JPS6028971A - N-substituted flavone-8-carboxamide derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The N-substituted-flavone-8-carboxamide derivative of formula I [R1 is H, methyl or ethyl; R2 is lower alkyl, lower alkoxy, halogen or nitro; A is -(CH2)n- or group of formula II; n is 2 or 3; X and Y are H or methyl; the group of formula III is amino group wherein R3 and R4 are lower alkyl or a cyclic amino group wherein R3 and R4 together form a ring] and its acid addition salt. EXAMPLE:N-(2-Diethylaminoethyl)-3,3'-dimethylflavone-8-carboxamide. USE:It has papaverine-like action, micturition reflex suppressing action, bladder contracting action, etc. and is useful as a remedy for the urethral disorder such as pollakiuria. PREPARATION:The compound of formula I is prepared by reacting the flavone-8- carboxylic acid halogenide derivative of formula IV (X is halogen) with the diamine derivative of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel N-substituted flavone-8-carboxamide derivative, a pharmacologically acceptable acid addition salt thereof, and a method for producing the same.

More specifically, the present invention relates to general formula (1) (wherein R1
represents a hydrogen atom, a methyl group or an ethyl group, R2 represents a lower alkyl group, a lower alkokene group, a halogen atom or a nitro group; It represents an atom or a methyl group, an amino group which is a lower alkyl group, or an amino group formed by combining R3 and R4 to form a ring. The present invention relates to a novel N-substituted furazano-8-carmexamide derivative represented by the following formula, a pharmacologically acceptable acid addition salt thereof, and a method for producing the same.

In the general formula (I) of the present invention, the lower alkyl group represented by R2 is methyl and ethyl.

Propyl, isoglobil, butyl, isobutyl.

tart -F fluorine, lower alkoxy groups include methoxy, ethquine, propoxy, isoglopoquine, butoxy groups, etc., and halogen atoms include fluorine, chlorine, and bromine atoms.

Examples of the amino group represented by include dimethylamino, diethylamino, dipropylamino, dibutylamino, methylbutylamino, hyrolidino, piperidino groups, and the like.

The compound represented by the general formula (1) of the present invention can be converted into a pharmacologically acceptable acid addition salt as desired, or a base can be liberated from the generated acid addition salt. .

Examples of pharmacologically acceptable acid addition salts of the compound represented by the general formula (1) of the present invention include mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. salt,
Or acetic acid.

Maric acid, hexamaric acid, citric acid, oxalic acid.

Examples include organic salts such as tartar source.

The novel N-substituted flavone-8-carzaxamide derivative represented by the general formula (1) of the present invention can be produced as follows.

That is, a furazoacid halide derivative represented by the general formula (II) (wherein R1 and R2 have the same meanings as above and X represents a halogen atom) and the following general formula ( 11) It can be produced by reacting with the diamine derivative shown in (11)).

A particularly preferred embodiment of the method of the present invention is the general formula (
Using at least 1 equivalent, preferably 1.1 equivalent, of the furan-8-carboxylic acid halide derivative represented by the general formula (II) per 1 equivalent of the diamine derivative represented by III), in an organic solvent. It's about getting them to react.

Any organic solvent may be used in the method of the present invention as long as it does not inhibit the reaction, for example,
Acetone, ether, tetrahydrofuran, dioxane, benzene, toluene, chloroform, etc. are used.

Further, the reaction is carried out under heating and reflux from room temperature, particularly preferably at room temperature.

The flavone-8-carzanoic acid halide derivative represented by the general formula (II), which is the starting material in the production method of the present invention, is represented by the following general formula (IV) (where R1 and R
2 represents the same meaning as above. )Flavone-8 indicated by
- Manufactured by converting a carboxylic acid derivative into an acid halide according to a conventional method before use.

Incidentally, the furazano-8-carbic acid derivative represented by the general formula (IT) is also a new substance, and is produced as shown in the figure below.

(In the formula, R1 and R2 have the same meaning as above or represent a halogen atom.) In addition, the raw material compound used in the production method of the present invention,
The diamine derivative It represented by the general formula (11) is a known substance, for example, as described in the Journal of the American Chemical Society 4 (Jour
nal of the A+nerioanChemi
cal 5ociety) Volume 72, Page 3004 (19
50).

Vol. 68, p. 100 (1946), Vol. 68, p. 1607 (19
4(S), Vol. 66, p. 725 (1944).

Vol. 65, p. 2012 (1943), Helvechi Riki, Kimi Riki,
Acta (He1vetica aimica Acts)
) Vol. 26, p. 1172 (1943), Annual Report of the Shiono Research Institute, Vol. 10, p. 1 (1960), Pharmaceutical Journal, Vol. 62, p. 224 (
1942) and others.

The structure of the compound represented by the general formula (1) of the present invention is:
Nuclear magnetic resonance (NMR) spectrum and infrared absorption (engineering
) is determined by the spectrum. NMR spectrum was measured at room temperature using a JEOL IFX-90Q spectrometer and using tetramethylsilane (TMS) as an internal standard. The SR vector was measured using JASCO Corporation RA-202. The data will be shown below in Example 1.

The novel N-substituted flavone-8-carboxamide derivatives represented by the general formula (1) and their pharmacologically deceptive acid addition salts produced in this way have papaverine-like effects, urination $i It has excellent effects on bladder function such as suppressive action and bladder contraction action, and is extremely useful as a therapeutic agent for urinary tract disorders such as frequent urination.

Hereinafter, the present invention will be explained by examples.

Example 1 N-(2-diethylaminoethyl/'')-313'-dimethylflavone-8-carboxamide31di-dimethylflavone-8-carmenic acid chloride (3,3'-dimethyl7Lab7-8-carboxylic acid1 Add 0.36 g of 2-diethylaminoethylamine to 30 g/solution of benzef (prepared from D Og and 0.50% thionyl chloride) and stir at room temperature for 2 hours. Add aqueous hydrochloric acid to the reaction solution and shake. The aqueous layer is made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer is washed with water and dehydrated. The solvent is distilled off, and the resulting residue is subjected to columnar centrifugation (ffi). Treatment with l alumina and chloroform gives 0.35 g of the title compound as yellow crystals with a melting point of 795-86°.

Engineering R spectrum v (KBr) rl :3320
(X:NH), 1665+ 1630(-aori,
;o=o) NMR spectrum (ODO13) δpp
m: 0.85 (6H, triple line + J” 7.0 Hz
).

2.16 (31i, - double line).

2.57 (4u, quartet, J=7.01!i).

2.46 (3m, - double line).

2.55 (2H, triple line +, y=6.5nz) +3.
52 (2g, triplet-doublet.

−r = 6.5” + 5.5 n” + triplet due to heavy water addition, J==6.5 Hz).

7.20-7.60C6H, multiplet.

1H disappears by adding heavy water).

8.34 (1m!, double line-double line.

J=8. Q Hys, 2.0H2).

8.37 (1 g, double line-double line.

-r = 7.5 H'', 2.0 Hz) Example 2 N-(6-biperidinoglovir)-3,3'-dimethyl7U-8-carboxamide 3,3'-dimethylflavone -8-force/I/+f acid chloride (3,3°-dimethylaramen-8-car, + --wm 4 n n
-lrt value IP 44 g of 3-biperidinoglobilamine α was added to a solution of 30 g/l of benzene (produced from thionyl 0-50m) and stirred at room temperature for 2 hours. Add an aqueous hydrochloric acid solution to the reaction mixture, shake it, and separate the aqueous layer. The aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer is washed with water and dehydrated. The solvent is distilled off, and isoglobil ether is added to the resulting residue. The precipitate was collected and 0.80 g of the title compound was obtained as reddish brown crystals. Recrystallized from a mixture of acetone and water, melting point 112~
Colorless needles of 114° are obtained.

Engineering R spectrum ν(KBr)tsl =3280 (
,NH), 1640(-ooNri, ”:)a=o
) NMR spectrum (ODO13)δppm: 1.
20-190 (8H, multiplet).

2.20 (311, - double line).

2.10-2.60 (611, multiple M).

2.46 (3H, - 111I).

3.52 (2H, triplet-doublet.

J = 6.5 H2l 5.5 Hml Triple line by addition of heavy water, J = 6.5 Hz).

7.30-7.55 (5H, multiple Iri.

zso~a, i　0　(I　H,　0-F.

Disappeared by adding heavy water).

8.29 (iH, double line-double, 11°J = 7.5
Hz, 2.0 Hz L8.56C111, double line -
Double line.

”~8.0 Hz, 2.Q Hz) Elemental analysis value 0
26H3ONI103 Theoretical value 0 = 74.61 + Hl 7.22 t
N, 6-69 actual value a, 74.24 lead H, 7,171
+ 6.65 Example 3 N-(2-diethylaminoethyl)-3,4'-dimethylflavone-8-carboxamide 3.4'-dimethylflame-8-carboxylic acid "Lido(3,4'-dimethyl 100g flavone-8-carboxylic acid and 0 thionyl chloride
．． (made from 50 ml) of benzene 30s? The solution and 0.36 g of 2-diethylaminoethylamine were treated in the same manner as in Example 2 to obtain 0.91 g of the title compound as pale yellow crystals with a melting point of 108-1135°.

Engineering R spectrum y (KBr) ml: 1510 (
, :NH), 1635(-0ONgu',";a=o>N
MR spectrum (ODO13) δppm: 0.84
(61 (, triple line, : r = 7.0 Hz) 12.1
7 (3H, - double line).

2.38 (4H, 4 weight + J = 7. Oaz)
+2.45 (!l)I, - double line).

2.55 (2H, triple line, r = 6.5Hz).

3.52 (2H, triplet-doublet.

, T = 6.5 Hz, 5.5 Hz.

Triple line 1.7 = 6.5H2) by adding heavy water.

7, 20-7.65 (6H, multiplet.

1H disappears by adding heavy water).

8.34 (IH, double line-double line.

J=8. QHz, 2. OHZ L8.37 (
1H, doublet-doublet.

J = 7.5 ng, 2-OHz) According to a conventional method, the 7-malate salt of the title compound is prepared. Recrystallization from ethanol gives colorless 1-rhythm crystals with a melting point of 150-151°.

Elemental analysis value 024H2BN203/04H404 theoretical value 0.66.13 + Hl 6.34 + Nl
5.51 Actual value a, 66.13+H+ 6.38+
N, 5.46 Example 4 N-[(2-dimethylamino/-1-methyl)ethyl]-
3,4°-dimethyl7-8-carboxamide 3.4'-dimethylflavone-8-carboxylic acid chloride (3,4'-dimethyl7-carboxylic acid 1.
OOg and thionyl chloride Q, 50 ml)
30 l solution of benzene and (2-dimethylamino-1
-Methyl)ethylamine (0.31 g) was treated in the same manner as in Example 2, and the title compound was formed as pale yellow crystals.
Obtain 97 g. Recrystallized from ethyl acetate,
Light brown needles with a melting point of 155-1560 are obtained.

Engineering R spectrum y(KBr)a+l:5520C
NH) + 1640 (-QO<,”::-a=0)
NMR spectrum (0DO13)δppm:t23
C5H, double ill J=6,51iz).

2.07 (<SH, - double line).

2.17C5H, - weight 41ri.

2.00-2.50 (211, multiplet).

2.46 (3H, -Jim).

4.00-4.40 CIH, multiplet).

710-7.65C6H, multiplet.

1H disappears by adding heavy water).

8.37 (IH, double line-double line.

J=8.0Hffi12.0Hffi) 18.4
4 (Ill, doublet-doublet.

J = 7.5Hsc, 2. QHg) Elemental analysis value 0pJ1261izOs Theoretical value o, 72.99 + Ml 6.92 +
pi, 7.40 actual value o, 72.92 f Hl
6.77 + Nl 7.40 According to a conventional method, prepare the 7-malate salt of the title compound. Recrystallized from ethanol,
Colorless platelet crystals with a melting point of 187.5-1895° are obtained.

