CN114432317A - Application of pyrrolopyrimidine compounds - Google Patents
Application of pyrrolopyrimidine compounds Download PDFInfo
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- CN114432317A CN114432317A CN202210218153.8A CN202210218153A CN114432317A CN 114432317 A CN114432317 A CN 114432317A CN 202210218153 A CN202210218153 A CN 202210218153A CN 114432317 A CN114432317 A CN 114432317A
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- inflammatory bowel
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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
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- 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
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- 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
Abstract
Description
Technical Field
The invention relates to application of a pyrrolopyrimidine compound.
Background
Inflammatory Bowel Disease (IBD) is a chronic Inflammatory Disease of intestinal tract, and the composition and structure of intestinal flora of IBD patients are obviously changed, namely the intestinal flora is disordered. The intestinal barrier function plays an important role in regulating and maintaining the intestinal function of human body in a steady state. Studies have shown that in IBD there is an impaired intestinal barrier function and an increased intestinal permeability. Imbalance of intestinal flora leads to an impaired intestinal barrier function, which disrupts the normal intestinal homeostasis function of the human body and aggravates the progression of IBD.
Inflammatory bowel Disease mainly comprises Ulcerative Colitis (UC) and Crohn Disease (CD), the Disease is closely related to autoimmune dysfunction, the Disease is common in western countries, and the number of IBD cases in China is increased rapidly in recent years, and the Disease becomes the main cause of common diseases of the digestive system and chronic diarrhea. Clinically, patients with inflammatory bowel disease have repeated abdominal pain, diarrhea, mucous bloody stool, and even various systemic complications such as blurred vision, arthralgia, and rash. The disease can be improved or relieved by itself after being treated. However, most patients have recurrent and persistent outbreaks, and a considerable part of the patients need surgical treatment due to complications. To date, the etiology and specific pathogenesis of the disease is still unclear, and a fundamental treatment for the disease is clinically lacking. The world health organization classifies the disease as one of the modern refractory diseases.
Tofacitinib was approved by the U.S. drug and food administration (FDA) for the treatment of the autoimmune disease rheumatoid arthritis in 11 months 2012 and for the treatment of moderate to severe ulcerative colitis in 5 months 2018 by the U.S. FDA with a high dose (10mg/kg) clinical remission rate of about 40%. But because the compound acts on the upstream target of the signal, a plurality of non-specific reactions can be caused, including toxic and side effects such as hyperlipemia, serious infection, malignant tumor, pulmonary embolism and the like, wherein part of the toxic side effects can endanger life, and the toxicity is in direct proportion to the dosage. In view of this, the european commission on drug administration safety began a comprehensive evaluation of tofacitinib at 2019, while the U.S. FDA also issued a black box warning (a rare safety warning) of the risk of tofacitinib causing blood clotting and death, while cautiously taking or discontinuing the clinical dose of 10mg/kg and compromising the clinical dose of 5 mg/kg.
In view of the low clinical remission rate and severe adverse effects of the latest drug tofacitinib. Therefore, research and development of a medicament capable of safely and effectively preventing and treating the inflammatory bowel disease have important guiding significance for clinically treating the inflammatory bowel disease.
Disclosure of Invention
The invention aims to provide a compound with good prevention and/or treatment effects on inflammatory bowel diseases, and therefore, the invention provides an application of a pyrrolopyrimidine compound.
The invention provides an application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing a medicament for treating and/or preventing inflammatory bowel diseases;
in some embodiments, the inflammatory bowel disease is ulcerative colitis.
In some embodiments, the inflammatory bowel disease is crohn's disease.
In some embodiments, the inflammatory bowel disease has symptoms of hematochezia and/or diarrhea.
In some embodiments, the medicament for treating and/or preventing inflammatory bowel disease comprises a pharmaceutical excipient.
In some embodiments, the compound of formula i or a pharmaceutically acceptable salt thereof is one or the only active ingredient of the pharmaceutical.
In some embodiments, a therapeutically effective amount of the compound of formula i, or a pharmaceutically acceptable salt thereof, may be administered to a subject in need thereof. The mode of administration may be any suitable mode, for example oral.
The therapeutically effective amount for administration may be 4-100 mg/kg/d, preferably 6-60 mg/kg/d, for example 6mg/kg/d, 20mg/kg/d or 60 mg/kg/d.
