WO2022253034A1 - Utilisation d'un composé pyrrolopyrimidinique - Google Patents

Utilisation d'un composé pyrrolopyrimidinique Download PDF

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Publication number
WO2022253034A1
WO2022253034A1 PCT/CN2022/094554 CN2022094554W WO2022253034A1 WO 2022253034 A1 WO2022253034 A1 WO 2022253034A1 CN 2022094554 W CN2022094554 W CN 2022094554W WO 2022253034 A1 WO2022253034 A1 WO 2022253034A1
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WIPO (PCT)
Prior art keywords
inflammatory bowel
acid
bowel disease
disease
compound
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PCT/CN2022/094554
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English (en)
Chinese (zh)
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李永国
陈小宁
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广州嘉越医药科技有限公司
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Publication of WO2022253034A1 publication Critical patent/WO2022253034A1/fr

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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to the use of a pyrrolopyrimidine compound.
  • IBD Inflammatory Bowel Disease
  • Inflammatory bowel disease mainly includes ulcerative colitis (Ulcerative Colitis, UC) and Crohn's disease (Crohn Disease, CD), the disease is closely related to autoimmune dysfunction, and the disease is very common in western countries. The number has increased sharply, and it has become the main cause of common diseases of the digestive system and chronic diarrhea. Clinically, patients with inflammatory bowel disease manifest as repeated abdominal pain, diarrhea, mucus and bloody stools, and even various systemic complications such as blurred vision, joint pain, and skin rashes. The disease can be improved after treatment, and can also be relieved by itself. However, most patients relapse and do not heal, and a considerable number of patients require surgical treatment due to complications. So far, its etiology and specific pathogenesis are still unclear, and there is no fundamental treatment plan for the disease clinically. The World Health Organization lists the disease as one of the modern refractory diseases.
  • Tofacitinib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of autoimmune disease rheumatoid arthritis in November 2012, and in May 2018 for the treatment of moderate to severe
  • FDA U.S. Food and Drug Administration
  • the clinical remission rate of high dose (10mg/kg) is about 40%.
  • it acts on the upstream target of the signal, it can cause a variety of non-specific reactions, including hyperlipidemia, severe infection, malignant tumor and pulmonary embolism, some of which can be life-threatening, and its toxicity is proportional to the dose.
  • the Safety Committee of the European Medicines Agency began to conduct a comprehensive evaluation of tofacitinib in 2019.
  • the US FDA also issued a black-box warning (a rare safety warning) on the risk of blood coagulation and death caused by tofacitinib.
  • the clinical dose of 10 mg/kg should be used with caution or discontinued, and the clinical dose of 5 mg/kg should be compromised.
  • the technical problem to be solved by the present invention is to provide a compound that has good preventive and/or therapeutic effects on inflammatory bowel disease. Therefore, the present invention provides a use of pyrrolopyrimidine compounds.
  • the present invention provides a use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating and/or preventing inflammatory bowel disease;
  • the inflammatory bowel disease is ulcerative colitis.
  • the inflammatory bowel disease is Crohn's disease.
  • the inflammatory bowel disease has blood in stool and/or diarrhea.
  • the medicament for treating and/or preventing inflammatory bowel disease contains pharmaceutical excipients.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof is one or the only active ingredient of the drug.
  • a therapeutically effective amount of the compound represented by formula I or a pharmaceutically acceptable salt thereof may be administered to a subject in need.
  • the mode of administration may be any suitable mode, such as oral administration.
  • the therapeutically effective amount administered may be 4-100 mg/kg/d, preferably 6-60 mg/kg/d, such as 6 mg/kg/d, 20 mg/kg/d or 60 mg/kg/d.
  • the administration frequency may be 1-3 times/day, for example, 1-2 times/day.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof can be administered to a subject by any suitable route, such as orally.
  • the present invention also provides a pharmaceutical composition for treating and/or preventing inflammatory bowel disease in a subject, which comprises: a compound represented by formula I or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.
  • the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • the present invention also provides a method for treating and/or preventing inflammatory bowel disease in a subject, which comprises: administering to the subject a therapeutically or preventively effective amount of a compound represented by formula I or a pharmaceutically acceptable Salt.
  • the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of reliable medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term "pharmaceutically acceptable salt” may be a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base.
  • base addition salts can be obtained by contacting the compound with a sufficient amount of base, either neat or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts may include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts and the like.
  • acid addition salts can be obtained by contacting the compound with a sufficient amount of acid, either neat or in a suitable inert solvent.
  • the pharmaceutically acceptable acid may include inorganic acid, which may include but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like.
  • the pharmaceutically acceptable acid may include organic acids, which may include, but are not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, Diacid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, Oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene- bis(3-hydroxy-2-naphthoic acid)), amino acids (eg glutamic acid,
  • the compounds of the present invention When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.
  • base addition salts For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camille G.Wermuth, ed., Wiley-VCH, 2002).
  • the medicament for treating and/or preventing inflammatory bowel disease can be in conventional dosage forms in the art, such as tablets, capsules, intravenous injections, intraperitoneal injections, inhalants, nebulizers, lyophilized agents, Patches, gels, sprays or suppositories, etc.
