KR20240084229A - A pharmaceutical composition comprising gpr40 agonist as an active ingredient with improved stability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment or prevention of metabolic diseases containing as an active ingredient a GPR40 agonist, a compound of formula (I) with a mechanism of inducing blood sugar-dependent insulin secretion, and the alkalinizing agent mixed with the active ingredient is optimized. It is characterized by improved stability by selecting . In particular, the pharmaceutical composition for the treatment or prevention of metabolic diseases according to the present invention can show the advantage of significantly reducing the production of related substances even when stored for a long time not only at room temperature (25 ± 5°C) but also under harsh conditions (about 80°C). .

Description

Pharmaceutical composition comprising a GPR40 agonist with improved stability as an active ingredient {A PHARMACEUTICAL COMPOSITION COMPRISING GPR40 AGONIST AS AN ACTIVE INGREDIENT WITH IMPROVED STABILITY}

The present invention relates to a pharmaceutical composition containing a GPR40 (G protein receptor 40) agonist as an active ingredient. More specifically, the present invention relates to a pharmaceutical composition that significantly reduces the production of related substances even when stored for a long period of time not only at room temperature but also under harsh conditions, thereby improving stability. It relates to a pharmaceutical composition containing an improved GPR40 agonist as an active ingredient.

The compound represented by the following formula (I) is a phenylpropionic acid derivative, a GPR40 agonist, and is a treatment for metabolic diseases such as type 2 diabetes that induces blood sugar-dependent insulin secretion and exhibits excellent blood sugar control effects.

[Formula I]

In the above formula (I), R ¹ is hydrogen, or C1-4 straight-chain or branched alkyl, R ² is hydrogen, cyano, hydroxy, C1-4 straight-chain or branched alkyl, or C1-4 straight-chain or branched alkoxy, and R ³ is hydrogen, halogen, cyano, C1-4 straight or branched alkoxy, or OR ⁸ , and R ⁴ is hydrogen, or OR ⁸ (provided that R ³ and R ⁴ cannot be hydrogen at the same time), R ⁸ is hydrogen; C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; or alkyl substituted with C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and R ⁵ and R ⁶ are each independently hydrogen, halogen, cyano, halo methyl, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy, Y is NH or O, Z ¹ and Z ² are each independently CR ⁷ or N, if Z ¹ is N Z ² is CR ⁷ , and if Z ¹ is CR ⁷ , Z ² is N, and W is each independently CR ⁷ or N, where R ⁷ is hydrogen, halogen, cyano, hydroxy, C1-4 straight chain or branched alkyl, or C1-4 straight or branched chain alkoxy.

In this regard, the novel compound represented by Formula I is a GPR40 agonist that can be used for the purpose of preventing or treating metabolic syndrome, including type 2 diabetes, and is disclosed in Korean Patent No. 10-2007633.

On the other hand, the novel compound represented by Formula I may have the property of being susceptible to decomposition and deterioration by light, air, or heat, so the content may decrease due to decomposition and deterioration during storage at room temperature or high temperature, resulting in insufficient medicinal efficacy or Unexpected side effects may occur due to the formation of flexible substances.

Therefore, by including the novel compound represented by Formula I as an active ingredient, stability can be further improved by suppressing the production of related substances even when stored for a long time not only at room temperature (25 ± 5 ℃) but also under harsh high temperature conditions (80 ℃). There is a need for the development of pharmaceutical compositions.

The purpose of the present invention is to provide a pharmaceutical composition containing the novel compound represented by the above formula (I) as an active ingredient, which can improve stability by minimizing the production of related substances even under room temperature and high temperature conditions.

The object of the present invention is not limited to the object mentioned above, and other objects and advantages of the present invention that are not mentioned can be understood through the following description and will be more clearly understood by the examples of the present invention. In addition, it will be readily apparent that the objects and advantages of the present invention can be realized by the means and combinations thereof indicated in the patent claims.

In order to solve the above problem, according to one aspect of the present invention, a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof; It is possible to provide a pharmaceutical composition for the treatment or prevention of metabolic diseases containing; and an alkalinizing agent.