The frequency of administration may be 1-3 times per day, for example 1-2 times per day.
In the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered to a subject by any suitable route, for example, orally.
The present invention also provides a pharmaceutical composition for treating and/or preventing inflammatory bowel disease in a subject, comprising: a compound shown as a formula I or pharmaceutically acceptable salt thereof, and a pharmaceutic adjuvant.
In some embodiments, the inflammatory bowel disease is ulcerative colitis or crohn's disease.
The present invention also provides a method of treating and/or preventing inflammatory bowel disease in a subject, comprising: administering to the subject a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, the inflammatory bowel disease is ulcerative colitis or crohn's disease.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" in the present context means those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
In the present invention, the term "pharmaceutically acceptable salt" refers to a salt prepared from the compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of a base, either in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts may include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt, etc. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid, either in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acid may include inorganic acids which may include, but are 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, suberic acid, 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, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular 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 Camile G.Wermuth, ed., Wiley-VCH, 2002).
In the present invention, the drug for treating and/or preventing inflammatory bowel disease may be in a form conventional in the art, such as a tablet, a capsule, an intravenous injection, an intraperitoneal injection, an inhalant, a nebulizer, a lyophilized preparation, a patch, a gel, a spray, a suppository, or the like.
The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and may be any substance contained in a pharmaceutical formulation, except for the active ingredient. See the pharmacopoeia of the people's republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).
The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.
The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to effectively treat a disease or condition described herein. The "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 desired by one of skill in the art.
The term "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 the recurrence of a disease or disorder.
The term "subject" refers to any animal, preferably a mammal, most preferably a human, that is to be or has received administration of the compound according to the embodiments of the present invention. The term "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, and the like, with humans being most preferred.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the compound I or a pharmaceutically acceptable salt thereof has a good preventive or therapeutic effect on inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
Drawings
FIG. 1 is a graph showing the effect of continuous administration of test compound I on the disease Activity index DAI in mice. Wherein A is the disease activity index total score, B is the weight change score, C is the bleeding score, and D is the stool score;
FIG. 2 is a graph showing the effect of continuous administration of test compound I on the pathological score in mice. Wherein A is inflammatory cell infiltration and B is tissue injury.
FIG. 3 is a photograph showing a typical pathology of compound I as a test substance. Where a is a G1 (normal control) representative plot (hematoxylin-eosin stain), inflammation: 0, occasional or no infiltration; and (3) damage: 0, no mucosal damage; b is a representative graph of G2 (model control) (hematoxylin-eosin stain), inflammation: 3, transmural infiltration; and (3) damage: 2, mucosal erosion or ulceration; c is G3 (compound I) representative pattern (hematoxylin-eosin stain), inflammation: 2, infiltrating into submucosa; and (3) damage: 1, focal lesions; d is a representative graph of G4 (cyclosporin a) (hematoxylin-eosin staining), inflammation: 2, infiltrating into submucosa; and (3) damage: 1, focal lesions; e is G5 (tofacitinib) representative graph (hematoxylin-eosin stain), inflammation: 2, infiltrating into submucosa; and (3) damage: focal lesions 1.
#, P < 0.05; #, P < 0.01; # #, P < 0.001; the normal control group was compared to the model control group.
P < 0.05; p < 0.01; p < 0.001; compared with the model control group.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. The solvents and controls used in the present invention are commercially available.
Compound i was prepared from california, guanzhou, prepared according to example 1 of WO2020244614a 1;
tofacitinib was purchased from Shanghai-derived leaf Biotech, Inc.
Cyclosporine A, tradename Sanremo, was purchased from NOVARTIS corporation.
Dextran sulfate sodium salt (Dextran sulfate sodium, DSS, MW 36,000-: item number 160110;
example 1
1. Laboratory animal
Animal species and strains: c57BL/6 mice; female, about 18-22g in weight, 6-8 weeks old; purchased from Beijing Wittiulihua laboratory animal technology Co., Ltd;
TABLE 1 animal grouping and administration regimen
a: the solvent is mixed water solution of 0.5% (w/v) hydroxypropyl methylcellulose (HPMC E5), 0.5% (w/v) polyvinylpyrrolidone (PVP K30) and 0.2% (w/v) Sodium Dodecyl Sulfate (SDS);
and b, the solvent is physiological saline.
