CA1088944A - Nitric ester of n-(2-hydroxyethyl)nicotinamide and a process for the preparation of same - Google Patents
Nitric ester of n-(2-hydroxyethyl)nicotinamide and a process for the preparation of sameInfo
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- CA1088944A CA1088944A CA274,696A CA274696A CA1088944A CA 1088944 A CA1088944 A CA 1088944A CA 274696 A CA274696 A CA 274696A CA 1088944 A CA1088944 A CA 1088944A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Abstract of the Disclosure:
A compound represented by the formula
A compound represented by the formula
Description
)t38949~
1 This invention relates to a novel pyridine derivative, process for preparing the same and a pharmaceutical composition.
More particularly, this invention relates to a pyridine deriva-tive represented ~y the formula ~ CONHC~2CI - R2 ~I) wherein Rl is hydrogen, lower alkyl or -ON02 and R2 is -ON02 or -CH20N02, or its salt; a process for preparing the same and a pharmaceutical composition containing the derivative or its salt.
Some nicotinic acid derivatives or nicotinamide der-ivatives have ~een reported in some references, for example, ' Japanese Patent Disclosure 1624/1976, U.S. Patent 3,092,634, U.S. Patent 3,168,438 and "Mie Medical Journal" Vol. 16(3), pp.
- 207-211, (1967).
The Japanese Patent Disclosure discloses that nicotinic ester derivatives are prepared ~y reacting l-nicotinyl-glycerine or l-nicotinyl-2,3~isopropylidene glycerine with fuming nitric acid, to o~tain 1 nicotinyl glycerine-2,3-dinitrate and then con-verting the compound to its dioxane addition compound which has-a coronary vasodilating action.
- U.S. Patent 3,092,634 and U.S. Patent 3,168,438 dis-close that bis-nitric ester of N,N-bis-(~-hydroxyethyl)nicotin-~ amide which has coronary vasodilating action is prepared by re--. acting nitric es~er of diethanolamine with nicotinic acid chlor-:. : ....
idec However, the compounds which have been reported have short term ac~ion or adverse action against blood pressure or function of heart and, thus, do not suffice ::
:
8~
1 as a drug to stimulate the circulatory system, for example, in the case of ischemic heart disease~ Under the circumstances, the development of an ideal druy has been desired.
In "Mie Medical Journal", Vol. 16(3), pp. 207 - 211 -~
(1967), 2-nicotinamido ethanol is mentioned. However, the compound is merely shown as a test compound for antitumor action and the Journal reported no remarkable pharmacological action.
The inventors of this invention have researched and tested for a long time to find a compound useful for a circulatory disease and finally completed the present invention.
To this end, in one of its aspects, the invention relates to a compound represented by the formula (I) ~ CO~HCH2lH 2 wherein Rl and R2 are as defined above and its salts, a process for preparing the same and a pharmaceutical composition contain-
1 This invention relates to a novel pyridine derivative, process for preparing the same and a pharmaceutical composition.
More particularly, this invention relates to a pyridine deriva-tive represented ~y the formula ~ CONHC~2CI - R2 ~I) wherein Rl is hydrogen, lower alkyl or -ON02 and R2 is -ON02 or -CH20N02, or its salt; a process for preparing the same and a pharmaceutical composition containing the derivative or its salt.
Some nicotinic acid derivatives or nicotinamide der-ivatives have ~een reported in some references, for example, ' Japanese Patent Disclosure 1624/1976, U.S. Patent 3,092,634, U.S. Patent 3,168,438 and "Mie Medical Journal" Vol. 16(3), pp.
- 207-211, (1967).
The Japanese Patent Disclosure discloses that nicotinic ester derivatives are prepared ~y reacting l-nicotinyl-glycerine or l-nicotinyl-2,3~isopropylidene glycerine with fuming nitric acid, to o~tain 1 nicotinyl glycerine-2,3-dinitrate and then con-verting the compound to its dioxane addition compound which has-a coronary vasodilating action.
- U.S. Patent 3,092,634 and U.S. Patent 3,168,438 dis-close that bis-nitric ester of N,N-bis-(~-hydroxyethyl)nicotin-~ amide which has coronary vasodilating action is prepared by re--. acting nitric es~er of diethanolamine with nicotinic acid chlor-:. : ....
idec However, the compounds which have been reported have short term ac~ion or adverse action against blood pressure or function of heart and, thus, do not suffice ::
:
8~
1 as a drug to stimulate the circulatory system, for example, in the case of ischemic heart disease~ Under the circumstances, the development of an ideal druy has been desired.
In "Mie Medical Journal", Vol. 16(3), pp. 207 - 211 -~
(1967), 2-nicotinamido ethanol is mentioned. However, the compound is merely shown as a test compound for antitumor action and the Journal reported no remarkable pharmacological action.
The inventors of this invention have researched and tested for a long time to find a compound useful for a circulatory disease and finally completed the present invention.
To this end, in one of its aspects, the invention relates to a compound represented by the formula (I) ~ CO~HCH2lH 2 wherein Rl and R2 are as defined above and its salts, a process for preparing the same and a pharmaceutical composition contain-
2~ ing the compound above or its salt.
In another of its aspects, the invention provides aprocess for preparing a nitric ester of N-(2-hydroxyethyl)nico-tinamide of the formula NJ
or a pharmaceutically acceptable salt thereof, which comprises a process selectecl from the group of processes consisting of:
~a) reacting a compound of the formula ,, .,. 1 ' 1~8~9~
-' ..
COOH
N
or its functional derivative at the carboxyl group, with a :~
compound of the forrnula NH2 ~ CH2CH2 ON02 or its functional derivative at the amino group; ~nd (b) reacting a compound of the formula N . :
with a nitrating agent.
In yet another of its aspects, the invention provides .
a novel compound of a nitric ester of N- (2-hydroxyethyl)nicotin- :--amide of the formula NHCH2CH2 - ONO~
' . ' The compound of the present invention or its salt is novel and has improved actions for treating circulatory disease, such as coronary vasodilating action, antihypertensive action, antiarrhythmic action, anticoagulative action and peripheral vasodilating action, and, thus, it is use~ul for treating ischemic heart disease, as an antihypertensive drug, anticoagulative drug, ~ .
antiarrhythmic drug, and as a peripheral vasodilator including cerebral vasodilator and renal vasodilator. .
According to the present invention the compound 1~)889~9~
1 of the formula (I~ may ~e prepared ~y one of the following methods:
(1) A compound represented ~y the formula 1~ .
l N ~ COOH tII) or its functional derivative at carboxyl group is reacted with a compound represented ~y the formula ,~
NH2 - CH21H R2 (III) Rl ' wherein Rl and R2 are as defined above or its functional deriv-ative at amino group; and (2) ~ compound represented ~y the formula ~ ~ONHCH2C~ ~ H4 (IV) wherein H3 is hydrogen, lower alkyl or hydroxy and R4 i~ hydroxy or -CH2OH is reacted with a nitrating agent.
The functional derivatives of the compound (II~ at car~oxyl group include, for example, acid halide, acid anhydride, active amide, active ester and the like. The derivatives which may ~e commonly used are acid chlorides; acid azides; acidanhyd-rides such as anhydrides derived from two moles of the compound CII~ and anhydrides of the compound wîth another acid for example dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, benzylphosphoric acid, halogenated phosphoric acid, di-alkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric .. . ~ ' 10~8g~4 1 acid, alkylcarbonic acid, fatty acid such as pi~alic acid, pen-tanoic acid! isopentanoic acid, 2-ethylbutanoic acid or trichloro-acetic acid, or aromatic carboxylic acid such as benzoic acid;
amides for example, amides with imidazole, 4-substituted imid-azole, dimethylpyrazole, triazole or tetrazole; and esters, for example, Gyanomethyl ester, 4-Nitrophenyl ester, 2,4-dinitro-phenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthio ester, 4-nitrophenylthio ester, p-cresylthio ester, carboxymethyl-thio ester, pyranyl ester, pyridyl ester, 8-quinolylthio ester and esters with N,N-dimethylhydroxyamine, l-hydroxyl-2-~lH)-pyri-done, N-hydroxysu~cinimide or N-hydroxyph*halimide.
The starting compounds (III) may be used as an activ-- ated form at amino group which can be activated by the use of phosphorous trichloride, ethyl chlorophosphite, methyl chloro~
phosphite or the like.
The process as defined in method ~1~ above may be carried out ~y reacting, for example, a reactive derivati~e of the compound (II2 at car~oxyl group with the compound (III) to condense them at a temperature of ~rom -10 to 50C, preferably ~ - 10C for 0.5 - 4 hours. The solvents which may be used for this reaction include water, benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, dimethyl~formamide, chloroform, methylene chloride, acetonitrile~ acetone~ carbon tetrachloride ethyl acetate and the like. An accelerator for the condensation re-action may be useclr which includes inorganic basic substances, for example~ hydroxide, carbonate or acetate of an alkali metal or alkaline earth metal, such as sodium acetate, sodium carbonate, potassium acetate, potassium car~onate, sodium hydroxide, calcium acetate, calcium carbonate; or amine compounds such as pyridine, .
., ' ' ' '. ' ' , ', ` ' ~L0889~4 1 triethylamine, dimethylaniline, picoline or the like~
The condensation reaction of the compound (II) with the compound (III) the amino group of which has been activated with phosphorous trichloride, èthyl chlorophosphite, methyl chlorophosph-ite or the like may ~e conveniently carried out at from room temperature to the reflux temperature of a solvent used for 0.5 - 3 hours. The solvent usually used for this invention includes a neutral solvent, such as ~en~ene, toluene, xylene, di-oxane or tetrahydrofuran; or a ~asic solvent such as pyridine, triethylamine, dimethylamine, dimethylaniline or picoline. In case the neutral solvent is used, it is preferable to add aminecompound such as pyridine, triethylamine dimethylaniline, picoline or the like.
In another em~odiment of the invention, the compound (III may ~e reacted with the compound (III) in an inert solvent in the presence of an amide-formation accelerator, for example, an imide compound such as N~N~-dicyclohexylcarbodimide~ N-cyclo-~exyl-N'-morpholino-et~ylcar~odiimide, N~N'-diethylcar~odiimide or the like; an imine compound such as diphenylketene-N-cyclo-hexylimine~ pentameth~leneketene-N-cyclohexylimine or the like;
or a phosphate or phosphite such as triethyl phosphite,~ethyl polyphosphate, isopropyl polyphosphate or the like at from room temperature to the reflux temperature of the solvent used for 1 - 5 hours. The inert solvent which may be used in this react-ion includes, for example~ benzene, toluene, tetrahydrofuran, chloroform, dioxane, acetonitrile and dimethylformamide.
.
" 1~88S~4~
, The reaction as previously defined in Method (2) may be carried out by reacting the compound (IV) with a nitrating agent in an inert solvent such as chloro~orm, dichloromethane or the like at a temperature of ~rom -5C to room temperature for 1 - 3 hours. The nitrating agent which may be generally used in this reaction is fuming nitric acid, nitril chloride or the like.
The compound (I) prepared by Method (1) or Method (2) may be converted to its organic or inorganic acid addition ' 10 salt such as hydrochloride, nitrate, oxalate, p-tolunensulfonate, maleate or the like.' The object compound, pyridine derivative (I) may be formulated by a conventional way into a pharmaceutical composition in the form of tablet, granule, powder, capsule, suspension, parenteral injection, suppository or the like. For the preparation of tablet, powder, granule or capsule filled with powder or granule, the object compound may be mixed with one or more p~armaceutical carriers such as lactose, starch, ' mannitol, kaolin, crystaline cellulose, talc, calcium caxbonate, ' magnesium stearate or the like. For'the preparation o~ soft capsule filled with liquid preparation, the object compound may be dissolved in an oil. The object compound may also be suspended in an arabic gum or sucrose aqueous solution and the pH adjusted.
On the other hand the object compound may be blended with mannitol to make it suitable for parenteral injection.
The pyridine derivative according to this invention may be present in any form of the pharmace'utical composi-tion in an amount sufficient to exhibit the actions for treating or preventing circulatory disease but not to _ 7 _ ~.:
89~
1 exhibit any adverse action ~y the administration of the composi-tion. A unit dosage form such as a tablet or capsule may contain usually 5 - 20 mg of the active compound when the composition is orally administered~ In case the composition is given parent-erally, a unit dosage such as a vial may usually contain about 1 - 10 mg of the compound.
It will be understood that the actual dosage changes, as a matter of course, depend upon.the conditions of individual patient and, therefore, it should be specifically determined when used~ However, it will ~e safe and convenient if the dosage in terms of the active cr~mpound is usually 10 - 100 mg, preferably - 60 mg per day for an adult when administered orally, and usually 1 - 100 mg, prefera~ly 1 - 50 mg, per day for an adult in the case of the parenteral injection.
Fig. 1 is a graph showing percent increase in coronary ~lood flow when the compound prepared according to Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Fig. 2 is a graph showing the duration of increase in coronary ~lood flow when the compound of Example 1 or nitrogly-cerin was intravenously administered in accordance with Experi-ment 1.
Fig. 3 is a graph showing the change in the left vent-ricular tension when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Fig. 4 is a graph.showing the change in heart rate - when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Figs. 5, 6 and 7 are graphs showing the change in elec-trocardiograms when the compound of Example 1 was intravenously administered.
1Fig, 8 is a graph showing the change in systemic blood pressure when ~he compound of Examp:Le 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Figs. g and 10 are graphs showing the change in systemic blood pressure when the compound of Example 1 was intravenously administered according to Experimenl 1.
Figs. 11 and 12 are graphs showing the change in aortic ~lood flo~ when the compound of Exa~ple 1 was intravenously administered.
lOFig. 13 is a test chart showing the effect of the com-pound of Example 1 to the platelet coagulation caused by adeno-sine diphosphate in accordance with Experiment 7.
Fig~ 14 is a test chart showing the effect of the com-pound to the platelet coagulation caused by collagen in accordance with Experiment 7, Experiment 1 .. , . . , :
The acute tQXiCity ~LD5Qi of the compound of Example 2 was determined ~y the use of SD strain male and female rats ~4 weeks oldl which were orally or intravenously administered the compound. LD50 against both male and female rats ranged from 1,20Q to 1,3Q0 mg/kg for oral administration and from 800 to l,OOQ mg/kg for intravenous administration, Ex~eriment 2 Adult mongrel dogs which had ~een anestetized by the intravenous administration of 30 - 40 mgjkg of pento~arbital sodium were subjected to thoracotomy under oxygenic ventilation by use of Bird's respirator and thereafter various physical phenomena were measured in the following manner.
12 Coronary ~lood flow ~CBF~
An electromagnetic flowmeter probe ~as attached to a _g_ ' ' ' ' ' ' .. . . . .
~{118l~5~44 1 circumflex branch or an origin of an anterior descending branch of the left coronary artery.
2) Coronary perfusion pressure ~CBP) The fine catheter connected to a pressure transducer was inserted into the distal side of the probe in the circumflex branch of the left coronary artery,
In another of its aspects, the invention provides aprocess for preparing a nitric ester of N-(2-hydroxyethyl)nico-tinamide of the formula NJ
or a pharmaceutically acceptable salt thereof, which comprises a process selectecl from the group of processes consisting of:
~a) reacting a compound of the formula ,, .,. 1 ' 1~8~9~
-' ..
COOH
N
or its functional derivative at the carboxyl group, with a :~
compound of the forrnula NH2 ~ CH2CH2 ON02 or its functional derivative at the amino group; ~nd (b) reacting a compound of the formula N . :
with a nitrating agent.
In yet another of its aspects, the invention provides .
a novel compound of a nitric ester of N- (2-hydroxyethyl)nicotin- :--amide of the formula NHCH2CH2 - ONO~
' . ' The compound of the present invention or its salt is novel and has improved actions for treating circulatory disease, such as coronary vasodilating action, antihypertensive action, antiarrhythmic action, anticoagulative action and peripheral vasodilating action, and, thus, it is use~ul for treating ischemic heart disease, as an antihypertensive drug, anticoagulative drug, ~ .
antiarrhythmic drug, and as a peripheral vasodilator including cerebral vasodilator and renal vasodilator. .
According to the present invention the compound 1~)889~9~
1 of the formula (I~ may ~e prepared ~y one of the following methods:
(1) A compound represented ~y the formula 1~ .
l N ~ COOH tII) or its functional derivative at carboxyl group is reacted with a compound represented ~y the formula ,~
NH2 - CH21H R2 (III) Rl ' wherein Rl and R2 are as defined above or its functional deriv-ative at amino group; and (2) ~ compound represented ~y the formula ~ ~ONHCH2C~ ~ H4 (IV) wherein H3 is hydrogen, lower alkyl or hydroxy and R4 i~ hydroxy or -CH2OH is reacted with a nitrating agent.
The functional derivatives of the compound (II~ at car~oxyl group include, for example, acid halide, acid anhydride, active amide, active ester and the like. The derivatives which may ~e commonly used are acid chlorides; acid azides; acidanhyd-rides such as anhydrides derived from two moles of the compound CII~ and anhydrides of the compound wîth another acid for example dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, benzylphosphoric acid, halogenated phosphoric acid, di-alkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric .. . ~ ' 10~8g~4 1 acid, alkylcarbonic acid, fatty acid such as pi~alic acid, pen-tanoic acid! isopentanoic acid, 2-ethylbutanoic acid or trichloro-acetic acid, or aromatic carboxylic acid such as benzoic acid;
amides for example, amides with imidazole, 4-substituted imid-azole, dimethylpyrazole, triazole or tetrazole; and esters, for example, Gyanomethyl ester, 4-Nitrophenyl ester, 2,4-dinitro-phenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthio ester, 4-nitrophenylthio ester, p-cresylthio ester, carboxymethyl-thio ester, pyranyl ester, pyridyl ester, 8-quinolylthio ester and esters with N,N-dimethylhydroxyamine, l-hydroxyl-2-~lH)-pyri-done, N-hydroxysu~cinimide or N-hydroxyph*halimide.
The starting compounds (III) may be used as an activ-- ated form at amino group which can be activated by the use of phosphorous trichloride, ethyl chlorophosphite, methyl chloro~
phosphite or the like.
The process as defined in method ~1~ above may be carried out ~y reacting, for example, a reactive derivati~e of the compound (II2 at car~oxyl group with the compound (III) to condense them at a temperature of ~rom -10 to 50C, preferably ~ - 10C for 0.5 - 4 hours. The solvents which may be used for this reaction include water, benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, dimethyl~formamide, chloroform, methylene chloride, acetonitrile~ acetone~ carbon tetrachloride ethyl acetate and the like. An accelerator for the condensation re-action may be useclr which includes inorganic basic substances, for example~ hydroxide, carbonate or acetate of an alkali metal or alkaline earth metal, such as sodium acetate, sodium carbonate, potassium acetate, potassium car~onate, sodium hydroxide, calcium acetate, calcium carbonate; or amine compounds such as pyridine, .
., ' ' ' '. ' ' , ', ` ' ~L0889~4 1 triethylamine, dimethylaniline, picoline or the like~
The condensation reaction of the compound (II) with the compound (III) the amino group of which has been activated with phosphorous trichloride, èthyl chlorophosphite, methyl chlorophosph-ite or the like may ~e conveniently carried out at from room temperature to the reflux temperature of a solvent used for 0.5 - 3 hours. The solvent usually used for this invention includes a neutral solvent, such as ~en~ene, toluene, xylene, di-oxane or tetrahydrofuran; or a ~asic solvent such as pyridine, triethylamine, dimethylamine, dimethylaniline or picoline. In case the neutral solvent is used, it is preferable to add aminecompound such as pyridine, triethylamine dimethylaniline, picoline or the like.
In another em~odiment of the invention, the compound (III may ~e reacted with the compound (III) in an inert solvent in the presence of an amide-formation accelerator, for example, an imide compound such as N~N~-dicyclohexylcarbodimide~ N-cyclo-~exyl-N'-morpholino-et~ylcar~odiimide, N~N'-diethylcar~odiimide or the like; an imine compound such as diphenylketene-N-cyclo-hexylimine~ pentameth~leneketene-N-cyclohexylimine or the like;
or a phosphate or phosphite such as triethyl phosphite,~ethyl polyphosphate, isopropyl polyphosphate or the like at from room temperature to the reflux temperature of the solvent used for 1 - 5 hours. The inert solvent which may be used in this react-ion includes, for example~ benzene, toluene, tetrahydrofuran, chloroform, dioxane, acetonitrile and dimethylformamide.
.
" 1~88S~4~
, The reaction as previously defined in Method (2) may be carried out by reacting the compound (IV) with a nitrating agent in an inert solvent such as chloro~orm, dichloromethane or the like at a temperature of ~rom -5C to room temperature for 1 - 3 hours. The nitrating agent which may be generally used in this reaction is fuming nitric acid, nitril chloride or the like.
The compound (I) prepared by Method (1) or Method (2) may be converted to its organic or inorganic acid addition ' 10 salt such as hydrochloride, nitrate, oxalate, p-tolunensulfonate, maleate or the like.' The object compound, pyridine derivative (I) may be formulated by a conventional way into a pharmaceutical composition in the form of tablet, granule, powder, capsule, suspension, parenteral injection, suppository or the like. For the preparation of tablet, powder, granule or capsule filled with powder or granule, the object compound may be mixed with one or more p~armaceutical carriers such as lactose, starch, ' mannitol, kaolin, crystaline cellulose, talc, calcium caxbonate, ' magnesium stearate or the like. For'the preparation o~ soft capsule filled with liquid preparation, the object compound may be dissolved in an oil. The object compound may also be suspended in an arabic gum or sucrose aqueous solution and the pH adjusted.
On the other hand the object compound may be blended with mannitol to make it suitable for parenteral injection.
The pyridine derivative according to this invention may be present in any form of the pharmace'utical composi-tion in an amount sufficient to exhibit the actions for treating or preventing circulatory disease but not to _ 7 _ ~.:
89~
1 exhibit any adverse action ~y the administration of the composi-tion. A unit dosage form such as a tablet or capsule may contain usually 5 - 20 mg of the active compound when the composition is orally administered~ In case the composition is given parent-erally, a unit dosage such as a vial may usually contain about 1 - 10 mg of the compound.
It will be understood that the actual dosage changes, as a matter of course, depend upon.the conditions of individual patient and, therefore, it should be specifically determined when used~ However, it will ~e safe and convenient if the dosage in terms of the active cr~mpound is usually 10 - 100 mg, preferably - 60 mg per day for an adult when administered orally, and usually 1 - 100 mg, prefera~ly 1 - 50 mg, per day for an adult in the case of the parenteral injection.
Fig. 1 is a graph showing percent increase in coronary ~lood flow when the compound prepared according to Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Fig. 2 is a graph showing the duration of increase in coronary ~lood flow when the compound of Example 1 or nitrogly-cerin was intravenously administered in accordance with Experi-ment 1.
Fig. 3 is a graph showing the change in the left vent-ricular tension when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Fig. 4 is a graph.showing the change in heart rate - when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Figs. 5, 6 and 7 are graphs showing the change in elec-trocardiograms when the compound of Example 1 was intravenously administered.
1Fig, 8 is a graph showing the change in systemic blood pressure when ~he compound of Examp:Le 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.
Figs. g and 10 are graphs showing the change in systemic blood pressure when the compound of Example 1 was intravenously administered according to Experimenl 1.
Figs. 11 and 12 are graphs showing the change in aortic ~lood flo~ when the compound of Exa~ple 1 was intravenously administered.
lOFig. 13 is a test chart showing the effect of the com-pound of Example 1 to the platelet coagulation caused by adeno-sine diphosphate in accordance with Experiment 7.
Fig~ 14 is a test chart showing the effect of the com-pound to the platelet coagulation caused by collagen in accordance with Experiment 7, Experiment 1 .. , . . , :
The acute tQXiCity ~LD5Qi of the compound of Example 2 was determined ~y the use of SD strain male and female rats ~4 weeks oldl which were orally or intravenously administered the compound. LD50 against both male and female rats ranged from 1,20Q to 1,3Q0 mg/kg for oral administration and from 800 to l,OOQ mg/kg for intravenous administration, Ex~eriment 2 Adult mongrel dogs which had ~een anestetized by the intravenous administration of 30 - 40 mgjkg of pento~arbital sodium were subjected to thoracotomy under oxygenic ventilation by use of Bird's respirator and thereafter various physical phenomena were measured in the following manner.
12 Coronary ~lood flow ~CBF~
An electromagnetic flowmeter probe ~as attached to a _g_ ' ' ' ' ' ' .. . . . .
~{118l~5~44 1 circumflex branch or an origin of an anterior descending branch of the left coronary artery.
2) Coronary perfusion pressure ~CBP) The fine catheter connected to a pressure transducer was inserted into the distal side of the probe in the circumflex branch of the left coronary artery,
3) Aortic blood flow (AoBF) An electromagnetic flowmeter probe was attached to the origin of aorta.
1~ 4~ Left ventricular tension (LVT) A strain gauge was sewn on the anterior wall of the left ventricle.
51 Systemic blood pressure (SBP) A catheter connected to a pressure transducer was in-serted into the right femoral artery, 6) Heart rate (HR) Heart rate was measured by a cardiotachometer using pulse pressure as trigger pulse.
7) Electrocardiogram ~ECG~
An electrocardiogram was recorded according to an uni-polar lead in the cardiac surface using different electrode set on a portion of anterior wall of left ventricle.
In addition to test Items 1 - 7 above, some of the test animals were subjected to the measurement of renal blood flow (RB~) and femoral blood flow ~BF) by attaching an electromagnetic flowmeter probe to the left renal artery and the left femoral artery.
The test compound of Example 1 was dissolved in the physiological saline solution ox in the distilled water and ad-ministered intravenously, orally or sublingually, Nitroglycerin , 10~ 4 1 was administered in the same manner as an acti~e control drug to compare with the test compound.
Results ~I) Intravenous Administration a~ Change in coronary ~lood f:Low Diastolic coronary flow began to increase 10 - 20 se-- conds after the intravenous administration of the test compound with a dose of 10 ~g/kg or more. Systolic coronary flow was in-creased with a dose of 250 ~g/kg or more, accompanied by tran-sient decrease just after the administxation. Mean coronary flowshowed a persistent increase after the administration of the test cQmpound.
The increasing degree of coronary flow is shown in Figs. 1 and 2 in terms of maximum percent change and duration against the values ~efore administration.
The administration of the compound of this invention even in a dose level of 10 ~g/kg i.v. produced a significant in-crease in coronary flow and in a dose level of 500 ~g/kg i v.
caused a increase so remarkable as to appear to be reactive hyperemia. In the latter case, the duration of increase in cor-onar~ flow ~ecame to near 3 hours. The effect of the compound of this invention was superior to that of nitroglycerin, particularly in the duration of action.
~2 Chan~e in left ventricular tension As shown in Fig. 3, the left ventricular tension caused a slight decrease after the intravenous administration of the compound of Example 1 in a dose level of 50 ~g/kg or more. The decrease was almost equivalent to t~at o~ nitroglycerin in the tested dose range. However, the maximum percent decrease was 33~ or less even in a dose level of 500 ~g/kg i,v, .
.: . . .. . .
.
. . .
~lL01~89~4 c) Change in heart rate As shown in Fig. 4, the heart rate showed almost no change ~y the administration of the compound of this invention in a dose level up to 20 ~g/kg i.v., while, in a dose level of 50 yg/kg i.v. or more, presented a s,light dose-dependent decrease to reach 17% in a dose level of 500 ~g/kg i.v. In contrast, the administration of nitroglycerin in a dose level of more than 10 ~g/kg i.v. increased the heart rate.
d~ Change in electrocardiogram As shown in Figs. 5 and 7, PP and QTc intervals were prolonged dose-dependently by the-intravenous administration of the compound of Example 1 with a dose more than 50 ~g/kg, while the PQ interval had almost no change ~y the administration of dose up to 1,000 ~g/kg i.v, e~ Chan~e in systemic blood pressure ~ As shown in Figs. 8, q and 10, the systemic blood pres-sure presented a significant, dose-dependent fall by the intra-venous a*ministration of the test compound in a dose level of more than 50 ~g/kg. The effect of the compound on blood pressure was not stronger thah that of nitroglycerin, but the duration was longer than that produced with nitroglycerin.
f) Change in aortic blood flow As shown in Figs. 11 and 12, the aortic blood flow pre-sented a slight, dose-dependent increase by the intravenous ad-ministration of the compound of Example 1 in a dose level of 10 ~g/ky or more. The percent increase in a dose level of 500 ~g/kg i~Y, reached maxi~um 40%, ~ut the duration was not so long in comparison with the degree of increase in coronary flow.
g) Ch~nge in renal or femoral flow The renal and femoral flows were increased in spite of .
' '. : . . .~ : ' ', : ., .. . . .
1()8~944 1 a fall in systemic blood pressure hy the intravenous administra-tion of the compound of Example 1 in a dose level of 100 to 250 yg/kg. However, the increase in the renal and femoral flows were less than that in coronary flow concerning the degree and the duration.
From the test results stated a~ove, it was confirmed that the compound of this invention had an increasing effect on coronary flow far superior to that of nitroglycerin and, in addition, it produced a fall in blood pressure, a decrease in '' heart rate and a reduction in cardiac tension, which were not excessive e~en in a high dose level.
Moreover, the fact that the compound of this ln~ention did not disturb the conduction of excitation in the heart as shown in no prolonged PQ interval of elctrocardiogram, indicates that it may be very useful as a drug for ischemic heart disease, The compound could ~e used as an antihypertensive drug or a peripheral vasodilator ~ecause it has a longlasting and mild a~tih~pertensive action and a dilating action ~or femoral and renal vessels, as well as a desira~le effect on ischemic 2~ heart.
~I~ Oral and Su~lingual Administration The compound prepared according to Example 2 was sub-lingually administered to dogs as a tablet containing 1 - 10 mg of the compound. About 2 minutes after the administration~ cor- '' onary flow was apparently increased~ The compound in a dose le~el of 10 mg showed almost no change in systemic blood pressure, cardiac tension and aortic flow. In contrast, the sublingual administration of a tablet containing the hydrochloride of the acti~e compound did not show any substantial increase in coronary flow~ When the compound prepared according to Example 1 or 2 in . ,' ', ,. , '.
1081~ 4 1 either its free form or hydrochloride was intraduodenally admin-istered in a dose level of 50 ~g/kg or more, an apparent, long-lasting increase in coronary flow was observed, From the test results, the compound of this invention may be used as various preparations, such as for parenteral in-jection; or in the form of capsule, tablet, granule or powder for oral administration or in sublingually administrative form.
In contrast, nitroglycerin is not absorbed through the intestinal wall and, therefore, only sublingual administration is available.
Experiment 3 Adultmongrel dogs which had been anesthetized by the intravenous administration of 30 - 40 mg/kg of pentobarbital sod-ium were subjected to thoracotomy under oxygenic ventilation by the use of Bird's respitator. A catheter was inserted towards a proximal direction into a branch of an origin of the left coron-ary artery and a contrast media such as Conlaxin H ~ or Angio-conrei ~ was injected through the catheter. The morphological change in the left coronary artery was filmed using a 35 mm cine-film before and after the injection of the compound. From the analysis, it was found that the coronary artery was remarkably dilated by the intravenous adminstration of the compound of this invention in a dose level of 100 ~g/kg or more.
Experiment 4 The same preparation as in Experiment 2 was set up using adult mongrel dogs anesthestized by the intravenous administration ; of pentobar~ital sodium. The left anterior descending branch or ci-rcumflex branch of the coronary artery was mechanically stric-tured or occluded in the distal side of the portion attaching the electromagnetic flowmeter probe to experimentally induce cardiac ischemic phenomenon, and then the efEect of the compound of Example 1 on the phenomenon was observed.
.. ; ' . ' , ': .
~ 8944 1 Under incomplete stricture, the coronary flow was slightly increased when the compound of Example 1 was intraven-~usly a~ministered in a dose level of 100 ~g/kg or less, while slightly decreased when administrated in a dose level of more than 250 ~g/kg. After the administration of the compound of this invention, ST elevation of the electrocardiogram in the car-diac ischemic portion was apparently improved and, at the same time, the recovery of ventricular tension in an ischemic part was also observed. Under complete occlusion, the compound did not improve ST elevation or ventricular tension in the midpoint of the ischemic pGrtion, but the improvement in the surrounding point of the ischemic portion was recognized.
Similarly, when the tablet containing 10 mg bf the free form of the compound prepared in Example 2 was sublingually administered, the coronary flow was increased and ST elevation in the electrocardiogram and a reduction inventricular tension . ,, i `were improved.
F~periment 5 ~ A papillary muscle isolated from a guinea pig was set in the organ hath filled with the oxygeni~ed Tyrode's solution ~Ca; 1 8 mM, K: 2,7 mMl at 30 C. One end of the muscle was fixed to the organ bath and the other end was connected to a tension meter by a thread. The effect of the compound of Example 1 on the muscle contraction force was observed by giving electric stimulation (2~V, 5 msec, lHz~ to the muscle with an Ag-AgCl electrode. The antagonistic action of the compound against calcium ion or isoproterenol was also investigated.
From the test results, it was found that the contraction of the papillary muscle induced by the electric stimulation was inhi~ited with the application of the compound of this invention ., : ~ .
10~8944 1 in a concentration level of more than 1 ~g/ml and that calcium ion had antagonistic effect against such inhibitory action. On the other hand, when isoproterenol was applied in a concentration level of 0.08 ~g/ml, the papillary muscle exhi~ited excessive excitement to produce two or more irregular contractions per single electric stimulation. Under this state, the addition of the compound of this invention to the solution in a concentration level of more than 2 ~g/ml inhi~ited the excessive excitement.
~II) A spiral strip isolated from the dog coronary artery was set in the organ ~ath filled with a Ca -free Lock's solution.
One end of the strip was fixed to the organ bath and the other end was connected to a tension meter, The effect of the compound of Example l on the contraction of the strip induced by the polar-ization of the solution with the addition of 43 mM of K and 1 mM
of Ca~+ was investigated.
The test results showed that the contraction induced by K depolarization was inhibited by the compound of this invention and such inhibitary action was diminished by the add-ition of Ca++.
(III~ The effect of Ca on the increase in coronary flow wasinvestigated using the dog anesthetized with pento~arbital sodium according to the same procedure as in Experiment 2-(Ij. The in-crease in coronary 10w induced by the administration of the com-pound of this invention was inhi~ited by a larger dose o Ca +.
(IV~ Taenia coli of a guinea pig was suspended in the organ bath filled with Tyrode's solution and the effect or the compound of Example 1 on the spontaneous contraction and the contraction induced ~y K depolarization was investigated.
The test results showed that the spontaneous contraction and the K depolarization induced contraction were inhi~ited ~y .. . . . . .
.
1~8~?9~
1 application of the co~pound in a concentration level of 2 ~g/ml and such inhibitary action was diminished ~ the addition of Ca Analysis of the test results indicates that the com-pound of the present invention has an antagonistic action to Ca r 50 that the inhibitory action to cardiac contraction the dilating action to smooth muscle of dog coronary artery and the inhibitory action to contraction of taenia coli of guinea pig induced by the application of the c~mpound were antagonized by the addition of Ca~. Further, it was also found that the com-pound of this invention has an antiarrhythmic action because thecompound inhibited the excessi~e excitement of papillary muscle induced ~y the administration of isoproterenol, Experiment 6 The ~lood flow was made insufficient by loading exper-imentally the coronary artery of a dog, for example, ~y strict-uring the coronary artery for a certain period of time, and the ^ , artery was allowed to sustain in this condition. According to this treatment~ its peripheral ~lood pressure and peripheral blood flow repeated periodical and spontaneous fluctuations with-in minutes order period accompanied with ST elevation in electro-cardiogram. This phenomenon was closely similar to the fit of variant angina pectoris in a clinical case, The periodical fluctuation has been proved to ~e caused by the periodical spas-mus in the strictured coronary artery. The effect of the com-pound on such a Yariant angina pectoris model was investigated.
The test results show that the periodical fluctuations -in the coronary ~lood pressure and coronary flow was inhibited ~y the intravenous administration of the compound of Example 1 in a dose level of 25Q ~g/kg or more. That is, the periodical fluctuation in blood flow apparently reduced, and only fine 10~3944 1 fluctuations remained. The effective duration o~ the inhi~itory action ranged from 25 to 40 minutes.
As stated ak,ove, the compound of this invention is ~elievea to ~e effective on the treatment of variant angina pect-oris.
Experiment 7 According to the procedure explained below, the compound of E~ample 1 was subjected to investigate as to whether or not it has an anticoagulative action to platelets, namely antiembolic 1 0 action.
1. Preparation of the test solution 1-1 Adjustment of platelet-rich plasma ~RP solution) A rabbit blood containing 38% sodium citrate (blood:
sodium citrate aqueous solution = 9:1~ was subjected to the cent-rifugation at 1,~00 r.p.m. for 10 minutes, and the supernatant fluid was used as PRP solution.
1-2 Adjustment of an adenosine diphosphate solution (ADP solution) Adenosine diphosphate CSigma Chemical Co., Ltd.) was dissolved in a physiological saline solution at a concentration of 10~ ~g/ml.
1-3 Adjustment o~ collagen suspension - Fifty mg of collagen o~,tained from ~ovine tendon (Sigma Chemical Co., Ltd.,3 was suspended in 5 ml of a physiological saline solution and homogenized by a glassey homogenizer for 5 minutes. Next, it was subjected to centrifugation at 500 r.p.m.
for S minutes, and the supernatant fluid was used as a collagen suspension, 1-4 The compound of Example 1 was dissolved in the physiological saline solution to obtain the test solution, 2. Method of measurement The measurement was performed by the use of Aggrego-meter ~vans Electroselenium htd., Model 169).
PRP solution ~0.5 ml) and the test solution ~0.025 ml) or a physiological saline solution as the control (0.025 ml) were charged into two cuvetts, respectively, and then subjected to incu~ation at 37 C for 2 minutes Further, after 0.025 ml of ADP solution or 0.025 ml of the collagen suspension was added to each cuvette, the e~fect of the compound on platelet aggregation induced by ADP or collagen was measured.
As shown in Figs. 13 and 14, the initial rate of ADP-induced aggregation in the test compound was the same as that in the control/but the test compound accelerated the dissociation of the aggregated platelets. On the other hand, the test c~mpound delayed the onset of the collagen-induced aggregation and made a maximum extent of the aggregation lower than the control. From these results~ the inhibitory effect of the compound on the plate-let aggregation was confirmed, so that the compound of this invention was also found to be useful as an anticoagulant.
E~periment 8 By the same method as disclosed in Experiment 2, item 5, change in systemic blood pressure when test compounds were intraYenously administered was measured. The results obtained are shown in the follo~ing Ta~le.
TABLE
.. _ _ Test Compound Dose Percent Change Duration C~s/kgl of S.B.P. ~1 ~in.) . .
Compound of E~ample 50 16 22 Compound of Example 50 20 17 Nitroglycerin 50 45 8 . . . ....
, ~. ' ' ", ' '.
8894~
Example 1 To a mixture of 5 g of sodium hydrogen car~onate, 15 ml of water, 1.69 g of the nitric ester of monoethanolamine nitrate and 20 ml of chloroform was added slowly 2.5 g of nicotinyl chloride hydrochloride o~er 10 to 30 minutes under stirring at 0 to 5C, The stirring was continued for an additional 30 min- ~-utes and then the chloroform layer was separated. The remained aqueous layer was extracted with chloroform and the extract was com~ined with t~e separated chloroform layer. The organic layer was washed with a potassium carbonate aqueous solution, dried oYer anhydrous sodium sulfate-and evaporated under reduced pres- '' sure to dryness. The residue was dissolved in ether-isopropanol ~ and then hydrogen chloride was ~u~led into the solution ' ~, under cooling to give 2.35 ~ of the nitric ester of N-~2-hydroxy-ethyl~ nicotinamide hydrochloride. Recrystallization from ethan- ' ol afforded colorless needle"crystals having a melting point of 132C.
Anal~sis:
Calcd. for C8HloN304Cl: C,38.80; H, 4~07; N, 16.96 (%~
Found C,38~89,-; H, 4.02; N, 16.72 (~) IR~cm ~
NH, 3255; CoO~ 166~; ON02, 1640 Ex:ample 2 To a solution of 1.69 g of the nitric ester of mono-ethanolamine in 20 ml of pyridine ~as added slowly 2.5 g of ni-cotinyl chloride hydrochloride over ln to 30 minutes under stirring at 5C. After stirring for an additional 30 minutes, the xeaction mixture was evaporated to dryness. The residue was "
dissolved in chloroform and the solution was washed with a sod-iumi hydrogen car~onate aqueous solution. The organic layer was , :
:. ~, ' 1()~894~4 1 separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. The residue was chromato-graphed on silica gel ~Takogel C-200; Wako Pure Chemical Indust-ries, Ltd., Japan) and eluted with ~enzene-ethanol (5:1). The eluent was evaporated to a semi-solid mass which was crystall-ized from diethyl ether to gi~e 1.97 g of the nitric ester of N-~2-h~dxox~rethyllnicotinamide~
Recrystallization of the crystals from diethyl ether-ethanol afforded colorless needles having a melting point of 9210 to 23C.
E~ample 3 A solution of 10 g of the nitric ester of N-~2-hydroxy-ethyl~ nicotinamide hydrochloride in water was neutralized with a sodium hydrogen carhonate aqueous solution. The solution was e~tracted with chloroform and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness.
The residue was crystallized from diethyl ether to give 7 g of the nitric ester of N-C2-hydrQxyethyl) nicotinamide. Recrystall-ization fro~ isopropanol-diethyl ether gave colorless needles ha~in~ a melting point of ~3C, IR ~m~l~
NH~ 3250, ONO2, 1630 Example 4 To a mixture of 1.6~ g of the nitric ester of mono-ethanolamine nitrate in 5 ml of water~ 3.8 ml of 35~ potassium carbonate solution and 17 ml of tetrahydrofuran were added alter-nately 3 g of isonicotinyl chloride hydrochloride and 11~2 ml of 35% potassium car~onate aqueous solution over 30 minutes under stirring at Q to 5C The reaction mixture was stirred for an - 30 additional 15 minutes, and the organic layer was separated. The lV~39~4 1 aqueous layer was extracted with tetrahydrofuran and the extrac~
was combined with the previously separated organic layer. The combined organic layers were dried over anhydrous sodium sul-fate and filtered. Evaporation of the solvent in vacuo and crystallization of the residue aforded the nitric ester of N-~2-hydroxyethyl) isonicotinamide.
The product was dissolved in diethyl ether and the dropwise addition of diethyl ether-fuming nitric acid under cooling gave 1.5 g of the nitric ester of N-~2-hydroxy-ethyl) isonicotinamide nitrate. Recrystallization from isopropanol afforded the crystals having a melting point of 105C ~decomposi-tion~.
Analysis:
8 10N407: C, 35.04; H, 3i68; N 20 43 (%) Found: C, 35.00; H, 3.59; N, 20.38 (~
IR~m~
- NH~ 328~; C=0, 1671; ON02, 1625 Example 5 To a mixture of 1.83 g of the nitric ester of isopropan-20 olamine nitrate in 5 ml of water, 3.8 ml of 35% potassium carbon-ate aqueous solution and 17 ml of tetrahydrofuran were added alternately 3 g of nicotinyl chloride hydrochloride and 11.2 ml of 35% potassium carbonate solution over 30 minutes under stirring at Q to 5C. The reaction mixture was stirred for an additional 15 minutes and the organic layer was separated. The aqueous layer was extracted with tetrahydrofuran and the extract was com- ;
~ined with the previously separated organic layer. The combined extracts were dried over anhydrous sodium sulfate and filtered.
E~aporation of the solvent under reduced pressure and crystall-ization of the residue gave the nitric ester of N-(2-hydroxypropyl) nicotinamide.
-22~
. .
- . ' '. ' , ,,;: ', ' " .. '.
08~9~4 The product was dissolved in acetone and then hydrogen chloride was bubbled into the solution to give 1.5 g of the nit-ric ester o~ N- (2-hydroxypropyl~ nicotinamide hydrochloride as colorless crystals. (mp: 161C (decomposition)).
Analysis:
Calcd- for C~H12N3O4Cl: C, 41,31; H, 4.62; N, 16.06 (~) Found : C, 41.38; H, 4.60; N, 16.11 (~) IR ~cm 11:
NH, 323Q; C=O, 1672; ONO2, 1620 Example 6 By the procedure similar to that of Example 4~ nico-tinyl chloride hydrochloride was reacted with nitric ester of propanol amine nitrate to o~tain nitric ester of N-(3-hydroxy- ~
propyl~ nicotinamide hydrochloride. ~Yield: 75%; mp: 127C -(decQmposition~
Analysis:
, . . -Calcd, for C~H12N3O4Cl: C, 41,31; H, 4.62; N, 16.06 (%) Found : C, 41,40; H, 4.53; N~ 16~15 (~) NH, 3235; C=O~ 1672; ONO2, 1617 ;
F~xa~le 7 By the procedure similar to that of Example 4, isonico-tin~l chloride hydrochloride was reacted with nitric ester of propanolamine nitrate to o~tain nitric ester o~ N~(3-hydroxy-propyll iæonicotinamide hydrochloride. (Yield: 72~, mp: 125C
~decomposition~.
Analysis:
Calcd- for CqH12N304Cl C, 41,31; H, 4.62; N, 16.06 (%) Found : C, 41.40; H, 4.58; N, 16.01 (%) IR (cm 12;
NH, 3230; C=O, 1672, ONO2, 1615 , . . . .
~l088~44 1 Example 8 By the procedure similar to that of Example 4, pico-linyl chloride hydrochloride was reacted with nitric ester of monoethanolamine nitric acid salt to obtain nitric ester of N-C2~hydrQxyethyl~ picolinamide~ (Yield: 78%, mp: 55 - 56C) Analysis:
Calcd, for C~HgN304: C, 45.5Q; H, 4~29; N, 19.89 ~) Found ; C~ 45.25; H, 4~10; N, 19.17 (~) IR ~cm-l~
NH, 3362; C=0, 1665; ON02, 162Q
Example ~ -By the procedure similar to that of Example 4, nico-tin~l chloride hydrochloride was reacted with 2,3-hydroxypropyl-amine to obtain dinitric ester of N- ~,3-di-hydroxypropyl) nico-tinamide as pale-yello~ oil.
Example lQ
, - N-C2-hydro~yethyl~ nicotinamide nitrate ~1.145 g) was gradually added to 3 ~1 of fuming nitric acid which had been ~ooled to a temperature of from -lQ to -5C while stirring.
~0 After stirrin~ for additional one hour at 0 - 5C, diethyl ether was added to the solution to precipitate 1.15 g of nitric ester of N- ~-hydrQxyethyl~ nicotinamide nitric acid ester as colorless crystals. The crystaIs were dissolved in a sodium carbonate aqueous solution and ethyl acetate was added to the solution.
The ethyl acetate layer was separated, dried over sodium sulfate and evaporated under reduced pressure~ The residue was crystall-ized from diethyl ether to give nitric ester of N-12-hydroxyethyl) nicotinamide~ Recrystallization from diethyl ether afforded colorless crystals havin~ a melting point of 90 - 92C.
, . . . .
.,: .
:
nalysis:
Calcd. for C8HgN3O4 C, 45.50; H, 4.29; N, 19.89 (~) Found : C, 45.37; H, 4.09; N, 19.71 (~) Example 11 By the procedure similar to that of Example 10, N-~2-hydroxyethyl)isonicotinamide nitrate was reacted with fuming nitric acid to obtain nitric ester of N-(2-hydroxy-ethyl) iso-nicotinamide nitrate. (Yield: 76%, mp: 105C (decomposition)).
Analysis:
Calcd, for C8HloN4O7: C, 34.04; H, 3.68; N, 20.43 (~) Found : C, 35.11; H, 3.57; N, 20.34 (~) Example 12 ~harmaceutical Preparation~
- a~ Su~lingual Tablet Compound prepared according 5 mg to Example 2 Lactose 19.7 mg Mannitol 25 mg Magnesium Stearate 0.3 mg Total 50 mg/
tablet The ingredients were uniformly blended in the propor-tions described above and the mixture was formed inta,tablets, each tablet ~eing 5 mm in diameter and 50 mg in weight.
bL Table for Internal ~se Compound prepared according 10 mg to E~ample 1 Lactose 44.5 mg Corn Starch 20 mg Crystalline Cellulose 25 mg Magnesium Stearate 0.5 mg Total 100 mg/
tablet ~1088S~4 The ingredients were uniforml~ ~lended in the propor-tions described a~oYe and the mixture was formed into tablets, each ka~let ~eing 7 mm in diameter and 100 mg in weight.
c) Hard Capsules Compound prepared according20 mg to Example 2 Lactose 176 mg Magnesium Stearate 4 mg Total 200 mg/capsule - The ingredients were uniformly ~lended in the propor-tions descri~ed a~ove and hard capsules each being identified as No. 3 were filled with 200 mg each of mixture ~y a packing machine to form capsules each weighing 250 mg.
d2 Granules Compound prepared according10 mg to Example 2 Lactose 710 mg Paste of Cornstarch 280 mg -Total 1,000 mg/wrapper The ingredients were uniformly kneaded and then gran-ulated to form granules, each granule having a diameter of about 1 ~n.
e~ Parenteral Injection Compound prepared according5 mg to Example 2 Mannitol 50 mg Total 55 mg/vial The ingredients were dissolved in 1 ml of distilled water and the solution was sterilized and filtered. The solution 30 was filled in a vial andfreeze-dried and the vial was sealed to ;
form a parenteral injection. Thefreeze-dried mixture was dissolved in 1 ml of distilled water when it is used as parenteral injection.
. :
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... ' : . , :, . . .
88s~
SUPPLEMENTARY DISCLOSURE
The applicants have conducted comparative tests with the nitric ester of N- (2-hydroxyethyl)nicotinamide (hereinafter, the compound of this invention) and the nitrate of the acid dinitrooxydiethyl amide nicotinate as disclosed in the prior art reference, namely, United States Patent Number 3,036,074, which issued on May 22, 1962 to Stieglitz et al (hereinafter, the reference)O
Figure 15 is a graph showing the percent increase in coronary blood flow when the compound of the present invention used in the comparative tests was administered and when the compound of the reference was administered.
Figure 16 is a graph showing the duration of increase in coronary blood flow when the compound of the present invention used in the comparative tests was administered and when the compound of the reference was administered.
Figure 17 is a graph showing the degree of drop of the systemic blood pressure induced by the administration of the compound of the-present invention used in the comparative tests and when the compound of the reference was used.
Figure 18 is a graph showing the change in heat rate after the administration of the compound of the present invention used in the comparative tests and when the compound of the reference was used.
Figure 19 is a graph showing the change in coronary blood flow under stricturing of the coronary artery after the administration of the compound of the present invention used in the comparative tests and when the compound of the reference was used.
`" 1~i~894~
1 Comparative Test:
Nitric ester of N-(2-hydroxyethyl)nicotinamide was compared in pharmacological activity with the nitrate of the acid dinitrooxydiethyl amide nicotinate disclosed in the prior art reference, United States Patent 3,036,074.
Experiment In accordance with the methods illustrated in Experiment 2, Items 1, 5 and 6, except that beagle dogs which had been anesthetized by the intravenous administration of 30 - 40 mg/kg of pentobarbital sodium were used as *est animals, the change of coronar~ blood flow (CBF), systemic blood pressure (SBP) and heart rate were measured upon administrating the compound of this invention or the compound of the reference.
Further, in accordance with the methods disclosed in Experiments
1~ 4~ Left ventricular tension (LVT) A strain gauge was sewn on the anterior wall of the left ventricle.
51 Systemic blood pressure (SBP) A catheter connected to a pressure transducer was in-serted into the right femoral artery, 6) Heart rate (HR) Heart rate was measured by a cardiotachometer using pulse pressure as trigger pulse.
7) Electrocardiogram ~ECG~
An electrocardiogram was recorded according to an uni-polar lead in the cardiac surface using different electrode set on a portion of anterior wall of left ventricle.
In addition to test Items 1 - 7 above, some of the test animals were subjected to the measurement of renal blood flow (RB~) and femoral blood flow ~BF) by attaching an electromagnetic flowmeter probe to the left renal artery and the left femoral artery.
The test compound of Example 1 was dissolved in the physiological saline solution ox in the distilled water and ad-ministered intravenously, orally or sublingually, Nitroglycerin , 10~ 4 1 was administered in the same manner as an acti~e control drug to compare with the test compound.
Results ~I) Intravenous Administration a~ Change in coronary ~lood f:Low Diastolic coronary flow began to increase 10 - 20 se-- conds after the intravenous administration of the test compound with a dose of 10 ~g/kg or more. Systolic coronary flow was in-creased with a dose of 250 ~g/kg or more, accompanied by tran-sient decrease just after the administxation. Mean coronary flowshowed a persistent increase after the administration of the test cQmpound.
The increasing degree of coronary flow is shown in Figs. 1 and 2 in terms of maximum percent change and duration against the values ~efore administration.
The administration of the compound of this invention even in a dose level of 10 ~g/kg i.v. produced a significant in-crease in coronary flow and in a dose level of 500 ~g/kg i v.
caused a increase so remarkable as to appear to be reactive hyperemia. In the latter case, the duration of increase in cor-onar~ flow ~ecame to near 3 hours. The effect of the compound of this invention was superior to that of nitroglycerin, particularly in the duration of action.
~2 Chan~e in left ventricular tension As shown in Fig. 3, the left ventricular tension caused a slight decrease after the intravenous administration of the compound of Example 1 in a dose level of 50 ~g/kg or more. The decrease was almost equivalent to t~at o~ nitroglycerin in the tested dose range. However, the maximum percent decrease was 33~ or less even in a dose level of 500 ~g/kg i,v, .
.: . . .. . .
.
. . .
~lL01~89~4 c) Change in heart rate As shown in Fig. 4, the heart rate showed almost no change ~y the administration of the compound of this invention in a dose level up to 20 ~g/kg i.v., while, in a dose level of 50 yg/kg i.v. or more, presented a s,light dose-dependent decrease to reach 17% in a dose level of 500 ~g/kg i.v. In contrast, the administration of nitroglycerin in a dose level of more than 10 ~g/kg i.v. increased the heart rate.
d~ Change in electrocardiogram As shown in Figs. 5 and 7, PP and QTc intervals were prolonged dose-dependently by the-intravenous administration of the compound of Example 1 with a dose more than 50 ~g/kg, while the PQ interval had almost no change ~y the administration of dose up to 1,000 ~g/kg i.v, e~ Chan~e in systemic blood pressure ~ As shown in Figs. 8, q and 10, the systemic blood pres-sure presented a significant, dose-dependent fall by the intra-venous a*ministration of the test compound in a dose level of more than 50 ~g/kg. The effect of the compound on blood pressure was not stronger thah that of nitroglycerin, but the duration was longer than that produced with nitroglycerin.
f) Change in aortic blood flow As shown in Figs. 11 and 12, the aortic blood flow pre-sented a slight, dose-dependent increase by the intravenous ad-ministration of the compound of Example 1 in a dose level of 10 ~g/ky or more. The percent increase in a dose level of 500 ~g/kg i~Y, reached maxi~um 40%, ~ut the duration was not so long in comparison with the degree of increase in coronary flow.
g) Ch~nge in renal or femoral flow The renal and femoral flows were increased in spite of .
' '. : . . .~ : ' ', : ., .. . . .
1()8~944 1 a fall in systemic blood pressure hy the intravenous administra-tion of the compound of Example 1 in a dose level of 100 to 250 yg/kg. However, the increase in the renal and femoral flows were less than that in coronary flow concerning the degree and the duration.
From the test results stated a~ove, it was confirmed that the compound of this invention had an increasing effect on coronary flow far superior to that of nitroglycerin and, in addition, it produced a fall in blood pressure, a decrease in '' heart rate and a reduction in cardiac tension, which were not excessive e~en in a high dose level.
Moreover, the fact that the compound of this ln~ention did not disturb the conduction of excitation in the heart as shown in no prolonged PQ interval of elctrocardiogram, indicates that it may be very useful as a drug for ischemic heart disease, The compound could ~e used as an antihypertensive drug or a peripheral vasodilator ~ecause it has a longlasting and mild a~tih~pertensive action and a dilating action ~or femoral and renal vessels, as well as a desira~le effect on ischemic 2~ heart.
~I~ Oral and Su~lingual Administration The compound prepared according to Example 2 was sub-lingually administered to dogs as a tablet containing 1 - 10 mg of the compound. About 2 minutes after the administration~ cor- '' onary flow was apparently increased~ The compound in a dose le~el of 10 mg showed almost no change in systemic blood pressure, cardiac tension and aortic flow. In contrast, the sublingual administration of a tablet containing the hydrochloride of the acti~e compound did not show any substantial increase in coronary flow~ When the compound prepared according to Example 1 or 2 in . ,' ', ,. , '.
1081~ 4 1 either its free form or hydrochloride was intraduodenally admin-istered in a dose level of 50 ~g/kg or more, an apparent, long-lasting increase in coronary flow was observed, From the test results, the compound of this invention may be used as various preparations, such as for parenteral in-jection; or in the form of capsule, tablet, granule or powder for oral administration or in sublingually administrative form.
In contrast, nitroglycerin is not absorbed through the intestinal wall and, therefore, only sublingual administration is available.
Experiment 3 Adultmongrel dogs which had been anesthetized by the intravenous administration of 30 - 40 mg/kg of pentobarbital sod-ium were subjected to thoracotomy under oxygenic ventilation by the use of Bird's respitator. A catheter was inserted towards a proximal direction into a branch of an origin of the left coron-ary artery and a contrast media such as Conlaxin H ~ or Angio-conrei ~ was injected through the catheter. The morphological change in the left coronary artery was filmed using a 35 mm cine-film before and after the injection of the compound. From the analysis, it was found that the coronary artery was remarkably dilated by the intravenous adminstration of the compound of this invention in a dose level of 100 ~g/kg or more.
Experiment 4 The same preparation as in Experiment 2 was set up using adult mongrel dogs anesthestized by the intravenous administration ; of pentobar~ital sodium. The left anterior descending branch or ci-rcumflex branch of the coronary artery was mechanically stric-tured or occluded in the distal side of the portion attaching the electromagnetic flowmeter probe to experimentally induce cardiac ischemic phenomenon, and then the efEect of the compound of Example 1 on the phenomenon was observed.
.. ; ' . ' , ': .
~ 8944 1 Under incomplete stricture, the coronary flow was slightly increased when the compound of Example 1 was intraven-~usly a~ministered in a dose level of 100 ~g/kg or less, while slightly decreased when administrated in a dose level of more than 250 ~g/kg. After the administration of the compound of this invention, ST elevation of the electrocardiogram in the car-diac ischemic portion was apparently improved and, at the same time, the recovery of ventricular tension in an ischemic part was also observed. Under complete occlusion, the compound did not improve ST elevation or ventricular tension in the midpoint of the ischemic pGrtion, but the improvement in the surrounding point of the ischemic portion was recognized.
Similarly, when the tablet containing 10 mg bf the free form of the compound prepared in Example 2 was sublingually administered, the coronary flow was increased and ST elevation in the electrocardiogram and a reduction inventricular tension . ,, i `were improved.
F~periment 5 ~ A papillary muscle isolated from a guinea pig was set in the organ hath filled with the oxygeni~ed Tyrode's solution ~Ca; 1 8 mM, K: 2,7 mMl at 30 C. One end of the muscle was fixed to the organ bath and the other end was connected to a tension meter by a thread. The effect of the compound of Example 1 on the muscle contraction force was observed by giving electric stimulation (2~V, 5 msec, lHz~ to the muscle with an Ag-AgCl electrode. The antagonistic action of the compound against calcium ion or isoproterenol was also investigated.
From the test results, it was found that the contraction of the papillary muscle induced by the electric stimulation was inhi~ited with the application of the compound of this invention ., : ~ .
10~8944 1 in a concentration level of more than 1 ~g/ml and that calcium ion had antagonistic effect against such inhibitory action. On the other hand, when isoproterenol was applied in a concentration level of 0.08 ~g/ml, the papillary muscle exhi~ited excessive excitement to produce two or more irregular contractions per single electric stimulation. Under this state, the addition of the compound of this invention to the solution in a concentration level of more than 2 ~g/ml inhi~ited the excessive excitement.
~II) A spiral strip isolated from the dog coronary artery was set in the organ ~ath filled with a Ca -free Lock's solution.
One end of the strip was fixed to the organ bath and the other end was connected to a tension meter, The effect of the compound of Example l on the contraction of the strip induced by the polar-ization of the solution with the addition of 43 mM of K and 1 mM
of Ca~+ was investigated.
The test results showed that the contraction induced by K depolarization was inhibited by the compound of this invention and such inhibitary action was diminished by the add-ition of Ca++.
(III~ The effect of Ca on the increase in coronary flow wasinvestigated using the dog anesthetized with pento~arbital sodium according to the same procedure as in Experiment 2-(Ij. The in-crease in coronary 10w induced by the administration of the com-pound of this invention was inhi~ited by a larger dose o Ca +.
(IV~ Taenia coli of a guinea pig was suspended in the organ bath filled with Tyrode's solution and the effect or the compound of Example 1 on the spontaneous contraction and the contraction induced ~y K depolarization was investigated.
The test results showed that the spontaneous contraction and the K depolarization induced contraction were inhi~ited ~y .. . . . . .
.
1~8~?9~
1 application of the co~pound in a concentration level of 2 ~g/ml and such inhibitary action was diminished ~ the addition of Ca Analysis of the test results indicates that the com-pound of the present invention has an antagonistic action to Ca r 50 that the inhibitory action to cardiac contraction the dilating action to smooth muscle of dog coronary artery and the inhibitory action to contraction of taenia coli of guinea pig induced by the application of the c~mpound were antagonized by the addition of Ca~. Further, it was also found that the com-pound of this invention has an antiarrhythmic action because thecompound inhibited the excessi~e excitement of papillary muscle induced ~y the administration of isoproterenol, Experiment 6 The ~lood flow was made insufficient by loading exper-imentally the coronary artery of a dog, for example, ~y strict-uring the coronary artery for a certain period of time, and the ^ , artery was allowed to sustain in this condition. According to this treatment~ its peripheral ~lood pressure and peripheral blood flow repeated periodical and spontaneous fluctuations with-in minutes order period accompanied with ST elevation in electro-cardiogram. This phenomenon was closely similar to the fit of variant angina pectoris in a clinical case, The periodical fluctuation has been proved to ~e caused by the periodical spas-mus in the strictured coronary artery. The effect of the com-pound on such a Yariant angina pectoris model was investigated.
The test results show that the periodical fluctuations -in the coronary ~lood pressure and coronary flow was inhibited ~y the intravenous administration of the compound of Example 1 in a dose level of 25Q ~g/kg or more. That is, the periodical fluctuation in blood flow apparently reduced, and only fine 10~3944 1 fluctuations remained. The effective duration o~ the inhi~itory action ranged from 25 to 40 minutes.
As stated ak,ove, the compound of this invention is ~elievea to ~e effective on the treatment of variant angina pect-oris.
Experiment 7 According to the procedure explained below, the compound of E~ample 1 was subjected to investigate as to whether or not it has an anticoagulative action to platelets, namely antiembolic 1 0 action.
1. Preparation of the test solution 1-1 Adjustment of platelet-rich plasma ~RP solution) A rabbit blood containing 38% sodium citrate (blood:
sodium citrate aqueous solution = 9:1~ was subjected to the cent-rifugation at 1,~00 r.p.m. for 10 minutes, and the supernatant fluid was used as PRP solution.
1-2 Adjustment of an adenosine diphosphate solution (ADP solution) Adenosine diphosphate CSigma Chemical Co., Ltd.) was dissolved in a physiological saline solution at a concentration of 10~ ~g/ml.
1-3 Adjustment o~ collagen suspension - Fifty mg of collagen o~,tained from ~ovine tendon (Sigma Chemical Co., Ltd.,3 was suspended in 5 ml of a physiological saline solution and homogenized by a glassey homogenizer for 5 minutes. Next, it was subjected to centrifugation at 500 r.p.m.
for S minutes, and the supernatant fluid was used as a collagen suspension, 1-4 The compound of Example 1 was dissolved in the physiological saline solution to obtain the test solution, 2. Method of measurement The measurement was performed by the use of Aggrego-meter ~vans Electroselenium htd., Model 169).
PRP solution ~0.5 ml) and the test solution ~0.025 ml) or a physiological saline solution as the control (0.025 ml) were charged into two cuvetts, respectively, and then subjected to incu~ation at 37 C for 2 minutes Further, after 0.025 ml of ADP solution or 0.025 ml of the collagen suspension was added to each cuvette, the e~fect of the compound on platelet aggregation induced by ADP or collagen was measured.
As shown in Figs. 13 and 14, the initial rate of ADP-induced aggregation in the test compound was the same as that in the control/but the test compound accelerated the dissociation of the aggregated platelets. On the other hand, the test c~mpound delayed the onset of the collagen-induced aggregation and made a maximum extent of the aggregation lower than the control. From these results~ the inhibitory effect of the compound on the plate-let aggregation was confirmed, so that the compound of this invention was also found to be useful as an anticoagulant.
E~periment 8 By the same method as disclosed in Experiment 2, item 5, change in systemic blood pressure when test compounds were intraYenously administered was measured. The results obtained are shown in the follo~ing Ta~le.
TABLE
.. _ _ Test Compound Dose Percent Change Duration C~s/kgl of S.B.P. ~1 ~in.) . .
Compound of E~ample 50 16 22 Compound of Example 50 20 17 Nitroglycerin 50 45 8 . . . ....
, ~. ' ' ", ' '.
8894~
Example 1 To a mixture of 5 g of sodium hydrogen car~onate, 15 ml of water, 1.69 g of the nitric ester of monoethanolamine nitrate and 20 ml of chloroform was added slowly 2.5 g of nicotinyl chloride hydrochloride o~er 10 to 30 minutes under stirring at 0 to 5C, The stirring was continued for an additional 30 min- ~-utes and then the chloroform layer was separated. The remained aqueous layer was extracted with chloroform and the extract was com~ined with t~e separated chloroform layer. The organic layer was washed with a potassium carbonate aqueous solution, dried oYer anhydrous sodium sulfate-and evaporated under reduced pres- '' sure to dryness. The residue was dissolved in ether-isopropanol ~ and then hydrogen chloride was ~u~led into the solution ' ~, under cooling to give 2.35 ~ of the nitric ester of N-~2-hydroxy-ethyl~ nicotinamide hydrochloride. Recrystallization from ethan- ' ol afforded colorless needle"crystals having a melting point of 132C.
Anal~sis:
Calcd. for C8HloN304Cl: C,38.80; H, 4~07; N, 16.96 (%~
Found C,38~89,-; H, 4.02; N, 16.72 (~) IR~cm ~
NH, 3255; CoO~ 166~; ON02, 1640 Ex:ample 2 To a solution of 1.69 g of the nitric ester of mono-ethanolamine in 20 ml of pyridine ~as added slowly 2.5 g of ni-cotinyl chloride hydrochloride over ln to 30 minutes under stirring at 5C. After stirring for an additional 30 minutes, the xeaction mixture was evaporated to dryness. The residue was "
dissolved in chloroform and the solution was washed with a sod-iumi hydrogen car~onate aqueous solution. The organic layer was , :
:. ~, ' 1()~894~4 1 separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. The residue was chromato-graphed on silica gel ~Takogel C-200; Wako Pure Chemical Indust-ries, Ltd., Japan) and eluted with ~enzene-ethanol (5:1). The eluent was evaporated to a semi-solid mass which was crystall-ized from diethyl ether to gi~e 1.97 g of the nitric ester of N-~2-h~dxox~rethyllnicotinamide~
Recrystallization of the crystals from diethyl ether-ethanol afforded colorless needles having a melting point of 9210 to 23C.
E~ample 3 A solution of 10 g of the nitric ester of N-~2-hydroxy-ethyl~ nicotinamide hydrochloride in water was neutralized with a sodium hydrogen carhonate aqueous solution. The solution was e~tracted with chloroform and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness.
The residue was crystallized from diethyl ether to give 7 g of the nitric ester of N-C2-hydrQxyethyl) nicotinamide. Recrystall-ization fro~ isopropanol-diethyl ether gave colorless needles ha~in~ a melting point of ~3C, IR ~m~l~
NH~ 3250, ONO2, 1630 Example 4 To a mixture of 1.6~ g of the nitric ester of mono-ethanolamine nitrate in 5 ml of water~ 3.8 ml of 35~ potassium carbonate solution and 17 ml of tetrahydrofuran were added alter-nately 3 g of isonicotinyl chloride hydrochloride and 11~2 ml of 35% potassium car~onate aqueous solution over 30 minutes under stirring at Q to 5C The reaction mixture was stirred for an - 30 additional 15 minutes, and the organic layer was separated. The lV~39~4 1 aqueous layer was extracted with tetrahydrofuran and the extrac~
was combined with the previously separated organic layer. The combined organic layers were dried over anhydrous sodium sul-fate and filtered. Evaporation of the solvent in vacuo and crystallization of the residue aforded the nitric ester of N-~2-hydroxyethyl) isonicotinamide.
The product was dissolved in diethyl ether and the dropwise addition of diethyl ether-fuming nitric acid under cooling gave 1.5 g of the nitric ester of N-~2-hydroxy-ethyl) isonicotinamide nitrate. Recrystallization from isopropanol afforded the crystals having a melting point of 105C ~decomposi-tion~.
Analysis:
8 10N407: C, 35.04; H, 3i68; N 20 43 (%) Found: C, 35.00; H, 3.59; N, 20.38 (~
IR~m~
- NH~ 328~; C=0, 1671; ON02, 1625 Example 5 To a mixture of 1.83 g of the nitric ester of isopropan-20 olamine nitrate in 5 ml of water, 3.8 ml of 35% potassium carbon-ate aqueous solution and 17 ml of tetrahydrofuran were added alternately 3 g of nicotinyl chloride hydrochloride and 11.2 ml of 35% potassium carbonate solution over 30 minutes under stirring at Q to 5C. The reaction mixture was stirred for an additional 15 minutes and the organic layer was separated. The aqueous layer was extracted with tetrahydrofuran and the extract was com- ;
~ined with the previously separated organic layer. The combined extracts were dried over anhydrous sodium sulfate and filtered.
E~aporation of the solvent under reduced pressure and crystall-ization of the residue gave the nitric ester of N-(2-hydroxypropyl) nicotinamide.
-22~
. .
- . ' '. ' , ,,;: ', ' " .. '.
08~9~4 The product was dissolved in acetone and then hydrogen chloride was bubbled into the solution to give 1.5 g of the nit-ric ester o~ N- (2-hydroxypropyl~ nicotinamide hydrochloride as colorless crystals. (mp: 161C (decomposition)).
Analysis:
Calcd- for C~H12N3O4Cl: C, 41,31; H, 4.62; N, 16.06 (~) Found : C, 41.38; H, 4.60; N, 16.11 (~) IR ~cm 11:
NH, 323Q; C=O, 1672; ONO2, 1620 Example 6 By the procedure similar to that of Example 4~ nico-tinyl chloride hydrochloride was reacted with nitric ester of propanol amine nitrate to o~tain nitric ester of N-(3-hydroxy- ~
propyl~ nicotinamide hydrochloride. ~Yield: 75%; mp: 127C -(decQmposition~
Analysis:
, . . -Calcd, for C~H12N3O4Cl: C, 41,31; H, 4.62; N, 16.06 (%) Found : C, 41,40; H, 4.53; N~ 16~15 (~) NH, 3235; C=O~ 1672; ONO2, 1617 ;
F~xa~le 7 By the procedure similar to that of Example 4, isonico-tin~l chloride hydrochloride was reacted with nitric ester of propanolamine nitrate to o~tain nitric ester o~ N~(3-hydroxy-propyll iæonicotinamide hydrochloride. (Yield: 72~, mp: 125C
~decomposition~.
Analysis:
Calcd- for CqH12N304Cl C, 41,31; H, 4.62; N, 16.06 (%) Found : C, 41.40; H, 4.58; N, 16.01 (%) IR (cm 12;
NH, 3230; C=O, 1672, ONO2, 1615 , . . . .
~l088~44 1 Example 8 By the procedure similar to that of Example 4, pico-linyl chloride hydrochloride was reacted with nitric ester of monoethanolamine nitric acid salt to obtain nitric ester of N-C2~hydrQxyethyl~ picolinamide~ (Yield: 78%, mp: 55 - 56C) Analysis:
Calcd, for C~HgN304: C, 45.5Q; H, 4~29; N, 19.89 ~) Found ; C~ 45.25; H, 4~10; N, 19.17 (~) IR ~cm-l~
NH, 3362; C=0, 1665; ON02, 162Q
Example ~ -By the procedure similar to that of Example 4, nico-tin~l chloride hydrochloride was reacted with 2,3-hydroxypropyl-amine to obtain dinitric ester of N- ~,3-di-hydroxypropyl) nico-tinamide as pale-yello~ oil.
Example lQ
, - N-C2-hydro~yethyl~ nicotinamide nitrate ~1.145 g) was gradually added to 3 ~1 of fuming nitric acid which had been ~ooled to a temperature of from -lQ to -5C while stirring.
~0 After stirrin~ for additional one hour at 0 - 5C, diethyl ether was added to the solution to precipitate 1.15 g of nitric ester of N- ~-hydrQxyethyl~ nicotinamide nitric acid ester as colorless crystals. The crystaIs were dissolved in a sodium carbonate aqueous solution and ethyl acetate was added to the solution.
The ethyl acetate layer was separated, dried over sodium sulfate and evaporated under reduced pressure~ The residue was crystall-ized from diethyl ether to give nitric ester of N-12-hydroxyethyl) nicotinamide~ Recrystallization from diethyl ether afforded colorless crystals havin~ a melting point of 90 - 92C.
, . . . .
.,: .
:
nalysis:
Calcd. for C8HgN3O4 C, 45.50; H, 4.29; N, 19.89 (~) Found : C, 45.37; H, 4.09; N, 19.71 (~) Example 11 By the procedure similar to that of Example 10, N-~2-hydroxyethyl)isonicotinamide nitrate was reacted with fuming nitric acid to obtain nitric ester of N-(2-hydroxy-ethyl) iso-nicotinamide nitrate. (Yield: 76%, mp: 105C (decomposition)).
Analysis:
Calcd, for C8HloN4O7: C, 34.04; H, 3.68; N, 20.43 (~) Found : C, 35.11; H, 3.57; N, 20.34 (~) Example 12 ~harmaceutical Preparation~
- a~ Su~lingual Tablet Compound prepared according 5 mg to Example 2 Lactose 19.7 mg Mannitol 25 mg Magnesium Stearate 0.3 mg Total 50 mg/
tablet The ingredients were uniformly blended in the propor-tions described above and the mixture was formed inta,tablets, each tablet ~eing 5 mm in diameter and 50 mg in weight.
bL Table for Internal ~se Compound prepared according 10 mg to E~ample 1 Lactose 44.5 mg Corn Starch 20 mg Crystalline Cellulose 25 mg Magnesium Stearate 0.5 mg Total 100 mg/
tablet ~1088S~4 The ingredients were uniforml~ ~lended in the propor-tions described a~oYe and the mixture was formed into tablets, each ka~let ~eing 7 mm in diameter and 100 mg in weight.
c) Hard Capsules Compound prepared according20 mg to Example 2 Lactose 176 mg Magnesium Stearate 4 mg Total 200 mg/capsule - The ingredients were uniformly ~lended in the propor-tions descri~ed a~ove and hard capsules each being identified as No. 3 were filled with 200 mg each of mixture ~y a packing machine to form capsules each weighing 250 mg.
d2 Granules Compound prepared according10 mg to Example 2 Lactose 710 mg Paste of Cornstarch 280 mg -Total 1,000 mg/wrapper The ingredients were uniformly kneaded and then gran-ulated to form granules, each granule having a diameter of about 1 ~n.
e~ Parenteral Injection Compound prepared according5 mg to Example 2 Mannitol 50 mg Total 55 mg/vial The ingredients were dissolved in 1 ml of distilled water and the solution was sterilized and filtered. The solution 30 was filled in a vial andfreeze-dried and the vial was sealed to ;
form a parenteral injection. Thefreeze-dried mixture was dissolved in 1 ml of distilled water when it is used as parenteral injection.
. :
- . . . .
... ' : . , :, . . .
88s~
SUPPLEMENTARY DISCLOSURE
The applicants have conducted comparative tests with the nitric ester of N- (2-hydroxyethyl)nicotinamide (hereinafter, the compound of this invention) and the nitrate of the acid dinitrooxydiethyl amide nicotinate as disclosed in the prior art reference, namely, United States Patent Number 3,036,074, which issued on May 22, 1962 to Stieglitz et al (hereinafter, the reference)O
Figure 15 is a graph showing the percent increase in coronary blood flow when the compound of the present invention used in the comparative tests was administered and when the compound of the reference was administered.
Figure 16 is a graph showing the duration of increase in coronary blood flow when the compound of the present invention used in the comparative tests was administered and when the compound of the reference was administered.
Figure 17 is a graph showing the degree of drop of the systemic blood pressure induced by the administration of the compound of the-present invention used in the comparative tests and when the compound of the reference was used.
Figure 18 is a graph showing the change in heat rate after the administration of the compound of the present invention used in the comparative tests and when the compound of the reference was used.
Figure 19 is a graph showing the change in coronary blood flow under stricturing of the coronary artery after the administration of the compound of the present invention used in the comparative tests and when the compound of the reference was used.
`" 1~i~894~
1 Comparative Test:
Nitric ester of N-(2-hydroxyethyl)nicotinamide was compared in pharmacological activity with the nitrate of the acid dinitrooxydiethyl amide nicotinate disclosed in the prior art reference, United States Patent 3,036,074.
Experiment In accordance with the methods illustrated in Experiment 2, Items 1, 5 and 6, except that beagle dogs which had been anesthetized by the intravenous administration of 30 - 40 mg/kg of pentobarbital sodium were used as *est animals, the change of coronar~ blood flow (CBF), systemic blood pressure (SBP) and heart rate were measured upon administrating the compound of this invention or the compound of the reference.
Further, in accordance with the methods disclosed in Experiments
4 and 6, the effects of both compounds upon the change of coronary blood flow under stricturing of the coronary artery and upon the variant angina pectoris model were measured.
Results a) Change in coronary blood flow (CBF~:
The increase in CBF and the duration of increase in CBF by the administration of the compound of this invention or the reference are shown in Fig. 15 and Fig. 16, respectively.
The intravenous administration of the compound of this invention even in a dose of 20 ~g/kg showed a significant increase in coronary flow. Further, the effect of the compound -of this invention on the increase in coronary blood flow was significantly superior to the effect of the compound of the reference with respect to each different dose.
Similarly, the intravenous administration of the compound of this invention in a dose of 100 pg/kg showed a duration of action of over 20 minutes, while the duration of ~: , . . .
1~88S~ 4 1 action given by the intravenous administration of the compound of the reference is remarkably short. Thus, the differences in their action are significant.
b) Change in systemic blood pressure (SBP):
AS shown in Fig. 17, the degree of drop of the systemic blood pressure induced by the administration of the compound of this invention was lower than that of the compound of the reference.
c) Change in heart rate (HR):
As shown in Fig. 18, the heart rate showed almost no change by the administration of the compound of this invention, while it was remarkably increased by the administra-tion of the reference compound.
- d) Change in coronary blood flow under stricturing of coronary artery:
As shown in Fig. 19, coronary flow showed an increase by the intravenous administration of the compound of this invention, but,~in contrast, it showed a drop by the admini-stration of the reference compound.
e) Effects of the compound on variant angina pectoris:
The intravenous administration of the compound of this invention in a dose of more than 150 ~g/kg had an inhibiting effect on abnormal change in electrocardiogram (ST-elevation) and on the periodical ~luctuation in the coronary blood flow. In contrast, the intravenous administration of the reference com-pound even in a dose of 300 ~g/kg showed no such inhibiting effect.
Discussion:
In general, the pharmacological activities required as an anti-anginal drug which is the subject of this invention ~lO~389~4 1 are to increase the coronary blood flow over a prolonged period of time without significantly changing the heart rate and blood pressure. From these viewpoints, the compound of this invention is, as shown in the test results a), b) and c) described above, far superior in the activity required for an antianginal drug to the compound disclosed in the reference.
Further, in the tests using pathological models, particularly, in the test using a variant angina pectoris model by stricturing the coronary artery, the compound of this invention showed excellent effects although no significant effects were seen with use of the reference compound.
--~0--:
Results a) Change in coronary blood flow (CBF~:
The increase in CBF and the duration of increase in CBF by the administration of the compound of this invention or the reference are shown in Fig. 15 and Fig. 16, respectively.
The intravenous administration of the compound of this invention even in a dose of 20 ~g/kg showed a significant increase in coronary flow. Further, the effect of the compound -of this invention on the increase in coronary blood flow was significantly superior to the effect of the compound of the reference with respect to each different dose.
Similarly, the intravenous administration of the compound of this invention in a dose of 100 pg/kg showed a duration of action of over 20 minutes, while the duration of ~: , . . .
1~88S~ 4 1 action given by the intravenous administration of the compound of the reference is remarkably short. Thus, the differences in their action are significant.
b) Change in systemic blood pressure (SBP):
AS shown in Fig. 17, the degree of drop of the systemic blood pressure induced by the administration of the compound of this invention was lower than that of the compound of the reference.
c) Change in heart rate (HR):
As shown in Fig. 18, the heart rate showed almost no change by the administration of the compound of this invention, while it was remarkably increased by the administra-tion of the reference compound.
- d) Change in coronary blood flow under stricturing of coronary artery:
As shown in Fig. 19, coronary flow showed an increase by the intravenous administration of the compound of this invention, but,~in contrast, it showed a drop by the admini-stration of the reference compound.
e) Effects of the compound on variant angina pectoris:
The intravenous administration of the compound of this invention in a dose of more than 150 ~g/kg had an inhibiting effect on abnormal change in electrocardiogram (ST-elevation) and on the periodical ~luctuation in the coronary blood flow. In contrast, the intravenous administration of the reference com-pound even in a dose of 300 ~g/kg showed no such inhibiting effect.
Discussion:
In general, the pharmacological activities required as an anti-anginal drug which is the subject of this invention ~lO~389~4 1 are to increase the coronary blood flow over a prolonged period of time without significantly changing the heart rate and blood pressure. From these viewpoints, the compound of this invention is, as shown in the test results a), b) and c) described above, far superior in the activity required for an antianginal drug to the compound disclosed in the reference.
Further, in the tests using pathological models, particularly, in the test using a variant angina pectoris model by stricturing the coronary artery, the compound of this invention showed excellent effects although no significant effects were seen with use of the reference compound.
--~0--:
Claims (30)
1. A process for preparing a nitric ester of N-(2-hydroxyethyl)nicotinamide of the formula (I) (I) or a pharmaceutically acceptable salt thereof, which comprises a process selected from the group of processes consisting of:
(a) reacting a compound of the formula (II) (II) or its functional derivative at the carboxyl group, with a compound of the formula NH2 - CH2CH2 ONO2 (III) or its functional derivative at the amino group; and (b) reacting a compound of the formula (IV) (IV) with a nitrating agent.
2. A nitric ester of N-(2-hydroxyethyl)nicotinamide of the formula (I)
(a) reacting a compound of the formula (II) (II) or its functional derivative at the carboxyl group, with a compound of the formula NH2 - CH2CH2 ONO2 (III) or its functional derivative at the amino group; and (b) reacting a compound of the formula (IV) (IV) with a nitrating agent.
2. A nitric ester of N-(2-hydroxyethyl)nicotinamide of the formula (I)
Claim 2 continued ......
whenever prepared by the process as claimed in claim 1 or an obvious chemical equivalent thereof.
whenever prepared by the process as claimed in claim 1 or an obvious chemical equivalent thereof.
3. A process for preparing a nitric ester of N-(2-hydroxy-ethyl)nicotinamide of the formula (I) as defined in claim 1 which comprises the process as set forth in claim 1(a).
4. A nitric ester of N-(2-hydroxyethyl)nicotinamide of the formula (I) as defined in claim 1 whenever prepared by the process as claimed in claim 3 or an obvious chemical equivalent thereof.
5. A process for preparing a nitric ester of N-(2-hydroxy-ethyl)nicotinamide of the formula (I) as defined in claim 1 which comprises the process as set forth in claim 1(b).
6. A nitric ester of N-(2-hydroxyethyl)nicotinamide of the formula (I) as defined in claim 1 whenever prepared by the process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 1(a) wherein the functional derivative of the compound II as defined in claim 1 is an acid halide, an active amide, an acid anhydride or an active ester thereof.
8. A process as claimed in claim 7 wherein said reaction is carried out at a temperature of from about -10°C to about 50°C for about 1/2 to about 4 hours.
9. A process as claimed in claim 8 wherein said process is carried out at a temperature of from about 0°C to about 10°C.
10. A process as claimed in claim 7 wherein said reaction is carried out in water or in an organic solvenk selected from the group consisting of benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, chloroform, methylene chloride, acetonitrile, acetone, carbon tetrachloride and ethyl acetate.
11. A process according to claim 7 wherein said reaction was carried out in the presence of an inorganic basic substance selected from the group consisting of potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, sodium hydroxide, calcium acetate, and calcium carbonate; or an amine compound selected from the group consisting of pyridine, triethylamine, dimethylaniline and picoline.
12. A process according to claim 1 wherein said functional derivative of the compound (II) in the process of claim l(a) is selected from the group consisting of the compound (II) activated by the reaction with phosphorous trichloride, methyl chlorophosphite or ethyl chlorophosphite.
13. A process as claimed in claim 12 wherein said reaction is carried out in a neutral solvent selected from the group consisting of benzene, toluene, xylene, dioxane and tetrahydro-furan.
14. A process as claimed in claim 13 wherein said reaction is carried out at a temperature of from room temperature to the reflux temperature of the solvent used for 1/2 to 3 hours.
15. A process as claimed in claim 13 wherein said reaction is carried out in the presence of an amine compound selected from the group consisting of pyridine, triethylamine, dimethyl-aniline and picoline.
16. A process as claimed in claim 12 wherein said reaction is carried out in an organic basic solvent selected from the group consisting of pyridine, triethylamine, dimethylaniline and picoline.
17. A process as claimed in claim 1 wherein said process of claim 1(a) is carried out in the presence of an amide-formation accelerator selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino-ethylcarbodiimide, N,N'-diethylcarbodiimide, diphenylketene-N-cyclohexylimine, pentamethyleneketene-N-cyclohexylimine, tri-ethyl phosphite, ethyl polyphosphate and isopropyl polyphosphate.
18. A process as claimed in claim 17 wherein said reaction is carried out in an inert solvent selected from the group con-sisting of benzene, toluene, tetrahydrofuran, chloroform, methylene chloride and acetonitrile.
19. A process as claimed in claim 18 wherein said reaction is carried out at a temperature of from room temperarure to the reflux temperature of the solvent used.
20. A process as claimed in claim 1 wherein said process of claim 1(b) is carried out by the use of fuming nitric acid or nitryl chloride as a nitrating agent.
21. A process as claimed in claim 1 wherein said process of claim 1(b) is carried out in an inert solvent selected from the group consisting of chloroform and dichloromethane.
22. A process as claimed in claim 1 wherein said process of claim 1(b) is carried out at a temperature of from about -5°C to about room temperature for about 1 to about 3 hours.
23. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 7 or or an obvious chemical equivalent thereof.
24. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 9 or 10, or an obvious chemical equivalent thereof.
25. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 11 or 12, or an obvious chemical equivalent thereof.
26. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 13 or 14, or an obvious chemical equivalent thereof.
27. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 15 or 16, or an obvious chemical equivalent thereof.
28. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 17 or 18, or an obvious chemical equivalent thereof.
29. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 19 or 20, or an obvious chemical equivalent thereof.
30. A compound of the formula (I) as defined in claim 1 whenever prepared by the process as defined in claims 21 or 22, or an obvious chemical equivalent thereof.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36101/1976 | 1976-04-02 | ||
| JP51036101A JPS5817463B2 (en) | 1976-04-02 | 1976-04-02 | Nicotinic acid amide derivatives |
| JP82458/1976 | 1976-07-13 | ||
| JP8245876A JPS6052685B2 (en) | 1976-07-13 | 1976-07-13 | Cardiovascular disease treatment |
| JP83522/1976 | 1976-07-15 | ||
| JP8352276A JPS539775A (en) | 1976-07-15 | 1976-07-15 | Pyridine derivatives and their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088944A true CA1088944A (en) | 1980-11-04 |
Family
ID=27288973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA274,696A Expired CA1088944A (en) | 1976-04-02 | 1977-03-24 | Nitric ester of n-(2-hydroxyethyl)nicotinamide and a process for the preparation of same |
Country Status (13)
| Country | Link |
|---|---|
| AR (2) | AR217423A1 (en) |
| AT (1) | AT360532B (en) |
| AU (1) | AU509591B2 (en) |
| CA (1) | CA1088944A (en) |
| CH (1) | CH633535A5 (en) |
| DE (1) | DE2714713C3 (en) |
| DK (1) | DK145608C (en) |
| ES (2) | ES457421A1 (en) |
| FI (1) | FI66598C (en) |
| FR (1) | FR2346334A1 (en) |
| MX (1) | MX5534E (en) |
| NL (2) | NL176674C (en) |
| SE (1) | SE436029B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU579431B2 (en) * | 1984-12-17 | 1988-11-24 | Chugai Seiyaku Kabushiki Kaisha | Method for production of stable nicorandil preparation |
| WO2010000673A1 (en) * | 2008-07-01 | 2010-01-07 | Politechnika Lódzka | N'-nitroxyalkylnicotinamides for the treatment of cardiovascular diseases |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223811A1 (en) * | 1985-05-22 | 1987-06-03 | Beecham Group Plc | Use of nicorandil or pinacidil for the treatment of peripheral vascular disease |
| WO1989010757A1 (en) * | 1988-05-10 | 1989-11-16 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis | New ophthalmic preparation for treating glaucoma |
| US4973565A (en) * | 1989-07-17 | 1990-11-27 | Corning Incorporated | Fluoroborosilicate glass and clad article |
| ZA91291B (en) * | 1990-01-16 | 1991-09-25 | Hoechst Ag | Di(nitroxyalkyl)amides of pyridine-2,4-and-2,5-dicarboxylic acids,a process for the preparation thereof,and the use thereof |
| AU4841700A (en) | 1999-05-12 | 2000-11-21 | Nitromed, Inc. | Nitrosated and nitrosylated potassium channel activators, compositions and methods of use |
| IT1403890B1 (en) | 2010-12-28 | 2013-11-08 | Procos Spa | NICORANDIL PRODUCTION PROCESS |
-
1977
- 1977-03-23 DK DK128277A patent/DK145608C/en not_active IP Right Cessation
- 1977-03-23 AU AU23532/77A patent/AU509591B2/en not_active Expired
- 1977-03-24 CA CA274,696A patent/CA1088944A/en not_active Expired
- 1977-03-30 MX MX559377U patent/MX5534E/en unknown
- 1977-03-31 ES ES457421A patent/ES457421A1/en not_active Expired
- 1977-04-01 AR AR26709977A patent/AR217423A1/en active
- 1977-04-01 CH CH415377A patent/CH633535A5/en not_active IP Right Cessation
- 1977-04-01 FI FI771024A patent/FI66598C/en not_active IP Right Cessation
- 1977-04-01 DE DE19772714713 patent/DE2714713C3/en not_active Expired
- 1977-04-01 SE SE7703868A patent/SE436029B/en not_active IP Right Cessation
- 1977-04-04 FR FR7710119A patent/FR2346334A1/en active Granted
- 1977-04-04 NL NL7703624A patent/NL176674C/en not_active IP Right Cessation
- 1977-04-04 AT AT235077A patent/AT360532B/en not_active IP Right Cessation
-
1978
- 1978-02-20 AR AR27116278A patent/AR220907A1/en active
- 1978-03-31 ES ES468462A patent/ES468462A1/en not_active Expired
-
1993
- 1993-05-28 NL NL930042C patent/NL930042I2/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU579431B2 (en) * | 1984-12-17 | 1988-11-24 | Chugai Seiyaku Kabushiki Kaisha | Method for production of stable nicorandil preparation |
| WO2010000673A1 (en) * | 2008-07-01 | 2010-01-07 | Politechnika Lódzka | N'-nitroxyalkylnicotinamides for the treatment of cardiovascular diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| ATA235077A (en) | 1980-06-15 |
| NL7703624A (en) | 1977-10-04 |
| DE2714713A1 (en) | 1977-10-20 |
| MX5534E (en) | 1983-09-27 |
| AR220907A1 (en) | 1980-12-15 |
| ES468462A1 (en) | 1979-10-01 |
| ES457421A1 (en) | 1978-11-16 |
| FI66598B (en) | 1984-07-31 |
| DK145608C (en) | 1983-07-11 |
| NL176674B (en) | 1984-12-17 |
| AU2353277A (en) | 1978-09-28 |
| FR2346334A1 (en) | 1977-10-28 |
| FR2346334B1 (en) | 1980-02-01 |
| FI66598C (en) | 1984-11-12 |
| CH633535A5 (en) | 1982-12-15 |
| SE7703868L (en) | 1977-10-03 |
| AU509591B2 (en) | 1980-05-15 |
| AT360532B (en) | 1981-01-12 |
| NL930042I1 (en) | 1993-08-02 |
| DK145608B (en) | 1982-12-27 |
| NL930042I2 (en) | 1993-09-16 |
| FI771024A (en) | 1977-10-03 |
| SE436029B (en) | 1984-11-05 |
| DE2714713C3 (en) | 1980-10-16 |
| DK128277A (en) | 1977-10-03 |
| NL176674C (en) | 1985-05-17 |
| AR217423A1 (en) | 1980-03-31 |
| DE2714713B2 (en) | 1980-02-21 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |