WO2021190647A1 - 小檗碱类似物与jak抑制剂在胃肠道炎症性疾病治疗中的用途 - Google Patents

小檗碱类似物与jak抑制剂在胃肠道炎症性疾病治疗中的用途 Download PDF

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WO2021190647A1
WO2021190647A1 PCT/CN2021/083421 CN2021083421W WO2021190647A1 WO 2021190647 A1 WO2021190647 A1 WO 2021190647A1 CN 2021083421 W CN2021083421 W CN 2021083421W WO 2021190647 A1 WO2021190647 A1 WO 2021190647A1
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berberine
active ingredient
jak inhibitor
composition
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PCT/CN2021/083421
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French (fr)
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寿建勇
江磊
金贤
刘胜洋
毛旭东
张建华
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轶诺(浙江)药业有限公司
上海轶诺药业有限公司
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Priority to CN202180024709.3A priority Critical patent/CN115361974B/zh
Priority to US17/907,394 priority patent/US20230293503A1/en
Publication of WO2021190647A1 publication Critical patent/WO2021190647A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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]

Definitions

  • the present invention relates to the field of small molecule drugs. Specifically, the present invention provides a preparation formula that uses berberine analogues and JAK inhibitors in combination, or uses berberine analogues as JAK inhibitors to treat gastrointestinal inflammatory diseases Strategy.
  • JAK inhibitors such as tofacitinib have been approved in the United States and many other countries for the treatment of certain patients with moderate to severe active rheumatoid arthritis (rheumatoid arthritis, RA).
  • Fatinib has been approved by the US FDA for the treatment of moderate to severe ulcerative colitis (UC).
  • Tofacitinib has systemic-mediated adverse events similar to those reported for RA in patients with ulcerative colitis.
  • tofacitinib In clinical trials for tofacitinib, a large number of systemic-mediated adverse events were reported, including increasing rates of serious infections, opportunistic infections, and malignancies; and laboratory abnormalities, such as lymphopenia, neutrophils Leukopenia, elevated liver enzymes, elevated lipids, and elevated serum creatinine. Therefore, the approved US product XELJANZ/XEJANZ XR (trade name) carries a boxed warning detailing various safety risks, including the risk of serious infection and malignant tumors. In addition, considering the overall safety profile of tofacitinib, the European Medicine Agency voted in 2013 not to recommend tofacitinib's marketing authorization in RA.
  • Berberine also known as berberine, is an isoquinoline alkaloid extracted from coptis and other plants. Berberine is a very safe medicine and has been used in traditional Chinese medicine for more than a thousand years. Its bioavailability is very low. Clinically, it is mainly used to treat gastrointestinal diseases such as diarrhea and intestinal infections. Research in recent years has also found that berberine has certain therapeutic prospects in cardiovascular disease and the regulation of glucose and lipid metabolism. Berberrubine is the main metabolite of berberine in the body. Animal model studies have found that berberine has a similar therapeutic effect on ulcerative colitis as berberine. However, up to now, there is still no effective way to improve the therapeutic effect of berberine or its analogues in this field.
  • Chronic enteritis mainly includes two types: ulcerative colitis and Crohn's disease. These chronic intestinal inflammatory diseases have a long course, often recurring, and long-term inflammation is prone to cancer. The incidence of chronic enteritis has been on the rise in recent years. It is currently believed that the pathogenesis of chronic enteritis may be related to genetics, environment, immunity and microorganisms, but the exact mechanism is not clear. Clinical treatment is based on aminosalicylic acid drugs, adrenal glucocorticoid drugs and immunosuppressive agents, but they all have certain adverse reactions, such as gastrointestinal discomfort and allergic reactions. In summary, chronic inflammatory bowel diseases urgently need to provide treatment programs for gastrointestinal inflammatory diseases with fewer adverse reactions and improved therapeutic effects.
  • JAK inhibitors have been clinically proven to have a good anti-inflammatory effect. Combined with berberine analogues to adjust the intestinal flora, protect the intestinal barrier function and regulate oxidative stress, the synergistic effect of the two can achieve even better The effect of treating inflammatory diseases of the gastrointestinal tract. At the same time, the drug combination can reduce the dose of a single drug, and it is expected to reduce the adverse effects related to the single drug dose in clinical practice.
  • the present invention provides a JAK inhibitor (preferably tofacitinib or SHR0302) and a berberine analog (preferably berberine) for combined use.
  • the drug combination uses a JAK inhibitor (preferably tofa (Tinib) and berberine analogues (preferably berberine) are prepared into pharmaceutical compositions, or administered sequentially, so as to achieve a better therapeutic effect than when used alone at the same dose.
