Pharmaceutical composition for preventing / treating ocular complication in chronic graft-versus-host disease

Abstract

The present invention relates to a pharmaceutical composition for preventing / treating an ocular complication in cGVHD, the composition containing, as an active ingredient, (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by formula (1) or an acid addition salt thereof, or a solvate of the compound or the acid addition salt.

Description

Pharmaceutical composition for the prevention and treatment of ocular complications in chronic graft-versus-host disease

[0001] The present invention relates to a pharmaceutical composition for preventing and treating ocular complications in chronic graft-versus-host disease (cGVHD).

[0002] In recent years, hematopoietic stem cell transplants, such as bone marrow transplants, have become increasingly common as a treatment for hematologic disorders caused by abnormalities in hematopoietic stem cells, such as leukemia and severe aplastic anemia. While the success rate of hematopoietic stem cell transplants has increased and the number of long-term survivors has increased, cGVHD, a late-stage complication following transplantation, has become a problem (see Non-Patent Document 1). cGVHD is a systemic immune response caused by donor-transplanted hematopoietic stem cells maturing within the host, and can affect a wide range of tissues and organs, including the eyes, mouth, kidneys, lungs, liver, small intestine, and skin. Despite the usual administration of immunosuppressants, more than half of transplant patients develop cGVHD, making prevention and treatment of cGVHD extremely important after hematopoietic stem cell transplantation. While cGVHD can affect a variety of tissues and organs, ocular symptoms (ocular complications) include dry eye, meibomian gland dysfunction, retinal hemorrhage, and acute conjunctivitis, with dry eye being the most common. Hematopoietic stem cell transplantation is a new treatment, and therefore the mechanism of onset of cGVHD, a late complication after transplantation, has not been fully elucidated. Regarding the ocular complications mentioned above, pathological analysis of lacrimal gland tissue has revealed that activation of immune cells such as T cells and lymphocytes in the lacrimal gland, followed by repair mechanisms, is observed locally. Therefore, it is believed that the core of the pathology is excessive fibrosis of the lacrimal gland due to interactions in the immune network, but many aspects remain unclear.

[0003] Currently, treatments for ocular complications associated with cGVHD include the immunosuppressant FK506 (ophthalmic ointment or oral medication) and steroid eye drops, which are immunomodulators. However, immunosuppressants have many problems with long-term administration, and steroid eye drops are difficult to use for long periods of time due to concerns about side effects such as increased intraocular pressure and cataracts. Therefore, it is common to discontinue administration of these drugs after a certain period and switch to symptomatic treatments. While such symptomatic treatments include eye drops containing hyaluronic acid preparations, vitamin A, and steroids, as well as serum eye drops and artificial tears, their effectiveness is not always sufficient, and new drugs that are highly effective and can be used continuously are desired. Ocular complications associated with cGVHD develop in approximately half of hematopoietic stem cell transplant patients. Furthermore, once they develop, they are generally difficult to treat, and in approximately half of patients, the condition worsens within a short period of approximately three months (see, for example, Non-Patent Document 2). Therefore, in treatment after hematopoietic stem cell transplantation such as bone marrow transplantation, it is important to prevent the onset of ocular complications in cGVHD, as well as to improve symptoms after onset and prevent them from becoming more severe, and there is a strong demand for methods and drugs for this purpose.

[0004] Rho kinase (ROCK) is a serine-threonine protein kinase identified as a target protein of the small GTP-binding protein Rho. It exists in two isoforms, ROCK1 and ROCK2, which share over 90% homology at the ATP-binding site. ROCK is involved in various important physiological functions, such as cell contraction, proliferation, migration, and gene expression induction. In recent years, ROCK has attracted attention as a target enzyme for therapeutic drugs for diseases such as cardiovascular disease, glaucoma, neurodegenerative diseases, and cancer, and several ROCK inhibitors have been clinically applied to date (Non-Patent Document 3). Belmosudil, among others, is used as a therapeutic agent for cGVHD, but its therapeutic effect on dry eye when administered by eye drop is unknown. Similarly, the ROCK inhibitor ripasudil is clinically used as an eye drop for the treatment of glaucoma, but its therapeutic effect on the aforementioned ocular complications is unknown. (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline is represented by the following formula (1):

[0005]

[0006] and Patent Document 1 discloses that it is useful as an active ingredient of a medicine for preventing or treating glaucoma, cardiovascular disease, or diseases or disorders caused by neurodegeneration or nerve damage. However, nothing is known about its preventive or therapeutic effect on ocular complications in cGVHD after hematopoietic stem cell transplantation.

