US20070254926A1 - Pyridylphenyl compounds for inflammation and immune-related uses - Google Patents

Pyridylphenyl compounds for inflammation and immune-related uses Download PDF

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Publication number
US20070254926A1
US20070254926A1 US11/701,170 US70117007A US2007254926A1 US 20070254926 A1 US20070254926 A1 US 20070254926A1 US 70117007 A US70117007 A US 70117007A US 2007254926 A1 US2007254926 A1 US 2007254926A1
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Prior art keywords
optionally substituted
pyridin
methyl
phenyl
alkyl
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US11/701,170
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Inventor
Jun Jiang
Zhi-Qiang Xia
Junyi Zhang
Gary Bohnert
Shoujun Chen
Yu Xie
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Synta Phamaceuticals Corp
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Synta Phamaceuticals Corp
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Priority to US11/701,170 priority Critical patent/US20070254926A1/en
Assigned to SYNTA PHARMACEUTICALS CORP. reassignment SYNTA PHARMACEUTICALS CORP. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: XIE, YU, XIA, ZHI-QIANG, CHEN, SHOUJUN, JIANG, JUN, BOHNERT, GARY, ZHANG, JUNYI
Publication of US20070254926A1 publication Critical patent/US20070254926A1/en
Priority to US12/749,317 priority patent/US8710083B2/en
Priority to US14/206,059 priority patent/US20140187586A1/en
Abandoned legal-status Critical Current

