JPS62185070A - Phthalimidine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is A-ONO2 (A is OH or alkylene which may have nitroxy) or B-NR4R5 (B is alkylene; R4 is H or alkyl; R5 is alkyl, aryl, etc., or together with adjacent N form cyclic amino); R2 is H, alkoxy, group of formula II (R4<a> and R5<a> are R4 and R5), etc., when R1 is A-ONO2 and R2 is O-A'-ONO2, CONH-A'-ONO2 (A' is A), etc., when R1 is B-NR4R5; R3 is H, NO2, alkanoylamino, etc.] and its acid addition salt. EXAMPLE:N-2-nitroxyethyl-5-chlorophthalimidine. USE:The compound has selective collateral vasodilating activity which is one of characteristics of nitroglycerol and is useful as a remedy for ischemic cardiopathy, especially remedy for stenocardia. PREPARATION:The objective compound of formula VI can be produced by reacting the compound of formula III (R2<a> is H, alkoxy, OH, etc.) with the compound of formula IV (A'' is A excluding nitroxy present as a substituent group) and subjecting the resultant compound of formula V to reduction and nitration.

Description

[Detailed Description of the Invention] As a nitrate ester drug, nitroglycerin has been clinically frequently used for angina pectoris under the sublingual administration method for a long time. -paJ,
9 There is a problem with B10aVai16bilit7 (bioavailability) due to its susceptibility to effect (first pass effect), so it is not used orally.Therefore, it should be taken prophylactically to prevent the onset of angina pectoris. Therefore, its use is always limited to emergency use after the onset of symptoms.In addition, depending on the dose, nitroglycerin may cause a decrease in blood pressure, orthostatic hypotension, reflex tachycardia (increase in heart rate), headache, dizziness, and nausea. , vomiting, and other undesirable effects, and improvement of these side effects is desired.

The present inventors have considered these issues.

As a result of repeated research, we found that a new phthalimidine conductor represented by the general formula (11) selectively has the collateral blood circulation expansion effect, which is one of the characteristics of nitroglycerin.
Furthermore, the first-pasg effect was recognized to be continuous, and the inventors discovered that it is useful as a therapeutic agent for ischemic heart disease and especially as a therapeutic agent for angina pectoris. .

Composition of the invention The phthalimidine derivative of the present invention is.

General formula.

and its pharmacologically acceptable salts.

In the above formula, a R1 represents a formula-A-0N02 group (in the formula, 5 represents a linear or branched lower alkyl group which may have a hydroxyl group or a nitroxy group as a substituent). or a branched lower alkylene group, R4 represents a hydrogen atom or a lower alkyl group, and R4 represents a hydrogen atom or a lower alkyl group.
R5 represents a lower alkyl group, cycloalkyl group, lower alkanoyl group, aryl group or aralkyl group,
In the case of R4 and R5 together, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, an imino group, or a carbonyl group may be interposed on the ring carbon atom together with the adjacent nitrogen atom, and further a lower alkyl group as a substituent. Group, ryor group.

Heteroaryl group, lower alkoxycarbonyl group, tyralkyloxycarbonyl i, ii alkylsulfonyl group, arylsulfonyl group, optionally substituted lower alkanoyl group, lower alkenoyl group, optionally substituted arylacyl group or heteroarylacyl group Indicates a cyclic amino group which may have. ).

When R1 represents a formula -A-0N02 group, R2 is a lower alkoxy group which may have a hydroxyl group and/or a nitroxy group as a substituent.

- or a group having the same meanings as P, 4 and R5 described above. ).

and R5 are the same or different groups and have the same meanings as B, R4 and R5 described above. )2 formula-CON)I
-R6 group [in the formula, sRd is a hydrogen atom, lower alkals R4 and R5 are the same, fc is different, and is B as described above.

Represents a group having the same meaning as R4 and R5. Indicates the

], hydroxyl group, lower alkanoylamino group.

Indicates a lower alkoxycarbonylamino group, a lower alkanoyloxy group, or a halogen atom.

-O-A'-0N02 group, 2→-(NO2)ncoNF
i-ALONo 2 groups Matach style-cONH=A"-ONo
2 groups (wherein A/ represents a group having the same meaning as A described above, and n represents 1 to 4 ruamino groups, lower alkoxycarbonylamino groups, lower alkoxy groups, or halogen atoms.

A contained in R1 and R2 in the general formula (1)
and A' are preferably, for example, methylene, ni0H2-
OH- NO2 Monobutylene (CHzOHs) s Pentamethylene, H0R-OH2- A linear or branched chain having 1 to 6 carbon atoms which may have a hydroxyl group or a nitroxy group, such as xamethylene. Indicates a branched fullkylene group, B, B
' and B11 represent a linear or branched alkylene group having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene hexamethylene, and R4, R4, R4 and R4 are hydrogen atoms or e.g. methyl, ethyl, n-propyl, isopropyl,
R represents a linear or branched alkyl group having 1 to 4 carbon atoms such as n-butyl or isobutyl;
5, R%, R5 and R5 are, for example, methyl, ethyl,
n-propyl.

