WO2004087720A1 - Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1) - Google Patents

Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1) Download PDF

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WO2004087720A1
WO2004087720A1 PCT/IB2004/000574 IB2004000574W WO2004087720A1 WO 2004087720 A1 WO2004087720 A1 WO 2004087720A1 IB 2004000574 W IB2004000574 W IB 2004000574W WO 2004087720 A1 WO2004087720 A1 WO 2004087720A1
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mmol
aryl
alkyl
membered
solution
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PCT/IB2004/000574
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Chuangxing Guo
Eleanor Ferronyalka Dagostino
Liming Dong
Xinjun Hou
Stephen Anthony Margosiak
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Pfizer Inc.
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Priority to EP04713610A priority Critical patent/EP1603926A1/fr
Priority to MXPA05009241A priority patent/MXPA05009241A/es
Priority to CA002517281A priority patent/CA2517281A1/fr
Priority to JP2006506287A priority patent/JP2006523669A/ja
Priority to BRPI0408477-2A priority patent/BRPI0408477A/pt
Publication of WO2004087720A1 publication Critical patent/WO2004087720A1/fr

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Definitions

  • This invention is directed to phosphate/sulfate ester compounds that modulate and/or inhibit the activity of protein interacting NIMA (PIN1), and to pharmaceutical compositions containing such compounds.
  • the invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating disorders characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders, by administering effective amounts of such compounds.
  • PIN1 is a member of the parvulin family of peptidyl-prolyl isomerases (PPIase) and catalyzes rotation about the peptide bond preceding a proline residue.
  • PPIase peptidyl-prolyl isomerases
  • PIN1 is a regulator of Cdc25, which depho ⁇ phorylates Cdc2/cyclinB to drive cells into mitosis.
  • PIN1 has been identified in all eukaiyotic organisms where examined, including plants, yeast, insects, and mammals.
  • the yeast (£ss1) and Dorosophilia (dodo) PIN1 orthologues have high identity to human-expressed sequence tags, which ultimately led to the cloning of the human docfo gene called PINL
  • the Dorosophilia dodo gene is reported to be 45% identical to the yeast gene, Esss
  • NIMA is a kinase that drives cells into mitosis and is reported to be negatively regulated by PIN1. Depletion of NIMA in A. nidulans cells is reported to lead to cell cycle arrest in G 2 while overexpression is reported to promote premature mitosis. SerThr kinase Cdc2/cyclin B may be the analogous NIMA kinase in human cells although another NIMA-like pathway in human cells is postulated to exist.
  • PIN1 activity is reported to result in dramatic morphological cellular phenotypes. For example, overexpression of PIN1 in Hela cells was reported to cause a G 2 arrest while depletion caused mitotic arrest— the opposite phenotypes observed with NIMA modulation. Additionally, decreasing PIN1 protein expression by full-length antisense expression has been reported to cause cells to progress into mitosis prematurely, to contain aberrant nuclei due to premature chromosome condensation and to induce apoptosis. These data indicate that PI 1 is a negative regulator of mitosis through interactions with a mammalian functional homoiog of NIMA and is required for progression through mitosis. Further, depletion of PIN1 is also postulated to play a role in Alzheimer's disease. Lu et al., Nature, 380, 544-547 (1996).
  • PIN1 has been reported to interact with mitotic proteins also recognized by the MPM- 2 antibody.
  • the MPM-2 monoclonal antibody recognizes a phospho-Ser/Thr-Pro epitope on about approximately 50 proteins associated with mitosis, including important mitotic regulators, such as Cdc25, Wee1, Cdc27, Map 4, and NIMA. See, e.g., Davis et al., Proc. Natl. Acad. Sci. U.S.A. 80, 2926 (1983).
  • PIN1 has also been reported to interact with important upstream regulators of Cdc2/cyclin B, including Cdc25 and its known regulator, PlxL See Shen et al., Genes Dev. 12, 706 (1998).
  • PIN1 due to its enzymatic action, may remove Cdc25 and Plx1 from play by causing their degradation within the cell.
  • PIN1 biological function of PIN1 depends on a functional PPIase active site. Lu et al., Science, 283, 1325-1328 (1999). Studies also indicate that PIN1 recognizes its substrates (mitosis-specific phosphoproteins) through the WW domain.
  • the WW domain is a protein recognition motif that is prevalent throughout biology. However, the PIN1 WW domain is unique in that it requires its ligand protein to contain a phosphorylated serine. As with the PPIase domain, a functional WW domain is reported to be essential for biological functions of PINL This is consistent with the model where PIN1 recognizes its substrates through the WW domain followed by completion of its essential catalytic role.
  • Full-length PIN1 protein and the nucleotide sequence encoding full-length PIN1 are disclosed in U.S. Patent Nos. 5,952,467 and 5,972,697. Additionally, sequences for PIN1 have been deposited in GenBank under accession numbers NM006221 (mRNA) and S68520 (protein). The mRNA sequence for dodo is deposited in GenBank under accession number U35140. Mouse PI 1 mRNA sequence is deposited in GenBank under accession number NM023371.
  • Lu et al. International Publication No. WO 01/38878
  • Wulf et al. EMBO J. 20, 3459- 3472 (2001)
  • PIN1 is upregulated in human tumors and is a biomarker for cell proliferation.
  • Inhibitors of PI 1 have been described in the literature. For example, Hennig et al.
  • juglone (5-hydroxy-1 ,4-naphthoquinone) selectively inhibits several parvulins, including human PINL Noel et al. in U.S. Patent Application No. 20010016346, using data based on the crystal structure derived from full-length human PIN1, disclose compounds postulated to be inhibitors of PINL Lu et al. in International Publication No. WO 99/12962 report inhibitors that mimic the phospho-Ser/Thr moiety of the phosphoserine or phosphothreonine-proiine 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 hypertension, inappropriate cell proliferation, including cancer, infectious diseases, and neurodegenerative brain disorders.
  • the invention provides such compounds that inhibit PINL Summarv Of The Invention
  • an objective of the invention is to discover compounds and methods for modulating or inhibiting PINL
  • Another objective of the invention is to provide compounds and methods for modulating or inhibiting PIN1 that can be used in pharmaceutical compositions for the treatment of disorders characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders.
  • compositions containing such agents are useful in treating diseases characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders.
  • the invention relates to compounds of the Formula I:
  • n 1 or 2;
  • R 1 is a C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 3 -C 10 aryl, or 4-10 membered heteroaryl group, wherein R 1 is unsubstituted or substituted with 1 to 4 R 10 groups;
  • R 2 is -S(0) 2 OH, -S(0) 2 NR d R e , or -P(0)(OR 4 ) 2 , wherein R 4 is an H, C r C 10 -alkyl, C 6 -C 0 aryl, or -CH 2 -0-C(0)R e CH 3 group, R d and R e are each independently an H or C r C 6 alkyl group, and R 4 is unsubstituted or substituted with 1 to 4 R 10 groups; and
  • R 3 is OH, C r C 7 -alkyl, C r C 7 -alkoxyl, C 6 -C 10 aryl, 4-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, -NH(R 5 ), or -N(R 5 ) 2 group, wherein R 5 is independently selected from H, C r C 7 alkyl, C 6 -C 10 aryl, or
  • ring B is a 5- or 6-membered heterocycloalkyl group
  • Z is a divalent C(0)Z ⁇ heteroaryl or heterocycloalkyl group wherein Z' is a divalent 0, S, NH, N(CH 3 ), C0 2 , or CH 2
  • the invention relates to compounds of Formula I, wherein n is 1 or 2; A is a divalent -NH-Y-, -NR d (CH 2 ) r Y-, or -0-Y-, and Y is C(0) or S(0) 2 ; X is a direct bond, CH 2 , O, or S; R 1 is a C 6 -C 10 aryl or 4-10 membered heteroaryl group unsubstituted or substituted with 1 to 4 R 10 groups; R 2 is -S(0) 2 OH, or -P(0)(0R 4 ) 2 , wherein R 4 is an H, C C ⁇ 0 alkyl, or C 6 -C 10 aryl group, and is unsubstituted or substituted with 1 to 4 R 10 groups; and R 3 is a C 6 -C ⁇ 0 aryl, 4-10 membered heteroaryl, -NH(C 6 H 5 ), or
  • ring B is a 5- or 6-membered heterocycloalkyl group
  • Z is a divalent C(0)Z', heteroaryl or heterocycloalkyl group wherein Z' is a divalent O, S, NH, N(CH 3 ), C0 2 , or CH 2
  • R 6 is H or a C ⁇ -C 10 alkyl group, wherein R 3 , B, and R 6 is unsubstituted or substituted with 1 to 4 R 10 groups; and wherein R 10 is as defined above.
  • the invention relates to compounds of Formula I, wherein n is 1 ; A is a divalent -NH-Y- or -0-Y-, wherein Y is C(O); X is a direct bond, CH 2 , or O; R 1 is a C 6 -C 10 aryl group unsubstituted or substituted with 1 to 4 R 10 groups; R 2 is -P(0)(OR 4 ) 2 , wherein R 4 is an H, CrCio alkyl, or C 6 -C ⁇ 0 aryl group, and is unsubstituted or substituted with 1 to 4 R 1 ⁇ groups; and R 3 is a C 6 -C 10 aryl, 4-10 membered heteroaryl, or
  • ring B is an unsubstituted 6-membered heterocycloalkyl
  • Z a divalent C(0)Z'
  • ⁇ is a divalent
  • R 6 is a CrCio alkyl group, wherein R 3 , B and R 6 are unsubstituted or substituted with 1 to 4 R 10 groups; and wherein R 10 is as defined above.
  • the invention relates to compounds of Formula
  • R 1 is a C B - C 0 aryl group unsubstituted or substituted with 1 to 4 R 10 groups
  • R 2 is -P(0)(0R 4 ) 2 , wherein R 4 is an H or a C 1 -C 10 alkyl group that is unsubstituted or substituted with 1 to 4 R 10 groups
  • R 3 is a C 6 -C 10 aryl or 4-10 membered heteroaryl group unsubstituted or substituted with 1 to 4 R 0 groups; and wherein R 10 is as defined above.
  • the invention includes compounds, and pharmaceutically acceptable salts thereof, selected from the following group: -7-
  • the invention also relates to a method of inhibiting PIN1 by administering a compound of Formula I or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof.
  • the invention also relates to pharmaceutical compositions, each comprising a therapeutically effective amount of an agent selected from compounds, prodrugs, metabolites, and salts of compounds of Formula I, and a pharmaceutically acceptable carrier or vehicle for such agent.
  • the invention further provides methods of treating mammalian disease conditions mediated by PIN1 activity, by administering to a mammal in need thereof a therapeutically effective amount of a compound, prodrug, active metabolite or salt of a compound of Formula I.
  • the mammalian disease conditions to be treated according to the invention are associated with hypertension, inappropriate cell proliferation (e.g., cancer), infectious diseases (e.g., bacterial and fungal infections), and neurodegenerative brain disorders (e.g., Alzheimer's disease).
  • the compounds of Formula I are useful for modulating or inhibiting PINL More particularly, the compounds are useful as modulating or inhibiting the activity of PIN 1, thus providing treatments for hypertension, infectious diseases, neurodegenerative disorders, and cancer or other diseases associated with cellular proliferation.
  • the terms "comprising” and “including” are used herein in their open, non-limiting sense.
  • abnormal cell proliferation includes diseases or disorders associated with uncontrolled or abnormal cellular proliferation.
