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WO2018134847A1 - Immunosuppressive agents - Google Patents

Immunosuppressive agents Download PDF

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Publication number
WO2018134847A1
WO2018134847A1 PCT/IN2018/050027 IN2018050027W WO2018134847A1 WO 2018134847 A1 WO2018134847 A1 WO 2018134847A1 IN 2018050027 W IN2018050027 W IN 2018050027W WO 2018134847 A1 WO2018134847 A1 WO 2018134847A1
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Prior art keywords
formula
bipyridin
hydroxylamine
methylidene
group
Prior art date
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PCT/IN2018/050027
Other languages
French (fr)
Inventor
Ravinder Singh JOLLY
Amar Nath SHARMA
Pradeep Mishra
Bhavna VAID
Neeraj KHATRI
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Council Of Scientific & Industrial Research
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Publication of WO2018134847A1 publication Critical patent/WO2018134847A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to 2,2 '-bipyridine derivatives compound of formula I and use thereof as immunosuppressive agents.
  • present invention relates to the use of said 2,2'- bipyridine derivatives as biologically active ingredients, more specifically as medicament for treating diseases due to abnormal immune response induced by the activated T cells, such as rejection of organ transplantation, autoimmune disease, inflammatory reaction, fibrosis or dysfunction caused by autoimmune disease or related disease thereof with tissue injury or infection, or allergic disease.
  • cyclosporine, FK506, and rapamycin are secondary metabolites which are used for immunosuppression. (Hung, D. T.; Jamison, T. F.; Schreiber, S. L., Understanding and controlling the cell cycle with natural products. Chem Biol 1996, 3 (8), 623-39.)
  • Pateamine A is isolated from marine life which shows immunosuppressive properties.
  • the stable and simple analogues or derivatives of this natural form have been synthesized and analysed for immunosuppression property.
  • 2,2 '-Bipyridine (2,2'-BP) molecular scaffold occurs in many natural products such as caerulomycins (Caes), collismycins (Cols), camptothecin, orelline, and streptonigrin. These products show wide range of biological activities.
  • Caes and Cols share similar scaffold, ring
  • A is di- or tri-substituted, conjugated with ring B which is not substituted by any functional group.
  • the caerulomycins (Caes) class include caerulomycins A-C (1-3), D (4) and E-J (5-10).
  • R 1 OCH 3
  • R 2 OCH 3
  • R 3 CHNOH
  • R 1 H
  • R 2 OCH 3
  • R 3 CH 2 OH
  • R 1 H
  • R 2 OCH 3
  • R 3 CH 2 OH
  • Caerulomycin A was extracted from Streptomyces caeruleus and antimicrobial properties of CaeA was also observed.
  • Various biological properties of CaeA have also been disclosed.
  • CaeA inhibits proliferation of Jurkat cells by targeting cellular iron.
  • CaeA causes intracellular iron depletion by reduced uptake and increased release by cells.
  • CaeA has multiple cellular targets, viz., iron containing ribonucleotide reductase enzyme and cell cycle control molecules cyclin Dl, p21CIPI/WAFl and cdk4, which are important for normal cell cycle progression.
  • Anti-asthmatic activity is also exhibited by CaeA (Sci Rep 2015, 5, 15396).
  • immunosuppressive drugs are isolated from natural resource in small amounts. Also, these are difficult to synthesise in pharmaceutical effective amount due to complexity in their structures.
  • the immunosuppressive therapy require molecules with higher efficacy, minimum side effect, simpler chemical structures, amenable to synthesis via simpler and fewer reaction steps.
  • the new immunosuppressant should have increased shelf-life at ambient temperature and increased stability to metabolic modification for providing effective relief to subject requiring immunosuppressive therapy.
  • T lymphocytes T cells
  • B lymphocytes B cells
  • TCRs T cell receptors
  • pMHC peptide-major histocompatibility complexes
  • APC antigen-presenting cell
  • CD28, CD40L co-stimulatory signals
  • a complementary set of co-stimulatory signals (CTLA-4, PD-I, BTLA) provide negative signal that reduce the immune response and help maintaining the peripheral T cell tolerance to protect against autoimmunity.
  • CTLA-4, PD-I, BTLA a complementary set of co-stimulatory signals
  • the main co-stimulatory molecules, CD28 and CTLA-4/CD152 are expressed on the surface of T cells.
  • CD28 co- stimulation is necessary for the initiation of most T cell responses, and this has therapeutic implications; in that blockade of CD28 co- stimulation can be profoundly immunosuppressive, preventing induction of pathogenic T cell responses in autoimmune disease models and allowing for prolonged acceptance of allograft in models of organ transplantation (Annu Rev Immunol 2001, 19, 225-52).
  • CTLA-4 (CD 152) mediates such an inhibitory signal. Whereas CD28 is constitutively expressed on T cells, CTLA-4 is not expressed constitutively on naive T cells. CTLA4 is only expressed after the CD4 + T cell becomes activated and upon engagement with B7 molecules, transduces a negative signal to T cells.
  • CTLA-4 blockade in vivo enhances antigen-specific and anti-parasite responses, tumor rejection, autoimmune disease, and exacerbates graft rejection.
  • the CaeA introduce the immunosuppression by various mechanisms such as down regulation of activation marker CD69, up regulation of negative co- stimulatory signals, reduce expression of various inflammatory cytokines and inhibiting proliferation of various types of B and T cells. ( PLoS One 2014, 9 (10), el07051).
  • TCRs T cell receptors
  • PMHC peptide-major histocompatibility complexes
  • Tregs Regulatory T cells play an important role in deactivation of immune response. Tregs can slow down the activity of T cell by competition of cytokines and up regulating CTLA-4.
  • the antiasthmatic activity of CaeA is proved by reduction in levels of Th2 cells, reduction in expression of GAT A- 3 and cytokines (IL-4, IL-5, IL-13) secreted by Th2 cells.
  • the IL-4, IL-5 and IL-13 help in stimulation of eosinophilis, mast cells and increase the level of IgE Abs.
  • the suppression of alloreactive T cells helps the survival of allogeneic skin graft.
  • CaeA exhibits reduction in proliferation of alloreactive T cells.
  • CaeA displays prolonged skin allograft rejection.
  • CaeA and CaeE are prepared by different pathways including metalation and cross-coupling reactions. Another method is reported from diketone and picolinic acid. The pyranone method of synthesis of CaeA is also explored using precursor 4-ethoxy-3-pentene-2-one.( Tetrahedron 2010, 66 (29), 5432-5434)
  • Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation.
  • ISDs are prescribed for the treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. ⁇ Expert Opin Emerg Drugs 2003, 8 (1), 47-62 & Experimental and clinical pharmacology 2006, 29, 99-101).
  • Immunosuppressive drugs are crucial for long-term graft survival following organ transplantation.
  • ISDs are prescribed for the treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc.
  • drugs in clinic such as cyclosporine A, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate, prednisone, etc. have provided significant relief to patients, these suffer from one or another drawback, such as poor oral bioavailability, side effects like nephrotoxicity and malignancy, non- specific mode of action, incomplete suppression of belligerent immune cells, unaffordable cost, etc.
  • the present invention is based on the finding that certain combinations of substituents at different positions of the 2,2-bipyridine ring system, said combinations not being suggested by the prior art, are able to meet one or more of the medical needs recited herein above.
  • many of these 2,2-bipyridine ring system have ketoxime substituent in place of aldoxime substituent present in CaeA.
  • the methoxyl group of CaeA has been replaced with H or methyl.
  • the ketoximes are prepared in lesser number of steps in the synthesis compared to aldoximes and also eliminates low yielding and hazardous steps involved in synthesis of aldoximes.
  • the main object of the present invention is to provide a compound of formula I.
  • Another object of the present invention is to provide compound of formula I useful as immunosuppressive agent.
  • Figure 1 represents displays the chemical structure of CaeA, and one methyl engaged analog.
  • Figure 2 represents scheme showing the example of synthesis of some molecules from cyano intermediate.
  • Figure 3 represents scheme showing the example of synthesis of some molecules from same precursors as describe in Figure 2, but following different reaction scheme.
  • Figure 4 represent effect of compounds 49, 51-56, 81 and 82 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 ⁇ ) of Con A, and CaeA, 49, 51-56, 81 or 82 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
  • Figure 5 represent effect of compounds 57-60, 62, 63 and 64 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 ⁇ ) of Con A, and CaeA, 57-60, 62, 63 or 64 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
  • Figure 6 represent effect of compounds 61 and 65-69 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 ⁇ ) of Con A, and CaeA, 61 or 65-69 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
  • Figure 7 represent effect of compounds 73-76 on proliferation of concanavaline A (Con A)- stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 ⁇ ) of Con A, and CaeA, or 73-76 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
  • Figure 8 represent effect of compounds 51, 70 and 71 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 ⁇ ) of Con A, and CaeA, 51, 70 or 71 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
  • a , B , C , and D are identical or non-identical and are selected from the group consisting of hydrogen, hydroxyl, chloro, fluoro, cyano, Ci to Cio normal or branched chain alkylamino, Ci to C 10 normal or branched chain dialkylamino, and Ci to Cio normal or branched chain alkoxy;
  • a and B are identical or non-identical and are selected from the group consisting of following formulae
  • R 1 is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, fluoro, and cyano;
  • R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • X is O or N
  • Y is O or N
  • n 1 to 10;
  • C and D are identical or non-identical and are selected from the group consisting of
  • R 4 is selected from the grou consisting of following formulae
  • R is hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Cio normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy;
  • R is hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Cio normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy;
  • R 9 is H, Ci to Cio normal or branched chain alkyl, heterocyclic ring, and poly aromatic hydrocarbon (PAH), wherein said heterocyclic ring or PAH group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, trifuoromethoxyl, bromo, chloro, flouro, and cyano;
  • R 10 is H or Q to Cio normal or branched chain alkyl
  • R 11 is H or Ci to Cio normal or branched chain alkyl
  • n l to 10;
  • R 5 is selected from roup consisting of following formulae
  • n 0 to 10;
  • R is hydroxyl or amino
  • R is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R 14 is H or Ci to Cio normal or branched chain alkyl
  • R 15 is H or Ci to Cio normal or branched chain alkyl
  • R 16 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R is selected from group consisting of H, Ci to Cio normal or branched chain alkyl, aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R 6 is selected from roup consisting of following formulae
  • n 0 to 10
  • R is H or Ci to Qo normal or branched chain alkyl
  • R 19 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • said compound is useful as immunosuppressive agent.
  • representative compound of formula 1 comprising:
  • N-[([2,2'-bipyridin]-6-yl)(naphthalen-2-yl)methylidene]hydroxylamine (Formula 67) N-[([2,2'-bipyridin]-6-yl)(6-methoxynaphthalen-2-yl)methylidene]hydroxylamine (Formula 68); N-[([2,2'-bipyridin]-6-yl)(phenanthren-9-yl)methylidene]hydroxylamine (Formula 69);
  • said compound is useful as a medicine for the prevention or treatment of immune disorders in an animal or human.
  • said immune disorder is an autoimmune disorder or an immune disorder as a result from organ transplantation.
  • Present invention provides an immunosuppressive compound of Formula 1
  • a , B , C , and D are identical or non-identical and are selected from the group consisting of hydrogen, hydroxyl, chloro, fluoro, cyano, Ci to Cio normal or branched chain alkylamino, Ci to C 10 normal or branched chain dialkylamino, and Ci to Cio normal or branched chain alkoxy;
  • a and B are identical or non-identical and are selected from the group consisting of following formulae
  • R 1 , R2 , R 3 is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, fluoro, and cyano;
  • X is O or N
  • Y is O or N
  • n 1 to 10;
  • C and D are identical or non-identical and are selected from the group consisting of syn or anti -
  • R 4 C NR 5 and -R 4 CH-NHR 6 ;
  • R 4 is selected from the group consisting of following formulae
  • R 7 , R 8 is selected from group consisting of hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Cio normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy;
  • R 9 is selected from group consisting of H, Q to Cio normal or branched chain alkyl, heterocyclic ring, and poly aromatic hydrocarbon (PAH), wherein said heterocyclic ring or PAH group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R 10 is H or Ci to Cio normal or branched chain alkyl
  • R 11 is H or Ci to Cio normal or branched chain alkyl
  • n l to 10;
  • R 5 is selected from group consisting of following formulae
  • R is hydroxyl or amino
  • n 0 to 10;
  • R is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R 14 is H or Ci to Cio normal or branched chain alkyl
  • n 1 to 10;
  • R 15 is H or Ci to Cio normal or branched chain alkyl
  • R 16 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R is selected from group consisting of H, Ci to Cio normal or branched chain alkyl, aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • R 6 is selected from group consisting of following formulae
  • n 0 to 10
  • R is H or Ci to Qo normal or branched chain alkyl
  • R 19 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
  • Present invention provides an immunosuppressive compound of Formula 2:
  • R are identical or non-identical and are selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, and Ci to Cio normal or branched chain alkoxy;
  • R is selected from group consisting of hydrogen, Ci to Cio normal, or branched chain alkyl, Ci to Cio normal or branched chain alkynyl, Ci to Cio normal or branched chain alkenyl, C3-C7 alicyclic ring, aryl, and heterocyclic group, wherein the said aryl or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, trifuoromethoxyl, bromo, chloro, flouro, and cyano;
  • Present invention provides an immunosuppressive compound of Formula 3:
  • R" and are identical or non-identical and are selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, and -OR 26 , wherein said R 26 is of Ci to Cio normal or branched chain alkyl;
  • R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl and aryl, wherein the said aryl is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, trifluoromethoxyl, bromo, chloro, flouro and cyano; and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
  • Present invention provides an immunosuppressive compound of Formula 4
  • n 0 to 10;
  • dotted line (— ) is single or double bond
  • R 27 , R 28 , FT 29 and R 3 J 0 U are identical or non-identical and are selected from group consisting of Ci to Cio normal or branched chain alkyl, Ci to C10 normal or branched chain alkoxy, Ci to C10 normal or branched chain alkylamino, and Ci to Cio normal or branched chain dialkylamino; and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or solvate thereof.
  • the oxidation and reduction reactions are used for synthesis of intermediates such as N-oxide, alcohols and aldehyde.
  • the intermediates N-oxide are prepared by oxidation of different derivatives of bipyridine with mCPBA in CH 2 CI 2 .
  • the cyanation of N-oxide is achieved by trimethylsilyl cyanide (TMSCN) and dimethylcarbmoyl chloride in dichloromethane.
  • TMSCN trimethylsilyl cyanide
  • the TMSCN is an alternative of KCN. This method gives cyanation in regio selective manner.
  • the ketone is prepared by reaction of nitrile with RMgBr in tetrahydrofuran or from oxidation of secondary alcohol.
  • the aromatic ketones, ethyl and methyl ketone are generated directly from nitrile group.
  • the derivatives having cyclic, branched alkyl, and long alkyl chain are prepared by different pathways.
  • the cyclic, branched alkyl and long alkyl chain ketones are prepared by addition of RMgBr on aldehyde, followed by swern oxidation.
  • the aldehyde is prepared in three step, (i) esterification of nitrile intermediate, (ii) reduction of ester and (iii) oxidation of alcohol.
  • the oxime formation of aldehyde or ketone is done by hydroxylamine hydrochloride and pyridine at refluxing in ethanol.
  • Compounds of Formula 4 can be prepared by reaction of aldehyde or ketone with hydrazine or ⁇ , ⁇ -diamine. Imine double bonds can be reduced with a borohydride reagent or by catalytic hydrogenation method. In yet another embodiment of the present invention, compound of Formula 1 to Formula 4 suppressed the proliferation of T-cell lymphocytes.
  • compound of Formula 1 to Formula 4 suppressed the proliferation of mitogen induced (Con A) T-cell lymphocytes.
  • the fluorescent dye 5,6-carboxylfluorescein diacetate succinimidyl ester (CFSE) is used for detection, identification and quantification of proliferated T cells in vitro. This assay is more sensitive than H-thymidine based assay.
  • compound of Formula 1 to Formula 4 increases the level of anti-inflammatory cytokines like IL-10 and reduces the level of proinflammatory cytokines like IL-2, TNF and IFN- ⁇ in mice. This perturbation of cytokines level is favourable for the prolongation of allograft survival.
  • compound of Formula 1 to Formula 4 significantly prolongs the survival of skin allograft in mice.
  • present invention provides pharmaceutically acceptable salts of any compound of Formula 1 to Formula 4.
  • the pharmaceutically acceptable salts may be obtained by treating any of Formula 1 to Formula 4 compound with an appropriate salt-forming acid.
  • appropriate salt-forming acids include, for instance, inorganic acids resulting in forming salts such as but not limited to hydrohalides (e.g.
  • hydrochloride and hydrobromide sulfate, nitrate, phosphate, diphosphate, carbonate, bicarbonate, and the like; and organic monocarboxylic or dicarboxylic acids resulting in forming salts such as, for example, acetate, propanoate, hydroxyacetate, 2-hydroxypropanoate, 2-oxopropanoate, lactate, pyruvate, oxalate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, methanesulfonate, ethanesulfonate, benzoate, 2-hydroxybenzoate, 4-amino-2-hydroxybenzoate, benzenesulfonate, p- toluenesulfonate, salicylate, p-aminosalicylate, palmoate, bitartrate, camphorsulfonate, edetate, 1,2-ethanedisulfonate, fumarate, glucoheptonate
  • the salt-forming acid will be selected so as to impart greater water-solubility, lower toxicity, greater stability and/or slower dissolution rate to any of Formula 1 to Formula 4 compound.
  • Present invention provides a pharmaceutical composition of the invention for use as a medicine, more particularly use of Formula 1 to Formula 4 compounds to treat or prevent an immune disorder in an animal, more particularly to treat or prevent autoimmune disorders, and particular organ rejections in an animal, more specifically a human.
  • this invention provides combinations, preferably synergistic combinations, of one or more Formula 1 to Formula 4 compounds of this invention with one or more biologically active drugs being preferably selected from the group consisting of immunosuppressant and/or immunomodulator drugs.
  • one or more biologically active drugs being preferably selected from the group consisting of immunosuppressant and/or immunomodulator drugs.
  • Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against immunosuppression or immuno-modulation may be readily determined by means of one or more lymphocyte activation tests.
  • Auto-immune disorders to be prevented or treated by the pharmaceutical compositions or combined preparations of this invention include systemic auto-immune diseases, auto-immune endocrine disorders, and organ-specific auto-immune diseases; such as, but not limited to, lupus erythematosus, psoriasis, multiple sclerosis, rheumatoid arthritis, thyroiditis, hemolytic or pernicious anemia, insulin-dependent diabetes mellitus, Crohn's disease, autoimmune hepatitis, and autoimmune pneumonitis.
  • systemic auto-immune diseases such as, but not limited to, lupus erythematosus, psoriasis, multiple sclerosis, rheumatoid arthritis, thyroiditis, hemolytic or pernicious anemia, insulin-dependent diabetes mellitus, Crohn's disease, autoimmune hepatitis, and autoimmune pneumonitis.
  • compositions or combined preparations of this invention may be used to prevent long-term or short-term transplant rejection.
  • the active compounds disclosed herein may be orally administered with an inert diluent or with an edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the diet.
  • the active compounds may be incorporated with excipients and used in the form of ingestible tablets, capsules, suspensions, syrups, and the like. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the tablets, pills, capsules and the like may also contain the following: a binder, excipients, a disintegrating agent, a lubricant, and a sweetening agent, and optionally a flavoring agent.
  • a binder examples of materials used for stated purpose are well known in the art and need be elaborated here.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup of elixir may contain sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring.
  • the active compounds may be incorporated into sustained-release preparation and formulations.
