[go: up one dir, main page]

WO2022194166A1 - Utilisation d'analogue de méthotrexate dans le traitement d'une maladie cutanée inflammatoire - Google Patents

Utilisation d'analogue de méthotrexate dans le traitement d'une maladie cutanée inflammatoire Download PDF

Info

Publication number
WO2022194166A1
WO2022194166A1 PCT/CN2022/081003 CN2022081003W WO2022194166A1 WO 2022194166 A1 WO2022194166 A1 WO 2022194166A1 CN 2022081003 W CN2022081003 W CN 2022081003W WO 2022194166 A1 WO2022194166 A1 WO 2022194166A1
Authority
WO
WIPO (PCT)
Prior art keywords
methotrexate
mtx
pharmaceutically acceptable
methotrexate analog
tautomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/081003
Other languages
English (en)
Chinese (zh)
Inventor
何颖
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nuomed Beijing Biomedicine Co Ltd
Original Assignee
Nuomed Beijing Biomedicine Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nuomed Beijing Biomedicine Co Ltd filed Critical Nuomed Beijing Biomedicine Co Ltd
Publication of WO2022194166A1 publication Critical patent/WO2022194166A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/495—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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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

  • This document relates to, but is not limited to, medical technology, especially but not limited to the use of methotrexate analogs for the treatment of inflammatory skin diseases.
  • Psoriasis commonly known as "psoriasis", seriously affects the quality of life of patients. Psoriasis is a chronic relapsing inflammatory skin disease with unknown etiology, complex pathogenesis, and numerous treatment methods, but there is no ideal cure at present. In particular, two severe types of psoriasis, generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP), are dangerous and can cause various complications and are difficult to treat. great pain. GPP is characterized by yellowish-white latent sterile small pustules on the basis of diffuse erythema on the trunk and extremities, often accompanied by symptoms such as high fever and general malaise.
  • GPP generalized pustular psoriasis
  • EP erythrodermic psoriasis
  • GPP erythema
  • MTX Tripterygium wilfordii
  • PUVA psoralen long-wave ultraviolet
  • glucocorticoids are mostly used.
  • tumor necrosis factor (TNF)- ⁇ inhibitors have also been gradually applied in the treatment of severe types of psoriasis.
  • Glucocorticoids have a fast onset and significant curative effect, but when the dose of glucocorticoids is reduced or withdrawn, the disease often recurs or even worsens; in recent years, the development of new drugs for psoriasis has become a hot spot in international research, biological agents and small molecule targets Xiangyao is two types of representative drugs.
  • Methotrexate is an antifolate antineoplastic drug. It mainly inhibits the synthesis of tumor cells through the inhibition of dihydrofolate reductase, and inhibits the growth and reproduction of tumor cells. The infiltration of lymphocytes in the dermis and the excessive proliferation of epidermal keratinocytes are one of the causes of psoriasis. MTX has an effective therapeutic effect on psoriasis from the aspects of anti-epidermal hyperplasia and anti-lymphocyte infiltration. Low-dose oral methotrexate is also used clinically for the treatment of psoriasis. However, its wide application in the clinical treatment of psoriasis is limited due to its large toxic and side effects.
  • MTX inhibits DNA synthesis, prevents epithelial proliferation, enhances apoptosis of activated T cells and inhibits neutrophil chemotaxis by inhibiting the action of dihydrofolate reductase.
  • MTX can also reduce the synthesis of a series of pro-inflammatory cytokines such as TNF- ⁇ and interleukin (IL)-1, so the anti-inflammatory effect of MTX can play a role in the treatment of psoriasis.
  • pro-inflammatory cytokines such as TNF- ⁇ and interleukin (IL)-1
  • methotrexate analog for the treatment of inflammatory skin diseases
  • methotrexate analog is shown in formula (I), or its tautomer, or stereoisomer, or Racemate, or pharmaceutically acceptable salt, or hydrate:
  • the methotrexate analog provided by the present application is used for the treatment of an inflammatory skin disease, and the inflammatory skin disease is psoriasis.
  • the use of the methotrexate analog provided by the present application for the treatment of inflammatory skin diseases is shown in formula (Ia), or its tautomerism Conforms, or pharmaceutically acceptable salts, or hydrates:
  • the pharmaceutically acceptable salts described in the present application include inorganic acid salts or organic acid salts, including salts formed with organic and inorganic acids or bases; here, the pharmaceutically acceptable salts Acid salts are selected from salts formed with one or more of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, ethylenedicarbonate acid, fumaric acid, maleic acid, butanone diacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and isethionic acid.
  • Pharmaceutically acceptable base salts are selected from ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and organic bases such as dicyclohexylamine and N-methyl- one or more of D-glucosamine) salts.
  • the use of the methotrexate analog provided by the present application for the treatment of inflammatory skin diseases is in the form of a pharmaceutical composition, and is administered to a patient in need thereof.
  • the pharmaceutical composition comprises a therapeutically effective amount of methotrexate analog as shown in formula (I) or as shown in formula (Ia), or a tautomer thereof, or a pharmaceutically acceptable salt, or hydrate, and a pharmaceutically acceptable carrier or excipient.
  • the effective dose may be 5 mg-200 mg in a unit dose.
  • parenteral dosage forms can be prepared according to methods known in the art for administering the pharmaceutical composition to patients in need thereof, which are suitable for human or animal use.
  • the compounds of the present application can be prepared into injection preparations, such as solutions, suspension solutions, emulsions, lyophilized powder injections, such preparations may be aqueous or non-aqueous, and may contain one or more pharmacological effects Scientifically acceptable carriers, diluents, preservatives, surfactants, cosolvents, buffers, pH adjusters. These excipients are commonly used in the art.
  • the medicament or pharmaceutical composition of the present application can be administered by any known administration method; it can be administered 1-6 times a day.
  • the methotrexate analog of the present application or its pharmaceutical composition can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs, when the methotrexate analog of the present application is used with other therapeutic drugs
  • those skilled in the art can adjust its dosage according to the actual situation.
  • the methotrexate analogs or the pharmaceutical compositions thereof provided by the present application are used for the treatment of inflammatory skin diseases, where the inflammatory skin diseases include but are not limited to psoriasis, or skin cancer.
  • the present application provides a preparation method of the above-mentioned methotrexate analogs, and the preparation method comprises the following steps:
  • methotrexate analog MTX-1 was synthesized by the following reaction formula through the hydroxylation of the 7-position of methotrexate.
  • methotrexate analog (MTX-1) provided in this application can be a metabolite of methotrexate in vivo, and its toxicity is significantly reduced compared to the original drug.
  • the experimental results also show that the methotrexate analogues provided by the present application can significantly target skin distribution in animals, significantly reduce systemic toxicity, especially liver toxicity, and the anti-psoriasis drug effect is significantly better than that of the same dose. Methotrexate, and thus MTX-1, can be made into a less toxic and effective anti-psoriasis drug.
  • Fig. 1 is the synthetic 1 H-NMR spectrum of the compound MTX-1 of the embodiment of the application;
  • Fig. 2 is the synthetic (-) ESI-MS spectrum of the compound MTX-1 of the embodiment of the application;
  • Figure 3 shows the body weight of mice before the animal experiment (left) and after the animal experiment (right);
  • Figure 4 shows the comparison results of the area of psoriasis-like skin lesions and the PASI score of the disease severity; among them, the three points in Figure 4 are added to obtain the total score; B, erythema at the mouse skin lesion, C, scale (scales), and D infiltration thickening degree (thickness);
  • FIG. 5 Comparison results of histopathological scores of psoriasis skin; wherein, in Fig. 5, A, stratum corneum; B, epidermis; C, dermis; D, total score;
  • Figure 6 is an image of methotrexate MTX and the methotrexate analog MTX-1.
  • Reagents methotrexate; methanol; BF3 - OEt3 : boron trifluoride diethyl ether; DEPC: diethyl cyanophosphate; TEA: triethylamine; NMP: N-methylpyrrolidone; THF: tetrahydrofuran.
  • the compound MTX-1 was synthesized by the following reaction formula through the hydroxylation of the 7-position of methotrexate.
  • the specific operations are as follows: accurately weigh 1 g of methotrexate, add 10 ml of methanol to dissolve, add an appropriate amount of BF 3 -OEt 3 and stir at room temperature overnight to obtain dimethyl methotrexate, drain and wash with water and filter; Add 10 ml each of deionized water, NMP, DEPC and TEA, stir at room temperature overnight to obtain 7-nitrile methotrexate dimethyl ester; add 10 ml of 10 mM NaOH aqueous solution to the reaction solution, stir at room temperature overnight, extract with THF, evaporate Dry, preparative liquid phase separation and purification to obtain the compound methotrexate analog MTX-1.
  • Liquid mass detection HPLC-MS/MS, LCMS-IT-TOF Shimadzu, ESI negative
  • MTX-1 7-hydroxymethotrexate
  • Molecular weight 470 (see Figure 2), [M-H]-, m/z 469 .
  • the rats were given by gavage or intraperitoneal injection, once a day, for 7 consecutive days.
  • Negative control group daily gavage with distilled water.
  • Positive control drug group MTX, 1.5 mg/kg, administered by gavage every day.
  • the area of psoriasis-like skin lesions and the severity of disease-PASI (psoriasis area and severity index) scores were performed on the animals every day from the day after the first modeling. According to the PASI scoring standard, erythema, scales, and infiltration thickness at the skin lesions of mice were given a score of 0-4, and the three scores were added up to obtain a total score.
  • PASI scoring standard erythema, scales, and infiltration thickness at the skin lesions of mice were given a score of 0-4, and the three scores were added up to obtain a total score.
  • PASI scoring criteria 0, none; 1, mild; 2, moderate; 3, severe; 4, very severe.
  • MTX-po-1.5mg/kg In the MTX administration group (MTX-po-1.5mg/kg), one died on the 6th day and two died on the 7th day. The animals in the other groups survived normally, indicating that the MTX group had high toxicity, and the MTX-1 group had significantly lower toxicity.
  • MTX-po 1.5mg/kg, MTX-1-po 1.5mg/kg, MTX-1-ip 1.5mg/kg dose groups significantly improved skin damage in mice; Oral or intravenous injection was better than MTX group.
  • methotrexate analog MTX-1 1.5mg/kg can significantly reduce the skin lesions symptoms of mouse psoriasis model, and it is better than the same dose of positive control drug MTX treatment group; MTX administration group 2 Only one animal died, and the animals in the methotrexate analog MTX-1 group had normal activities, indicating that the structural modification of the methotrexate analog MTX-1 significantly reduced the toxicity.
  • mice weighing about 20g, were randomly divided into two groups (MTX and MTX-1 administration groups), and were administered by tail vein injection at a dose of 1.5 mg/kg. , 2, 4 h CO 2 were sacrificed, 3 at each time point, fixed in 2.5% sodium carboxymethyl cellulose gel solution after sacrifice, and frozen at -80 °C.
  • a CM1860 XP cryostat was used to make 25 ⁇ m sagittal whole animal sections to expose major organs such as brain, heart, liver, spleen, lung, and kidney. After the sections were freeze-dried, the optical photos of the sections were obtained by scanning, and the distribution of MTX and MTX-1 in the whole animal was obtained by mass spectrometry imaging analysis.
  • MTX-1 After MTX is structurally modified to MTX-1, the target organ is changed from liver to skin. Therefore, MTX-1 has significant targeting to the skin, and provides effective experimental data support for reducing the liver toxicity of MTX and improving the therapeutic index.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un analogue de méthotrexate dans le traitement d'une maladie cutanée inflammatoire. L'analogue de méthotrexate présente non seulement une forte activité et une faible toxicité et de faibles effets secondaires, mais peut également cibler la peau d'une manière distribuée de façon à être utilisé en tant que médicament anti-psoriasis ou anti-cancer cutané de nouvelle génération.
PCT/CN2022/081003 2021-03-17 2022-03-15 Utilisation d'analogue de méthotrexate dans le traitement d'une maladie cutanée inflammatoire Ceased WO2022194166A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110305060.4 2021-03-17
CN202110305060 2021-03-17

Publications (1)

Publication Number Publication Date
WO2022194166A1 true WO2022194166A1 (fr) 2022-09-22

Family

ID=81775017

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/081003 Ceased WO2022194166A1 (fr) 2021-03-17 2022-03-15 Utilisation d'analogue de méthotrexate dans le traitement d'une maladie cutanée inflammatoire

Country Status (2)

Country Link
CN (1) CN114569615B (fr)
WO (1) WO2022194166A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007961A1 (fr) * 2001-07-20 2003-01-30 Iomed, Inc. Methodes permettant de traiter des irregularites oculaires neoplasiques, angiogeniques, fibroplastiques et/ou immuno-suppressives par l'administration de medicaments a base de methotrexate et dispositifs iontophoretiques oculaires destines a administrer lesdits medicaments a base de methotrexate
IN2004MU01108A (fr) * 2004-10-15 2005-11-18 Khandelwal Sanjeev
WO2007017512A1 (fr) * 2005-08-09 2007-02-15 Cellzome Ag Traitement de maladies inflammatoires
WO2011133748A1 (fr) * 2010-04-21 2011-10-27 University Of Medicine And Dentistry Of New Jersey Traitements pour troubles de type prolifération cellulaire et leur identification

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007961A1 (fr) * 2001-07-20 2003-01-30 Iomed, Inc. Methodes permettant de traiter des irregularites oculaires neoplasiques, angiogeniques, fibroplastiques et/ou immuno-suppressives par l'administration de medicaments a base de methotrexate et dispositifs iontophoretiques oculaires destines a administrer lesdits medicaments a base de methotrexate
IN2004MU01108A (fr) * 2004-10-15 2005-11-18 Khandelwal Sanjeev
WO2007017512A1 (fr) * 2005-08-09 2007-02-15 Cellzome Ag Traitement de maladies inflammatoires
WO2011133748A1 (fr) * 2010-04-21 2011-10-27 University Of Medicine And Dentistry Of New Jersey Traitements pour troubles de type prolifération cellulaire et leur identification

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EIVIND SMELAND, ROY M. BREMNES, ANDERS ANDERSEN, RAGNHILD JÆGER, TOR J. EIDE, NILS-E HUSEBY, JARLE AARBAKKE : "Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat", CANCER CHEMOTHERAPY AND PHARMACOLOGY, SPRINGER VERLAG , BERLIN, DE, vol. 34, no. 2, 1 March 1994 (1994-03-01), DE , pages 119 - 124, XP009539759, ISSN: 0344-5704, DOI: 10.1007/BF00685928 *
M I DAWSON, D O'KRONGLY, P D HOBBS, J R BARRUECO, F M SIROTNAK: "Synthesis of the 7-Hydroxy Metabolites of Methotrexate and 10-Ethyl-10-Deazaaminopterin", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN CHEMICAL SOCIETY AND AMERICAN PHARMACEUTICAL ASSOCIATION, US, vol. 76, no. 8, 1 August 1987 (1987-08-01), US , pages 635 - 638, XP009539761, ISSN: 0022-3549, DOI: 10.1002/jps.2600760810 *

Also Published As

Publication number Publication date
CN114569615A (zh) 2022-06-03
CN114569615B (zh) 2024-03-29

Similar Documents

Publication Publication Date Title
JP7742226B2 (ja) 新たな医薬品使用
JP2018048178A (ja) オキサビシクロヘプタン類、および再灌流障害の治療のためのオキサビシクロヘプタン類
CN112716930A (zh) 贝壳杉烷类化合物在制备抑制组织、器官病理性纤维化和重构的药物应用
KR0124817B1 (ko) 4-퀴놀린 카복실산 유도체를 포함하는 피부 및 점막-상피성 질환 치료용 약제학적 조성물
WO2019206159A1 (fr) Utilisation d'acide chlorogénique et d'une composition de ce dernier dans la préparation d'un médicament pour le traitement du sarcome
CA2656017C (fr) Utilisation de derives de pyridone destines a prevenir et traiter par radioactivite une lesion des poumons
EP0373663B1 (fr) Les esters de castanospermine pour l'inhibition de la métastase de tumeurs
CN116549602B (zh) Awrk6多肽在制备治疗银屑病药物中的用途
CN116655654A (zh) 一类n-取代苯基-2-吡啶酮内过氧化物及其应用
WO2022194166A1 (fr) Utilisation d'analogue de méthotrexate dans le traitement d'une maladie cutanée inflammatoire
WO2019214723A1 (fr) Application de l'acide chlorogénique et de compositions de ce dernier dans la préparation de médicaments pour le traitement du carcinome épidermoïde
CN114699410A (zh) 千金藤素用于制备治疗类风湿关节炎药物的用途
CN111228319A (zh) 鸦胆子提取物及其制备方法和在防治乳腺癌方面的应用
US20250000819A1 (en) Anti-hypoxic/anoxic injury use of a magnolol and/or honokiol aromatic ring amino-substituted derivative, and a pharmaceutical composition
CN117357523A (zh) 利拉萘酯在制备预防和治疗肺纤维化药物中的用途
CN117229147A (zh) 一类3,4-二羟基苯甲酸酯化合物及其制备方法与用途
EP3608313B1 (fr) Dérivé de 15-idène-14-désoxy-11,12-déshydroandrographolide et son application dans la préparation de médicaments anti-fibrose
JP2002523361A (ja) 白金錯化合物含有医薬並びにその使用
CN114788822A (zh) 野黄芩素在制备治疗胰腺癌药物中的应用
CN112851626A (zh) 一类左旋双环吗啉，其制备方法、药物组合物和应用
JP3834089B2 (ja) ベンズイミダゾール誘導体を含有するぜん息治療剤
CN119970717B (zh) β-内酰胺类化合物在制备抗炎药物中的应用
CN119431337B (zh) 含酰胺和三嗪结构化合物及其抗肺纤维化应用
CN114681476B (zh) 一种环烯醚萜苷化合物抗特发性肺纤维化的用途
CN111606909B (zh) 吡唑并嘧啶类化合物及其药物组合物及制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22770519

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22770519

Country of ref document: EP

Kind code of ref document: A1