DK146509B - METHOD OF ANALOGY FOR PREPARING PYRIDOXIN DERIVATIVES - Google Patents

Description

(19) DENMARK (w) rf4- V Ray

^ (12) PUBLICATION MANUAL (n) 146509 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No .: 0697/77 (51) Int.CI.3: C 07 D 213/66 (22) Filing Date: 18 Feb 1977 C 07 D 491/056 (41) Aim. available: 21 Aug 1977 (44) Submitted: 24 Oct 1983 (86) International Application No: - (30) Priority: 20 Feb 1978 FR 7604825 (71) Applicant: 'PARCOR; 75008 Paris, FR.

(72) Inventor: Jean-Pierre 'Maffrand; FR, Jean-Marie * Pereillo; FR.

(74) Plenipotentiary: Patent Office Magnus Jensens Eflf._ (54) Analogous procedure for the preparation of pyridoxine derivatives

This invention relates to an analogous process for the preparation of novel pyridoxine derivatives which can be used in human and veterinary medicine and which have the general formula I as set forth in claim 1,

The process according to the invention for the preparation of the compound of formula I is characterized by the part of claim 1, wherein the process compound of formula II is one. known compound and its preparation are described by W. Korytnik and W. Wiedman ^ (J. Ohem, Soc., 1962, 2531).

The haloalkylamines of formula III are known compounds.

They can be produced by Douglas C. Kriesel and Ole Gisvold (J. Pharm.

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Sci., 1967, £ 6,327) and J. Bourdais (Bull.Soc.Chim.Fr. 1968, (8), 3246).

The condensation which enables the compounds Ia to be obtained is usually carried out in the presence of a concentrated aqueous hydroxide solution, especially of an alkali metal such as, for example, sodium hydroxide having a strength of 10-60 and preferably 50% by weight.

The reagents of formulas Π and ΙΠ are preferably used in this reaction in stoichiometric amounts, but one of the two reagents can also be used in excess. The temperature of the reaction environment is preferably maintained between 50 and 100 ° C.

In this method of preparation, a reaction occurs. .

heterogeneous environment with phase transfer catalyst. The catalysis is ensured using quaternary ammonium salts of formulas „3 χθ. ø 3 3

r4 / 0 ^ r4 R

arising from dimerization and intramolecular cycling of haloalkylamines of formula III, respectively, under the reaction conditions.

The conversion of the compounds of formula Ia to 1b is carried out by treatment with a mineral acid or organic acid in an aqueous or anhydrous environment at a temperature of 20-100 ° C. "

The compounds in question have not only sedative but also vasodilatory effect. The latter effect is not considered to be present in related compounds according to "Arzneimittelforschung", Vol. 11 (1961), pp. 922-929.

The following examples illustrate the method of the invention.

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Example 1

Preparation of 5-R ((3-morpholinoethyl) -oxy) -methyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine (derivative 1), R + R = iso -2 4 propylidene, NR R »morpholino, n = 2.

A mixture of 23 g of hydrochloride of N- (2-chloroethyl) morpholine in 60 ml of 50% sodium hydroxide solution and 20 g of hydrochloride of 5-hydroxymethyl-2,2,8 is heated to 100 ° C for 5 hours. trimethyl-4H-m-dioxino (4,5-c) pyridine.

The mixture is then diluted with water and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated to dryness. The solution obtained by dissolving the residue in chloroform is filtered on silica gel and evaporated under vacuum.

The oil obtained is converted to dihydrochloride hydrate. Recrystallization of a mixture of ethanol and ethyl acetate yields 6.20 g of white crystals (yield 65.590 m.p. determined on K8 multiple block 216 ° C.

Example 2

Preparation of 5 - ((3- (4-P-chlorophenylpiperazinyl-1) -propyl) -oxy) -methyl-2,2,8-4H-m-dioxino (4,5-c) pyridine (derivative 2) , R1 + R = * 2 h isopropylidene, NR 1 R = 4-p-chlorophenylpiperazinyl, n = 3.

