The quartz is a heterogeneous liter of alkaline and extra hot ethers. Ether extracts were added (Na 2 SO 4), filtered and evaporated. The oil is fractionated by vacuum distillation. The anhydrous product is then obtained at 101 ° C (0.7 mm Hg); n ^ = 1.5395. 2,6-Dimethyl-4-propoxyaniline (6.86 g, 51%) was obtained. Found for C 11 H 17 NO: C 73.7 S H 9.56; 0 8’93 * Funnet c 73, 3; H 9.82; 0.76.

C. Synthesis of 2-bromo-2 ', 6'-dimethyl-4'-propoxypropionanilide The title compound can be obtained as an analogous compound with an exempted 9C from p-butoxy homologue. After uptake of 88%, the crystallization from methanol was adjusted to 147.5-148 ° C. Found for C 12 H 20 BrNO 2: C 53.5; H 6.41; Br 25.4. Funnet: C, 53.6; H 6.32; Br 25.4.

D. Synthesis of 2-amino-2 ', 6'-dimethyl-4, -propoxypropionanilides For the purposes of this step, 2-amino-4'-butoxy-2 ·, 6'-dimethylpropionanilides are exempted from 9D. The mixture is basically 94% and exacerbated to give the hydrochloride and the crystalline salt with absolute alcohol-ether; mp 226-227 ° C.

Found for C12.H2, C1N2O2: C, 58.6; H 8.08; 0 11.2. Funnet: C, 58.5; H 8.08; 0 11.2.

Exempel 13. A. Synthesis of 2-bromo-2f-ethyl-6'-methylpropionanilide

A complete system of sodium hydroxide solution (20 g of sodium hydroxide in 200 ml of water) and a mixture of 13.5 g of 2-ethyl-6-methyl-aniline and 75 ml of toluene (8 ° C) is added. ) 25 g of 2-bromopropionyl bromide are added dropwise under omröring.

After this time, the mixture was refluxed for 15 minutes with a crystal filter. (Tillage of petroleum products filtered through other substances, all of which may be used). Total yield: 22.8 g (84%). After crystallization from ether-petroleum ether at a temperature of 188-182 ° C.

B. Synthesis of 2-amino-2'-ethyl-6'-methyl-propionanilide

20.9 g of 2-bromo-2'-ethyl-6'-methylpropionanilide, 125 ml of 95% alcohol and 75 ml of concentrated ammonia are added, which is treated with 55 ° C of ammonia and a mixture of 55 ° C at 30 ° C. Karl-tryck. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The mixture was dissolved in 2-M salts and extracted with ethyl acetate. The salt is then alkaline to pH 9 and extra green with methylene chloride to give 15.5 g of a crystalline oil. After crystallization from ether-petroleum ether, the resulting (2-amino-2'-ethyl-6'-methylpropionanilide) was heated to 68.5-70 ° C. Found for C 11 H 20 N 2 O: C, 69.8; H 8.79; N 13.6. Punnet: C, 69.7; H 8.72; N 13.5 · 12

Example 14. Synthesis of 2-amino-N-ethyl-2 *, 61-acetoxylide

The mixture of 3, 6 g of 2-chloro-N-ethyl-2 ', 6'-acetoxylide (with the addition of chloroacetyl chloride and the analogue of N-ethyl-2,6-xylidine in the same manner as the exemption 13A), 450 ml of ethanol and 650 ml of concentrated ammonia water are added to the exemptions 13B. Hydrochlorides are added in the form of a solid, gulaktiga, oljiga basen och klorväte. Saltet omkris-talliserades ur en blandning av methylenklorid-ethylyletat. Melting point 173.5-176 ° C. Yield: 2-Amine-N-ethyl-2 ', 6'-acetoxylide: 29.2 g. Calculated for hydrochloride C12HX9ClN2O: C, 59.3; H 7.88; N 11.6. Weight: C, 59.5; H 8.03; N 11.5-

Example 15 »Synthesis of 3-amino-2T, 4 ', 6'-propionomesides

13.5 g of 3-amino-2 ', 4', 6'-propionomeside and 10.2 g of potassium phthalimide in 50 ml of dimethylformamide are then added dropwise to 3 ml of a solution which is analogous to the product. 3-Amino-2'-ethyl-6'-methylpropionanilide 11B.

