WO2008121685A1 - Methods of use for inhibitors of akt activity - Google Patents
Methods of use for inhibitors of akt activity Download PDFInfo
- Publication number
- WO2008121685A1 WO2008121685A1 PCT/US2008/058383 US2008058383W WO2008121685A1 WO 2008121685 A1 WO2008121685 A1 WO 2008121685A1 US 2008058383 W US2008058383 W US 2008058383W WO 2008121685 A1 WO2008121685 A1 WO 2008121685A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- methyl
- ethyl
- compound
- inhibitors
- Prior art date
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Classifications
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- This invention relates to the use of 1 H-imidazo[4,5-c]py ⁇ din-2-yl compounds, compounds known to inhibit protein kinase B (hereinafter PKB/Akt, PKB or Akt) activity, in the treatment of specified cancers.
- PKB/Akt, PKB or Akt protein kinase B
- the present invention relates to 1 H-imidazo[4,5-c]pyridin-2-yl containing compounds that are inhibitors of the activity of one or more of the isoforms of the serine/threonine kinase, Akt (also known as protein kinase B).
- the present invention also relates to pharmaceutical compositions comprising such compounds and methods of using the instant compounds in the treatment of specified cancers.
- Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. Recent work has led to the identification of various pro- and anti-apoptotic gene products that are involved in the regulation or execution of programmed cell death.
- anti-apoptotic genes such as Bcl2 or BCI-X L
- pro-apoptotic genes such as Bax or Bad
- the execution of programmed cell death is mediated by caspase -1 related proteinases, including caspase-3, caspase- 7, caspase-8 and caspase-9 etc (Thornberry et al. Science, 281 :1312-1316 (1998)).
- PI3K phosphatidylinositol 3'-OH kinase
- Akt/PKB pathway appears important for regulating cell survival/cell death (Kulik et al. MoI. Cell. Biol. 17:1595-1606 (1997); Franke et al, Cell, 88:435-437 (1997); Kauffmann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science, 275:628-630 (1997); Dudek et al., Science, 275:661-665 (1997)).
- PDGF platelet derived growth factor
- NEF nerve growth factor
- IGF-I insulin-like growth factor-1
- Activated PI3K leads to the production of phosphatidylinositol (3,4,5)-triphosphate (Ptdlns (3,4,5)- P3), which in turn binds to, and promotes the activation of, the serine/ threonine kinase Akt, which contains a pleckstrin homology (PH)-domain (Franke et al Cell, 81 :727-736 (1995); Hemmings Science, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998), Alessi et al., EMBO J. 15: 6541-6551 (1996)).
- PH pleckstrin homology
- PI3K or dominant negative Akt/PKB mutants abolish survival-promoting activities of these growth factors or cytokines. It has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt/PKB by upstream kinases. In addition, introduction of constitutively active PI3K or Akt/PKB mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al. 1997, Dudek et al. 1997).
- Akt2 is overexpressed in a significant number of ovarian (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 89:9267- 9271 (1992)) and pancreatic cancers (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 93:3636-3641 (1996)).
- Akt3 was found to be overexpressed in breast and prostate cancer cell lines (Nakatani et al. J. Biol.Chem. 274:21528-21532 (1999).
- Akt-2 was over-expressed in 12% of ovarian carcinomas and that amplification of Akt was especially frequent in 50% of undifferentiated tumors, suggestion that Akt may also be associated with tumor aggressiveness (Bellacosa, ef al., Int. J. Cancer, 64, pp. 280-285, 1995). Increased Akt1 kinase activity has been reported in breast, ovarian and prostate cancers (Sun et al. Am. J. Pathol. 159: 431-7 (2001 )).
- the tumor suppressor PTEN a protein and lipid phosphatase that specifically removes the 3' phosphate of Ptdlns(3,4,5)-P3, is a negative regulator of the PI3K/Akt pathway (Li et al. Science 275:1943-1947 (1997), Stambolic et al. Ce// 95:29-39 (1998), Sun et al. Proc. Nati. Acad. Sci. U.S.A. 96:6199-6204 (1999)).
- Germline mutations of PTEN are responsible for human cancer syndromes such as Cowden disease (Liaw et al. Nature Genetics 16:64-67 (1997)).
- PTEN is deleted in a large percentage of human tumors and tumor cell lines without functional PTEN show elevated levels of activated Akt (Li et al. supra, Guldberg et al. Cancer Research 57:3660-3663 (1997), Risinger et al. Cancer Research 57:4736-4738 (1997)). These observations demonstrate that the PI3K/Akt pathway plays important roles for regulating cell survival or apoptosis in tumorigenesis.
- Akt/PKBs Three members of the Akt/PKB subfamily of second-messenger regulated serine/threonine protein kinases have been identified and termed Akt1/ PKB ⁇ , Akt2/PKB ⁇ , and Akt3/PKB ⁇ respectively.
- the isoforms are homologous, particularly in regions encoding the catalytic domains.
- Akt/PKBs are activated by phosphorylation events occurring in response to PI3K signaling.
- PI3K phosphorylates membrane inositol phospholipids, generating the second messengers phosphatidyl- inositol 3,4,5- trisphosphate and phosphatidylinositol 3,4-bisphosphate, which have been shown to bind to the PH domain of Akt/PKB.
- Akt/PKB activation proposes recruitment of the enzyme to the membrane by 3'-phosphorylated phosphoinositides, where phosphorylation of the regulatory sites of Akt/PKB by the upstream kinases occurs (B.A. Hemmings, Science 275:628-630 (1997); B.A. Hemmings, Science 276:534 (1997); J. Downward, Science 279:673-674 (1998)).
- Akt1/PKB ⁇ Phosphorylation of Akt1/PKB ⁇ occurs on two regulatory sites, Thr 308 in the catalytic domain activation loop and on Ser 473 near the carboxy terminus (D. R. Alessi et al. EMBO J. 15:6541-6551 (1996) and R. Meier et al. J. Biol. Chem. 272:30491-30497 (1997)).
- Equivalent regulatory phosphorylation sites occur in Akt2/PKB ⁇ and Akt3/PKB ⁇ .
- the upstream kinase, which phosphorylates Akt/PKB at the activation loop site has been cloned and termed 3 '-phosphoinositide dependent protein kinase 1 (PDK1 ).
- PDK1 phosphorylates not only Akt/PKB, but also p70 ribosomal S6 kinase, p90RSK, serum and glucocorticoid-regulated kinase (SGK), and protein kinase C.
- the upstream kinase phosphorylating the regulatory site of Akt/PKB near the carboxy terminus has not been identified yet, but recent reports imply a role for the integrin-linked kinase (ILK-1 ), a serine/threonine protein kinase, or autophosphorylation.
- ILK-1 integrin-linked kinase
- serine/threonine protein kinase or autophosphorylation.
- Akt activation and activity can be achieved by inhibiting PI3K with inhibitors such as LY294002 and wortmannin.
- inhibitors such as LY294002 and wortmannin.
- PI3K inhibition has the potential to indiscriminately affect not just all three Akt isozymes but also other PH domain- containing signaling molecules that are dependent on Pdtlns(3,4,5)- P3, such as the Tec family of tyrosine kinases.
- Akt can be activated by growth signals that are independent of PI3K.
- Akt activity can be inhibited by blocking the activity of the upstream kinase PDK1.
- the compound UCN-01 is a reported inhibitor of PDK1. Biochem. J. 375(2):255 (2003).
- Akt small molecule inhibitors of Akt are useful in the treatment of tumors, especially those with activated Akt (e.g. PTEN null tumors and tumors with ras mutations).
- PTEN is a critical negative regulator of Akt and its function is lost in many cancers, including breast and prostate carcinomas, glioblastomas, and several cancer syndromes including Bannayan-Zonana syndrome (Maehama, T. et al.
- Akt3 is up-regulated in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer cell lines and Akt2 is over-expressed in pancreatic and ovarian carcinomas.
- Akt1 is amplified in gastric cancers (Staal, Proc. Natl. Acad. Sci. USA 84: 5034-7 (1987) and upregulated in breast cancers (Stal et al. Breast Cancer Res. 5: R37-R44 (2003)). Therefore a small molecule Akt inhibitor is expected to be useful for the treatment of these types of cancer as well as other types of cancer.
- Akt inhibitors are also useful in combination with further chemotherapeutic agents.
- compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.
- This invention relates to a method of treating specified cancers, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I):
- X is absent or selected from the group consisting of: O, S and CR20R21 ; where R20R21 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R2R2 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R3 is selected from the group consisting of: hydrogen, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclopropylmethyl, substituted cyclopropylmethyl, -C-
- R4R4 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R ⁇ is selected from the group consisting of: hydrogen, -C-
- R1 when X is absent or CR20R21 ; R1 can additionally be fluorine; or a pharmaceutically acceptable salt thereof.
- compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.
- Also included in the present invention are methods of co-administering the presently invented Akt/PKB inhibiting compounds with further active ingredients.
- the compounds of this invention are disclosed as being useful as inhibitors of serine/threonine kinase, Akt (also known as protein kinase B), particularly in the treatment of cancer and arthritis, in International Application No. PCT/US2006/043513, having International Filing date November 9, 2006.
- Akt serine/threonine kinase B
- the compounds of Formula (I) inhibit Akt/PKB activity.
- the compounds disclosed herein inhibit each of the three Akt/PKB isoforms.
- X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are j nc
- R3 is selected from the group consisting of: hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and -C-
- R4R4 are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-
- R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-
- R ⁇ is selected from the group consisting of: hydrogen and -C-
- R1 when X is absent or CR20R21 I R1 can additionally be fluorine; rmaceutically acceptable salt thereof.
- X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R2R2' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R3 is selected from the group consisting of: hydrogen, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R4R4 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R ⁇ is selected from the group consisting of: hydrogen, -C-
- X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are j nc
- R2R2' are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-
- R3 is selected from the group consisting of: hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and -C-
- R ⁇ R ⁇ ' are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-
- R5R5 are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-
- R ⁇ is selected from the group consisting of: hydrogen and -C-
- R1 ca n additionally be fluorine; rmaceutically acceptable salt thereof.
- X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are j nc
- R2R2' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cycolpentyl, -C-
- R3 is selected from the group consisting of: hydrogen, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-
- R4R4' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cycolpentyl, -C-
- R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cycolpentyl, -C-
- R1 when X is absent or CR20R21 ; R1 can additionally be fluorine;
- _C4alkyl are optionally substituted with from 1 fluorine atom to where the substituent is perfluorinated.
- the substituent is optionally substituted with from 1 to 8 fluorine atoms.
- the substituent is optionally substituted with from 1 to 5 fluorine atoms.
- the substituent is optionally substituted with from 1 to 3 fluorine atoms.
- perfluorinated as used herein is meant a substituent where all of the hydrogen atoms have been replaced by fluorine atoms.
- substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety is substituted with from 1 fluorine atom to where the chemical moiety is perfluorinated.
- the chemical moiety is substituted with from 1 to 8 fluorine atoms.
- the chemical moiety is substituted with from 1 to 5 fluorine atoms.
- the chemical moiety is substituted with from 1 to 3 fluorine atoms.
- .C4alkyl is meant a linear or branched, saturated or unsaturated hydrocarbon chain, containing from 1 to 4 carbon atoms.
- the compounds disclosed herein also include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
- treating is meant prophylatic and therapeutic therapy.
- Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.
- to a therapeutic extent is meant that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
- therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, lessening in severity or amelioration of specified cancers.
- Certain compounds described herein may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I a salt thereof) and a solvent.
- solvents for the purpose of the invention may not interfere with the biological activity of the solute.
- suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
- the solvent used is a pharmaceutically acceptable solvent.
- suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
- esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations.
- the reaction can be carried out in the absence of solvent.
- the reduction of the nitro group with concomitant introduction of the chloro group is achieved using tin (II) chloride according to the method described by Kelley et al. J. Med. Chem. 1995, 38(20), 4131-34.
- the corresponding 5-bromo-2-chloro diaminopyridine is condensed with an appropriate acid or ester such as ethyl cyanoacetate.
- an appropriate acid or ester such as ethyl cyanoacetate.
- Reaction with NaNO 2 in concentrated HCI following by reaction with hydroxylamine gives a bis-oxime that cyclodehydrates in the presence of an appropriate base such as triethylamine to give an aminofurazan such as 5-Scheme 1.
- the hydroxyl group is introduced by generating an aryl anion by halogen-metal exchange using a suitable base such as n-butyl lithium, reacting the anion with an appropriate boron electrophile such as trimethyl borate and oxidizing the resulting aryl boronate with an appropriate oxidizing agent such as hydrogen peroxide in aqueous base to give imidazopyridinols such as 6-Scheme 1.
- Etherification of the imidazopyridinol is carried out with an appropriate alcohol such as 1 ,1-dimethylethyl 3-(hydroxymethyl)-1-piperidinecarboxylate using the methods described by Mitsunobu, Synthesis 1981 , 1 to give ethers such as 7-Scheme 1.
- the etherification can be carried out by reacting an appropriate halide such as 1 ,1- dimethylethyl 3-(chloromethyl)-1-piperidinecarboxylate with a suitable alcohol such as 6- Scheme 1 in the presence of a suitable base such as potassium carbonate.
- an appropriate aryl halide such as 7-Scheme 1 Treatment of an appropriate aryl halide such as 7-Scheme 1 with an appropriate catalyst such as tetrakistriphenylphosphine palladium and a terminal alkyne in the presence of a suitable base such as di-isopropylamine in an appropriate solvent such as dioxane gives the corresponding aryl alkyne such as 8-Scheme 1. Removal of the protecting groups is achieved using a protic or Lewis acid such as trifluoroacetic acid in a polar solvent such as methylene chloride giving compounds of Formula (I) such as 9-Scheme 1.
- an appropriate aryl halide such as 7-Scheme 1
- an appropriate catalyst such as tetrakistriphenylphosphine palladium and a terminal alkyne in the presence of a suitable base such as di-isopropylamine in an appropriate solvent such as dioxane gives the corresponding aryl alkyn
- co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of an AKT inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
- further active ingredient or ingredients includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
- the compounds are administered in a close time proximity to each other.
- the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
- any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of specified cancers in the present invention.
- examples of such agents can be found in Cancer Principles and Practice of Oncology by VT. Devita and S. Hellman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers.
- a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
- Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase Il inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
- anti-microtubule agents such as diterpenoids and vinca alkaloids
- Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented AKT inhibiting compounds are chemotherapeutic agents.
- Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
- anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
- Diterpenoids which are derived from natural sources, are phase specific anti - cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following.
- diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
- Paclitaxel 5 ⁇ ,20-epoxy-1 ,2 ⁇ ,4,7 ⁇ , 10 ⁇ , 13 ⁇ -hexa-hydroxytax-11 -en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971 ), who characterized its structure by chemical and X-ray crystallographic methods.
- Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 11 1 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56,
- the compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria.
- Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, RJ. et. al, Cancer Chemotherapy Pocket Guid ⁇ j. 1998) related to the duration of dosing above a threshold concentration (5OnM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
- 5OnM threshold concentration
- Docetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-te/t-butyl ester, 13-ester with 5 ⁇ -20-epoxy-1 ,2 ⁇ ,4,7 ⁇ , 10 ⁇ , 13 ⁇ -hexahydroxytax-11 -en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®.
- Docetaxel is indicated for the treatment of breast cancer.
- Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
- Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
- Vinblastine vincaleukoblastine sulfate
- VELBAN® an injectable solution.
- Myelosuppression is the dose limiting side effect of vinblastine.
- Vincristine vincaleukoblastine, 22-oxo-, sulfate
- ONCOVIN® an injectable solution.
- Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non- Hodgkin's malignant lymphomas.
- Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
- Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R * ,R * )-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
- Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
- Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
- the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
- Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
- Cisplatin cis-diamminedichloroplatinum
- PLATINOL® an injectable solution
- Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
- the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
- Carboplatin, platinum, diammine [1 ,1-cyclobutane-dicarboxylate(2-)-O,O'] is commercially available as PARAPLATI N® as an injectable solution.
- Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma.
- Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
- alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
- Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
- Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
- Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
- Busulfan 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
- Carmustine 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®.
- Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
- dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide is commercially available as single vials of material as DTIC-Dome®.
- dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
- Antibiotic anti-neoplasties are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
- antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
- Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
- Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy- ⁇ -L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
- Doxorubicin (8S, 10S)-10-[(3-amino-2,3,6-trideoxy- ⁇ -L-lyxo-hexopyranosyl)oxy]- 8-glycoloyl, 7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®.
- Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
- Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
- Topoisomerase Il inhibitors include, but are not limited to, epipodophyllotoxins.
- Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase Il and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows.
- Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
- Etoposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene- ⁇ -D- glucopyranoside]
- VePESID® an injectable solution or capsules
- VP-16 an injectable solution or capsules
- Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non- small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
- Teniposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene- ⁇ -D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26.
- Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.
- Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
- antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
- 5-fluorouracil 5-fluoro-2,4- (1 H, 3H) pyrimidinedione
- fluorouracil is commercially available as fluorouracil.
- Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
- 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5- fluorouracil.
- Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
- Cytarabine 4-amino-1- ⁇ -D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
- Mercaptopurine 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®.
- Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
- Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
- a useful mercaptopurine analog is azathioprine.
- Thioguanine 2-amino-1 ,7-dihydro-6H-purine-6-thione
- TABLOID® Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
- Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
- Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration.
- Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
- Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
- Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
- Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate.
- Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
- Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
- Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,1 i-ethylenedioxy-20-camptothecin described below.
- lrinotecan HCI, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1 H-pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.
- lrinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex.
- cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes.
- lrinotecan is indicated for treatment of metastatic cancer of the colon or rectum.
- the dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
- Topotecan HCI (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®.
- Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule.
- Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
- the dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia.
- camptothecin derivative of formula A following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:
- Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
- hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5 ⁇ -reductases
- GnRH gonadotropin-releasing hormone
- LH leutinizing hormone
- FSH follicle stimulating hormone
- Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
- Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
- protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth.
- protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
- Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over- expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods.
- Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
- EGFr epidermal growth factor receptor
- PDGFr platelet derived growth factor receptor
- erbB2 erbB4
- VEGFr vascular endothelial growth factor receptor
- TIE-2 vascular endothelial growth factor receptor
- TIE-2 t
- inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
- Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT VoI 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
- Non-receptor tyrosine kinases which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases.
- Non-receptor tyrosine kinases for use in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
- Such non- receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, SJ. , (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15: 371-404.
- SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
- SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
- Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, and TGF beta receptor kinases.
- Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of
- Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention.
- Such kinases are discussed in Abraham, RT. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.
- Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
- signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
- Ras Oncogene Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene.
- Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
- Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents.
- Ras oncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.
- antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
- This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
- lmclone C225 EGFR specific antibody see Green, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
- Herceptin ® erbB2 antibody see Tyrosine Kinase Signalling in Breast cance ⁇ erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183
- 2CB VEGFR2 specific antibody see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51 17-5124).
- Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention.
- Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases).
- Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention.
- anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v betas) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds.
- VEGFR the receptor tyrosine kinase
- small molecule inhibitors of integrin alpha v betas
- endostatin and angiostatin non-RTK
- Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I).
- immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations.
- the efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
- Agents used in proapoptotic regimens may also be used in the combination of the present invention.
- Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance.
- EGF epidermal growth factor
- mcl-1 mcl-1 . Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide.
- Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle.
- a family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle.
- CDKs cyclin dependent kinases
- Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
- the cancer treatment method of the claimed invention includes the co-administration a compound of formula I and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase Il inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
- anti-neoplastic agent such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase Il inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyros
- the compounds of the present invention are active as AKT inhibitors and exhibit therapeutic utility in treating specified cancers in a mammal, including a human.
- cancers means one or more cancers selected from: inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,
- Lymphoblastic T cell leukemia Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, lmmunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesotheli
- Insect cells expressing His-tagged AKT1 were lysed in 25 mM HEPES, 100 mM NaCI, 20 mM imidazole; pH 7.5 using a polytron (5 ml_s lysis buffer/g cells). Cell debris was removed by centrifuging at 28,000 x g for 30 minutes. The supernatant was filtered through a 4.5-micron filter then loaded onto a nickel-chelating column pre-equilibrated with lysis buffer. The column was washed with 5 column volumes (CV) of lysis buffer then with 5 CV of 20% buffer B, where buffer B is 25 mM HEPES, 100 mM NaCI, 300 mM imidazole; pH 7.5.
- buffer B is 25 mM HEPES, 100 mM NaCI, 300 mM imidazole; pH 7.5.
- His-tagged AKT1 (aa 136-480) was eluted with a 20-100% linear gradient of buffer B over 10 CV. His-tagged AKT1 (136-480) eluting fractions were pooled and diluted 3-fold with buffer C, where buffer C is 25 mM HEPES, pH 7.5. The sample was then chromatographed over a Q-Sepharose HP column pre- equilibrated with buffer C. The column was washed with 5 CV of buffer C then step eluted with 5 CV 10%D, 5 CV 20% D, 5 CV 30% D, 5 CV 50% D and 5 CV of 100% D; where buffer D is 25 mM HEPES, 1000 mM NaCI; pH 7.5.
- His-tagged AKT1 (aa 136-480) containing fractions were pooled and concentrated in a 10-kDa molecular weight cutoff concentrator. His-tagged AKT1 (aa 136-480) was chromatographed over a Superdex 75 gel filtration column pre-equilibrated with 25 mM HEPES, 200 mM NaCI, 1 mM DTT; pH 7.5. His-tagged AKT1 (aa 136-480) fractions were examined using SDS-PAGE and mass spec. The protein was pooled, concentrated and frozen at -80C.
- His-tagged AKT2 (aa 138-481 ) and His-tagged AKT3 (aa 135-479) were isolated and purified in a similar fashion.
- AKT 1 , 2, and 3 protein serine kinase inhibitory activity were tested for AKT 1 , 2, and 3 protein serine kinase inhibitory activity in substrate phosphorylation assays.
- This assay examines the ability of small molecule organic compounds to inhibit the serine phosphorylation of a peptide substrate.
- the substrate phosphorylation assays use the catalytic domains of AKT 1 , 2, or 3.
- AKT 1 , 2 and 3 are also commercially available from Upstate USA, Inc.
- the method measures the ability of the isolated enzyme to catalyze the transfer of the gamma-phosphate from ATP onto the serine residue of a biotinylated synthetic peptide SEQ. ID NO: 1 (Biotin-ahx-ARKRERAYSFGHHA-amide).
- Substrate phosphorylation was detected by the following procedure:
- Assays were performed in 384well U-bottom white plates. 10 nM activated AKT enzyme was incubated for 40 minutes at room temperature in an assay volume of 2OuI containing 5OmM MOPS, pH 7.5, 2OmM MgCl2, 4uM ATP, 8uM peptide, 0.04 uCi [g- P] ATP/well, 1 mM CHAPS, 2 mM DTT, and 1 ul of test compound in 100% DMSO.
- the reaction was stopped by the addition of 50 ul SPA bead mix (Dulbecco's PBS without Mg 2+ and Ca 2+ , 0.1 % Triton X-100, 5mM EDTA, 5OuM ATP, 2.5mg/ml Streptavidin-coated SPA beads.)
- 50 ul SPA bead mix Dulbecco's PBS without Mg 2+ and Ca 2+ , 0.1 % Triton X-100, 5mM EDTA, 5OuM ATP, 2.5mg/ml Streptavidin-coated SPA beads.
- the plate was sealed, the beads were allowed to settle overnight, and then the plate was counted in a Packard Topcount Microplate Scintillation Counter (Packard Instrument Co., Meriden, CT).
- Full-length human AKT1 gene was amplified by PCR from a plasmid containing myristylated-AKT1-ER (gift from Robert T. Abraham, Duke University under MTA, described in Klippel et al. in Molecular and Cellular Biology 1998 Volume 18 p.5699) using the 5' primer: SEQ. ID NO: 2 5' TATATAGGATCCATGAGCGACGTGGC 3' and the 3' primer: SEQ. ID NO: 3
- the 5' primer included a BamHI site and the 3'primer included an Xhol site for cloning purposes.
- the resultant PCR product was subcloned in pcDNA3 as a BamHI / Xhol fragment.
- a mutation in the sequence (TGC) coding for a Cysteine 25 was converted to the wild-type AKT1 sequence (CGC) coding for an Arginine 25 by site-directed mutagenesis using the QuikChange ® Site Directed Mutagenesis Kit (Stratagene).
- the AKT 1 mutagenic primer SEQ. ID NO: 4 5' ACCTGGCGGCCACGCTACTTCCTCC and selection primer: SEQ.
- AKT1 was isolated as a BamHI / Xhol fragment and cloned into the BamHI / Xhol sites of pFastbacHTb (Invitrogen).
- Invitrogen (catalog # 10359-016). Briefly 1 ) the cDNA was transferred from the FastBac vector into bacmid DNA, 2) the bacmid DNA was isolated and used to transfect Sf9 insect cells, 3) the virus was produced in Sf9 cells, 4) T. ni cells were infected with this virus and sent for purification.
- sf9 cells For the purification of full-length AKT1 , 130 g sf9 cells (batch # 41646W02) were resuspended in lysis buffer (buffer A, 1 L, pH 7.5) containing 25 mM HEPES, 100 mM NaCI, and 20 mM imidazole. The cell lysis was carried out by Avestin (2 passes at 15K- 2OK psi). Cell debris was removed by centrifuging at 16K rpm for 1 hour and the supernatant was batch bound to 10 ml Nickel Sepharose HP beads at 4 C for over night.
- buffer A buffer A, 1 L, pH 7.5
- the beads were then transferred to column and the bound material was eluted with buffer B (25 mM HEPES, 100 mM NaCI, 300 mM imidazole, pH 7.5).
- buffer B 25 mM HEPES, 100 mM NaCI, 300 mM imidazole, pH 7.5.
- AKT eluting fractions were pooled and diluted 3 fold using buffer C (25 mM HEPES, 5 mM DTT; pH 7.5).
- the sample was filtered and chromatographed over a 10 ml.
- Q-HP column pre-equilibrated with buffer C at 2 mL/min.
- the Q-HP column was washed with 3 column volume (CV) of buffer C, then step eluted with 5 CV 10%D, 5 CV 20% D, 5 CV 30% D, 5 CV 50% D and 5 CV of 100% D; where buffer D is 25 mM HEPES, 1000 mM NaCI, 5 mM DTT; pH 7.5. 5 mL fractions collected. AKT containing fractions were pooled and concentrated to 5 ml. The protein was next loaded to a 120 ml Superdex 75 sizing column that was pre-equilibrated with 25 mM HEPES, 200 mM NaCI, 5 mM DTT; pH 7.5. 2.5 mL fractions were collected.
- CV column volume
- AKT 1 eluting fractions were pooled, aliquoted (1 ml) and stored at -80C. Mass spec and SDS-PAGE analysis were used to confirm purity and identity of the purified full-length AKT1.
- AKT 1 , 2, and 3 protein serine kinase inhibitory activity were tested for AKT 1 , 2, and 3 protein serine kinase inhibitory activity in substrate phosphorylation assays.
- This assay examines the ability of small molecule organic compounds to inhibit the serine phosphorylation of a peptide substrate.
- the substrate phosphorylation assays use the catalytic domains of AKT 1 , 2, or 3.
- the method measures the ability of the isolated enzyme to catalyze the transfer of the gamma-phosphate from ATP onto the serine residue of a biotinylated synthetic peptide SEQ. ID NO: 1 (Biotin-ahx-ARKRERAYSFGHHA-amide). Substrate phosphorylation was detected by the following procedure.
- Assays were performed in 384well U-bottom white plates. 10 nM activated AKT enzyme was incubated for 40 minutes at room temperature in an assay volume of 2OuI containing 5OmM MOPS, pH 7.5, 2OmM MgCI2, 4uM ATP, 8uM peptide, 0.04 uCi [g-33P] ATP/well, 1 mM CHAPS, 2 mM DTT, and 1 ul of test compound in 100% DMSO.
- the reaction was stopped by the addition of 50 ul SPA bead mix (Dulbecco's PBS without Mg 2+ and Ca 2+ , 0.1 % Triton X-100, 5mM EDTA, 5OuM ATP, 2.5mg/ml Streptavidin-coated SPA beads.)
- Vmax is the upper asymptote and K is the IC50.
- the compound of Example 1 demonstrated an IC50 (uM) activity of: 0.003 um, FL AKT1 ; 0.016 um, FL AKT2; and 0.016, FL AKT3 in the above full-Length AKT enzyme assay.
- Cell proliferation studies were assessed using the CellTiter GIo luminescent cell viability assay (Promega, Maddison, Wl). Cells were plated at a density of 1000 cells/well in 96 well plates and incubated overnight. Cells were then treated with the compound of Example 1 (ranging from 30 ⁇ M-1.5 nM) for 72 h. The anti-proliferative effect was determined using CellTiter GIo following manufacture's protocol. Data were plotted as percent of DMSO control and the EC 50 values were calculated using the XLFit (IDBS Ltd., Guildford, UK) curve-fitting tool from Microsoft Excel. The data from at least one experiment is recorded in Table A below.
- Table A Anti-prolifeartive activity of the compound of Example 1 against cell lines originated from hematological malignacies.
- the pharmaceutically active compounds within the scope of this invention are useful in the treatment of specified cancers in mammals, particularly humans, in need thereof.
- the present invention therefore provides a method of treating specified cancers which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof.
- the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
- Solid or liquid pharmaceutical carriers are employed.
- Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
- the carrier may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
- the preparation will, for example, be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
- the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
- Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg.
- the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
- Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
- Oral and/or parenteral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound.
- Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular Akt inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
- the method of this invention of treating specified cancers in mammals, including humans comprises administering to a subject in need of such activity an effective Akt inhibiting amount of a pharmaceutically active compound of the present invention.
- the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use as an Akt inhibitor.
- the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy.
- the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating specified cancers.
- the invention also provides for a pharmaceutical composition for use as an Akt inhibitor which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
- the invention also provides for a pharmaceutical composition for use in the treatment of specified cancers which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
- compositions of the invention are administered in accordance with the present invention.
- pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat specified cancers.
- Example 1 (c) The compound of Example 1 (c) (35.0 g, 66.6 mmol) and TFA (350 ml. of a 20% solution in methylene chloride, 808 mmol) was stirred at ambient temperature for 2.5 h. The solution was poured slowly into rapidly stirring mixture of water, NaOH (36 g, 900 mmol), ethyl acetate (200 ml.) and THF (1000 ml_). The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate/THF (1 :5 v/v, 150 ml_). The combined organic extract were washed with sat. NaCI, dried over Na 2 SO 4 .
- the aqueous layer was extracted with ethyl acetate and combined extracts were washed with water, 1 N NaOH, water, brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 1.83 g of the desired material.
- a thick-walled pressure vessel was charged with the compounds of Example 3(a) (0.18 g, 1.35 mmol), Zn dust (0.03 g, 0.40 mmol), NaI (0.06 g, 0.40 mmol), DBU (0.61 ml_, 4.00 mmol), TEA (0.56 ml_, 4.00 mmol), 2-methyl-3-butyn-2-ol (0.48 ml_, 5.70 mmol), (Ph 3 P) 4 Pd (0.08 g, 0.08 mmol) and dioxane (35 ml_). After purging the mixture with nitrogen for 10 min., the vessel was sealed and heated at 80 0 C for 2.5 h.
- Example 4(a) The compound of Example 4(a) (28.1g, 0.1 16 mol) was added to (2S)-2- ⁇ [(phenylmethyl)oxy]methyl ⁇ oxirane (19 g, 0.122mol) in methanol/water (75 mL/75 mL) in an ice bath.
- Sodium hydroxide (6M, 29 mL) was added over 5 min and once completed the bath was removed and allowed to stir at room temperature for 15 min.
- the reaction was then stirred at 40 0 C in an oil bath for 3h.
- the reaction was quickly cooled in an ice bath and sodium hydroxide (28 g, 0.7 mol) and toluene (150 mL) were added. After 10 min, the reaction was heated to 65 0 C for 3hr.
- Example 4(b) To a solution of the compound of Example 4(b) (22.4 g, 0.075 mol) in ethanol (400 ml.) was added 10% palladium on carbon (2.4 g) and trifluoroacetic acid (7.0 ml_, 0.09 mol). The mixture was shaken under hydrogen at 50 psi for 24h. The reaction was filtered and concentrated in vacuo. A solution of potassium carbonate (26 g) in water (260 ml.) was added to the residue followed by a solution of di-tert-butyl-dicarbonate (17 g) in ethyl acetate (500 ml_).
- Example 4(c) The compound of Example 4(c) (6.9 g, 0.032 mol) and carbon tetrabromide (15.8 g, 0.048 mol) were dissolved in methylene chloride (100 ml.) and cooled in an ice bath. A solution of triphenylphosphine (12. 2g, 0.046 mol) in methylene chloride (10OmL) was added dropwise over 30min. After 1 hr at 0 0 C, the reaction was allowed warm to room temp and was stirred overnight. The reaction volume was reduced by Vz- in vacuo and poured onto a pad of silica gel and the product eluted with 15% ethyl acetate in hexane. The filtrate was concentrated in vacuo to afford the desired compound as an oil (8g, 90%). MS(ES) + m/e 281 [M+H] + .
- reaction vessel was sealed and heated at 80 0 C for 3 h. After cooling to RT, the reaction was quenched by pouring into sat. ammonium chloride (1 L) and stirred for 30 min. The solid was collected by filtration. Purification by flash chromatography (silica gel, gradient, 1% to 10% methanol in chloroform) gave the desired compound as a solid (10.5 g, 95%). MS(ES) + m/z 528 [M+H] + .
- Example 5(c) The compound of Example 5(c) (75 mg, 0.15 mmol) was stirred in a 20% solution of TFA in methylene chloride (3 ml.) at room temperature for 20 min. Toluene (3 ml.) was added and all volatiles removed at reduced pressure. The residue was purified by preparative reversed phase HPLC to afford the title compound as the di-TFA salt (40 mg, 43%). MS (ES+) m/z 412 (M+H) + .
- a thick-walled pressure vessel was charged with the compound of Example 1 (b) (0.140 g, 0.35 mmol), Zn dust (0.02 g, 0.30 mmol), NaI (0.04 g, 0.27 mmol), DBU (0.10 ml_, 0.66 mmol), TEA (0.075 ml_, 0.53 mmol), 2-methyl-3-butyn-2-ol (0.40 ml_, 4.14 mmol) and (Ph 3 P) 4 Pd (0.04 g, 0.03 mmol) in DMSO (2 ml_).
- a thick-walled pressure vessel was charged with the compound of Example 9(i) (0.124 g, 0.25 mmol), Zn dust (0.02 g, 0.30 mmol), NaI (0.04 g, 0.27 mmol), DBU (0.20 mL, 1.32 mmol), TEA (0.15 mL, 1.07 mmol), 2-methyl-3-butyn-2-ol (0.20 mL, 2.07 mmol) and (Ph 3 P) 4 Pd (0.04 g, 0.03 mmol) in DMSO (5 mL). After purging with nitrogen for 10 min., the reaction vessel was sealed and heated at 80 0 C for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate.
- Example 1 1 - Capsule Composition An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
- An injectable form for administering the present invention is produced by stirring 1.5% by weight of 4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7- ⁇ [(2S)-2- thiomorpholinylmethyl]oxy ⁇ -1 H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol, in 10% by volume propylene glycol in water.
- sucrose, calcium sulfate dihydrate and an Akt inhibitor as shown in Table Il below are mixed and granulated in the proportions shown with a 10% gelatin solution.
- the wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.
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Abstract
Invented is the use of 1 H-imidazo[4,5-c]pyridin-2-yl compounds in the treatment of specified cancers.
Description
METHODS OF USE FOR INHIBITORS OF Akt ACTIVITY
FIELD OF THE INVENTION This invention relates to the use of 1 H-imidazo[4,5-c]pyιϊdin-2-yl compounds, compounds known to inhibit protein kinase B (hereinafter PKB/Akt, PKB or Akt) activity, in the treatment of specified cancers.
BACKGROUND OF THE INVENTION The present invention relates to 1 H-imidazo[4,5-c]pyridin-2-yl containing compounds that are inhibitors of the activity of one or more of the isoforms of the serine/threonine kinase, Akt (also known as protein kinase B). The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using the instant compounds in the treatment of specified cancers. Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. Recent work has led to the identification of various pro- and anti-apoptotic gene products that are involved in the regulation or execution of programmed cell death. Expression of anti-apoptotic genes, such as Bcl2 or BCI-XL, inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes, such as Bax or Bad, leads to programmed cell death (Adams et al. Science, 281 : 1322-1326 (1998)). The execution of programmed cell death is mediated by caspase -1 related proteinases, including caspase-3, caspase- 7, caspase-8 and caspase-9 etc (Thornberry et al. Science, 281 :1312-1316 (1998)). The phosphatidylinositol 3'-OH kinase (PI3K)/Akt/PKB pathway appears important for regulating cell survival/cell death (Kulik et al. MoI. Cell. Biol. 17:1595-1606 (1997); Franke et al, Cell, 88:435-437 (1997); Kauffmann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science, 275:628-630 (1997); Dudek et al., Science, 275:661-665 (1997)). Survival factors, such as platelet derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-I), promote cell survival under various conditions by inducing the activity of PI3K (Kulik et al. 1997, Hemmings 1997). Activated PI3K leads to the production of phosphatidylinositol (3,4,5)-triphosphate (Ptdlns (3,4,5)- P3), which in turn binds to, and promotes the activation of, the serine/ threonine kinase Akt, which contains a pleckstrin homology (PH)-domain (Franke et al Cell, 81 :727-736 (1995); Hemmings Science, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998), Alessi et al., EMBO J. 15: 6541-6551 (1996)). Specific inhibitors of PI3K or dominant negative Akt/PKB mutants abolish survival-promoting activities of these growth
factors or cytokines. It has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt/PKB by upstream kinases. In addition, introduction of constitutively active PI3K or Akt/PKB mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al. 1997, Dudek et al. 1997).
Analysis of Akt levels in human tumors showed that Akt2 is overexpressed in a significant number of ovarian (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 89:9267- 9271 (1992)) and pancreatic cancers (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 93:3636-3641 (1996)). Similarly, Akt3 was found to be overexpressed in breast and prostate cancer cell lines (Nakatani et al. J. Biol.Chem. 274:21528-21532 (1999). It was demonstrated that Akt-2 was over-expressed in 12% of ovarian carcinomas and that amplification of Akt was especially frequent in 50% of undifferentiated tumors, suggestion that Akt may also be associated with tumor aggressiveness (Bellacosa, ef al., Int. J. Cancer, 64, pp. 280-285, 1995). Increased Akt1 kinase activity has been reported in breast, ovarian and prostate cancers (Sun et al. Am. J. Pathol. 159: 431-7 (2001 )).
The tumor suppressor PTEN, a protein and lipid phosphatase that specifically removes the 3' phosphate of Ptdlns(3,4,5)-P3, is a negative regulator of the PI3K/Akt pathway (Li et al. Science 275:1943-1947 (1997), Stambolic et al. Ce// 95:29-39 (1998), Sun et al. Proc. Nati. Acad. Sci. U.S.A. 96:6199-6204 (1999)). Germline mutations of PTEN are responsible for human cancer syndromes such as Cowden disease (Liaw et al. Nature Genetics 16:64-67 (1997)). PTEN is deleted in a large percentage of human tumors and tumor cell lines without functional PTEN show elevated levels of activated Akt (Li et al. supra, Guldberg et al. Cancer Research 57:3660-3663 (1997), Risinger et al. Cancer Research 57:4736-4738 (1997)). These observations demonstrate that the PI3K/Akt pathway plays important roles for regulating cell survival or apoptosis in tumorigenesis.
Three members of the Akt/PKB subfamily of second-messenger regulated serine/threonine protein kinases have been identified and termed Akt1/ PKBα, Akt2/PKBβ, and Akt3/PKBγ respectively. The isoforms are homologous, particularly in regions encoding the catalytic domains. Akt/PKBs are activated by phosphorylation events occurring in response to PI3K signaling. PI3K phosphorylates membrane inositol phospholipids, generating the second messengers phosphatidyl- inositol 3,4,5- trisphosphate and phosphatidylinositol 3,4-bisphosphate, which have been shown to bind to the PH domain of Akt/PKB. The current model of Akt/PKB activation proposes recruitment of the enzyme to the membrane by 3'-phosphorylated phosphoinositides, where phosphorylation of the regulatory sites of Akt/PKB by the upstream kinases occurs
(B.A. Hemmings, Science 275:628-630 (1997); B.A. Hemmings, Science 276:534 (1997); J. Downward, Science 279:673-674 (1998)).
Phosphorylation of Akt1/PKBα occurs on two regulatory sites, Thr308 in the catalytic domain activation loop and on Ser473 near the carboxy terminus (D. R. Alessi et al. EMBO J. 15:6541-6551 (1996) and R. Meier et al. J. Biol. Chem. 272:30491-30497 (1997)). Equivalent regulatory phosphorylation sites occur in Akt2/PKBβ and Akt3/PKBγ. The upstream kinase, which phosphorylates Akt/PKB at the activation loop site has been cloned and termed 3 '-phosphoinositide dependent protein kinase 1 (PDK1 ). PDK1 phosphorylates not only Akt/PKB, but also p70 ribosomal S6 kinase, p90RSK, serum and glucocorticoid-regulated kinase (SGK), and protein kinase C. The upstream kinase phosphorylating the regulatory site of Akt/PKB near the carboxy terminus has not been identified yet, but recent reports imply a role for the integrin-linked kinase (ILK-1 ), a serine/threonine protein kinase, or autophosphorylation.
Inhibition of Akt activation and activity can be achieved by inhibiting PI3K with inhibitors such as LY294002 and wortmannin. However, PI3K inhibition has the potential to indiscriminately affect not just all three Akt isozymes but also other PH domain- containing signaling molecules that are dependent on Pdtlns(3,4,5)- P3, such as the Tec family of tyrosine kinases. Furthermore, it has been disclosed that Akt can be activated by growth signals that are independent of PI3K. Alternatively, Akt activity can be inhibited by blocking the activity of the upstream kinase PDK1. The compound UCN-01 is a reported inhibitor of PDK1. Biochem. J. 375(2):255 (2003). Again, inhibition of PDK1 would result in inhibition of multiple protein kinases whose activities depend on PDK1 , such as atypical PKC isoforms, SGK, and S6 kinases (Williams et al. Curr. Biol. 10:439-448 (2000). Small molecule inhibitors of Akt are useful in the treatment of tumors, especially those with activated Akt (e.g. PTEN null tumors and tumors with ras mutations). PTEN is a critical negative regulator of Akt and its function is lost in many cancers, including breast and prostate carcinomas, glioblastomas, and several cancer syndromes including Bannayan-Zonana syndrome (Maehama, T. et al. Annual Review of Biochemistry, 70: 247 (2001 )), Cowden disease (Parsons, R.; Simpson, L. Methods in Molecular Biology (Totowa, NJ, United States), 222 (Tumor Suppressor Genes, Volume 1): 147 (2003)), and Lhermitte-Duclos disease (Backman, S. et al. Current Opinion in Neurobiology, 12(5): 516 (2002)). Inhibition of Akt has also been implicated in the treatment of leukemias, (J. C. Byrd, S. Stilgenbauer and I. W. Flinn "Chronic lymphocytic leukemia." Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program (2004), 163-83). Akt3 is up-regulated in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer cell lines
and Akt2 is over-expressed in pancreatic and ovarian carcinomas. Akt1 is amplified in gastric cancers (Staal, Proc. Natl. Acad. Sci. USA 84: 5034-7 (1987) and upregulated in breast cancers (Stal et al. Breast Cancer Res. 5: R37-R44 (2003)). Therefore a small molecule Akt inhibitor is expected to be useful for the treatment of these types of cancer as well as other types of cancer. Akt inhibitors are also useful in combination with further chemotherapeutic agents.
It is an object of the instant invention to provide compounds that are inhibitors of Akt/PKB.
It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.
It is also an object of the present invention to provide a method for treating specified cancers that comprises administering such inhibitors of Akt/PKB activity.
SUMMARY OF THE INVENTION
This invention relates to a method of treating specified cancers, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I):
X is absent or selected from the group consisting of: O, S and CR20R21 ; where R20R21 are independently selected from: hydrogen, fluorine, cyclopropyl,
substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl, or R20R21 taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl;
R2R2 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl, or R2R2' taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl;
R3 is selected from the group consisting of: hydrogen, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclopropylmethyl, substituted cyclopropylmethyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl;
R4R4 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl, or R4R4' taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl;
R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl, or R5R5 taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl; and
R^ is selected from the group consisting of: hydrogen, -C-|_C4alkyl and substituted -C-|_C4alkyl; and
when X is absent or CR20R21 ; R1 can additionally be fluorine;
or a pharmaceutically acceptable salt thereof.
Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and compounds useful in the methods of the invention.
Also included in the present invention are methods of co-administering the presently invented Akt/PKB inhibiting compounds with further active ingredients.
DETAILED DESCRIPTION OF THE INVENTION International Application No. PCT/US2004/024340, having an International filing date of July 28, 2004; International Publication Number WO 2005/011700 and an International Publication date of February 10, 2005, the schemes, processes and assays of which are hereby incorporated by reference, discloses and claims 1 H-imidazo[4,5- c]pyridin-2-yl containing compounds, along with pharmaceutically acceptable salts, hydrates, solvates and pro-drugs thereof, as being useful as inhibitors of serine/threonine kinase, Akt (also known as protein kinase B), particularly in the treatment of cancer and arthritis. International Application No. PCT/US2004/024340 does not specifically disclose any of the compounds within the scope of this application.
The compounds of this invention are disclosed as being useful as inhibitors of serine/threonine kinase, Akt (also known as protein kinase B), particularly in the treatment of cancer and arthritis, in International Application No. PCT/US2006/043513, having International Filing date November 9, 2006.
While the compounds of International Application No. PCT/US2004/024340 are useful as inhibitors of serine/threonine kinase, AKT (also known as protein kinase B), the compounds of Formula (I) herein, particularly the compounds of Examples 1 , 3, 4 and 9, are useful in treating specified cancers.
The compounds of Formula (I) inhibit Akt/PKB activity. In particular, the compounds disclosed herein inhibit each of the three Akt/PKB isoforms.
Included among the compounds of Formula (I) are those wherein:
X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are jnc|epenc|ent|y selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl, or R20R21 taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl;
R2R2 are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl, or R2R2 taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl;
R3 is selected from the group consisting of: hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl;
R4R4 are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl, or R4R4 taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl;
R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl, or R5R5' taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl; and
R^ is selected from the group consisting of: hydrogen and -C-|_C4alkyl; and
when X is absent or CR20R21 I R1 can additionally be fluorine; rmaceutically acceptable salt thereof.
Included among the compounds of Formula (I) are those wherein:
X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl, or R20R21 taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl;
R2R2' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl,
or R2R2 taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl;
R3 is selected from the group consisting of: hydrogen, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|.C4alkyl and substituted -C-|_C4alkyl;
R4R4 are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl, or R4R4' taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl;
R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl, and substituted -C-|_C4alkyl, or R5R5 taken together with the carbon to which they are attached form cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl or substituted cyclopentyl; and
R^ is selected from the group consisting of: hydrogen, -C-|_C4alkyl and substituted -C-|_C4alkyl; and
when X is absent or CR20R21 I R1 can additionally be fluorine; rmaceutically acceptable salt thereof.
Included among the compounds of Formula (I) are those wherein:
X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are jnc|epenc|ent|y selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl;
R2R2' are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl;
R3 is selected from the group consisting of: hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl;
R^R^' are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl;
R5R5 are independently selected from: hydrogen, fluorine, cyclopropyl, cyclobutyl, cyclopentyl, and -C-|_C4alkyl; and
R^ is selected from the group consisting of: hydrogen and -C-|_C4alkyl; and
when X is absent or CR20R21 ; R1 can additionally be fluorine; rmaceutically acceptable salt thereof.
Included among the compounds of Formula (I) are those wherein:
X is absent or selected from the group consisting of: O, S and CR20R21 I where R20R21 are jnc|epenc|ent|y selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cycolpentyl, -C-|_C4alkyl and substituted -C-|_C4alkyl;
R2R2' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cycolpentyl, -C-|_C4alkyl and substituted -C-|_C4alkyl;
R3 is selected from the group consisting of: hydrogen, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, -C-|_C4alkyl and substituted -C-|_C4alkyl;
R4R4' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cycolpentyl, -C-|_C4alkyl and substituted -C-|_C4alkyl;
R5R5' are independently selected from: hydrogen, fluorine, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cycolpentyl, -C-|_C4alkyl and substituted -C-|_C4alkyl; and
R^ is selected from the group consisting of: hydrogen, -C-|.C4alkyl and substituted -C-|_C4alkyl; and
when X is absent or CR20R21 ; R1 can additionally be fluorine;
or a pharmaceutically acceptable salt thereof.
Included among the compounds of Formula (I) are:
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;
4-{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-[(2-morpholinylmethyl)oxy]-1 H- imidazo[4,5-c]pyridin-4-yl}-2-methyl-3-butyn-2-ol;
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}- 1 H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol; 4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;
4-{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-[(3-pyrrolidinylmethyl)oxy]-1 H- imidazo[4,5-c]pyridin-4-yl}-2-methyl-3-butyn-2-ol;
4-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(3S)-1-methyl-3- piperidinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;
4-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2S)-4-methyl-2- thiomorpholinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;
4-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2S)-4-methyl-2- morpholinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;
4-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2- morpholinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol; and
4-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2S)-4-ethyl-2- morpholinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;
or a pharmaceutically acceptable salt thereof.
Compounds of Formula (I) are included in the pharmaceutical compositions of the invention and used in the methods of the invention. As used herein, the substituents cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and -C-|_C4alkyl, are optionally substituted with from 1 fluorine atom to where the substituent is perfluorinated. Suitably, the substituent is optionally substituted with
from 1 to 8 fluorine atoms. Suitably, the substituent is optionally substituted with from 1 to 5 fluorine atoms. Suitably, the substituent is optionally substituted with from 1 to 3 fluorine atoms.
By the term "perfluorinated" as used herein is meant a substituent where all of the hydrogen atoms have been replaced by fluorine atoms.
By the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety is substituted with from 1 fluorine atom to where the chemical moiety is perfluorinated. Suitably, the chemical moiety is substituted with from 1 to 8 fluorine atoms. Suitably, the chemical moiety is substituted with from 1 to 5 fluorine atoms. Suitably, the chemical moiety is substituted with from 1 to 3 fluorine atoms.
By the term "-C-|.C4alkyl" as used herein, is meant a linear or branched, saturated or unsaturated hydrocarbon chain, containing from 1 to 4 carbon atoms. Examples of - C-|.C4alkyl as used herein include: -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, -CH2- CF3, -C(CH3)3, -(CH2)3-CH3, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH=CH2, and - C=C-CH3.
Unless otherwise stated, the compounds disclosed herein also include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
By the term "treating" and derivatives thereof as used herein, is meant prophylatic and therapeutic therapy. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen. By the phrases "to a therapeutic extent", "treating" and "therapeutically effective amount" and derivatives thereof as used herein, unless otherwise defined, is meant that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, lessening in severity or amelioration of specified cancers.
Certain compounds described herein may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents
include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
Compounds of Formula (I) are included in the pharmaceutical compositions of the invention and used in the methods of the invention. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics, for use as sustained release or prodrug formulations.
The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art.
The compounds of Formula I are prepared as shown in Scheme 1 below, or by analogous methods. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art.
Scheme 1
(a) Br2, NaOAc; (b) EtNH2; (c) SnCI2, HCI; (d) ethyl cyanoacetate, 190 0C; (e) NaNO2, HCI; (f) NH2OH; (g) Et3N, dioxane; (h) n-BuLi, THF; (i) B(OMe)3; G) H2O2, NaOH; (k) 1 ,1- dimethylethyl 3-(hydroxymethyl)-1-piperidinecarboxylate, DEAD, polymer bound PPh3, CH2CI2; (I) Pd(PPh3)4, IPr2NH, dioxane, 100 0C; (m) TFA, CH2CI2.
Compounds of Formula (I) can be prepared in a manner analogous to those shown in Scheme 1. Bromination of 3-nitro-4-ethoxy pyridine (1-Scheme 1 ) using bromine buffered in sodium acetate gives 3-bromo-4-(ethyloxy)-5-nitropyridine (2-Scheme 1 ). Other alternative methods exist and are known to those skilled in the art for carrying out this transformation. A compilation of these methods can be found in standard organic synthesis texts such as Larock, "Comprehensive Organic Transformations," VCH, N.Y.(1989). The ethoxy group is then displaced by a primary amine such as ethyl amine in a polar solvent such as ethanol to give compounds such as 3-Scheme 1. In the case liquid amines, the reaction can be carried out in the absence of solvent. The reduction of the nitro group with concomitant introduction of the chloro group is achieved using tin (II) chloride according to the method described by Kelley et al. J. Med. Chem. 1995, 38(20), 4131-34. The corresponding 5-bromo-2-chloro diaminopyridine is condensed with an appropriate acid or ester such as ethyl cyanoacetate. Continued heating affects a cyclodehydration reaction to give imidazopyridines such as 4-Scheme 1. Reaction with NaNO2 in concentrated HCI following by reaction with hydroxylamine gives a bis-oxime that cyclodehydrates in the presence of an appropriate base such as triethylamine to give an aminofurazan such as 5-Scheme 1. The hydroxyl group is introduced by generating an aryl anion by halogen-metal exchange using a suitable base such as n-butyl lithium, reacting the anion with an appropriate boron electrophile such as trimethyl borate and oxidizing the resulting aryl boronate with an appropriate oxidizing agent such as hydrogen peroxide in aqueous base to give imidazopyridinols such as 6-Scheme 1. Other bases such as Grignard reagents can also be used to affect the halogen metal exchange. Etherification of the imidazopyridinol is carried out with an appropriate alcohol such as 1 ,1-dimethylethyl 3-(hydroxymethyl)-1-piperidinecarboxylate using the methods described by Mitsunobu, Synthesis 1981 , 1 to give ethers such as 7-Scheme 1. Alternatively, the etherification can be carried out by reacting an appropriate halide such as 1 ,1- dimethylethyl 3-(chloromethyl)-1-piperidinecarboxylate with a suitable alcohol such as 6- Scheme 1 in the presence of a suitable base such as potassium carbonate. Treatment of an appropriate aryl halide such as 7-Scheme 1 with an appropriate catalyst such as tetrakistriphenylphosphine palladium and a terminal alkyne in the presence of a suitable base such as di-isopropylamine in an appropriate solvent such as dioxane gives the corresponding aryl alkyne such as 8-Scheme 1. Removal of the protecting groups is
achieved using a protic or Lewis acid such as trifluoroacetic acid in a polar solvent such as methylene chloride giving compounds of Formula (I) such as 9-Scheme 1.
By the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of an AKT inhibiting compound, as described herein, and a further active ingredient or ingredients, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active ingredient or ingredients, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of specified cancers in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by VT. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase Il inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented AKT inhibiting compounds are chemotherapeutic agents.
Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
Diterpenoids, which are derived from natural sources, are phase specific anti - cancer agents that operate at the G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
Paclitaxel, 5β,20-epoxy-1 ,2α,4,7β, 10β, 13α-hexa-hydroxytax-11 -en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971 ), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435- 10441 (1981 ). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P. W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 11 1 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56,
1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, RJ. et. al, Cancer Chemotherapy Pocket Guidβj. 1998) related to the duration of dosing above a threshold concentration (5OnM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-te/t-butyl ester, 13-ester with 5β-20-epoxy-1 ,2α,4,7β, 10β, 13α-hexahydroxytax-11 -en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted
from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine.
Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non- Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur. Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
Carboplatin, platinum, diammine [1 ,1-cyclobutane-dicarboxylate(2-)-O,O'], is commercially available as PARAPLATI N® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin. Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
Carmustine, 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
Antibiotic anti-neoplasties are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin. Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]- 8-glycoloyl, 7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
Topoisomerase Il inhibitors include, but are not limited to, epipodophyllotoxins. Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase Il and DNA causing DNA
strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene-β-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non- small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene-β-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia. Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
5-fluorouracil, 5-fluoro-2,4- (1 H, 3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5- fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.
Thioguanine, 2-amino-1 ,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical
forms of 7-(4-methylpiperazino-methylene)-10,1 i-ethylenedioxy-20-camptothecin described below. lrinotecan HCI, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1 H-pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®. lrinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. lrinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia.
Also of interest, is the camptothecin derivative of formula A following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers:
known by the chemical name "7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy- 20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino-methylene)-10,11- ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)- 10,11-ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos.
