JPS60166679A - 4,5-dihydro-6-(2-(4-(1h-imidazol-1-yl)phenyl)-ethenyl)-3(2h)-pyridazinones and related compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION 6-Pyricyl-vinyl-pyridazin-3(2H)-one and 4,5-dihydro compounds have been reported as having cardiotonic and/or antihypertensive effects in European Patent Application No. 81.
It is described in the specification of No. 906.

The present invention l'i4.5-dihydro-6-[2-44-(I
TJ-11'7'-ru1-1l)phenylcoalkylenyl-3(2H)-pyridazinone and 4,5-dihydro-6-[2-[4-(IH-imidazol-1-yl)phenyl It concerns core alkylene-3(2H)-pyridazinones and their derivative compounds, which have valuable pharmacological properties, in particular cardiotonic, antihypertensive and antithrombotic effects.

Therefore, the present invention provides the formula (where == means a single bond or a double bond, R1,
R2 and R3 are each independently hydrogen, lower alkyl,
hydroxy lower alkyl or R2 and R
When 3 are together they can form a 5- ring with 5 to 7 carbon atoms or a benzene ring, R4 and R5 are each independently hydrogen or lower alkyl, and A is 1 ~ alkylene having 4 carbon atoms or alkenylene having 2 to 4 carbon atoms) or a pharmaceutically acceptable acid addition salt thereof, and an effective amount of a compound of formula a method of preparing a compound of formula I, comprising administering an effective amount of a pharmaceutical composition containing a compound of formula I to a mammal in need of increasing cardiac contractility; A method of increasing cardiac contractility in an animal, a method of lowering blood pressure comprising administering an effective amount of the above pharmaceutical composition to a mammal with hypertension, and administering an effective amount of the above pharmaceutical composition to a mammal with thromboembolism. The present invention relates to the treatment and prevention of thromboembolism.

6- The term "alkylene having 1 to 4 carbon atoms" denotes a straight or branched hydrocarbon chain bonded at each end to another group, examples include - Methylethylene, propylene, methylene, 1-methylpropylene, 2-methylpropylene or 1,1-dimethylethylene.

The term "alkenylene having 2 to 4 carbon atoms" refers to a straight or branched hydrocarbon chain having a double bond and attached at each end to another group, e.g. Examples include ethenylene, arylene, 1-methylethylene, 6-methyl-1-propenylene, 1-butenylene, 2-7'tenylene, 2-methyl-1-propenylene, and the like.

Compounds of formula (II) are useful in both free base and acid addition salt forms. Both forms are within the scope of this invention. Acid addition salts are the more convenient form to use; in fact, use in the salt form is equivalent to use in the base form. It has been found convenient to produce sulfates, phosphates or methanesulfonates in the practice of the invention. However, other suitable pharmaceutically acceptable salts within the scope of this invention include inorganic acids such as hydrochloric acid and sulfamic acid and salts such as ethanesulfonic acid, hensensulfonic acid, p-)luenesulfonic acid, etc. salts derived from organic acids such as hydrochloride, sulfamate, ethanesulfonate, and benzenesulfone salts, respectively.
gives p-toluenesulfonate h.

Acid addition salts of the basic compounds can be prepared by dissolving the free base in a suitable acid-containing aqueous or alcoholic solution or other suitable solvent and isolating the salt by evaporating the solution; It is prepared by reacting an acid in an organic solvent and either separating the salt directly or by concentrating the solution.

Compounds of formula I in which R4 is hydrogen and ; : means a double bond are in tautomeric form, i.e., as shown below, compounds of formula I
6-[2-(4-(1a-imidazol-1-yl))
Phenyl"J-"f-renyl-3(2H)-pyridazinone or 6-[2-[4-(1■-imidazole-
1-yl)phenylcoalkylene-3(2H)-pyridazinone or 6-[2-(4-C1H) of the formula
-ImIll'l-l-1-yl)phenyl]argylenyl-6-pyridazinol or 6-(2-(4-(IH
-imidazol-1-yl)phenylcoalkylene-3
-Pyridacinol 9- may exist.

II I[A A preferred embodiment of the present invention is a formula in which == represents a single bond or a double bond, R1, R2, R5, R4 and R5 are each independently hydrogen or methyl, and A is 2- A compound of formula I which is an alkenylene having 4 carbon atoms or an alkylene having 1 to 4 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment is where -111 is a single bond or a double bond, R1, R2, R3, R4 and R5 are each independently hydrogen or methyl, and A is methylene, ethylene, Compounds of formula I which are propylene or particularly preferably vinylene.

10- A particularly preferred embodiment of the present invention is 4,5-dihydro-6-[
2-[4-(IH-imidazol-1-yl)phenyl]ethynyl]-3(2H)-pyridazinone.

Another preferred embodiment of the invention is 4,5-dihydro-6-[
2-44-(IH-imidazol-1-yl)phenyl]ethynyl]-5-methyl-! +(2H)-pyridazinone.

Compounds of formula I can be dissolved in alcoholic solvents (e.g. ethanol) or acids/at elevated temperatures, e.g.
R-oxobutanoic acid of the formula (where A%R1, R2, R3 and R5 have the above definitions) in an alcohol mixture (e.g. ethanol/acetic acid) is combined with R4- and dorazine (
where R4 has the above definition 2) or a hydrate thereof to prepare a compound of formula W, V as desired.

C! urran and A, Ros5 [,T
, Mea.

Ohem, J 17.273 (1974), for example, by a process consisting of conversion with an oxidizing agent such as manganese dioxide or m-nitrobenzenesulfonic acid to a compound of formula.

The r-oxobutanoic acid used as starting material is known or, if new, is disclosed, for example in European Patent Application No. 8
1,906 and 85,227, as appropriate.
It can be prepared by known means by condensing phenylcarboxaldehyde with oxobutanoic acid.

The following scheme is an example, where A is ethenylene and /
or ethylene. Ethylene compounds can be obtained by catalytic hydrogenation of vinylene compounds. Pd/carbon (10%) is preferably used in an alcoholic solvent such as ethanol.

13- The usefulness of the compounds of the invention as cardiotonic agents includes, for example, 6 strokes and blood pressure, with small or minimal changes;
This is evidenced by their effectiveness in standard pharmacological tests such as significantly increasing cardiomyopathic contractility in dogs anesthetized with parbital. This test method is shown below.

Test for In Vivo Cardiomyopathy Inotropic Activity in Anesthetized Dogs This screen tests cardiomyopathy contractility (left ventricular pressure aP/at maximum), 6°C, and aortic blood pressure in dogs anesthetized with Suntobarbital. It consists of determining the effect of increasing intravenous doses of the compound on the effect.

Method: Administer Mongrel intravenously to adult dogs of either sex from 35 to 9
Anesthetized with bendoparbital and then! A
Anesthetized state is maintained by continuous infusion of toparbital at 5 my/Ky/hour. A trachea is inserted, but each animal is allowed to breathe at the same time. A cannula is inserted into the femoral vein to administer the test agent. A Millar catheter tip pressure transducer or fluid-filled catheter is inserted into the aorta upstream via the femoral artery to measure aortic blood pressure. A mirror catheter tip pressure transducer is passed into the left ventricle via the left carotid artery for left ventricular blood pressure measurements. During the visit ■ A needle electrode is placed subcutaneously to record an electrocardiogram (maG).

Left ventricular and aortic blood pressures are recorded on an elongated chart recorder. Six beats were also recorded using a biotachometer resulting from the R-wave of the EOG and the first lead of left ventricular pressure (aP/dt) obtained using a differentiator amplifier coupled to a corresponding pressure amplifier. recorded.

A period of at least 30 minutes is used to obtain control data prior to administration of test compound.

Depending on solubility, each test compound is dissolved in 0.9 T saline or dilute HCλ or dilute NaOH (0.1 N or 1. ON) and diluted to a constant volume with normal saline. Ethanol or dimethylacetamide can be used as solvents if appropriate dilution can be made.

Each administration of test compound-it was 1 minute before 0.1-7K
Administered in a volume of g.

When tested by the anesthetized dog method described above, the compounds of the present invention produced only small or minimal changes in the frequency and blood pressure when administered intravenously at a rate of about 0.01-0.61/Kf1 min. produced a significant dose-related increase in cardiac contractility, although with only a small decrease in . That is, the compounds of the present invention are also useful as antihypertensive agents.

1aO. Also encompassed are pharmaceutical compositions for increasing cardiac contractility and/or for treating hypertension, containing a compound of formula I as defined, together with a pharmaceutically acceptable carrier.

The present invention provides compounds of the formula I as defined above in a unit dosage form suitable for mammals with diseases of cardiac contractility and/or hypertension.
Also encompasses a method for increasing cardiac contractility and/or treating hypertension in such a mammal, which comprises orally or parenterally administering a corresponding pharmaceutical composition containing a compound of the invention.

The usefulness of the compounds of the invention as antithrombotic agents is demonstrated by their effectiveness in inhibiting human platelet aggregation to normal in an in vitro platelet aggregation test using human platelet-rich plasma.

Platelet Source 18 - Blood will be collected from volunteers who have not used aspirin or other non-steroidal anti-inflammatory drugs within 2 weeks prior to blood collection and have not eaten within 9 hours prior to blood collection. Blood is 0
．． Collected in 4.5 d increments into Pacutainer 1M6462B silicone-coated tubes containing 5 rllll of 3.8 polysodium citrate. Usually 4.57! Six pieces of blood will be collected from the Gu Nan Shisha. Blood collected from three or four volunteers is pooled before centrifugation.

This pooled blood was placed in a 50-polyethylene tube and centrifuged in an internal model equipped with a No. 240 rotor for 20 minutes at room temperature.
(approximately 60 Orpm). A portion of the supernatant platelet-rich plasma (PRP) (approximately 2A
), set aside and centrifuge the remaining blood sample for 15 minutes at 1400Xf (approximately ZAOORPM) to Nff platelet-poor plasma (p:pp).

The platelet content of PRP is measured with a Counter Thrombocounter. PRP is adjusted to a total number of 250,000 platelets per microliter using PPP.

Preparation of drug solution The test drug was added to a small amount of dimethyl sulfoxide (]:ME]O
), then diluted with physiological saline (final concentration of DMEIO is 1%). Other lower concentrations are prepared by serial dilutions in saline.

Method of Aggregation Measurement Platelet-rich plasma adjusted to 250,000 platelets per microliter is dispensed in 0.36 +nl aliquots into 0.312 inch diameter silicone coated Couvettes. Drug solution or physiological saline (0,02-
) after the addition of flocculant (ADP or coscegen suspension,
0.02m)'. Payton Scientific Channel Aggregation Module (Payton Scientific Dua)
l Channel Aggregation Mod
ule), model 600B is used to measure the degree of aggregation (ADP stimulation) or the aggregation rate (collagen stimulation). The appropriate concentration of flocculant is determined by a simple initial titration.

Calculation Method: The flattened height of the agglutination curve for ADP-induced aggregation control (no drug addition, saline only) aggregation is compared with the height of the curve obtained after drug addition at various appropriate concentrations. The height after addition of the drug is finally expressed as the "chi" value of the control object. These values are plotted against drug concentration on semi-log paper. The engineering CSO can then be evaluated from the generated curve.

21- Collagen-induced aggregation Determine the main slope (i.e. the slope of the longest straight line) of the collagen-induced aggregation curve and compare it to the slope obtained with the control aggregation curve (only saline and flocculant added). Compare with.

The values obtained are expressed as "control chi" values.

These values are plotted against drug concentration on semi-log paper. The engineering aSO is evaluated from the generated curve.

When tested according to the above procedure, 4,5-dihydro-6-
1:z-[4-(1H-imidazol-1-1)phenyl]ethynyl-5-methyl-3(2H)-piridazinone 7X1010M against collagen-induced aggregation
It had a very strong coefficient of 050 of I x 107M for ADP-stimulated aggregation.

Accordingly, the present invention provides for the administration orally or parenterally of a corresponding pharmaceutical composition containing a compound of formula (2) as defined above in a [suitable unit dosage form] to a mammal suffering from thrombosis. It also includes a method of treating thrombosis consisting of:

For preparing pharmaceutical compositions from the compounds described herein, inert, pharmaceutically acceptable carriers can be either solid or liquid. Examples of solid form preparations include powders, tablets, dispersible granules, capsules,
Examples include cachet and herbal medicines. The solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, thinning agent, suspending agent, binder or tablet leavening agent, and it can also be used as an encapsulating material. It can also be.

In powders, the carrier is a finely divided solid that is mixed with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary binding properties in appropriate proportions and prepared in the desired shape and size. Preferably, powders and tablets contain from 5 or 10 grams to about 70 grams of active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,
Dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose,
These include low-melting waxes, cocoa, and butter. "formulation"
The term refers to a formulation of the active compound with an encapsulating material as a carrier providing a capsule in which the active ingredient (with or without other carriers) is surrounded by and thus associated with the carrier. It is something. Similarly, cachets are included. Tablets, powders, coffees and capsules can be used as solid dosage forms suitable for oral administration.

To prepare herbal medicines, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is then dispersed homogeneously therein, for example by stirring.

The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

Examples of liquid form preparations include solutions, suspensions, and emulsions. One example is an aqueous solution or a water-propylene glycol solution for parenteral injection. Liquid formulations can also be prepared in solution in polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickeners, as desired. Aqueous suspensions suitable for oral use include finely divided active ingredients dispersed in water with viscous substances such as natural or synthetic gums, 25-resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. It can be prepared by

Also included are solid form preparations that are converted, shortly before use, to liquid form preparations for either oral or parenteral administration.

Examples of such liquid forms include, for example, solutions, suspensions and emulsions. These particular solid form preparations are most conveniently presented in unit dosage form and, as such, are used to provide a single liquid dosage unit. Alternatively, after conversion to liquid form, a number of individual liquid doses can be obtained by measuring a predetermined volume of the liquid form preparation, e.g. with a syringe, teaspoon or other volumetric container. Sufficient solids can be provided so that When multiple liquid doses 26-4 are prepared in this manner, it is preferred to maintain the unused portions of the liquid doses at low temperatures (i.e., under refrigeration) to retard possible decomposition. Solid form preparations intended to be converted into liquid form may contain, in addition to the active substance, flavourings, colorants, stabilizers, buffers, artificial or natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The liquid used to prepare liquid form formulations can be water, isotonic water, ethanol, glycerin, propylene glycol, and the like, as well as mixtures thereof. Naturally, the liquid used will be selected with regard to the route of administration, for example liquid formulations containing large amounts of ethanol are not suitable for parenteral use.

Preferably, the formulation is presented in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a package, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in tablets or ampoules. Also, the unit dosage form can be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form.

The amount of active compound in a unit dose of the formulation can be varied or adjusted from 1 to 500, preferably from 5 to 100, depending on the particular application and the potency of the active ingredient. If desired, the compositions may also contain other compatible therapeutic agents.

In said treatment, the dosage range for a 70Kf patient is from 0.105 to 100, preferably from 0.1 to 50 per 4 parts of body weight per day. However, these dosages can be varied depending on the needs of the patient, the severity of the condition being treated and the compound being used.

Determination of the appropriate dosage for a particular condition will be apparent to those skilled in the art.

Generally, treatment is less than the optimal dose of the compound,
Start with lower doses. Thereafter, the dosage is increased in small increments until the optimum effect under the given circumstances is achieved. For convenience, the total daily dosage may be divided and administered in several portions during the day, if desired.

The present invention will be further explained below with reference to Examples.

Example 1 4.5-dihydro-6-[2-44-(IH-iotasol-1-yl)phenyl]ethynyl]-3(2H)-
Pyridazinone (1a) 2f0IC)-6-29-[4-(IH-imidazol-1-yl)phenylcou 4-oxo-5] in 60-ethanol containing 0.51 80-thihydrazine hydrate - Heat a solution of hexenoic acid to reflux for 3 hours. The solution is concentrated to a small volume (approximately 10-) and filtered. The residue is crystallized from THF/methanol [] to give 6f, 4,5-dihydro-pyridazinone. Melting point: 260-261°C.

Elemental analysis value (as 015H14N40) Calculated value 267
:65 5.30 21.04 Actual value: 67.50 5
．． 32 21°00 Similarly, by following the procedure of Example 1, the following compound is obtained.

4,5-dihydro-6-C2-C4-[4,5,6,7
-Tetrahydro-1H-benzimidazol-1-yl)phenyl]ethynyl:]-3(2H)-pyridazinone, 30- Melting point 264-235°C (1b) Elemental analysis value (as 019H2ON40) Calculated value: 7
1.22 6.29 17.49 Actual value: 71.06
6.16 17.194.5-dihydro-6-[2-
[4-(1a-iotasol-1-yl)phenyl]ethynyl-5-methyl-3(2H)-pyridazinone, melting point 183-184°C (1C) Elemental analysis value (as 016H16N40) Calculated value: 6
8.55 5.75 19.79 Actual value: 68.24
5.76 19.74 Example 2 4.5-dihydro-6-[244-(1H-iotasol-1-yl)phenyl]ethyl]-3(2H)-pyridazinone containing 0.5v of 10% palo 100-2
-4,5-dihydro-6-[2-[4-(IH-imidazole-1-) of 2,61 in methoxyethanol
yl)phenyl]ethynyl]-3(2H)-pyridazinone is shaken under an atmosphere of hydrogen for 13 hours. The catalyst is filtered, the p-liquid is evaporated to dryness and the residue is crystallized from ethanol to give 2v of the product. Melting point 19
5-196℃.

Elemental analysis value (as C15H16N40) Calculated value: 6
7.14 6.01 20.88 Actual value 2 66.96
6.18 20.85 Production example (Fri-6-C4-(IH-imidazol-1-yl)phenyl)-4-oxy/-5-hexenoic acid 0.5-
of 100- in toluene containing piperidine! 1-[4-(IH-imidazol-1-yl)phenyl]carboxaldehyde of c4F (0,02 mol) [L, M, 5itkina and A, M,
Whim, Geterots by s1monov
iki.

5oe41n, Akaa, Nauk, La1iv
, SSR, 143 (1966) - Chemicals, Abstracts, prepared by the general method described in 136B6 (1966)] and 2.61 (0.02 mol) of levulinic acid were added continuously with water. Reflux for 4 hours with removal. The reaction mixture is cooled, filtered, and the residue is washed with methanol to obtain the 3-acid. Melting point: 264-265°C.

Similarly, 1-[4-(4,5,6,7-tetrahydro-1
By replacing H-benzimidazol-1-yl)phenyl]carboxaldehyde (g))-
One sample of 6-[4-(4,5,is,733-1tetrahydro1H-benzimidazol-1-yl)phenyl-4-oxo-5-hexenoic acid is obtained.

Similarly, methyllevulinic acid [R,p, according to Evstigneeva et al., 2h, 0bshch, Khlm, 34.10] was substituted for the levulinic acid in the above example.
．． 3308-12 (1964) - Chemical Abstracts Niece, 3949h (1965)].
-(IH-iotasol-1-yl)phenyl)-3-
One sample of methyl-4-oxo-5-hexenoic acid is obtained.

Patent applicant Warner-Lampert Kompany 34- Continuation of page 1

Claims (1)

[Claims] 1) Formula (where; = is a single bond or a double bond, R1, R
2 and R3 are each independently hydrogen, lower alkyl, hydroxy lower alkyl, or R2 and R3
when together they can form a ring having 5 to 7 carbon atoms or a benzene ring, R4 and R5 are each independently hydrogen or lower alkyl;
alkylene having 1 to 4 carbon atoms or 2 to 4 carbon atoms
alkenylene having 4 carbon atoms) or a pharmaceutically acceptable acid addition salt thereof. 2) In the formula, R1, R2, R3, R4 and R5 are each
A compound according to claim 1, which is independently hydrogen or methyl. 6) In the formula, A is vinylene, said claim 2
Compounds described in Section. 4) 4.5-dihydro-6-(2-1:4-(1H-
imyl'l-1-yl)phenyl]ethynyl]-3
Claim 6 which is (2H)-pyridazinone
Compounds described in Section. 5) 4,5-dihydro-6-[2-[4-(4,5t
6,7-Titrahitol:l-1H-benzimidazol-1-yl)phenyl]ethynyl:] -3(2H)-
A compound according to claim 1 which is a pyridazinone. 6) 4.5-dihydro-6-(2-44-(IH-imidazol-1-yl)phenyl]ethynyl-5-methyl-3(2H)-pyridazinone according to claim 3; Compound. 7) 4.5-dihydro-6-[2-44-(IH-imitasol-11l)phenylcouethyl:]-3(2
A compound according to claim 1 which is H)-pyridazinone. 8) A pharmaceutical composition containing an effective amount of a compound according to claim 1, together with a pharmaceutically acceptable carrier. 9) A compound of formula is reacted with R4-hydrazine or a hydrate thereof in an alcohol or alcohol/acid medium at elevated temperature and optionally produces a compound of formula =
The compound of the formula (1) according to claim 1, in which = is a single bond, is converted with an oxidizing agent into the corresponding compound in which -1 is a double bond, and then, if desired, the compound of the formula I is formed. A process for preparing a compound according to claim 1, comprising converting the free base of the compound into the corresponding pharmaceutically acceptable acid addition salt.