JPS5818362A - Isoquinoline derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:An isoquinoline derivative expressed by formulaI(R is H or lower alkyl; n is an integer 1-7) and a pharmacologically acceptable salt thereof when R is H. EXAMPLE:Ethyl 2-(7-isoquinolyloxy)acetate. USE:An anti-inflammatory agent, remedy for disturbance of obstructive peripheral circulation, endotoxic shock, pulmonary embolism, etc. having the anti-inflammatory action and inhibitory action on blood platelet agglutination and biosynthesis of thromboxane A2. PROCESS:7-Hydroxyisoquinoline is reacted with a halogenated ester expressed by formula II (R<1> is lower alkyl; X is halogen) in the presence of a base, e.g. sodium hydride or potassium hydride, and if desired hydrolyzed and subjected to the salt forming reaction to afford the compound expressed by formulaIand a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel inquinoline misconductor useful as a pharmaceutical product. More specifically, the present invention provides anti-inflammatory effects, platelet aggregation inhibiting effects, and tropoxane A2.
The present invention relates to a novel inquinoline misconductor that has pharmacological effects related to biosynthesis inhibition and is therefore useful as a pharmaceutical, its pharmacologically acceptable salts, and its production method.

The novel isoquinoline derivative of the present invention is represented by the following formula.

The compound of the present invention has an antagonistic inflammatory effect and an inhibitory effect on platelet aggregation.
．． ) Since it has an rx7 boxane A2 biosynthesis inhibitory effect, it is expected to be an anti-inflammatory mulberry, a therapeutic agent for obstructive peripheral V4 barrier disorder, a therapeutic agent for endotoxic shock, and a pulmonary embolism therapeutic agent, which are expected from these four physical effects.

It is useful for treating asthma, as a preventive or therapeutic agent for myocardial infarction and stroke, as a coronary artery dilator, as a therapeutic agent for arteriosclerosis, as a therapeutic agent for nephritis, etc.

In the above formula CI), R represents a hydrogen atom or a lower alkyl group. Preferred examples of the lower furkyl group include furkyl groups having carbon atoms of 1 to 6, such as methyl, ethyl, propyl, isobutyl, butyl, pentyl, and hexyl. Groups are preferred. n represents an integer from 1 to 7. Among them, n is preferably 2 or 6. Specific examples of such compounds include 2-(7-quinolyloxy)acetic acid, 3-(7-quinolyloxy)vinic acid, and 4-(7-quinolyloxy)butyric acid.

5-(7-inquinolyloxy)valeric acid, 6-(7-inquinolyloxy)hexanoic acid, 7-(7-inquinolyloxy)hebutanoic acid, and methyl esters, ethyl esters, and purpuric acids of the above compounds. These include pyl ester and butyl ester.

The compound of the present invention can be produced as follows. That is, 7-hypxyinquinoline and a conjugated ester represented by the following formula Cn) It can be manufactured by following the salt-forming reaction. The red label, 7-hyF-roxyisoquinoline, can be easily produced by treating the Schiff fraction obtained from α3-hydroxybenzaldehyde and 7mino7cetaldehyde diethyl 7secur with sulfuric acid. This manufacturing method is published in the Literature Journal Ano American Gummy Power Society (J.
Amer, Chem, SOC,) Volume 67, 860
It is not mentioned in the negative (1945).

In the above formula (n), 0 is an integer of 1 to 7, and R' is a lower furkyl group, and examples of such lower alkyl group include a methyl group and an ethyl group as in A11.

Examples include purpyl group and butyl group. X is a hapgun atom, such as a chlorine atom, a bromine atom, or an iodine atom.

The reaction between 7-hydroxyinquinoline and the +ρ-gated ester represented by the above formula [:n) is as follows.

1j in the presence of a base, and the bases used here include sodium hydride, potassium hydride, sodium, methacrylate, sodium 5-toxide, sodium 1-butoxide, potassium methoxide, Inorganic bases such as potassium t-butoxide, sodium carbonate, potassium carbonate, 1,5-diazabicyclo [
4,λ0]non-5-ene, 1,4-diazabicyclo
(2, 2, 2) Just tan.