  • composition comprising:
  • a therapeutically effective amount of the first active ingredient, the first active ingredient is a berberine analog, and the berberine analog has a structure selected from the following group:
  • Ro, Rp, Rq, Rr, Rs and Rt are each independently selected from the following group: H, hydroxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;
  • substitution means that the H atom on the group is substituted by one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, and phenyl;
  • the mass ratio of the first active ingredient to the second active ingredient is 1-1000:1000-1.
  • the mass ratio of the first active ingredient to the second active ingredient is 1-10:10-1.
  • the berberine analogue is selected from the following group:
  • the berberine analogue is selected from the following group:
  • the berberine analogue is selected from the following group:
  • the JAK inhibitor can be selected from but not limited to the following group: Tofacitnib, Ruxolitinib, Oclacitinib, Barre Baricitinib, Peficitinib, Abrocitinib, Filgotinib, Upadacitinib, Delgocitinib and Ittatinib Itacitinib, Fedratinib, Decernotinib, SHR-0302, AZD-4205, ASN-002, BMS-986165, PF-06700841, PF-06651600, R-348, INCB-52793 , ATI-501, ATI-502, NS-018, KL-130008, Deuterium modified JAK inhibitor, etc.
  • the JAK inhibitor is selected from the following group:
  • the pharmaceutical composition is an enteric-coated preparation.
  • a medicine kit in the second aspect of the present invention, includes:
  • berberine analogue has a structure selected from the following group:
  • Ro, Rp, Rq, Rr, Rs, and Rt are each independently selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;
  • substitution means that the H atom on the group is substituted by one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, and phenyl.
  • a combination of active ingredients includes or is composed of the following components:
  • the first active ingredient, the first active ingredient is a berberine analog or a derivative thereof;
  • the fourth aspect of the present invention provides the use of the composition as described in the first aspect of the present invention for preparing a pharmaceutical composition for treating diseases selected from the group consisting of gastrointestinal inflammatory diseases (such as Ulcerative colitis, Crohn’s disease, colitis related to immune checkpoint inhibitor therapy, collagenous colitis, lymphocytic colitis, pouchitis, acute/chronic gastritis, acute/chronic appendicitis), stomach Intestinal autoimmune diseases (such as graft-versus-host disease, stomatitis, autoimmune bowel disease), peptic ulcer, irritable bowel syndrome, gastric cancer, esophageal cancer, colon cancer.
  • gastrointestinal inflammatory diseases such as Ulcerative colitis, Crohn’s disease, colitis related to immune checkpoint inhibitor therapy, collagenous colitis, lymphocytic colitis, pouchitis, acute/chronic gastritis, acute/chronic appendicitis
  • stomach Intestinal autoimmune diseases such as graft-versus-host disease, sto
  • FIG. 1 The effects of tofacitinib, berberine and tofacitinib combined with berberine on the disease activity index (DAI) in the oxazolone-induced colitis model. The medication and dosage of each group are shown in the figure.
  • Tofa tofacitinib
  • BBR berberine
  • Oxa oxazolone.
  • FIG. 3 The effect of JAK inhibitor SHR0302, berberine and SHR0302 combined with berberine on the disease activity index (DAI) in the oxazolone-induced colitis model.
  • DAI disease activity index
  • BBR berberine
  • Oxa oxazolone.
  • FIG. 4 SHR0302 combined with berberrubine significantly reduced the disease activity index (DAI) AUC from day 1 to day 5 of the oxazolone-induced colitis model and the analysis of the synergistic effect of the Bliss independent model based on the average of each group. The medication and dosage of each group are shown in the figure.
  • BBR berberine; Oxa: oxazolone.
  • the inventors have discovered through long-term and in-depth research that the combined use of JAK inhibitors and berberine analogs has a better therapeutic effect for the treatment of gastrointestinal diseases than a single drug at the same dose. Based on the above findings, the inventor completed the present invention.
  • the term "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “substantially consisting of” or “consisting of”.
  • alkyl refers to a fully saturated linear or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, having, for example, 1 to 12 (Preferably 1 to 8, more preferably 1 to 6) carbon atoms, and are connected to the rest of the molecule through a single bond, such as but not limited to methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3 -Methylhexyl, octyl, nonyl and decyl, etc.
  • C1-C6 alkyl refers to an alkyl group containing 1
  • 6-10 membered aromatic ring means an aromatic ring having 6-10 ring atoms, and the ring atoms are carbon atoms.
  • the aromatic ring may be monocyclic or bicyclic.
  • benzene ring, naphthalene ring and similar groups are examples of aromatic ring having 6-10 ring atoms, and the ring atoms are carbon atoms.
  • C1-C4 alkoxy refers to a linear or branched alkoxy group having 1 to 4 carbon atoms; for example, methoxy , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • 5-7 membered heterocyclic ring means a partially saturated or saturated heterocyclic ring having 5-7 ring atoms, and the ring atoms have at least 1 One (may be 1, 2, or 3) is a heteroatom selected from nitrogen, oxygen and sulfur.
