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WO2009124756A1 - Use of aprepitant and derivatives thereof for the treatment of cancer - Google Patents

Use of aprepitant and derivatives thereof for the treatment of cancer Download PDF

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Publication number
WO2009124756A1
WO2009124756A1 PCT/EP2009/002621 EP2009002621W WO2009124756A1 WO 2009124756 A1 WO2009124756 A1 WO 2009124756A1 EP 2009002621 W EP2009002621 W EP 2009002621W WO 2009124756 A1 WO2009124756 A1 WO 2009124756A1
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WIPO (PCT)
Prior art keywords
defined above
alkyl
alkoxy
phenyl
cor
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PCT/EP2009/002621
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French (fr)
Inventor
Michael Kuhn
Monica Campillos
Peer Bork
Lars Juhl Jensen
Anne-Claude Gavin
Maria Paola Costi
Rosaria Luciani
Robert Preissner
Hua FAN
Julia Hossbach
Hu Jing
Jessica Ahmed
Original Assignee
European Molecular Biology Laboratory (Embl)
University Of Modena E Reggio Emilia
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Application filed by European Molecular Biology Laboratory (Embl), University Of Modena E Reggio Emilia filed Critical European Molecular Biology Laboratory (Embl)
Publication of WO2009124756A1 publication Critical patent/WO2009124756A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of a heterocyclic compound according to general structural formula (I) for the treatment of cancer.
  • the compound according to formula (I) is aprepitant.
  • Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms that normally govern proliferation and differentiation.
  • Therapeutic agents used in clinical cancer therapy can be categorized into several groups, including, alkylating agents, antibiotic agents, antimetabolic agents, biologic agents, hormonal agents, and plant-derived agents.
  • Cancerous cells display uncontrolled growth (growth and division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). Much effort has been spent to find novel anti-cancer agents. Cancer therapy is also being attempted by modulating the enzymatic activity of target proteins in cancer cells. For example, compounds were found which inhibit enzymes used in purine and pyrimidine synthesis such as thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT).
  • TS thymidylate synthase
  • DHFR dihydrofolate reductase
  • GARFT glycinamide ribonucleotide formyl transferase
  • the invention provides the use of a compound according to formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of:
  • R 2 and R 3 are independently selected from the group consisting of:
  • aryl or heteroaryl optionally substituted; and the groups R 1 and R 2 may be joined together to form a heterocyclic ring which may be optionally substituted; and the groups R 2 and R 3 may be joined together to form a carbocyclic ring or a heterocyclic ring which may be optionally substituted;
  • R , R and R are independently selected from the group consisting of:
  • R R are independently selected from:
  • R 11 , R 12 and R 13 are independently selected from the groups as defined for R 6 , R 7 and R 8 ;
  • R 14 is in each instance hydrogen or alkyl;
  • X is selected from the group consisting of:
  • Y is selected from the group consisting of:
  • R 15 and R 16 are independently selected from the group consisting of:
  • alkyl "heteroalkyl”, “cycloalkyl”, “heterocycloalkyl”, “alicyclic system”, “aryl”, “aralkyl”, “heteroaryl”, “heteroaralkyl”, "alkenyl”, “cycloalkenyl”, “alkynyl” and “optionally substituted” are provided.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, ter/-butyl, pentyl, hexyl, heptyl, or octyl.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, sec-butyl, tert-buty ⁇ , pentyl, hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms.
  • the heteroatoms are selected from O, S, and N, e.g.
  • Heteroalkyl groups are optionally substituted.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • heterocycloalkyl preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.
  • Cycloalkyl and “heterocycloalkyl” groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 di
  • alicyclic system refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond.
  • an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs.
  • the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds.
  • the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system.
  • Alicyclic systems are optionally substituted.
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.
  • aralkyl refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above.
  • An example is the benzyl radical.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, sec-butenyl, tert-butyl, pentyl, hexyl, pentyl, octyl.
  • the aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
  • heteroaryl preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S.
  • Examples are oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1 ,2-benzisothi
  • heteroarylkyl refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above.
  • An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
  • alkenyl and cycloalkenyl refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl.
  • the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.
  • cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g.
  • alkynyl refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds.
  • An example is the propargyl radical.
  • the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
  • substituents e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents which are in each instance independently selected from the group consisting of halogen, in particular F, Cl, Br or I; -R', -NO 2 , -CN, -OR', -NR'R", -COOR', -CONR'R", -NR'"COR”", -NR'"COR”", -NR'"C0NR'R", -NR"SO 2 A, -COR'”; -SO 2 NR 5 R", -OOCR'", -CR'"R””OH, R'"0H, and -E;
  • R' and R" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, or heterocycloalkyl; o
  • R'" and R"" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R"; E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • the term "a compound according to the invention” refers to a compound according to formula I through IV including all preferred respective embodiments of such a compound and physiological acceptable salts thereof.
  • Aprepitant (5-[[(2S,3R)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4- fluorophenyl)morpholin-4-yl] methyl]-l,2-dihydro-l,2,4-triazol-3-one) is currently used for prevention of nausea and vomiting. It was approved by the FDA in 2003. Aprepitant may also be useful in the treatment of cyclic vomiting syndrome but there are few studies to date. WO
  • aprepitant has antiproliferative properties and can be used as an anti-cancer agent.
  • R 1 is selected from the group consisting of:
  • alkyl preferably Cl-IO alkyl, e.g. methyl, ethyl methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, ter/-butyl, pentyl, hexyl, heptyl, or octyl; optionally substituted; (3) alkenyl; optionally substituted;
  • R 2 and R are independently selected from the group consisting of: (1) hydrogen; (2) alkyl; optionally substituted;
  • aryl or heteroaryl optionally substituted; and the groups R 1 and R 2 may be joined together to form a heterocyclic ring which may be optionally substituted; and the groups R 2 and R 3 may be joined together to form a carbocyclic ring or a heterocyclic ring which may be optionally substituted;
  • R 6 , R 7 and R 8 are independently selected from the group consisting of:
  • halo preferably fluoro, chloro, bromo or iodo; most preferably fluoro; (7) -CN,
  • R 9 and R 10 are independently selected from: (i) hydrogen,
  • R 11 , R 12 and R 13 are independently selected from the substituents indicated for R 6 , R 7 and R 8 ; and preferably R 11 , R 12 and R 13 are independently selected from H and Halo, e.g. H, fluoro, chloro, bromo and iodo;
  • R 14 is in each instance hydrogen or alkyl; X is selected from the group consisting of:
  • R 15 and R 16 are independently selected from the group consisting of:
  • aryl or heteroaryl optionally substituted; and preferably Y is -0-; and Z is alkyl; preferably Cl-IO alkyl, e.g. methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl; optionally substituted; for the treatment of cancer.
  • Cl-IO alkyl e.g. methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl; optionally substituted; for the treatment of cancer.
  • R 1 is selected from the group consisting of: (1) hydrogen; (2) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with one or more of the substituents selected from:
  • Cl-6 alkyl i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with halo,-CF 3 , -OCH 3 , or phenyl,
  • R 9 is as defined above; R and R are independently selected from the group consisting of:
  • C2-6 alkenyl i.e. C2, C3, C4, C5 or C6-alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from the group consisting of:
  • R , R and R are independently selected from the group consisting of:
  • C 1 -6 alkyl i.e. C 1 , C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with one or more of the substituents selected from:
  • halo e.g. F, I, Br, or Cl
  • halo e.g. F, I, Br, or Cl
  • R 14 is hydrogen or C 1-5 alkyl, i.e. Cl, C2, C3, C4 or C5-alkyl,
  • R 11 , R 12 and R 13 are independently selected from the substituents indicated for R 6 , R 7 and R ; preferably R 1 ' and R 12 are hydrogen and R 13 is Halogen, e.g. F, I, Br, or Cl;
  • X is selected from the group consisting of:
  • X is -0-, or -S-, most preferably -0-;
  • Y is selected from the group consisting of:
  • R 15 and R 16 are independently selected from the group consisting of: (a) C 1-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with one or more of the substituents selected from: (i) hydroxy,
  • R 9 is as defined above; preferably Y is -0-, or -S-, most preferably -0-; and Z is C 1-6 alkyl. i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, /s ⁇ -propyl, butyl, /so-butyl, ter/-butyl, pentyl or hexyl, and most preferably methyl. Further preferred is the use according to the invention, wherein
  • R 1 is C 1-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, /s ⁇ -propyl, butyl, /50-butyl, tert-butyl, pentyl or hexyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of:
  • R 1 is
  • R 2 and R 3 are independently selected from the group consisting of: (1) hydrogen,
  • Cl-6 alkyl i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso- propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl,
  • R 6 , R 7 and R 8 are independently selected from the group consisting of:
  • Cl-6 alkyl i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso- propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl,
  • R 11 , R 12 and R 13 are independently selected from the group consisting of: (1) hydrogen,
  • Cl-6 alkyl i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso- propyl, butyl, /so-butyl, tert-butyl, pentyl or hexyl,
  • Y is -O-
  • Z is C 1-4 alkyl i.e. Cl, C2, C3, or C4-alkyl, e.g. methyl, ethyl, propyl, zso-propyl, butyl, iso- butyl or ter/-butyl and most preferably methyl.