A linear or branched alkyl group having 1 to 4 carbon atoms, such as inpropyl, n-butyl, and isobutyl; 1 to 6 carbon atoms, such as cycloglovir, cy/loftyl, cyclopentyl, and cyclohexyl. A cycloalkyl group having 1 such as acetyl, glopionyl,
n le, 0. al, p-trill &'I me p
-methoxyphenyl% o, m, p-nitrophenyl,
0゜m, p-/lorophenyl j-5 7! Jh group.

Examples Evahensyl, o, m, p-methylbenzyl.

o,m,p-methoxybenzyl%011nj represents an aralkyl group such as p-chlorobenzyl, phenethyl, 3-phenylpropyl, or R4 and R5,R”
4 and R%, R'4 and R% or R2 and R171-together form with the adjacent nitrogen atom, e.g. 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 2-oquino-1-pyrrolidinyl, 2-oxopiperidino , 4-oxopiperidino, 2-oxomorpholino, 3
- represents a cyclic amino group such as 2-methylpiperidino, 4-methylpiperidino.

z6-dimethylbiperidino, 2-ethylbiperidino, 4
-Methyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 4-p-methylphenyl-1-piperazinyl, 4-p-methoxyphenyl-1-piperazinyl, 4-
1)-/clophenyl-1-piperazinyl, 4-(2-
pyridyl)-1-piperazinyl% 2-methoxycarbonyl-1-pyrrolidinyl, 2-ethoxycarbonyl-1
-pyrrolidinyl, 4-ethoxycarbonyl-1-piperazinyl, 4-benzyloxycarbonyl-1-piperazinyl, 4-methanesulfonyl-1-piperazinyl, 4-
Benzenesulfonyl-1-piperazinyl, 4-polζru-1-? 'Perazinyl, 4-acetyl-1-piperazinyl, 4-hexanoyl-1-piperazinyl, 4-acroyl-1-piperazinyl & 4-penzoyl-1-piperazinyl, 4-p-methylbenzoyl-1-piperazinyl, 4-P-methoxy benzoyl-1-piperazinyl,
4-Nicotinoyl-1-piperazinyl, 4-(sonicotinoyl-1-piperazinyl) as a substituent such as lower alkyl, aryl, heteroaryl.

It may be a cyclic amino group having lower alkoxycarbonyl, aralkyloxycarbonyl, lower alkylsulfonyl, arylsulfonyl, lower alkanoyl, lower alkenoyl, arylacyl or wokoheteroarylacyl<h R2&! , R1 is -A -01
In the case of 02, a hydrogen atom or, for example, methoxy, ethoxy, n-propoxy, impropoxy, 2-hydroxy-
3-ditrooxypropoxy, 2,3-dinitrooxypropoxy, n-butoxy, and isobutoxy, which may have a hydroxyl group and/or a nitroΦ group as a substituent, and have 1 to 4 carbon atoms. The linear or branched Alco0)I terminal and 4 have the same meanings as R4 and R5 described above.

).

indicates the same @ as B, Ra and R5 described above. hmm.

Formula -0ONH-16 group [In the formula, R4 is a hydrogen atom such as methyl, ethyl, n-propyl, isopropyl.

A linear or branched alkali having 1 to 4 carbon atoms such as n-butyl and isobutyl, and R5 have the same meanings as B, R4 and R5 described above. ) is shown. ]
, hydroxyl group 1, such as acetylamino, propionylamino, n-butyrylamino, inobutylated amino, and alkanoylamino group having 2 to 4 flA, such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, n-butoxy Alkoxycarbonylamino group having 2 to 4 carbon atoms such as carbonylamino, isobutoxycarbonylamino, for example acetoxy, propionyloxy,
Represents an alkanoyloxy group having 2 to 4 carbon atoms such as n-butyryloxy and isobutyryloxy, or an I/rogen atom such as fluorine, chlorine, and bromine.

is the formula -0-A'-0N02 group 1 formula → -(CH2)nOO
NH-A'-01102 group or formula -coNu et al'-
0N02 group (in the formula, A/ has the same meaning as the above-mentioned A,
n represents an integer from 1 to 4. Indicates the

R3 is a hydrogen atom, a nitro group 1 such as acetylamino, globionylamino, n-butyrylamino), an alkanoylamino group having 2 to 4 carbon atoms such as imbutyrylamino 5 such as methoxycarbonylamino, ethoxycarbonylamino Sn-propoxycarbonylamino.

Carbon atoms from 2 to 41m, such as isopropoxycarbonylamino, n-butoxycarbonylamino, and isobutoxycarbonylamino! Alkoxycarbonylamino groups 1 having the following: methoxy, ethoxy, n-propoxy, impropoxy.

Straight-chain or branched alkoxy groups having a return number of 1 to 4, such as n-butoxy and imbutoxy, represent halogen atoms such as fluorine, chlorine, and bromine.

A more preferable compound in the general formula (1) is ft'f! AfiR1 can be a compound represented by the general formula -A-0NO2 (wherein b A* R2 and R3 have the same meanings as described above).

