JP2022120834A - Sjogren's syndrome treatment agent - Google Patents

Abstract

To provide a new treatment agent for Sjogren's syndrome.SOLUTION: A treatment agent for Sjogren's syndrome contains 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octane-1-yl]-3-oxopropanenitrile or a salt thereof.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a therapeutic agent for Sjögren's syndrome.

Sjögren's syndrome is a disease of unknown cause that occurs due to chronic inflammation in exocrine glands such as lacrimal glands and salivary glands, and presents dry symptoms in mucous membranes such as the intraocular and oral cavities. However, treatment of Sjögren's syndrome is still focused on symptomatic treatment aimed at improving symptoms of dryness, and the creation of a radical treatment method is desired (Non-Patent Document 1).

MSD MANUAL Professional Version, Sjogren Syndrome, February 2020, https://www.msdmanuals.com/en-us/professional/musculoskeletal-and-connective-tissue-disorders/autoimmune-rheumatic-disorders/sj%c3%b6gren-syndrome

An object of the present invention is to provide a new therapeutic agent for Sjögren's syndrome.

As a result of intensive studies to solve the above problems, the present inventors have found that 3-[(3S,4R)-3-methyl-6-( 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile (generic name: dergocitinib) is used for Sjögren's symptoms It was found that the infiltration of CD4-positive cells (see Non-Patent Document 1), which is a major finding, is suppressed. The present invention is based on this finding, and provides the following inventions.

[1]
3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]- A therapeutic agent for Sjögren's syndrome containing 3-oxopropanenitrile or a salt thereof.
[2]
3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]- A method for treating Sjögren's syndrome, comprising administering 3-oxopropanenitrile or a salt thereof to a subject.
[3]
3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3 for the production of a therapeutic agent for Sjögren's syndrome .4]octan-1-yl]-3-oxopropanenitrile or its salts.
[4]
3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3 for use in treating Sjögren's syndrome .4]octan-1-yl]-3-oxopropanenitrile or a salt thereof.

According to the present invention, a new therapeutic agent for Sjögren's syndrome can be provided.

1 is a graph showing the effect of suppressing the infiltration of CD4-positive cells in the conjunctiva by repeated eye drop administration of delgocitinib using CAE model mice in Test Example 1. FIG. 2 is a graph showing the effect of suppressing the infiltration of CD4-positive cells in the conjunctiva by repeated eye drop administration of delgocitinib using D-LGE model rats in Test Example 2. FIG.

DETAILED DESCRIPTION OF THE INVENTION Embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

The therapeutic agent for Sjögren's syndrome according to the present embodiment (hereinafter also referred to as the "agent according to the present embodiment") is 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile or a salt thereof.

で表される化合物である（以下、本化合物を「デルゴシチニブ」ともいう）。デルゴシチニブ又はその塩は、例えば国際公開第２０１７／００６９６８号、国際公開第２０１８／１１７１５１号に記載の方法により製造することができる。 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]- 3-Oxopropanenitrile (generic name: delgocitinib) has the formula:

(hereinafter, this compound is also referred to as "dergocitinib"). Delgocitinib or a salt thereof can be produced, for example, by the methods described in WO2017/006968 and WO2018/117151.

The salt of delgocitinib is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with basic amino acids, and the like. .

Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts with organic acids include, for example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid. Salts such as Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts and ammonium salts. Salts with organic bases include, for example, salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine and the like. Salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid and the like. Salts with basic amino acids include, for example, salts with arginine, lysine, ornithine and the like.

The agent according to the present embodiment can be used to treat Sjögren's syndrome, more specifically, to improve various symptoms (dry eyes, dry mouth, etc.) caused by Sjögren's syndrome.

The content of delgocitinib or a salt thereof in the agent according to the present embodiment is not particularly limited, and is appropriately set according to the type and content of other compounding ingredients, formulation form, and the like. The content of delgocitinib or a salt thereof is, for example, 0.001% by mass to 10% by mass, 0.001% by mass, based on the total amount of the agent according to the present embodiment, from the viewpoint of exhibiting the effects of the present invention more remarkably. % to 5% by mass, 0.003% to 3% by mass, 0.005% to 1% by mass, 0.01% to 0.5% by mass, 0.015% to 0.4% by mass, 0 0.02 wt% to 0.3 wt%, or 0.03 wt% to 0.3 wt%. Further, the content of delgocitinib or a salt thereof is, for example, 0.001 w/v% to 10 w/v%, based on the total amount of the agent according to the present embodiment, from the viewpoint of exhibiting the effects of the present invention more remarkably. 0.001 w/v% to 5 w/v%, 0.003 w/v% to 3 w/v%, 0.005 w/v% to 1 w/v%, 0.01 w/v% to 0.5 w/v%, It may be from 0.015 w/v % to 0.4 w/v %, from 0.02 w/v % to 0.3 w/v %, or from 0.03 w/v % to 0.3 w/v %.

Agents according to the present embodiment, in addition to delgocitinib or a salt thereof, excipients, lubricants, binders, disintegrants, coating agents, stabilizers, tonicity agents, buffers, pH adjusters, Solubilizers, thickeners, preservatives, antioxidants, sweeteners, colorants, flavors and the like may also be included.

Formulations of the agent according to the present embodiment include, for example, oral administration formulations such as tablets, capsules, granules, and powders; injections, eye drops, nasal drops, suppositories, ointments, lotions, and creams. preparations for parenteral administration such as agents, gels, sprays, patches, inhalants, and percutaneous absorption preparations. The formulation can be appropriately prepared according to the purpose, for example, by a known method described in the Japanese Pharmacopoeia 17th Edition, General Rules for Pharmaceutical Preparations.