A mixture of 10 g of hydrochloride of 5-hydroxymethyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine and 14.1 g was heated to 100 ° C for 6 hours with good stirring. 1-Chlorophenyl-4- (3-chloropropyl) -piperazine in 50 ml of 50 $ sodium hydroxide. The reaction environment is then diluted with water and extracted with chloroform. The chloroform extracts are dried over sodium sulfate and filtered on silica gel.

After evaporation under vacuum of the solvent, 14 g of an oily product is obtained which is converted to dihydrochloride hydrate. Recrystallization from ethanol gives 12 g of white crystals (yield 56%), m.p. determined on K8fler block is 188 ° C.

Example 3

Preparation of 3-hydroxy-4-hydroxymethyl-2-methyl-5 '((β-aorpholino-ethyl, -my) -methylpyridine (derivative 3), R 1 = R 2 = H, NR 2 R 4 = morpholino, n = 2 .

A solution of 11.4 g 5 - ((p-morpholinoethyl) -oxy) -methyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) is heated to 100 ° C for 3 hours. After cooling and evaporation to dryness, the residue is taken up in a saturated aqueous sodium chloride solution and made basic by the addition of sodium carbonate and extracted with chloroform. The chloroform extracts are dried over sodium sulfate, filtered on silica gel and evaporated to dryness.

A solid is obtained whose recrystallization from ethyl acetate gives 5.5 g of white crystals (yield 56%). Mp. determined on Kbfler block 98 ° C.

Example 4

Preparation of 5 - ((3- (4-p-chlorophenylpiperazinyl-1) -propyl) -oxy) -methyl-3-hydroxy-4-hydroxymethyl-2-methylpyrid in (derivative 4), R = R, =%, = 4-p-chlorophenylpiperazinyl, n = 3.

A solution of 6 g of dihydro chloro-id hydrate of 5 - ((3r (4-p-chlorophenylpiperazinyl) -1) -propyl-oxy) -methyl-2,2,8-trimethyl is heated at 90 ° C for 6 hours. -4H-α-dioxino (4 »5-e) pyridine in 100 ml of 70% acetic acid Evaporation under vacuum of the solvent leaves a solid residue whose recrystallization of 90% of ethanol gives 2.6 g of white crystals of dihydrochloride. hydrate (yield 5090, mp 186 ° C.

Derivative 5τ ((β-d ime thylaminoe thy 1) -oxy) -methyl-2,2,8-trimethyl 1-4H-mdio-xino (4,5-c) pyridine, + R 2 = isopropylidene, R 2 = R 2 = methyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 192 ° C (ethanol), prepared according to the procedure described in Example 1, yields 20%.

Derivative 6 (β (Mlie thylaminoeyl) -K5xy) -me thyr 1-4H-m-dioxolo (4,5-c) pyrldine,.

R1 + R2 = isopropylidene, R4 = R4 = ethyl, n = 2.

Dihydrochloride: white crystals, m.p. = 200 ° C (ethyl acetate and ethanol) prepared by the method of Example 1, yield 62%. Derivative 5- ((2- (1-pyrrolidinyl) ethyl) -oxy) -ethyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine, R = isopropylidene, NR 1 R 2 = pyrrolidinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 170 ° C (isopropanol), prepared according to the procedure of Example 1, yield 65%.

Derivative 8 5 ° C β -piperidinylethyl-oxy-methyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine, R1 + R2 = isopropylidene, NR R 2 = piperidino, n = 2.

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Dihydrochloride hydrate: white crystals, m.p. 143 ° C (ethanol), prepared according to the procedure of Example 1, yield 25%.

Derivative 5 - ((2- (4-phenylpiperazinyl-1) -ethyl) -oxy) -methyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine, R1 + R2 = isopropylidene, NR -% ^ = 4 - phenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 206 ° C (ethanol), prepared according to the method of Example 2, yield 42%.

Derivative 5β (2- (4-o-chlorophenylpiperazinyl-1) -ethyl) -oxy) -methyl-2,2,8-1,2-trimethyl-4H-m-dioxino (4,5-c) pyridine, R + R = isopropylidene, NR 2 R 4 = 4-o-chlorophenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 190 ° C (ethanol), prepared according to the method of Example 2, yield 36%.