The phthalimide derivative was obtained to give 14.5 g (90% yield).

This derivative is shown in Exemption 11B, which can be used to reduce the amount of hydrochloride in the hydrochloride genome to give chloroform in the chloroform. After crystallization from alcohol, the mixture is heated to 272.5-273.5 ° C. Dess pka ^ p -värde befanns property omkring 8.7-8.8. Found for C 12 H 12 ClN 2 O: C, 59.4; H 7.89;

Cl 14.6; N 11.5. Funnet: C, 59.2; H 7.78; Cl 14.5; N 11.6.

Exempel 16. Synthesis of 3-amino-21,6 * -dimethyl-41-propoxypropionanilide A. Synthesis of 3-bromo-2 *, 6'-dimethyl-4'-propoxypropionanilide

3-Bromo-2f-ethyl-6'-methylpropionanilide is thus obtained in the form of 11A with 20 g of 4-propoxy-2,6-xylidine, 95 ml of sodium acetate, 37 g of sodium acetate trihydrate, 150 ml of water and 21.2 g of 3 -brompropionylbromid. 93% of the material is crystallized (methanol-water), m.p. 121.5-122.5 ° C.

45 5 7 2 5 4 B. Synthesis of 3-amino-2 ', 6'-dimethyl-4 * -propoxypropionanilide

The corresponding analog of 3-amino-2'-ethyl-6'-propionanilide is liberated from 11B with 15 * 7 g of 3-bromo-2 *, 6'-dimethyl-4'-propoxypropionanilide and 10.2 g of potassium phthalimide. in 50 ml of dimethylformamide. The intermediate phthalimide derivatives are present in 88% yield. The resulting genome was adjusted to 250 ml with 95% alcohol and 4 ml with 64% hydrazine and doping for 90 minutes. The hydrochloride is refluxed at a temperature: mp 208-210 ° C. Found for C 12 H 12 ClN 3: C 59.6; H 8.08; Cl 12.4; N 9.77-Funnet: C 58.8; H 8.20; Cl 12.3; N 9.96.

Exempel 17 «2-Amino-2 ', 3 *, 6'-trimethylacetanilide A. 2-Chloro-2', 3 ', 6'-trimethylacetanilide

7.8 g of 2,3,6-trimethylaniline (RA Schemer and HR Beatty, J.Org.Chem., 37, 1681 (1972)) are added and 50 ml of the mixture are stirred at 10 ° C in a glass flask. , 7.23 g of chloroacetyl chloride are added, which is stirred and added to a solution of 19.3 g of sodium acetate trihydrate in 80 ml of water. After drying for 30 minutes, the material is filtered and treated with water. After loading, 9.9 g (8%) were added. Melting point 145-146 ° C. Analyst Calculated for H 2 ClNO: C, 62.4; H 6.67; Cl 16.8. Funnet: C, 62.4; H 6.78;

Cl 16.8.

B. 2-Amino-2 ', 3', 6'-trimethylacetanilide

9.7 g of 2-chloro-2 ', 3', 6'-trimethylacetanilide, 9.45 g of potassium phthalimide and 4 l of dimethylformamide are added under the cut-off and mechanically controlled under TV & Timmar. After bleaching, 16.4 ml of isätika is used with 4 l of water for 30 minutes. The material was filtered off and filtered to give 13.9 g (9%) of adduct with a melting point of 270-271 ° C. The adduct was added to 75 ml of 95% alcohol as a solution in 3.7 ml of 85% aqueous hydrazine hydrate. Blandningen upphettades under kraftig omröring, 4o ml 95% alcohol tillsattes varefter dterloppskokningen fortsattes under 1 timme. 5, g ml of concentrated salt and 40 ml of 95% alcohol are added to the mixture and the mixture is stirred for 30 minutes.

