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WO2006040646A1 - Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1 - Google Patents

Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1 Download PDF

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WO2006040646A1
WO2006040646A1 PCT/IB2005/003019 IB2005003019W WO2006040646A1 WO 2006040646 A1 WO2006040646 A1 WO 2006040646A1 IB 2005003019 W IB2005003019 W IB 2005003019W WO 2006040646 A1 WO2006040646 A1 WO 2006040646A1
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mmol
alkyl
added
solution
nmr
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PCT/IB2005/003019
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Quyen-Quyen Thuy Do
Chuangxing Guo
Paul Stuart Humphries
Joseph Timothy Marakovits
Liming Dong
Xinjun Hou
Mary Catherine Johnson
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Pfizer, Inc.
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Publication of WO2006040646A1 publication Critical patent/WO2006040646A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to carboxylic acids and tetrazoles that are useful in the treatment of abnormal cell growth, such as cancer, in mammals.
  • This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
  • the cell cycle represents a series of ordered processes that ultimately results in the duplication of a cell.
  • somatic cell division consists of two sequential processes - DNA replication and chromosome separation.
  • the cell spends most of its time preparing for these events in a growth cycle (interphase), which in turn consists of three subphases: initial gap (G1), synthesis (S), and secondary gap (G2).
  • G1 the cell undergoes a high rate of biosynthesis.
  • the S phase begins when DNA synthesis starts and ends when the DNA content of the nucleus has doubled.
  • the cell then enters G2, which lasts until the cell enters the final phase of division, mitosis (M).
  • the M phase begins with nuclear envelope breakdown, chromosome condensation, and the formation of two identical sets of chromosomes that are separated into two new nuclei. This is followed by cell division (cytokinesis), which results in two daughter cells, terminates the M phase, and marks the beginning of interphase for the new cells.
  • cytokinesis cell division
  • Cdc2/cyclin B a Ser/Thr kinase, regulates entry into mitosis (Nurse, Nature, 344, 503-508 (1990)).
  • Cdc2/cyclin B when activated by dephosphorylation by Cdc25, drives cells into mitosis.
  • PIN1 a peptidyl-prolyl isomerase
  • PPIase a peptidyl-prolyl isomerase
  • PIN1 a member of the parvulin family of PPIases, is an enzyme that catalyzes the cis/trans isomerization of the peptidyl- prolyl peptide bond which can be the rate-limiting step in protein folding or assembly under some circumstances (Schmid, Curr. Biol., 5, 993-994 (1995)).
  • PIN1 has been identified in various eukaryotic organisms, including plants, yeasts, insects, and mammals (Hanes et al., Yeast, 5, 55-72 (1989); Lu et al., Nature, 380, 544-547 (1996); Maleszka et al., Proc. Natl. Acad. ScL USA, 93, 447-451 (1996); and U.S. Patent No. 5,952,467). It was first isolated through its interaction with the Ser/Thr kinase NIMA, a protein essential for cell cycle progression in Aspergillus nidulans (Osmani et al., Cell, 53, 237 (1988)).
  • NIMA's phosphotransferase activity is regulated by Ser/Thr phosphorylation and thus, it has been surmised that NIMA kinase corresponds to its closest human ortholog nek2 which is activated downstream of Cdc2/cyclin B (Lu et al., Cell, 81 , 413-424 (1995)).
  • PIN1 can behave either as two independent domains connected by a flexible linker or as a single intact domain with a certain amount of hinge bending motion depending on the sequence of the peptide that binds to PIN1 (Jacobs et al., J. Bio. Chem., 278, 26174-26182 (2003)).
  • PIN1 has a putative role in neurodegeneration in Alzheimer's disease (Holzer et al., Acta Neuropathol., 104, 471-481 (2002)). PIN1 levels have been shown to be elevated in patients afflicted with Alzheimer's disease as PIN1 can bind to the tau protein that has been shown to be a major component of the intracellular neurofibrillary tangles found in Alzheimer's disease brain lesions. More specifically, PIN1 binding is elevated in the neurofibrillary tangle-rich cytoplasm of Alzheimer's disease-affected neurons and thus, is thought to be involved in the vulnerability of certain neurons to neurofibrillary degeneration.
