WO2023003416A1 - 전신경화증의 예방 또는 치료용 약학적 조성물 - Google Patents
전신경화증의 예방 또는 치료용 약학적 조성물 Download PDFInfo
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- WO2023003416A1 WO2023003416A1 PCT/KR2022/010751 KR2022010751W WO2023003416A1 WO 2023003416 A1 WO2023003416 A1 WO 2023003416A1 KR 2022010751 W KR2022010751 W KR 2022010751W WO 2023003416 A1 WO2023003416 A1 WO 2023003416A1
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- systemic sclerosis
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- skin
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- the present invention is to provide a pharmaceutical composition for preventing or treating systemic sclerosis.
- Systemic sclerosis is a degenerative disease that causes thickening (thickening) or hardening (hardening) of skin, blood vessels, and internal organs, and belongs to autoimmune rheumatic diseases. The disease is chronic and can progress over a long period of time. Although the cause of systemic sclerosis has not yet been identified, there are reports that certain chemicals (toluene, benzene, vinyl chloride, silica, etc.) are also related to the onset, and the diagnosis is made by combining the medical history, physical examination, biopsy, and blood test. Upper and lower gastrointestinal tract examination, X-ray examination, lung function examination, electrocardiogram, echocardiography, etc. can confirm the degree of internal damage to the organ.
- Systemic sclerosis generally has a good prognosis, but can be life-threatening if it metastasizes to the lungs, kidneys, or heart. Interstitial lung disease and pulmonary arterial hypertension may progress, resulting in dyspnoea, and renal crisis accompanied by severe hypertension.
- Systemic sclerosis is a type of autoimmune disease caused by errors in the internal immune system. Systemic sclerosis is treated at the Department of Rheumatology and treated to improve various symptoms caused by autoimmune inhibition. Systemic sclerosis is broadly classified into limited or diffuse cutaneous systemic sclerosis according to the degree of skin involvement. Some patients with systemic sclerosis have immunoregulatory disorders and symptoms of systemic sclerosis-associated lung disease (SSc-ILD). . Systemic sclerosis-associated pulmonary disease is more commonly observed in diffuse systemic sclerosis. In addition, 25 to 30% of these patients develop progressive SSc-ILD, which is known as the main cause of death in patients with systemic sclerosis (Lancet, 2017; 390:1685-1699).
- SSc-ILD systemic sclerosis-associated lung disease
- Systemic sclerosis-associated lung disease is a respiratory disease that occurs in patients with systemic sclerosis, and is treated at the Department of Pulmonary Medicine to improve lung function.
- Systemic sclerosis-related lung disease is highly associated with early mortality in patients with systemic sclerosis, and as a result of a survey in the United States, the mortality rate due to pulmonary fibrosis in patients with systemic sclerosis increased more than fivefold, from 6% to 33% in approximately 20 years, resulting in interstitial lung disease. Disease became the most frequent cause of systemic sclerosis-related deaths, and EULAR research revealed that it affects the mortality rate of more than 35% of systemic sclerosis patients. (Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66:940-4)
- Risk factors for development or progression of interstitial lung disease in patients with systemic sclerosis include presence of diffuse cutaneous systemic sclerosis (dcSSc), African American, age at onset (elderly age), shorter duration of disease, and anti-Scl-70 It develops when the conditions for developing interstitial lung disease are fulfilled for various reasons that have not yet been identified, such as the absence of anti-topoisomerase I antibodies and anti-centromere antibodies.
- dcSSc diffuse cutaneous systemic sclerosis
- African American age at onset (elderly age)
- shorter duration of disease such as the absence of anti-topoisomerase I antibodies and anti-centromere antibodies.
- anti-Scl-70 anti-Scl-70
- systemic sclerosis-related lung diseases are derived from patients with systemic sclerosis, but show significant differences in various cytokines in the blood and various biomarkers such as IGFBP-1, MMP-9, and H3.1. It is thought that the disease characteristics of the patients show differences.
- biomarkers such as IGFBP-1, MMP-9, and H3.1.
- MMP-7 and MMP-9 are specifically increased in blood in patients with systemic sclerosis-related lung disease than in patients with systemic sclerosis is the reason for the occurrence of lung fibrosis and 1/3 of patients with systemic sclerosis-related lung disease. It is not only evidence supporting rapid and high mortality, but also interpreted as evidence for distinguishing systemic sclerosis-related lung disease and systemic sclerosis clinically as well as pathologically ((i) Clin Epigenetics. 2020 Aug 17;12(1) :124, (ii) Sarcoidosis Vasc Diffuse Lung Dis. 2015 Sep 14;32(3):228-36, (iii) European Respiratory Journal 2021 58: 2101560).
- NSAIDs Nonsteroidal anti-inflammatory drugs
- Ca channel blockers can relieve the symptoms of Raynaud's phenomenon, but can cause gastrointestinal problems.
- Corticosteroids can alleviate symptoms of myositis, alleviate pulmonary inflammation through immunosuppressive drugs, and alleviate acute kidney damage and elevated blood pressure through high blood pressure drugs. .
- Neintedanib and Actemra® (tocilizumab) have been approved for the treatment of systemic sclerosis-associated lung disease.
- Nintedanib is known to improve lung function in patients with pulmonary fibrosis as a treatment for idiopathic pulmonary fibrosis.
- nintedanib is only effective in improving pulmonary fibrosis and failed to prove its therapeutic effect on scleroderma, it is prescribed only as an adjuvant treatment to improve lung function in patients with end-stage systemic sclerosis-related lung disease accompanied by progressive interstitial lung disease.
- Tocilizumab is an immunosuppressant for the treatment of rheumatoid arthritis and is known to alleviate the symptoms of rheumatoid disease.
- tocilizumab has not been proven to alleviate/improve fibrosis, so it is used as a prophylactic adjuvant treatment for patients with early-stage systemic sclerosis-related lung disease in which severe lung function impairment has not yet occurred.
- both licensed drugs do not provide a fundamental therapeutic effect to patients with systemic sclerosis as well as lung disease accompanied by systemic sclerosis, so they are not prescribed as first-line treatment, and patients are still treated with immunosuppressive drugs with severe side effects such as cyclophosphamide and mycophenolate. should depend on
- PRS prolyl-tRNA synthetase
- ARS aminoacyl-tRNA synthetase family of enzymes, and serves to activate amino acids for protein synthesis. That is, ARS performs a translational function of moving an activated amino acid to the 3-terminus of the corresponding tRNA after forming aminoacyl adenylate (AA-AMP). Since ARS plays a key role in protein synthesis, ARS inhibition inhibits the growth and growth of all cells. Accordingly, ARS is recognized as a promising target for antibiotics or disease treatments that require inhibition of cell overexpression (Nature, 2013, 494: 121-125).
- PRS exists and functions as a multisynthetase complex (MSC) in the form of EPRS (Glutamyl-Prolyl-tRNA Synthetase).
- MSC multisynthetase complex
- EPRS Glutamyl-Prolyl-tRNA Synthetase
- VEGF A vascular endothelial growth factor A
- angiogenesis a key factor in angiogenesis
- the present invention is to provide a pharmaceutical composition that can be usefully used for the prevention or treatment of systemic sclerosis.
- the present invention provides a pharmaceutical composition for preventing or treating systemic sclerosis as follows:
- a pharmaceutical composition for preventing or treating systemic sclerosis comprising a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof:
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is a compound described in Korean Patent Registration No. 10-2084772, and is specifically a material described in Example 40 of the specification.
- the pharmaceutical composition according to the present invention can be usefully used for preventing or treating systemic sclerosis associated interstitial lung disease (SSc-ILD).
- SSc-ILD systemic sclerosis associated interstitial lung disease
- the pharmaceutical composition according to the present invention has dual effects of alleviating skin sclerosis and improving lung function in systemic sclerosis-related lung diseases.
- improved lung function used in the present invention means that the ability to supply blood to the body, which is a substantial basic function of the lung, is improved, which is not an effect that naturally follows from the improvement of lung fibrosis, and, apart from the lung fibrosis index, oxygen saturation in the body is also improved. can be checked through
- prevention refers to any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administration of the composition of the present invention
- treatment refers to the disease by administration of the composition of the present invention. means any action that improves or beneficially changes the symptoms of
- the compound represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
- a pharmaceutically acceptable salt formed by a pharmaceutically acceptable free acid
- inorganic acids and organic acids can be used as the free acid.
- Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. can be used as an inorganic acid
- citric acid, acetic acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid, or aspartic acid can be used as an organic acid.
- the pharmaceutically acceptable salt of the compound represented by Formula 1 is a hydrochloride salt.
- the compound represented by Formula 1 may be prepared in a crystalline form or an amorphous form, and when prepared in a crystalline form, it may be optionally hydrated or solvated.
- compounds containing various amounts of water may be included as well as stoichiometric hydrates of the compound represented by Formula 1.
- Solvates of the compound represented by Formula 1 include both stoichiometric solvates and non-stoichiometric solvates.
- compositions of the present invention may be formulated for oral or parenteral administration according to standard pharmaceutical practice. These formulations may contain additives such as pharmaceutically acceptable carriers, adjuvants, or diluents in addition to active ingredients.
- Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil and isopropyl myristate, and diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or or glycine, but is not limited thereto.
- the compounds of the present invention can be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injection solutions.
- the compounds of the present invention may be formulated as ointments or creams.
- compositions of the present invention may be used in the form of pharmaceutically acceptable salts or solvates thereof, and may also be used alone or in combination with other pharmacologically active compounds as well as in a suitable set.
- the pharmaceutical composition according to the present invention may further contain other active ingredients used for the prevention or treatment of systemic sclerosis. Examples of such other active ingredients include Ofev® (Nintedanib) or Actemra® (tocilizumab).
- the pharmaceutical composition according to the present invention further includes other active ingredients, the weight ratio of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to the other active ingredients is 1:0.1 to 1: 10 is preferred.
- the compounds of the present invention are formulated as injections by dissolving, suspending or emulsifying the compounds in aqueous solvents such as saline, 5% dextrose or non-aqueous solvents such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol. It can be.
- aqueous solvents such as saline, 5% dextrose or non-aqueous solvents such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol. It can be.
- the formulation of the present invention may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
- composition according to the present invention may be administered via an oral or parenteral route.
- the composition according to the present invention may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition of the present invention can be administered to mammals including rats, mice, livestock and humans through various routes. All modes of administration can be envisaged, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine or intracerebroventricular injection.
- the pharmaceutical composition according to the present invention can be usefully used for preventing or treating systemic sclerosis.
- Figure 2 shows the result of confirming the skin thickness of the systemic scleroderma skin organoid transplanted mouse model through immunochemical staining in Experimental Example 2 of the present invention.
- FIG. 3 shows the results of confirming the fibrosis factors Collagen I, Collagen III, and ⁇ SMA of the skin tissue of the systemic scleroderma skin organoid transplanted mouse model in Experimental Example 2 of the present invention through immunochemical staining.
- Figure 5 in Experimental Example 3-1 of the present invention, shows the result of the weight change of the mouse.
- Figure 6 in Experimental Example 3-2 of the present invention shows the results of changes in lung weight of mice.
- Figure 9 shows the results of measuring the collagen content in the body of mice in Experimental Examples 3-5 of the present invention.
- a 3D skin organoid was prepared using iPSC-derived fibroblasts from a patient with systemic scleroderma according to the method described in the literature (Lancet. 2009 Nov 21;374(9703):1745-53), and 1 uM of the active ingredient was treated with a DMSO solution. When, it was confirmed through H&E immunochemical staining that the thickness of the 3D skin organoid was reduced (Fig. 1). The control group was treated only with DMSO.
- a systemic scleroderma mouse model was established by transplanting the 3D skin organoid derived from systemic scleroderma patient iPSCs constructed above to SCID mice. After cutting the mouse skin tissue into 1 x 2 cm, the 3D skin organoid skin tissue was sutured to the mouse skin. Skin transplantation was performed on the back of mice using the tie-over dressing method used clinically. After putting gauze on the suture site, it was tied with a suture and dressed with a band.
- Systemic sclerosis-associated lung disease model was designed by injecting an osmotic pump. For that reason, if it is not a modeling using an osmotic pump, it is a model in which BLM is subcutaneously injected into the back of a test animal every day for 4 weeks, and this test can cause very severe pain at the injection site.
- the drug administration rate using the osmotic pump was 0.5 ul/hr (7 days), and the size of the osmotic pump was 1.5 cm.
- This pulmonary function evaluation is an experiment to show the therapeutic effect of this active substance in patients with systemic sclerosis-related lung disease. It is the most direct and important evaluation index that has the greatest impact on This is an experiment that can most directly show the effect of improving lung function in an animal model of systemic sclerosis-related lung disease by measuring the oxygen concentration in the body.
- SpO2 was measured using an SpO2 measuring device (Berry, Veterinary Pulse Oximeter) through the ventral side of the mouse. The results are shown in FIG. 7 .
