WO2013064672A2 - Oxazaphosphorines en dose unique utilisées pour le traitement de maladies - Google Patents

Oxazaphosphorines en dose unique utilisées pour le traitement de maladies Download PDF

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Publication number
WO2013064672A2
WO2013064672A2 PCT/EP2012/071772 EP2012071772W WO2013064672A2 WO 2013064672 A2 WO2013064672 A2 WO 2013064672A2 EP 2012071772 W EP2012071772 W EP 2012071772W WO 2013064672 A2 WO2013064672 A2 WO 2013064672A2
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WIPO (PCT)
Prior art keywords
oxazaphosphorines
formula
ido
trofosfamide
dose
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PCT/EP2012/071772
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German (de)
English (en)
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WO2013064672A3 (fr
Inventor
Ulf Niemeyer
Jörg POHL
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the single use of low-dose
  • Oxazaphosphorinen (especially Cydophosphannid and its derivatives Ifosfannid, Trofosfamide and mafosfamide) for the treatment of diseases.
  • the invention relates to oxazaphosphorines of the formula (I)
  • R1 and R2 is 2-chloroethyl or H and R3 is 2-sulfonatoethylthio or H, for the therapy of diseases caused or sustained by the tolerogen indolamine 2,3-dioxygenase (IDO).
  • IDO indolamine 2,3-dioxygenase
  • Such diseases include, for example:
  • IDO expression Infectious diseases with lacking or insufficient immunoreactivity associated with activation of IDO expression, such as Malaria, tuberculosis, leishmaniasis, HIV diseases
  • IDO indole-2,3-dioxygenase
  • TRP Amino Acid Tryptophan
  • Kynurenine Kynurenine
  • Tolerance which expires at the end of pregnancy IDO is a local tolerance inducer during pregnancy and can be termed tolerogen.
  • IDO may occasionally also be expressed in some cells of the body's defense system.
  • macrophages are sometimes able to stimulate the production of IDO, thus locally converting TRP to kynurenine.
  • IDO production may also be responsive to a variety of infectious agents (influenza, HIV, TB, malaria, etc.) as well as chronic inflammatory diseases (polyarthritis, multiple myeloma, etc.).
  • US Pat. No. 6,482,416 B2 describes a method for increasing the rejection of cells in patients, which method comprises the administration of an effective amount of a pharmaceutical agent containing an IDO inhibitor.
  • the cells to be rejected may be, inter alia, the cells of a fetus, cells that are chronically infected by a virus, or tumor cells.
  • the IDO inhibitor can be administered inter alia together with a cytokine or a vaccine and can be, inter alia, one of the following compounds: 1-methyl-DL-tryptophan, ß- (3-benzofuranyl) -DL-alanine, ß- (3-benzo (b) thienyl) -DL-alanine and 6-nitro-L-tryptophan.
  • the classical method of treatment in chemo-chemo-alkylated chemotherapy includes oxazaphosphorines having the characteristic oxazaphosphorine or oxazaphosphorinane ring of formula (I):
  • R1 is 2-chloroethyl and R2 and R3 is H (cyclophosphamide 1, CAS No. 50-18-0,
  • R1 and R3 are H and R2 is 2-chloroethyl (Ifosfamide 2, CAS No. 3778-73-2, molecular weight 261, 09 g / mol) or
  • R1 and R2 are 2-chloroethyl and R3 is H (trofosfamide 3, CAS No. 22089-22-1, molecular weight 323.59 g / mol) or R1 is 2-chloroethyl and R2 is H and R3 is 2-sulfonatoethylthio (mafosfamide, as
  • L-lysine salt 4 CAS No. 98845-64-8, molecular weight 547.46 g / mol or as
  • Cyclohexylamine salt 5 CAS No. 84210-80-0, molecular weight 500.45 g / mol.
  • Compounds 1 to 3 are commercial products.
  • Compound 4 was in clinical development (Phase I and II).
  • Compounds 4 and 5 are used today, especially for in vitro laboratory experiments, as a precursor of activated cyclophosphamide or of the primary metabolite 4-hydroxycyclophosphamide for chemosensitivity tests (Brock, N., et al., Cancer Invest 6, 513-532 ( 1988)).
  • Cyclophosphamide, ifosfamide and trofosfamide require enzymatic activation in the liver in the first step, whereas mafosfamide is activated by spontaneous hydrolysis to give 4-hydroxycyclophosphamide.
  • cytostatics In clinical chemotherapy, the oxazaphosphorines are used several times within a few days in high doses as cytostatics. Their cytostatic effect is based on the fact that they transfer as alkylating agents alkyl groups on the DNA, which prevent a correct duplication of the DNA strands during cell division, whereby the affected cell usually can not continue to divide. As a result, highly proliferating cell systems - as present in malignant tumors - are damaged as selectively as possible, thus enabling healings or partial improvements in this deadly disease.