[0007] WO 2010 / 146881

[0008] Yoko Ogawa, Ophthalmology, 2003, Volume 45, p. 309-322 Yoko Ogawa, 11 others, Br. J. Ophthalmol. , 1999, Vol. 83, p. 1125-1130J. Med. Chem. 2016, 59, 2269-2300

[0009] An object of the present invention is to provide a pharmaceutical composition for preventing and treating ocular complications in cGVHD.

[0010] The present inventors investigated the enzyme inhibitory effects of Compound 1 on ROCK1 and ROCK2, and found that Compound 1 exhibited IC 50 Furthermore, while investigating the pharmacological effects based on the ROCK inhibitory activity, the inventors discovered that Compound 1, when administered by eye drop, has the effect of improving ocular complications in cGVHD model mice, and thus completed the present invention.

[0011] That is, the present invention provides the following inventions [1] to [8]. [1] A compound represented by the following formula (1):

[0012]

[0013] [2] The pharmaceutical composition according to [1], wherein the composition is in the form of an eye drop composition. [3] A pharmaceutical composition for preventing and treating ocular complications in cGVHD, comprising (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by the following formula (1):

[0014]

[0015] [4] The compound according to [3], wherein the pharmaceutical form is eye drops. [5] A compound according to the following formula (1) for the manufacture of a preventive or therapeutic agent for ocular complications in cGVHD:

[0016]

[0017] [6] Use of (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline, its acid addition salt, or a solvate thereof, represented by the following formula (1):

[0018]

[0019] [8] A method for preventing or treating ocular complications in cGVHD, comprising administering (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by the formula:

[0020] According to the present invention, a pharmaceutical composition for preventing and / or treating ocular complications in cGVHD can be provided.

[0021] Figure 1 shows the GVHD scores for the 0.5% Compound 1 (H-1129) group, vehicle group, and control group. Figure 2 shows the tear volume measured by the cotton thread method for the 0.5% Compound 1 (H-1129) group, vehicle group, and control group. Figure 3 shows the effect on Snail-positive cells, a major transcription factor indicating epithelial-mesenchymal transition, for the 0.5% Compound 1 (H-1129) group, vehicle group, and control group. Figure 4 shows the effect on eyelid fibrosis for the 0.5% Compound 1 (H-1129) group, vehicle group, and control group.

[0022] Terms used in this specification are used in the sense commonly used in the art unless otherwise specified.

[0023] The terms "contain" or "comprise" as used herein include "consist of," "consist essentially of," and "may further contain other ingredients." Furthermore, "as an active ingredient" means that the relevant ingredient is contained as an active ingredient, and does not preclude the inclusion of ingredients other than this ingredient. Furthermore, "prophylaxis and treatment" includes all of prevention, treatment, and prevention and treatment.

[0024] Graft-versus-host disease (GVHD) as used herein is one of the complications associated with hematopoietic stem cell transplants, such as organ transplants and bone marrow transplants, and is a general term for symptoms caused by the donor's organ attacking the recipient's organ through an immune response. GVHD includes acute GVHD, which develops approximately one to two weeks after transplantation, and chronic GVHD, which occurs regardless of the time of onset after transplantation, known as overlap syndrome, in which both conventional chronic GVHD (cGVHD) and acute GVHD coexist. In the present invention, cGVHD is preferably the target.

[0025] cGVHD develops in a variety of tissues and organs, and ocular complications of cGVHD include dry eye, meibomian gland dysfunction, retinal hemorrhage, acute conjunctivitis, etc. The present invention targets all of these ocular complications, but since dry eye is the most frequent of these ocular complications, it is particularly preferable to target dry eye.

[0026] One aspect of the present invention is a pharmaceutical composition for preventing or treating ocular complications in cGVHD, which comprises, as an active ingredient, (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by formula (1) (hereinafter also referred to as "Compound 1"), an acid addition salt thereof, or a solvate of the same.

[0027] Compound 1, which is the active ingredient of the pharmaceutical of the present invention, is a compound described in Patent Document 1, and is known to be effective for glaucoma, cardiovascular disease, or diseases or disorders caused by neurodegeneration or nerve damage, but its preventive or therapeutic effect on ocular complications in cGVHD is not known.

