JPS58213759A - 2(1h)-pyridinone derivative, manufacture and medicine - 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 relates to a 2(IH) viridinone derivative, a method for producing the same, and a pharmaceutical composition containing the same.

In particular, the present invention provides for formula CI
2), Y (in the formula, m is an integer of O to 4, n is an integer of 1 to 4, 1 to 4 alkylsulfinyl, ■ represents hydroxy, alkoxy having 1 to 4 carbon atoms, halogen having atomic number 9 to 35, or amino), phenyl mono- or independently di-substituted, 11) the group -( CH2)mx or -(CH2)nY, where mln% phenyl disubstituted with 35 halogens, R2 is hydrogen or C1-C4 alkyl, or 1)) R1 is hydrogen or C1-C4 alkyl, or a) for R0 above; R2 has the same meaning as shown in the definition of a) for R1 above (hereinafter referred to as "compound of this invention").

For convenience, the compounds of this invention will be shown in their tautomeric forms of formula (I). However, the invention includes all tautomeric forms, such as the imino form.

k is preferably cyano or amine, especially cyano. k□ is preferably as defined in a) above. When it is defined in a), it preferably has the meaning of 1). In the case defined under b) it is preferably hydrogen or alkyl, especially alkyl. R2 is preferably as defined under a) above. When it is defined in b), it preferably has the meaning of 1).

Preferably, the phenyl ring is monosubstituted.

When monosubstituted, the substituent is preferably in the para position. When di-substituted, the substituents are preferably present in the meta and para positions. If di-substituted and/or □ and R2 both have the meaning defined in a) above, it is preferred that the phenyl ring substituents of ko are the same.

Those having the meaning 1) are preferable to those having the meaning II). Preferred in the sense of i) is the group -(CH2)m
X is mono- or independently di-substituted phenyl. Preferred in the sense of 11) is the group -(CICll2)
and independently disubstituted by alkyl, alkoxy or halogen.

m is preferably 0.1 or 2, especially O or 1, especially O. n is preferably 1 or 2, especially 1.

X is preferably cyano or carboxy, especially cyano. Y is preferably hydroxy or amine, especially hydroxy.

Preferred as alkyl, alkoxy, the alkoxy moiety of alkoxycarbonyl and/or alkylsulfinyl have 1 or 2 carbon atoms, especially 1. Preferred halogens are chlorine or bromine, especially chlorine.

A preferred group of compounds of the present invention is represented by the formula (■a) (wherein 艮 has the above meaning, k□ and R2 have the above-mentioned - and 2).
It is a compound represented by the meaning defined in a)). Its subgroups include those in which all phenyl group substituents are the same except for hydrogen.

A preferred subgroup in the compound of formula (■a) is formula (■1) (wherein k has the above meaning, and 艮 means 1 for 0 as above)
R2 represents alkyl having 1 to 4 carbon atoms).

A subgroup of compounds of formula (Iaa) include those where k is cyan. Other subordinate groups include those of Atai or Amino. Another subgroup is those in which all phenyl group substituents are the same except for hydrogen.

A preferred subgroup of the compounds of formula (Iaa) is the compound of formula (■aa
a) Goose [wherein K and R2 have the above meanings, ko is a group -(
C112) rn/Xa or -(CII2)m'Y
a (m' is an integer of 0 to 2, n' is an integer of 1 or 2, X is cyano or carboxy, ya is hydroxy or amine) mono-substituted or independently di-substituted phenyl] It is a compound.

Defined group -(CH2)r11'Xa or -(C■4
□) There is a phenyl monosubstituted with m'Ya.

Other dependent groups include those in which R is cyano. Another subgroup is those in which k is an amine. Still other dependent groups include those where m' is 0 and n is 1. Yet another dependent group is where X is cyan. Furthermore, other dependent groups include
There is one in which Ya is hydroxy.

Yet another subgroup is those in which all the substituents on the phenyl groups are the same, other than hydrogen.

Another group of compound compounds of this invention is represented by formula (Ib) (wherein k
is a compound represented by the above-mentioned meaning, k□b and ni2 have the meanings defined in b) for - and ni-2 above. Its subgroups include those in which all phenyl group substituents are the same except for hydrogen.

A more preferable group of compounds of the present invention has the formula (wherein,
R, R□ and R2 have the meanings defined above for R, Ri and l, or when k is amino, X is cyan and Y is hydroxy or C1-C4 alkoxy ) is the compound proboscis shown by .

