IE44696B1 - Pyrodoxine derivatives - Google Patents

Abstract

Process for preparing pyridoxine derivatives of formula ** (Formula) ** in which R1 and R2 are hydrogen or together form the isopropylidene radical, R3 and R4, identical or different from each other, are lower alcohol or lower aralcoyl or form , together with the nitrogen atom to which they are attached, a saturated heterocycle of 4 to 8 secondary chains that optionally includes, as a second heteroatom, a sulfur, oxygen or nitrogen atom, the latter may be substituted by a phenyl, itself, possibly, a halogen, a trifluoromethyl, a lower alcohol or a lower alkoxy and n is 2 or 3.

Description

The present invention relates to new pyridoxine derivatives, a process for preparing them and their applications in human and veterinary medicine.

The new compounds of the invention correspond to the following general formula; wherein R^ and Rg represent hydrogen or together form an isopropylidene group, R^ and R^ represent an alkyl or aralkyl group or form, together with the nitrogen atom to which they are attached, a saturated 4- to 8-membered heterocyclic group (which optionally contains a second heteroatom such as oxygen, sulphur or nitrogen, which latter nitrogen atom may optionally be substituted by an organic group, particularly phenyl, which in turn may carry a halogen, tri fluoromethyl, lower alkyl or alkoxy substituent); and n is 2 or 3.

Preferably, the aralkyl group is a phenylalkyl group and the alkyl and alkoxy groups are Cj_g groups, preferably having - 2 44696 up to 4 carbon atoms. The halogen is advantageously chlorine or bromine. The preferred heterocyclic groups are morpholine, piperazino, pyrrolidino and piperidino.

In particular, CnB2n“KR3R4 may be a 2-aminoethyl, 3aminopropyl or 2-aminopropyl group.

The invention also includes the pharmaceutically acceptable acid addition salts with inorganic or organic acids and the quaternary ammonium derivatives of the compounds of formula I. The invention further includes a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier or excipient.

The invention also relates to a process for preparing the compounds of formula (I), characterised in that a pyridoxine derivative of formula: and a haloalkylamine of formula: X—C Η,-—N n 2n /R3 \ (III) wherein X represents a halogen, such as chlorine, and 20 Ry and R4 have the same meanings as before, are condensed to obtain the compound of formula (la): 4 4 6©® CIL· /0 CII X)' /R3 (la) .ch3^HzZ which is converted into the compound of formula (lb) by treatmentwith an acid The compound of formula (II) is a known compound and its preparation has been described by W. Korytnik and W. Wiedman (j. Chem. Soc., 1962, 2531).

The haloalkylamines of formula (III) are known compounds; they may be prepared using the methods described by Douglas C. Kriesel and Ole Gisvold (j. Pharm. Sci., 1967, 56, 327) and J. Bourdais (Bull. Soc. Chim. Fr. 1968, (8), 3246).

The condensation resulting in compound (la) is effected in the presence of a concentrated aqueous solution of hydroxide, especially an alkali metal hydroxide such as for examplej sodium hydroxide, at a concentration of 10-60% preferably 50% by weight.

The reagents of formulae II and III are preferably used in stoichiometric quantities in this reaction, but it is also possible to use one of the two reagents in excess. The temperature of the reaction medium is preferably maintained at between 50° and 100°C.

This preparative process uses an original reaction in a heterogeneous medium with a phase transfer catalyst. Catalysis is provided by the quaternary ammonium salts © R3 R3\^X ® /θ\.

An originating from the dimerisation and intramolecular cyclisation, respectively, of the haloalkylamines of formula III.

The conversion of the compounds of formula (la) into those of formula (lb) is effected by treating these compounds with an inorganic or organic acid in an aqueous 44SSS or anhydrous medium at a temperature of between 20° and 100 °C.' The following examples illustrate the preparation of the compounds according to the invention.

EXAMPLE 1 Preparation of 5-t(g-morpholinoethoxy)°'methyl·]2,2 )8-trimethyl-ZjH- m-dioxino [4,5-cjpyridine (derivative no. 1); + = isopropylidene, = morpholino, Ώ = 2.

A raixture of N-(2-chloroethyl)morpholine in 60 cc of 50% sodium hydroxide solution and 20 g of 5-hydroxymethyl2,2,8-trimethyl-4H-m - dioxino(4,5-c)pyridine hydrochloride is heated to 100°C for 5 hours with vigorous stirring.

