- Preparation process of milrinone
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The invention discloses a preparation method of milrinone, and belongs to the technical field of drug synthesis. According to the method, 1-(4-pyridyl)-2-acetone is used as a raw material and is subjected to a heating reaction with alpha-(substituted methylene) cyanoacetamide under an alkaline condition, and milrinone is obtained. The method for preparing milrinone is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and the purity of the obtained milrinone finished product both reach the standard.
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Paragraph 0114-0119
(2021/10/13)
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- New process for preparing milrinone
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The invention discloses a preparation method of milrinone, and belongs to the technical field of drug synthesis. According to the method, 1-(4-pyridyl)-2-acetone is used as a raw material and is subjected to a heating reaction with alpha-(substituted methylene) malononitrile under an alkaline condition, and milrinone is obtained. The method for preparing milrinone is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and the purity of the obtained milrinone finished product both reach the standard.
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Paragraph 0084-0089
(2021/10/13)
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- Preparation method of 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one
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The invention discloses a preparation method of a compound 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one, and belongs to the technical field of medicine synthesis. The method comprises the following steps: reacting a solid compound intermediate I with N, N-dimethylformamide dimethyl acetal to obtain 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one; the invention also provides a method for preparing milrinone by using 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one, and the method is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and purity of the obtained milrinone finished product reach the standard.
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Paragraph 0104-0105; 0106-0107; 0108-0109; 0110-0111; ...
(2021/10/13)
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- Synthesis method of milrinone
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The invention discloses a synthesis method of milrinone, and belongs to the technical field of drug synthesis. According to the method, 1-(4-pyridyl)-2-acetone is taken as a raw material to react with alpha-(N, N-dimethylamine methylene) malononitrile, so as to obtain an off-white solid milrinone. The method for synthesizing milrinone is simple and convenient to operate, high in yield and suitable for industrial large-scale production. The appearance and the purity of the obtained milrinone finished product both reach the standard.
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Paragraph 0045-0066
(2021/10/13)
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- Milrinone intermediate compound
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The invention provides a milrinone intermediate compound, discloses a preparation method of the milrinone intermediate compound, and belongs to the technical field of medicine synthesis. Alpha-substituted acetyl acetaldehyde (SM-1) reacts with 4-pyridylboronic acid (alkyl) (SM-2) so as to obtain the milrinone intermediate compound I. A method of using the milrinone intermediate compound to preparea milrinone agricultural product is simple and convenient to operate, high in safety, high in yield and suitable for industrial scale-up production, and the appearance and purity of the obtained high-purity milrinone finished product both reach the standards.
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- Preparation method of high-purity milrinone
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The invention provides a preparation method of milrinone, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: adding a milrinone intermediate compound I and alpha-cyanoacetamide into an organic solvent at the room temperature, uniformly stirring, carrying out a temperature controlled reaction in an alkaline environment, cooling the reaction solution to the room temperature after the reaction is finished, crystallizing, filtering, and drying to obtain milrinone. The method for preparing a milrinone product is simple and convenient to operate, high in safety, high in yield and suitable for industrial scale-up production, and the appearance and purity of the obtained high-purity milrinone finished product both reach the standards.
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- Synthetic method of milrinone
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The invention discloses a synthesis method of milrinone, and belongs to the technical field of medicine synthesis. According to the method, 1-(4-pyridyl)-2-acetone is taken as a raw material and is subjected to a heating reaction with 2-cyano-3-dimethylamino acrylamide under an alkaline condition, and milrinone is obtained. The synthetic method of milrinone is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and purity of the obtained high-purity milrinone finished product can both reach the standards.
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Paragraph 0022; 0046-0069
(2020/07/24)
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- Preparation method of milrinone
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The invention discloses a preparation method of milrinone, and belongs to the technical field of medicine synthesis. According to the method, 1-(4-pyridyl)-2-acetone is taken as a raw material and issubjected to a heating reaction with 2-cyano-3-ethoxyacrylamide under an alkaline condition, and milrinone is obtained. The preparation method of milrinone is simple and convenient to operate, high insafety, high in yield and suitable for industrial large-scale production. The appearance and purity of the obtained high-purity milrinone finished product can both reach the standards.
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Paragraph 0022; 0044-0067
(2020/07/24)
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- Preparation method of medical intermediate milrinone
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The invention discloses a preparation method of a medical intermediate milrinone. The preparation method comprises the following steps: S1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, dropwise adding concentrated sulfuric acid, stirring and reacting for 20-30 minutes, continuing reaction at 40-60 DEG C, completely reacting by TLC (Thin Layer Chromatography), cooling in an ice bath, dropwise adding ethanol, stirring for 1 hour, heating and refluxing for 6-8 hours, extracting dichloromethane, drying, filtering, carrying out rotary evaporation on filtrate toremove a solvent dichloromethane, distilling out 4-methylpyridine by reduced pressure distillation, cooling, and carrying out reduced pressure distillation to obtain 1-(4-pyridyl)-acetone; S2, mixing1-(4-pyridyl)-acetone, triethyl orthoformate, glacial acetic acid and acetic anhydride, adding alpha-cyanoacetamide, and performing cyclization under the alkaline condition to obtain crude milrinone;and S3, adding DMF into the crude milrinone obtained in the S2, stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 8-20 minutes, filtering, and cooling thefiltrate to separate out refined milrinone. According to the method, the raw material cost is saved, and the product purity, yield and color degree are improved.
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Paragraph 0027; 0030-0031; 0040; 0043-0044; 0053; 0056-0057;
(2020/08/18)
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- A high-purity process for preparing milrinone
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The invention discloses a preparation method for high-purity milrinone (shown as a formula (I), 1,6-dihydro-2-methyl-6-oxo-3,4-bipyridine-5-carbonitrile), and belongs to the field of chemical medicines. The method comprises: employing 4-methylpyridine as a raw material and acetylating with acetyl chloride, and hydrolyzing after the reaction is finished, so as to obtain a compound of a formula (III); mixing the compound of the formula (III) with glacial acetic acid, acetic anhydride and triethyl orthoformate, and reacting at 35 DEG C-45 DEG C, so as to obtain a compound of a formula (IV); performing cyclization on the compound of the formula (IV) and alpha-cyanoacetamide, so as to obtain a crude product of a compound of the formula (I); and refining the crude product of the formula (I) compound through an ethanol-water system, so as to obtain a high-purity refined product with the maximum interplanar spacing d of 8.39 +/- 0.02 Angstrom. The technology is relatively mild in reaction conditions and relatively simple in operation, and is capable of preparing the milrinone product with high purity and a single crystal form. The obtained milrinone crystal form is relatively excellent in solubility in normal saline or glucose, and is beneficial for improvement of the preparation quality.
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Paragraph 0050; 0054; 0058; 0062; 0063; 0066; 0068; 0072
(2018/03/02)
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- A method for synthesizing milrinone
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The invention discloses a new method for synthesizing milrinone. The method is characterized in that a compound of formula 3 and 4-pyridineboronic acid undergo a Suzuki coupling reaction to synthesize milrinone. The method has the advantages of easily available raw materials, high yield and simple post-treatment.
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Paragraph 0054; 0055
(2018/03/13)
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- Method for preparing milrinone
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The invention provides a method for preparing milrinone, wherein the method comprises the following steps: with 4-methyl pyridine (SM) as a raw material, in ethyl acetate, generating 1-(4-pyridyl)-2-acetone (represented by the formula I); then under action of triethyl orthoformate, acetic acid and acetic anhydride, generating 1-ethoxy-2-(4-pyridyl)vinyl methyl ketone (represented by the formula II); and finally, under an alkaline condition, carrying out a reaction of 1-ethoxy-2-(4-pyridyl)vinyl methyl ketone with cyanoacetamide to generate milrinone. The method has the advantages of simple and efficient operation, mild reaction conditions, strong safety, easy control and relatively high yield, and is suitable for industrialized production.
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Paragraph 0035; 0036; 0042; 0043
(2017/08/25)
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- A method for preparing Mulinong
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The invention discloses a preparation method of high-purity milrinone. The method comprises the steps of dissolving 1-ethoxyl-2-(4-pyridyl) methyl vinyl ketone, cyanoacetamide and alkali into a monohydric alcohol-water system, reacting for 15-18 hours at -5 DEG C to 10 DEG C, adding water into reaction liquid and diluting to 1.5 times of the original volume after completing reaction, then adding activated carbon, stirring for 15-25 minutes at room temperature, filtering, regulating the pH value of filtrate to be 7 by using a hydrochloric acid solution, filtering, washing a filter cake by using water until the filtrate is colorless, refluxing and dissolving the filter cake by using 50vt% ethanol, filtering, and stirring and crystallizing the filtrate at -5 DEG C to 10 DEG C to obtain white solid milrinone with the purity of more than 99.9%. The method disclosed by the invention is simple and fast in process, high in yield and pure in product, and is more suitable for industrial production.
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Paragraph 0040-0041
(2017/03/23)
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- Preparation method of milrinone
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A preparation method of milrinone comprises the following steps: reacting n-butyl lithium with 4-methyl pyridine to generate pyridine methyl lithium, then reacting pyridine methyl lithium with propyl acetate to generate 1-(4-pyridyl)-acetone; reacting 1-(4-pyridyl)-acetone with tripropyl orthoformate and acetic anhydride to generate 1-propoxyl-2-(4-pyridyl)-vinyl methyl ketone; finally reacting 1-propoxyl-2-(4-pyridyl)-vinyl methyl ketone with cyanoacetamide in the presence of sodium ethoxide taken as the alkalizer, adding the reaction product into a mixed solution of dimethyl formamide and water, and carrying out recrystallization. The preparation method has the advantages that the yield of milrinone is prominently improved, the product purity is increased, and the color and crystal form of product are both improved.
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Paragraph 0043; 0045
(2016/11/28)
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- SYNTHESIS OF MILRINONE, A CARDIOTONIC AGENT
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A new synthesis of milrinone (6) from 6-methyl-5-(4-pyridinyl)-2(1H)-pyridone (4) is reported.A convenient synthesis of 3,4'-bipyridines (3a) and (3b) is achieved. 3a and 3b can be converted into pyridone 4 by hydrogenolysis and hydrolysis, respectively.Bromination at C-3 of the pyridone ring of 4 followed by cyanation affords milrinone (6).
- Shiao, Min-Jen,Shyu, Li-Ming,Chen, Chieh-Fu
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p. 523 - 527
(2007/10/02)
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- Process for preparing 5 pyridyl pyridine-2 (1H)-ones
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5-Pyridinyl-6-R2 -3-R1 -2(1H)-pyridinones (I), where R2 is hydrogen or lower alkyl and R1 is a cyano, a carbamoyl or an amino group are prepared: by reaction of 1-R2 -1-oxo-2-pyridinyl-3-dialkylaminopropane (II) with malonamide under solid-liquid or liquid-liquid phase transfer catalysis conditions to obtain 1,2-dihydro-2-oxo-6-R2 -5-pyridinylnicotinamide (IV), or by reaction of II with cyanoacetamide under solid-liquid or liquid-liquid phase transfer catalysis conditions to obtain 1,2-dihydro-2-oxo-6-R2 -5-pyridinylnicotinonitrile (III) and partially hydrolizing III to yield IV; finally the carbamoyl group of IV is converted to amino and 1,2-dihydro-2-oxo-6-R2 -5-pyridinyl-3-aminopyridin-2-one are obtained.
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- Bipyridine Cardiotonics: The Three-Dimensional Structures of Amrinone and Milrinone
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The cardiotonic drug milrinone (1,6-dihydro-2-methyl-6-oxo--5-carbonitrile) is superior to its analogue amrinone (5-amino--6(1H)-one) by virtue of its greater potency and reduced side effect profile.We confirmed initial reports on the potencies of milrinone and amrinone and found that after intravenous administration to phenobarbital anesthetized dogs, the drug had cumulative inotropic ED50's of 37 and 1891 μg/kg, respectively; relative effects on heart rate and blood pressure were comparable.There are two structural differences between amrinone and milrinone: (1) milrinone has a pyridone 2-methyl substituent and (2) the pyridone 5-amino substituent of amrinone is replaced with a nitrile in milrinone.We confirmed structure-activity studies that indicated that the 2-methyl substituent appears to be primarily responsible for the dramatic difference in the potencies of amrinone and milrinone.A plausible explanation for the effect of the methyl substituent is an altered molecular topology resulting from its steric interaction with the 3',5'-hydrogen atoms.Consequently, we probed the three-dimensional structures of these two compounds by X-ray crystallography.The dihedral angle between the planes formed by the two aromatic rings of amrinone was 1.3 deg.In marked contrast, the corresponding angle for milrinone was 52.2 deg.Moreover, 1H NMR studies revealed conformational differences in solution.Whereas the 2-methyl substituent undoubtedly produces some electronic and hydrophobic perturbations in the bipyridine cardiotonic series, the most significant effect, from a global viewpoint, is the altered molecular topology.
- Robertson, David W.,Beedle, E. E.,Swartzendruber, John K.,Jones, Noel D.,Elzey, T. K.,et al.
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p. 635 - 640
(2007/10/02)
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- A NOVEL SYNTHESIS OF 1,6-DIHYDRO-2-METHYL-6-OXO-5-CARBONITRILE (MILRINONE)
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Milrinone (3) was prepared either by reacting ethoxymethylenemalononitrile with 1-(4-pyridinyl)-2-propanone or malononitrile with 4-ethoxy-3-(4-pyridinyl)-3-buten-2-one.
- Singh, Baldev
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p. 1479 - 1482
(2007/10/02)
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- Process for preparing 2-(lower-alkoxy)-1-(pyridinyl) ethenyl lower-alkyl ketones
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One aspect of the invention resides in the three step process for preparing cardiotonically active 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles or 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinamides which comprises reacting a pyridinylmethyl lower-alkyl ketone with tri-(lower-alkyl) orthoformate, acetic anhydride and acetic acid to produce 2-(lower-alkoxy)-1-(pyridinyl)ethenyl lower-alkyl ketone reacting the latter with cyanoacetamide or malonamide in the presence of a basic condensing agent and neutralizing the reaction mixture, where pyridinyl is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. Other aspects of the invention reside in the intermediate 2-(lower-alkoxy)-1-(pyridinyl)ethenyl lower-alkyl ketones, their salts and their two step conversion, as described above, to 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)-nicotinonitriles or corresponding nicotinamides.
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- Preparation of 1,2-dihydro-6-(lower alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles
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The invention resides in a process for preparing cardiotonically active 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles (III) which comprises reacting a pyridinylmethyl lower-alkyl ketone (I) with tri-(lower-alkyl) orthoformate, acetic anhydride and acetic acid to produce 2-(lower-alkoxy)-1-(pyridinyl)ethenyl lower-alkyl ketone (II) and then reacting II with malononitrile in a lower-alkanol, where pyridinyl is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.
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- Process for preparing 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles
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A process for preparing cardiotonically active 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles which comprises reacting a pyridinylmethyl methyl ketone with ethoxymethylenemalononitrile, where pyridinyl is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.
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- 3-Substituted-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones, their cardiotonic use and intermediates therefor
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1-R1 -3-[amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino]-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones or pharmaceutically-acceptable acid-addition or cationic salts thereof are useful as cardiotonic agents, where R1 is hydrogen, lower-alkyl or lower-hydroxyalkyl. 1-R1 -3-amino-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by hydrolyzing the corresponding 3-cyano compounds to produce the corresponding 3-carbamyl compounds and reacting the latter with a reagent capable of converting carbamyl to amino. The 1-R1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by reacting (pyridinylmethyl) lower-alkyl ketones with dimethylformamide di-(lower-alkyl) acetal to produce 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone and reacting said ketones with N-R1 -α-cyanoacetamide to produce the 1-R1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones. Also shown are the conversions: of the 3-cyano compounds to the 3-H compounds; of the 3-H compounds to the 3-halo compounds; of the 3-halo compounds to the 3-[mono-(lower-alkyl)- or di-(lower-alkyl)-amino]compounds; and, of the 3-amino compounds to the 3-lower-acylamino or 3-[mono-(lower-alkyl)- or di-(lower-alkyl)amino] compounds.
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- 5-(Pyridinyl)pyridine-2-hydrazines, their preparation and their cardiotonic use
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2-[R1 NHN(R)]-3-Q'-5-Py-6-Q-pyridines or pharmaceutically-acceptable acid-addition salts thereof are useful as cardiotonic agents, where Q is hydrogen or lower-alkyl, PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, Q' is hydrogen or halo, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R1 is hydrogen or when R is other than hydrogen R1 is the same as R. These compounds are prepared by reacting a 2-halo-3-Q'-5-PY-6-Q-pyridine with R1 NHNHR where 2-halo is bromo or chloro. Also shown are: the use of said 2-[R1 NN(R)]-3-Q'-5-PY-6-Q-pyridines as cardiotonic agents; and, the intermediates, 2,3-dihalo-5-PY-6-Q-pyridines, and their preparation from 3-nitro-5-PY-6-Q-2(1H)-pyridinones.
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- 5-(Pyridinyl)-6-(lower-alkyl)-2(1H)-pyridinones, 1,2-dihydro-2-oxo-5-(pyridinyl)-6-(lower-alkyl)nicotinic acids and lower-alkyl esters thereof, and cardiotonic use thereof
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1-R1 -6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones or 1-R1 -1,2-dihydro-2-oxo-6-(lower-alkyl)-5-(pyridinyl)nicotinic acids or lower-alkyl esters thereof or pharmaceutically-acceptable acid-addition or cationic salts thereof are useful as cardiotonic agents, where R1 is hydrogen, lower-alkyl or lower-hydroxyalkyl. These compounds are prepared by hydrolyzing the corresponding 3-cyano compounds to produce the corresponding 3-carboxylic acids and then either by decarboxylating or esterifying the acids.
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- 5-(Pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-amines and their cardiotonic use
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1-R-3-(NB)-5-PY-6-Q-1H-pyrazolo[3,4-b]pyridines or pharmaceutically-acceptable acid-addition salts thereof, which are useful as cardiotonics, are prepared by reacting a 1-R-5-PY-6-Q-1H-pyrazolo[3,4-b]pyridin-3-amine with a lower-alkanoic acid and reducing agent to produce 1-R-3-(NB)-5-PY-6-Q-1H-pyrazolo[3,4-b]pyridine (I) where NB is NHR1 or NR1 R2, with a mixture of formic acid and formaldehyde to produce I where NB is N(CH3)2 or with a lower-acylating agent to produce I where NB is NHAc and, if desired, reacting the 3-(NHAc) compound with a reducing agent to prepare the corresponding 3-NHR1 compound, where R is lower-alkyl, lower-hydroxyalkyl, lower-acyloxy-(lower-alkyl) or lower-alkoxy-alkyl, Q is hydrogen or lower-alkyl, PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, and NB is selected from NHR1, NR1 R2 or NHAc where R1 and R2 are each lower-alkyl and Ac is lower-acyl. Also shown are cardiotonic compositions and method for increasing cardiac contractility using said compounds or salts.
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- 5-(Pyridinyl)-1H-pyrazolo[3,4-b]pyridine-3-amines, their use as cardiotonics and their preparation
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1-R-5-PY-6-Q-1H-pyrazolo[3,4-b]pyridin-3-amines or pharmaceutically-acceptable acid-addition salts thereof, which are useful as cardiotonics, are prepared by reacting a 2-halo-5-PY-6-Q-nicotinonitrile with 1-R-hydrazine, where R is hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl or lower-alkoxyalkyl, Q is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. Also shown are cardiotonic compositions and method for increasing cardiac contractility using said compounds or salts.
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- 1,2-Dihydro-5-pyridinyl-3H-pyrazolo[3,4-b]pyridin-3-ones and their use as cardiotonics
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1,2-Dihydro-1-R-5-PY-6-Q-3H-pyrazolo[3,4-b]pyridin-3-ones or pharmaceutically-acceptable acid-addition salts thereof, which are useful as cardiotonic agents, are prepared by reacting lower-alkyl 2-halo-5-PY-6-Q-nicotinate with 1-R-hydrazine. Also disclosed are cardiotonic compositions and method for increasing cardiotonic contractility using said compounds or salts.
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- Lower-alkyl 2-halo-5-(pyridinyl)nicotinates, their preparation and use as cardiotonics
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Cardiotonic composition and method for increasing cardiac contractility using an effective amount of a cardiotonic lower-alkyl 2-halo-5-PY-6-Q'-nicotinate or pharmaceutically-acceptable acid-addition salt thereof, where halo is chloro or bromo, Q' is hydrogen or lower-alkyl and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. Also shown are novel lower-alkyl 2-halo-5-PY-6-(lower-alkyl)nicotinates or pharmaceutically-acceptable acid-addition salt thereof, useful as intermediates or cardiotonics and preparation thereof.
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- Compositions and their preparation
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2-R2 -3-R3 -6-PY-5-Q-3H-imidazo[4,5-b]pyridines (I) or 1-R1 -2-R2 -6-PY-5-Q-1H-imidazo[4,5-b]pyridines (IA) or pharmaceutically-acceptable acid-addition salts thereof, where Q and R2 are each hydrogen or lower-alkyl, R1 and R3 are each hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene having at least two carbon atoms between its connecting linkages and NB is di-(lower-alkyl)amino or 4-morpholinyl, at least one of R1 or R3 being hydrogen, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, which are useful as cardiotonics, are prepared by reacting 2-R3 NH-3-R1 NH-5-PY-6-Q-pyridine (II) with a tri-(lower-alkyl) ortho-(lower-alkanoate). Also shown are: the use of I or IA or salts in cardiotonic compositions and a method for increasing cardiac contractility; and, the preparation of the intermediates II, as well as intermediates used to prepare II.
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- N-Hydroxy-1,2-dihydro-2-oxo-5-(pyridinyl)-nicotinimidamide and their cardiotonic use
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N-Hydroxy-1-R1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamides or pharmaceutically-acceptable acid-addition salts thereof, useful as cardiotonic agents, are prepared by reacting 1-R1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles with hydroxylamine and are converted by reaction with polyphosphoric acid to the corresponding cardiotonically useful 1-R1 -3-amino-5-PY-6-R-2(1H)-pyridinones, where R1 is hydrogen, lower-alkyl and lower-hydroxyalkyl, R is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.
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- 1,3-Dihydro-6-(pyridinyl)-2H-imidazo[4,5-b]pyridin-2-ones and -imidazo[4,5-b]pyridine-2-thiones and their cardiotonic use
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1,3-Dihydro-1-R1 -3-R3 -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones or -2-thiones or pharmaceutically-acceptable acid-addition salts thereof, which are useful as cardiotonic agents, where Q is hydrogen or lower-alkyl, R1 and R3 are each hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene and NB is di-(lower-alkyl)amino or 4-morpholinyl, at least one of R1 and R3 being hydrogen, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two substituents, are prepared by reacting a 2-R3 NH-3-R1 NH-5-PY-6-Q-pyridine with urea or carbonyldiimidazole to produce said -2-one or with an alkali metal xanthate, thiourea or thiocarbonyldiimidazole to produce said -2-thione. Also shown and claimed are cardiotonic compositions and a method for increasing cardiac contractility using said cardiotonic agents. Also shown are processes for preparing said intermediate 2-R3 NH-3-R1 NH-5-PY-6-Q-pyridines and other intermediates used in said processes.
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- 5-(Pyridinyl)pyridine-2,3-diamines, preparation thereof and their cardiotonic use
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2-R3 RN-3-R1 R'N-5-PY-6-Q-pyridines (I) or pharmaceutically-acceptable acid-addition salts thereof are useful as intermediates in the preparation of 1- or 3-substituted-1,3-dihydro-5-Q-6-PY-2H-imidazo[4,5-b]pyridin-2-ones or -2-thiones and also as intermediates for preparing 1- or 3-substituted-5-Q-6-PY-3H(or 1H)-imidazo[4,5-b]pyridines, where R1, R3, R, R', PY and Q are defined hereinbelow. Also shown are processes for preparing I and the following intermediates used therein: 2-halo-3-nitro-5-PY-6-Q-pyridines (III), 2-R3 RN-3-nitro-5-PY-6-Q-pyridines (V), 2-halo-5-PY-6-Q-pyridines (VII), 2-R3 RN-5-PY-6-Q-pyridines (VIII) and 2-R3 RN-3-halo-5-PY-6-Q-pyridines (IX) or salts thereof. Certain embodiments of II and VIII also are useful as cardiotonics and are shown as active components of cardiac compositions and methods for increasing cardiac contractility.
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