EP1523312A1 - Erhöhung der haem-oxygenase mit rheinderivaten - Google Patents

Erhöhung der haem-oxygenase mit rheinderivaten

Info

Publication number
EP1523312A1
EP1523312A1 EP03750824A EP03750824A EP1523312A1 EP 1523312 A1 EP1523312 A1 EP 1523312A1 EP 03750824 A EP03750824 A EP 03750824A EP 03750824 A EP03750824 A EP 03750824A EP 1523312 A1 EP1523312 A1 EP 1523312A1
Authority
EP
European Patent Office
Prior art keywords
rhein
use according
diacerein
derivative
treatment
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.)
Withdrawn
Application number
EP03750824A
Other languages
English (en)
French (fr)
Inventor
Suzy Charbit
François SCHUTZE
Diego Provvedini
Hervé FICHEUX
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.)
Negma Lerads SA
Original Assignee
Negma Lerads SA
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 Negma Lerads SA filed Critical Negma Lerads SA
Publication of EP1523312A1 publication Critical patent/EP1523312A1/de
Withdrawn legal-status Critical Current

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the treatment in human or animal therapy of conditions requiring an increase in the level of the enzyme heme oxygenase, by administration of an effective dose of rhein or diacerein or one of their salts or esters, as well as the use of rhein or diacerein or a salt or ester thereof for the manufacture of a medicament for the treatment of conditions requiring an elevation of the level of the enzyme heme oxygenase, by acting on the causes of certain conditions acute and chronic, ensuring the prevention and inhibition of the effects of stress on cells and tissues, and ensuring the prevention and treatment of rejection of organ and tissue transplants.
  • the reaction of the immune system is a pathophysiological mechanism of response to several types and forms of aggression that target the body ("stress"). This reaction can be responsible for several important pathological forms, referenced for example in Harrison's Principles of Internai Medicine, 14th edition (1998), 749-754.
  • Stress a pathophysiological mechanism of response to several types and forms of aggression that target the body
  • This reaction can be responsible for several important pathological forms, referenced for example in Harrison's Principles of Internai Medicine, 14th edition (1998), 749-754.
  • a large number of studies have been devoted to the mediators responsible for triggering the reaction of the elements of the immune system, and to the pharmacological and therapeutic control of this reaction in its initial phases. These studies have made it possible to produce and market effective drugs, for example in the treatment of acute inflammation.
  • the protective mechanisms and the body's response to stress can control the causes that underlie the reaction, and stop the process. Indeed, researchers have often found that the reaction of elements of the immune system, after a first acute phase, could then decrease in a second phase. However, few studies have addressed the question of the spontaneous benign evolution of this reaction, and of its pharmacological and therapeutic control. Because of the persistence of the causes, and / or the ineffectiveness of the treatment, the reaction of the elements of the immune system to stress can become chronic. The transition to chronicity is frequent, can present itself under several important pathological aspects, referenced in particular in Tar owski A. et al. Mol. Med.
  • HO-1 represents the level of the heme oxygenase -1
  • iNOS the inducible nitric oxide synthetase
  • PGE 2 prostaglandin E 2
  • HSP heat-shock proteins
  • HSP32 heat-shock protein 32K
  • HSPs form a family of proteins whose expression is stimulated by stress (heat, hypoxia, oxidation, poisoning by metals, etc.), as verified in experiments carried out by the applicant in vitro on cultures of mouse macrophages , human chondrocytes, and cartilage isolated from the rat femoral head.
  • HSPs play a very important role in defense mechanisms and cellular repair in the face of stress.
  • HO-1 exerts a very important modulating effect during the inflammatory response: a rise in the level of the enzyme is accompanied by a suppression of the inflammation, while an inhibition results in an increase in the inflammatory response (Nature Medicine (1996) 2: 87-90).
  • the discovery of HO-1 and the appreciation of its effects suggested the possibility of pharmacological and therapeutic control of the cellular response to stress; indeed, it would be advantageous to be able to have drugs capable of promoting and / or maintaining the elevation of the level of the HO-1 enzyme, to be used during the treatment of several conditions which induce cellular and tissue stress, such as than observed especially in immunosuppressed patients.
  • diacerein In human medicine, diacerein has been administered to patients with osteoarthritis, who have pain and difficulty moving. In addition, treatment with diacerein slows the progression of osteoarthritis disease, with good job security. However, diacerhein as well as rhein have moderate symptomatic anti-inflammatory and analgesic activity in the acute phase of osteoarthritis (Nguyen et al., Arthritis and Rheumatism (1994) 37: 529-536).
  • rhein, or diacerein, or their salts or esters also has the effect of protecting the organism against the degradation of organs and tissues, and in particular cartilage, on the part of the cells of the system. immune, and to control the phenomena that occur in response to organ and tissue transplants, which makes it possible to envisage their use in the prevention and treatment of rejection of organ and tissue transplants.
  • the present invention therefore relates to the use of diacerein, and more generally rhein and rhein derivatives, in human and veterinary therapy in the treatment of conditions requiring a high level of the enzyme heme oxygenase, in the prevention and the inhibition of the effects of stress on cells and tissues, and for the prevention and treatment of organ and tissue transplant rejection.
  • Another subject of the invention is the use of rhein and rhein derivatives, in particular diacerein, for the manufacture of a medicament for the treatment of a condition requiring a high level of heme oxygenase.
  • R represents a hydrogen atom, or an alkyl group, for example a methyl, ethyl or propyl group, or an alkali or alkaline earth metal atom, for example a sodium, potassium or calcium atom
  • Ri and R 2 identical or different, represent a hydroxy group or an acyloxy group of formula R'-COO- in which R 'is an alkyl group of 1 to 4 carbon atoms, for example a methyl, ethyl or isopropyl group.
  • R preferably represents a hydrogen atom
  • R 1 and R 2 preferably represent a hydroxy or acetoxy group.
  • the general formula (I) above in which R is a hydrogen atom and Ri and R 2 are an acetoxy group -COOCH 3 is that of diacerein.
  • Diacerein and rhein can be prepared by methods known in the art, and for example from extracts of aloe or senna leaf, such as sennosides, or by acetylation of barbaloin followed by oxidation by chromium oxide.
  • the diacerein obtained by these processes can be purified if necessary to achieve a product that perfectly meets pharmaceutical standards and offers all the desired guarantees.
  • the studies carried out by the applicant to demonstrate the effect of diacerein, rhein and their salts or esters on HO-1 were carried out using validated models, as indicated below.
  • the work and experiments in vi tro used the following models: 1.- A validated tissue culture model, and in particular the cartilage of the femoral head of a rat, treated with erythrocytes (in% w / v), erythrocyte lysate (3xl0 6 ), or hemoglobin (in% w / v) , without and after heat stress (lh at 43 ° C). Cartilage integrity was measured by the incorporation of radioactive sulfate ( 35 SO 4 ; in counts per minute, CPM). In this model, erythrocytes, erythrocyte lysate and hemoglobin cause cell destruction, demonstrated by decreased cell viability and the incorporation of radioactive sulfate by cells, as shown in Figures 3 and 4.
  • The- A validated cell culture model, and in particular human chondrocytes, treated with erythrocytes (in% w / v), erythrocyte lysate (3xlO ⁇ ), or hemoglobin (in% w / v), without and after thermal stress (lh at 43 ° C).
  • Cell integrity was measured by cell viability (living cells versus control), presence of apoptosis (nuclear fragmentation; number and percentage versus control), and incorporation of radioactive sulfate ( 3 S0 4 ; in strokes per minute, CPM).
  • Figures 7b and 7c are also "Western blots" of cells (model: mouse macrophages) cultivated without and with diacerein (Figure 7b: columns' ⁇ and columns “D €", respectively) or rhein (Figure 7c) to a concentration of 10 "5 M, and then analyzed at 15, 30 and 60 minutes ( Figure 7b) and 0, 15, 30, 60, 120 minutes as well as 18 hours ( Figure 7c).
  • the identity of the protein interest, HO-1 was confirmed with respect to its molecular weight (32 kilodalton; kDa) determined on a reference scale (first column left in Figures).
  • FIG. 9 shows that treatment with rhein prevents apoptosis caused by the erythrocyte lysate.
  • Diacerheine, rhein, and their salts or esters increase in a dose-dependent manner the levels of the enzyme HO-1 which plays a role in the protection of cellular integrity;
  • diacerein, rhein, and their salts or esters preserve the integrity of cells and tissues in the face of deleterious reactions induced by stress; - Diacerheine, rhein, and their salts or esters prevent apoptosis (fragmentation of the nucleus, followed by the destruction and death of cells).
  • the Applicant has also carried out work and experiments in vivo, with the use of the model described below.
  • the method includes the following steps:
  • the isolated tissues istar rat, male
  • the subcutaneous implants are stored over a period of 2 weeks;
  • Figure 10 shows that the treatment with diacerhein decreases the tissue reaction (formation of the reactive granuloma) depending on the dose (diacerhein: 5, 15 and 50 mg / kg, orally; ** statistically significant difference compared to the control : p ⁇ 0.01).
  • Figure 11 shows that the tissue reaction caused by the implantation of rat tissue in mice is reduced by the dose-dependent treatment with diacerein. (left in Figure 11: number of inflammatory cells; right: volume of exudate) (Cont .: control; diacerein: 5, 15 and 50 mg / kg, orally; * statistically significant difference compared to control: p ⁇ 0.05).
  • Figure 12 shows that treatment with diacerein preserves the integrity of the transplanted tissue as a function of the dose of diacerein, which is demonstrated by the conservation of the content of collagen (on the left in Figure 12) and of glycosamino. -glycan (GAG; right) in the transplanted tissue (diacerhein: 5, 15 and 50 mg / kg, orally; statistically significant differences versus control: * p ⁇ 0.05: ** p ⁇ 0.01).
  • tissue reaction size of the granuloma, number of inflammatory cells, volume of exudate caused by the implantation of rat tissue in the mouse;
  • - diacerein, rhein, and their salts or esters preserve the integrity of the transplanted tissues in the face of the tissue reaction; - diacerein, rhein, and their salts or esters prevent the destruction and rejection of the transplanted tissue.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-1 constitutive isoform
  • COX-2 isoform induced in the establishment of inflammation
  • COX-2 inhibitors such as celecoxib and rofecoxib, have been developed for the symptomatic treatment of inflammatory diseases.
  • Figure 13 shows the comparison of the effects of treatment with a COX-2 inhibitor (rofecoxib) on the one hand, and diacerein on the other hand, on the decrease in tissue reaction (formation of a reactive granuloma) caused by the implantation of rat tissue in mice (diacerhein: 5, 15 and 50 mg / Kg, and rofecoxib: 3 mg / kg, orally; statistically significant differences from the control: * p ⁇ 0.05 ; ** p ⁇ 0.01).
  • Figure 14 compares the effects of treatment with rofecoxib on the one hand, and diacerein on the other, on the decrease in tissue reaction caused by implantation of rat tissue in mice.
  • the graph on the left illustrates cell infiltration, and the graph on the right shows the volume of exudate (Cont .: control; DAR: diacerein: 2, 10 and 50 mg / kg, and rofecoxib: 3 mg / Kg, orally; statistically significant difference compared to control: * p ⁇ 0.05).
  • Figure 15 compares the differences in the effects of treatment with rofecoxib on the one hand, and diacerein on the other, on preserving the integrity of the transplanted tissue.
  • the graph on the left corresponds to the collagen content, that on the right to the glycosaminoglycan (GAG) content in the tissue (diacerhein: 5, 15 and 50 mg / Kg, and rofecoxib: 3 mg / Kg, by oral route; statistically significant differences versus control: * p ⁇ 0.05: ** p ⁇ 0.01).
  • GAG glycosaminoglycan
  • diacerhein and rhein have significantly different properties from those of other drugs, such as conventional non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors, in particular on the preservation of transplanted tissue and rejection of that tissue.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 inhibitors in particular on the preservation of transplanted tissue and rejection of that tissue.
  • diacerhein, or rhein, or their salts and esters with a conventional NSAID or with a COX-2 inhibitor, the actions of which may be complementary, depending on the pathology. treated.
  • Diacerein can therefore be combined with an NSAID such as diclofenac at a dose between 25 and 150 mg per day, or with a COX-2 inhibitor like rofecoxib at a dose between 10 and 50 mg per day.
  • diacerhein, rhein, as well as their salts and esters can be advantageously used in human and veterinary therapy for the treatment of conditions requiring a high level of the enzyme heme oxygenase, in the prevention and inhibition of effects of stress on cells and tissues, and for prevention and treatment of rejection of tissue and organ transplants.
  • their use at the doses indicated is very particularly useful for the treatment of the conditions indicated below.
  • - inflammations associated with Type I and II diabetes such as peripheral neuropathy and chronic skin ulcer
  • connectivities such as lupus erythematosus, scleroderma, sarcoidosis
  • Diacerein and rhein have a low solubility in water and in alcohols, and are therefore preferably administered orally.
  • the usual oral administration forms in the pharmaceutical field are suitable, and for example, the medicament can be administered in the form of tablets, gelatin capsules or soft gelatin capsules, or any other suitable galenical form.
  • a particularly suitable form of administration is that described in patent EP 862423 describing capsules or gelatin capsules in which the diacerein is mixed with a liquid oil and a nonionic surfactant, making it possible to obtain good bioavailability.
  • Another form which can be used in the invention, described in US Pat. No. 6,124,358, is prepared by comicronisation of rhein or diacerein with a lauryl sulfate, for example sodium lauryl sulfate.
  • the dosage is determined by the practitioner depending on the condition of the patient, but it is generally between 25 mg and 500 mg per day, preferably between 50 mg and 100 mg per day. It is relatively independent of the patient's weight in adults.
  • Unit doses, for oral administration are generally between 25 mg and 50 mg.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Toxicology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP03750824A 2002-07-23 2003-07-18 Erhöhung der haem-oxygenase mit rheinderivaten Withdrawn EP1523312A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0209340A FR2842738B1 (fr) 2002-07-23 2002-07-23 Utilisation d'une rheine pour la preparation d'un medicament pour le traitement de l'inflammation chronique, la prevention et le traitement du rejet des transplantations d'organes et de tissus
FR0209340 2002-07-23
PCT/FR2003/002286 WO2004010990A1 (fr) 2002-07-23 2003-07-18 Elevation du taux d’ heme oxygenase avec des derives de la rheine

Publications (1)

Publication Number Publication Date
EP1523312A1 true EP1523312A1 (de) 2005-04-20

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EP03750824A Withdrawn EP1523312A1 (de) 2002-07-23 2003-07-18 Erhöhung der haem-oxygenase mit rheinderivaten

Country Status (9)

Country Link
US (1) US20060058392A1 (de)
EP (1) EP1523312A1 (de)
JP (1) JP2005538098A (de)
AU (1) AU2003269037A1 (de)
CA (1) CA2493074A1 (de)
FR (1) FR2842738B1 (de)
IL (1) IL166434A0 (de)
MX (1) MXPA05000904A (de)
WO (1) WO2004010990A1 (de)

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TWI473610B (zh) * 2008-10-28 2015-02-21 Twi Biotechnology Inc 包含雙醋瑞因（ｄｉａｃｅｒｅｉｎ）之醫藥組合物
BR112012003573A2 (pt) * 2009-08-20 2016-03-08 Twi Biotechnology Inc métodos para determinar uma eficácia de um composto para o tratamento de diabete e para diagnosticar diabete.
US8652540B2 (en) 2012-06-04 2014-02-18 Hong Kong Baptist University Method of using rhein for treating fibrotic conditions and tumors
US10195170B2 (en) * 2015-08-17 2019-02-05 Twi Biotechnology, Inc. Methods for inhibiting expression of ASC, expression of NLRP3, and/or formation of NLRP3 inflammasome complex using diacerein or its analogs
TW201739448A (zh) * 2016-05-06 2017-11-16 安成生物科技股份有限公司 用於治療及/或預防血液相關疾病之方法及配方
KR102563841B1 (ko) * 2017-01-19 2023-08-03 티더블유아이 바이오테크놀로지 인코포레이티드 면역염증성 피부 장애를 예방 또는 치료하기 위한 방법 및 약학적 조성물

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Also Published As

Publication number Publication date
FR2842738B1 (fr) 2006-02-10
US20060058392A1 (en) 2006-03-16
JP2005538098A (ja) 2005-12-15
FR2842738A1 (fr) 2004-01-30
CA2493074A1 (fr) 2004-02-05
MXPA05000904A (es) 2005-03-23
IL166434A0 (en) 2006-01-15
AU2003269037A1 (en) 2004-02-16
WO2004010990A1 (fr) 2004-02-05

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