  • PIN1 has been shown to have a variety of other functions and interactions.
  • PIN1 can interact with other cell cycle regulators (Messenger et al., J. Bio. Chem., 277, 23054-23064 (2002)) and affect the proliferation of mammalian primordial germ cells and embryonic development (Atchison et al., Development, 130, 3579-3586 (2003)).
  • PIN1 knockout mice display developmental defects during pregnancy particularly with respect to mammary epithelial duct development and gland development (WuIf et al., Breast Cancer Research, 5, 76-82 (2003)).
  • the possible role of PIN1 in mammary gland physiology is underscored by the observation that PIN1 is overexpressed in human breast cancer cells (WuIf et al., Breast Cancer Research, 5, 76-82 (2003)).
  • Inhibitors of PIN1 have been described in the literature. For example, Hennig et al. ⁇ Biochemistry, 37, 5953-5960 (1998)) report that juglone (5-hydroxy-1 ,4-naphthoquinone) selectively inhibits several parvulins, including human PIN1. Noel et al. in U.S. Patent Application no. 20030096387, using data based on the crystal structure derived from full-length human PIN1 , suggest compounds postulated to be inhibitors of PIN1. Lu et al. in International Publication No. WO 99/12962 report inhibitors that mimic the phospho-Ser/Thr moiety of the phosphoserine or phosphothreonine-proline peptidyl prolyl isomerase substrate.
  • PIN1 plays in the regulation of the cell cycle
  • additional compounds that inhibit PIN1 are needed.
  • These compounds, along with pharmaceutical compositions thereof, can serve as effective chemotherapeutic agents for the treatment of a variety of disorders characterized by inappropriate cell proliferation, including cancer, infectious diseases, and neurodegenerative brain disorders.
  • Q, Q 1 , Q 2 , Q 3 is independently selected from N, CH 2 or CH and wherein not more than two of Q are
  • T is CH, or N;
  • T 1 is O, NH, or NCH 3;
  • Y is -C(O)-, -CH 2 - or -C(O)NR 2 -, or N wherein R 2 is H or C-, to C 3 alkyl;
  • Z is H, alkyl, alkyl substituted with halogen, hydroxyl, amine, or carboxyl; or
  • X Y and Z can form a heterocyclic ring or X and Y can form a heterocyclic ring;
  • R and V are independently H, halogen, alkyl, halogenated alkyl, alkoxy, hydroxyl, NH 2 and nitrile;
  • R is optionally substituted aryl, heteroaryl or -L-aryl wherein L is O, S, vinyl,
  • R 3 is -COOH, tetrazole, CO 2 CHR 4 OCOR 4 , -CONHR 5 , OH wherein R 4 is independently selected from H or alkyl and R 5 is H, alkoxy, OH, -SO 2 -alkyl Or -SO 2 H.
  • the present invention includes the compounds of formula 1 wherein:
  • Q, Q 1 , Q 2 , Q 3 is independently selected from N, CH 2 or CH and wherein not more than two of Q are
  • T is CH, or N;
  • T is O, NH, or NCH 3;
  • X is NH, O, or NR' wherein R' can be alkyl or alkyl substituted with halogen, hydroxyl, amine, or carboxyl;
  • Y is -C(O)-, -CH 2 - or -C(O)NR 2 -, or N wherein R 2 is H or C 1 to C 3 alkyl;
  • Z is H, alkyl, alkyl substituted with halogen, hydroxyl, amine, or carboxyl;
  • R and V are independently H, halogen, alkyl, halogenated alkyl, alkoxy, hydroxyl, NH 2 and nitrile;
  • R is optionally substituted aryl, heteroaryl or -L-aryl wherein L is O, S, vinyl,
  • R 3 is -COOH, tetrazole, CO 2 CHR 4 OCOR 4 , -CONHR 5 , OH wherein R 4 is independently selected from H or alkyl and R 5 is H, alkoxy, OH, -SO 2 -alkyl Or -SO 2 H.
  • the present invention also includes the compounds of formula 2
  • X' and X" are independently selected from CR 2 or N wherein R 2 is H or C 1-3 alkyl;
  • T is CH, or N;
  • T' is O, NH or NCH 3 ;
  • Z is H, alkyl or alkyl substituted with halogen, hydroxyl, amine or carboxy;
  • R and V are independently H, halogen, alkyl, halogenated alkyl, alkoxy, hydroxyl, NH 2 and nitrile
  • R 1 is optionally substituted aryl, heteroaryl or -L-aryl wherein L is O, S, vinyl,
  • R 3 is -COOH, tetrazole, CO 2 CHR 4 OCOR 4 , -CONHR 5 , OH wherein R 4 is independently selected from H or alkyl and R 5 is H, alkoxy, OH, -SO 2 -alkyl Or -SO 2 H.
  • the present invention also includes the compounds of formula 3
  • X' and X" are independently selected from CR 2 or N wherein R 2 is H or C 1-3 alkyl; T is O, NCH 3 or N;
  • T CH or N
  • Z is H, alkyl, alkyl substituted with halogen, hydroxyl, amine, or carboxyl;
  • R and V are independently H, halogen, alkyl, halogenated alkyl, alkoxy, hydroxyl, NH 2 and nitrile
  • R 1 is optionally substituted aryl, heteroaryl or -L-aryl wherein L is O, S, vinyl,
  • R 3 is -COOH, tetrazole, CO 2 CHR 4 OCOR 4 , -CONHR 5 , OH wherein R 4 is independently selected from H or alkyl and R 5 is H, alkoxy, OH, -SO 2 -alkyl or -SO 2 H.
  • the compounds of the invention further include compounds of formula 4 having the following structure
  • T' is O, NH or NCH 3;
  • T is CH, or N;
  • E is selected from CH 2 , O, S, and NR' wherein R' can be H, alkyl or alkyl substituted with halogen, hydroxyl or nitrile;
  • R and V are independently H, halogen, alkyl, halogenated alkyl, alkoxy, hydroxyl, NH 2 and nitrile
  • R 1 is optionally substituted aryl, heteroaryl or -L-aryl wherein L is O, S, vinyl,
  • A is H, aryl, substituted aryl or A and Ar can form a bicyclic or tricyclic ring or A and Ar can form a bicyclic or tricyclic heteroaryl ring; and R 3 is -COOH, tetrazole, CO 2 CHR 4 OCOR 4 , -CONHR 5 , OH wherein R 4 is independently selected from H or alkyl and R 5 is H, alkoxy, OH, -SO 2 -alkyl Or -SO 2 H.
  • the compounds of the invention further include compounds of formula 5 having the following structure
  • T is CH, or N;
  • T is O, NH or NCH 3;
  • Z is H, alkyl, substituted alkyl
  • M, M', G and G' are independently H, halogen or M and N together form a cycloalkyl or an aromatic ring or M and M" and G and G' form a cycloalkyl or aromatic ring;
  • R and V are independently H, halogen, alkyl, halogenated alkyl, alkoxy, hydroxyl, NH 2 and nitrile
  • 1 is optionally substituted aryl, heteroaryl or -L-aryl wherein L is O, S, vinyl,
  • R 3 is -COOH, tetrazole, CO 2 CHR 4 OCOR 4 , -CONHR 5 , OH wherein R 4 is independently selected from H or alkyl and R 5 is H, alkoxy, OH, -SO 2 -alkyl Or -SO 2 H.
  • the present invention also relates to the inhibition of PIN1 and the treatment of abnormal cell growth by the inhibition of PIN1.
  • the invention provides a method of treating abnormal cell growth in a mammal, including a human, the method comprising administering to the mammal any of the pharmaceutical compositions of the invention.
  • the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvi
  • the method further comprises administering to the mammal an amount of one or more substances selected from anti-tumor agents, anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth with the compounds of the invention exemplified by formula 1 above.
  • substances include those disclosed in PCT Publication Nos. WO 00/38715, WO 00/38716, WO 00/38717, WO 00/38718, WO 00/38719, WO 00/38730, WO 00/38665, WO 00/37107 and WO 00/38786, the disclosures of which are incorporated herein by reference in their entireties.
  • anti-tumor agents include mitotic inhibitors, for example vinca alkaloid derivatives such as vinblastine vinorelbine, vindescine and vincristine; colchines allochochine, halichondrine, N- benzoyltrimethyl-methyl ether colchicinic acid, dolastatin 10, maystansine, rhizoxine, taxanes such as taxol (paclitaxel), docetaxel (Taxotere), 2'-N-[3-(dimethylamino)propyl]glutaramate (taxol derivative), thiocholchicine, trityl cysteine, teniposide, methotrexate, azathioprine, fluorouricil, cytocine arabinoside, 2'2'-difluorodeoxycytidine (gemcitabine), adriamycin and mitamycin.
  • mitotic inhibitors for example vinca alkaloid derivatives such as vinblastine vinorelbine
  • Alkylating agents for example cis- platin, carboplatin oxiplatin, iproplatin, Ethyl ester of N-acetyl-DL-sarcosyl-L-leucine (Asaley or Asalex), 1 ,4-cyclohexadiene-1 ,4-dicarbamic acid, 2,5 -bis(1-azirdinyl)-3,6-dioxo-, diethyl ester (diaziquone), 1 ,4- bis(methanesulfonyloxy)butane (bisulfan or leucosulfan) chlorozotocin, clomesone, cyanomorpholinodoxorubicin, cyclodisone, dianhydroglactitol, fluorodopan, hepsulfam, mitomycin C, hycantheonemitomycin C, mitozolamide, 1-(2-chloroethyl)-4-(3-chloro
  • DNA anti-metabolites for example 5-fluorouracil, cytosine arabinoside, hydroxyurea, 2-[(3hydroxy-2- pyrinodinyl)methylene]-hydrazinecarbothioamide, deoxyfluorouridine, 5-hydroxy-2-formylpyridine thiosemicarbazone, alpha-2'-deoxy-6-thioguanosine, aphidicolin glycinate, 5-azadeoxycytidine, beta- thioguanine deoxyriboside, cyclocytidine, guanazole, inosine glycodialdehyde, macbecin II, pyrazolimidazole, cladribine, pentostatin, thioguanine, mercaptopurine, bleomycin, 2- chlorodeoxyadenosine, inhibitors of thymidylate synthase such as raltitrexed and pemetrexed disodium, clofarabine, floxur
  • DNA/RNA antimetabolites for example, L-alanosine, 5- azacytidine, acivicin, aminopterin and derivatives thereof such as N-[2-chloro-5-[[(2, 4-diamino-5- methyl-6-quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, N-[4-[[(2, 4-diamino-5-ethyl-6- quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, N -[2-chloro-4-[[(2, 4- diaminopteridinyl)methyl]amino]benzoyl]-L-aspartic acid, soluble Baker's antifol, dichloroallyl lawsone, brequinar, ftoraf, dihydro-5-azacytidine, methotrexate, N-(phosphonoacetyl)-L-aspartic acid
  • Anti-angiogenesis agents include MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix- metalloprotienase 9) inhibitors, and COX-Il (cyclooxygenase II) inhibitors.
  • MMP-2 matrix-metalloprotienase 2
  • MMP-9 matrix- metalloprotienase 9
  • COX-Il cyclooxygenase II
  • useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
  • Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No.
  • MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases ⁇ i.e. MMP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13).
  • MMP inhibitors include AG-3340, RO 32-3555, RS 13-0830, and the following compounds: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]- propionic acid; 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclot3.2.1]octane-3- carboxylic acid hydroxyamide; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3- hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4-[4-(4-fluoro-phenoxy)- benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[[4-(4
  • signal transduction inhibitors include agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of South San Francisco, California, USA).
  • EGFR epidermal growth factor receptor
  • VEGF vascular endothelial growth factor
  • erbB2 receptor inhibitors such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of South San Francisco, California, USA).
  • EGFR inhibitors are described in, for example in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), and United States Patent 5,747,498 (issued May 5, 1998).
  • EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, New York, USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusettes).
  • VEGF inhibitors for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, California, USA), can also be combined or co-administered with the composition.
  • VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11 , 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO
  • VEGF inhibitors include IM862 (Cytran Inc. of Kirkland, Washington, USA); anti- VEGF monoclonal antibody bevacizumab (Genentech, Inc. of South San Francisco, California); and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).
  • ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), may be administered in combination with the composition.
  • Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein incorporated by reference in its entirety.
  • ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No. 60/117,341 , filed January 27, 1999, and in United States Provisional Application No. 60/117,346, filed January 27, 1999, both of which are herein incorporated by reference in their entirety.
  • antiproliferative agents include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31 , 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds disclosed and claimed in the following United States provisional patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed November 30, 1999), and 60/200834 (filed May 1 , 2000).
  • Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference in their entirety.
  • compositions of the invention can also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors.
  • agents capable of enhancing antitumor immune responses such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors.
  • CTLA4 cytotoxic lymphocite antigen 4
  • anti-proliferative agents such as other farnesyl protein transferase inhibitors.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
  • alkyl as used herein, unless otherwise indicated, includes saturated and unsaturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • alkoxy as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
  • Me means methyl
  • Et means ethyl
  • Ac means acetyl
  • cycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms.
  • exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • 4 to 10 membered heterocyclic includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl.
  • Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, ind
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1 -yl (N-attached) or imidazol-3-yl (C-attached).
  • the 4 to 10 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
  • heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl.
  • Other illustrative examples of 4 to 10 membered heterocyclic are derived from, but not limited to, the following:
  • phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula L
  • the compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acid ' s that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula I are those that form non-toxic acid addition salts, Le 1 , salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl
  • Certain compounds of formula I may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula 1, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula I, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • This invention also encompasses pharmaceutical compositions containing and methods of treating abnormal cell growth through administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula I.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety. Oral Administration
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • compositions include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties. Parenteral Administration
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • Topical Administration The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free ⁇ e.g. PowderjectTM, BiojectTM, etc.) injection.
  • electroporation iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free ⁇ e.g. PowderjectTM, BiojectTM, etc.
  • iontophoresis iontophoresis
  • phonophoresis phonophoresis
  • sonophoresis and microneedle or needle-free ⁇ e.g. PowderjectTM, BiojectTM, etc.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ L to 100 ⁇ L
  • a typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing a desired mount of the compound of the invention.
  • the overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day. Rectal/lntravaginal Administration
  • Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable [e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • Other Technologies Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties. Kit-of-Parts
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically includes directions for administration and may be provided with a memory aid.
  • the compounds of the invention can be synthesized by the following reaction schemes. Starting materials, the synthesis of which is not specifically described above, are either commercially available or can be prepared using methods well known to those of skill in the art.
  • pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable and ambient pressure, i.e. about 1 atmosphere, is preferred as a matter od convienence.
  • the examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.
  • molecules with a single chiral center unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
  • HPLC chromatography is referred to in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows.
  • the column used is a ZORBAX RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter.
  • the samples are run on a Hewlett Packard- 1100 systemA gradient solvent method is used running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes.
  • the system then proceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes.
  • the flow rate over this period is a constant 3 ml / minute.
  • N,O-bis(trimethylsilyl)acetamide (0.223 g; 1.0 mmole) was added to a solution of amino acid 18a (0.112 g; 0.5 mmole) in NMP (1.0 mL), and the mixture was allowed to stir at room temperature overnight.
  • Maleic anhydride (0.05 g; 0.51 mmole) was added, and the reaction was allowed to stir at room temperature.
  • An aqueous HCI solution (5.0 equiv) was added, and the mixture was allowed to stir. The solvents were removed to afford a white solid (0.15 g; 98 %).
