JPH04503944A - Pyridazinone, pyrazolone and pyridone-naphteridinone compounds, cardiotonic compositions containing them, and uses thereof - 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] pyridazinone-, pyrazolone- and pyridone-naphthyridinone compounds; Cardiotropic compositions comprising and their use Field of the invention The present invention provides diazani ring-substituted pyridyl compounds useful as cardiotonic agents for the treatment of congestive heart failure. Concerning Don and Diazanone. The present invention also provides cardiac contractility using the above-mentioned compounds. and pharmaceutical compositions containing said compounds.

Congestive heart failure is a condition in which the heart is unable to transport enough blood back to it. It is a condition that reduces muscle contractility and shortens lifespan. Normal pathological sequelae are reduced. increased cardiac output, venous pooling, increased venous pressure, edema, increased heart size. stiffness, increased myocardial wall tension, and eventual cessation of contractility.

Reported development Drugs that increase myocardial tone are described as having positive inotropic activity and are called inotropic drugs. It is characterized as. Digitalis glycosides increase myocardial contractility and cause congestive It has been used for many years to reverse the deleterious changes seen in heart failure. Recently, Do Pamin, dobutamine, and amrinone provide the necessary inotropic support to the failing heart. It is used to

Cardiotropes described as having positive inotropic activity are described in U.S. Patent No. 4.004.　 Q, No. 12, No. 4.072.746, No. 4.107.315, No. 4, 137.233, 4.199.586 and 4.271.168; British Patent No. 2070606A; and International Patent Application No. PCT/CH8 1100023. other strong-willed The drug is disclosed in U.S. Patent Nos. 4.414.390 and 4.415.572. European Patent Application No. 84308925 , the cardiotonic pyridyl-substituted carbostyryl compounds disclosed in U.S. Pat. Cardiotropes disclosed in No. 4.657.915 5-substitution=■.

Contains 6-naphthyridin-2(IH)-one compound.　Heterotropin composition -5-Substituted Pyridyl Compounds International Patent Application No. PCT/US8310 No. 1285 and PCT/US87101489 (Wo 88100188) and the cardiotonic diazaheterocycle-5-substituted pyridyl compounds have been disclosed in the United States. Permit No. 4.432.979, No. 4.514.400 and No. 4,539.3 It is disclosed in No. 21. Each of the above patents is assigned to the same applicant as the present application. ing.

Cardiotropes 4.5-dihydro-5-[4-(H-imidazol-1-yl)phenyl ]-3(2)-pyridazinone as described by Bristol et al., J. Med. Chem, Vol. 22, p. 1099 (1984). Dazolyl-substituted pyridazinones are disclosed in U.S. Pat. No. 4,521.416 and , the cardiotonic benzodiazinone-substituted pyridazinone and pyrazolyl are disclosed in U.S. Patent No. 4.7. No. 25.686, the cardiotonic benzothiazolone-substituted pyridazinone Published European Patent Application No. 84108656.4 (Publication No. 0132817 No.). European patent published for cardiotonic compositions containing pyrazole groups Application No. 84303456.2 (Publication No. 0126651) and U.S. Pat. No. 4,526,895 and No. 4,526,982.

Summary of the invention The present invention provides pyridadiyl compounds useful for increasing cardiac contractility in humans and other mammals. The present invention relates to non-, pyrazolone- and pyridone-naphthyridone compounds.

Compounds of the invention have formula I: R.

electric A is 10= or -N=; B is -C=C-1-C=N- or -N=C-; provided that A or B is nitrogen represents a containing group; X is (CR, R5), -; Z is CRm or N; a is 1.2 or 3; b is 0 or 1; R, Rs and Ro are hydrogen, alkyl, or aralkyl; R1 is hydrogen, alkyl; Kyl, aralkyl, alkoxyalkyl, hydroxyalkyl, nitro, halo, Cyano, carbamoyl, alkylcarbamoyl, formyl, aminoalkylene or or amino; R2 is hydrogen, alkyl, aralkyl, -(CH,), -Y (wherein y is 1 to 3) is; R4 is hydrogen, alkyl, aryl or aralkyl; R6 is hydrogen, alkyl aralkyl, aryl, acyl, carbalkoxy, carbalkoxyal Kyl, hydroxyalkyl, alkoxyalkyl, amidino, alkoxy, ami ni, nitro, carboxy, cyano, alkylamino, halo, hydroxy, merca Butyl, alkylmercaptyl, carboalkyl or carbamoyl.

