KR20200016613A - New dha derivatived and their use method as medicaments - Google Patents

Abstract

The present invention relates to: a compound of general formula 1, pharmaceutically acceptable salt, solvate, complex, and pro-drug thereof; and uses as a drug to treat various diseases and conditions, specifically to decrease high triglyceride levels (i.e., hyperlipidemia), reduce non-HDL cholesterol, reduce glucose and HbAlc, and improve insulin resistance. According to chemical formula 1, R_1 and R_2 are same or different and are selected from a group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group. The present invention also relates not only to a pharmaceutical composition comprising the compound of chemical formula 1 but also to a method for producing the compound of chemical formula 1.

Description

New DHA derivatives and their use as drugs {NEW DHA DERIVATIVED AND THEIR USE METHOD AS MEDICAMENTS}

The present invention provides compounds of general formula (I), and pharmaceutically acceptable salts, solvates, complexes and pro-drugs thereof; Treatment of various diseases and conditions. For example, the present invention relates to a decrease in high triglyceride levels (ie, hyperlipidemia), a decrease in non-HDL cholesterol, a decrease in glucose and HbAlc, and an improvement in insulin resistance:

[Formula I]

R ₁ and R ₂ are the same or different and are hydrogen atom, hydroxyl group, alkyl group, halogen atom, alkoxy group, acyloxy group, acyl group, alkenyl group, alkynyl group, aryl group, alkylthio group, alkoxy Carbonyl group, alkylsulfinyl group, alkylsulfonyl group, amino group, alkylamino group. The invention also relates to a pharmaceutical composition comprising the compound of formula (I) as well as to a process for the preparation of the compound according to formula (I).

EPA and DHA affect a variety of physiological processes that affect chronic health, such as normal health and plasma lipid regulation, cardiovascular and immune functions, insulin action, neurodevelopment and visual function. There is solid evidence that EPA and DHA play a beneficial role in coronary heart disease, dyslipidemia, type 2 diabetes, insulin resistance and hypertension (Simonopoulos, AP Am. J. Clin. Nutr. (1999) 70 (Suppl): 560S-569S; Geleijnse, JM et al. J. Hypertension (2002) 20: 1493-1499; Storlien, LH et al. Curr. Opin. Clin. Nutr. Metab. Care (1998) 1: 559-563).

One such form of omega-3 fatty acid is described, for example, in U.S. Patent 5,502,077; 5,656,667; And an ethyl ester described in 5,698,594, a concentrate of omega-3, long chain polyunsaturated fatty acids from fish oils containing DHA and EPA, sold under the trademark Omacor® or Lovaza®. In particular, EPA ethyl esters and DHA ethyl esters are present in relative amounts of 1: 2 to 2: 1 and comprise at least 80% by weight of high levels of omega- Fatty acid compositions comprising 3 fatty acids have a beneficial effect on a number of risk factors for cardiovascular disease. In particular, it has a beneficial effect on hypertriglyceridemia, mild hypertension, coagulation factor Ⅶ phospholipid complex activity. These compounds, including Omacor® and Lovaza®, lower serum LDL-cholesterol, raise serum HDL-cholesterol, lower serum triglycerides, lower systolic and diastolic blood pressure and pulse rate, and blood clotting factors. Lowers the activity of the phospholipid complex. EPA and DHA appear to be synergistic. In addition, the compounds according to formula (I) described herein, as well as EPA and DHA, are very resistant and do not cause any serious side effects.

As type 2 diabetes and cardiovascular disease increase worldwide, a wide range of public health and medical challenges are underway to successfully prevent and treat it. Overweight and obesity, which are strongly associated with type 2 diabetes, occur simultaneously to interfere with diabetes treatment and increase the likelihood of developing hypertension, dyslipidemia, and atherosclerosis related diseases.

Pathophysiological conditions that signal the development of type 2 diabetes are associated with reduced insulin effects in peripheral tissues called insulin resistance. The tissue is mainly muscle, fat and liver. Muscle tissue is the major tissue involved in insulin resistance of type 2 diabetes. Syndromes due to insulin resistance, hypertension, dyslipidemia and systemic proinflammatory states are called metabolic syndrome. The incidence of metabolic syndrome is 22-39% among adult populations in developed countries (Meighs, J.B. et al. Diabetes (2003) 52: 2160-2167).

At present, the most effective approach to alleviate and prevent metabolic syndrome is to improve lifestyle with weight loss, reduced saturated fatty acid intake, and increased physical activity with appropriate drug therapy. Healthy diets that avoid excessive energy intake include replacing saturated fats with mono- and polyunsaturated fatty acids. In particular, the long chain omega-3 fatty acids of fatty fish, namely EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), have been shown to be effective in preventing type 2 diabetes.

In recent studies, omega-3 fatty acids regulate nuclear receptors such as PPARs (peroxisome proliferator-activated receptors) while regulating the expression of genes involved in lipid and glucose metabolism and lipoogenesis. Acting through Plays an important mediator in gene expression (Jump, DBJ Biol. Chem. (2002) 277: 8755-8758). PPAR is a nuclear fatty acid receptor that plays an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance and coronary heart disease.

Recently, drugs that act as ligands on the PPARγ receptor have emerged as therapeutic agents for type 2 diabetes (Yki-Jarvinen, H. New Engl. J. Med. (2004) 351: 11106-1118).