Derivative 5 - ((2- (4-m-chlorophenylpiperazinyl-1-yl) -ethyl) -oxy) methyl-2,2,8-X 2-trimethyl-4H-m-dioxino (4,5- c) pyridine, R + R = isopropylidene, 3 4 NR-1R = 4-m-chlorophenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 208 ° C (ethanol), prepared according to the procedure of Example 2, yield 57.5%.

Derivative 12 - ((- 2- (4-p-chlorophenylpiperazinyl-1) -ethyl) -pxy) -methyl-2,2,8-1,2-trimethyl-4H-m-dioxino (4,5- c) pyridine, R + R = isopropylidene, NR 4 NR = R = 4-p-chlorophenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 214 ° C (ethanol), prepared according to the procedure of Example 2, yield 52%.

Derivative 13 - ((2- (4-m-trifluoromedylphenylpipe razinyl-1) -ethyl) -oxyxymethyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine, R 2 = R 2 = H,% 4 NR 2 R = 4-m-trifluoromethylphenylpiperazinyl, n = 2. Dihydrochloride hydrate: white crystals, mp 168 ° C (ethyl acetate and ethanol), prepared according to the procedure of Example 2, yield 31%.

Derivative 14 - ((2- (4-p-tolipiperazinyl) -1) -ethyl) oxy) -methyl-2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine, R 2 + R 2 = isopropylidene, NR% 2 = 4-tolylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 177 ° C (ethanol), prepared according to the method of Example 2, yield 44%.

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Derivative 5- (2- (4-o-aethoxyphenylpiperazinyl) -ethyl) -ethyl-trimethyl-4H-m-dioxino (4,5-c) pyridine, Rx + R2 = isopropylidene, NR -o-methoxyphenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 216 ° C (ethanol), prepared according to the method of Example 2, yields $ 16.

Derivative 16 5 - ((3-Dimethylaminopropyl) oxy) -methyl1,2,2,8-trimethyl-4H-m-dioxino (4,5-c) pyridine, R1 + R2 = isopropylidene, R4 = R4 = methyl, n = 3.

Dihydrochloride hydrate: white crystals, m.p. 208 ° C (isopropanol), prepared according to the procedure of Example 1, yield 29 $.

Derivative 13 5 - ((β-dime thy laminoe thy l), - oxy) -me thy 1-3 -hydroxy-4-hydroxy t -yl-2-methylpyridine, R1 = R2 = H, R = R 2 = methyl, n = 2. Dihydrochloride hemihydrate: pale yellow crystals, m.p. 170 ° C (ethanol), prepared according to the procedure of Example 4, yield 73 $. Derivatives lg 3 -hydro oxyr4 uhyd r oxyme thyl «= 2 Hne (2-pyrrylli inyl (1l) -e thy 1 \ - -oxy) -methylpyr.1 din? R 1 = R 2 = H, NR 2 R 2 = pyrrolidinyl, n = 2. Dihydrochloride hydrate: ivory crystals, m.p. 152 ° C (isopropanol), prepared according to the procedure of Example 4, yield 40 $.

Derivative 19 5- (3 "hydroxy-4-hydroxymethyl-2-methyl) - (5- (3-piperidinoethyl) oxy-methylpyridine, R 1 = R 2 = H, NR 2 R 2 = piperidino, n = 2 .

Beige colored crystals, m.p. 76 ° C (ether and methanol), prepared according to the procedure of Example 3, yields $ 50.

Derivative 2D

(3 "Hyaroxy-4-hydroxymethyl-2-methyl-5 ((2- (4 * phenylpiperazinyl-1H) --1H * -ethyl) -oxy) - methylpyridine, R = R = H, NR -'R4 = 4-phenylpipe-razinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 169 ° C (ethanol), prepared according to the procedure of Example 4, yield 35 $.

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Derivative 21 5- ((2- (4-o-chlorophenylpiperazinyl) -1-ethyl) -6xy) -ae thy 1-3-hydroxy-4-hydroxymethyl-2-methylpyridine, = R2 = H, NR R 4 = 4-o-chloro-phenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 176 ° C (95% ethanol), prepared according to the procedure of Example 4, yield 40%.