  • 2-Amino-3-(6-fluoro-1H-benzoimidazol-2-yl)-propionic acid 18a (0.263 g; 0.93 mmole) was dissolved in water (10 mL), and sodium carbonate (0.17 g; 1.60 mmole) and 1 ,3-dioxo-1 ,3-dihydro- benzo[f]isoindole-2-carboxylic acid ethyl ester (0.275 g; 1.02 mmole; prepared from the reaction of 2,3-naphthalenedicarboximide with ethyl chloroformate) were added. The reaction was briefly heated with a heat gun and then allowed to stir at room temperature overnight.
  • the yellow syrup (90a, 3.9g) was dissolved in a co-solvent of chloroform (150mL) and isopropanol (45mL). With stirring, silica gel powder (3Og) was added, followed by slow addition of NaBH 4 (2.59g, 68.5mmol). The slurry was stirred for 2h, acetic acid (3mL) was then added drop-wise. All solid was filtered off. The filtrate was washed with water (3x50mL), dried (Na 2 SO 4 ) and concentrated. The residue was purified with silica gel flash column chromatography (30% EtOAc in hexanes), affording the title compound (90b, 3g, 83% yield) as an oil.
  • Example 132 Ethyl (2S)-2-[(6-fluoro-1H-indol-2-yl)methyl]-5-(6-methoxy-3-oxo-2,3-dihydro-1H- inden-1 -yl)-4-oxopentanoate
  • 155c was synthesized from ethyl indole-2-carboxylate (0.51 g, 2.71 mmol) and aliyl iodide.
  • the amine 103d (0.10g, 0.41 mmol) and acid 155b (0.078g, 0.41 mmol) were dissolved in DMF (1.5 mL ).
  • Diisopropylamine (0.14 mL , 0.82 mmol) was added, and the reaction cooled to 0°C.
  • HATU (0.16g, 0.41 mmol) was added, and the reaction stirred at 0°C two hours, then warmed to ambient temperature.
  • the DMF was removed in vacuo, and the residue was dissolved in EtOAc/ sat. NaHCO 3 .
  • the organic layer was separated, washed successively with water and brine, dried (MgSO 4 ), and concentrated.
  • Example 159 Ethyl 3-(6-fluoro-1H-indol-2-yl)- ⁇ /-[(1-isopropyl-1H-indol-2-yl)carbonyl]-D- alaninate
  • 6-Methoxy-2H-chromene-3-carboxylic acid (2.82g, 13.70 mmol) was dissolved in CH 2 CI 2 (70 mL ). Oxalyl chloride (1.35 mL , 15.07 mmol) was added followed by a drop of DMF.
  • Amine salt 174a (2.03g, 11.42 mmol) was dissolved in MeOH (30 mL) and cooled to 0°C. Dry ammonia gas was bubbled through the solution for 1 hour. The flask was capped with a rubber suba- seal septa and secured with copper wire. The reaction warmed to room temperature and stirred overnight. A second charge of ammonia gas was performed as before, and the reaction stirred an additional 2 days. The solvent was removed in vacuo, and the material used without further purification.
  • the resulting amide was suspended in CH 2 CI 2 (75 mL) and treated with triethylamine (1.91 mL, 13.70 mmol) and 174b (6-methoxy-2H-chromene-3-carbonyl chloride, 3.08g, 13.70 mmol), stirring overnight.
  • the reaction was poured into saturated NaHCO 3 solution, and the organic phase was separated, washed successively with water and brine, dried (MgSO 4 ), and concentrated.
  • Nitrile 174f (0.12g, 0.31 mmol), sodium azide (0.06g, 0.93 mmol), and triethylamine hydrochloride (0.064g, 0.47 mmol) were suspended in N-methylpyrrolidinone and heated to 150 °C for 5 hours. A few drops of cone. HCI were added to the reaction, and the solvent evacuated to dryness. The crude product was purified by preparative HPLC (acetonitrile/water).