The mixture is then diluted with water and extracted with ether. The ethereal extracts are washed with water, dried over sodium sulphate and evaporated to dryness. The solution obtained by dissolving the residue in chloroform is filtered on a bed of silica and concentrated in vacuo.

The oil obtained is converted into tfe dihydrochloride hydrate. Reerystallisation from a mixture of ethanol and ethyl acetate yields 6.20 g of white crystals (yield 65.6%), the m.p. of which, determined by the Kofler block, is 216°C.

Example 2 : Preparation of 5-^[3-(4-£-chlorophenyl-1-piperazinyl) -propoxy]-methyl! -2,2,8-trimethyl- 4H-m-dioxino[4,5-c]pyridine (derivative no. 2), + = isopropylidene, NRgR^ = 4-£-chlorophenyl-piperazinyl, n=3.

A mixture of 10 g of 5-hydroxymethyl-2,2,8-trimethyl4H-m-dioxino (4,5-c)pyridine hydrochloride and 14.1 g of l-(3-chloropropyl)-4-£-chlorophenyl-piperazine in 50 cc of 50% sodium hydroxide solution is heated to 100°C for 6 hours with thorough stirring. The reaction mixture is then diluted with water and extracted with chloroform.

The chloroform extracts are dried on sodium sulphate and filtered on a bed of silica. After evaporation of the solvent in vacuo, 14 g of an oily product are obtained which is then converted into the dihydrochloride hydrate. Recry15 stallisation from ethanol gives 12 g of white crystals (yield 56%), m.p. 188°C, determined by the Kofler block. Example 3 ; Preparation of 3-hydroxy-4-hydroxymethyl-2methy1-5-[(β-morpholinoethoxy)-methyl]-pyridine (derivative no.’ 3) R^ =1 R2 = H; NR^R^ = morpholino, n = 2 A solution of 11.4 g of 5-[(p-morpholinoethoxy)-methyl] 2,2,8 - trimethyl- 4H- m-dioxino (4,5- c) pyridine in 500 cc of 9% aqueous formic acid is heated to 100°G for 3 hours.

After cooling and evaporating to dryness, the residue is - 7 10 taken up in a saturated aqueous solution of sodium chloride, then made basic by addition of sodium carbonate and extracted with chloroform. The chloroform extracts are dried on sodium sulphate, filtered on a bed of silica and evaporated to dryness. A solid product is obtained which, when recrystallised from ethyl acetate, yields .5 g of white crystals (yield: 56%). The m.p. is 98°G determined by the Kofler block.

Example 4 : Preparation of 5-£ [3-(4£-chlorophenyl-lpiperazinyl)-propoxy]-methyl-3-hydroxy-4-hydroxymethy12“methy1-pyridine (derivative no. 4) R^ = = H, NR^R^ = 4-o-chlorophenyl-piperazinyl, n = 3.

A solution of 6 g of 5-^ [3-(4-£-chlorophenyl-lpiperaziny1)-propoxy]-methyl^ -2,2,8-trimethyl-4H-mdioxino(5-c)pyridine dihydrochloride hydrate in 100 cc of 70% acetic acid is heated to 90°C for 6 hours. Evaporation of the solvent in vacuo leaves a solid residue which when recrystallised from 90° ethanol, yields 2.60 g of white crystals of the dihydrochloride hydrate (yield: 50%), m.p. 186°C.

DERIVATIVE no. 5 5-[(β-dimethylaminoethoxy)-methylJ-2,2,8trimethyl-4H-m-dioxino (4,5-c)pyridine; &Ί + R^ = isopropyli20 4469 6 dene; R^ = R^ = methyl, n = 2. dihydrochloride hydrate: white crystals, m.p. 192°C (ethanol) prepared analogously to Example 1; yield = 20%. DERIVATIVE no. 6 5-[(β-diethylaminoethoxy)-methyl]-2,2,85 trimethyl-4H-m-dioxino(4,5,-c)pyridine, + R2 = isopropylidene; R, = R^ = ethyl; n = 2. dihydrochloride: white crystals, m.p. 200°C (ethyl acetate/ ethanol) prepared analogously to Example 1; yield 62%. DERIVATIVE no. 7 5- [2-(l-pyrrolidinyl)-ethoxy]-methyl 10 2,2,8-trimethyl-AH-m-dioxino(4,5-c)pyridine; + ^R3R4 = pyrrolidinyl, n = 2. dihydrochloride hydrate: white crystals, m.p. 17O°C (isopropanol) prepared analogously to Example 1; yield 65%.' DERIVATIVE no. 8 5-[(p-piperidinoethoxy)-methyl]-2,2,8trimethyl-4H-irt-dioxino(4,5-c)pyridine; R^ + R2 = isopropylidene; NR^R^ = piperidino, n = 2 dihydrochloride hydrate; white crystals, m.p. 143°G (ethanol) prepared analogously to Example 1; yield 25%.

.DERIVATIVE no, 9 5- £[2-(4-phenyl-l-piperazinyl)-ethoxy]methyl^-2,2,8-trimethyl-4H-m-dioxino(4,5-c)pyridine; R^ + R^ “ isopropylidene, NR^R^ = A-phenyl-piperazinyl, . c, _ n = 2. dihydrochloride hydrate: white crystals, m.p. 206°C (ethanol) prepared analogously to Example 2; yield 42% . DERIVATIVE no. 10 5- £[2-(4£-chlorophenyl-l-piperazinyl)5 ethoxy] -methyl-^2,2,8-trimeth.yl-4H-m-dioxino (4,5-c)pyridine, Rj + &2 ~ isopropylidene, NR^R^ = 4-£-chlorophenylpiperazinyl; n = 2 dihydrochloride hydrate: white crystals, m.p. 190°G (ethanol) prepared analogously to Example 2; yield 36%.

IQ DERIVATIVE no. 11 5= [2=(4°m=chlorophenyl-1-piperazinyl)ethoxy]-methyl^ -2,2,8-trimethyl-4H-m-dioxino ( 4,5-c)pyridine; R^ 4- R^ = isopropylidene, NRjR^ = 4-m-chlorophenyl piperazinyl; *n = 2 dihydrochloride hydrate: white crystals, m.p. 208°C (ethanol) prepared analogously to Example 2; yield 57.5%.

DERIVATIVE no. 12 5- £[2-(4-£-chlorophenyl-l-piperazinyl)ethoxy]-methyl^ “2,2,8-trimethyl-4H- m-dioxino (4,5-c)pyridine; R^ + R^ = isopropylidene, NR^R^ = 4-£-chlorophenylpiperazinyl; n = 2 dihydrochloride hydrate = white crystals, m.p. 214°G (ethanol) prepared analogously to Example 2, yield 52%.' - 10 44696 DERIVATIVE no. 13 5- £ [2-(4-m-trifluoromethylphenyl-lpiperazinyl) -ethoxy] -methyl^ -2,2,8-trimethyl- 4H-mdioxino(4,5-c)pyridine, R^ = Rg = H, NRgR^ = 4-mtrifluoromethylphenylpiperazinyl; n = 2 dihydrochloride hydrate; white crystals, m.p. I68°C (ethyl acetate/ethanol) prepared analogously to Example 2, yield 31%.

DERIVATIVE no. 14 5- [2-(4-£-tolyl-l-piperazinyl)-ethoxy]methyl^-2,2,8-trimethyl-4H-m-dioxino (4,5-c)pyridine; R^ + Rg = isopropylidene; NRgR^ = 4-£-tolyl-piperazinyl; n = 2 dihydrochloride hydrate; white crystals, m.p. 177°C (ethanol) prepared analogously to Example 2, yield 44%. DERIVATIVE no. 15 5-^[2-(4-o~methoxyphenyl-l-piperazinyl)ethoxy]-methylJ -2,2,8-trimethyl-4H-m-dioxino (4,5-c)pyridine; R^ + Rg = isopropylidene, NR^R^ = 4-o-methoxyphenyl piperazinyl, n = 2 dihydrochloride hydrate: white crystals, m.p. 216°C (ethanol) prepared analogously to Example 2, yield 16%.

DERIVATIVE no. 16 mixture of 5-[(l-dimethylaminomethylethoxy) -methyl] -2,2,8-trimethyl - 4H- m-dioxino ( 4,5-c) pyridine and 5-[(2-dimethylamino-propoxy)-methyl]-2,2,8-trimethyl4H-1,3-dioxolo(4,5-c)pyridir· dihydrochloride; white crystals (ethyl acetate/ethanol), prepared analogously to Example 1; yield 38%.

DERIVATIVE no. 17 5-[(3-dimethylamino-propoxy)-methyl]2,2,8=trimethyl-4H-m-dioxino ( k, 5-c)pyridine; R^ + R^ = isopropylidene; R^ = R^ = methyl; n = 3. dihydrochloride hydrate: white crystals, m.p, 208°C (iso propanol), prepared analogously to Example 1, yield 29% DERIVATIVE no. 18 5-[(β-dimethylaminoethoxy)-methyl]3-hydroxy-4-hydroxymethyl-2-methyl pyridine; R^ = R = H = = methyl, n = 2 dihydrochloride hemihydrate: pale yellow crystals, m.p. 170°C (ethanol) prepared analogously to Example 4, yield 75% DERIVATIVE no. 19 3-hydroxy-4-hydroxymethyl-2-methyl-515 |[2-(l-pyrrolidinyl)-ethoxy]-methyl^ -pyridine; R^ = RQ H; NR^R^ = pyrrolidinyl, n = 2 dihydrochloride hydrate: ivory crystals, m.p. 152°C (iso propanol) prepared analogously to Example 4, yield 40%. DERIVATIVE no. 20 3-hydroxy-4-hydroxymethyl-2=methy1-520 [(P“piperidinoethoxy)-methyl]-pyridine; R^ = R^ = H, ^3R4 ~ piPerLdino, n = 2 - 12 44696 beige crystals, m.p. 76°G (ethyl ether/methanol) prepared analogously to Example 3; yield 50%.

DERIVATIVE no. 21 3-hydroxy-4-hydroxynethyl-2-methyl-5[ 2-( 4-phenyl- 1-piperazinyl) -ethoxy]-methyl^ -pyridine ; = NR3R2| = A-pheny 1-piperazinyl, n = 2. dihydrochloride hydrate; white crystals, m.p. 169°C (ethanol) prepared analogously to Example'4; yield 35%.

DERIVATIVE no. 22 5- [2-(4-o-chlorophenyl-I-piperazinyl[ethoxy]-methylJ -3-hydroxy-4-hydroxymethyl-2~methylpyridine; R^ = Rj = H; NR^R^ = 4-o-chlorophenylpipera2inyl; n = 2 dihydrochloride hydrate: white crystals, m.p. 176°C (95° ethanol) prepared analogously to Example 4; yield 40%. DERIVATIVE no. 23 5- £[2-(4-m-chlorophenyl-1-piperazinyl)ethoxy]-methyl -3-hydroxy-4-hydroxymethyl-2-methylpyridine; = = NR3R4 “ A-m-chloropheny1-piperazinyl; n - 2 pale cream crystals, m.p. 110°C (isopropyl ether/ethyl acetate), prepared analogously to Example 3; yield 69%. DERIVATIVE no. 24 5-^ [2-(4-£-chlorophenyl-1-piperazinyl)ethoxy]-methyl J -3-hydroxy-4-hydroxymethyl-2-methyl-pyridine, R^ » R^ - H;-NR^R^ = 4-£-chloropheny1-piperazinyl; n = 2 dihydrochloride hydrate; white crystals, m.p. 186°C (ethanol) - 13 prepared analogously to Example 4, yield 65%. methyl }-pyridine; R.

DERIVATIVE no. 25 3-hydroxy-4-hydroxymethyl-2-methyl-52-(4-m-trifluoromethy1-phenyl-1-piperazinyl)-ethoxy]= Hy = H; NR^R^ = 4-m-trifluoromethy1phenyl-piperazinyl; n = 2 dihydrochloride hydrate; white crystals, m.p. 198°G (95° ethanol) prepared analogously to Example 4, yield 76%. DERIVATIVE no. 26 3-hydroxy-4-hydroxymethyl-2-methyl-5[2-(4-j>=tolyl«l=piperazinyl)-ethoxy]-methyl^ -pyridine; R^ = Rj = H; = 4-n-tolyl-piperazinyl; n=2 dihydrochloride hydrate; white crystals, m.p. 156°C (ethanol) prepared analogously to Example 4; yield 60%. DERIVATIVE no. 27 3-hydroJty-4-hydroxymethyl-5- ^[2-(40-methoxyphenyl-1-piperazinyl)-ethoxy]-methyl^ -2-methylpyridine; R^ = R^ = H, NRgR^ - 4-o-methoxyphenylpiperazinyl, n = 2 dihydrochloride hydrate; white crystals, m.p. 188°G (ethanol) prepared analogously to Example 4, yield 45%.

DERIVATIVE no. 28 mixture of 5-[(l»dimethylaminomethylethoxy)-methyl]-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine and 5-[(2-dimethylamino-propoxy)-methyl]-3-hydroxy-4-hydroxymethyl- 2 -methyl-pyridine dihydrochloride hemihydrate: white crystals (isopropanol) prepared analogously to Example 3; yield 61%.

The results of the toxicological and pharmacological tests reported below demonstrate the interesting activities of the compounds of the invention, notably their sedative effect and peripheral vasodilatory activity.

The invention therefore also provides a medicament having, in particular, sedative and peripheral vasodilatory activities, characterised in that it contains, as active principle, a compound of formula I or a pharmaceutically acceptable acid addition salt or quaternary ammonium derivative thereof. 0 I - TOXICOLOGICAL STUDY The compounds of the invention are very well tolerated and have a low toxicity. Thus, the LD^q/24 hrs/kg of animal, determined in mice using the method of Miller and Tainter, by the intravenous route, is 250 mg for derivative no. 1, 38 mg for derivative no. 2, 310 mg for derivative no. 3, 115 mg for derivative no. 4, 74 mg for derivative no. 5, 89 mg for derivative no. 6, 79 mg for derivative no. 7, 70 mg for derivative no. 8, 42 mg for derivative no. 9, 43 mg for derivative no 10, 61 mg for derivative no. 11, 55 mg for derivative no. 12, 49 mg for derivative no. 13, 65 mg for derivative no. 14, mg for derivative no. 15, 86 mg for derivative no. 16, mg for derivative no. 17, 300 mg for derivative no. 18, 125 mg for derivative no. 19, 160 mg for derivative no. 20, 120 mg for derivative no. 21, 69 mg for derivative no. 22, mg for derivative no. 23, 63 mg for derivative no. 24, mg for derivative no. 25, 87 mg for derivative no. 26, mg for derivative no. 27 and 266 mg for derivative no 28.

II - PHARMACOLOGICAL STUDY This study demonstrated the activities of the compounds forming the active principle of the medicament of the invention - lb 44696 1, Sedative effect a) Study of behaviour This study was made using the method of Samuel Irwin (PhD. Animal and Clinical Pharmacology Technics in Drug evaluation). The derivatives of the invention are administered, by gastric tube, in a single dose of 30 mg/kg, to mice which have fasted for 16 hours. A study of their behaviour and different physiological parameters (temperature, heart rate and respiratory rate) demonstrates the clear sedative and muscle-relaxant actions of these derivatives: in fact, from the fifth minute, a significant reduction in spontaneous motor activity, a lowering of muscle tone and alertness, a respiratory reduction and a reduced reactivity to sounds and the environment are observed in all the animals. 44®®® b) Activity with regard to hypnotics The compounds of the invention are administered orally in a dose of 30 mg/kg to different batches mice, 30 minutes before an intraperitoneal injection of a subhypnotic dose of sodium pentobarbital. The number of animals which fall asleep, the time taken to fall asleep and the duration of sleep were noted. The results collected in Table I below show the clear potentiating effect of the compounds tested, compared with the control animals. - 18 = TABLE I treatment % of animals which tell asleep average time taken to fall asleep average duration of sleep (control animal) Derivative 1 0 3 0 It 2 70 9 mn 15 s 1 h 38 mn If 3 80 8 mn 26 s 1 h 45 mn II 4 • 90 9 mn 24 s 1 h 40 mn II 5 80 9 inn 38 s 1 h 55 mn 11 6 80 9 mn 04 s 2 h 04 mn 11 8 100 9 mn 51 s 2 h IS mn 11 1190 8 mn 12 s 1 h 44 mn II 15 80 9 mn 45 s 1 h 38 mn 11 16 80 8 mn 33 s 1 h 50 mn It 20 100 9 mn 28 s 1 h 58 mn 11 21 90 8 mn 50 s 1 h 45 mn It 22 90 9 inn 12 s 2 h 10 mn II 25 70 8 mn 45 s 1 h 46 mn II 27 80 S mn 52 s 1 h 42 mn II 28 90 9 mn 10 s 1 ft 55 mn c) 4 plate test (Boissier, Simon and Aron Europ.

J. of Pharmacol. 4, 1968, 145-151) A mouse placed in an enclosure containing 4 electrified plates is given an electric shock, causing it to run at random, each time it moves from one plate to another.

After n electric shocks, the mouse stops moving. The degree of tranquillisation obtained is considered to be proportional to the number n of electric shocks which the treated mouse is given before staying motion less in a comer. In this way, it is found that, in a dose of 30 mg/kg administered orally, the derivatives of the invention result in a substantial percentage increase in the number of shocks n after 15, 45 and 90 minutes.

The results are summarised in Table II: -20 44696 TABLE II treatment derivative lip. percent increase in n after 90 min after 15 min. after 45 min 1 54 59 31 2 58 62 30 4 61 62 33 5 60 61 28 6 62 64 32 8 57 61 34 11 59 63 30 15 62 62 31 16 56 58 29 20 61 60 26 21 65 61 28 22 58 60 28 25 57 56 25 27 63 60 32 28 57 59 34 2. Vasodilatory effect This effect was studied using two methods: a) Activity on gangrene induced by ergotamine The 'administration of high doses of ergotamine causes a prolonged vascular spasm of the arteriolar ' tree by acting directly on the vascular smooth muscle, this spasm is followed by symptoms of obstructive arteritis and asphyxia of the tissues, appearing 44(3® © chiefly in the less well supplied extremities (rat's tail) and taking the form of more or less intense cyanosis, followed by cell destruction which may even become gangrene. The administration of the substances to be tested, having a vasodilatory effect, makes it possible to alternate or suppress the vasoconstriction effects caused by ergotamine. Tests were carried out on the rat using the method of&iglbock (Arch.Exp.Path, Pharmacol, 1962, 217,430)s the control animals are given injections of ergotamine-adrenalin in the base of the tail everyday for 11 days. The treated batch are also given 30 mg/kg of the test derivative by the intramuscular route for 12 days. The animals are observed daily and the changes resulting from the action of the ergotamine are evaluated; slight cyanosis (Cl), medium cyanosis (Cm), intense cyanosis (Gi) and gangrene (G).

The results are summarised in the following Table, which represents the percentage of animals showing the different symptoms as defined above, as a function of time. - 22 44696 TABLE III u> 40 ! o o o o o o o o o O o •H O o o o o o o o o o o o cj Ό K) *? tn pH pH 04 pH 04 pH • £ e o o o o o o o o o o o CJ o in rH 04 K <· 04 04 tn tn tn tn 04 rH K CJ © © o © o o © O o o o o 04 *4· *3* Ό in vp \O in in in MJ CJ 20 o o o o o o o o o o o o o o o o o o o o o o o CJ co tn ^3- in tn *3* 04 04 tn rH rH X R! Ό a © o © o o o o o o © o o 5 pH rH in PH M· 04 tn tn pH CJ O O o o o o o o o O o o in Ό m tn tn \O \o m o o o o o o o o o o o o © 04 •pf o o o o o o o o o o o o u >. (0 Ό Ό E CJ o o o o o o o o o o © o β 04 rH o o o o o o o o o o © o CJ •cf 04 si ip σ» o CM cn 0- ¢0 rH pH rH pH rH rH 4- Φ £ > pH •rl 1 £ jj 0 Id 4J £ . - * - £ - - it 44 > 0 •rl )4 O o )4 44 ϋ 0 Ό 23· TABLE III continued © O o o o •H O o K o en o 10 10 ix cd TO ί Cm o tn 30 o o M· 30 CM rM . F—J Q o Ο o tn o tn o tn SO a to o o o o o •rl U o rd o <· © o’ C4 o tn ii day S U O ve 10 30 i o tn 10 4J tO r-4 U O tn so o VO os o Ό u © o o o o Ci o o o o o o 2nd day υ o o o o o P-4 CJ o o o o o treatment derivative 19 CM cn CM CM to CM 44686 b) Perfusion of the rat's hindquarters The tests are carried out on the rat anaesthetised with an intraperitoneal injection of Ig/kg of ethyl urethane. Perfusion of Ringer solution is effected by gravity in the abdominal aorta of the animal. The solution is recovered from the lower vena cava. The increase in the blood flow is measured by collecting each drop by means of a funnel, so that it falls on a recording stylus, thus enabling it to be recorded graphically.

The products tested are administered by the intraperitoneal route in a dose of 30 mg/kg, The results are summarised in the following Table which indicates, for each derivative tested, the percentage vasodilation obtained and the duration of the vasodilatory activity produced.

