JPS5982380A - N-substituted flavone-8-carboxamide derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 is H, methyl or ethyl; R2 is lower alkyl; n is 2 or 3) and a pharmacologically acceptable salt thereof. EXAMPLE:N-[2-(N',N'-Dimethylamino)ethyl]-3-methylflavone-8-carboxamide. USE:A remedy for disorder in urinary tracts, having improved action on the urinary bladder, e.g. papaverine like action, inhibitory action on urinary reflex, contraction action on the urinary bladder, etc. and useful for treating the disorder in the urinary tracts, e.g. thamuria. PROCESS:At least one equivalent or more preferably 1.1 equivalents, flavone-8- carboxylic acid halogenide derivative of formula II (X is halogen) is reacted with one equivalent diamine derivative of formula III in an organic solvent, e.g. acetone or ether, to give the aimed compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel N-substituted flavo/-8-calhoki'4 conductor and its pharmacologically compatible acid and its manufacturing method.

In more detail, the present invention is based on the general formula (1) (wherein,
R] +- represents a hydrogen atom, methyl group or LI ethyl group, R2 represents a lower alkyl group, and n represents an integer of 2 to 6. The present invention relates to a novel N-substituted flavone-8-carboxy→nomide derivative represented by the following formula, its pharmacological salt addition, and its production method.

In the general formula (1) of the present invention, examples of the lower alkyl group represented by R2 include methyl, ethyl, propyl, intenvir, and butyl groups.

The compound represented by the general formula (1) of the present invention has a desired t
Accordingly, the pharmacologically acceptable acid salt can be converted, or the base can be liberated from the produced acid salt.

Examples of the pharmacologically acceptable acid addition 'fu1 of the compound represented by the general formula (1) of the present invention include f-acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Mineral acid salts, ru, ru, acetic acid.

Maleic acid, fumaric acid, citric acid, citric acid.

It! Examples include organic acid salts such as chloric acid.

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

flavone-8-carboxylic acid halide derivative represented by o-X (wherein R1 has the same meaning as O1J and represents X-bald/atom) and the following general formula (Il+) (formula It can be produced by reacting with a cyamine derivative represented by the following formulas (wherein, R2, and n are the same as above, and represent !).

In a particularly preferred embodiment of the method of the present invention, a flavone-8-carboxylic acid-containing rogenide derivative represented by the general formula (11) is added to 1 filtration of the diamine derivative represented by the general formula (II+). The reaction is carried out in an organic solvent using at least 1 portion of IrI, preferably 11 portions of IrI.

The organic solvent used in the method of the present invention and 1.
, anything can be used as long as it does not harm the anti-1+ii+, for example, 7′ seton, ether, te-rahi
' + 3 francs, 20%, benzene, 1 - chloroform, 9 are used.

Also, the reaction is carried out under heating and reflux from the chamber n1lX, and! This is carried out in the refluxed organic crystal [Wl:] which is preferably used for l'ii.

In the h-method of the present invention, the furan d(n-8-)) and lζ acid halide derivative represented by the general formula (If), which is the starting material, is as follows σ)-□li&5k(IV )
(In the formula, the same meaning as R1 digit tail statement 2 i J) -4
-0) flavone-8-car+11-acinoic acid ii
M'n (4\) is produced by a conventional method (acid), by converting it into II3 (conversion 1-i).

In addition, as shown in the general formula (1v) above,
Carboxylic acid derivatives H-4, y-1' 11 are also yam-like, for example, Ohe+n1Sche Berichte,
99, 1962 (1966), etc.).

'Furthermore, all of the cyamine derivatives A represented by the general formula (II+) are known σ) substances. +), f Kotoe (1゛, Journal 1 Bushi Ame 1) Bunon Umikano 1 no Sozaetei (Journal of the
Amr+rican nhemjcalsociety
)+68.1607 (1946), 65°2 0
1 2 (1943) etc. #Self + 1 glare (') direction t7
2F-ffSU Te11I! ! Be served as a samurai.

In this way, a novel I4-substituted 7-rabone-8-carboxylic acid derivative represented by the general formula (1) which is crushed by straining, and its pharmacologically g] Added salt has a bapaverine-like effect and suppresses the micturition reflex.
It has excellent effects on bladder function such as bladder constriction and bladder constriction, and is useful as a therapeutic agent for urinary tract disorders such as frequent urination.

Example 1 N-[2-(N', N'-dimethylamino)ethyl]-methylflavone-8-carboxamide 6-methylflavone-8-carboxylic acid Ost: 1
．． 53 g of benzene 6 [] ml 'far yl
In b, 0.41 g of N, Itl-dimethylethyenecyamine was processed and heated under reflux for 2 hours. After 4,
Extract the diluted liquid with an aqueous hydrochloric acid solution using a trowel. The aqueous layer (I) is washed with water and dehydrated. The solvent is distilled off, and ether is added to the residue. The precipitated crystals are collected with F. Then, 0.76 g of colorless crystals with a melting point of 133-735.5° was
ryru.

Prepare fumarate according to conventional method. It is recrystallized from ethanol and has a colorless nail disease with a melting point of 168-1705°.

Elemental analysis value 021H22N203 ・C4,H4,0
4 Theoretical value 0,64.37; H, 5,62: N,
6.01 Experimental value C164,48,', 5.70 i
N+ 5.96 Example 2 N -C2-(DingJ',N'-diethylamino]ethyl]fusibon-8-carpogisamide flavone-8-carboxylic acid chloride 3.20g of benzene 100m/ffJ1, N, Add 119 g of N-diethylethylenecyamine and heat under reflux for 1 hour.

After 4, count the precipitate. After dissolving the precipitate in water, it is made alkaline with potassium carbonate and extracted with chloroporum.