  • diseases and disorders include, but are not limited to, the following: a variety of cancers, 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 lymph
  • HIV human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus
  • autoimmune diseases including, but not limited to, systemic lupus erythematosus rheumatoid arthritis, psoriasis, autoimmune mediated glomerulonephritis inflammatory bowel disease and autoimmune diabetes mellitus
  • neurodegenerative disorders including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration
  • myelodysplastic syndromes aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including, but not limited to, chronic anemia and aplastic
  • alkyl refers to a straight- or branched-chain, saturated or partially unsaturated, alkyl group having one to twelve carbon atoms. Preferred alkyl groups have from 1-10, and more preferably from 1-7, carbon atoms. Exemplary alkyl groups include methyl (Me, which also may be structurally depicted by ), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like.
  • the term “lower alkyl” designates an alkyl having from 1 to 6 carbon atoms (a C C 6 alkyl).
  • aryl refers to a monocyclic, or fused or spiro polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having from three to twelve ring atoms per ring, preferably 6-10 ring atoms atoms and more preferably 5-7 ring atoms.
  • aryl groups include the following moieties:
  • heteroaryl refers to a monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from three to twelve ring atoms per ring, preferably 4-10 ring atoms and more preferably 5-7 ring atoms.
  • aryl groups include the following moieties:
  • cycloalkyl refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle having from three to twelve ring atoms per ring, preferably 3-10 carbon atoms and more preferably 5-7 carbon atoms.
  • Illustrative examples of cycloalkyl groups include the following moieties:
  • heterocycloalkyl refers to a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated and has from three to twelve ring atoms per ring selected from C atoms and N, O, and S heteroatoms, preferably 4-10 ring atoms and more preferably 5-7 ring atoms.
  • ring atoms selected from C atoms and N, O, and S heteroatoms, preferably 4-10 ring atoms and more preferably 5-7 ring atoms.
  • Illustrative examples of heterocycloalkyl groups include:
  • alkoxy refers to -O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like.
  • halogen represents chlorine, fluorine, bromine or iodine.
  • halo represents chloro, fluoro, bromo or iodo.
  • haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifiuoromethyl, 1- chloro-2-fluoroethyl and the like.
  • Heteroalkyl is an alkyl group (as defined herein) wherein at least one of the carbon atoms is replaced with a heteroatom. Preferred heteroatoms are nitrogen, oxygen, sulfur, and halogen. A heteroatom may, but typically does not, have the same number of valence sites as carbon.
  • the number of hydrogens bonded to the heteroatom may need to be increased or decreased to match the number of valence sites of the heteroatom. For instance, if carbon (valence of four) is replaced with nitrogen (valence of three), then one of the hydrogens formerly attached to the replaced carbon must be deleted. Likewise, if carbon is replaced with halogen (valence of one), then three (i.e., all) of the hydrogens formerly bonded to the replaced carbon must be deleted.
  • trifiuoromethyl is a heteroalkyl group wherein the three methyl groups of a t-butyl group are replaced by fluorine.
  • Preferred heteroalkyls of the invention have 2 to 10 member atoms, including both heteroatoms and carbon atoms.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • the compounds of the invention may exhibit the phenomenon of tautomerism. While Formula I cannot expressly depict all possible taufomeric forms, it is to be understood that Formulas I is intended to represent any tautomeric form of the depicted compound and are not to be limited merely to a specific compound form depicted by the formula drawings.
  • the compounds of Formula I may have one or more asymmetric centers designated by an asterisk as shown below in Formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule.
  • the compounds of Formula I may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
  • the inventive compounds that are optically active are used in optically pure form.
  • ' is used in structural formulae herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess (“d.e.”)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
  • Formula I is intended to cover solvated as sell as unsolvated forms of the identified structures.
  • Formula I includes compounds of the indicated structure in both hydrated and non-hydrated forms.
  • Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites.
  • a pharmaceutically acceptable prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • a pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof.
  • Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Che ., 40, 2011-2016 (1997); Shan, et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
  • a pharmaceutically acceptable salt is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as gluc ⁇ ronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochlor
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • Lu et al. International Publication No. WO 01/38878; incorporated herein by reference in its entirety disclose that PI 1 is overexpressed in a variety of cancers, including breast, colon, and prostate. Additionally, the authors disclose that P1 1 is overexpressed in proliferating cells.
  • the agents of the invention would have use for treating a variety of cell proliferative diseases associated with overexpression of PIN1.
  • Therapeutically effective amounts of the agents of the invention may be used to treat diseases mediated by modulation or regulation of PINL
  • An "effective amount" is intended to mean that amount of an agent that, when administered to a mammal in need of such treatment, is sufficient to effect treatment for a disease modulated or inhibited by the activity of PINL
  • a therapeutically effective amount of a compound of the Formula I, salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of PIN1 such that a disease condition which is mediated by that activity is reduced or alleviated.
  • treating refers to:
  • compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I and an inert, pharmaceutically acceptable carrier or diluent.
  • efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulation of PINL
  • efficacious levels is meant levels in which the effects of PIN1 activity are, at a minimum, regulated.
  • An inventive agent can be administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • a variety of pharmaceutical forms can be employed.
  • a solid carrier used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
  • a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid.
  • an organic or inorganic acid such as 0.3M solution of succinic acid or citric acid.
  • the agent may be dissolved in a suitable cosolvent or combinations of cosolvents.
  • suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the like in concentrations ranging from 0-60% of the total volume.
  • a compound of Formula I is dissolved in DMSO and diluted with water.
  • compositions may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution. It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated.
  • compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations, which can be used pharmaceutically.
  • the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient io be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • co-solvent component may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions of the invention may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible sails may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Sails lend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
  • inventive agents may be prepared using the reaction routes and synthesis schemes as described below, employing the general techniques known in the art using starting materials that are readily available.
  • the preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other PIN1 inhibitors of the invention.