[Formula I]

In formula (I) above, R ¹ may be hydrogen, or C1-4 straight or branched chain alkyl, and R ² may be hydrogen, cyano, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy; , R ³ is hydrogen, halogen, cyano, C1-4 straight or branched chain alkoxy, or OR ⁸ , and R ⁴ may be hydrogen, or OR ⁸ (provided that R ³ and R ⁴ cannot be hydrogen at the same time) None.) R ⁸ is hydrogen; C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; Or it may be alkyl substituted with C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and R ⁵ and R ⁶ are each independently hydrogen, halogen, cyano , halomethyl, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy, Y may be NH or O, and Z ¹ and Z ² are each independently CR ⁷ or N. , if Z ¹ is N, Z ² is CR ⁷ , if Z ¹ is CR ⁷ , Z ² may be N, W may each independently be CR ⁷ or N, and R ⁷ is hydrogen, halogen, cyano, It may be hydroxy, C1-4 straight or branched chain alkyl, or C1-4 straight or branched chain alkoxy.

According to one aspect of the present invention, the compound of Formula I may include one selected from the group consisting of the following compounds:

(S)-3-(4-(((R)-4-(6-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)pyridin-3-yl)- 7-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(6-((3-methyloxetan-3-yl)methoxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-4-(6-(2-(1,1-dioxidothiomorpholino)ethoxy)pyridin-3-yl)-7-fluoro -2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(6-(oxetan-3-yloxy)pyridin-3-yl)-2,3-dihydro-1H- inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(6-(((S)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(4-methyl-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl )-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(2-methyl-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl )-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-4-(5-chloro-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-7-fluo Ro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(5-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(4-methyl-6-((3-methyloxetan-3-yl)methoxy)pyridin-3-yl) -2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(2-methyl-6-((3-methylooxetan-3-yl)methoxy)pyridin-3-yl )-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(5-((3-methyloxetan-3-yl)methoxy)pyridin-2-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(5-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-4-(5-chloro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-7-fluoro -2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-4-(5-cyano-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-7- fluoro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-4-(5-cyano-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-7-fluo Ro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-5-cyano-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-5-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-5-methoxy-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-5-cyano-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-5-fluoro-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-5-methoxy-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;

(S)-3-(4-(((R)-7-fluoro-4-(6-(((R)-tetrahydro-3-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)amino)phenyl)hex-4-inoic acid; and

3-(6-(((R)-7-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro -1H-inden-1-yl)oxy)pyridin-3-yl)hex-4-inoic acid.

According to one aspect of the present invention, the alkalizing agent may include one or more selected from the group consisting of magnesium carbonate, magnesium oxide, sodium bicarbonate, meglumine, magnesium aluminometasilicate, and sodium citrate hydrate. .

According to one aspect of the present invention, the pharmaceutical composition for treating or preventing metabolic diseases may further include other pharmaceutically acceptable additives.

According to one aspect of the present invention, the additive may include one or more selected from the group consisting of excipients, binders, disintegrants, and lubricants.

According to one aspect of the present invention, the alkalizing agent may be included in an amount of 0.2 to 60 parts by weight based on 1 part by weight of the compound of Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof.

According to one aspect of the present invention, the alkalinizing agent may be included in an amount of 1 to 10 parts by weight based on 1 part by weight of the compound of Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof.

According to one aspect of the present invention, the metabolic disease is one selected from the group consisting of obesity, type 2 diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, and dyslipidemia. It may include more.

According to one aspect of the present invention, an oral preparation containing a pharmaceutical composition for treating or preventing the metabolic disease can be provided.

The pharmaceutical composition of the present invention contains a novel compound represented by Formula I as an active ingredient, and can minimize the production of related substances at room temperature and high temperature, thereby improving stability, and the pharmaceutical composition can be conveniently used. It can be manufactured.

In addition to the above-described effects, specific effects of the present invention are described below while explaining specific details for carrying out the invention.

The above-described objects, features, and advantages will be described in detail below, and accordingly, those skilled in the art will be able to easily implement the technical idea of the present invention.

In describing the present invention, if it is determined that a detailed description of known technologies related to the present invention may unnecessarily obscure the gist of the present invention, the detailed description will be omitted.