  • Oxazaphosphorinen used to achieve optimum curative or palliative efficacy is due to the clinical controllability of undesired side effects, which can occur as a result of the relatively nonspecific interaction of the alkylating agents with the genetic material DNA, especially in fast-growing cells, in addition to cancer cells e.g.
  • Oxazaphosphorines are nausea, anemia and immunosuppression. In addition, you can Oxazaphosphorines are carcinogenic and mutagenic because of their interaction with the DNA itself.
  • Oxazaphosphorinen as these are traditionally used in cancer therapy, can also act antitumoral.
  • N. Brock et al., Cancer Invest 6, 513-532 (1988) described that mice and rats carrying experimental tumors - even with tumor masses greater than 50% of total body mass - were cured with doses of cyclophosphamide or mafosfamide. the far below the
  • Oxazaphosphorines of the formula (I) correspond to each other, even if this is in
  • the invention thus oxazaphosphorines of the formula (I), wherein R1 and R2 is 2-chloroethyl or H and R3 is 2-sulfonatoethylthio or H, for the therapy of diseases caused or maintained by the tolerogen indolamine 2,3-dioxygenase (IDO), the oxazaphosphorines of the formula ( I) once administered in a dose of at most 0.3 mmol / m 2 .
  • Dosage can be used. This effect differs markedly from the alkylating effects of oxazaphosphorines, which are administered multiple times in high doses.
  • the oxazaphosphorines of the formula (I) can be administered locally or systemically (p.o., i.V., i.m., s.c., etc.).
  • Trofosfamide is especially preferred because of its higher efficacy on experimental tumors, its good oral counterparts, compared to the molar level
  • oxazaphosphorines of the formula (I) are employed as a mixture of at least two oxazaphosphorines from the group consisting of cyclophosphamide, ifosfamide and trofosfamide, where a total dose this oxazaphosphorine is at most 0.3 mmol / m 2 .
  • a mixture of cyclophosphamide and ifosfamide is particularly preferred.
  • the oxazaphosphorines of the formula (I) are used once in a dose of at most 0.3 mmol / m 2 , preferably in a dose in the range of 15 to 300 mol / m 2 and most preferably in a dose in the range of 60 to 240 ⁇ / ⁇ 2 administered.
  • the average dose is therefore about 150 ⁇ / ⁇ 2 , ie for
  • Cyclophosphamide and ifosfamide about 39 mg / m 2 , for trofosfamide 49 mg / m 2 and for mafosfamide 82 mg / m 2 .
  • the therapeutic doses for oxazaphosphorines are thus far below the hitherto clinically used dosages for tumor therapy and immunosuppressive therapy.
  • Cyclophosphamide is used clinically in single or combination chemotherapy in a variety of cancers, including leukosis, plasmocytomas, breast cancers, ovarian cancers, soft tissue sarcomas and non-Hodgkin's lymphomas.
  • the dosage is done individually, with a maximum tolerable dose of 600 mg / m 2 is usually administered up to 6 times every three weeks, ie a total dose of 3600 mg / m 2 . That means the
  • Treatment according to the invention with a mean dose of 39 mg / m 2 ) with a 90 times lower dose of cyclophosphamide than the conventional cancer therapy.
  • Ifosfamide has been clinically used in single or combination chemotherapy for various cancers, such as testicular tumors, cervical carcinoma,
  • Trofosfamide In contrast to ifosfamide, clinically only i.v. Trofosfamide is only available for oral use. It is known to be used for solid tumors and haemoblastoses for palliative treatment (E. Burgis, Intensive General and Special Pharmacology, Urban & Fischer Verlag, 2008). In recent years, (palliative) metronomic chemotherapy has become increasingly important in advanced cancers. In contrast to classical chemotherapy, the oxazaphosphorines are administered daily in relatively low doses over a longer period of time. The mechanism of action of oxazaphosphorines in metronomic chemotherapy is based primarily on their ability to inhibit angiogenesis and thus reduce the supply of the tumor via the bloodstream. Due to its oral availability and comparatively good tolerability, trofosfamide plays a major role, with 100 mg of trofosfamide being administered daily over several months. For example, for 3 months treatment with trofosfamide is the
  • Total dose thus about 9 g (equivalent to about 5 g / m 2 in an average adult with about 1, 7 to 2.2 m 2 body surface area).
  • the single dose according to the present invention (with a mean dose of 49 mg / m 2 ), however, is about 100 times lower.
  • the oxazaphosphorines of the formula (I) are used according to the invention for the therapy of diseases caused or sustained by the tolerogen indolamine-2,3-dioxygenase (IDO). These diseases include:
  • the oxazaphosphorines of formula (I) are administered in a single dose.
  • a "single dose” within the meaning of the invention does not exclude that after a longer period, a renewed “single dose” takes place.
  • the herein The term “single dose” used generally means that the interval between "one-time doses" is several weeks, preferably at least 2 weeks, more preferably at least 4 weeks.