  • the synthesis of non-exempiified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • other reactions disclosed herein or generally known in the art will be recognized as having applicability for preparing other compounds of the invention. Examples
  • NMR spectra were recorded on a Bruker or Varian instrument operating at 300 MHz and 13 C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as CDCl 3 solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm and 77.00 ppm) or CD 3 OD (3.4 and 4.8 ppm and 49.3 ppm), or internally tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents were used as needed.
  • Mass spectrometry was conducted with various techniques. Mass spectra were obtained using liquid chromatograph electrospray ionization mass spectrometry, MS (ESP). Matrix- Assisted Laser Desorption/lonization (MALDI) Fourier Transform Mass Spectrometry was performed on an lonSpec FTMS mass spectrometer. The following compounds of the invention were made according to the general synthetic pathways shown in Schemes 1-10 and the detailed experimental procedures that follow thereof.
  • Example 3a 1-(2-Phenyl-1-sulfooxymethyl-ethylsulfamoyl)-pyrrolidine-2S-carboxylic acid benzyl ester
  • Example 3b1 1-(2-Phenyl-1-sulfooxymethyl-ethylsulfamoyl)-piperidine-2S-carboxylic acid 4- phenyl-butyl ester
  • Example 3b3 1-(2-Phenyl-1-sulfooxymethyI-ethylsulfamoyl)-piperidine-2S-carboxylic acid 4- phenyl-1 -(3-phenyl-propyl)-butyl ester
  • Example 3b4 3,3-Dimethyl-1-(2-phenyl-1-sulfooxymethyl-ethylsulfamoyl)-piperidine-2R- carboxylic acid benzyl ester
  • Example 555 Phosphoric acid mono- ⁇ (R)-2-[(S)-2-(5-ben2yl-[1,3 l 43o ⁇ adia2 ⁇ l-2-yl)-p!peridine- 1 -suIfonylamino3-3-phenyl-propyl ⁇ ester
  • amine 8b 0.265 g, 1 mmol was added to a methylene chloride solution (5 mL) of phosgene (0.544 mL, 20% in toluene, 1.1 mmol) and triethylamine (0.5 mL). The solution was slowly warmed up to 25 °C over 30 min, and was cooled to 0 °C again. The pipecolate ester 6b (0.05 g, 0.143 mmol) was introduced at once. The mixture was stirred at 25 °C for 20 h, diluted with EtOAc (50 mL), washed with concentrated NaHCOs solution (1x50 mL), dried (Na 2 S0 4 ) and concentrated.
  • Example 14b 1-(2-Phenyl-1-sulfooxymethyl-ethylcarbamoyi)-piperidine-2-carboxylic acid 3- (7-nitro-benzo[1 ,2,5]oxadiazol-4-ylamino)-propyl ester
  • Example 14a 1-(2-Phenyl-1-sulfooxymethyl-ethylcarbamoyl)-piperidine-2S-carboxylic acid 4- phenyl-1-(3-phenyl-propyI)-butyl ester
  • Example 16a 1-(2-Phenyl-1-phosphonooxymethyI-ethylcarbamoyl)-piperidine-2S-carboxylic acid 4-phenyl-1-(3-phenyl-propyl)-butyl ester
  • Example 23d Phosphoric acid mono- ⁇ 2-p-(3,5-dimethoj y-phenyl)-ureido3-3-phenyl-propyl ⁇ ester
  • Example 25-1 Phosphoric acid mono- ⁇ 3-phen I-2- (1-phenyl-methanoyl)-®mino3-propylJ ester
  • E ⁇ ampl ⁇ 25-2' Phosphoric acid mono-(2- ⁇ [1-(1-oxo-foenzo[bJthiophen-2-yl)- aminoH-p e ⁇ yi ⁇ propyl) ester
  • Example 25-4 Phosphoric acid mono-[2-( ⁇ 1-[5-(3,5-dichloro-pheno ⁇ y)-furan-2-yl]-methanoyl ⁇ - amino)-3-ph ⁇ nyl-propyl] ⁇ ter
  • Example 25-6 Phosphoric acid mono-(2- ⁇
  • Example 25-8 Phosphoric acid mono-(2- ⁇ 1-(3-chloro-phenyl)-methanoyl3-amino ⁇ -3-phen l- propyl) ester
  • Example 25-11 Phosphoric acid mon ⁇ - ⁇ 3-phenyl-2-j;(1-quino ali ⁇ -2-yl-methanoyl)-amino3- propyl ⁇ ester
  • Example 25-13 Phosphoric acid mono-(2- ⁇ [1-(2-hydroxy-phenyl)-methanoyl]-amino ⁇ -3- phenyl-propyl) ester
  • Example 25-16 Phosphoric acid mono-[(R)-2-(2,2-dimethyl-propanoylamino)-3-phenyl-propyl] ester
  • Example 25-19 Phosphoric acid mono- ⁇ 2-I(1-benzofuran-2-yl-methanoyl)-amino3-3-phenyl- propyl ⁇ ⁇ ster
  • Example 25-22 Phosphoric acid mono-(2- ⁇ [1-(3-hydroxy-naphthalen-2-yI)-methanoyl]-amino ⁇ - 3-phenyl-propyl) ester
  • Example 25-23 Phosphoric acid mono- ⁇ (R)-2-[(1H-benzoimidazole-5-carbonyl)-amino]-3- phenyl-propyl ⁇ ester
  • Example 25-26 Phosphoric acid mono- ⁇ 2-[(1-benzo[b]thiophen-2-yl-methanoyl)-amino]-3- phenyl-propyl ⁇ ester
  • Example 25-28 Phosphoric acid mono- ⁇ 3-(3-fluoro-phenyl)-2-[(1-naphthalen-2-yl-methanoyl)- amino]-propyl ⁇ ester
  • Example 25-30 Phosphoric acid mono-[(R)-2-(2,2-dimethyl-propanoylamino)-3-(3-fluoro- phenyl)-propyl] ester
  • Example 25-31 Phosphoric acid mono-[(R)-2- ⁇ [1-(1-bromo-naphthalen-2-yl)-methanoyl]- amino ⁇ -3-(3-fluoro-phenyl)-propyl] ester
  • Example 25-32 Phosphoric acid mono-((R)-3-(3-fluoro-phenyl)-2- ⁇ [1-(6-methoxy-naphthalen- 2-yl)-methanoyl]-amino ⁇ -propyl) ester
  • Example 25-33 Phosphoric acid mono-[(R)-2- ⁇ [1-(diethylamino-oxo-2H-chromen-3-yl)- methanoyl]-amino ⁇ -3-(3-fluoro-phenyl)-propyl] ester
  • Example 25-34 Phosphoric acid mono- ⁇ 2- [1-(1-bromo-naphthalen-2-yI)-methano l3- aminoJ-3-m-tolyl-propyl) ester
  • Example 25-35 Phosphoric acid mono-((R)-2- ⁇ [1-(6-methoxy-naphthalen-2-yl)-methanoyl]- amino ⁇ -3-m-tolyl-propyl) ester
  • Example 25-36 Phosphoric acid mono- ⁇ 2-[(1-n ⁇ phthalen-2-yl-methanoyI)-arnino3-3-m-tolyl- propyl] ester
  • Example 25-30 Phosphoric acid mono- ⁇ 2-[(1-naphthalen-2-yl-methanoyI)-aminoJ-3-pyridin-3- yl-propyl ⁇ ester
  • Example 42 Phosphoric acid mono-[(R)-2-(5-dimethylamino-naphthalene-1-sulfonylamino)-3- (3-fluoro-phenyI)-propyl] ester
  • D-3-Fluorophenylalanine (7.98 g, 43.8 mmol) was dissolved in 1 M sulfuric acid solution (140 mL). To the solution at 0 °C was slowly added 6 M NaN0 2 solution (36 mL, 216 mmol) and 3.2 M sulfuric acid (36 mL). The mixture was stirred at 0 °C for 3 h and then at 25 °C for 0.5 h. The solution was extracted with EtOAc (7x75 mL). The combined organic layers were dried and concentrated. Recrystalization from EtOAc/hexanes afforded 5.36 g (67% yield) of the compound ⁇ - hydroxycarboxylic acid.
  • Example 54 Phosphoric acid mono- ⁇ 2-[(1-benso[b3 hiophen-2-yI-methanoyl)-amino3-3-(3- fIuoro-phenyl)-propyl] ester
  • Example 58 Phosphoric acid mono-f[me ⁇ hyl-(1-nap halen-2-yl-methanoyI)-amino3-phenyl- propyl ⁇ ester
  • Example 66 Phosphoric acid mono- ⁇ 3-(2,3-difTuoro-phenyI)-2-[(1-naphthalen-2-yl-methanoyl)- amino3-propyl ⁇ ester
  • Alcohol 69 (1.77 g, 5.14 mmol) was partially dissolved in CH 2 CI 2 (50 mL) and cooled to 0 °C.
  • Example 72 Sulfamic acid 2-[(1-naphthalen-2-yl-methanoyl)-aminoJ-3-phenyJ-propyl ester
  • Alcohol 47a was prepared as described in the synthesis of compound 47.
  • hydroxyl carboxylic acid 760 mg, 4.13 mmol
  • 2-naphthoyl chloride 866 mg, 4.54 mmol
  • triethylamine 2.9 mL
  • 1 M borane in THF 4.73 mL
  • column chromatography 40% EtOAc in hexanes
  • Benzyl Ester 48a was prepared as described in the synthesis of 48 using the alcohol 47s (137 mg, 0.423 mmol), 1H-tetrazole (68 mg, 0.973 mmol), dibenzyl N,N-diisopropylphosphoramidite (0.213 mL, 0.634 mmol), and MCPBA (380 mg, 77% pure, 1.69 mmol). After column chromatography purification (10% to 20% EtOAc in hexanes), the compound 48a was obtained as crude oil (330 mg), which was carried forward to the next step.
  • Example 74 Naphthalene-2-carboxylic acid (R)-1 -(3-fluoro-ben ⁇ yl)-2-phosphonooxy-ethyl ester
  • Example 74 was prepared as described in the synthesis of 49 using the crude benzyl ester (330 mg) and 10% palladium on carbon (70 mg). Preparative HPLC purification gave 70 mg of the title compound 74 (31% yield from the alcohol).
  • Example 81 Acetic acid acetoxymethoxy-(2- ⁇ [1-(1-bromo-naphthalen-2-yI)-methanoyl]- amino ⁇ -3-phenyl-propoxy)-phosphoryloxymethyl ester
  • Example 81 was prepared as described in the synthesis of Example 80 using 25-24 (23 mg,
  • Example 82 was prepared as described in the synthesis of Example 80 using 23b (22 mg, 0.0498 mmol), bromomethyl acetate (24 ⁇ L, 0.249 mmol) and diisopropylethylamine (0.05 mL). Purification by Et 3 N deactivated column chromatography (50% EtOAc in hexanes) gave 9 mg (31 % yield) of the title compound 82.
  • Example 83 Acetic acid acetoj ymetho ⁇ y-[2-( ⁇ 1-[5-(3 s 5-dichIoro-phenoJ y)-furan-2-yl3- methanoyi ⁇ -amino)-3-phenyl-propo ⁇ 5y]-phosphorylo2 ⁇ ymeth l ester
  • Example 84 Acetic acid acetoxymethoxy- ⁇ (R)-3-(3-fluoro-phenyl)-2-[(1-naphthalen-2-yI- methanoyl)-amino]-propoxy ⁇ -phosphoryloxymethyl ester
  • Example 84 was prepared as described in the synthesis of Example 80 using 25-28 (50 mg, 0.124 mmol), bromomethyl acetate (61 ⁇ L, 0.620 mmol) and diisopropylethylamine (0.13 mL). Purification by Et 3 N deactivated column chromatography (30-50% EtOAc in hexanes) gave 17 mg (25% yield) of the title compound 84.