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Definitions

  • R 8 for each occurrence, is independently —H, a halo, an alkyl, —OR 5 , —NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , or —C(O)NR 6 R 7 ;
  • the invention further encompasses methods for treating or preventing inflammatory conditions, allergic disorders, and immune disorders, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • methods may also comprise administering to the subject an additional agent separately or in a combination composition with the compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • an “aromatic ring” or “aryl” means a monocyclic or polycyclic-aromatic ring or ring radical comprising carbon and hydrogen atoms.
  • suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • An aralkyl group refers to an aryl group that is attached to another moiety via an alkylene linker.
  • Aralkyl groups can be substituted or unsubstituted.
  • alkenyl means a straight chain or branched, hydrocarbon radical typically having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond.
  • Representative straight chain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like.
  • Alkenyl groups can be substituted or unsubstituted.
  • cycloalkyl means a saturated, mono- or polycyclic alkyl radical typically having from 3 to 10 carbon atoms.
  • Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly, decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and the like. Cycloalkyl groups can be substituted or unsubstituted.
  • Suitable substituents for an alkyl, alkoxy, alkyl sulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl groups include any substituent which will form a stable compound of the invention.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, but they may have activity in their unreacted forms.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of any one of formulas (I) through (II) or Table 1 having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • allergic disorders include any hypersensitivity that occurs upon re-exposure to the sensitizing allergen, which in turn causes the release of inflammatory mediators.
  • Allergic disorders include without limitation, allergic rhinitis (e.g., hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitis media, drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma and food allergies.
  • an “inflammatory disorder” means a disease, disorder or condition characterized by inflammation of body tissue or having an inflammatory component. These include local inflammatory responses and systemic inflammation. Examples of such inflammatory disorders include: transplant rejection, including skin graft rejection; chronic inflammatory disorders of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung disorders such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory disorders of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disorders of the gums, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic
  • a systemic inflammation of the body exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent used in cancer chemotherapy.
  • an “effective amount” is the quantity of compound in which a beneficial outcome is achieved when the compound is administered to a subject or alternatively, the quantity of compound that possess a desired activity in-vivo or in-vitro.
  • a beneficial clinical outcome includes reduction in the extent or severity of the symptoms associated with the disease or disorder and/or an increase in the longevity and/or quality of life of the subject compared with the absence of the treatment.
  • the precise amount of compound administered to a subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of inflammatory disorder or autoimmune disorder or the degree of immunosuppression sought.
  • a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to all chiral centers in the molecule.
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of any one of formulas (I) through (II) or Table 1.
  • one of X 1 or X 2 is CH or CZ and the other is N;
  • k is for each occurrence, is independently, an integer from 1 to 4;
  • each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, —S(O) p -alkyl, —C(O)NRR, —(CH 2 ) k NRR, —(CH 2 ) k OR, —(CH 2 ) k SR, cyano, nitro, or lower haloalkoxy;
  • R 6 and R 7 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 6 and R 7 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;
  • n is zero, 1 or 2;
  • R 4 is —C(O)OR 5 , a haloalkyl, an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thiophenyl, an optionally substituted furanyl, an optionally substituted thiadiazolyl, an optionally substituted oxadiazolyl, or an optionally substituted tetrazolyl.
  • Y is a phenyl substituted with one to two substituents. In one aspect, Y is a phenyl substituted with one to two substituents, wherein the one to two substituents are each independently a lower alkyl or a halo. In one aspect, Y is 2,6-difluorophenyl or 4-methyl-1,2,3-thiadiazol-5-yl. In one aspect, Y is a difluorophenyl. In one aspect, Y is 2,6-difluorophenyl. In one aspect, Y is 4-methyl-1,2,3-thiadiazol-5-yl. In one aspect, Y is an optionally substituted pyridinyl.
  • Y 1 is an optionally substituted phenyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyridazinyl, an optionally substituted isothiazolyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted thiadiazolyl, or an optionally substituted thiophenyl.
  • L 1 is —NR—C(O)—. In one aspect, L 1 is —NH—C(O)—.
  • the invention in another embodiment, relates to methods for immunosuppression or for treating or preventing inflammatory conditions, immune disorders, or allergic disorders in a patient in need thereof comprising administering an effective amount of a pharmaceutical composition that comprises a compound represented by any one of formulas (I) through (II), or in or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL 200 a syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Plano, Tex.
  • CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Immunosuppressive agents include glucocorticoids, corticosteroids (such as Prednisone or Solumedrol), T cell blockers (such as cyclosporin A and FK506), purine analogs (such as azathioprine (Imuran)), pyrimidine analogs (such as cytosine arabinoside), alkylating agents (such as nitrogen mustard, phenylalanine mustard, buslfan, and cyclophosphamide), folic acid antagonists (such as aminopterin and methotrexate), antibiotics (such as rapamycin, actinomycin D, mitomycin C, puramycin, and chloramphenicol), human IgG, antilymphocyte globulin (ALG), and antibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5, anti-CD7, anti-1 L-2 receptor, anti-alpha/beta TCR, anti-ICAM-1, anti-CD20 (Ritux
  • Compounds of the invention having —C(O)— linkers can be prepared by a Friedel-Craft acylation reaction, for example, by reacting a pyradinyl derivative (XXIII) with an acid chloride (XXIV) in the presence of AlCl 3 to form an intermediate which can then be reacted with an [1,3,2]dioxaborolan-2-yl-aryl or -heteroaryl (XXV) in the presence of a palladium catalyst and a base to form a compound of the invention having a carbonyl linker (XXVI) (see Scheme IV).
  • a Friedel-Craft acylation reaction for example, by reacting a pyradinyl derivative (XXIII) with an acid chloride (XXIV) in the presence of AlCl 3 to form an intermediate which can then be reacted with an [1,3,2]dioxaborolan-2-yl-aryl or -heteroaryl (XXV) in
  • Compounds of the invention having —CH 2 —NH— or —NH—CH 2 — linkers can be prepared by contacting compounds having —NHC(S)— or —C(S)NH— linkers with Raney Ni.
  • compounds of the invention having a —CH 2 —NH— or —NH—CH 2 — linker can be prepared by reducing a compound having a —C(O)—NH— or —NH—C(O)— linker, respectively, with, for example, sodium borohydride.
  • the IC 50 value was calculated as the concentration at which 5% of maximum IL-2 production after stimulation was inhibited versus a non-stimulation control.
  • Each compound was diluted from a 10 mM stock in series using DMSO.
  • the final DMSO concentration was always kept at 0.1%.
  • Jurkat T cells are grown on glass coverslips, transferred to the recording chamber and kept in a standard modified Ringer's solution of the following composition: NaCl 145 mM, KCl 2.8 mM, CsCl 10 mM, CaCl 2 10 mM, MgCl 2 2 mM, glucose 10 mM, HEPES.NaOH 10 mM, pH 7.2.
  • PBMCs Peripheral blood mononuclear cells
  • PHA phytohemagglutinin
  • CsA cyclosporine A
  • the compounds of the invention are expected to be potent inhibitors of IL-2, IL-4, IL-5, IL-13, GM-CSF, INF- ⁇ and TNF- ⁇ in primary human PBM cells.
  • compounds of the invention are not expected to inhibit the anti-inflammatory cytokine, IL-10.
  • the cells are washed once with PRS (2.6 mM glucose and 0.1% BSA) and 160 ⁇ L of PRS is added to each well.
  • PRS 2.6 mM glucose and 0.1% BSA
  • a test compound is added to a well in a 20 ⁇ L solution at 10 ⁇ of the desired concentration and incubated for 20 to 40 minutes at 37° C.
  • 20 ⁇ L of 10 ⁇ mouse anti-IgE (10 ⁇ L/mL) is added. Maximum degranulation occurs between 15 to 40 minutes after addition of anti-IgE.
  • the non-adherent T cell populations are eluted by washing of the columns with additional media.
  • the T cell preparations are centrifuged, resuspended in 5 ml of incomplete RPMI, and counted using a hemocytometer.
  • ⁇ l aliquots of the cell suspensions are placed on the membrane (pore size 5 ⁇ m) of a Neuroprobe ChemoTx 96 well chemotaxis unit that have been affixed over wells containing 10 ng/ml MIP-1 ⁇ in HHBSS.
  • the T cells are allowed to migrate for 2 hr at 37° C., after which the apical surface of the membrane is wiped clean of cells.
  • the chemotaxis units are then placed in a CytoFlour 4000 (PerSeptive BioSystems) and the fluorescence of each well measured (excitation and emission wavelengths of 450 and 530 nm, respectively).
  • the number of migrating cells in each well is determined from a standard curve generated from measuring the fluorescence of serial two-fold dilutions of the labeled cells placed in the lower wells of the chemotaxis unit prior to affixing the membrane.

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