HK1091484B

HK1091484B - Cyclohexanecarboxylic acid compound

Info

Publication number: HK1091484B
Application number: HK06112004.3A
Authority: HK
Inventors: 小野诚; 野口滋
Original assignee: 第一制药株式会社
Priority date: 2003-07-24
Filing date: 2004-07-23
Publication date: 2011-02-18

Description

Cyclohexanecarboxylic acids

Technical Field

The present invention relates to cyclohexanecarboxylic acids which have an excellent inhibitory activity against VLA-4 (Very Late Antigen-4), have good water solubility and good long-term storage stability, and are useful as preventive and/or therapeutic agents for diseases caused by cell adhesion (cell adhesion), and to drugs containing the cyclohexanecarboxylic acids.

Background

With the clear relationship between cell adhesion and various diseases, it is known that various diseases can be prevented and treated by inhibiting cell adhesion. This cell adhesion is closely related to cell adhesion molecules, VLA-4 is known to be a mediator of leukocyte adhesion. Under these circumstances, various VLA-4 inhibitors have been developed, and patent document 1 describes a compound having an excellent VLA-4 inhibitory activity and useful as a prophylactic and/or therapeutic agent for diseases caused by cell adhesion.

In example 170 of patent document 1, it is described that trans-4- [1- [2, 5-dichloro-4- [ (1-methyl-1H-3-indolylcarbonyl) amino ] phenylacetyl ] - (4S) -methoxy- (2S) -pyrrolidinylmethoxy ] cyclohexanecarboxylic acid (hereinafter referred to as compound (a)) is isolated as a colorless solid.

Patent document 1 international publication No. 02/053534 pamphlet

Disclosure of The Invention

Problems to be solved by the invention

The compound (a) separated as a colorless solid in the above patent document 1 has low water solubility and has a problem of long-term stability. Water solubility and long-term storage stability are very important for the development of the compound (a) as a drug.

Means for solving the problems

The present inventors have conducted studies to find a compound useful as a drug not only in pharmacological actions but also in water solubility and long-term storage stability, and as a result, have found that the sodium salt 5 hydrate of the above-mentioned compound (a) has higher water solubility than other various salts, does not have the problem of moisture absorption and desorption, has good long-term storage stability, and is useful as a drug, and have completed the present invention.

Namely, the present invention provides the following formula (1)

Trans-4- [1- [2, 5-dichloro-4- [ (1-methyl-1H-3-indoylcarbonyl) amino ] phenylacetyl ] - (4S) -methoxy- (2S) -pyrrolidinylmethoxy ] cyclohexanecarboxylic acid sodium salt 5 hydrate (hereinafter referred to as compound (1)).

Further, the present invention provides a crystal of the above compound (1).

The present invention also provides a medicament containing the above-mentioned compound (1) as an active ingredient.

The invention also provides a pharmaceutical composition containing the compound (1) and a pharmaceutically acceptable carrier.

The invention also provides application of the compound (1) in preparation of medicaments.

The present invention also provides a method for treating a disease caused by cell adhesion, which is characterized by administering an effective amount of the above-mentioned compound (1).

Effects of the invention

The compound (1) of the present invention has high water solubility, is less likely to undergo weight change due to moisture absorption and desorption, is excellent in storage stability, and has excellent VLA-4 inhibitory activity, and therefore is useful as a prophylactic and/or therapeutic agent for diseases caused by cell adhesion.

Brief description of the drawings

FIG. 1 shows the moisture absorption and desorption properties of the compound (a).

[ FIG. 2] shows the hygroscopicity and the hygroscopicity of the tert-butylamine salt of the compound (a).

FIG. 3 shows the moisture absorption and desorption properties of the compound (1).

FIG. 4 is a powder X-ray diffraction chart showing the type I crystal and the type II crystal of the compound (1).

FIG. 5 shows the moisture absorption and desorption properties of the I-type crystal (A) and the II-type crystal (B) of the compound (1).

Best Mode for Carrying Out The Invention

The compound (1) is a sodium salt 5 hydrate of the compound (a) described in the above patent document 1. Accordingly, the compound (1) is obtained by reacting the compound (a) or a reaction mixture containing the compound (a) with a compound capable of providing sodium ions, followed by crystallization from an aqueous solvent. The compound for providing sodium ions used herein may be, in addition to sodium hydroxide, sodium salts such as sodium carbonate, and sodium hydroxide is particularly preferred. The reaction of the compound (a) with the sodium ion-donating compound can be carried out by adding an aqueous solution of the sodium ion-donating compound in an amount of 1.0 to 1.2 mol relative to the compound (a) and at 20 to 35 ℃.