TABLE IV treatment % vasodilation Duration of vasodilation activity (minutes) derivative 2 160 90 u A 210 95 ¢3 δ 180 85 #1 · 7 170 75 II 9 230 : 95 tt 10 190 105 II 12 180 80 It 13 220 75 ii 14 240 80 . h 17 220 100 it · 18 180 110 tt 19 200 95 II 21 210 90 ' tt. 23 160 80 II . 24 190 90. | it 26 95 | - 2644696 The toxicological and pharmacological studies reported above show that the compounds of the invention have a low toxicity together with high tolerance levels and have important sedative and vasodilator properties.

The medicament of the invention may, for oral administration, take the form of tablets, coated tablets, capsules, drops or syrup. For rectal administration it may also be in the form of suppositories and, for parenteral administration, injectable solutions.

Each dosage unit of 0.1 to 5 g advantageously contains 0.010 g to 0.250 g of active principle, whilst the daily doses may vary from 0.010 g to 1 g of active principle.

Some pharmaceutical formulations of the medicament of the invention will now be given as nonrestrictive examples Examples A-F A. COATED TABLETS Core derivative No. 6 . 0.075 g sugar, lactose, talc, magnesium stearate, kaolin, starch - 27 .

Coating shellac, colophony, starch, gelatine,saccharose tartrazine yellow 3· TABLETS derivative No. 19 0.050 g excipients starch, dextrine, hydrated silica, officinal, gelatine, magnesium stearate C. CAPSULES derivative No. 11 0.100 g excipient: talc, lactose, magnesium stearate D. SYRUP derivative No. 21 0,500 g excipient: sweetened and flavoured q.s.p. 100 ml E. SUPPOSITORIES derivative No. 15 0.100 g excipient: semi-synthetic triglycerides F. INJECTABLE SOLUTION derivative No. 26 0.050 g isotonic solution q.s.p, 5 ml Thanks to its important sedative and vasodilatory properties, the medicaments of the invention may be used in human and veterinary medicine. - 28 44686 They may usefully be administered as sedatives for alleviating emotional tension in everyday use.

They calm and tranquillise and promote physiological sleep. Without prejudicing alertness and the intactness of the intellectual functions, they are indicated in states of anxiety and emotion and in irritability and insomnia.

By virtue of their peripheral vasodilatory activity whereby they take effect on the microcirculation and the larger arteries, without appreciably affecting the blood pressure levels, they are indicated in vasomotor disorders in the extremities, arteritis, atherosclerosis, frostbite and chilblains, and acrocyanosis.

Claims (1)