  • pharmaceutical excipients refers to the excipients and additives used in the production of medicines and formulation of prescriptions, which can be all substances contained in pharmaceutical preparations except active ingredients. See the Pharmacopoeia of the People's Republic of China (2020 edition) four, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a subject.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • prophylactically effective amount refers to an amount sufficient to prevent a disease or disorder, or to prevent one or more symptoms associated with a disease or disorder, or to prevent recurrence of a disease or disorder.
  • subject refers to any animal that is about to or has received the administration of the compound according to the embodiments of the present invention, preferably a mammal, and most preferably a human.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that compound I or its pharmaceutically acceptable salt has good preventive or therapeutic effects on inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
  • Figure 1 is the effect of continuous administration of the test compound I on the disease activity index (DAI) of mice.
  • A is the total score of the disease activity index
  • B is the weight change score
  • C is the bleeding score
  • D is the stool score;
  • Figure 2 is the impact of continuous administration of the test substance Compound I on the pathological scores of mice.
  • A is inflammatory cell infiltration
  • B is tissue damage
  • Figure 3 is a representative pathological picture of the test compound I.
  • A is the representative picture of G1 (normal control) (hematoxylin-eosin staining), inflammation: 0, occasional or no infiltration; damage: 0, no mucosal damage;
  • B is the representative picture of G2 (model control) (Hematoxylin-eosin staining), inflammation: 3, transmural infiltration; injury: 2, mucosal erosion or ulceration;
  • C is a representative picture of G3 (compound I) (hematoxylin-eosin staining), inflammation: 2.
  • Compound I was provided by Guangzhou Jiayue Pharmaceutical Technology Co., Ltd. and prepared according to Example 1 in WO2020244614A1;
  • Tofacitinib was purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Cyclosporin A trade name Sandiming, was purchased from NOVARTIS.
  • the vehicle is 0.5% (w/v) hydroxypropylmethylcellulose (HPMCE5), 0.5% (w/v) polyvinylpyrrolidone (PVP K30) and 0.2% (w/v) sodium lauryl sulfate ( SDS) mixed aqueous solution;
  • the vehicle is physiological saline.
  • mice were randomly divided into normal control group (G1), model control group (G2), compound I group (G3), positive drug cyclosporine A group (G4), tofacitinib group (G5), compound I group (G6) and compound I group (G7), animal grouping and administration methods are shown in Table 1 for details.
  • Model control group (G2) and model administration group animals (G3-G7) were given drinking water containing 2% DSS (dextran sodium sulfate) continuously for 6 days for model building, and then replaced with normal drinking water, and samples were collected 4 days later. Mice in the normal control group were not subjected to modeling and drank normal drinking water all the time.
  • DSS extran sodium sulfate
  • mice All animals were dosed at a volume of 10 mL/kg. Animal body weight and clinical disease scores were recorded daily during the experiment. The body weight, diarrhea and hematochezia of mice in all groups were recorded every day. Daily scoring is done according to the scoring system below.
  • Body weight change (0, ⁇ 1%; 1, 1-5%; 2, 6-10%; 3, 11-20%;);
  • Bleeding score (0, occult blood negative; 1, occult blood positive; 2, trace blood visible to the naked eye in stool; 3, obvious rectal bleeding);
  • the scores of the three parts are added to obtain the daily disease index value DAI.
  • the colon was fixed in 10% formalin solution.
  • the fixed intestinal tissues were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and graded using the following scoring criteria.
  • DAI Disease Activity Index
  • the DAI total score is the sum of the three parameter scores of blood in the stool, diarrhea and weight loss. Most of the animals in the model control group had clinical symptoms such as blood in the stool and watery diarrhea, which indicated that the enteritis model in this experiment was successfully established.
  • the positive control cyclosporine A can significantly improve the clinical symptoms, and the area under the curve (AUC) of the total score of the disease activity index DAI was significantly reduced.
  • the test compound I can also significantly reduce the AUC of the total DAI score at a dose of 6 mg/kg/d.
  • the positive control cyclosporine A significantly improved the symptoms of blood in the stool, and the test compound I also had a significant relief effect on the blood in the stool at a dose of 6 mg/kg/d, while the reference drug tofacitinib had no significant improvement in the blood in the stool.
  • the AUC analysis of the area under the curve of the DAI stool score showed that the test compound I significantly relieved the diarrhea symptoms at 6 mg/kg/d, while the positive controls cyclosporine A and tofacitinib had no significant improvement on the diarrhea symptoms. Therefore, compound I is better than tofacitinib in improving enteritis DAI.
  • test substance Compound I for 10 days significantly improved the inflammatory response of the colon, and the dosage group 6mg/kg/d, 20mg/kg/d and 60mg/kg/d significantly reduced the inflammatory infiltration, and the dosage group 6mg/kg/d had a significant effect on Tissue damage was also significantly improved.
  • Tofacitinib only had some effect on inflammatory infiltration. Therefore, the test compound I is better than tofacitinib in improving the histopathology of enteritis.
  • compound I significantly improved the disease activity index and histopathology of DAI in the mouse enteritis model, and was superior to tofacitinib.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
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  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne l'utilisation d'un composé pyrrolopyrimidinique. La structure du composé pyrrolopyrimidinique est représentée par la formule I, et le composé pyrrolopyrimidique peut être utilisé pour préparer un médicament destiné à traiter et/ou à prévenir une maladie intestinale inflammatoire.
PCT/CN2022/094554 2021-05-31 2022-05-23 Utilisation d'un composé pyrrolopyrimidinique WO2022253034A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202110601810.2 2021-05-31
CN202110601810 2021-05-31
CN202210218153.8A CN114432317A (zh) 2021-05-31 2022-02-28 吡咯并嘧啶类化合物的用途
CN202210218153.8 2022-02-28