In the adduct having general formula (1), the compound exhibiting cyclic grouping can be in the form of a pharmacologically acceptable acid addition salt, if necessary. In this case, acid addition salts include, for example, salts of mineral acids such as hydrochloric acid, hydrobromic acid, m-acid, nitric acid, phosphoric acid, metaphosphoric acid, and acetic acid, oxalic acid, tartaric acid,
Mention may be made of salts of acids such as citric acid, succinic acid, fumaric acid, maleic acid, conic acid, and benzoic acid.

In addition, in the compound having the general formula fil, a compound in which an asymmetric carbon atom exists has optical isomers. Therefore, when the target compound (11) is obtained as a mixture of optical isomers, each isomer can be obtained by optical resolution using a conventional method. Although all isomers and mixtures of optical isomers are shown in a single formula, this is not intended to limit the scope of the description of the invention.

Representative compounds represented by the general formula (1) according to the present invention are specifically illustrated below.

L-0H2ha01202 FiEl
// 5-OMe
4-No 2 & //
5-OMe
6-IJO2l N 5-Or 0NO24
2N02RI R2R5IL
tt iy
8-N021 peek 11#
6-NO2 2(L tt M
6-N02RI
R2B521 // 5-o/'y
y”) HR〃To 6-0/○ H RL # D-ul)
\/'m a-=, H6r.

-, NORI R2R1141tt
5-04/NIiOOMe
H44, If 6-0/1/NHc! O
Me H4L //
5-OH4-no21'L 1R2R3 41L-OH2/\0N02 G-01115-N0
24 Z // 8-OH7-
Ho241L #6-0ON
)12 H41#
6-6-0ONii
H Tsuru α #6-COll
HKtH! i l
// B-00) [”1/ N OH
(,] R2 RI
R358, n6-NH
(:!OMe H
59, I/8-N! I(:!OEt
H6Q,
// 8-)THOO(!gH7-
n H61, l/
6-NH(:!QC!3H7-1H6Z
// 6-NHOOOMB
H63,#
6-NHC! OO]1Iit
HRI
R3st -0H2△0N
02 B-NHOOOPr H
65, // 6-NHOOBu-n
H61L
tt 6-NHcooBu-1, HI
IL/l 5-OIH@! L#8-OI
RI&
// 6-NO2H α -υchi~
O.N. et al.

7 L at tt
4-N021L/
/ #
6-N02RI R2R11
71-“H5-0/l/I
H80, // 11-○0NH2
H8L // 8-Cj
ONHEt H82
, // 6-0ONH-Bun
HRI
R2R58L //
6-NHOOMe
HRI R2R3111-
0H2No〇NOz 6-NHOOEt
FlQ&”
8 NHCOOBt
HR4II 8-CI
II91#6-NO2H lol // 5-0//N OkLRI
R2R3101II
6-001JH? :t
H10! LI/ 1l-0ON11/1/1
”) R107, # ・-NH
COMe HIn
s 8-NHOOOkft
Hlol //
6-CII
HRt R2HB In -CI2"701102 HH11&
#5-OAlo H11&
// 6-co'11a2
Hl 17, /
/ 8-0ONH1t
Hl 11L tt e-c
oNaAvcb! ! (,) Heart111L-(Hl 0NO2a-NHCOMe
lK12(L
II 6-Nacoa3u7+n
HInLs
6-NHt3001t
R121# 6-(jl
H12 & II
6-yo2
H12L-oa2A7'Vono2 8-c7
H12@, -0H2△N
N-Me, 5-0δ and 0N02
H-0] 12″1.# tt
6-=N O2RI R
2R5 txa, -on2△Q 5-0-'LzOi(02
Hl 2 ttt //
8-N0213L〃〃6-N02 131 tt 5-0-A 0ONH le 0NO2H184″ “ “
5-102131L I/
// 6-1! . 2R1R2R3 137, -cu2△Convex 5-CONH'Vono2
H13&N 5-0ON
H--CMO2) 114 L #5
-0 /1/ N N-Coo) 13 H
14ζ 〃 5-0 le'NNbeQ~
H14 L // 5-0 /
X/N N-ao-@)H-IchinoRI R2R5 14 & -0NO25-OEI to cx2'
4-MHAcl 4 Z //
5-0M8 4-MHA.

14LI/5-OMe
6-11! AOI A & //
5-0M0 @-11TI
! 0OO1t1511// 5-OMe
4-C1151, // !
1-0M8 @-C! J151
// 5-0M8
g-Br153, tt
6-NHAa H The phthalimidine-conductor of the present invention having the general formula +11 can be prepared according to the synthetic route shown below.

A method R2 is a hydrogen atom, a lower alkoxy group, or an aqueous group.

When R2 represents a lower alkanoylamino group or a halogen atom (1a) (When R2 represents a lower alkoxy group having a hydroxyl group and/or a nitroxy group according to method 51B).

σe (1b) D method case (10 D method R2 is R2 with the formula -0011-R6 group Bazeng E method R2 is the formula -0 -A' -0N02 group Bazeng F method R2d1 Formula-0-(OH2)n-0ONH-A'ON0
2 The group R2 is the group G method R2 formula -aONH-A'-0N02 group "C' 6
Le R'2 Teh Le Case @ Kan (1g) a'b In the above formula, Ae ''* R2* R2* R2* R2
+R2ef g, a b
a bR2, R2, R5, Ra,
R4, R4, Rs, R5, Rs, R6.