Elemental analysis value 023H26N203°04H404 Theoretical value 0.65.58 + H+ 6.11 + N+
5.66 Actual value 0.65.64 i H, 6,26+
II 5.59 Example 5 N-(2-diethylaminoethyl)-3°-methoxy-
3-Methyl 7-men-8-carboxamide 3-methoxy-6-methylflavone-8-carphonic acid chloride (from 2.00 g of 6'-methoxy-6-methyl 7-rabone-8-carbic acid and 4.72 ml of thionyl chloride) The same treatment as in Example 2 was carried out using a solution of 60 am. Acetic acid: Recrystallized from a mixture of L f At 1 X ethyl and isopropyl ether, melting point 90.5-91
．． Colorless needles of 5° are obtained.

Engineering R Spectrum (KE r) (11-1.

3450(,>N)I), 1670.1630(-0
ON, ;o=o) NMR spectrum (0DO13
) δppm: 0.85 (61 (, Mie Ml, T
= 7.0 H2).

2.18 (3H, - double line).

2.39 (4H, quartet ry = 7.0H2) 12
．． 56 (2H, triple line, J = 6.5H2)13.
53 (2H, triplet-doublet.

J=65H2+5.5Hz.

Triple line 1 from heavy water addition, r = 6.51 (z)
.

3.87 (3H, -fEM).

695-7.60 (6H, multiplet.

Addition of heavy water - 1H disappears).

8.36 (2H, double line 1.7 = 7.5Hz) Elemental analysis value 024H28N204 Theoretical value 0.70.57 stones H, 6,91iN+ 6.8
6 Actual value 0.70.34-H, 6,71-N, 6.7
2 Example 6 N-(2-hyheridinoprobil)-3°-methoxy-3
-Methyl 7 Annoyance No 8-Calzaxamilo °-Methoki V
5-Methyl 7Uzanocal chloride (3'-
Using methoxy-3-methyl solution and 0.41 g of 2-piperidinopropylamine, the same procedure as in Example 2 was carried out to obtain 0.61 g of the title compound as pale yellow crystals. Recrystallization from a mixture of ethyl acetate and isopropyl ether gives colorless needles with a melting point of 95-97°.

Engineering R spectrum '(KEr)aR-1.

3450 (>NH), 1660.17530 (-CoN
Gu,, :O=O) NMR spectrum (ODO13)
δppm: 0.91 (3H, doublet 1 y-7,0H
2L1.10-1.4DC6H, multiplet).

2.19 (3H, - Heavy J.

1.80-2.85 (5H, multiplex, IJ).

6.00-3.75 (2H, multiplet.

By adding heavy water, δ: 3.221) pm+1ii+double line-double 11J+ J-13,5H2+9.5Hz+
δ: 6.57 ppm+I H1 doublet-doublet+J-13.5Hz, 5.5Hz).

3.87 (3H, - double line).

6.90-7.60iH, multiplet.

1H disappears from addition of heavy water).

8.31 (IH, double line-double line.

J = 7y5az + 2.0Hz).

8.37 (IH, double line-double line.

, r = 8.0H2l 2.0Hz) Elemental analysis value 026H3ON204 Theoretical value o, 71.87; H,6,96+N,
6.45 actual value o, 71.80 soaked H, 6,91;
N, 6.47 Example 7 N-(2-diethylaminoethyl)-4'-methoxy-3-methylflavone-8-carboxamide 4'-methquine-6-methylflavone-8-carzanoyl chloride (4' -methoxy-6-methyl7rabone-8-
Using a benzene 50d solution of 100 g of carboxylic acid and 0.71 s of thionyl chloride and 0.34 g of 2-diethylaminoethylamine, the same procedure as in Example 2 was carried out to obtain 1.05 g of the title compound as pale yellow crystals. obtain. Recrystallization from ethyl acetate gives colorless needle-like crystals with a melting point of 125°5-127°.

Engineering R spectrum ν(KBr)a+ 1 :3320(
in), 1635 (-0ON,', a=o)
/ MMR spectrum (ODO13) δppm: 0.8
5 (6H, triple line 1.7 = 7.0azL2.18(
3H, - double line).

2.40 (4H, quartet +, y=7.ouz).

2.57 (2I (, triple line + J = 6.5”s)
+3.53 (2g, triplet-doublet.

J = 6.5Hz, 5.5az.

By adding heavy water, Mie II, , T = 6.5Hz) 13
．． 90(31(,-heavy!13).

7.04 (21, double line I J = 9.0H2) 17, 2
0-7.50 (IH, broad.

Disappeared by adding heavy water).

7.45 (IH, triple line + J = 7.5Hz) +7, 6
4 (2T1. double line, , r=9.0Hz) 18.3
2 (IH, double line-double line.

J=75 Hzl 2-OHz) Elemental analysis value 024H2BN204 Theoretical value o, 70.57 iH, 6,911N+ 6
．． 86 Actual value 0.70.42 iJ 7.04 i
Ml 6.85 Example 8 y-(2-diethylaminoethyl)-3'-chloro-
3-Methylflavone-8-carzaxamide 3°-chloro-3-methyl7-Cno8-carboxylic acid chloride (1.00 g of 3'-chloro-3-methylwallamen-8-carboxylic acid and 0 thionyl chloride) 0.33 g of 2-diethylaminoethylamine was added to a benzene 40-resistant solution of (prepared from .46 ml) and stirred at room temperature for 80 minutes. Add an aqueous hydrochloric acid solution to the reaction mixture, shake it, and separate the aqueous layer.

The aqueous layer is made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer was washed with water and dehydrated. The solvent is evaporated and the resulting residue is treated with column chromatography (carrier Nisilica gel, eluted with chloroform and chloroform containing 1% methanol) to obtain 0.39 g of the title compound as yellow crystals. Recrystallization from inglobil ether gives colorless plate crystals with a melting point of 116-117°.

Engineering R spectrum ν(KBr)3-1:3280(/N
u) 11660.1630 (-0ON, ;o=o)N
MR spectrum (ODO13) δppm: 0.84
(6■, triple line 1.7 = 7.oHz) +2.15
(3H, - heavy 41ri.

2.39 (4H, quartet + J = 7.oHz) + 2.5
6C2H, triple line 1. 7=6.5Hz) 13.52(
2H, triplet-doublet.

By adding heavy water, triplet line 1.7 = 6.5Hz)17.
46CIH, triplet, y = 7.5Hs).

7.10-770 (5H, multiplet.

1H disappears by adding heavy water).

8.31 (IM, double line-double line.

, T = 7.5Hz, 2. p H2).

8.35 (IH, double line-double line.

I=7.5Hz, 2.0Hz) Elemental analysis value 0
23H2501N203 theoretical value o, 66.90 +
H, 6, 10+ L 6.78 Actual value a, 66.
67 i H, 6,18+ N, 6.56 Example 9 N-(2-5/ethylaminoethyl)-3-methylfurazano-8-calxamidoza-methyl 7men-8-carboxylic acid chloride ( 6°−
A solution of 100 g of methylflavone-8-carboxylic acid and thionyl chloride Q (prepared from 52 ssl) in benzene 40 and 2-diethylaminoe gives 0.90 g of the title compound as pale yellow crystals. Recrystallized from ethyl acetate, melting point 1<50.5 to 1/i2.5°
colorless needle crystals are obtained.

Engineering R spectrum ν(KBr)011:3530C
':;NH), 1670.1635(-0ON, n0
=0)NMRXpeI)ru(0DO13)δppm
: 0.88 (61(, Mie s, J = 7. QHz
).

2.45 (3H, - weight I weight.

2.49 (4H, quartet, J=y, ouzL2.
69C2H, Mie II + J=' 6. DH!
).

3.63 (2H, triplet-doublet.

J=6. OHz, 5.5HzI By adding heavy water, triple Ml, r = 6.0H2)16.
77 (1H, - double line).

7.10-7.80 (6H, multiplet.

1H disappears by adding heavy water).

8.14 (IH, double line-double line.

J=7.5 Hz + 2. [IHz)+8.2
9 (IH, double line-double line.

J = 7.5H2,2, DI (Z) elemental analysis value 0
, 23H26N203 Theoretical value 0.72.99 + H, 6, 92 N, 7.
40 Actual value 0.72.59 + Hl 6.85 N
17.28 Prepare the fumarate salt of the title compound according to a conventional method. Recrystallized from ethanol, melting point 167-168.
50 colorless needles are obtained.

Elemental analysis value 023H26N203°04H404 Example 1O N-((2-dimethylamino-1-methyl)ethyl)
-3'-Methylflavone-8-carbixamide 3'-Methylflavone-8-carboxylic acid chloride (3-
40 tons of benzene (prepared from 1.00 g of methyl 7-rabone-8-carboxylic acid and 0.52 ml of thionyl chloride)
* Using the liquid and 0.33 g of (2-dimethylamino-1-methyl)ethylamine, the same procedure as in Example 2 was carried out to obtain 1.0'1 g of the title compound as pale yellow crystals. Recrystallized from ethyl acetate, melting point 156-151
5° colorless needle crystals are obtained.

Engineering R spectrum ν (KBr) "l :3310 (
〉)iH)+1660.1660 (-0ON”, 〉
0=O) HMR spectrum (ODO13) δppm
: 1.41 (3H, double line * J = 6.5Hg) + 2
．． 1(S(6B, -heavy+il).

2.1o-2,65C2H, polyjl[H.

2.4+5 (3H, -heavy, 11ri.

4.10-4.50 (IH, multiplet).

6.77 (IH, - double line).

7i5 (IH, triple line I J=75Hz) 17.10~
7.80 (5H, 1H disappeared by multiple 1IJI heavy water additions).

8.25 (il!, double line-double line.

J=15 Hz, 2. OH2).

8.29 (IH, double line-double line.

J=Z5H+a, 2. OH2) Elemental analysis value 022H24”203 Physical Wa value a, 72.51+H,6,64+W17.69
Actual flA value C972,61+ Hl6.64 BMl
7.69 Prepare the fumarate salt of the title compound according to a conventional method. Recrystallized from methanol, melting point 185-1815
° colorless needles are obtained.

Elemental analysis value 022H24N203 ・04H404'
; I(20Theoretical value 0.64.39 T Hl 5
．． 92 +N+ 5.78 Actual value 0.64.28 i
Example 11 n-(2-diethylaminoethyl)-4'-methylflagen-8-carboxamide 4-methyl7rabone-8-carmenic acid chloride 1J do(4-
A benzene 60 solution of 100 g of methylfuran-8-carboxylic acid and 0.60 # of thionyl chloride) and 0.37 g of 2-diethylaminoethylamine were used and treated in the same manner as in Example 2, and expressed as brown crystals. 0.96 g of compound is obtained.

Engineering R spectrum ν(KBr)α-1: Ml at 3320
(), 1670+ 163Q (-ooy<,'o=o
) NMR spectrum (ODO13) δppm +0.
90 (6n, triple line, , r = 7. [1) 1ff
i) 12.441H, - double line).

2.51 (4H, 4 weight, J=7.0mg)+2.
70 (2H, triplet 1, rJ, Ql(z).

3.63(21(, Triplet-Doublet.

-r = 6-D H1' + 5.5 H2I triplet by addition of heavy water, J = 6.0)IZ).

6.78 (IH, - heavy! 13).

7.32 (2H, double line I J = 8. [1Hz)
.

7.46C1H, triple line, y = 75Hz).

7.00-7.50 (IH, Broad.

Disappeared by adding heavy water).

7, 79 (2H, double line * J” 8.0H2).

-8,15 (IH, 2 lines) - Double line.

1 = Z5Hz, 2. OH2)+8.32(1
3. Double line - double line.

1 = 7.5Hz, 2.0H2) Example 12 N-(2-diethylaminoethyl)-3'-methoxyflavone-8-cal Cxamide 31-methoxyV7ugino8-carphosphoric acid chloride (3
Benzene 30 (prepared from '-methoxyfurano8-carboxylic acid 1, ODg and 0.49d thionyl chloride)
ml solution and 2-diethylaminoethylamine 0.35
The following treatment was carried out in the same manner as in Example 2 using g, to obtain the title compound 0° as pale brown crystals.

Engineering R spectrum　ν(KBr)m-1.

331 o<'>11>+ 16551163[1(-
oo<,:a=o>NMR spectrum (ODO13)
δpp+n: 0.89 (6H, triple line, J = 7
0H2).

2.49C4H, quartet, :r = 7.01(2)
12.69C2H, triple line, , T = 6.5Hz)
13.62 (2m, triple line-double line.

-T = 6.5HIg, 5.0Hz.

Triple line IJ = 6.51 due to addition of heavy water.

3.89 (31 (, -1m).

6.80 (IH, - heavy M).

7.47 (IH, Mie M + J = 7.5 Hm
).

6.95-7.60 (5H, multiplet.

1H disappears by adding heavy water).

8.15 (1H, double line-double line.

J = 7.5Hz, 2.0Hz).

8.32 (IH, double line-double line.

J = 75 Hm l 2.0 Hzg) Elemental analysis value 0°H26N204 Theoretical value 0.70.0516.64117. "r.

Actual value a, 70.06 + 1 (16,65i M
T 6.96 Prepare the 7-malate salt of the title compound according to a conventional method. Recrystallized from ethanol, melting point 172-173
0 colorless needle crystals are obtained.

Single element analysis value 0g5H2sN20a・04H404 Theoretical value a, 63.52+H15,92115,49 Actual value o, <53.42 +)It 6.20 i
y, 5.45 Example 13) i-(2-piperidinoglovir)-3'-methoxyV7
Ravone-8-carboxamide 3'-methoxyfuraC-8-carbic acid chloride (3
Benzene 30 (prepared from 1,00 g of '-methoxy V7 labone-8-carboxylic acid and 0.494 g of thionyl chloride)
Using d solution and 0.43 g of 2-piperidinoglobilamine, the same procedure as in Example 2 was carried out to obtain 1.09 g of the title compound as pale yellow crystals. Recrystallization from ethanol gives pale brown platelets with a melting point of 163-164°.

Engineering R spectrum　ν(KBr)as-1.

52yo<'), 1655.1625 (→Obit>O=O) NMR spectrum ('0DO13)δpp
m: 100 (3I (, double line, , r = 6.5Hf
fi) 11.10-1.40 (6)1, multiplet).

1.85-3.00 (5H, multiple M).

3.23(11(, double line-double line-double line.

J=13.5Hz, 10.5Hz, 2. QHz.

Double line-double line due to addition of heavy water.

J=1 3.51(z, 1 0.5Hz)+3.74(
IH, double line-double line-double line.

, r = i 3.5H2l 6.5H2,5,QHz
.

Double line-double line due to addition of heavy water.

J=13.5H215,0H2).

3.88 (3H, - double line).

6.81 (IH, - heavy I!ri.

7.48 (IH, triple line 1.7 = 7.5Hz) 17
, 00-7.60 (5H, multiplet.

1H disappears from addition of heavy water).

8.15 (IH, double line-double line.

, T = 7.5Hz + 2. QHz)+8.3
4 (IH, doublet - doublet 1 J=7.5H2+2.0H2) Elemental analysis value 025H28N204 Theoretical value 0.71.41+H, 6,711,6,66 Actual value o, 71366H16,82i Nl 6 .58
According to the conventional method P-, the 7-malate salt of the title compound is prepared. Recrystallization from methanol gives light brown needles with a melting point of 175-176.5° (decomposed).

Elemental analysis value 025H28N204・04H404・-
1H20 theoretical value a, 63.84 + H, 6,10
+ N15.15 actual value 0.63.94iH, 6,0
21,5,10 Example 14 N-(2-diethylaminoethyl)-4''-1toxyflavone-8-carboxamide 4'-methoxyfurazano 8-carphosphoric acid chloride Cd
30-solution of benzene (prepared from 1,00 g of methoxy 7-rabone-8-carzanoic acid and 0.74 ml of thionyl chloride) and 0.5 g of 2-diethylaminoethylamine.
Using 5g, the following treatment was carried out in the same manner as in Example 2, and the melting point was 156.
．． Compound 0.5-158.5° as light brown crystals.
Obtain 91g.

Engineering R spectrum ν (KBr) “1:33100
■) + 1655 + 1635 ('aO<+>=o
) NMR spectrum (OI1013) δμm: 0.9
3 (6H, triple line + J = l OHz) + 2.53
(4H, quadruple i11., r = 7: 0uz) +2
．． 71 (2H, triplet 1'J = 6.QHz).

”r, 65c2H, triplet-doublet.

J=6.0 H45, 5Hz.

By adding heavy water, triple line, y = 0.0HII).

3.89 (a, - double line).

6.70 (IH, -weight 1s).

7, 02 (21 (, double line, , T: 9. oaz
) +7, 00-730 (1a, Broad.

Disappeared by adding heavy water).

7, 42 (I H, triple line + J” 75H2) +7
85 (2H, double line + J” 9.0azL8.09(
IH, double line-double line.

J=Z5H2,2,0H2)1 8.28 (1H, double line-double line.

J=75 Hz + 2.0 Hz) colorless platelets of 154° are obtained.

Elemental analysis value 023H26N204°04H404°H
20 Theoretical value 0.61.56 + Hl 610 +
Nil 5.30 actual value a, 61.26-Ml 5.
89 + N15.37 Example 15 N-(2-biperidinoglovir)-4°-MethokiV7 Uzano 8-Carboxamide 4'-Methoxyfurazano 8-Calphosphoric acid chloride (4
2-piperidinoprobylamine was added to a suspension of 60 g of benzene (prepared from 3.00 g of ``-methoxyflavone-8-carmenic acid and 1.48 wl of thionyl chloride)''.
Add 30 g of the mixture, stir at room temperature for 40 minutes, and heat under reflux for an additional 1 hour. Next, add an aqueous hydrochloric acid solution to the reaction solution, shake it, and separate the aqueous layer. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The acetic acid ethyl ester layer was washed with water and dehydrated. The solvent is distilled off, and ether is added to the resulting residue. The precipitate was collected and 1.80 g of the title compound was obtained as light brown crystals. Recrystallization from ethanol gives colorless needles with a melting point of 171.5-174.5°.

Engineering R spectrum ν(KBr) scratch-1:3300 to N
H), 1660.1640<-0ON,>o=o)N
MR spectrum (ODO13) δppm: 1,06
(5H, double line 1, r = 6.5g”) +1.1
5-150 (6H, multiple M).

2.05-3.95 (7H, multiple M).

0.89 (3H1-double line).

6.75C1H, - weight 11J).

7.03 (2u, double line I J = 9.0az) +74
7 (in, triplet, , T = 7.5H2).

7.35-7.65<1H, broad.

Disappears from the addition of heavy water).

7.88 (2H, double line 1.7 = 9.oHz)+
8.12 (11 (, double line - double line.

J” 7.5Hz, 2.0’Hz).

8.34 (IH, double line-double line.

J=7.5H2,2,OH2) Elemental analysis value 025H28N204 Theoretical value a, 71.41 B56.71 +N, 6
．． 66 actual value a, 71.54+H, 6,74+H+
6.50 Conventional method - Accordingly, the fumarate salt of the title compound is obtained. Recrystallized from methanol, melting point 216-219
° (decomposition) to obtain colorless needle crystals.

Elemental analysis value 025N (28N204・04H404 Theoretical value 0.64.911.6,011.5.22 Actual value 0+ 65.01+ H, 5,87t Nl 5.1
1 Example 16 N-(2-diethylaminoethyl)-6-chloroflavone-8-carboxamide 3'-chloroarameri-8-carboxylic acid chloride (7)
- Benzene 30j (prepared from 91.00 g of chloroaramen-8-carvone and 0.73 ml of thionyl chloride)
I! solution and 2-diethylaminoethylamine 0.55
The following treatment was carried out in the same manner as in Example 2 using g, to obtain 1.06 g of the title compound as light brown crystals.

Engineering R spectrum ν(KBr)am-123320 (
';NH), 1670.1635(-0ONgu, :;a
mo) NMR spectrum (ODG13) δppm:
0.94(6)1. Triple line, T = 7.0H2).

2.58 (4H, quartet, , T = 7.01(z)
.

2.79 (2H, triple line + J = 6.0'b") + 3
, 69 (2H, triple silver doublet.

, r = 6.0H2l 5.5H21 By adding heavy water, the triplet line 1, T = 6: 0nz) + 6.76 (1H,
- weight 11J).

7.15-7.90C6H, multiplet.

rain disappears by adding heavy water).

8.09 (IH, double line-double line.

J=75Hz+2. QHg).

8.25 (1H, double line-double line.

J=8-OH2+ 2.0 Hz) According to a conventional method, the fumarate of the title compound is obtained. Recrystallization from ethanol gives colorless needles with a melting point of 186-188°.

Elemental analysis value 022H, B501N203・04H40
4.-H2O2 Theoretical value or 59.601+ 5.39+N+ 5.
35 actual measurement value a, 5958 蓓H, 5,48+L 5
．． 37 Example 17 N-(3-piperidinoglovir)-31-chloro7men-8-calCxamide 3'-chloroflavone-8-carboxylic acid chloride (3'
The following procedure was carried out in the same manner as in Example 2 using 60 liters of benzene solution of chloroflavone-8-carboxylic acid (1.00 g and thionyl chloride 0.73 ml) and 0.43 g of 3-piperidinoglobilamine. 1.14 g of the title compound are obtained as pale brown crystals.

Engineering R spectrum ν(1(Br) “1:3315(
〉NH), 1665.1635 (-0ON, 〉amo
) NMR spectrum (ODO13)δppm: 1.
00-1.40 (1 (, multiplet).

1.70-2.00 (2H, multiplex + IJ).

2.05-2.55 (4, multiplet).

2.49 (2H, triple line, , r = 6.0H2)1
3.72 (2H, triplet-doublet.

J=6.0Hz, 5. Q　Hz　.

By adding heavy water, triple line, y = 6.0H2)++S
, 82 (1H, - double line).

730-760 (3H, multiplet).

7, 70-8.05 (2H, multiple #).

8.04 (1H, double line-double line.

J = 7.5Hz, 2. OH2).

8.27 (IH, double line-double line.

J = 8.0Hz, 2. OH2)+ 8.55-8.85 (IH, Broad.

Disappears by adding heavy water) According to the conventional method, make the fumaric acid solution of the listed compound. Recrystallization from a mixture of ethanol and ether gives a melting point of 151.
Light brown needles of 5° to 153.5° are obtained.

Elemental analysis value 024H2501N203 ・04H40
4 Theoretical value 0,62.16 + H,5,40-N,5
．． 18 Actual value 0.62.16 + Ml 5. i+
N, 5.22 Example 18 N-(2-e)ethylaminoethyl)-4°-chloro-
FuraC-8-CalCxamide 4°-Chlorofurano8-carboxylic acid chlori1' (
40w of benzene (produced from 1.00g of 4'-chloro7-mene-8-caldonic acid and 0.73m of thionyl chloride)
Using 0.35 g of 1 and 2-diethylaminoethylamine, the same procedure as in Example 2 was carried out to obtain 0.83 g of the title compound as pale brown crystals. Recrystallization from ethyl acetate gives colorless needles with a melting point of 181.5-184°.

IR spectrum ν(KBr)am-1.

3325(,,NH)1165511640(-0ON
So, ;o=o) NMR spectrum (0DO13)δp
pm: 0.92 (6! (, triple line, J=70uz).

2.52 (4H, quartet, r = 7.0H2).

2.69C2H, triple line + J = 6.0H2)13.
62 (2H, triplet-doublet.

J = 6. QHz, 5. QHz.

By adding heavy water, triplet 1, r = 6. (]Hz)
.

6.77 (IH, - heavy is).

7.45 (IH, Mie III + J = 7.5 a
z).

7, 50 (2H, double line, J = 9Q Hz).

6.95-7.20 (1H, broad.

Disappeared by adding heavy water).

7.8 (S (211, double line, J = 9.0 Hz)
+8.07 (IH, double line - double line.

J = 7.5Hz, 2. QHz).

8.50 (IH, double line-double, W.

J = 75Hz, 2,0IIIZ) Elemental analysis value
022H2301N, 203 theoretical value a, 66.24
+H, s, al + N, 7.02 actual value o,
66.08 + H, 5,70 + N, 7.04 According to conventional method #C, prepare the fumarate salt of the indicated compound. Recrystallization from methanol gives pale yellow needles with a melting point of 174.5-176°.

Elemental analysis value 022H23CJIN203 ・04H4
04.H2O2 Theoretical value o, 59.60+H, 5,39+N, 5.
35 actual measurement o, 59.72 + H, 5,45S
N, 5.38 Example 19 N-((2-dimethylamino-1-methyl)ethyl)
-4'-Chloro7Uzano8-Carboxamide4'-Chlorofurazano8-Calphosphoric acid chloride (4'
40 ml of benzene (prepared from 1.00 g of -chloroflavone-8-carboxylic acid and 0.73 ml of thionyl chloride)
Using the solution and 0.31 g of (2-dimethylamino-1-methyl)ethylamine, the following treatment was carried out in the same manner as in Example 2,
0.80 g of the title compound is obtained as pale brown crystals. Recrystallized from ethyl acetate, melting point 215.5-217
Obtain colorless needle crystals.

Engineering R spectrum ν(KEr)m 1 :3330(X
/NH)+1660+1660 (-aow3.”
,,amo) NMR spectrum (ODO13)δpp
m: 1.401H, double line, r = 6.5uz
>+2.20C6H, - double line).

2.10-2.65 (2H, multiple!I).

4.00-4.50 (IH, multiple #).

6.76 (In, - double line).

6.90-7.10 (IH, Broad.

Disappeared by adding heavy water).

7.60-7.60 (IH, multiple M).

7.50 (2H, double line, J=9.0uz)+7.
85 (2H, double line + J = 90Hz).

8.15 (1H, double line-double line.

J = 7.5Hz, 2. Qllg).

8.2<5(1H, doublet-doublet.

J=8. OHg, 2.0Hz) Elemental analysis value 021H2101N203 theoretical value 0.65.54
+ III 5.50 + 1.728i measurement value 0.6
5.191+5.54+N, 717 According to the conventional method, make 7 marl brewed salt of the listed compound. Recrystallization from methanol gives pale yellow needles with a melting point of 1995-203°.

Elemental analysis value 021H2101N203 ・04H40
4.H2Q theoretical value a, 57.86 +H,5,24
5, 5.40 actual value 0.57.59; H, 5, 23
+N, 5.40 Example 2O N-(2-diethylami/ethyl)-4'-fluoro7
Lagen-8-carbixamide 4”-fluoroflavone-8-carboxylic acid chloride (4
Benzene 50
g (solution and 2-diethylaminoethylamine 0.37
The following treatment was carried out in the same manner as in Example 2 using g, to obtain 0.90 g of the title compound as pale brown crystals. Recrystallization from ethanol gives pale yellow needles with a melting point of 173.5-175°.

Engineering R spectrum ν(xBr)am-1:N to 3280
H), 1665.1645.1640 (-0ONg,]C=0) NMR spectrum (0DO13)δ卯m
:0.92 (61!, triple line + :r = 7. [1
) 1z) 12.52 (4H, quartet, , r = 70
112).

2.69C2H, triple line, J=6, □nz).

5.61 (2u, triplet-doublet.

’6-[IHz, 5.5uz.

By adding heavy water, triple line, , T=6. OHg)16.7
3 (IH, -heavy 1s).

7, 00-735 (3H, multiplet.

1H disappears by adding heavy water).

7.44 (IH, triple line, J = 7.5Hz).

7.80-8.05 (2H, multiplet).

8.0(S(IH, double line-double line.

J = 7.5Hs l 2. QHg).

8.29 (IH, double line-double line.

J = 7.5Hss, 2.011g) Elemental analysis value C part H237N203 Theoretical value o, 69.09+) I+ 6.06tL 7
．． 33 actual value 0.69131H, 5,79-N, 7.
55 The indicated compound was destroyed with fumaric acid according to a conventional method. Recrystallization from ethanol gives light brown needles with a melting point of 181-183.5°.

Elemental analysis value 02211.23N203°04H404
-H20 theoretical value 0.61.551.5.56+N,
5.52 Actual value 0.61.33+H, 5,90+N+
5.21 Example 21 -(2-biperidinoglovir)-4'-fluoro7rabone-8-casimexamide 4'-fluoroflavone-8-carzanoyl chloride (4
'-Fluorofurane-8-carboxylic acid 1,0g and 0.77 ml of thionyl chloride) in benzene 3011 and 2-piperidi/propylamine 0.4
Using 5 g, the following treatment was carried out in the same manner as in Example 2 to obtain 0.90 g of the title compound as pale brown crystals. Recrystallization from ethyl acetate gives colorless needles with a melting point of 177.5-1795°.

Engineering R spectrum y (KBr)m-1:3310 (
, rm), 16ss□1640 (>o==o)NM
R spectrum (0DO13) J ppm: 1, 0
2 (3K, doublet, :r = 6.5Hz).

1.10-1.50 C6H, Taji [#).

2.00-3.05 (5I(, multijiM).

6.05-3.40 (1) 1. Multiple lines.

By adding heavy water, δ: 3.23 ppm.

Double line-double line, J=13.514z, 10.5
Hz).

355-3.90 (IH, multiplet.

By adding heavy water, δ: 3.74 ppm.

Double line-double line, r=13.5 Hz, 5.0
H2).

6.77 (IH, -41, 1/I>.

7.10-745 (3H, multiplet.

1H disappears by adding heavy water).

7.48 (IH, triple line + J = Z5a”) + 7.8
0-8.10 (2H, 311s).

8.0a (1a, double line-double line.

J=7.5H2+2. QHz).

8.34 (IH, double line-double line.

:r = 15Hz, 2.0Hz) Elemental analysis value 0
24) ip;al+N2O3 theoretical value a, 70.57
s L 6.17; y, 6.86 actual value 0.
70.47 tii, 6.191.6.89 According to the conventional method, prepare the hexamarate salt of the title compound. Recrystallization from methanol gives colorless needles with a melting point of 233-236°.

Elemental analysis value 024H25FN203°04H404 Theoretical value 0.64.11 + 1(,5,57+N,
5.34 actual value o, 64.12 i 1(15,5
2+ N, 5.36 Example 22 If-(2-diethylaminoethyl)-/l'-nitroatrophlavone-8-carboxamide 4'lo7rabone-8-carboxylic acid chloride (4-
The same procedure as in Example 2 was carried out using a benzene 30 d solution of (prepared from 1.00 g of nitrowalamen-8-carboxylic acid and 1.40 m of thionyl chloride) and 0.34 g of 2-diethylamine ethylamine, and yellow crystals were obtained. 0.78 g of the title compound is obtained. Recrystallization from methanol gives tan crystals with a melting point of 2 [17-209°].

Engineering R spectrum v (KBr) cr-1:z, 5oo
Q), 166011640 (-0011:l)o
=o) NMR spectrum (ODO:L3) δppm
:0.95 (6M, triple line, r=7.0uz).

2.53 (4H, quartet 1.r=7.014Z)12.
70 (2!H, triplet, , r = 6.0 H2).

3.62 (2H, triplet-doublet.

J=6. □nz, 5.5Hz+ Triple line from heavy hydrogenated TfrUt, , T=6.0H2)
16.92 (IH, - double line).

6.90-7.15 (1H, Broad.

(disappeared by adding heavy water).

7, 49 (I M , triplet, , r = 7.5H
z).

8.04 (1H, double line-double line.

J = 7.5Hz, 2. QHz).

8.13 (211, double line 1.7 = 9.0Hz) 1
8.33 (IH, double line-double line.

, r = 7.5Hz, 2.011 ri 18.39 (2H
, double line 1. r=9.0H2) Elemental analysis value 022H2
3N305 Theoretical value a, 64.54 + H, 5,66-N, 1
0.26 Actual value 0.64.50 薯H, 5,40+N
, 10.06 Example 23 N-(3-piperidinoprovir)-3'-chloro-3
-Methylfuran-8-carzaxamide 3°-chloro-
6-Methyl 7-men-8-carboxylic acid salt (3'-
Chloro-6-methy/I/7 labone-8-carboxylic acid 1.
00 g and 1.39 ml of thionyl chloride)
Using 30 g of benzene/solution and 0.41 g of 3-piperidinoprobylamine, the following treatment was carried out in the same manner as in Example 2,
1.19 g of the title compound are obtained as pale brown crystals. Recrystallization from ethyl acetate gives colorless needles with a melting point of 128-131°.

IR spectrum v (KBr)am 1 :3310
()iH), 1665.1(530(-0ONgu,'':
10=0) NMR spectrum (0DO13)δppm
: 1.20 to 1.45 (6H, multiple M).

1.71 (2H, triple line, J=6.5Hz).

2.22111. - Heavy II).

2.10-2.40 (4u, multiplet).

2.55 (triple line in 2! J = 6.5 Hz)
+3.57 (2H, triplet-doublet.

-r = (S, 5H2, 5, 5Hz.

Triple line 1.7 = 6.51 (z) due to addition of heavy water.

7.46 (IH, triple line r J = 7.5ag) +7.
40-7.80 (4H, multiple II).

7, 95-8.20 (IH, Broad.

Disappeared by adding heavy water).

8.22 (IH, double line-double line.

J==7.5Hz, 2.0H2).

8.35 (11 (, double line - double line.

J=75H2,2,0Hz) Elemental analysis value 025H27CIN203 theoretical value 0.6
8.41 + Hl 6.20 t Nl 6.38 Actual value 0.68.41 +H, 6,23; N, 75.
17 According to a conventional method, the fumarate salt of the title compound is prepared. Recrystallization from ethanol gives light brown needles with a melting point of 124-125.5°.

Elemental analysis value ○25H2701N203・0aH404
Theoretical value 0.62.76: Hr 5.63+N, 5.
05 Actual value 0.62.75 + H,5,7it
N. 4.89 Patent applicant Hokuriku Pharmaceutical Co., Ltd.

Claims (1)

[Scope of Claims] (In the formula, R1 is a hydrogen atom, a methyl group, or an ethyl group,
2 represents a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group, and in the group -(OH2)n-, n is 2 or 3! The l number represents a hydrogen atom or a methyl group, and the amine 7 group, which is a different lower alkyl group, is a small number, or the amine 7 group in which R3 and R4 are combined to form a cyclic structure.
represents a group. ) and pharmacologically acceptable acid addition salts thereof. 2. General formula (wherein, R1 is a hydrogen atom, a methyl group, or an ethyl group,
2 represents a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group, and in the group -(OH2)n-, n represents an integer of 2 or 3, a hydrogen atom or a methyl group, and a different lower Represents an amine 7 group which is an alkyl group, or represents an amine 7 group in which R3 and R4 are combined to form a cyclic structure.
represents a group. ) In the method for producing an N-substituted flavone-8-carboxamide derivative represented by A method characterized by reacting a flavone-8-carboxylic acid halokenide derivative represented by a halogen atom with a diamine derivative represented by the following general formula.