Among the contents not described in this specification, descriptions of those that can be sufficiently inferred technically by a person skilled in the art will be omitted.

In this specification, the unit “part by weight” may refer to the weight ratio between each component.

As used herein, singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as “comprises,” “contains,” “has,” and the like should not be construed as necessarily including all of the various components described in the specification, and some of the components are not included. It may not be present, or it should be interpreted as containing additional components.

In the present invention, “heterocycloalkyl” refers to a cyclic group containing heteroatoms. Examples, but not limited to, are oxetane, tetrahydrofuran, pyran, azetidine, pyrrolidinyl, piperazinyl, morpholine, thiomorpholine.

As used herein, “straight-chain or branched alkyl” refers to a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. For example, but not limited to, methyl, ethyl, propyl, butyl, 1-methylethyl, diethyl or dimethyl.

In the present invention, “straight chain or branched alkoxy” is an OR group where R is a C1-4 alkyl group as defined above. For example, but not limited to, methoxy, ethoxy, propoxy, butoxy, 1 -methyl ethoxy, 1,1-dimethyl ethoxy.

In the present invention, “alkyl” means a linear or branched saturated hydrocarbon group having 1 to 2 carbon atoms, and may mean, for example, methyl or ethyl.

In the present invention, “alkoxy” is an OR group where R is a C1-2 alkyl group as defined above, and may mean, for example, methoxy or ethoxy.

In the present invention, “halogen” is a bromine, fluorine, or chlorine atom.

In the present invention, the term "pharmaceutically acceptable" refers to a compound or composition within medical standards that is safe for use in contact with the tissue of a biological subject, such as a human, without toxicity, irritation, or other problems or complications that pose an unreasonable risk. Includes.

The compounds of the present invention contain asymmetric or chiral centers and may exist in stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, such as diastereomers, enantiomers and racemic mixtures, are considered to form part of the invention. Here, a mixture of isomers is called an enantiomer, and a mixture of enantiomers in a 50:50 ratio is called a racemate.

In the present invention, “diastereomers” refer to stereoisomers with two or more chiral centers, the molecules of which are not mirror images of each other. Diastereomers have different physical properties, for example in terms of melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated through high-resolution analytical processes such as electrophoresis and chromatography.

In the present invention, “enantiomers” refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

In the present invention, the expression “pharmaceutically acceptable salt” as used refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention. Exemplary salts include sulfate, citrate, acetate, oxalate, hydrochloride, bromate, iodate, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, and tartrate. , oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, genticinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate. , methanesulfonate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salt, but are not limited thereto. Pharmaceutically acceptable salts may involve the inclusion of other molecules such as acetate ions, succinate ions or other counter ions. The counter ion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. Moreover, pharmaceutically acceptable salts may have one or more charged atoms in their structure. If multiple charged atoms are part of the pharmaceutically acceptable salt, it may have multiple counter ions. Accordingly, a pharmaceutically acceptable salt may have one or more charged ions and/or one or more counter ions.

If the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available to those skilled in the art, for example, by combining the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid). , phosphoric acid, etc.) or organic acids (e.g. acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (e.g. glucuronic acid or brown acid) lacturonic acid), alpha hydroxy acids (e.g. citric acid or tartaric acid), amino acids (e.g. aspartic acid or glutamic acid), aromatic acids (e.g. benzoic acid or cinnamic acid), sulfonic acids (e.g. p-toluenesulfonic acid or ethanesulic acid) It can be prepared by treatment with ponic acid, etc.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method available to those skilled in the art, for example, by reacting the free acid with an inorganic or organic base, such as an amine, alkali metal hydroxide or It can be manufactured by treatment with alkaline earth metal hydroxide, etc. Examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, organic salts derived from cyclic amines such as piperidine, morpholine and piperazine, or sodium. , calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

In the present invention, unless specifically limited, the term “compound represented by Formula I” can be used as a concept that includes all compounds represented by Formula I, isomers thereof, or pharmaceutically acceptable salts thereof.

“Prevention” in the present invention refers to all actions that inhibit or delay the onset of a disease by administering the composition according to the present invention.

