GB2122195A - Pyridazinones - Google Patents

Pyridazinones Download PDF

Info

Publication number
GB2122195A
GB2122195A GB08316516A GB8316516A GB2122195A GB 2122195 A GB2122195 A GB 2122195A GB 08316516 A GB08316516 A GB 08316516A GB 8316516 A GB8316516 A GB 8316516A GB 2122195 A GB2122195 A GB 2122195A
Authority
GB
United Kingdom
Prior art keywords
accordance
pyridazinone
novel
compounds
och3
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB08316516A
Other versions
GB8316516D0 (en
Inventor
Henri Chibret
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Thea Therapeutique & Applicat
Original Assignee
Thea Therapeutique & Applicat
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thea Therapeutique & Applicat filed Critical Thea Therapeutique & Applicat
Publication of GB8316516D0 publication Critical patent/GB8316516D0/en
Publication of GB2122195A publication Critical patent/GB2122195A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

Compounds of the general formula: <IMAGE> (in which R1, R2, R3, R4 and R5 have the following meanings: R1 = H F Cl, NO2 or CH3; R2 = H, Cl, NO2, CF3 or OCH3; R3 = H, F, Cl, CH3, NO2, OCH3 or OH; R4 = H or OCH3; R5 = H or Cl; whilst R2 and R3 can be combined in a bridge O-CH2-O and R6 is -CH= or -CHOH-) are cardiovascular drugs and sedatives.

Description

SPECIFICATION Derivatives of pyridazinones for use as drugs and methods for the manufacture of said derivatives This invention relates to novel derivatives of pyridazinones which offer advantageous pharmaceutical properties and also to the methods for the production of such derivatives. The invention is more specifically directed to pyridazinones-3 substituted in position 5.
A large number of pyridazinones-3 have been prepared in the course of the past ten years. Many of them have exhibited an activity on the cardiovascular system as antihypertensive agents but also in other fields: analgesia, inflammation, central nervous system. More than half the products prepared have also been studied as herbicides.
A number of substitutions have been performed on the pyridazine cycle but the compounds substituted in position-5 are less numerous since they are difficult of access.
The invention is directed to novel pyridazinone derivatives constituted by arylidene-5 (2H, 4H) pyridazinone-3 corresponding to the formula:
wherein R1, R2, R3, R4 and R6 have the following meaning: R, = H, F, Cl, NO2orCH3;R2=H, Cl, NO2, CF3 orOCH3;R3=H, F, Cl, CH3, NO2, OCH3 or OH; R4=H or OCH3, Rs = H or Cl, but cannot all be a hydrogen atom at the same time, and in which R2 and R3 can also be combined in a bridge -O-CH2-O- and R6 is CH= or CHOH.
In accordance with the invention, preference is given to those compounds in which R6 is-CH= or, if R6 is -CHOH-, those in which R2 and R4 are in that case hydrogen atoms. Among these derivatives, an outstanding advantage appears to be offered by the use of derivatives in which: R1=H or Cl, R2=H, Cl or CF3, R3=H, Cl or NO2, R4=H or Cl, and even more so when R1 and R5 = Cl whereas R2, R3 and R4 = H.
The invention is also directed to novel drugs which have a low neuroleptic activity but produce a substantial increase in the femoral flow rate, said drugs being distinguished by the fact that they contain an effective quantity of at least one pyridazinone derivative in accordance with the invention.
In this connection, a particularly attractive advantage appears to be offered by drugs which contain a pharmaceutically active proportion of methyl-6-(dichloro-2',6'-benzylidene 1') 5 (2H, 4H) pyridazinone-3 and/or methyl-6 (dichloro 2', 6' phenyl hydroxymethyl 1')-5 dihydro 4,5 (2H) pyridazinone-3.
The compounds in accordance with the invention can be prepared from aryl-4-acetyl-3 butanolide, which can be obtained by condensation between an aromatic aidehyde and a-angelicalactone by means of a method known per se which is described hereinafter. The reaction is as follows:
These compounds which serve as raw material can be reacted with hydrazine hydrate in a polar organic solvent in order to obtain a compound in accordance with the invention in which Re is -CHOH-. Dehydration of a compound of this type results in the corresponding compound in which R6 is -CH=.
EXAMPLE 1 Preparation of aryl-4 acetyl-3 butanolide-4 (or dichloro-2',6' phenyl)-4 acetyl-3 butanolide-4).
In a reaction vessel having a capacity of one liter, there are introduced 0.05 mole of aangelicalactone and 0.05 mole of dichloro 2,6 benzaldehyde in solution in 200 ml of methylene chloride. A solution of 0.05 mole of boron trifluoride etherate in 100 ml of methylene chloride at room temperature is added drop by drop for a period of 30 minutes with agitation which is maintained over a period of 70 hours.
300 ml of a saturated sodium chloride solution are then added with brisk agitation. The solution becomes turbid and agitation is maintained for a further period of 1 5 minutes. The contents are transferred into a separating funnel and the two phases are separated-out. The organic phase is dried on sodium sulfate, whereupon the solvent is evaporated under low pressure. The oily residue is transferred into a beaker and crystallized in the presence of ethanol at low temperature (20 ).
The raw product is recrystallized in ethanol.
The dihydro 4,5 (2H) pyridazinones-3 are prepared from the aryl-4 acetyl-3 butanolides-4 which are reacted with hydrazine hydrate in a polar organic solvent which is preferentially a lower alcohol.
EXAMPLE 2 Methyl-6 (dichloro 2',6' phenyl hydroxymethyl-1')-5 dihydro-4,5 (2H) pyridazinone-3.
In a balloon flask having a capacity of 250 ml, 0.01 mole of dichloro 2', 6' phenyl-4 acetyl-3 butanolide-4 is dissolved in the hot state in the minimum quantity of ethanol; after complete dissolution, 0.01 mole of hydrazine hydrate is added. The complete solution is heated and refluxed with agitation during a period of 2 hours. The corresponding pyridazinone precipitates by cooling. It is sometimes necessary to carry out preliminary evaporation of part of the solvent. The raw product is recrystallized in ethanol.
Yield = 90% Mol. wt. = 287 m.p. = 211 OC Analysis for C,2H,202N2Cl2: C H N O CI Calculated % 50.2 4.20 9.80 11.1 24.7 Found % 50.6 4.23 9.68 10.9 24.7 The proton NMR is in agreement with the proposed formula.
Examples of dihydro 4,5 (2H) pyridazinones-3 prepared in accordance with the method of Example 2 from corresponding butanolides prepared in accordance with Example 1:
No. R, R, R3 R4 R5 m.p. C 19 H H H H H 95 20 H H CH3 H H 180 21 Cl H H H H 205 22 H Cl H H H 152 23 H H Cl H H 215 24 CI H H H Cl 211 25 F H H H H 165 26 H H F H H 170 27 F H H H Cl 192 28 NO2 H H H H 235 29 H NO2 H H H 188 30 H CF3 H H H 140 31 H H OCH3 H H 169 32 OCH3 H OCH3 OCH3 H 190 33 H H O - CH2 - 0 H 106 The dihydro-4,5 (2H) pyridazinone which has been prepared can be converted to arylidene-5 (2H, 4H) pyridazinone-3 by dehydration. The operation will be carried out more effectively in the presence of a dehydrating agent.
EXAMPLE 3 Methyl-6 (dichloro-2',6' benzylidene-1 ')-5 (2H, 4H) pyridazinone-3.
In a beaker having a capacity of 100 ml, 0.01 mole of hydroxymethyl-pyridazinone-3 in accordance with Example 1 is put in suspension in 30 ml of concentrated sulfuric acid. After a few minutes of agitation, the product solubilizes and the solution is transferred into a beaker containing 100 ml of iced water. The arylidene-5 pyridazinone precipitates, whereupon it is filtered, dried and recrystallized in ethanol.
Yield = 87% Mol. wt. = 269 m.p.=2560C Analysis for C12H 100N2Cl2: C H N O Cl Calculated % 53.5 3.72 10.4 5.95 26.4 Found % 53.7 3.72 10.4 5.91 26.2 The proton NMR is in agreement with the proposed formula.
The infrared spectrum shows the disappearance of the OH band located in the vicinity of 3400 cam~' and the persistance of the carbonyl peak of lactam in the vicinity of 1 660 cm-'. Furthermore, the intensity of the adjacent peak of 1 600 cm-l corresponding to the vibrations V (C = C) increases significantly.
The methyl-6-(dichloro-2',6' benzylidene-1 ')-5 (2H, 4H) pyridazinone-3 compound which has been studied in dogs exhibits an essentially vascular activity without any appreciable modification of the hemodynamic parameters. There is noted in particular an elective increase in the femoral flow rate, a slight cardiac stimulation and little modification of the arterial blood pressure.
In addition, a sedative effect is noted in the case of mice; catalepsy, however, is obtained only at high doses.
The compound under consideration finds applications in human medicine for the treatment of vascular disorders and in particular arteritis.
Examples of arylidene-5 (2H, 4H) pyridazinone-3 compounds prepared in accordance with the method of Example 3:
No. R, R, R3 R R, m.p. 0C 37 Cl H H H H 210 38 H Cl H H H 166 39 H H Cl H H 198 40 Cl H H H CI 256 41 H CF3 H H H 148 42 H H NO2 H H 234 EXAMPLE 4 Toxicity test by mouth The compound in accordance with Example 3 was put in suspension in a 0.5% methylcellulose solution; this suspension was administered by gastric probe to mice of 20 + 2 g at increasing doses; six animals were employed for each dose. It was thus possible to establish the approximate DL 50 in the vicinity of 800 mg/kg by mouth.
EXAMPLE 5 Determination of sedative activity The sedative action of the compound in accordance with Example 3 has been demonstrated by the test of sleep potentialization induced by pentobarbital in mice. After forming batches of ten mice, the 0.5% methylcellulose suspension of the compound in accordance with Example 3 (No 40) was administered to each batch in increasing doses by gastric probe. Sodium pentobarbital was administered 30 minutes layer by intraperitoneal injection at a dose of 50 mg/kg. Under these conditions, the duration of sleep induced by the barbiturate was doubled in the case of animals which had received 100 mg/kg of compound No. 40. Similar results were obtained with compounds Nos 22 and 31 of Example 2 but at a dose of 4 to 6 mg/kg.
EXAMPLE 6 Action on the cardiovascular system Derivative No. 40 in accordance with Example 3 was admihistered by intravenous injection to anaesthetized dogs with a view to studying its hemodynamic effects. Eight parameters were taken into account: heartbeat frequency, left intraventricular pressure, derivative of this pressure with respect to time (dp/dt), aortic flow rate, aortic pressure, coronary arterial flow rate, femoral arterial flow rate, femoral arterial pressure. Three doses were injected: 0.3, 1 and 3 mg/kg, each dose being solubilized in 5 ml of a solution of polyethyleneglycol (PEG) and physiological serum. Said doses were administered cumulatively from the lowest to the highest dose.
At a dose of 0.3 mg/kg, the observed effect was of very short duration and was no different from that of the solvent. There was observed an increase in the blood flow rates which was constant in the case of the femoral flow rate but variable in the case of the coronary and aortic flow rates associated with a very slight hypotension. At the dose of 1 mg/kg, there was a very sharp increase in flow rates. All the rates were affected in a comparable manner and became about four times higher than the reference values. The peak value was located at the end of the first minute. The variation was transient in the case of the aortic and coronary flow rates whereas it lasted 13 minutes on an average in the case of the femoral flow rate. This effect was not accompanied by any appreciable variation in blood pressure.A transient bradycardia was noted immediately on completion of the injection and even produced a pause in the case of one of the animals. The dp/dt and the left intraventricular pressure increased in 50% of the cases during the first minute. The effects were no different when the dose was increased to 3 mg/kg.
EXAMPLE 7 Action on the cardiovascular system Derivative No. 24 in accordance with Example 2 was administered to anaesthetized dogs and was studied under the same technical conditions as those described in Example 6. By comparison with the results obtained in the study of the compound of Example 3, an equivalent hemodynamic activity was obtained in respect of doses which were approximately eight times larger, namely 3 mg/kg in the case of the activity threshold and 20 mg/kg in the case of maximum action.
EXAMPLE 8 Clinical study of the compound in accordance with Example 3 This study was made on patients suffering from arterial circulatory insufficiency of the lower limbs and in whom it was sought to determine the effect of the compound in accordance with Example 3 on the arterial blood flow of the lower limbs.
The test was performed in accordance with the double-blind technique involving the use of a placebo. During two successive experimental sessions, each patient received one oral dose of the compound in accordance with Example 3 or a placebo in a random order (crossed test).
The arterial flow rate was determined by means of occlusive plethysmography (Periflow Janssen SI) in two ways: - at the level of one of the two big toes by continuous measurement of the arterial flow rate in the state of rest; - at the level of the second big toe by means of a series of measurements of post-ischemic reaction hyperhemia.
The results obtained were as follows:
Effect of the compound in accordance with Example 3 Effect of a placebo (lactose) Arterial flow rate Reactlon Arterial flow rate Reaction Patient Dose in sate of rest hyperhemia in state of rest hyperhemia NO. mg (varation in %) (variation in %) (varation in %) (variation in %) 1 125 + 10 % + 40 % + 10 % 0 % 2 125 + 30 % + 60 % + 10 % 0 % 3 250 +100 % + 50 % 0 % 0 % 4 375 + 80 % + 50 % + 20 % + 10 % The compound in accordance with Example 3 therefore has an activity on the peripheral vascularization which produces an increase in the arterial flow rate and in the pulsatility. No.
concomitant change in heart-beat frequency has been observed.
The compound in accordance with Example 3 is therefore advantageous for the treatment of arterial circulatory insufficiencies of the lower limbs.
The following examples relate to applications of the compounds in accordance with the invention in human therapeutics, especially for the treatment of arteriopathy of the lower limbs - EXAMPLE 9 Pharmaceutical forms: capsules There can be employed in human therapeutics capsules which advantageously have the following composition: - compound No. 22 100 mg - excipient q.s. 1 capsule The posology can vary between 2 and 6 capsules per day.
EXAMPLE 10 Pharmaceutical forms: tablets There can be employed in human therapeutics tablets which advantageously have the following composition: compound No. 30 100 mg - excipient q.s. 1 tablet The daily doses will be from 2 to 6 tablets.
EXAMPLE 11 Pharmaceutical form: injectable solution There can be employed in human therapeutics an injectable solution which advantageously has the following composition: - compound No. 40 of Example 3 50 mg - solvent for injectable preparation q.s. 10 ml The posology will advantageously be 50 mg, once or twice per day by intramuscular or slow intravenous injection.
EXAMPLE 12 Pharmaceutical form: concentrated solution for perfusions There can be employed in human therapeutics a concentrated solution for perfusions which advantageously has the following composition: compound No. 40 of Example 3 200 mg - solvent for injectable preparation q.s. 20 ml The posology will advantageously be 200 to 400 mg of compound of Example 3 in 500 ml of isotonic solution to be perfused intravenously for a period of 3 hours.
As will readily be understood, the invention is not limited in any sense to the examples described in the foregoing. Depending on the applications which may be contemplated, consideration may accordingly be given to many alternative forms within the capacity of those versed in the art without thereby departing either from the scope or the spirit of the invention.

Claims (12)

1. Novel pyridazinone derivatives constituted by arylidene-5 (2H, 4H) pyridazinone-3 corresponding to the formula:
wherein R1, R2, R3, R4 and R5 have the following meaning: R1=H, F, Cl, NO2 or OCH3; R2=H, Cl, NO2, CF3 or OCH3; R3=H, F, Cl, CH3, NO2, OCH3 or OH; R4=Hor OCH3 R5 R5=H or Cl, but cannot all be a hydrogen atom at the same time, whilst R2 and R3 can be combined in a bridge O- CH2-O and R8 is -CH= or -CHOH-.
2. Novel compounds in accordance with claim 1, characterized in that R6 is the -CH= group.
3. Novel compounds in accordance with claim 1, characterized in that R6 is the -CHOH- group and R2 and R4 are hydrogen atoms.
4. Novel compounds in accordance with claim 2, characterized in that R, = H or Cl; R2 = H, Cl or CF R3 = Cl or NO or H; R4 = H and R5 = H or Cl.
5. Novel compounds in accordance with claim 1, claim 2 or claim 3, characterized in that R, and R5=Cl;R2,R3and R4=H.
6. A method of manufacture of compounds in accordance with claim 1, characterized in that an aryl-4 acetyl-3 butanolide-4 having the formula
wherein R, to R5 have the same meaning as in claim 1 is reacted with hydrazine hydrate in a polar organic solvent, in which case R6 is -CHOH- in the compounds obtained.
7. A method of manufacture of compounds in accordance with claim 1, in which Re is -CH=, characterized in that dehydration is carried out on a dihydro-4,5 (2H) pyridazinone having a corresponding formula in which R6 is -CHOH-.
8. Novel drugs having low sedative activity but producing a considerable increase in femoral flow rate, characterized in that the said drugs contain an effective quantity of at least one pyridazinone derivative in accordance with any one of claims 1 to 5.
9. Novel drugs in accordance with claim 5, characterized in that they contain a pharmaceutically active proportion of methyl-6- (dichloro 2', 6' benzylidene 1') 5 (2H, 4H) pyridazinone-3.
10. Novel drugs in accordance with claim 8, characterized in that they contain a pharmaceutically active proportion of methyl-6 (dichloro 2', 6' phenyl hydroxymethyl 1')-5 dihydro-4,5 (2H) pyridazinone-3.
11 Novel pyridazinone derivatives for use as drugs, substantially as hereinbefore described with reference to the Examples.
12. A method of manufacture of the said derivatives substantially as hereinbefore described.
GB08316516A 1982-06-18 1983-06-17 Pyridazinones Withdrawn GB2122195A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8210630A FR2528837A1 (en) 1982-06-18 1982-06-18 ARYLACETYL BUTANOLIDES AND THEIR PYRIDAZINONE DERIVATIVES AS MEDICAMENTS, AND METHODS FOR THEIR MANUFACTURE

Publications (2)

Publication Number Publication Date
GB8316516D0 GB8316516D0 (en) 1983-07-20
GB2122195A true GB2122195A (en) 1984-01-11

Family

ID=9275129

Family Applications (1)

Application Number Title Priority Date Filing Date
GB08316516A Withdrawn GB2122195A (en) 1982-06-18 1983-06-17 Pyridazinones

Country Status (10)

Country Link
JP (1) JPS5910571A (en)
KR (1) KR860001339B1 (en)
BE (1) BE897085A (en)
CH (1) CH657125B (en)
DE (1) DE3321772A1 (en)
FR (1) FR2528837A1 (en)
GB (1) GB2122195A (en)
GR (1) GR78284B (en)
IT (1) IT1194281B (en)
NL (1) NL8302087A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0210530A1 (en) * 1985-07-27 1987-02-04 MERCK PATENT GmbH 6-Arylalkenyl pyridazinones

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4666902A (en) * 1983-06-20 1987-05-19 Cassella Aktiengesellschaft Tetrahydropyridazinone derivatives, processes for their preparation and their use
JPS63220512A (en) * 1987-03-09 1988-09-13 松下電器産業株式会社 Electrode foil for electrolytic capacitor
JPH04100106U (en) * 1991-02-12 1992-08-28
JPH0776050B2 (en) * 1991-07-25 1995-08-16 実 近藤 Work transfer device

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2304977A1 (en) * 1973-02-01 1974-08-08 Basf Ag 3-Aminoaryl-5-alkyl-4,5-dihydro-6(1H)-pyridazones - prepd. by reacting 2-alkyl-3-aminoaroyl-propionic acids with hydrazines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0210530A1 (en) * 1985-07-27 1987-02-04 MERCK PATENT GmbH 6-Arylalkenyl pyridazinones

Also Published As

Publication number Publication date
IT1194281B (en) 1988-09-14
CH657125B (en) 1986-08-15
DE3321772A1 (en) 1983-12-22
FR2528837A1 (en) 1983-12-23
IT8321684A0 (en) 1983-06-17
KR860001339B1 (en) 1986-09-15
GR78284B (en) 1984-09-26
JPS5910571A (en) 1984-01-20
BE897085A (en) 1983-12-19
FR2528837B1 (en) 1984-12-07
GB8316516D0 (en) 1983-07-20
NL8302087A (en) 1984-01-16
KR840005105A (en) 1984-11-03

Similar Documents

Publication Publication Date Title
CN101402565A (en) Halogenated 2-(a-hydroxyl pentyl) benzoate, production method and uses thereof
Sunkel et al. Synthesis, platelet aggregation inhibitory activity, and in vivo antithrombotic activity of new 1, 4-dihydropyridines
JPH0469377A (en) Diphenylmethylpiperazine derivative
JPS6028979A (en) Imidazoquinazoline compound
JP2001508400A (en) Isatin derivatives as acetylcholinesterase inhibitors and analgesics
US4599355A (en) Treatment of sleep disorders
GB2122195A (en) Pyridazinones
JPS6322082A (en) 1-(hydroxystiryl)-5h-2, 3-benzodiazepine derivative and its production, drug containing said derivative and its production
HU191753B (en) Process for preparing 5-acyl-2-/1h/-pyridinine deriva-tives
KR900006116B1 (en) Process for preparing dihydropyridines
US5681843A (en) Parabanic acid derivatives
WO1994005290A1 (en) Platelet aggregation inhibitor
JPH02108688A (en) Quinoline compound
JP6054102B2 (en) Nitric oxide production promoter or inducer
US4727090A (en) Process for preparing and therapeutical applications of the 2,4,6-triiodophenol
EP0238883A1 (en) Oxabicycloheptane derivatives, pharmaceutical composition and use
JPS58103377A (en) 2-phenyl-morpholine derivative and antidepressive containing same
JPS63104960A (en) Alpha ((phenylmethoxy)methyl)pyridinealkanol derivative
JPH04230285A (en) Drug having diuresis and preparation thereof and novel 3,7-diazabicyclo(3,3,1)nonane compound and preparation thereof
US4992457A (en) Pharmacologically active cholinergic compositions, and methods for making same and use thereof in treating disease
FR2636065A1 (en) NOVEL 2,3-DIHYDRO-ARYLACOYLAMINOALCOYL-3H-BENZOXAZINE-1,3-ONES-4 DERIVATIVES, THEIR PREPARATION AND THEIR USE AS THERAPEUTIC USEFUL MEDICAMENTS
KR20040007477A (en) Remedies for vesical stimulation in association with prostatauxe
HU206830B (en) Process for producing pharmaceutical compositions containing pafantagonists for treating heart diseases produced by diminished beta-receptor-stimulant
WO2000004000A1 (en) Piperazinone derivatives and their uses
US3472868A (en) 1-(2-5-dioxo-pyrrolidino-4-(perhydroazepino)-butyne-2

Legal Events

Date Code Title Description
WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)