FR2528837A1 - ARYLACETYL BUTANOLIDES AND THEIR PYRIDAZINONE DERIVATIVES AS MEDICAMENTS, AND METHODS FOR THEIR MANUFACTURE - Google Patents

Abstract

THE INVENTION CONCERNS NEW CHEMICAL COMPOUNDS ARYL-4 ACETYL-3 BUTANOLIDES-4 AND THEIR DERIVATIVES DIHYDRO 4,5 (2H) PYRIDAZINONES AND ARYLIDENE-5 (2H, 4H) PYRIDAZINONES-3. THE ARYL-4 ACETYL-3-BUTANOLIDES-4 ARE PREPARED: (CF DRAWING IN BOPI) OUR H, F, CL, NO OR OCH; R H, CL, NO, CF OR OCH; R H, F, CL, CH, NO, OCH OR OH; R H OR OCH; R H OR CL; R, R, R, R AND R MAY BE THE SAME OR DIFFERENT R AND R MAY BE COMBINED INTO AN O-CH-O BRIDGE BY CONDENSATION OF A-ANGELICALACTONE WITH ALDEHYDE IN THE PRESENCE OF LEWIS ACID. THE PYRIDAZINON DERIVATIVES ARE PREPARED: (CF DRAWING IN BOPI) OR R CHOH BY REACTION OF ARYLACETYL BUTANOLIDE WITH HYDRAZINE HYDRATE. THEN DEHYDRATE TO OBTAIN THE DERIVATIVES OR R - CH APPLICATION MORE PARTICULARLY OF PYRIDAZINON DERIVATIVES AS A MEDICINE IN PARTICULAR AS A CARDIOVASCULAR AND SEDATIVE.

Description

.1 252883?

  The present invention relates to novel butanolides and their pyridazinone derivatives, which have interesting pharmaceutical properties, as well as processes for the production of polybutylides and their pyridazinone derivatives as medicaments, and processes for their manufacture.

for their manufacture.

  The invention is more particularly arylacetyl butanolides, aryl-4-acetyl-3-butanolide-4, dihydro-4,5 (2 H)

  Pyridazinone-3, arylidene-5 (2H, 4H) pyridazinone-3.

  Many pyridazinones-3 have been prepared in the last ten years; many of them showed activity on the cardiovascular system as antihypertensives, but also in other fields: analgesia, inflammation, central nervous system More than half of the prepared products were furthermore studied.

as herbicides.

  Various substitutions have been made on the pyridazine ring, but the substituted compounds in the -5 position

  are few because of their difficulty of access.

  The present invention aims at new compounds

  -pyridazinones-3 having in particular a pharmaceutical activity

  original cardiovascular and sedative medicine.

  These compounds can be obtained according to the invention from arylacetyl butanolides which therefore constitute

  intermediate products of great interest for the indus-

chemical and pharmaceutical.

  The subject of the present invention is new compounds

  aryl-4-acetyl-3-butanolide-4, characterized in that they correspond to the formula

CH 3 4

R 3 '

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  in which: R 1 = H, F, Cl, NO 2 or OCH 3 R 2 = H, Cl, NO 2, CF 3 or OCH 3 R 3 = H, F, Cl, CH 3, NO 2, OCH 3 or OH R 4 = H or OCH 3 R 5 = H or C 1 R 1, R 2, R 3, R 4 and R 5 may be the same or different, R 2 and R 3 may be combined in an O-CH 2 bridge These compounds can be prepared by a process

  according to the invention in which 1 'o is reacted.

  Angelicalactone by condensation with an aromatic aldehyde enprésenoed of a Lewis acid with rearrangement acyl butanolide. The invention also relates to novel pyridazinone derivatives consisting of 4,5-dihydro (2H) pyridazinones-3 corresponding to the formula

2 1 CH 3 N

\

R 3 R 6 NH

R R 5 '

  in which R 1, R 2, R 3, R 4 and R have the signifi-

  following formula: R 1 = H, F, C 1, NO 2 or CH 3 R 2 = H, C 1, NO 2, CF 3 or OCH 3 R 3 = H, F, C 1, CH 3, NO 2, OCH 3 or OH A 3. R = H or OCH R = H or Cl R = CHOH

4 3 5 6

  R 1, R 2, R 3, R and R may be the same or different

2 # 3 4 5

  R and R can be combined in a bridge O-CH 2 -0

2 3 2

  These derivatives can be manufactured by a process according to the invention in which a 4-aryl-3-acetyl-butanolide 4 is reacted with hydrazine hydrate in a

polar organic solvent.