1.8-Diazabicyclo [5,4,O)wantesu7
Organic bases such as 1-ene and triethylamine are preferred.
<Used. The base is used in an amount of 10 to 10 equivalents, particularly preferably 11 to 5 equivalents, per equivalent of 7-hydroxypoxyisoquinoline. The reaction is carried out using 1 to 1 K of 7-hydroxyisoquinoline and a halogenated ether represented by the above formula [11]. The reaction usually proceeds smoothly in an inert organic solvent, and the organic solvents used include dimethylformamide and dimethyl sulfoxide.

Polar solvents such as hexamethylphosphoramide, aromatic hydrocarbons such as benzene and toluene, and ethers such as tetrahydrofuran, ethyl ether and dioxane are preferably used.

6- The reaction temperature is -]0°C ~]0 (]'C1 reaction time is preferably (-1) from 05 hours to 24 hours.The reaction product is separated by a method such as continuous extraction. To further purify the obtained crude product,
It is achieved by 8 manual processes such as ladle, columnar mudgraphy, and distillation.

(The isoquinoline a conductor prepared by
1. The hydrolysis of Esrael can be done as follows:
Bases such as sodium hydroxide and potassium hydroxide are usually mixed with water or water and water in organic solvents such as alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran and dioxane. It is hydrolyzed by the method described.

The isoquinoline derivative in which l is a hydrogen atom is then neutralized with an acid such as hydrochloric acid or sulfuric acid, or a phosphoric acid such as acetic acid, and then recrystallized, columnar + r-v togerafy, etc. It can be isolated and purified.

Further, if necessary, the isoquinoline derivative may be treated with an organic solvent such as an alcohol such as methanol or ethanol, or an ether such as tetrahydrofuran or dioxane.
Alternatively, dissolve in a mixed solvent of these organic solvents and water and hydroxylate.

Sodium, potassium hydroxide, barium hydroxide.

Inorganic bases such as calcium hydroxide, or
, monomethylamine, dimethylamine.

Addition of an organic base such as trimethylamine followed by filtration or concentration provides the respective isoquinoline derivatives.

The thus obtained isoquinoline derivatives of the present invention and their pharmacologically acceptable salts can be used as anti-inflammatory drugs, therapeutic agents for obstructive peripheral circulation disorders, therapeutic agents for endotoxic shock, therapeutic agents for pulmonary embolism, therapeutic agents for asthma, and myocardial infarction. It also has anti-inflammatory effects, platelet aggregation inhibiting effects, and tompoxane anti-inflammatory effects, making it useful as a stroke prevention or treatment, coronary artery dilator, arteriosclerotic agent, ulcer treatment, etc. For example, to give an example of specific efficacy evaluation of the novel isoquinoline derivative of the present invention, the platelet aggregation inhibiting effect of 2-(7-inquinolyloxy)acetatebutyethyl (in virro evaluation on 7-rachidonic acid aggregation in rabbit platelets) was shown. As a result, the 50% stopping concentration (IC,.) was 100μ9/-. The present invention will be specifically explained below with reference to Examples.

Example 1 1.0 g of 7-hydro p-xyin 4-noline was dissolved in dimethylformamide]+nj, and the solution was dissolved in dimethylformamide of sodium hydride (60% oil dispersion, 330IIIi? was washed three times with pentane). ] m, in solution,
Added under water cooling. Hydrogen generation was immediately observed. 20 minutes later,
After confirming that the generation of hydrogen had stopped, 1.49 g of ethyl acetate bromide was added under water cooling, and the mixture was stirred at the same temperature for 1 hour.

The mixture was then stirred at room temperature for 4 hours. Added 20ml of water, extracted 3 times (a o mt) with ethyl acetate, and separated for 1 minute.
9- After washing the organic layer with 20+ a/ml of water, the organic mixture was dried over anhydrous sodium sulfate. The crude product obtained by distilling off the organic solvent under reduced pressure was subjected to column chromatography (silica gel,
Purify the desired ethyl 2-(7-inquinolyloxy)acetate with pp form/ethyl acetate 93 nia).
] l/ was obtained.