After the compound (a) is completely dissolved, insoluble matter is removed as necessary, and the compound (1) is crystallized with a water-containing solvent. Examples of the aqueous solvent to be used include aqueous acetone, aqueous acetonitrile, aqueous 1-propanol, aqueous 2-propanol and aqueous ethanol, and particularly preferred is aqueous acetone.

As shown in examples described later, the obtained compound (1) has higher water solubility than other salts such as the compound (a), ethanolamine salt, dibenzylethylenediamine salt, lithium salt and the like.

In addition, the moisture absorption and desorption properties of various salts of the compound (a) were investigated as an index of long-term storage stability. As a result, compound (a) undergoes weight change, and thus the hydrated form is difficult to specify. In addition, the compound (1), the lithium salt of the compound (a), ethanolamine salt, dibenzylethylenediamine salt were stable without weight change under normal humidity conditions, but the tert-butylamine salt showed some weight change.

Among them, only the compound (1) having excellent water solubility and moisture absorption and removal properties (storage stability)

In addition, depending on the degree of stirring at the time of crystallization, compound (1) may form a polymorph. When the stirring during crystallization is slight, plate crystals (form II) are formed, and when the stirring is vigorous, needle crystals (form I) are formed. By powder X-ray diffraction, the form II crystal had characteristic peaks at 7.2, 17.3, 18.9, 19.4, 20.4 and 21.6(°) as diffraction angles (2 θ). On the other hand, by powder X-ray diffraction, the form I crystal had characteristic peaks at 7.2, 12.9, 17.3, 18.9, 19.8, 21.6, 26.8 and 30.5(°) as diffraction angles (2 θ).

These type I and type II crystals of the compound (1) are high in water solubility and also good in storage stability (moisture absorption and desorption properties). However, the type II crystal is preferred from the viewpoint of controlling the crystallization conditions and the ease of handling in mass production.

Thus, the compound (1) of the present invention has good water solubility and storage stability, and can selectively inhibit the binding of a cell adhesion molecule to VLA-4 as described in patent document 1. Therefore, the compound (1) of the present invention is useful as a prophylactic and/or therapeutic agent for diseases caused by VLA-4-associated cell adhesion, i.e., various diseases caused by migration and adhesion of leukocytes, such as inflammatory diseases, autoimmune diseases, cancer metastasis, bronchial asthma, nasal congestion, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel diseases, transplant rejection and the like.

The drug of the present invention can be administered by various methods typified by oral administration. In addition, when prepared into injections, the injection can be administered by any method such as intravenous injection, intramuscular injection, subcutaneous injection, etc.

The preparation can be prepared by selecting an appropriate formulation according to the administration method and preparing the preparation by a conventional method for preparing various preparations.

Examples of the oral preparation include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. As an injection, a stabilizer, a preservative, and a cosolvent may be used, and a solution containing these adjuvants may be stored in a container and, if necessary, freeze-dried to prepare a solid preparation which needs to be dissolved. The liquid preparation may, for example, be a solution, a suspension or an emulsion, and these preparations may be prepared using a suspension or an emulsifier as an additive.

The drug containing the compound (1) of the present invention is preferably administered 1 time a day to 1 person in an adult at appropriate intervals, and the amount of the drug to be administered is 0.01mg to 2000mg, preferably 0.1mg to 1000mg, in terms of the compound (1).

The drug of the present invention may be used in combination with an anti-inflammatory agent, an anti-arthritic agent, an adrenal cortex steroid (steroid), an immunosuppressive agent, an antipsoriatic agent, a bronchodilator, an anti-bronchial asthma agent, or an antidiabetic agent as required within a range not to impair the effects of the present invention.

Examples

The present invention is specifically illustrated by the following examples.