B, B' and n have the same meanings as above.

l R2t2 After adding 2.3-epoxypropoxy as a substituent, a lower alkoxy group having a hydroxyl group and/or a nitroxy group as a substituent is removed from 1, It has the same meaning as R2 described above, and has the same meaning as A described above except for the presence of a nitroxy group in place of A''12, and R7 is a hydrogen atom and te is a lower alkanoyl group such as acetyl, propionyl, butyryl. &R8 represents a hydrogen atom or a lower alkyl group such as methyl or ethyl, and x represents a halogen atom such as gochlorine, bromine or iodine.

Jinsha 1st process, 1ri 1st process 8. The imidization reactions in the first step and the first step of Method 5 and the imidization reactions in the fourth step of Method A and the second step of Method G are carried out using the general formula (2) according to conventional methods.
1. Achieved by reacting a phthalic acid derivative having the general formula (71 or 5) or a phthalide visiting conductor with the general formula (51 or 5) with a general anne having the general formula (6) or (to) under heating. In carrying out this reaction, if necessary, the raw material compound can be dissolved in an organic solvent such as methanol or ethanol, and after homogenization, the solvent can be distilled off and heating can be carried out.Usually 1 reaction temperature is 15G to 270℃, and 1 reaction time is 1
The duration ranges from 0 minutes to several hours.

The reduction reactions in the second step of method B, the second step of method B, the second step of method D, and the second step of method E are carried out according to the conventional method using the general formula +31
．． This is achieved by using a metal such as magnesium, tin, or zinc as a reducing agent for a phthalimide rust conductor having (81, α! or (to)) in acetic acid.The reaction temperature is 100 to 130 °C under heating. and the reaction time is 1 to 10 hours.

The alkylation reactions in the third step of Method B, the third step of Method E, and the first step of Method F are expressed by the general formula +9), ! or r2υ
Oxylated adducts having the general formula αD, α2t or (2)
This is achieved by reacting a halogen compound with a base in the presence of a base.

The reaction can be suitably carried out in a solvent, but the solvent used is 1+: There is no particular limitation as long as it does not participate in the reaction. Preferred are fatty acid dimethylamides, ketones such as acetone and methyl ethyl ketone, and alcohols such as methanol and ethanol. Examples include alkali carbonates such as potassium carbonate, alkali metal hydrides such as sodium hydride, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and organic bases such as triethylamine and pyridine. The reaction temperature is 0 to 150°C, preferably room temperature to 110°C, and the reaction time varies depending on the reaction temperature.
Usually it takes 30 minutes to 20 hours.

The epoxy cleavage reaction in the first step of method C is based on the general formula (10
This is achieved by reacting an epoxy compound having the formula a41 with an amine having the general formula a41. The reaction can be suitably carried out in a solvent, but the solvent to be used is not particularly limited as long as it does not take part in the reaction; for example, alcohols such as methanol and ethanol are preferred. The reaction temperature is usually room temperature or around the reflux temperature of the solvent used, and the reaction time varies depending on the reaction temperature, but is usually 10
The duration ranges from minutes to 10 hours.

The amidation reactions in the 3rd step & F@M2 step of method D and the 1st step of method G are carried out by converting the carboxylic acid or its ester derivative having the general formula This is achieved by reacting with an amine having (6) under heating.The reaction temperature is usually 1
The reaction time is 30 minutes to 5 hours, depending on the reaction temperature.

The nitric acid esterification reaction in the third step of the G method is expressed by the general formula (4), (1(1, (13, (18, J W Mataha(
This is achieved by reacting an oxy compound with a nitric acid esterifying agent. Examples of the nitric acid esterification agent used in this reaction include fuming nitric acid, a mixture of fuming nitric acid and acetic anhydride, and a mixture of concentrated nitric acid and concentrated sulfuric acid. The reaction is carried out in the presence or absence of a solvent, and the solvents used include ethers such as ethyl ether, tetrahydrofuran, and dioxane, fatty acid esters such as methyl acetate and ethyl acetate, and acetone. ,
Ketones such as methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane and chloroform, and nitriles such as acetonitrile are preferred. Usually, the reaction temperature is around -30°C to room temperature, and one reaction time is several minutes to several hours.

In addition, in the single nitric acid esterification reaction, a product in which a nitro group is introduced into the substituent R3 and a nitrooxy group is introduced into the 1i1 substituent A of the target compound can also be obtained by changing the two reaction conditions.

In addition, the above-mentioned oxy compound was prepared according to a conventional method.

The desired nitroesterified product can also be produced by forming a halide and reacting this with silver nitrate in a solvent such as acetonitrile at room temperature to 100° C. for 1 to 10 hours.

The reaction products of each step above are obtained after the reaction is completed.

It can be obtained by subjecting the reaction mixture to post-treatments such as concentration under reduced pressure, filtration, or extraction according to conventional methods, and can be further purified by column chromatography, recrystallization, and the like.