However, these agents generally involve weight gain and increase the amount of subcutaneous fat tissue (Adams, M. et al. J. Clin. Invest. (1997) 100: 3149-3153). The use of thiazolidinediones causes peripheral edema, with weight gain as well as some patient groups showing fluid retention and increased plasma volume. Weight gain and edema are associated with increased incidence of heart failure / heart failure, which is why the US Food and Drug Administration has prescribed prescription drugs for rosiglitazone (available by Avandia) and pioglitazone (available by Takeda). Include warnings in the information. These side effects limit the use of thioglitazone, especially in patients with coronary heart disease. Therefore, there is a need for the development of new drugs that have a positive effect on weight loss activity and insulin resistance without fluid retention.

Compared with pharmacological agents such as thioglitazone, omega-3 fatty acids are weak as agents of PPAR, but have demonstrated improved glucose uptake and insulin sensitivity (Storlien, LH et al. Science (1987) 237: 885 -888). When the ratio of polyunsaturated fatty acids to saturated fatty acids in food is increased, fat cells are reported to be more insulin sensitive and transport more glucose (Field, CJ et al. J. Biol. Chem. (1990) 265: 11143-11150). Overall, the data indicate that 20- and 22-carbon fatty acids such as EPA and DHA can play a preventive role in the development of insulin resistance.

Due to limited stability and lack of biological specificity in vivo, PUFA has not been widely used as a therapeutic agent. In order to alter or increase the metabolic efficacy, a number of study groups have conducted studies on the chemical modification of n-3 polyunsaturated fatty acids.

For example, the serum lipid reducing effect of EPA was made possible by introducing methyl or ethyl groups at the α- or β-position of EPA (Vaagenes, H. et al. Biochem. Pharmacol. (1999) 58: 1133-1143). . EPA ethyl ester (EE) was ineffective, while the compound also reduced plasma free fatty acids.

In a study published by L. Larsen (Larsen, L. et al. Lipids (2005) 40: 49-57), the authors found that the α-methyl derivatives of EPA and DHA have the activity of nuclear receptor PPARα compared to EPA / DHA. And thereby increased expression of L-FABP. EPA having an ethyl group in the α-position activates PPARα with the same effect as α-methyl EPA. The authors suggest that delayed metabolism of α-methyl fatty acids may contribute to this increased effect due to reduced β-oxidation in the mitochondria leading to peroxysome oxidation.

α-methyl EPA is potent platelet aggregation stronger than EPA in vitro (Larsen, L. et al. Biochemical Pharmacology (1998) 55: 405) and in vivo (Willumsen, N. Biochim Biophys Acta (1998) 1369: 193-203) Shows that it is an inhibitor.

In Japanese Patent Application Laid-Open No. 05-00974, DHA in which the α-position is substituted with a hydroxyl group is described as only a reaction intermediate. No mention is made of the possibility of the pharmaceutical efficacy of these compounds.

Laxdale Limited also describes the use of alpha substituted derivatives of EPA in the treatment of mental or central neurological disorders (U.S. Patent No. 6,689,812).

(A) α-메틸 EPA

(A) α-methyl EPA

However, none of these modified fatty acids showed satisfactory pharmaceutical activity and did not enter the pharmaceutical market.

WO 2006/117664, which describes DHA derivatives with alpha substituents, may also be cited.

It is an object of the present invention to provide new DHA-derivatives with therapeutic activity.

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, solvates, complexes, or pro-drugs thereof:

[Formula I]

R ₁ and R ₂ may be the same or different and represent a hydrogen atom, a hydroxyl group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, or an alkyl group. Sulfinyl group, alkylsulfonyl group, amino group, alkylamino group.

In at least one embodiment, the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, n-hexyl, and benzyl.

In at least one embodiment, the halogen atom is selected from fluorine, chlorine, bromine, and iodine.

In at least one embodiment, the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, sec-butoxy, phenoxy, benzyloxy, OCH ₂ CF ₃ , and OCH ₂ CH ₂ OCH ₃ .

In at least one embodiment, the alkenyl group is selected from allyl, 2-butenyl, and 3-hexenyl.

In at least one embodiment, the alkynyl group is selected from propargyl, 2-butynyl, and hexynyl.

In at least one embodiment, the aryl group is a phenyl group.

In at least one embodiment, the alkylthio group is selected from methylthio, ethylthio, isopropylthio, and phenylthio.

In at least one embodiment, the alkoxycarbonyl group is selected from methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl and butoxycarbonyl.

In at least one embodiment, the alkylsulfinyl group is selected from methanesulfinyl, ethanesulfinyl, and isopropanesulfinyl.

In at least one embodiment, the alkylsulfonyl group is selected from methanesulfonyl, ethanesulfonyl, and isopropanesulfonyl.

In at least one embodiment, the alkylamino group is selected from methylamino, dimethylamino, ethylamino, and diethylamino.

In at least one embodiment, R ₁ and R ₂ are selected from hydrogen atom, hydroxyl group, alkyl group, halogen atom, alkoxy group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, amino group and alkylamino group .

In at least one embodiment, R ₁ and R ₂ are a hydrogen atom, a hydroxyl group, a C ₁ -C ₇ alkyl group, a halogen atom, a C ₁ -C ₇ alkoxy group, a C ₁ -C ₇ alkylthio group, C ₁ -C ₇ alkylsulfinyl group, C ₁ -C ₇ alkylsulfonyl group, amino group and C ₁ -C ₇ alkylamino group.

1 shows the plasma triglyceride levels measured in Example 1. FIG.
2 shows plasma cholesterol levels measured in Example 2. FIG.
3 shows receptor activity measured in Example 2. FIG.

The inventors have found that monoglycerides in alpha substituted DHA derivatives have a potent lipid lowering effect in animal models. The compound also has an affinity for the nuclear receptor PPARα and PPARγ. For this reason, the compounds are likely as agents for the treatment of various diseases and conditions.