The I'llr spectrum of this product was as follows.

+117Ir(CDCA’3)δ: 1.28 (3H, I, J=7Hz).

4.30 (2I (, q, J = 7Hz), 4.77 (2H
, a) 7.20 (IH, d, J=3Hz).

7.43 (IH, dd, J=3H, 911z).

7.60 (IH, d, J=6Hz).

7.80 (] H, d, J = 9 Hz).

8.47 (]H, d, J=6Hz), 9.18
(IH,s) Example 2 Ethyl 2-(7-inquinolyloxy)acetate 41(+1
n9 in 2N NaOH 15tnt methanol 2-
When the mixture was stirred for 10 - 10 days, the spots of the raw ester completely disappeared in % layered p mudgraphy. After concentrating under reduced pressure, it was neutralized with 5-dishucic acid, and the white crystals were thoroughly washed with water to obtain 350~ of 2-(7-inquinolyloxy)acetic acid. The melting point of this product was 260-261°C.

Example 3 7-hydro p-? Diinkin 9F10 Sodium 33011+IIL, Dimethylform 7
2 ml and 3-bromide sorone #R methyl 1.
The reaction was carried out in the same manner as in Example 1 using 5 fl.
Work-up and subsequent purification provided methyl 3-(7-inquinolyl 4-cy)propionate 12I.

The seed r spectrum of this product was as follows.

nff1r (ct) cJ. ) δ: 2, 2 0 (2H, I, J=7) 1x).

4, 0 (2H, 1, J = 71 (z), 3.63 (3
H,s).

7, 2 0 ( ] H, d, J = 3Hz).

7, 4 5 (IH, dd, J=3Hz, 9Hz)
.

7, 6 2 (IH, d, J=6Hz)
.

7, 7 8 ( ] H, d, J = 9Hz).

8, 44 (IH, d, J=6Hz), 9.1 5
(IH, S).

Example 4 7-Hydroρoxyisoquinoline 1. The reaction was carried out in the same manner as in Example] using 3 g of hydrogenated sodium triglyceride A410, 10 g of dimethylformfamide and 3 g of methyl 7-iodohebbutanoate. 14 g of methyl-(7-inquinolyloxy)hebutanoate was obtained.

The nmr vector of this product was 11 as follows.

olTlr(CDC4)δ: 1, 2-2.3 (]OH, rn), 3.9
(2H, m).

365 (3H, s), 7.15 (IH, d).

7, 4 0 ( 1 1 (, dd, J=3 H
z, 9 Hz, ) + 7, 6 0 ( ] H, d
, J=6Hz).

7, 80 ( ] H, d, J-911z
).

8, 45 (IH, d, J=6Hz), 9.20 (IH,
s).

Patent applicant Teijin Ltd. Agent Patent Attorney Former 1) Hiroshi Jun 13 - Continuation of page 1 ・Council leader Kenji Manabe 3-5-18 Tamadaira, Hino City

Claims (1)

[Scope of Claims] 18. An isoquinoline derivative represented by the following formula [I] and a pharmacologically acceptable hydrogen atom thereof when R is a hydrogen atom. 2'' In the formula [1], R is a hydrogen atom, a methyl group or an ethyl group, and n is an integer of 1.2 or 6. In the case of a hydrogen atom, its pharmacologically acceptable salt. 37-Hydoxyinquinoline and the following formula (II)X
(CH,)ncOl R' -- (11) In the formula, R1 is a lower fulkyl group, X is an atom, and n14 is the same as the above definition. '' in the presence of a base to carry out hydrolysis and/or salt-forming reactions as desired.
The following formula (1) [wherein R and n are the same as defined above] ] A method for producing an intaganoline derivative represented by the following and a Pharmacology 11j-acceptable salt thereof when R is a hydrogen atom.