In the present invention, “treatment” includes therapeutic effects such as inhibiting or stopping the progression of a disease or condition, reducing the rate of progression, improving and alleviating symptoms, or preventing disease in a biological subject (e.g., human or animal).

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount, and the dosage varies depending on the patient's condition and weight, degree of disease, drug form, administration route and time, but can be appropriately selected by a person skilled in the art. there is. Additionally, there is no limitation to the subject, and preferably, it may be a mammal, including a human.

The present invention will be described in detail below.

The present invention provides a pharmaceutical composition containing a compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient that acts as an agonist of GPR40, and specifically provides a pharmaceutical composition for treating diseases in which GPR40 is involved. A pharmaceutical composition for treating or preventing metabolic diseases can be provided.

[Formula I]

In formula (I) above, R ¹ may be hydrogen, or C1-4 straight or branched chain alkyl, and R ² may be hydrogen, cyano, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy; , R ³ is hydrogen, halogen, cyano, C1-4 straight or branched chain alkoxy, or OR ⁸ , and R ⁴ may be hydrogen, or OR ⁸ (provided that R ³ and R ⁴ cannot be hydrogen at the same time) None.) R ⁸ is hydrogen; C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; Or it may be alkyl substituted with C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and R ⁵ and R ⁶ are each independently hydrogen, halogen, cyano , halomethyl, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy, Y may be NH or O, and Z ¹ and Z ² are each independently CR ⁷ or N. , if Z ¹ is N, Z ² is CR ⁷ , if Z ¹ is CR ⁷ , Z ² may be N, W may each independently be CR ⁷ or N, and R ⁷ is hydrogen, halogen, cyano, It may be hydroxy, C1-4 straight or branched chain alkyl, or C1-4 straight or branched chain alkoxy.

Generally, when preparing an oral preparation of a pharmaceutical composition, a large number of various additives are included in addition to the active ingredient, and the present inventors have found that the compound represented by Formula I is unstable under acidic conditions and stable under basic conditions. This was confirmed experimentally. Furthermore, the present invention was completed after confirming that the pharmaceutical composition containing the compound represented by Formula I becomes basic when it contains an alkalinizing agent, so the production of related substances can be suppressed or minimized.

Accordingly, the pharmaceutical composition of the present invention is characterized by essentially including an alkalinizing agent as an additive to the compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.

According to one embodiment of the present invention, the alkalizing agent may include one or more selected from the group consisting of magnesium carbonate, magnesium oxide, sodium bicarbonate, meglumine, magnesium aluminometasilicate, and sodium citrate hydrate. , for example, magnesium oxide may be selected, but is not necessarily limited thereto.

According to one embodiment of the present invention, the alkalizing agent may be included in an amount of, for example, 0.2 to 60 parts by weight, based on 1 part by weight of the compound of Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof, e.g. For example, it may be included in 1 to 10 parts by weight, and for example, it may be included in 3 to 7.5 parts by weight, but is not necessarily limited thereto. If the alkalizing agent is included in less than 0.2 parts by weight, the effect of suppressing the production of related substances may be reduced, making it difficult to achieve the effect of the present invention, and if the alkalizing agent is included in more than 60 parts by weight, the amount is too excessive compared to the general usage amount of the additive. As it is included, problems may arise in the manufacturing and safety of oral preparations.

According to one embodiment of the present invention, in addition to the alkalinizing agent, it may further include a pharmaceutically acceptable additive, and the additive may include one or more selected from the group consisting of excipients, binders, disintegrants, and lubricants, , but is not necessarily limited to this.

According to one embodiment of the present invention, the pharmaceutical composition of the present invention may include excipients, binders, disintegrants, and lubricants as additives in addition to the alkalinizing agent.

From the viewpoint of suppressing the production of related substances by using the above additives together with the compound represented by formula (I), which is an active ingredient, it is preferable to select and use those described below.

According to one embodiment of the present invention, the excipient may be one or more selected from the group consisting of lactose (lactose hydrate), mannitol, starch, microcrystalline cellulose, and silicified microcrystalline cellulose, and for example, the two types may be used in combination. However, it is not necessarily limited to this.