Throughout this specification, in the abbreviation “PRB-x MG,” x is an integer and will be used to describe certain compounds according to the invention.

Preferred categories of compounds according to the invention include:

Category A: R ₁ is an alkyl group and R ₂ is a hydrogen atom .

Example:

(All-Z) -1,3-dihydroxypropan-2-yl2-methyl-docosa-4,7,10,13,16,19-hexanoate (PRB-1 MG), wherein R ₁ Is a methyl group and R ₂ is a hydrogen atom.

Example ii:

(All-Z) -1,3-dihydroxypropan-2-yl2-ethyl-docosa-4,7,10,13,16,19-hexanoate (PRB-2 MG) (Ia), Wherein R ₁ is an ethyl group and R ₂ is a hydrogen atom.

Example

(All-Z) -1,3-dihydroxypropan-2-yl2-propyl-docosa-4,7,10,13,16,19-hexanoate (PRB-3 MG), R ₁ is Is a propyl group and R ₂ is a hydrogen atom.

Category B: R ₁ and R ₂ are both alkyl groups .

Example

(All-Z) -1,3-dihydroxypropan-2-yl2,2-dimethyl-docosa-4,7,10,13,16,19-hexanoate (PRB-4 MG), Wherein R ₁ and R ₂ are methyl groups.

Category C: R ₁ is an alkoxy group and R ₂ is a hydrogen atom .

Example

(All-Z) -l, 3-dihydroxypropan-2-yl 2-methoxy-docosa-4,7,10,13,16,19-hexanoate (PRB-5 MG), wherein R ₁ is a methoxy group and R ₂ is a hydrogen atom.

Example

(All-Z) -1,3-dihydroxypropan-2-yl2-ethoxy-docosa-4,7,10,13,16,19-hexanoate (PRB-6 MG), wherein R ₁ is an ethoxy group and R ₂ is a hydrogen atom. The invention is to be understood as encompassing all pharmaceutically acceptable salts, solvates, complexes, and prodrugs of the compounds of formula (I).

A “prodrug” may or may not have some pharmacological activity, may be administered orally or parenterally, and then bioactive (eg metabolized) in the body to effect pharmacological activity. Eggplant may be a medicament of the present invention.

A “therapeutically effective amount” or “pharmaceutically effective amount” refers to an amount that exhibits the desired therapeutic and / or pharmaceutical effect. As it varies with the individual patient, determination of the optimal range of effective amounts of the compound of formula (I) is in accordance with one skilled in the art. In general, dosage regimens for treating diseases using the compounds and / or compositions of the present invention are selected according to a variety of factors including the patient's body type, age, weight, sex, diet, and medical condition.

"Pharmaceutical" means any form of the compound of formula (I) that can be used for medical purposes, and exists in various forms, such as pharmaceuticals, drug preparations or products, dietary products, foods, or food supplements.

In the context of the present specification, the term "treatment" also includes "prevention" and "prevention" unless otherwise indicated. The terms "therapeutic" and "therapeutic" are described accordingly.

Treatment (or treatment) includes all therapeutic applications beneficial to humans or non-human animals. Treatment with mammals is preferred. Both human and animal treatments are within the scope of the present invention. The treatment may be for an existing disease or may be prophylactic; the treatment may be an adult, adolescent, infant, fetus, or part of the aforementioned (eg, organ, tissue, cell, or nucleic acid molecule). It may be about. “Chronic treatment” means treatment that lasts for weeks or years.

The compounds according to the invention can be included, for example, in food, food supplements, nutritional supplements, or dietary products. Alpha-substituted DHA derivatives and EPA (or DHA for it) are esters between alpha-derivatives, EPA, and mixtures of glycerol catalyzed by Novozym 435 (commercial lipases made from the fixed form Candida antarctia) It can be combined and mixed with each other in triglyceride form by the saponification process. Compounds of formula (I) have activity as drugs, in particular as inducers of nuclear receptor activity.

In at least one embodiment, the novel compounds of formula (I), pharmaceutically acceptable salts, solvates, complexes and prodrugs thereof, control weight loss and / or prevent weight gain, treat obesity or overweight disease and / or Prevention, prevention and / or treatment of diabetes (eg type 2 diabetes), treatment and / or prevention of amyloidosis, treatment or prevention of a number of risk factors for heart disease, triglycerides and non-HDL cholesterol (eg Treatment of elevated blood lipids such as LDL cholesterol and VLDL cholesterol), treatment of elevated insulin levels, treatment of dyslipidemia, hypertension, post-myocardial infarction (MI), depression, and treatment of IgA nephropathy, plasma HDL Increase levels, prevent and / or treat inflammatory diseases or conditions, and / or prevent stroke, cerebral ischemic attacks or transient ischemic attacks associated with atherosclerosis of multiple arteries It can be used.

Diabetes has two main forms. One is insulin-dependent diabetes mellitus (IDDM) as type 1 diabetes and the other is non-insulin-dependent diabetes mellitus (IDDM) as type 2 diabetes. Type 2 diabetes is associated with obesity / overweight and lack of exercise, is predominantly chronic in adults and is caused by a decrease in insulin sensitivity called peripheral insulin resistance. This leads to increased compensation of insulin production. This stage, before the onset of complete type 2 diabetes, is called metabolic syndrome and is characterized by hyperinsulinemia, insulin resistance, obesity, glucose tolerance, hypertension, abnormal blood lipids, coagulation disorders, dyslipidemia and inflammation, and often Causes atherosclerosis. If insulin production stops after this, type 2 diabetes develops.

