JPS5823693A - Imidazoquinoxaline compounds - 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 novel organic compounds with unique pharmacological activities. In particular, the present invention relates to imidazoquinogyzalines of formulas l and l.

tt! [R1, Rs, Re and R in the formula? Hiro independently H, alkyl, 7'J-l, alkenyl, alkynyl, hydroxy7, human ``Jxyalkyl, alkoxy, mercapto,
Is mercaptoalkyl, alkylthio, amine, alkylamino, aminoalkyl, carboxaldehyde, carboxylic acid and its salts, carbalkoxy, alkanoyl, cyano, nitro, trifluoromethyl, sulfonyl, alkylsulfonylmata a sulfonamide? , or R15R5, R11 and R7 together with adjacent groups form a methylenedioxy group;
Ra FiH, alkyl, alkenyl, alkynyl,
Aryl, aralkyl, hydroxy, alkanoyl or alkanoyloxy, 9; R, #'i, H,
Derivatives such as cyano, tetracylo, carboxaldehyde, hydroxyalkyl, carboxylic acids and their salts, or their esters and amides, provided that the ester oxygen or amide nitrogen is substituted with alkyl, aryl, hydroxyalkyl, alkoxypurkyl, or aminoalkyl. R1 and R*V
i independently H, alkyl, aryl, halo, amino, alkylamino, arylamino, hydroxyamino, hydroxy, alkoxy, mercapto is alkylthio; and

Alkyl groups in alkyl itself, hydroxyalkyl, alkoxy, aminoalkyl, alkylamino, alkylthio, mercaptoalkyl, alkanoyl, aralkyl, and carbalkoxy preferably contain from 1 to 8 carbon atoms, more preferably from 1 to 8 carbon atoms. The lower alkyl group may be straight-chain or branched. These groups include methyl, ethyl, propyl, isopropyl, sec-butyl, isoamyl, hexyl, 2-ethylhexyl, and the like.

Alkenyl and alkynyl groups can be straight chain or branched, preferably containing from 142 to 8 carbon atoms, and this group includes vinyl, 10-hardyl, ethynyl, hydrovinyl, and the like. Ru.

Preferred compounds are those in which R6 and R1 are independently H, alkyl, alkoxy, hydroxy, nocturnal, trifluoromethyl, or alkylsulfonyl; R4 is H5 alkyl, alkenyl, aryl, aralkyl, hydroxy, or alkanoyl; ; R, is H, carboxylic acids and their salts and esters (where the group on the ester oxygen is alkyl, (alkoxyalkyl or aminoalkyl); R2 is H, hydroxy, mercapto or alkylthio; t): Compounds of the above formulas (1) and (2) when Rs is no, amino, alkoxy, alkoxyamino, hydrazino or mercahoot; X is oxygen, sulfur or imino; R0 and R5 are hydrogen It is.

The compound of formula Xia is produced by the following series of reactions.

The novel compounds of formula (1) of the present invention are found by reductive ring closure of compounds of the following formula.

R in the above formula is lower alkyl, R1, R5, R6
and R't are as defined above. In this case, R
Compounds of formula (2) in which 4 is OH may be substituted. Such compounds can be converted to compounds in which 84 is hydrogen by acylation with lower acanoic acids such as acetic acid and pivalic acid and heating at elevated temperatures, such as about 200°C.

Other standard reactions well known to those skilled in the art, such as alkylation,
Halogenation, nucleophilic substitution reactions, hydrolysis, decarboxylation, etc. can be used to introduce one or other functional groups to effect modification.

Compounds in which R4 is hydrogen are subjected to a substitution reaction and the hydrogen is converted into alkyl, alkenyl,
Can be substituted with alkynyl, aryl, aralkyl or alkanoyl. Other conversion and substitution reactions can be used to introduce groups representing Rv, Rs, Ras Rt, Ra, Rs and R1. Such reactions include, for example, nitro to amino reduction, amine substitution via diazonium salt substituents, and the like.

In the compound of Nirin, the enol OH group representing R8 is substituted by a conventional substitution reaction, such as substitution with a halide, ether formation with a lower alkyl sulfate, substitution of the -.ride group at the 4-position with an amino, alkylamino, hydrazine or mercapto group, obtained by.

If desired, the novel compounds of the invention can be converted into salts when basic and/or acidic groups are present. These salts include those formed between a basic nitrogen and an acid (for example, salts I!, (ilEl!, common hydrophilic salts such as benzenesulfonic acid, toluenesulfonic acid, and similar acids). Historically, these salts include those formed between a free carboxy group and a metal ion (e.g., sodium ion, potassium ion, calcium ion, etc.) or ammonia and aminos. Of course, these salts must be pharmaceutically acceptable, as is well known in the art.

In the series of reactions mentioned above, the reaction operations are generally carried out in the presence of a solvent such as dimethylformamide, dioxane, tetrahydrofuran, a hydrocarbon solvent (eg, benzene, toluene), or an aqueous alcohol (eg, ethanol). Usually these reactions are quickly completed upon increasing the temperature from room temperature to the reflux temperature of the reaction mixture. Temperatures below room temperature can also be used, but reaction times must be increased to obtain adequate yields.

The present invention will be better understood from the following embodiments.

Example 1 11! of orthofluoronitrobenzene (106F) and imidazole-4,5-dicarboxylic acid diethyl ester (10
Anhydrous calcium carbonate (200f) was added to the solution of 6f).

The reaction mixture was stirred vigorously for over 4 hours. After removing the solvent under oil pump vacuum, the residue was treated with water and then extracted with chloroform (800dx8). The combined chloroform extract was washed with water, dried over magnesium sulfate, and then concentrated under vacuum to give an oil. Treatment with ether solidified the oil to give the product as a white solid (1862; 1% yield). Recrystallized from chloroform-hexane.

Melting point 98-95°C.

Catalyst 1 t (5% Pd/C) in an ethanolic solution (2
50m) was hydrogenated for 1 hour at a pressure of about 501ss. After removing the catalyst, the solution was evaporated under water aspirator vacuum to give an off-white solid (6.2 t,; yield 80-)
. Recrystallized from DMF. Melting point: 800℃.

Example 2 Derivative catalyst o, containing 5g (5*Pd/C)' tr2- (4'
An ethanolic solution (1#) of 5'-dicarpethoxyimidazolo)-5-methylsulfonyl-nitrobenzene (12F) was hydrogenated for 1 hour at a pressure of about 501 si. After removing the catalyst, the solution was evaporated under water-aspirator vacuum to yield a bright colored solid, mostly characterized as the 5-hydroxy derivative. This solid was dissolved in boiling acetic anhydride (100d) and refluxed for over 10 minutes. After cooling, the 5-acetoxy derivative precipitated as an off-white crystalline solid (6.2 f; yield 55 g). Recrystallized from acetonitrile. Melting point: 251-252°C. A pivaloyloxy compound was obtained by replacing acetic anhydride with pivaloyl chloride. Melting point: 198-200°C. The 5-acetoxy derivative (8f) was dissolved in a boiling Dowtherm (boiling point ˜248° C.) and the solution was refluxed for more than 10 minutes. After cooling to room temperature, the precipitate was collected, washed with chloroform, and then DM
The desired 7-methylsulfonyl-4-
Oxo-4,5-dihydroimidazo[1,5-α]-quinoxaline-8-carboxylic acid ethyl ester was obtained as an off-white black body. Melting point: 800℃.

Example 8 4-oxo-4,5-dihydroimidazo[l,5-α]-quinoxaline-8-carboxylic acid ethyl ester (12,4t ) and methyl iodide (98
Silver oxide (651) f was added to the solution of 9) while stirring. The reaction mixture was stirred at room temperature for 18 hours. After removing the insoluble material, the solution was evaporated to dryness under oil pump vacuum. The residue was extracted several times with chloroform and the combined chloroform extracts were washed with water, dried over magnesium sulfate and then evaporated under water-aspirator vacuum to give the product as a white solid (8.2 f; rate 63
blood). Acetonitrile) was recrystallized from IJ. Melting point 28
8~L36℃.

Example number α 5 (8-carbuethoxy-4-oxo-4,5-
Dihydroimidazo[l,5-α]quinoxalyl)acetic acid tertiary butyl ester (7,9f) was dissolved in 5014 trifluoroacetic acid. After standing for 18 hours at room temperature, the solution was
Evaporated under Asvita vacuum. The residue was washed with chloroform and then recrystallized from DMF to give the product as a white crystalline solid (5.9 f; yield 88 fk).

Melting point: 297-299°C.

Example 5 4-benzyl and 4- and droxyethyl-1-(α-
Compound of Example 4 (3,
1? ) and piparoyl chloride (1,5f ), triethylamine (1,22
) was added. The mixture was stirred at 0°C for 1 hour. To this cold mixture was added a solution of benzylbizelazine in DMF (21).
was added and the solution was stirred at 0° C. for 1 to 8 hours. Ether was added to cause a solid to precipitate, which was collected and taken up in chloroform. The chloroform solution was washed with water, dried over magnesium sulfate and then evaporated in vacuo to give the product as a cream solid (8.2f; yield 6
9-). Recrystallized from DMF. Melting point 254-256
℃. The corresponding 4-hydroxyethyl derivative was obtained in the same manner using hydroxyethylpyrazine in place of benzylbi-4-lazine. Melting point 248-247°C.

Example 6 4-oxo-4,5-dihydroimidazo (1,5-eL
]-Kinogyzalin-8-carboxylic acid ethyl ester (8
, 5f) was dissolved in 0.5N sodium hydroxide solution 1001. The solution was heated on a steam bath for 1 hour, cooled to room temperature, and then acidified with concentrated hydrochloric acid (5 wJ). The product precipitated as a white solid (8.Of; yield 95
blood). Melting point>800℃.

Example 7 4-oxo-4,5-dihydroimidazo (1,5-aJ
Quinoxaline-8-carboxylic acid ethyl ester (9F)
to phosphorus oxychloride 20 low! The mixture was heated with stirring until it became a clear solution. After cooling to room temperature, the solution was concentrated under vacuum. The residual oil was taken up in chloroform and passed through a short silica gel drying column (chloroform as eluent). The product was obtained from the column as an off-white solid (4.5 f; yield 47 g). Melting point: 128-180°C.

Example 8 4-chloroimidazo(1,5-a)kinogyzarin-8-
To a methanolic solution (250 sd) of carboxylic acid ethyl ester (4f) was added sodium bicarbonate (10f) with stirring. Place this mixture on a steam bath for 2
heated for an hour. After removing the solvent under vacuum, the residue was taken into water and then extracted several times with chloroform. The combined chloroform extract was washed with water, dried over magnesium sulfate, and evaporated to give the product as an off-white solid (2.2 f; yield 55 m). Recrystallized from acetonitrile. Melting point 189-191"GO Example 9 4-chloroimidazo[1,5-α]quinoxaline-8-
Thiourea (1,5f) was added to an ethanolic solution (200111) of carboxylic acid ethyl ester (4,8F). This mixture was heated on a steam bath for 1 hour. After cooling to room temperature, the precipitated product was transformed into a yellow crystalline solid (8.2 t
; Yield: 67 cm). Recrystallized from methanol-chloroform. Melting point 251-258°C.

Example 1O Ethyl carbate (9t) and triethylamine (20
m) was added.

The mixture was refluxed for 18 hours and then evaporated to dryness under a water-aspirator vacuum. The residue was taken up in chloroform, washed with water, dried over magnesium sulfate, concentrated to a small volume and then passed through a silica gel drying column (29G methanol in chloroform as eluent). The product was isolated from the column as an off-white solid (4t; yield 58t). Recrystallized from a mixture of chloroform and hexane. Melting point 126-128°C.

Example 11 4-Chloro-7 trifluoromethylimidazo[1,5-α]Kinoki Zaryi 7-31 Fulponic Acid Ethyl Ester (5,4f) in Chloroform-Ethanol (100d each)
f) A small stream of anhydrous ammonia was passed through solution H for 80 minutes. The precipitate was collected and recrystallized from DMF to give the product as an off-white crystalline solid (2.9f; yield 57g). Melting point>300℃.

Example 12 4-chloroimidazo[l] in carbon tetrachloride (5011A)
, 5-a3 quinoxaline-8-carboxylic acid (2,??
) was added with N-chlorosuccinimide (3f) and a trace amount of benzoyl peroxide. The mixture was stirred and refluxed for 48 hours and then evaporated to dryness. Wash the remainder with chloroform and water,
It was dried, reduced to a small volume, and then passed through a silica gel drying column (chloroform as eluent). The product was obtained from the column as an off-white solid (1,6r; 50% yield). Melting point 182-135°C.

Example 13 5-Methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[l,5-α]quinoxaline-8-carboxylic acid ethyl ester in carbon tetrachloride (2501117) (3.9f) N-promosuccinimide (20f) was added to the solution. The mixture was refluxed for 18 hours with vigorous stirring. After removing the solvent under water-aspirator vacuum, the residue was chromatographed on a short silica gel drying column (chloroform was used as eluent). The product was isolated as an off-white solid (1.9f; yield 89g). Acetonitrile) was recrystallized from IJ. Melting point 205-207°C.

Example 14 1 in dimethyl sulfoxide (DMSO) (80d)
-Promo 5-methyl-4-okine-? -Trifuromethyl-4,5-dihydroimidazo(1,5-a)quinogyzaline-8-carboxylic acid ethyl ester (8,2t)
Add potassium acetate ('!,,5
f) was added. This mixture was heated on a steam bath for 1 hour. Water was then added to precipitate the crude product as a white solid (2.ar; 83% yield). It was recrystallized from a mixture of acetonitrile, chloroform and metal chloride.

Melting point>800℃.

Example 15 1-Promo5-methyl-4-okyne-7-trifluoromethyl-4,5-dihydroimidazo[l,5-α]quinoxaline-8-carboxylic acid ethyl ester (1,8t
) in an ethanolic solution (20 om) of thiourea (0,
4F) was added. This mixture was refluxed on a steam bath for 2 hours. After cooling to room temperature, the precipitate was collected, taken up in chloroform and passed through a short silica gel drying column (5-thimethanol in chloroform as eluent).

The product from the column was a white solid (0.71; yield 44%)
isolated as. P+ was crystallized from acetonitrile.

Melting point: 282°C.

Example 16 1-Mercapto-5-methyl-4- in dichloromethane
Oxo-7-trifluoromethyl-4,5-dihydroimida:/(1,5-α)quinoxaline-8-carboxylic acid ethyl ester (0,29) is added to a solution of methyl iodide (O12f) and triethylamine ( 0
, 1f) r added.

The mixture was heated on a steam bath for 1 hour, then cooled and washed with water. After drying, the organic phase was evaporated under water-aspirator vacuum to give the product as a white solid (0.1t; yield 49t). Acetonitrile) was recrystallized from IJ. Melting point: 202-204°C.

Example 17 Acid ■-promo 5-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid ethyl ester (1,5F) and 0.5N sodium hydroxide solution ( 4011t) was heated on a steam bath for 18 hours. After cooling and acidification with concentrated hydrochloric acid, the product was transformed into a cream solid (0.9f; yield 81
%).

Melting point>800℃.

Example 18 1-Hydroxy-5-methyl-4-oxo-4,5-dihydroimidazo (1,5-aJ quinoxaline-8-carbo II (Q2f) 1-boiling di-orthoxylylethane (
1Od) asked. The solution was refluxed for 10 minutes and then cooled to room temperature. The product precipitated as a brown solid (0.1f; yield 60g). Melting point>800℃.

Example 19 N-4',5'-dicarpeethoxyimiguzolonitropenase (7)2,4-') in DMF (800 ml)
7 o o = ) o to y4! (8f) and imidazole-4,5'-dicarboxylic acid diethyl ester (
Anhydrous potassium carbonate (40?) was added to the solution of 21,2f). The reaction mixture was stirred vigorously with gentle heating for about 1 hour. After removing the solvent under oil pump vacuum, the residue was treated with water and then extracted with chloroform. Wash the collected chloroform extract with water,
Dry with magnesium chloride and then concentrate in vacuo to give an oil. This oil was strained in a small amount of chloroform and then passed through a short silica gel drying column (chloroform as eluent). The product was obtained from this column as a cream solid (22.5f; 42% yield). Recrystallized from chloroform-hexane. Melting point: 188-186°C.

Example zO A mixture of 4-oquino-5-propyl-4,5-dihydroimidazo[1,5-α]quinoxaline-8-carboxylic acid (1,6t) and oxalyl chloride (5-) in toluene (125yd) Refluxed overnight. After concentration under vacuum, the residue was taken up in dioxane (75M). Triethylamine (lOd) and N
, N-dimethylaminoethanol (81) was added. The mixture was stirred at room temperature for one hour and then evaporated under vacuum. The residue was washed with 0.1# sodium hydroxide in chloroform and water. Evaporate the dry chloroform solution to 0,? fv) 4-oxo-5
-propyl A/-4,5-dihydroimidazo (1,5-c
L) Kinogyzaline-8-carboxylic acid β-N,N-dimethylaminoethyl ester was obtained as an off-white solid. Melting point 115-118°C.

The hydrochloride salt was prepared by treating the above free base in methanolic hydrogen chloride. After evaporation and washing through an ethyl acetate trap, the hydrochloride salt was obtained as a white solid. Melting point: 210°C (decomposed).

Following the procedures in the examples described above, the following additional intermediates and compounds of the invention were obtained.

1st batter intermediate HH98-5J5 CH8H76-78 HCHs 110 -112 HF 139-141 CF, H108-110SOxCHs
H135-138NOt
H165,5167,5H* ]J8
-136 Certain woodcutter compounds of the present invention, for example, where X is 0. S or imino and R4 is OH, or R2 is O
H or SH can exist in both the keto and enol forms, and both of these types of compounds are intended to be included within the scope of this invention.

The compounds of this invention are valuable for their activity as cardiotonic agents. These compounds are of particular value because the desired inotropic activity is achieved with only minimal changes in pulse rate and blood pressure.

Activity was measured in a model of open chest anesthesia. Chemical polyethylene glycol-2001! Administered intravenously in suspension over a dosage range of 0.1-10 ow/'q. An increase in contractility of up to 49% was observed with a maximum increase in pulse rate of only 14%.

The compounds of this invention may be administered orally or intraperitoneally in the form of oral solutions, tablets and capsules, and determining the optimum dosage and mode of administration is within the judgment of the physician.

Patent applicant: USV Pharmaceutical Corporation Representative: Patent attorney: Ryoji Kawase Patent attorney: Takehiko Saito

Claims (1)

[Claims] 1. The following formulas ■ and ■ [In the formulas, R8, R3, R6 and R1 are independent KH, alkyl, aryl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, mercapto, mercaptoalkyl, alkylthio, Amine, alkylamino, aminoalkyl, carboxaldehyde, carboxylic acid and its salts, carbalkoxy, alkanoyl, cyano, nitro, halo, trifluoromethyl, sulfonyl,
an alkylsulfonyl chain-branched sulfonamide, or R, , R, , R6 and R together with adjacent groups form a methylenedioxy group; R4 is H
, alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, alkanoyl or alkanoyloxy; alkyl, aryl, hydroxyalkyl, alkoxyalkyl or aminoalkyl substituent on the nitrogen; R2 and R, independently; and X is oxygen, sulfur, imino, hydroxyimino, or hydrazino. 2, R, and R3 are hydrogen; Ft; R, is hydrogen;
hydroxy, halo, mercapto or alkylthio; t; Rs is hydrogen, a carboxylic acid and its salts, or an ester (the group on the ester oxygen is alkyl, alkoxyethyl or aminoalkyl); R4 is hydrogen, alkyl , alkenyl, aryl, aralkyl, hydroxyalkanoyl, or alkanoyloxy; R@ and R7 are independently hydrogen, alkyl, alkoxy, hydroxy, norogen, trifluoromethyl, or alkylsulfonyl; & is halo, amino , alkoxy, alkoxyamino, hydrazino or mercapto; and X is oxygen, sulfur or imino. 8 The above alkyl, hydroxyalkyl, alkoxy,
The alkyl moiety in minoalkyl, alkylamino, alkylthio, mercaptoalkyl, alkanoyl, aralkyl and carboalkoxy contains 1 to 8 carbon atoms; the above alkenyl and alkynyl contain 2 to 8 carbon atoms;
2. A compound according to claim 1, containing 5 carbon atoms. 4, R, and R5 are hydrogen, and taRs is hydrogen, a carboxylic acid and its salt, or an ester (provided that the group on the ester oxygen is an alkyl having 1 to 8 carbon atoms, or an aminoalkyl); ; R4 is hydrogen, hydroxy, alkyl having 1 to 8 carbon atoms, aralkyl having 1 to 8 carbon atoms in the alkyl group, and fil
alkanoyl or alkoxy having ~8 carbon atoms; R. is hydrogen, alkyl, trifluoromethyl, or alkylsulfonyl having 1 to 8 carbon atoms; R, is hydrogen or 1 to 8; and X is oxygen. 5, R1 is hydrogen or hydroxy; R is hydrogen,
Carboxylic acids and their salts, or restesters (however, the group on the ester oxygen is an alkyl group having 1 to 8 carbon atoms, or an aminoalkyl group); 7?4 is 1 to
is an alkyl group having 8 carbon atoms: R6 is hydrogen;
It is ノ・口 or trifluoromethyl and 1. is hydrogen; and X is oxygen. 6.5-Methyl-4-oxo-7-trifluoromethyl-
The compound according to any one of claims 1 to 8, which is 4゜5-dihydroimidazo(i,5-a)quinogyzaline-8-carboxylic acid ethyl ester 7.4-oxo-5-propyl -4,5-dihydroimidazo(1,5-5J quinoxaline-8-carboxylic acid ethyl ester) The compound according to any one of claims 1 to 8. 8.7-chloro-4-oxo -5-propyl-4,5-
The compound according to any one of claims 1 to 8, which is dihydroimidazo(1,5-83 quinoxaline-8 carboxylic acid ethyl ester). 9.7-chloro-1-hydroxy-4-oxo-5 -Propyl-4,5-dihydroimidazo(1,5-(ZJ) The compound according to any one of claims 1 to 3, which is quinoxaline. 10.7-chloro-1-hydroxy-4-okino 5-
The compound according to any one of claims 1 to 8, which is propyl-4,5-dihydroimidazo[1,54J quinoxaline-8-carboxylic acid. 11. 7-chloro-1-hydroxy-4-okino 5
-propyl-4,5-dihydroimidazo[l,5-α]
The compound according to any one of claims 1 to 8, which is quinoxaline-8-carboxylic acid ethyl ester. 12.7-chloro-1-hydroxy-4-oxo-5-
Propyl-4,5-dihydroimidazo (1, “5-α”)
The compound according to any one of claims 1 to 8, which is quinoxaline-8-carboxylic acid-β-N,N-dimethylaminoethyl ester or its hydrochloride. 13. Next formula! [In the formula, Rl, Rs, R6 and R7 are independently H1 alkyl, aryl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, mercapto, mercaptoalkyl, alkylthio, amine, alkylamino, aminoalkyl, carboxaldehyde, carboxylic acid and its salts, carbalkoxy, alkanoyl,
is cyano, nitro, halo, trifluoromethyl, sulfonyl, alkylsulfonyl or sulfonamide;
Or A'+, Rs, 7? a and R7 together with adjacent groups form a methylenedioxy group: R4 is H, alkyl, alkenyl, alkynyl,
Aryl, aralkyl 1. hydroxy, alkanoyl or alkanoyloxy;
Tetracylo, carboxaldehyde, hydroxyalkyl, carboxylic acid and its salts, or ester and amide derivatives (provided that the ester oxygen or amide nitrogen has an alkyl, aryl, hydroxyalkyl, alkoxyalkyl or aminoalkyl substituent) AF);R. Ifi, H, alkyl, aryl, halo, amino, alkylamino, arylamino, hydroxyamino, hydroxy, alkoxy, mercapto or alkylthio; and In the production of the above formula I, in which R4 is OH, a compound of the following formula (R5) [in which R,, R,, Rm, R7, and R3 are as defined above] is reductively ring-closed. and converting this OH group to another substituent of R4 by a substitution reaction: and converting this compound of formula (1) to the following formula I 5 [wherein R8 is H1 alkyl, aryl, halo, amino, alkylamino, arylamino, hydroxyamino, hydroxy, alkoxy, mercapto or alkylthio, and R1, R, , R2H, , R1 and R3 are as defined above], the enol OH of Rm is added to By replacing R8 with another substituent by a substitution reaction, in particular OH can be replaced with H! IC substitution and conversion by K replacing H with alkyl, alkanoyl, aryl, aralkyl or alkonyl; and optionally forming pharmaceutically acceptable acid addition salts of these compounds; A method for producing a compound selected from the group consisting of the above formula (1) and (2).