WO2007123686A2 - Inhibiteurs de la dipeptidyle peptidase (dpp) et leurs utilisations - Google Patents

Inhibiteurs de la dipeptidyle peptidase (dpp) et leurs utilisations Download PDF

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Publication number
WO2007123686A2
WO2007123686A2 PCT/US2007/007918 US2007007918W WO2007123686A2 WO 2007123686 A2 WO2007123686 A2 WO 2007123686A2 US 2007007918 W US2007007918 W US 2007007918W WO 2007123686 A2 WO2007123686 A2 WO 2007123686A2
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WIPO (PCT)
Prior art keywords
agent
infection
cancer
formula
antibody
Prior art date
Application number
PCT/US2007/007918
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English (en)
Other versions
WO2007123686A3 (fr
Inventor
Paul A. Mclean
Michael I. Jesson
Glenn T. Miller
Barry Jones
Geoffrey Alan Cole
Original Assignee
Point Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Point Therapeutics, Inc. filed Critical Point Therapeutics, Inc.
Publication of WO2007123686A2 publication Critical patent/WO2007123686A2/fr
Publication of WO2007123686A3 publication Critical patent/WO2007123686A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • This invention relates to dipeptidyl dipeptidase inhibitors (such as DPP-IV inhibitors) and methods of use thereof in the treatment of disease.
  • T is a reactive group as described above; and R2 is a peptide, peptidomimetic, or amino acid, whether naturally or non-naturally occurring.
  • the bond between the carbon in the pyrolidine ring and T may be in the L or D configuration.
  • the amino terminal amino acid residue may be in the L or D configuration, although in some embodiments, it is preferably in the L configuration.
  • the dipeptide moiety can be an isostere.
  • the pyrrolidine may be replaced with an azetidine or a thiazolidine.
  • the pyrrolidine-T moiety is replaced with a 4-cyanothiazolidine.
  • the agents of Formula Va include agents of Formula Vb
  • Xl and X2 are independently selected from hydroxyl groups or groups capable of being hydrolyzed to a hydroxyl group in aqueous solution at physiological pH.
  • the bond between the C and B is preferably in the L configuration (otherwise referred to as the R configuration).
  • agents of Formula Xb further include agents of Formula Xc
  • the vaccine is a hepatitis vaccine, a mumps vaccine, a measles vaccine, a rubella vaccine, a flu vaccine, a polio vaccine, a tetanus vaccine, a DTaP vaccine, an HiB vaccine, a Pneumococcus vaccine, a MMR vaccine, a varicella vaccine, a DPT vaccine, or a Td vaccine.
  • the agents of Formula Ia include agents of Formula Ib
  • the invention embraces variants in which the amino terminal side chain (e.g., Rl in the structure above) is in the R or S (or L or D) configuration, and the invention is no limited solely to the stereoisomer configurations of the "e" structures provided herein.
  • agents of Formula Vc even further include agents of Formula Vd
  • All amino acids contain an asymmetric or chiral carbon and may contain more than one chiral carbon atom.
  • the asymmetric ⁇ carbon atom of the amino acid is referred to as a chiral center and can occur in two different isomeric forms. These forms are identical in all chemical and physical properties with one exception, the direction in which they can cause the rotation of plane-polarized light.
  • These amino acids are referred to as being "optically active," i.e., the amino acids can rotate the plane-polarized light in one direction or the other.
  • the four different substituent groups attached to the ⁇ carbon can occupy two different arrangements in space.
  • These agents can be provided in linear or cyclic form or as mixtures thereof, as described in U.S. Patent No. 6,355,614, issued March 12, 2002.
  • the percentage of cyclic forms (relative to linear forms) in these mixtures may vary (e.g., less than 20% to more than 90% including at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more cyclic) depending on the formulation.
  • the amino acid residues may be naturally and non-naturally occurring amino acids.
  • Aromatic groups include carbocyclic aromatic groups such as phenyl and naphthyl and heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl and acridintyl.
  • refractory cancers include but are not limited to leukemia, Non-Hodgkin's lymphoma, melanoma, renal cell carcinoma, colon cancer, colon cancer, liver (hepatic) cancer, pancreatic cancer, and lung cancer.