  • Example ⁇ 5 Ace ⁇ ic acid aceto ⁇ cymeth ⁇ 2 ⁇ y-[(R)-2-[(1-ben2 ⁇ [b]thiophen-2-yl-methanoyi)-amino3- 3-(3-fluoro-phenyl)-propoxy]-phosphoryioxymethyl ester
  • Example 85 was prepared as described in the synthesis of Example 80 using 25-29 (45 mg,
  • Example 89 was prepared as described in the synthesis of Example 86 using the alcohol 88 (40 mg, 0.122 mmol), Et 3 N (0.1 mL), DMAP (4 mg) and diphenyl chlorophosphate (0.29 ⁇ L, 37.6 mg, 0.14 mmol). Column chromatography purification (40% EtOAc in hexanes)' gave 62 mg (97% yield) of the title compound 89.
  • Example 90 1-[1-Bis-acetoxymethoxy-phospgoryloxymethyJ)-2-phenyl-ethylsulfamoyI)3- piperidine-28-carboxylie acid 4-phenyl-foutyl ester
  • Example 90 was prepared as described in the synthesis of Example 80 using 5b1 (20 mg, 0.036 mmol), bromomethyl acetate (36 ⁇ L, 0.36 mmol) and diisopropylethylamine (0.1 mL). Purification by Et 3 N deactivated column chromatography (40% EtOAc in hexanes) gave 25 mg (100% yield) of the title compound 90.
  • Example 91 was prepared as described in the synthesis of Example 80 using 16d (60 mg, 0.155 mmol), bromomethyl acetate (0.15 ⁇ L, 1.55 mmol) and diisopropylethylamine (0.4 mL, 2.33 mmol). Purification by Et 3 N deactivated column chromatography (40% EtOAc in hexanes) gave 45 mg (55% yield) of the title compound 91.
  • Example 92 Acetic acid aceto2iymetho ⁇ , -[(R)-2-[(7-diethylam ⁇ no-2-o ⁇ o-2H-chromene-3- carbonyl)-amino]-3-(3-fluoro-phenyl)-propoxy3-phosphoryloxymethyl ester
  • Example 92 was prepared as described in the synthesis of Example 80 using Example 25-33
  • Example 93 Acetic acid acetoxymethoxy-[3-[(benzo[6]thiophene-2-carbonyl)-amino3-4-(3- fIuoro-phenyl)-butylJ-phosphinoyloxymethyl ester
  • Example 93 was prepared as described in the synthesis of Example 80 using Example 71 (22 mg, 0.0541 mmol), bromomethyl acetate (0.05 mL, 0.52 mmol) and diisopropylethylamine (0.13 mL, 0.77 mmol). Purification by flash column chromatography (100% EtOAc in hexanes) gave 23 mg (77% yield) of the title compound 93.
  • Example 99 Acetic acid acetoxymethoxy-[2-[benzo[ ⁇ ]thiophene-2-carbonyl)-amino]-3-(3- fluoro-phenyl)-propyl]-phosphinoyloxymethyl ester
  • Example 100 2,2-Dimethyl-propionic acid [3-[(foen2:oE&3thiophene-2-carfoonyI)-amino3-4-(3- fluoro-phenyl)-butyl3-(2,2-dimethyl-propionyl ⁇ 5cymethoxy)-phosphinoylo ⁇ ymethyl ester
  • Example 71 To an acetonitrile solution (5 mL) of Example 71 (50 mg, 0.123 mmol) was added tetrabutylamonium iodide (5 mg), diisopropylethylamine (0.2 mL), and chloromethyl pivalate (132 ⁇ L, 0.92 mmol) at 0 °C. The solution was heated at 60 °C for 4 h and concentrated in vacuo. The residue was purified by column chromatography (35% EtOAc in hexanes), affording 20 mg (26% yield) of the title compound 100.
  • PIN1 is a phosphorylation dependent peptidyl-prolyl isomerase.
  • the PIN1 assay is a spectrophotometric assay based on the coupled chymotrypsin or subtilisin catalyzed, cis-trans conformation dependent cleavage of a para-nitroanaline containing peptide substrate. This improved general rotamase assay was first described by Kofron, et al. (Biochemistry, 30, 6217-6134 (1991)) and applied to PIN1 isomerase activity by Yaffe, et al. (Science, 278, 1957-1960 (19g7)).
  • the peptide substrate Upon dilution into an aqueous assay mixture containing PIN1 , the peptide substrate undergoes PIN1 catalyzed isomerization to the trans conformation.
  • Chymotrypsin or subtilisin subtilisin (subtilisin Carisberg protease, available from Sigma, catalog number P-5380) cleaves the trans product to form free para-nitroanaline.
  • reactions are performed at 15 °C.
  • a typical reaction contains 25 mM MOPS pH 7.5, 0.5 mM TCEP, 2% DMSO, 5 ⁇ l of a 25 mg/ml solution of subtilisin Carisberg, 50 nM PINI-PPiase, and 100 ⁇ M Suc-AEPF-pNA peptide substrate. Reactions are cooled to 15 °C and initiated with the addition of Suc-AEPF-pNA. The absorbance at 390 nm is monitored continuously until all substrate has been converted to the cleaved product. This data, the progress curve, is then fitted to an exponential equation to determine a rate constant k for the reaction.
  • the rate constant k is linearly proportional to the concentration of active enzyme present in the assay mixture once the rate constant for the spontaneous isomerization is subtracted.
  • the m for this substrate is much higher than 100 ⁇ M ([S3 «Km). Therefore, during inhibition experiments, the IC 50 , for non-tight binding inhibitors, is essentially the inhibition constant K
  • the Ki data reported under the PIN1-CD heading corresponds to testing with PIN1 peptide containing the catalytic peptidyl-prolyl isomerase domain but devoid of the PIN1 WW domain.