  • Z is C 1-4 alkyl i.e. Cl, C2, C3 or C4 -alkyl, e.g. methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl or tert-butyl or, preferably, -CH 3 .
  • R and R 3 is hydrogen and Z is -CH 3 .
  • R 6 and R 7 is -CF 3 and R 13 is F.
  • R and R is hydrogen and R and R is -CF 3 .
  • R 1 is selected from the group consisting of:
  • X is -O- and Y is -O- and R 6 and R 7 is -CF 3 and R 13 is F.
  • R 2 and R 3 are hydrogen and X and Y are -O-.
  • X and Y is - O- and Z is -CH 3 .
  • Z is -CH 3 and R 6 and R 7 is -CF 3 and R 13 is F.
  • R 2 and R 3 are hydrogen, Z is -CH 3 , X and Y are -O- and R 6 and R 7 is -CF 3 and R 13 is F.
  • the compound has a structure according to formula IV:
  • the cancer is a cancer selected from the group consisting of: a solid tumor, a hematological malignancy, a carcinoma, a neuroblastoma and a melanoma.
  • aprepitant also effectively reduces the cell proliferation of cancer cell lines which are not derived from lung or pleural tissue.
  • a solid tumor is a tumor of the head or neck, lung, breast, colon, prostate, bladder, rectum, brain, gastric tissue, bone, ovary, thyroid, or endometrium.
  • a hematological malignancies is a leukaemia, lymphoma or myeloma.
  • Preferred embodiments of a carcinoma include a bladder carcinoma, a renal carcinoma, a breast carcinoma, a colorectal carcinoma.
  • the cancer is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T- cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, brain neuroblastoma, retinoblastoma, glioma, Wilms' tumor, bone cancer and soft-tissue sarcoma
  • DLBCL diffuse large B-cell lymph
  • the cancer treatable with the compound of the invention is selected from the group consisting of a leukemia, renal cancer, colon cancer, non-small cell lung carcinoma, breast cancer, melanoma and brain cancer. Most preferably, the cancer is leukemia.
  • Another aspect of the invention is the compound of the invention for the treatment of cancer, in particular or of the aforementioned specific forms of cancer.
  • the compound according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Parenteral administration and particular intravenous administration, preferably by depot injection, is preferred. Depending on the route of administration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in, for example, the digestive tract.
  • a compound of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation.
  • the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.
  • Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid.
  • a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils.
  • a compound of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
  • Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
  • preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal.
  • isotonic agents such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
  • sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary.
  • Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • Excipients which can be used with the various pharmaceutical forms of a compound of the invention can be chosen from the following non-limiting list: a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like; b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates, c) disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
  • binders such as lactose, mannitol, crystalline sorb
  • the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g serum per kg body weight.
  • a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 10 to 200 mg/kg body weight, preferably ranging from 50 to 150 mg/kg body weight, preferably ranging from 90 to 100 mg/kg body weight.
  • the duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
  • the pharmaceutically effective amount of a given composition will also depend on the administration route. In general the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g. intravenous.
  • a compound of the invention will be admim ' stered in ranges of 50 mg to 1 g/kg body weight, preferably 100 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight, if parenteral administration is used.
  • a prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible.
  • the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, between 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, a compound of the invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or improving.
  • Fig. 7 The inhibitory growth effect on cancer cells induced by aprepitant at a concentration of 1.0 x 10 s M.
  • Folate is important for cells and tissues that rapidly divide. Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer.
  • the antifolate methotrexate is a drug often used to treat cancer because it inhibits the production of the active form, tetrahydrofolate.
  • methotrexate can be toxic, producing side effects such as inflammation in the digestive tract that make it difficult to eat normally.
  • Thymidylate synthase (EC 2.1.1.45) is the enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair.
  • dTMP thymidine monophosphate
  • dUMP deoxyuridine monophosphate
  • N5,N10-methylene tetrahydrofolate are together used to form dTMP, yielding dihydrofolate as a secondary product.
  • aprepitant is a noncompetitive inhibitor of human thymidylate synthase with respect to the N5,N10-methylenetetrahydrocofolate cofactor.
  • the inhibition effect can be observed only upon incubation of the enzyme with the inhbitor.
  • the time dependent effect can be observed in the range of 60-180 minutes without affecting control stability.
  • the apparent Ki value is between 1.5 and 0.5 microMolar.
  • An incubation effect can be observed.
  • the IC 50 range in this case is in the range of 200 microMolar with an incubation time between 60 and 180 minutes.
  • Example 2 Inhibition pattern of Aprepitant versus human Thymidylate synthase (TYMS)
  • the inhibition assays were carried out changing the substrate concentration and observing the effect of the inhibitor concentration on enzyme activity.
  • the temperature was kept between 25° C and 37° C and the incubation time was kept between 0 and 240 minutes. 1.Data collection The assays have been conducted using three series of solutions.
  • Each reaction mixture contains:
  • hTS refers to human Thymidylate synthase
  • dUMP 7 ⁇ l (concentration of 116.16 ⁇ M) to start the reaction.
  • Experiment B Enzyme Inhibition study of hTS considering the substrate dUMP as competitor substrate.
  • the Inhibitor (Aprepitant) was varied between 0 and 1 mM, dUMP concentration was varied between 0 and 400 ⁇ M while the folate concentration was kept fixed. The temperature was kept between 25° C and 37° C and the incubation time was kept between 0 and 240 minutes.
  • the assay has been conducted incubating hTS, with dUMP and inhibitor (aprepitant) at 30°C for 0, 60, 120 and 180 minutes.
  • the reactions have been initiated by cofactor addition. This has been repeated for concentration of inhibitor ranging between 0 and 1 mM and dUMP ranging between 0 and 400 ⁇ M.
  • IC 50 is in the range of 200 ⁇ M after 60 minutes and it slightly decreases with time, showing an incubation effect.
  • Example 3 Cell assays.
  • the inhibition of proliferation induced by aprepitant was measured at concentration ranges of l-5 ⁇ M and 10-50 ⁇ M and at 24, 48 and 72h after initiation of treatment in the following cell lines:
  • the cell-division was assayed using cell counting.
  • MCF-7 cells breast cancer: 60% % inhibition at 10 ⁇ M. More than 60% inhibition at 2 ⁇ M after 72h.
  • Molt-4 (leukemia cell line): 40% inhibition at 10 ⁇ M
  • HT29 (Adenocarcinoma): 60% % inhibition at 10 ⁇ M. 60% inhibition at 2 ⁇ M after 48 and 72h.
  • HCTl 15 (Adenocarcinoma): 30% inhibition at 10 ⁇ M. More than 60% inhibition at 2 ⁇ M after 48 and 72h.
  • L929 (mouse cell line): 40% inhibition at 10 ⁇ M MDA-MB-231 (Adenocarcinoma): 60% inhibition at 2 ⁇ M after 72.
  • the inhibition on cell division obtainable with aprepitant suggests that the compound of the invention can be used to treat a wide variety of cancer types. See also figure 6 for a graphical representation of the inhibition.
  • the screen utilizes 26 different human tumor cell lines, representing leukemia, melanoma and cancers of the lung, colon, brain, breast and kidney.
  • the screening evaluates aprepitant and a control substance against the 26 cell lines at a single dose of 10 ⁇ M.
  • the human tumor cell lines of the cancer screening panel are grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. Cells are inoculated into 96 well microtiter plates in 100 ⁇ L at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates are incubated at 37 0 C, 5 % CO 2 , 95 % air and 100 % relative humidity for 24 h prior to addition of drugs.
  • the plates are incubated for an additional 48 h at 37°C, 5 % CO 2 , 95 % air, and 100 % relative humidity.
  • the assay is terminated by the addition of cold TCA.
  • Cells are fixed in situ by the gentle addition of 50 ⁇ l of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried.