Effects of the Invention The phthalimidine conductor of the present invention having the general formula (1) exhibits excellent pharmacological effects as described above, and the results of pharmacological tests will be explained below.

Collateral vasodilation (Comparison of intravenous administration and portal vein administration) using dogs anesthetized with bendoparbital.

The method of IriuOhijima et al.
Kolkel H,.

MaTaau (La K-: Am-J-phyai
ol, 218. II 78-1171 (eye 17G)), the collateral blood circulation function of the carotid artery basin was evaluated. When nitroglycerin was administered intravenously to this specimen, *the collateral vessels dilated; however, when administered intraportally, 12-5 times the dose of intravenous administration was required to exhibit the same collateral vasodilating effect. It took.

This result is considered to be because nitroglycerin is easily inactivated by the liver (first-pass effect).

In contrast, one compound of the present invention exhibits a significant collateral vasodilatory effect, and its intraportal/intravenous dose ratio is smaller than that of nitroglycerin.
It was found that it is less susceptible to s effect.

As explained in the above pharmacological test, the compound of the present invention having the general formula (1) has an effect of increasing lateral blood circulation function, and is persistent in receiving the first-pasation effect. , is useful as an orally administrable therapeutic agent for ischemic heart disease.

The administration form of the object compound (1) of the present invention is as follows.

For oral administration, tablets, capsules, and powders are available.

Examples include fine granules, granules, and liquid solutions.

For parenteral administration, injections, suppositories, and bags are available.

Examples include tape agents. The dosage i varies depending on the symptoms, age, body weight, etc., but usually, when administered orally for adults, it is 0.1 to 100 μg/day, preferably about 0.3η to 3 μg/day.
0■, and can be administered once or in divided doses.

Next, examples of the compounds of the present invention will be given to explain more specifically.

Example 1 1,82 4-hydroxyphthalic acid in 20 ml of ethanol
F (α01 mol) and 2-amine ethanol [1
61? (0.01 mol), the solution was distilled under reduced pressure to remove ethanol, and the distillate A was heated to 185-190° C. for 50 minutes. After the reaction is complete, it crystallizes when left to cool.
The target compound was obtained as white needles of 1.90 f (92%). Recrystallized from ethyl acetate, melting point 161-162°C.

Elemental analysis: Calculated value as 0IOH9NO4, 0.57.97;H, 4,33,;N, 6
．． 76 actual value, C, 57, 85; H, 4, 35; N
, 6.65 Example 2 N-2-hydroxyethyl-4- to 100aj of pyridine
Hydroxyphthalimide 20.7r (0.1 moAp),
After adding O and anhydrous vinegar [3G,6Y(,0.3mol), and stirring at room temperature for 3 hours, remove the sulfur by distillation under reduced pressure.When water is added to the residue and stirred well, crystallization occurs. White crystals 2 having a melting point of 120-121°C and recrystallized from
3f (19chi) was obtained.

Calculated as original cumulative analysis 2014H13N06 IvL, C, 57, 73; H, 4, 50; N
, 482 measured value, c, 57.69; H, 4,
47;N, 4.89 Example I Vinegar 1j! 751) N-2-acetoxyethyl-4 in xJ
-Acetoxyphthalimide 4 & 7? (0,15
Add Morun, heat to 50-60℃, and add sub-I powder 9 while stirring.
Add 4.5F (1.45 mol) in several portions. Then, after refluxing the first reaction product for 3 hours, the first reaction mixture was filtered, the P solution was distilled off under reduced pressure, water was added to the residue, and hydrogen carbonate was added. After neutralization with IJium, extraction with ethyl acetate and washing with water was carried out. , After drying, feed with a. Add 30 Gi of 10% hydrochloric acid to the obtained nine-oil autumn product (3L5?)
Add d and stir at 50-60°C for 4 hours. After the reaction, the solution was distilled off under reduced pressure, and the residue was recrystallized from ethanol.
Crystal 1-2F (514%
) was obtained.

Elemental analysis: Calculated value as 010H1INo5, C
, 62, 16; H, 74; N, 7.25 actual value, 0
．． 8105;H,! 71 ; N, 7.13 Example 4゜Lumidine - Smoking steel cooled to -20 to -15°C [N in 10 m, -
2-Hydroxyethyl-5-chlorophthalimidine 0.
Calorie 6f [183 mmoln] little by little. After stirring the reaction mixture for 30 minutes.

1) E17 in ice water and sodium bicarbonate aqueous solution
．． The precipitated crystals were washed with water to obtain a pale yellow powder. (0,67F) Further recrystallized twice from ether, giving pale yellow needle crystals with a melting point of 98 to 9℃.
．． 15 f was obtained.

Elemental analysis: CtoH9NzO40A! Calculated value as,
C, 46,80; H, 3,53; N, 10.92
;C1゜13.81 Measured value, 0.4178;H,3,47;li, 1(
L83; Ol.

13.82 gA Example 5°, N-dimethylaminonidoxin phthalimidine Ei dimethylformamide 4014 with sodium hydride (,5
5%') Q, 68f (0,0158 mol) was added with a sieve, and after stirring for 30 minutes, N-2-hydroxyethyl-5-hydroxyphthalimidine 3.0f (0,0155 mol)
was gradually added at room temperature and stirred for 1 hour. 1.839 (0,011 mol) of dimethylaminoethyl chloride was added to this, and after stirring at room temperature for 1 hour, the temperature was raised to 100°C and stirred for 3 hours. After the reaction was completed, dimethylformamide was distilled off under reduced pressure and the residue Add a small amount of water.

After extraction with chloroform, washing with water, and drying, chloroform was distilled off to obtain an oily product zef (614%).

Elemental analysis: 014H2ON2031:, Lte calculated value, c, 6161; B, 1. aa;N, 1
o, g.

Actual measurement @, 0.113.21;H,? ,411;N,
10.45 The reaction was carried out according to Example 5 to obtain the compounds listed in Table 1.

Table 1 oil 5-o'ui○ OHOt 7H24N2
05c, ay, ss; 3 tss; x, 12GC, 61
L75; mit, ss; n, 9.00c, 6!72; J
7.24;N, 11. t4-
〇, 6150; H, 1111; N, 11.40 Example 6 - N in 10 ml of fuming nitric acid cooled to 15°C to -10°C
-2-Hydroxyethyl-5-(2-Selfolinoethyl)phthalimidine TSP Neutralized with an aqueous sodium solution, extracted with ethyl acetate, washed with water, dried, concentrated, and subjected to silica gel chromatography 2E [Elution solvent: Perform purification with ethyl acetate-ethanol (3:1).

Furthermore, it crystallized from ethyl acetate, with a melting point of 66 to 7℃ (D
M&A 119? (513%)'&'4fC0 original analysis: C16H21Hsob7 and calculated value, 0
．． 546@;H, a, 02;N, 11.96 meisowa,
0.154811; H, 6,01; N, I L8
1 Example 7゜4-Carboxyphthalic anhydride 5.76y' (0゜03
mol), 2-amine ethanol 1.83 r (0,03
mol) mixture is heated to 160-170°C for 2 hours.

After cooling, one reaction product was dissolved in a chloroform-methanol mixture and a small amount of insoluble matter was removed. The r liquid was distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography [elution solvent: chloroform-methanol-triethylamine (,8
:1:1)) with a melting point of 131-134°C.
Crystal 3.5 f (49.6%) was obtained. Elemental analysis: Calculated value as 04IH9NO5, C15 17; H, 3,86; N, 5.9
4 actual value, c, 56.3a; H, 3,99; N,
6.14゜Example 8゜Vinegar rR41rdlCM-2-human o? rshixfh-4
-carboxyphthalimide 3.06 r (Q, 013
Add 4.77 r (0,073% mol) of zinc powder and reflux for 3 hours with stirring. After cooling, the reaction mixture was filtered and the liquid was concentrated under reduced pressure. A 2 mol equivalent of diazomethane 10 tetrahydrofuran solution Q was added thereto, and the mixture was allowed to stand for 1 hour.

After distilling off the tetrahydro 7 run under reduced pressure, purification was performed by silica gel column chromatography [elution solvent: chloroform-methanol (Ill: 1)], and the melting point was SS ~ 10.
Crystal o, a 3 y (t o, 8
%) was obtained.

Elemental analysis: Calculated value as C+2H+5NOa, 0
．． 61.27;i(,5,57;N, L96 measurement value,
C, 61, 19; H, 5, 71; N, 5.90 Example 9゜Lidinoethyl) carbamoylphthalimidine N-2-Hydroxyethyl-6-methoxydicarbonylphthalimidine 3.6? (13 milli7 run and 2-aminoethylpipe I) Schiff 3. ,．． A mixture of 6Bf (286 mmol) is heated to 120° to 130° C. for 3 hours. After cooling, the two reactants were subjected to silica gel color chromatography [bathing solvent:
Ethyl acetate-triethylamine-t-nor (8:1:1
)), crystals having a melting point of 137-138°C2.
8? (45.1%) was obtained.

Elemental analysis: Total 1m as c18H25N3o5, c
, 1m5.23;H,7,60,;N, 12B8 tiger measurement (ttL, 0.64.97;H,7,53;N,
12.48 Example 10. N-2-Hydroxyethyl-6-(N-biperidinoethylncarbamoyl lucimidine 1f (3 mmol)) was dissolved in ethyl acetate in fuming nitric acid cooled to 10°C. Add stone dust solution to 2d.The reaction mixture was stirred for 1 hour, then poured into ice water, and after neutralization with sodium bicarbonate,
After extraction with ethyl acetate, washing with water and drying, the ethyl 6-acetate was distilled off, and the obtained crystals were recrystallized from methanol-ethyl acetate to give 0.33 t of crystals with a melting point of 134-135°C.
(21L 9%) was obtained.

Elemental analysis: Calculated value as 018H24N405,
c, 57.44; H, 6,43; N, 14.88 actual measurement, a, S″7.37;) i, 6.20; N, 1
473 Actual Axis Example 11 Dissolve 4-carboxylphthalic anhydride 31L4P (12 mol) in 400atj of limidotetrahydrofuran, add 244f of 2-aminoethanol (A47L), and reflux for 2 hours. Then, under reduced pressure Distill tetrahydrofuran,
40B of acetic anhydride in the residue? (4% L) & reflux for 6 hours.

After concentrating the reaction mixture under reduced pressure, the residual liquid was added to water and extracted with ethyl acetate. After washing with water and drying, ethyl acetate was distilled off, and the obtained target product was used for the next reaction without purification. did.

Practical Example 1z The above acetate was dissolved in 300 d of rimethanol, and an ether solution of diazomethane (equivalent to 121%) was added under stirring.After standing overnight, methanol was distilled off and subjected to silica gel column chromatography [elution solvent: Purification was performed with ethyl acetate-hexane (3:1), and the obtained crystals were recrystallized from ethyl acetate-hexane to obtain 37.2 r (618%) of crystals having a melting point of 80-82°C.

Element analysis: Calculated value as 0141i13No6 0.
5? ,73;I! , 4.50; M, 4111 actual value 0.51.62; ,02
mol) mixture is heated to 170° C. for 2 hours. After the reaction was completed, it was allowed to cool and crystallized, and recrystallized from ethyl acetate to obtain crystals 3416j' (78 tons) having a melting point of 162-163°C. 90 Elemental analysis: Calculated value as 014HtaNzOs, 0
．． 64.10; H, 6,112; N, IQ4B actual value, C, 6430; H0118! i;N, la! It
gA-Example 14 Vinegar li! N-2-diethylaminoethyl-4 in IOOd
- and 28 f (0.1 mol) of siphthalimide were added to the slurry, heated to 50-6G℃, and 85.4 f of zinc powder was added under stirring.
(1 mol) is added in several portions. Then, the temperature was raised, and after refluxing for 3 hours, one reactant was passed through, and the solution F was distilled off under reduced pressure.
Water was added to the residue, neutralized with sodium hydrogen carbonate, extracted with dichloroform, washed with water, dried, finely ground, and subjected to silica gel column chromatography [eluent: chloroform].
f! with methanol (,5:1)). The process was repeated to obtain 111 tons (447 tons) of an oily substance.

Elemental analysis: Calculated value as 014H2G14202 C
! , 87.71; H, 8, 12; N, 11.28
Actual value c, 87.59; H, 8,04; N, 11
．． 31 Example 1! L Sodium hydride (55
%) 0.44 f (Q, 01 mol) was added, and after stirring for 30 minutes, N-2-morpholyl 1 chloro-5-hydroxyphthalimidine λ6t (0.01 mol) was added, and 1
Stir for an hour. Add 1.3 f of 2-bromoethanol to this
(0.01 mol) was added.

Stir at 70°C for 4 hours. After the reaction, dimethylformamide was distilled off under reduced pressure, a small amount of water was added to the residue, extracted with ethyl acetate, and after drying, ethyl acetate was distilled off, and the resulting oil was subjected to silica gel column chromatography [eluent: chloroform] - methanol (10:1)] and crystallized with ethyl acetate-hexane, melting point 1.
Obtain 0.35 t (11,4 t) of crystals with a temperature of 20-123 °C.

Elemental analysis: Calculated value as 0161'122N204,
c, e2. r2;a, ? , 24; N, 9.1
4 Actual value, 0.62.52; III, 7.10; N
, 9.01 (Illustrative Attachment 132) Add N-2- to 15d of fuming nitric acid cooled to -20 to -15°C.
Add 1.5 f (5 mmol) of morpholinated 5-42-hydroxyethoxyphthalimidine.The reaction mixture was stirred for 1 hour, then placed in ice water and neutralized with sodium carbonate. After extraction with ethyl, washing with water and drying, ethyl acetate was distilled off, and silica gel column chromatography [
Elution solvent: chloroform-methanol (5:1)], crystallized from hexane, and further recrystallized from ethyl acetate to give 0.4 crystals with a melting point of 143-144°C.
A PC of 20.6% was obtained.

Elemental analysis: Calculated value as 016H2oNaoB,
c, 4 &48; L 5.09; N, 14.14 actual measurement, C, 48,58; Fl, 5.16; N, 11
911 Example IL Dimethylformamide 3ONI! Sodium hydride (
55 饅), 0.44f(,0.01 morn, 1
After stirring for 0 minutes, 2.6f (α01 mol) of N-2-morpholysacrifice-5-hydroxyphthalimidine was added and 1
After stirring for an hour, ethyl chloroacetate was added dropwise to 60-70°C.
Heat for 4 hours. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography [elution solvent: chloroform-methanol (10:1)] to obtain an oil.

After crystallization from hexane, recrystallization from ethyl acetate-hexane resulted in crystal 1 with a melting point of 8G-87°C! Obtained IP (7LII).

Elemental analysis: Calculated as C18■24N205 (directly,
0.6105; H, 94; N, ILO4 cusp A straight
C, 6141; 10 mmol) is heated to 130-140° C. for 3 G minutes. After cooling,
Crystallize by adding hexane and recrystallize from ethanol to obtain crystals with a melting point of 157 to 158°C (1.4 f (77,
1%).