  • the immune response of the single-dose oxazaphosphorine therapy of formula (I) should not be compromised by treatment with immunosuppressive drugs. So should not be treated simultaneously with oxazaphosphorines, in particular cyclophosphamide, in high dosage, since thereby the
  • Stem cells are suppressed for at least 2 weeks.
  • conventional chemotherapy can be additionally performed after the therapy according to the invention.
  • the new therapy and the known therapies can complement each other.
  • Treatment with a low-dose oxazaphosphorine should be associated with contraception in women of childbearing potential as embryo resorption may occur.
  • the invention also relates to the use of oxazaphosphorines of the formula (I),
  • R1 and R2 is 2-chloroethyl or H and R3 is 2-sulfonatoethylthio or H for the manufacture of a medicament for use in the treatment of
  • the invention has numerous advantages. It allows a new immunological treatment of many diseases, such as an immunological one
  • metastatic disease course can be applied.
  • the present invention enables the treatment of diseases caused or maintained by the expression of the tolerogen IDO.
  • the single use of a low-dose oxazaphosphorine should cure
  • 1-MT was used as a classical and proven IDO inhibitor.
  • a dose range of 5 - 200 ⁇ was tested using the parameters determined above. The results showed that more than 50% of the TRP is already converted at 5 ⁇ 1 -MT, with the increasing 1 MT dose the TRP turnover continues to increase and thus reaches its maximum value at the highest dose (200 ⁇ ).
  • trofosfamide and mafosfamide were compared using the known IDO inhibitor 1-MT and an "IDO control" (without inhibitor) All IDO inhibitors (trofosfamide, mafosfamide and 1-MT) were each tested in doses of 1, 10 or 100 ⁇ The results showed a similar TRP conversion of trofosfamide, mafosfamide and 1-MT.
  • Oxazaphosphorines have a completely different chemical structure than the previously known IDO inhibitors.
  • Example 2 In another study, pregnant rats were treated with a single dose of 1, 6 mg / kg trofosfamide (Sprague-Dawley rats, female, pregnant, peroral administration of trofosfamide on the 9th day of pregnancy). Immediately prior to treatment with trofosfamide, the kynurenine / TRP ratio was determined in the blood plasma of the animals. In the days following the single trofosfamide treatment, the kynurenine / TRP ratio of the animals was repeatedly determined to monitor systemic changes in TRP turnover and, subsequently, IDO activity. In addition, the immune status of the animals was observed as well
  • trofosfamide achieved complete resorption of all fetuses.
  • Lymphocytes, CD4 / CD8 ratio, B-cells as CD3-negative lymphocytes no significant differences to untreated control animals were found. This finding shows that the effect of IDO inhibition is locally limited to the uterus.
  • an oxazaphosphorine of formula (I) particularly trofosfamide, exhibits the same immunological activity with respect to the resorption of fetuses as 1-MT (see DH Munn et al., Science, 281, 1991-1193 (1998)). ) and thus the resorption of the fetuses based on immunological reactions in the dams or on an IDO inhibition.
  • Trofosfamide tablets are dosed per os at a dose of about 49 mg / m 2 .
  • One coated tablet contains 50 mg trofosfamide.
  • the coated tablet contains calcium hydrogen phosphate dihydrate, microcrystalline cellulose, gelatin, glycerol 85%, lactose monohydrate, magnesium stearate (Ph.Eur.),
  • Corn starch povidone (Kollidon 25), fumed silica, talc and the dyes yellow orange S (E 1 10) and iron hydrate XH 2 O (E 172).
  • a tablet is optionally comminuted to obtain the individually required amount.
  • ifosfamide vial with 500 mg ifosfamide powder are added to 13 ml of water for injection to prepare a 4% solution ready for injection.
  • the substance dissolves easily when the vial after injecting the water for
  • Injection is vigorously shaken for half to one minute. If the dissolution does not take place immediately, it is advisable to leave the solution for a few minutes to let stand.
  • Trofosfamide-containing tablets for oral administration can be obtained, for example, according to the preparation method described in WO 2006/089651 A2.
  • Cyclophosphamide dragees are dosed per os at about 39 mg / m 2 .
  • One tablet contains 50 mg cyclophosphamide.
  • the dragee contains calcium hydrogen phosphate dihydrate, glycerol 85%, lactose monohydrate,
  • Magnesium stearate (Ph.Eur.), Corn starch, polyvidone (Kollidon 25), fumed silica, talc, polysorbate, carmelose sodium, macrogol, sucrose, dye E 171, calcium carbonate, gelatin and montan glycol wax.
  • a tablet is optionally comminuted to obtain the individually required amount.