  • Sulforhodamine B (SRB) solution (100 ⁇ l) at 0.4 % (w/v) in 1 % acetic acid is added to each well, and plates are incubated for 10 minutes at room temperature.
  • the screening results indicating mean growth percent at a dose of 10 ⁇ M aprepitant relative to a control compound and relative to the time zero number of cells are shown in figure 7 below.
  • a value of "mean growth percent" of 40 would mean 60% growth inhibition.
  • the results show effective growth inhibition of several cancer cells lines originating from non-small cell lung cancer, colon cancer, breast cancer, leukaemia, renal cancer, melanoma and CNS cancer.

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Abstract

The present invention relates to the use of a heterocyclic compound according to general structural formula (I) for the treatment of cancer. In a preferred aspect the compound according to formula (I) is aprepitant.

Description

USE OF APREPITANT AND DERIVATIVES THEREOF FOR THE TREATMENT OF CANCER
The present invention relates to the use of a heterocyclic compound according to general structural formula (I) for the treatment of cancer. In a preferred aspect the compound according to formula (I) is aprepitant.
BACKGROUND OF THE INVENTION
Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms that normally govern proliferation and differentiation. Therapeutic agents used in clinical cancer therapy can be categorized into several groups, including, alkylating agents, antibiotic agents, antimetabolic agents, biologic agents, hormonal agents, and plant-derived agents.
Cancerous cells display uncontrolled growth (growth and division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). Much effort has been spent to find novel anti-cancer agents. Cancer therapy is also being attempted by modulating the enzymatic activity of target proteins in cancer cells. For example, compounds were found which inhibit enzymes used in purine and pyrimidine synthesis such as thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT). By inhibiting the formation of precursor purine and pyrimidine nucleotides, the formation of DNA and RNA is comprimised, which are necessary for the growth and survival of both normal cells and cancer cells. As cancer cells are rapidly dividing they heavily rely on a sufficient supply of nucleotides to afford such rapid divisions. However, therapeutic target proteins, such as the aforementioned enzymes respond differently to treatment depending on the type of cancer and the the genetic predisposition of the patient.
Due to the multiple different forms of cancer there is a need for additional pharmaceutically active substances which can be used to treat cancer.
SUMMARY OF THE INVENTION
The inventors have identified a compound which unexpectedly is useful to effectively treat cancer. Thus, in a first aspect, the invention provides the use of a compound according to formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of:
(1) hydrogen;
(2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted;
(4) alkynyl; optionally substituted; and (5) aryl or heteroaryl; optionally substituted;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted; (4) alkynyl; optionally substituted; and
(5) aryl or heteroaryl; optionally substituted; and the groups R1 and R2 may be joined together to form a heterocyclic ring which may be optionally substituted; and the groups R2 and R3 may be joined together to form a carbocyclic ring or a heterocyclic ring which may be optionally substituted;
R , R and R are independently selected from the group consisting of:
(1) hydrogen;
(2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted; (4) alkynyl; optionally substituted;
(5) aryl or heteroaryl; optionally substituted;
(6) halo,
(7) -CN,
(8) -CF3, (9) -NO2,
(10) -SR14,
(H) -SOR14,
(12) -SOOR14,
(13) -NR9COR10,
(14) -CONR9R10,
(15) -NR9R10,
(16) -NR9COOR10,
(17) hydroxy,
(18) alkoxy,
(19) -COR9, and
(20) -COOR9;
9 a .nd j •
R R are independently selected from:
(i) hydrogen, (ii) alkyl,
(iii) hydroxy-alkyl, and (iv) aryl;
R11, R12 and R13 are independently selected from the groups as defined for R6, R7 and R8; R14 is in each instance hydrogen or alkyl; X is selected from the group consisting of:
(1) -0-,
(2) -S-,
(3) -SO-, and
(4) -SO2-; Y is selected from the group consisting of:
(1) a single bond,
(2) -0-,
(3) -S-,
(4) -CO-, (5) -CH2-,
(6) -CHR15-, and
(7) -CR15R16-, wherein R15 and R16 are independently selected from the group consisting of:
(a) alkyl; optionally substituted; and (b) aryl or heteroaryl; optionally substituted; and Z is alkyl; optionally substituted; for the treatment of cancer.
DETAILED DESCRIPTION OF THE INVENTION Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland). Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
In the following definitions of the terms: "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "alicyclic system", "aryl", "aralkyl", "heteroaryl", "heteroaralkyl", "alkenyl", "cycloalkenyl", "alkynyl" and "optionally substituted" are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings.
The term "alkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, ter/-butyl, pentyl, hexyl, heptyl, or octyl. Alkyl groups are optionally substituted.
The term "heteroalkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, sec-butyl, tert-buty\, pentyl, hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably the heteroatoms are selected from O, S, and N, e.g. -0-CH3, -S-CH3, -CH2-O-CH3, - CH2-O-C2H5, -CH2-S-CH3, -CH2-S-C2H5, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-S-CH3, -C2H4-S- C2H5 etc. Heteroalkyl groups are optionally substituted. The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. If more than one cyclic ring is present such as in bicyclic, tricyclic and polycyclic versions, then these rings may also comprise one or more aryl- or heteroaryl ring. The term "heterocycloalkyl" preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro- indenyl, decahydro-azulenyl, adamantly, or decahydro-naphthalenyl. Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1- ■ aza-7,l l-dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The term "alicyclic system" refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond. However, an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs. Thus, the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds. Thus, the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system. Alicyclic systems are optionally substituted.
The term "aryl" preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.
The term "aralkyl" refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above. An example is the benzyl radical. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, sec-butenyl, tert-butyl, pentyl, hexyl, pentyl, octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
The term "heteroaryl" preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S. Examples are oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, 1,2,3- benzotriazinyl, or 1,2,4-benzotriazinyl.
The term "heteroaralkyl" refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above. An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, iso-pτopyl, butyl, wo-butyl, sec-butenyl, ter/-butyl, pentyl, hexyl, pentyl, octyl. The heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
The terms "alkenyl" and "cycloalkenyl" refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl. Preferably, the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethenyl, 1 -propenyl, 2-propenyl, /so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl. The term also comprises CH2, i.e. methenyl, if the substituent is directly bonded via the double bond. Preferably the cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl, spiro[3,4]octenyl, spiro[4,3]octenyl, spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or octahydro-naphthalenyl.
The term "alkynyl" refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds. An example is the propargyl radical. Preferably, the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
The term "optionally substituted" in each instance if not further specified refers to between 1 and 10 substituents, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents which are in each instance independently selected from the group consisting of halogen, in particular F, Cl, Br or I; -R', -NO2, -CN, -OR', -NR'R", -COOR', -CONR'R", -NR'"COR"", -NR'"COR"", -NR'"C0NR'R", -NR"SO2A, -COR'"; -SO2NR5R", -OOCR'", -CR'"R""OH, R'"0H, and -E;
R' and R" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, or heterocycloalkyl; o
R'" and R"" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R"; E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted; As used throughout the specification, the term "a compound according to the invention" refers to a compound according to formula I through IV including all preferred respective embodiments of such a compound and physiological acceptable salts thereof.
Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. When bonds to the chiral carbon are depicted as straight lines in the formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
Aprepitant (5-[[(2S,3R)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4- fluorophenyl)morpholin-4-yl] methyl]-l,2-dihydro-l,2,4-triazol-3-one) is currently used for prevention of nausea and vomiting. It was approved by the FDA in 2003. Aprepitant may also be useful in the treatment of cyclic vomiting syndrome but there are few studies to date. WO
95/16679 discloses a possible chemical synthesis of aprepitant.
The inventors have surprisingly found that aprepitant has antiproliferative properties and can be used as an anti-cancer agent.
Thus, in a first aspect the invention provides the use of a compound according to formula I:
Figure imgf000010_0001
(I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of:
(1) hydrogen;
(2) alkyl; preferably Cl-IO alkyl, e.g. methyl, ethyl methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, ter/-butyl, pentyl, hexyl, heptyl, or octyl; optionally substituted; (3) alkenyl; optionally substituted;
(4) alkynyl; optionally substituted; and
(5) aryl or heteroaryl; optionally substituted;
R2 and R are independently selected from the group consisting of: (1) hydrogen; (2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted;
(4) alkynyl; optionally substituted; and
(5) aryl or heteroaryl; optionally substituted; and the groups R1 and R2 may be joined together to form a heterocyclic ring which may be optionally substituted; and the groups R2 and R3 may be joined together to form a carbocyclic ring or a heterocyclic ring which may be optionally substituted;
R6, R7 and R8 are independently selected from the group consisting of:
(I) hydrogen; (2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted;
(4) alkynyl; optionally substituted;
(5) aryl or heteroaryl; optionally substituted;
(6) halo, preferably fluoro, chloro, bromo or iodo; most preferably fluoro; (7) -CN,
(8) -CF3,
(9) -NO2,
(10) -SR14,
(I I) -SOR14, (12) -SOOR14,
(13) -NR9COR10,
(14) -CONR9R10,
(15) -NR9R10,
(16) -NR9COOR10, (17) hydroxy, (18) alkoxy,
(19) -COR9, and
(20) -COOR9;
R9 and R10 are independently selected from: (i) hydrogen,
(ϋ) alkyl,
(iii) hydroxy-alkyl, and (iv) aryl;
R11, R12 and R13 are independently selected from the substituents indicated for R6, R7 and R8; and preferably R11, R12 and R13 are independently selected from H and Halo, e.g. H, fluoro, chloro, bromo and iodo;
R14 is in each instance hydrogen or alkyl; X is selected from the group consisting of:
(1) -0-, (2) -S-,
(3) -SO-, and
(4) -SO2-; and preferably X is -O-; Y is selected from the group consisting of:
(1) a single bond, (2) -0-,
(3) -S-,
(4) -CO-,
(5) -CH2-,
(6) -CHR15-, and (7) -CR15R16-, wherein R15 and R16 are independently selected from the group consisting of:
(a) alkyl; optionally substituted; and
(b) aryl or heteroaryl; optionally substituted; and preferably Y is -0-; and Z is alkyl; preferably Cl-IO alkyl, e.g. methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl; optionally substituted; for the treatment of cancer.
In a preferred embodiment of the use of the invention,
R1 is selected from the group consisting of: (1) hydrogen; (2) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo, (c) Cl-6 alkoxy, i.e. Cl5 C2, C3, C4, C5 or C6-alkoxy,
(d) -phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo, wherein halo is fluoro, chloro, bromo or iodo, (h) -NR9R10, wherein R9 and R10 are independently selected from:
(i) hydrogen,
(ii) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl,
(iii) hydroxy-Cl-6 alkyl, i.e. hydroxy-Cl, -C2, -C3, -C4, -C5 or -C6-alkyl, and (iv) phenyl, (i) -NR9COR10, wherein R9 and R10 are as defined above,
G) -NR9COOR10, wherein R9 and R10 are as defined above, (k) -CONR9R10, wherein R9 and R10 are as defined above, (1) -COR9, wherein R9 is as defined above, (m) -COOR9, wherein R9 is as defined above; (n) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzoxazolyl, (E) furanyl,
(F) imidazolyl,
(G) indolyl, (H) isooxazolyl, (I) isothiazolyl, (J) oxadiazolyl,
(K) oxazolyl,
(L) pyrazinyl,
(M) pyrazolyl,
(N) pyridyl, (O) pyrimidyl, (P) pyrrolyl, (Q) quinolyl, (R) tetrazolyl, (S) thiadiazolyl, (T) thiazolyl,
(U) thienyl,
(V) triazolyl, preferably l,2-dihydro-[l ,2,4]triazol-3-one; (W) azetidinyl, (X) 1,4-dioxanyl,
(Y) hexahydroazepinyl, (Z) piperazinyl,
(AA) piperidinyl,
(AB) pyrrolidinyl, (AC) tetrahydrofuranyl, and
(AD) tetrahydrothienyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with halo,-CF3, -OCH3, or phenyl,
(ii) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(iii) oxo,
(iv) hydroxy,
(v) thioxo, (vi) -SR9, wherein R9 is as defined above,
(vii) halo,
(viii) cyano,
(ix) phenyl,
(x) trifluoromethyl, (xi) -(CH2)m-NR9R10, wherein m is 0, 1 or 2, and R9 and R10 are as defined above,
(xii) -NR9COR10, wherein R9 and R10 are as defined above,
(xiii) -CONR9R10, wherein R9 and R10 are as defined above,
(xiv) -COOR9, wherein R9 is as defined above, and (xv) -(CH2)m-OR9, wherein m and R9 are as defined above; (3) C2-6 alkenyl, i.e. C2, C3, C4, C5 or C6-alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) oxo, (c) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo, (h) -CONR9R10 wherein R9 and R10 are as defined above,
(i) -COR9 wherein R9 is as defined above, Q) -COOR9, wherein R9 is as defined above, and (k) heterocycle, wherein the heterocycle is as defined above;
(4) C2-6 alkynyl; i.e. C2, C3, C4, C5 or C6-alkenyl,and (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) C 1-6 alkoxy,
(c) Cl-6 alkyl, (d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2, (h) -CF3, (i) -(CH2)m-NR9R10, wherein m, R9 and R10 are as defined above,
G) -NR9COR10, wherein R9 and R10 are as defined above,
(k) -NR9COOR10, wherein R9 and R10 are as defined above,
( 1 ) -CONR9R1 °, wherein R9 and R1 ° are as defined above,
(m) -COONR9R10, wherein R9 and R10 are as defined above, (n) -COR9, wherein R9 is as defined above; and
(o) -COOR9, wherein R9 is as defined above; R and R are independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy,
(b) oxo,
(c) C 1 -6 alkoxy, i.e. C 1 , C2, C3, C4, C5 or C6-alkoxy,
(d) phenyl-C 1-3 alkoxy, (e) phenyl,
(f) -CN,
(g) halo,
(h) -NR9R10, wherein R9 and R10 are as defined above,
(i) -NR9COR10, wherein R9 and R10 are as defined above, G) -NR9COOR10, wherein R9 and R10 are as defined above,
. (k) -CONR9R1 °, wherein R9 and R1 ° are as defined above,
(1) -COR9, wherein R9 is as defined above, and
(m) -COOR9, wherein R9 is as defined above;
(3) C2-6 alkenyl, i.e. C2, C3, C4, C5 or C6-alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) oxo,
(c) C 1-6 alkoxy,
(d) phenyl-C 1-3 alkoxy, (e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10 wherein R9 and R10 are as defined above,
(i) -COR9 wherein R9 is as defined above, (j) -COOR9, wherein R9 is as defined above;
(4) C2-6 alkynyl; i.e. Cl, C2, C3, C4, C5 or C6-alkynyl, and
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) Cl-6 alkoxy, (c) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2, (h) -CF3, (i) -(CH2)m-NR9R10, wherein m, R9 and R10 are as defined above,
(j) -NR9COR10, wherein R9 and R10 are as defined above,
(k) -NR9COOR10, wherein R9 and R10 are as defined above,
(1) -CONR9R10, wherein R9 and R10 are as defined above, (m) -COONR9R10, wherein R9 and R10 are as defined above,
(n) -COR9, wherein R9 is as defined above; and
(o) -COOR9, wherein R9 is as defined above; and the groups R1 and R2 may be joined together to form a heterocyclic ring selected from the group consisting of: (a) pyrrolidinyl,
(b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl, (f) oxazolyl, and
(g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) from:
(i) C 1-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, (ii) oxo,
(iii) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(iv) -NR9R10, wherein R9 and R10 are as defined above,
(v) halo, and
(vi) trifluoromethyl; and the groups R2 and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl,
(b) cyclohexyl,
(c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl,
(ii) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(iii) -NR9R10, wherein R9 and R10 are as defined above, (iv) halo, and Io
(V) trifluoromethyl; and the groups R2 and R3 may be group consisting of:
(a) pyrrolidinyl,
(b) piperidinyl,
(C) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl, ω fiiranyl,
(g) oxazolyl,
(h) thienyl, and
(i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted withone or more substituent(s) from: (i) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl,
(ii) oxo,
(iii) C 1-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(iv) -NR9R10, wherein R9 and R10 are as defined above,
(v) halo, and (vi) trifluoromethyl; and preferably, R2 and R3 are hydrogen;
R , R and R are independently selected from the group consisting of:
(1) hydrogen;