Mice were randomly divided into a normal control group (G1), a model control group (G2), a compound I group (G3), a cyclosporin a positive drug group (G4), tofacitinib group (G5), a compound I group (G6), and a compound I group (G7), and the animal groups and administration modes are detailed in table 1. Model control group (G2) and model administration group animals (G3-G7) were continuously administered drinking water containing 2% DSS (dextran sulfate sodium) for 6 days of molding, and then changed to normal drinking water, and were harvested after 4 days. The normal control group mice did not undergo molding and had normal drinking water all the time. From the day of molding to the end point, animals in compound I group (G3) received oral administration of compound I (twice daily, 6mg/kg/d), animals in cyclosporin a group (G4) received oral administration of cyclosporin a (once daily, 25mg/kg/d), animals in tofacitinib group (G5) received oral administration of tofacitinib (twice daily, 60mg/kg/d), animals in compound I group (G6) received oral administration of compound I (twice daily, 20mg/kg/d), animals in compound I group (G7) received oral administration of compound I (twice daily, 60mg/kg/d), and animals in control group received oral administration of compound I (vehicle mixed aqueous solution of 0.5% (w/v) hydroxypropylmethylcellulose (HPMC E5), 0.5% (w/v) polyvinylpyrrolidone (PVP K30) and 0.2% (w/v) Sodium Dodecyl Sulfate (SDS). All animals were dosed at a volume of 10 mL/kg. Animal body weights and clinical disease scores were recorded daily throughout the experiment. All groups of mice were recorded daily for weight, diarrhea and hematochezia. Daily scoring was performed according to the following scoring system.
Weight change (0, < 1%; 1, 1-5%; 2, 6-10%; 3, 11-20%;);
bleeding scores (0, negative occult blood; 1, positive occult blood; 2, macroscopic trace blood in feces; 3, significant rectal bleeding);
the daily disease index value DAI was obtained by adding the scores of three parts of stool scores (0, normal; 1, mild soft stools; 2, very soft stools, wet; 3, watery diarrhea).
2. Histopathological examination
After taking the material, the colon was immersed in 10% formalin solution for fixation. The fixed intestinal tissues were embedded in paraffin, sectioned and then stained with hematoxylin and eosin and then graded using the following scoring criteria.
TABLE 2 histopathological scoring criteria for enteritis
TABLE 3 histopathological scoring criteria for enteritis
3. Test results
A. Disease Activity Index (DAI) (Table 3, FIG. 1)
TABLE 3 Effect of continuous administration of test substance Compound I on mouse Disease Activity Index (DAI) score
The total DAI score was the sum of scores for three parameters, hematochezia, diarrhea and weight loss. The model control group shows obvious clinical symptoms such as hematochezia, watery diarrhea and the like in most animals, and the model building success of the enteritis model in the test is shown. Compared with a model control group, the positive control cyclosporin A can obviously improve clinical symptoms, and the area under the disease activity index DAI total partial curve (AUC) is obviously reduced. The compound I test substance can also significantly reduce the AUC of the total DAI score at the dose of 6 mg/kg/d. The positive control cyclosporin A obviously improves animal hematochezia symptoms, the test compound I also has obvious relieving effect on hematochezia at the dose of 6mg/kg/d, and the reference medicament tofacitinib does not obviously improve the hematochezia. Analysis of the area AUC under the DAI feces score curve shows that the test compound I can remarkably relieve the diarrhea symptoms at 6mg/kg/d, and the positive controls of cyclosporin A and tofacitinib can not remarkably improve the diarrhea symptoms. Therefore, compound I improved DAI in enteritis better than tofacitinib.
