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  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
  • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
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  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K2035/122—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells for inducing tolerance or supression of immune responses
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  • A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells

Definitions

• the present invention relates to a method of treating patients who undergo hematopoietic stem cell transplantation (HSCT) with peripheral blood mobilized stem cells for hematological malignancies and for whom the risk for severe acute graft versus host disease (GVHD) is considerable.
• HSCT hematopoietic stem cell transplantation
• GVHD severe acute graft versus host disease
• Acute graft-versus-host disease may occur after allogeneic hematopoietic stem cell transplant and is usually a reaction of donor immune cells against host tissues. Activated donor T cells typically damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen. Statistically, about 35%-50% of hematopoietic stem cell transplant (HSCT) recipients/patients may develop acute GVHD. The exact risk is usually dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis/treatment used. Patients usually may have involvement of three organs such as skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea).
• HSCT hematopoietic stem cell transplant
• Acute GVHD is typically staged and graded (grade 0-IV) by the number and extent of organ involvement. Patients with grade III/IV acute GVHD tend to have a poor outcome (life threatening). Generally a patient may be treated by optimizing the immunosuppression and for example by adding methylprednisolone. About 50% of patients may have a solid response to methylprednisolone. If patients progress after 3 days or are not improved after 7 days, they will get salvage (second-line) immunosuppressive therapy for which there is unfortunately no standard-of-care therapy.
• the present invention relates to a method of treating and/or preventing GVHD in a patient undergoing HSCT, which method comprises:
• R 2 is H, halogen, trihalomethyl, C 1-4 alkoxy, C 1-7 alkyl, phenethyl or benzyloxy;
• each of R 4 and R 5 independently is H or a residue of formula (a)
• each of R 8 and R 9 independently, is H or C 1-4 alkyl optionally substituted by halogen; and n is an integer from 1 to 4; and R 6 is hydrogen, halogen, C 1-7 alkyl, C 1-4 alkoxy or trifluoromethyl.
• the invention relates to a method of treating and/or preventing GVHD in patient undergoing HSCT, wherein in the compound of formula (I) or a pharmaceutically acceptable salt thereof R 3 is chlorine, and wherein the remaining variables are as defined above.
• the invention relates to a method of treating and/or preventing GVHD in patient undergoing HSCT, wherein in the compound of formula (I) or a pharmaceutically acceptable salt thereof R 2 is H, R 3 is chlorine, and R 6 is hydrogen, and wherein the remaining variables are as defined above.
• the invention relates to a method of treating and/or preventing GVHD in patient undergoing HSCT, wherein in the compound of formula (I) or a pharmaceutically acceptable salt thereof R 2 is H, R 3 is chlorine, R 6 is hydrogen, each of R 4 and R 5 , independently is H or a residue of formula (a)
• the invention relates to a method of treating and/or preventing GVHD in patient undergoing HSCT, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II).
• the invention relates to a method of treating and/or preventing GVHD in patient undergoing HSCT, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol.
• the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof in the use in the treatment and/or prevention of GVHD in a patient who was first conditioned as described above and who then received a hematopoietic stem cell transplantation (HSCT) from a donor.
• HSCT hematopoietic stem cell transplantation
• 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol and/or its hydrochloride salt may also be referred to as KRP203.
• halogen refers to fluoro, chloro, bromo, and iodo.
• alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety having from 1 to 7 carbon atoms, or 1 to 4 carbon atoms.
• Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, and the like.
• a substituted alkyl is an alkyl group containing one or more, such as one, two or three substituents selected from halogen, hydroxy or alkoxy groups.
• alkoxy refers to alkyl-O—, wherein alkyl is defined herein above.
• Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like.
• alkoxy groups typically have 1-7, or 1-4 carbon atoms.
• a substituted alkoxy is an alkoxy group containing one or more, such as one, two or three substituents selected from halogen, hydroxy or alkoxy groups.
• pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
• the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
• Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
• the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
• Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
• the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
• such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
• a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
• Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
• use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
• conditioning or “conditioned” in the context of a patient pretreatment in need of HSCT typically means destroying substantially the bone marrow and immune system by a suitable procedure such as: Reduced intensity conditioning (RIC) or myeloablative conditioning, e.g. Mini-Seattle Conditioning, e.g. fludarabin or another chemotherapeutic agent typically at 30 mg/m2/day for three days followed by total body irradiation (TBI) typically at 1 ⁇ 200 cGy/day;
• RIC Reduced intensity conditioning
• myeloablative conditioning e.g.
• Mini-Seattle Conditioning e.g. fludarabin or another chemotherapeutic agent typically at 30 mg/m2/day for three days followed by total body irradiation (TBI) typically at 1 ⁇ 200 cGy/day
• TBI total body irradiation
• e.g. high dose chemotherapy and total body irradiation is typically performed according to national guidelines adapted to institutional practices, and includes the administration of fludarabin, busulphan, methotrexate, cyclosporin A and cyclophosphamide.
• the following dosing regimens are given as examples: 1) Fludarabin at 25 mg/m2/day i.v. ⁇ 3 days (for approximately 2-3 days) for a total dose of 75 mg/m2. 2) Busulphan at 0.8 mg/kg/6 h (for approximately 2 to 4 days) 3) Cyclophosphamide at 60 mg/kg/day i.v. ⁇ 2 days (approximately for 2 days) for a total dose of 120 mg/kg.
• TBI will occur from approximately days 8 to 10 (days ⁇ 8 and ⁇ 1 relative to HSCT).
• the recommended TBI dose is 200 cGy given twice daily for a total dose of 1200 cGy.
• Embodiment 1 describes a method of treating and/or preventing graft versus host disease (GVHD) in a patient undergoing hematopoietic stem cell transplantation (HSCT), which method comprises:
• R 2 is H, halogen, trihalomethyl, C 1-4 alkoxy, C 1-7 alkyl, phenethyl or benzyloxy;
• each of R 4 and R 5 independently is H or a residue of formula (a)
• each of R 8 and R 9 independently, is H or C 1-4 alkyl optionally substituted by halogen; and n is an integer from 1 to 4; and R 6 is hydrogen, halogen, C 1-7 alkyl, C 1-4 alkoxy or trifluoromethyl.
• Embodiment 2 describes a method in accordance to embodiment 1, wherein the compound of formula (I) is a compound of formula (II)
• Embodiment 3 describes a method in accordance to embodiment 1, wherein the compound of formula (I) is a compound of formula (II)
• Embodiment 4 describes a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in embodiment 1 for use in the treatment and/or prevention of GVHD in a patient who was first conditioned as described in embodiment 1 and who then received a hematopoietic stem cell transplantation (HSCT) from a donor.
• HSCT hematopoietic stem cell transplantation
• Embodiment 5 describes a compound for use in accordance to embodiment 4, wherein said compound is a compound of formula (II), (IIa) and/or (IIb) or a pharmaceutically acceptable salt thereof as defined in embodiment 2.
• Embodiment 6 describes a method or a compound according to any of the preceding embodiments, e.g. embodiments 1-3, or 4-5, wherein said conditioning is selected from e.g. reduced intensity conditioning (RIC) or myeloablative conditioning:
• RIC reduced intensity conditioning
• myeloablative conditioning e.g. reduced intensity conditioning (RIC) or myeloablative conditioning:
• Mini-Seattle Conditioning characterized by using fludarabin or another chemotherapeutic agent typically at 30 mg/m2/day for three days followed by total body irradiation (TBI) typically at 1 ⁇ 200 cGy/day;
• TBI total body irradiation
• Embodiment 7 describes a method or a compound in accordance to any of the preceding embodiments, e.g. embodiments 1-3, or 4-5, wherein said conditioning is a high dose chemotherapy comprising one or more agents selected from fludarabin, busulphan, methotrexate, cyclosporin A and cyclophosphamide.
• Embodiment 8 describes a method or a compound in accordance to any of the preceding embodiments, e.g. embodiments 1-3, or 4-5, wherein said conditioning is a total body irradiation (TBI) according to national guidelines.
