JPH0372422A - Antilipemia agent - Google Patents

Abstract

NEW MATERIAL:A biphenyl derivative expressed by formula I or salt of said derivative (R<1> is H or lower alkoxy carbonyl; R<2> is lower alkoxy carbonyl, or R<1> and R<2> are mutually bonded to form group expressed by formula II; R<3> and R<4> are lower alkoxy; ring A forms sulfur-containing or nitrogen- containing heterocyclic group having or not having substituted group). EXAMPLE:4-hydroxy-5,6-bis(methoxycarbonyl)-7-(3,4-dimethoxyphenyl) benzo[b]thiophene. USE:Useful as antilipemia agent. Especially total cholesterol value in blood is decreased and high specific gravity lipoprotein cholesterol value is increased without any adverse effect. PREPARATION:A compound expressed by formula III (X is H, etc.; R<5> is lower alkyl) is reacted with 3,4-di(lower alkyl alkoxy) benzaldehyde and subjected to heat treatment, then the resultant compound is reacted with a compound expressed by formula IV (R<11> is H, etc.; R<21> is lower alkoxycarbonyl) to afford the objective compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an antilipemic agent containing a biphenyl derivative or a pharmacologically acceptable salt thereof as an active ingredient.

(Prior Art) Hyperlipidemia is considered to be one of the main causes of arteriosclerosis, which is an adult disease, and hypercholesterolemia in particular has a strong relationship with arteriosclerosis. On the other hand, cholesterol is a very low density riboprotein (VLD) in the blood.
L) Cholesterol exists in the form of low-density riboprotein (LDL) cholesterol, high-density riboprotein (HDL) cholesterol, etc. Among these, VLDL and LDL promote the deposition of cholesterol on the arterial wall and cause arteriosclerosis. However, HDL is known to have therapeutic and preventive effects on arteriosclerosis by preventing the deposition of cholesterol on arterial walls (Annals of Internal Medicine).
ine), Vol. 90, pp. 85-91 (1979)]. Therefore, in the field of treatment and prevention of arteriosclerosis, in recent years, it has become necessary to reduce the total amount of cholesterol in the blood while at the same time
It has been desired to develop an antilipemic agent that can increase the amount of L-cholesterol.

(Structure and Effects of the Invention) The present inventors have discovered that a biphenyl derivative represented by the following general formula or a pharmacologically acceptable salt thereof has an excellent antilipidemic effect.

H+ (In the formula, R+ is a hydrogen atom or a lower alkoxycarbonyl group, R2 is a lower alkoxycarbonyl group, or R1 and R1 are bonded to each other. Ring A is a sulfur-containing or Compound (I), which represents the formation of a nitrogen-containing heterocyclic group, and which is an active ingredient of the antilipidemic agent of the present invention, or a pharmacologically acceptable salt thereof, is a novel compound and an excellent antilipidemic agent. It has blood effects, particularly in lowering blood total cholesterol levels but increasing HDL-cholesterol levels.

In addition, compound (I) or a pharmacologically acceptable salt thereof has low toxicity and does not show side effects such as liver dysfunction (e.g. fatty liver). For example, when administered orally to mice at 1 g/kg,
Even after 5 days of observation, no deaths were observed, and there was no increase in body weight.

Therefore, compound (1) or a pharmacologically acceptable salt thereof is a compound useful as an antilipidemic agent, and can be used to treat hyperlipidemia and arteriosclerosis (e.g., atherosclerosis, Mönckeberg's arteriosclerosis). It can be used for the treatment and prevention of. Furthermore, since it has the feature of increasing HD L-cholesterol levels while lowering total blood cholesterol levels, it can be used particularly for the treatment and prevention of arteriosclerosis.

Specific examples of the compound (1) which is an active ingredient of the present invention include, for example, a compound in which ring A is a 5- to 10-membered sulfur-containing or nitrogen-containing heterocyclic group which may be substituted with a phenylsulfonyl group. I can give it to you. Among these, compounds in which ring A is preferably a 5- to 6-membered sulfur-containing or nitrogen-containing heteromonocyclic group or a 9- to 10-membered nitrogen-containing heterofused cyclic group optionally substituted with a phenylsulfonyl group It is a compound that is More preferred compounds are compounds in which Ring A is a thiophene ring, a pyridine ring, or an indole ring optionally substituted with a phenylsulfonyl group, particularly compounds in which Ring A is a thiophene ring or an indole ring substituted with a phenylsulfonyl group. preferable.