In a preferred embodiment, the compounds according to formula (I) can be used to treat type 2 diabetes. Compounds according to formula (I) may also be used for metabolic syndrome, pancreatic, extrapancreatic / endocrine, or secondary diabetes, such as drug-induced diabetes, and atrophy, muscle relaxation, or insulin receptors. It can be used for the treatment of other types of diabetes selected from exceptional forms of diabetes such as diseases caused by the disorder.

In at least one embodiment, the compound of formula (I) may activate nuclear receptors such as PPAR (peroxysome proliferator-activated receptor) α and / or γ.

Compounds of formula (I) may also be used for the treatment and / or prevention of obesity. Obesity is usually associated with increased insulin resistance, and obese people are at higher risk for type 2 diabetes, a major risk factor for the development of cardiovascular disease. In western societies, obesity is a chronic disease in which an increasing population suffers and is associated not only with social problems, but also with a number of problems such as reduced lifespan and diabetes, insulin resistance, and hypertension.

The compounds according to formula (I) can also be used for the prevention and / or treatment of amyloidosis. Amyloidosis related diseases or diseases associated with amylose accumulation include Alzheimer's disease or dementia, Parkin's disease, amyotropic lateral sclerosis (Creutzfeld-Jacob disease) as a result of fibril or plaque formation Infectious spongiform encephalopathies such as cystic fibrosis, primary or secondary renal amyloidoses, IgA nephropathy, and amyloid accumulation in arteries, myocardium and neutral tissue. Treatment of amyloidosis can be carried out acutely or chronically.

Compounds of formula (I) are administered to patients suffering from atherosclerosis of the cerebral arteries (eg, stroke, transient febrile seizures) to reduce the risk of a more serious illness that may be fatal.

Compounds of formula (I) may also be used for the treatment of elevated blood lipids in humans.

In addition, the compounds of formula (I) may also be used for the treatment and / or prevention of a number of risk factors known as cardiovascular diseases such as hypertension and hypertriglyceridemia. In a preferred embodiment the compounds of formula (I) can be used for the treatment of elevated blood lipids in humans.

Compounds of formula (I), pharmaceutically acceptable salts, solvates, prodrugs and / or complexes thereof may be used on their own, while compounds of formula (I) (active ingredients) may be used as pharmaceutically acceptable additives, It can be administered in the form of a pharmaceutical composition in combination with a diluent, or carrier (including combinations thereof).

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier, diluent, or additive, including combinations thereof.

Acceptable carriers, diluents, and additives for therapeutic / pharmaceutical use are very well known in the pharmaceutical art. Pharmaceutical carriers, additives and / or diluents (including combinations thereof) may be selected according to the desired route of administration and standard practice in the pharmaceutical art. The pharmaceutical composition may comprise a carrier, an additive, or a diluent, or a suitable binder, lubricant, suspending agent, coating agent, and solubilizing agent.

Pharmaceutical compositions within the scope of the present invention include one or more of the following: preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, exploitative agents, salts (compounds of the present invention are pharmaceutically acceptable Possible salts), buffers, coatings, antioxidants, suspending agents, adjuvants, additives, and diluents.

In at least one embodiment, the pharmaceutical compositions according to the invention may be formulated for oral administration to humans or animals. The pharmaceutical compositions may also be formulated for administration via other routes in which the active ingredient is efficiently absorbed and available (eg, intravenous, subcutaneous, intramuscular, nasal, rectal, vaginal, or topical routes).

In at least one embodiment of the present invention, the pharmaceutical composition is in the form of a capsule, and the capsule may also be a microcapsule making a powder or sachet. The capsule can be tasted. This embodiment also includes capsules and flavored capsules of both fatty acids compositions according to the invention. Flavored capsules can attract users even more. For the aforementioned therapeutic uses, the dosage will vary depending on the compound to be used, the dosage form, the therapeutic purpose and the indication of the disease.

In at least one embodiment, the pharmaceutical composition may be formulated to provide a daily dosage of 10 mg to 10 g. In a preferred embodiment, the pharmaceutical composition is formulated to provide a daily dosage of 50 mg to 5 g of the composition. In another preferred embodiment, the pharmaceutical composition is formulated to provide a daily dosage of 100 mg to 1 g of the composition. The daily dose means the dose every 24 hours. The dosage will naturally be adjusted according to the compound used, the dosage form, the purpose of treatment, and the indication of the disease present. The doctor will determine the actual dose in the amount that will be most appropriate for the individual patient. The specific dosage and frequency of administration for each patient are determined by the activity of the compound of formula (I) used, its metabolic stability and duration of activity, the patient's age, weight, state of health, sex, diet, mode and time of administration, rate of release, drug It depends on various factors, including the combination, the severity of the individual condition, and the treatment the individual is receiving. The pharmaceutical and / or pharmaceutical compositions of the invention may be administered 1 to 10 times per day, such as once or twice a day. The daily dose of medicament for oral and non-oral administration to human patients may be single or divided doses.

Another embodiment of the invention relates to a fatty acid composition comprising a compound of formula (I).

The fatty acid composition may comprise 60% to 100% by weight of the compound of formula (I). All weight percentages are relative to the total weight of the fatty acid composition. In a preferred embodiment of the invention, the compound of formula (I) is present in an amount of at least 80% by weight, such as 90%, 95% by weight of the fatty acid composition.

The fatty acid composition according to the present invention comprises (all-Z Omega-3) -6,9,12,15,18-heneicosapentanoic acid (HPA) or derivatives thereof at least 1% or 1% to 4% by weight. Include in amounts of%.