A subgroup of compounds of formula (Ic) include those where k is cyano or carbamoyl.

One group of compounds of this invention has the formula (Ipa) 1-1 [wherein RPa is cyano or carbamoyl, a) Rr
a is I) phenyl mono- or independently di-substituted by C1 -C4 alkylsulfinyl; 11) by C1 -C4 alkylsulfinyl and C1 -C4 alkyl, carbon atoms; phenyl monosubstituted with alkoxy of number 1 to 4 or halogen of atomic number 9 to 35, or 111) phenyl monosubstituted with cyano or carboxy; 3 is hydrogen or alkyl of carbon number 1 to 4; or b) "Ko" is hydrogen or alkyl having 1 to 4 carbon atoms, or has the same meaning as shown in the definition of a) for RPa above, and R2 has the same meaning as shown in the definition of a) for 0 above. have the same meaning].

Another group of compounds of the present invention are compounds represented by the formula CI, l)) (wherein Rr5 and R5 have the meanings defined for R1 and R2 above).

One group of compounds of the present invention has the formula CI, c) 1 [wherein k has the above meaning, a)<0 is a group -(CH3) mp Xp or -(CI
(2). Yp (mp is an integer of 1 to 4, n has the meaning above, XP is carboxy or alkoxycarbonyl having a total number of carbon atoms of 2 to 5, YP hahydroxy or alkoxy having 1 to 4 carbon atoms) monosubstituted; phenyl, it2 is hydrogen or C1-C4 alkyl, or 10 k□ is hydrogen or C1-C4 alkyl, or has the same meaning as given in the definition of a) for Ri above. , R2 has the same meaning as shown in the definition of a) for □ above, and the substituents on the two phenyl rings are the same].

One particular group of compounds of this invention is represented by formula (Is) [wherein k
is the above meaning, k□ha, +)M-(CH2)m, Xsmaf: is-(CH
2).

011 (ms LJ an integer from 0 to 2, ns is an integer from 1 to 2, X is cyano, carboxy or carbamoyl, or 11) by alkylsulfinyl having 1 or 2 carbon atoms, and by 1 to 4 carbon atoms phenyl di-substituted with alkoxy, R2 represents alkyl having 1 or 2 carbon atoms.

The compound of this invention is prepared by formula (it) (wherein k□ and R2 are b) a compound of the formula (Ill) (in which k' is as defined above), or b) a compound of the formula
In order to produce a compound represented by the formula (JV) (wherein R1b and 2 have the above meanings, (indicates a group that can be converted into a primary amine group) can be produced by a method consisting of aminating a compound represented by the following.

One method, a), can be carried out by analogous conventional methods for the preparation of 3-cyano or 3-carbamoyl-2(1F-ri-viridinone derivatives).

Itx may be a group customary for ring-closing reactions with acetamide compounds, such as di(lower)alkylamino, especially dimethylamino or diethylamino. The reaction is
Preferably it is carried out in an inert solvent such as ethanol. The reaction temperature is suitably between room temperature and around the boiling point of the reaction mixture. Further, it is preferable to use strongly alkaline conditions.

However, the reaction can also be carried out in an acidic medium, for example in the presence of acetic acid. In this case, k in equation (■)
The compound proboscis can be obtained directly starting from the corresponding compound of formula (Ill) in which k is cyano.

Ring closure of a substance having a phenyl ring substituent such as cyanmethyl is carried out in the form of a precursor such as bromomethyl,
After carrying out the ring closure, the precursor substituent can be converted to the desired substituent, for example bromomethyl to cyanomethyl.

The other method b) can be carried out by conventional methods for the preparation of analogous 3-amino-2(IH)-pyridinone derivatives. k may be a group customarily used for conversion to primary amine 7 groups such as nitro and especially carbamoyl. For example, when k is carbamoyl, reaction conditions for Hoffman degradation can be used. This reaction is preferably carried out under strongly alkaline conditions, such as in the presence of an alkali metal hydroxide and bromine. As a solvent,
Preference is given to using water. The reaction temperature is suitably about 50°C to about 100°C, preferably about 100°C.

The amination of those bearing substituents on the phenyl ring, such as carbamoyl or cyano, is carried out in the form of a precursor such as cyano or bromine, respectively, and after the amination is carried out, the precursor substituent is converted to the desired substituent, for example cyano. can be converted to carbamoyl or bromine to cyano.

The compound of this invention can be isolated from the reaction system and purified in the same manner as known methods.

The compound proboscis of this invention can exist in free form or in salt form. The free form can be converted into the salt by conventional methods;
The reverse is also possible. Suitable acids for forming acid addition salts include hydrochloric acid, malonic acid, p-toluenesulfonic acid and methanesulfonic acid. Suitable bases for forming anionic salts include sodium and potassium hydroxide. Compounds in the form of anionic salts are usually predominant in the im/=l form.

Starting materials can be obtained by known methods.

In the formula (II), Rx is a di(lower) alkylamino compound, for example, the corresponding compound represented by the formula (V) (wherein k and 1t2 have the above meanings) is replaced with N,N-di(lower)alkylamino compound. Beef formamide (lower grade) Al-beef formamide, preferably N, N-
It can be obtained by reacting with dimethylformamide and dimethyl or diethyl acetal.

Compounds of formula (V) can be obtained according to known methods. For example, in formula (V), k□ is phenyl mono- or identically di-substituted with the group -(CH2)mX or -(CH2)Y as defined above, and 2 is hydrogen or alkyl having 1 to 4 carbon atoms; Certain compounds can be obtained according to the method of the reaction scheme below, where this reaction step can be used repeatedly for the preparation of compounds where m and/or n are up to 4, and the carbonyl group can be used, for example, as a ketal. It is preferable to use it in the reaction in a protected form.

C00N
COOalkyl Furthermore, compounds of formula (V) can also be obtained in a similar manner. Alkylsulfinyl substituents can be obtained by oxidizing alkylthio substituents, for example with hydrogen peroxide or m-chloroperbenzoic acid.

If the manufacturing method of each starting material is not specifically described, it can be manufactured by a known method or a method similar to the above.

In the following examples, all temperatures are in degrees Celsius;
It is uncorrected.

Example 1 5-(4-cyanophenyl)-1,2-dihydro-6-
Preparation of methyl-2-oxopyridine-3-carbonitrile (modification of method a).

Cyanacetamide 6.2! i' is sodium 1.149
and 200 ml of absolute ethanol. 4-dimethylamino-3-(4-cyanophenyl)-
10.67 g of 3-buten-2-one are added and the solution is stirred at boiling point for 5 hours, whereupon the sodium salt of the title compound begins to precipitate out. The mixture is allowed to cool and the crystalline product is separated and washed with ethanol and ether. (Sodium salt: mp>300°C) (educt: mp>300°C
).

Starting material 4-dimethylamino-3-(4-cyanophenyl)-3-buten-2-one Cbp (0°005 W
III(Li) -155-160℃] is 1-(4-
It is obtained by heating cyanophenyl)-2-propanone with 4,4-dimethylformamide dimethyl acetal at 80°C for 1 hour.

Example 2 4-(3-cyano-1,2-dihydro-6-methyl-2
-Oxopyridin-5-yl)phenylacetic acid (modification of method a).

When 4-dimethylamino-3-(4-methoxycarbonylmethylphenyl)-3-buten-2-one 11P is reacted with cyanacetamide in the same manner as in Example 1, the title compound is obtained. (mP 280-282°C after recrystallization from dimethylformamide/ethanol).

The starting material is obtained as follows.

4-(2-oxopropyl)benzonitrile is heated in concentrated aqueous hydrochloric acid at boiling point for 5 hours. The resulting 4-(2-oxopropyl)benzoic acid (mp 163-165°C) is reacted with hydrogen chloride gas in methanol. Obtained 4-
(?-oxopropyl) methyl benzoate (mp48-5
The carbonyl iV group at 0 DEG C.) is protected as a ketal by reaction with ethylene glycol in the presence of -toluenesulfonic acid, and the ketal is reacted with lithium aluminum hydride in tetrahydrofuran. The resulting 2-(4-hydroxymethylbenzyl)-2-y'
f Roux 1.3-') yk+V Run Cbp(o, o
7+nHf)-130-135°C] to 2N-
Removed with aqueous hydrochloric acid and brominated the deprotected compound with phosphorous tribromide in ether. The resulting 1-(4-bromomethylphenyl)-2-propanone is directly reacted with excess sodium cyanide in ethanol without being purified to produce 4-(2-oxopropyl)phenylacetonitrile Cbp (0.1 mmf). (fi'
) = 140°C) is hydrolyzed with 8-hydrochloric acid aqueous solution.

The resulting 4-(2-oxopropyl)phenylacetic acid (m
P92-94°C) is esterified with methanol. Methyl 4-(2-oxopropyl)phenylacetate C produced
')P(0,06mm HS')=120-130℃]
is reacted with N,N-dimethylformamide/dimethylacetal at 50°C for 2 hours. The resulting 4-dimethylamino-3-(4-methoxycarbonylmethylphenyl)
-3-Buten-2-one is used in the reaction in its crude form.

Example 3 Preparation of 3-amino-5-(2-methoxy-4-methylsulfinylphenyl)-6-methyl-2(IH)-viridinone (modification of process).

Bromine 3.7- is added dropwise to a stirred solution of sodium hydroxide 157- and water 230- at 0°C. Then 1,2-dihydro-5-(2-methoxy-4-methylthiophenyl)-6
- 17.6 f of methyl-2-oxonicotinamide are added and the mixture is heated at 100° C. for 3 hours. The mixture was allowed to cool to room temperature, carefully acidified with 6N hydrochloric acid, stirred for an additional 30 minutes, and the brown precipitate was removed. The p solution is extracted with ethyl acetate, the aqueous layer is concentrated and made alkaline with ammonium hydroxide. When the precipitate is removed and the supernatant is concentrated, the title compound precipitates out in the form of crystals. (mp224-226°C of hydrochloride recrystallized from methylene chloride/methanol)
.

Starting material 1,2-dihydro-5-(2-methoxy-4
-Methylthiophenyl)-6-methyl-2-oxonicotinamide [recrystallized from methylene chloride/methanol, mP 278-281°C (decomposed)] was prepared by combining]2-methoxy4-methylthiobenzaldehy and nitroethane with n-butylamine. 1-(2-Methoxy-4-methylthiophenyl)-2-propanone Cbp (0°02
4-dimethylamino-3-(2-methoxy-4- Methylthiophenyl)-3
-Butene-2-t7 (ff--recrystallized from chill/petroleum ether, mpHl -112°C) is obtained by reacting with cyanacetamide in glacial acetic acid at 100°C.

Similarly, the following compounds of the present invention can be obtained.

The compounds of this invention have pharmacological effects.

The compounds of this invention have cardiotonic effects as shown by standard test results. For example, approximately 0.0 for a normotonic Numa l anesthetized dog.
2 m? /to? When administered intravenously to about 2 mfl/9, an increase in the contractile force of the left ventricle is observed.

The test method is as follows.

Weight 10 to 15 KI? Dogs of each sex were used. As an anesthetic, Numar is injected intravenously at a dose of 65 rng/M. Fix the animal in supine position on the operating table.

After normal operation, the heparinized catheter is radiologged.
It is inserted into the left ventricle along the petrosal artery under control, and a Toner membrane (Gould Statum p23c) is used to transmit pressure.
b) Record your shoulders. Increase in blood pressure as a function of time r
Is F, - Calculate and record with physiodifferentiator. Increased left ventricular blood pressure is an indicator of the heart's contractility. The size of the blood pressure difference is rrtn HS'/fr'J
). Maintain an appropriate body temperature (approximately 36 to 37°C). After a control period of approximately 40 minutes, the test substance is injected into the femoral vein and the recorded or calculated parameters are observed.

Cardiac activity is accompanied by an afterload reducing effect.

Therefore, in the above anesthesia dog test, approximately 0.2'Q
A decrease in arterial blood pressure and total peripheral resistance is observed after intravenous injections of 1/2 to about 2/M.

For measurement of arterial blood pressure, a heparinized catheter is inserted under radiolog-control into the aortic root via the left condylar artery. Arterial blood pressure is measured using a Statham Pressure Transducer-P23AC to accurately determine systolic and diastolic blood pressure. The mean arterial blood pressure is calculated by adding 1/3 of the width CP (systolic) (diastolic) to the diastolic blood pressure.

Total peripheral resistance (PR) was determined in units of dynes, seconds, and C according to the f formula.

(Measurement of cardiac output is carried out using a catheter inserted into the petrosal vein under radiolog control and according to the thermodilution method.) Furthermore, the compound of this invention can be used as shown in the compound of Example 1. , has an unexpectedly long-lasting effect and is unexpectedly well tolerated. For example, tachycardia is surprisingly rare.

The compounds of this invention are therefore particularly useful as cardiotonic agents, for example in the treatment of heart failure.

Preferred compounds are the compounds of Examples 1.2 and 5, especially the compound of Example 1.

The indicated daily dose is from about lθ to about 500 Wtg, for example, by oral administration, in suitably divided doses 2 to 4 times a day, or as a sustained release formulation. Examples of daily doses are 1011v to 100■.

The compounds of this invention can be administered analogously to known standards for digoxin, for example. The appropriate daily dose for a particular compound will vary depending on a number of factors, such as its relative activity. For example, when the test results of the compound of Example 1 in the above-mentioned Newmar Anesthesia are compared with those of digoxin, it has the following properties.

It is therefore seen that this compound can be administered at doses comparable to or lower than known doses for digoxin.

The compounds of this invention can be administered in free form or in the form of pharmaceutically acceptable salts. Such salts exhibit activity on the same order of magnitude as the educt and are readily prepared by conventional methods. This invention also provides a pharmaceutical composition comprising a free form or a pharmaceutically acceptable salt of a compound of this invention and a pharmaceutical carrier or diluent. Such a composition is
For example, it can be in the form of a solution or a tablet. For solution preparation, solubilizers or stabilizers such as cyclodextrins, for example β-cyclodextrins, can be added as appropriate.

Continued from page 1 C07D 317/20 8214-
4C priority claim 0 May 18, 1982 [Phase] Switzerland (CH) ■3091782 0 February 15, 1983 [Phase] Switzerland (CH) ■837
783

Claims (1)

[Claims] (1) Formula (I) ■ In the formula C, tt is cyano, carbamoyl, or amino, a) R1 is 1) a group -(CH2)mX or -(CII
2) 11Y (where m is an integer of 0 to 4, n is an integer of 1 to 4, X is cyano, carboxy, alkoxycarbonyl having a total number of carbon atoms of 2 to 5, carbamoyl, or alkylsulfinyl, Y is hydroxy, alkoxy having 1 to 4 carbon atoms, /% rogen with atomic number 9 to 35, or amino), phenyl mono- or independently di-substituted, iD group -(CH2) mX or -(CII2)nY, in which m1n, X and Y have the same meanings as before; phenyl disubstituted by halogen, k2 is hydrogen or C1 -C4 alkyl, or b) R, is hydrogen or C1 -C4 alkyl, or as defined in a) above for □ R2 has the same meaning as given above in the definition of a) for 0]. f215-(4-Cyanophenyl)-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile free form or salt, the compound according to claim 1, item 1'. (3) A pharmaceutical composition comprising a free form or a pharmaceutically acceptable salt of the compound according to claim 1. (4) A medicament prepared by blending a free form or a pharmaceutically acceptable salt of the compound according to claim 1, in which k in formula (I) is cyano or carbamoyl, with a pharmaceutical carrier or diluent. Composition. (5) A compound represented by formula (1) (wherein Rt and R2 have the meaning defined in claim 1, Rx represents a leaving group) or formula (IV) (wherein, ko and 艮. have the meanings defined in claim 1, and k represents a group that can be converted into a primary amino group. (6) a) In order to produce a compound number represented by formula (I') (in the formula, 艮□ and R2 have the meanings given below, and R' represents cyano or carbamoyl), formula (11) (in the formula , Kyo and R2 have the meanings given below, ~ represents a leaving group) with a corresponding compound represented by the formula (Ill) (wherein nail has the same meaning as before), or b) Equation (
I) In order to produce a compound represented by 1 (wherein R1 and R2 have the meanings given below), a compound of formula (IV) (wherein, 艮 and R
2 has the meaning given below, and k represents a group that can be converted into a primary amino group.
) [1 [wherein k is cyano, carbamoyl, or amine, a) R, is 1) group -(CH2)mX or -(CII
2) nY (where m is an integer of O to 4, n is an integer of 1 to 4, alkylsulfinyl, Y is hydroxy, alkoxy having 1 to 4 carbon atoms, halogen having atomic number 9 to 35, or amino) phenyl mono- or independently di-substituted, ii) the group -(CH2)mX or -(CH3)', V(
in which m, n, phenyl, R2 is hydrogen or C1-C4 alkyl, or b) R, is hydrogen or C1-C4 alkyl, or as given in the definition of a) for □ above; R2 has the same meaning as shown in the definition of a) for □ above.