The material is filtered, the filter upstream and the water filtered. The procedure is described in detail. The same filtrate (which can be filtered) is used to give a color of 9.5 g of the substance which is crystallized from alcohol and then added to the water. Crystalline 1.6 57254 melted at 283.5-184.5 ° C (sonication). Analysis: Calculated for C 11 H 17 ClN 2 O: C 57.8 and H 7.49; Cl 15.5 »N 12.2. Punnet: C, 57.7; H 7.50; Cl 15.4; N 12.4.

Exempel 18. 3-Amino-2 ', 6'-propionoxylide 5 g (0.026 mol) of 2-cyano-2', 6'-acetoxylide (N. Löfgren and C. Tegnlr, Acta Chem. Scand. 9, 293-496 , 1955) in 50 ml of 10% ethanol-halate ammonia hydrated at room temperature at 25-40 ° C and triturated at 2.5 atm. i närvaro av 1 gram rhodium / aluminiumoxid. Afterwards, hydrogenation from the filtration catalyst and filtration is induced. The mixture was taken up in ethanol and the hydrochloride salt in the form of a genome of chloroform. Full-time utilization of the salt is up to the genome of the ether. After filtration, the hydrochloride salt is crystallized from ethanol / ether. The products are melted at 2-18-221 ° C and can be identical to the 6 products.

Exempel 19. (+) - 2-amino-2 ', 6'-propionoxylides

Carbobenzoxy-L-Alanine (4.50 g, 0.020 mol) and 2,6-xylidide (2.72 g, 0.0224 mol) were added to 50 ml of methylene chloride. Dicyclohexylcarbodiimide (4.6 g, 0.0223 mol) was added dropwise to 20 ml of methylene chloride. Blandningen upphettades to the point and after which the temperature is reached at room temperature. After this time, the mixture is heated at room temperature, filtered through a portion of methylene chloride and throat; 4.38 g (97%) of melting point 226.5 DEG-230 DEG C. are obtained in the form of diphenylurea. The filtrate was stirred at room temperature and then dried at 6.69 g (102%), m.p. 167-169.5 ° C.

To give (3.25 g, 0.010 mol) of the desired product, N- (carbobenzoxy-L-alanyl) -2,6-xylidine, is obtained with 25 ml of absolute ethanol and 25 ml of methylene chloride. Palladium / triacol catalyst (1.0 g) was added and the mixture was hydrated and the reaction mixture was stirred at 3.4 atm. After filtration, the catalyst was filtered off and filtered. The mixture was taken up in 1 M chloroform (25 mL) and filtered. The filtrate was alkalized with 7-M sodium hydroxide. The base is extracted with methylene chloride, and the extracts are extracted from the genome without the use of potassium carbonate. The extracts (15 ml) were added dropwise with water-rich potassium carbonate and treated with 30 ml of water-ether. The reaction is carried out with chlorine and hydrochloride fractions and crystals with ethanol / ether. 1.89 g of a färklösa crystal. After crystallization 47 57254, a product with a melting point of 264.5-265.5 ° CC is added to 0.2640 g of 10.0 ml of methanol to give a specific rotation, / Ä Jl5, head + 41.7 °, flash antithers and yields of 95% · The yield of L-2-amino-2 ', 6'-propionoxylides can be identical to that of 4 free products. The reaction of the product with the (-) - enantiomers is free from 1 to 234-251 ° C, in which case it is possible to reach a temperature of 234-251 ° C.

The therapeutic alternatives are described in the following examples:

Exempel 20

These antiarrhythmic effects can be demonstrated by genomic chloroform-inducing chamber polymers.

Experiments were performed in addition to the modification of the method described in J.W. Lawson, "Antiarhythmic activity of some isoquinoline derivatives determined by a rapid screening procedure in the mouse," J. Pharm. Exp. Therap., Vol. 160, pp. 22-31, (1968). This method is based on the observation method, which includes the use of chloroforms in the form of an electrocardiographic device for all inspections. 0m must be used in the form of chloroform, and the warmth of the diatomaceous earth is determined by the action of the diatomaceous earth in the chamber.

Modifications to the standard for up to 20 minutes are standard for the use of the same standard. I will not be responsible for the construction of the case.

To reduce the amount of ED ^ Q-coil by coarse-feeding with ED ^ Q-flesh for standard lidocaine. The relative strain is ED ^ Q for test substance / ED ^ Q for lidocaine. Administrationssättet var subcutan till-försel:

Test substance Relative structure x 2-amino-2T, 6'-propionoxylide (T -) - form7 0.45 (0.26 - 0.78) 2-amino-2 *, 6'-propionoxylide (T +) - form7 0, 11 (0.06-0.21) 2-Amino-2 ', 6'-dimethyl-4'-propoxy-propionanilide 0.61 (0.40-1.1) 2-Amino-4'-butoxy-2 ', 6'-dimethylpropionanilide 0.84 (0.48-1.5) 3-amino-2'-ethyl-6'-methylpropionanilide 0.29 (0.09-0.8l) 2-amino -2'-ethyl-6'-methylpropionanilides not 0.7 48 57254

Testsubstans Relativ styrka * 3-Amino-2 ', 4', 6'-propionomeside 0,30 (0,2 - 0,6) 2-Amino-N-ethyl-2 ', 6'-acetoxylides 1,02 (0 .5 - 2,4) 3-Amino-21,6'-dimethyl-4'-n-propoxypropionanilide 0.20 (0.12-0.34) 2-Amino-2 ', 6'-butyroxylide .35 (0.21 - 0.56) 2-amino-N-methyl-2 *, 6'-propionic oxide 0.36 (0.24 - 0.52) 2-amino-N-ethyl-2 ' , 6'-propionic oxide 0.73 (0.44 - 1.0) 2-Amino-2'-ethyl-6'-methylacetanilide 0.27 (0.14 - 0.40) 2-amino-2 ' , 6'-diethylpropionanilide 0.48 (0.27-0.73) 2-amino-N-methyl-2 ', 6'-acetoxylide 0.51 (0.19-1.3) 2-amino-2' , 6'-diethylacetanilide 0.22 (0.13 - 0.36) 3-amino-2 ', 6'-propionoxylide 0.4 (0.2-0.8) 3-amino-2', 6'- butyroxylidid 0,99 (0,60 - 1,9) * The value of the parent compound is statistically significant. Siffrorna innanför parentesen anger konfidensintervallet.

Exempel 21

That is to say, in particular, the aid is granted in the first instance. the chlorine-inducer of the chloroform-inducer flimmer hos marsvin. Marsvin (250-350 g) placerads individually in a series of 4000 ml of white wine and 100 ml of chloroform. Sedan andningen upphört avlägsnades djuret frän bägaren, bröstkorgen öppnades och hjärtat undersöktes pä närvaro eller fränvaro av kammar-flimmer. The use of electrocardiographs is limited. The air conditioner can be removed from the tweezers without tweezers. Flimmer ansägs föreligga om fina vibrationer förefanns päytan av ventrikeln och kvarstod i ätminstone 5 secunder efter det att bröstkorgen tappnats eller efter den Mekaniska stimuleringen. The chamber conditioner may be used for the purpose of coordinating the ventricular activity or further to the procedure.

A portion (1-5 ml) was added to the mixture for intraperitoneal addition and the mixture was dried at 25 g for a minute and then treated with chloroform.

The table contains the observation tables with the test table in the test case: 57254 Ί9

Percentage of popularity

Test substance Dosage (mg / kg) of thiones in the form of 2-amino-N-methyl-2 *, 6'-acetoxylide 328 100% 165 90% 3-amino-2 ', 6'-butyroxylide 326 100% 2-amino -N-methyl-2 ', 6'-propionoxylide 200 87% 2-amino-2', 6'-butyroxylide 63 50% 3-amino-2 ', 6'-dimethyl-4'-propoxypropionanilide 200 33% of the total number of upstream data upstream is subject to antiarrhythmic effects. However, the local anesthetic network has been shown to be anesthetic and antiarrhythmic.

The use of anti-arrhythmias and local anesthetic effects is considered to be an adverse effect and the primary amenity is not particularly affected by the use of anti-arrhythmias and other local anesthetics. A.P. Truant and B. Takman, ‘Local Anesthetics’, Drills, Pharmacology and Medicine, J.R. DiPalma, ed., McGraw-Hill Book Co., New York, (1965) and F.F. Doerge, ‘Local Anesthetic Agents’, Testbook of Organic Medicine and Pharmaceutical Chemistry, 5: th Ed. C/O. Wilson et al., Lippincott, Philadelphia, Pa., Pp. 597 ”598 (1966).

For example, a mixture of methemoglobin and blodcirculation is used in addition to the above-mentioned methemoglobin. This type of substituent may be used as an alternative to the orthogonal pd gas ring.

Claims (9)