Derivative 225 - ((2- (4-m-chlorophenylpiperazinyl-1) -ethyl) -oxy) -methyl-3-hydroxy-4-hydroxymethyl-2-methylpyridine, R ^ = R₂ = H, NR- R 4 = 4-m-chloro-phenylpiperazinyl, n = 2.

Light cream colored crystals, m.p. 110 ° C (isopropyl ether and ethyl acetate), prepared according to the procedure of Example 3, yield 69%. Derivative 23 ((2-4-p-ehlorophenylpiperazinyl-1-ethyl) -oxy) -methyl-3-hydroxy-4-hydroxymethyl-2-methylpyridine, R 1 = R 2 = H, NR 2 R 2 = 4 -p-chloro-phenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 186 ° C (ethanol), prepared according to the procedure of Example 4, yield 65%.

Derivative .2.4 3-Hydroxy-4-hydroxymethyl-2-methyl-5- ((2- (4-m-trifluoromethylphenyl-piperazinyl-1) -ethyl) -oxy) -methylpyridine, R 2 = R 2 = H, NR R 4 = 4-m-trifluoromethylphenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 198 ° C (95% ethanol), prepared according to the procedure of Example 4, yield 76%.

Derivatives 3-Hydroxy-4-hydroxymethyl-2-methyl-5 ((2- (4-p-tolylpiperazinyl-1H) -ethyl) -oxy) -methylpyridine, R1 = R2 = H, NR R 4 = 4-p-tolylpipe-razinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 156 ° C (ethanol), prepared according to the procedure of Example 4, yield 60%.

Derivative 2,6 3-hydroxy-4-hydroxymethyl-5 - ((2- (4-o-methoxyphenylpiperazinyl-1) -ethyl) oxy] - methyl-2-methylpyridine, R 2 = R 2 = H, NR 2 R 4 = 4-o-methoxyphenylpiperazinyl, n = 2.

Dihydrochloride hydrate: white crystals, m.p. 188 ° C (ethanol), prepared according to the procedure of Example 4, yield 45%.

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The results of the toxicological and pharmacological studies reported below clearly show the interesting properties of the derivatives prepared by the process of the invention, in particular their sedative and peripheral vasodilator properties.

I - TOXICOLOGICAL INVESTIGATION

The compounds of the present invention have excellent tolerance and low toxicity. Thus, DL 50 / 24h / kg for animals, determined on mice by the method of Miller and Tainter, by intravenous route, 250 mg for derivative 1, 38 mg for derivative 2, 310 mg for derivative 3, 115 mg for derivative 4, 74 mg for derivative 5, 89 mg for derivative 6, 79 mg for derivative 7, 70 mg for derivative 8, 42 mg for derivative 9, 43 mg for derivative 10, 61 mg for derivative 11, 55 mg for derivative 12, 49 mg for derivative 13, 65 mg for derivative 14, 74 mg for derivative 15, 78 mg for derivative 16, 300 mg for derivative 2-7, 125 mg for derivative 18, 160 mg for derivative 19, 120 mg for derivative 20, 69 mg for derivative 21, 31 mg for derivative 22, 63 mg for derivative 23, 74 mg for derivative 24, 87 mg for derivative 25 and 55 ag for derivative 26.

II - PHARMACOLOGICAL RESEARCH

This study demonstrates the effects of the compounds in question.

1. Sedative effect a) Behavioral study

This study is conducted according to the method of Samuel Irwin (Ph.D. Animal and Clinical Pharmacology Technics in Drug evaluation). The studied derivatives are administered through the esophageal probe at a single dose of 30 mg / kg in mice that have been fasting for 16 hours. The study of their behavior and various physiological parameters (temperature, heart and respiratory rate) demonstrates the distinct sedative and myorelaxative effect of these derivatives: A clear decrease in spontaneous motor activity, a decrease in muscular activity, was observed in all animals after 5 minutes. tone and in the degree of alertness and a respiratory depression as well as a less responsive to noise and other environmental influences.

b) Effect on hypnotic agents

The compounds of the invention are administered orally by various mice to a dose of 30 mg / kg for 30 minutes. prior to intraperitoneal injection of an infrahypnotic dose of sodium pentobar - 9 146509 bital. The number of sleeping animals, the time of sleep and the duration of the induced sleep are observed. From the results obtained in Table I, the clear potentializing effect of the compounds studied is clearly evident in comparison with the control animals.