(2) C 1 -6 alkyl, i.e. C 1 , C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C 1-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(d) phenyl-Cl-3 alkoxy, (e) phenyl,
(f) -CN,
(g) halo, e.g. F, I, Br, or Cl;
(h) -NR9R10, wherein R9 and R10 are as defined above, (i) -NR9COR10, wherein R9 and R10 are as defined above, G) -NR9COOR10, wherein R9 and R10 are as defined above, (k) -CONR9R10, wherein R9 and R10 are as defined above, (1) -COR , wherein R is as defined above, and (m) -COOR9, wherein R9 is as defined above;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) from:
(a) hydroxy,
(b) oxo,
(c) C 1 -6 alkoxy, i.e. C 1 , C2, C3, C4, C5 or C6-alkoxy,
(d) phenyl-Cl-3 alkoxy, (e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10, wherein R9 and R10 are as defined above, (i) -COR9, wherein R9 is as defined above; and Q) -COOR9, wherein R9 is as defined above;
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(c) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl,
(d) C2-5 alkenyl, i.e. C2, C3, C4 or C5-alkenyl,
(e) halo, e.g. F, I, Br, or Cl;
(f) -CN, (g) -NO2,
(h) -CF3,
(i) -(CH2)m-NR9R10, wherein m, R9 and R10 are as defined above, Q) -NR9COR10, wherein R9 and R10 are as defined above, (k) -NR9COOR10, wherein R9 and R10 are as defined above, (1) -CONR9R10, wherein R9 and R10 are as defined above,
(m) -COONR9R10, wherein R9 and R10 are as defined above, (n) -COR9, wherein R9 is as defined above; and (o) -COOR9, wherein R9 is as defined above;
(6) halo, e.g. F, I, Br, or Cl; (7) -CN, o
(8) -CF3,
(9) -NO2,
(10) -SR14, wherein R14 is hydrogen or C 1-5 alkyl, , i.e. Cl, C2, C3, C4 or C5-alkyl,
(11) -SOR14, wherein R14 is as defined above,
(12) -SOOR14, wherein R14 is as defined above,
(13) -NR9COR10, wherein R9 and R10 are as defined above,
(14) -CONR7R , wherein R7 and R'υ are as defined above,
(15) -NR9R10, wherein R9 and R10 are as defined above,
(16) -NR9COOR10, wherein R9 and R10 are as defined above,
(17) hydroxy,
(18) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(19) -COR9, wherein R9 is as defined above;
(20) -COOR9, wherein R9 is as defined above;
(21) 2-pyridyl,
(22) 3-pyridyl,
(23) 4-pyridyl,
(24) 5-tetrazolyl,
(25) 2-oxazolyl, and
(26) 2-thiazolyl;
R11, R12 and R13 are independently selected from the substituents indicated for R6, R7 and R ; preferably R 1 ' and R12 are hydrogen and R13 is Halogen, e.g. F, I, Br, or Cl;
X is selected from the group consisting of:
(1) -0-,
(2) -S-,
(3) -SO-, and
(4) -SO2-; preferably X is -0-, or -S-, most preferably -0-;Y is selected from the group consisting of:
(1) a single bond,
(2) -0-,
(3) -S-,
(4) -CO-,
(5) -CH2-,
(6) -CHR15-, and
(7) -CR15R16-, wherein R15 and R16 are independently selected from the group consisting of: (a) C 1-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with one or more of the substituents selected from: (i) hydroxy,
(ii) oxo, (iii) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(iv) phenyl-Cl-3 alkoxy,
(v) phenyl,
(vi) -CN,
(vii) halo, (viii) -NR9R10, wherein R9 and R10 are as defined above,
(ix) -NR9COR10, wherein R9 and R10 are as defined above,
(x) -NR9COOR10, wherein R9 and R10 are as defined above,
(xi) -CONR9R10, wherein R9 and R10 are as defined above,
(xii) -COR9, wherein R9 is as defined above; and (xiii) -COOR9, wherein R9 is as defined above; and
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) from:
(i) hydroxy, (ii) Cl-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(iii) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl,
(iv) C2-5 alkenyl, i.e. C2, C3, C4 or C5-alkenyl,
(v) halo,
(vi) -CN, (vii) -NO2,
(viii) -CF3,
(ix) -(CH2)In-NR9R10, wherein m, R9 and R10 are as defined above,
(x) -NR9COR10, wherein R9 and R10 are as defined above,
(xi) -NR9COOR10, wherein R9 and R10 are as defined above, (xii) -CONR9R10, wherein R9 and R10 are as defined above,
(xiii) -COONR9R10, wherein R9 and R10 are as defined above,
(xiv) -COR9, wherein R9 is as defined above; and
(xv) -COOR9, wherein R9 is as defined above; preferably Y is -0-, or -S-, most preferably -0-; and Z is C 1-6 alkyl. i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, /sø-propyl, butyl, /so-butyl, ter/-butyl, pentyl or hexyl, and most preferably methyl. Further preferred is the use according to the invention, wherein
R1 is C 1-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, /sø-propyl, butyl, /50-butyl, tert-butyl, pentyl or hexyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) imidazolyl, (C) isooxazolyl,
(D) isothiazolyl,
(E) oxadiazolyl,
(F) pyrazinyl,
(G) pyrazolyl, (H) pyridyl,
(I) pyrrolyl,
(J) tetrazolyl,
(K) thiadiazolyl,
(L) triazolyl, preferably l,2-dihydro-[l ,2,4]triazol-3-one;and
(M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C 1-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, unsubstituted or substituted with halo,-CF3, -OCH3, or phenyl,
(ii) C 1-6 alkoxy, i.e. Cl, C2, C3, C4, C5 or C6-alkoxy,
(iii) oxo,
(iv) thioxo,
(v) cyano, (vi) -SCH3,
(vii) phenyl,
(viii) hydroxy,
(ix) trifluoromethyl, and
(x) -(CH2)m-NR9R10, wherein m is 0, 1 or 2; and wherein R9 and Rl 0 are independently selected from: (I) hydrogen,
(II) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl,
(III) hydroxy-Cl-6 alkyl, and
(IV) phenyl; (xi) -NR9COR10, wherein R9 and R10 are as defined above, and
(xii) -CONR9R10, wherein R9 and R10 are as defined above;
Figure imgf000023_0001
and wherein in a preferred embodiment R1 is
Further preferred is the use according to the invention, wherein R2 and R3 are independently selected from the group consisting of: (1) hydrogen,
(2) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso- propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl,
(3) C2-6 alkenyl, i.e. C2, C3, C4, C5 or C6-alkenyl,and
(4) phenyl; R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso- propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl,
(3) fluoro, (4) chloro,
(5) bromo,
(6) iodo, and
(7) -CF3;
R11, R12 and R13 are independently selected from the group consisting of: (1) hydrogen,
(2) Cl-6 alkyl, i.e. Cl, C2, C3, C4, C5 or C6-alkyl, e.g. methyl, ethyl, propyl, iso- propyl, butyl, /so-butyl, tert-butyl, pentyl or hexyl,
(3) fluoro,
(4) chloro, (5) bromo,
(6) iodo, and
(7) -CF3; X is -O-;
Y is -O-; and
Z is C 1-4 alkyl i.e. Cl, C2, C3, or C4-alkyl, e.g. methyl, ethyl, propyl, zso-propyl, butyl, iso- butyl or ter/-butyl and most preferably methyl.
Further preferred is the use according to the invention, wherein Z is C 1-4 alkyl i.e. Cl, C2, C3 or C4 -alkyl, e.g. methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl or tert-butyl or, preferably, -CH3.
Also preferred is the use according to the invention, wherein the compound has a structure according to formula II:
Figure imgf000024_0001
(II).
In a further preferred embodiment of the use of the invention R and R3 is hydrogen and Z is -CH3.
Also preferred is the use, wherein X is -O- and Y is -O-. In a further preferred embodiment R6 and R7 is -CF3 and R13 is F. In another preferred embodiment of the use of the invention R and R is hydrogen and R and R is -CF3.
Further preferred is the use according to the invention, wherein R1 is selected from the group consisting of:
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000025_0002
N
Figure imgf000026_0001
N ^. NMe2 S- N
Figure imgf000026_0002
H N-N N-N
,N
N^S N H H
H H N~N N-N
N
N ^ O N Me
Figure imgf000026_0003
Also preferred is the use according to the invention wherein X is -O- and Y is -O- and R6 and R7 is -CF3 and R13 is F. In another preferred embodiment of the use of the invention R2 and R3 are hydrogen and X and Y are -O-. In a further preferred embodiment of the use, X and Y is - O- and Z is -CH3. Also preferred is the use of the invention wherein Z is -CH3 and R6 and R7 is -CF3 and R13 is F. In another preferred embodiment of the use of the invention R2 and R3 are hydrogen, Z is -CH3, X and Y are -O- and R6 and R7 is -CF3 and R13 is F.
Further preferred is the use according to the invention, wherein the compound according to formula I or II has a structure according to formula III:
Figure imgf000027_0001
(III).
In a most preferred embodiment of the use of the invention, the compound has a structure according to formula IV:
Figure imgf000027_0002
(IV).
Further preferred is the use according to the invention, wherein the cancer is a cancer selected from the group consisting of: a solid tumor, a hematological malignancy, a carcinoma, a neuroblastoma and a melanoma.
Further preferred is the use according to the invention, wherein the cancer is a lung cancer. As shown by the examples, aprepitant also effectively reduces the cell proliferation of cancer cell lines which are not derived from lung or pleural tissue. Thus, preferably, a solid tumor is a tumor of the head or neck, lung, breast, colon, prostate, bladder, rectum, brain, gastric tissue, bone, ovary, thyroid, or endometrium.
Preferably a hematological malignancies is a leukaemia, lymphoma or myeloma. Preferred embodiments of a carcinoma include a bladder carcinoma, a renal carcinoma, a breast carcinoma, a colorectal carcinoma.
Further preferred is the use according to the invention, wherein the cancer is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T- cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, brain neuroblastoma, retinoblastoma, glioma, Wilms' tumor, bone cancer and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal, and colon), lung cancer (e.g., small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin carcinoma, squamous cell carcinoma of both ulcerating and papillary type, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary carcinoma, osteosarcoma, soft-tissue sarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's sarcoma. Also included are pediatric forms of any of the cancers described herein. Preferably, the cancer treatable with the compound of the invention is selected from the group consisting of a leukemia, renal cancer, colon cancer, non-small cell lung carcinoma, breast cancer, melanoma and brain cancer. Most preferably, the cancer is leukemia.
Another aspect of the invention is the compound of the invention for the treatment of cancer, in particular or of the aforementioned specific forms of cancer. The compound according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Parenteral administration and particular intravenous administration, preferably by depot injection, is preferred. Depending on the route of administration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in, for example, the digestive tract.
Thus, preferably, a compound of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation. Preferably the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.
Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for injectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid. Typically, such a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. A compound of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
Production of sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary. Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions. Preferred carriers are cocoa butter and vitebesole. Excipients which can be used with the various pharmaceutical forms of a compound of the invention can be chosen from the following non-limiting list: a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like; b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates, c) disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
Other suitable excipients can be found in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association, which is herein incorporated by reference. Zo
It is to be understood that depending on the severity of the disorder and the particular type which is treatable with one of the compounds of the invention, as well as on the respective patient to be treated, e.g. the general health status of the patient, etc., different doses of the respective compound are required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. It is contemplated that the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g serum per kg body weight. However, in a preferred use of the present invention a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 10 to 200 mg/kg body weight, preferably ranging from 50 to 150 mg/kg body weight, preferably ranging from 90 to 100 mg/kg body weight. The duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
As is known in the art, the pharmaceutically effective amount of a given composition will also depend on the administration route. In general the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g. intravenous. Typically, a compound of the invention will be admim'stered in ranges of 50 mg to 1 g/kg body weight, preferably 100 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight, if parenteral administration is used.
If a person is know to be at risk of developing a disorder treatable with a compound of the invention, a prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible. In these cases the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, between 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, a compound of the invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or improving.
Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.
The following figures and examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 Raw data from measurements according to experiment A.
Fig. 2 Data from experiment A
Data from experiment A are reported in the Lineweaver and Burk format where 1/V and 1/S are given in the Y and X axes respectively.
Fig. 3 Lineweaver and Burk plot (LB) to determine Km and Ki
Data from experiment A. The LB plot has been graphically represented for the different incubation times. As examples incubation time of 60 minutes and 120 minutes have been reported. The graphically derived Km is the same, 12,5 μM as a check point.
Fig. 4 Dixon plot for Ki calculation
Data from experiment A. The LB plot has been graphically represented for the different incubation times, and the plotting of the slope against the inhibitor concentration gave the Dixon plot and the intersection with x axes for y=0 gives the "-Ki" value. As examples incubation time of 60 minutes and 120 minutes have been reported. The time dependent effect of the inhibition can be observed.
At 0 time the inhibition effect cannot be observed clearly.
Fig. 5 Enzyme Inhibition study of human thymidylate synthase (see experiment B below)
Fig. 6 The inhibition of proliferation induced by aprepitant (see cellular experiments below)
Fig. 7 The inhibitory growth effect on cancer cells induced by aprepitant at a concentration of 1.0 x 10 s M. EXAMPLES
Example 1: Enzymatic assays:
Folate is important for cells and tissues that rapidly divide. Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate methotrexate is a drug often used to treat cancer because it inhibits the production of the active form, tetrahydrofolate. Unfortunately, methotrexate can be toxic, producing side effects such as inflammation in the digestive tract that make it difficult to eat normally.
Thymidylate synthase (EC 2.1.1.45) is the enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair. By means of reductive methylation, deoxyuridine monophosphate (dUMP) and N5,N10-methylene tetrahydrofolate are together used to form dTMP, yielding dihydrofolate as a secondary product.
As shown herein, aprepitant is a noncompetitive inhibitor of human thymidylate synthase with respect to the N5,N10-methylenetetrahydrocofolate cofactor. The inhibition effect can be observed only upon incubation of the enzyme with the inhbitor. The time dependent effect can be observed in the range of 60-180 minutes without affecting control stability. The apparent Ki value is between 1.5 and 0.5 microMolar. There is also an inhibition effect with respect to dUMP substrate, but this can be observed at higher concentration and it is time dependent. An incubation effect can be observed. The IC50 range in this case is in the range of 200 microMolar with an incubation time between 60 and 180 minutes.
Example 2: Inhibition pattern of Aprepitant versus human Thymidylate synthase (TYMS)
The inhibition assays were carried out changing the substrate concentration and observing the effect of the inhibitor concentration on enzyme activity.
Experiment A The Inhibitor (Aprepitant) was varied between 0 and 100 μM, the folate (mTHF) concentration was varied between 5 and 250 μM and dUMP concentration was kept fixed at a concentration between 100 μM and 120 μM.
The temperature was kept between 25° C and 37° C and the incubation time was kept between 0 and 240 minutes. 1.Data collection The assays have been conducted using three series of solutions.
Series 1: mTHF 10, 20, 40 and 120 μM and I=O
Series 2: mTHF 10, 20, 40 and 120 μM and I=I OμM
Series 3: mTHF 10, 20, 40 and 120 μM and I=50μM
In 4 cuvettes and the incubation time was 0, 60, 120, 180 minutes.
Each reaction mixture contains:
TES: 300μl*4=1200 μl hTS: 2μl *4=8μl; as used herein hTS refers to human Thymidylate synthase; dUMP: 7μl (concentration of 116.16μM) to start the reaction.
Figure imgf000033_0001
The results from Experiment A are shown in figures 1 -4.
Experiment B: Enzyme Inhibition study of hTS considering the substrate dUMP as competitor substrate.
The Inhibitor (Aprepitant) was varied between 0 and 1 mM, dUMP concentration was varied between 0 and 400 μM while the folate concentration was kept fixed. The temperature was kept between 25° C and 37° C and the incubation time was kept between 0 and 240 minutes.
The assay has been conducted incubating hTS, with dUMP and inhibitor (aprepitant) at 30°C for 0, 60, 120 and 180 minutes. The reactions have been initiated by cofactor addition. This has been repeated for concentration of inhibitor ranging between 0 and 1 mM and dUMP ranging between 0 and 400 μM.
Below the data as example. IC50 is in the range of 200 μM after 60 minutes and it slightly decreases with time, showing an incubation effect.
Figure imgf000034_0001
See also figure 5 for a graphical representation.
Example 3: Cell assays.
The inhibition of proliferation of various cell lines has been studied when treated with aprepitant.
The inhibition of proliferation induced by aprepitant was measured at concentration ranges of l-5μM and 10-50μM and at 24, 48 and 72h after initiation of treatment in the following cell lines:
The cell-division was assayed using cell counting.
MCF-7 cells (breast cancer): 60% % inhibition at 10 μM. More than 60% inhibition at 2 μM after 72h.
Molt-4 (leukemia cell line): 40% inhibition at 10 μM
HT29 (Adenocarcinoma): 60% % inhibition at 10 μM. 60% inhibition at 2 μM after 48 and 72h. HCTl 15 (Adenocarcinoma): 30% inhibition at 10 μM. More than 60% inhibition at 2 μM after 48 and 72h.
L929 (mouse cell line): 40% inhibition at 10 μM MDA-MB-231 (Adenocarcinoma): 60% inhibition at 2 μM after 72. The inhibition on cell division obtainable with aprepitant suggests that the compound of the invention can be used to treat a wide variety of cancer types. See also figure 6 for a graphical representation of the inhibition.