[0028] Compound 1 can be produced by the method described in Patent Document 1, and can also be used in the form of an acid addition salt or a solvate thereof. Examples of acids that form acid addition salts include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, and salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid. Examples of solvates include hydrates and ethanol solvates.

[0029] As shown in the Examples below, Compound 1 has the effect of reducing increased tear secretion and eyelid tissue fibrosis, which are symptoms of ocular complications in cGVHD, and is useful as a preventive / therapeutic drug for ocular complications in cGVHD, particularly as a preventive / therapeutic drug for dry eye in cGVHD. Furthermore, since Compound 1 has the effect of reducing eyelid tissue fibrosis by inhibiting epithelial-mesenchymal transition, it is also useful for the preventive / therapeutic treatment of meibomian gland dysfunction in cGVHD.

[0030] The pharmaceutical composition of the present invention contains Compound 1, an acid addition salt thereof, or a solvate thereof as an active ingredient, and may contain a pharmaceutically acceptable carrier suitable for the form of the composition (administration form).

[0031] The pharmaceutical composition of the present invention may be administered orally or parenterally, preferably by eye drops, eye ointment, or subconjunctival injection. Dosage forms include tablets, capsules, granules, powders, injections, eye drops, and eye ointments, with eye drops, eye ointments, and injections being preferred.

[0032] For example, oral preparations such as tablets, capsules, granules, and powders can be prepared by combining Compound 1, as needed, with excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, and calcium hydrogen phosphate; lubricants such as stearic acid, magnesium stearate, and talc; binders such as starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone; disintegrants such as carboxymethylcellulose, low-substituted hydroxypropyl methylcellulose, and calcium citrate; coating agents such as hydroxypropyl methylcellulose, macrogol, and silicone resin; stabilizers such as ethyl parahydroxybenzoate and benzyl alcohol; and flavorings such as sweeteners, acidulants, and fragrances.

[0033] In addition, parenteral preparations such as eye drops and injections may contain, for example, isotonic agents such as glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, and mannitol; buffers such as phosphoric acid, phosphate salts, citric acid, glacial acetic acid, ε-aminocaproic acid, and trometamol; pH adjusters such as hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate; solubilizers or dispersants such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, purified soybean lecithin, and polyoxyethylene (160) polyoxypropylene (30) glycol; Cellulose-based polymers such as methylcellulose and hydroxypropylcellulose, thickeners such as polyvinyl alcohol and polyvinylpyrrolidone, stabilizers such as edetic acid and sodium edetate, preservatives or antiseptics such as commonly used sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol, and soothing agents such as chlorobutanol, benzyl alcohol, and lidocaine can be combined with Compound 1 as needed to prepare the ointment, and the pH is preferably set to 4.0 to 8.0, and the osmotic pressure ratio is preferably set to around 1.0. Eye ointments can also be formulated using commonly used bases such as white petrolatum and liquid paraffin as needed.

[0034] The dosage can be selected appropriately depending on symptoms, age, dosage form, etc. For example, oral preparations can be administered at a dose of typically 0.01 to 1000 mg, preferably 1 to 100 mg, per day, once or several times a day. In the case of eye drops, a concentration of typically 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v), can be administered once or several times a day. In the case of injections, a concentration of typically 0.0001 mg to 1000 mg / mL can be administered once or several times a day. In the case of eye ointments, a concentration of typically 0.01% to 10% (w / w), preferably 0.1% to 5% (w / w), can be administered once or several times a day.

[0035] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0036] (Test Example 1) <Evaluation of ROCK Inhibitory Effect> Using various concentrations of Compound 1, the concentration at which the phosphorylation reaction of a substrate by ROCK1 or ROCK2 is inhibited by 50% in vitro (hereinafter referred to as "IC 50 The results are shown in Table 1.

