4-methyl dihydropyrimidinone compound and pharmaceutical use thereof
阅读说明：本技术 4-甲基二氢嘧啶酮化合物及其药物用途 (4-methyl dihydropyrimidinone compound and pharmaceutical use thereof ) 是由 坂井孝行 池上拓 于 2019-02-27 设计创作，主要内容包括：本发明涉及具有RORγ拮抗剂活性的4-甲基二氢嘧啶酮化合物或其可药用盐、包含它的药物组合物、以及其药物用途。提供了式(1)或(2)的化合物或其可药用盐、包含它的药物组合物、以及其药物用途。<Image he="167" wi="548" file="DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to a 4-methyldihydropyrimidone compound or a pharmaceutically acceptable salt thereof having an ROR γ antagonist activity, a pharmaceutical composition comprising the samePharmaceutical compositions, and pharmaceutical uses thereof. Provided are a compound of formula (1) or (2) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and a pharmaceutical use thereof.)
1. A compound of formula (1) or (2):
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound is of formula (1):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, wherein the compound is of formula (2):
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A ROR γ antagonist comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
6. A therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
7. A method of antagonizing rory comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
8. A method for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
9. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a ROR γ antagonist.
10. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension and periodontal disease.
11. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use as a rory antagonist.
12. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension and periodontal disease.
Technical Field
The present invention relates to a 4-methyldihydropyrimidone compound or a pharmaceutically acceptable salt thereof having an ROR γ antagonist activity, a pharmaceutical composition comprising the same, and a pharmaceutical use thereof.
Background
ROR γ (i.e., retinoid-related orphan receptor γ) is a nuclear receptor that is important for the differentiation and activation of Th17 cells. ROR γ t is also known as a splice variant of ROR γ (non-patent document 1). ROR γ and ROR γ t differ only in their N-terminal domains and share the same ligand binding domain and DNA binding domain. ROR γ is reported to be expressed in tissues other than Th17 cells (non-patent document 1).
Inhibition of ROR γ may inhibit differentiation and activation of Th17 cells. IL-17 produced in Th17 cells is involved in the induction of various chemokines, cytokines, metalloproteinases and other inflammatory mediators and migration of neutrophils, and therefore, inhibition of IL-17 can lead to inhibition of such induction and migration (non-patent documents 2 and 3). It is known that Th17 cells are involved in autoimmune diseases (such as rheumatoid arthritis, psoriasis, inflammatory bowel disease (such as crohn's disease and ulcerative colitis), multiple sclerosis, Systemic Lupus Erythematosus (SLE), behcet's disease, sarcoidosis, plasmogamia, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, graft-versus-host disease, alopecia areata and vitiligo), allergic diseases, dry eye, fibrosis (such as pulmonary fibrosis and primary biliary cirrhosis) and cancer (such as malignant melanoma and prostate cancer).
ROR γ in adipose tissue is involved in regulation of lipogenesis, and inhibition of ROR γ can improve insulin resistance (non-patent document 4). Adipose tissue is known to be involved in metabolic diseases (e.g., hepatic steatosis).
IL-17 and Th17 cells are also known to be involved in ischemia, cardiomyopathy, hypertension, and periodontitis.
For example, with respect to rheumatoid arthritis, it has been reported that administration of an anti-IL-17 antibody can improve swelling and joint destruction associated with collagen-induced arthritis (non-patent document 5). It has also been reported that swelling and joint destruction associated with collagen-induced arthritis can be improved in an experiment using IL-17 deficient mice (non-patent document 6).
With respect to psoriasis, it has been reported that administration of an anti-IL-17 antibody is effective in treating psoriasis in a clinical trial (non-patent document 7). anti-IL-17 antibodies have been marketed for psoriasis (non-patent document 8).
Regarding inflammatory bowel diseases such as crohn's disease and ulcerative colitis, adaptive transfer of T cells derived from ROR γ -KO mice does not increase IL-17 in the mucosa in a colitis model induced by adaptive transfer of T cells, whereby the onset of colitis can be suppressed (non-patent document 9). It has also been reported that an anti-IL-23 antibody, an antibody against IL-23 that activates Th17 cells, is effective in treating crohn's disease in clinical trials (non-patent document 20).
Regarding multiple sclerosis, the disease state of a mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, can be suppressed in ROR γ -KO mice (non-patent document 10). It has also been reported that an anti-IL-17A antibody can improve the MRI observation result of relapsing-remitting multiple sclerosis in a clinical trial (non-patent document 21).
Regarding systemic lupus erythematosus, it has been reported that administration of an anti-IL-17 antibody can suppress the onset of a GBM nephritis model, which is an animal model of glomerulonephritis, in ROR γ t-KO mice (non-patent document 11). Administration of an anti-IL-17 antibody also potentially inhibits SLE-associated nephritis (non-patent document 12).
With regard to ankylosing spondylitis, it has been reported that administration of an anti-IL-17 antibody is effective in treating ankylosing spondylitis (non-patent document 13).
With respect to uveitis, it has been reported that administration of an anti-IL-17 antibody is effective in treating uveitis associated with behcet's disease, sarcoidosis, and plasmopathy (non-patent document 7).
With respect to polymyalgia rheumatica, the efficacy of anti-IL-17 antibodies is currently evaluated in clinical trials of polymyalgia rheumatica.
With respect to type I diabetes, administration of an anti-IL-17 antibody can inhibit the progression of the disease state in an NOD mouse model, which is a type I diabetes model (non-patent document 14). The efficacy of anti-IL-17A antibodies is currently evaluated in clinical trials (non-patent document 22).
Regarding graft-versus-host disease, it has been reported that transfection of ROR γ -KO-mouse-derived cells can improve survival and rejection in a host in a mouse transplantation model (non-patent document 19).
Regarding alopecia areata, the efficacy of anti-IL-17A antibodies is currently evaluated in clinical trials (non-patent document 25).
Regarding vitiligo, increases in IL-17 and Th17 cells were recognized in the serum and pathological groups of patients, respectively (non-patent document 39).
With respect to allergic diseases such as asthma, decreased eosinophilic pneumonia, decreased CD4+ lymphocyte numbers and decreased Th2 cytokine/chemokine levels were shown in ROR γ -KO mice in an OVA-sensitized model, which could then suppress allergic reactions (non-patent document 15). The efficacy of anti-IL-17A antibodies is currently evaluated in clinical trials of atopic dermatitis (non-patent document 23). The efficacy of anti-IL-23 antibodies is currently evaluated in clinical trials in asthma (non-patent document 24).
Regarding dry eye, it is reported that Th17 cells are increased in animal models of dry eye, and the efficacy of anti-IL-17 antibodies is currently evaluated in clinical trials of dry eye patients (non-patent document 16).
Regarding fibrosis, administration of an anti-IL-17 antibody can suppress inflammation and fibrosis of the lung and prolong the survival of animals in a bleomycin-induced pulmonary fibrosis model, which is an animal model of pulmonary fibrosis (non-patent document 17).
Regarding primary biliary cirrhosis, it has been reported that Th17 cells are increased in lesion regions of patients with primary biliary cirrhosis, and the efficacy of anti-IL-23 antibodies is currently evaluated in clinical trials (non-patent document 18).
Regarding malignant melanoma, the efficacy of anti-IL-17 antibodies is currently evaluated in clinical trials (non-patent documents 26 and 27).
Regarding prostate cancer, it is recognized that anti-IL-17 antibody treatment reduces the development of minimally invasive prostate cancer in Pten-null mice (non-patent document 33).
Regarding insulin resistance, insulin resistance induced by feeding a high-fat diet can be suppressed in ROR γ KO mice (non-patent document 4).
Regarding hepatic steatosis, it is recognized that anti-IL-17 antibodies improve steatosis in pathological tissues in an alcoholic liver disease model (non-patent document 34).
Regarding non-alcoholic fatty liver disease, it is recognized that anti-IL-17 antibody treatment improves liver function, reduces liver lipid accumulation, inhibits kupffer cell activation, and lowers proinflammatory cytokine levels in a high-fat diet-induced non-alcoholic fatty liver disease model (non-patent document 35).
Regarding ischemia and cardiomyopathy, it has been reported that IL-17A promotes myocardial ischemia/reperfusion injury by modulating cardiomyocyte apoptosis and neutrophil infiltration. It is recognized that anti-IL-17A antibody treatment or IL-17A knockout reduces infarct size, improves cardiac function, and thereby improves ischemia/reperfusion injury (non-patent document 36).
Regarding hypertension, it has been reported that treatment with an antibody against IL-17A or IL-17RA suppresses an increase in blood pressure caused by administration of angiotensin II (non-patent document 37).
With respect to periodontitis, an increase in Th17 cells or IL-17 was recognized in an experimental periodontitis model. It has been reported that treatment with ROR γ antagonist, GSK805, or anti-IL-17A antibody reduces bone loss in models (non-patent document 38).
Based on these findings, ROR γ antagonists are considered to be useful for the prevention or treatment of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers (such as malignant melanoma and prostate cancer), metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease.
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Disclosure of Invention
The invention provides a 4-methyl dihydropyrimidinone compound with ROR gamma antagonist activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same and medical application thereof. One aspect of the present invention includes the following illustrative embodiments:
[ item 1]
A compound of formula (1) or (2):
or a pharmaceutically acceptable salt thereof.
[ item 2]
The compound of
or a pharmaceutically acceptable salt thereof.
[ item 3]
The compound of
or a pharmaceutically acceptable salt thereof.
[ item 4]
A pharmaceutical composition comprising a compound according to any one of
[ item 5]
A ROR γ antagonist comprising a compound according to any one of
[ item 6]
A therapeutic or prophylactic agent for a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising a compound according to any one of
[ item 7]
A method of antagonizing rory comprising administering to a mammal a therapeutically effective amount of a compound of any one of
[ item 8]
A method for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of
[ item 9]
Use of a compound according to any one of
[ item 10]
Use of a compound according to any one of
[ item 11]
A compound according to any one of
[ item 12]
A compound according to any one of
[ item 13]
A commercial package comprising the pharmaceutical composition of item 4 and a package insert for the pharmaceutical composition, the insert describing that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease.
[ item 14]
A kit comprising a pharmaceutical composition according to item 4 and a package insert for the pharmaceutical composition describing that the pharmaceutical composition is useful for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension and periodontal disease.
[ item 15]
A crystalline form of a compound of formula (1):
a powder X-ray diffraction pattern is shown having any three or more peaks at diffraction angles (2 θ) measured with CuK α radiation selected from 7.4 ± 0.2 °, 9.9 ± 0.2 °, 10.5 ± 0.2 °, 11.4 ± 0.2 °, 11.6 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 17.4 ± 0.2 °, 18.3 ± 0.2 °, 18.7 ± 0.2 ° and 19.4 ± 0.2 °.
[ item 16]
A monohydrate of a compound of formula (1):
。
[ item 17]
A crystalline form of a monohydrate of a compound of formula (1):
a powder X-ray diffraction pattern is shown having any three or more peaks at diffraction angles (2 θ) measured with CuK α radiation selected from 4.2 ± 0.2 °, 9.7 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 15.2 ± 0.2 °, 15.4 ± 0.2 °, 16.9 ± 0.2 °, 18.8 ± 0.2 °, 20.5 ± 0.2 °, 21.9 ± 0.2 ° and 22.4 ± 0.2 °.
Drawings
[ FIG. 1]
Figure 1 shows the powder X-ray diffraction pattern of form a. The vertical axis shows diffraction intensity (cps: count/second), and the horizontal axis shows diffraction angle 2 θ (°).
[ FIG. 2]
Figure 2 shows a Differential Scanning Calorimetry (DSC) curve of form a. The vertical axis shows heat flow (watts/gram) and the horizontal axis shows temperature (. degree. C.).
[ FIG. 3]
Figure 3 shows a powder X-ray diffraction pattern of form B. The vertical axis shows diffraction intensity (cps: count/second), and the horizontal axis shows diffraction angle 2 θ (°).
[ FIG. 4]
Figure 4 shows the DSC curve for form B. The vertical axis shows heat flow (watts/gram) and the horizontal axis shows temperature (. degree. C.).
[ FIG. 5]
Figure 5 shows a powder X-ray diffraction pattern of form C. The vertical axis shows diffraction intensity (cps: count/second), and the horizontal axis shows diffraction angle 2 θ (°).
[ FIG. 6]
Figure 6 shows the DSC curve for form C. The vertical axis shows heat flow (watts/gram) and the horizontal axis shows temperature (. degree. C.).
[ FIG. 7]
Figure 7 shows a powder X-ray diffraction pattern of form D. The vertical axis shows diffraction intensity (cps: count/second), and the horizontal axis shows diffraction angle 2 θ (°).
[ FIG. 8]
Fig. 8 shows the TG-DTA curve for form D. The upper part of the vertical axis shows weight (g), the lower part of the vertical axis shows temperature (. degree. C.), and the horizontal axis shows temperature (. degree. C.).
[ FIG. 9]
Figure 9 shows the DSC curve for form D. The vertical axis shows heat flow (watts/gram) and the horizontal axis shows temperature (. degree. C.).
[ FIG. 10]
Figure 10 shows a powder X-ray diffraction pattern of form E. The vertical axis shows diffraction intensity (cps: count/second), and the horizontal axis shows diffraction angle 2 θ (°).
[ FIG. 11]
Fig. 11 shows the TG-DTA curve for form E. The upper part of the vertical axis shows weight (g), the lower part of the vertical axis shows temperature (. degree. C.), and the horizontal axis shows temperature (. degree. C.).
[ FIG. 12]
Figure 12 shows the DSC curve for form E. The vertical axis shows heat flow (watts/gram) and the horizontal axis shows temperature (. degree. C.).
Detailed Description
The definitions of the terms used herein are shown below.
The "compound of formula (1)" and the "compound of formula (2)" are optionally also referred to as "compound (1)" and "compound (2)" respectively. "Compound (1) or Compound (2) (,) or a pharmaceutically acceptable salt thereof" means Compound (1) or Compound (2) or a pharmaceutically acceptable salt of Compound (1) or Compound (2), and is intended to include any of the pharmaceutically acceptable salts of Compound (1) and the pharmaceutically acceptable salts of Compound (2).
The term "pharmaceutically acceptable salt" can be any salt known in the art that does not have undue toxicity. Specifically, it includes, for example, a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, and a salt with an organic base. Pharmaceutically acceptable salts in various forms are well known in the art and are listed, for example, in the following references:
(a) berge et al, j. pharm. sci., 66, p1-19 (1977);
(b) stahl et al, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002);
(c) paulekuhn et al, J. Med. chem., 50, p6665-6672 (2007).
Compound (1) or compound (2) may be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base according to a known method to obtain a pharmaceutically acceptable salt of each thereof.
Such salts with inorganic acids include, for example, salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Preferred salts include salts with hydrochloric, nitric, sulfuric, phosphoric and hydrobromic acids.
Such salts with organic acids include, for example, those with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1, 2-disulfonic acid, dodecylsulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylaspartic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis (salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1, 5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, citric acid, benzoic acid, benzenesulfonic acid, Salts of propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theachloric acid (teoclic acid), thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, and glutamic acid. Preferred salts include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-hydroxy-1-ethanesulfonic acid.
Such salts with inorganic bases include, for example, salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, and ammonium. Preferred salts include salts with sodium, potassium, calcium, magnesium and zinc.
Such salts with organic bases include, for example, the salts with arecoline, betaine, choline, clotrimazole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris (hydroxymethyl) methylamine, arginine and lysine. Preferred salts include salts with tris (hydroxymethyl) methylamine, N-methylglucamine and lysine.
The compound (1) or the compound (2) or a pharmaceutically acceptable salt thereof may be present in the form of a solvate.
The term "solvate" refers to compound (1) or compound (2) or a pharmaceutically acceptable salt thereof, coordinated to a solvent molecule, and includes hydrates. Such solvates are preferably pharmaceutically acceptable solvates, and include hydrates, ethanolates and solvates with dimethyl sulfoxide of compound (1) or compound (2) or a pharmaceutically acceptable salt thereof.
Specifically, such solvates include hemihydrate, monohydrate, dihydrate or monoethanol of compound (1) or compound (2), or 2/3 ethoxide of monohydrate or dihydrochloride of hydrochloride of compound (1) or compound (2). Preferred solvates include the monohydrate of compound (1). Such solvates may be obtained according to known methods.
The compound (1) or the compound (2) or a pharmaceutically acceptable salt thereof may be substituted with an isotopic atom such as2H、3H、14C and35s is marked.
For example, any hydrogen atom of the compound (1) or the compound (2) includes protium1H (H), deuterium2H (D) and tritium3H（T）。
The compound (1) or the compound (2) or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound (1) or compound (2) or a pharmaceutically acceptable salt thereof. More preferred is compound (1) or compound (2) or a pharmaceutically acceptable salt thereof having a purity of 80% or more.
Preferred crystalline forms of compound (1) or compound (2) or a pharmaceutically acceptable salt thereof include crystalline forms of compound (1) which exhibit a powder X-ray diffraction pattern having at least 3 peaks, for example at least 3,4 or 5 peaks, at diffraction angles (2 Θ) measured using CuK α radiation of any of 7.4 ± 0.2 °, 9.9 ± 0.2 °, 10.5 ± 0.2 °, 11.4 ± 0.2 °, 11.6 ± 0.2 °, 13.4 ± 0.2 °, 14.2 ± 0.2 °, 17.4 ± 0.2 °, 18.3 ± 0.2 °, 18.7 ± 0.2 ° or 19.4 ± 0.2 °. A more preferred crystalline form of compound (1) may exhibit a powder X-ray diffraction pattern having peaks at 2 θ of 7.4 ± 0.2 °, 9.9 ± 0.2 °, and 13.4 ± 0.2 °. A more preferred crystalline form of compound (1) may exhibit a powder X-ray diffraction pattern having peaks at 2 θ of 7.4 ± 0.2 °, 9.9 ± 0.2 °, 13.4 ± 0.2 °, 18.7 ± 0.2 ° and 19.4 ± 0.2 °.
Another preferred crystalline form of compound (1) or compound (2) or a pharmaceutically acceptable salt thereof includes a crystalline form of a monohydrate of compound (1) which exhibits a powder X-ray diffraction pattern having at least 3 peaks, e.g., at least 3,4, or 5 peaks, at diffraction angles (2 Θ) as measured with CuK α radiation of any of 4.2 ± 0.2 °, 9.7 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 15.2 ± 0.2 °, 15.4 ± 0.2 °, 16.9 ± 0.2 °, 18.8 ± 0.2 °, 20.5 ± 0.2 °, 21.9 ± 0.2 °, or 22.4 ± 0.2 °. A more preferred crystalline form of the monohydrate of compound (1) may exhibit a powder X-ray diffraction pattern having peaks at 2 θ of 4.2 ± 0.2 °, 9.7 ± 0.2 ° and 16.9 ± 0.2 °. A further preferred crystalline form of the monohydrate of compound (1) may exhibit a powder X-ray diffraction pattern having peaks at 2 θ of 4.2 ± 0.2 °, 9.7 ± 0.2 °, 13.7 ± 0.2 °, 15.2 ± 0.2 ° and 16.9 ± 0.2 °.
The error range of the diffraction angle (2 θ) in the powder X-ray diffraction spectrum is preferably ± 0.2 °, more preferably ± 0.1 °, and still more preferably ± 0.05 °.
The pharmaceutical compositions herein can be prepared, for example, by mixing compound (1) or compound (2), or a pharmaceutically acceptable salt thereof, with at least one or more pharmaceutically acceptable carriers in an appropriate amount according to a method known in the art of pharmaceutical formulation. The content of compound (1) or compound (2) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition (also referred to herein as "therapeutically effective amount") varies depending on the dosage form and dose, and is, for example, 0.1 to 100% by weight of the composition.
Dosage forms of compound (1) or compound (2) or a pharmaceutically acceptable salt thereof include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions and suspensions, and parenteral preparations such as external preparations, suppositories, injections, eyedrops, nasal preparations and pulmonary preparations.
The term "pharmaceutically acceptable carrier" includes various conventional organic or inorganic carrier materials used in formulating materials, such as excipients, disintegrants, binders, fluidizers, and lubricants in solid preparations; solvents, solubilizers, suspending agents, tonicity agents, buffers and soothing agents in liquid formulations; and bases (bases), emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, fillers, cosolvents, solubilizers and suspending agents in semisolid formulations. Preservatives, antioxidants, coloring agents or sweeteners may also optionally be used as additives.
Such "excipients" include, for example, lactose, soft sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic.
Such "disintegrants" include, for example, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose and crystalline cellulose.
Such "binders" include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, soft sugar, dextrin, starch, gelatin, sodium carboxymethylcellulose, and gum arabic.
Such "fluidizing agents" include, for example, light anhydrous silicic acid and magnesium stearate.
Such "lubricants" include, for example, magnesium stearate, calcium stearate, and talc.
Such "solvents" include, for example, purified water, ethanol, propylene glycol, polyethylene glycol (macrogol), sesame oil, corn oil, and olive oil.
Such "solubilizers" include, for example, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.
Such "suspending agents" include, for example, benzalkonium chloride, carboxymethyl cellulose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, and glyceryl monostearate.
Such "tonicity agents" include, for example, dextrose, D-sorbitol, sodium chloride and D-mannitol.
Such "buffers" include, for example, sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.
Such "soothing agents" include, for example, benzyl alcohol.
Such "bases" include, for example, water, animal or vegetable oils such as olive oil, corn oil, peanut oil, sesame oil and castor oil, lower alcohols such as ethanol, propanol, propylene glycol, 1, 3-butylene glycol and phenol, higher fatty acids and esters thereof, waxes, higher alcohols, polyols, hydrocarbons such as white petrolatum, liquid paraffin and paraffin, hydrophilic petrolatum, refined lanolin, water-absorbing ointments, lanolin hydrate, hydrophilic ointments, starches, pullulan, gum arabic, tragacanth, gelatin, dextran, cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose, synthetic polymers such as carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol and polyvinyl pyrrolidone, propylene glycol, polyethylene glycols such as
Such "preservatives" include, for example, ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
Such "antioxidants" include, for example, sodium sulfite and ascorbic acid.
Such "colorants" include, for example, food dyes such as food reds nos. 2 and 3, food yellows nos. 4 and 5, and beta-carotene.
Such "sweeteners" include, for example, sodium saccharin, dipotassium glycyrrhizinate, and aspartame.
The pharmaceutical compositions herein may be administered orally or parenterally, such as topically, rectally, intravenously, intramuscularly, and subcutaneously to mammals other than humans, such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, and monkeys, as well as humans. The dosage may vary depending on the subject to be administered, the disease, the symptoms, the dosage form, the route of administration, and the like. For example, in oral administration to an adult patient, the dose (effective ingredient) of compound (1) or compound (2) is usually about 0.01 mg to about 1g per day, which may be administered once or in divided amounts several times.
Kits, such as kits for administration, treatment and/or prevention, packages, such as packaged goods, and kits and/or kits of parts, which comprise a pharmaceutical composition containing compound (1) or compound (2) or a pharmaceutically acceptable salt thereof as an active ingredient or agent and written materials on the composition, are also useful indicating that the composition can or should be used for treatment and/or prevention. Such kits, packages and drug packs may comprise one or more containers containing a pharmaceutical composition or one or more active ingredients and other drugs or drugs (or ingredients) for use in the composition. Examples of such kits, packages and drug panels include commercial kits, commercial packages and commercial drug panels, as appropriate for treating and/or preventing the desired disease. The written material contained in such kits, packages, and groups of drugs includes notes or package inserts, in a form specified by a governmental organization, that regulates the manufacture, use, or sale of pharmaceutical or biological products, which ensures that governmental organization approval for the manufacture, use, or sale of products involving administration to humans is obtained. Kits, packages, and drug panels can include packaged products and structures configured for appropriate administration steps and configured to enable more preferred medical treatment and/or prevention, including treatment and/or prevention of a desired disease.
The compound (1) or the compound (2) or a pharmaceutically acceptable salt thereof has ROR γ antagonistic action and is useful as a ROR γ antagonist.
The term "having ROR γ antagonist activity", "having ROR γ antagonism" or "antagonizing ROR γ" refers to antagonizing, preferably specifically antagonizing, the function of ROR γ to eliminate or reduce its activity, and includes antagonizing, preferably specifically antagonizing, the function of ROR γ, for example, according to the conditions described in test example 1 below.
The term "ROR γ antagonist" refers to any substance that antagonizes the function of ROR γ, preferably any substance that specifically antagonizes the function of ROR γ.
The term "ROR γ" is preferably "human ROR γ".
The compound (1) or the compound (2) or a pharmaceutically acceptable salt thereof has ROR γ antagonistic action, and is expected to be effective against diseases in which a function of ROR γ is involved.
Specifically, the compound (1) or the compound (2) or a pharmaceutically acceptable salt thereof is expected to be useful for the treatment or prevention of a disease selected from the group consisting of an autoimmune disease, an allergic disease, dry eye, fibrosis, cancer, a metabolic disease, ischemia, cardiomyopathy, hypertension and periodontal disease.
The term "autoimmune disease" refers to the general name of a disease in which a subject's immune system overreacts and attacks even normal cells and tissues to cause symptoms, and specifically includes rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as crohn's disease and ulcerative colitis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), behcet's disease, sarcoidosis, plasmosis, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, graft-versus-host disease, alopecia areata, and vitiligo.
The term "allergic disease" refers to a disease originating from a condition in which an excessive immune reaction against a specific antigen occurs, and specifically includes atopic dermatitis, allergic rhinitis such as pollen allergy, allergic conjunctivitis, allergic gastroenteritis, asthma such as bronchial asthma and pediatric asthma, food allergy, drug allergy and urticaria.
The term "fibrosis" refers to a condition of fibrous desmosis and specifically includes pulmonary fibrosis and primary biliary cirrhosis.
The term "cancer" specifically includes malignant melanoma and prostate cancer.
The term "metabolic disease" refers to a disease caused by abnormal metabolic conversion, or a disease including metabolic abnormality as a factor constituting pathogenesis, and includes, for example, diabetes such as type I diabetes and type II diabetes, hepatic steatosis and non-alcoholic fatty liver disease.
The term "treating" as used herein also includes ameliorating symptoms, preventing from becoming severe, maintaining remission, preventing exacerbations, and preventing relapse.
The term "prevention" as used herein refers to inhibition of the pathogenesis of the symptoms.
Compound (1) or compound (2) or a pharmaceutically acceptable salt thereof has the following demonstrated properties:
(i) high metabolic stability, reference test example 2;
(ii) beneficial pharmacokinetic profiles, including a favourable plasma half-life, were determined in reference to test example 5;
(iii) low potential for inducing drug metabolizing enzymes such as CYP3a4, see test example 3;
(iv) advantageously high solubility, see test example 4; and
(v) sustained and/or potential pharmacological effects, see test examples 6 and 7.
These properties make compound (1) or compound (2) or a pharmaceutically acceptable salt thereof particularly advantageous. For example, compound (1) or compound (2) or a pharmaceutically acceptable salt thereof:
(i) exhibit sustained pharmacological effects, which may enable a reduction in dosing frequency or an extension of dosing intervals, which may advantageously affect patient compliance and thereby improve overall treatment outcome;
(ii) exhibit low induction of drug metabolizing enzymes such as CYP3A4, which may result in reduced metabolism of combinations metabolized by such enzymes, and thus the present compounds may be more suitable for patients taking multiple therapeutic drugs simultaneously; and
(iii) may have advantageous oral bioavailability based on high solubility and may thus exhibit a dose-dependent increase in plasma concentration even at high administration amounts and/or exhibit small individual differences during absorption.
Combinations of any two or more of the embodiments disclosed herein are also intended to be included in the invention, provided that the embodiments are compatible with another embodiment disclosed in another part of the specification.
The process for preparing compound (1) or compound (2) or a pharmaceutically acceptable salt thereof is illustrated in the following examples. However, the method for producing compound (1) or compound (2) or a pharmaceutically acceptable salt thereof is not intended to be limited thereto.
If necessary, each compound obtained in each step may be isolated and/or purified by a known method such as distillation, recrystallization and column chromatography, but each reaction may be optionally continued to the sequential steps without isolation and/or purification.
Room temperature herein refers to an uncontrolled temperature and includes, as one embodiment, from 1 ℃ to 40 ℃.