  • the dissociation constant (Ka) data under PIN1-CD refers to testing with a peptide containing the catalytic PIN1 domain but devoid of the PIN1 WW domain.
  • the exemplary compounds described above may be formulated into pharmaceutical compositions according to the following general examples.
  • Example 1 Parenteral Composition
  • a parenteral pharmaceutical composition suitable for administration by injection 100 mg of a water-soluble salt of a compound of Formula I is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.
  • a pharmaceutical composition for oral delivery 100 mg of a compound of Formula I is mixed with 750 mg of lactose. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.

Abstract

Composés à base d'esters de sulfate/phosphate modulant et/ou inhibant l'activité de NIMA interagissant avec des protéines (PIN1) et compositions pharmaceutiques contenant de tels composés. L'invention se rapporte également à l'utilisation thérapeutique ou prophylactique de ces composés et compositions, et à des méthodes de traitement de troubles caractérisés par l'hypertension, la prolifération cellulaire indésirable, des maladies infectieuses et des troubles neurodégénératifs du cerveau, consistant à administrer des quantités efficaces de ces composés.
PCT/IB2004/000574 2003-03-10 2004-02-23 Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1) WO2004087720A1 (fr)

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EP04713610A EP1603926A1 (fr) 2003-03-10 2004-02-23 Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1)
MXPA05009241A MXPA05009241A (es) 2003-03-10 2004-02-23 Compuestos ester fosfato/sulfato y composiciones farmaceuticas para inhibir la proteina que interacciona con nima (pin1).
CA002517281A CA2517281A1 (fr) 2003-03-10 2004-02-23 Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1)
JP2006506287A JP2006523669A (ja) 2003-03-10 2004-02-23 Ｎｉｍａ調節タンパク質（ｐｉｎ１）を阻害するための、リン酸／硫酸エステル化合物および医薬組成物
BRPI0408477-2A BRPI0408477A (pt) 2003-03-10 2004-02-23 compostos de éster de fosfato/sulfato e composições farmacêuticas para inibir a nima de interação com proteìna (pin 1) e uso dos mesmos

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US60/453,163 2003-03-10

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Publication number Priority date Publication date Assignee Title
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WO2006040646A1 (fr) * 2004-10-14 2006-04-20 Pfizer, Inc. Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1
EP1742907A2 (fr) * 2004-05-06 2007-01-17 Cytokinetics, Inc. Entites, compositions chimiques et procedes
US7504413B2 (en) 2004-05-06 2009-03-17 Cytokinetics, Inc. N-(4-(imidazo[1,2A]pyridin-YL)phenethyl)benzamide inhibitors of the mitotic kinesin CENP-E for treating certain cellular proliferation diseases
US7795448B2 (en) 2004-05-06 2010-09-14 Cytokinetics, Incorporated Imidazoyl-benzamide anti-cancer agents
EP2845588A1 (fr) * 2013-09-09 2015-03-11 Centre National de la Recherche Scientifique (C.N.R.S.) Inhibiteurs PIN1 destiné à être utilisé dans la prévention et/ou le traitement de theileriosis et applications associées
WO2017063756A1 (fr) * 2015-10-12 2017-04-20 Polyphor Ag Utilisation de composés macrocycliques à conformation limitée comme modulateurs de pin1
WO2017063754A1 (fr) 2015-10-12 2017-04-20 Polyphor Ag Utilisation de composés macrocycliques à conformation limitée comme modulateurs de pin1
WO2017063755A1 (fr) 2015-10-12 2017-04-20 Polyphor Ag Composés macrocycliques à conformation limitée
WO2017063757A1 (fr) 2015-10-12 2017-04-20 Polyphor Ag Composés macrocycliques à conformation limitée
WO2017167994A1 (fr) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Dérivés d'imidazole pentacycliques condensés utilisés en tant que modulateurs de l'activité du tnf
WO2017167995A1 (fr) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Dérivés d'imidazole hexacycliques condensés utilisés en tant que modulateurs de l'activité du tnf
WO2017167993A1 (fr) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Dérivés d'imidazole pentacycliques condensés utilisés en tant que modulateurs de l'activité du tnf
WO2018101329A1 (fr) 2016-11-29 2018-06-07 国立大学法人広島大学 Nouveau composé ester et inhibiteur de pin1, agent thérapeutique pour maladie inflammatoire et agent thérapeutique pour cancer du côlon dans lesquels ledit composé ester est utilisé
WO2018167176A1 (fr) 2017-03-15 2018-09-20 Ucb Biopharma Sprl Dérivés d'imidazole pentacycliques condensés utilisés en tant que modulateurs de l'activité du tnf
US10202405B2 (en) 2014-10-03 2019-02-12 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives
WO2019031470A1 (fr) 2017-08-07 2019-02-14 国立大学法人広島大学 Nouveau composé à base d'amide, et inhibiteur de pin1, agent thérapeutique contre les maladies inflammatoires ainsi qu'agent thérapeutique contre le cancer mettant en œuvre celui-ci
WO2019031471A1 (fr) 2017-08-07 2019-02-14 国立大学法人広島大学 Agent thérapeutique contre la stéatose hépatique, et agent thérapeutique contre l'obésité
WO2019031472A1 (fr) 2017-08-07 2019-02-14 国立大学法人広島大学 NOUVEAU COMPOSÉ À BASE D'ACIDE ANTHRANILIQUE, ET INHIBITEUR DE Pin1, AGENT THÉRAPEUTIQUE CONTRE LES MALADIES INFLAMMATOIRES AINSI QU'AGENT THÉRAPEUTIQUE CONTRE LE CANCER METTANT EN ŒUVRE CELUI-CI