According to one embodiment of the present invention, for 1 part by weight of the compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, the excipient may be included in an amount of, for example, 10 to 250 parts by weight, for example It may be included in 40 to 200 parts by weight, for example, 100 to 150 parts by weight, but is not necessarily limited thereto. If the content of the excipient is less than 10 parts by weight, tablets may not be formed, and if the content of the excipient exceeds 250 parts by weight, there may be a problem in that the content of the active ingredient drug per tablet decreases.

According to one embodiment of the present invention, the binder is one selected from the group consisting of povidone, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, starch, gelatin, and gum arabic. It may be more than this, but is not necessarily limited thereto.

According to one embodiment of the present invention, for 1 part by weight of the compound of Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof, the binder may be included in an amount of, for example, 0.05 to 20 parts by weight, for example It may be included in 0.5 to 15 parts by weight, for example, 1 to 10 parts by weight, but is not necessarily limited thereto. If the binder content is less than 0.05 parts by weight, the tablet may be easily broken due to low hardness, and if the binder content exceeds 20 parts by weight, the dissolution rate of the active ingredient may be reduced.

According to one embodiment of the present invention, the disintegrant may be one or more selected from the group consisting of starch, starch derivatives, croscarmellose sodium, crospovidone, carboxymethyl cellulose calcium, carboxymethyl cellulose derivatives, and crospovidone. , but is not necessarily limited to this.

According to one embodiment of the present invention, for 1 part by weight of the compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, the disintegrant may be included in an amount of, for example, 0.05 to 25 parts by weight, for example For example, it may be included in 0.5 to 20 parts by weight, and for example, it may be included in 1 to 10 parts by weight, but is not necessarily limited thereto. If the content of the disintegrant is less than 0.05 parts by weight, disintegration may not occur in the body, and if the content of the binder exceeds 25 parts by weight, the tablet may absorb a lot of moisture when stored, which may reduce the stability of the tablet. You can.

According to one embodiment of the present invention, the lubricant is one selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG), and talc. There may be more than one species, but it is not necessarily limited thereto.

According to one embodiment of the present invention, for 1 part by weight of the compound of Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof, the lubricant may be included in an amount of, for example, 0.005 to 15 parts by weight, for example For example, it may be included in 0.05 to 10 parts by weight, and for example, it may be included in 0.5 to 5 parts by weight, but is not necessarily limited thereto. If the content of the lubricant is less than 0.005 parts by weight, fluidity may worsen and the weight per tablet may vary significantly, and if the content of the lubricant exceeds 15 parts by weight, tabletting may be difficult and dissolution may be delayed.

According to one embodiment of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition for the treatment or prevention of metabolic diseases, and may further include pharmaceutically acceptable additives, the types of which may inhibit the effect of the present invention. There are no particular restrictions unless otherwise specified.

According to one embodiment of the present invention, the metabolic disease is one selected from the group consisting of obesity, type 2 diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, and dyslipidemia. It may include more than one condition, and preferably type 2 diabetes.

The oral preparation according to the present invention can be manufactured using a conventional manufacturing method of a pharmaceutical preparation for oral administration.

The form of the oral preparation according to the present invention may be tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc., but from the viewpoint of ease of administration, tablets are most preferable. However, other suitable preparations such as pills, capsules, granules, and syrups can also be appropriately selected from the viewpoint of improving immediate effect and bioavailability, and can be prepared into various preparations for oral administration by conventional methods, preferably It can be manufactured as an oral solid preparation.

Hereinafter, the present invention will be described in more detail through preferred embodiments of the present invention. However, this is presented as a preferred example of the present invention and should not be construed as limiting the present invention in any way.

Example

Experimental Group 1: Examples 1 to 6 and Comparative Examples 1 to 4

Tablets according to Examples 1 to 6 and Comparative Examples 1 to 4 were prepared with the compositions shown in Table 1 below. As shown in Table 1 below, various alkalizing agents were added in Examples 1 to 6, and various acidifying agents were added in Comparative Examples 2 to 4, where the contents of the alkalizing agent and acidifying agent were all the same. Comparative Example 1 differs in that neither an alkalizing agent nor an acidifying agent was added. The detailed tablet manufacturing method is as follows.

