DK145892B - PROCEDURE FOR THE PREPARATION OF PYRAZINAMIDE DERIVATIVES - Google Patents

Description

(19) DENMARK (®)

| p (12) PUBLICATION ON 145892 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 4292/68 (51) IntCI.3 C 07 D 2 Λ1 / 2 6 (22) Filing Day 6. s ep. 1968 C 07 D A01 / 12 (24) Running day Sep 6 1968 C 07 D A03 / 12 (41) Aim. available Mar 8 1969 (44) Submitted 5 · Apr · 1 9 ^ 5 (86) International Application No. - (86) International Filing Day (85) Continuation Day - (62) Stock Application No. -

(30) Priority Sep 7 1967, 666004, US Mar 21 1968, 718976, US

(71) Applicant MERCK & CO. INC., Rahway, US.

(72) Inventor Edward Jethro Cragoe Jr., US: Kenneth Leroy Shepard, US.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Process for the preparation of pyrazinamide derivatives.

The present invention relates to a particular process for the preparation of pyrazinamide derivatives of the general formula set forth in the preamble of claim 1. This formula includes both known and novel compounds which can be used as active diuretic and natriuretic agents.

To date, the compounds of the general formula set forth in which halo is chloro, bromo or iodo, R ° is alkyl, alkoxymethylalkyl, cyanoalkyl, alkoxycarbonylalkyl, phenylalkyl, 2- (2- Πimidazolinyl) aminomethylalkyl, alkenyl, alkynyl, phenyl, halo-phenyl, alkylphenyl, alkoxyphenyl, amino, di (alkyl) amino, (alkylphenylalkyl) amino, pyridylamino, pyrimidinylamino, quinolinylamino, 4 m

J

1-Pyrrolidinyl, 1-piperidino, 1-hexahydro-1-azepinyl, 4-morpholino or 4- (3,5-diamino-1,2,4-triazolyl).

The process according to the invention, which is characterized by the characterizing part of claim 1, uses a novel intermediate, namely a high-conversion pyrazinoyloxyacrylamide which reacts with primary amines. This reaction can be illustrated by the following reaction scheme: R1 R1 ^

Ργν "2 S YT

halo ^^ \ -0-C = C-C-NHR5 + HoNR6 - ^ halo / ^ N '\, _ NHR6 o r ¥ o o

I II III

in which formulas R 1, R 1, R 2, R 1, R 2 and halo have the meaning set forth in claim 1.

It has previously been proposed to prepare compounds similar to the above-mentioned pyrazinamides (III) by reaction of the amino compound concerned and an alkyl pyrazinoate. However, it has been found that these esters do not or only slowly react. If one tries to promote the reaction using more powerful reaction conditions, the side reactions become dominant. Therefore, there has been a need for more reactive derivatives of pyrazic acids. According to the invention, it has surprisingly been found that the pyrazinoyloxyacrylamides in question are highly reactive derivatives. The reaction proceeds particularly smoothly and in high yield under the reaction conditions of claim 2.

The starting materials are readily available as they can be prepared according to the following reaction scheme: 145892 3 R1 r3 K v. Η n N m0 4 R \ * TI ♦ A κξ,. ^ Γ · γ *! "" / "-" ο ""> y · "" ΛΑ L · £ ~ ° ~ 9 = 9-coNHR5 R 8 i3 I4

IV V I

12345 wherein R, R, R, R, R and halo have the above meaning.

About equivalent amounts of pyrazinic acid IV, an isoxazolium site V and a tertiary amine are dissolved in a solvent and stirred. Examples of a suitable amine are a trialkylamine such as trimethylamine, triethylamine or tripropylamine. Suitable solvent may be used dimethylformamide, dimethylsulfoxide, dimethylsulfone, acetonitrile or tetrahydrofuran, with dimethylformamide and acetonitrile being preferred. First, the pyrazinic acid and the tertiary amine are dissolved, the solution being stirred for a period of time between 5 minutes and several hours. Then the isoxazolium salt is added and the mixture is stirred for 1 to 4 hours, e.g. 2 hours at room temperature, however, if desired, the mixture may be heated to 50 ° C. Product I is usually so stable that it can be isolated and purified. The isolation occurs simply by adding water to the reaction mixture, whereby pyrazinoyloxyacrylamide precipitates. Instead, product (i) can be obtained by evaporating the reaction mixture. The resulting products can be recrystallized, usually by a polar organic solvent such as acetonitrile or isopropanol.

It is sometimes advantageous to tooth-isolate the intermediates, the pyrazinoyloxyacrylamides, but on the other hand convert them in situ to the desired substituted pyrazinamides (III). In this case, one can approx. 1 hour after the mixture of reagents IV and V and the tertiary amine add 1-10 equivalents of the amine (II) and the reaction mixture is stirred at room temperature to 150 ° C for 2 to 24 hours. The amide formed is isolated by diluting the reaction mixture with water or in some cases with an alcohol such as ethanol or isopropyl alcohol which precipitates the desired substituted amide.

145892 4

If it is convenient to first isolate the pyra 'inoyloxyacrylamides (I), the reaction is carried out as described above with the change that the precursor intermediate (i) and the amino compound (II) are mixed in a molar ratio of 1: 1. and 1:10 in a solvent such as dimethylformamide, dioxane, dichloromethane, tetrahydrofuran, acetonitrile or t-butanol, preferably tetrahydrofuran or acetonitrile, and the mixture is stirred for 2 to 24 hours between room temperature and the boiling point. Reaction time and temperature depend on the nature of the reagents.

The pyrazic acids can be prepared by hydrolysis of the corresponding methyl esters (VI) as shown below. The hydrolysis can be carried out with an aqueous base such as sodium hydroxide or potassium hydroxide and a solvent such as isopropanol or ethanol and the mixture is boiled for 1 to 10 hours. The pyrazinic acid is then isolated by cooling and adding acid, such as hydrochloric or sulfuric acid.

NS \ ^

halo C00CH, halo / C00H

3

VI IV

The process of the invention is illustrated by the following examples.

EXAMPLE_1 N-Ethyl-3,5-diamino-6-chloropyrazinamide N- (t-Butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (0.10 g, 0.3 mole) ) is dissolved in a minimum of tetrahydrofuran.

A 70 $ aqueous ethylamine solution (1.0 ml) is added and the solution is boiled for 4 minutes. The solution is evaporated under reduced pressure and the residue is treated with water (5 ml). On standing, a solid which is collected and dried crystallizes 0.05 g (769 e), mp: 204 - 6 ° C. Recrystallization of benzene gives N-ethyl-3,5-diamino-6-chloropyrazinamide which melts at 205 - 206 ° C.

5 U5832

Calcd for CyH 2 ClCl 2 O: C 38.98, Η 4.67, N 32.48.

Found: C, 38.65; H, 4.60; N, 33.28.

EXAMPLE 2 N-Ethoxycarbonylmethyl-5,5-diamino-6-chloropyrazinamide

Ethyl glycinate hydrochloride (5.60 g, 0.04 mol) is dissolved in a mixture of water (50 ml) and sodium bicarbonate (5.0 g, 0.06 mol). A solution of N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazine oyloxy) acrylamide (3.27 g, 0.01 mole) in tetrahydrofuran (100 ml) is added, and the mixture is heated on a steam bath for 2 hours. Water (500 ml) is added and the solution is cooled. The solid precipitate is collected and dried, 2.17 g (80%), mp: 172 - 174 ° C. After recrystallization from isopropanol, the N-ethoxycarbonylmethyl-3,5-diamino-6-chloropyrazinamide melts at 174 - 175 ° C.

Analysis calculated for C 9 H 12 ClN 5 O 3: C 39.49, H 4.42, N 25.59.

Found: C 39.77, H 4.38, N 25.45.

EXAMPLE 3 N- (2-Morpholinoethyl) -3,5-diamino-6-chloropyrazinamide

A solution of N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (3.27 g, 0.01 mole) and 2-morpholinoethylamine, (1, 50 g, 0.0115 m) in tetrahydrofuran are boiled for 2 hours. The tetrahydrofuran is evaporated under reduced pressure and the residue is suspended in hexane (40 ml) and filtered, 3.0 g (100%), mp: 153 -166 ° C. By recrystallization of the N- (2-morpholinoethyl) -3,5-diamino-6-chloropyrazinamide of absolute ethanol, the melting point is raised to 178-180 ° C.

Analysis calculated for c11 H17 ClN6 ° 2: c3 3.93, H 5.70, N 27.95.

Found: C 44.22, H 5.68, N 27.84.

EXAMPLE 4 N-Phenyl-5,5-Diamino-6-chloropyrazinamide

A mixture of N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (3.27 g, 0.01 mole), aniline (4.65 g , 0.05 mole) and n-amyl alcohol (20 ml) are heated to reflux. The resulting solution is boiled for 24 hours and filtered hot to remove any insoluble matter. The filtrate is evaporated under reduced pressure and the oily residue is dissolved in dichloromethane (50 ml). This solution extracts s with 1N hydrochloric acid (two 20 ml portions), dichloromethane is dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue is triturated with butyl chloride to give 0.30 g of N-phenyl-3,5-diamino-6-chloropyrazinamide, mp: 193 ° C. After recrystallization from cyclohexane, the product melts at 198 - 202 ° C.

Analysis calculated for C CH H qClN ^O: C 50.10, H 3.82, N 26.56.

Found: C 49.98, H 3.84, N 26.39.

Example 5 3.5-Diamino-6-chloropyrazinic acid. 2,2-tetramethylenhydrazid

A mixture of 1-aminopyrrolidine (2.15 g, 0.025 mol), N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (6.56 g, O (2 ml) and acetonitrile (100 ml) are heated under reflux for 2 hours.

The precipitate is collected and dried, 3.45 g (67%), m.p. 222-224.5 ° C. Recrystallization from acetonitrile gives 3,5-diamino-6-chloro-pyrazinic acid, 2,2-tetramethylene hydrazide, mp: 224 - 225.5 ° C.

Analysis calculated for C C CH ClClNgO: C 42.11, H 5.10, N 32.74.

Found: C 42.44, H 4.88, N 32.38.

EXAMPLE 6 Diamino-6-chloropyrazinic acid. 2- (2-pyridyl) hydrazide

A mixture of 2-hydrazine pyridine (2.18 g, 0.02 mol), N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (3.39 g, O 01 mol) and acetonitrile (75 ml) are heated under reflux for 3 hours.

The precipitate is collected and dried, 2.21 g (79%), mp: 283 -286 ° C, dec. This sample is further purified by dissolving dilute methanesulfonic acid and re-precipitating by adding 10% sodium hydroxide solution to give 3,5-diamino-6-chloro-pyrazinic acid, 2- (2-pyridyl) hydrazide, mp: 286-290 ° C, dec ..

Analysis calculated for C10 H10 ClN3 O: C 42.94, H 3.60, N 35.00.

Pound: C 42.74, H 3.96, N 34.75.

EXAMPLE 7 3.5 - Diamino-6-chloropyrazinic acid, 2- (2-pyrimidinyl) hydrazide hydrate

A mixture of 3,5-diamino-6-chloropyrazinic acid (1.90 g, 0.01 mole) and triethylamine (1.0 g, 0.01 mole) in dimethylformamide (20 ml) is stirred for 10 minutes. To this solution is added N- (t-butyl) -5-methylisoxazolium perchlorate (2.40 g, 0.01 mol) and the resulting solution is stirred for 1 hour. A solution of 2-hydrazinopyrimidine (4.40 g, 0.04 mol) in dimethylformamide (20 ml) is added, the solution is stirred for 4 hours and then heated on a steam bath for 3 hours. Water (200 ml) is added and the precipitate is collected and dried. The yield is 2.25 g (80.5%), mp: 257-260 ° C. Recrystallization from 80% acetonitrile gives pale yellow crystals, mp: 262-226 ° C of 3,5-diamino-6-chloropyrazinic acid, 2- (2-pyrimidinyljhydrazid hydrate.

Analysis calculated for C C HH ^NNO₂H₂O: C 36.19, H 3.71, N 37.52.

Pound: C 36.18, H 3.75, N 37.74.

EXAMPLE 8 5 ♦ 5-Diamino-6-chloropyrazinic acid. 2,2-hexamethylene hydrazide 8 145892

A solution of 1-aminohomopiperidine (4.56 g, 0.04 mol) and N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (3.28 g, 0.01 mol) in tetrahydrofuran (50 ml) is boiled for 24 hours. The solvent is evaporated under reduced pressure and the oily residue is dissolved in isopropanol (100 ml). On cooling, a substance which is collected and dried is 1.06 g (37%), mp: 181 ”1S0 ° C. Recrystallization from acetonitrile yields 3,5-diamino-6-chloropyrazinic acid, 2,2-hexamethylene hydrazide, mp: 190 -192 ° C.

Analysis calculated for C C ^H ClClNgO: C 46.39, H 6.02, N 29.52.

Pound: C 46.80, H 5.85, N 29.96.

EXAMPLE 9 3.5- Diamino-6-chloropyrazinic acid. 2.2-pentamftt.h we pnhvrtr- *? -i ή

A mixture of 3,5-diamino-6-chloropyrazinic acid (3.80 g, 0.02 mol) and triethylamine (2.0 g, 0.02 mol) in dimethylformamide (40 ml) is stirred for 10 minutes. To this solution is added N- (t-butyl) -5-methylisoxazolium perchlorate (4.80 g, 0.02 mol) and the resulting solution is stirred for 1 hour. 1-Aminopiperidine (5.2 g, 0.52 mol) is added and the solution is heated on a steam bath for 4 hours. Isopropanol (25Ο ml) is added and the solid, which is separated by cooling and dried, 2.22 g (41%), mp: 238 - 243 ° C. Recrystallization from acetonitrile gives yellow crystals of 3,5-diamino-6-chloropyrazinic acid, 2,2-pentamethylene hydrazide, mp: 244 - 245 ° C.

Analysis calculated for C C CH ^ClNgO: C 44.36, H 5.59, N 31.05.

Found: C 44.52, H 5.28, N 31.37.

EXAMPLE_12 3.5- Diamino-4- (3,5-diamino-6-chloropyrazinamido) -4H-1,2,4-triazole hemihydrate

A mixture of 3,5-diamino-6-chloropyrazinic acid (1.90 g, 0.01 mole) and triethylamine (1.0 g, 0.01 mole) in dimethylformamide (20 ml) is stirred for 10 minutes. To this solution is added N- (t-butyl) -5-methylisoxazolium perchlorate (2.40 g, 0.01 mol) and the resulting solution is stirred for 1 hour. A mixture of 3,4,5-triamino-4H-1,2,4-triazole (3.06 g, 0.03 mol) and dimethylformamide (10 ml) is added and the reaction mixture is heated on a steam bath for 16 hours.

Water (200 ml) is added and the resulting precipitate is collected and dried; yield 1.50 g (51%), gradual decomposition above 200 ° C.

Recrystallization of water gives brown crystals of 3,5-diamino-4- (3,5 "diamino-6-chloropyrazinamido) -4H-1,2,4-triazole hemihydrate, mp: 275-280 ° c, deck ..

Analysis calculated for C 7 H 9 ClN 1 () 0. 1 / 2H 2 O: C 28.63, H 3.43, N 47.70. Found: C 28.58, H 3.37, N 47.45.

EXAMPLE_11 N- (3,5-Diamino-6-chloropyrazinoyl) benzamidine

Sodium hydroxide (1.20 g, 0.03 mol) is dissolved in water (30 ml) and benzamidine hydrochloride (5.60 g, 0.036 mol) is added. This solution is stirred for two minutes, N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (3.28 g, 0.01 mol) is added and the mixture stir for 2 hours. The precipitate is collected, dried and recrystallized from acetonitrile to give 0.83 g (29%) mp: 220 - 224 ° C, dec. On recrystallization from ethanol-acetonitrile, N- (3,5-diamino-6- chlorpyrazinoyl) benzamidine, mp: 221 -224 ° C, dec.

Analysis calculated for C C ^H ^ClNgO: C 49.57, H 3.81, N 28.91 *

Found: C 49.95, H 3.90, N 29.12.

EXAMPLE 12 (3,5-Diamino-6-chloropyrrazinyl) guanidine hydrochloride dihydrate

A mixture of 3,5-diamino-6-chloropyrazinic acid (1.90 g, 0.01 mole) and triethylamine (1.0 g, 0.01 mole) in dimethylformamide (20 ml) is stirred for 10 minutes. . N- (t-butyl) -5-methylisoxazolium perchlorate (2.40 g, 0.01 mol) is added and the resulting solution is stirred for 1 hour.

Sodium (1.15 g, 0.05 mole) is dissolved in absolute ethanol (50 ml). Guanidine hydrochloride (4.75 g, 0.05 mol) is added and the mixture is stirred for 1/2 hour. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in dimethylformamide (10 ml) and added to the above solution. This reaction mixture is stirred for 24 hours, poured into water (100 ml) and cooled. The precipitate is collected and dried. The yield is 0.88 g, mp: 229 -233 ° C, dec.

The product is dissolved in a mixture of water (15 ml) and methanesulfonic acid (2 ml) by heating, concentrated hydrochloric acid (4 ml) is added and the solution is left to stand. The precipitated substance is collected and dried. The yield of (3,5-diamino-6-chloropyrazinoyl) guanidine hydrochloride dihydrate is 36%, mp: 295 ° C (dec.). This substance behaves similarly to chromatographic studies, has the same infrared spectra as a otherwise prepared sample, and exhibits no freezing-point depression with such a sample.

EXAMPLE_13 3,5-Diamino-6-chloropyrazinoylguanidine hydrochloride dihydrate

Sodium (0.09 g, 0.004 mol) is dissolved in absolute ethanol (10 ml) and guanidine hydrochloride (0.382 g, 0.004 mol) is added. This mixture is stirred 1/2 hour, N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (0.300 g, 0.0009 mol) is added and the mixture is boiled for 1 hour. hour. The reaction mixture is cooled, diluted with water (25 ml) and acidified with dilute hydrochloric acid. Upon standing, a precipitate is collected which is collected and dried to give 0.15 g (60%) of (3> 5-diamino-6-chloropyrazinoyl) guanidine hydrochloride dihydrate mp: 295 ° C (dec).

1- (5,5-Diamino-6-chloropyrazinyl) -5-isopropylidene aminoguanidine EXAMPLE 14 11 US892

A mixture of 3,5-diamino-6-chloropyrazinic acid (3.80 g, 0.02 mol) and triethylamine (2.0 g, 0.02 mol) in dimethylformamide (40 ml) is stirred for 10 minutes. To this solution is added N- (t-butyl) -5-methylisoxazolium perchlorate (4.80 g, 0.02 mol) and the resulting solution is stirred for 1 hour. A solution of isopropylideneamino guanidine (9.12 g, 0.08 mol) in dimethylformamide (20 ml) is added and the reaction mixture is stirred at room temperature for 18 hours.

Water (250 ml) is added and the precipitate is collected and dried. The yield of 1- (3,5-diamino-6-chloropyrazinoyl) 3-isopropyl-denaminoguanidine is 4.35 g (76%); mp: 171 - 178 ° c. Recrystallization from acetonitrile gives pale yellow crystals, mp: 183 -186 ° C.

Analysis calculated for C CHHClNgO: C 37.96, H 4.60, N 39.36.

Found: C, 38.01; H, 4.65; N, 39.15.

Example 15 1- (5,5-Diamino-6-chloropyrazinoyl) -3-hydroxyguanidine

Sodium (1.0 g, 0.044 mol) is dissolved in boiling isopropanol (200 ml). Hydroxyguanidine sulfate hydrate (6.38 g, 0.024 mol) is added and this mixture is boiled for 1 hour. N- (t-butyl) -3-methyl-3- (3,5-di-amino-6-chloropyrazinoyloxy) acrylamide (6.54 g, 0.02 mol) is added, boiling is continued for 1 hour, then the mixture is cooled and filtered. The yellow substance is washed with water and isopropanol and dried to give 2.75 g (56%) of 1- (3,5-diamino-6-chloropyrazinoyl) -3-hydroxyguanidine, mp: 188 - 200 ° C (effervescence) . Recrystallization of dimethylformamide-water gives a product, mp: 200-202 ° C (dec).