The gem-R4 and gem-Ra groups together form a spiro substituent, -(CH2) , - (in the formula, d is 2 to 5); Rゎ is hydrogen, alkyl, alkyl, Larkyl, aryl, acyl, carbalkoxy, carbamyl, carbalkoxy sialkyl, hydroxyalkyl, alkoxyalkyl or amidino; R and R groups on adjacent carbon atoms together form a carbon-carbon double bond (However, the R group requires that R6 is hydrogen and b = 1. ); Y is hydrogen, -0-R-8-R or -NRc1R, and αゝ　α R is hydrogen, alkyl or acyl; α RB is hydrogen or alkyl; Ra and R5 together with the nitrogen atom to which they are bonded form a 3- to 7-membered ring ( It may also contain 0-2 further N, O or S atoms). stomach) This includes compounds represented by and pharmaceutically acceptable salts thereof.

The present invention also provides the use of a pharmaceutical composition comprising an effective inotropic amount of the above-mentioned compound II. Relating to a method of increasing cardiac contractility.

detailed description The following terms used above and throughout this disclosure, unless otherwise specified: shall be understood to have the following meanings:

“Alkyl” means a saturated aliphatic hydrocarbon containing about 1 to about 6 carbon atoms (which is directly may be chain or branched).

"Lower argyl" means an alkyl group as defined above having from 1 to about 4 carbon atoms. means.

“Aralkyl” means an alkyl group substituted with an aryl group, in which means phenyl or phenyl substituted with one or more substituents; substituents are alkyl, alkoxy, amino, nitro, carboxy, carboalco xy, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mel Can be captyl, alkylmercaptyl, carboalkyl or carbamoyl Ru. Preferred aralkyl groups are benzyl or phenethyl.

“Alkylcarbamoyl” means a carbamoyl substituted with one or two alkyl groups. means an yl group. A preferred group is a lower alkylcarbamoyl group.

"Hydroxyalkyl" means an alkyl group substituted with a hydroxy group. Hi A droxy lower alkyl group is preferred. Examples of preferred groups are hydroxymethyl, 2 -Contains hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl nothing.

“Alkoxy” means an alkyl-oxy group, where “alkyl” is as defined above. It's uri. A lower alkoxy group is preferred. Examples of these groups are methoxy, ethoxy xy, n-propoxy, i-propoxy and n-butoxy.

“Alkoxyalkyl” means a group as defined above substituted with an alkoxy group as defined above. means an alkyl group.

"Aminoalkylene" has the formula -(CH2). -NH, (where n is 1 to about 6) means the group of A preferred group is a lower alkylene amino group, in which A class alkylene group is a group of 1 to about 4 carbon atoms. Most preferred aminoalkyl The ren group is aminomethylene.

Certain compounds of the invention may exist in enol or tautomeric forms; All of these forms are considered to be within the scope of this invention.

Compounds of the invention may be useful in free base form, salt form, and hydrated form. . All forms are within the scope of this invention. Acid addition salts may be formed and simply used This is a more convenient form for In practice, the use of salt forms is primarily based on Corresponds to the use of form. Acids that can be used to prepare acid addition salts can be combined with the free base. A pharmaceutically acceptable salt, i.e. an anion, can be used in animal life at pharmaceutical doses of the salt. It is non-toxic to the body and the beneficial cardiotonic properties inherent to the free base prevent side effects caused by the anion. It is preferred to include acids that produce less damaging salts. Basicization as described above Pharmaceutically acceptable salts of the compound are preferred, but e.g. or if it is produced by ion-exchange operations with pharmaceutically acceptable salts. The special salt itself is an intermediate, such as when used as an intermediate in the preparation of All acid addition salts are the source of the free base form, even if only desired as the product. It is useful as such. Pharmaceutically acceptable salts within the scope of this invention are derived from the acids listed below. It is salt. Mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and acetic acid, Citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, Organic acids such as quinic acid, etc.

Corresponding acid addition salts include the following salts, respectively. hydrochloride, sulfate, phosphate, sulfa mate, acetate, citrate, lactate, tartrate, methanesulfonate, eta sulfonate, benzenesulfonate, p-toluenesulfonate, cyclo Xylsulfamate and quinate.

Acid addition salts of the compounds of this invention can be prepared by adding the free base to an aqueous or aqueous solution containing the appropriate acid. Dissolving in alcoholic solution or other suitable solvent and evaporating the solution or by reacting the free base and acid in an organic solvent. by separating the salts directly or by concentrating the solution. (obtainable by).

A preferred class of compounds is where b is 1 and adjacent R groups form a double bond. Described by Formula I.

Another preferred class of cardiotonic compounds of the invention are those in which the bicyclic ring of the molecule has the formula I Described by formula I, represented by Ia-IIc.

(wherein R2, R4 and R5 are as above, and a is 1 or 2 . ) A more preferred class of compounds is where b is 1, R1 is cyano, and Z is C-lower is alkyl, adjacent R groups form a double bond, and R,, R+, Rt , R1, R4, and R3 are hydrogen or lower alkyl; It is a thing.

The most preferred compounds are those in which R1 is cyano, R is hydrogen, and R7 is methyl. and R8 to R3 are hydrogen or methyl.

A more preferred class of compounds is where R7 is -(CH,), -Y and Y is of the formula -N (Ra) is a compound of the above formula 1-11 which is a group of (R,). Ra and R11 is a lower alkyl, and together with the nitrogen to which they are attached, they form a heterocycle. The most preferred case is

A special embodiment of the invention includes compounds of formula ]Ic, wherein a is 2.

A more particular embodiment includes compounds of formula (1) in which R4 and R3 form a spiro ring system. Two examples of these are shown by formulas ① and II[a below.

n The compounds of the present invention incorporate a pyridone ring substituent as shown in Scheme I below. It can be prepared by making it into a bicyclic part of a product.

Reaction formula I Halogenation of compounds of formula VI yields the corresponding halogenated products ■. Bromination is The preferred reaction is that the bicyclic compound is in the rose position relative to the lactam nitrogen. Occurs on the pyrido ring. Bromination may be carried out using brominating reagents known in the art. good A preferred method is to prepare N-bromosuccinic acid in a polar aprotic solvent such as DMF. It's Mido. Subsequent alkylation of the lactam nitrogen with a suitable alkylating agent or Aralkylation yields an adduct of formula ■, which is an acylated isopropenyl reagent and It is oxopropylated by treatment with a catalyst. A preferred catalyst system is tree o- Including the use of tolylphosphine, palladium acetate, and tributyltin methoxide. nothing.

Preferred reaction conditions include using a non-polar solvent such as benzene, and a reaction time of about 10 minutes. involves heating the reaction to a temperature that results in the preparation of the product in a fairly short period of ~2 days. nothing. A preferred temperature range is about 78 to about 80°C. Compound of formula ■ and N,N-dime Condensation of thylformamide dimethyl acetal yields α,β unsaturated keto compound X Ru.

Cyclization to compounds of formula Ia is carried out by treatment with a suitable amide-containing nucleophile. , this nuclear reagent undergoes a 1.2 addition to an unsaturated ketone, condenses with the ketone, and forms dimethylamine. and eliminate water. A preferred nuclear reagent is sodium cyanoacetamide, which This is sodium hydride and cyanoacetamide or sodium ether in ethanol. It can be prepared by reaction of toxides. In addition, compound X is condensed with nitroacetamide to yield compounds of formula Ia where R is NO2. The cyclization reaction is DM 70 to about 90°C under inert conditions in a polar medium such as F or ethanol. Preferably, it is carried out at elevated temperatures.

Cyano substituents in formula 1a are converted to other substituents as defined for R in formula I It is possible. For example, a cyano group can be hydrolyzed to an acid, which in turn can be esterified, or or amide. Esters can be converted to formyl by known methods; This in turn can be reduced to an alkyl or hydroxyalkyl substituent. Alkoxia Rukyl can be generated from hydroxyalkyl.

Nitro-containing compounds can be reduced to amino compounds, from which hydroxy-substituted compounds and and halo-substituted compounds may be formed. These methods and reaction conditions are, of course, dependent on the desired location. Varies depending on the substituents and substituents present and known to those skilled in the art.

The compounds of the present invention can be used in the bicyclic portion of the compound, as shown in Scheme II below. can be prepared by creating a pyridazinone or pyrazolone ring substituent on the compound.

Reaction formula■ Halogenation of compounds of formula (1) yields the corresponding halogenated products (2). Bromination is preferable This is a desirable reaction, which occurs when the pi of the bicyclic compound is located para to the nitrogen of the lactam. Occurs on the lido ring. Bromination can be carried out using brominating reagents known in the art. , the preferred reagent is N-bromosuccinimide. Subsequent appropriate alkylation Alkylation or aralkylation of the lactam nitrogen with an agent yields an adduct of formula ■ . The replacement of the bromine atom by a trimethylstannyl group to obtain a compound of formula IXa is , lithium trimethylene in an aprotic solvent at temperatures of about -20°C to about room temperature. by treatment with rustanate or t-butyllithium and trimethyltin This is done by treatment with chloride. Aprotic such as toluene or THF A catalyst in a solvent, e.g. Suitably substituted carboalkoxypropionyl or aryl in the presence of a catalyst Treatment of tin(II) compound IXa with the cetyl halide reagent This yields the oxycarbonyloxo-alkyl compound Xa. Cyclization is suitable for hydrazine Treatment with reagents provides compounds of formula Ib.

The preparation of a preferred class of compounds is shown in Scheme 1 below. Keto acid derivatives of formula Xa When a compound is treated with an amine of formula HNR,R, and formaldehyde, the equivalent A Mannich base XI is formed. This is then reacted with hydrazine R-substituted products can be obtained. A compound in which Y is 10-R, The rate anion is treated with ethyl formate, which is reduced with hydrazine and cyclized to give the desired is prepared by obtaining the hydroxymethylene product Ic. Equivalent thousand o conversion The compound converts the hydroxymethyl intermediate X to the corresponding mesylate and then mesylates. Treatment of sylate with thiol and DBU in benzene to obtain sulfide It can be prepared from Cyclization is carried out using a suitable hydrazine reagent.

Reaction formula eeee Starting materials useful in the preparation of the compounds of this invention are known and can be prepared by known methods. or can be prepared according to the reaction sequence below.

The bicyclic portion of the compound can be prepared according to one of the reaction sequences shown in Scheme IV below. It can be manufactured. 3- as shown in Reaction Scheme IV with triphenylphosphine ylide reagent Treatment of carbonyl-2-trimethylmethylamide pyridine compounds produces an addition product. The ylide chosen for the addition reaction has R1 and R3 positions other than hydrogen. May contain substituents. Additionally, the R8 substituent of the ylide can be as shown in Scheme IV. Determine the size of the resulting saturated ring of the final bicyclic product. Ylide addition product water Reaction and acidic cyclization to the lactam gives a bicyclic system.

Reaction formula■ N-alkylation and halogenation of the bicyclic ring refers to the above-mentioned oxygen-containing bicyclic rings. Proceed as described.

Bicyclic ring (in this case, the carbon atom α to the lactam carbonyl is substituted) The introduction of the spiro group into a strong base such as amide and l,2-bromoethane or 1,4-dibromobutane. This is carried out by reacting with a suitable dibromoalkane such as.

Specific examples of the preparation of compounds of the invention are described below.

Example 1 6-[3'-cyano-6'-methyl-2°-oxo-(IH)pyridine-5 "-yl]-3.4-dihydro=1-methyl-1°8-naphthyridine-2 (LH )-one preparation process 1. 2-(pivaloylamino)pyridine methylene chloride (2 A solution of pivaloyl chloride (96 g) in methylene chloride (650 m/) d) of 2-aminopyridine (50g) and triethylamine (108g) in cold Add dropwise to the cooled mixture. The reaction mixture was stirred at room temperature overnight and poured into water. , this is made basic, the organic layer is separated and concentrated under reduced pressure. Add hexane to the oil This results in the precipitation of a crystalline solid, which is filtered and the solid is absorbed into an aqueous acid solution. let The desired pyridine compound is recrystallized as a white crystalline solid.

Step 2. 3-formyl-2-(pivaloylamino)pyridine N-butyllithium (112rd) was prepared by step 1 in THF (250-) at -78 °C. Add dropwise to a stirred solution of pyridine (20 g). The reaction mixture was reduced to zero in about 4 hours. Warm to ℃ and cool to -78℃. Cool reaction mixture with dimethylformamide (30d) and the mixture is stirred at room temperature overnight. The reaction mixture was diluted with a saturated aqueous solution of NH, CI. Stop the reaction and dilute with ethyl acetate. Separate the organic layer, concentrate and treat with aqueous acid. Understand. The aqueous layer is washed with ethyl acetate, brought to neutral pH and extracted with ethyl acetate. Yes The machine extract was dried, concentrated under reduced pressure, and cooled resulting in the formation of a crystalline material, which was further The white crystalline solid was purified on silica gel and used in the next step with methylene chloride. (100rnl) above step 2. A solution of the formyl compound (9.8 g) , carbomethoxymethylidetriphenylphosph in methylene chloride (125ml) Add dropwise to a solution of fin (16 g). The reaction mixture was stirred at reflux overnight; Cool to room temperature, concentrate under reduced pressure and add petroleum ether. Cool the ether solution This results in the precipitation of the desired material as a white crystalline solid. Melting point 148-150 ℃.

Step 3 above in ethanol (4007,/). carbomethoxyvinyl compound of (9 g), lo% Pd/C solution was introduced into the Parr apparatus, and water was added until the reaction was completed. Stir in the presence of The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with 6N of MCI and stirred at 110°C overnight. Neutralize the reaction mixture and add chloroform Extract with filtrate, dry, filter, and concentrate under reduced pressure. The obtained solid was washed with silica gel. Chromatography gives a purified white crystalline product. melting point 16 0-162℃.

of N-bromosuccinimide (3.7g) in dimethylformamide (70d) Step 4 above where the solution was kept at about -10°C. dropwise into a stirred solution of naphthyridine. and add. The reaction mixture is allowed to warm to room temperature and stirred overnight. add water to the mixture; The resulting suspension was stirred for 15 minutes, filtered, and the filtered solid was washed with water and reconstituted with DMF. Crystallization gives the desired product as a white crystalline solid.

A 1M solution of lithium bistrimethylsilylamide in THF (6,6J) was added to 0 Stirred solution of bromide (1,2 g) from step 5 above in THF (100 d) at °C. Add dropwise to the liquid. The mixture is allowed to warm to room temperature and stirred for approximately 1 hour. dimethyl sulfate (0.8 g) is added to the mixture and it is stirred for about 2 hours. Saturate the reaction with NH,C Stop with aqueous I solution, separate the organic layer, wash with saturated NH4C1 solution and concentrate under reduced pressure. and take up the residue in chloroform. Wash the chloroform solution with water, dry it, Concentrate and chromatograph on silica gel to obtain the desired product as a clean white product. obtained as a crystalline solid.

Melting point 78-80°C0 Para-trioltotolylphosphine (0,1gL Palladium acetate (0,05g) , 2-acetoxyprope; (0,6 g) and tributyltin methoxide (2 g) is added to the solution of bromide (Ig) from step 6 above in benzene (40d), The resulting reaction mixture is stirred at 80° C. for about 2.5 hours in the presence of N2. mixture Filter, concentrate under reduced pressure and take up the residue in acetonitrile. Filter the solution; Wash the filtrate with hexane. Dry the acetonitrile layer, filter, and concentrate under reduced pressure. The desired product is obtained as a crystalline solid.

Melting point 93-95℃ Step 8. 6-(1-N,N'-dimethylamino-3-oxobuten-2-y )-2-oxopropyl)-3,4-dimethylformamide dimethylacecou (4.6 ml) of the above step 7. in methylene chloride (25 mA'). of the compound of solution and the reaction mixture is stirred under nitrogen overnight. Evaporate the mixture; The desired product is obtained as an oil, which is used in the next step.

Step 8 above in absolute ethanol (45 rnl). dimethylaminoenamine ( 0.7 g) of sodium methoxide in ethanol (1.5 ml) A 1% solution of cyanoacetamide (0.3 g) in ethanol (25 mA) Add to the mixture prepared by adding. Reaction mixture in the presence of nitrogen Bring to reflux and stir overnight. The mixture was cooled to room temperature and concentrated under reduced pressure on silica gel. chromatography. Isopropyl fraction containing the solid desired product Recrystallization twice from alcohol gives the desired product as a crystalline material. Melting point 23 0°C (decomposition).

Calculated value C, 63, 73, H, 4, 94, N, 18.58 Actual value C, 63, 84;H,4,94,N, 18.30gMPA (0.4J) and THF ( 6-bromo-3,4-dihydro-1,8-naphthyridine-2 in the mixture of 5d) A solution of (IH)-one (0.25 g) was dissolved in sodium hydride in THF (3 m/). (0,03 g) and stirred for about 90 minutes at room temperature in the presence of nitrogen. . The resulting solution of the sodium salt was dissolved in lithium trichloride in THF (5 rnl) at -20°C. Added dropwise to a solution of methyl stannate (2.4 mmol) and purged the reaction mixture with nitrogen. Stir at -20° C. for 4 hours in the presence of hydrogen and overnight at room temperature. Mixture with ethyl acetate diluted with water, washed with aqueous sodium bicarbonate, separated the organic layer, dried, and dried under reduced pressure. to give a crystalline solid, which was chromatographed on silica gel. The desired product was converted to nyl-1,8-naphthyridine as an off-white crystalline solid. -2(LH)-one lithium bistrimethylsilylamide (0,9rITl) Add to the solution of the tin compound (0.2 g) from step 6 above in THF (10-). , the reaction mixture is stirred at 0° C. for about 45 minutes. Mixture of dimethyl sulfate (0.1 g) and stirred at room temperature overnight under nitrogen.

The reaction is quenched with saturated aqueous NH,CI and diluted with ethyl acetate.

The organic layer was separated, washed with saturated aqueous NH,CI, water, brine, and dried. Dry and concentrate under reduced pressure to obtain a crystalline solid. Chromatograph the solid on silica gel Ruffy yields the desired product as a white crystalline solid.

Step 3. 6-(3-carbomethoxypropionoyl)-3,4-dihydro-1 -Methyl-1,8-naphthyridin-2(IH)-one 2-Carbomethoxypropionoyl chloride (0.06g) was dissolved in benzene (5d ) and the tin compound (0.1 g) of step 2 above and bistriphenylphosphine. Add to the mixture of palladium chloride (0.01 g). The reaction mixture was heated in the presence of nitrogen. Stir overnight at 90°C, cool to room temperature, add methylene chloride and dilute with sodium bicarbonate. Wash with saturated aqueous solution. The organic layer was dried, concentrated under reduced pressure, and purified with silica gel. Romatography gives the desired product as a crystalline solid. Melting point 106 ~108℃.

Hydrazine hydrate (13 m/) was added to the above step 3 solution in absolute ethanol (8-). Rubomethoxy compound (0.25 g) was added and the reaction mixture was stirred at reflux overnight. Ru. The mixture is cooled in a water bath, the precipitate is filtered and dried under reduced pressure to crystallize the desired product. Obtained as a crystalline solid. Melting point 276-278°C. (Calculated value: C59,42, H 5,56; N 21.32) (actual value: C59,77; H5,50; N 21.56) Compounds of formula I have positive inotropic activity and It is useful as a cardiotonic agent in the treatment of diseases in humans and other mammals. strong heart The effectiveness of the compounds of the present invention as drugs is determined by the ability of the heart to contractile force upon exposure to said compounds. can be measured by the following pharmacological tests that evaluate changes in Ganglion beta blockade anesthesia hole operation This is one such standard test procedure. The inotropic results of this procedure are generally There is a correlation with inotropic activity seen in individuals.

Ganglion β blockade anesthesia hole manipulation Biological mongrel dogs of both sexes weighing 10 to 16 kg were fasted overnight and treated with Bendoparvita. Anesthetized with 35kg/kg, v, and intubated, the patient was transferred to the room using a lz-hard respirator. They are made to breathe with internal air, and surgical instruments are attached to measure myocardial contractile force, heart rate, arterial blood pressure, and blood pressure. Monitor arterial flow and EKG limb lead ■. Record the above measurements on a strip chart Continuously record with a meter.

Myocardial contractile force is determined by the Walton loop sutured to the left ventricular myocardium parallel to the left anterior descending coronary artery. Monitored by Walton-Brodie strain gauge . Intra-arterial blood pressure was measured using a pressure transducer introduced via the right femoral artery and placed in the ampulla Measured using a liquid-filled catheter attached to the The mean arterial blood pressure is , measured by electrically clamping the pulsatile pressure signal. The aortic flow rate is , using a precalibrated non-tubular electromagnetic flow probe placed around the ampulla will be monitored. Heart rate is induced by the QR3 complex in limb lead II EKG Monitored using a cardiotachometer. Right femoral vein for intravenous infusion in dogs A cannula is inserted. Body temperature is maintained at 37°C.

Control values are recorded after a 30 minute stabilization period after surgery. Myocardial depression is caused by ganglia and Induced by β receptor blockade. First, the responsiveness of the autonomic nervous system increased for 30 seconds. It is evaluated by performing left and right carotid artery occlusion (BCO). After 10 minutes, isopro Telenol 0.3■/kg, i, v, saline solution was administered, and β receptors were completely restored. Assess gender. 10 minutes later, mecamylamine 2/) cg, i, v, salt Water was injected, then propranolol 1 mg/kg Si, v, + 0 ．． 3 mg/kg/hr of saline solution is injected. 20 minutes later, second BCO was performed to demonstrate ganglionic blockade, followed by isoproterenol 0.3■/kg, i. A second saline injection of , v, is performed to demonstrate β-blockade. After 10 minutes, test The compound or vehicle is increased at 1.5 yd/min in 30 minute intervals at a total volume of 3.5- It is administered intravenously at a dose that At the end of the experiment, BCO and isoprotereno repeat challenge to confirm ganglion and beta blockade.

The results of the blockade large study showed that the compounds of the present invention showed a dose-related effect while maintaining intra-arterial blood pressure. It has been shown to increase contractile force and heart rate, as well as aortic blood flow.

Another method that has been found to be an effective means of ascertaining the inotropic activity of the compounds of the invention is The test procedure is described below.

Guinea pig atrial inotropy screening concentration in guinea pigs with a sudden blow to the head More stunning. Their chests were opened, their hearts removed, and 95% 0. Passed with a mixture of Kreb's medium (concentration, mM: NaCl, 118, 39; KCI, 4. TO; Mg5On, 1.18; KH, PO,, 1, 18; NaHCOs, 2 5.00; Glucose, 11.66 and CaCl! , 1, 25).

The left atrium was removed and placed in warm (33 °C) containing oxygenated Kreb's medium (as above). Insert into a double jacketed tissue chamber. Statham microscale the top of each tissue. Statham Microscale Accessor y) via the Statham Universal Transducing Cell (Stat ham Universal Transducing Cell) . The tension on each tissue is set to Ig and adjusted periodically.

or a silver electrode. The electrode is wound into a tight coil with a diameter of approximately 12-14 mm. The electrodes are made of glass. Connected to the glass stimulator via a constant current unit. Organizations are concerned with continuous beats. Stimulate at 90 pulses/min with a duration of 5 ms at a current level 20% greater than the limit be done.

The cumulative concentration of test agent causes the generated tension to peak at a new level. added to the tissue bath at sufficient intervals to

The increase in tension generated in each tissue for each compound concentration is measured and the results are averaged and used to create a cumulative concentration-response curve. Finne (1971), the slopes for these regressions are Students are compared using the test.

The in vitro method described below provides another means for determining the inotropic potential of compounds of the invention. It is. This method was developed by Thompson and Appleman. Pleman) (1970) and Thompson et al. (1974). This is an improved method of inhibiting enzymes, and is thought to have a correlation with inotropic activity in humans. be exposed.

Beak m cAMP phosphogesterase activity inhibition test compound adenosine 3':5'-monophosphate (cyclic AMP) and quanine- A radiolabeled substrate such as a 3':5'-nucleotidase isolate (3H-ring nucleotides). cN for the corresponding nucleoside Inhibition of enzymatic hydrolysis of the 5'-nucleotide product of Uc-PDBase It is measured by separating the charged unhydrolyzed substrate from the electrohydrolysis products. Ru. Separation is performed by ion exchange resin from the uncharged nucleoside products of the assay. It can be done by chromatography and as a result it is a liquid scintillation is not quantified by the counter.

anesthesia dog operation A male mongrel dog was anesthetized with bendoparbital (35 kg/kg, v) and intubated. It will be done. Cannulations were placed in the femoral artery and vein, respectively, to measure blood pressure and infuse compounds. is inserted. For measurement of left ventricular pressure, left ventricular pressure end diastolic blood pressure and dP/dt. The catheter connected to the Statham transducer was inserted through the right carotid artery. inserted into the left ventricle. Also, lead II ECG and heart rate are monitored. all pa The meter is Beckman Dynagraph. ) is measured.

Two methods have been found to be effective in determining the inotropic activity of the compounds of the present invention. Another test procedure is described below.

conscious appliance-wearing dog A female mongrel dog (18.0-18.5 kg) was treated with sodium bendoparbital (3 The patient was anesthetized with 5 kg/kg, v, supplemented as needed during surgery) and intubated. Connected to Barbard respirator. The left side of the chest was opened at the fifth intercostal space and Konigsbe Konigsberg transducer passes the tip of the puncture into the left ventricle. is inserted and fixed. Fluid-filled polyethylene catheter for measurement of left ventricular pressure A terminal is inserted into the left atrium through the slit and secured. For measuring blood pressure and heart rate , a second fluid-filled catheter is inserted into the aorta and secured to the vessel wall. two The catheter and Konigsberg transducer are inserted into the chest through the sixth intercostal space. It is threaded outward from the neck and advanced subcutaneously to the back of the neck, where it is threaded through the skin. liquid container The tube is filled with a 50% heparinized dextrose solution and is closed and evacuated.

The dog is trained and acclimated to its environment and human presence during the experiment.

Dogs are fasted overnight before intravenous or oral administration of compounds. On the test day, the dog is placed in a triangular cloth, left ventricular pressure, left ventricular pressure dP/dt,..., blood pressure, heart rate (from the blood pressure signal), and a recorder (Gold Instrument) for measuring the electrocardiogram. Instruments or Glass Instruments). In various experiments, the compound The product is administered both intravenously and orally (in liquid form and soft gelatin capsule form). ), blood samples were taken for determination of blood concentrations of the compounds.

The compounds of the present invention may be used in the treatment of heart diseases such as heart failure in humans or other mammals. The products can be administered orally or parenterally.

The compounds of the invention (preferably in salt form) can be prepared in any convenient manner for administration. The present invention is suitable for use in animal or veterinary medicine. Included within its scope are pharmaceutical compositions containing one compound. Such a composition is a type of It can be formulated in a conventional manner using the above pharmaceutically acceptable carriers or excipients.

Suitable carriers include diluents or fillers, sterile aqueous media and various non-toxic organic solvents. including. Compositions include tablets, capsules, lozenges, troches, hard candy-1 In the form of powder, aqueous suspension or solution, injectable solution, elixir, syrup, etc. Sweetening agents, flavoring agents, coloring agents and It may also contain one or more agents selected from the group including preservatives and preservatives.

The particular carrier and inotropic active compound-to-carrier ratio will depend on the solubility and chemical properties of the compound; This will depend on the particular mode of administration as well as normal pharmaceutical practice. For example, lactose, Excipients such as sodium citrate, calcium carbonate and dicalcium phosphate; In addition, disintegrants such as starch, alginic acid, and certain complex silicates are added to the stearate matrix. The tablets are made with lubricants such as magnesium, sodium lauryl sulfate and talc. It can be used to build. Regarding capsule form, lactose and high molecular weight polyester Ethylene glycol is among the preferred pharmaceutically acceptable carriers. Oral aqueous suspension When a suspension is being formulated, the carrier can be an emulsifying or suspending agent. ethanol, Propylene glycol, glycerin and chloroform and combinations thereof Diluents such as, as well as other substances, may be used.

For parenteral administration, sesame or peanut oil or aqueous propylene glycol Solutions or suspensions of these compounds in solution, as well as pharmaceuticals described herein. Sterile aqueous solutions of the above acceptable soluble salts may be employed. Solutions of salts of these compounds are , particularly suitable for intramuscular and subcutaneous injection purposes. of salts dissolved in pure distilled water Aqueous solutions containing aqueous solutions should have their pH appropriately adjusted, be appropriately buffered, and have sufficient Isotonic with saline or glucose and heated or microfiltrated. It is also useful for intravenous injection purposes, provided that it is sterilized.

The dosing regimen implementing the method of the invention maintains maximal therapeutic response until improvement is achieved. evidence, and then a dosing regimen that ensures the lowest effective dose that produces relief. . Thus, dosages are generally designed to increase the force of the heart's contractions or to treat heart failure. at a dosage that is therapeutically effective. In general, oral dosages are, of course, The patient's weight, general health, age and Note that attention should be paid to other factors that may influence response to drugs. approximately 0.01■/kg to approximately 50■/kg (preferably 0.1 to 10■/kg g), i, v, dosage is about 0.005 to about 30 μg/kg (preferably Or 0. O1-3 Asahi/kg). the drug obtains the desired therapeutic response , and may be administered as frequently as necessary to sustain the effect. relatively many patients with Rapid response to low dosages with little or no need for maintenance dosages Sometimes it is not necessary. On the other hand, other patients may Continuous dosing from about 1 to about 4 times a day may be required.

Typically, the drug may be administered orally from one to four times daily. Most patients receive approximately 1 to 2 doses per day. It is expected that the following medications will be required:

Additionally, the present invention is useful as an injection dosage form that can be administered urgently to patients suffering from acute heart failure. This is expected to be profitable. Such treatment is followed by intravenous infusion of the active compound. and the amount of compound injected into such patients to obtain the desired therapeutic response, and should be effective to maintain.

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Claims (12)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A is -C= or -N=; B is -C=C-, -C=N- or -N=C-; provided that A or B is nitrogen represents a containing group; X is (CR4R5)a-; Z is CR6 or N; a is 1, 2 or 3; b is 0 or 1; R, R3 and R6 are hydrogen, alkyl, or aralkyl; R1 is hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl , nitro, halo, cyano, carbamoyl, alkylcarbamoyl, formyl, a is minoalkylene or amino; R2 is hydrogen, alkyl, aralkyl, or -(CH2)y-Y (wherein y is 1 to 3) is; R4 is hydrogen, alkyl, aryl or aralkyl; R5 is hydrogen, alkyl aralkyl, aryl, acyl, carbalkoxy, carbalkoxyal Kyl, hydroxyalkyl, alkoxyalkyl, amidino, alkoxy, ami ni, nitro, carboxy, cyano, alkylamino, halo, hydroxy, merca butyl, alkylmercaptyl, carboalkyl or carbamoyl; The gem-R4 and gem-R5 groups together form a spiro substituent, -(CH2) d- (wherein d is 2 to 5); Rn is hydrogen, alkyl, aralkyl, aryl, acyl, carbalkoxy, carbon rubamyl, carboalkoxyalkyl, hydroxyalkyl, alkoxyalkyl or amidino; the R and R groups on adjacent carbon atoms taken together A carbon-carbon double bond may be formed (provided that the R group is such that R6 is hydrogen and b = 1); Y is hydrogen, -O-Rα, -S-Rα or -N RαRβ; Rα is hydrogen, alkyl or acyl; Rβ is hydrogen or alkyl; Rα and Rβ together with the nitrogen atom to which they are bonded form a 3- to 7-membered ring ( It may also contain 0-2 further N, O or S atoms). Compounds represented by (i) and their pharmaceutically acceptable salts. 2. Claim 1, wherein b is 1 and adjacent R groups form a double bond. Compounds listed. 3. Z is C-lower alkyl, R1 is cyano, and R, R■, R2, Claim 2, wherein R3, R4, and R5 are hydrogen or lower alkyl. Compound. 4. R1 is cyano, R■ is hydrogen, R2 is methyl, and R3, 4. A compound according to claim 3, wherein R4 and R5 are hydrogen or methyl. 5. The compound according to claim 2, wherein A is -C= and B is -C=N- thing. 6. Claim 1, wherein R2 is -(CH2)y-N(Rα)(Rβ) Compound. 7. The compound according to claim 1, wherein a is 2. 8. The gem-R4 group and the gem-R5 group at α-position to the carbonyl carbon are together. to form a spiro substituent of -(CH2)d- (wherein d is 2 to 5). A compound according to item 7 of the desired scope. 9.6-(4,5-dihydro-3(2H)-3-oxo-pyridazinyl)-3, 4-dihydro-1-methyl-2(1H)-1,8-naphteridine-2(1H)- 2. The compound according to claim 1, which is 1 or a pharmaceutically acceptable salt thereof. 10.6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridine- 5'-yl]-3,4-dihydro-1-methyl-1,8-naphteridine-2(1 The compound according to claim 1, which is H)-one or a pharmaceutically acceptable salt thereof. 11. Claim 1 describes an effective amount for patients in need of increasing cardiac contractility. A method of increasing inotropic contractility in a patient, the method comprising administering a compound of: 12. The active ingredient is a compound according to claim 1 mixed with a pharmaceutical carrier. A pharmaceutical composition characterized by: