JPS61204183A - Cardiac stimulant 1,6-naphthylidine-2(1h)-ones and manufacture - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides L6-naphthyridine-2 (I
H)-ones, processes for their preparation, intermediates, and the use of intermediates in said processes.

Prior Art U.S. Pat. No. 4,415,580 describes 5-(lower alkyl)-L6-naphthyridin-2(IM)-ones (I) and 5-(lower alkanoyl)-6-methyl-2(1) as cardiotonic agents. )1)-Viridinone is reacted with di(lower alkyl)formamidine)acetal to form 5-(lower alkanoyl)
-6-[2-(di-lower alkylamino)ethynyl)-2
Discloses a process for preparing (IH)-pyridinone (II) and their preparation by reacting compound (If) with formamidine or ammonia or a salt thereof to produce compound TI)t-.

Po1 of Czuba et al.
゜J, Chem, ) 52.236 '1-76 (1
978) is 4-bromo-L6-sutyridin-2(IH)-one and 4-hydrazino-L6 as intermediates.
-naphthyridin-2(IB)-one is disclosed. This document also describes 2-4-dibromo-L6-naphthyridine.
4-bromo-L6 by heating with 0 thihydrobromic acid
-naphthyridin-2(IH)-one and 4-hydrazino-L6 by heating 4-bromo-L6-naphthyridin-2(IH)-one with hydrazine
- Discloses the preparation of naphthyridin-2(1)1)-one.

Journal of Heterocyclic Chemistry ('J,
Heter.

cyclic Chem,) 2 (4L 393~
13 (1965) discloses the synthesis of various 4-substituted-L6-naphthyridines and their NMR spectra, for example, reacting 4-hydroxy-L6-naphthyridine with POBr3 and POCfL3 to form 4-
Bromo-L6-naphthyridine or 4-chloro-L6-
It has been shown to produce naphthyridine.

Furthermore, 4-dimethylamino-L6- by reacting 4-bromo-L6-naphthyridine with dimethylamine
Discloses the production of naphthyridine and the production of 4-(1-piperidinyl)-L6-naphthyridine or 4-hydrazino-L6-naphthyridine by reacting 4-chloro-L6-naphthyridine with piperidine or hydrazine.

U.S. Pat. No. 3,993,656 discloses substituted 58-7thyrin-2(lti)-ones of yuzu, such as 6-(2-imidazolyl)-58-naphthyridin-2, which have bronchodilatory and hypotensive effects. (LH)-one and its preparation from 2-amino-6-(2-imidazolyl)-L8-su7tyridine.

Structure of the Invention The present invention relates to the formula I: [wherein R is a hydrogen atom, halogen or a lower alkyl group; R' is a hydrogen atom or a methyl group; R1
is a hydrogen atom, a lower alkyl group, a hydroxymethyl group, a halogen, a trifluoromethyl group, a nitro group, or a phenyl group; Z is N, C-H.

C-C lower fulkyl), C-halogen, C-hydroxymethyl or C-phenyl; and Y is N, C
-H, C-halogen, C- (lower alkyl) or C-
5-(IH-(5-membered-heteryl-aromatic heteryl)-1-yl)-7-R'-1,6- The present invention relates to naphthyridin-2'(IH)-ones and acid addition salts and cation salts thereof. Compounds of Formula ■ are useful as cardiotonic agents when tested by standard pharmacological evaluation methods.

A cardiotonic composition for increasing cardiac contractility comprises a pharmaceutically acceptable carrier and, as the active ingredient, an inotropic amount of 5-(IH-(5-membered-heteryl)-1-yl) of formula I.
-7-1('-L6-naphthyridine-2(ll'i)-
or a pharmaceutically acceptable acid addition salt or cation salt thereof.

Increasing cardiac contractility is associated with the use of 5-(1kl-(5-membered-N-hetyryl)-) of formula I in inotropic amounts in solid or liquid excision in patients in need of this treatment. 1-yl)-7-R'-1,6-naphthyridine-2(11-one or a pharmaceutically acceptable acid addition salt or cationic salt thereof fm can be administered orally or parenterally. be.

The present invention also provides the formula ■: ■ five (wherein X is bromo, chloro or hydrazino group;
5-X-7-1 ('-1,6-naphthyridine-2(l
i-I)-ones or pharmaceutically acceptable acid addition salts or cationic salts thereof. Compounds of Formula ■, where X is bromo or chlor, are useful as cardiotonic agents when tested by standard pharmacological methods and, like compounds of Formula I, may be used in cardiotonic compositions to increase cardiac contractility. It is also useful as an intermediate for the production of the compound of formula 1 above, and when used as an intermediate, compounds in which X is bromo are preferred. A compound of formula (3) in which X is a hydrazino group is useful as an intermediate for the production of a compound of formula I (wherein Y is N, Z is ch, and R' is a hydrogen atom or a methyl group). be.

The present invention also provides 2-(2-(di-lower alkylamino)-1-
zorobenyl]-6-medoxy-3-pyridinecarbonitrile or an acid addition salt thereof. Reacting 2-(2-(di-lower alkylamino)-1-zrobenyl]-6-medoxy-3-pyridinecarbonitrile with hydrogen bromide or hydrogen chloride produces 5-(bromo or chloro)-2-methoxy-7 -Methyl-L6-naphthyridine-2(11(
)-on can be produced.

DESCRIPTION OF PREFERRED EMBODIMENTS Intermediates for the preparation of compounds of formula I are of the formula ■: where X is a bromo, chloro or hydrazino group;
5-X-7-1('-1,6-naphthyridine-2(1)
1) -ones. Compounds of formula (1) suitable as intermediates are those in which X is bromine and R' is a hydrogen atom or a methyl group. Formula ■ where X is human 9radino group
are useful as intermediates for the preparation of compounds of formula I, where Y is N and 2 is C-H.

A compound of formula ■ (where X is bromo or chloro and R
/ is a hydrogen atom) The intermediate for producing L6-sihydro-2-(2-(di-lower alkylamino)ethynyl-6- Oxo-3-pyridinecarbonitrile or an acid addition salt thereof.

Hydrogen bromide or hydrogen chloride and L6- of formula ■:) hydro-2
The reaction with -[2-(di-lower alkylamino)ethynyl]-6-oquine-3-pyridinecarbonitrile is the reaction with 5-(bromo or chloro)-7-R'-1,6-7 of formula
This produces tyridin-2(IH)-one (where X is bromo or chloro and R/ is a hydrogen atom).

Compounds of the formula... (where X is bromo or chlorine, R
The intermediate for producing 2-a: 2-(2-(di-lower alkylamino)-1-, in which R2 and R3 are each a lower alkyl group) is a
[propenyl]-6-medoxy 3-2 lysine carbonitrile or an acid addition salt thereof.

The reaction of 6-medoxy 2-methyl-3-pyridinecarbonitrile with N,N-(di-lower alkyl)acetamide dimethyl acetal produces 2-[2-(di-lower alkylamino)-1-propenyl]-6 of formula 111a. - reaction of a compound of formula lea with hydrogen bromide or hydrogen chloride to produce medoxy 3-pyridine carbonitrile and subsequent reaction of the resulting 5-(bromo or chloro)-2-methoxy 7
-Methyl-1,6-naphthyridine-2(11()-)-methyl-1,6-naphthyridine-2(11()-
Generate on.

5-bromo (or chloro)-7-R'-t, 6-naphthyridin-2(lfi)-one and formula ■:■ (wherein Y%Z%R', R□ and R are defined in formula I 1l-1- (5-membered -N-
The reaction with a 5-(IH aromatic)heteryl compound of formula I
-(5-membered-N-aromatic heteryl)-1-yl] -7-
R'-1,6-su7tyridin-2(IH)-one is produced.

R6-hydro-2-methyl-6-oxo-3-pyridinecarbonitrile and 2V: (l(2R3N)2CH
Bis(di-lower alkylamino)-t of OC(CH3)3
- The reaction with Zutkin methane is R6-dihyto1O of formula (■)
-2-(2-(di-lower alkylamino)ethynyl]-6
-Produces oxo-3-pyridinecarbonitrile.

Br i or Cfl and R' is a hydrogen atom or a methyl group) and hydrazine (especially hydrazine hydrate) can be reacted with the corresponding 5-hydrazino-7-R'-1,6-
Naphthyridin-2(IM)-one (in the formula 1, X is a hydrazino group, and R' is a hydrogen atom or a methyl group)
f! : Generate.

5-hydrazino-7-R'-1,6-naphthyridine-2
(lfi)-one (in the formula ①, X is a hydrazino group, R
' is a hydrogen atom or a methyl group) and LLa3-tetramethquine propane.
IH)-one (in formula I, Y is N, 2 is C-H, R' is a hydrogen atom or a methyl group, and Ro and R are each a hydrogen atom).

Preferred compounds of formula (2) are those in which Z is N, R and R are each a hydrogen atom or a methyl group, and R' is a hydrogen atom, and Y is C1 (; or Z is CH and R ' is a hydrogen atom, and when R and R are each a hydrogen atom, Y is N; or R', R
When 1 and R are each a hydrogen atom, Y and 2 are each N.

1 As used herein, the term lower alkyl group 1 (e.g. the meaning for R or R1 in formula I, the meaning for C-(lower alkyl) in 2 or Y of formula I, or the meaning for R2 in formula 111, In& and or meaning of R3)
means an alkyl group having 1 to 4 carbon atoms which may be linear or branched, such as methyl, ethyl, n-propyl, inglovir, n-butyl, 5ee-butyl, t
ert-butyl and isobutyl groups.

The term 1 nomerogen 1 as used herein (
For example, the meaning of R or R1 in formula I or the meaning of C -/% rogene in Y or 2 of formula I) preferably means bromo or chloro.

Compounds of Formula I and Formula II are useful in both free base and acid addition salt forms, and both graphic forms are included within the scope of this invention. Acid addition salts are merely one preferred form of use; the use of the salt form is essentially equivalent to the use of the base form. Acids that can be used to prepare acid addition salts of compounds of Formula I and Formula ■ are preferably those that, when combined with the free base, produce pharmaceutically acceptable salts, i.e., the anion of the salt is It produces a salt that is relatively non-toxic to animals at pharmaceutical doses such that the inherent beneficial inotropic effects of the free base are not compromised by the side effects caused by the anion. Suitable pharmaceutically acceptable salts within the scope of this invention include mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and sul-7 amino acids; and lactic, acetic, citric, tartaric, methanesulfonic, Organic acids such as ethanesulfonic acid, benzenesulfone[, p-)luenesulfonic acid, cyclohekylinsulfamic acid, and quinic acid: are derived from the hydrochloride, hydrobromide, and sulfate salts, respectively. , phosphate, sulfaminate, lactate, acetate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate% p-toluenesulfonate, chlorohexylsulfamate and quinate.

Acid addition salts of the basic compounds of Formula I and Formula II can be prepared by dissolving the free salt in an aqueous or aqueous-alcoholic acid or other suitable solvent containing the appropriate acid and evaporating the solution. It is prepared either by isolation or by reacting the free base with the acid in an organic solvent, in which case the salt is obtained either by direct separation or by concentration of the solution.

Although pharmaceutically acceptable salts of the basic compounds of Formula I and Formula II are preferred, all acid addition salts are included within the scope of this invention. Even if the particular salt itself is desired only as an intermediate product, e.g. when the salt is formed only for purification or identification purposes, or when producing pharmaceutically acceptable salts by ion exchange methods. All acid addition salts are useful as a source of free base, even if the salt is used as an intermediate.

Other pharmaceutically acceptable salts of the compounds of Formula I and Formula II are salts of compounds of Formula I and Formula II prepared with strong inorganic or organic bases, e.g.
um, potassium hydroxide, -basic or dibasic lower alkyl amines or tetra(18-ary alkyl) hydroxide
It is a cationic salt derived from ammoniums.

Formula 11 ■, l [l, lit a Oyo UN (D compound'
The Dfk structure was confirmed based on evidence obtained by infrared, ultraviolet, nuclear magnetic resonance and mass spectroscopy, by comparing calculated and measured values of elemental analysis, and by their manufacturing methods. .

The methods of making and using the compounds of this invention will now be described in a general manner so that one skilled in the art of medicinal chemistry can carry them out.

L6-:) Hydrogen 2-methyl-6-oxo-3-pyridinecarbonitrile and bis(di-lower alkylamino)
-2-C2- of formula (■) by reacting with 1-butoxymethane
(Dilower alkylamino)ethynyl)-L6-:) Hydro-6-oquino-3-pyridinecarbonitrile is produced by heating the reactants at about 100°C to 160°C, preferably in a suitable neutral solvent. It is implemented by

The reaction is conveniently carried out by refluxing in the reactants gold dimethylformamide or dioxane (p-diochitin), preferably using bis(dimethylamino)-1-butquine methane.

The intermediate bis(di-lower alkylamino)-t-butoxymethane of formula V is a known compound or can be prepared by conventional methods.

Furthermore, a compound of formula (1) in which lower alkyl groups R2 and R3 have 2 to 4 carbon atoms can be prepared by combining a compound of formula (1) in which R2 and R3 are each a methyl group with an excess amount of a suitable amine of formula R2R3N)l. is conveniently prepared by refluxing it in an alkanol (particularly methanol).

The production of the intermediate L6-:) hydalo-2-methyl-6-oxo-3-pyridinecarbonitrile is covered by the German patent of C1ba-Geigy! 2256
No. 288 (issued May 24, 1973). 3-7 Minocrotononitrile is reacted with 3-ditoxyacrylic acid silyl at 5°C to -10'C in a mixture of pyridine, tetrahydrolane and dimethylformamide, and the reaction mixture is then diluted with water. Process with.

As shown below, L6-cyhydro-2-methyl-6-
Oquino 3-pyridinecarbonitrile is successfully prepared by refluxing a mixture of 3-aminocrotononitrile and methyl gropiolate in dimethylformamide.

6-Medoxy 2-methyl-3-pyridine carbonitrile and di(lower alkyl)acetamibidimethyl acetal are reacted to form 2-[2-(di-lower alkylamino)-1-propenyl2 of formula 1 [a] - A method for producing medoxy 3-pyridine carbonitrile includes adding a reactant to a suitable neutral solvent (preferably dimethylformamide) to
It is carried out by heating to 20-140°C, preferably using dimethylacetamide P dimethylacetal.

Reacting hydrogen bromide or hydrogen chloride with 2-C2-Cdiloweralkylamino)ethynyl]-L6-cyhydro6-oxo3-pyridinecarbonitrile of formula (1) produces 5-bromo (or chloro)-L6-naphthyridine. -2(IH
)-one (X in the formula ■ is bromo or chlorine R/
is a hydrogen atom), a solution containing the compound in a suitable solvent (for example, a mixture of chloroform and acetic acid) is cooled and stirred, and an odor, a hydrogen gas, or hydrogen chloride is added to the solution. This is carried out by bubbling gas and then stirring the reaction mixture at room temperature.

Reacting with hydrogen bromide or hydrogen chloride to produce 2-C2-(:)lower alkylamino)-1-pro(nyl)-6-medoxy-3-pyridinecarponitrile of formula (a)
(bromo or chlor)-2-methoxy-7-methyl-
The process for preparing L6-naphthyridine is carried out as described in the paragraph immediately above and comprises treating the 2-methquine compound and an aqueous solution of sodium or potassium hydroxide at room temperature to produce 5-(bromo or chloride). )-7-Methyl-L6-cattyridin-2(1)i)-one (formula ■
where X is chromium or chlorine and R' is a methyl group).

5-bromo (or chloro)-7-14'-1,6-naphthyridin-2(IH)-one is reacted with 1) i-(5-membered-N-aromatic)heteryl compound of formula (1) to form formula I 5
-[1)1-(5-membered-N-aromatic hetyryl)-1-yl]-7-R'-1,6-naphthyridine-2(lf()-
The method for producing on is to heat the reactants at about 125°C to 225°C.
(preferably from 140°C to 180°C) in the presence or absence of an acid acceptor in a suitable inert solvent. The solvent is, for example, dimethylformamyl
, N-methylpyrrolidinone, and the acid acceptor is, for example, anhydrous potassium carbonate, sodium methoxide, sodium hydride, etc. The reaction uses N-methylpyrrolidinone as a solvent and in the absence of an acid acceptor, IH of formula V per mole of 5-bromo-7-R'-1,6-naphthyridin-2(IH)-one. -(5-membered-N-aromatic)heteryl compound is advantageously used in a 2- to 4-fold excess (preferably a 3-fold excess).

The intermediate 1fi-(5-membered-N-aromatic)heteryl compound of formula (1) is a known compound and can be prepared by conventional methods or is commercially available.

5-hydrazino-7-R'-1,6-naphthyridine-2
(IH)-one and LLa3-tetramethoxypropane are reacted to form 5-(11-1-pyrazol-1-yl).
The method for producing -7-R'-L6-su7thirin-2(IH)-one involves using a mixture of reactants, a suitable solvent (e.g. ethylene glycol), and a temperature of 150°C to 200°C (preferably about 100°C).
60° C. to 180° C.).

5-hydrazino-7-R'-1,6-naphthyridine-2
(14)-one is 5-bromo (or chloro)-7-
It is advantageously produced by heating R'-1,6-7teridin-2(1)1)-one and hydrazine hydrate.

The following examples are intended to further illustrate the invention and are not intended to be limiting.

Example Luponitrile dimethylformamide '1 in 100 mJ
6-dihydro-2-methyl-6-oxo-3-pyridine 6.7 gk of bis(dimethylamino)-1-butoxymethane was added to a stirred mixture containing 11.7 g of gold.
5m7! was quickly added and the reaction mixture was heated at 110° C. for 3 hours with full stirring. After verifying by tic analysis that some starting VIJ material was still present, an additional 2.3 m/e of bis(dimethylamino)-1-butquine methane was added and the reaction mixture was refluxed with stirring for 90 min. Heated to the bottom. Thereafter, it was cooled to room temperature and left overnight.

The mixture was cooled and the separated product was collected, washed with cold ethanol and dried at 90°C in an open vacuum, whereby 8.29 of 90-6-okine-3-pyridinecarbonitrile was obtained.

The above intermediate L6-sihydro-2-methyl-6-oxo-3-pyridinecarbonitrile was prepared as follows:
A mixture containing 85% 3-amino-2-butenenitrile and 8.4 g of methyl propiolate was heated on a steam bath for about 15 minutes, during which a violently exothermic reaction occurred. External heating was discontinued until this exothermic reaction subsided. To this reaction mixture was added 25 m/dimethylformamide and refluxed for 8 hours, then cooled to room temperature and left overnight. The separated solids were collected, washed with ethanol and dried at 90°C in a vacuum open, thereby producing L6-
DihyF-low 2-methyl-6-okino-3-pyridinecarbonitrile was obtained.

The acid addition salt of 2-(2-(dimethylamino)ethynyl)-b6-dihyto90-6-oquine-3-pyridinecarbonitrile is prepared by diluting the 2-
A mixture containing 2 g of (:2-(dimethylamino)ethynyl)-L6-sihydro-6-oxo-3-pyridinecarbonitrile is added with a suitable acid (e.g. methanesulfonic acid,
14A acid, concentrated phosphoric acid) to about pH 2-3, cooling the mixture after partial evaporation, and collecting the precipitate (e.g., tumethane sulfonate, sulfate, phosphate). Well manufactured.

Rubonitrile (chain point 218-220°C) is 2-[2-
(dimethylamine)ethynyl]-16-sihydro6-
Oxo-3-pyridinecarbonitrile and 3-4 molar excess of diethylamine were refluxed for about 70 hours, the reaction mixture was allowed to cool, the precipitated product was collected, recrystallized in Inglovil alcohol, and 90° C. in a vacuum oven. It was manufactured by drying.

Also, 2-[2-(diethylamino)ethynyl]-16
-dihy V-low 6-oxo-3-pyridinecarbonitrile using a molar equivalent of bis(:)ethylamino)-1-butoxymethane instead of bis(dimethylamino)-t-butoxymethane and Example It can be manufactured by performing the method described in 1.

was prepared as in Example 2, using excess di-n-propylamine in place of diethylamine.

4.5-Bromo-L6-naphthyridin-2(IH)-one-Chloroform cooled in an ice bath 71400dA2-
(2-(diethylamino)ethynyl]-L6-one human 1
0-6-okino 3-pyridinecarbonitrile 9.5
G? Hydrogen bromide was bubbled through the stirred gold-containing suspension for approximately 25 minutes. The reaction mixture was stirred in a water bath for 1 hour, warmed to room temperature and stirred overnight. tIC analysis (using diethyl ether:methanol:triethylamine 7:2:1) showed only the starting* quality and no final product.

150 m/l of acetic acid was added to the reaction mixture, and hydrogen bromide was blown into the mixture while stirring at room temperature. At this time, the reaction mixture turned pale yellow. The reaction mixture was then stirred at room temperature overnight and 1
Concentrate to dryness on a rotary evaporator.

Residue 10% potassium carbonate aqueous solution approximately 300r! Stir in a water bath with Ll. The solids were collected by filtering the mixture through a glass filter, washed with water, and dried at 50°C in a vacuum open, which resulted in a melting point of 278-2.
5-bromo-1,6-naphthyridine-2 (IH
)-one 10.59 was obtained.

In subsequent experiments, reactions were initiated using a mixture of chloroform and acetic acid as shown below: 2-(2-(
Odor 1 arsenic was bubbled for 45 minutes into a mixture (cooled in a water bath) containing 40 g of dimethylamine)ethynyl]-L6-enhydro-6-okino-3-pyridinecarbonitrile, 400 g of chloroform and 202 m/m of acetic acid. is. At this time, the reaction mixture turned from dark yellow to off-white.

The reaction mixture was stirred in a water bath for 15 minutes, warmed to room temperature, and then stirred at room temperature over the weekend. The precipitate was collected, washed with chloroform and dried at 60°C in a vacuum oven, thereby reducing the solid content to 83tji including some inorganic substances.
Obtained. This solid was slurried in water with the concentrate obtained by evaporating the mother ffi on a rotary evaporator, and the mixture was stirred at room temperature. The solids were collected, washed with water and dried at 90°C in a vacuum open, thereby reducing the melting point to 2.
5-bromo L6-naphthyridine-2 at 72-274°C
(IM)-one 41.29 was obtained.

The acid addition salt of 5-bromoL6-naphthyridin-2(1)1)-one is prepared by adding 5-bromo-L6-naphthyridin-2(1)1)-one in about 40 d of aqueous methanol.
2 g of L6-naphthyridin-2(IH)-one (i) was added to the mixture containing a suitable acid (e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid) to a concentration of about -2 to 3, and after partial evaporation, this Cool the mixture and precipitate (e.g. dimethane sulfonate).

It is conveniently produced by recovering sulfates, phosphates). Alternatively, acid addition salts (e.g., mono- The lactate or monohydrochloride) can be advantageously produced.

The cationic salt of 5-bromo-L6-naphthyridin-2(IM)-one can be prepared using an equal amount of a suitable base (e.g. hydroxylated).
IJum, potassium hydroxide or tetramethylammonium hydroxide) to form the corresponding salt (e.g. sodium salt, potassium salt or tetramethylammonium salt)
It can be conveniently manufactured by producing . These salts contain equal amounts of 5-bromo-L6-naphthyridine-2(1)
I) in solution or in solid form by suspending the -one and the base in water or water-methanol to form a salt solution or by evaporating the solvent from the solution to obtain a solid salt. Manufactured in

By using hydrogen chloride of
()-on will be obtained.

Hydrogenate with stirring a solution of 15 g of imidazole dissolved in 200 d of IJum2.
7 g was added and the resulting mixture was stirred at room temperature for 10 minutes. Next, this reaction mixture was added with 5-bromo-L6-naphthyridine-
11.39 of 2(IH)-one was added and refluxed overnight. The reaction mixture was concentrated on a rotary evaporator to remove large amounts of solvent. Water and 7.5 tug of concentrated hydrochloric acid were added to the concentrate and the mixture was allowed to stand at room temperature. The separated solids were collected, washed successively with water and n-hexane, and dried at 90° C. in a vacuum open chamber to obtain 4.5 g of off-white powder. The powder was recrystallized from hot methanol, washed with methanol and dried at 90°C in an open vacuum, thereby giving a melting point of 291-292
5-(if(-imidazol-1-yl)-1,6 at °C
4.0 g of -su7tiridin-2(1)1)-one was obtained.

The acid addition salt of 5-(IH-imidazol-1-yl)-L6-naphthyridin-2(IH)-one is prepared as 5-(11(-imidazol-1-yl)-L6-naphthyridin- A suitable acid (e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid) is added to a mixture containing 2 g of 2(1H)~one to a pH of about 2-3, the mixture is cooled after partial evaporation, and the precipitate ( dimethane sulfonate, sulfate, phosphate).
-imidazol-1-yl)-L6-su7tylidine-2
(If()-one and a suitable acid (e.g. lactic acid or hydrochloric acid)
Acid addition salts (eg monolactate or monohydrochloride) can be advantageously prepared in aqueous solution by adding to water with stirring.

The cationic salt of 5-(1)i-imidazol-1-yl)-L6-naphthyridin-2(IH)-one can be prepared using an equal amount of a suitable base (e.g., sodium hydroxide, potassium hydroxide,
It is advantageously prepared by reacting ethylamine, trimethylamine or tetramethylammonium hydroxide to form the corresponding salts, such as the sodium salt, potassium salt, ethylammonium salt, trimethylammonium salt or tetramethylammonium salt. These salts contain equal amounts of 5-(1)i-imidazol-1-yl)
- Obtaining a solid salt by suspending the L6-naphthyridine-2(1) ion and a base in water or water-methanol to form a solution of the salt, or by evaporating the solvent from the solution. can be produced in solution or in solid form.

On□5-bromo1,6-naphthyridine-2 (IH)
-one 6, 759.4-methyl-IB-imidazole 7
409 and dimethylformamide)'Zo.

The mixture containing d was refluxed with stirring for 33 hours and then concentrated on a rotary evaporator. The residue was slurried in water and the mixture was treated with a small amount of acetic acid. The solids were collected, washed with water, and dried in a vacuum open at 9.0°C. The solid was dissolved in boiling isopropyl alcohol and the hot solution was treated with decolorizing charcoal and filtered. The hot P solution was concentrated and cooled. The separated solid was collected, washed sequentially with isopropyl alcohol and ether, and dried at 90° C. in an open vacuum to obtain 1.9 g of product. The product was recrystallized once more from isopropyl alcohol and dried under reduced pressure at 105°C, thereby giving a compound containing 2-propanol (4:1) and water (4:1')'It with a melting point of 257-2.
5-(4-methyl-IH-imidazole-1-
1.1
I got a 9.

each of isodulovir alcohol and water per mole of said compound. Mol containing 5-(4-methyl-1)1-
imidazol-1-yl) -1,6-naphthyridine-
19.6 g of z(1a)-one was recrystallized from 1.3 JI ethanol, and the recrystallized solid was washed with Ablerhalden drying pis.
tol) at a pressure of 1 mH9 or less and at 115° C. for 2 days. The resulting compound (yield 15.19) contained 4 moles of ethanol per mole of compound. This compound 15.19 was recrystallized from Honsuri 2500-1000 in a dry pistol at 1 tm k19 or less O pressure at 125°C for 3 hours.
5-( with a melting point of 263-264°C)
4-Methyl-IH-imidazol-1-yl)-L6-
12.09 gold of s7 tyridin-2(IH)-one was obtained.

5-(4-methyl-1h-imidazol-1-yl)-
Acid addition salts and cationic salts of L6-naphthyridine-2(11-one) are prepared according to the method described in Example 6.

on-5-bromo-1,6-+phthyrisin-2(11(
)-one 5.6 g, 2-methyl-LM-imidazole 8
A mixture containing 25 t/9, N-methylpyrrolidinone, 3.4 g of anhydrous potassium carbonate and 50111i of copper powder was refluxed for 6 hours, cooled to room temperature and poured into 100 d of water. The resulting solution was neutralized by adding acetic acid, and the solution was left overnight at room temperature.

The separated solid was collected, recrystallized from dimethylformamide and dried at 90-95°C in an open vacuum, thereby giving 5-(2-methyl-1)1-imidazol-1-yl)-1 with a melting point of >310°C. ,6-su7 chiridin-2 (1f
lI)-on λ49 turi.

Lysin-2(1)1)-one 5.69.2-methyl-5
-Nitro-1fl-imidazole 12.71 anhydrous potassium carbonate 3.45 g and N-methylpyrrolidinone 50 m
The mixture containing 1 was refluxed for 5.5 hours, cooled and evacuated in vacuo to remove most of the solvent.

To this concentrate was added 100 ml of water and 10 R1' of a 35% aqueous sodium hydroxide solution, treated with decolorizing charcoal and cooled. The precipitate was acidified with acetic acid, the precipitate was collected, washed with water, dried, recrystallized from dimethylformamide 9 and dried at 90-95 °C in an open vacuum, thereby giving a melting point of 300 °C.
The above 5-(2-methyl-5-nitro-11-1-imidazol-1-yl)-L6-naphthyridine-2(IH
)-one (4.5 g) was obtained.

To the mixture of 5-hydrazino-L6-cathyridin-2(11()-one monohydrochloride monohydrate) suspended in 100d of sodium methoxy y 1.359 was added and the mixture was stirred for 20 minutes at room temperature. , and then evaporated to dryness in vacuo to give the free base form of 5-human9radino-L6-naphthyridin-2(11-i)-one.
Add La3-tetramethoxypropane 6,159 and 25d of ethylene glycol and heat to about 170°C while stirring.
methanol was boiled and removed from the reaction mixture.

The mixture was allowed to stand at room temperature over the weekend and then concentrated on a rotary evaporator. The residue was slurried in boiling methanol, cooled, and filtered.

The solid was slurried in water, collected, and dried in a vacuum oven at about 90°C. The solid was dissolved in boiling dimethylformamide, the hot solution was treated with decolorizing charcoal and filtered, and the filtrate was allowed to cool. The separated product was collected, washed with methanol and dried at 90°C in a vacuum open to a melting point of 30°C.
5(IH-pyrazol-1-yl)-L6- at 0°C or higher
2.89% of naphthyridin-2(IH)-one was obtained.

The acid addition salt of 5-(l H-pyrazol-1-yl)-L6-naphthyridin-2(IM)-one was prepared by preparing 5-(IM-pyrazol-1-yl)- in about 40 d of aqueous methanol.
A mixture of 2 g of L6-naphthyridin-2(IH)-one with a suitable acid (e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid)
was added to bring the pH to about 2-3, and after partial evaporation, the mixture was cooled 1-1 and the precipitates (e.g. dimethane sulfonate,
It is conveniently produced by recovering VfL salt, phosphate). Alternatively, molar equivalents of 5-(11-1-pyrazol-1-yl)-L6-naphthyridine-2(IH
)-one and a suitable acid (eg lactic acid or hydrochloric acid) t?
Acid addition salts (eg monolactate or monohydrochloride) can be advantageously prepared in aqueous solution by addition to water with stirring.

The cationic salt of 5-(lfi-pyrazol-1-yl)-L6-naphthyridin-2(1'ki)-one can be prepared using an equal amount of a suitable base (e.g. sodium hydroxide, potassium hydroxide or tetramethyl hydroxide). ammonium) to form the corresponding salt, such as the sodium, potassium or tetramethylammonium salt. These salts contain an equal amount of the 5-(1M
-pyrazol-1-yl)-L6-su7tylidine-2(
IH)-one and the base can be prepared in solution or in solid form by suspending them in water or water-methanol to form a solution of the salt, or by evaporating the solvent from the solution to obtain a solid salt. It can be manufactured in any shape.

Intermediate 5-human 1 radino L6-naphthyridine-
2(IH)-one monohydrochloride monohydrate was prepared as follows: 5-bromo-1,6-naphthyridine-2 (lk
i)-one 309 and hydrazine hydrate 20.2 a
The mixture containing g was heated under reflux and further heated for 2 hours. The reaction mixture was concentrated on a rotary evaporator and the residue was slurried in concentrated hydrochloric acid. The solids were collected, washed with concentrated hydrochloric acid, and dried at 75°C in an open vacuum. The solid was then slurried in water, collected by filtration, washed with water, and dried at 90°C in a vacuum open, which resulted in a melting point of 31°C.
5-hydrazino-1,6-su7tyridin-2(LH)-one monohydrochloride monohydrate at 0°C or above (f+ solution) 25.
2 g was obtained.

A mixture containing 5.69 i of -5-bromo-L6-naphthyridin-2(IM)-one, 100 m/l of dimethylformamide) and 6,99 i of 1,2.4-triazole was refluxed on an oil bath for 21 h. , cooled with an arrow.

The separated solid was collected, washed with ethanol, and dried at 90°C in a vacuum open to give 5-(11(-
2.89 of L2.4-)liazol-1-k)-L6-naphthyridin-2(lli)-one was obtained.

5-(1)i-1,2,4-triazol-1-yl)
The acid addition salt of -1,6-su7tilidin-2(li-1)-one is approximately 40 mA in aqueous methanol! Middle 5-(IH-L
A suitable acid (e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid) is added to a mixture of 2 g of 24-triazol-1-yl)-L6-naphthyridin-2(IM)-one until the pH is about 2~2.
3 and is conveniently prepared by cooling the mixture after partial evaporation and recovering the precipitate (e.g. dimethane sulfonate, disulfuric acid salt, phosphate). Also,
Add molar equivalents of 5-(lfi-1,2) to water without stirring.
,4-triazol-1-yl)-16-naphthyridin-2(IH)-one and a suitable acid (e.g. lactic acid or hydrochloric acid) to form the corresponding acid addition salt (e.g. monolactate or monohydrochloride) can be produced.

5-(lfi-1,44-triazol-1-yl)-
The cationic salt of L6-naphthyridin-2(IH)-one can be prepared by reacting with an equal amount of a suitable base (e.g. sodium hydroxide, potassium hydroxide or tetramethylammonium hydroxide) to form the corresponding salt (e.g. sodium salt, It is conveniently prepared by forming the potassium salt or the tetramethylammonium salt). These salts are water or water-
An equal amount of 5-(IH-L2,4-triazol-1-yl)-L6-su7tyridine-2(IH)- in methanol
It can be prepared in solution form by suspending the salt and the base to form a solution of the salt, or in solid form by evaporating the solvent from the solution to yield the solid salt.

5-bromo-L6-naphthyridine-2 (I
B) A mixture containing 1,259 kg of methane, 3,300 kg of dimethylformamide, 13.85 kg of anhydrous potassium carbonate, 10.85 kg of 45-dimethylimidazole and 200 kg of steel bromide was refluxed with stirring for 8 hours. Approximately 20 dt of solvent was distilled off using a water separator to remove all water from the reaction mixture.

The remaining reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in water, acidified with acetic acid and evaporated to dryness on a rotary evaporator. The residue was treated with 50 txl water and the brown solid was collected, washed with water and recrystallized from ethanol in the presence of decolorizing charcoal. The resulting light yellow solid was dried at 80-85°C to give 5-(45-dimethyl-IH-imidazol-1-yl)-L6-naphthyridin-2(IH)-one with a melting point of 256-258°C 6.49 I got it.

A mixture containing (IH)-one 11.39.4-phenylimidazole 1B9 and 500d in dimethylformamide was refluxed with stirring for 90 hours, after which the solvent was removed by distillation in vacuo. This gummy residue was slurried with a mixture of 250 g of water and 250 g of ether until no gum remained. The residual solid was collected, washed successively with water and ethanol, and dried under vacuum at 85°C to obtain 10.8 g of solid. This solid was suspended in 375 g of boiling absolute ethanol and dissolved using a small amount of hot dimethylformamide. This solution was allowed to cool in the refrigerator overnight. The white solid was collected, washed with a small amount of cold absolute ethanol, and dried under vacuum at 90°C to give 5-(, melting point 263-265°C).
4-phenyl-IH-imidazol-1-yl)-L6
5.0 g of -naphthyridin-2 (11-one) were obtained. An additional 1.99 g of product with a melting point of 263-265°C was obtained from the mother liquor.

By substituting the corresponding molar equivalent of the appropriately substituted IH-imidazole for imidazole and following the method described in Example 6, the compounds of Examples 14-24 would be obtained.

-on, using 4-dimethyl-1h-imidazole.

1a)-one, using 2,4.5-trimethyl-1ki-imidazole.

Use H-imidazole.

-imidazol-1-yl)-L6-naphthyriditro IH-imidazole.

on, using 2-ethyl-111-imidazole.

H)-one, using 2-improvir-1ki-imidazole.

on, using 4-ethyl-IH-imidazole.

21.5-(45-diethyl-IH-imidacyone, using 45-diethyl-18-imidazole.

Using 5-di-n-propyl-IH-imidazole.

H)-off, using 4-tart-methyl-IM-imidazole.

Use imidazole.

Molar equivalents of corresponding substitutions in place of imidazole-16
- By using pyrazole and following the method described in Example 6, the compounds of Examples 25-32 would be obtained.

One ion, 3,4-dimethyl-IH-pyrazole was used.

One-on, 35-dimethyl-IH-vidizol was used.

using 3-methyl-1ki-pyrazole.

-yl)-L6-naphthyridin-2(1ki)-one,
Using 4-methyl-IH-pyrazole.

H)-one, using 345-trimethyl-1ki-pyrazole.

Lu IH-pyrazole was used.

One, 3-n-propyl-IH-pyrazole was used.

32.5-(3-phenyl-IH-pyrazol-one,
3-phenyl-IB-pyrazole was used.

Example 6
By carrying out the method described in , the compounds of Examples 33-39 would be obtained.

Using 4-triazole.

IHo)-one, using 5-methyl-IH-L2.4-triazole.

11()-one, using 3-methyl-IM-1,2,4-triazole.

36.5-(3-phenyl-IH-12,4-tritriazole was used.

Use azole.

12. Using 4-triazole.

Using 4-triazole.

H)-one 13. A stirred mixture containing 59.3-methyl-IH-pyrazole 18- and N-methylpyrrolidinone 75- was heated at 170-180 °C in an oil bath for 18 h, after which tIC analysis revealed some residual starting showed the substance. The temperature of the oil bath was increased to 200°C and the reaction mixture was heated for an additional 5
Heat for an hour and then pour into water. The separated solid was collected, dried, and combined with 1.79 of the corresponding product from another experiment started with 2.259 of 5-bromo-L6-naphthyridin-2 (11()-one). The solid was recrystallized from dimethylformamide and dried in an open oven at 100°C for 3 days, thereby giving 5-(3-methyl-IH-pyrazol-1-yl)- with a melting point above 300°C.
L6-naphthyridin-2(IM)-one 6,69' was obtained.

11()-one-5-bromo-1,6-naphthyridine-
2(In)-one 13.5 g, 3-methyl-IH-LZ
A stirred mixture containing 209 4-triazole and 75d N-methylpyrrolidinone was heated in an oil bath at 170-180°C.
The mixture was heated for 18 hours and then cooled to room temperature. At this time, a yellowish brown solid crystallized.

The mixture was diluted with 125- of water, the solid that separated was collected, washed with water, air-dried, and 5-bromo-
Combined with 1.2 g of the same material obtained in a separate experiment starting with L6-naphthyridin-z(xH)-one 2.259'. The combined solids were recrystallized from dimethylformamide and dried at 95-100 °C for 3 days in an open chamber.
As a result, the melting point is 300°C or higher 05- (3-, i'fk
-1,2,4-triazol-1-yl)-L6-naphthyridin-z(tH)-one 6.19t- was obtained.

The mixture containing 31.49 g of (Droxymethyl)-1H-imidazole and 75 N-methylpyrrolidinone was heated with stirring at 135-150 DEG C. in an oil bath for 38 hours. The reaction mixture was cooled to room temperature, diluted with water, and the black solution was filtered although no precipitate separated. The P solution was concentrated in vacuo to give a viscous brown oil, which was further concentrated on a rotary evaporator to give a brown semi-solid. Residual N-methylpyrrolidinone was removed by heating the semi-solid residue at 120-130 DEG C. in a vacuum bath and a semi-solid 75.49 was obtained. , add 50wLl of water to this substance.
was added and allowed to stand at room temperature for 2 days. At this time, some pale orange product crystallized. The 'a awards were collected, washed with cold water and dried. This material was recrystallized several times from water and finally from methanol and dried in an open oven at 90-95°C to give 5-(4-(hydroxymethyl)-1H-imidazole- 1-yl: 1-
4.5 f of L6-naphthyridin-2(IH)-one was obtained.

on-5-bromo-L6-naphthyridine-2(lH)-
on 11.259.4-from-1a-imidazole 1
A stirred mixture containing 6.69 and 100 d of N-methylpyrrolidinone was heated in an oil bath at 135-140<0>C for 22 hours. The reaction mixture was cooled and diluted with 200 d of water. Collect the resulting precipitate, wash with water, air dry,
-NoromuL6-naphthyridin-2(IH)-one 1.
5-(4
-Brom-II:1-imidazol-1-yl)-L6
It was combined with 1.5 g of -naphthyridin-2(11-1)-one, recrystallized twice from dimethylformamide and dried at 90° C. for 22 hours in an Anderhalten drying pistol.

At this stage, the sample contained approximately 0.2 mol of dimethylformamide per mol of product. This material was then dissolved in 100 ml of aqueous sodium hydroxide solution and filtered. The fluffy solid that crystallized was collected, washed with distilled water, and placed in an oven for 10 minutes.
Dry over a weekend at 0°C, thereby achieving a melting point of 278
5-(4-bromo-1kl-imidazol-1-yl)-L6-su7tylidine-2(1fi)- at ~280°C
On got 10.3'j.

-imidazol-1-yl]-L6-naphthyryle 100
m/in 5-bromo-L6-naphthyridine-2(1d)-
2.259.4-(trifluoromethyl)-1b-
A stirred mixture containing 4.1 g of imidazole and 59 g of potassium carbonate was refluxed for 12 hours and then allowed to cool to room temperature. The insoluble inorganic material was filtered off and the P solution was concentrated in vacuo to give a brown gummy residue, which was dissolved in 150 ml of acetonitrile, treated with the soluble An decolorizing charcoal, filtered, and then dissolved in about 75 g. Concentrate the filtrate to volume. This solution was chromatographed on t-silica gel using a mixture of ether:methanol:triethylamine (7:2:1) as eluent to give 1.1 g of crude product.

The above process was repeated by changing the heating time from 12 hours to 39 hours and performing the finishing operations as described above, thereby obtaining 800 ml of crude product.

In the third experiment, 3.5 g of 5-bromo-1,6-naphthyridin-2 (if()-one, 8.59 g of 4-(trifluoromethyl)-18-imidazole, potassium carbonate &
The mixture containing 79 and dimethylformamide 1150 was refluxed for 29 hours with stirring and after working up as described above 1.9 g of crude product was obtained. The products of the three experiments were combined and recrystallized three times from isopropyl alcohol,
Dry in the open for 2 days at 100°C, thereby producing 5-[:4-(trifluoromethyl)-1B-imidazol-1-yl]-L6-naphthyridin-2(lH)-one 1 with a melting point of 216-218°C. .95g was obtained.

Tolyl-6-medquin-2-methyl-3-pyridinecarbonitrile 47.2g, dimethylacetamide 9 dimethylacetal 100d and dimethylformamide)'1
0011tl'! The i-containing mixture was heated in an oil bath at 130° C. for 1 hour and 45 minutes without stirring.

The temperature of the oil bath was raised to 150°C, and the methanol produced by this reaction was poured into a 12-inch Vigreau ("l/
1greux) was removed using a distillation column, during which time it was heated to 150°C.
Heating was continued for 14 hours. The reaction mixture was concentrated, and 50 mJe of ether was added thereto to crystallize the product. The mixture was cooled to collect a crystalline solid. The solid was washed with cold ether, dried and recrystallized from ethyl acetate using decolorizing charcoal, whereby 2-(
2-(dimethylamino)-1-propenyl]-6-medoxy 3-pyridinecarbonitrile 33.59t” obtained 7
'C0 The above intermediate 6-medoxy 2-methyl-3-pyridine carbonitrile was prepared as follows.

6-chloro-2-methyl-3-pyridinecarbonitrile 699 was dissolved in 700 rttl VC of warm methanol.

To this solution, 279 ka of sodium methoxide was added with stirring, at which time an exothermic reaction occurred. After the solution was cooled, additional 59'lr of sodium metquine was added and refluxed for 15 minutes. The precipitated sodium chloride is removed by filtration, and P
Approximately 400 g of ether was added to the solution, and the ether solution was treated with decolorizing charcoal and filtered. The filtrate was evaporated to dryness in vacuo to obtain 64 g of 6-medoxy 2-methyl-3-pyridinecarbonitrile having a melting point of 80-80.5°C.

25rILl of acetic acid and 1501ml of chloroform cooled with
! 2-(2-(dimethylamino)-1-
Zoro(nyl)-6-medquin-3-pyridinecarbonitrile 10.89e was dissolved and hydrogen bromide gas was bubbled into this solution f while keeping it below 20°C. A solid separated and the mixture was heated at room temperature. Stirred for 2 hours. This solid (
5-bromo-2-methoxy-7-methyl-L7-naphthyridine) was collected, dried, suspended in 200 g of water, and neutralized by stirring with about 2 g of aqueous potassium hydroxide solution. The separated product vlJ was collected, dried and recrystallized from dimethylformamide to a melting point of 276-278°C.
5-bromo-7-methyl-L6-naphthyridine-2 (
LH)-one was obtained at 9°Og.

2(If()-one-5-bromo-7-methyl-L6-
Catchilysin-2(IH)-one 9.561i), 4-
A mixture containing 8.2 g of methyl-IH-imidazole and 22 sti of N-methylpyrrolidinone was heated with stirring at 140 DEG C. in an oil bath for 20 hours.

This reaction mixture, containing some separated solids, was
Dilute with -, collect the solid, grind finely with water, wash with ethanol, dry and dry with 7-
Methyl-5-(4-methyl-1H-imidazole-1-
yl)-L6-naphthyridin-2(LH)-one 6.0
I got a 9.

Onni-5-bromoL6-naphthyridine-2(IH)-
on13.29.4-nitro-1)1-imidazole2
A stirred mixture containing 0.49 and N-methylpyrrolidinone 50- was heated in an oil bath at 170-180°C for 8 hours. The reaction mixture was cooled and diluted with 200ml of water.

The separated solid was collected, washed with water and dried. The dry solid was dissolved in boiling dimethylformamin, the hot solution was treated with decolorizing charcoal and filtered, and the P liquid was concentrated in a rotary evaporator. The residue was recrystallized from dimethylformamide and dried in an oven at 90-95° C. over the weekend to give product 20.49 containing some starting 4-nitro-IH-imidazole. The mixture was treated with 5% aqueous potassium carbonate solution for 30 minutes and then filtered.

Insoluble material was filtered off and washed with water. The washing solution and P solution were combined and acidified with acetic acid. The separated solid gold collection was washed with water, air dried and recrystallized from dimethylformamide V to give 5-(4-nitro-IH-
imidazol-1-yl)-L6-naphthyridine-2(
6.8 g of IH)-one were obtained.

By substituting a molar equivalent of the corresponding appropriately substituted -IH-imidazole for 4-bromo-1H-imidazole and following the method described in Example 43, the following compounds of Examples 49-51 were obtained. It will be done.

on, using 4-chloro-IH-imidazole.

Use H-imidazole.

No 2 (11-one, 2-bromo-415-dimethyl-
1) 1-imidazole? use.

Examples 52 to 55 were obtained by replacing 3-methyl-1u-pyra/-r with a molar equivalent of the corresponding appropriately substituted -IE-pyrazole and following the entire procedure described in Example 40.
will be obtained.

and 4-nitro-1d-pyrazole.

53.5-(4-Chlor-IH-pyrazol-1-yl)-L6-naphthyridin-2(LH)-one, using 4-chloro-18-pyrazole.

Use Lazor.

- Use Virazole.

3-Methyl-11-1-1,2,4-) lyazole in place of molar equivalents of the corresponding appropriate substituted -IM-1゜2,
4-) Using 177zole and following the method described in Example 41, the compounds of Examples 56-60 would be obtained.

Ifi)-one, using 3-bromo-IH-1,2,4-triazole.

Lysin-2CIH)-one, 3-bromo-5-methyl-
IH-1,2,4-triazole was used.

1f()-1-y, 5-rio-IH-Lg4-)riazole was used.

1B)-one, using 3-nitro-11(-1,2,4-) riazole.

Using lysin-2(1)i)-one, 3-trifluoromethyl-IM-1,2,41 riazole.

61.5-Hrradino L6-naphthyridine-2 (IH
)-one instead of a molar equivalent of 5-human 1radino.7
-Methyl-L6-naphthyridin-2(IH)-one and by following the method described in Example 10, 7
-Methyl-5-(IH-pyrazol-1-yl)-L6
-naphthyridin-2(IH)-one will be obtained. The intermediate 5-human 9radino-7-methyl-L6-naphthyridin-2(LH)-one is substituted for the molar equivalent of 5-bromo-L6-naphthyridin-2(IH)-one.
-Bromo-7-methyl-L6-naphthyridine-2(1)
1)-one and by following the method described in Example 10 for producing 5-human 9radino-1,6-naphthyridin-2(11-1)-one.

Invention effect formula! and the usefulness of the compound of formula ■ as a cardiotonic agent can be determined using standard pharmacological test methods, such as significantly increasing the contractile force of the atrial and papillary muscles of isolated cats or guinea pigs, and/or changes in heart rate and blood pressure. evidenced by the effectiveness of these compounds in a manner that significantly increases cardiac contractility in anesthetized dogs with relatively little or minimal A detailed description of these test methods can be found at 198
No. 4,072,746, filed February 7, 2007.

*=In the above method using isolated atrial and papillary muscles of rt or guinea pigs, inotropy is defined as a significant increase in papillary muscle contractile force, i.e. 25% or more (cats) or 30%.
(in guinea pigs), and a significant increase in right atrial contractile force, i.e., an increase in right atrial contractility of over 25 cm (cats) or 30% (guinea pigs), in which case the percentage increase in right atrial rate is relatively low; approximately half or less of the percentage increase in atrial contractile force or papillary muscle contractile force). Due to the relatively low control activity tension of the guinea pig tissue, the percentage change from the control value for both heart rate and contractile force responses is slightly increased (ie, by 5 cm). Therefore, in cat tests, papillary muscle contraction force (pm
Inotropy can be confirmed by an increase in r) or right atrial contractile force (RAil'), and in guinea pig tests, an increase in PMli'''!l or R input F of 31 or more.Formula I Representative compounds of formula (1) and (2) were tested using the above method using guinea pig atrium and papillary muscle.The results are as follows.

For test methods in anesthetized dogs, Formula I and Formula ■
It is shown that intravenous administration of the cardiotonic compound at doses of about 0.030 to 3.01 q/9 results in a significant increase in cardiac contractile force or contractility, ie, an increase of more than 25%. Moreover, in this case, changes in heart rate and blood pressure are relatively small. Representative compounds of the invention were tested in this manner and demonstrated increased contractile force as shown below.

Dose 4 0.100 1357 0
．． 030 340, 100 96 0.300 124 12 1.00 543.00
136 13 1.00 403.00
87 47 0.100 710.300
125 1.00 183 Cardioactive compounds of Formula It or Formula ■ will usually be administered clinically orally or parenterally in various forms.

Solid compositions for oral administration include compressed tablets, oats, powders and granules. In this woodcutter solid composition,
At least one active compound is starch, calcium carbonate,
Mixed with at least one inert diluent such as sucrose or lactose. These compositions may further contain additives other than inert diluents, lubricants such as magnesium stearate and talc.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions;
Solutions, suspensions, syrups and elixirs are included, which contain inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents, the oak compositions may also include adjuvants such as wetting agents, suspending agents, sweetening, flavoring, perfuming and preservative agents.

According to the invention, formulations for oral administration include capsules of absorbent material such as gelatin, which contain the active ingredient as described above and optionally include diluents or excipients.

Vehicles of the present invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions, and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils (eg olive oil) and injectable organic esters (eg ethyl oleate). These compositions may contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing aids.

They are sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating a sterilizing agent into the composition, by irradiation, or by heating. They are also manufactured in the form of sterile solid compositions that can be dissolved in sterile water or other sterile injectable media immediately before use.

The proportion of active ingredients in the composition for increasing cardiac contractility can be varied to obtain a suitable dosage. The dosage for an individual patient will vary according to the judgment of the clinician having regard to the following criteria: route of administration, duration of treatment, size and condition of the patient, potency of the active ingredient and patient's response thereto. Accordingly, effective dosages of active ingredients are determined by the clinician, considering all criteria and using his best judgment on behalf of the patient.

(5 other people)

Claims (22)

[Claims] (1) Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R is a hydrogen atom, a halogen, or a lower alkyl group; R' is a hydrogen atom or a methyl group; R_1 is a hydrogen atom, a lower is an alkyl group, hydroxymethyl group, halogen, trifluoromethyl group, nitro group or phenyl group; Z is N, C-H, C-(lower alkyl), C
-halogen, C-hydroxymethyl or C-phenyl; and Y is N, C-H, C-halogen, C-(
(lower alkyl) or C-NO_2; provided that at least one of Y and Z is R] or an acid addition salt or cation salt thereof. (2) The compound according to claim 1, wherein Z is N, and when R_1 and R are each a hydrogen atom or a methyl group, Y is CH. (3) 5-(1H-imidazol-1-yl)-1,6
-naphthyridin-2(1H)-one. (4) The compound according to claim 1, which is 5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one. (5) 5-(2-methyl-5-nitro-1H-imidazol-1-yl)1,6-naphthyridine-2(1H)-
The compound according to claim 1, which is (6) The compound according to claim 1, which is 5-(2-methyl-1H-imidazol-1-yl)1,6-naphthyridin-2(1H)-one. (7) 5-(1H-pyrazol-1-yl)-1,6-
A compound according to claim 1 which is naphthyridin-2(1H)-one. (8) The compound according to claim 1, which is 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one. (9) 5-(4,5-dimethyl-1H-imidazole-
1-yl)-1,6-naphthyridin-2(1H)-one. (10) 5-(4-phenyl-1H-imidazole-1
2. The compound according to claim 1, which is (1H-yl)-1,6-naphthyridin-2(1H-one). (11) (A) Formula II: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II The compound represented by (X in the formula is bromine or chlor) is expressed by Formula IV: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ IV or (b) with a compound represented by formula I.
The compound I (where X is a hydrazino group) is 1,1,
3,3-tetramethoxypropane to form a compound of formula I, where Y is N, Z is C-H, and R_1
and R are each a hydrogen atom) and optionally converting the compound obtained in free base form into its acid addition salt or converting the compound obtained into its cationic salt. , a method for producing the compound according to claim 1. (12) Formula II: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼II (In the formula, X is bromo, chloro or hydrazino group,
R' is a hydrogen atom or a methyl group) or a pharmaceutically acceptable acid addition salt or cation salt thereof. (13) 5-bromo-1,6-naphthyridine-2 (1H
)-one according to claim 12. (14) 5-hydrazino-1,6-naphthyridine-2 (
13. A compound according to claim 12 which is 1H)-one. (15) (A) Formula III: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ By reacting the compound represented by III with hydrogen bromide or hydrogen chloride, formula II: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II ( (wherein X is bromine or chlorine and R' is a hydrogen atom) or (b) Formula IIIa: ▲ Numerical formula, chemical formula, table, etc.▼II
Ia (wherein R_2 and R_3 are each a lower alkyl group) is reacted with hydrogen bromide or hydrogen chloride to 5-(bromo or chloro)-2-methoxy-7-
Methyl-1,6-naphthyridine is produced and this 2
- subjecting a methoxy compound to alkaline hydrolysis to produce a compound of formula II, where X is bromo or chloro and R' is a methyl group, and to produce a compound of formula II in which X is a hydrazino group; If desired, the compound thus obtained is reacted with hydrazine, optionally converting the compound obtained in free base form into its acid addition salt, or the compound obtained into its cationic salt. A method for producing the compound according to claim 12, comprising: (16) Formula III: ▲There are mathematical formulas, chemical formulas, tables, etc.▼II
A compound represented by I (wherein R_2 and R_3 are each a lower alkyl group) or an acid addition salt or cation salt thereof. (17) 2-[2-(dimethylamino)ethenyl]1,
17. The compound according to claim 16, which is 6-dihydro-6-oxo-3-pyridinecarbonitrile. (18) Formula IIIa: ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼
A compound represented by IIIa (in the formula, R_2 and R_3 are each a lower alkyl group) or an acid addition salt thereof. (19) 1,6-dihydro-2-methyl-6-oxo-
3-Pyridinecarbonitrile is reacted with a compound of formula V: (R_2R_3N)_2CHOC(CH_3)_2 and optionally R_2 and R_3
are each a methyl group, are reacted in an alkanol with an excess of an amine of the formula: R_2R_3NH, where R_2 and R_3 are alkyl groups having 2 to 4 carbon atoms, and Claim 16 consisting of optionally converting the compound obtained in free base form into its acid addition salt or the compound obtained into its cationic salt.
Method for producing the compound described in Section 1. (20) Reacting 6-methoxy-2-methyl-3-pyridinecarbonitrile with N,N-(dilower alkyl)acetamide dimethyl acetal and optionally converting the resulting free base to its acid addition salt. A method for producing the compound according to claim 18, which comprises: (21) A pharmaceutically acceptable carrier and the formula according to claim 1 in an amount that exhibits a cardiotonic effect as an active ingredient.
I or claim 12 or 13
A cardiotonic composition for increasing cardiac contractility comprising a compound of Formula II as described in Section 1, wherein X is bromo or chlor, or a pharmaceutically acceptable acid addition salt or cationic salt of said compound. (22) The compound according to claim 1 or the formula according to claim 12 for increasing cardiac contractility in a patient in need of an increase in cardiac contractility
A compound of II, where X is bromo or chlor, or a pharmaceutically acceptable acid addition salt or cationic salt of said compound.