  The invention also relates to novel pyridazinone derivatives consisting of arylidene-5 (2H, 4H) pyridazinone-3 corresponding to the formula: CH 3 RR i 3 N wherein R 1, R 2, R 3, R 4 and R 5 have the significati Dn Fuiva RI = H, F, CL, NO 2 or CH 3 R 2 = H, Cl, NO 2, CF 3 or OCH 3 R 3 = H, F, CL, CH 3, NO 2 OCH or OH R 4 = H or OCH R = H cur

3 3 2 # 3 4 3 5

R 6 = CH.

  These last derivates can be obtained following.

  the invention by dehydration of 4,5-dihydro-2-pyridazo Among the pyridazinone derivatives which are the object of the invention, it seems that a very particular interest is presented by the derivatives in which: Ri = H or Cl R 2 = HC 1 or CF 3 R 3 = Cl or NO R 4 = H or C 1 and even more when R 1 and R 5 = Cl while R 2, R 3 and R = H The invention finally relates to new drugs low neuroleptic activity but causing a marked increase in femoral flow characterized by

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  they contain an effective amount of at least one

  pyridazinone derivative according to the invention.

  In this respect, it seems that an interest

  In the case of drugs containing a pharmaceutically active proportion of methyl-6- (dichloro 2 ', 6'-benzylidene 1') (2H, 4H) -3-pyridazinone and / or 6-methyl-2-dichloro, 6 'phenyl hydroxymethyl 1') -5 dihydro 4,5 (2H) pyridazinone-3. According to the invention, aryl-4-acetyl-3 butanolide-4

  which is the subject of the invention can be obtained by

aromatic

  tion between an aldehyde / and 1 ', -angelicalactone.

  The latter plays the role of generator of

  carbanion that attacks the carbon of the aldehyde carbonyl.

  This reaction is only possible in the presence of a Lewis acid, generally boron trifluoride; the latter, by reinforcing the positive charge density on the carbon of the aldehyde carbonyl, allows its attack by 1-alkyl-lactone. The intermediate formed then rearranges itself.

in? -acyl butanolide.

R 2 RR 1 R 2 R CH 3

Y N H C 3 Q \

R 3 C + E

3 - 3 y I

R 4 R 5 R 4 R 5

Example 1

  Preparation of 4-aryl-3-acetyl-4-butanolide (or 3- (4-dichloro-6'-phenyl) -3-acetyl-4-butanolide) 0.05 mole of Angelicalactone and 0.05 mol of aldehyde dissolved in 200 ml of methylene chloride are added dropwise during 30 minutes, with stirring, a solution of 0.05 mol of boron trifluoride etherate in 100 ml of methylene chloride at room temperature; agitation

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is maintained for 70 hours.

  The addition of 300 ml of a

  saturated solution of sodium chloride with vigorous stirring.

  A turbidity is formed and stirring is maintained for another fifteen minutes. The contents are transferred to a separating funnel and the two phases are separated. The organic phase is collected and dried overnight over sodium sulfate.

  sodium, and the solvent is evaporated under reduced pressure.

  The butanolide can then be en masse, in which case it is collected directly and then recrystallized in ethanol in other cases, the oily residue is transferred into a

  beaker and crystallized in the presence of low temperature ethanol

  ture (-200) Finally, some derivatives have been separated by

matography on thick layer.

  The raw product is generally recrystallized

in ethanol.

  Example of butanolides prepared according to Example 1 CH 3

At R 2 R 1 2 =

R 3 O

  Point: N: R 1: R 2: 3 R 4 R Points C 1: H: H: H: H H: liquid

To: H: H ::

: 2: H: H: CH 3: H H: 600 C

  H, H: H: C: 5: H: H: Cl: HH: C: 6: C: HH: H Cl: 9: 10:: 1 il: 12:: 13 - -14:: 15: 16-17: F. NO 2 HHHHH OCH 3 HR 2 HRHH: FH: HH the

NO 2: H

H N:

CF 3: H

H: O <

0 CH 3: OC

H: O

O CH 2-O

H 3. 3. 3. 0 I

R 4 R 5

oc

H H -30:

H H: 37:

HCl: 68:

H H: 116:

H H: 15

H H: 47:

H H: Sl:

H H: 135:

OCH 3 H 85:

H: 65:

  HH: 1 OS: According to the invention, (2 H) pyridazinonoye-3 from 4,5-dihydroxy-4-butyledioledi-4-butylediide which is reacted with hydrazine hydrate in a polar organic solvent, preferably a lower alcohol / H 3 O = C

0 H 2 N-NH 2

CH 3 N R R

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Example 2

  6-Methyl-2 ', 6'-dichloro-phenyl-hydroxymethyl-1,5-dihydro-4,5 (2H) pyridazinone-3 In a 250-ml flask, 0.01 moles of dichloro-2' are dissolved in hot water. 4-phenyl-3-acetyl-4-butanolide in ethanol minimum, after complete dissolution, is added 0, C mole of hydrazine hydrate The mixture is refluxed for 2 hours stirring The corresponding pyridazinone precipitates It is sometimes necessary to evaporate some of the solvent

  crude product is recrystallized from ethanol.

C Hi ci 3 N

CHOH H

  Yield: 90% P M = 287 F = 211 C Analysis for C 12 H 1202 N 2 Ci 2

Y P 12 12 2 2 2

  C H N O Ci Calc% 50.2 4.20 9.80 11.1 24.7 Tr% 50.6 4.23 9.68 10.9 24.7 The proton R M N is consistent with the proposed formula. Examples of 4.5 (2H) pyridazinon dihydro% 3 prepared according to the method of Example 2

CH

Rv R 3 N

R 3 CHOH -NH

R 4 R 5

* NI: R R R R

R 1 2: 3: 4

  19: ::: ::: 21 ::: 22: ::: 23:: 23:: 24:: 25 ::: 2 ::

29

  : 31: 3: 33: :: H H C 1 H H C 1 F H F NO 2 H H H H H H OCH 3 H H H H H H H H H H H NO 2 H CF 3 H OCH 3 H H: H: H:: H:

: CH 3:

  : H: H: ::: H:: H F F: H: H:: H NO 2:: H: :: H

O C 13

: OCH:

: OCH 3:

: C

: O-CH 2

  H H H H H H H H H H H H H OCH 3 -0 O

R: F -C

:

H 95

H 180

H 205

H 152

H 215

Cl 211

H 165

H 170

Cl 192

H: 235

H: 188

H: 21 o

H 140

H 169

H: 165

H: 190

H: 106

  The prepared 4,5-dihydro (2H) pyridazinone can be converted into

  5-Arylidene (2H, 4H) pyridazinone-3 by dehydration The operation will be better carried out in the presence of a dehydrating agent. CH 3 CH 3 CH R R _% O

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Example 3

  6-Methyl-2- (2'-dichloro-6'-benzylidene) - (2H, 4H) -3-pyridazinone: 0.01 mole of hydroxymethylpyridazin-3-one is suspended in a 100 ml beaker Example 1 in 30 ml of concentrated sulfuric acid After a few minutes of stirring the product solubilizes and the solution

  is transferred to a beaker containing 100 ml of ice water.

  5-arylidene pyridazinone precipitates; it is filtered,

  dried and recrystallized from ethanol.

Ci C 3 N

QC CH -NH

  Cl O Yield 87% P M = 269 F = 256 C Analysis for C 12 H 10 N 2 C 12

YP 12 10 2 2

  C H N _ Ci calc% 53.5 3.72 10.4 5.95 26.4 Tr% 53.7 3.72 10.4 5.91 26.2

  The protonic R M N is in agreement with the proposed formula

  See. The infrared spectrum shows the disappearance of the OH band located around 3400 cm 1 and the persistence of the lactam carbonyl peak around 1660 cm 1 Moreover, the intensity of the neighboring peak of 1600 cm -1 corresponding to the vibrations / (C = C) ) increases significantly. The compound methyl-6 (2-dichloro-2 ', 6' benzylidene-1 ') - (2H, 4H) pyridazinone-3 studied in dogs shows essentially vascular activity without significant modification of hemodynamic parameters. elective increase in femoral flow, a slight stimulative

  cardiac and little change in blood pressure.

  In addition, an effect S 6 is noted in the mouse; however, catalepsy is only obtained for high doses. The present compound is likely to lend itself to applications in human medicine in the treatment of

  vascular disorders, in particular arteritic.

  Examples of arylidenes (2H, 4H) pyridazinones-3 prepared according to the method of example 3 R 2 R 3 CH NH

N: N: R R: R: R 5 FC

: 36: H: H: H: H: H 172.

: 37: C 1: H: H: H H 210

:: "::

: 38: H: C 1: H: H: H: 166:

: 39: H: H: C 1: H: H: 198:

: 40: C 1: H: H: H: C 1 256

: 41: H: CF 3: H H: H: H: 148:

: 42: H: H: H: H 234:

02

Example 4

  Oral Toxicity Assay: The compound of Example 3 was a 0.5% methylcellulose solution suspended in this suspension and was administered by gastric tube to 2 g, increasing dose mice. ; six animals were used for each dose The approximate LD 50 could thus be fixed in the vicinity

of '8 O Omgkg orally.

Example 5

  Investigation of sedative activity: The sedative effect of the compound according to Example 3 was demonstrated by the test of pentobarbital-induced sleep potentiation in the mouse.

  consisting of 10 mice, the methylcellulose suspension

  0.5% lulose of the compound according to Example 3 /% t 4) mined

  each batch in increasing doses by gastric tube

  barbital sodium is injected 30 minutes later intraperitoneally at a dose of 50 mg / kg. Under these conditions the duration of sleep induced by barbiturate is doubled

  in animals that received 100 mg / kg of compound 40.

  Similar results are obtained with the compounds n 22 and

  and 31 of Example 2 but at a dose of 4 to 6 mg / kg.

Example 6

  Action on the cardiovascular system: The derivative n 40 according to Example 3 was administered intravenously to anesthetized dogs, in order to study its hemodynamic effects Eight parameters were taken into account: heart rate, left intraventricular pressure , Derived from this pressure with respect to time (dp / dt Aortic flow, Aortic pressure, Coronary arterial flow, Femoral arterial flow, Femoral blood pressure Three

  doses were injected: 0.3 1 and 3 mg / kg, each solubilized

  5 ml of a solution of polyethylene glycol (PEG) and saline solution were administered from

  cumulatively from lowest to highest.

  At the dose of 0.3 mg / kg the effect observed, of very short duration, is not different from that of the solvent.

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  note an increase in flow rate, constant for the femoral flow rate, variable for coronary and aortic flow, associated with a very slight hypotension At the dose of 1 mg / kg, the increase in flow becomes very frank They are all affected in a comparable way and become about four times higher than the control values The acme is at the first minute The variation is fleeting for the aortic and coronary flow while it lasts on average 13 minutes

  This effect is not accompanied by varia-

  We have noted that at the end of the injection

  elephant bradycardia up to a break in one animal The dp / dt and the left intraventricular pressure are increased in 50% of the cases, at the first minute The effects are not different, when the dose is increased

up to 3 mg / kg.

Example 7

  Action on the Cardiovascular System The derivative according to Example 2 was administered to

  anesthetized dogs and has been studied under the same conditions.

  than those described in Example 6.

  In comparison with the results obtained in the study of compound N O 3, equivalent hemodynamic activity was obtained for doses approximately 8 times higher, ie 3 mg / kg for the activity threshold and 20 mg / kg for a

maximum effect.

  The following examples relate to applications of the compounds according to the invention in human therapy, in particular for the treatment of osteoarthritis of the

legs.

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Example 8

  Pharmaceutical forms capsules It is possible to use in

  human therapy of capsules with advantageous

  the following composition: compound n I 22 100 mg excipient q s p 1 capsule

  the dosage may vary from 2 to 6 capsules per day.

Example 9

Dosage forms: tablets

  In human therapy, it is possible to use

  Advantageously, the following composition is composed of: ## EQU1 ##

  Daily doses will be 2 to 6 tablets.

Example 10

  Pharmaceutical form: injectable solution.

  It is possible to use in human therapy an injectable solution advantageously having the following composition: ## EQU1 ##

injectable q s p 10 ml.

  The dosage will advantageously be 50 mg, 1 to 2 times

  per day intramuscularly or intravenously slowly.

  EXAMPLE 11 Pharmaceutical form: Concentrated solution for infusions A concentrated infusion solution with advantageously the following compound composition can be used in human therapy: No. 3,200 mg solvent for injection for injection 20 ml

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  The dosage will advantageously be 200 to 400 mg of compound N O 3 in 500 ml of isotonic perfusion solution.

  intravenously for 3 hours.

  Of course, the invention is not limited to the examples described, it is capable of many variants accessible to those skilled in the art, depending on the intended applications and without departing from the scope of the invention.

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Claims (2)

1 New 4-aryl-3-acetyl-butanolide-4 compounds characterized in that they correspond to the formula: RR 3 3 QR 4 -R 5 in which: 2 3 R 1 = HF, C 1, NO or OCH R 2 H , Cl, NO 2 3 3 R 2 = H, Cl, NO, CF or OCH R 3 = H, F, C, CH 3, NO, OCH or OH R = H or OCH 4 3 R 5 = H or Cl R 1, R 2, R 3, R and R may be the same or different R 2 and R 3 may be combined in a bridge O CH 2 -OR 2 and 3 2- 2 Process for the production of the compounds of claim 1, characterized in that the aromatic aromatic kelicalac is reacted by condensation with an aldehyde / in the presence of a Lewis acid with rearrangement to> acyl butanolide. 3 New pyridazinone derivatives of the compounds of claim 1, characterized in that they are constituted by 4,5-dihydro-4,5 (2H) pyridazinone-3 corresponding to the formula R 2 R CH 3 0 in NRXR QRV 36 in which R 1, R 2, R 3, R 4 and R 5 have the same meaning K 4 16. as in claim 1 and R = CHOH 4 Process for the manufacture of the derivatives of claim 3 characterized in that 4-aryl-3-acetyl-butanol-4 according to one of claims 1 and 2 is reacted with hydrazine hydrate in a polar organic solvent. Novel pyridazinone derivatives of the compounds of claim 1 characterized in that they consist of arylidene-5 (2H, 4H) pyridazinones-3 corresponding to the formula: CH 3 RR CH 3 2 N 3 R 6 NH R 4 in wherein R, R 2, R, R 4, and R 5 have the same meaning as in claim 1 and R 6 = CH. 6 Process for the manufacture of the derivatives of claim 5 characterized in that they are obtained by dehydration of a dihydro 4,5 (2 H) pyridazinone according to claim 3. 7 new pyridazinone derivativesnextuant one Claims 3 to 6, characterized in that R 1 = H or Cl R 2 = H, Cl or CF 3 R = Cl or NO R = H and 4 R 5 = H or Cl 8 New compounds according to Claim 7 charac- terized in that: R and R = Ci 1 1 53   R 2, 3 e 4 = 17. 9 New drugs with low sedative activity   put in place causing a rise in femoral   in that they contain an effective amount of   minus a pyridazinone derivative according to one of the claims 3 to 7.   New drugs according to claim 9   characterized by the fact that they contain a pharmaco-   ectively active methyl-6-dichloro 2 ', 6'-benzylidene.   1 ') 5 (2H, 4H) pyridazinone-3 and / or methyl-6 (dichloro)   2 ', 6' phenyl hydroxymethyl 1 ') dihydro 4,5 (2H) pyridine zinone-3.