1. CLAIMS: 1. Compounds of formula wherein R^ and R^ are hydrogen or together form an isopropylidene group, R^ and R^, which may be the same or different,are C^-g a lkyl ον aralkyl groups having a C^_g alkyl portion or form,together vzith the nitrogen atom to which they are attached, a saturated 4= to 8- membered heterocyclic group (which optionally contains as a second heteroatom a sulphur, oxygen or nitrogen atom, which latter nitrogen atom may optionally be substituted by an unsubstituted phenyl group or a phenyl group substituted by a halogen, trifluoromethyl, alkyl or alkoxy substituent), and n is 2 or 3j and the pharmaceutically acceptable salts thereof. 2. , Compounds as claimed in claim I, wherein the halogen is chlorine or bromine. 30 “ 44686 3. Compounds as claimed in claim 1 or claim 2 wherein the heterocyclic group is a morpholino, piperazino, pyrrolidino or piperidino group. 4. 5- [(β-Morpholino-ethoxy)-methyl] -2,2,8-trimethy1-4H5 m-dioxino(4,5-c)-pyridine and the salts thereof. 5. 5-{[3-(4-p-chlorophenyl-l-piperazinyl)-propoxyl]methyl}-2,2,8-trimethyl-4H-m-dioxino(4,5-c)-pyridine and the salts thereof. 6. 3-Hydroxy-4-hydroxymethyl-2-methyl-5- C(g-morpholino10 ethoxy)-methyl]-pyridine and the salts thereof. 7. 5-{[3-(4-£-Chlorophenyl-l-piperazinyl)-propoxy]-methyl}3-hydroxy-4-hydroxymethyl -2-methyl pyridine and the salts thereof. 8. 5- [(8~Dimethylamino)-ethoxy)-methyl]-2,2,8-trimethyl 15 4H-m-dioxino(4,5-c)pyridine and the salts thereof. 9. 5-i[2-(1-Pyrrolidinyl)-ethoxy3-methyl}-2,2,8-trimethyl4H-m-dioxino-(4,5-c)pyridine and the salts thereof. 10. 5- ββ-Piperidino-ethoxy)-methyl]-2,2,8-trimethy1 -4Hm-dioxino(4,5-c)pyridine and the salts thereof. 11. 12. 13. 10 14. 15. 15 1S ' 17. 18. 11. 12. 13. 10 14. 15. 15 1δ · 17. 18. trimethyl-4H- m-dioxino (4 3 5-c)pyridine and the salts thereof , 2 ,2,8-trimethyl-4H- m-dioxino (4,5-c)-pyridine and the salts thereofs 2j2,8“trimethyl“4H= m-dioxino (4,5-c)-pyridine and the salts thereof} trimethyl-4H-m-dioxino(4,5-c)pyridine and the salts thereof, trimethyl=4H= m-dioxino (4,5-c)-pyridine and the salts thereof , 5«^r [2-(4”2;“niethoxyphenyl=l=pipera2inyl)-ethoxy ]-methyi^2,2,8-trimethyl-4H- m-dioxino (4,5-c)pyridine and the salts thereof. ’ ι 5-[(1-dimethylaminomethyl-ethoxy)=methyl]-2,2,8-trimathyl4H-m-dioxino '(4j5=c)pyridine and the salts thereof, - 32 = 5-[(2-dimethylamino-propoxy)-methylj-2,2,8-trimethyl4H-m-dioxino (4,5-c)pyridine and the salts thereof, 5-[(3-dimethylamino-propoxy)-methyi]-2,2,8-trimethyl4H-m-dioxino (4,5-c)pyridine and the salts thereof, 5-[(p-dimethylamino-ethoxy)-methyl]-3-hydroxy-4hydroxymethyl-2-methyl-pyridine and the salts thereof, 3-hydroxy-4-hydroxymethyl-2-methyl-5-£[2-(1-pyrrolidinyl) ethoxy]-methy 1^-pyridine and the salts thereof, 3-hydroxy-4-hydroxymethyl-2-methyl-5-[(3-piperidinoethoxy)-methyl]-pyridine and the salts thereof, 3-hydroxy-4-hydroxymethyl-2-methyl-5-£[2-(4-phenyl-lpiperazinyl)-ethoxy]-methylj-pyridine and the salts thereof, 5·|[2-(4-o-chlorophenyl-l-piperazinyl)-ethoxy ]-methyl^ 3-hydroxy-4-hydroxymethyl-2-methyl pyridine and the salts thereof, 3-hydroxy-4-hydroxymethyl-2-methyl-pyridine and the salts thereof, 3-hydroxy-4«hydroxymethyl-2-methyl pyridine and the salts thereof, the salts thereof, - 33 _ 29. 3=hydroxy-4“hydroxymethyl=2-methyl-5-j[2-(4-2”tolyl1-piperazinyl)-ethoxy]-methy1^- pyridine and the salts thereof } 30. 3-hydroxy-4-hydroxymethyI-5=^[2-(4-o-methoxyphenyl-1piperazinyl)-ethoxy]-methyl^.-2-methyl pyridine and the salts thereof, 31. 5-[(1-dimeth.ylaminomethyl-ethoxy)-methyl]“3-hydroxy-4hydroxymethyl-2-methyl-pyridine and the salts thereof^and 32. 5-[(2-dimethylamino-propoxy)=methyl]-3-hydroxy»4hydroxymethyl-2-methyl-pyridine and the salts thereof. 33. A process for preparing the compounds of formula I, in claim 1, which comprises condensing a pyridoxine derivative of formula ch 2 oh wherein X is a halogen and and are defined as in claim 1, to obtain a compound Qa) of formula 1 wherein X-C H_ n 2n - 34= 44686 R^ and R£ together form an isopropylidene radical, and (where a compound in which R^ and If are hydrogen is required) treating this compound la with an acid. 34. A process as claimed in claim 33,wherein the condens5 ation is carried out in the presence of a concentrated aqueous solution of an alkali metal hydroxide. 35. A process as claimed in claim 34 wherein the condensation is effected at between 50 and 100°C. 36. A process as claimed in any one of claims 33 to 35 wherein the treatment with acid is effected at between 16. 20 and 100°C. 37. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 32 together with a pharmaceutically acceptable carrier or excipient. 15 38. A process as claimed in claim 33 substantially as described herein in or with regard to any one of the Examples 1 to 4. 39. A compound as claimed in claim 1 when prepared by a process as claimed in any one of claims 33 to 36 or 38. 2o 40. A pharmaceutical composition 5110313.1)513117 as described herein in any one of Examples A-F.