6,063,923; 5,342,947; 5,559,235; 5,491 ,237 and pending U.S. patent Application No. 08/977,217 filed November 24, 1997.
Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5α-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681 ,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.
Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over- expression or mutation, has been shown to result in uncontrolled cell growth.
Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT VoI 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such non- receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, SJ. , (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15: 371-404.
SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of
Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1 107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.
27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391 ; and Martinez-lacaci, L., et al, Int. J. Cancer (2000), 88(1 ), 44-52. Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention. Such kinases are discussed in Abraham, RT. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545. Also of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.
As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example lmclone C225 EGFR specific antibody (see Green, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast canceπerbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51 17-5124).
Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the
compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav betas) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).
Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I). There are a number of immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.
Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of formula I and/or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents,
platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase Il inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
The compounds of the present invention are active as AKT inhibitors and exhibit therapeutic utility in treating specified cancers in a mammal, including a human.
By the term "specified cancers" as used herein, means one or more cancers selected from: inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,
Rhabdomyosarcoma, ependymoma, medulloblastoma, osteosarcoma, giant cell tumor of bone,
Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, lmmunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
Isolation and Purification of His-taqqed AKT1 (aa 136-480)
Insect cells expressing His-tagged AKT1 (aa 136-480) were lysed in 25 mM HEPES, 100 mM NaCI, 20 mM imidazole; pH 7.5 using a polytron (5 ml_s lysis buffer/g cells). Cell debris was removed by centrifuging at 28,000 x g for 30 minutes. The supernatant was filtered through a 4.5-micron filter then loaded onto a nickel-chelating column pre-equilibrated with lysis buffer. The column was washed with 5 column volumes (CV) of lysis buffer then with 5 CV of 20% buffer B, where buffer B is 25 mM HEPES, 100 mM NaCI, 300 mM imidazole; pH 7.5. His-tagged AKT1 (aa 136-480) was eluted with a 20-100% linear gradient of buffer B over 10 CV. His-tagged AKT1 (136-480) eluting fractions were pooled and diluted 3-fold with buffer C, where buffer C is 25 mM HEPES,
pH 7.5. The sample was then chromatographed over a Q-Sepharose HP column pre- equilibrated with buffer C. The column was washed with 5 CV of buffer C then step eluted with 5 CV 10%D, 5 CV 20% D, 5 CV 30% D, 5 CV 50% D and 5 CV of 100% D; where buffer D is 25 mM HEPES, 1000 mM NaCI; pH 7.5. His-tagged AKT1 (aa 136-480) containing fractions were pooled and concentrated in a 10-kDa molecular weight cutoff concentrator. His-tagged AKT1 (aa 136-480) was chromatographed over a Superdex 75 gel filtration column pre-equilibrated with 25 mM HEPES, 200 mM NaCI, 1 mM DTT; pH 7.5. His-tagged AKT1 (aa 136-480) fractions were examined using SDS-PAGE and mass spec. The protein was pooled, concentrated and frozen at -80C.
His-tagged AKT2 (aa 138-481 ) and His-tagged AKT3 (aa 135-479) were isolated and purified in a similar fashion.
His-taqqed AKT Enzyme Assay Compounds of the present invention were tested for AKT 1 , 2, and 3 protein serine kinase inhibitory activity in substrate phosphorylation assays. This assay examines the ability of small molecule organic compounds to inhibit the serine phosphorylation of a peptide substrate. The substrate phosphorylation assays use the catalytic domains of AKT 1 , 2, or 3. AKT 1 , 2 and 3 are also commercially available from Upstate USA, Inc. The method measures the ability of the isolated enzyme to catalyze the transfer of the gamma-phosphate from ATP onto the serine residue of a biotinylated synthetic peptide SEQ. ID NO: 1 (Biotin-ahx-ARKRERAYSFGHHA-amide). Substrate phosphorylation was detected by the following procedure:
Assays were performed in 384well U-bottom white plates. 10 nM activated AKT enzyme was incubated for 40 minutes at room temperature in an assay volume of 2OuI containing 5OmM MOPS, pH 7.5, 2OmM MgCl2, 4uM ATP, 8uM peptide, 0.04 uCi [g- P] ATP/well, 1 mM CHAPS, 2 mM DTT, and 1 ul of test compound in 100% DMSO. The reaction was stopped by the addition of 50 ul SPA bead mix (Dulbecco's PBS without Mg2+ and Ca2+, 0.1 % Triton X-100, 5mM EDTA, 5OuM ATP, 2.5mg/ml Streptavidin-coated SPA beads.) The plate was sealed, the beads were allowed to settle overnight, and then the plate was counted in a Packard Topcount Microplate Scintillation Counter (Packard Instrument Co., Meriden, CT).
The data for dose responses were plotted as % Control calculated with the data reduction formula 100*(U1-C2)/(C1-C2) versus concentration of compound where U is the unknown value, C1 is the average control value obtained for DMSO, and C2 is the
average control value obtained for 0.1 M EDTA. Data are fitted to the curve described by: y = ((Vmax * x) / ( K + x )) where Vmax is the upper asymptote and K is the IC50.
Cloning of full-length human (FL) AKT1 :
Full-length human AKT1 gene was amplified by PCR from a plasmid containing myristylated-AKT1-ER (gift from Robert T. Abraham, Duke University under MTA, described in Klippel et al. in Molecular and Cellular Biology 1998 Volume 18 p.5699) using the 5' primer: SEQ. ID NO: 2 5' TATATAGGATCCATGAGCGACGTGGC 3' and the 3' primer: SEQ. ID NO: 3
AAATTTCTCGAGTCAGGCCGTGCTGCTGG 3'. The 5' primer included a BamHI site and the 3'primer included an Xhol site for cloning purposes. The resultant PCR product was subcloned in pcDNA3 as a BamHI / Xhol fragment. A mutation in the sequence (TGC) coding for a Cysteine25 was converted to the wild-type AKT1 sequence (CGC) coding for an Arginine25 by site-directed mutagenesis using the QuikChange® Site Directed Mutagenesis Kit (Stratagene). The AKT 1 mutagenic primer: SEQ. ID NO: 4 5' ACCTGGCGGCCACGCTACTTCCTCC and selection primer: SEQ. ID NO: 5 5' CTCGAGCATGCAACTAGAGGGCC (designed to destroy an Xbal site in the multiple cloning site of pcDNA3) were used according to manufacturer's suggestions. For expression/purification purposes, AKT1 was isolated as a BamHI / Xhol fragment and cloned into the BamHI / Xhol sites of pFastbacHTb (Invitrogen).
Expression of FL human AKT1 :
Expression was done using the BAC-to-BAC Baculovirus Expression System from
Invitrogen (catalog # 10359-016). Briefly 1 ) the cDNA was transferred from the FastBac vector into bacmid DNA, 2) the bacmid DNA was isolated and used to transfect Sf9 insect cells, 3) the virus was produced in Sf9 cells, 4) T. ni cells were infected with this virus and sent for purification.
Purification of FL human AKT1 :
For the purification of full-length AKT1 , 130 g sf9 cells (batch # 41646W02) were resuspended in lysis buffer (buffer A, 1 L, pH 7.5) containing 25 mM HEPES, 100 mM NaCI, and 20 mM imidazole. The cell lysis was carried out by Avestin (2 passes at 15K- 2OK psi). Cell debris was removed by centrifuging at 16K rpm for 1 hour and the
supernatant was batch bound to 10 ml Nickel Sepharose HP beads at 4 C for over night. The beads were then transferred to column and the bound material was eluted with buffer B (25 mM HEPES, 100 mM NaCI, 300 mM imidazole, pH 7.5). AKT eluting fractions were pooled and diluted 3 fold using buffer C (25 mM HEPES, 5 mM DTT; pH 7.5). The sample was filtered and chromatographed over a 10 ml. Q-HP column pre-equilibrated with buffer C at 2 mL/min.
The Q-HP column was washed with 3 column volume (CV) of buffer C, then step eluted with 5 CV 10%D, 5 CV 20% D, 5 CV 30% D, 5 CV 50% D and 5 CV of 100% D; where buffer D is 25 mM HEPES, 1000 mM NaCI, 5 mM DTT; pH 7.5. 5 mL fractions collected. AKT containing fractions were pooled and concentrated to 5 ml. The protein was next loaded to a 120 ml Superdex 75 sizing column that was pre-equilibrated with 25 mM HEPES, 200 mM NaCI, 5 mM DTT; pH 7.5. 2.5 mL fractions were collected.
AKT 1 eluting fractions were pooled, aliquoted (1 ml) and stored at -80C. Mass spec and SDS-PAGE analysis were used to confirm purity and identity of the purified full-length AKT1.
Full-length (FL) AKT2 and (FL) AKT3 were isolated and purified in a similar fashion.
Full-Lenqth AKT Enzyme Assay
Compounds of the present invention were tested for AKT 1 , 2, and 3 protein serine kinase inhibitory activity in substrate phosphorylation assays. This assay examines the ability of small molecule organic compounds to inhibit the serine phosphorylation of a peptide substrate. The substrate phosphorylation assays use the catalytic domains of AKT 1 , 2, or 3. The method measures the ability of the isolated enzyme to catalyze the transfer of the gamma-phosphate from ATP onto the serine residue of a biotinylated synthetic peptide SEQ. ID NO: 1 (Biotin-ahx-ARKRERAYSFGHHA-amide). Substrate phosphorylation was detected by the following procedure.
Assays were performed in 384well U-bottom white plates. 10 nM activated AKT enzyme was incubated for 40 minutes at room temperature in an assay volume of 2OuI containing 5OmM MOPS, pH 7.5, 2OmM MgCI2, 4uM ATP, 8uM peptide, 0.04 uCi [g-33P] ATP/well, 1 mM CHAPS, 2 mM DTT, and 1 ul of test compound in 100% DMSO. The reaction was stopped by the addition of 50 ul SPA bead mix (Dulbecco's PBS without Mg2+ and Ca2+,
0.1 % Triton X-100, 5mM EDTA, 5OuM ATP, 2.5mg/ml Streptavidin-coated SPA beads.)
The plate was sealed, the beads were allowed to settle overnight, and then the plate was counted in a Packard Topcount Microplate Scintillation Counter (Packard Instrument Co.,
Meriden, CT).
The data for dose responses were plotted as % Control calculated with the data reduction formula 100*(U1-C2)/(C1-C2) versus concentration of compound where U is the unknown value, C1 is the average control value obtained for DMSO, and C2 is the average control value obtained for 0.1 M EDTA. Data are fitted to the curve described by: y = ((Vmax * x)
/ ( K + X )) where Vmax is the upper asymptote and K is the IC50.
The compound of Example 1 demonstrated an IC50 (uM) activity of: 0.003 um, FL AKT1 ; 0.016 um, FL AKT2; and 0.016, FL AKT3 in the above full-Length AKT enzyme assay.
Cell proliferation assay
Cell proliferation studies were assessed using the CellTiter GIo luminescent cell viability assay (Promega, Maddison, Wl). Cells were plated at a density of 1000 cells/well in 96 well plates and incubated overnight. Cells were then treated with the compound of Example 1 (ranging from 30 μM-1.5 nM) for 72 h. The anti-proliferative effect was determined using CellTiter GIo following manufacture's protocol. Data were plotted as percent of DMSO control and the EC50 values were calculated using the XLFit (IDBS Ltd., Guildford, UK) curve-fitting tool from Microsoft Excel. The data from at least one experiment is recorded in Table A below.
Table A
Table A: Anti-prolifeartive activity of the compound of Example 1 against cell lines originated from hematological malignacies.
The pharmaceutically active compounds within the scope of this invention are useful in the treatment of specified cancers in mammals, particularly humans, in need thereof. The present invention therefore provides a method of treating specified cancers which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or pro-drug thereof. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will, for example, be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of treatment of a specified cancer as disclosed herein, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral and/or parenteral dosage
units for human administration preferably contain from 0.05 to 3500 mg of active compound.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular Akt inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
The method of this invention of treating specified cancers in mammals, including humans, comprises administering to a subject in need of such activity an effective Akt inhibiting amount of a pharmaceutically active compound of the present invention.
The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use as an Akt inhibitor.
The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy. The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating specified cancers.
The invention also provides for a pharmaceutical composition for use as an Akt inhibitor which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides for a pharmaceutical composition for use in the treatment of specified cancers which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat specified cancers.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following
Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
Experimental Details
The compounds of Examples 1 to 10 are readily made according to Scheme 1 or by analogous methods.
Intermediate VII
I Il III IV
V Vl VII
Preparation of 2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H-imidazoKδ-clpyridin- 7-QI
a) 5-Bromo-2-chloro-N4-ethyl-pyridine-3,4-diamine (II) 3-Bromo-5-nitropyridin-4-yl)amine (I, 700 g, 2.86 mol) was dissolved in cone HCI
(7L) and heated to 85 0C. Tin (II) chloride (1626 g, 8.58 mol) was added in portions. The reaction was heated at reflux for 1 h and then allowd to cool to ambient temperature overnight. The resulting yellow precipitate was collected by filtration, suspended in ice water (5L) and the mixture was adjusted to pH 12 with 12N NaOH. The resulting solution was extracted with CH2CI2 (2 x 4 L) and the combined organic extracts were dried over Na2SO4. The solvent was removed under reduced pressure to give 550 g (77% yield) of the desired compound (II). This was used in the next step without further purification. MS (ES+) m/z 250(M+H)+.
b) N-[5-Bromo-2-chloro-4-(ethylamino)-3-pyridinyl]-2-cyanoacetamide (III)
To a solution of 5-bromo-2-chloro-N4-ethyl-pyridine-3,4-diamine (II, 550 g, 2.21 mol) in CH2CI2 (5.5 L) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (634.5 g, 3.31 mol), cyanoacetic acid (282 g, 3.31 mol) and N- methylmorpholine (897 g, 8.84 mol). A significant exotherm (-20 0C) was observed upon the addition of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and cyanoacetic acid. After stirring at ambient temperature for 2 h, the solvent was removed under reduced pressure. The resulting reside was extracted with warm EtOAc (40 0C, 20 L) and water (40 0C, 8 L). The aqueous layer was washed with addition EtOAc (10 L) and the combined organic extracts were washed with water (10 L). The organic extract was concentrated under reduced pressure to a slurry and filtered. The solid was wahed with EtOAc and dried to give 534 g (76% yield) of the desired compound (III) as a white crystalline solid. This was used in the next step without further purification. MS (ES+) m/z 317(M+H)+.
c) (7-Bromo-4-chloro-1-ethyl-1 H-imidazo[4,5-c]pyridin-2-yl)-hydroxyimino-acetonitrile (V)
A solution of N-[5-bromo-2-chloro-4-(ethylamino)-3-pyridinyl]-2-cyanoacetamide III, (458 g, 1.45 mol) in glacial acetic acid (4.6 L) was heated to 100 0C. After 3 h, LC/MS analysis indicated that the conversion to (7-bromo-4-chloro-1-ethyl-1 H-imidazo[4,5- c]pyridin-2-yl)acetonitrile (IV) was completed. After allowing to cool to ambient temperature, the reaction was charged with sodium nitrate (230 g, 3.34 mol) in portions. Vigorous gas evolution and foaming was observed together with a -10 0C exotherm. After stirring at ambient temperature for 16 h, the solid was collected by filtration and dried to a constant weight to give 545 g of the desired product (V) as a light yellow solid. This was used in the next step without further purification. MS (ES+) m/z 328(M+H)+.
d) 4-(7-Bromo-4-chloro-1-ethyl-1 H-imidazo[4,5-c]pyridin-2-yl)-1 ,2,5-oxadiazol-3-amine (Vl)
To a mixture of (7-bromo-4-chloro-1-ethyl-1 H-imidazo[4,5-c]pyridin-2-yl)- hydroxyimino-acetonitrile (V, 545 g, 1.45 mol) in dioxane (5 L) was added triethylamine (1 L) and hydroxylamine (143 g, 55% in water). The reaction was heated at reflux for 6 h. After cooling the reaction to ambient temperature, the mixture was filtered and the filtrate concentrated under reduced pressure to give a brown solid. The solid was suspended in methanol (1 L) and the suspension was stirred at 65 0C for 0.5 h. The solid was collected by filtration and dried to give 321 g (70% yield) of the desired compound (Vl). This was used in the next step without further purification. MS (ES+) m/z 343(M+H)+.
e) 2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H-imidazo[4,5-c]pyridin-7-ol (VII)
A suspension of 4-(7-bromo-4-chloro-1-ethyl-1 H-imidazo[4,5-c]pyιϊdin-2-yl)-1 ,2,5- oxadiazol-3-amine (Vl, 50 g, 0.14 mol) in THF (1 L) was cooled in a dry-ice/acetone bath until the internal temperature was below -75 0C. lsopropyl magnesium chloride (225 ml_, 2M in ether, 0.45 mol) was added slowly at a rate to keep the reaction temperature below -70 0C. After an additional 10 min., trimethyl borate (54 ml_, 0.48 mol) was added and the reaction was maintained in the dry-ice acetone bath for 1 h. The bath was removed and the reaction was allowed to reach ambient temperature. After 18 h., the resultant yellow suspension was cooled to 0 0C. A solution of 30% hydrogen peroxide (250 ml.) and 3N NaOH (100 ml.) was added at a rate to keep the reaction temperature below 40 0C. The ice bath was then removed and the reaction was stirred vigorously at ambient temperature for 2 h. The bulk of the organic solvent was removed under reduced pressure and the aqueous layer was acidified to pH 3 with 1 N HCI. After stirring the resulting suspension for 30 min., ethyl acetat (200 ml.) was added. After stirring for another 1 h, the solid was collected by filtration. The filter cake was washed sequentially with water, ethyl acetate, toluene and ethyl acetate. The solid was dried to a constant weight to give 35.9 g (88% yield) of the desired compound (VII) as a pale yellow solid. This was used without further purification. MS (ES+) m/z 281.3 (M+H)+.
Example 1
Preparation of 4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{r(3S)-3- piperidinylmethylloxy}-1 H-imidazor4,5-clpyridin-4-yl)-2-methyl-3-butvn-2-ol
a) 1 ,1-Dimethylethyl (3S)-3-(bromomethyl)-1-piperidinecarboxylate
To a solution of 1 ,1-dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (30.0 g, 139 mmol) and carbon tetrabromide (72.0 g, 217 mmol) in methylene chloride (150 mL) was added dropwise a solution of triphenyl phosphine (42.4 g, 162 mmol) in methylene chloride (150 mL). An ice-bath was used to maintain an internal temperature between 20 and 25 0C during the addition. After stirring the mixture at ambient temperature for 1 h, cyclohexane (500 mL) was added. Approximately one-half of the solvent was removed under reduced pressure. The remaining solution was cooled in an ice bath and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the residue subjected to flash chromatography (0% to 25% ethyl acetate/hexanes, silica gel) to give 35.1 g (91 % yield) of the desired product as a solid. MS (ES+) m/z 278 (M+H)+.
b) 1 ,1-Dimethylethyl 3-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H- imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-1-piperidinecarboxylate A mixture consisting of the compound of intermediate VII (25.0 g, 89.1 mmol), cesium carbonate (41.0 g, 126 mmol) and the compound of Example 1 (a) (35.0 g, 126 mmol) in DMF (200 mL) was stirred at 40 0C for 8 h and then at 35 0C for 18 h. The mixture was poured into rapidly stirring ice water (800 ml). After 10 min., ethyl acetate (300 mL) was added and the stirring continued for an additional 20 min. The solid was collected by filtration, washed with ethyl acetate (50 mL) and dried to give 36 g (85% yield) of the desired compound. MS (ES+) m/z 478 (M+H)+.
c) 1 ,1-Dimethylethyl 3-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methyl- 1-butyn-1-yl)-1 H-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-1-piperidinecarboxylate A thick-walled pressure vessel was charged with the compound of Example 1 (b)
(36 g, 75.3 mmol), 2-methyl-3-buty-2-ol (16 mL, 165 mmol), (Ph3P)4Pd (1 g, 0.86 mmol), Zn dust (1.0 g., 14.8 mmol), NaI (2.20 g, 14.8 mmol), DBU (16 mL, 107 mmol), triethylamine (15 mL, 109 mmol) and DMSO (300 mL). The mixture was purged with argon for 10 min. The pressure vessel was then sealed and heated at 80 0C for 4 h. The mixture was then poured into rapidly stirring ice water (1000 mL). After 10 min., ethyl acetate (300 mL) was added and stirring continued for an additional 20 min. The solid was collected by filtration, washed with ethyl acetate (50 mL) and dried to give 35.5 g (90% yield) of the desired compound. MS (ES+) m/z 526 (M+H)+.
d) 4-{2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-[(3-piperidinylmethyl)oxy]-1 H- imidazo[4,5-c]pyridin-4-yl}-2-methyl-3-butyn-2-ol
The compound of Example 1 (c) (35.0 g, 66.6 mmol) and TFA (350 ml. of a 20% solution in methylene chloride, 808 mmol) was stirred at ambient temperature for 2.5 h. The solution was poured slowly into rapidly stirring mixture of water, NaOH (36 g, 900 mmol), ethyl acetate (200 ml.) and THF (1000 ml_). The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate/THF (1 :5 v/v, 150 ml_). The combined organic extract were washed with sat. NaCI, dried over Na2SO4. The solvent was removed under vacuum and the resulting solid was recrystallized from hot ethanol (1200 ml.) to give 26.3 g (93% yield) of the title compound as a white crystalline solid. MS (ES+) m/z 426 (M+H)+.
Example 2
Preparation of 4-(2-(4-amino-1.2.5-oxadiazol-3-ylV1-ethyl-7-fr(2RV2- morpholinylmethylloxy}-1 H-imidazor4,5-clpyridin-4-yl)-2-methyl-3-butyn-2-ol difluoroacetic acid salt
a) 1 ,1-Dimethylethyl 2-(hydroxymethyl)-4-morpholinecarboxylate
A solution of 4-{[(1 ,1-dimethylethyl)oxy]carbonyl}-2-morpholinecarboxylic acid (2.0 g, 21.6 mmol) in THF (45 ml.) was cooled to 0 0C. A solution of borane (39 ml_, 39.0 mmol, 1 M in THF) was added over 25 min via addition funnel. After warming to RT, the reaction was quenched by dropwise addition of methanol/acetic acid (18 ml_, 9:1 v/v).
The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 1 N HCI. The aqueous layer was extracted with ethyl acetate and combined extracts were washed with water, 1 N NaOH, water, brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 1.83 g of the desired material. 1H NMR (400 MHz, CDCI3) δ ppm 1.49 (s, 9 H) 2.30 (br d, J= 11.37 Hz, 1 H) 2.69 - 2.79 (m, J=9.51 , 6.41 , 3.28, 3.28 Hz, 1 H) 2.84 (ddd, J=13.77, 10.86, 3.16 Hz, 2 H) 3.27 - 3.38 (m, 1 H) 3.47 (br s, 1 H) 3.63 - 3.75 (m, 2 H) 4.10 - 4.19 (m, 1 H) 4.27 (br s, 1 H).
b) 1 ,1-dimethylethyl-2-(bromomethyl)-4-morpholinecarboxylate
To a solution of the compound of Example 2(a) (1.80 g, 8.30 mmol) in dichloromethane (100 ml.) at -20 0C was added CBr4 (5.50 g, 16.6 mmol) followed by dropwise addition of a solution of PPh3 (4.60 g, 17.0 mmol) in dichloromethane (80 ml_).
After allowing the mixture to warm to RT, the solvent was removed under reduced pressure. Flash chromatography (silica gel, EtOAc/hexanes) gave 2.40 g of the desired compound.
c) 1 ,1-Dimethylethyl-2-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H- imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4-morpholinecarboxylate The compound of intermediate VII (0.80 g, 2.90 mmol), the compound of Example
2(b) (0.80 g, 2.90 mmol) and cesium carbonate (2.8Og, 8.50 mmol) in DMF (50 ml.) were stirred at 35 0C for 22 h. The reaction was quenched with sat. NH4CI and extracted with EtOAc. The organic extracts were washed with water, brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue subjected to flash chromatography (silica gel, MeOH/CH2Cl2) to give 0.57 g of the desired compound. MS (ES+) m/z 480 (M+H)+.
d) 4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-{[2-morpholinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol, ditrifluoroacetic acid salt A thick-walled pressure vessel was charged with the compound of Example 2(c)
(0.50 g, 1.04 mmol), DBU (0.46 ml_, 3.10 mmol), Et3N (0.44 ml_, 3.10 mmol), NaI (0.047 g, 0.31 mmol), zinc dust (0.020 g, 0.31 mmol) 2-methyl-3-butyn-2-ol (0.26 g, 3.10 mmol), Pd(PPh3)4 (0.12 g, 0.10 mmol) and dioxane (20 ml_). The pressure vessel was then sealed and heated at 80 0C for 17 h. After cooling to RT, the reaction was quenched by adding sat NH4CI. The aqueous layer was extracted with EtOAc and the combined extracts were washed with water, brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue subjected to flash chromatography
(silica gel, MeOH/CH2CI2) to give 1 ,1-dimethylethyl 2-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)- 1 -ethyl-4-(3-hydroxy-3-methyl-1 -butyn-1 -yl)-1 /-/-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4- morpholinecarboxylate. This was dissolved in dichloromethane (4 ml.) and treated with TFA (2 mL) at RT for 1 h. The solvent was removed under reduced pressure and the residue subjected to reverse phase HPLC (YMC Combiscreen ODS-A 50x20mm, 20ml_/min, gradient, A:acetonitrile-0.1 %TFA, B:water-0.1 % TFA, 10-80% A during 7min, UV detection at 214) to give 0.15 g of the title compound. MS (ES+) m/z 428 (M+H)+.
Example 3
Preparation of 4-(2-(4-amino-1.2.5-oxadiazol-3-ylV1-ethyl-7-fr(2SV2- thiomorpholinylmethylloxy}-1 H-imidazor4,5-clpyridin-4-yl)-2-methyl-3-butyn-2-ol, dihvdrochloride
a) 1 ,1-Dimethylethyl (2S)-2-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H- imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4-thiomorpholinecarboxylate
To a solution of the compound of intermediate VII (2.36 g, 8.40 mmol) in DMF (160 mL) was added anhydrous cesium carbonate (8.32 g, 25.0 mmol) and 1 ,1- dimethylethyl (2S)-2-(bromomethyl)-4-thiomorpholinecarboxylate (2.50 g, 8.40 mmol). After stirring at ambient temperature for 16 h, sat NH4CI was added and the reaction was extracted with EtOAc. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue subjected to flash chromatography (MeOH/CH2CI2, silica gel) to give the 2.3 g of the desired compound contaminated with 1 ,1-dimethylethyl 6-{[2-(4-amino-1 ,2,5-
oxadiazol-S-yl^-chloro-i-ethyl-I H-imidazo^^-clpyridin-y-y^oxyJtetrahydro-i ^- thiazepine-4(5H)-carboxylate. This was used without further purification in the next step. MS (ES+) m/z 496 (M+H)+.
b) 4-(2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol
A thick-walled pressure vessel was charged with the compounds of Example 3(a) (0.18 g, 1.35 mmol), Zn dust (0.03 g, 0.40 mmol), NaI (0.06 g, 0.40 mmol), DBU (0.61 ml_, 4.00 mmol), TEA (0.56 ml_, 4.00 mmol), 2-methyl-3-butyn-2-ol (0.48 ml_, 5.70 mmol), (Ph3P)4Pd (0.08 g, 0.08 mmol) and dioxane (35 ml_). After purging the mixture with nitrogen for 10 min., the vessel was sealed and heated at 80 0C for 2.5 h. After allowing the reaction to cool to ambient temperature, sat NH4CI was added and the reaction was extracted with EtOAc. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue subjected to flash chromatography (MeOH/CH2CI2, silica gel). The Boc-protected product was dissolved in 25% TFA/CH2CI2 (10 ml_). Afte 30 min., the solvent was removed under reduced pressure. The residue was partitioned between 1 N NaOH and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate. The solvent was removed under reduced pressure. Flash chromatography (MeOH/CH2CI2, silica gel) gave 0.22 g (37% yield) of the desired compound. MS (ES+) m/z 444 (M+H)+.
c) 4-(2-(4-Am in o-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol, dihydrochloride A solution of the compound of Example 3(b) (0.22 g, 5.00 mmol) in dichloromethane (5 ml.) was treated with 4N HCI in dioxane (0.25 ml_, 1.00 mmol). After 30 min., the precipitate was isolated by filtration to give 0.21 g (82% yield) of the title compound as a pale yellow solid. MS (ES+) m/z 444 (M+H)+.
Example 4
Preparation of 4-(2-(4-amino-1.2.5-oxadiazol-3-ylV1-ethyl-7-fr(2SV2- morpholinylmethylloxy}-1 H-imidazor4,5-clpyridin-4-yl)-2-methyl-3-butyn-2-ol
a) 2-[(Phenylmethyl)amino]ethyl hydrogen sulfate
Chlorosulfonic acid (13.3 mL, 0.2 mol) was added very slowly to (2- [(phenylmethyl)amino]ethanol (30.2 g, 0.2 mol) in carbon tetrachloride (100 mL) in an ice bath. The resulting thick white suspension was stirred at room temperature overnight The suspension was diluted with chloroform and ethanol, warmed to 45 0C and then cooled in an ice bath. The precipitate was collected by filtration, washed with ethanol and dried under vaccum for 16 hrs at 40 0C to afford the desired compound (34 g, 74%). MS(ES)+ m/z 232 [M+H]+.
b) (2S)-4-(Phenylmethyl)-2-{[(phenylmethyl)oxy]methyl}morpholine
The compound of Example 4(a) (28.1g, 0.1 16 mol) was added to (2S)-2- {[(phenylmethyl)oxy]methyl}oxirane (19 g, 0.122mol) in methanol/water (75 mL/75 mL) in an ice bath. Sodium hydroxide (6M, 29 mL) was added over 5 min and once completed the bath was removed and allowed to stir at room temperature for 15 min. The reaction was then stirred at 40 0C in an oil bath for 3h. The reaction was quickly cooled in an ice bath and sodium hydroxide (28 g, 0.7 mol) and toluene (150 mL) were added. After 10 min, the reaction was heated to 65 0C for 3hr. After allowing the reaction to cool to RT, the organic layer was separated and the aqueous layer was further extracted with
toluene. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient, 15% to 30% ethyl acetate in hexane) to afford the desired compound as an oil (22.4 g, 65%). MS(ES)+ m/e 298 [M+H]+.
c) 1 , 1 -Dimethylethyl (2S)-2-(hydroxymethyl)-4-morpholinecarboxylate
To a solution of the compound of Example 4(b) (22.4 g, 0.075 mol) in ethanol (400 ml.) was added 10% palladium on carbon (2.4 g) and trifluoroacetic acid (7.0 ml_, 0.09 mol). The mixture was shaken under hydrogen at 50 psi for 24h. The reaction was filtered and concentrated in vacuo. A solution of potassium carbonate (26 g) in water (260 ml.) was added to the residue followed by a solution of di-tert-butyl-dicarbonate (17 g) in ethyl acetate (500 ml_). After 1 h, the aqueous layer was removed and the organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient, 15% to 100% ethyl acetate in hexane) to afford the desired compound as an oil (8 g, 50%). MS(ES)+ m/e 218 [M+H]+.
d) 1 ,1 -Dimethylethyl (2S)-2-(bromomethyl)-4-morpholinecarboxylate
The compound of Example 4(c) (6.9 g, 0.032 mol) and carbon tetrabromide (15.8 g, 0.048 mol) were dissolved in methylene chloride (100 ml.) and cooled in an ice bath. A solution of triphenylphosphine (12. 2g, 0.046 mol) in methylene chloride (10OmL) was added dropwise over 30min. After 1 hr at 0 0C, the reaction was allowed warm to room temp and was stirred overnight. The reaction volume was reduced by Vz- in vacuo and poured onto a pad of silica gel and the product eluted with 15% ethyl acetate in hexane. The filtrate was concentrated in vacuo to afford the desired compound as an oil (8g, 90%). MS(ES)+ m/e 281 [M+H]+.
e) 1 ,1 -Dimethylethyl (2S)-2-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H- imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4-morpholinecarboxylate To a solution of the compound of Example 4(d) (10.9 g, 0.039 mol) in dimethylformamide (150 ml.) was added intermediate VII (7.8 g, 0.028 mol) and cesium carbonate (11 g, 0.034mol). After 72 h at 45°C, the reaction was poured into ammonium chloride and water (1.5L) with stirring. The resulting precipitate was collected by filtration and washed with 1 M NaOH and water. The solid was dissolved in tetrahydrofuran and ethyl acetate (hot) and dried with sodium sulfate, filtered and concentrated V-≥ volume in
vacuo and cooled in an ice bath, the reslting precipitate was collected, washed with ethyl acetate and dried under vaccum for 2 h at 40 0C to afford the desired compound (10.2 g, 76%). MS(ES)+ m/e 480 [M+H]+.
f) 1 ,1-Dimethylethyl (2S)-2-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3- methyl-1-butyn-1-yl)-1 /-/-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-4-morpholinecarboxylate A thick-walled pressure vessl was charged with the compound of Example 4(e) (10.1 g, 0.021 mol), 2-methyl-3-butyn-2-ol (10.2 ml_, 100 mmol), zinc (0.27 g, 4.2 mmol), sodium iodide (0.63g, 4.2 mmol), triethylamine (5.8 ml_, 0.42mmol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (5.8 ml_, 42 mmol), tetrakis(triphenylphosphine) palladium (0) (1.0 g, 0.84 mmol) and dimethylsufoxide (100 ml_). The reaction vessel was sealed and heated at 80 0C for 3 h. After cooling to RT, the reaction was quenched by pouring into sat. ammonium chloride (1 L) and stirred for 30 min. The solid was collected by filtration. Purification by flash chromatography (silica gel, gradient, 1% to 10% methanol in chloroform) gave the desired compound as a solid (10.5 g, 95%). MS(ES)+ m/z 528 [M+H]+.
g) 4-(2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol To a suspension of the compound of Example 4(f) (14.2 g, 0.027 mol) in methylene chloride (150 ml.) was added trifluoroacetic acid (40 ml_). After 1 h, the solvent was removed in vacuo. The residue was evaporated from ethyl acetate (2x) to give a solid. The residue was suspended in water and treated with 1 N NaOH in an ice bath until the mixture was basic (pH 8). The precipitate was isolated by filtration, washed with water, ethyl acetate and dried in a vaccum oven at 400C for 4h. The resulting solid was suspended in ethanol (1.5 L). Darco G60 activated charcoal (3.9 g) was added and the mixture heated at reflux for 90 min. and filtered while hot through celite. The solvent was removed and the resulting solid was dried under high vaccum for 24 hr at 400C to afford the title compound (78.5 g, 68%). MS(ES)+ m/e 428 [M+H]+.
Example 5
Preparation of 4-{2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3-pyrrolidinylmethyl)oxy1- 1 /-/-imidazor4,5-clpyridin-4-yl}-2-methyl-3-butyn-2-ol, bis-trifluoroacetic acid salt
a) 1 ,1-Dimethylethyl 3-(bromomethyl)-1-pyrrolidinecarboxylate.
To a solution of 1 ,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.56 g, 2.8 mmol) with carbon tetrabromide (1.39 g, 4.2 mmol) in methylene chloride (10 ml.) was added drop wise a solution of triphenyl phosphine (0.73 g, 2.8 mmol in 5 ml. of methylene chloride). Upon completion the mixture was stirred 18 h at room temperature. The solvent was removed at reduced pressure and the residue stirred in 10% ethyl acetate 90% hexane. The mixture was filtered and the resulting solution chromatographed on silica eluting with a gradient of 0 - 25% EtOAc in hexane to afford the desired compound (0.41 g, 55%). MS (ES+) m/z 264 (M+H)+.
b) 1 ,1-Dimethylethyl 3-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H- imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-1-pyrrolidinecarboxylate. A mixture consisting of intermediate VII (100 mg, 0.35mmol) in DMF (2 ml.) with cesium carbonate (290 mg, 0.9 mmol) and the compound of Example 5(a) (290 mg, 1.1 mmol) was stirred at room temperature for 44 h. The mixture was poured into rapidly stirring ice water (7 ml.) and stirring continued for 10 min. To this was added cyclohexane (7 ml.) and stirring continued for an additional 20 min. The solid was
collected by filtration then washed with cyclohexane and dried in vacuo to afford the desired compound (11 1 mg, 69%). MS (ES+) m/z 464 (M+H)+.
c) 1 ,1-Dimethylethyl 3-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methyl- 1-butyn-1-yl)-1 /-/-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-1-pyrrolidinecarboxylate.
In a thick walled pressure vessel was charged with the compound of Example 5(b) (100 mg, 0.22 mmol), 2-methyl-3-butyn-2-ol (0.25 ml_, 2.6 mmol), (Ph3P)4Pd (30 mg), diisopropy amine (0.4 ml.) and dioxane (4 ml_). The vessel was sealed andstirred under an argon atmosphere at 100 0C for 6h. The mixture was concentrated at reduced pressure then triturated with ethyl acetate (4 ml.) to afford the desired compound (82 mg, 75%). MS (ES+) m/z 512 (M+H)+.
d) 4-{2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3-pyrrolidinylmethyl)oxy]-1H- imidazo[4,5-c]pyridin-4-yl}-2-methyl-3-butyn-2-ol, bis-trifluoroacetic acid salt
The compound of Example 5(c) (75 mg, 0.15 mmol) was stirred in a 20% solution of TFA in methylene chloride (3 ml.) at room temperature for 20 min. Toluene (3 ml.) was added and all volatiles removed at reduced pressure. The residue was purified by preparative reversed phase HPLC to afford the title compound as the di-TFA salt (40 mg, 43%). MS (ES+) m/z 412 (M+H)+.
Example 6
Preparation of 4-r2-(4-amino-1.2.5-oxadiazol-3-ylV1-ethyl-7-({r(3SV1-methyl-3- piperidinyllmethyl}oxy)-1 H-imidazor4,5-clpyridin-4-yll-2-methyl-3-butyn-2-ol, dihydrochloride
a) [(3S)-1-Methyl-3-piperidinyl]methanol
To a stirred solution of lithium aluminum hydride (10.5 ml of 1 M solution in THF, 10.5 mmol) in ether (15 ml.) at 20 0C was added dropwise a solution of 1 ,1-dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (1.50 g, 7.0 mmol) in THF (5 ml_). After 1.5 h at room temperature, water (0.4 ml.) was added followed by 15% aqueous sodium hydroxide solution (0.4 ml.) then water (1.2 ml_). This was stirred 20 min then filtered. The filtrate was concentrated under reduced pressure to give 0.87 g used in the next step without further purification. MS (ES+) m/z 130.2 (M+H)+.
b) 4-[4-Chloro-1-ethyl-7-({[(3S)-1-methyl-3-piperidinyl]methyl}oxy)-1 /-/-imidazo[4,5- c]pyridin-2-yl]-1 ,2,5-oxadiazol-3-amine
To a stirred mixture consisting of compound of Example 6(a) (0.260 g, 2 mmol) with triphenyl phosphine polymer bound (1.56 g of 1.6 mmol/g polymer, 2.5 mmol) at 0 0C was added a dropwise a solution of diethyl azodicarboxylate (0.33 ml_, 2.2 mmol) in methylene chloride (5 ml_). The cooling bath was removed and stirring continued for 20 min. To this mixture at room temperature was added a solution of the compound of intermediate VII (280 mg, 1 mmol) in THF (40 ml_). The mixture was filtered and to the filtrate was added ethyl acetate (60 ml_). The resulting solution was washed with water (50 ml.) then brine (50 ml_). The organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure to give 0.40 g crude solid that was used in the next step without further purification. MS (ES+) m/z 392.3 (M+H)+.
c) 4-[2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-({[(3S)-1 -methyl-3-piperidinyl]methyl}oxy)- 1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol dihydrochloride salt
A thick-walled pressure vessel was charged with the compound of Example 1 (b) (0.140 g, 0.35 mmol), Zn dust (0.02 g, 0.30 mmol), NaI (0.04 g, 0.27 mmol), DBU (0.10 ml_, 0.66 mmol), TEA (0.075 ml_, 0.53 mmol), 2-methyl-3-butyn-2-ol (0.40 ml_, 4.14 mmol) and (Ph3P)4Pd (0.04 g, 0.03 mmol) in DMSO (2 ml_). The mixture was poured into rapidly stirring water (10 ml.) with ethyl acetate (5 ml.) and cyclohexane (5 ml_). The resulting solid was collected then crystallized from ethanol. The crystalline solid was dissolved in hot ethanol then HCI (0.175 ml. of 4M solution in dioxane 0.70 mmol) was added. The
precipitate was collected and dried under reduced pressure to afford the title compound (0.148 g) MS (ES+) m/z 440.3 (M+H)+.
Example 7
Preparation of 4-r2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({r(2S)-4-methyl-2- thiomorpholinyllmethyl}oxy)-1 H-imidazor4,5-clpyridin-4-yll-2-methyl-3-butyn-2-ol
To a solution of the compound of Example 3(b) (0.88 g, 1.98 mmol) in MeOH (38 ml.) at 0 0C was added NaCNBH3 (0.14 g, 2.20 mmol) and acetic acid (0.57 ml_). This was followed by dropwise addition of formaldehyde (0.25 ml_). The reaction was allowed to warm to RT. After 18 h, the reaction was poured into 50% aq. NaHCO3. The solution was cooled to 0 0C and the resultant precipitate was collected to give 0.90 g of the desired compound. MS(ES+) m/z 458.4 (M+H)+.
Example 8
Preparation of 4-r2-(4-amino-1.2.5-oxadiazol-3-ylV1-ethyl-7-({r(2SV4-methyl-2- morpholinyllmethyl}oxy)-1 H-imidazor4,5-clpyridin-4-yll-2-methyl-3-butvn-2-ol
To the compound of Example 4 (0.13 g, 0.30 mmol) suspended in methanol (2 ml.) was added formaldehyde (37% in water, 0.045 ml_, 0.6 mmol). After 5 min, acetic acid (0.051 ml_, 0.9 mmol) was added following by sodium triacetoxyborohydride (0.16 g, 0.75 mmol). After 1 h. the solvent was removed in vacuo and the residue suspended in 1 N NaOH and extracted with ethyl acetate/tetrahydrofuran. The combined organic extracts were washed with brine and dried sodium sulfate. Removal of the solvent gave 0.10 g of the desired compound as a solid. MS(ES+) m/z 442 [M+H]+.