The fatty acid composition according to the invention may comprise at least 1.5% or at least 3% by weight of omega-3 fatty acids or derivatives thereof having 20-, 21-, or 22-carbon atoms other than EPA and DHA.

In at least one embodiment of the invention, the fatty acid composition is a pharmaceutical composition, nutritional composition, or dietary composition. The fatty acid composition may further comprise an effective amount of a pharmaceutically acceptable antioxidant such as tocopherol or a mixture of tocopherols. In a preferred embodiment, the fatty acid composition further comprises tocopherol, or a mixture of tocopherols, up to 4 mg per g of the total weight of the fatty acid composition. In at least one embodiment, the fatty acid composition comprises from 0.2 mg to 0.4 mg per g of tocopherol relative to the total weight of the composition.

Another aspect of the invention provides a fatty acid composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, or complex thereof, for therapeutic and / or therapeutic purposes. Such fatty acid compositions can be used for the prevention and / or treatment of the same diseases already listed for the compounds of formula (I).

When the fatty acid composition is used as a medicament, a therapeutic or pharmaceutically active amount can be administered.

In one embodiment, the fatty acid composition can be administered orally to humans or animals.

The invention also provides for the manufacture of a medicament for controlling weight loss and / or preventing weight gain; Preparation of a medicament for the treatment and / or prevention of obesity or overweight disease; Preparation of a medicament for the prevention and / or treatment of diabetes; Preparation of a medicament for treating and / or preventing amyloidosis; Preparation of a medicament for the treatment or prevention of a number of risk factors known for heart disease such as hypertension and hypertriglyceridemia; Preparation of a medicament for the prevention of stroke, cerebral ischemic attack or transient ischemic attack associated with atherosclerosis of a plurality of arteries; Preparation of a medicament for lowering triglycerides in the blood and / or raising levels of HDL cholesterol in serum; And / or a compound of formula (I), a pharmaceutically acceptable salt, solvate, prodrug thereof, and / or for the manufacture of a medicament for the treatment and / or prophylaxis of multiple metabolic syndrome termed “metabolic syndrome” Or the use of a complex. All examples include the use of fatty acid compositions comprising a compound of formula (I) for the preparation of a drug as listed above.

The invention also relates to a method for controlling weight loss and a method for preventing weight gain, wherein a fatty acid composition comprising at least one compound of formula (I) is administered to a human or animal.

In another embodiment, the present invention relates to a method for the treatment and / or prevention of obesity or overweight disease, wherein the fatty acid composition comprising at least one compound of formula (I) is administered to a human or animal.

In one preferred embodiment of the invention, the invention relates to a method for the prevention and / or treatment of diabetes wherein the fatty acid composition comprising at least one compound of formula (I) is administered to a human or animal. In at least one embodiment, the diabetes is type 2 diabetes.

Fatty acid compounds of formula (I) may be prepared from DHA. If the starting material is not pure DHA (ie not 100% DHA), the final fatty acid composition will comprise a mixture of DHA derivatives and amounts of fatty acids other than DHA, as mentioned above, wherein these fatty acids are of formula (I). Like the novel fatty acid compounds of), they are substituted in the same way in the alpha-position. Such embodiments are also included herein.

In another embodiment of the invention, the compound of formula (I) is prepared from (all-Z) -4,7,10,13,16,19-docosahexaenoic acid (DHA), wherein the DHA is a vegetable , Microorganisms, and / or animals. In at least one embodiment, the DHA is obtained from marine oils such as fish oil.

Fatty acids in the composition may be obtained from vegetables, microorganisms, or animals or combinations thereof. Thus, the present invention also encompasses fatty acid compositions prepared from microbial oils.

The present invention includes a process for the preparation of the novel fatty acid compounds of formula (I).

DHA is produced from biological sources such as oceans, microorganisms, or vegetable fats. Possible raw materials include mixtures of fatty acids in the form of triglycerides in which DHA forms part of the fatty acids. Typical DHA levels are 40% in microbial fats and 10-25% in marine fats. Contains DHA

Small fats are under development, and fats with high levels of DHA will be expected in the future.

The first process step involves the conversion of triglycerides to free fatty acids or monoesters. Preferred esters include methyl or ethyl esters, although other esters are possible. In this way, the fatty acids bound together with the triglycerides are separated from each other. Some methods of separating DHA from other fatty acids are known. The most common methods include short path distillation (fatty acid separation by volatilization) and urea precipitation (fatty acid separation by degree of unsaturated). Other reported methods include silver nitrate complexation (fatty acid separation according to degree of unsaturated), esterification catalyzed by fatty acid selective lipase in combination with monodistillation, and countercurrent extraction of supercritical carbon dioxide.

The challenge associated with the production of pure DHA is to separate the DHA from other C20-22 polyunsaturated fatty acids present in the available sources of DHA. These other fatty acids have properties very similar to DHA and may not be separated to a sufficient degree by the methods mentioned above. Some microbial DHA-containing fats having very low levels of C20-22 polyunsaturated fatty acids may be provided in 90% or more purity alone or in combination with other methods mentioned.

Most DHA-containing fats also contain significant amounts of C20-22 polyunsaturated fatty acids, such as EPA (20: 5n-3), n-3 DPA (22: 5n-3), HPA (21: 5n-3), And other materials. An available method of separating DHA from these fatty acids is preparative high performance liquid chromatography (HPLC), wherein the stationary phase is silica gel or silica gel impregnated with nitrate and the mobile phase is selected from organic solvents or supercritical carbon dioxide. In this way, DHA with a purity of at least 97% can be obtained. However, an increase in the manufacturing cost according to the numerical value is pointed out. For example, the manufacturing cost of 97% DHA is five times more than 90% DHA.

90%, 95%, and 97% DHA contain a small amount of other fatty acids. For example, DHA having a purity of 97% is not only n-3 DPA (22: 5n-3) but also long chain fatty acids (eg, EPA (20: 5n-3)), HPA (21: 5n-3). )), And other materials. However, other fatty acids can react in a similar manner to DHA and provide alpha substituted derivatives.

Since only DHA and n-6 DPA (and generally 22: 5n-6, which are present at very low levels) can provide gamma-lactone by the cyclization of the first double bond, organic synthesis is provided as a purification method. Can be. Lactonation, purification and hydrolysis back to DHA are possible, but this is expected to be a more expensive process than HPLC.

In one embodiment, the compound of formula (I) wherein R ₁ (or R ₂ ) is a hydrogen atom is prepared via the following process (Scheme 1). Appropriately applied, this process can be used for the preparation of compounds of formula (I) in which both R ₁ and R ₂ are C ₁ -C ₇ alkyl groups, benzyl, halogen, alkenyl or alkynyl.

The compound of formula (I) represented by R ₁ is hydrogen and R ₂ is C ₁ -C ₇ alkyl group, benzyl, halogen, alkenyl, alkynyl is DHA ester with lithium diisopropyl amine or potassium / sodium hexamethyldi An ester enoleate is provided by reacting a strong non-nucleophilic base such as silazide in a solvent such as tetrahydrofuran or diethyl ester at a temperature of -60 ° C to -78 ° C (step 1).

Scheme 1

The ester enolates are ethyl iodine, alkyl halides such as benzyl chloride, acetyl chloride, acyl halides such as benzoyl bromide, anhydrous carboxylic acids such as acetic anhydride, or aprotic such as N-fluorobenzene sulfonimide (NFSI). Reaction with an electrophilic reagent such as an electronic halogenation reagent provides a monosubstituted derivative (step 2). The ester is further hydrolyzed to carboxylic acid derivatives at temperatures ranging from 15 ° C. to 40 ° C. by addition of a base such as an aqueous lithium / sodium hydroxide solution in an ethanol or methanol solvent.

Klaisen condensation of DHA EE occurs during the treatment of DHA EE with strong bases. This condensation product will have an interesting biological activity. Thus, the above-mentioned condensation (intermediate) products and the use of these products for the treatment and / or prevention of the diseases according to the invention are described.

In another embodiment, compounds of Formula (I) are synthesized through the following process (Scheme 2).

Scheme 2

Compounds of formula (I) wherein R ₁ is hydrogen and R ₂ is hydroxy, alkoxy group, acyloxy, have a strong non-nucleophilic base such as DHA ester and lithium diisopropyl amine or potassium / sodium hexamethyldisilazide The ester enolate is provided by reacting at a temperature of -60 ° C to -78 ° C in a solvent such as tetrahydrofuran or diethyl ester (step 4). The ester enoleate is reacted with an oxygen molecule together with other catalysts such as dimethyldioxane, 2- (phenylsulfonyl) -3-phenyloxaziridine, trimethylphosphite or nickel (II) complexes to react with alpha hydroxy DHA. An ester is provided (step 5). The reaction of a base alcohol such as sodium hydroxide with a THF or DMF solvent produces an alkoxide, which alkoxides are alkyliodide such as methyl iodide, ethyl iodide, benzyl bromide or React with different electrophilic reagents such as acyl halides such as acetyl chloride, benzoyl bromide (step 6). The ester is hydrolyzed to a carboxylic acid derivative in the temperature range of 15 ° C. to 40 ° C. by adding a base such as an aqueous lithium / sodium hydroxide solution in an ethanol or methanol solvent (step 7).

Such hydroxy-DHA esters are useful intermediates for introducing other functional groups at the alpha-position according to the invention. The hydroxyl groups can be converted to halides or tosylate and activated before reacting with other nucleophilic materials such as ammonia, amines, and thiols. The Mitsunobu reaction is also useful for converting hydroxy groups to other functional groups (Mitsunobu, O. Synthesis (1981) 1-28).

Compounds represented by compounds of formula (I) can also be synthesized by a combination of the other processes described above. The present invention includes the above mentioned process.

The invention also relates to mixing at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, complex, or prodrug thereof with at least one pharmaceutically acceptable additive, diluent, or carrier. It provides a process for preparing a pharmaceutical composition comprising the step.

Pure compounds of the enantiomer can be prepared by digesting the racemic compound of formula (I) as defined above. Decomposition of the compound of formula (I) is a known decomposition method, for example, of a diastereomer which can be separated by chromatography by reacting a compound of formula (I) with an enantiomerically pure adjuvant. It can be carried out in the same manner as making a mixture. The two enantiomers of the compound of formula (I) can then be regenerated from the separated diastereomers by means of transformation such as hydrolysis.

In addition, stoichiometric chiral auxiliaries can be used stoichiometrically for the effect of asymmetric introduction of substituents to the alpha position of DHA, as defined above. The use of chiral 2-oxazolidin-2-ones proves to be a particularly effective method. Enolates derived from chiral N-acyloxazolidine can remove various electrophiles in a high stereoregulated manner (Ager, DJ et al. Chem. Rev. (1996) 96: 835-876 ).

Example

The invention is illustrated in more detail by the following examples, which are not intended to limit the scope of the invention. In the examples below, the structural formulas were identified by a mass spectrometer (Mass Spectrometer, MS). It is evident that fatty acid compounds can also be produced from starting materials containing low or medium levels of DHA (ie, about 40-60% by weight DHA).