Compound (1), which is an active ingredient of the present invention, can be used for pharmaceutical purposes either as a free substance or in the form of a salt thereof. Examples of pharmacologically acceptable salts include alkali metal salts (e.g. sodium salts), alkaline earth metal salts (
For example, calcium salts), quaternary ammonium salts (e.g., tetramethylammonium salts, tetraethylammonium salts), etc., and inorganic acid addition salts (e.g., hydrochloride salts) when ring A is a heterocycle containing a nitrogen atom. , hydrobromide, sulfate), organic acid addition salts (for example, acetate, chelate, benzenesulfonate), and the like.

Compound H) and its pharmacologically acceptable salts, which are the active ingredients of the present invention, can be administered either orally or parenterally.
It is especially preferable to use it for oral administration17, such as tablets, capsules, granules, syrups, emulsions, suspensions,
It can be used as a pharmaceutical preparation such as an injection.

In addition, one of compound (1) or a pharmacologically acceptable salt thereof
The daily dose depends on the type and severity of the disease; the age, weight, and condition of the patient, but the daily dose is usually 1. 5-35rag/kg, especially 5-25■
/kg is preferred.

Compound (1), which is an active ingredient of the present invention, is represented by, for example, the general formula (wherein, X represents a hydrogen atom or a bromine atom, R1 represents a lower alkyl group, and Ring A has the same meaning as above). The acetal compound and 3,4-di(lower alkoxy)benzaldehyde are reacted in the presence of alkyl lithium, and the resulting product is heat-treated with boric acid if necessary, or the resulting product is hydrolyzed. death,
If desired, alkylation or acylation may be performed to form a compound of the general formula (wherein, Rs represents a lower alkyl group, R6 represents a hydrogen atom, a lower alkyl group, or a lower aliphatic acyl group, and 11?l
, R4 and ring A have the same meanings as above. ) or di-lower alkyl acetal of compound (IV) is obtained, and the compound is combined with the general formula % formula % () (where R1 represents a hydrogen atom or a lower alkoxycarbonyl group, R1 represents a lower alkoxycarbonyl group, ) in the presence of an acid (e.g., acetic acid, trifluoroacetic acid, P-toluenesulfonic acid, etc.), or react compound (■) with compound (V) in the presence of a base (e.g., lithium diisopropylamide, etc.).

In addition, the compound (IV) in which R is a lower alkyl group is
After alkylating the hydroxyl group of the compound represented by the general formula (where R1, R4 and ring A have the same meanings as above) according to a conventional method, the product is reacted with dimethylformamide in the presence of an alkyl lithium. It can also be manufactured.

On the other hand, in compound (1), R1 and R2 are bis(lower alkoxycarbonyl ) The biphenyl compound can be reduced (for example, treated with a reducing agent such as a borane-methyl sulfide complex), and then the product can be appropriately treated with an acid (for example, trifluoroacetic acid, etc.) to produce the product.

Furthermore, the compound (1) in which ring A is a nitrogen-containing heterocycle having no substituent on the nitrogen atom can be used by reducing the compound (1) having a substituent on the corresponding nitrogen atom of ring A (for example, It can also be produced by subjecting it to a cathodic reduction reaction and removing the substituent.

