JPS58174342A - Benzoquinone derivative - Google Patents

Abstract

NEW MATERIAL:The benzoqunone derivative of formula I (A is CO or CH2; one of R1 and R2 is H and the other is methyl; m is 0-21). USE:It has activities to inhibit the protocollagen.proline hydroxylase and suppress the collagen biosynthesis. It is useful as an agent for suppressing the fibrinosis of animal tissue, for the prevention and remedy of organofibrosis of animals especially mammals such as rabbit, rat, dog, etc. For example, the compound is useful as a remedy for pulmonary fibrosis, hepatocirrhosis, nephrosclerosis, arteriosclerosis, scleroderma, myelofibrosis, chronic arthritis, etc. PROCESS:The compound of formula I wherein A is CH2 can be prepared e.g. by reaction the quinone of formula II or the (protected) hydroquinone of formula III(R3, R4 and R5 are H or acyl) with a metal hydride, e.g. lithium aluminum hydride, etc. in an organic solvent such as ether, and oxidizing the resultant compound with an oxidizing agent such as silver oxide.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel benzoquinone derivative having protocollagen/glolin hydroxylase inhibitory activity, collagen biosynthesis inhibitory activity, and the like.

Protocollagen proline hydroxylase is an enzyme that is synthesized in ribosomes in animal cells and specifically hydroxylates glolin in protocollagen, and is one of the important factors that rate-limits collagen biosynthesis. Conventionally, iron gilators (e.g. a,
cl-ziviri-5lpy, etc.), SH# inhibitors (e.g., P-chloromercury benzoate, etc.), and certain heavy metals (e.g., Cu'', Z-, etc.), but none of these substances It non-specifically inhibits the biosynthesis of collagen and non-collagen proteins and has significant side effects, so it could not be used as a drug.

If a substance is found that specifically inhibits collagen biosynthesis without inhibiting the biosynthesis of non-collagen proteins, that substance could be used to treat arteriosclerosis, liver cirrhosis, hyperplasia, keloids, rheumatoid arthritis, and pulmonary fibrosis. It can be used in the preventive treatment of diseases including organ fibrosis that is accompanied by excessive accumulation of collagen, such as fibrosis.

The present inventors conducted an intensive search for substances that inhibit protocollagen glolin hydroxymerase activity and found that the general formula (wherein M is co or CfI, R is hydrogen, and R2 is hydrogen one atom and the other is a methyl group, m is 0 to 2
Indicates an integer of 1. The present invention was completed based on the finding that the benzoquinone derivative represented by ) specifically inhibits the biosynthesis of cofugen.

That is, the present invention is a benzoquinone derivative represented by general formula (1).

The benzoquinone derivative (1) of the present invention has protocollagen/prolyl hydroxylase inhibitory activity as shown below.

Measurement of protocollagen/prolyl hydroxylase inhibitory activity is as follows: 1. The method of Kivirriko et al. and J, HJLlvne et al. (J, BioL Ch*
z 242, 4007 (1967) and Biochi
m, Biophya, Acta 198.460 (
(Pro-Pro Gly) 5-4H2 using a partially purified enzyme preparation prepared from chicken embryos according to K. 1967))
0 (Protein Research Foundation, Osaka) as the base trade, RK,
The method of Rhoada et al.
szywro-1ogy lvl B, 306(1
971) ) In ffC quasi-site ff Natsumourin - Water Drop, the partially purified enzyme has a protein content of 100μ.

Compound (1) of the present invention can be used as an animal tissue fibrosis inhibitor for animals, especially mammals (e.g. rabbits, rats, etc.).
It can be used for the prevention and treatment of organ fibrosis in laboratory animals such as Maunus; pet animals such as dogs and cats; and humans. Organs, i1! Fibrosis is a general term for diseases caused by excessive cofugen accumulation, and includes, for example, pulmonary fibrosis, liver cirrhosis, nephrosclerosis, arteriosclerosis, scleroderma, bone marrow dysplasia, and chronic arthritis. be.

When the compound (1) of the present invention is used for the purpose of preventing or treating the above-mentioned 9-organ syndrome, it may be used by itself or mixed with an appropriate pharmacologically acceptable carrier, excipient, or S diluent; powder,
9 M tablets, capsules.

It can be administered orally in the form of injections and the like. The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but for example, it is recommended to use as a prophylactic/curative agent for adult liver cirrhosis, arteriosclerosis, chronic arthritis, etc. When administered, it is desirable to administer about 2 to 50 sF per day orally in 1 to 3 divided doses.

Among the compounds represented by the general formula (1), compounds in which m is CH2 are, for example, quinones represented by the formula (in the formula, Otori has the same meaning as above), or optionally protected hydroquinones represented by the formula (In the formula, the door has the same fold as above, and R3, R4, and R5 are hydrogen atoms, and each represents an AV group) with a metal hydride compound, and then it can be produced by subjecting it to an oxidation step.

In this case, when R5 is an acyl group, it goes without saying that it is further subjected to a hydrolysis step. Examples of the acyl group for R3, R4, and R5 include acetyl, propionyl/I/, butyryl, and oleyl. The above metal hydride compounds include lithium aluminum hydride,
A metal hydride compound such as sodium borohydride is used, and the reaction is carried out by dissolving the compound (1) in an organic solution of tetophhydro, dioxane, ether, and the like in a state of nine.

The reaction proceeds at room temperature, but may be heated if desired. The reaction time varies depending on the raw materials and solvent used, but
For example, when compound (1) (-:9) is reacted with lithium aluminum hydride, the reaction completes within one hour when dioxane is introduced. The progress of this reaction can be determined by thin-layer chromatography to determine the end point.

In this reaction, hydroquinones represented by the general formula (wherein R1, R2, !1 and R5 have the same meanings as above) are used regardless of whether Compound (1) is used as a starting material. The resulting residue is then subjected to an oxidation step. As the arsenic, any arsenic that is generally used for oxidizing vitroquinones to quinones may be used, such as silver oxide, ferric monide, etc.;

The reaction is carried out in a state in which the above reaction product is dissolved in ethanol-μ, ether-μ, or the like. It goes without saying that this oxidation step is not necessary if the above reaction product has already been oxidized to thonone'@ by an extraction operation or the like.

When using a compound in which R5 is an AV group as a starting material, it is necessary to subject the above reaction product to a hydrolysis step to lead to the compound (1) of the present invention. . Any hydrolysis reaction may be used as long as it does not change the compound (1); for example, in the presence of a mineral acid such as hydrochloric acid,
For example, Me! The reaction is carried out in alcohols such as alcohol and ethanol.

The product of this reaction is generally alt or R2 in compound (1).
One is hydrogen, the other is methyl, and a trace amount of a mixture of the formula and the compound represented by the formula □1:1+ [wherein the form has the same meaning as above] is rounded, and then subjected to a separation step. As a separation method, for example, Kabumuku Pmatogufui, which uses silicic acid such as alumina, silicic acid, or magnesium silicate as an adsorbent, is used, and as an eluent, a polar organic solvent, a mixture thereof, or a mixture of these and a non-polar organic solvent is used as an eluent. A mixed solution is used, for example a mixed solution of ethanol and 70% chloroform.

In addition, the metal compound represented by the general formula (1) can be formed by combining the nons represented by the formula (in which R1 and R2 have the same meanings as above) and the general formula % ([) (in the formula R61; A peroxide (hereinafter referred to as peroxide) of a carboxylic acid or an acid anhydride (hereinafter referred to as acid anhydride (W)) represented by an optionally protected hydroxyl group It can also be produced by reacting things.

This reaction can be carried out using a suitable inert solvent, such as n-hexane,
The reaction temperature is preferably about 80° to 100° C.
is preferred, and the reaction time is preferably about 0.5 to 3 hours.

This reaction proceeds under very mild conditions with the generation of leg acid gas O, with few side reactions and the desired product obtained in good yield.After the reaction, unreacted raw materials are recovered without loss.
be done.

The reaction may also be carried out under conditions such that peroxide ([) is produced in the reaction system, for example, in the presence of a tetravalent lead compound (for example, lead tetraacetate), a compound (■) is produced in the reaction system. This is carried out by reacting the compound (■) or the acid anhydride (W). The reaction is carried out using a suitable inert solution K (e.g. n
-Hexane.

It is preferable to carry out the reaction in a medium (ligroin, toluene, dichloromethane, acetic acid, propionic acid, etc.), and the reaction temperature is 50＠~
150°C is preferred.

In this reaction, when R6 of the metal compound (■) is protected and the carboxylic acid is a hydroquinyl group or a carboxyμ group, the peroxide of its acid anhydride is used. The compound of the invention (by subjecting it to
1) K can be derived. Such hydrolysis reactions are conveniently carried out in the presence of, for example, mineral acids (sulfuric acid, hydrochloric acid, etc.), caustic substances (sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). In addition, a general formula (wherein, R, and R2 have the same meanings as above) is produced by hydrolysis in the presence of an appropriate antioxidant (such as pyrogallo-y) and a reducing agent (such as hydrosulfite F). ) The metal compound (1) can be obtained by oxidizing the compound represented by, for example, ferric chloride, silver saponide, air, or the like.

The quinones <l) thus obtained are collected by suitable means known per se, such as liquid conversion, dissolution, concentration, vacuum distillation, chromatography, crystallization, and recrystallization.
You can easily do 11 K.

Example/Lithium hydride, s/l=um (20f) was suspended in dioxane (300 s/l) and heated under reflux for 2 hours to form a circle. This suspension was added to 1(m:9.1Of)4Ds) oxane (
A solution of 350 mg) was added dropwise over 4 hours, then heated under reflux for 40 minutes, water and 3N hydrochloric acid were added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate and treated in a conventional manner. The residue was dissolved in aqueous methanol and 40g of ferric chloride (100s
Add f) and stir. The reaction solution was extracted with ethyl acetate, the extract was treated in a conventional manner, and the resulting residue was purified by column chromatography using V9 Kagel. The first minute fraction eluted with Taroro umbrella filter (m: 9) was then sequentially eluted with ethanol-μm chloroform (1:50). :ca2) and l (R1:H, R2:CH3, ll:
9. m: C11g), and i (R1:
H, R2: Cfl3. After remardography under the same conditions, recrystallization from ethyl acetate-hexane yielded m(m:9, 0.439).
) is a yellow needle crystal with a melting point of 96-107°C, l (R1
:Cll3. R2:il.

m:9. M: CH2) and l (R1:H, R2:CH
3, *:9゜: CH2) iso-situation compound (1,2f)
is a dark red crystal with a melting point of 90-97°C.
1:R9R2:CH3,111:9. cn2) was obtained as dark red needles with a melting point of 97.1s-xoo1'c.

Elemental analysis value Ma (m:9) Calculated value as C engineering 8H2804 C
70,10〼R9-15〇measured value C70,33〼
R9,201 (R Engineering:) I, R2: Cfl,, Otori: 9.
M:CH2) Calculated value as C181112805
C66,64! I 8.7G dormitory measurement C66,4
0 薔 18.99 Example λ 'rHF' (100sf)il of compound 1 (mu:9)
T of lithium aluminum hydride (2#) when cold.
Add aF(100j) to Ilfi solution. The reaction mixture was heated under reflux for 63 hours. Add reaction water little by little to decompose excess lithium aluminum hydride, then add S-hydrochloric acid and extract with ethyl acetate. Um (
Flori Hatake11)! Purification was performed using column chromatography, and the fraction eluted with ethanol was evaporated to dryness under reduced pressure to yield I (R1:H, R2:CH3, m:9.A
:CH2) and 1(R1:CH3, R2:H, Otori: 9
．． A mixture of CH2) was obtained as dark red crystals. Nuclear magnetic resonance spectrum (δ value in deuterated chloroform): t,
33(i6I(,b,CH2).

2.09(31(,s,Cfl3 on ring)454(2H
, t, CH2 on the ring), 3.74 (zg, t, CH2o
), tt4(3H,8,0CR3).

Example 3 Fumigatin (■, R1:H, R2:CH3,1,59
) toluene (10.8 m?) solution K at 85-95°C, add bis(11-acetoxyundecanoyl A/) beoxide (8.75 f) little by little over 5.5 hours. After the addition was completed, the mixture was heated for 0.5 hour, and then a saturated aqueous solution of acidic sodium carbonate was added, followed by extraction with ethyl ether. The extract obtained by treating the extract in a conventional manner is
Purified by column chromatography using lica gel,
Acetic acid-carbon tetrachloride-ethyl-ether (1:45:5)
It was eluted. The eluate (1,29) was recrystallized from hexane-ethyl acetate to give l (R4:H, R2:CH3, m
:9. Acetite of CH2) can be obtained as dark red needles. Melting point 59-61℃ Elemental analysis value Calculated value as C2oH3006 C65,55; H8,25 dormitory measurement C
65,47i H&31 Ippon A7i) (1,
13f) with methanol-fi/(55sg) and salt production #(
The reaction solution was concentrated under reduced pressure, ethyl acetate A/(1 oosg) was added to the concentrated solution, washed with saturated water, and treated in a conventional manner to remove the resulting residue. When the product is recrystallized from ethyl acetate-hexane, l (R1:H,R
2:CH5゜m:9. CH2,0,9f) was obtained as dark red needles. Melting point 9g-99℃ Elemental analysis value Calculated value using C engineering 8'2805 C66,64; H8,70 actual value C
6a60 GB 8.81 Dormitory Example Hongzi (R3,R4,R5:COCH3,m:3) was treated with lithium aluminum hydride and then ferric chloride under the same conditions as in Example/. , R2:CH
3゜m: 3. R,:C0CH5) and l[(R1:CH
3, R2: I! , m: 3, R5: C0CH5) was obtained.
RE! :CH3, Otori:9. Mu: I (R1:
H, R2: CH3, Otori: 3. m: ca2 ) and l (
R1:CH3, R2:H,! l:9-mu:CH2)
A mixture of nine is obtained.