US10793578B2 (en) 2016-04-01 2020-10-06 UCB Biopharma SRL Fused pentacyclic imidazole derivatives as modulators of TNF activity
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
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
US11440928B2 (en) 2017-01-31 2022-09-13 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3223875A1 (fr) * 2021-06-25 2022-12-29 Shigeru Matsuoka Derive de polyheteroazole substitue par heterocycloalkyle utilise en tant que medicament pour le traitement et/ou la prevention d'une maladie infectieuse a virus rs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004751A1 (fr) * 1993-08-04 1995-02-16 Glycomed Incorporated Glycopeptides se liant a des selectines
WO2004005315A2 (fr) * 2002-07-09 2004-01-15 Pfizer Inc. Polypeptides isomerase peptidyl-prolyl pin1, leurs structures cristallines, et leur utilisation dans la conception de medicament

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004751A1 (fr) * 1993-08-04 1995-02-16 Glycomed Incorporated Glycopeptides se liant a des selectines
WO2004005315A2 (fr) * 2002-07-09 2004-01-15 Pfizer Inc. Polypeptides isomerase peptidyl-prolyl pin1, leurs structures cristallines, et leur utilisation dans la conception de medicament

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
B.A.SCHWEITZER ET AL.: "Design and Synthesis of beta-Carboxamido Phosphonates as Potent Inhibitors of Imidazole Glycerol Phosphate dehydratase", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 9, no. 14, 1999, pages 2053 - 2058, XP002285312 *
BIN XU, ANDREW STEPHENS, GARY KIRSCHENHEUTER,ARTHUR F GRESLIN,XIAOQUIN CHENG,JOE SENELLO,MARCO CATTANEO ET AL: "Acyclic Analogues of Adenosine Biphosphates as P2Y Receptor Antagonists: Phosphate Substitution Leads to Multiple Pathways of Inhibition of Platelet Aggregation", J. MED. CHEM., vol. 45, 2002, pages 5694 - 5709, XP002285317 *
BROUWER A J ET AL: "AN EFFICIENT SYNTHESIS OF N-PROTECTED BETA-AMINOETHANESULFONYL CHLORIDES: VERSATILE BUILDING BLOCKS FOR THE SYNTHESIS OF OLIGOPEPTIDOSULFONAMIDES", SYNTHESIS, GEORG THIEME VERLAG. STUTTGART, DE, no. 11, 2000, pages 1579 - 1584, XP001041496, ISSN: 0039-7881 *
C.M. SUTER, W.E. TRUCE: "Sulfonation of the Phenylpropylenes", J. AM. CHEM. SOC., vol. 66, 1944, pages 1105 - 1109, XP002285314 *
CHOUNG UN KIM ET AL.: "A New Class of Acyclic Phosphonate Nucleotide Analogues: Phosphate Isosteres of Acyclovir and Gancyclovir Monophosphates as Antiviral Agents", J. MED. CHEM., vol. 34, 1991, pages 2286 - 2294, XP002285315 *
HAK SUNG KIM, DOV BARAK, T. KENDALL HARDEN, JOSÉ L. BOYER, KENNETH A. JACOBSON: "Acyclic and Cyclopropyl Analogues of Adenosine Biphosphate Antagonists of the P2Y1 Receptor: Structure-Activity Relationships and Receptor Docking", J. MED. CHEM., vol. 44, 2001, pages 3092 - 3108, XP002285318 *
JUNG DAE PARK, DONG H. KIM, SEUNG-JUN KIM, JOO-RANG WOO, SEONG EON RYU: "Sulfamide-Based Inhibitors for Carboxypeptidase A. Novel Type Transition State Analogue Inhibitors for Zinc Proteases", J. MED. CHEM., vol. 45, 2002, pages 5295 - 5302, XP002285319 *
MICHAEL R. HANDEN, RICHARD L. JARVEST, MALCOLM R. BOYD, DAVID SUTTON, R. ANTHONY VERE HODGE: "Prodrugs of the Selective Antiherpesvirus Agent 9-(4-Hydroxy-3-(hydroxymethyl)but-1-yl)guanine (BRL39123) with Improved Gastrointestinal Absorption Properties", J. MED. CHEM., vol. 32, 1989, pages 1738 - 1743, XP002285316 *
R.A.AITKEN, D.P.ARMSTRONG, R.H.B. GALT, S.T.E.MESHER: "Synthesis and Oxidation of Chiral 2-Thiazolines (4,5-dihydro-1,3-thiazoles)", J.CHEM.SOC.,PERKIN TRANS 1, no. 6, 1997, pages 935 - 943, XP002285313 *

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US7504413B2 (en) 2004-05-06 2009-03-17 Cytokinetics, Inc. N-(4-(imidazo[1,2A]pyridin-YL)phenethyl)benzamide inhibitors of the mitotic kinesin CENP-E for treating certain cellular proliferation diseases
EP1742907A2 (fr) * 2004-05-06 2007-01-17 Cytokinetics, Inc. Entites, compositions chimiques et procedes
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US8207340B2 (en) 2004-05-06 2012-06-26 Cytokinetics, Incorporated Imidazopyridinyl benzamide mitotic kinesin inhibitors
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WO2006040646A1 (fr) * 2004-10-14 2006-04-20 Pfizer, Inc. Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1
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WO2019031472A1 (fr) 2017-08-07 2019-02-14 国立大学法人広島大学 NOUVEAU COMPOSÉ À BASE D'ACIDE ANTHRANILIQUE, ET INHIBITEUR DE Pin1, AGENT THÉRAPEUTIQUE CONTRE LES MALADIES INFLAMMATOIRES AINSI QU'AGENT THÉRAPEUTIQUE CONTRE LE CANCER METTANT EN ŒUVRE CELUI-CI
WO2019031471A1 (fr) 2017-08-07 2019-02-14 国立大学法人広島大学 Agent thérapeutique contre la stéatose hépatique, et agent thérapeutique contre l'obésité
WO2019031470A1 (fr) 2017-08-07 2019-02-14 国立大学法人広島大学 Nouveau composé à base d'amide, et inhibiteur de pin1, agent thérapeutique contre les maladies inflammatoires ainsi qu'agent thérapeutique contre le cancer mettant en œuvre celui-ci
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

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