  • the heterocyclic ring may be monocyclic or bicyclic.
  • the compound of the present invention is a compound represented by formula I or a stereoisomer or racemate or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and therefore can produce enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethyl
  • the compounds described herein may contain one or more chiral centers.
  • the depiction or naming of a specific stereoisomer means that the indicated stereocenter has the specified stereochemistry, wherein it should be understood that unless otherwise specified, there may also be a small amount of other stereoisomers, which The limitation is that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer.
  • the first active ingredient is a berberine analog
  • the berberine analog has a structure selected from the following group:
  • Ro, Rp, Rq, Rr, Rs and Rt are each independently selected from the following group: H, hydroxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;
  • substitution means that the H atom on the group is substituted by one or more substituents selected from the group consisting of halogen, C1-C4 alkyl, and phenyl;
  • the mass ratio of the first active ingredient to the second active ingredient is 1-1000:1000-1.
  • the mass ratio of the first active ingredient to the second active ingredient is 1-10:10-1.
  • the berberine analogue is selected from the following group:
  • the berberine analogue is selected from the following group:
  • the berberine analogue is selected from the following group:
  • the JAK inhibitor can be selected from but not limited to the following group: Tofacitnib, Ruxolitinib, Oclacitinib ), Baricitinib, Pefitinib, Abrocitinib, Filgotinib, Upadacitinib, Delgocitinib Itacitinib, Fedratinib, Decernotinib, SHR-0302, AZD-4205, ASN-002, BMS-986165, PF-06700841, PF-06651600, R-348 , INCB-52793, ATI-501, ATI-502, NS-018, KL-130008, Deuterium modified JAK inhibitors, etc.
  • the JAK inhibitor is selected from the following group:
  • the pharmaceutical composition of the present invention has an excellent therapeutic effect on gastrointestinal inflammatory diseases
  • the pharmaceutical composition in which the compound of the invention is the main active ingredient can be used for the prevention and/or treatment of intestinal dysfunction.
  • the term "pharmaceutical composition” refers to a preparation of the compound of the present invention and a medium generally accepted in the art for the delivery of a biologically active compound to a mammal (such as a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which is conducive to the absorption of the active ingredient and thus the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing Undesirable biological reactions or interactions with any components included in the composition in an undesirable manner.
  • the term "pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, Sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • prevention includes reducing the likelihood of the occurrence or exacerbation of a disease or condition in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • the terms “administration”, “administration”, “administration”, etc. refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remingtonemin Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drugs obtained by mixing or combining more than one active ingredient Treatment, which includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • non-fixed combination refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • Oxazolone (4-Ethoxymethy-lene-2-phenyl-2-oxazolin-5-one) was purchased from Sigma; stool occult blood kit was purchased from BASO Biology; olive oil was purchased from Adamas company; acetone was purchased from Greagent company.
  • mice 51 C57 BL/6 mice, of which 3 were used as blank controls, and the remaining 48 mice were established as oxazolone-induced colitis models by referring to Heller and other methods.
  • the skin on the back of the neck of the mouse was shaved (2cm ⁇ 2cm), and 150ul of 3% oxazolone solution (dissolved in a 4:1 mixed solution of acetone and olive oil) was applied to sensitize.
  • the sensitized mice were observed daily for body weight, mobility, coat color and other conditions.
  • mice On the 6th day of sensitization, the mice were randomly divided into 7 groups, model group, tofacitinib (2mg/kg) group, tofacitinib (10mg/kg) group, berberine (2mg/kg) group, small group Berberine (20mg/kg) group, tofacitinib (2mg/kg) + berberine (2mg/kg) group and tofacitinib (10mg/kg) + berberine (2mg/kg) Group, the model group has 8 animals, and the remaining 7 animals in each group. Corresponding drugs were given by gavage every day, and the blank control group and model group were given solvents with a gavage volume of 10 mL/kg body weight.
  • mice on the 7th day of sensitization. Before the enema, the mice were fasted for 12 hours without water. The mice were anesthetized by inhalation with isoflurane. Observe the activity and breathing. Avoid excessive anesthesia. The anus of the mouse was slowly inserted into the intestinal tract about 3.5 cm deep. The model group and the treatment group were injected with 50 ⁇ L of 1.2% oxazolone solution (dissolved in 50% ethanol), left for 20 seconds, then the catheter was pulled out, and the mouse was placed upside down for 30 seconds. The blank control group was injected with pure water. They were fed normally after anesthesia awake.
  • DAI Disease activity index
  • the DAI curve of the animal disease activity index for 5 consecutive days is shown in Figure 1.
  • the calculated AUC value of DAI for 5 consecutive days and the analysis of the synergistic effect of the Bliss independent model based on the average value of each group are shown in Figure 2.
  • the results show that the JAK inhibitor tofacitinib combined with berberine can significantly improve the disease activity index compared with the model group.
  • the analysis of the synergistic effect based on the mean value of the Bliss independent model showed that compared with the single-drug group tofacitinib and berberine, the combined administration group has significant synergy of the combined administration.
  • Corresponding drugs were given by gavage every day, and the blank control group and model group were given solvents with a gavage volume of 10ml/kg body weight.
  • Enema on the 7th day of sensitization. Before the enema, the mice were fasted for 12 hours without water. The mice were anesthetized by inhalation with isoflurane. Observe the activity and breathing. Avoid excessive anesthesia. The anus of the mouse was slowly inserted into the intestinal tract about 3.5 cm deep. The model group and the treatment group were injected with 50 ⁇ L of 1.2% oxazolone solution (dissolved in 50% ethanol), left for 20 seconds, then the catheter was pulled out, and the mouse was placed upside down for 30 seconds. The blank control group was injected with pure water. They were fed normally after anesthesia awake.
  • DAI Disease activity index
  • the DAI curve of the animal disease activity index for 5 consecutive days is shown in Figure 3.
  • the calculated AUC value of DAI for 5 consecutive days and the analysis of the synergistic effect of the Bliss independent model based on the average of each group are shown in Figure 4.
  • the results showed that the JAK inhibitor SHR0302 combined with berberine can significantly improve the disease activity index compared with the model group.
  • the analysis of the synergistic effect based on the mean value of the Bliss independent model showed that the combined administration group has a significant synergy of drug effect compared with the single-drug group.

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Abstract

本发明涉及一种小檗碱类似物与JAK抑制剂联合治疗胃肠道炎症性疾病的策略，具体地，本发明提供了含有小檗碱类似物与JAK抑制剂的药物组合物，及其在胃肠道炎症性疾病治疗中的用途。所述的组合物可以表现出比小檗碱或JAK抑制剂单独使用情况下改善的效果。

Description

小檗碱类似物与JAK抑制剂在胃肠道炎症性疾病治疗中的用途 技术领域
本发明涉及小分子药物领域，具体地，本发明提供了一种联合使用小檗碱类似物与JAK抑制剂，或者使用小檗碱类似物作为JAK抑制剂的制剂配方治疗胃肠道炎症性疾病的策略。
背景技术
JAK抑制剂如托法替尼已在美国和多个其它国家经审批通过以用于治疗患有中度到重度活动性类风湿性关节炎(rheumatoid arthritis，RA)的某些患者，近来，托法替尼已被美国FDA批准用于治疗中重度溃疡性结肠炎(ulcerative colitis，UC)。托法替尼在溃疡性结肠炎病人中具有类似于针对RA报道的全身性介导的不良事件。在针对托法替尼的临床试验中，报道了大量全身性介导的不良事件，包含增加比率的严重感染、机会性感染和恶性肿瘤；及实验室异常，例如淋巴球減少症、嗜中性白细胞减少症、肝酶升高、脂质升高和血清肌酐升高。因此，审批通过的美国产品XELJANZ/XEJANZ XR(商品名)带有详述各种安全风险的加框警告，包含严重感染和恶性肿瘤的风险。另外，由于考虑到托法替尼的总体安全概况，欧洲药品管理局(European Medicine Agency)在2013年投票决定不推荐托法替尼在RA的上市许可。因此，开发新一代更安全的JAK抑制剂药物在治疗局部发炎疾病时将需要限制其全身性暴露量。例如治疗UC时，增加托法替尼在胃肠道中的分布量，同时最小化托法替尼的全身性暴露量。
小檗碱(Berberine)又名黄连素，是从黄连等植物中提取的一种异喹啉生物碱。小檗碱是一种非常安全的药物，在传统中药的应用中已有一千多年历史。其生物利用度很低。临床上主要用于治疗腹泻、肠道感染等胃肠道疾病。近年来的研究也发现小檗碱在心血管疾病、糖脂代谢调控方面也具有一定的治疗前景。小檗红碱(Berberrubine)是小檗碱在体内的主要代谢产物。动物模型研究发现，小檗红碱对溃疡性结肠炎具有与小檗碱类似的治疗效果。然而截止目前，本领域尚缺乏提高小檗碱或其类似物的治疗效果的有效途径。
慢性肠炎主要包括溃疡性结肠炎和克罗恩病两种类型。这些慢性肠道炎性疾病病程漫长，常反复发作，且长期的炎症易发生癌变。近年来慢性肠炎发病率呈上升趋势。目前认为慢性肠炎的发病可能与遗传、环境、免疫和微生物有关，但其确切机制并不清楚。临床上的治疗以氨基水杨酸类药物、肾上腺糖皮质激素类药物及免疫抑制剂为主，但都存在一定的不良反应，如胃肠道不适、过敏反应等。综上所述，慢性炎症性肠道疾病迫切需要提供不良反应更少，治疗效果改善的胃肠道炎症性疾病治疗方案。JAK抑制剂在临床上已得到验证具有良好的抗炎 症效果，结合小檗碱类似物在调整肠道菌群，保护肠道屏障功能以及调节氧化应激等作用，两者协同作用可以达到更加优越的治疗胃肠道炎症性疾病的效果。同时药物组合可降低单药给药剂量，预期在临床上能减少单个药物剂量相关的不良反应。
发明内容
本发明提供了一种JAK抑制剂(优选为托法替尼或SHR0302)和小檗碱类似物(优选为小檗红碱)联合用药，所述的药物组合采用JAK抑制剂(优选为托法替尼)和小檗碱类似物(优选为小檗红碱)制备成药物组合物，或者先后施用，从而起到较相同剂量下单独使用更佳的治疗效果。
本发明的第一方面，提供了一种药物组合物，所述组合物包括：
(A)治疗有效量的第一活性成分，所述第一活性成分为小檗碱类似物，且所述的小檗碱类似物具有选自下组的结构：
Figure PCTCN2021083421-appb-000001
其中，
虚线表示化学键或无；
Ro、Rp、Rq、Rr、Rs和Rt各自独立地选自下组：H、羟基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基；
或位于同一原子上的两个Ro、Rp、Rq、Rr、Rs和Rt共同构成氧原子；
或位于相邻两个原子上的Ro、Rp、Rq、Rr、Rs和Rt与其连接的原子共同构成5-7元杂环；
其中，所述的取代指基团上的H原子被一个或多个选自下组的取代基取代：卤素、C1-C4烷基、苯基；
(B)治疗有效量的第二活性成分，所述第二活性成分为JAK抑制剂；
并且所述第一活性成分与所述第二活性成分的质量比为1-1000：1000-1。
在另一优选例中，所述第一活性成分与所述第二活性成分的质量比为1-10：10-1。
在另一优选例中，所述的小檗碱类似物选自下组：
Figure PCTCN2021083421-appb-000002
在另一优选例中，所述的小檗碱类似物选自下组：
Figure PCTCN2021083421-appb-000003
在另一优选例中，所述的小檗碱类似物选自下组：
Figure PCTCN2021083421-appb-000004
Figure PCTCN2021083421-appb-000005
在另一优选例中，所述的JAK抑制剂可以选自但不局限于下组：托法替尼(Tofacitnib)、鲁索替尼(Ruxolitinib)、奥拉西替尼(Oclacitinib)、巴利替尼(Baricitinib)、培非替尼(Peficitinib)、阿布罗替尼(Abrocitinib)、非戈替尼(Filgotinib)、乌帕替尼(Upadacitinib)、迪高替尼(Delgocitinib)伊他替尼(Itacitinib)、菲卓替尼(Fedratinib)、得克替尼(Decernotinib)、SHR-0302、AZD-4205、ASN-002、BMS-986165、PF-06700841、PF-06651600、R-348、INCB-52793、ATI-501、ATI-502、NS-018、KL-130008、Deuterium修饰的JAK抑制剂等。
在另一优选例中，所述的JAK抑制剂选自下组：
Figure PCTCN2021083421-appb-000006
Figure PCTCN2021083421-appb-000007
在另一优选例中，所述的药物组合物为肠溶制剂。
本发明的第二方面，提供了一种药盒，所述的药盒包括：
(A)含有小檗碱类似物的第一制剂；
(B)含有JAK抑制剂的第二制剂；和
(C)使用说明书；
且所述的小檗碱类似物具有选自下组的结构：
Figure PCTCN2021083421-appb-000008
其中，
虚线表示化学键或无；
Ro、Rp、Rq、Rr、Rs和Rt各自独立地选自下组：H、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基；
或位于相邻两个原子上的Ro、Rp、Rq、Rr、Rs和Rt与其连接的原子共同构成5-7元杂环；
其中，所述的取代指基团上的H原子被一个或多个选自下组的取代基取代：卤素、C1-C4烷基、苯基。
本发明的第三方面，提供了一种活性成分的组合，所述组合包括以下组分或由以下组分组合而成：
(A)第一活性成分，所述第一活性成分为小檗碱类似物或其衍生物；
(B)第二活性成分，所述第二活性成分为JAK抑制剂。
本发明的第四方面，提供了如本发明第一方面所述的组合物的用途，所述组合物用于制备治疗选自下组的疾病的药物组合物：胃肠道炎症性疾病(如溃疡性结肠炎、克罗恩氏病、与免疫检查点抑制剂疗法相关的结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、结肠袋炎、急/慢性胃炎，急/慢性阑尾炎)、胃肠道的自身 免疫病(如移植物抗宿主疾病、口炎性腹泻、自身免疫性肠病)、消化性溃疡、肠易激综合征、胃癌、食道癌、结肠癌。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1.托法替尼、小檗红碱以及托法替尼联合小檗红碱在恶唑酮诱导结肠炎模型中对疾病活动指数(DAI)的影响。每组用药及剂量如图所示。Tofa：托法替尼；BBR：小檗红碱；Oxa：恶唑酮。
图2.托法替尼联合小檗红碱显著性降低恶唑酮诱导结肠炎模型第1天至第5天的疾病活动指数DAI AUC以及基于每组平均值的Bliss独立模型协同效应分析。每组用药及剂量如图所示。Tofa：托法替尼；BBR：小檗红碱；Oxa：恶唑酮。
图3.JAK抑制剂SHR0302、小檗红碱以及SHR0302联合小檗红碱在恶唑酮诱导结肠炎模型中对疾病活动指数(DAI)的影响。每组用药及剂量如图所示。BBR：小檗红碱；Oxa：恶唑酮。
图4.SHR0302联合小檗红碱显著性降低恶唑酮诱导结肠炎模型第1天至第5天的疾病活动指数(DAI)AUC以及基于每组平均值的Bliss独立模型协同效应分析。每组用药及剂量如图所示。BBR：小檗红碱；Oxa：恶唑酮。
具体实施方式
本发明人经过长期而深入的研究发现，将JAK抑制剂与小檗碱类似物进行联用，对于胃肠道疾病的治疗相比较单药在同剂量下具有更优的治疗效果。基于上述发现，发明人完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
在本申请中，作为基团或是其它基团的一部分，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如 包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“C1-C6烷基”指含有1至6个碳原子的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“6-10元芳环”意指具有6-10个环原子的芳环，所述环原子为碳原子。所述芳环可以单环或双环。例如苯环、萘环等类似基团。
在本申请中，作为基团或是其它基团的一部分,术语“C1-C4烷氧基”是指具有1-4个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等
在本申请中，作为基团或是其它基团的一部分，术语“5-7元杂环”意指具有5-7个环原子的部分饱和或饱和的杂环，所述环原子至少有1个(可以是1个、2个或3个)是选自氮、氧和硫的杂原子。所述杂环可以单环或双环。例如，嘧啶并吡唑环、吡嗪并咪唑环、吡啶并吡唑环、吡啶并咪唑环、吡啶并嘧啶环、吡啶并吡啶环。
本发明化合物
本发明的化合物为式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐。
本发明的化合物可能含有一个或多个手性碳原子，因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald G消bitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL VOGEL 201002010and Protocols,Methods in Molecular Biology,Vol.243,2004,2004 Vol.243,20042004谱等方法。反应，如胃肠道不适、过敏反应等；Heller,Acc.Chem.Res.1990,23,128。
术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
本文所描述的化合物可含有一或多个手性中心。在这类情况下，特定立体异构体的描绘或命名意指所指示的立构中心具有指定的立体化学，其中应理解，除非另外指明，否则也可存在少量的其它立体异构体，其限制条件为所描绘或命名的化合物的效用并不由另一立体异构体的存在消除。
第一活性成分
本发明的药物组合物或药物组合中，第一活性成分为小檗碱类似物，且所述的小檗碱类似物具有选自下组的结构：
Figure PCTCN2021083421-appb-000009
Figure PCTCN2021083421-appb-000010
其中，
虚线表示化学键或无；
Ro、Rp、Rq、Rr、Rs和Rt各自独立地选自下组：H、羟基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基；
或位于同一原子上的两个Ro、Rp、Rq、Rr、Rs和Rt共同构成氧原子；
或位于相邻两个原子上的Ro、Rp、Rq、Rr、Rs和Rt与其连接的原子共同构成5-7元杂环；
其中，所述的取代指基团上的H原子被一个或多个选自下组的取代基取代：卤素、C1-C4烷基、苯基；
(B)治疗有效量的第二活性成分，所述第二活性成分为JAK抑制剂；
并且所述第一活性成分与所述第二活性成分的质量比为1-1000：1000-1。
在另一优选例中，所述第一活性成分与所述第二活性成分的质量比为1-10：10-1。
在另一优选例中，所述的小檗碱类似物选自下组：
Figure PCTCN2021083421-appb-000011