The dosage of the agent according to the present embodiment is the route of administration; the age and sex of the patient; the degree of symptoms, etc., and is appropriately determined. 10 μg to 200 mg, preferably 30 μg to 100 mg, more preferably 50 μg to 75 mg can be administered once or several times a day.

When the agent according to the present embodiment is an eye drop, its usage and dosage are not particularly limited as long as they are effective and have few side effects. Children: 1, 2, 3, 1-2, 1-3, or 2-3 drops once, twice, three times, four times, five times, six times daily , 1 to 2 times, 2 to 3 times, 3 to 4 times, 4 to 5 times, or 5 to 6 times.

An embodiment of the present invention provides a method for treating Sjögren's syndrome, comprising administering delgocitinib or a salt thereof to a subject. Further, as another embodiment of the present invention, use of delgocitinib or a salt thereof for manufacturing a therapeutic agent for Sjögren's syndrome is provided. Further, in another embodiment of the present invention there is provided delgocitinib or a salt thereof for use in treating Sjögren's syndrome.

The present invention will be specifically described below based on test examples, but the present invention is not limited to these. In the following test examples, unless otherwise specified, the content unit "%" means "w/v%" and is synonymous with "g/100 mL".

[Test Example 1: Suppressive effect of infiltration of CD4-positive cells in the conjunctiva by repeated eye drop administration of delgocitinib using CAE model mice]
Controlled Adverse Environment (CAE) model mice have been reported to show some phenotypes of Sjögren's syndrome, such as infiltration of CD4-positive cells into the conjunctiva (J. Immunol., 2006; 176: 3950-3957). . Using this mouse model, the inhibitory effect of delgocitinib on CD4-positive cell infiltration in the conjunctiva was evaluated.
Delgocitinib was dissolved in a borate buffer to prepare delgocitinib 0.03% ophthalmic solution. Also, scopolamine hydrobromide trihydrate (Tokyo Chemical Industry Co., Ltd.) was dissolved in PBS (Kohjin Bio Co., Ltd.) to prepare a 0.167% scopolamine dosing solution.
A CAE model mouse was prepared by subcutaneously administering a scopolamine administration solution to female C57BL/6J mice (Japan SLC, Inc.) for 7 days while rearing them under low-humidity and ventilation conditions. During these 7 days, the vehicle (borate buffer) or delgocitinib 0.03% ophthalmic solution was repeatedly instilled four times a day at a dose of 3 μL/eye.
After that, the eyeball of each mouse was sampled and embedded in an OCT compound (Sakura Fine Tech Japan Co., Ltd.). Frozen sections were prepared and immunostained using an anti-mouse CD4 antibody (Becton Dickinson, Inc.) and Simple Stain Mouse MAX-PRO (Nichirei Corporation). Bright-field imaging of the upper eyelid tissue and lower eyelid tissue was performed on the prepared immunostained slide using a microscope (Keyence Corporation). The total number of stained cells present in each conjunctival lamina propria was measured for the obtained photographed images of the upper and lower eyelids, and the total number was defined as the number of CD4-positive cell infiltration per eye. The results are shown in FIG.

As shown in FIG. 1, compared with untreated mice, the number of CD4-positive cells in the conjunctiva was significantly increased in the CAE model mice administered with the vehicle, whereas the CAE model mice administered delgocitinib 0.03% ophthalmic solution In mice, the increase in the number of CD4-positive cells in the conjunctiva was remarkably suppressed (Student T-test).

[Test Example 2: Suppressive effect of infiltration of CD4-positive cells in the conjunctiva by repeated eye drop administration of delgocitinib using double lacrimal gland enucleation (D-LGE) model rats]
The double lacrimal gland enucleation (D-LGE) model has been reported to exhibit an ocular surface phenotype similar to that of Sjögren's syndrome (Sci.Rep., 2018;8:1483). A D-LGE model was created using rats with reference to this document, and the inhibitory effect of delgocitinib on CD4-positive cell infiltration in the conjunctiva was evaluated.
Delgocitinib was dissolved in a borate buffer to prepare delgocitinib 0.3% ophthalmic solution.
D-LGE model rats were prepared by removing the intraorbital lacrimal glands and extraorbital lacrimal glands from male SD rats. The vehicle (borate buffer) or delgocitinib 0.3% ophthalmic solution was repeatedly administered to the prepared D-LGE model rats at a dose of 5 μL/eye four times a day for 7 days.
After that, the eyeball of each rat was sampled and embedded in an OCT compound (Sakura Fine Tech Japan Co., Ltd.). Frozen sections were prepared and immunostained using an anti-rat CD4 antibody (Becton Dickinson, Inc.) and simple stain rat MAX-PRO (Nichirei Corporation). Bright-field imaging of the upper eyelid tissue was performed on the prepared immunostained slide using a microscope (Keyence Corporation). The total number of stained cells present in the conjunctival lamina propria was measured for the obtained photographed image, and was defined as the number of infiltrating CD4-positive cells per eye. The results are shown in FIG.

As shown in FIG. 2, the number of CD4-positive cells in the conjunctiva was significantly increased in the D-LGE model rats to which the vehicle was administered, compared with the sham-operated rats (Sham group). In D-LGE model rats to which 3% ophthalmic solution was administered, the increase in the number of CD4-positive cells in the conjunctiva was remarkably suppressed (Student T-test).

These results suggest that delgocitinib is effective in Sjögren's syndrome.

Claims (1)

3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]- A therapeutic agent for Sjögren's syndrome containing 3-oxopropanenitrile or a salt thereof.

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