  • 3-(6-fluoro-1 H-benzimidazol-2-yl)-D-alanine trifluoroacetate 18a was dissolved in anhydrous NMP, and ⁇ /,O-bis(trimethylsilyl)acetamide (2.2 equivalents) and diisopropylethylamine were added. The reaction mixture was allowed to stir for 16h at room temperature. 4,5-Dichlorophthalic anhydride was added, and the reaction was allowed to stir at room temperature. Water (20 ml_) and aqueous HCI solution (4.0 M, 40PDL) were added. The reaction was filtered, and the crude material was dried in a vacuum oven.
  • the reaction was again cooled to -30°C, and solid paraformaldehyde (8.25g, 274 mmol) which had been dried under vacuum (> 0.5 mm Hg) was added in one portion.
  • the reaction was warmed to room temperature and stirred overnight.
  • the reaction was quenched with 10% NaHCO 3 (10 mL), and the solvent removed in vacuo.
  • the residue was dissolved in EtOAc/10% NaHCO 3 .
  • the organic phase was separated, washed sequentially with water and brine, dried (MgSO 4 ), and the solvent removed.

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Abstract

La présente invention a trait à des composés de formule (1), dans laquelle les variables sont tels que définis dans la description et à des sels et solvates pharmaceutiquement acceptables de ceux-ci. L'invention a également trait à des procédés de traitement de croissance cellulaire anormale chez des mammifères par l'administration des composés de formule (1) et à des compositions pharmaceutiques qui contiennent les composés de formule (1) pour le traitement de tels troubles. L'invention a trait en outre à des procédés de préparation des composés de formule (1).
PCT/IB2005/003019 2004-10-14 2005-10-03 Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1 WO2006040646A1 (fr)

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KR20200037363A (ko) 2017-08-07 2020-04-08 고쿠리츠다이가쿠호진 히로시마다이가쿠 신규 아미드계 화합물, 및 이것을 사용한 Pin1 저해제, 염증성 질환의 치료제 및 암의 치료제
CN111182896A (zh) * 2017-08-07 2020-05-19 国立大学法人广岛大学 脂肪性肝病的治疗剂以及肥胖症的治疗剂
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JP7189203B2 (ja) 2017-08-24 2022-12-13 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ボロン酸誘導体
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CN112601744B (zh) * 2018-07-05 2024-03-29 拜耳公司 作为抗菌剂的取代的噻吩甲酰胺及类似物
CN112601744A (zh) * 2018-07-05 2021-04-02 拜耳公司 作为抗菌剂的取代的噻吩甲酰胺及类似物
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CN110862374A (zh) * 2019-12-03 2020-03-06 临沂大学 一种萘酰亚胺苯并咪唑类化合物及其制备方法与应用
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JP2023510220A (ja) * 2020-01-17 2023-03-13 テグ－キョンプク メディカル イノベーション ファウンデーション 新規化合物、その調製方法、及びその使用
WO2021182457A1 (fr) 2020-03-12 2021-09-16 国立大学法人広島大学 Nouveau composé d'acide 3,5-diaminobenzoïque, et inhibiteur de la pin1 et agent thérapeutique pour maladies inflammatoires le mettant en œuvre
KR20220152535A (ko) 2020-03-12 2022-11-16 고쿠리츠다이가쿠호진 히로시마다이가쿠 신규 3,5-디아미노벤조산계 화합물, 및 이것을 사용한 Pin1 저해제 및 염증성 질환의 치료제
WO2022032179A1 (fr) * 2020-08-07 2022-02-10 The Regents Of The University Of California Inhibiteurs de pin1 et utilisations associées
WO2022107745A1 (fr) 2020-11-17 2022-05-27 国立大学法人広島大学 Agent thérapeutique ou agent prophylactique contre la covid-19
KR20230110723A (ko) 2020-11-17 2023-07-25 고쿠리츠다이가쿠호진 히로시마다이가쿠 Covid-19의 치료제 또는 예방제
WO2022187206A1 (fr) * 2021-03-01 2022-09-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Ligands à double cible des récepteurs des opiacés mu et dopaminergiques d3 ; préparation et utilisation correspondants

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