  • the active compounds may also be administered parenterally or intraperitoneally.
  • Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Optionally these preparations may contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • antibacterial and antifungal agents such as but not limited to, parabens, chlorobutanol, phenol, sorbic acid, thimerosal may be included.
  • isotonic agents for example, sugars or sodium chloride may be included.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminummonostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the compositions.
  • the present invention also concerns a compound having Formula 1 to Formula 4, for use as a medicine.
  • the present invention also concerns a compound having Formula 1 to Formula 4, for use as a medicine for the prevention or treatment of immune disorders in an animal including a mammal.
  • said immune disorder is an autoimmune disorder or an immune disorder as a result from an organ or cells transplantation.
  • said mammal is human.
  • the present invention also concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound having Formula 1 to Formula 4, and one or more pharmaceutically acceptable excipients.
  • Said composition may further comprise one or more biologically active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, and antineoplastic drugs.
  • the present invention also concerns a process for preparation of compounds of Formula 1 to Formula 4.
  • Example 8 Synthesis of 4,4'-di-tert-butyl[2,2'-bipyridine]-6-carbonitrile (6-cyano-4,4'-Di- tert-butyl-2,2'-bipyridine) (Formula 12) It was synthesized from compound of formula 7 by following a procedure similar to that described for 6-cyano-2,2'- bipyridine in Example 6.
  • HC1 (12M, 10 mL) was added with stirring to a solution of 6-cyano-2,2'-bipyridine (lg) in methanol (50 mL) and contents heated on an oil bath at 80 °C for 48 Hr., when tic showed absence of starting material. Solvents were evaporated on a rotary evaporator under reduced pressure at 45 °C, contents neutralized with saturated solution of NaHC0 3 at 4 °C and extracted with ethyl acetate. The organic layer was dried over NaS0 4 and evaporated at rotary evaporator, to yield ester as colorless solid.
  • Example 12 Synthesis ofmethyl 4,4'-dimethyl[2,2'-bipyridine]-6-carboxylate (Formula 16) It was synthesized from compound of formula 11 by following a procedure similar to that described for 6-methoxycarbonyl-2, 2 '-bipyridine in Example 11.
  • the 6-methoxycarbonyl-2, 2'-bipyridine (lg, 4.67 mmol) was dissolved in dry THF (10 mL) and NaBH 4 (0.69 lg, 18.69 mmol) added to it in small portions.
  • the reaction mixture was refluxed for 2 hr at 80°C, cooled to 0°C and then ethanol added to quench excess borohydride.
  • the solvent was evaporated on rotary evaporator under reduced pressure at 45 °C.
  • saturated solution of ammonium chloride was added to mixture and contents extracted with ethyl acetate.
  • the organic layer was dried over NaS0 4 and solvents removed on rotary evaporator under reduced pressure at 45 °C to yield alcohol as transparent oil.
  • Example 14 Synthesis of (4,4'-dimethyl[2,2'-bipyridin]-6-yl)methanol (Formula 18) It was synthesized from compound of formula 16 by following a procedure similar to that described for 6-hydroxymethyl-2,2'-bipyridine in Example 13.
  • the cooling bath was removed and the reaction mixture allowed to warm to 25 °C and stirring continued at this temperature for another 1 Hr.
  • the solvent was removed on a rotary evaporator under reduced pressure at 45°C and the contents extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous Na 2 C0 3 followed by saturated brine solution and dried over anhydrous Na 2 S0 4 . After removal of the solvent under reduced pressure on rotary evaporator, the crude product was purified by column chromatography.
  • Example 23 Synthesis of([2,2'-bipyridin]-6-yl)(cyclopentyl)methanone (Formula 27) It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)- 2-methylpropan-l-one in Example 17.
  • Example 26 Synthesis of l-(4,4'-di-tert-butyl[2,2'-bipyridin]-6-yl)ethan-l-one (Formula 30) It was synthesized from compound of formula 12 by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)ethan-l-one in Example 24
  • Example 45 Synthesis of N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine (Formula 49)
  • the solvents were removed under reduced pressure, water (10 mL) added and contents extracted with ethyl acetate (50 mL).
  • the organic layer was washed with saturated brine, dried over Na 2 S0 4 and evaporated under reduced pressure on a rotary evaporator at 45 °C to leave a residue, which was re-crystallised from methanol.
  • Example 46 Synthesis of N-[(4,4'-dimethyl[2,2'-bipyridin]-6- yl)methylidene] hydroxylamine (Formula 50) It was synthesized from compound of formula 11 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
  • 6-Cyano-2,2'-bipyridine was reacted with phenylmagnesium bromide by procedure described in Example 24 to yield ([2,2'-bipyridin]-6-yl)(4-methylphenyl)methanone.
  • Example 74 Synthesis of 6-[ ⁇ 2-[([2,2'-bipyridin]-6-yl)methyl]hydrazinylidene ⁇ methyl]-2,2'- bipyridine (Formula 78)
  • Sodium borohydride (20 mg, 0.54 mmol) was added to a solution of compound of Formula 77 (50 mg, 0.13 mmol) in 5 mL methanol in small portions.
  • the reaction mixture was stirred for 30 min, solvents removed under reduced pressure on a rotary evaporator at 45 °C, saturated solution of Na 2 C0 3 was added to crude and contents extracted with ethyl acetate.
  • the organic layer was dried over anhydrous Na 2 S0 4 and solvents removed on rotary evaporator to give a product as colorless solid.
  • 6-cyano-4,4'-dimethyl-2,2'-bipyridine was reacted with phenylmagnesium bromide by procedure described in Example 24 to yield (4,4'-dimethyl[2,2'-bipyridin]-6-yl)(2- methoxyphenyl)methanone.
  • Synthesized compounds were assayed for suppression of T- lymphocytes by fluorescent intracellular labeling of live cells CFSE (5(6)-Carboxyfluorescein N-hydroxysuccinimidyl ester). Splenic cells were suspended in PBS at concentration of 1.5x10 cells/ml). 5 mM of stock solution of CFSE (abeam) in DMSO was added to make the final concentration of 2.5 ⁇ and contents incubated for 9 min at 37°C. After the incubation, cells were given 3 washings with 20% FBS in PBS.
  • CFSE 6-Carboxyfluorescein N-hydroxysuccinimidyl ester
  • Stained cells (2xl0 5 cells/well) were cultured with 100 ⁇ RPMI media in round bottom 96- well plate with 2 ⁇ g/ml Concanavalin A (ConA) and different concentration of synthesized molecules (0-2.5 ⁇ 72 hr.
  • the control cultures consisted of cells incubated with medium alone, ConA or DMSO.
  • CaeA was used as positive control. Each experiment was repeated at least three times. Data was acquired using flow cytometer with 488 nm laser and FL1 detector. CaeA was used as positive control. Each experiment was repeated at least three times.
  • Example 82 In vivo efficacy of N- ⁇ ([2,2'-bipyridin]-6-yl)[4- (trifluoromethoxy)phenyl]methylidene ⁇ hydroxylamine (Formula 60) Graft survival The in vivo efficacy of the Compound of Formula 60 was studied in a mouse model of skin allograft transplantation as described in example 76. The data is shown in Table 4 (Entry 4 and 5). These data indicate that compound of Formula 60 can suppress a robust in vivo allogeneic response.
  • Example 83 In vivo efficacy of N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6- yl)ethylidene]hydroxylamine (Formula 73) Graft survival
  • Present invention discloses new molecules which possess much simpler structures, amenable via chemical synthesis in lesser number of steps, eliminates low yielding and hazardous steps and require significantly lower dose for achieving the desired immunosuppressive effect and therefore lower toxicity and lower metabolic load. Moreover, this invention provides more efficacious molecules at significantly lower cost.

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Abstract

Provided herein is a compound having the Formula 1, all of its related stereoisomers and their pharmaceutically acceptable salts with immunosuppressive property and process for preparation thereof. The said molecule provides potent anti-proliferative activity in lymphocyte proliferation assay and in mouse skin graft rejection assay. Further, the said molecule is a valuable lead compound in development of improved immunosuppressive agents.

Description

IMMUNOSUPPRESSIVE AGENTS
FIELD OF THE INVENTION
The present invention relates to 2,2 '-bipyridine derivatives compound of formula I and use thereof as immunosuppressive agents. Particularly, present invention relates to the use of said 2,2'- bipyridine derivatives as biologically active ingredients, more specifically as medicament for treating diseases due to abnormal immune response induced by the activated T cells, such as rejection of organ transplantation, autoimmune disease, inflammatory reaction, fibrosis or dysfunction caused by autoimmune disease or related disease thereof with tissue injury or infection, or allergic disease.
BACKGROUND OF THE INVENTION
The large numbers of natural products show several types of biological activities. These natural products are used for treatment of autoimmune, inflammatory, antiviral and cardiovascular diseases. (Dias, D. A.; Urban, S.; Roessner, U. C. P., A historical overview of natural products in drug discovery. Metabolites 2012, 2 (2), 303-36). The several types of scaffolds including ployketides, fatty acid derivatives, cyclic peptide and polypeptide are used as immunosuppressive agents. These molecules are isolated from various microorganism and various plants. (Mann, J., Natural products as immunosuppressive agents. Nat Prod Rep 2001, 18 (4), 417-30.)
The cyclosporine, FK506, and rapamycin are secondary metabolites which are used for immunosuppression. (Hung, D. T.; Jamison, T. F.; Schreiber, S. L., Understanding and controlling the cell cycle with natural products. Chem Biol 1996, 3 (8), 623-39.)
The Pateamine A is isolated from marine life which shows immunosuppressive properties. The stable and simple analogues or derivatives of this natural form have been synthesized and analysed for immunosuppression property.
2,2 '-Bipyridine (2,2'-BP) molecular scaffold occurs in many natural products such as caerulomycins (Caes), collismycins (Cols), camptothecin, orelline, and streptonigrin. These products show wide range of biological activities. The Caes and Cols share similar scaffold, ring
A is di- or tri-substituted, conjugated with ring B which is not substituted by any functional group.
In Cols sulphur-containing group is attached at the C5 position of ring A, but in Caes hydrogen is attached instead of sulphur-containing group. ( J Am Chem Soc 2012, 134 (22), 9038-41).
The caerulomycins (Caes) class include caerulomycins A-C (1-3), D (4) and E-J (5-10).
{Canadian Journal of Chemistry 1978, 56 (13), 1836-1842 and Journal of Natural Products 2011,
74 (8), 1751-1756.) Structure of all forms is shown below: 1
Figure imgf000003_0001
: R1 = H, R2 = OCH3 R3 = CHNOH
4
2: R1 = OH, R2 = OCH3 R3 = CHNOH
3: R1 = OCH3, R2 = OCH3 R3 = CHNOH
5: R1 = H , R2 = OCH3 R3 = CHO
6: R1 = H, R2 = OCH3 R3 = CH2OH
7: R1 = H, R2 = OCH3 R3 = CH2OH
8: R1 = H , R2 = OH R3 = CHNOH
9: R1 = H , R2 = OCH3 R3 = CON H-OCH3
10 : R1 = H , R2 = OH R3 = CH2-NHCOCH3
Recently, immunosuppressive property of CaeA has been disclosed in patent (US 8,114,895). The Caerulomycin A prompts immunosuppression by up regulating CTLA-4 and reducing CD28 expression on T cells. The CaeA down regulated the expression of cytokines interferon-γ and interleukin-4. This document is herewith incorporated by reference in to present application.
Originally, Caerulomycin A (CaeA) was extracted from Streptomyces caeruleus and antimicrobial properties of CaeA was also observed. Various biological properties of CaeA have also been disclosed. CaeA inhibits proliferation of Jurkat cells by targeting cellular iron. CaeA causes intracellular iron depletion by reduced uptake and increased release by cells. CaeA has multiple cellular targets, viz., iron containing ribonucleotide reductase enzyme and cell cycle control molecules cyclin Dl, p21CIPI/WAFl and cdk4, which are important for normal cell cycle progression. Anti-asthmatic activity is also exhibited by CaeA (Sci Rep 2015, 5, 15396).
Some immunosuppressive drugs are isolated from natural resource in small amounts. Also, these are difficult to synthesise in pharmaceutical effective amount due to complexity in their structures. The immunosuppressive therapy require molecules with higher efficacy, minimum side effect, simpler chemical structures, amenable to synthesis via simpler and fewer reaction steps. Moreover, the new immunosuppressant should have increased shelf-life at ambient temperature and increased stability to metabolic modification for providing effective relief to subject requiring immunosuppressive therapy.
Immune system of an organism has been developed such that it respond efficiently to eliminate foreign microorganism (non-self-antigens), whereas it does not respond to the self- ant gens, or respond to them having the failure to mount immune response. T lymphocytes (T cells) and B lymphocytes (B cells) are the primary cells of the adaptive arm of the immune system. T cells are specific for foreign antigens and their number must increase enormously in response for specific host defence. Optimum activation of T cell depends on two discrete receptor-ligand recognition events. The major event is the interaction of T cell receptors (TCRs) with peptide-major histocompatibility complexes (pMHC) that are displayed on the surface of the antigen-presenting cell (APC) such as B cell, macrophage and dendritic cell. Other event is the interaction of a family of related co-stimulatory receptors with their respective ligands that furnishes the co- stimulatory signals (CD28, CD40L), which are required for efficient T cell activation. Moreover, a complementary set of co-stimulatory signals (CTLA-4, PD-I, BTLA) provide negative signal that reduce the immune response and help maintaining the peripheral T cell tolerance to protect against autoimmunity.( Science 2001, 291 (5502), 319-22 & Immunity 2001, 14 (2), 145-55). The main co-stimulatory molecules, CD28 and CTLA-4/CD152 are expressed on the surface of T cells. CD28 co- stimulation is necessary for the initiation of most T cell responses, and this has therapeutic implications; in that blockade of CD28 co- stimulation can be profoundly immunosuppressive, preventing induction of pathogenic T cell responses in autoimmune disease models and allowing for prolonged acceptance of allograft in models of organ transplantation (Annu Rev Immunol 2001, 19, 225-52). CTLA-4 (CD 152) mediates such an inhibitory signal. Whereas CD28 is constitutively expressed on T cells, CTLA-4 is not expressed constitutively on naive T cells. CTLA4 is only expressed after the CD4+ T cell becomes activated and upon engagement with B7 molecules, transduces a negative signal to T cells. As the binding affinity of B7-1 and B7-2 for CTLA4 is higher than for CD28, negative signaling would dominate on activated T cells, thereby terminating the immune response. CTLA-4 blockade in vivo enhances antigen-specific and anti-parasite responses, tumor rejection, autoimmune disease, and exacerbates graft rejection. (Curr Opin Immunol 1996, 8 (6), 822-30 & Annual Review of Immunology 2001, 19, 565-594).
The CaeA introduce the immunosuppression by various mechanisms such as down regulation of activation marker CD69, up regulation of negative co- stimulatory signals, reduce expression of various inflammatory cytokines and inhibiting proliferation of various types of B and T cells. ( PLoS One 2014, 9 (10), el07051).
The communication of T cell receptors (TCRs) with peptide-major histocompatibility complexes (PMHC) is not sufficient for activation of immune response. The second activation signal is completed by interaction of B7 (CD80/86) molecules with CD28 which is present on T cells. The corresponding event of co- stimulatory signals such as interaction of CTLA-4 with B7 molecule reduces the immune response. The Caerulomycin A prompts immunosuppression by up regulating CTLA-4 and reducing CD28 expression on T cells. The CaeA down regulated the expression of cytokines interferon-γ and interleukin-4.
Regulatory T cells (Tregs) play an important role in deactivation of immune response. Tregs can slow down the activity of T cell by competition of cytokines and up regulating CTLA-4. The antiasthmatic activity of CaeA is proved by reduction in levels of Th2 cells, reduction in expression of GAT A- 3 and cytokines (IL-4, IL-5, IL-13) secreted by Th2 cells. The IL-4, IL-5 and IL-13 help in stimulation of eosinophilis, mast cells and increase the level of IgE Abs.
The T cells play crucial role in graft rejection. The suppression of alloreactive T cells helps the survival of allogeneic skin graft. In the mixed lymphocyte reaction CaeA exhibits reduction in proliferation of alloreactive T cells. CaeA displays prolonged skin allograft rejection.
CaeA and CaeE are prepared by different pathways including metalation and cross-coupling reactions. Another method is reported from diketone and picolinic acid. The pyranone method of synthesis of CaeA is also explored using precursor 4-ethoxy-3-pentene-2-one.( Tetrahedron 2010, 66 (29), 5432-5434)
Immunosuppressive drugs (ISDs) are crucial for long-term graft survival following organ transplantation. In addition ISDs are prescribed for the treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. {Expert Opin Emerg Drugs 2003, 8 (1), 47-62 & Experimental and clinical pharmacology 2006, 29, 99-101).
Although, currently used drugs in clinic, such as cyclosporine A, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate, prednisone, etc. have provided significant relief to patients, these suffer from one or another drawback, such as poor oral bioavailability, side effects like nephrotoxicity and malignancy, non-specific mode of action, incomplete suppression of belligerent immune cells, unaffordable cost, etc.
Therefore there is a continuous need in the art for discovering efficacious, selective and safer new immunosuppressive drugs for improved sustenance of organ transplants and treatment of autoimmune disorders. In particular, there is a need in the art to provide immunosuppressive compounds, which are active in a low dose and decrease the treatment cost.
Immunosuppressive drugs (ISDs) are crucial for long-term graft survival following organ transplantation. In addition ISDs are prescribed for the treatment of autoimmune diseases, inflammatory disorders, hypersensitivity to allergens, etc. Although, currently used drugs in clinic, such as cyclosporine A, tacrolimus, rapamycin, azathioprine, cyclophosphamide, methotrexate, prednisone, etc. have provided significant relief to patients, these suffer from one or another drawback, such as poor oral bioavailability, side effects like nephrotoxicity and malignancy, non- specific mode of action, incomplete suppression of belligerent immune cells, unaffordable cost, etc.
Therefore, there is a continuous need in the art for discovering efficacious, selective and safer new immunosuppressive drugs for improved sustenance of organ transplants and treatment of autoimmune disorders. In particular, there is a need in the art to provide immunosuppressive compounds, which are active in a low dose and to decrease treatment costs.
The present invention is based on the finding that certain combinations of substituents at different positions of the 2,2-bipyridine ring system, said combinations not being suggested by the prior art, are able to meet one or more of the medical needs recited herein above. For example, many of these 2,2-bipyridine ring system have ketoxime substituent in place of aldoxime substituent present in CaeA. Further, in many of the 2,2-bipyridine ring system, the methoxyl group of CaeA has been replaced with H or methyl. The ketoximes are prepared in lesser number of steps in the synthesis compared to aldoximes and also eliminates low yielding and hazardous steps involved in synthesis of aldoximes. The replacement of methoxyl group with H or methyl leads to further reduction in number of steps in synthesis. Moreover, some of these molecules require significantly lower dose compared to CaeA, whereas some other have activity similar to CaeA in in vitro lymphocyte proliferation assays.
OBJECT OF THE INVENTION
The main object of the present invention is to provide a compound of formula I.
Another object of the present invention is to provide compound of formula I useful as immunosuppressive agent.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 represents displays the chemical structure of CaeA, and one methyl engaged analog. Figure 2 represents scheme showing the example of synthesis of some molecules from cyano intermediate.
Figure 3 represents scheme showing the example of synthesis of some molecules from same precursors as describe in Figure 2, but following different reaction scheme.
Figure 4 represent effect of compounds 49, 51-56, 81 and 82 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 μΜ) of Con A, and CaeA, 49, 51-56, 81 or 82 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
Figure 5 represent effect of compounds 57-60, 62, 63 and 64 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 μΜ) of Con A, and CaeA, 57-60, 62, 63 or 64 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
Figure 6 represent effect of compounds 61 and 65-69 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 μΜ) of Con A, and CaeA, 61 or 65-69 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
Figure 7 represent effect of compounds 73-76 on proliferation of concanavaline A (Con A)- stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 μΜ) of Con A, and CaeA, or 73-76 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
Figure 8 represent effect of compounds 51, 70 and 71 on proliferation of concanavaline A (Con A)-stimulated mouse T-lymphocytes: Splenocytes of BALB/c mice were labelled with CFSE and treated with different concentration (0 to 2.5 μΜ) of Con A, and CaeA, 51, 70 or 71 for 72 hr. % cell proliferation was determined by CFSE assay. Results are mean values + SD of three similar experiments.
SUMMARY OF THE INVENTION
Accordingly, present invention provides compound of Formula 1
Figure imgf000007_0001
Formula 1
and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof
wherein A , B , C , and D are identical or non-identical and are selected from the group consisting of hydrogen, hydroxyl, chloro, fluoro, cyano, Ci to Cio normal or branched chain alkylamino, Ci to C 10 normal or branched chain dialkylamino, and Ci to Cio normal or branched chain alkoxy;
A and B are identical or non-identical and are selected from the group consisting of following formulae
Figure imgf000008_0001
wherein
R1 is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, fluoro, and cyano;
R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
X is O or N;
Y is O or N;
n = 1 to 10;
C and D are identical or non-identical and are selected from the group consisting of
syn or anti -R4C=NR5, and -R4CH-NHR6
wherein
R4 is selected from the grou consisting of following formulae
Figure imgf000008_0002
wherein R is hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Cio normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy;
R is hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Cio normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy;
R9 is H, Ci to Cio normal or branched chain alkyl, heterocyclic ring, and poly aromatic hydrocarbon (PAH), wherein said heterocyclic ring or PAH group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, trifuoromethoxyl, bromo, chloro, flouro, and cyano;
R10 is H or Q to Cio normal or branched chain alkyl;
R11 is H or Ci to Cio normal or branched chain alkyl;
n =l to 10;
R5 is selected from roup consisting of following formulae
Figure imgf000009_0001
wherein
n = 0 to 10;
m = 1 to 10;
12
R is hydroxyl or amino
13
R is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R14 is H or Ci to Cio normal or branched chain alkyl;
R15 is H or Ci to Cio normal or branched chain alkyl;
R16 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
17
R is selected from group consisting of H, Ci to Cio normal or branched chain alkyl, aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano; R6 is selected from roup consisting of following formulae
Figure imgf000010_0001
wherein
n = 0 to 10
18
R is H or Ci to Qo normal or branched chain alkyl;
R19 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
In an embodiment of the present invention, said compound is useful as immunosuppressive agent. In another embodiment of the present invention, representative compound of formula 1 comprising:
N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine (Formula 49);
N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)methylidene]hydroxylamine (Formula 50);
N-[l-([2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 51);
N-[l-([2,2'-bipyridin]-6-yl)propylidene]hydroxylamine (Formula 52);
N-[l-([2,2'-bipyridin]-6-yl)-2-methylpropylidene]hydroxylamine (Formula 53);
N-[l-([2,2'-bipyridin]-6-yl)-3-methylbutylidene]hydroxylamine (Formula 54);
N-[l-([2,2'-bipyridin]-6-yl)-4-methylpentylidene]hydroxylamine (Formula 55);
N-[l-([2,2'-bipyridin]-6-yl)nonylidene]hydroxylamine (Formula 56);
N-[([2,2'-bipyridin]-6-yl)(phenyl)methylidene]hydroxylamine (Formula 57);
N-[([2,2'-bipyridin]-6-yl)(4-methylphenyl)methylidene]hydroxylamine (Formula 58);
N-[([2,2'-bipyridin]-6-yl)(4-fluorophenyl)methylidene]hydroxylamine (Formula 59);
N-{ ([2,2'-bipyridin]-6-yl)[4-(trifluoromethoxy)phenyl]methylidene}hydroxylamine (Formula 60); N-{ ([2,2'-bipyridin]-6-yl)[4-(dimethylamino)phenyl]methylidene}hydroxylamine (Formula 61);
N-[([2,2'-bipyridin]-6-yl)(4-methoxyphenyl)methylidene]hydroxylamine (Formula 62);
N- [( [2,2'-bipyridin] -6-yl)(2-methoxyphenyl)methylidene]hydroxylamine (Formula 63 ) ;
N- [( [2,2'-bipyridin] -6-yl)(3 -methoxyphenyl)methylidene]hydroxylamine (Formula 64) ;
N-[([2,2'-bipyridin]-6-yl)(2,5-dimethoxyphenyl)methylidene]hydroxylamine (Formula 65);
N-[([2,2'-bipyridin]-6-yl)(3,4,5-trimethoxyphenyl)methylidene]hydroxylamine 9 Formula 66);
N-[([2,2'-bipyridin]-6-yl)(naphthalen-2-yl)methylidene]hydroxylamine (Formula 67) N-[([2,2'-bipyridin]-6-yl)(6-methoxynaphthalen-2-yl)methylidene]hydroxylamine (Formula 68); N-[([2,2'-bipyridin]-6-yl)(phenanthren-9-yl)methylidene]hydroxylamine (Formula 69);
N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)-2-methylpropylidene]hydroxylamine (Formula 70); N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)(4-methoxyphenyl)methylidene]hydroxylamine (Formula
71);
N-{ (4,4'-dimethyl[2,2'-bipyridin]-6-yl)[4-(trifluoromethoxy)phenyl]methylidene}hydroxylamine (Formula 72);
N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 73);
N-[l-(4,4'-dimethoxy[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 74);
N-[l-(4,4'-di-ieri-butyl [2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 75);
N-[l-(4,4'- dinonyl[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 76);
6,6'-[hydrazinediylidenedimethanylylidene]di(2,2'-bipyridine) (Formula 77);
6- [ { 2- [([2,2'-bipyridin] -6-yl)methyl]hydrazinylidene } methyl] -2,2'-bipyridine (Formula 78);
6-(l-hydrazonoethyl)-2,2'-bipyridine (Formula 79);
N-[([2,2'-bipyridin]-6-yl)(2,4-dimethoxyphenyl)methylidene]hydroxylamine (Formula 80);
N-[(E)-([2,2'-bipyridin]-6-yl)(cyclopentyl)methylidene]hydroxylamine (Formula 81);
N-[(lE)- l-([2,2'-bipyridin]-6-yl)but-2-yn-l-ylidene]hydroxylamine (Formula 82);
N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)(2-methoxyphenyl)methylidene]hydroxylamine (Formula
83).
In yet another embodiment of the present invention, said compound is useful as a medicine for the prevention or treatment of immune disorders in an animal or human.
In yet another embodiment of the present invention, said immune disorder is an autoimmune disorder or an immune disorder as a result from organ transplantation.
DETAILED DESCRIPTION OF THE INVENTION
Present invention provides an immunosuppressive compound of Formula 1
Figure imgf000011_0001
Formula 1
wherein A , B , C , and D are identical or non-identical and are selected from the group consisting of hydrogen, hydroxyl, chloro, fluoro, cyano, Ci to Cio normal or branched chain alkylamino, Ci to C 10 normal or branched chain dialkylamino, and Ci to Cio normal or branched chain alkoxy;
A and B are identical or non-identical and are selected from the group consisting of following formulae
(1 (2) (3)
Figure imgf000012_0001
wherein
R 1 , R2 , R 3 is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, fluoro, and cyano;
X is O or N;
Y is O or N;
n = 1 to 10;
C and D are identical or non-identical and are selected from the group consisting of syn or anti -
R4C=NR5 and -R4CH-NHR6;
wherein
R4 is selected from the group consisting of following formulae
(1) 2) (3) (4) (5)
Figure imgf000012_0002
wherein
R 7 , R 8 is selected from group consisting of hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Cio normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy; R9 is selected from group consisting of H, Q to Cio normal or branched chain alkyl, heterocyclic ring, and poly aromatic hydrocarbon (PAH), wherein said heterocyclic ring or PAH group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R10 is H or Ci to Cio normal or branched chain alkyl;
R11 is H or Ci to Cio normal or branched chain alkyl;
n =l to 10;
R5 is selected from group consisting of following formulae
(1) 2)
Figure imgf000013_0001
wherein
12
R is hydroxyl or amino
n = 0 to 10;
13
R is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R14 is H or Ci to Cio normal or branched chain alkyl;
Figure imgf000013_0002
wherein
n = 1 to 10;
R15 is H or Ci to Cio normal or branched chain alkyl;
R16 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
4)
Figure imgf000013_0003
wherein R is selected from group consisting of H, Ci to Cio normal or branched chain alkyl, aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R6 is selected from group consisting of following formulae
Figure imgf000014_0001
wherein
n = 0 to 10
18
R is H or Ci to Qo normal or branched chain alkyl;
R19 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
Present invention provides an immunosuppressive compound of Formula 2:
Figure imgf000014_0002
Formula 2
wherein
20 21
and R are identical or non-identical and are selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, and Ci to Cio normal or branched chain alkoxy;
22
R is selected from group consisting of hydrogen, Ci to Cio normal, or branched chain alkyl, Ci to Cio normal or branched chain alkynyl, Ci to Cio normal or branched chain alkenyl, C3-C7 alicyclic ring, aryl, and heterocyclic group, wherein the said aryl or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, trifuoromethoxyl, bromo, chloro, flouro, and cyano;
and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
Preferred combinations are established in Table 1. Table 1
Figure imgf000015_0001
H H
H H
H H
H H
H H H H
Me Me H H
Present invention provides an immunosuppressive compound of Formula 3:
Figure imgf000016_0001
Formula 3
wherein
23 24
R" and are identical or non-identical and are selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, and -OR26, wherein said R26 is of Ci to Cio normal or branched chain alkyl;
25
R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl and aryl, wherein the said aryl is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, trifluoromethoxyl, bromo, chloro, flouro and cyano; and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
Preferred combinations are established in Table 2.
Table 2
Figure imgf000017_0002
Present invention provides an immunosuppressive compound of Formula 4
Figure imgf000017_0001
Formula 4
wherein
n = 0 to 10;
dotted line (— ) is single or double bond;
R 27 , R 28 , FT 29 and R 3J0U are identical or non-identical and are selected from group consisting of Ci to Cio normal or branched chain alkyl, Ci to C10 normal or branched chain alkoxy, Ci to C10 normal or branched chain alkylamino, and Ci to Cio normal or branched chain dialkylamino; and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or solvate thereof.
Chemical structure of compounds:
Figure imgf000018_0001
Formula 17 Formula 18 Formula 19 Formula 20
Figure imgf000019_0001

Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
21
Figure imgf000023_0001
Figure imgf000023_0002
Formula 81 Formula 82 Formula 83
Synthesis of 2,2-bipyridine derivatives: The oxidation and reduction reactions are used for synthesis of intermediates such as N-oxide, alcohols and aldehyde. The intermediates N-oxide are prepared by oxidation of different derivatives of bipyridine with mCPBA in CH2CI2. The cyanation of N-oxide is achieved by trimethylsilyl cyanide (TMSCN) and dimethylcarbmoyl chloride in dichloromethane. The TMSCN is an alternative of KCN. This method gives cyanation in regio selective manner. The ketone is prepared by reaction of nitrile with RMgBr in tetrahydrofuran or from oxidation of secondary alcohol. The aromatic ketones, ethyl and methyl ketone are generated directly from nitrile group.
The derivatives having cyclic, branched alkyl, and long alkyl chain are prepared by different pathways. The cyclic, branched alkyl and long alkyl chain ketones are prepared by addition of RMgBr on aldehyde, followed by swern oxidation. The aldehyde is prepared in three step, (i) esterification of nitrile intermediate, (ii) reduction of ester and (iii) oxidation of alcohol. The oxime formation of aldehyde or ketone is done by hydroxylamine hydrochloride and pyridine at refluxing in ethanol.
Compounds of Formula 4 can be prepared by reaction of aldehyde or ketone with hydrazine or α,ω-diamine. Imine double bonds can be reduced with a borohydride reagent or by catalytic hydrogenation method. In yet another embodiment of the present invention, compound of Formula 1 to Formula 4 suppressed the proliferation of T-cell lymphocytes.
In yet another embodiment of the present invention, compound of Formula 1 to Formula 4 suppressed the proliferation of mitogen induced (Con A) T-cell lymphocytes. The fluorescent dye 5,6-carboxylfluorescein diacetate succinimidyl ester (CFSE) is used for detection, identification and quantification of proliferated T cells in vitro. This assay is more sensitive than H-thymidine based assay.
In yet another embodiment of the present invention, compound of Formula 1 to Formula 4 increases the level of anti-inflammatory cytokines like IL-10 and reduces the level of proinflammatory cytokines like IL-2, TNF and IFN-γ in mice. This perturbation of cytokines level is favourable for the prolongation of allograft survival.
In yet another embodiment of the present invention, compound of Formula 1 to Formula 4 significantly prolongs the survival of skin allograft in mice.
In yet another embodiment, present invention provides pharmaceutically acceptable salts of any compound of Formula 1 to Formula 4. The pharmaceutically acceptable salts may be obtained by treating any of Formula 1 to Formula 4 compound with an appropriate salt-forming acid. Examples of such appropriate salt-forming acids include, for instance, inorganic acids resulting in forming salts such as but not limited to hydrohalides (e.g. hydrochloride and hydrobromide), sulfate, nitrate, phosphate, diphosphate, carbonate, bicarbonate, and the like; and organic monocarboxylic or dicarboxylic acids resulting in forming salts such as, for example, acetate, propanoate, hydroxyacetate, 2-hydroxypropanoate, 2-oxopropanoate, lactate, pyruvate, oxalate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, methanesulfonate, ethanesulfonate, benzoate, 2-hydroxybenzoate, 4-amino-2-hydroxybenzoate, benzenesulfonate, p- toluenesulfonate, salicylate, p-aminosalicylate, palmoate, bitartrate, camphorsulfonate, edetate, 1,2-ethanedisulfonate, fumarate, glucoheptonate, gluconate, glutamate, hexylresorcinate, hydroxynaphthoate, hydroxyethanesulfonate, mandelate, methylsulfate, pantothenate, stearate, as well as salts derived from ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2- butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutane-dioic, 2-hydroxy- 1,2,3 - propanetricarboxylic and cyclohexanesulfamic acids and the like.
Preferably, the salt-forming acid will be selected so as to impart greater water-solubility, lower toxicity, greater stability and/or slower dissolution rate to any of Formula 1 to Formula 4 compound. Present invention provides a pharmaceutical composition of the invention for use as a medicine, more particularly use of Formula 1 to Formula 4 compounds to treat or prevent an immune disorder in an animal, more particularly to treat or prevent autoimmune disorders, and particular organ rejections in an animal, more specifically a human.
In another embodiment, this invention provides combinations, preferably synergistic combinations, of one or more Formula 1 to Formula 4 compounds of this invention with one or more biologically active drugs being preferably selected from the group consisting of immunosuppressant and/or immunomodulator drugs. The evaluation of a synergistic effect in a drug combination is well known in the art and will not be described further.
Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against immunosuppression or immuno-modulation may be readily determined by means of one or more lymphocyte activation tests.
Auto-immune disorders to be prevented or treated by the pharmaceutical compositions or combined preparations of this invention include systemic auto-immune diseases, auto-immune endocrine disorders, and organ-specific auto-immune diseases; such as, but not limited to, lupus erythematosus, psoriasis, multiple sclerosis, rheumatoid arthritis, thyroiditis, hemolytic or pernicious anemia, insulin-dependent diabetes mellitus, Crohn's disease, autoimmune hepatitis, and autoimmune pneumonitis.
The pharmaceutical compositions or combined preparations of this invention may be used to prevent long-term or short-term transplant rejection.
The active compounds disclosed herein may be orally administered with an inert diluent or with an edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, capsules, suspensions, syrups, and the like. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
The tablets, pills, capsules and the like may also contain the following: a binder, excipients, a disintegrating agent, a lubricant, and a sweetening agent, and optionally a flavoring agent. Examples of materials used for stated purpose are well known in the art and need be elaborated here. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring. In addition, the active compounds may be incorporated into sustained-release preparation and formulations.
The active compounds may also be administered parenterally or intraperitoneally. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Optionally these preparations may contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Optionally antibacterial and antifungal agents, such as but not limited to, parabens, chlorobutanol, phenol, sorbic acid, thimerosal may be included. Optionally isotonic agents, for example, sugars or sodium chloride may be included. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminummonostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the compositions.
The present invention also concerns a compound having Formula 1 to Formula 4, for use as a medicine.
The present invention also concerns a compound having Formula 1 to Formula 4, for use as a medicine for the prevention or treatment of immune disorders in an animal including a mammal. In an embodiment, said immune disorder is an autoimmune disorder or an immune disorder as a result from an organ or cells transplantation. In an embodiment, said mammal is human. The present invention also concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound having Formula 1 to Formula 4, and one or more pharmaceutically acceptable excipients. Said composition may further comprise one or more biologically active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, and antineoplastic drugs.
The present invention also concerns a process for preparation of compounds of Formula 1 to Formula 4.
EXAMPLES
Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
General
For all reactions, analytical grade reagents and solvents were used. All moisture- sensitive reactions were carried out in oven-dried glass-ware (135 °C). All Experiments were performed at 25°C unless otherwise specified. 1H NMR spectra were obtained at 300 MHz (Jeol ECX 300) and referenced to TMS (0.0 ppm) or the residual solvent peak (CHC13 7.26 ppm). 13 C NMR spectra were recorded at 75 MHz and referenced either to TMS (0.0 ppm) or internal solvent (CDCI3 77.0 ppm). Chemical shifts are reported as parts per million (ppm) using the δ scale. Abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s = broad signal. Values of coupling constants 7 are reported in Hz. Pre-coated aluminum sheets (MERCK Silica gel 60 F254/TLC-cards, 254 nm) were used for TLC. Column chromatography was performed on MERCK silica gel 60-120 mesh.
Example 1: Synthesis of 2,2'-bipyridine N-oxide (Formula 5)
To a stirred solution of 2,2'-bipyridine (lg, 6.41 mmol) in chloroform (50 mL), 3- chloroperoxybenzoic acid (1.62 g of 75 % w/w, 7.05 mmol) in chloroform (300 mL) was slowly added over 24 hr at 25 °C. The stirring was continued overnight (12 Hr) at 25 °C and then chloroform was evaporated on a rotary evaporator under reduced pressure at 45 °C to leave a residue, which was subjected to purification by column chromatography (silica gel, 5% MeOH in EtOAc) to yield N-oxide as clear oil.
1H NMR (300 MHz, CDCI3): δ = 8.88 (ddd, 7 =7.91, 1.05, 1.02 Hz, 1H, H-3), 8.71 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz, H-6), 8.31(dd, 1H, 7 = 6.54, 1.03 Hz, H-6'), 8.17 (dd, 1H, 7 = 8.26, 2.41 Hz, Η-3'), 7.82 (dt, 1H, = 7.91, 1.72 Hz, H-4), 7.38-7.23 (m, H5, H-4', H-5'). C NMR (75 MHz, CDC13): δ = 149.71, 149.49, 147.45, 140.78, 136.36, 127.99, 125.89, 125.63, 125.34, 124.38.
Example 2: Synthesis of 4,4'-dimethyl-2,2'-bipyridine N-oxide (Formula 6)
It was synthesized from 4,4'-dimethyl-2,2'-bipyridine by following a procedure similar to that described for 2,2'-bipyridine N-oxide in Example 1.
1H NMR (300 MHz, CDC13): δ = 8.66 (d, = 0.69 Hz, 1H, H-3), 8.51 (d, 1H, = 4.82 Hz, H-6), 8.16 (d, 1H, = 6.88 Hz, H-6'), 7.88 (d, 1H, = 2.75 Hz, H-3'), 7.10 (dd, 1H, = 4.82, 0.69 Hz, H-5), 7.02 (dd, 1H, = 6.88, 2.75 Hz, H-5') 2.39 (s, 3H, Me), 2.34 (s, 3H, Me). 13C NMR (75MHz, CDCI3): δ = 149.61, 149.12, 147.58, 146.65, 140.07, 137.67, 128.38, 126.55, 126.11, 125.30, 21.39, 20.46.
Example 3: Synthesis of 4,4'-di-tert-butyl-2,2'-bipyridine N-oxide (Formula 7)
It was synthesized from 4,4'-di-ie/t-butyl-2,2'-bipyridine by following a procedure similar to that described for 2,2'-bipyridine N-oxide in Example 1.
1H NMR (300 MHz, CDC13): δ = 8.90 (d, 1H, = 2.06 Hz, H-3), 8.62 (d, 1H, = 5.16 Hz, H-6), 8.21 (d, lH, / = 6.88 Hz, H-6'), 8.07 (d, 1Η, = 2.75 Hz, H-3'), 7.32 (dd, 1H, = 5.16, 2.06 Hz, H-5), 7.24 (dd, 1H, = 6.88, 2.75 Hz, H-5') 1.368 (s, 9H, i-Bu) 1.362 (s, 9H, ί-Bu). 13C NMR
(75MHz, CDCI3): δ = 160.23, 150.38, 150.14, 149.27, 146.72, 139.92, 124.82, 122.97, 122.56, 121.35, 35.09, 34.77, 30.64.
Example 4: Synthesis of 4,4'-dimethoxy-2,2'-bipyridine N-oxide (Formula 8)
It was synthesized from 4,4'-dimethoxy-2,2'-bipyridine by following a procedure similar to that described for 2,2'-bipyridine N-oxide in Example 1.
1H NMR (300 MHz, (CD3)2SO): δ = 8.60 (d, 1H, = 2.41 Hz, H-3), 8.50 (d, 1H, = 5.5 Hz, H- 6), 8.19 (d, 1H, = 7.22 Hz, H-6'), 7.68 (d, 1H, = 3.44 Hz, H-3'), 7.07-7.02 (m, 2H, H-5, 5') 3.847 (s, 3H, OMe), 3.844 (s, 3H, OMe). 13C NMR (75 MHz, (CD3)2SO): δ = 165.77, 156.73, 151.10, 150.96, 146.59, 142.09, 113.61, 112.16, 111.81, 110.71, 56.69, 55.99.
Example 5: Synthesis of 4,4 '-dinonyl-2, 2 '-bipyridine N-oxide (Formula 9)
It was synthesized from 4,4'-dinonyl-2, 2'-bipyridine by following a procedure similar to that described for 2,2'-bipyridine N-oxide in Example 1. 1H NMR (300 MHz, CDC13): δ = 8.74 (d, 1H, 7 = 1.72 Hz, H-3), 8.56 (dd, 1H, = 5.16, 0.69 Hz, H-6), 8.18 (d, 1H, = 6.54 Hz, H-6'), 7.93 (d, 1H, = 2.75 Hz, H-3'), 7.13 (dd, 1H, = 5.16, 1.72 Hz, H-5), 7.04 (dd, 1H, = 6.54, 2.75 Hz, H-5') 2.69-2.59 (m, 4H, Ph-CH2 ), 1.69-1.59 (m, 4H, Ph-CH2), 1.37-1.18 (m, 24H, Ph-CH2), 0.87-0.82 (m, 6H, -CH3). 13C NMR (75 MHz, CDC13): δ = 152.26, 149.76, 149.14, 146.77, 142.19, 140.13, 127.61, 125.86, 125.18, 124.50, 35.59, 34.65, 31.92, 30.43, 30.32, 29.52, 29.49, 29.43, 29.36, 29.24, 22.73, 14.17.
Example 6: Synthesis of [2,2'-bipyridine]-6-carbonitrile (6-cyano-2,2'- bipyridine) (Formula 10)
A solution of 2,2'-bipyridine-N-oxide (2.0 g, 11.62 mmol), N, N'-dimethylcarbamoyl chloride (4.97 g, 46.51 mmol) and Me3SiCN (4.60 g, 46.51mmol) in CH2C12 (50 mL) was stirred at 25 °C till complete consumption of N-oxide occurred (48 Hr). The progress of reaction was observed by TLC. Solvent was removed on a rotary evaporator under reduced pressure at 45 °C to leave an orange coloured residue. Saturated solution of NaHC03 was added to this residue and contents extracted with ether (100 mL). The organic layer was dried over NaS04 and solvents evaporated on a rotary evaporator under reduced pressure at 45 °C to leave a residue, which was crystallized from ether/hexane to yield product as colourless crystals.
1H NMR (300 MHz, CDC13): δ = 8.69-8.66 (m, 2H, H-3 and H-6'), 8.47 (dd, 1H, = 8.26, 1.03 Hz, H-3'), 7.94 (dd, 1H, = 7.91, 7.56 Hz, H-4), 7.85 (dt, 1H, = 7.56, 1.72 Hz, H-4'), 7.69 (dd, 1H, = 7.56, 1.03 Hz, H-5), 7.37 (ddd, 1H, = 7.56, 4.82, 1.38 Hz, H-5'). 13C NMR (75 MHz, CDC13): δ = 157.77, 154.06, 149.39, 138, 137.31, 133.27, 128.23, 124.87, 124.31, 121.65, 117.49.
Example 7: Synthesis of 4,4'-dimethyl[2,2'-bipyridine]-6-carbonitrile (6-cyano-4,4'-dimethyl- 2,2'-bipyridine) (Formula 11)
It was synthesized from compound of formula 6 by following a procedure similar to that described for 6-cyano-2,2'- bipyridine in Example 6.
1H NMR (300 MHz, CDC13): δ = 8.51 (d, 1H, = 4.82 Hz, H-6'), 8.45 (d, 1H, = 0.69 Hz, H-3), 8.26 (d, 1H, = 0.69 Hz, H-3'), 7.50 (d, 1H, = 0.69 Hz, H-5), 7.17 (dd, 1H, = 4.82, 0.69 Hz, H- 5') 2.45 (s, 3H, Me), 2.48 (s, 3H, Me). 13C NMR (75 MHz, CDC13): δ = 57.61, 154.06, 149.69, 149.07, 148.62, 133.14, 129.05, 125.70, 125.14, 122.62, 117.66, 21.31, 21.16.
Example 8: Synthesis of 4,4'-di-tert-butyl[2,2'-bipyridine]-6-carbonitrile (6-cyano-4,4'-Di- tert-butyl-2,2'-bipyridine) (Formula 12) It was synthesized from compound of formula 7 by following a procedure similar to that described for 6-cyano-2,2'- bipyridine in Example 6.
1H NMR (300 MHz, CDC13): δ = 8.65 (d, 1H, =1.72 Hz, H-3), 8.58 (dd, 1H, = 5.16, 0.69 Hz, H-6'), 8.44 (dd, 1H, = 2.06, 0.69 Hz, H-3'), 7.68 (d, 1H, 7 = 1.72 Hz, H-5), 7.34 (dd, 1H, = 5.16, 2.06 Hz, H-5') 1.40 (s, 9H, t-Bu), 1.39 (s, 9H, t-Bu). 13C NMR (75 MHz, CDCI3): δ = 162.58, 161.50, 158.06, 154.44, 149.21, 133.23, 125.69, 121.75, 121.51, 118.84, 118.07, 35.44, 35.16, 34.77, 30.69, 30.51.
Example 9: Synthesis of 4,4'-dimethoxy[2,2'-bipyridine]-6-carbonitrile (6-cyano-4,4'- Dimethoxy-2,2' -bipyridine) (Formula 13)
It was synthesized from compound of formula 8 by following a procedure similar to that described for 6-cyano-2,2'- bipyridine in Example 6.
1H NMR (300 MHz, CDCI3): δ = 8.45 (d, 1H, =5.5 Hz, H-6'), 8.18 (d, 1H, = 2.41 Hz, H-3), 8.00 (d, 1H, = 2.41 Hz, H-3'), 7.21 (d, 1H, = 2.41 Hz, H-5), 6.87 (dd, 1H, = 5.5, 2.41 Hz, H- 5') 3.99 (s, 3H, OMe), 3.96 (s, 3H, OMe). 13C NMR (75 MHz, CDC13): δ = 167.01, 166.89, 159.40, 155.93, 150.23, 134.03, 117.41, 116.48, 112.00, 108.76, 106.74, 56.04, 55.54.
Example 10: Synthesis of 4,4'-dinonyl [2,2'-bipyridine]-6-carbonitrile ( 6-cyano-4, 4'- dinonyl-2, 2 '-bipyridine) (Formula 14)
It was synthesized from compound of formula 9 by following a procedure similar to that described for 6-cyano-2,2'- bipyridine in Example 6.
1H NMR (300 MHz, CDC13): δ = 8.53 (d, 1H, J = 5.16 Hz, H-6'), 8.46 (d, 1H, 7 = 1.72 Hz, H- 3), 8.28 (d, lH, = 1.72 Hz, H-3'), 7.50 (d, 1Η, = 1.72 Hz, H-5), 7.16 (dd, 1H, = 5.16, 1.72 Hz, H-5'), 2.75-2.67 (m, 4H, Ph-CH2), 1.73-1.63 (m, 4H, Ph-CH2), 1.41-1.22 (m, 24H, Ph-CH2), 0.89- 0.84 (m, 6H, Me). 13C NMR (75 MHz, CDC13): δ = 157.74, 154.40, 154.20, 153.36, 149.10, 133.17, 128.35, 124.93, 124.41, 121.90, 117.79, 35.60, 35.37, 31.92, 30.54, 30.28, 29.57, 29.50, 29.42, 29.37, 29.33, 29.27, 22.74, 14.18.
Example 11: Synthesis of methyl [2,2'-bipyridine]-6-carboxylate (6-methoxycarbonyl-2, 2'- bipyridine) (Formula 15)
HC1 (12M, 10 mL) was added with stirring to a solution of 6-cyano-2,2'-bipyridine (lg) in methanol (50 mL) and contents heated on an oil bath at 80 °C for 48 Hr., when tic showed absence of starting material. Solvents were evaporated on a rotary evaporator under reduced pressure at 45 °C, contents neutralized with saturated solution of NaHC03 at 4 °C and extracted with ethyl acetate. The organic layer was dried over NaS04 and evaporated at rotary evaporator, to yield ester as colorless solid.
1H NMR (CDC13): δ = 8.67 (ddd, 1H, 7 = 4.82, 1.72, 0.69,Hz), 8.60 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.53 (ddd, 1H, 7 = 7.91, 1.38, 0.69 Hz), 8.13 (dd, 1H, 7 = 1.03, 7.57 Hz), 7.96 (dd, 1H, 7 = 7.91, 7.57 Hz), 7.84 (dt, 1H, 7 = 1.38, 4.82, 7.57 Hz) 7.33 (ddd, 1H, 7 = 1.38, 4.82, 7.57 Hz) 4.03 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 165.93, 156.54, 155.30, 149.27, 147.60, 137.98, 137.16, 125.08, 124.38, 124.29, 121.76, 52.94.
Example 12: Synthesis ofmethyl 4,4'-dimethyl[2,2'-bipyridine]-6-carboxylate (Formula 16) It was synthesized from compound of formula 11 by following a procedure similar to that described for 6-methoxycarbonyl-2, 2 '-bipyridine in Example 11.
1H NMR (300 MHz, CDC13): δ = 8.47 (d, 1H, 7 = 4.28 Hz, H-6'), 8.36 (s, 1H, H-3), 8.28 (s, 1H, H-3'), 7.91 (s, 1H, H-5), 7.09 (d, 1H, 7 = 4.82, H-5'), 3.98 (s, 3H, MeO), 2.44 (s, 3H, Me), 2.39 (s, 3H, Me). 13C NMR (75 MHz, CDC13): δ = 166.11 , 156.47, 155.13, 149.39, 148.94, 148.35, 147.42, 126.02, 125.17, 122.56, 52.86, 21.24.
Example 13: Synthesis of ([2,2'-bipyridin]-6-yl)methanol (6-hydroxymethyl-2,2' -bipyridine) (Formula 17)
The 6-methoxycarbonyl-2, 2'-bipyridine (lg, 4.67 mmol) was dissolved in dry THF (10 mL) and NaBH4 (0.69 lg, 18.69 mmol) added to it in small portions. The reaction mixture was refluxed for 2 hr at 80°C, cooled to 0°C and then ethanol added to quench excess borohydride. The solvent was evaporated on rotary evaporator under reduced pressure at 45 °C. Then saturated solution of ammonium chloride was added to mixture and contents extracted with ethyl acetate. The organic layer was dried over NaS04 and solvents removed on rotary evaporator under reduced pressure at 45 °C to yield alcohol as transparent oil.
1H NMR (300 MHz, CDC13): δ = 8.67 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.40 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.31 (dd, 1H, 7 = 7.91, 0.69 Hz), 7.84-7.78 (m, 2H), 7.31 (ddd, 1H, 7 = 7.56, 4.82, 1.03 Hz), 7.24 (dd, 1H, 7 = 7.91, 0.69 Hz), 4.82 (s, 2H). 13C NMR (75 MHz, CDC13): δ =158.31, 155.7, 154.9, 149.32, 137.75, 137, 123.95, 121.12, 120.51, 119.8, 64.04.
Example 14: Synthesis of (4,4'-dimethyl[2,2'-bipyridin]-6-yl)methanol (Formula 18) It was synthesized from compound of formula 16 by following a procedure similar to that described for 6-hydroxymethyl-2,2'-bipyridine in Example 13.
1H NMR (300 MHz, CDC13): δ = 8.50 (d, 1H, = 4.82 Hz, H-6'), 8.19 (s, 1H, H-3), 8.09 (s, 1H, H-3'), 7.10 (d, 1H, = 4.82 Hz, H-5'), 7.04 (s, 1H, H-5), 4.76 (s, 2H, CH2), 2.40 (s, 6H, Me). 13C NMR (75 MHz, CDCI3): δ = 158.31, 155.64, 154.77, 149, 148.16, 124.82, 122.1, 121.21, 120.86, 64.06, 21.31, 21.25.
Example 15: Synthesis of [2,2'-bipyridine]-6-carbaldehyde (2,2'-bipyridine-6- carbaldehyde) (Formula 19)
Anhydrous CH2C12 (5 mL) followed by oxalyl chloride (3.07g, 24.19 mmol) was introduced through a syringe in a flame dried two-necked round bottom flask equipped with rubber septum and nitrogen balloon and magnetic spin bar and contents cooled to -78 °C. DMSO (3.77g, 48.38 mmol) was added and contents stirred for 15 min. A solution of 6-hydroxymethyl-2,2'-bipyridine (2g, 10.75 mmol) in 5 mL CH2C12 and after 5 min, Et3N (4.88g, 48.38 mmol) were added. The cooling bath was removed and the reaction mixture allowed to warm to 25 °C and stirring continued at this temperature for another 1 Hr. The solvent was removed on a rotary evaporator under reduced pressure at 45°C and the contents extracted with ethyl acetate. The organic layer was washed with saturated aqueous Na2C03 followed by saturated brine solution and dried over anhydrous Na2S04. After removal of the solvent under reduced pressure on rotary evaporator, the crude product was purified by column chromatography.
1H NMR (300 MHz, CDC13): δ = 10.16 (s, 1H), 8.68 (ddd, 1H, = 4.82, 1.72, 1.03 Hz), 8.62 (dd, 1H, = 5.85, 2.75 Hz), 8.51 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 7.98-7.92 (m, 2H), 7.83 (dt, 1H, = 7.57, 1.72 Hz), 7.33 (ddd, 1H, = 7.57, 4.82, 1.03 Hz). 13C NMR (75 MHz, CDC13): δ = 193.75, 156.74, 155, 152.38, 149.39, 138, 137.15, 125.22, 124.39, 121.47, 121.38. Example 16: Synthesis of 4,4'-dimethyl[2,2'-bipyridine]-6-carbaldehyde (Formula 20)
It was synthesized from compound of formula 18 by following a procedure similar to that described for 2,2'-bipyridine-6-carbaldehyde in Example 15.
1H NMR (300 MHz, CDC13): δ = 10.12 (s, 1H), 8.51 (d, 1H, = 4.82 Hz, H-6'), 8.42 (s, 1H, H- 3), 8.32 (s, 1H, H-3'), 7.75 (s, 1H, H-5), 7.14 (d, 1H, = 4.82 Hz, H-5'), 2.47 (s, 3H, Me), 2.44 (s, 3H, Me). 13C NMR (75 MHz, CDC13): δ = 194.03, 156.68, 154.99, 152.38, 149.52, 149.12, 148.44, 126.09, 125.3, 122.35, 122.28, 21.35, 21.29. Example 17: Synthesis of l-([2,2'-bipyridin]-6-yl)-2-methylpropan-l-one (Formula 21)
A solution of 2,2'-Bipyridine-6-carbaldehyde (0.4 g, 2.17 mmol) in anhydrous THF (10 niL) was introduced through a syringe in a flame dried two-necked round bottom flask equipped with rubber septum and nitrogen balloon and magnetic spin bar. Isopropylmagnesium bromide (0.958g, 6.52 mmol) was added to the solution and contents stirred for 15 min. Saturated aqueous Na2C03 solution was added to the reaction mixture and contents extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine solution and dried over sodium sulphate. The solvents were removed on a rotary evaporator under reduced pressure at 45 °C to yield product as oil. The alcohol product, without purification was subjected to swern oxidation following a procedure similar to that described in Example 15.
1H NMR (300 MHz, CDC13): δ = 8.69 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.60 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.51 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.05 (dd, 1H, 7 = 7.57, 1.38 Hz), 7.95 (dd, 1H, 7 = 7.91, 7.57 Hz), 7.86 (dt, 1H, 7 = 7.91, 1.72 Hz) 7.35 (ddd, 1H, 7 = 7.57, 4.82, 1.03 Hz), 4.28 (sep, 1H, 7 = 6.88 Hz), 1.27 (d, 6H, 7 = 6.88 Hz). 13C NMR (75 MHz, CDC13): δ = 205.82, 155.59, 155.28, 152.23, 149.3, 138, 137.11, 124.18, 124.15, 122.39, 121.19, 34.51, 18.86.
Example 18: Synthesis of l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)-2-methylpropan-l-one (Formula 22)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)- 2-methylpropan-l-one in Example 17.
1H NMR (300 MHz, CDC13): δ = 8.54 (d, 1H, 7 = 4.82 Hz), 8.41 (s, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.16 (d, 1H, 7 = 4.82 Hz), 4.28 (sep, 1H, 7 = 6.88 Hz), 1.26 (d, 6H, 7 = 6.88 Hz) 2.49 (s, 3H), 2.48 (s, 3H). 13C NMR (CDC13): δ = 206.22, 155.37, 155.31, 152.29, 149.29, 148.98, 148.27, 125.07, 125, 123.20, 122.10, 34.55, 21.50, 21.36, 18.87.
Example 19: Synthesis of l-([2,2'-bipyridin]-6-yl)-3-methylbutan-l-one (Formula 23)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)- 2-methylpropan-l-one in Example 17.