- 1 ml dye was added to 100 ul of the prepared sample and mixed for 30 minutes. After centrifugation at 12,000 rpm for 10 minutes, it was transferred to a new tube. Dye was removed with 750 ul of ice-cold Acid-Salt Wash Reagent. After centrifugation at 12,000 rpm for 10 minutes, it was transferred to a new tube. The tube was mixed with the collagen-binding dye solution using a vortex mixer, the collagen-binding dye was dissolved within 10 minutes, and measurement preparation was completed (the measurement should be completed within 2 to 3 hours). The tubes were capped until ready to measure absorbance.
- the active ingredient of the present invention exhibited two completely different effects of treating systemic sclerosis and improving inhibition of lung function in systemic sclerosis-related pulmonary disease. This dual effect is an unpredictable part through a therapeutic effect on any one, and is identified as a characteristic of the active substance of the present invention.
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Abstract
Description
동물수 (마리) |
투여경로(Osmotic pump) | 투여경로(경구) | |||||
시험군 | 투여 물질 | 투여량 (U/kg) |
투여액량 (㎕) |
투여 물질 | 투여량 (mg/kg) |
투여액량 (㎕) |
|
G1 | 9 | Saline | - | 100 | Saline | - | 100 |
G2 | 9 | BLM | 100U/kg | 100 | Saline | - | 100 |
G3 | 9 | BLM | 100U/kg | 100 | Nintedanib | 60 | 100 |
G4 | 9 | BLM | 100U/kg | 100 | 활성 성분 | 3 | 100 |
G5 | 9 | BLM | 100U/kg | 100 | 활성 성분 | 10 | 100 |
G6 | 9 | BLM | 100U/kg | 100 | 활성 성분 | 30 | 100 |
Saline | BLM | 활성성분 (3 mg/kg) |
활성성분 (10 mg/kg) |
활성성분 (30 mg/kg) |
NIN | |
1 | 16.94 | -0.73 | 8.65 | 0.48 | 9.52 | 2.46 |
2 | 16.1 | -1.15 | 3.02 | 0.14 | 5.35 | 4.14 |
3 | 17.47 | -1.19 | -0.36 | 4.88 | -2.86 | 1.78 |
4 | 11.99 | -5.16 | 1.07 | 4.78 | 7.57 | 4.49 |
5 | 10.58 | -4.1 | -2.45 | 4.62 | 12.09 | -0.45 |
6 | 7.85 | -5.9 | -2.14 | 2.54 | 7.78 | 0.58 |
7 | 8.63 | -0.75 | 1.34 | 1.96 | 2.13 | 8.79 |
8 | 13.47 | -4 | -0.33 | -4.1 | 2.34 | 0.44 |
9 | 12.59 | -2.17 | -1.93 | -2.48 | 1.45 | -2.94 |
Saline | BLM | 활성성분 (3 mg/kg) |
활성성분 (10 mg/kg) |
활성성분 (30 mg/kg) |
NIN | |
1 | 0.8 | 1.03 | 1.14 | 1.16 | 0.94 | 0.99 |
2 | 0.8 | 1.05 | 0.98 | 0.99 | 0.98 | 0.98 |
3 | 0.8 | 1.14 | 1.15 | 0.93 | 1.09 | 1.16 |
4 | 0.8 | 1.19 | 0.92 | 1.08 | 0.97 | 0.89 |
5 | 0.8 | 1.19 | 1.01 | 0.98 | 1.10 | 0.96 |
6 | 0.8 | 1.14 | 1.14 | 1.22 | 0.99 | 0.99 |
7 | 0.8 | 1.26 | 1.08 | 1.14 | 0.90 | 1.04 |
8 | 0.9 | 1.20 | 0.98 | 1.12 | 0.98 | 0.95 |
9 | 0.9 | 1.14 | 1.08 | 0.95 | 1.03 | 1.01 |
μm | Saline | BLM | 활성성분 (3 mg/kg) |
활성성분 (10 mg/kg) |
활성성분 (30 mg/kg) |
NIN |
1 | 436.567 | 663.945 | 677.319 | 593.826 | 443.336 | 620.302 |
2 | 412.602 | 723.118 | 744.986 | 601.558 | 601.558 | 651.572 |
3 | 445.578 | 844.957 | 904.141 | 809.106 | 558.530 | 856.355 |
4 | 437.536 | 819.822 | 641.841 | 708.308 | 479.961 | 664.973 |
5 | 378.447 | 835.348 | 809.254 | 526.170 | 475.515 | 675.558 |
6 | 494.174 | 926.507 | 771.562 | 521.027 | 412.271 | 623.019 |
7 | 458.348 | 706.216 | 778.660 | 425.415 | 525.311 | 651.831 |
8 | 420.379 | 681.761 | 688.725 | 456.862 | 593.963 | 660.809 |
9 | 443.032 | 768.854 | 759.037 | 672.616 | 526.388 | 649.479 |
Saline | BLM | 활성성분 (3 mg/kg) |
활성성분 (10 mg/kg) |
활성성분 (30 mg/kg) |
NIN | |
1 | 1.00 | 2.19 | 1.74 | 1.57 | 1.75 | 1.37 |
2 | 1.24 | 2.08 | 1.51 | 2.16 | 1.77 | 1.43 |
3 | 1.28 | 2.20 | 1.57 | 1.82 | 2.09 | 1.65 |
4 | 1.13 | 1.98 | 2.01 | 2.10 | 1.28 | 1.45 |
5 | 1.16 | 1.76 | 1.51 | 2.27 | 1.70 | 1.34 |
6 | 1.13 | 2.05 | 1.96 | 2.26 | 1.48 | 1.83 |
7 | 1.00 | 1.89 | 1.66 | 1.70 | 1.81 | 1.63 |
8 | 1.06 | 2.04 | 1.94 | 2.26 | 2.04 | 1.53 |
9 | 1.08 | 2.40 | 1.85 | 1.93 | 2.09 | 1.08 |
Claims (6)
- 제1항에 있어서,상기 전신경화증은, 전신경화증 연관 폐질환(systemic sclerosis associated interstitial lung disease; SSc-ILD)인,약학적 조성물.
- 제2항에 있어서,상기 약학적 조성물은 전신경화증 연관 폐질환의 피부 경화 완화 및 폐기능 개선의 이중 효과를 가지는,약학적 조성물.
- 제1항에 있어서,상기 약학적으로 허용 가능한 염은 염산염인,약학적 조성물.
- 제1항에 있어서,상기 약학적 조성물은 섬유화증의 예방 또는 치료에 사용되는 다른 유효 성분을 추가로 포함하는,약학적 조성물.
- 제5항에 있어서,상기 섬유화증의 예방 또는 치료에 사용되는 다른 유효 성분은, 닌테다닙 또는 토실리주맙인,약학적 조성물.
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CN202280051585.2A CN117693343A (zh) | 2021-07-23 | 2022-07-22 | 用于预防或治疗系统性硬化症的药物组合物 |
CA3225425A CA3225425A1 (en) | 2021-07-23 | 2022-07-22 | Pharmaceutical composition for preventing or treating systemic sclerosis |
EP22846286.7A EP4374859A1 (en) | 2021-07-23 | 2022-07-22 | Pharmaceutical composition for prevention or treatment of systemic sclerosis |
AU2022316021A AU2022316021A1 (en) | 2021-07-23 | 2022-07-22 | Pharmaceutical composition for prevention or treatment of systemic sclerosis |
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AR (1) | AR126552A1 (ko) |
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Citations (2)
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WO2013106702A1 (en) * | 2012-01-13 | 2013-07-18 | President And Fellows Of Harvard College | Halofuginol derivatives and their use in cosmetic and pharmaceutical compositions |
KR102084772B1 (ko) | 2017-02-07 | 2020-03-04 | 주식회사 대웅제약 | 신규한 헤테로 고리 화합물, 이의 제조 방법 및 이를 포함하는 약학적 조성물 |
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- 2022-07-22 WO PCT/KR2022/010751 patent/WO2023003416A1/ko active Application Filing
- 2022-07-22 CN CN202280051585.2A patent/CN117693343A/zh active Pending
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WO2013106702A1 (en) * | 2012-01-13 | 2013-07-18 | President And Fellows Of Harvard College | Halofuginol derivatives and their use in cosmetic and pharmaceutical compositions |
KR102084772B1 (ko) | 2017-02-07 | 2020-03-04 | 주식회사 대웅제약 | 신규한 헤테로 고리 화합물, 이의 제조 방법 및 이를 포함하는 약학적 조성물 |
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CN117693343A (zh) | 2024-03-12 |
EP4374859A1 (en) | 2024-05-29 |
AR126552A1 (es) | 2023-10-18 |
CA3225425A1 (en) | 2023-01-26 |
KR20230015858A (ko) | 2023-01-31 |
TW202320772A (zh) | 2023-06-01 |
AU2022316021A1 (en) | 2024-01-18 |
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