B. Pathological evaluation (Table 4, Table 5, FIG. 2)
TABLE 4 Effect of continuous administration of test Compound I on pathological Scoring (inflammation) in mice
TABLE 5 Effect of continuous administration of test Compound I on pathological Scoring (Damage) in mice
The test takes materials at the test end point, and carries out pathological analysis on colon to evaluate inflammatory cell infiltration and tissue injury. The pathological results show that the animals in the model control group have obvious pathological changes, inflammatory cells infiltrate to submucosa and even transmural infiltration, and intestinal mucosa is eroded or ulcerated. Compared with the model control group, the positive control cyclosporin a significantly improved inflammatory cell infiltration and tissue damage. A representative picture is shown in figure 3. The test compound I is continuously administrated for 10 days, the inflammatory response of colon is obviously improved, the inflammatory infiltration is obviously reduced by the dosage groups of 6mg/kg/d, 20mg/kg/d and 60mg/kg/d, and the tissue injury is also obviously improved by the dosage group of 6 mg/kg/d. Tofacitinib has only a certain therapeutic effect on inflammatory infiltrates. Therefore, compound I, the test compound, is superior to tofacitinib in the improvement of histopathology of enteritis.
In conclusion, compound I has a significant improvement in both disease activity index and histopathology of DAI in the murine enteritis model, and is superior to tofacitinib.
Claims (10)
2. the use of claim 1, wherein the inflammatory bowel disease is ulcerative colitis.
3. The use of claim 1, wherein the inflammatory bowel disease is crohn's disease.
4. The use of any one of claims 1 to 3, wherein the inflammatory bowel disease has symptoms of hematochezia and/or diarrhea.
5. The use according to any one of claims 1 to 4, wherein the medicament for the treatment and/or prevention of inflammatory bowel disease comprises a pharmaceutical excipient.
6. The use according to any one of claims 1 to 5, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is one or the only active ingredient of the medicament.
7. The use of claims 1-6, wherein a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.
8. The use of claim 7, wherein the mode of administration is oral;
and/or, the therapeutically effective amount for administration is 4-100 mg/kg/d, preferably 6-60 mg/kg/d, such as 6mg/kg/d, 20mg/kg/d or 60 mg/kg/d;
and/or the frequency of administration is 1-3 times per day, for example 1-2 times per day.
10. the pharmaceutical composition for treating and/or preventing inflammatory bowel disease in a subject according to claim 9, wherein said inflammatory bowel disease is ulcerative colitis or crohn's disease;
and/or, the compound shown in the formula I or the pharmaceutically acceptable salt thereof is used in a therapeutically effective amount.
Priority Applications (2)
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TW111119062A TWI828155B (en) | 2021-05-31 | 2022-05-23 | Uses of pyrrolopyrimidines |
PCT/CN2022/094554 WO2022253034A1 (en) | 2021-05-31 | 2022-05-23 | Use of pyrrolopyrimidine compound |
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CN2021106018102 | 2021-05-31 | ||
CN202110601810 | 2021-05-31 |
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WO2022242768A1 (en) * | 2021-05-21 | 2022-11-24 | 广州嘉越医药科技有限公司 | Use of pyrrolopyrimidine compound |
Citations (1)
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WO2020244614A1 (en) * | 2019-06-05 | 2020-12-10 | 南京明德新药研发有限公司 | Pyrrolopyrimidine compound and use thereof |
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BR112019011968A2 (en) * | 2016-12-16 | 2019-11-05 | Janssen Pharmaceutica Nv | small molecule inhibitors of the jak family of kinases |
GB201807312D0 (en) * | 2018-05-03 | 2018-06-20 | Index Pharmaceuticals Ab | Formulation |
JP7248256B2 (en) * | 2019-03-14 | 2023-03-29 | 上海華匯拓医薬科技有限公司 | JAK Kinase Inhibitors, Preparation Methods Thereof, and Uses Thereof in the Pharmaceutical Field |
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- 2022-02-28 CN CN202210218153.8A patent/CN114432317A/en active Pending
- 2022-05-23 TW TW111119062A patent/TWI828155B/en active
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WO2020244614A1 (en) * | 2019-06-05 | 2020-12-10 | 南京明德新药研发有限公司 | Pyrrolopyrimidine compound and use thereof |
Non-Patent Citations (1)
Title |
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SILVIO DANESE等: "JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?", 《GUT》 * |
Cited By (1)
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WO2022242768A1 (en) * | 2021-05-21 | 2022-11-24 | 广州嘉越医药科技有限公司 | Use of pyrrolopyrimidine compound |
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TWI828155B (en) | 2024-01-01 |
WO2022253034A1 (en) | 2022-12-08 |
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