1H NMR (300 MHz, CDC1 ): δ = 8.69 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.61 (dd, 1H, 7 = 7.91, 1.38 Hz), 8.51 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.05 (dd, 1H, 7 = 7.57, 1.38 Hz), 7.95 (dd, 1H, 7 = 7.91, 7.57 Hz), 7.87 (dt, 1H, 7 = 7.57, 1.72 Hz) 7.35 (ddd, 1H, 7 = 7.57, 4.82, 1.03 Hz), 3.21 (d, 2H, 7 = 6.88 Hz), 2.44-2.31 (m, 1H), 1.04 (d, 6H, 7 = 6.88 Hz). 13C NMR (75 MHz, CDC13): δ =202.01, 155.47, 155.18, 153.15, 149.2, 137.95, 137.24, 124.27, 124.21, 121.76, 121.26, 46.56, 25.16, 23.01.
Example 20: Synthesis of l-([2,2'-bipyridin]-6-yl)-4-methylpentan-l-one (Formula 24)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)- 2-methylpropan-l -one in Example 17.
1H NMR (300 MHz, CDC13): δ = 8.69 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.61 (dd, 1H, = 7.91, 1.38 Hz), 8.51 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.04 (dd, 1H, = 7.57, 1.38 Hz), 7.94 (dd, 1H, = 7.91, 7.57 Hz), 7.87 (dt, 1H, = 7.57, 1.72 Hz) 7.34 (ddd, 1H, = 7.57, 4.82, 1.03 Hz), 3.33 (dd, 2H, = 7.22, 6.54 Hz), 1.75-1.64 (m, 3H), 0.98 (d, 6H, = 6.54 Hz). 13C NMR (75 MHz, CDC13): δ = 202.68, 155.56, 155.38, 152.93, 149.31, 137.91, 137.07, 124.24, 124.16, 121.73, 121.15, 35.81, 33.33, 28.10, 22.61.
Example 21: Synthesis of l-([2,2'-bipyridin]-6-yl)nonan-l-one (Formula 25)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)- 2-methylpropan-l -one in Example 17.
1H NMR (300 MHz, CDC13): δ = 8.69 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.61 (dd, 1H, = 7.91 , 1.38, Hz), 8.51 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.04 (dd, 1H, = 7.57, 1.38 Hz), 7.94 (dd, 1H, = 7.91, 7.57 Hz), 7.86 (dt, 1H, = 7.57, 1.72 Hz) 7.33 (ddd, 1H, = 7.57, 4.82, 1.03 Hz), 3.32 (t, 2H, = 7.22 Hz), 1.83-1.73 (m, 2H), 1.43- 1.28 (m, 10H), 1.04 (t, 3H, = 6.88 Hz). 13C NMR (75 MHz, CDC13): δ =202.47, 155.56, 155.36, 152.96, 149.31, 137.89, 137.04, 124.22, 124.15, 121.69, 121.19, 37.80, 31.96, 29.60, 29.30, 24.37, 22.75, 14.21.
Example 22: Synthesis of l-([2,2'-bipyridin]-6-yl)but-2-yn-l-one (Formula 26)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)- 2-methylpropan-l -one in Example 17.
1H NMR (300 MHz, CDC13): δ = 8.69 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.64 (dd, 1H, = 7.91, 1.03, Hz), 8.61 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.12 (dd, 1H, J = 1.51, 1.03 Hz), 7.97 (dd, 1H, = 7.91, 7.57 Hz), 7.87 (dt, 1H, = 7.91, 1.72 Hz) 7.35 (ddd, 1H, = 7.57, 4.82, 1.38 Hz), 2.24 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 178.53, 156.18, 155.24, 152.57, 149.29, 137.95, 137.18, 124.78, 124.37, 123.09, 121.54, 95.16, 79.98, 4.85.
Example 23: Synthesis of([2,2'-bipyridin]-6-yl)(cyclopentyl)methanone (Formula 27) It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)- 2-methylpropan-l-one in Example 17.
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.58 (dd, 1H, 7 = 7.91, 1.03, Hz), 8.50 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.06 (dd, 1H, 7 = 7.93, 1.38 Hz), 7.93 (dd, 1H, 7 = 7.91, 7.57 Hz), 7.85 (dt, 1H, 7 = 7.57, 1.72 Hz), 7.34 (ddd, 1H, 7 = 7.57, 4.82, 1.03 Hz), 4.44- 4.33 (m, 1H), 2.09-1.99 (m, 2H), 1.93-1.84 (m, 2H ), 1.77-1.68 (m, 4H ). 13C NMR (75 MHz, CDCI3): δ = 204.26, 155.65, 155.27, 152.88, 149.28, 137.86, 137.12, 124.15, 124.04, 122.31, 121.22, 45.53, 29.82, 26.6.
Example 24: Synthesis of l-([2,2'-bipyridin]-6-yl)ethan-l-one (Formula 28)
A solution of 6-cyano-2,2'-bipyridine (0.4 g, 2.20 mmol) in anhydrous THF (5 mL) was introduced through a syringe in a flame dried two-necked round bottom flask equipped with rubber septum and nitrogen balloon and magnetic spin bar. Methylmagnesium bromide (0.78g, 6.62 mmol) was added drop-wise and contents stirred for 30 min. 20 mL water was added to reaction mixture and contents extracted with ethyl acetate. Organic layer was dried over NaS04, solvents removed under reduced pressure on a rotary evaporator at 45 °C to leave a residue which was purified by column chromatography.
1H NMR (300 MHz, CDCI3): δ = 8.68 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.60 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.51 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.04 (dd, 1H, 7 = 7.57, 1.03 Hz), 7.95 (dd, 1H, 7 = 7.91, 7.57 Hz), 7.84 (dt, 1H, 7 = 7.91, 1.72 Hz) 7.34 (ddd, 1H, 7 = 7.57, 4.82, 1.03 Hz) 2.82 (s, 3H, COMe). 13C NMR (75 MHz, CDC13): δ = 200.26, 157.77, 155.45, 153.01, 149.31, 137.87, 137.04, 124.37, 124.19, 121.53, 121.18, 25.81.
Example 25: Synthesis of l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)ethan-l-one (Formula 29)
It was synthesized from compound of formula 11 by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDCI3): δ = 8.54 (d, 1H, 7 = 4.82 Hz, H-6'), 8.43 (d, 1H, 7 = 1.03 Hz, H- 3), 8.32 (d, 1H, 7 = 1.03 Hz, H-3'), 7.87 (d, 1H, 7 = 1.03 Hz, H-5), 7.16 (dd, 1H, 7 = 4.82, 1.03 Hz, H-5') 2.83 (s, 3H, COMe), 2.49 (s, 3H, Me), 2.48 (s, 3H, Me). 13C NMR (300 MHz, CDC13): δ = 200.68, 155.47, 155.38, 152.98, 149.19, 149, 148.20, 125.17, 125.09, 122.32, 122.08, 25.97, 21.42, 21.30.
Example 26: Synthesis of l-(4,4'-di-tert-butyl[2,2'-bipyridin]-6-yl)ethan-l-one (Formula 30) It was synthesized from compound of formula 12 by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.65 (dd, 1H, 7 = 5.16, 0.69 Hz, H-6'), 8.62 (d, 1H, 7 =1.72 Hz, H-3), 8.55 (dd, 1H, 7 = 2.06, 0.69 Hz, H-3'), 8.07 (d, 1H, 7 = 1.72 Hz, H-5), 7.33 (dd, 1H, 7 = 5.16, 2.06 Hz, H-5'), 2.84 (s, 3H, Me), 1.40 (s, 18H, t-Bu). 13C NMR (75 MHz, CDCI3): δ = 200.96, 162.35, 161.07, 155.91, 155.79, 153.09, 149.19, 121.52, 121.20, 118.56, 118.35, 35.45, 35.03, 30.70, 30.65, 25.90.
Example 27: Synthesis ofl-(4,4'-dimethoxy[2,2'-bipyridin]-6-yl)ethan-l-one (Formula 31)
It was synthesized from compound of formula 13 by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.49 (d, 1H, 7 = 5.85 Hz, H-6'), 8.14 (d, 1H, 7 = 2.41 Hz, H- 3), 8.07 (d, 1H, 7 = 2.75 Hz, H-3'), 7.57 (d, 1H, 7 = 2.41 Hz, H-5), 6.87 (dd, 1H, 7 = 5.85, 2.75 Hz, H-5') 3.97 (s, 3H, OMe), 3.96 (s, 3H, OMe), 2.80 (s, 3H, Me). 13C NMR (75 MHz, CDCI3): δ = 201.14, 167.67, 166.71, 157.12, 154.73, 150.46, 110.38, 110.00, 107.91, 107.21, 55.27, 55.78, 25.94.
Example 28: Synthesis of l-(4,4'- dinonyl [2,2'-bipyridin]-6-yl)ethan-l-one (Formula 32)
It was synthesized from compound of formula 14 by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDCI3): δ = 8.56 (d, 1H, 7 = 5.16 Hz, H-6'), 8.42 (d, 1H, 7 = 1.72 Hz, H- 3), 8.32 (d, 1H, 7 = 1.72 Hz, H-3'), 7.87 (d, 1H, 7 = 1.72 Hz, H-5), 7.16 (dd, 1H, 7 = 5.16, 1.72 Hz, H-5'), 2.83 (s, 3H, Me) 2.76-2.70 (m, 4H, Ph-CH2), 1.73-1.65 (m, 4H, Ph-CH2), 1.41-1.25 (m, 24H, Ph-CH2), 0.88-0.84 (m, 6H, Me). 13C NMR (75 MHz, CDCI3): δ = 200.80, 155.62, 155.56, 154.08, 153.08, 153.36, 152.58, 149.07, 124.58, 124.35, 121.60, 121.43, 35.64, 31.94, 30.47, 29.59, 29.53, 29.37, 29.27, 26.00, 22.75, 14.19.
Example 29: Synthesis of l-([2,2'-bipyridin]-6-yl)propan-l-one (Formula 33)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDCI3): δ = 8.69 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.61 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.52 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.05 (dd, 1H, 7 = 7.57, 1.03 Hz), 7.95 (dd, 1H, 7 = 7.91, 7.57 Hz), 7.85 (td, 1H, 7 = 7.57, 1.72 Hz), 7.34 (ddd, 1H, 7 = 7.57, 4.82, 1.38 Hz), 3.38 (q, 2H, = 7.22 Hz), 1.27 (t, 3H, = 7.22 Hz). "C NMR (75 MHz, CDC13): δ = 202.76, 155.54, 155.37, 152.73, 149.31, 137.90, 137.05, 124.25, 124.17, 121.61, 121.20, 31.20, 8.14.
Example 30: Synthesis of ([2,2'-bipyridin]-6-yl)(phenyl)methanone (Formula 34)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan-l -one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.67 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.63 (dd, 1H, = 7.57, 1.38 Hz), 8.33 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.19-8.16 (m, 2H), 8.08-7.98 (m, 2H), 7.75 (dt, 1H, = 7.91, 1.72 Hz) 7.64-7.58 (m, 1H), 7.52-7.48 (m, 2H), 7.30 (ddd, 1H, = 7.57, 4.82, 1.38 Hz). 13C NMR (75 MHz, CDC13): δ = 193.61, 155.44, 154.95, 154.30, 138.12, 137.15, 136.51, 132.89, 131.36, 128.11, 124.58, 124.21, 123.42, 121.38.
Example 31: Synthesis of ([2,2'-bipyridin]-6-yl)(4-methoxyphenyl)methanone (Formula 35)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.69 (ddd, 1H, = 4.82, 1.72, 1.03 Hz), 8.63-8.60 (m, 1H), 8.37 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.24 (d, 2H, = 8.94 Hz), 8.04-8.00 (m, 2H ), 7.80 (dt, 1H, = 7.57, 1.72 Hz), 7.32 (ddd, 1H, = 7.57, 4.82, 1.03 Hz), 6.99 (d, 2H, = 8.94 Hz), 3.91 (s, 3 H). 13C NMR (75 MHz, CDC13): δ = 192.05, 163.57, 155.60, 155.03, 154.77, 149.28, 138.07, 137.13, 133.84, 129.25, 124.52, 124.14, 123.07, 121.39, 113.46, 55.57.
Example 32: Synthesis of ([2,2'-bipyridin]-6-yl)(4-fluorophenyl)methanone (36)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.69 (ddd, 1H, = 4.82 , 1.72, 0.69 Hz), 8.65 (dd, 1H, = 7.57, 1.38 Hz), 8.33-8.24 (m, 3H), 8.10-8 (m, 2H), 7.79 (dt, 1H, = 7.57, 1.72 Hz), 7.33 (ddd, 1H, = 7.57, 1.72, 0.69 Hz), 7.18 (t, 2H, = 8.06 Hz). 13C NMR (75 MHz, CDC13): δ = 191.92, 167.44, 164.07, 155.37, 154.54, 154.94, 149.35, 138.24, 137.18, 134.14, 132.8, 124.63, 124.26, 123.57, 121.27, 115.4, 115.11. Example 33: Synthesis of ([2,2'-bipyridin]-6-yl)[4-(trifluoromethoxy)phenyl]methanone (Formula 37) It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan- l-one in Example 24
1H NMR (300 MHz, CDC13): = 8.70-8.65 (m, 2H), 8.31-8.27 (m, 3H), 8.12-8.01 (m, 2H), 7.80 (dt, 1H, = 7.91, 1.72 Hz), 7.35-7.32 (m, 3H). 13C NMR (75 MHz, CDCI3): δ = 191.79, 155.28, 155.04, 153.82, 152.51, 149.36, 138.29, 137.21, 134.72, 133.41, 124.67, 124.29, 123.79, 121.26, 119.82, 122.17, 118.74.
Example 34: Synthesis of ([2,2'-bipyridin]-6-yl)[4-(dimethylamino)phenyl]methanone (38)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan- l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82, 1.72, 0.69 Hz), 8.57 (dd, 1H, = 7.22, 1.72 Hz), 8.43 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.19 (d, 2H, = 9.29 Hz), 8.00-7.92 (m, 2H), 7.78 (td, 1H, = 7.91, 1.72 Hz), 7.31 (ddd, 1H, = 7.57, 4.82, 1.03 Hz), 6.70 (d, 2H, = 9.29 Hz), 3.09 (s, 6 H). 13C NMR (75 MHz, CDCI3): δ = 191.38, 156.17, 155.86, 154.53, 153.52, 149.18, 137.84, 137.03, 133.83, 124.36, 123.96, 122.43, 121.49, 110.54, 40.14.
Example 35: Synthesis of ([2,2'-bipyridin]-6-yl)(2-methoxyphenyl)methanone (Formula 39)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan- l-one in Example 24
1H NMR (300 MHz, CDCI3): δ = 8.61 (ddd, 1H, = 4.82, 1.72, 0.69 Hz), 8.56 (dd, 1H, = 7.91, 1.38, Hz), 8.12 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.03-7.91 (m, 2H), 7.69-7.63 (m, 1H), 7.59 (dd, 1H, = 7.22, 1.72 Hz), 7.25-7.21 (m, 1H), 7.48 (dd, 1H, = 8.60 , 8.26 Hz), 7.06 (td, 1H, = 7.57, 0.69 Hz), 6.97 (d, 1H, = 8.68 Hz), 3.58 (s, 3H). 13C NMR (75 MHz, CDCI3): δ = 196.09, 158.68, 155.97, 155.09, 154.51, 149.13, 137.69, 136.98, 132.64, 130.72, 128.57, 124.01, 123.42, 123.07, 121.15, 120.43, 111.51, 55.75.
Example 36: Synthesis of ([2,2'-bipyridin]-6-yl)(3-methoxyphenyl)methanone (Formula 40)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan- l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82, 1.72, 0.69 Hz), 8.64 (dd, 1H, = 7.22, 1.38 Hz), 8.36 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.07-7.99 (m, 2H), 7.81-7.73 (m, 3H), 7.41 (dd, lH, = 8.26, 7.91 Hz), 7.31 (ddd, 1H, J = 1.51, 4.82, 1.03 Hz), 7.17 (ddd, 1H, = 8.26, 2.75, 1.03 Hz), 3.83 (s, 3H). 13C NMR (75 MHz, CDCI3): δ = 193.29, 159.43, 155.42, 154.92, 154.37, 149.27, 138.1, 137.68, 137.14, 129.06, 124.6, 124.36, 124.22, 123.41, 121.38, 119.71, 115.22, 55.52.
Example 37: Synthesis of ([2,2'-bipyridin]-6-yl)(2,4-dimethoxyphenyl)methanone (Formula 41)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.63 (ddd, 1H, 7 = 4.82, 1.72, 0.69 Hz), 8.57-8.50 (m, 1H) 8.22 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 7.97-7.90 (m, 2H), 7.73-7.66 (m, 2H), 7.28-7.24 (m, 1H), 6.58 (dd, 1H, 7 = 8.62, 2.06 Hz), 6.49 (d, 1H, 7 = 2.06 Hz), 3.87 (s, 3H), 3.58 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 194.55, 164.15, 161.08, 155.7, 155.66, 154.84, 149.14, 137.64, 137.03, 133.48, 124, 123.17, 122.93, 121.25, 121.06, 104.72, 98.8, 55.72, 55.63.
Example 38: Synthesis of ([2,2'-bipyridin]-6-yl)(2,5-dimethoxyphenyl)methanone (Formula 42)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.64 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.58 (dd, 1H, 7 = 7.22 , 2.06 Hz), 8.17 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.03-7.94 (m, 2H ), 7.71 (dt, 1H, 7 = 7.57, 1.72 Hz) 7.27 (ddd, 1H, 7 = 7.57, 4.82, 1.38 Hz), 7.16 (d, 1H, 7 = 3.10 Hz), 7.07 (dd, 1H, 7 = 8.94, 3.10, Hz), 6.90 (d, 1H, 7 = 8.94 Hz), 3.81 (s, 3H), 3.54 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 195.92, 155.54, 155.09, 154.57, 153.47, 153.05, 149.16, 137.74, 137.03, 129.04, 124.06, 123.44, 123.06, 121.2, 118.8, 114.9, 113.2, 56.48, 55.95.
Example 39: Synthesis of ([2,2'-bipyridin]-6-yl)(3,4,5-trimethoxyphenyl)methanone (Formula 43)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.70 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.65 (dd, 1H, 7 = 6.88, 2.06 Hz), 8.43 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.09-8.01 (m, 2H), 7.58 (s, 2H), 7.80 (dt, 1H, 7 = 7.91, 1.72 Hz), 7.34 (ddd, 1H, 7 = 7.57, 4.82, 1.03 Hz), 3.97 (s, 3 H), 3.87 (s, 6 H). 13C NMR (300 MHz, CDC13): δ = 191.88, 155.48, 154.72, 154.59, 152.7, 149.43, 142.62, 138.26, 137.08, 131.27, 124.85, 124.31, 123.3, 121.16, 109.11, 61.1, 56.31. Example 40: Synthesis of ([2,2'-bipyridin]-6-yl)(naphthalen-2-yl)methanone (Formula 44)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan- l-one in Example 24
1H NMR (300 MHz, CDC13): = 8.80 (s, 1H), 8.71-8.67 (m, 2H), 8.36 (ddd, 1H, 7 = 7.91, 1.03, 0.69 Hz), 8.23 (dd, 1H, J = 8.60, 1.72 Hz), 8.15-8.04 (m, 2H), 7.97-7.91 (m, 3H), Ί .65-1.52 (m, 2H), 7.75 (dt, 1H, = 7.57, 1.72 Hz, H-3), 7.32 (ddd, 1H, = 7.57, 4.82, 1.03 Hz). 13C NMR (75 MHz, CDCI3): δ =193.48, 155.92, 154.95, 154.55, 149.30, 138.20, 137.19, 135.56, 133.87, 132.50, 129.86, 128.56, 127.83, 126.67, 126.60, 124.66, 124.21, 123.41, 121.38. Example 41: Synthesis of ([2,2'-bipyridin]-6-yl)(6-methoxynaphthalen-2-yl)methanone (Formula 45)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan- l-one in Example 24
1H NMR (300 MHz, CDC13): = 8.74 (d, 1H, J = 1.03 Hz), 8.69 (ddd, 1H, J = 4.82, 1.72, 1.03 Hz), 8.66 (dd, 1H, = 7.57, 1.38 Hz), 8.37 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.22 (dd, 1H, = 8.60, 1.72 Hz), 8.11-8.01 (m, 2H), 7.84-7.81 (m, 2H), 7.74 (dt, 1H, J = 7.91, 2.06 Hz), 7.30 (ddd, 1H, = 7.57, 4.82, 1.38 Hz), 7.21-7.11 (m, 2H), 3.96 (s, 3H). 13C NMR (300 MHz, CDCI3): δ = 193.07, 159.94, 155.58, 154.87, 149.28, 138.11, 137.30, 137.13, 133.87, 131.71, 131.48, 127.85, 127.37, 126.60, 124.61, 124.15, 123.22, 121.36, 119.60, 105.82, 55.50.
