WO2013064672A2

WO2013064672A2 - Oxazaphosphorines dosed one time for treating diseases

Info

Publication number: WO2013064672A2
Application number: PCT/EP2012/071772
Authority: WO
Inventors: Ulf Niemeyer; Jörg POHL
Original assignee: Ulf Niemeyer; Pohl Joerg
Priority date: 2011-11-03
Filing date: 2012-11-02
Publication date: 2013-05-10
Also published as: WO2013064672A3; DE102011085695A1

Abstract

The invention relates to oxazaphosphorines of formula (I), wherein R1 and R2 are 2-chloroethyl or H and R3 is 2-sulfonatoethylthio or H, for treating diseases that are caused or maintained by the tolerogen indolamine-2,3-dioxygenase (IDO), wherein the oxazaphosphorines of formula (I) are administered one time in a dose of at most 0.3 mmol/m² and thus act against the tolerogen IDO. The invention further relates to the use of said oxazaphosphorines to produce a medication for use in treating diseases that are caused or maintained by the activation of the expression of indolamine-2,3-dioxygenase (IDO), wherein the oxazaphosphorines of formula (I) are administered one time in a dose of at most 0.3 mmol/m².

Description

One-time dosed oxazaphosphorines for the treatment of diseases

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)

wherein 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).

Such diseases include, for example:

• Cancer

Infectious diseases with lacking or insufficient immunoreactivity associated with activation of IDO expression, such as Malaria, tuberculosis, leishmaniasis, HIV diseases

• autoimmune reactions

• Local immune tolerance or suppression

· Arteriosclerosis

The enzyme indole-2,3-dioxygenase (IDO) starts the metabolism of the

Amino Acid Tryptophan (TRP) to Kynurenine. For example, IDO is used by

embryonic cells produced in the uterus, thereby creating the fundamental prerequisite for intrauterine embryonic development during the

Pregnancy is provided (D.H. Munn et al., Science 281, 1 191 -1 193

(1998)). In the process, embryonic cells produce contact area between the implanted blastocyst and the maternal host IDO. Although maternal T-cells attacking "stranger" remain capable of the "genetically foreign" embryo However, local depletion of TRP as a result of the expression of the IDO gene makes them unable to proliferate and succumb to apoptosis.

This prevents the absorption of the embryo. Consequently, the IDO production in the uterus is the causative biological mechanism of the "maternal

Tolerance ", which expires at the end of pregnancy IDO is a local tolerance inducer during pregnancy and can be termed tolerogen.

Under certain physiological or pathological conditions, IDO may occasionally also be expressed in some cells of the body's defense system. Thus, macrophages are sometimes able to stimulate the production of IDO, thus locally converting TRP to kynurenine. In this way some immune reactions or autoimmune reactions are regulated (D.H. Munn et al., J Exp Med 189, 1363-1372 (1999)). In addition, 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

Sclerosis, diabetes, etc.) are induced by interferon-gamma (S.R. Thomas et al., Redox Reports 4, 199-219 (1999)). Inhibition of IDO by competitive inhibitors causes a reduction in the IDO effect and thereby successful immune reactions and possibly a cure in many diseases (Pohl et al., DE 10 2004 050 1 1 1 A1). As competitive inhibitors, DE 10 2004 050 1 1 1 A1 proposes chemical compounds which have a closer structural relationship to the natural substrate TRP, such as, for example, 1-methyl-DL-tryptophan, β- (3

Benzofuranyl) -DL-alanine, β- (3-benzo (b) thienyl) -DL-alanine and their L and D forms (see Munn et al., US 6,482,416 B2 and US 6,451,840 B2, SG Cady et al., Arch Biochem Biophys 291, 326-333 (1991)). 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.

In animal experiments with the IDO inhibitor 1-MT it was shown that in pregnant mice treated with 1-MT a T-cell-induced resorption of the allogeneic fetuses took place (DH Munn et al., Science, 281, 1991-1 193 (1998)). 1-MT was a potent inhibitor of IDO in vitro and effective as an anticancer agent in

Chemotherapy regimens together with cyclophosphamide, paclitaxel or

Gemcitabine (D-Y., Hou et al., Cancer Research 67, 792-801 (2007)). The D-form of 1-MT is in Phase I clinical trials in patients with advanced

Cancer. Experiments with cancer cells and tumor bearing animals suggest that 1-MT is well tolerated and enhances the ability of the immune system to eliminate cancer cells (clinicalTrials.gov). Patients receive once or twice daily from 1. to 28th day 200 to 3200 mg 1 -MT. The treatment is repeated every 28 days for up to 12 courses.

The classical method of treatment in chemo-chemo-alkylated chemotherapy includes oxazaphosphorines having the characteristic oxazaphosphorine or oxazaphosphorinane ring of formula (I):

wherein

R1 is 2-chloroethyl and R2 and R3 is H (cyclophosphamide 1, CAS No. 50-18-0,

Molecular weight 261, 09 g / mol) or

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.

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.

In classic cancer therapy, maximum tolerable doses of

Oxazaphosphorinen used to achieve optimum curative or palliative efficacy. The maximum tolerable dose 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.

Count mucosal, hair root and gonadal cells. Other

Main side effects of the cytostatics used in high doses

Oxazaphosphorines are nausea, anemia and immunosuppression. In addition, you can Oxazaphosphorines are carcinogenic and mutagenic because of their interaction with the DNA itself.

Findings from animal experiments show that much lower doses of

Oxazaphosphorinen, as these are traditionally used in cancer therapy, can also act antitumoral. Thus, 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

known to be therapeutically antitumor effective doses. An increase in dosage led in the case of cyclophosphamide initially to a

Loss of effect and only in the range of the maximum tolerable dose healings were achieved again. Re-implantation of the experimental tumor cells into the experimental animals healed with low doses of cyclophosphamide resulted in complete resorption of the tumor cells and no new tumor growth.

In contrast, new tumor cells grew in the animals tolerated with the maximum tolerated dose, and the animals died from the cancer.

Against this background, it was an object of this invention to provide substances for improved therapy of diseases caused or sustained by the tolerogen indolamine 2,3-dioxygenase (IDO).

This object is achieved by the oxazaphosphorines and their use according to the respective independent claim. Preferred embodiments are shown in the respective dependent claims. preferred

Embodiments of oxazaphosphorines and the use of

Oxazaphosphorines of the formula (I) correspond to each other, even if this is in

The following is not particularly emphasized. 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 .

Surprisingly, it has been found that the oxazaphosphorines of the formula (I) act as IDO inhibitors in vitro and in vivo when in single and lower

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.).

Preferably, the oxazaphosphorines of formula (I) are cyclophosphamide (R1 = 2-chloroethyl and R2 and R3 = H), ifosfamide (R1 and R3 = H and R2 = 2-chloroethyl), trofosfamide (R1 and R2 = 2-chloroethyl and R3 = H) or mafosfamide (R1 2-chloroethyl and R2 = H and R3 = 2-sulfonatoethylthio as L-lysine salt or

Cyclohexylamine salt), more preferably ifosfamide (R1 and R3 = H and R2 = 2-chloroethyl) or trofosfamide (R1 and R2 = 2-chloroethyl and R3 = H). Trofosfamide is especially preferred because of its higher efficacy on experimental tumors, its good oral counterparts, compared to the molar level

Compatibility and availability and its special ability, one

Immune reaction against foreign tissue, e.g. Rat fetuses (see Example 2).

In a preferred embodiment of the invention, 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 μηηοΙ / ηη ² administered. The average dose is therefore about 150 μηηοΙ / ηη ² , ie for

Cyclophosphamide and ifosfamide about 39 mg / m ² , for trofosfamide 49 mg / m ² and for mafosfamide 82 mg / m ² .

According to the invention, 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,

Breast carcinoma, bronchial carcinoma, soft tissue sarcoma, Ewing's sarcoma, non-Hodgkin's lymphoma and Hodgkin's disease. Dosage is individualized, with the most common dose being monotherapy

Adult represents the fractionated application. In general, 1, 2 - 2.4 g lfosfamide / m ² are administered intravenously over a period of 30 to 120 minutes on five consecutive days. The therapy cycles can be repeated every 3 - 4 weeks. As a result, 6-12 g / m ^{2 of} ifosfamide are administered within one cycle of therapy. The dose according to the present invention (with a mean dose of 39 mg / m ² ), however, is about 150 times to 300 times lower.

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

in particular cancer, infectious diseases with absent or insufficient immunoreactivity (malaria, tuberculosis, leishmaniasis, HIV diseases), autoimmune reactions, local immune tolerance or suppression and arteriosclerosis. These diseases are generally associated with increased production of IDO and are characterized by maladaptation of the immune system, which could be modulated by inhibition of IDO.