Example 4: Cancer cell growth inhibition screen
The screen utilizes 26 different human tumor cell lines, representing leukemia, melanoma and cancers of the lung, colon, brain, breast and kidney. The screening evaluates aprepitant and a control substance against the 26 cell lines at a single dose of 10 μM. The human tumor cell lines of the cancer screening panel are grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. Cells are inoculated into 96 well microtiter plates in 100 μL at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates are incubated at 370C, 5 % CO2, 95 % air and 100 % relative humidity for 24 h prior to addition of drugs.
After 24 h, two plates of each cell line are fixed in situ with TCA, to represent a measurement of the cell population for each cell line at the time of drug addition (Tz). The drugs are solubilized in dimethyl sulfoxide at 400-fold the desired final maximum test concentration and stored frozen prior to use. At the time of drug addition, an aliquot of frozen concentrate is thawed and diluted to twice the desired final maximum test concentration with complete medium containing 50 μg/ml gentamicin. Aliquots of 100 μl of the experimental drug aprepitant and a control substance are added to the appropriate microtiter wells already containing 100 μl of medium, resulting in the required final drug concentrations.
Following drug addition, the plates are incubated for an additional 48 h at 37°C, 5 % CO2, 95 % air, and 100 % relative humidity. For adherent cells, the assay is terminated by the addition of cold TCA. Cells are fixed in situ by the gentle addition of 50 μl of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (100 μl) at 0.4 % (w/v) in 1 % acetic acid is added to each well, and plates are incubated for 10 minutes at room temperature. After staining, unbound dye is removed by washing five times with 1 % acetic acid and the plates are air dried. Bound stain is subsequently cold TCA. Cells are fixed in situ by the gentle addition of 50 μl of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (100 μl) at 0.4 % (w/v) in 1 % acetic acid is added to each well, and plates are incubated for 10 minutes at room temperature. After staining, unbound dye is removed by washing five times with 1 % acetic acid and the plates are air dried. Bound stain is subsequently solubilized with 10 mM trizma base, and the absorbance is read on an automated plate reader at a wavelength of 515 nm. For suspension cells, the methodology is the same except that the assay is terminated by fixing settled cells at the bottom of the wells by gently adding 50 μl of 80 % TCA (final concentration, 16 % TCA). Using the seven absorbance measurements [time zero, (Tz), control growth, (C), and test growth in the presence of drug at the five concentration levels (Ti)], the percentage growth is calculated. Percentage growth inhibition is calculated as:
[(Ti-Tz)/(C-Tz)] x 100 for concentrations for which Ti>/=Tz; and
[(Ti-Tz)ATz] x 100 for concentrations for which Ti<Tz.
The screening results indicating mean growth percent at a dose of 10 μM aprepitant relative to a control compound and relative to the time zero number of cells are shown in figure 7 below. A value of "mean growth percent" of 40 would mean 60% growth inhibition. The results show effective growth inhibition of several cancer cells lines originating from non-small cell lung cancer, colon cancer, breast cancer, leukaemia, renal cancer, melanoma and CNS cancer.

Claims

1. Use of a compound according to formula I:
Figure imgf000037_0001
(I) or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of:
(1) hydrogen;
(2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted;
(4) alkynyl; optionally substituted; and
(5) aryl or heteroaryl; optionally substituted;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted;
(4) alkynyl; optionally substituted; and
(5) aryl or heteroaryl; optionally substituted; and the groups R1 and R2 may be joined together to form a heterocyclic ring which may be optionally substituted; and the groups R and R may be joined together to form a carbocyclic ring or a heterocyclic ring which may be optionally substituted;
R , R and R are independently selected from the group consisting of:
(1) hydrogen;
(2) alkyl; optionally substituted;
(3) alkenyl; optionally substituted;
(4) alkynyl; optionally substituted;
(5) aryl or heteroaryl; optionally substituted; (6) halo,
(7) -CN,
(8) -CF3,
(9) -NO2,
(10) -SR14,
(H) -SOR14,
(12) -SOOR14,
(13) -NR9COR10,
(14) -CONR9R10,
(15) -NR9R10,
(16) -NR9COOR10,
(17) hydroxy,
(18) alkoxy,
(19) -COR9, and
(20) -COOR9;
R9 and R10 are independently selected from:
C) hydrogen,
(ϋ) alkyl,
(iii) hydroxy-alkyl, and
(iv) aryl;
R11, R12 and R13 are independently selected from the definitions of R6, R7 and R8;
R14 i s in each instance hydrogen or alkyl;
X is selected from the group consisting of:
(1) -0-,
(2) -S-,
(3) -SO-, and
(4) -SO2-;
Y is selected from the group consisting of:
(1) a single bond,
(2) -0-,
(3) -S-,
(4) -CO-,
(5) -CH2-,
(6) -CHR15-, and (7) -CR15R16-, wherein R15 and R16 are independently selected from the group consisting of:
(a) alkyl; optionally substituted; and
(b) aryl or heteroaryl; optionally substituted; and Z is alkyl; optionally substituted; for the treatment of cancer.
2. Use according to claim 1, wherein
R1 is selected from the group consisting of:
(1) hydrogen;
(2) C 1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) -phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo, wherein halo is fluoro, chloro, bromo or iodo,
(h) -NR9R10, wherein R9 and R10 are independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl,
(iii) hydroxy-Cl-6 alkyl, and
(iv) phenyl,
(i) -NR9COR10, wherein R9 and R1 ° are as defined above, (j) -NR9COOR10, wherein R9 and R10 are as defined above, (k) -CONR9R10, wherein R9 and R10 are as defined above, (1) -COR9, wherein R9 is as defined above, (m) -COOR9, wherein R9 is as defined above; (n) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzoxazolyl, JO
(E) fiiranyl,
(F) imidazolyl,
(G) indolyl, (H) isooxazolyl, (I) isothiazolyl, (J) oxadiazolyl, (K) oxazolyl, (L) pyrazinyl, (M) pyrazolyl, (N) pyridyl, (O) pyrimidyl, (P) pyrrolyl, (Q) quinolyl, (R) tetrazolyl, (S) thiadiazolyl, (T) thiazolyl, (U) thienyl, (V) triazolyl, (W) azetidinyl, (X) 1,4-dioxanyl,
(Y) hexahydroazepinyl, (Z) piperazinyl,
(AA) piperidinyl,
(AB) pyrrolidinyl,
(AC) tetrahydrofuranyl, and
(AD) tetrahydrothienyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C 1-6 alkyl, unsubstituted or substituted with halo,-CF3, -OCH3, or phenyl,
(ii) Cl-6 alkoxy,
(iii) oxo,
(iv) hydroxy,
(v) thioxo,
(vi) -SR9, wherein R9 is as defined above, (vii) halo,
(viii) cyano,
(ix) phenyl,
(x) trifluoromethyl,
(xi) -(CH2)In-NR9R1 °, wherein m is 0,1 or 2, and R9 and R10 are as defined above,
(xii) -NR9COR10, wherein R9 and R10 are as defined above,
(xiii) -CONR9R10, wherein R9 and R10 are as defined above,
(xiv) -COOR9, wherein R9 is as defined above, and
(xv) -(CH2)m-OR9, wherein m and R9 are as defined above;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10 wherein R9 and R10 are as defined above,
(i) -COR9 wherein R9 is as defined above,
(j) -COOR9, wherein R9 is as defined above, and
(k) heterocycle, wherein the heterocycle is as defined above;
(4) C2-6 alkynyl; and
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) C 1-6 alkoxy,
(c) Cl-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2, (h) -CF3,
(i) -(CH2)m-NR9R10, wherein m, R9 and R10 are as defined above, (j) -NR9COR10, wherein R9 and R10 are as defined above, (k) -NR9COOR10, wherein R9 and R10 are as defined above, ( 1 ) -CONR9R1 °, wherein R9 and R1 ° are as defined above, (m) -COONR9R10, wherein R9 and R10 are as defined above, (n) -COR9, wherein R9 is as defined above; and
(0) -COOR9, wherein R9 is as defined above;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -NR9R10, wherein R9 and R10 are as defined above,
(1) -NR9COR10, wherein R9 and R10 are as defined above, (j) -NR9COOR10, wherein R9 and R10 are as defined above, (k) -CONR9R10, wherein R9 and R10 are as defined above, (1) -COR9, wherein R9 is as defined above, and
(m) -COOR , wherein R9 is as defined above;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) oxo,
(c) C 1-6 alkoxy,
(d) phenyl-C 1-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10 wherein R9 and R10 are as defined above, (i) -COR9 wherein R9 is as defined above, (j) -COOR9, wherein R9 is as defined above;
(4) C2-6 alkynyl; and
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) Cl-6 alkoxy,
(c) Cl-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2, (h) -CF3,
(i) -(CH2)m-NR9R10, wherein m, R9 and R10 are as defined above,
(j) -NR9COR10, wherein R9 and R10 are as defined above,
(k) -NR9COOR10, wherein R9 and R10 are as defined above,
(1) -CONR9R10, wherein R9 and R10 are as defined above,
(m) -COONR9R10, wherein R9 and R10 are as defined above,
(n) -COR9, wherein R9 is as defined above; and
(o) -COOR9, wherein R9 is as defined above; and the groups R1 and R2 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl,
(b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl,
(f) oxazolyl, and
(g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) from:
(i) Cl-6 alkyl,
(ii) oxo,
(iii) Cl-6 alkoxy,
(iv) -NR9R10, wherein R9 and R10 are as defined above, (v) halo, and
(vi) trifluoromethyl; and the groups R and R may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl,
(b) cyclohexyl,
(c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) Cl-6 alkyl,
(ii) Cl-6 alkoxy,
(iii) -NR9R10, wherein R9 and R10 are as defined above,
(iv) halo, and
(v) trifluoromethyl; and the groups R2 and R3 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl,
(b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl,
(f) furanyl,
(g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) from:
(i) Cl-6 alkyl,
(ii) oxo,
(iii) Cl-6 alkoxy,
(iv) -NR9R10, wherein R9 and R10 are as defined above,
(v) halo, and
(vi) trifluoromethyl; R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen;
(2) C 1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -NR9R10, wherein R9 and R10 are as defined above, (i) -NR9COR10, wherein R9 and R10 are as defined above, G) -NR9COOR10, wherein R9 and R10 are as defined above, (k) -CONR9R10, wherein R9 and R10 are as defined above, (1) -COR9, wherein R9 is as defined above, and (m) -COOR9, wherein R9 is as defined above;
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) from:
(a) hydroxy,
(b) oxo,
(c) C 1-6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10, wherein R9 and R10 are as defined above, (i) -COR9, wherein R9 is as defined above; and Q) -COOR9, wherein R9 is as defined above;
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) C 1-6 alkoxy,
(c) C 1-6 alkyl,
(d) C2-5 alkenyl, (e) halo,
09 -CN,
(g) -NO2,
(h) -CF3,
(i) -(CH2)m-NR9R10, wherein m, R9 and R10 are as defined above,
(j) -NR9COR10, wherein R9 and R10 are as defined above,
(k) -NR9COOR10, wherein R9 and R10 are as defined above,
( 1 ) -CONR9R1 °, wherein R9 and R1 ° are as defined above,
(m) -COONR9R10, wherein R9 and R10 are as defined above,
(n) -COR9, wherein R is as defined above; and
(o) -COOR9, wherein R9 is as defined above;
(6) halo,
(7) -CN,
(8) -CF3,
(9) -NO2,
(10) -SR14, wherein R14 is hydrogen or C 1-5 alkyl,
(11) -SOR14, wherein R14 is as defined above,
(12) -SOOR14, wherein R14 is as defined above,
(13) -NR9COR10, wherein R9 and R10 are as defined above,
(14) -CONR9R10, wherein R9 and R10 are as defined above,
(15) -NR9R10, wherein R9 and R10 are as defined above,
(16) -NR9COOR10, wherein R9 and R10 are as defined above,
(17) hydroxy,
(18) Cl-6 alkoxy,
(19) -COR9, wherein R9 is as defined above;
(20) -COOR9, wherein R9 is as defined above;
(21) 2-pyridyl,
(22) 3-pyridyl,
(23) 4-pyridyl,
(24) 5-tetrazolyl,
(25) 2-oxazolyl, and
(26) 2-thiazolyl;
R11, R12 and R13 are independently selected from the definitions of R6, R7 and R8; X is selected from the group consisting of: (1) -O-,
(2) -S-,
(3) -SO-, and
(4) -SO2-;
Y is selected from the group consisting of:
(1) a single bond,
(2) -O-,
(3) -S-,
(4) -CO-,
(5) -CH2-,
(6) -CHR15-, and
(7) -CR15R16-, wherein R15 and R16 are independently selected from the group consisting of:
(a) C 1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy, (ii) oxo, (iii) Cl-6 alkoxy, (iv) phenyl-Cl-3 alkoxy, (v) phenyl, (vi) -CN, (vii) halo,
(viii) -NR9R10, wherein R9 and R10 are as defined above, (ix) -NR9COR10, wherein R9 and R10 are as defined above, (x) -NR9COOR10, wherein R9 and R10 are as defined above, (xi) -CONR9R10, wherein R9 and R10 are as defined above, (xii) -COR , wherein R is as defined above; and (xiii) -COOR , wherein R9 is as defined above; and
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) from: (i) hydroxy,
(ii) C 1-6 alkoxy,
(iii) C 1-6 alkyl,
(iv) C2-5 alkenyl,
(v) halo, (vi) -CN,
(vii) -NO2,
(viii) -CF3,
(ix) -(CH2)In-NR9R1 °, wherein m, R9 and R10 are as defined above,
(x) -NR9COR10, wherein R9 and R10 are as defined above,
(xi) -NR9COOR10, wherein R9 and R10 are as defined above,
(xii) -CONR9R10, wherein R9 and R10 are as defined above,
(xiii) -COONR9R10, wherein R9 and R10 are as defined above,
(xiv) -COR9, wherein R9 is as defined above; and
(xv) -COOR9, wherein R9 is as defined above; and Z is Cl-6 alkyl.
3. Use according to claim 1 or 2, wherein
R1 is C 1-6 alkyl, substituted with one or more of the substiruents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) imidazolyl,
(C) isooxazolyl,
(D) isothiazolyl,
(E) oxadiazolyl,
(F) pyrazinyl,
(G) pyrazolyl, (H) pyridyl, (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C 1-6 alkyl, unsubstituted or substituted with halo,-CF3, -OCH3, or phenyl,
(ii) C 1-6 alkoxy,
(iii) oxo,
(iv) thioxo, (v) cyano, (vi) -SCH3, (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, and
(x) -(CH2)Hi-NR9R1 °, wherein m is 0, 1 or 2; and wherein R9 and RlO are independently selected from:
(I) hydrogen,
(II) Cl-6 alkyl,
(III) hydroxy-Cl-6 alkyl, and
(IV) phenyl;
(xi) -NR9COR10, wherein R9 and R10 are as defined above, and (xii) -CONR9R10, wherein R9 and R10 are as defined above.
4. Use according to any of claims 1-3, wherein
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) C2-6 alkenyl, and
(4) phenyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) -CF3;
R11, R12 and R13 are independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) fluoro,
(4) chloro,
(5) bromo, (6) iodo, and
(7) -CF3; X is -O-;
Y is -O-; and
Z is Cl-4 alkyl.
5. Use according to any of claims 1-4, wherein Z is C 1-4 alkyl or, preferably, -CH3.
6. Use according to any of claims 1-5, wherein the compound has a structure according to formula II:
Figure imgf000050_0001
(II).
7. Use according to any of claims 1-6, wherein R2 and R3 is hydrogen and Z is -CH3.
8. Use according to any of claims 1-7, wherein X is -O- and Y is -O-.
9. Use according to any of claims 1-8, wherein R6 and R7 is -CF3 and R13 is F.
10. Use according to any of claims 1 -9, wherein R 2 and i τ R> 3 is hydrogen and R » 6 a „„nd, R is -CF3
11. Use according to any of claims 1-10, wherein R1 is selected from the group consisting of:
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
Me
Figure imgf000052_0004
Figure imgf000053_0001
12. Use according to any of claims 1-11, wherein the compound has a structure according to formula III:
Figure imgf000053_0002
(III).
13. Use according to any of claims 1-12, wherein the cancer is a cancer selected from the group consisting of: a solid tumor, a hematological malignancy, a carcinoma, a neuroblastoma and a melanoma.
14. Use according to any of claims 1-13, wherein the cancer is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T- cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, brain neuroblastoma, retinoblastoma, glioma, Wilms' tumor, bone cancer and soft- tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal, and colon), lung cancer (e.g., small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin carcinoma, squamous cell carcinoma of both ulcerating and papillary type, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary carcinoma, osteosarcoma, soft-tissue sarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's sarcoma.
PCT/EP2009/002621 2008-04-08 2009-04-08 Use of aprepitant and derivatives thereof for the treatment of cancer WO2009124756A1 (en)

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