JPS59164716A - Biosynthetic inhibitor for fatty acid - Google Patents

Abstract

PURPOSE:A biosynthetic inhibitor for fatty acids, containing a specific dicarboxylic acid as an active constituent, and capable of inhibiting acetyl CoA carboxylase and treating obesity due to excess fat causing arteriosclerosis, diabetes, etc. CONSTITUTION:A biosynthetic inhibitor for fatty acids containing a dicarboxylic acid of the formula (R is alkyl or alkenyl; n is 0 or an integer 1-6), anhydride or a salt thereof as an active constituent. The compound of the formula is capable of inhibiting acetyl CoA carboxylase which is a rate determining enzyme of a synthetic system for the fatty acids. Thus, the accumulation of excess fat which is a direct or indirect cause for arteriosclerosis, diabetes or gout, etc. having a tendency to cause complication is inhibited. The above-mentioned inhibitor can be orally or parenterally administered. The daily dose thereof is usually 0.1-2,000mg/kg. The compound of the formula can be produced by the well-known method.

Description

[Detailed description of the invention] The present invention relates to fatty acid biosynthesis inhibitors.

Obesity is a state of excess adipose tissue, and it is well known that so-called adult diseases are more common in obese people.

Diseases that are likely to be associated with obesity include those related to metabolic abnormalities associated with obesity, such as arteriosclerosis, diabetes, and gout, as well as osteoarthritis and skin diseases associated with physical phenomena associated with obesity. In any case, the ingested glucose
It is clear that the direct or indirect cause of this is excessive accumulation of fat produced by the body.

On the other hand, acetyl OOA carboxylase (Il'i0A
, 4', /, 2) is considered to be the rate-limiting enzyme in the fatty acid synthesis system. Therefore, with the aim of developing an agent that lowers the synthesis of neutral lipids, which are a cause of obesity, we conducted an intensive search for inhibitors of this enzyme, and as a result, we arrived at the present invention.

That is, the gist of the present invention is that the general formula (T)R-0HOOO
H (OH2)n(I) 00H (wherein, R represents an alkyl group or an alkenyl group, and n represents an integer from 7 to O)], an anhydride thereof, or a salt thereof. It is a fatty acid biosynthesis inhibitor as an active ingredient.

The present invention will be explained in detail below.

R in the general formula (1-1) represents an alkyl group or an alkenyl group, and the alkyl group usually has about 1 to 30 carbon atoms, preferably A -, 20, and the alkenyl group and 12 usually have about 2 to 30 carbon atoms. , preferably about 20 to 20.

The above carboxylic acids according to the present invention can be prepared by a known method.
It can be crushed.

For example, in general formula (I), R is an alkyl group.
ill, 21112, ProceecL
ings J/B 137~, etc., can be applied.

In addition, when R is an alkenyl group, etc.).

The salt of dicarboxylic acids according to the present invention is not limited to bamboo as long as it is pharmaceutically acceptable. Examples include calcium, magnesium, potassium 4, and sodium.

The fatty acid biosynthesis inhibitor according to the present invention can be administered orally or parenterally.

The dosage is determined according to the age, health condition, and weight of M, the type of concurrent treatment (if any), the type of treatment, the nature of the desired effect, etc.

In general, the daily dosage of the active ingredient is usually O0l~ko, o
o o rng/kg body weight, administered 7 or more times.

3- Orally [1 administration - in the form of tablets, capsules, powders, liquids, elixirs, etc., or in the form of sterile liquids such as liquid or cloudy in the case of closed oral administration used in When used in the form described above, solid or liquid non-toxic formulations may be included in the composition.

Examples of solid carriers include (1) conventional gelatin-type capsules taken monthly; the active ingredient, with or without adjuvants, may be tabletted or packaged as a powder.

These capsules, tablets, and powders generally contain 5%,
Preferably, it contains a weight active ingredient of type 2j to 0φ.

That is, these administration formats preferably contain between 7j and 200m, preferably 7j-, 2jOm9 of the active ingredient.

As the liquid carrier, water or synthetic oils such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. are used.

In general, physiological saline, dextrose or similar sucrose solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as liquid carriers, particularly in the case of injections using physiological saline. is usually 0. 70%, preferably 1 to 10% by weight of active ingredient.

In the case of liquid preparations for oral administration, suspensions or syrups containing 0.3-10% by weight of the active ingredient are preferred.

As carriers in this case, use aqueous excipients such as perfumes, syrups, pharmaceutical micelles, etc.

Hereinafter, the present invention will be further explained in detail with reference to Examples.

Example / Dry ethanol / z o ml with metallic sodium,
Gradually add 7-glue I and stir until homogeneous. 75℃
After cooling to , 1411 g of diethyl malonate/J was immediately added dropwise, and the mixture was stirred at room temperature for 30 minutes.

After heating the reaction solution to 10° C., n-octyl bromide and Og were added dropwise over 10 minutes, and the mixture was further refluxed for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in Jθθml of ethyl ether, washed with water, and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure and the residue was γf-empty fumigation 11Y-r and rh-octylmalonic acid diethyl ester/41.7g
is obtained as an oil. Boiling point/77ri~ljhaVA
zH,T(g.

T!・Dissolve potassium hydroxide in 13% ethanol, and add n-octylmalonic acid diethyl ester 3. ! 9 was added, and after refluxing for 1 hour, the solvent was distilled off under reduced pressure, and the residue was dissolved in 1 l of water. , 2N
- pHJ with hydrochloric acid, bind, precipitate white crystals, wash with water and dry to obtain n-octylmalonic acid i,sg as powder crystals.

Melting point: 9 μm to 7° C. Example: Dry ethanol, 30 tonnes of metallic sodium, 1 μm
Gradually add y and stir until uniform. After cooling to 75° C., diethyl malonate was carefully added dropwise, and the mixture was stirred at room temperature for 30 minutes. n-)lysosyl bromide under reflux, 211. ! ,! iT was added dropwise over ljf minutes, and after further refluxing for 3 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl ether JjOml, washed with water, and dried over 11 um of anhydrous sulfuric acid. The solvent was distilled off under reduced pressure,
Vacuum distillation of the residue yields n-)lysosylmalonic acid diethyl ester, 2.2.09, as an oil.

Production/jt~It, 0℃/not Hg 30%-sodium hydride/,, 2 A fl was suspended in n-hexane, stirred, and allowed to stand, to give a clear n-
Decant off the hexane. Next, 71 ml of benzene was added, the water-accumulated sodium was suspended and stirred, and n-)lysosylmalonic acid diethyl ester r, jg was added dropwise at room temperature over 70 minutes. After further reaction at 10°C for 3 hours, under smooth flow,
11.3 t, q of ethyl bromoacetate was gradually added dropwise, and reflux was continued for 2 hours. After distilling off the solvent under reduced pressure, what remains! The snout was dissolved in ljOml of ethyl ether, washed with water, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the residue is vacuum distilled to obtain 2-ethoxycarbonyl-coated lysosylsuccinic acid diethyl ester f,/9 as an oil. Boiling point / 74- ~17℃7o, Noj To Hj gs% - Potassium hydroxide U, O≠g! Dissolve in ethanol, add -monoethoxycarbonyl-cotridecyl succinic acid diethyl ester 7, jfJ, and add 6
After refluxing for a period of time, the solvent is distilled off under reduced pressure and the residue is dissolved in 70 ml of water. The mixture was adjusted to pH with 4N hydrochloric acid, and the precipitated oil was extracted twice with ethyl ether/00 ml, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the remaining white crystals were recrystallized from ethyl acetate/n-hexane to obtain λ-carboxycoat lysosylsuccinate I.
'+t −t, −29 is obtained as a powder crystal. Melting point lθJ - 107°C When cocarboxycoat tridecylconomonolyric acid s, og is added at 190°C for 20 minutes, a pale yellow oil is obtained. A solution of 2.4 lg of rj chi potassium hydroxide dissolved in m/m water saw was added to the mixture, and the mixture was refluxed for 3 hours. After cooling xN
- Adjust the pH to / with LHo1, extract the precipitated oil twice with ethyl ether 1,0111, wash with water, and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the remaining white crystals were collected as n-
When recrystallized from hexane, J-tridecylsuccinic acid tt
, og are obtained as powder crystals.

Melting point: 99 to IO °C Example 3 2.33 g of 50% sodium hydride to g of n-hexane
Stir the suspension with Ome, leave it to stand, and remove the atomized n-hexane by decantation. Next, 4 puffs of 90 mtf were added to suspend sodium hydride, and Example! n-octylmalonic acid diethyl ester/2.09 obtained at room temperature was added dropwise.
Down. After heating reaction at SO℃ for 3 hours, γ-bromo n-
Ethylta butyrate! Gradually drop 1. g under reflux. , and 3 more
Reflux for an hour. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl ether (0θmlK), washed with water, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is distilled under vacuum to obtain J-[toxycarbonyl-Jn-octyladipate diethyl ester B, g as an oily substance. Boiling point 'IA1~/ A J' ””/ / Dragon Hg
rs%-potassium hydroxide/, 211 g was dissolved in LI-ethanol, and coethoxycarbonyl, 2-
n-octyladipate diethyl ester, 2. j, q
Apply pressure and reflux for an hour. After distilling off the solvent under reduced pressure, the residue was dissolved in IAO ml of water and adjusted to pH/f with 4N hydrochloric acid to precipitate an oily substance.

This was extracted twice with 110 ml of ethyl ether, washed with water, and dried over +1 um of anhydrous ether. The solvent was distilled off under reduced pressure (17), and the remaining white crystals were crystallized from ethyl acetate/n-hexane to give nocarboxy-Jn-octyladipine 6/, C#. Melting point lj! ~l
7°C 1.1 g of ruboxyco n-octyl adipic acid
When heated at 75Pθ°C for 20 minutes, a slightly yellow oily substance is obtained. The mixture was subjected to hydroxylation, and the precipitated oil was extracted J times with 10 ml of ethyl ether, washed with water, and dried over anhydrous sodium sulfate. By distilling off the solution I under reduced pressure and recrystallizing the residual white crystals from n-hexane, 0.7 jl of J-n-octyl adipic acid is obtained as powder crystals. Melting point 70-72°C Example G~/6 Inhibitory activity of acetyl OOA carboxylase by α-n-octylgeltaric acid Partial concentrate obtained from rat liver by j-IA (Ivy/)) Acetyl OOA carboxylase 0. /SmTJ 111't; NaoOmM) Limey's hydrochloric acid buffer pH 7, + (/Qm)l of citric acid/
OmM MgO 12°J, 7J-mM glutathione, 0
．． 779M bovine serum albumin) at 37°C.
After activation for 30 min, α-n-octylgeltaric acid (LDl, o: too mgAgJJ) was added.

mouse oral administration] and H+4r1o, - malonyl O.
Fixation to OA is fixed at Oki 1 fixed. When α-n-octylgeltaric acid jjμg/m/ was added, about jO% activity inhibition was observed.

Similarly, inhibitory activity tests were conducted on the dicarboxylic acids shown in Table 1, and the results are shown in Table 1-1.

Table-no =12= Applicant: Mitsubishi Chemical Industries, Ltd. Agent Patent Attorney for Nagakam - Other names 15- 131-

Claims (1)

[Claims] (1) General formula (T) 00H (wherein, It represents an alkyl group or an alkenyl group,
A fatty acid biosynthesis inhibitor containing a dicarboxylic acid, anhydride thereof, or a salt thereof as an active ingredient.