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WO2022253034A1 true WO2022253034A1 (fr) 2022-12-08

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202245783A (zh) * 2021-05-21 2022-12-01 大陸商廣州嘉越醫藥科技有限公司 一種吡咯并嘧啶類化合物的應用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110088105A (zh) * 2016-12-16 2019-08-02 詹森药业有限公司 Jak家族激酶的小分子抑制剂
WO2020182159A1 (fr) * 2019-03-14 2020-09-17 上海华汇拓医药科技有限公司 Inhibiteur de kinase jak, son procédé de préparation et ses applications dans le domaine de la médecine
WO2020244614A1 (fr) * 2019-06-05 2020-12-10 南京明德新药研发有限公司 Composé de pyrrolopyrimidine et son utilisation
CN112770762A (zh) * 2018-05-03 2021-05-07 英德克斯制药公司 制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110088105A (zh) * 2016-12-16 2019-08-02 詹森药业有限公司 Jak家族激酶的小分子抑制剂
CN112770762A (zh) * 2018-05-03 2021-05-07 英德克斯制药公司 制剂
WO2020182159A1 (fr) * 2019-03-14 2020-09-17 上海华汇拓医药科技有限公司 Inhibiteur de kinase jak, son procédé de préparation et ses applications dans le domaine de la médecine
WO2020244614A1 (fr) * 2019-06-05 2020-12-10 南京明德新药研发有限公司 Composé de pyrrolopyrimidine et son utilisation

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TWI828155B (zh) 2024-01-01
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