• TBI total body irradiation
• Embodiment 9 describes a method or a compound in accordance to any of the preceding embodiments, e.g. embodiments 1-3, or 4-5, wherein hematopoietic stem cell transplantation (HSCT) is carried out following to conditioning, e.g. immediately after conditioning, or 0-1 day after conditioning, or 1-8 days, or 1-10 days after conditioning.
• HSCT hematopoietic stem cell transplantation
• Embodiment 10 describes a method or a compound in accordance to any of the preceding embodiments, e.g. embodiments 1-3, or 4-5, wherein treatment of the patient with a compound of formula (I) as defined in embodiment 1 is commenced 5 days before conditioning, in particular 3 days before conditioning and especially 1 day before conditioning.
• HLA human leukocyte antigen
• Deviation from any entry criterion excludes a subject from enrollment into the study.
• Such malignancies include but are not limited to acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), marginal zone and follicular lymphomas, large-cell lymphoma, lymphoblastic, Burkitt's and other high grade lymphomas; mantle-cell lymphoma, lymphoplasmacytic lymphoma; prolymphocytic leukemia or multiple myeloma. 3.
• Recipients must be of good general health defined as having a Karnofsky score 60% 4.
• Suitable stem cell source must be available according to the graft selection algorithm as defined by JACIE* adapted to institutional standards using T-cell replete peripheral stem cells as a graft source.
• JACIE The Joint Accreditation Committee Europe comprising the International Society for Cellular Therapy & European Group for Blood and Marrow Transplantation
• the donor must be 9/10 or 10/10 matched with the recipient using molecular HLA matching techniques.
• Female and male patients have to fulfill the standard prerequisites for such studies e.g. relating to fertility, pregancy, sexual activity and the like.
• Patients must be able to communicate well with the Investigator, to understand and to comply with the requirements of the study and to understand and sign the written informed consent.
• Untreated or uncontrolled systemic bacterial, viral or fungal infections (including infection with Aspergillus or other mold within 30 days) considered active and clinically significant by the investigator 10.
• Diagnosis of AIDS, Hepatitis B or Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests, respectively.
• the drug a compound of formula (I), in particular a compound of formula (II), especially capsules comprising 1, 2, 3 or 5 mg of 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof are provided.
• the treatment typically comprises:
• a screening period (Days ⁇ 50 to ⁇ 2), Baseline (Day ⁇ 1)
• B Drug treatment period from Day 1 to Day 111 and a follow-up period up to 365 days (from transplant), wherein the drug is a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• C Myeloablative conditioning will be performed between Day 2 and Day 10 as per standard of care using chemotherapy (e.g. fludarabin, busulphan, cyclophosphamide, methotrexate) with total body irradiation (TBI), see below).
• D Transplanation (infusion of stem cells), i.e. HSCT will be performed on Day 11. Standard activities, in addition to the investigative treatment may include standard GVHD prophylaxis, pre and post transplant supportive care and follow-up assessments according to the institutional practices.
• Subject numbers will be assigned in ascending, sequential order to eligible subjects (see below for details).
• Each subject screened is assigned a unique screening number.
• study medication will be administered by the study center personnel with approximately 180-240 ml of water.
• Study drug dose adjustments may be permitted and drug interruptions will be allowed based on the judgment of the Investigator.
• Conditions/events that may lead to the study drug interruptions based on investigator judgment and overall clinical assessment include:
• Concomitant medications/Significant non-drug therapies section of the CRF should be specific to trade name, the single dose and unit, the frequency and route of administration, the start and discontinuation date and the reason for therapy.
• Medication entries should be specific to trade name, the single dose and unit, the frequency and route of administration, the start and discontinuation date and the reason for therapy.
• GVHD propylaxis, HSCT and overall peritransplant care any or all of which may vary significantly across different sites and may also vary patient by patient at the same site. Therefore, such concomitant treatments will be used according to institutional practices.
• Potent CYP3A4 Inhibitors e.g. selected from Atazanavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Amiodarone, Cimetidine, Clarithromycin, Ciprofloxacin, Diltiazem, Erythromycin, Fluvoxamine and the like.
• This Potent CYP3A4 inhibitors may be administered to patients as standard of care.
• PK samples will be analyzed on an ongoing basis.
• Mini-Seattle Conditioning with Fludarabin will be used at 30 mg/m2/day for three days followed by total body irradiation (TBI) (1 ⁇ 200 cGy/day)
• High dose chemotherapy and total body irradiation will be performed according to national guideines adapted to institutional practices, and may include the use of fludarabin, busulphan, methotrexate, cyclosporin A and cyclophosphamide.
• the following dosing regimens are given as examples:
• TBI TBI will occur from approximately days 8 to 10 (days ⁇ 8 and ⁇ 1 relative to HSCT). The recommended TBI dose is 200 cGy given twice daily for a total dose of 1200 cGy.
• a compound of formula (I) will be given as an add-on-treatment to the normal treatment drug given to patients to prevent GVHD.
• the standard of care for prophylaxis of GVHD has many side effects and in a high percentage of patients does not prevent GVHD.
• patients may receive prophylaxis as per institutional practices using for example cyclosporin A (CsA), mycophenolate or methotrexate.
• CsA cyclosporin A
• patients begin CsA on Day 8 (day ⁇ 3 relative to HSCT) at an initial dose of 2.5 mg/kg IV over 2 hours every 12 hours. Dose adjustments may be made on the basis of toxicity and CsA levels with a targeted trough level of 150-400 mg/L.
• CsA is typically converted to an per oral (p.o.) form.
• Initial p.o. dosing might be the current intra venious (i.v.) dose given twice daily.
• CsA dosing is typically monitored at least weekly and may be altered as clinically appropriate.
• Methotrexate schedule and dosing may be adapted according to internal standards of an institution (e.g. 10 mg/kg on Day 11, 6 mg/kg on Day 13 and on Day 16).
• Mycophenolate may typically be given according to the institutional practices (e.g. 2 ⁇ 100 mg per day after mini-Seattle conditioning). Dose adjustments may be made based on clinical side effects.
• HSCT Hematopoetic Stem Cell Transplant
• Peripheral mobilized stem cell will be used according to institutional practices. Suitable stem cell source must be available according to the graft selection algorithm as defined by JACIE* adapted to institutional standards using T-cell replete peripheral stem cells as a graft source.
• JACIE The Joint Accreditation Committee Europe comprising the International Society for Cellular Therapy & European Group for Blood and Marrow Transplantation.
• the donor must be 9/10 or 10/10 matched with the recipient using molecular HLA matching techniques.
• mice and female Crj:BDF1 mice were purchased from CHARLES RIVER JAPAN and used at 10 weeks of age as donors and recipients, respectively.
• Spleens were collected from donor BALB/c mice.
• the spleens were placed in a RPMI-1640 medium (GIBCO) and were gently pressed two slide glasses to make a single cell suspension.
• the single cell suspension was passed through a cell strainer (70 um, FALCON).
• the filtrate was centrifuged to collect the cell pellet.
• the pellet was re-suspended in RPMI-1640 medium.
• the number of nucleated cells in the suspension was calculated by staining using Turk's solution.
• the suspension was diluted appropriately with RPMI-1640 medium to finally make a suspension of 2 ⁇ 10 8 cells/mL. This suspension served as a splenic cell suspension.
• Recipient BDF1 mice were treated with a dose of cyclophosphamide (SHIONOGI & CO., LTD.) at 300 mg/kg intraperitoneally on day0.
• cyclophosphamide SHIONOGI & CO., LTD.
• the BDF1 mice were intravenously injected with 0.25 mL (5 ⁇ 10 7 cells/mouse) of the splenic cell suspension from BALB/c mice to induce lethal GvHD.
• the compounds were orally administrated once a day from day 1 (just after injection of the splenic cells) to day 20. The mice were observed until day 70.

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