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.

As a result, an overdose of the immune response is generally avoided and the chances for a successful immunotherapy are improved.

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. However, 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),

wherein 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

Diseases caused or sustained by the tolerogen indoleamine-2,3-dioxygenase (IDO) wherein the oxazaphosphorines of formula (I) are administered once at a dose of at most 0.3 mmol / m ² . The invention has numerous advantages. It allows a new immunological treatment of many diseases, such as an immunological one

Cancer therapy, which - due to their low side effects - after a

Cancer or preventive after a cancer operation or at

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

various diseases or immunization against numerous pathogenic agents. The clinical development of an oxazaphosphorine as an IDO inhibitor is made possible by the demonstration of the relationship between IDO inhibition and healing effects. This will enable a new therapy against cancer and numerous pathogens. This is a curative therapy and not a palliative therapy as in classical chemotherapy.

According to the invention is a unique, extremely low and almost non-toxic

Dosage quite unlike classical chemotherapy possible. A

Long-term treatment will be unnecessary. In addition, a very long-lasting and even lifelong immunization against a new infection or a new implantation of tumor cells can be achieved.

In the following, the invention is illustrated in more detail by way of non-limiting examples. Examples

example 1

The in vitro inhibition experiments with recombinant IDO described in more detail below were carried out. In order to determine the optimal dose of IDO for in vitro inhibition experiments, a kinetic enzyme assay based on the method of Takikawa et al., J Biol Chem 263 (1988) was performed. Here, only the IDO dosage was varied, whereas the incubation time and temperature (1 h at 37 ° C) and the substrate concentration (50 μΜ TRP) constant were held. The dose range of 1 to 1000 U IDO was tested, with optimal results achieved at a concentration of 62.5 U IDO. At higher IDO concentrations, the TRP was fully reacted, regardless of the level of IDO concentration tested. At lower IDO concentrations, however, there was no or minimal TRP sales. As a result, 62.5 U IDO were used for the following experiments.

In another preliminary experiment, 1-MT was used as a classical and proven IDO inhibitor. A dose range of 5 - 200 μΜ was tested using the parameters determined above. The results showed that more than 50% of the TRP is already converted at 5 μΜ 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 μΜ). Similarly, the ability of trofosfamide and mafosfamide to inhibit IDO was 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 μΜ The results showed a similar TRP conversion of trofosfamide, mafosfamide and 1-MT.

These in vitro experiments demonstrated that the IDO-induced degradation of TRP to kynurenine by trofosfamide and mafosfamide is reduced similarly to the known IDO inhibitor 1-MT. Inhibition by the oxazaphosphorines was thus comparable to that of 1-MT. The new findings are surprising since

Oxazaphosphorines have a completely different chemical structure than the previously known IDO inhibitors.

Since in vitro IDO inhibition has been achieved by trofosfamide, which has not been "activated" in the liver, it can not be based on its alkylating activity, thus presenting a hitherto unknown, novel and surprising quality of action of the oxazaphosphorines.

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

Taken urine samples. On day 10 after the single treatment with trofosfamide, the animals were euthanized and the number of fetuses and placental sites present was determined.

In the control group treated with water instead of trofosfamide, the number of fetuses per animal was identical with the number of placental sites, whereas in the trofosfamide-treated group with the same number of placentas on day 10 post-treatment, no fetus was present. Thus, trofosfamide achieved complete resorption of all fetuses. In the parameters measured in the experiment in serum (tryptophan and

Kynurenine content, immune status in the form of NK-pan T, pan B, CD4 and

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. These experiments illustrate that 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. Most notably, IDO inhibition is possible with respect to absorption of fetuses with a single dose of oxazaphosphorine, and no long-term treatment is required, as described for 1-MT. Taking into account Example 1, it can be assumed that the efficacy of an oxazaphosphorine of the formula (I), in particular that of trofosfamide, does not depend on its activation in the liver is dependent. This is noteworthy because liver activation is an essential prerequisite for the known alkylating chemotherapeutic effect of trofosfamide. Activation of trofosfamide in the enzyme itself to 4-hydroxytrofosfamide in addition to alkylation of the enzyme is possible. This may be an important mechanism for the effectiveness of trofosfamide in the low

Be dosage.

These experiments also suggest that the oxazaphosphorines can cure tumor-bearing animals by inhibiting IDO, since inhibition of IDO activity inhibits tumor growth (DY, Hou et al., Cancer Research 67, 792-801 (2007). ). This means that as an IDO inhibitor, immunological therapies against cancer and other diseases are possible. Furthermore, a permanent or even lifelong immunization should be achieved. Examples 3 to 7 are examples of pharmaceutical dosage forms:

Example 3

Trofosfamide tablets are dosed per os at a dose of about 49 mg / m ² . One coated tablet contains 50 mg trofosfamide. In addition to 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.

Example 4

In order to inject ifosfamide with about 39 mg / m ^2, a 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. For intravenous infusion, dilute the solution in 250 ml Ringer's solution, 5% glucose solution or 0.9% saline. The solution is injected intravenously over 30 to 120 minutes. The individually required amount is determined by the applied volume of the 4% active ingredient solution.

Example 5

Trofosfamide-containing tablets for oral administration can be obtained, for example, according to the preparation method described in WO 2006/089651 A2.

Example 6

Cyclophosphamide dragees are dosed per os at about 39 mg / m ² . One tablet contains 50 mg cyclophosphamide. In addition to 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.

Example 7

In order to inject mafosfamide L-lysine with about 82 mg / m ^2, a plurality of

Injection bottles containing 20 mg mafosfamide lyophilisate with 2 ml sterile aqueous

0.9% sodium chloride solution (physiological saline) reconstituted to make a 10% solution. The substance dissolves easily. For intravenous infusion, dilute the solution further with 0.9% saline. Mafosfamide solutions must be used immediately after manufacture. The individually required amount is determined by the applied volume of the drug solution.

Claims

claims

1 . 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), characterized in that the oxazaphosphorines of the formula (I) are administered once in a dose of at most 0.3 mmol / m ² .

Oxazaphosphorines of the formula (I) according to claim 1, wherein the

Oxazaphosphorine cyclophosphamide (R1 = 2-chloroethyl and R2 and R3 = H), ifosfamide (R1 and R3 = H and R2 = 2-chloroethyl), trofosfamide (R1 and R2 = 2-chloroethyl and R3 = H) or mafosfamide (R1 = 2-chloroethyl and R2 = H and R3 = 2-sulfonatoethylthio as L-lysine salt or cyclohexylamine salt).

Oxazaphosphorines of the formula (I) according to claim 2, wherein the

Oxazaphosphorine trofosfamide (R1 and R2 = 2-chloroethyl and R3

Oxazaphosphorines of the formula (I) according to claim 2, wherein a mixture of at least two oxazaphosphorines from the group cyclophosphamide, ifosfamide and trofosfamide is used, wherein a total dose of these oxazaphosphorines is at most 0.3 mmol / m ² .

5. oxazaphosphorines of the formula (I) according to one of claims 1 to 4, characterized in that once a dose in the range of 15 to

300 mol / m ^{2 is} administered. Oxazaphosphorines of the formula (I) according to any one of claims 1 to 5, characterized in that the diseases include cancer, infectious diseases with absent or insufficient immunoreactivity, autoimmune reactions, local immune tolerance or suppression, and arteriosclerosis.

7. oxazaphosphorines of the formula (I) according to claim 6, characterized in that the disease is cancer. 8. oxazaphosphorines of the formula (I) according to one of claims 1 to 7, characterized in that a time interval between unique

Dosage is at least two weeks. 9. Use of oxazaphosphorines of the formula (I),

wherein 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 diseases caused or sustained by the tolerogen indolamine 2,3-dioxygenase (IDO) , characterized in that the oxazaphosphorines of the formula (I) are administered once in a dose of at most 0.3 mmol / m ² . 10. Use of Oxazaphosphorinen of formula (I) according to claim 8, wherein the oxazaphosphorin cyclophosphamide, ifosfamide, trofosfamide or

Mafosfamide L-lysine salt or mafosfamide cyclohexylamine salt.

1 1. Use of oxazaphosphorines of formula (I) according to claim 10, wherein the oxazaphosphorine is trofosfamide. Use of oxazaphosphorines of the formula (I) according to any one of claims 9 to 11, characterized in that a single dose range of 15 to 300 mol / m ^{2 is} administered.

3. Use of oxazaphosphorines of the formula (I) according to one of

Claims 9 to 12, characterized in that the diseases include cancer, infectious diseases with absent or insufficient immunoreactivity, autoimmune reactions, local immune tolerance or suppression, and arteriosclerosis.