Reference example 1 (Synthesis of Compound (a))

Methyl trans-4- [ (4S) -methoxy- (2S) -pyrrolidinylmethoxy ] cyclohexanecarboxylate (100mg, 0.37mmol) was dissolved in DMF (2mL), and [2, 5-dichloro-4- [ (1-methyl-1H-3-indoylcarbonyl) amino ] phenyl ] acetic acid (140mg, 0.37mmol), 1-hydroxybenzotriazole (HOBt) (95mg, 0.70mmol), Dimethylaminopyridine (DMAP) (catalytic amount), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl) (107mg, 0.56mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction solution was poured into 1MHCl and extracted 3 times with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using silica gel (middle pressure Yamazen, chloroform/methanol 10: 0 to 97: 3, 20mL/min,. phi.50 mm. times.150 mm). The resulting ester was dissolved in THF (4mL), 0.25M NaOH (2.4mL, 0.61mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the resulting residue was crystallized by adding 1M HCl, and the precipitated crystals were filtered under reduced pressure, washed with water, and dried under reduced pressure to obtain compound (a) (150mg, 66%) as a colorless solid.

¹H-NMR(DMSO-d₆)δ：1.10-1.40(m，4H)，1.80-2.20(m，8H)，3.15-4.30(m，8H)，3.28(s，3H)，3.90(s，3H)，7.21(t，J＝7.5Hz，1H)，7.28(t，J＝7.5Hz，1H)，7.50(d，J＝15.2Hz，1H)，7.56(d，J＝8.3Hz，1H)，7.88(d，J＝4.1Hz，1H)，8.15(d，J＝8.0Hz，1H)，8.31(s，1H)，9.39(s，1H).

MS(ESI)m/z617(M+1)⁺；

Anal.Calcd for C₃₁H₃₅Cl₂N₃O₆·0.5H₂O：C，59.52；H，5.80；N，6.72.

Found：C，59.36；H，5.72；N，6.68.

Example 1 (Synthesis of Compound (1): type I)

Compound (a) (5.0 g, 8.1mol) was suspended in 100mL of acetone, and 1M aqueous NaOH solution (8.1mL) was added thereto, followed by stirring at room temperature for 18 hours with a stirrer. The precipitated crystals were filtered under reduced pressure, washed with acetone, and then dried under reduced pressure. The dried crystals were conditioned at a relative humidity of 52% or more. Compound (1) was obtained as white needle crystals (5.6 g, 95%). Form I was confirmed by powder X-ray diffraction.

Anal.Calcd.For C₃₁H₃₄Cl₂N₃NaO₆·5H₂O：C，51.10；H，6.09；N，5.76；Cl，9.73；Na，3.16

Found：C，50.80；H，5.99；N，5.60；Cl，9.70；Na，3.41

Example 2 (Synthesis of Compound (1): type II)

After dissolving 15.0g of compound (1) in 90mL of 50% aqueous acetone by heating (30 to 40 ℃), the insoluble matter was filtered, 360mL of acetone was added to the filtrate, and the mixture was stirred with a stirring blade at room temperature for 20 hours. The precipitated crystals were filtered under reduced pressure, washed with acetone containing 10% water, and then dried under reduced pressure. The dried crystals were conditioned at a relative humidity of 52% or more. 14.2g (95%) of Compound (1) was obtained as white plate crystals. Form II was confirmed by powder X-ray diffraction.

Comparative example 1 (Synthesis of lithium salt of Compound (a))

112mg (0.18mmol) of the compound (a) was suspended in 5mL of ethanol, a 1M aqueous LiOH solution (0.18mL) was added, and the solvent was evaporated under reduced pressure and dried to a solid. To the residue was added 3mL of acetonitrile containing 20% water, and the mixture was dissolved by heating and then allowed to stand at 4 ℃ for 2 days. The precipitated crystals were filtered under reduced pressure and air-dried at room temperature for 1 day to obtain 98mg (78%) of a lithium salt of compound (a) as white crystals.

Anal.Calcd.For C₃₁H₃₄Cl₂LiN₃O₆·4H₂O：C，53.61；H，6.10；N，6.05；Cl，10.21

Found：C，53.47；H，6.08；N，6.02；Cl，10.33

The same procedure gave the ethanolamine salt, dibenzylethylenediamine salt and tert-butylamine salt of compound (a).

Test example 1

The compound (1), the compound (a) and various salts of the compound (a) obtained in example 1, reference example 1 and comparative example 1 were evaluated for moisture absorption and desorption properties. That is, about 20mg of the crystal was placed on a microbalance (automatic water vapor adsorption apparatus), and the amount of moisture absorbed and removed was evaluated by measuring the change in weight with time in an environment with a Relative Humidity (RH) of 10 to 90%.