Xelaglifam, the active ingredient in Table 1 below, is “(S)-3-(4-(((R)-7-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy )Pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid”.

Additives except the active ingredients Xelaglifam and magnesium stearate were passed through a 30 mesh sieve and mixed. Magnesium stearate was separately passed through a 30 mesh sieve and then added to the above mixture for final mixing. The final mixture was compressed into tablets using a round punch (7.5 mm in diameter) using a tablet press (AutoTab-200TR (Ichihachi Seiki Co., Ltd)), and the total weight of one tablet was 150.0 mg.

The results of experiments conducted according to experiments (1) to (3) below for the tablets of Examples 1 to 6 and Comparative Examples 1 to 4 are shown in Table 1 below.

Experiment (1) 1% w/w suspension pH measurement test A purified sample was taken, added to purified water to make it 1% w/w, sonicated for 20 minutes, and the pH was measured with a pH meter (SevenEasy, Mettler Toledo).

Experiment (2) Measurement of initial related substance content

A solution in which the concentration of the active ingredient, Xelaglifam, was adjusted to 50ug/mL in the extract (50% acetonitrile) was used as the sample solution, and high-performance liquid chromatography (HPLC) was performed to measure the total related substance content of the purified sample. The HPLC analysis conditions and the calculation formula for the content of related substances analyzed from HPLC are as follows.

[HPLC analysis conditions]

◎ Column: C18 column (4.6 x 150 mm, 2.6 ㎛) ◎ Detector: UV, 225nm

◎ Mobile phase: mixture of purified water and trifluoroacetic acid or a mixture of acetonitrile and trifluoroacetic acid

[Calculation formula for content of related substances]

◎ Individual related substances (%) = peak area of individual related substances / total peak area of test solution x 100

◎ Total related substances (%) = Total of individual related substances (%)

Experiment (3) Measurement of total related substances content after storage under harsh conditions - stability test

The tablet sample was packaged and stored in an aluminum bag under a temperature condition of 80°C, and the total content of related substances was measured after 7 days from the time of storage, and the measurement method was the same as described in (2) above.

[Table 1]

As can be seen from the results in Table 1, Comparative Examples 2 to 4, in which an acidifying agent was added, were stored under harsh conditions at 80°C for 7 days compared to Comparative Example 1 in which neither the acidifying agent nor the alkalizing agent was added. As the total amount of related substances increased significantly, it was confirmed that stability was low. On the other hand, in Examples 1 to 6 in which an alkalizing agent was added, the total related substances after being stored under harsh conditions at 80°C for 7 days were significantly lower than those in Comparative Examples 1 to 4, confirming improved stability.

Experimental Group 2: Examples 1 and 7-10

Tablets were prepared using magnesium oxide as an alkalizing agent in the same manner as in Example 1, but the tablets of Examples 7 to 10 were prepared by varying the content of magnesium oxide as shown in Table 2 below.

The results of experiments conducted according to experiments (1) to (3) above for the tablets of Examples 1 and 7 to 10 are shown in Table 2 below.

[Table 2]

As can be seen from the results in Table 1 above, as a result of the stability test, it was found that among alkalizing agents, magnesium oxide had the best effect in suppressing the generation of related substances. The results of additional experiments were conducted by adjusting the content of magnesium oxide. It is shown in Table 2.

As can be seen from the results in Table 2, when the content of the alkalizing agent is increased, the effect of suppressing the generation of related substances increases. However, when the content of the alkalizing agent is increased to 60 parts by weight as in Example 10, the effect of suppressing the generation of related substances is somewhat reduced. Although a decrease was observed, the suppression of related material generation was still superior to Comparative Example 1 in which no alkalizing agent was added.

As described above, the present invention has been described with reference to the illustrative embodiments, but the present invention is not limited to the embodiments disclosed herein, and various modifications may be made by those skilled in the art within the scope of the technical idea of the present invention. It is self-evident that this can be achieved. In addition, although the operational effects according to the configuration of the present invention were not explicitly described and explained in the above description of the embodiments of the present invention, it is natural that the predictable effects due to the configuration should also be recognized.

Claims (9)

A compound represented by the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof; and an alkalinizing agent; a pharmaceutical composition for the treatment or prevention of metabolic diseases comprising:
[Formula I]
In Formula I above,
R ¹ is hydrogen, or C1-4 straight or branched chain alkyl,
R ² is hydrogen, cyano, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy,
R ³ is hydrogen, halogen, cyano, C1-4 straight or branched alkoxy, or OR ⁸ ,
R ⁴ is hydrogen, or OR ⁸ ,
However, R ³ and R ⁴ cannot be hydrogen at the same time,
R ⁸ is hydrogen; C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; or alkyl substituted with C3-10 heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S,
R ⁵ and R ⁶ are each independently hydrogen, halogen, cyano, halomethyl, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy,
Y is NH or O,
Z ¹ and Z ² are each independently CR ⁷ or N. In this case, if Z ¹ is N, Z ² is CR ⁷ , and if Z ¹ is CR ⁷ , Z ² is N,
W is each independently CR ⁷ or N, and R ⁷ is hydrogen, halogen, cyano, hydroxy, C1-4 straight or branched alkyl, or C1-4 straight or branched alkoxy.
According to paragraph 1,
A pharmaceutical composition for the treatment or prevention of metabolic diseases, wherein the compound of Formula 1 includes one selected from the group consisting of the following compounds:
(S)-3-(4-(((R)-4-(6-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)pyridin-3-yl)- 7-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(6-((3-methyloxetan-3-yl)methoxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-4-(6-(2-(1,1-dioxidothiomorpholino)ethoxy)pyridin-3-yl)-7-fluoro -2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(6-(oxetan-3-yloxy)pyridin-3-yl)-2,3-dihydro-1H- inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(6-(((S)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(4-methyl-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl )-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(2-methyl-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl )-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-4-(5-chloro-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-7-fluo Ro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(5-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(4-methyl-6-((3-methyloxetan-3-yl)methoxy)pyridin-3-yl) -2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(2-methyl-6-((3-methylooxetan-3-yl)methoxy)pyridin-3-yl )-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(5-((3-methyloxetan-3-yl)methoxy)pyridin-2-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(5-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-4-(5-chloro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-7-fluoro -2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-4-(5-cyano-6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-7- fluoro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-4-(5-cyano-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-7-fluo Ro-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-5-cyano-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-5-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-5-methoxy-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2, 3-dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-5-cyano-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-5-fluoro-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-5-methoxy-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)oxy)phenyl)hex-4-inoic acid;
(S)-3-(4-(((R)-7-fluoro-4-(6-(((R)-tetrahydro-3-yl)oxy)pyridin-3-yl)-2,3 -dihydro-1H-inden-1-yl)amino)phenyl)hex-4-inoic acid; and
3-(6-(((R)-7-fluoro-4-(6-(((R)-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro -1H-inden-1-yl)oxy)pyridin-3-yl)hex-4-inoic acid.
According to paragraph 1,
The alkalizing agent is a pharmaceutical for the treatment or prevention of metabolic diseases, comprising at least one selected from the group consisting of magnesium carbonate, magnesium oxide, sodium bicarbonate, meglumine, magnesium aluminometasilicate, and sodium citrate hydrate. Composition.
According to paragraph 1,
A pharmaceutical composition for the treatment or prevention of metabolic diseases, further comprising a pharmaceutically acceptable additive.
According to paragraph 4,
A pharmaceutical composition for the treatment or prevention of metabolic diseases, wherein the additive includes at least one selected from the group consisting of excipients, binders, disintegrants, and lubricants.
According to paragraph 1,
A pharmaceutical composition for the treatment or prevention of metabolic diseases, comprising 0.2 to 60 parts by weight of the alkalinizing agent based on 1 part by weight of the compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to paragraph 1,
A pharmaceutical composition for the treatment or prevention of metabolic diseases, comprising 1 to 10 parts by weight of the alkalinizing agent based on 1 part by weight of the compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to paragraph 1,
The metabolic disease includes at least one selected from the group consisting of obesity, type 2 diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, and dyslipidemia. Pharmaceutical composition for treatment or prevention.
An oral preparation comprising the pharmaceutical composition for the treatment or prevention of metabolic diseases according to any one of claims 1 to 8.