[0037]

[0038] <Evaluation of the effect of improving ocular complications using a cGVHD animal model> Using a cGVHD model mouse, we evaluated whether drug administration improves ocular complications associated with cGVHD. Mice were created using the following method. Bone marrow transplants were performed between allogeneic mice aged 7-9 weeks. Specifically, male B10.D2 mice were used as donors and female BALB / c mice as recipients. This transplant was a major histocompatibility complex (MHC)-matched, minor histocompatibility antigen (MiHA)-mismatched hematopoietic stem cell transplant. As a control, a non-cGVHD model was also created, and this model underwent allogeneic hematopoietic stem cell transplantation (both donor and recipient mice were BALB / c mice). The transplantation method involved irradiating the recipient with 7 Gy of radiation, followed by 1 × 106 bone marrow cells and 2 × 10 6 Each spleen cell was dissolved in 0.1 mL of RPMI solution and loaded into the same syringe, and a total of 0.2 mL was administered via the tail vein. These transplants were performed in a specific pathogen-free (SPF) environment, and all experimental animals were provided with sterilized water and food in the same manner. cGVHD model mice and non-cGVHD model mice were analyzed 4 weeks after transplantation. GVHD model mice were divided into a treatment group (hereinafter referred to as the H-1129 group) that received Compound 1 (concentration: 0.02%-0.5%) by eye drop administration and a vehicle group that received phosphate-buffered saline (PBS) placebo by eye drop administration. These two groups were compared with a control group of non-GVHD mice that received PBS placebo by eye drop administration. Eye drop administration was performed from the day before transplantation until day 27 after transplantation, and on the final day, systemic GVHD scores and tear volume measurements were performed using the cotton thread method. The mice were dissected 28 days after transplantation, and the eyelids, eyeballs and lacrimal glands were examined histopathologically.

[0039] The 0.5% Compound 1 (H-1129) and vehicle groups had significantly higher GVHD scores than the control group, indicating the development of chronic GVHD (Figure 1). Tear secretion volume was significantly higher in the 0.5% Compound 1 (H-1129) group (3.42 ± 0.41 mm3) than in the vehicle group (2.09 ± 0.29 mm3) (p < 0.001), demonstrating an improvement (Figure 2). Compared with the vehicle group, the 0.5% Compound 1 (H-1129) group showed improvement in eyelid fibrosis and fewer Snail-positive cells, a key transcription factor indicative of epithelial-mesenchymal transition (EMT) (Figures 3 and 4).

[0040] These results suggest that Compound 1 has a ROCK inhibitory effect and ameliorates ocular complications associated with cGVHD, particularly dry eye symptoms. Furthermore, Compound 1 reduces eyelid tissue fibrosis by inhibiting epithelial-mesenchymal transition. This effect is not only the mechanism by which dry eye symptoms are improved, but also suggests that Compound 1 may be useful for the prevention and treatment of other ocular complications, such as meibomian gland dysfunction.

[0041] (Formulation Example 1) Eye drops (in 100 mL) Compound 1 0.5 g Sodium dihydrogen phosphate hydrate 0.6 g Disodium hydrogen phosphate hydrate 1.4 g Benzalkonium chloride 0.01 g Sodium chloride 0.3 g Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount

[0042] (Formulation Example 2) Eye drops (in 100 mL) Compound 1 0.5 g Boric acid 0.2 g Concentrated glycerin 0.25 g Benzalkonium chloride 0.005 g Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount

[0043] (Formulation Example 3) Eye drops (in 100 mL) Compound 1 0.5 g Sodium edetate 0.05 g Concentrated glycerin 2.0 g Benzalkonium chloride 0.005 g Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount

[0044] (Formulation Example 4) Eye drops (in 100 mL) Compound 1 0.5 g Sodium dihydrogen phosphate 0.8 g Sodium chloride 0.5 g Benzalkonium chloride 0.005 g Sodium hydroxide appropriate amount Purified water appropriate amount

Claims

1. The following formula (1) The present invention relates to a pharmaceutical composition for preventing and treating ocular complications in cGVHD, comprising as an active ingredient (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by the following formula:

2. The pharmaceutical composition according to claim 1, wherein said composition is in the form of an eye drop composition.

3. A compound represented by the following formula (1) for preventing and treating ocular complications in cGVHD: The present invention relates to (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by the following formula:

4. The compound according to claim 3, wherein the pharmaceutical form is eye drops.

5. For the manufacture of a preventive and therapeutic drug for eye complications in cGVHD, Use of (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by the following formula:

6. The use according to claim 5, wherein the pharmaceutical form is eye drops.

7. The following formula (1) A method for preventing and treating ocular complications in cGVHD, comprising administering (R)-6-(2-methyl-1,4-diazocan-1-ylsulfonyl)isoquinoline represented by the following formula:

8. The method of claim 7, wherein said administration means is an eye drop.

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