Example 42: Synthesis of ([2,2'-bipyridin]-6-yl)(phenanthren-9-yl)methanone (Formula 46)
It was synthesized by following a procedure similar to that described for l-([2,2'-bipyridin]-6- yl)ethan- l-one in Example 24
1H NMR (300 MHz, CDC13): 8.77 (t, 2H, = 8.60 Hz), 8.67 (dd, 1H, = 7.91, 1.03 Hz), 8.62 (ddd, 1H, = 4.82, 1.72, 1.03 Hz), 8.31 (d, 1H, = 7.57 Hz), 8.26 (dd, 1H, = 7.57, 0.69 Hz), 8.13 (s, 1H), 8.00 (dd, 1H, J = 7.91, 7.57 Hz) 7.97 (ddd, 1H, J = 7.91,1.03, 0.69 Hz) 7.90 (d, 1H, = 7.91 Hz) 7.80-7.53 (m, 5H), 7.23 (ddd, 1H, = 7.57, 4.82, 1.03 Hz). 13C NMR (300 MHz, CDCI3): δ = 196.39, 155.51, 155.30, 154.52, 149.09, 138.06, 137.04, 134.13, 132.19, 131.79, 130.66, 130.24, 129.95, 129.84, 128.64, 127.22, 127.11, 127, 124.42, 124.11, 123.90, 122.91, 122.83, 121.40. Example 43: Synthesis of (4,4'-dimethyl[2,2'-bipyridin]-6-yl)(4-methoxyphenyl)methanone (Formula 47)
It was synthesized from compound of formula 11 by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDC13): δ = 8.53 (d, 1H, J = 5.16 Hz), 8.42 (s, 1H), 8.23 (d, 2H, = 8.94 Hz), 8.18 (s, 1H), 7.81 (s, 1H), 7.14 (d, 1H, J = 5.16 Hz), 6.99 (d, 2H, = 8.94 Hz), 3.90 (s, 3H, OMe), 2.52 (s, 3H, Me), 2.40 (s, 3H, Me). 13C NMR (300 MHz, CDC13): δ = 192.49, 163.58, 155.54, 155.03, 154.86, 149.39, 148.98, 148.3, 133.88, 129.36, 125.24, 125.05, 123.94, 122.39, 113.4, 55.58, 21.43.
Example 44: Synthesis of (4,4'-dimethyl[2,2'-bipyridin]-6-yl)[4- (trifluoromethoxy)phenyl]methanone (Formula 48)
It was synthesized from compound of formula 11 by following a procedure similar to that described for l-([2,2'-bipyridin]-6-yl)ethan-l-one in Example 24
1H NMR (300 MHz, CDCI3): δ = 8.54 (d, 1H, = 4.82 Hz), 8.46 (s, 1H), 8.27 (d, 2H, = 8.94 Hz), 8.11 (s, 1H), 7.91 (s, 1H), 7.34 (d, 2H, = 8.94 Hz), 7.15 (ddd, 1H, = 4.82, 1.72, 0.69 Hz), 2.54 (s, 3H, Me), 2.39 (s, 3H, Me). 13C NMR (300 MHz, CDC13): δ = 192.29, 155.26, 155.06, 153.74, 152.2, 149.74, 149.07, 148.39, 134.91, 133.44, 125.4, 125.2, 124.61, 122.29, 119.82, 21.44, 21.41.
Example 45: Synthesis of N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine (Formula 49) A solution of 2,2'-bipyridine-6-carbaldehyde (0.5 g, 2.71mmol), hydroxylamine hydrochloride (1.87g, 27.17 mmol) and pyridine (2.1g, 27.17 mmol) in 10 mL ethanol was refluxed for 30 min. The solvents were removed under reduced pressure, water (10 mL) added and contents extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over Na2S04 and evaporated under reduced pressure on a rotary evaporator at 45 °C to leave a residue, which was re-crystallised from methanol.
1H NMR (300 MHz, CDCI3): δ = 8.69 (ddd, 1H, = 4.82, 1.72, 1.03 Hz), 8.45 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.38 (dd, 1H, = 6.88, 1.72 Hz), 8.34 (s, 1H), 7.87 -7.79 (m, 3H), 7.33 (ddd, 1H, J = 7.57, 4.82, 1.03 Hz). 13C NMR (300 MHz, CDC13): δ = 156.05, 155.72, 151.35, 149.25, 137.51, 137.16, 124.04, 121.54, 121.44, 120.79. Calculated Mass: 199.0746, Observed Mass: 199.0938.
Example 46: Synthesis of N-[(4,4'-dimethyl[2,2'-bipyridin]-6- yl)methylidene] hydroxylamine (Formula 50) It was synthesized from compound of formula 11 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.54 (d, 1H, = 4.82 Hz), 8.34 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.62 (s, 1H), 7.14 (d, 1H, = 4.82 Hz), 2.45 (s, 3H, Me), 2.43 (s, 3H, Me). 13C NMR (75 MHz, CDCI3): δ = 155.96, 155.64, 151.14, 148.94, 148.74, 148.45, 124.94, 122.71, 122.47, 121.55, 21.35, 21.27. Calculated Mass: 227.10586, Observed Mass: 227.1067.
Example 47: Synthesis of N-[l-([2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 51)
It was synthesized from compound of formula 28 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDCI3): δ = 8.69 (ddd, 1Η, = 4.82, 1.72, 1.03 Hz), 8.51 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.41 (dd, 1H, J = 7.57, 1.03 Hz), 7.88-7.78 (m, 3H), 7.32 (ddd, 1H, = 7.57, 4.82, 1.03 Hz) 2.50 (s, 3H). 13C NMR (75 MHz, CDCI3): δ = 157.87, 156.07, 155.07, 153.6, 149.16, 137.35, 137.09, 123.91, 121.36, 120.97, 120.44, 10.69. Calculated Mass: 213.0902, Observed Mass: 213.0716.
Example 48: Synthesis of N-[l-([2,2'-bipyridin]-6-yl)propylidene]hydroxylamine (Formula 52)
It was synthesized from compound of formula 33 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.50 (dd, 1H, = 7.91, 1.03 Hz), 8.41 (dd, 1H, = 6.88, 2.06 Hz), 7.86-7.80 (m, 3H), 7.32 (ddd, 1H, = 7.57, 4.82, 1.03 Hz), 3.11 (q, 2H, = 7.57 Hz), 1.27 (t, 3H, = 7.57 Hz). 13C NMR (75 MHz, CDCI3): δ = 161.85, 156.16, 155.17, 153.02, 149.17, 137.36, 137.03, 123.87, 121.25, 120.83, 18.24, 11.07. Calculated Mass: 227.10586, Observed Mass: 227.0134.
Example 49:Synthesis of N-[l-([2,2'-bipyridin]-6-yl)-2-methylpropylidene]hydroxylamine (Formula 53)
It was synthesized from compound of formula 21 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.45 (dd, 1H, = 7.91, 1.03 Hz), 8.51 (dd, 1H, = 7.91, 1.03 Hz), 7.85-7.77 (m, 2H), 7.62 (dd, 1H, = 7.91, 1.38 Hz), 7.31 (ddd, 1H, = 7.57, 4.82, 1.03 Hz), 3.88 (sep, 1H, = 7.22 Hz), 1.42 (d, 6H, = 7.22 Hz). 13C NMR (75 MHz, CDC13): δ = 163.72, 156.13, 155.03, 154.77, 154.18, 151.13, 149.37, 149.13, 137.86, 137.5, 137.34, 137.14, 124.27, 123.89, 122.16, 121.53, 121.34, 120.5, 32.17, 26.88, 20.74, 19.41. Calculated Mass: 241.12151, Observed Mass: 241.1357.
Example 50: Synthesis of N-[l-([2,2'-bipyridin]-6-yl)-3-methylbutylidene]hydroxylamine (Formula 54)
It was synthesized from compound of formula 23 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.47 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.40 (dd, 1H, = 7.22, 1.38, Hz), 7.89 -7.77 (m, 3H), 7.31 (ddd, 1H, = 7.57, 4.82, 1.03 Hz), 3.03 (d, 2H, = 7.22 Hz), 2.26-2.15 (m, 1H, = 6.88 Hz), 1.00 (d, 6H, = 6.88 Hz). 13C NMR (75 MHz, CDC13): δ = 160.28, 156.2, 155.01, 153.63, 149.15, 137.28, 136.99, 123.8, 121.1, 120.72 33.15, 26.81, 23.12. Calculated Mass: 255.13716, Observed Mass: 255.1298.
Example 51: Synthesis of N-[l-([2,2'-bipyridin]-6-yl)-4-methylpentylidene]hydroxylamine (Formula 55)
It was synthesized from compound of formula 24 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82, 1.72, 1.03 Hz), 8.49 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.41 (dd, 1H, = 6.88, 1.72 Hz), 7.85-7.78 (m, 3H), 7.31 (ddd, 1H, = 7.22, 4.82, 1.03 Hz), 3.13-3.07 (m, 2H), 1.59-1.51 (m, 2H ), 1.79-1.66 (m, 1H), 0.99 (d, 6H, = 6.54 Hz).13C NMR (75 MHz, CDC13): δ = 161.14, 156.18, 155.1, 153.2, 149.14, 137.32, 136.99, 123.83, 121.17, 120.81, 120.76, 35.31, 28.73, 22.85, 22.57. Calculated Mass: 269.15281, Observed Mass: 269.1675. Example 52: Synthesis of N-[l-([2,2'-bipyridin]-6-yl)nonylidene]hydroxylamine (Formula 56)
It was synthesized from compound of formula 25 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82, , 1.72, 1.03 Hz), 8.49 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.41 (dd, 1H, = 6.88, 2.02 Hz), 7.88-7.78 (m, 3H), 7.32 (ddd, 1H, = 7.22, 4.82, 1.03 Hz), 3.09 (dd, 2H, = 7.91, 7.57 Hz ), 1.73-1.63 (m, 2H ), 1.48-1.25 (m, 10H ), 0.87- 0.83 (t, 3H, = 6.88 Hz ). 13C NMR (75 MHz, CDC13): δ = 160.98, 156.18, 155.11, 153.27, 149.16, 137.34, 136.99, 122.85, 121.21, 120.76, 31.98, 30.1, 29.47, 29.33, 26.45, 24.7, 22.74, 14.2. Calculated Mass: 311.19976, Observed Mass: 311.1786.
Example 53: Synthesis of N-[([2,2'-bipyridin]-6-yl)(phenyl)methylidene]hydroxylamine (Formula 57)
It was synthesized from compound of 34 by following a procedure similar to that described for N- [([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.73 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.63 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.56 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.42 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.25 (ddd, 1H, 7 = 7.91, 1.38, 1.03 Hz), 8.17 (ddd, 1H, 7 = 7.91, 1.55, 1.03 Hz), 7.97 (t, 1H, 7 = 7.91 Hz), 7.90-7.80 (m, 2H), 7.72-7.65 (m, 2H), 7.57-7.23 (m, 13H). 13C NMR (75 MHz, CDC13): δ = 156.83, 155.82, 155.64, 154.33, 154.24, 153.68, 153.07, 151.54, 149.6, 148.99, 138.73, 137.5, 137.1, 135.52, 131.91, 129.72, 129.27, 129.11, 128.95, 128.62, 128.02, 124.97, 124.63, 123.93, 122.76, 122.45, 121.6, 121.38, 121.05. 275.10586, Observed Mass: 275.2004 Example 54: Synthesis of N-[([2,2'-bipyridin]-6-yl)(4- methylphenyl)methylidene]hydroxylamine (Formula 58)
6-Cyano-2,2'-bipyridine was reacted with phenylmagnesium bromide by procedure described in Example 24 to yield ([2,2'-bipyridin]-6-yl)(4-methylphenyl)methanone.
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, 7 = 4.95 , 1.72, 0.69 Hz), 8.63 (dd, 1H, 7 = 7.15, 1.93 Hz), 8.35 (d, 1H, 7 = 7.98 Hz), 8.12-7.98 (m, 2H), 8.10 (d, 2H, 7 = 8.25 Hz), 7.77 (dt, 1H, 7 = 7.98, 1.65 Hz), 7.30 (d, 3H, 7 = 7.98 Hz), 2.45 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 193.15, 155.53, 154.84, 154.66, 149.24, 143.71, 138.04, 137.10, 133.85, 131.55, 128.87, 124.52, 124.14, 123.23, 121.40, 21.88. ([2,2'-bipyridin]-6-yl)(4-methylphenyl)methanone was then converted to oxime of Formula 58 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6- yl)methylidene]hydroxylamine in Example 45.
1H NMR (300 MHz, CDC13): δ = 8.72 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.63 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.54 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.41 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.27-8.22 (m, 3H), 7.95 (t, 2H, 7 = 7.91 Hz), 7.88-7.80 (m, 3H), 7.70-7.60 (m, 2H), 7.47-7.22 (m, 8H), 2.44 (s, 3H, Me) 2.40 (s, 3H, Me). 13C NMR (75 MHz, CDC13): δ = 157.08, 155.9, 155.63, 154.27, 153.88, 152.99, 151.66, 149.59, 148.99, 139.22, 139.08,138.68, 137.44, 137.02, 132.68, 129.72, 129.29, 128.85, 128.72, 124.94, 124.59, 123.87, 122.82, 122.36, 121.55, 121.33, 120.95, 21.64, 21.44. Calculated Mass: 289.12151, Observed Mass: 289.1785.
Example 55: Synthesis of
N-[([2,2'-bipyridin]-6-yl)(4-fluorophenyl)methylidene]hydroxylamine (Formula 59)
It was synthesized from compound of formula 36 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
NMR (300 MHz, CDC13): δ = 8.73 (ddd, 1H, 7 = 4.82 , 1.72, 0.69 Hz), 8.65 (ddd, 1H, 7 = 4.82, 1.72, 0.69 Hz), 8.56 (dd, 1H, 7 = 7.91, 1.03 Hz) 8.43 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.25 (d, 1H, 7 = 7.91 Hz), 8.18 (d, 1H, 7 = 7.91 Hz), 7.97 (dd, 1H, 7 = 8.26, 7.91 Hz), 7.82 (dd, 1H, 7 = 8.26, 7.91 Hz), 7.71-7.66 (m, 2H), 7.60-7.51 (m, 4H), 7.40-7.35 (m, 2H) 7.30-7.08 (m, 6H). 13C NMR (75 MHz, CDCI3): δ = 164.62, 161.33, 159.92, 155.73, 155.6, 153.56, 151.29, 149.58, 149.04, 137.56,
137.12, 132.07, 131.97,130.78, 130.68, 127.68, 127.63, 124.87, 124.61, 123.99, 122.57, 122.45, 121.49, 121.15, 115.8, 115.51, 115.18, 114.89. Calculated Mass: 293.09644, Observed Mass: 293.1754.
Example 56: Synthesis of N-{([2,2'-bipyridin]-6-yl)[4-
(trifluoromethoxy)phenyl]methylidene}hydroxylamine (Formula 60)
It was synthesized from compound of formula 37 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13):5 = 8.73 (ddd, 1H, 7 = 4.82 , 1.72, 0.69 Hz), 8.64 (ddd, 1H, 7 = 4.82 , 1.72, 0.69 Hz), 8.56 (dd, 1H, 7 = 7.91, 1.03 Hz) 8.40 (dd, 1H, 7 = 7.91, 1.03 Hz) 8.24 (d, 1H, 7 = 7.91 Hz) 8.11 (d, 1H, 7 = 7.91 Hz) 7.99 (t, 1H, 7 = 7.91 Hz), 7.89-7.81 (m, 2H), 7.72-7.58 (m, 7H), 7.40-7.25 (m, 6H). 13C NMR (75 MHz, CDC13): δ = 155.83, 155.66, 155.57, 154.61,154.19,153.3, 152.16, 151.02, 149.93, 149.62, 149.49, 149.07, 138.8, 137.63, 137.54,
137.13, 134.15,131.61, 130.45, 130.37, 124.8, 124.7, 124.04, 122.63, 122.45, 121.47, 121.39, 121.22, 120.99, 120.29, 118.89. Calculated Mass: 359.08816, Observed Mass: 359.1549.
Example 57: Synthesis of N-{([2,2'-bipyridin]-6-yl)[4- (dimethylamino)phenyl]methylidene}hydroxylamine (Formula 61)
It was synthesized from compound of formula 38 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45 1H NMR (300 MHz, CDC13): δ = 8.71 (ddd, 1H, 7 = 4.82, 1.72, 0.69 Hz), 8.63 (ddd, 1H, 7 = 4.82, 1.72, 0.69 Hz), 8.52 (d, 1H, 7 = 7.91 Hz), 8.40 (d, 1H, 7 = 7.91 Hz), 8.31-8.28 (m, 3H), 7.95 (t, 1H, 7 = 7.91 Hz), 7.86-7.78 (m, 3H), 7.69 (t, 1H, 7 = 7.91 Hz), 7.62 (d, 1H, 7 = 7.91 Hz), 7.55 (d, 2H, 7 = 8.94 Hz), 7.43-7.33 (m, 4H), 7.25-7.23 (m, 1H), 6.78-6.66 (m, 3H), 3.02 (s, 6H, Me) 2.99 (s, 6H, Me). 13C NMR (75 MHz, CDC13): δ = 154.61, 154.44, 153.8, 152.1, 151.12, 150.89, 149.48, 148.98, 138.42, 137.35, 137.01, 131.6, 129.67, 125.09, 124.43, 123.81, 123.5,
123.1, 121.92, 121.69, 121.42, 120.74, 111.96 111.17, 40.42, 40.34. Calculated Mass: 318.14806, Observed Mass: 318.1947.
Example 58: Synthesis of N-[([2,2'-bipyridin]-6-yl)(4- methoxyphenyl)methylidene]hydroxylamine (Formula 62)
It was synthesized from compound of formula 35 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.72 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.64 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.53 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.42 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.28-8.25 (m, 2H), 7.95 (t, 1H, 7 = 7.91 Hz), 7.86-7.78 (m 2H), 7.69 (dt, 1H, 7 = 7.57, 1.72 Hz), 7.63 (dd, 1H, 7 = 7.57, 1.03 Hz), 7.57 (d, 2H, 7 = 8.94 Hz), 7.48 (d, 1H, 7 = 8.94 Hz), 7.40-7.37 (m 2H),7.29-7.24 (m 2H), 7.00 (d, 2H, 7 = 8.94 Hz), 6.94 (d, 2H, 7 = 8.94 Hz), 3.88 (s, 3H) ,3.84 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 160.49, 160.11 , 156.26, 155.9, 155.62, 154.5, 154.13, 151.74, 149.52, 149.01, 138.51, 137.47, 137.1, 131.67, 130.12, 127.96, 125.04, 124.92, 123.91, 123.03, 122.16, 121.63, 121.43, 120.97, 114, 113.37, 55.4. Calculated Mass: 305.11643, Observed Mass: 305.0978.