50 57254 An analogous method according to any one of claims 1 to 3 of patent 55 492 for the treatment of primary aminoacylanilides of the formula R 1 β 2 c 79 (R 1) R 1 * - (/ - N - CO - C - (C ) „NH, (I) \ = / R1 p8 r10 V or their optically active isomers, except for the racemic form of 2-amino-2 ', 6'-propionoxylide, in which R represents hydrogen, methyl or ethyl, R1 represents methyl or ethyl, R1 represents hydrogen or methyl, represents hydrogen, methyl or an alkoxy group having 1 to 4 carbon atoms, R® represents methyl, ethyl or chlorine, R 7 represents 8 Q is hydrogen, methyl or ethyl, R is hydrogen, R is hydrogen, methyl or ethyl, R10 is hydrogen, and n is 0 or 1., provided that when n is 0 and R1, R1, R2, and R® all represent hydrogen and R2 and R® are each methyl, R1 is not methoxy, n-butoxy, hydrogen or methyl when n = 0 and R1, R1, R1, R1 and R® represent hydrogen and R2 is methyl, R® is not chlorine; as well as for the preparation of their therapeutically acceptable salts, characterized in that a) ammonia is reacted with a compound of the general formula r3 \ _yR2 r7 r9 R1 · - ({\ -N - 00 - C - (C) - X 18 ^ 10 \ c R1 R ° R1U \ 6 wherein R1-R1 and R®-R10 and n are as defined above and wherein X is chlorine, bromine, iodine or p-toluenesulfonyloxy, or b) a compound of formula R3 r2 V / r7 f R1 * - (f VN - 00 - 0 - (C) _ - X 8 R 10 51 57254 wherein R 1 - * 1 * and R 1 --R 10 and n have the same meaning as above and wherein X represents chlorine, bromine or iodine, is reacted with potassium phthalimide, after which the n-substituted phthalimide formed is reacted with hydrazine hydrate and then heating the formed intermediate in the presence of an acid; or c) for the preparation of compounds of general formula I wherein n is 1, reacting ammonia with a compound of general formula R 4 - ((fv) -N - CO - C = CH 2 wherein R 1 -R 2 and R 2 have the same meaning) as above and A and B are selected. 7.8. q. in the group consisting of R 'and R and R7 and R, respectively; or d) For the preparation of compounds of general formula I in which R 1 and R 2 are each hydrogen and h 'is 1, a compound of general formula SC ϊΓ - (/ \\ - N-CO-CC = N \ = <R 8 \ r 6 wherein R 1 -R 2 and R 2 -R® are as defined above, to react with a reducing agent or hydrogen, or e) a compound of formula r 3wr 2 r ** - v_y - | H 1. ii 6 wherein R -R and R are as defined above are reacted with a compound of formula R7 r9 tf XCO - C - (C) n - NHP I t r8 R10 7 10 wherein R -R and n are as defined above, X is chlorine or 52 5 7 2 5 4 bromine and P is an amine protecting group to form an intermediate which is then reacted with a suitable substance to remove amine protecting groups, followed by reaction of the compound obtained according to any one of methods a) to e) to an optical isomer, if desired, and and / or a therapeutically acceptable salt. Analogous process according to Claim 1, characterized in that the (+) form of 2-amino-2 ', 6'-propionoxylide is prepared. Analogous process according to Claim 1, characterized in that the (-) form of 2-amino-2 ', 6'-propionoxylide is prepared. Analogous process according to Claim 1, characterized in that 3-amino-2 ', 6'-butyroxylide is prepared. P atentkrav 1. An analogous form according to claims 1-3 of patent 55 ** 92 for the preparation of antiarrhythmic active primary aminoacyl anilides with the formula r3 \ / r2 r7 r9 ny ~ ii 1 R4 - (/ -N - CO - C - (C ) - NH0 (I) - - [1 -Lo ho x R1 R8 R10 or optically active isomeric compounds, which are obtained in the racemic form to give 2-amino-2 *, 6'-propionoxylides, in the form of 1. R betecknar Väte, methyl or ethyl, R R betecknar methyl or ethyl, 3 k R betecknar Väte or methyl, R betecknar Väte, methyl or alkoxy group with l-1 * cholatom, R ^ betecnar methyl, ethyl or chloro, R? betecknar väte, methyl or ethyl, R® betecknar väte, r9 betecknar väte, methyl or ethyl, R ^ betecknar väte, och n är 0 eller 1, ffcfutsatt att-när-n = 0 och R1, R ^, R ^ och R a substituent of R 2 and R 2 of R 2 is methyl, which is a group of methoxy, n-butoxy, methyl or methyl; when n = 0 and R 2, R 2, R 2 and R 8 down to R 2 and R 2 or methyl; and therapeutic therapies for the treatment of: (a) ammonia with the formulation of the formulation * * o: 57254 53 r3 v ^ r2 f? 9 R1 * -V \ - N - CO - 0 - (C) n - X 41 18 is selected from the group consisting of R 1 -R * 1 and R 2 -R 10 as well as an enantiomeric residue, and X is selected from the group consisting of Cl, Br, I and p-toluenesulfonyl; or b) a mixture of the compounds of formula r5 \ / r2 R7 R9 R ^ - & -N “CO - C - (C) - X '“ O'1 le j, io XR6 i vilken R ^ -R ^ och R ^ -R1 ^ samt n har ovan angivna betydelser, och i vilken X betecknar chloro, Brom eller iod, med potassiumphthalimide, var-efter man omsätter den bildade N-substituted phthalimiden med hydrazinhydrat och därpä uppvärmer den bildade mellanproduct ; or (c) for fractions of the formula I and n = 1, the ammonia content of the formula r3v <r2 R1 * -K vN - CO - C = CH \ = / il II Λ, β AB i vilken R ^ -R ^ och R ^ har ovan angivna betydelser och A och B är Valda ur Gruppen bestäende av R? and R® is respecting R 1 and R 10; or (d) for the purposes of the formulation of the subformals of formula I, i is denoted by R ^ oc and R ^ ®, the value being och n = 1, the equivalents being derived from the subformals of formulas R3y- (R2 f R4 '- ([\ -N “ CO-CC = N i-