Analysis calculated for C CHgClNyO₂: C 29.34, H 3.28, N 39.92.

Found: C 29.42, H 3.25, N 40.01.

12 1- (3,5-Diamino-6-chloropyrazinoyl) -5-benzyloxyguanldine

PREVIEW

145892

A solution of N- (t-butyl) -3-methyl-3- (3,5-diamino-6-chloropyrazinoyloxy) acrylamide (1.08 g, 0.0033 mol) and benzyloxyguanidine (1.1 g, 0.0067 mol) in tetrahydrofuran (30 ml) is boiled for 48 hours. The solution is evaporated under reduced pressure and isopropanol (20 ml) is added to the residue. The solid is collected and dried, 0.95 g, mp: 105 - 110 ° C, solidifies again and melts again at ca.

160 ° C. Recrystallization of benzene gives pale yellow crystals of 1- (3,5-diamino-6-chloropyrazinoyl) -3-benzyloxyguanidine, mp: 163 -166 ° C.

Analysis calculated for C C HH ^ClN ^ And: C 46.50, H 4.20, N 29.21.

Pound: C 46.72, H 4.23, N 29.45.

By the method of the above examples, the following compounds can be prepared: 1 (3,5-diamino-6-chloropyrazinamido) guanidine, mp: 281 - 282 ° C, 1- (3,5-diamino-6-chloropyrazinamido) -3-benzylguanidine, which becomes liquid at 120-130 ° C, solidifies red again at 200 ° C and then has a melting point of 243 - 246 ° C (shared), 1- (3,5-diamino-6-chloropyrazinamido) -3-aminoguanidine hydrate, mp: 196-200 ° C while effervescent, and 1- (3,5-diamino-6-chloropyrazinamido) -2,3-ethylene guanidine, mp: 250 - 251 ° C (dec.).

Claims (2)

13 145892 P_a_t_e_n_t k r av: A process for the preparation of pyrazinamide derivatives of the general formula: R 1 XX e halo ^ 'CONHR ° wherein R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl), dialkylaminoalkyl, hydroxyalkylmethyl, polyhydroxyalkylmethyl, J, U / -trifluoroalkyl, phenylalkyl, halo-phenylalkyl, furylalkyl, phenyl, halophenyl, alkoxy or amino; O is hydrogen or alkyl; or 1 2 R and R may together form an azacyclic ring with the associated nitrogen atom; halo is chlorine, bromine or iodine; R 2 is alkyl, alkoxymethylalkyl, cyanoalkyl, alkoxycarbonylalkyl, phenylalkyl, dialkylaminomethylalkyl, 2- (2-imidazolinyl) aminomethylalkyl, 1-pyrrolidinylalkyl, piperidinoalkyl, hexahydro-1-azeoinylalkyl, morpholinoalkyl, 4-alkyl-alkyl, 4-alkyl-alkyl alkynyl, phenyl, halophenyl, alkylphenyl, alkoxyphenyl, amino, dialkylamino, alkylphenylalkylamino, pyridylamino, pyrimidinylamino, quinolinylamino, 1-pyrrolidinyl, 1-piperidino, 1-hexahydro-1-azepinyl, 4-morpholino -diamino-1,2,4-tria-7zolyl), -OR / where R is alkyl, phenyl, halo-1h phenyl, alkylphenyl or alkoxyphenyl; -C-NR R 9 wherein R is hydrogen or alkyl; t8 g R is hydrogen, alkyl, hydroxyalkyl, phenylalkyl, halophenylalkyl, alkylphenylalkyl, naphthylalkyl, pyridylalkyl, morpholinoalkyl, furylalkyl, alkoxyalkyl, alkenyl, alkylideneamino, phenylalkylideneamino, hydroxy, phenyl, alkylphenyl, alkoxyphenyl, alkoxyphenyl, alkoxyphenyl, alkoxyphenyl phenylalkoxy;