TABLE I

Treatment% sleeping animals average mean duration -___ sleep duration of sleep 0 0 0 0 (control animal) derivative 1 70 9 min 15 sec 1 h 38 min derivative 2 80 8 min 26 sec 1 h 45 min derivative 4 90 9 min 24 sec 1 h 40 min derivative 5 80 9 min 38 sec 1 h 55 min derivative 6 80 9 min 04 sec 2 h 04 min derivative 8 100 9 min 51 sec 2 h 15 min derivative 11 90 8 min 12 sec 1 h 44 min derivative 15 80 9 min 45 sec 1 h 38 min derivative 3-9 100 9 min 28 sec 1 h 58 min derivative 20 90 8 min 50 sec 1 h 45 min derivative 21 90 9 min 12 sec 2 h 10 min derivative 24 70 8 min 45 sec 1 h 46 min derivative 26 80 8 min 52 sec 1 h 42 min c) 4 plate sample (Boissier, Simon and Aron, Europ. J. of Pharmacol. 4, 1968. 145-151)

A mouse placed in an enclosure containing 4 plates of electrical voltage receives at each passage from one plate to another an electrical stimulus which produces an disordered escape.

After n electric shock, the mouse does not move anymore. It is assumed that the degree of reassurance achieved is proportional to the number n of electric shocks the treated mouse receives before placing it in a hook. It is thus determined what percentage increase in the number of shocks in the derivatives, administered orally, at a dose of 30 mg / kg "" will result after 15, 45 and 90 minutes. The results are shown in the following Table II.

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TABLE II

Treatment% increase of n after 15 min. after 45 min. after 90 min.

derivative 1 54 59 31 derivative 2 58 62 30 derivative 4 61 62 33 derivative 5 60 61 28 derivative 6 62 64 32 derivative 8 57 61 34 derivative 11 59 63 30 derivative 15 62 62 31 derivative 19 61 60 26 derivative 20 65 61 28 derivative 21 58 60 28 derivative 24 57 56 25 derivative 26 63 60 32 2. Vasodilatory effect

This effect is investigated by two methods: a) Activity on the ergotamine gut

Administration of large doses of ergotamine induces prolonged vascular spasm in the arteriolar trunk by a direct effect on the smooth vascular musculature, and this spasm is followed by obliterative artery and tissue asphyxia phenomena, which appear especially in the extremities with less blood flow ( is expressed by a more or less intense cyanosis and then a cell destruction that can go as far as gangrene. Administration of the substances to be investigated and having a vasodilatory effect makes it possible to weaken or eliminate those vasoconstriction phenomena induced by ergotamine. The test is performed on rats according to the method of Beigl-bock (Arch.Exp.Path.Pharmacol., 1962, 217, 430): the control animals receive at the root of the tail every day through 11 days of ergotamine-adrenaline injections. In addition, the treated team receives 30 mg / kg of the studied derivative by intra-muscular route for 12 days. The animals are monitored daily and the modifications called for by the effect of ergotamine are evaluated: weak cyanosis (Cl), medium cyanosis (Cm), intense cyanosis (Ci) and gangrene (G).

The results are summarized in the following table, showing the percentage of animals exhibiting the various symptoms as defined above, depending on the time.