Example 59: Synthesis of N-[([2,2'-bipyridin]-6-yl)(2- methoxyphenyl)methylidene]hydroxylamine (Formula 63)
It was synthesized from compound of formula 39 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.61 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.38 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.15 (dd, 1H, 7 = 7.91, 1.03 Hz), 7.79 (dd, 1H, 7 = 7.91, 7.22 Hz), 7.67-7.60 (m, 2H), 7.49-7.43 (m, 1H), 7.38 (dd, 1H, 7 = 7.57, 1.72 Hz), 7.25-7.21 (m, 1H), 7.11 (dd, 1H, 7 = 7.57, 7.22 Hz), 7.04 (d, 1H, 7 = 7.91 Hz), 3.71 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 156.87, 156, 155.84, 155.4, 153.31, 148.93, 137.35, 137, 130.4, 130.36, 123.78, 121.79, 121.69, 121.45, 120.79, 120.52, 111.41, 55.9. Calculated Mass: 305.11643, Observed Mass: 305.19247. Example 60: Synthesis of N-[([2,2'-bipyridin]-6-yl)(3- methoxyphenyl)methylidene]hydroxylamine (Formula 64)
It was synthesized from compound of formula 40 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.73 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.64 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.55 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.41 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.24 (ddd, 2H, 7 = 7.91, 1.38, 0.69 Hz), 7.96 (dd, 1H, 7 = 8.26, 7.91 Hz), 7.89-7.78 (m, 2H), 7.71-7.62 (m, 2H), 7.44-7.31 (m, 4H),7.28-7.24 (m, 1H), 7.14-7.08 (m, 4H), 7.03-6.97 (m, 2H), 3.83 (s, 6H). 13C NMR (75 MHz, CDCI3): δ = 159.78, 159.28, 155.83, 155.7, 154.19, 154.13, 153.53, 152.6, 151.45, 149.64, 149.07, 138.85, 137.49, 137.08, 136.81, 133.08, 129.61, 129.14, 124.91, 124.66, 123.98, 122.76, 122.57, 121.98, 121.54, 121.32, 121.07, 115.27, 115.01, 114.24, 55.46, 55.41. Calculated Mass: 305.11643, Observed Mass: 305.1781.
Example 61: Synthesis of N-[([2,2'-bipyridin]-6-yl)(2,5- dimethoxyphenyl)methylidene]hydroxylamine (Formula 65)
It was synthesized from compound of formula 42 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.73 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.62 (ddd, 1H, 7 = 4.82 , 1.72, 1.03 Hz), 8.52 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.37 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.20 (d, 7 = 7.91, 2H), 7.94 -7.85 (m, 2H), 7.78 (t, 1H, 7 = 7.91 Hz), 7.68-7.60 (m, 2H), 7.41-7.37 (m, 1H), 7.26-7.22 (m, 1H), 7.06-6.89 (m, 7H), 3.80 (s, 6H), 3.65 (s, 6H). 13C NMR (75 MHz, CDC13): δ = 155.96, 155.45, 155.23, 153.95, 156.9, 153.52, 153.23, 152.06, 151.69, 151.17, 149.68, 148.93, 139.08, 137.57, 137.39, 137.04, 125.23, 124.67, 124.44, 123.82 122.7, 122.63, 121.91, 121.55, 121.2, 120.87, 116.73, 116.26, 115.6, 112.95, 112.63, 56.71, 56.31, 55.96, 55.90. Calculated Mass: 335.12699, Observed Mass: 335.1145.
Example 62: Synthesis of N-[([2,2'-bipyridin]-6-yl)(3,4,5- trimethoxyphenyl)methylidene]hydroxylamine (Formula 66)
It was synthesized from compound of formula 43 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45.
1H NMR (300 MHz, CDCI3): δ = 8.73 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.64 (ddd, 1H, 7 = 4.82, 1.72, 1.03 Hz), 8.56 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.42 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.25 (d, 2H, 7 = 7.91 Hz), 7.99 (t, 1H, 7 = 7.91 Hz), 7.91-7.81 (m 2H), 7.72-7.65 (m, 2H), 7.41-7.37 (m 2H), 7.30-7.25 (m 1H), 6.786 (s, 2H), 6.780 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.84 (s, 6H), 3.83 (s, 6H). 13C NMR (75 MHz, CDC13): δ= 155.79,155.68, 154.23, 154.06, 153.59, 153.36, 152.97, 152.65, 151.4, 149.68, 149.13, 139.01, 138.92, 138.55,137.53, 137.07, 130.93,126.94,124.94, 124.72, 124.02, 122.86, 122.64,121.46,121.26, 121.13, 107.13, 106.36, 61.04, 56.32, 56.27. Calculated Mass: 365.13756, Observed Mass: 365.1745.
Example 63: Synthesis of N-[([2,2'-bipyridin]-6-yl)(naphthalen-2- yl)methylidene]hydroxylamine (Formula 67)
It was synthesized from compound of formula 44 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.74 (ddd, 1H, 7 = 4.82 , 1.72, 0.69 Hz), 8.62-8.57 (m, 2H), 8.44 (dd, 1H, 7 = 7.91, 1.03 Hz), 8.28 (d, 1H, 7 = 7.91 Hz), 8.14 (d, 1H, 7 = 7.91 Hz), 8.07(s, 1H), 8.00-7.81 (m, 10H), 7.74-7.70 (m, 2H), 7.64 (dd, 1H, 7 = 8.68, 1.38 Hz), 7.60-7.50 (m, 5H), 7.40- 7.36 (m, 2H), 7.27-7.19 (m, 2H). 13C NMR (75MHz, CDC13): δ = 157.24, 155.8, 155.69, 154.44, 154.26, 153.77, 153.14, 151.54, 149.62, 148.99, 138.79, 137.48, 137.04, 133.64, 133.53, 133.21, 132.92, 129.61, 129.27,128.88, 128.65, 128.52, 128.31, 127.87, 127.83, 127.41, 127.13, 126.89, 126.57, 126.28, 126.04, 125.01, 124.63, 123.88, 122.75, 122.49,121.49, 121.36, 121.06. Calculated Mass: 325.12151, Observed Mass: 325.1745. Example 64: Synthesis of N-[([2,2'-bipyridin]-6-yl)(6-methoxynaphthalen-2- yl)methylidene]hydroxylamine (Formula 68)
It was synthesized from compound of formula 45 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.73 (ddd, 1H, 7 = 4.82 , 1.72, 0.69 Hz), 8.62 (ddd, 1H, 7 = 4.82 , 1.72, 0.69 Hz), 8.56 (d, 1H, 7 = 7.91 Hz), 8.43 (d, 1H, 7 = 7.91 Hz), 8.29 (d, 1H, 7 = 7.91 Hz), 8.18 (d, 1H, 7 = 7.91 Hz), 8.02-7.94 (m, 3H), 7.88-7.55 (m, 10H), 7.42-7.34 (m, 3H), 7.23-7.14 (m, 4H), 3.95 (s, 3H), 3.93 (s, 3H) 13C NMR (300 MHz, CDCI3): δ = 158.5, 155.85, 155.64, 154.55, 154.44, 154.02, 153.53, 151.7, 149.56, 148.96, 138.61, 137.43, 137.04, 134.98, 134.87, 130.72, 130.19, 130.04, 129.63, 128.64, 128.58, 128.36, 127.8, 127.09, 126.91, 126.21, 125.07, 124.55, 123.86, 122.93, 122.29, 121.56, 121.41, 121, 119.38, 119.12, 105.83, 55.44. Calculated Mass: 355.13208, Observed Mass: 355.1823. Example 65: Synthesis of N-[([2,2'-bipyridin]-6-yl)(phenanthren-9- yl)methylidene] hydroxy lamine (Formula 69)
It was synthesized from compound of formula 46 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, DMSO): 11.79 (s, 1H), 8.90-8.85 (m, 2H), 8.54 (d, 1H, = 4.47 Hz), 8.31 (d, 1H, = 7.57 Hz), 8.06-7.97 (m, 3H), 7.76-7.64 (m, 5H), 7.56-7.48 (m, 3H), 7.25-7.22 (m, 1H). 13C NMR (75 MHz, DMSO): δ = 155.72, 155.37, 155.05, 154.76, 149.65, 138.46, 137.5, 131.58, 131.51, 130.29, 130.16, 129.96, 129.24, 127.67, 127.46, 127.33, 127.16, 126.85, 124.59, 123.67, 123.43, 121.58, 120.61, 120.42. Calculated Mass: 375.13716, Observed Mass: 375.1763. Example 66: Synthesis of N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)-2- methylpropylidene]hydroxylamine (Formula 70)
It was synthesized from compound of formula 22 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.53 (d, 1H, = 5.16 Hz), 8.26 (s, 1H), 8.23 (s, 1H), 7.42 (s, 1H), 7.13 (d, 1H, = 5.16 Hz), 3.85 (sep, 1H, = 7.22 Hz), 1.40 (d, 6H, = 7.22 Hz) 2.45 (s, 3H), 2.43 (s, 3H). 13C NMR (75 MHz, CDC13): δ = 164.27, 156, 154.79, 154, 148.76, 148.58, 148.28, 124.80, 123.04, 122.29, 121.57, 32, 21.52, 21.33, 19.43. Calculated Mass: 269.15281, Observed Mass: 269.1489.
Example 67: Synthesis of N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)(4- methoxyphenyl)methylidene]hydroxylamine (Formula 71)
It was synthesized from compound of formula 47 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.56 (d, 1H, = 4.82 Hz), 8.40 (d, 1H, J = 5.16 Hz), 8.35 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.54 (d, 1H, = 8.94 Hz), 7.47 (d, 1H, = 8.94 Hz), 7.29 (s, 1H), 7.18 (d, 1H, = 4.82 Hz), 7.07 (d, 1H, = 4.82 Hz), 6.99 (d, = 8.94 Hz), 6.95 (d, 1H, = 8.94 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 2.44 (s, 6H), 2.39 (s, 3H, Me), 2.25 (s, 3H, Me). 13C NMR (75 MHz, CDC13): δ = 160.38, 160.09, 156, 155.74, 154.21, 154.16, 153.91, 152.86, 151.6 150.39, 149.24, 148.8, 148.69, 148.33, 131.52, 130.28, 128.1, 125.51, 124.83, 124.17, 123.3, 122.67, 122.28,122, 114.01, 133.48, 55.44, 55.4, 21.68, 21.44, 21.35, 21.17. Calculated Mass: 333.14773, Observed Mass: 333.1561. Example 68: Synthesis of N-{(4,4'-dimethyl[2,2'-bipyridin]-6-yl)[4-
(trifluoromethoxy)phenyl]methylidene}hydroxylamine (Formula 72)
It was synthesized from compound of formula 48 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.57 (d, 1H, = 4.82 Hz), 8.48 (d, 1H, = 4.82 Hz), 8.38 (s, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.59 (d, 4H, J = 8.94 Hz), 7.38-7.28 (m, 5H),7.21 (d, 1H, = 4.82 Hz), 7.08 (s, 2H ), 2.46 (s, 6H, Me), 2.41 (s, 3H, Me), 2.21 (s, 3H, Me). 13C NMR (300 MHz, CDCI3): δ = 155.61, 155.51, 154.26, 153.96, 153, 151.86, 150.91, 150.75, 149.86, 149.44, 149.34,148.92, 148.77, 148.4, 134.32, 131.53, 130.7, 130.61, 125.67, 125.2, 124.94, 123.72, 123.38, 122.5, 122.26, 122.19, 121.03, 120.47, 118.89, 21.73, 21.44, 21.38, 20.99. Calculated Mass: 387.11946, Observed Mass: 387.1123.
Example 69: Synthesis of N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 73)
It was from compound of formula 29 synthesized by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDCI3): δ 8.53 (d, 1H, = 4.82 Hz, H-6'), 8.31 (s, 1H, H-3), 8.23 (s, 1H, H-3'), 7.68 (s, 1H, H-5), 7.14 (d, 1H, = 4.82 Hz, H-5'), 2.49 (s, 3H, COMe), 2.46 (s, 3H, Me), 2.44 (s, 3H, Me). 13C NMR (300 MHz, CDC13): δ = 156.97, 155.98, 155.02, 153.62, 148.85, 148.46, 148.35, 124.84, 122.36, 122.14, 121.19, 21.44, 21.34, 10.99. Calculated Mass: 241.12151, Observed Mass: 241.1243.
Example 70: Synthesis of N-[l-(4,4'-dimethoxy[2,2'-bipyridin]-6- yl)ethylidene]hydroxylamine (Formula 74)
It was synthesized from compound of formula 31 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDCI3 + (CD3)2SO): δ = 8.36 (d, 1H, = 5.50 Hz, H-6'), 7.82 (d, 1H, = 2.41 Hz, H-3), 7.95 (d, 1H, = 2.75 Hz, H-3'), 7.33 (d, 1H, = 2.41 Hz, H-5), 6.74 (dd, 1H, = 5.50, 2.75 Hz, H-5'), 3.82 (s, 3H, OMe), 3.83 (s, 3H, OMe), 2.32 (s, 3H, Me) . 13C NMR (75 MHz, CDCI3 + (CD3)2SO): δ = 166.77, 166.59, 157.78, 156.30, 155.85, 150.20, 110.20, 106.96, 106.60, 106.29, 55.41, 55.20, 10.62. Calculated Mass: 273.11134, Observed Mass: 273.1123.
Example 71: Synthesis of N-[l-(4,4'-di-tert-butyl [2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 75)
It was synthesized from compound of formula 30 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDC13): δ = 8.59 (d, 1H, J = 5.16 Hz, H-6'), 8.53 (d, 1H, 7 = 2.06 Hz, H- 3'), 8.42 (d, 1H, 7 =1.72 Hz, H-3), 7.88 (d, 1H, 7 = 1.72 Hz, H-5), 7.31 (dd, 1H, 7 = 5.16, 2.06 Hz, H-5'), 2.50 (s, 3H, Me),1.39 (s, 18H, t-Bu). 13C NMR (75 MHz, CDCI3): δ = 161.45, 160.97, 157.97, 156.38, 155.48, 153.48, 149.06, 120.28, 118.42, 117.25, 35.28, 35.02, 30.75, 30.66, 30.51, 10.74. Calculated Mass: 325.21541, Observed Mass: 325.2234.
Example 72: Synthesis of N-[l-(4,4'- dinonyl[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 76)
It was synthesized from compound of formula 32 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45
1H NMR (300 MHz, CDCI3): δ = 8.55 (d, 1H, 7 = 5.16 Hz, H-6' ), 8.30 (d, 1H, 7 = 1.72 Hz, H- 3), 8.23 (d, 1H, 7 = 1.72 Hz, H-3'), 7.68 (d, 1H, 7 = 1.72 Hz, H-5), 7.13 (dd, 1H, 7 = 5.16, 1.72 Hz, H-5'), 2.50 (s, 3H, Me), 2.73-2.66 (m, 4H, Ph-CH2), 1.71-1.64 (m, 4H, Ph-CH2), 1.34-1.25 (m, 24H, Ph-CH2), 0.88-0.84 (m, 6H, Me). 13C NMR (75 MHz, CDC13): δ = 157.77, 156.14, 155.25, 153.48, 153.28, 152.91, 148.95, 124.03, 121.48, 121.40, 120.42, 35.73, 35.64, 31.94, 30.58, 29.55, 29.51, 29.44, 29.37, 22.74, 14.19, 10.78. Calculated Mass: 465.37191, Observed Mass: 465.3819. Example 73: Synthesis of 6,6'-[hydrazinediylidenedimethanylylidene]di(2,2'-bipyridine) (Formula 77)
Hydrazine hydrate (6.75 mg, 0.135 mmol) was added to solution of 2,2'-bipyridine-6- carboxaldehyde (50 mg, 0.27 mmol) in methanol (1 mL) and contents stirred for 30 min, when the desired compound precipitated out as colorless solid.
1H NMR (300 MHz, CDC13): δ = 8.77 (s, 2H), 8.70 (ddd, 2H, 7 = 4.82, 1.72, 1.03 Hz), 8.53-8.48 (m, 4H), 8.21 (dd, 2H, 7 = 7.91, 1.03 Hz), 7.93 (t, 2H, 7 = 7.91 Hz), 7.85 (td, 2H, 7 = 7.57, 1.75 Hz), 7.34 (ddd, 2H, 7 = 7.57, 4.82, 1.38 Hz). 13C NMR (75 MHz, CDCI3): δ = 162.28, 156.36, 155.71, 152.63, 149.3, 137.53, 137.07, 124.06, 122.5, 121.97, 121.35 ppm. Calculated Mass: 364.1436, Observed Mass: 364.1622.
Example 74: Synthesis of 6-[{2-[([2,2'-bipyridin]-6-yl)methyl]hydrazinylidene}methyl]-2,2'- bipyridine (Formula 78) Sodium borohydride (20 mg, 0.54 mmol) was added to a solution of compound of Formula 77 (50 mg, 0.13 mmol) in 5 mL methanol in small portions. The reaction mixture was stirred for 30 min, solvents removed under reduced pressure on a rotary evaporator at 45 °C, saturated solution of Na2C03 was added to crude and contents extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04 and solvents removed on rotary evaporator to give a product as colorless solid.
1H NMR (300 MHz, CDC13): δ = 8.67 (s, 2H), 8.46 (d, 1H, = 7.91 Hz), 8.39 (d, 1H, = 7.91 Hz) , 8.32 (d, 1H, = 7.57 Hz), 8.21 (d, 1H, = 7.22 Hz), 7.88-7.74 (m , 6H), 7.36-7.25 (m, 3H), 6.86 (s, 1H), 4.68 (d, 2H, = 4.82 Hz) ppm. 13C NMR (75 MHz, CDC13): δ = 156.42, 156.34, 156.01, 155.82, 155.52, 154.95, 149.28, 137.76, 137.25, 137.12, 136.97, 136.91, 123.89, 123.65, 122.34, 121.29, 121.19, 119.82, 119.69, 119.23, 53.29 ppm. Calculated Mass: 366.1593, Observed Mass: 366.1805.
Example 75: Synthesis of 6-(l-hydrazonoethyl)-2,2'-bipyridine (Formula 79)
It was synthesized from compound of formula 28 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45.
1H NMR (300 MHz, CDC13):5 = 8.66 (ddd, 1H, = 4.82, 1.72, 1.03 Hz), 8.49 (d, 1H, = 7.91 Hz), 8.30 (dd, 1H, = 7.91, 1.03 Hz), 7.96 (dd, 1H, = 7.91, 1.03 Hz), 7.84-7.74 (m, 2H), 7.29 (ddd, 1H, = 7.57, 4.82, 1.38 Hz), 5.57(s, 2H), 2.37 (s, 3H) ppm. 13C NMR (75 MHz, CDC13):5 = 156.46, 155.78 154.54, 149.17, 148.04, 137.07, 136.9, 123.67, 121.1, 119.74, 9.55. Calculated Mass: 212.1062, Observed Mass: 212.1377.
Example 76: Synthesis of N-[([2,2'-bipyridin]-6-yl)(2,4- dimethoxyphenyl)methylidene]hydroxylamine (Formula 80)
It was synthesized from compound of formula 41 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45.