As a result, the compound (a) showed weight change in 40 to 60% RH, and its hydrated form was difficult to be made to specification (FIG. 1). In addition, the tert-butylamine salt of compound (a) also showed some weight change and remained problematic in terms of storage stability (FIG. 2). In contrast, compound (1) was stable without weight change under normal humidity conditions (fig. 3). In addition, the lithium salt, ethanolamine salt and dibenzylethylenediamine salt of the compound (a) are also stable under normal humidity conditions.

Test example 2

The solubility in water (37 ℃ C.) was evaluated for the compound (1), the compound (a) and various salts of the compound (a) obtained in example 1, reference example 1 and comparative example 1.

As a result, as shown in Table 1, the water solubility of the compound (a) was extremely low. On the other hand, the tert-butylamine salt of compound (1) and compound (a) has extremely high water solubility.

[ Table 1]

Example 3

It is clear that crystals having different crystal forms can be obtained by the conditions of examples 1 and 2 at the time of crystallization. The control of the polymorphism is carried out here. The results clearly show that the crystallization temperature, the water content of the aqueous solvent and the stirring time can not control the polymorphism, and the stirring degree can control the crystal form. When the degree of stirring is small (paddle stirring), form II (plate crystal) is formed, and when the degree is large (stirring by a stirrer), form I (needle crystal) is formed.

The crystal form transformation in 10% acetone containing water with stirring by a blade was investigated, and the X-ray diffraction pattern of the obtained powder was measured, and after 3 days, a diffraction peak of 20 ° in 2 θ derived from form I was found, and the proportion thereof was gradually increased with the lapse of the stirring time. From the results, it is considered that the conversion to form I is caused even with stirring with a blade at room temperature.

The powder X-ray diffraction patterns of the form I crystal and the form II crystal are shown in FIG. 4, and the peaks thereof are shown in Table 2.

[ Table 2]

The moisture absorption and desorption properties and water solubility were evaluated for the type I crystal and the type II crystal, respectively, in the same manner as in test examples 1 and 2. The results are shown in fig. 5 and table 3.

[ Table 3]

In addition, the compound (1) of the present invention has an inhibitory activity against VLA-4 equivalent to that of the compound (a).

Claims

1. Trans-4- [1- [2, 5-dichloro-4- [ (1-methyl-1H-3-indolylcarbonyl) amino ] phenylacetyl ] - (4S) -methoxy- (2S) -pyrrolidinylmethoxy ] cyclohexanecarboxylic acid sodium salt 5 hydrate.

2. The compound of claim 1, wherein the compound is in the form of plate crystals.

3. The compound according to claim 1 or 2, wherein said compound is a crystal having characteristic peaks in powder x-ray diffraction at 7.2, 17.3, 18.9, 19.4, 20.4 and 21.6(°) as diffraction angle (2 Θ).

4. The compound of claim 1, wherein the compound is in the form of needle crystals.

5. The compound according to claim 1 or 4, wherein said compound is a crystal having characteristic peaks in powder X-ray diffraction at 7.2, 12.9, 17.3, 18.9, 19.8, 21.6, 26.8 and 30.5(°) as diffraction angles (2 θ).

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a prophylactic or therapeutic agent for a disease caused by cell adhesion.

8. The pharmaceutical composition of claim 7, wherein the disease caused by cell adhesion is a disease selected from the group consisting of inflammatory diseases, autoimmune diseases, cancer metastasis, bronchial asthma, nasal congestion, diabetes, psoriasis, multiple sclerosis, inflammatory bowel disease, and transplant rejection.

9. The pharmaceutical composition of claim 7, wherein the disease caused by cell adhesion is selected from the group consisting of arthritis.

10. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament which is a prophylactic or therapeutic agent for a disease caused by cell adhesion.

11. The use of claim 10, wherein the disease caused by cell adhesion is a disease selected from the group consisting of inflammatory diseases, autoimmune diseases, cancer metastasis, bronchial asthma, nasal congestion, diabetes, psoriasis, multiple sclerosis, inflammatory bowel disease, and transplant rejection.

12. The use according to claim 10, wherein the disease caused by cell adhesion is selected from arthritis.