Experimental example (serum cholesterol level lowering effect and HDL-cholesterol level increasing effect) SD male and female rats (body weight: 110-170 g, 5 rats per group) were given cholesterol at 2w/wX and sodium cholate at 0.5w/%. The animals were given free access to feed containing 1z for 4 days. After this, the control group received the above feed, and the sample administration group received 100% of the test compound listed in Table 1 below.
The mice continued to receive ad libitum feed mixed at a ratio of mgX. Three days later, the rats were anesthetized with ether, their weight was measured, and blood was collected from the abdominal aorta. After the blood was left at room temperature for 1 hour, it was centrifuged to obtain serum, and the amount of serum cholesterol was measured using an enzymatic method [Clinical Chemistry (C1in, C
Hew, Vol. 20, p. 470 (1974)]. On the other hand, the amount of HDL-cholesterol was determined after removing VLDL- and Lu1l-cholesterol in the serum by precipitation using dextran sulfate [Canadian Journal of Biochemistry].
J, Biochem, ), Volume 47, Page 1043 (
(1969)],] HDL-cholesterol was measured by the enzymatic method described above. Based on these experimental results, the serum cholesterol lowering rate and ID of the test compound are calculated according to the following formula.
0L-cholesterol increase rate Kimoto: average serum cholesterol amount of control group: 152-230 increase g/di Umbrella snoring average +1 DL-cholesterol amount of control group; 13.
6 to 21.6 rag/+H The experimental results are shown in Table 1 below (In the table, Me represents a methyl group and Et represents an ethyl group, the same applies hereinafter). The liver was removed, the liver weight was measured, and the relative liver weight (weighed f
fi .

Production Example 1 (1) To a solution of 10.0 g of 3-dimethoxymethylthiophene in tetrahydrofuran was added 45 ml of 55Mn-butyllithium in hexane under stirring and cooling. After stirring the mixture under cooling, a solution of 10.5 g of 3,4-dimethoxybenzaldehyde in tetrahydrofuran is added to the mixture. After stirring, the reaction solution is poured into water, ethyl acetate is added, and the organic layer is separated. After washing and drying the organic layer, the solvent was distilled off under reduced pressure, and the residual aroma was purified using a silica gel column to obtain 2-
(α-hydroxy-3,4-dimethoxybenzyl) ~3
-18.0 g of dimethoxymethylthiophene are obtained as an oil.

M, 9.91-92"C (recrystallized from ethyl acetate-hexane) (2) Add 1.9 g of boric acid to a toluene solution of 1.0 g of the product from (1) above and heat to reflux. After cooling, The solvent was distilled off from the reaction solution under reduced pressure, the residual aroma was washed with ethyl acetate, and after drying, the solvent was distilled off under reduced pressure and purified with a silica gel column to obtain 2-(α-hydroxy-34-dimethoxybenzyl).
470 mg of -3-thiophenecarbaldehyde is obtained as colorless crystals.

(3) 1.5 g of the product from (2) above, 661 m of acetic anhydride
To a solution of 20 g, N, N-dimethylaminopyridine in tetrahydrofuran was added 818 g of triethylamine under ice water.
Add methanol to the stirred reaction solution and evaporate the solvent under reduced pressure. Add ethyl acetate to the residual aroma, wash with saturated aqueous sodium bicarbonate solution,
After drying, the solvent is distilled off under reduced pressure and the residue is purified using a silica gel column to obtain 1.7 g of 2-(α-ace,toxy-3,4-dimethoxybenzyl)-3-thiophenecarbaldehyde as colorless crystals.

M, p, 91-92 °C (recrystallized from ethyl acetate-hexane) (4) Add 29 μm of trifluoroacetic acid to a solution of 1.5 g of the product from (3) above and 1.8 g of acetylene dicarboxylic acid dimethyl ester in 25 d of benzene. After cooling the reaction solution, which was heated under reflux for 1 hour, the solvent was distilled off under reduced pressure, and the residual aroma was purified by silica gel column chromatography [solvent: hexane-ethyl acetate (1:1)]. The solvent was distilled off from the eluate under reduced pressure to obtain 350 cm of 4-hydroxy-5,6-bis(methoxycarbonyl)-7-(3,4-dimethoxyphenyl)benzo(b)-F-,t-phen as colorless crystals. obtain.

The crystals are recrystallized from ethyl acetate-hexane to obtain colorless prisms.

M, p, 147-148°C Production Examples 2-5 The corresponding starting compounds were treated in the same manner as in Production Example 1 to obtain the compounds listed in Table 2 below.

Obtained as a shirub.

Production Example 6 (1) 2-bromo-3-dimethoxymethylpyridine was treated in the same manner as in Production Example 1-(1) to produce 2-(α-hydroxy-3,4-methoxybenzyl)-3-dimethoxymethylpyridine. is obtained as yellow crystals.