There are several general synthetic methods for the preparation of monoglycerides in the 2-position with fatty acids. One method is glycidyl using esterification of fatty acids with glycidol in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimidehydrochloride (EDC) and 4-dimethylamino pyridine (DMAP). To prepare derivatives. Treatment of glycidyl derivatives with anhydrous trifluoroacetic acid (TFAA) prior to the trans esterification reaction produces monoglycerides (Parkkari et al, Bioorg . Med . Chem . Lett . (2006) 2437).

Other general methods of preparing mono-, di-, or triglycerides of fatty acid derivatives are described in International Patent Application No. PCT / FR02 / 02831.

In addition, enzymatic processes (lipase reactions) can be used for the conversion of fatty acids to mono-, di-, or triglycerides. Mythology Mucor The 1,3-position specific lipase of miehei can be used to produce triglycerides or diglycerides from the reaction of polyunsaturated fatty acids and glycerol. Non-position specific yeast lipases from another lipase, Candida antartica , are very effective in the production of triglycerides from polyunsaturated fatty acids (Haraldsson, Pharmazie (2000) 3).

Synthesis protocol

Precursors of compounds of formula (I), such as free fatty acids and / or ethyl ester derivatives, can be prepared in the manner described in WO 2006/117664.

α-Ethyl DHA EE  ( PRB - 2)  synthesis

Butyl lithium (440 ml, 0.76 mol, 1.6 M in nucleic acid) was added dropwise to a stirring solution of diisopropylamine (111 ml. 0.78 mol) in dry THF (750 ml) under a nitrogen atmosphere at 0 ° C. The resulting solution was stirred for 45 min at -78 ° C and then added dropwise to DHA EE (200 g, 0.56 mol) in dry THF (1.61 ml). Ester was added over 4 hours. The dark green solution was stirred at −78 ° C. for 30 minutes, and then EtI (65 ml. 0.81 mol) was added thereto. When the temperature of the solution reached −40 ° C., EtI (5 ml, 0.06 mol) was further added. After finally raising the solution to -15 ° C (3 hours at -78 ° C), the mixture was poured into water and extracted with hexane (2x). The combined organic layers were washed with 1M hydrochloric acid and water, dried under Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The result was eluted with heptane / EtOAc (from 99: 1 to 50: 1) by flash chromatography on silica gel to give 42.2 g (20%) of a yellow oil compound;

¹ H-NMR (200 MHz; CDCl ₃ ) δ 0.8-1.0 (m, 6H), 1.2-1.4 (m, 411), 1.5-1.7 (m, 2H), 2.12 (m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, 10H), 4.18 (t, J = 7.1 Hz, 211), 5.3-5.6 (m, 12H);

MS (electrospray); 407 [M + Na].

PRB Preparation of -2 mg

PRB -A

PRB-2 FA ((all-Z) 4,7,10,13,16,19-2-ethyldocosahexaenoic acid) (5.081 g, 14.25 mmol) in CH ₂ Cl ₂ (60 ml), glycidol (0.63 ml, 9.5 mmol), a solution of N-ethyl-N '(3-dimethylaminopropyl) carbodiimide chloride (2.745 g, 14.3 mmol) and DMAP (1.752 g, 14.3 mmol) at room temperature under a nitrogen atmosphere 113 After stirring for hours, the solvent was evaporated under reduced pressure. Flash chromatography on silica gel eluted with heptane: EtOAc (95: 5) to yield 1.396 g (36%) of a yellow liquid product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.99 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.6 Hz, 3H), 1.55-1.64 (m, 2H), 2.05 (quint, J = 7.4 Hz, 2H), 2.25-2.37 (m, 3H), 2.60-2.63 (m, IH), 2.77-2.84 (m, 11H), 3.15-3.19 (m, IH), 3.89 (ddd, J = 12.3 Hz, 6.3 Hz, 3.8 Hz, IH), 4.39 (dd, J = 12.3 Hz, 3.1 Hz, IH), 5.27-5.42 (m, 12H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ11.7, 14.3, 20.5, 24.8, 24.9, 25.5, 25.6 (2 C), 29.47, 29.53, 44.6, 47.07, 49.4, 64.6, 64.7, 126.5, 127.0, 127.8, 128.01, 128.04, 128.08, 128.18, 128.21, 128.5, 129.9, 132.0, 175.3

MS (electrospray); 435 [M + Na] ⁺

PRB -B

The solution of PRB-A (1.368 g, 3.31 mmol) in dry CH ₂ Cl ₂ (15 ml) was cooled to −20 ° C. under nitrogen atmosphere and then trifluoroacetic anhydride (TFAA) in dry CH ₂ Cl ₂ (1.85 ml, 13.3) mmol) solution was added portionwise wise. The cooling bath was removed and the mixture was stirred for 1 hour. Solvent and unreacted TFAA were evaporated under reduced pressure. The residue was dissolved in 30 ml of toluene and passed through a pad of silica gel (30 g) with 700 ml of toluene. The solvent was evaporated under reduced pressure to afford crude product, 1,3-bis (trifluoroacetyl) -2-PRB-2.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.87 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H), 1.60 (m, 2H), 2.05 (quint, J = 7.3 Hz, 2H), 2.21-2.38 (m, 3H), 2.79-2.83 (m, 10H), 4.39-4.48 (m, 2H), 4.56-4.63 (m, 2H), 5.29-5.42 (m, 13H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 11.5, 14.2, 20.5, 24.8, 25.5, 25.6 (2 C), 29.4, 47.0, 64.8, 66.9, 125.9, 127.0, 127.76, 127.83, 128.0, 128.3, 128.4, 128.6, 130.3, 132.0, 174.6 (Unfortunately not enough scans to see the COCF ₃ signal)