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  • 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)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
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  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des oxazaphosphorines de formule (I), dans laquelle R1 et R2 représentent 2-chloroéthyle ou H et R3 représente 2-sulfonatoéthylthio ou H, utilisées pour le traitement de maladies induites ou entretenues par le tolérogène indolamine-2,3-dioxygenase (IDO), lesquelles oxazaphosphorines de formule (I) sont administrées en dose unique à un dosage d'au plus 0,3 mmol/m2 et s'opposent ainsi au tolérogène IDO. L'invention concerne également l'utilisation de ces oxazaphosphorines pour produire un médicament utilisé dans le traitement de maladies induites ou entretenues par l'activation de l'expression de l'indolamine-2,3-dioxygenase (IDO), lesquelles oxazaphosphorines de formule (I) sont administrées en dose unique à un dosage d'au plus 0,3 mmol/m2.
PCT/EP2012/071772 2011-11-03 2012-11-02 Oxazaphosphorines en dose unique utilisées pour le traitement de maladies Ceased WO2013064672A2 (fr)

Applications Claiming Priority (2)

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DE102011085695.1 2011-11-03
DE102011085695A DE102011085695A1 (de) 2011-11-03 2011-11-03 Einmalig dosierte Oxazaphosphorine zur Therapie von Krankheiten

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WO2013064672A2 true WO2013064672A2 (fr) 2013-05-10
WO2013064672A3 WO2013064672A3 (fr) 2013-07-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6451840B1 (en) 1997-12-05 2002-09-17 Medical College Of Georgia Research Institute, Inc. Regulation of T cell-mediated immunity by tryptophan
DE102004050111A1 (de) 2004-10-13 2006-04-27 Pohl, Jörg, Dr. Modulation der Immunregulation
WO2006089651A2 (fr) 2005-02-25 2006-08-31 Baxter International Inc. Comprimes pelliculaires a base de trofosfamide et procede permettant de les produire

Family Cites Families (5)

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Publication number Priority date Publication date Assignee Title
JP4562815B2 (ja) * 1997-05-21 2010-10-13 ジェネンテック， インコーポレイテッド トロンボポエチンの新規な投与
EP1005531A2 (fr) * 1997-07-21 2000-06-07 Cerus Corporation Traitement des leucocytes, compositions leucocytaires, et leur procede d'utilisation
WO2003103389A2 (fr) * 2002-06-10 2003-12-18 Avax Technologies Inc. Cryo-conservation de cellules tumorales haptenisees
RU2253478C1 (ru) * 2003-10-01 2005-06-10 Эпштейн Олег Ильич Средство для потенцирования лечебных эффектов - усиления действия лекарственного вещества
TWI395591B (zh) * 2004-04-01 2013-05-11 Oncothyreon Inc 黏液性糖蛋白（ｍｕｃ-１）疫苗

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6451840B1 (en) 1997-12-05 2002-09-17 Medical College Of Georgia Research Institute, Inc. Regulation of T cell-mediated immunity by tryptophan
US6482416B2 (en) 1997-12-05 2002-11-19 Medical College Of Georgia Research Institute, Inc. Regulation of T cell-mediated immunity by tryptophan
DE102004050111A1 (de) 2004-10-13 2006-04-27 Pohl, Jörg, Dr. Modulation der Immunregulation
WO2006089651A2 (fr) 2005-02-25 2006-08-31 Baxter International Inc. Comprimes pelliculaires a base de trofosfamide et procede permettant de les produire

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
D. H. MUNN ET AL., J EXP MED, vol. 189, 1999, pages 1363 - 1372
D. H. MUNN ET AL., SCIENCE, vol. 281, 1998, pages 1191 - 1193
D-Y. HOU, CANCER RESEARCH, vol. 67, 2007, pages 792 - 801
E. BURGIS: "Intensivkurs Allgemeine und Spezielle Pharmakologie", 2008, URBAN & FISCHER VERLAG
N. BROCK ET AL., CANCER INVEST, vol. 6, 1988, pages 513 - 532
S. G. CADY ET AL., ARCH BIOCHEM BIOPHYS, vol. 291, 1991, pages 326 - 333
S. R. THOMAS ET AL., REDOX REPORTS, vol. 4, 1999, pages 199 - 219
TAKIKAWA ET AL., J BIOL CHEM, 1988, pages 263

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WO2013064672A3 (fr) 2013-07-04
DE102011085695A1 (de) 2013-05-08

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