Example! A toluene (5d) solution of fumigatin (■, R1:H, R2:CH3,374 da) was heated to 95°C, and diglutaryl bay oxide (1,759) was added little by little over 9 hours. The reaction solution was stirred for an additional 0.5 hour,
After cooling, water was added and extracted with ethyl acetate. The extract was treated in a conventional manner, and the resulting residue was purified by column chromatography using 6-year-old hydrous silica gel. The fraction eluted with hequinane-ether (7:3) was evaporated to dryness under reduced pressure to yield compound 1 (R1:H, R2:CH3, 11:3.M:
co) was obtained as a red oil. Boiling point 106-108℃ Elemental analysis value Calculated value as C1, H engineering, 06 c 56.69; 'fi 5.55s
J! Measured value C56,88i 115.52 reference example/
Bis(11-acetokiVundecanoy~)be~oxide R, G, Jonesa (J, Mumer, CheL8
11-acetokyundecanoyl chloride (
10.5f) was dissolved in petroleum ether l&/(50sJ)K and 20s of ice water was added. Next, sodium peroxide (4) was added little by little, followed by extraction with ether, and the extract was treated in the usual manner and evaporated to dryness under reduced pressure to yield bis(11-acetylVunderikikneu~)be~oxide (8, 6f) was obtained in the form of a white rice ball and was round.

Reference Example 2 Jig~Tari~Beluoki V Dro% hydrogen peroxide solution (18 mg) and sodium acetate (
0,1? ) Gluta=fi/# anhydride was added little by little at 10° C. while stirring. The mixture was further stirred for 1 hour, and the precipitated crystals were collected in #3, washed with cold water for 2 hours, and dried after death to obtain crystals of diglutary yberoxide V.

Special d'E palace 1. Incident display Zuno Hitotsu~7 (1773'
□Patent application 2 filed on April 6, 1981, Invention of 6-cup benzoquinone derivative 3, Related to the f-yama Shokin Suru name incident Ms. Patentee 1 Address 2-27 Doshomachi, Higashi-ku, Osaka City Name Name (2
93) Takeda Pharmaceutical Co., Ltd. + Representative: Iku Kurabayashi, Department 4, Agent Address: 2 Jusohonmachi, Yodogawa-ku, Osaka City] Old No. 17-85 Takeda Ryohin Pharmaceutical Co., Ltd., Osaka Factory Resident b Buried by masu (5844)・□゛Matsu Isho Nibeikyo contact information (Special Edition Law Present Division)” I Sodeyama 27B-22195
, Amendment pair W 6'V of the invention of the light phase 1 screen, suma 3 light column (1) Specification 41
No. 6, line 5, page 7, line 8, and page 7, page 19, sof.
Insert "R3, R4," before "R5" in .

(2) The general formula (mV) on page 1, lines 5 to 7 of the same book is corrected as follows.

(3) "A mixture of and" is inserted after rVJO on page 12, line 12, page 12, line 19, and page 13, line 7 of the same book.

(4) Ibid., page 16, lines 3-8, NorlV(R,:H.

R: CH--'--12 when treated with methanol
′! ! - Delete all. .

ゝ1 Continuation of the amendment (to myself) 1, 11G
r'l's! (Showa 57'+4) Application No. 5'717 'J' h2
Name of the invention Benz,\-Non-induction D[4\:3. Supplementary II etc. It 1'L t, ') Seki (al ↑) Permission 1f
i Personnel Isu1 personHanzan Higashi-ku l-111-cho 21'
1127 address 8 (4, (:!93) Take + 1 bag of office lady stock company? 1 generation no (person (τ ft;
-1 wo Town 2] -1117 No. 85Y; 6 Amendment 1) Insert ``in some cases'' after ``if'' on page 7, line 20 of the specification.

2) Correct "9" in line 9 of page 16 of the WI book to "3".

3) Insert the description of ri ware 9, JOI & nirigi on page 16, line 1θ of the same book.

“Elemental Analysis 1” 1! ”Calculated value as 1606 C5
9,99 gate H6,71 Actual measurement C59,83i H6,87J4) Ibid. No. 1
Insert the following statement between page 7, line 5 and line 6.

"Implementation Compound 1 (R: H, R2: CI
[3, Iris: 9. A: CO) is obtained as reddish brown needles f5
．． cncl, Jj [0 nuclear magnetic resonance smooth μ-(ppm
): 130 (14H, - double line, CH2), 2.
．． 02C3■, - double line, cm3'), Z204S3 (
41, ◆Double line.

Nuclear CH2 and CH2 dissolved in carboxylic acid), 405
(3M, - electric wire, nuclear ocn3), Elemental analysis Calculated value as C engineering 8H2606 C63,89 〼 H7,74 Fresh measured value C63,78i H7,68J or more

Claims (1)

[Claims] General formula (in the formula, M is CO or Cu2, one of R1, R, ij is a hydrogen atom and the other is a methyl carrier, - is 0 to 21
C) indicates an integer. ) A benzoquinone derivative represented by