2nd day 6th day 12th day

Treatment ci Cm Ci G Cl I Cml Cil G Cl I Cml Cil G '0 control_ ^ 0__0 40 20__0__0 80 20 0 _0 60 40 derivative 2 0 0 0 0 50 10 30 0 20 50 30 _0_ derivative 4 0 0 0 0 60 0 40 0 40 10 40 0 derivative 6__0 0 0 0 50 _0 50 0 40 20 40 0 derivative 7 0 0 0 0. 50 10 30 0 60 10 30 0 derivative Q 0__0 0 0 50 50 0 0 50 40 10 0 derivative 10 0__0 0 0 60__0 40 0, 60 20 10 0 derivative 12 0__0__0 0 60 10 20 0 60 20 20 0 derivative 15 0__0 0 0 | 40 40 20 0 50 50 10 0 derivative * 14 0 0 _0 0 50 20 50 0 50 30 20 0 derivative 16__0__0__0 0 60 50 10 0 50 50 10 0 derivative 17__0 0 _0 0 60 50 10 0 60 50 0 0 derivative 18 0__0__0 0 50 40 10 0 60 30 10 0 derivative 2Q 0__0__0 0 50 10 40 0 30 30 30 0 derivative 22 0__0__0 0 60 30 0 0 50 40 0 0 derivative 2 5 0__0__0 0 50 30 20 0 50 40 10 0 derivative 25 Q 0 I 0 I 0, ΙβΟ I 10 1 30 I 0 l50 i 30 I lol 0 b) Perfusion of rat's hindquarters

The test is performed on a rat anesthetized with an intraperitoneal injection of lg / kg of ethyl urea. The perfusion of Ringer's fluid is done by simple gravity in the animal's abdominal aorta. The fluid is absorbed into the lower cavity. The increase in blood flow is measured by recording with each funnel every drop that falls on a writing pen, allowing a graphical record.

The products studied are administered by intraperitoneal route at a dose of 30 mg / kg. The results are summarized in the table below, which indicates for each derivative examined the percentage of vasodilatation obtained as well as the duration of the vasodilator activity produced.

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Treatment vasodilatation duration of the percent vasodilatory effect derivative 2__160 # _ 90 min.

derivative 4__210 #__ 95 min._ derivative 6__180 #__ 85 min.

derivative 7__170 #__ 75 min.

derivative 9__230 # _ 95 min._ derivative 10__190 #__ 105 min._ derivative 12__180 #__ 80 min._ derivative 13 220 #__ 75 min._ derivative 14__240 #__ 80 min._ derivative 16 220 #__ 100 min._ derivative 17 180 # 110 min «_ derivative 1§ 200 #__ 95 min._ derivative ZO__210 #__ 90 min._ derivative 22__160 # _ 80 min._ derivative Z3__190 #__ 90 min._ derivative 25 220 # 95 min.

The toxicological and pharmacological studies reported above show that the compounds of the present invention have a weak toxicity as well as a good tolerance and that they have significant sedative and vasodilatory properties.

The subject compounds may be administered by oral route in the form of tablets, dragees, capsules, drops or syrups, or may be administered rectally in the form of suppositories or parenterally in the form of injectable aqueous solutions.

Each unit dose of 1.5g preferably contains 0.01-0.250g of active ingredient, the daily doses may vary from 0.010g to 1g of active substance.

lacquered by its considerable sedative and vasodilatory properties, the compounds in question are used advantageously in human and veterinary medicine.

Tea can be used as a sedative to dampen emotional tension in daily practice. Tea soothes and promotes a physiological sleep. While respecting the alertness and integrity of the intellectual functions, they are indicated in anxiety, emotion, irritability and insomnia states.

By the peripheral vasodilat to exert an effect by which they affect the microcirculation and arteries, with a larger diameter without significant effect on the tension, they are indicated by the vasomotor disorders, arteritis, atherosclerosis, frostbite, frosty nodes and acrocyanosis.

Claims (2)

146509 14 Patent Claims. 1, Analogous Process for the Preparation of Pyridoxine Derivatives of General Formula I # 0 '' 'CCH 2' '' N \ 4 (I 1 2 wherein R and R represent hydrogen or together form an isopropylidene group, R which may be the same or different, represent alkyl of 1-4 earbone atoms or together with the nitrogen atom to which they are attached form a saturated 4-8 membered heterocyclic ring optionally comprising as a further heteroatom a sulfur, oxygen or nitrogen atom , which may be substituted by phenyl, which may again be substituted by a halogen atom, a trifluoromethyl group, an alkyl group of 1-4 carbon atoms or an alkoxy group of 1-4 earbone atoms, and n has the value of 2 or 3 »or pharmaceuticals. acceptable salts thereof, characterized by condensing a pyridoxine derivative of the formula II CH3- / O \ ch3 1 (Π) CH2 ° H