  • agents of the invention induces memory within the immune cell compartment, for example, by the induction of memory T cells, and B cells. This is believed to occur via the cytokine cocktail that is induced by agents of the invention, particularly the induction of EL-I ⁇ and the downstream activation of the immune system by the secreted mature form of IL-I ⁇ .
  • the ability to generate memory T cells can enhance immune responses to, for example, cancerous cells that are remaining following a surgical procedure, or following chemotherapy or radiation.
  • the agent is administered at the time of surgery as well as following surgery in order to inhibit the formation and development of metastatic lesions.
  • the administration of the agent may continue for several hours, several days, several weeks, or in some instances, several months following a surgical procedure to remove a tumor mass.
  • the subjects can also be administered the agents in combination with non-surgical anti-proliferative (e.g., anti-cancer) drug therapy.
  • Interferon Alfa-2a Interferon Alfa-2b; Interferon Alfa-nl ; Interferon Alfa-n3; Interferon Beta-I a; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate;
  • Trimetrexate Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil
  • the agents of the invention are administered together with one or more anti-cancer compounds selected from the group consisting of aldesleukin, asparaginase, bleomycin sulfate, carboplatin, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, docetaxel, doxorubicin, doxorubicin hydrochloride, epirubicin hydrochloride, etoposide, etoposide phosphate, floxuridine, fludarabine, fluorouracil, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferons, interferon- ⁇ 2a, interferon- ⁇ 2b, interferon- ⁇ n3, interferon- ⁇ lb, interleukins,
  • the CDK inhibitor may be p21, p27, p57, pi 5, pi 6, pi 8, or pl9.
  • the MAP kinase inhibitor may be KY12420 (C 23 H 24 O 8 ), CNI-1493, PD98059, or 4-(4- Fluorophenyl)-2-(4-methylsulfinyl phenyl)-5-(4-pyridyl) lH-imidazoIe.
  • the invention also contemplates the use of the agents of the invention together with antigens such as cancer antigens and microbial agents.
  • the cancer antigen is VEGF, Anti-idiotypic mAb (GD3 ganglioside mimic), CD20, CD52, Anti-idiotypic mAb (CEA mimic), ERBB2, EGFR, CD22, ERBB2 X CD65 (fc ⁇ RI), EpCam, PEM and CD33.
  • the method may involve, in another embodiment, administering to a subject in need of immunization an agent of the invention in an amount effective to induce an antigen-specific immune response to a vaccine administered in a vaccination course, wherein the vaccination course is shortened by at least one day.
  • the vaccination course is shortened by one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, one month, two months or more.
  • an agent of the invention is administered substantially simultaneously with the vaccine.
  • the invention embraces the use of antibodies of all iso types including IgM, IgAl, IgA2, slgA, IgD, IgE, IgGl, IgG2, IgG3, and IgG4, having light chains that are either kappa or lambda chains.
  • the covalent binding can be achieved either by direct condensation of existing side chains or by the incorporation of external bridging molecules.
  • Many bivalent or polyvalent agents are useful in coupling protein molecules to other proteins, peptides or amine functions, etc.
  • the literature is replete with coupling agents such as carbodiimides, diisocyanates, glutaraldehyde, diazobenzenes, and hexamethylene diamines. This list is not intended to be exhaustive of the various coupling agents known in the art but, rather, is exemplary of the more common coupling agents.
  • anti-TNF ⁇ antibody such as infliximab (Remicade) and etanercept (Enbrel) for rheumatoid arthritis and Crohn's disease palivizumab
  • anti-RSV antibody for pediatric subjects
  • bevacizumab breast cancer
  • alemtuzumab Campath-IH
  • breast and renal cancer melanoma
  • B cell chronic lymphocytic leukemia Millennium and ILEX
  • BLyS-mAb fSLE and rheumatoid arthritis
  • anti-VEGF2, melanoma breast cancer
  • anti-Trail receptor B3 mAb, breast cancer
  • ml 70 mAb breast cancer
  • mAB BR96 breast cancer
  • Abx-Cbl mAb graft versus host disease.
  • PARP Antibodies Anti-Human PARP Antibodies (Monoclonal), Anti-Human PARP Antibodies (Polyclonal) Anti-Murine PARP Antibodies;
  • fungal infections include candidiasis infection, ringworm, histoplasmosis infection, blastomycosis infections, paracoccidioidomycosis infections, cryptococcosis infections, aspergillosis infections, chromomycosis infections, mycetoma infections, pseudallescheriasis infection, and tinea versicolor infection.
  • Cefmetazole Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium;
  • anti-microbials include Difloxacin Hydrochloride; Lauryl Isoquinolinium
  • the subject may be genetically immunocompromised, meaning that they harbor a genetic mutation that renders them immunocompromised even in the absence of an infection or exogenous procedure.
  • Such subjects may have for example a genetic mutation such as in agammaglobulinemia or SCID.
  • SCID genetic mutation
  • These subjects may be treated according to the invention routinely or only when they are at a higher risk of, for example, developing an infectious disease e.g., when traveling to a region where infections are common, when having surgery, when having a skin abrasion, etc.
  • Agents of the invention may be therapeutically and prophylactically useful for conditions which are responsive to IFN therapy.
  • the IFN therapy may be IFN ⁇ , IFN ⁇ , or IFN ⁇ therapy, but is not so limited.
  • FXR antagonist is Guggulsterone.
  • SCAP activator is GW532 (GlaxoSmithKline).
  • MTP inhibitors include but are not limited to Implitapide and R- 103757.
  • squalene synthase inhibitors include but are not limited to zaragozic acids.
  • PPAR agonists include but are not limited to GW-409544, GW-501516, and LY-510929.
  • Angiotensin I and angiotensin II are synthesized by the enzymatic renin-angiotensin pathway. The synthetic process is initiated when the enzyme renin acts on angiotensinogen, a pseudoglobulin in blood plasma, to produce the decapeptide angiotensin I.
  • Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II (angiotensin-[l-8] octapeptide).
  • ACE angiotensin converting enzyme
  • angiotensin II angiotensin-[l-8] octapeptide
  • the latter is an active pressor substance which has been implicated as a causative agent in several forms of hypertension in various mammalian species, e.g., humans.
  • Angiotensin (renin-angiotensin) system inhibitors are compounds that act to interfere with the production of angiotensin II from angiotensinogen or angiotensin I or interfere with the activity of angiotensin II.
  • Such inhibitors are well known to those of ordinary skill in the art and include compounds that act to inhibit the enzymes involved in the ultimate production of angiotensin II, including renin and ACE. They also include compounds that interfere with the activity of angiotensin II, once produced.
  • angiotensin II antagonists include but are not limited to peptidic compounds (e.g., saralasin, [(San 1 ⁇ VaI 5 J(AIa 8 )] angiotensin -(1-8) octapeptide and related analogs); N- substituted imidazole-2-one (US Patent Number 5,087,634); imidazole acetate derivatives including 2-N-butyl-4-chloro-l-(2-chlorobenzile) imidazole-5-acetic acid (see Long et al., J. Pharmacol. Exp. Ther.
  • peptidic compounds e.g., saralasin, [(San 1 ⁇ VaI 5 J(AIa 8 )] angiotensin -(1-8) octapeptide and related analogs
  • N- substituted imidazole-2-one US Patent Number 5,087,634
  • imidazole acetate derivatives including 2-N-butyl
  • the subjects are at risk of developing an infection due to an impending surgical procedure, travel to a region where one or more infections are common, or they have experienced a skin abrasion, for example as a result of a trauma.
  • the method intends to treat subjects free of symptoms calling for hemopoietic stimulation.
  • the invention intends, in certain embodiments, to treat subjects at a time when they are free of symptoms requiring hemopoietic stimulating treatment or to treat subjects who have such symptoms with amounts or dosages or administration schedules that differ from those used to protect or restore normal or protective levels of hemopoietic cells.
  • the methods of the invention are directed towards subjects who possess normal or protective levels of hemopoietic cells, as described herein.
  • Subjects with normal or protective levels of hemopoietic cells are considered to have normal hemopoietic activity.
  • the invention is directed for use in subjects who are not immunocompromised.
  • immunocompromised and immunosuppressed are used interchangeably.
  • An example of an immunocompromised subject is one infected with HIV and experiencing AIDS-related symptoms such as low CD4+ T lymphocyte levels.
  • the agent may be given at timed intervals, such as, for example, every two days, every three days, every four days, every week or every two weeks.
  • the agent may be delivered intravenously and continuously, for example, or by injection, such as, in single bolus administrations.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating compounds, and inert gases and the like.
  • the pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy.
  • 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.
  • Assay reaction mixtures consisted of 120 ⁇ l 140 mM NaCl buffered with 50 mM HEPES/Na pH 7.6 for DPP-IV, DPP 8 and FAP, or 140 mM NaCl buffered with 120 ⁇ l 100 mM MES/Na pH 5.5 for DPP 2 mixed with 15 ⁇ l of each enzyme preparation in a 96-well plate. 15 ⁇ l of varying amounts of Norleucine- boroPro or buffer were added so as to obtain a concentration range of 0 to 100,000 nM in the final reaction mixture.
  • Example 10 This Example illustrates the activation of caspase-1 (also called IL-I ⁇ converting enzyme or ICE) in cells of the THP-I human monocytic line by the compounds described in Example 9.
  • caspase-1 also called IL-I ⁇ converting enzyme or ICE
  • THP-I cells were incubated with each compound for a total of 11.5 hours and determinations of caspase-1 activity after 2, 3, 4, 5, 6, 1, 8 and 11.5 hours indicated progressive activation of caspase-1 (FIG. 9).
  • the compounds activated caspase-1 when added to the THP-I cell cultures at concentrations of 1, 10 and 100 ⁇ M.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne, entre autres, des agents de dipeptides d'acide aminoboronique, des compositions à base de ceux-ci et des procédés d'utilisation de compositions à base de dipeptides d'acide aminoboronique dans le traitement de troubles caractérisés par une prolifération cellulaire anormale, de troubles cardio-vasculaires, et de maladies infectieuses.
PCT/US2007/007918 2006-03-31 2007-03-30 Inhibiteurs de la dipeptidyle peptidase (dpp) et leurs utilisations WO2007123686A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US78782006P 2006-03-31 2006-03-31
US60/787,820 2006-03-31
US85971606P 2006-11-17 2006-11-17
US60/859,716 2006-11-17

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WO2007123686A2 true WO2007123686A2 (fr) 2007-11-01
WO2007123686A3 WO2007123686A3 (fr) 2008-07-03

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013078059A1 (fr) * 2011-11-22 2013-05-30 Trustees Of Tufts College Activateurs de type petites molécules pour vaccins à base de cellules dendritiques contre le cancer
CN108864250A (zh) * 2018-05-29 2018-11-23 北京大学 一种FAPα酶敏感的吉西他滨前体药物及其制备方法和应用
US11957657B2 (en) 2016-09-07 2024-04-16 Trustees Of Tufts College Combination therapies using immuno-dash inhibitors and PGE2 antagonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6911467B2 (en) * 1999-11-30 2005-06-28 Ferring Bv Antidiabetic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6911467B2 (en) * 1999-11-30 2005-06-28 Ferring Bv Antidiabetic agents

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013078059A1 (fr) * 2011-11-22 2013-05-30 Trustees Of Tufts College Activateurs de type petites molécules pour vaccins à base de cellules dendritiques contre le cancer
CN104039952A (zh) * 2011-11-22 2014-09-10 塔夫茨大学信托人 用于树突状细胞癌症疫苗的小分子增强剂
JP2014533727A (ja) * 2011-11-22 2014-12-15 トラスティーズ オブ タフツ カレッジ 樹状細胞癌ワクチンのための小分子エンハンサー
US9284337B2 (en) 2011-11-22 2016-03-15 Trustees Of Tufts College Small molecule enhancer for dendritic cell cancer vaccines
CN106075450A (zh) * 2011-11-22 2016-11-09 塔夫茨大学信托人 用于树突状细胞癌症疫苗的小分子增强剂
EP3106173A1 (fr) * 2011-11-22 2016-12-21 Trustees Of Tufts College Activateurs de type petites molécules pour vaccins à base de cellules dendritiques contre le cancer
JP2017214420A (ja) * 2011-11-22 2017-12-07 トラスティーズ オブ タフツ カレッジ 樹状細胞癌ワクチンのための小分子エンハンサー
US9839646B2 (en) 2011-11-22 2017-12-12 Trustees Of Tufts College Small molecule enhancer for dendritic cell cancer vaccines
US11957657B2 (en) 2016-09-07 2024-04-16 Trustees Of Tufts College Combination therapies using immuno-dash inhibitors and PGE2 antagonists
CN108864250A (zh) * 2018-05-29 2018-11-23 北京大学 一种FAPα酶敏感的吉西他滨前体药物及其制备方法和应用

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