Elemental analysis: Calculated value as Cl8H25N505,
C, 59, 49; 193 t b, 6 actual measurements,
0.511.83; H, 7, 15; N, 11.21
1 Example day.

Phthalide 5-ethoxycarbonyl phthalide'LO6,f(,0
,011 morn and 2-aminoethanol 0,67
A mixture of r (0,011 mol) is heated to 130° C. for 2 hours. After cooling, the reaction product was subjected to silica gel column chromatography [Elution solvent: ethyl acetate-methanol (9:1)
) to obtain 0.42L of crystals with a melting point of 180-182°C 18. t%) was obtained.

Elemental analysis: Calculated value as 0111t11NO4, 0
．． 59.72; H, lot; N, 8.33 measured value,
(!, 51L62; H, 108,; N, 132 Example 2 G.

19
Heat to 0-200°C for 3 hours. After cooling, the reactant was reduced to -15
Add to fuming glass #5d cooled to ~-10°C. The reaction mixture was stirred for 1 hour, placed in ice water for 6 hours, neutralized with sodium bicarbonate, and extracted with ethyl acetate.

After washing with water and drying, it was concentrated and purified by silica gel column chromatography [elution solvent: ethyl acetate-methanol-root-triethyl Ap7my (@mO,s: 0.C5)] to obtain 80 kg of oil (1t7 t). ) was obtained.

Elemental analysis: C! t7H2zN4061/2 Calculated value as H2O, 0.5170;H,'&9@;M, 1
4.46 memorized value, C! , ! 1152; H, 1L21
1;N, 14. ``J3 Example 21゜6-Hydroxyphthalide 1.Of (& 7 mmol and 2-aminoethanol 0.41 f (lL7
The mixture (mmol) is heated under stirring to 190-200° C. for 1 hour. After cooling, it was dissolved in a small amount of ethanol-dichloromethane and purified by silica gel column chromatography [eluent dichloromethane-ethanol (20:1)], and the obtained oil was further crystallized with ethanol, with a melting point of 161~ Pale yellow prismatic crystals α116 f (47.6 cm) at 169°C were obtained.

Elemental analysis: C! Calculated value as 1gH11NO5,
a, azle; a, 5.74; 47.25 actual value,
・c, 62.39; a, a4s; N, 7.1
3. The reaction was carried out earlier in Example 21 to obtain the compounds shown in Table 2.

Table 2 174-1766-NT (2A10HC, 0HI21J
2020.62.49;H,8,29;IJ,14.5
7C, 62, 57; H, 1L21; N, 14.4195
-1166-CI Af-OH0BH12NO2RC!
,5154;H,! L36; N, 1L21; O1, 11
71C! , 5B, 50; H, 5211; 11, f
L15; ('1.15.515 The reaction was carried out according to Example 4, 6.16 to obtain the compounds shown in Tables 3 and 4.

Claims (1)

[Claims] ▲ There are mathematical formulas, chemical formulas, tables, etc. (In the formula, B represents a straight or branched lower alkylene group. , R_4 represents a hydrogen atom or a lower alkyl group, R_5 represents a lower alkyl group, cycloalkyl group, lower alkanoyl group, aryl group or aralkyl group, or R_4 and R_5
together with the adjacent nitrogen atom, an oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, imino group, or carbonyl group may be present on the ring carbon atom, and as a substituent, a lower alkyl group, aryl group, hetero Having an aryl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, lower alkylsulfonyl group, arylsulfonyl group, optionally substituted lower alkanoyl group, lower alkenoyl group, optionally substituted arylacyl group or heteroarylacyl group Indicates an optionally cyclic amino group. ), and when R_1 represents a formula -A-ONO_2 group, R_2 is a hydrogen atom, a lower alkoxy group which may have a hydroxyl group and/or a nitroxy group as a substituent, a formula ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ groups (in the formula, R^a_4 and R^a_5 are the same or different and represent groups having the same meaning as R_4 and R_5 described above), formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ group (in the formula, B', R^b_4 and R^b_5 are the same or different and represent a group having the same meaning as the above-mentioned B, R_4 and R_5), a group of the formula -CONH-R_6 [in the formula, R_6 is a hydrogen atom, a lower alkyl group, or a formula ▲ Numerical formula, chemical formula, table, etc. ▼ group (in the formula, B'', R
^c_4 and R^c_5 represent the same or different groups having the same meaning as B, R_4 and R_5 described above. ) is shown. ], represents a hydroxyl group, a lower alkanoylamino group, a lower alkoxycarbonylamino group, a lower alkanoyloxy group, or a halogen atom, and R_1 is the formula ▲ formula,
There are chemical formulas, tables, etc.▼When indicating a group, R_2 is the formula -O-A'-ONO_2 group, the formula -O-(CH_2)_n
-CONH-A'-ONO_2 group or formula -CONH-
A'-ONO_2 group (wherein A' represents a group having the same meaning as A described above, and n represents an integer of 1 to 4), R_3 is a hydrogen atom, a nitro group, a lower alkanoylamino group , lower alkoxycarbonylamino group, lower alkoxy group or halogen atom. A phthalimidine derivative and a pharmacologically acceptable acid addition salt thereof.