1H NMR (300 MHz, CDC13): δ = 8.62 (ddd, 1H, = 4.82, 1.72, 1.03 Hz), 8.37 (dd, 1H, = 7.91, 1.03 Hz), 8.21 (ddd, 1H, J = 7.91, 1.03, 0.69), 7.78 (dd, 1H, 7 = 7.91, 7.57 Hz), 7.70-7.62 (m, 2H), 7.33 (d, 1H, = 8.26 Hz), 7.24 (ddd, 1H, = 7.57, 4.82, 1.38 Hz), 6.65 (dd, 1H, = 8.62, 2.41 Hz), 6.59 (d, 1H, = 2.41), 3.89 (s, 3H), 3.67 (s, 3H) ppm. 13C NMR (CDC13): δ = 161.70, 158.29, 156.09, 155.38, 153.74, 148.92, 137.25, 136.99, 131.24, 123.72, 121.85, 121.49, 120.69, 114.04, 99.06, 55.82, 55.53. Calculated Mass: 335.12699, Observed Mass: 335.1014. Example 77: Synthesis of N-[(E)-([2,2'-bipyridin]-6- yl)(cyclopentyl)methylidene]hydroxylamine (Formula 81)
It was synthesized from compound of formula 27 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45.
1H NMR (300 MHz, CDC13): δ = 8.71 -8.68 (m, 1H), 8.38 (d, 2H, J = 7.91 Hz), 8.47 (d, 1H, = 7.91 Hz), 7.87-7.77 (m, 2H), 7.63-7.59 (m, 1H), 7.37-7.28 (m, 1H), 3.88 (quint, 1H, = 8.94), 2.23- 1.64 (m, 8H) ppm 13C NMR (CDC13): δ = 162.86, 156.13, 154.97, 154.86, 154.69, 154.5, 154.32, 151.81, 149.45, 149.15, 138.27, 137.5, 137.42, 137.1, 124.39, 123.87, 123.34, 122.26, 121.76, 121.32, 120.54, 43.23, 37.09, 30.79, 29.79, 26.65, 25.28 ppm. Calculated Mass: 267.1372, Observed Mass: 267.1562.
Example 78: Synthesis of N-[(lE)-l-([2,2'-bipyridin]-6-yl)but-2-yn-l-ylidene]hydroxylamine (Formula 82)
It was synthesized from compound of formula 26 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine in Example 45.
1H NMR (300 MHz, CDC13): δ = 8.68 (ddd, 1H, = 4.82 , 1.72, 1.03 Hz), 8.50 (dd, 1H, = 7.91, 1.03, Hz), 8.44 (ddd, 1H, = 7.91, 1.03, 0.69 Hz), 8.05 (dd, 1H, = 7.57, 1.03 Hz), 7.91- 7.75 (m, 2H), 7.31 (ddd, 1H, = 7.22, 4.82, 1.03 Hz), 2.51 (s, 3H). 13C NMR (75 MHz, CDCI3): δ = 170.06, 163.66, 159.90, 155.76, 149.23, 148.13, 137.86, 137.41, 136.99, 124.03, 121.60, 121.51, 121.29, 12.48. Calculated Mass: 237.0902, Observed Mass: 237.1094.
Example 79: Synthesis of N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)(2- methoxyphenyl)methylidene]hydroxylamine (Formula 83)
6-cyano-4,4'-dimethyl-2,2'-bipyridine was reacted with phenylmagnesium bromide by procedure described in Example 24 to yield (4,4'-dimethyl[2,2'-bipyridin]-6-yl)(2- methoxyphenyl)methanone.
1H NMR (300 MHz, CDCI3): δ = 8.49 (d, 1H, = 4.82 Hz), 8.39 (s, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.60 (dd, lH, = 7.57, 1.72 Hz), 7.54-7.48 (m, 1H), 7.10-7.05 (m, 2H), 7.00 (d, 1Η, = 8.60 Hz), 3.64 (s, 3H, OMe), 2.51 (s, 3H, Me), 2.33 (s, 3H, Me). 13C NMR (300 MHz, CDC13): δ = 196.23, 158.71, 155.56, 155.18, 154.43, 148.98, 148.84, 148.09, 132.56, 130.85, 128.66, 124.91, 124.29, 124.06, 122.29, 120.35, 111.46, 55.78, 21.37. (4,4'-dimethyl[2,2'-bipyridin]-6-yl)(2-methoxyphenyl)methanone was then converted to oxime of Formula 83 by following a procedure similar to that described for N-[([2,2'-bipyridin]-6- yl)methylidene]hydroxylamine in Example 45.
1H NMR (300 MHz, CDC13): δ = 8.57 (d, 1H, = 4.82 Hz), 8.45 (d, 1H, = 4.82 Hz), 8.33 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.47-7.36 (m, 4H), 7.20-6.97 (m, 8H), 6.78 (s, 1H), 3.72 (s, 3H, OMe), 3.71 (s, 3H, OMe), 2.46 (s, 3H, Me), 2.38 (s, 3H, Me) 2.36 (s, 3H, Me), 2.13 (s, 3H, Me) 13C NMR (300 MHz, CDC13): δ = 156.96, 155.80, 155.55, 153.02, 148.55, 148.36, 130.42, 130.29, 124.68, 122.97, 122.75, 122.02, 121.71, 120.66, 111.43, 55.90, 21.35, 20.99. Calculated Mass: 333.14773, Observed Mass: 333.1235. Example 80: Suppression of proliferation of mitogen induced T- lymphocytes by synthesised compounds (CFSE assay)
Synthesized compounds were assayed for suppression of T- lymphocytes by fluorescent intracellular labeling of live cells CFSE (5(6)-Carboxyfluorescein N-hydroxysuccinimidyl ester). Splenic cells were suspended in PBS at concentration of 1.5x10 cells/ml). 5 mM of stock solution of CFSE (abeam) in DMSO was added to make the final concentration of 2.5μΜ and contents incubated for 9 min at 37°C. After the incubation, cells were given 3 washings with 20% FBS in PBS. Stained cells (2xl05 cells/well) were cultured with 100 μΐ RPMI media in round bottom 96- well plate with 2^g/ml Concanavalin A (ConA) and different concentration of synthesized molecules (0-2.5 μΜ 72 hr. The control cultures consisted of cells incubated with medium alone, ConA or DMSO. CaeA was used as positive control. Each experiment was repeated at least three times. Data was acquired using flow cytometer with 488 nm laser and FL1 detector. CaeA was used as positive control. Each experiment was repeated at least three times.
The results for examples of synthesised compounds are shown in Figure 4 to Figure 8. IC50 values, concentration of derivatives at which 50% inhibition was observed for each oximes was calculated by nonlinear regression method through inhibitor vs normalised response using GraphPad Prism®. Examples of IC50 values obtained for various synthesised compounds are reported in Table 3. Table 3: Examples of IC50 values obtained for various synthesised compounds
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Compounds of formula 77 and 79 were about 2-fold less active than CaeA. Compound of formula 78 was about 4-fold less active than CaeA. Compound of formula 76 was found to be the least active. Example 81: In vivo efficacy of N-[(4, 4'-dimethyl[2,2'-bipyridin]-6- yl)methylidene]hydroxylamine (Formula 50) Graft survival
The in vivo efficacy of the compound of Formula 50 was studied in a mouse model of skin allograft transplantation. Drug vehicle (n = 4) or compound Formula 50 (n = 4) or cyclclosporin A was given by oral gavage or intra peritoneal (i.p.) daily prior to 5 days of grafting procedure to until the allograft rejection. Trunk skin (1 cmx 1 cm) of donor mice BALB/c (H2d) was implanted onto lateral thorax of recipient mice C57/BL6(H2b), which is genetically distinct strain.47 The recipient mice were monitored daily. After 7 days, bandage was removed and monitored the allograft region daily until the allograft rejection. The data is shown in Table 4 (Entry 2 and 3). These data indicate that compound of Formula 50 can suppress a robust in vivo allogeneic response.
Table 4: Skin allograft survival by CaeA analogs in mouse model
Figure imgf000058_0001
Example 82: In vivo efficacy of N-{([2,2'-bipyridin]-6-yl)[4- (trifluoromethoxy)phenyl]methylidene}hydroxylamine (Formula 60) Graft survival The in vivo efficacy of the Compound of Formula 60 was studied in a mouse model of skin allograft transplantation as described in example 76. The data is shown in Table 4 (Entry 4 and 5). These data indicate that compound of Formula 60 can suppress a robust in vivo allogeneic response.
Example 83: In vivo efficacy of N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6- yl)ethylidene]hydroxylamine (Formula 73) Graft survival
The in vivo efficacy of the compound of Formula 73 was studied in a mouse model of skin allograft transplantation as described in example 76. The data is shown in Table 4 (Entry 6 and 7). These data indicate that compound of Formula 73 can suppress a robust in vivo allogeneic response.
ADVANTAGES OF THE INVENTION
Present invention discloses new molecules which possess much simpler structures, amenable via chemical synthesis in lesser number of steps, eliminates low yielding and hazardous steps and require significantly lower dose for achieving the desired immunosuppressive effect and therefore lower toxicity and lower metabolic load. Moreover, this invention provides more efficacious molecules at significantly lower cost.

Claims

WE CLAIM
1. A compound of Formula 1
Figure imgf000060_0001
Formula 1
and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof
wherein
A1, B1, C1, and D1 are identical or non-identical and are selected from the group consisting of hydrogen, hydroxyl, chloro, fluoro, cyano, Ci to Cio normal or branched chain alkylamino, Ci to C io normal or branched chain dialkylamino, and Ci to Cio normal or branched chain alkoxy;
A and B are identical or non-identical and are selected from the group consisting of following formulae
Figure imgf000060_0002
wherein
R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, fluoro, and cyano;
R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R is selected from group consisting of hydrogen, Ci to Cio normal or branched chain alkyl, aryl, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano; X is O or N;
Y is O or N;
n = 1 to 10;
C and D are identical or non-identical and are selected from the group consisting of
syn or anti -R4C=NR5, and -R4CH-NHR6
wherein
R4 is selected from the roup consisting of following formulae
Figure imgf000061_0001
wherein
R is hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Qo normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy;
R is hydrogen, alkyl, amino, Ci to Cio normal or branched chain alkylamino, Ci to Cio normal or branched chain dialkylamino, fluoro, chloro, bromo, cyano, hydroxyl, trifluoromethoxyl, and Ci to Cio normal or branched chain alkoxy;
R9 is H, Ci to Cio normal or branched chain alkyl, heterocyclic ring, and poly aromatic hydrocarbon (PAH), wherein said heterocyclic ring or PAH group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, trifuoromethoxyl, bromo, chloro, flouro, and cyano;
R10 is H or Ci to Cio normal or branched chain alkyl;
R11 is H or Ci to Cio normal or branched chain alkyl;
n =l to 10;
R5 is selected from roup consisting of following formulae
Figure imgf000061_0002
wherein
n = 0 to 10;
m = 1 to 10;
R 12 is hydroxyl or amino R is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl or heterocyclic ring is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R14 is H or Ci to Cio normal or branched chain alkyl;
R15 is H or Ci to Cio normal or branched chain alkyl;
R16 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
17
R is selected from group consisting of H, Ci to Cio normal or branched chain alkyl, aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
R6 is selected from roup consisting of following formulae
Figure imgf000062_0001
wherein
n = 0 to 10
18
R is H or Ci to Cio normal or branched chain alkyl;
R19 is selected from group consisting of aryl, bipyridine, and heterocyclic ring, wherein said aryl, bipyridine or heterocyclic group is optionally substituted with one or more substituent selected from the group consisting of hydrogen, hydroxyl, methoxyl, chloro, flouro, and cyano;
and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
2. The compound of formula 1 as claimed in claim 1, wherein said compound is useful as immunosuppressive agent.
3. The compound of formula 1 as claimed in claim 1, wherein representative compound of formula 1 comprising:
N-[([2,2'-bipyridin]-6-yl)methylidene]hydroxylamine (Formula 49);
N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)methylidene]hydroxylamine (Formula 50);
N-[l-([2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 51);
N-[l-([2,2'-bipyridin]-6-yl)propylidene]hydroxylamine (Formula 52);
N-[l-([2,2'-bipyridin]-6-yl)-2-methylpropylidene]hydroxylamine (Formula 53);
N-[l-([2,2'-bipyridin]-6-yl)-3-methylbutylidene]hydroxylamine (Formula 54); N-[l-([2,2'-bipyridin]-6-yl)-4-methylpentylidene]hydroxylamine (Formula 55);
N-[l-([2,2'-bipyridin]-6-yl)nonylidene]hydroxylamine (Formula 56);
N-[([2,2'-bipyridin]-6-yl)(phenyl)methylidene]hydroxylamine (Formula 57);
N-[([2,2'-bipyridin]-6-yl)(4-methylphenyl)methylidene]hydroxylamine (Formula 58);
N-[([2,2'-bipyridin]-6-yl)(4-fluorophenyl)methylidene]hydroxylamine (Formula 59);
N-{ ([2,2'-bipyridin]-6-yl)[4-(trifluoromethoxy)phenyl]methylidene}hydroxylamine (Formula 60);
N- { ( [2,2'-bipyridin] -6-yl) [4-(dimethylamino)phenyl] methylidene jhydroxylamine (Formula 61);
N-[([2,2'-bipyridin]-6-yl)(4-methoxyphenyl)methylidene]hydroxylamine (Formula 62);
N- [( [2,2'-bipyridin] -6-yl)(2-methoxyphenyl)methylidene]hydroxylamine (Formula 63 ) ;
N- [( [2,2'-bipyridin] -6-yl)(3 -methoxyphenyl)methylidene]hydroxylamine (Formula 64) ;
N-[([2,2'-bipyridin]-6-yl)(2,5-dimethoxyphenyl)methylidene]hydroxylamine (Formula 65);
N-[([2,2'-bipyridin]-6-yl)(3,4,5-trimethoxyphenyl)methylidene]hydroxylamine 9 Formula 66);
N-[([2,2'-bipyridin]-6-yl)(naphthalen-2-yl)methylidene]hydroxylamine (Formula 67)
N-[([2,2'-bipyridin]-6-yl)(6-methoxynaphthalen-2-yl)methylidene]hydroxylamine (Formula 68);
N-[([2,2'-bipyridin]-6-yl)(phenanthren-9-yl)methylidene]hydroxylamine (Formula 69);
N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)-2-methylpropylidene]hydroxylamine (Formula 70);
N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)(4-methoxyphenyl)methylidene]hydroxylamine (Formula
71);
N-{ (4,4'-dimethyl[2,2'-bipyridin]-6-yl ^
(Formula 72);
N-[l-(4,4'-dimethyl[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 73);
N-[l-(4,4'-dimethoxy[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 74);
N-[l-(4,4'-di-ieri-butyl [2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 75);
N-[l-(4,4'- dinonyl[2,2'-bipyridin]-6-yl)ethylidene]hydroxylamine (Formula 76);
6,6'-[hydrazinediylidenedimethanylylidene]di(2,2'-bipyridine) (Formula 77);
6-[{2-[([2,2'-bipyridin]-6-yl)methyl]hydrazinylidene}methyl]-2,2'-bipyridine (Formula 78);
6-(l-hydrazonoethyl)-2,2'-bipyridine (Formula 79);
N-[([2,2'-bipyridin]-6-yl)(2,4-dimethoxyphenyl)methylidene]hydroxylamine (Formula 80);
N-[(E)-([2,2'-bipyridin]-6-yl)(cyclopentyl)methylidene]hydroxylamine (Formula 81);
N-[(lE)- l-([2,2'-bipyridin]-6-yl)but-2-yn-l-ylidene]hydroxylamine (Formula 82);
N-[(4,4'-dimethyl[2,2'-bipyridin]-6-yl)(2-methoxyphenyl)methylidene]hydroxylamine (Formula 83). The compound as claimed in claim 1, wherein said compound is useful as a medicine for the prevention or treatment of immune disorders in an animal or human.
The compound as claimed in claim 4, wherein said immune disorder is an autoimmune disorder or an immune disorder as a result from organ transplantation.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12043609B1 (en) 2023-10-13 2024-07-23 King Faisal University 6′(4-methoxyphenyl)-2′-alkoxy-3,4′-bipyridine-3′-carbonitrile as antimicrobial compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0588146A2 (en) * 1992-09-10 1994-03-23 BASF Aktiengesellschaft Substituted pyridin derivatives and parasiticides containing them
WO2007031832A2 (en) * 2005-09-12 2007-03-22 Council Of Scientific And Industrial Research Use of bipyridine compound 'caerulomycin a' derivatives and analogs thereof as immunosuppressive agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0588146A2 (en) * 1992-09-10 1994-03-23 BASF Aktiengesellschaft Substituted pyridin derivatives and parasiticides containing them
WO2007031832A2 (en) * 2005-09-12 2007-03-22 Council Of Scientific And Industrial Research Use of bipyridine compound 'caerulomycin a' derivatives and analogs thereof as immunosuppressive agents
US8114895B2 (en) 2005-09-12 2012-02-14 Council Of Science And Industrial Research Use of bipyridine compound ‘Caerulomycin A’ derivatives and analogs thereof as immunosuppressive agents

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
ANNU REV IMMUNOL, vol. 19, 2001, pages 225 - 52
ANNUAL REVIEW OF IMMUNOLOGY, vol. 19, 2001, pages 565 - 594
CANADIAN JOURNAL OF CHEMISTRY, vol. 56, no. 13, 1978, pages 1836 - 1842
CURR OPIN IMMUNOL, vol. 8, no. 6, 1996, pages 822 - 30
DIAS, D. A.; URBAN, S.; ROESSNER, U. C. P.: "A historical overview of natural products in drug discovery", METABOLITES, vol. 2, no. 2, 2012, pages 303 - 36
EXPERIMENTAL AND CLINICAL PHARMACOLOGY, vol. 29, 2006, pages 99 - 101
EXPERT OPIN EMERG DRUGS, vol. 8, no. 1, 2003, pages 47 - 62
HUNG, D. T.; JAMISON, T. F.; SCHREIBER, S. L.: "Understanding and controlling the cell cycle with natural products", CHEM BIOL, vol. 3, no. 8, 1996, pages 623 - 39, XP026897150, DOI: doi:10.1016/S1074-5521(96)90129-5
IMMUNITY, vol. 14, no. 2, 2001, pages 145 - 55
JAM CHEM SOC, vol. 134, no. 22, 2012, pages 9038 - 41
JOHN MANN: "Natural products as immunosuppressive agents", NATURAL PRODUCT REPORTS, vol. 18, no. 4, 1 January 2001 (2001-01-01), pages 417 - 430, XP055013899, ISSN: 0265-0568, DOI: 10.1039/b001720p *
JOURNAL OF NATURAL PRODUCTS, vol. 74, no. 8, 2011, pages 1751 - 1756
MANN, J.: "Natural products as immunosuppressive agents", NAT PROD REP, vol. 18, no. 4, 2001, pages 417 - 30, XP055013899, DOI: doi:10.1039/b001720p
PLOS ONE, vol. 9, no. 10, 2014, pages e107051
SCI REP, vol. 5, 2015, pages 15396
SCIENCE, vol. 291, no. 5502, 2001, pages 319 - 22
TETRAHEDRON, vol. 66, no. 29, 2010, pages 5432 - 5434

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12043609B1 (en) 2023-10-13 2024-07-23 King Faisal University 6′(4-methoxyphenyl)-2′-alkoxy-3,4′-bipyridine-3′-carbonitrile as antimicrobial compounds
US12065424B1 (en) 2023-10-13 2024-08-20 King Faisal University 6′(4-methoxyphenyl)-2′-alkoxy-3,4′-bipyridine-3′-carbonitrile as antimicrobial compounds

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