Preparation of 4-r2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({r(2R)-6-methyl-2- morpholinyllmethyl}oxy)-1 H-imidazor4,5-clpyridin-4-yll-2-methyl-3-butyn-2-ol, dihydrochloride
a) (2S)-1-({[2,4-Bis(methyloxy)phenyl]methyl}amino)-3-[(phenylmethyl)oxy]-2-propanol To a stirred solution of 2,4-dimethoxybenzylamine (1.00 g, 5.99 mmol) in MeOH
(30 ml.) at room temperature was added benzyl (S)-(+)-glycidyl ether (0.88g, 5.40 mmol). After 12 h the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (75 ml.) and washed sequentially with 1 N HCI (25 ml.) and brine (25 ml_). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure to give 1.35 g of the crude oil that was used in the next step without further purification. MS (ES+) m/z 332.2 (M+H)+.
b) N-{[2,4-Bis(methyloxy)phenyl]methyl}-2-bromo-N-{(2R)-2-hydroxy-3- [(phenylmethyl)oxy]propyl}propanamide To a stirred solution of the compound of Example 9(a) (0.50 g, 1.50 mmol) and triethylamine (0.25 ml_, 3.0 mmol) in CH2CI2 (30 ml.) at 0 0C was added 2-bromopropionyl chloride (0.280 g, 1.65 mmol). After 12 h at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (75 ml.) and washed sequentially with 1 N HCI (25 ml.) and brine (25 ml_). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure to give 0.51 g of the
crude oil that was used in the next step without further purification. MS (ES+) m/z 467.2 (M+H)+.
c) (6R)-4-{[2,4-Bis(methyloxy)phenyl]methyl}-2-methyl-6-{[(phenylmethyl)oxy]methyl}-3- morpholinone
A mixture of the compound of Example 9(b) (0.40 g, 0.86 mmol) and sodium hydride (0.067 g, 1.37 mmol) in THF (15 ml_) was stirred under nitrogen at room temperature for 16 h. The reaction was diluted with ethyl acetate (50 ml.) washed with water (3x15 ml.) and brine (20 ml_). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure to give the desired product. Preparative HPLC (YMC-Pack ODS-A column, 30 mm i.d. x 75 mm, 20 mL/min, gradient, A: water-0.1 % trifluoroacetic acid, B: acetonitrile-0.1% trifluoroacetic acid, 10-90% acetonitrile during 12 min, UV detection at 254 nm) gave 0.245 g (74% yield) of the title compound. MS (ES+) m/z 386.2 (M+H)+.
d) (6R)-4-{[2,4-Bis(methyloxy)phenyl]methyl}-2-methyl-6- {[(phenylmethyl)oxy]methyl}morpholine
A solution of the compound of Example 9(c) (0.200 g, 0.51 mmol) in THF was added LAH (1 M, 0.60 mL) at 0 0C under nitrogen. The reaction was warmed to ambient temperature and stirred for 12 h. To the reaction was added water (0.02 mL), slowly at 0 0C and 1 N NaOH (0,02 mL), the mixture was allowed to stir at room temperature for 1 h. Additional water (0.07 mL) was added and stirred for 30 min. The mixture was filtered. The solids were washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give 0.12 g of the crude oil that was used in the next step without further purification. MS (ES+) m/z 372.2 (M+H)+.
e) (6R)-2-Methyl-6-{[(phenylmethyl)oxy]methyl}morpholine
A solution of the compound of Example 9(d) (0.12 g, 0.32 mmol) in CH2CI2 (5 mL) at ambient temperature was treated with 1-chloroethyl chloroformate (0.10 mL, 1.4 mmol). The reaction was stirred at refluxed for 2 h, the solvent was removed under reduced pressure to give a crude residue. The residue was dissolved in MeOH (5 mL) and stirred at refluxed for 1 h. The solvent was removed under reduced pressure to give a crude residue 0.51 g of the crude oil that was used in the next step without further purification. MS (ES+) m/z 222.2 (M+H)+.
f) 1 ,1-Dimethylethyl (6R)-2-methyl-6-{[(phenylmethyl)oxy]methyl}-4- morpholinecarboxylate
A solution of the compound of Example 9(e) (0.20 g, 0.90 mmol) in CH3CN (5 ml.) at ambient temperature was treated with di-tert-butyl dicarbonate (0.22 g, 1.0 mmol). Removal of the organics gave the crude residue. Preparative HPLC (YMC-Pack ODS-A column, 30 mm i.d. x 75 mm, 20 ml_/min, gradient, A: water-0.1% trifluoroacetic acid, B: acetonitrile-0.1 % trifluoroacetic acid, 10-90% acetonitrile during 12 min, UV detection at 254 nm) gave 0.214 g (79% yield) of the title compound. MS (ES+) m/z 322.2 (M+H)+.
g) 1 ,1-Dimethylethyl (2R)-2-(hydroxymethyl)-6-methyl-4-morpholinecarboxylate
A solution of the compound of Example 9(f) (0.20 g, 0.62 mmol) in EtOH (5 ml.) was treated with palladium hydroxide (0.10 g). The mixture was placed in a Parr apparatus and shaken for 16 h under 55 psi of H2 atmosphere. The mixture was filtered over a pad of Celite and washed with MeOH (25 ml_). The filtrate was concentrated under reduced pressure to give 0.15 g of the crude oil that was used in the next step without further purification. MS (ES+) m/z 232.2 (M+H)+.
h) 1 ,1-Dimethylethyl (6R)-2-methyl-6-({[(4-methylphenyl)sulfonyl]oxy}methyl)-4- morpholinecarboxylate A solution of the compound of Example 9(g) (0.15 g, 0.65 mmol) in CH2CI2 (5 ml.) was added triethylamine (0.10 ml_), dimethylaminopyridine (0.02 g) and tosyl chloride (0.15 g, 0.79 mmol). After 12 h the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (75 ml.) and washed sequentially with 1 N HCI (25 ml.) and brine (25 ml_). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure to give of the crude residue. The crude residue was subjected to flash chromatography (25-100% EtOAc/Hex, silica gel) to give 0.14g of the desired compound as light yellow solid. MS (ES+) m/z 286.2 (M+H-BOC)+ , no parent ion was observed.
i) 1 ,1-Dimethylethyl (2S)-2-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1 H- imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-6-methyl-4-morpholinecarboxylate
A mixture of the compound of Example 9(h) (0.14 g, 0.36 mmol), the compound of intermediate VII (0.1 1 g, 0.40 mmol), and cesium carbonate (0.20 g, 0.55 mmol) in DMF (9 ml.) was stirred under nitrogen at 50 0C for 16 h. After allowing the reaction to cool to ambient temperature, the mixture was diluted with ethyl acetate (50 ml.) washed with
water (3x15 mL) and brine (20 ml_). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure to give the desired product. Preparative HPLC (YMC-Pack ODS-A column, 30 mm i.d. x 75 mm, 20 ml_/min, gradient, A: water-0.1 % trifluoroacetic acid, B: acetonitrile-0.1% trifluoroacetic acid, 10-90% acetonitrile during 12 min, UV detection at 254 nm) gave 0.124 g (70% yield) of the title compound as a white solid. MS (ES+) m/z 494.2 (M+H)+.
j) 1 ,1-Dimethylethyl (2S)-2-({[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3- methyl-1-butyn-1-yl)-1 H-imidazo[4,5-c]pyridin-7-yl]oxy}methyl)-6-methyl-4- morpholinecarboxylate
A thick-walled pressure vessel was charged with the compound of Example 9(i) (0.124 g, 0.25 mmol), Zn dust (0.02 g, 0.30 mmol), NaI (0.04 g, 0.27 mmol), DBU (0.20 mL, 1.32 mmol), TEA (0.15 mL, 1.07 mmol), 2-methyl-3-butyn-2-ol (0.20 mL, 2.07 mmol) and (Ph3P)4Pd (0.04 g, 0.03 mmol) in DMSO (5 mL). After purging with nitrogen for 10 min., the reaction vessel was sealed and heated at 80 0C for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford a light yellow residue. The crude residue was subjected to flash chromatography (0-10% MeOH/CHCI3, silica gel) to give an additional 0.10 g of the desired compound as light yellow solid. MS (ES+) m/z 541 (M+H)+.
k) 4-[2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-({[(2S)-6-methyl-2- morpholinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol dihydrochloride salt A solution of the compound of Example 9(j) (0.10 g, 0.18mmol) in methanol (5mL) was added 4N HCI in 1 ,4-dioxane (3.5 mL, 16.0 mmol). After 3 h at ambient temperature, the solvent was removed under reduced pressure. The residue was triturated with dichloromethane and the solid was collected by filtration to give 0.063 g of the title compound as light yellow solid. MS (ES+) m/z 441 (M+H)+.
Preparation of 4-r2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({r(2S)-4-ethyl-2- morpholinyllmethyl}oxy)-1 H-imidazor4,5-clpyridin-4-yll-2-methyl-3-butyn-2-ol
To a solution of the compound of Example 4 (0.13 g, 0.30 mmol) in MeOH (4 ml.) at 0 0C was added acetaldehyde (0.034 ml_, 0.61 mmol) and acetic acid (0.052 ml_. 0.90 mmol). This was followed by the addition of NaCNBH3 (0.048 g, 0.76 mmol). The reaction was allowed to warm to RT. After 18 h, the reaction was poured into 50% aq. NaHCOs. The solution was cooled to 0 0C and the resultant precipitate was collected to give 0.10 g of the desired compound. MS (ES+) m/z 456.4 (M+H)+.
Example 1 1 - Capsule Composition An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
Table
INGREDIENTS AMOUNTS
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3- 25 mg piperidinylmethyl]oxy}-1 H-imidazo[4,5-c]pyridin-4-yl)-2- methyl-3-butyn-2-ol
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg
Example 12 - Injectable Parenteral Composition
An injectable form for administering the present invention is produced by stirring 1.5% by weight of 4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2- thiomorpholinylmethyl]oxy}-1 H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol, in 10% by volume propylene glycol in water.
Example 13- Tablet Composition
The sucrose, calcium sulfate dihydrate and an Akt inhibitor as shown in Table Il below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.
Table Il
INGREDIENTS AMOUNTS
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2- 20 mg thiomorpholinylmethyl]oxy}-1 H-imidazo[4,5-c]pyridin-4-yl)-
2-methyl-3-butyn-2-ol, dihydrochloride calcium sulfate dehydrate 30 mg
Sucrose 4 mg
Starch 2 mg
Talc 1 mg stearic acid 0.5 mg
While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.
Claims
1. A method of treating cancer in a mammal, including a human, where the cancer is selected from: inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, osteosarcoma, giant cell tumor of bone,
Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, lmmunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer; which method comprises administering a compound selected from:
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}- 1 H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol; and
4-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2- morpholinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 where the compound is:
4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol; or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 where the compound is: 4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-thiomorpholinylmethyl]oxy}-
1 H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 where the compound is: 4-(2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1 H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol;
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 where the compound is: 4-[2-(4-amino-1 ,2,5-oxadiazol-3-yl)-1-ethyl-7-({[(2R)-6-methyl-2- morpholinyl]methyl}oxy)-1 H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol;
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 wherein the mammal is a human.
7. The method of claim 2 wherein the mammal is a human.
8. Use of a compound as described in claim 1 , in the manufacture of a medicament for use in treating a specified cancer as described in claim 1.
9. A method of treating a specified cancer, as described in claim 1 , in a mammal in need thereof, which comprises: co-administering to such mammal a therapeutically effective amount of a) a compound of claim 1 ; and b) at least one anti-neoplastic agent.
10. The method claim 9, wherein the at least one anti-neoplastic agent is selected from the group consisting essentially of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase Il inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
11. The method of claim 9, wherein the at least one anti-neoplastic agent is an anti-microtubule agent selected from diterpenoids and vinca alkaloids.
12. The method of claim 9, wherein the at least one anti-neoplastic agent is a diterpenoid.
13. The method of claim 9, wherein the at least one anti-neoplastic agent is a vinca alkaloid.
14. The method of claim 9, wherein the at least one anti-neoplastic agent is a platinum coordination complex.
15. The method of claim 9, wherein the at least one anti-neoplastic agent is paclitaxel, carboplatin, or vinorelbine.
16 The method of claim 9, wherein the at least one anti-neoplastic agent is paclitaxel.
17. The method of claim 9, wherein the at least one anti-neoplastic agent is carboplatin.
18. The method of claim 9, wherein the at least one anti-neoplastic agent is vinorelbine.
19. The method of claim 9, wherein the at least one anti-neoplatic agent is a signal transduction pathway inhibitor.
20. The method of claim 19, wherein the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase selected from the group consisting of VEGFR2, TIE2, PDGFR, BTK, IGFR-1 , TrkA, TrkB, TrkC, and c-fms.
21. The method of claim 19, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of rafk, akt, and PKC-zeta.
22. The method of claim 19, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the src family of kinases.
23. The method of claim 22, wherein the signal transduction pathway inhibitor is an inhibitor of c-src.
24. The method of claim 19, wherein the signal transduction pathway inhibitor is an inhibitor of Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase.
25. The method of claim 19, wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of PI3K.
26. The method of claim 9, wherein the at least one anti-neoplastic agent is a cell cycle signaling inhibitor.
27. The method of claim 26, wherein the cell cycle signaling inhibitor is selected from inhibitors of the group CDK2, CDK4, and CDK6.
28. A pharmaceutical combination as claimed in claim 9 for use in therapy.
29. The use of a pharmaceutical combination as claimed in claim 9 for the preparation of a medicament useful in the treatment of specified cancers.
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WO2020078865A1 (en) | 2018-10-16 | 2020-04-23 | F. Hoffmann-La Roche Ag | Use of akt inhibitors in ophthalmology |
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US8273782B2 (en) | 2007-02-07 | 2012-09-25 | Glaxosmithkline Llc | Inhibitors of Akt activity |
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US8946278B2 (en) | 2007-02-07 | 2015-02-03 | Glaxosmithkline Llc | Inhibitors of AkT activity |
US8609711B2 (en) | 2009-01-30 | 2013-12-17 | Glaxosmithkline Llc | Crystalline N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamic hydrochloride |
WO2020078865A1 (en) | 2018-10-16 | 2020-04-23 | F. Hoffmann-La Roche Ag | Use of akt inhibitors in ophthalmology |
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