在另一优选例中，所述的小檗碱类似物选自下组：
Figure PCTCN2021083421-appb-000012
在另一优选例中，所述的小檗碱类似物选自下组：
Figure PCTCN2021083421-appb-000013
Figure PCTCN2021083421-appb-000014
第二活性成分
本发明的药物组合物或药物组合中，所述的JAK抑制剂可以选自但不局限于下组：托法替尼(Tofacitnib)、鲁索替尼(Ruxolitinib)、奥拉西替尼(Oclacitinib)、巴利替尼(Baricitinib)、培非替尼(Peficitinib)、阿布罗替尼(Abrocitinib)、非戈替尼(Filgotinib)、乌帕替尼(Upadacitinib)、迪高替尼(Delgocitinib)伊他替尼(Itacitinib)、菲卓替尼(Fedratinib)、得克替尼(Decernotinib)、SHR-0302、AZD-4205、ASN-002、BMS-986165、PF-06700841、PF-06651600、R-348、INCB-52793、ATI-501、ATI-502、NS-018、KL-130008、Deuterium修饰的JAK抑制剂等。
在另一优选例中，所述的JAK抑制剂选自下组：
Figure PCTCN2021083421-appb-000015
Figure PCTCN2021083421-appb-000016
应用
由于本发明的药物组合物具有优异的胃肠道炎症性疾病治疗效果，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗肠道功能疾病。
在本申请中，术语“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，术语“药学上可接受的赋形剂”包括但不限于任何被相关的政 府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
在本申请中，术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
在本申请中，术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
在本申请中，术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and RemingtoneminPharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
在本申请中，术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通 常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1 小檗红碱与托法替尼联合用药实验
1.1材料与方法
C57 BL/6雄性小鼠51只，6-10周，体重20-25g，由上海南方模式生物科技股份有限公司按无特殊病原体(SPF)动物饲养要求饲养。恶唑酮(4-Ethoxymethy-lene-2-phenyl-2-oxazolin-5-one)购自Sigma公司；便隐血试剂盒购自BASO生物；橄榄油购自Adamas公司；丙酮购自Greagent公司。
动物模型建立及处理:51只C57 BL/6小鼠，其中3只作为空白对照，其余48只小鼠参考Heller等方法建立恶唑酮诱导结肠炎模型。第1天将小鼠颈背部皮肤剃毛(2cm×2cm)，并涂抹3％恶唑酮溶液(溶解于丙酮加橄榄油4：1混合溶液中)150ul以致敏。致敏后的小鼠每日观察体重、活动度、毛色等情况。致敏第6天将小鼠随机分成7组，模型组、托法替尼(2mg/kg)组、托法替尼(10mg/kg)组、小檗红碱(2mg/kg)组、小檗红碱(20mg/kg)组、托法替尼(2mg/kg)+小檗红碱(2mg/kg)组和托法替尼(10mg/kg)+小檗红碱(2mg/kg)组，模型组8只动物，其余每组7只。每日灌胃给予相应药物，空白对照组和模型组给予溶剂，灌胃体积10mL/kg体重。致敏第7天灌肠，灌肠前将小鼠禁食12h不禁水，小鼠异氟烷吸入麻醉，观察活动和呼吸情况，忌麻醉过深，麻醉后，用一根一头接注射器的软管经小鼠肛门缓慢插入肠道深约3.5cm，模型组和治疗组各注入1.2％恶唑酮溶液(溶于50％乙醇)50μL，留置20秒后拔出导管，并将小鼠倒置30秒。空白对照组注入纯水。待麻醉清醒后均正常喂养。
1.2结果与分析
疾病活动指数(DAI)评分：动物给药后每天观察小鼠的体重、大便性状和便血情况，并根据表1进行DAI评分。连续评分5天。DAI＝体重下降分数+大便性状分数+便血分数。大便隐血的检测采用匹拉米洞半定量检测法。DAI评分标准如表1中所示：
表1 DAI评分标准
Figure PCTCN2021083421-appb-000017
Figure PCTCN2021083421-appb-000018
动物连续5天疾病活动指数DAI曲线如图1所示。计算得到连续5天DAI的AUC值以及基于每组平均值的Bliss独立模型协同效应分析见图2。结果显示，JAK抑制剂托法替尼联合小檗红碱和模型组比较，能显著改善疾病活动指数。且基于均值的Bliss独立模型协同效应分析表明，联合给药组与单药组托法替尼、小檗红碱相比较，具有显著的联合用药协同性。
实施例2 JAK抑制剂SHR0302与小檗红碱联合用药实验
2.1材料与方法
每日灌胃给予相应药物，空白对照组和模型组给予溶剂，灌胃体积10ml/kg体重。致敏第7天灌肠，灌肠前将小鼠禁食12h不禁水，小鼠异氟烷吸入麻醉，观察活动和呼吸情况，忌麻醉过深，麻醉后，用一根一头接注射器的软管经小鼠肛门缓慢插入肠道深约3.5cm，模型组和治疗组各注入1.2％恶唑酮溶液(溶于50％乙醇)50μL，留置20秒后拔出导管，并将小鼠倒置30秒。空白对照组注入纯水。待麻醉清醒后均正常喂养。
2.2.结果与分析
疾病活动指数(DAI)评分：动物给药后每天观察小鼠的体重、大便性状和便血情况，并根据表1进行DAI评分。连续评分5天。DAI＝体重下降分数+大便性状分数+便血分数。大便隐血的检测采用匹拉米洞半定量检测法。DAI评分标准如表1中所示。
动物连续5天疾病活动指数DAI曲线如图3所示。计算得到连续5天DAI的AUC值以及基于每组平均值的Bliss独立模型协同效应分析见图4。结果显示，JAK抑制剂SHR0302联合小檗红碱和模型组比较，能显著的改善疾病活动指数。且基于均值的Bliss独立模型协同效应分析表明，联合给药组与单药组相比较，具有显著药效协同性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种药物组合物，其特征在于，所述组合物包括：
    (A)治疗有效量的第一活性成分，所述第一活性成分为小檗碱类似物，且所述的小檗碱类似物具有选自下组的结构：
    Figure PCTCN2021083421-appb-100001
    其中，
    虚线表示化学键或无；
    Ro、Rp、Rq、Rr、Rs和Rt各自独立地选自下组：H、羟基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基；
    或位于同一原子上的两个Ro、Rp、Rq、Rr、Rs和Rt共同构成氧原子；
    或位于相邻两个原子上的Ro、Rp、Rq、Rr、Rs和Rt与其连接的原子共同构成5-7元杂环；
    其中，所述的取代指基团上的H原子被一个或多个选自下组的取代基取代：卤素、C1-C4烷基、苯基；
    (B)治疗有效量的第二活性成分，所述第二活性成分为JAK抑制剂；
    并且所述第一活性成分与所述第二活性成分的质量比为1-1000：1000-1。
    在另一优选例中，所述第一活性成分与所述第二活性成分的质量比为1-10：10-1。
  2. 如权利要求1所述的组合物，其特征在于，所述的小檗碱类似物选自下组：
    Figure PCTCN2021083421-appb-100002
  3. 如权利要求1所述的组合物，其特征在于，所述的小檗碱类似物选自下组：
    Figure PCTCN2021083421-appb-100003
  4. 如权利要求1所述的组合物，其特征在于，所述的小檗碱类似物选自下组：
    Figure PCTCN2021083421-appb-100004
    Figure PCTCN2021083421-appb-100005
  5. 如权利要求1所述的组合物，其特征在于，所述的JAK抑制剂可以选自但不局限于下组：托法替尼(Tofacitnib)、鲁索替尼(Ruxolitinib)、奥拉西替尼(Oclacitinib)、巴利替尼(Baricitinib)、培非替尼(Peficitinib)、阿布罗替尼(Abrocitinib)、非戈替尼(Filgotinib)、乌帕替尼(Upadacitinib)、迪高替尼(Delgocitinib)伊他替尼(Itacitinib)、菲卓替尼(Fedratinib)、得克替尼(Decernotinib)、SHR-0302、AZD-4205、ASN-002、BMS-986165、PF-06700841、PF-06651600、R-348、INCB-52793、ATI-501、ATI-502、NS-018、KL-130008、Deuterium修饰的JAK抑制剂等。
  6. 如权利要求1所述的组合物，其特征在于，所述的JAK抑制剂选自下组：
    Figure PCTCN2021083421-appb-100006
    Figure PCTCN2021083421-appb-100007
  7. 如权利要求1所述的药物组合物，其特征在于，所述的药物组合物为肠溶制剂。
  8. 一种药盒，其特征在于，所述的药盒包括：
    (A)含有小檗碱类似物的第一制剂；
    (B)含有JAK抑制剂的第二制剂；和
    (C)使用说明书；
    且所述的小檗碱类似物具有选自下组的结构：
    Figure PCTCN2021083421-appb-100008
    其中，
    虚线表示化学键或无；
    Ro、Rp、Rq、Rr、Rs和Rt各自独立地选自下组：H、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基；
    或位于相邻两个原子上的Ro、Rp、Rq、Rr、Rs和Rt与其连接的原子共同构成5-7元杂环；
    其中，所述的取代指基团上的H原子被一个或多个选自下组的取代基取代：卤素、C1-C4烷基、苯基。
  9. 一种活性成分的组合，其特征在于，所述组合包括以下组分或由以下组分组合而成：
    (A)第一活性成分，所述第一活性成分为小檗碱类似物或其衍生物；
    (B)第二活性成分，所述第二活性成分为JAK抑制剂。
  10. 如权利要求1所述的组合物的用途，其特征在于，所述组合物用于制备治疗选自下组的疾病的药物组合物：胃肠道炎症性疾病(如溃疡性结肠炎、克罗恩氏病、与免疫检查点抑制剂疗法相关的结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、结肠袋炎、急/慢性胃炎，急/慢性阑尾炎)、胃肠道的自身免疫病(如移植物抗宿主疾病、口炎性腹泻、自身免疫性肠病)、消化性溃疡、肠易激综合征、胃癌、食道癌、结肠癌。
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