PRB -2 mg

20 ml of a PRB-B solution in pentane / CH ₂ Cl ₂ (2: 1) was cooled to −20 ° C. under a nitrogen atmosphere, and then pyridine (1.6 ml, 19.8 mmol) and methanol (1.2 ml, 29.6 mmol) were added dropwise. The cooling bath was removed and the mixture was stirred for 4 hours and then the solvent was removed under reduced pressure. Flash chromatography on silica gel eluted with heptane: EtOAc 1: 1 solution to give 670 mg (80%) of PRB-2 MG as a light yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.90 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H), 1.50-1.70 (m, 2H), 2.05 (quint., J = 7.3 Hz, 2H), 2.19-2.31 (m, 3H), 2.32-2.43 (m, 2H), 2.74-2.87 (m, 10H), 3.77 (m, 4H), 4.91 (m, IH), 5.11-5.46 (m, 12H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 11.7, 14.2, 20.5, 25.0, 25.5, 25.6 (2C), 29.7, 47.3, 62.2, 75.0, 126.6, 126.9, 127.8, 128.0, 128.2, 128.3, 128.5, 130.0, 132.0, 175.9 (5 signals hidden)

MS (electrospray); 453 [M + Na] ₊

HPLC; 98%

Test Example  1: Demonstration of lipid metabolism effect in vivo

Compositions comprising PRB-2MG were tested in animal models as described below.

Because 3-thia fatty acids, such as tetradecylthioacetic acid (TTA), are known to reduce serum triglycerides, cholesterol and free fatty acid levels in animal models (Journal of Lipid Research, 1999, 2099), we have studied this material in our animal studies. Used as a positive control at.

Mice

Female heterozygous APOE ^* 3Leiden mice were used and during the experiment macrolon cages (3 or 4 mice per cage), clean existing animal rooms (relative humidity 50-60%, temperature ˜21 ° C., light cycle: 7 am-7 pm). Each animal was marked with a hole in its ear. Mice were fed with food and acidified tap water ( ad libitum ).

Diets

As described in Nishina et al. (J Lipid Res 1990; 31: 859), mice received semi-synthetic modified Weston-type diets containing cholesterol (0.25% w / w, final value) and 15% cacao butter. -synthetic modified Western-type diet (WTD).

drug injection

PRB-2 Mg and TTA were mixed with Weston-type food and orally administered at 0.3 mmol / kg bw / day. Lyophilized large chunks of food were placed in a vacuum bag and stored in a dark room at -20 ° C. with a warning-safety. Our diet with mice was changed twice a week.

Research design

APOE * 3 Leiden mice were fed a semisynthetic Westton-type diet. After 4 weeks, mice with low response were removed from the study and the remaining mice were divided into groups of 10 each to correspond to plasma cholesterol, triglycerides, free fatty acids, and age (t = 0).

After t = 0 and 4 weeks, weight and food intake were measured and blood samples were taken after the 4 hour fasting period to determine plasma cholesterol, triglycerides, and lipoprotein profiles. After 4 weeks, all animals died. The results are shown in FIGS. 1 and 2. As shown in the above results, the compound of the present invention has a lowering effect of lipids and TTA, a positive control, was better than the lowering effect of lipids.

Data of triglycerides and cholesterol of ApoE mice are shown in FIGS. 1 and 2, respectively.

Test Example  2: in the lab PPAR  Proof of activity

Way

Assays were carried out in the laboratory to include chimeric proteins comprising ligand binding domains (LBDs) of human PPARα, human PPARδ and human PPARγ fused with a yeast transactivator GAL4 DNA binding domain (DBD). (chimera protein) was performed on three stable receptor cell types, PPARα, PPARδ and PPARγ.

The luciferase reporter gene is driven by the pentamers of the GAL4 recognition sequence before the β-globin promoter. The use of GAL4-PPARα, GAL4-PPARδ and GAL4-PPARγ chimeric receptors allows the quantification of relative activity across three PPAR subtypes with the same receptor genes as the elimination of background activity of endogenous receptors.

PPAR activity of PRB-2 MG (10 μM) was measured by comparison with known drug guidelines (1 μM GW7647 for PPARα, 1 μM L-165041 for PPARδ and 1 μM BRL49653 for PPARγ) and negative control (0.1% DMSO). The results were expressed as percentage activity compared to the positive control (set at 100%).

PPAR activation data is shown in FIG. 3.

Claims (10)

Compounds of formula (I) and pharmaceutically acceptable salts thereof:
[Formula I]

R ₁ and R ₂ are the same or different and are selected from a hydrogen atom and an alkyl group, provided that R ₁ and R ₂ are not both hydrogen atoms.  The compound of claim 1, wherein the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and n-hexyl. The compound of claim 1, wherein R ₁ and R ₂ are selected from alkyl groups. The compound of claim 1, wherein R ₁ and R ₂ are selected from C ₁ -C ₇ alkyl groups. The compound of claim 4, wherein the C ₁ -C ₇ alkyl group is selected from methyl, ethyl, and propyl. The compound of claim 1, wherein R ₁ and R ₂ are different.  The compound of claim 6, wherein the compound is racemic.  The compound of claim 6, wherein the compound is in its R stereoisomeric form.  The compound of claim 6, wherein the compound is in its S stereoisomeric form. The compound of claim 1, wherein one of R ₁ and R ₂ is selected from C ₁ -C ₇ alkyl groups and the other is a hydrogen atom.

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