M, p, 91-92 °C (recrystallized from ethyl acetate-hexane) (2) 11 g of the product from (1) above was dissolved in toluene by heating, 32 g of boric acid was added, and the 0 reaction solution heated to reflux was cooled. Afterwards, the solvent is distilled off under reduced pressure. Ethyl acetate was added to the residual aroma, washed with water, dried, the solvent was distilled off under reduced pressure, and purified with a silica gel column to give 3-(3,4-dimethoxyphenyl)-1-methoxy-IH,3L(-pyridino(2, 3-c) 6.5g of furan to light brown (3) 7.0g of diisopropylamine
-70 to 100ml of tetrahydrofuran solution with stirring.
Add 45 ml of a 1.55 M n-butyllithium hexane solution at -50°C. The mixture was heated at 0 to 10°C for 30
After stirring for a minute, the mixture is cooled again to -70°C. Approximately 10% of the mixture
5. minutes, the product of (2) above is produced. Add a solution of Og in tetrahydrofuran 201d and stir at the same temperature for 10 minutes. To the reaction solution, add 4.2 g of acetic acid and 1 d of tetrahydrofuran.
0 m solution and a solution of 2.7 g of acetylene dicarboxylic acid dimethyl ester in 1 OIti of tetrahydrofuran,
After stirring at the same temperature for 10 minutes, cooling was stopped and acetic acid 4.2
Add a 10 mL solution of 1.g in tetrahydrofuran and stir for 10 minutes.The reaction mixture is poured into 3001d of water and extracted with ethyl acetate. After drying the extract, the solvent was distilled off under reduced pressure, and the residual aroma was purified by silica gel column chromatography [solvent: hexane-ethyl acetate (1:2)]. The solvent was distilled off from the eluate under reduced pressure to obtain a pale brown oil. Obtain 1.8 g. Dissolve the nuclear oil in benzene, add 1.6 g of trifluoroacetic acid, stir at room temperature for 1 hour, and remove the solvent under reduced pressure from the reaction solution.
Add 100 d of ethyl acetate to the residual aroma and neutralize with 100 iffi of saturated aqueous sodium bicarbonate solution. After drying the organic layer, the solvent was distilled off under reduced pressure, and the resulting pale brown crystals were washed with ether to give 5-hydroxy-6,7-bis(methoxycarbonyl)-8-(3,4-dimethoxyphenyl).
1.3 g of quinoline are obtained.

The crystals are recrystallized from an ethyl acetate-hexane mixture to give light brown needles.

M, p, 183-184°C Production Example 7 (1) A tetrahydrofuran solution of 19 g of 1-phenylsulfonyl-3-dimethoxymethylindole and 6.5 g of N,N,N',N',-tetramethylethylenediamine was stirred and cooled. , 40d of a 1.55M n-butyllithium solution in hexane is added. After stirring the mixture at room temperature, a solution of 9.3 g of 3.4-dimethoxybenzaldehyde in tetrahydrofuran was added under cooling again, and after stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After drying the extract, the solvent is distilled off under reduced pressure and purified with a silica gel column to obtain 17 g of 1-phenylsulfonyl-2-(α-hydroxy-3,4-dimethoxybenzyl)-3-dimethoxymethylindole as a silica lump. .

(2) Add 0.6 g of boric acid to a toluene solution of 0.5 g of the product of (1) above and heat to reflux. After cooling the reaction solution,
The solvent is removed under reduced pressure. After adding ethyl acetate to the residual aroma, washing with water, and drying, the solvent was distilled off under reduced pressure and purified with a silica gel column to give 3-(3,4-dimethoxyphenyl)-1-methoxy-4-phenylsulfonyl-IH,3H-indolo. (2
, 3-c) 370+ng of furan are obtained as pale yellow crystals.

M, p, 131-132°C (3) 31.4 g of the product from (2) above, dimethyl acetylene dicarboxylate 2B, and 5 g of benzene 400xi solution were heated under reflux for 30 minutes. To the reaction solution was added p-)luenesulfonic acid.・Add 127 μl of hydrate and heat under reflux for an additional hour. After cooling, the solvent was distilled off under reduced pressure, and 40% ether was added to the residual aroma.
Add 0d. The precipitated crystals were collected by suction filtration to give 4-hydroxy-2,3-bis(methoxycarbonyl)-1-(3,4
27.5 g of -dimethoxyphenyl)-9-phenylsulfonylcarbazole are obtained.