The chloroholt layer was washed with water and dehydrated. The solvent was distilled off and ether was added to the residue. The melting point of the precipitated 5 crystals is 169.
225 g of colorless crystals of ~171° are obtained.

Prepare fumarate according to conventional method. Recrystallization from ethanol gives colorless cylindrical crystals with a melting point of 7795-1805°.

Elemental analysis value 022H24+4203 ・04■(40
41'(lj logical value', 64.99, H+ 5.87
i N, 5.83 real IFll! i+# 0.65.
06 Pickled H, 5,96: N, 5.78 Example 6 N-[2-(ri', N'-diethylamino)ethyl]-ro-methylflavone-8-carboxyrimide 6-methylflavone-8-nonorboxylic acid chloride 38.
72 g of benzene 50[J] into solution, N.

Add 11.30 g of N-diethylethylenediamine and
Heat to reflux for 5 hours. The mixture was treated in the same manner as in Example 2 to obtain 34.38 g of colorless crystals. Recrystallized from isopropyl ether to give a colorless Φ1 with a melting point of 1055-108°.
The state crystal is child II.

Elemental analysis value 0231126N203 Theoretical value c, 72.99; H96,92; tl, 7
．． 40 Experimental value a, 72.79; 11.7.16; N
, 7.2? ) Prepare fumarate according to the conventional method. Eta/
Recrystallization from a glass of 1,000 to obtain colorless platelets having a melting point of 1,725° to 9,745°.

Elemental analysis value 023Hz6NgO:s ゛C4H404
Theoretical value c, 65.58; [(, 611 + N,
5.66 Experimental value 0.65.35; H, 6,08; N
+ 5.77 Example 4 N-[2-(N',N'-diethylamino)ethyl]-
6-Nitylflavone-8-Kalhoki → Nomi 1 ・11,
(Acid 6-ethylfuran-8-carphonic acid chloride 1 filter 15
To a solution of Pl in 100 ml of benzene was added 1.06 g of N,N-ethylethylene amine, and heated under IiR for 10 minutes. One portion of the crystals precipitated by cold welding is taken and crystallized from ethanol to obtain 315 g of colorless Φ1 crystals with a melting point of 178-1805°.

Elemental analysis value 024HgsN20s・HOI theoretical value (
! , 67.20: H, 6,81; N, 6.5
3 Experimental values C, 67, 38; H, 6, 97; N,
6.43 Example 5 I-[3(N",N-diethylamino)brohyal]-3-methylflavone-8-carboxy→flea 1-6-methylflavone-8-carboxylic acid chloride 1'
Add 060 g of N,N-diethyl-1,3-propa/diamine to a solution of 70 liters of benzene in 1.5 liters and stir at room temperature for 41 hours. Extract the anti-11h chlorine with an aqueous salt solution. Make the aqueous layer alkaline with potassium carbonate and garlic, and extract with acetic acid and 1,000 ml of acetic acid.

The solvent was distilled off and needles were added to the residue). (Take out the punched crystals and pour out 0.92 g of light brown crystals.

Recrystallized from isopropyl ether, square 1: point 106
~104.5° colorless Φ1 item? IIru.

Elemental content IJ7 value C24Hp, 8τ relaxation 03 theoretical value a,
7ro44: H, 71911,714 Experimental value (J, 7ro39; H,729+N, 7.O [J Example 6 NC3-(N', +J'-Jigji'bilamino)brohydr] 3-ethyl Flavone-8-carboxylic acid → Nomide 3-ethylflavone-8-carboxylic acid ("Lido" 16
Add 0g of benzene to 60ηf and add 73g of N,N-dipropyl-1,6-bropa-7diamine C and heat under reflux for 15 hours. 125 g of crystals are obtained.

Recrystallized from isopropyl ether, melting point 105.5
Colorless Φ1 crystals with an angle of ~106° are obtained.

Elemental analysis value (!27H34N203 theoretical value c, 74.62; H, 7,89; N,
6.45 experimental value c, 74.75: H, 8,2
2; N, 6.32Special 4'+Ell'f person Hokuriku Pharmaceutical Co., Ltd. 71 hair continuation 011 +l:,l'
i December 7, 1982 [1 Kazuo Wakasugi, Director General of the Patent Office 1 Display of the case Special issue of 1981; ti [i No. 191
No. 803 2 Title of the invention N-; Hexafunctional flavone-
8-Cal f1? Kirimi l'' derivative and its preparation/j'
Relationship with old case to be amended 'J'J'6'+ Application Personal matter
Address: 1J'' Tatsuyo-cho, Katsuyama City, Fukui Prefecture [1ro-144 Date of amendment order] Spontaneous 5 Number of inventions increased by amendment +76 Detailed explanation of 1 invention in the specification subject to amendment - 1 ( 1・v Schiff Contents of the amendment As shown in the attached document, contents of 7th supplement 11mi (1) Specification J) Page 4, line 1-12, "i.e., general formula" is changed to 1, that is, general formula (11) l. correct.

739-

Claims (1)

[Claims] (In the formula, R] represents a hydrogen atom, a methyl group, or an ethyl group,
2 represents a lower alkyl group, where n is an integer of 2 or 3; ) N-substituted flavone-8-force/l/bokylimit 11-5 conductor, and its salt with an acid that can be chemically J↑. (In the formula, l (l is a hydrogen atom 1 methyl group or -In'
R2 represents a lower alkyl group, and η represents an integer of 2 or 6. ) N-substituted flavone-8-carboxamide derivatives represented by A flavone-8-carbono acid halide derivative represented by the following formula (in which R2 and n represent the same meanings as above) are combined in anti-1+3+ form. 2) A method characterized by: