KR101850119B1 - Novel Fenofibric Acid Prodrugs with Improved Bioavailability - Google Patents
Novel Fenofibric Acid Prodrugs with Improved Bioavailability Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
- C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
Abstract
The present invention relates to novel penofibric acid prodrugs with improved bioavailability. According to the present invention, the penofibric acid prodrug of the present invention exhibits higher bioavailability than the existing phenobibrate. Therefore, the penofibric acid prodrug of the present invention can be developed as an effective therapeutic agent for the treatment of hyperlipemia and the like.
Description
The present invention relates to novel penofibric acid prodrugs with improved bioavailability.
Fenofibrate is a fibrate-based drug that is mainly used to lower cholesterol in patients at risk for cardiovascular disease. Fenofibrate is one of the most commonly prescribed fibrates, similar to other fibrates, reducing low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and increasing high density lipoprotein (HDL).
PPAR (peroxisome proliferator-activated receptor) is a type of hormone receptor present in the nucleus and plays an important role in regulating the metabolism of fatty acids. PPARα, PPARβ, and PPARγ are known. Fenofibrate is known to promote low-density lipoprotein (LDL) while promoting the activity of PPARα, while increasing HDL (high density lipoprotein). In the case of mice deficient in PPARα, it was reported that they failed to respond to phenobibrate and thereby the expression of target genes was inhibited, resulting in obesity (Costep P. et al., J. Biol. Chem. (1998) 273: 29577-29585). In addition, there has been a report that when phenobibrate is treated with C57BL / 6 mice fed diabetes, obesity or insulin resistance and high fat diets, weight loss is reduced and the body fat reduction effect of fenofibrate is confirmed (Guerre-Millo M. et al., J. Biol. Chem. (2000), 275: 16638-16642).
On the other hand, phenobibrate is a prodrug of fenofibric acid, which rapidly converts to phenobipuric acid in vivo.
Both phenobarbital and phenobipric acid are poorly soluble and there is a good food effect to take with the food. That is, there is a problem that the absorption rate increases in the high fat diet and the absorption rate decreases in the fasting state, and the deviation of the absorption rate of the drug between individuals becomes large. Various methods have been attempted to overcome these problems. As a method of disinfection, there is a method of micronizing the phenobibrate, a method of using a nanocrystal or a solid dispersion or the like, and a combination thereof, such as an insoluble drug delivery-microparticle (IDD-P) and a microcoated-micronized product Was released. However, this was merely a pharmaceutical approach and did not fundamentally solve the problem of absorption of phenobarbital.
On the other hand, in the case of choline penofibrate from Abbott, basic cholinesalt is made and it is made into a delayed capsule of enteric coating, so that the drug is delivered to the small intestine irrespective of the residence time from above, And thus can be administered irrespective of the meal. In the case of Hanmi Pharm's phenocide, the same method as Abbott's method was used, except that free acid and alkali excipients such as meglumine were used instead of choline salt. However, these products do not solve the problem of absorption rate, and when designing a combination agent, there is a problem that the solubility is not sufficient compared with the usage and the dosage. Therefore, the problem of improving the absorption rate of the phenobarbital remains as a problem to be solved.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
The present inventors have made efforts to develop a substance capable of improving the bioavailability of fenofibrate. As a result, the present inventors confirmed that the newly synthesized penofibric acid prodrugs had a high bioavailability, thereby completing the present invention.
It is an object of the present invention to provide a novel penfibric acid prodrug with improved bioavailability.
It is another object of the present invention to provide a method for enhancing the bioavailability of phenobipuric acid by esterifying phenobiphilic acid.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
According to one aspect of the present invention, there is provided a method for producing a novel phenobipuric acid, which comprises esterifying a carboxyl group of fenofibric acid represented by the following formula (1) To < RTI ID = 0.0 >
[Chemical Formula 1]
Fenofibrate is a prodrug of fenofibric acid that is converted into phenobipuric acid in vivo as follows.
Fenofibrate is primarily used to lower cholesterol in patients at risk for cardiovascular disease and has been shown to reduce low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and to increase high density lipoprotein (HDL) .
The phenobibrate and phenobipric acid have a problem that the absorption rate of the drug is increased due to the increase of the absorption rate in the high fat diet and the decrease of the absorption rate in the fasting state. The method of the present invention is a method for solving the problem of the absorption rate of the phenobarbital as a method of solving the problem of the absorption of the phenobarbital, which is different from that of the existing phenobarbate so that the absorption of the existing phenobarbate is maximized without the food effect, unlike the case where the food effect is caused by passive permeation An ester derivative of phenobipuric acid is prepared and the bioavailability is enhanced.
In the method of the present invention, the ester derivative of phenobiphilic acid is characterized by an increase in absorption in the gastrointestinal tract. According to a specific embodiment of the present invention, the ester derivative of phenobiphilic acid has a bioavailability of 100-300% when it is orally administered to rats not fed with food, and the AUC of phenobipuric acid in blood (0-12 hr) is 130-350 占 퐂 / hr, and the maximum blood concentration of penofibric acid in blood is 25-40 占 퐂 / ml.
According to a specific embodiment of the present invention, the ester derivative of phenobiphric acid is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof:
(2)
acetoxymethyl-2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoate
(3)
2-acetoxyethyl-2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoate
[Chemical Formula 4]
2- (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) -N, N, N-trimethylethanaminium chloride
[Chemical Formula 5]
2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) methyl pivalate
[Chemical Formula 6]
4- (3,5-dimethoxystyryl) phenyl-2- (4- (4-chlorobenzoyl) phenoxy) -2-methyl propanoate
(7)
(S) -2- (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) ethyl 2-amino-3-methylbutanoate mono benzenesulfonate
[Chemical Formula 8]
2- (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) ethyl 2-amino-3-methylbutanoate monotosylate
According to another aspect of the present invention, there is provided a prodrug of fenofibric acid represented by the above formulas 2 to 8.
The penofibric acid prodrugs of the present invention exhibit a higher bioavailability than the phenobibrate. According to a specific embodiment of the present invention, the phenobipartic acid prodrugs represented by Formulas 2 to 8 have a bioavailability of about 100 to 300% as compared with the conventional phenobyphate in rats. According to a more specific embodiment, in the case of 2-acetoxyethyl-2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoate represented by the above formula 3, 2.7 times higher bioavailability And the like.
The features and advantages of the present invention are summarized as follows:
(a) The present invention provides a method for enhancing the bioavailability of penofibric acid by esterifying a novel penfibric acid prodrug and a phenobiphilic acid with improved bioavailability.
(b) The penofibric acid prodrug of the present invention exhibits a remarkably high bioavailability as compared with the conventional phenobibrate, and thus can be developed as an effective therapeutic agent for the treatment of hyperlipemia and the like.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments.
Example
Example One: Phenobipuric acid Of prodrug synthesis
A novel ester prodrug of phenobipuric acid was designed to increase absorption by the transporter of the gastrointestinal tract in order to overcome the absorption rate problem of penovibrate. Unlike conventional phenobarbital, which is caused by passive permeation, it is designed to maximize absorption without food effect. Once absorbed, it is decomposed into ubiquitous esterase by phenobipuric acid to be effective. Seven new phenobiphenyl acid prodrugs were designed and synthesized as follows. The reagents used in the synthesis were those of Sigma-Aldrich.
One. Acetoxymethyl -2- (4- (4- Chlorobenzoyl ) Phenoxy )-2- Methyl propanoate
Acetoxymethyl-2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoate of the following formula (2) Was synthesized as follows.
(2)
2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid (3.18 g, 0.01 mol) and K2CO3 (2.76 g, 0.02 mol) were added to N, N-dimethylacetamide (64 ml) -bromomethyl acetate (3.12 g, 0.02 mol) was added.
The reaction product was stirred at a temperature of 60 to 65 占 폚 for 12 hours or longer. The reaction mixture was cooled to 0 C and slowly added purified water (100 mL). The resulting mixture was stirred at room temperature for 0.5 hour. The mixture was extracted with 100 ml of ethyl acetate, washed three times with 150 ml of brine, and distilled under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3: 1 mixed solvent as eluent) and then concentrated under reduced pressure to give a pale cream solid. Yield 75%.
1 HNMR (300MHz, DMSO- d 6 ) 7.8 (d, J = 6.3Hz, 2H), 7.75 (d, J = 6.3Hz, 2H), 7.5 (d, J = 6.3Hz, 2H), 7.0 (d, 2H), 4.75 (s, 2H), 3.8 (s, 3H), 1.8 (s, 6H)
2. 2- Acetoxyethyl -2- (4- (4- Chlorobenzoyl ) Phenoxy )-2- Methyl propanoate
2-acetoxyethyl-2- (4- (4-chlorobenzoyl) phenoxy) -2 (4-chlorobenzoyl) phenoxy) -2-methylpropanoate -methylpropanoate) was synthesized as follows.
(3)
2-bromoethyl acetate (3.34 g, 0.02 mol) was used instead of 2-bromomethyl acetate in the synthesis of acetoxymethyl-2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoate The remaining synthesis method was the same except that an off-white solid was obtained in a yield of 80%.
1 HNMR (300MHz, DMSO- d 6 ) δ7.70-7.68 (m, 4H), 7.60-7.58 (d, J = 6.3Hz, 2H), 6.90-6.88 (d, J = 6.3Hz, 2H), 4.34 (T, J = 3.3 Hz, 2H), 1.88 (s, 3H), 1.60 (s, 6H)
3. 2- (2- (4- (4- Chlorobenzoyl ) Phenoxy )-2- Methylpropanoyloxy ) - N, N, N - Trimethylethane Chloride
N, N, N-trimethylethanaminium chloride (2- (2- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) - (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) -N, N, N-trimethylethanaminium chloride) was synthesized as follows.
[Chemical Formula 4]
2-chloro-N, N, N-trimethylethanaminium chloride (prepared in Example 1) was used instead of 2-bromomethyl acetate in the synthesis of acetoxymethyl-2- (4- (4-chlorobenzoyl) phenoxy) 6.28 g, 0.04 mol), and the other synthesis procedures were the same, yielding a white solid in 84% yield.
1 H NMR (300 MHz, DMSO- d 6) δ7.70-7.67 (m, 4H), 7.60-7.57 (d, J = 6.3Hz, 2H), 6.92-6.90 (d, J = 6.3Hz, 2H) , 3.56 (s, 9H), 2.59 (t, J = 3.6 Hz, 2H), 2.38 (t,
4. (2- (4- (4- Chlorobenzoyl ) Phenoxy )-2- Methylpropanoyloxy ) methyl Pivarate
(2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) methyl (4-chlorobenzoyl) phenoxy) pivalate were synthesized as follows.
[Chemical Formula 5]
Bromomethyl pivalate (3.9 g, 0.02 mol) was used instead of 2-bromomethyl acetate in the synthesis of acetomethyl-2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoate The rest of the synthesis was the same and yielded a white solid in 84% yield.
1 H NMR (300 MHz, DMSO- d 6) δ7.69-7.67 (m, 4H), 7.60-7.58 (d, J = 6.3Hz, 2H), 6.90-6.88 (d, J = 6.3Hz, 2H) , 5.80 (s, 2H), 1.59 (s, 6H), 1.07 (s, 9H)
5. 4- (3,5- Dimethoxystilyl ) Phenyl-2- (4- (4- Chlorobenzoyl ) Phenoxy )-2- methyl Propanoate
4- (3,5-dimethoxystyryl) phenyl (2-methylphenyl) -2- (4- -2- (4- (4-chlorobenzoyl) phenoxy) -2-methyl propanoate) was synthesized as follows.
[Chemical Formula 6]
SOCl2 (2.76 g, 0.02 mol) and 2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid (3.18 g) were added to a mixed solution of methylene chloride / N, N-dimethylacetamide 20/1 g, 0.01 mol) was added, and the mixture was stirred at room temperature for 2 hours. After adding (E) -4- (3,5-dimethoxystyryl) phenol (5.12 g, 0.02 mol), the reaction was stirred overnight at 60-65 캜. The reaction mixture was cooled to 0 < 0 > C and slowly added 100 ml of purified water. The resulting mixture was stirred at room temperature for 0.5 hour. The reaction mixture was extracted with 100 ml of ethyl acetate, washed three times with 150 ml of brine, and distilled under reduced pressure. Purification by column chromatography (30% ethyl acetate in hexanes) afforded a white solid in 65% yield.
1 HNMR (300MHz, DMSO- d 6 ) δ7.8 (d, J = 6.3Hz, 2H), 7.7 (d, J = 6.3Hz, 2H), 7.5 (m, 4H), 7.0 (m, 6H), 2H), 6.4 (s, 1H), 3.8 (s, 6H), 1.8 (s, 6H)
6. 2- (2- (4- (4- Chlorobenzoyl ) Phenoxy )-2- Methylpropanoyloxy ) Ethyl 2-amino-3- Methyl butanoate Mono Benzenesulfonate
(2-amino-3-methylbutanoate monobenzenesulfonate ((S) - (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) ethyl 2- 2- (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) ethyl 2-amino-3-methylbutanoate mono benzenesulfonate) was synthesized as follows.
(7)
(S) -2-bromoethyl 2- (tert-butoxycarbonylamino) amide in the synthesis of acetoxymethyl-2- (4- (4-chlorobenzoyl) phenoxy) ) -3-methylbutanoate (6.48 g, 0.02 mol) was used in the same manner as in Synthesis Example 1, and a white solid was obtained in 84% yield.
1 H NMR (300 MHz, DMSO- d 6) δ8.27 (s, 2H), 7.71-7.57 (m, 6H), 7.31-7.27 (m, 3H), 6.91-6.89 (d, J = 6.3Hz, 2H), 4.44-4.34 (m, 4H), 3.88-3.87 (d, J = 3.0 Hz, 1H)
7. 2- (2- (4- (4- Chlorobenzoyl ) Phenoxy )-2- Methylpropanoyloxy ) Ethyl 2-amino-3- Methyl butanoate Monotosylate
2- (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) ethyl 2-amino-3-methyl butanoate monotosylate (2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoyloxy) ethyl 2-amino-3-methylbutanoate monotosylate) was synthesized as follows.
[Chemical Formula 8]
(S) -2-bromoethyl 2- (tert-butoxycarbonylamino) amide in the synthesis of acetoxymethyl-2- (4- (4-chlorobenzoyl) phenoxy) ) -3-methylbutanoate (6.48 g, 0.02 mol) was used in the same manner as in Synthesis Example 1, and a white solid was obtained in 84% yield.
1 H NMR (300 MHz, DMSO- d 6) δ8.26 (s, 2H), 7.71-7.61 (m, 4H), 7.61-7.59 (d, J = 6.3Hz, 2H), 7.47-7.45 (d, J = 6.3 Hz, 2H), 4.44-4.30 (m, 4H), 3.87-3.86 (d, J = , 2.2 (s, 3H), 2.11 (q, 1H), 1.60 (s, 6H), 0.91-0.86
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.
Example 2: Phenobibrate Of prodrug Absorption rate comparison
Male Sprague Dawley rats (6-8 weeks old, body weight 220300 g) were purchased and used in the experiments (Sam Taco Co., Korea). Food was not administered overnight before the drug administration and fasting was maintained for 4 hours after administration of the drug. The drugs 1 to 7 synthesized in Example 1 were dissolved in PEG400: distilled water = 1: 1 (v / v), adjusted to a concentration of 5 mg / ml and then orally administered at a concentration of 20 mg / kg. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 12 hours after the administration. Centrifuged at 3000 rpm, stored at 4 ° C for 10 minutes, and stored at -70 ° C until analysis. A commercially available micronized phenobibrate (Asta, China) was used as a reference drug.
Drug uptake (AUC012) and maximum blood concentration (Cmax) were measured using Winnowin 5.2 (Pharsight, USA) and bioavailability was calculated as the ratio of the absorbed dose of the test drug to that of the reference drug.
The experimental results are shown in Table 1 below.
As shown in Table 1, most of the phenobipartite prodrugs synthesized showed higher bioavailability than the reference compound, phenobibrate. In particular, 2- (2- (4- (4-chlorobenzoyl) phenoxy) Propanoyloxy) -N, N, N-trimethylethanamine chloride showed a bioavailability nearly three times higher than that of phenobibrate.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit and scope of the invention as defined by the appended claims. And its equivalents.
Claims (7)
(2)
(3)
[Chemical Formula 4]
(7)
[Chemical Formula 8]
(2)
(3)
[Chemical Formula 4]
(7)
[Chemical Formula 8]
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008157537A2 (en) * | 2007-06-19 | 2008-12-24 | Ironwood Pharmaceuticals, Inc | Compositions and methods of use for treating or preventing lipid related disorders |
| JP2009522258A (en) | 2005-12-28 | 2009-06-11 | テバ ファーマシューティカル インダストリーズ リミティド | Pharmaceutical formulation of fenofibrate with increased bioavailability |
| CN102516166A (en) | 2011-11-29 | 2012-06-27 | 北京阜康仁生物制药科技有限公司 | Nicotinic acid derivative of fenofibrate and preparation method of nicotinic acid derivative |
| KR101300654B1 (en) | 2002-05-24 | 2013-08-28 | 풔니어 래버러토리 아일랜드 리미티드 | Nanoparticulate fibrate formulations |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101300654B1 (en) | 2002-05-24 | 2013-08-28 | 풔니어 래버러토리 아일랜드 리미티드 | Nanoparticulate fibrate formulations |
| JP2009522258A (en) | 2005-12-28 | 2009-06-11 | テバ ファーマシューティカル インダストリーズ リミティド | Pharmaceutical formulation of fenofibrate with increased bioavailability |
| WO2008157537A2 (en) * | 2007-06-19 | 2008-12-24 | Ironwood Pharmaceuticals, Inc | Compositions and methods of use for treating or preventing lipid related disorders |
| CN102516166A (en) | 2011-11-29 | 2012-06-27 | 北京阜康仁生物制药科技有限公司 | Nicotinic acid derivative of fenofibrate and preparation method of nicotinic acid derivative |
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| Synthesis and Biological Evaluation of Orally Active Hypolipidemic Agents, J. of Medicinal Chemistry, 54, 5915-5926(2011.07.19.)* |
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