M, p, 192-193°C Production Example 8 The corresponding raw material compound was treated in the same manner as in Production Example 7 to obtain 4-hydroxy-2,3-bis(ethoxycarbonyl)-1-(3
, 4-dimethoxyphenyl)-9-phenylsulfonylcarbazole is obtained.

M, p, 202-203°C Production Example 9 4-hydroxy-5,6-bis(methoxycarbonyl)
-7-(3,4-dimethoxyphenyl)-benzo(b)
Thiophene 5.0g Tetrahydrofuran 50d? Reflux the borane-methyl sulfide complex into the solution. Add methanol 801R1 and trifluoroacetic acid drops to the reaction solution, heat under reflux for 2.5 hours, and after cooling, concentrate the reaction solution under reduced pressure, wash the residual aroma with methanol,
4-hydroxy-5-hydroxymethyl-7-(3.4
-dimethoxyphenyl)benzo(b)thiophene-6-
95 g of carboxylic acid lactone 3 are obtained as pale yellow crystals.

The crystals are recrystallized from a mixture of ethyl acetate and tetrahydrofuran to obtain yellow-green amorphous crystals.

M, p. 223-224°C (decomposition) Production Examples 10 and 11 The corresponding starting compounds were treated in the same manner as in Production Example 9 to obtain the compounds listed in Table 3 below.

Production Example 12 4.0 g of 4-hydroxy-2,3-bis(methoxycarbonyl)-1-(3,4-dimethoxyphenyl)-9-phenylsulfonylcarbazole was placed on the cathode side of the mercury pool cathode/graphite anode electrode reaction device. 50 d solution of N,N-dimethylformamide and 4.2 g of toluenesulfonic acid tetraethylammonium salt are placed, and 10 m of N,N-dimethylformamide and toluenesulfonic acid tetraethylammonium salt 4.2 g are placed on the anode side.

Under water cooling, a current of 200a+A was applied, and the reaction was stopped when a current of 1351 chlorine was applied. The reaction solution was drained from the cathode side with 50 m of methanol, 09 m of acetic acid was added, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate solution is added to the residual aroma, and the resulting crystals are washed with water to obtain 2.2 g of 4-hydroxy-2,3-bis(methoxycarbonyl)-1-(3,4-dimethoxyphenyl)carbazole.

The crystals are recrystallized from a methanol-tetrahydrofuran mixture to obtain colorless prism crystals.

M, p, 252-253°C (decomposition) Production example I3
and I4 The corresponding raw material compound was treated in the same manner as in Production Example 12 to obtain the following 4th
The compounds listed in the table are obtained.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a hydrogen atom or a lower alkoxycarbonyl group, and R^2 is a lower alkoxycarbonyl group. , or R^1 and R^2 are combined with each other to form the formula: ▲
There are mathematical formulas, chemical formulas, tables, etc. It represents forming a group shown by ▼, R^3 and R^4 represent lower alkoxy groups, and ring A is a sulfur-containing or Represents the formation of a nitrogen-containing heterocyclic group. ) or a pharmacologically acceptable salt thereof as an active ingredient. 2. The antilipemic agent according to claim 1, wherein ring A is a 5- to 10-membered sulfur-containing or nitrogen-containing heterocyclic group optionally substituted with a phenylsulfonyl group. 3. 9-- in which ring A may be substituted with a 5- to 6-membered sulfur- or nitrogen-containing heteromonocyclic group or phenylsulfonyl group
The antilipidemic agent according to claim 2, which is a 10-membered nitrogen-containing heterofused cyclic group. 4. The antilipidemic agent according to claim 3, wherein ring A is an indole ring optionally substituted with a thiophene ring, a pyridine ring, or a phenylsulfonyl group. 5. The antilipemic agent according to claims 1 to 4, which is a prophylactic/therapeutic agent for hyperlipidemia and/or arteriosclerosis.