WO2008004798A1 - Compounds that inhibit hif-1 activity, the method for preparation thereof and the pharmaceutical composition containing them as an effective component - Google Patents
Compounds that inhibit hif-1 activity, the method for preparation thereof and the pharmaceutical composition containing them as an effective component Download PDFInfo
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- WO2008004798A1 WO2008004798A1 PCT/KR2007/003216 KR2007003216W WO2008004798A1 WO 2008004798 A1 WO2008004798 A1 WO 2008004798A1 KR 2007003216 W KR2007003216 W KR 2007003216W WO 2008004798 A1 WO2008004798 A1 WO 2008004798A1
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- Prior art keywords
- phenoxy
- aromatic
- adamantan
- mmol
- acetylamino
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- 0 CC*CC*1C[C@@](C)(*C([C@@]2C=*C[O+])C2N(C)C)CC1 Chemical compound CC*CC*1C[C@@](C)(*C([C@@]2C=*C[O+])C2N(C)C)CC1 0.000 description 16
- UKADZNPWGMDEJQ-QBZPPBECSA-N C[C@H](C/C(/C(O)=O)=C\N=C\O)NCCCO[C@]1(C=CC2(C3C2)C2(C4)C[C@H](CC5C6)CC45C6C2)C3=C1 Chemical compound C[C@H](C/C(/C(O)=O)=C\N=C\O)NCCCO[C@]1(C=CC2(C3C2)C2(C4)C[C@H](CC5C6)CC45C6C2)C3=C1 UKADZNPWGMDEJQ-QBZPPBECSA-N 0.000 description 1
- VEOFBYQGXOORLV-UHFFFAOYSA-N N#CC1=CCC=CC(NC(COC(CC2)C(Cl)=CC2Cl)=O)=C1 Chemical compound N#CC1=CCC=CC(NC(COC(CC2)C(Cl)=CC2Cl)=O)=C1 VEOFBYQGXOORLV-UHFFFAOYSA-N 0.000 description 1
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/54—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings
- C07C13/605—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings with a bridged ring system
- C07C13/615—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with three condensed rings with a bridged ring system with an adamantane ring
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- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
- C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
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- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/72—Nitrogen atoms
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- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Definitions
- the present invention relates to compounds that inhibit HEF-I activity, the method for preparation thereof and a pharmaceutical composition containing the same as an active ingredient
- HIF-l Hypoxia Inducible Factor-1
- HIF-l ⁇ subunit an oxygen-dependent decomposition domain
- HEF-l ⁇ subunit a constitutively expressed domain
- the HEF-l ⁇ protein Under normal oxygen concentrations, the HEF-l ⁇ protein is hydroxylated depending on the oxygen at proline residues 402 and 564, thereby it will be ubiquitinated by interacting the tumor suppressor pVHL(von Hippel-Lindau) and decomposed by proteasome. In hypoxia, however, these consecutive reactions are inhibited, so that the HEF-l ⁇ protein is accumulated and translocated as a dimeric complex associated with the preexisting BQOF-l ⁇ protein into the nucleusfScience 292, 468472, 2001; Science 292, 468-472, 2001].
- the stability of HEF- Ia depends not only on partial oxygen pressure but also on factors involved in an oxygen sensing pathway, including transition metal ions, iron chelators, and antioxidants.
- the HIF- l ⁇ protein can accumulate irrespective of oxygen concentrations by activation of growth factors, such as epidermal growth factor, heregulin, insulin-like growth factor-I, insulin-like growth factor- H, etc., or of oncogenes, such as ErbB2, etc..
- growth factors such as epidermal growth factor, heregulin, insulin-like growth factor-I, insulin-like growth factor- H, etc., or of oncogenes, such as ErbB2, etc.
- these growth factors bind to respective receptors, it is increase that HIF-l ⁇ protein is synthesized by activating the PBK- AKT or MAPK signal transduction pathway, with the result that the HEF-I ⁇ protein accumulates.
- HJDF is associated with an HRE(Hypoxia Responsive Element, 5 -ACGTG-3') on the promoter of a target gene to induce the expression of the gene.
- HIF vascular endothelial growth factor
- hypoxia is usual in cancer, in particular solid cancer. Because solid cancer cells are adapted to a low oxygen condition after being subjected to various genetic alterations, they become more malignant and resistant to anticancer agents. In fact, hypoxia is known to play an important role in malignant cancer in over 70% of all cancer lypesENature 386, 403, 1997; Hockel M and Vaupel P, Semin. Oncol. 28, 36-41, 2001, Nature Med. 6,
- HIF-I is one of ⁇ e most important molecules regulating the adaptation of cancer cells to hypoxia, and the amount of HEF-l ⁇ protein is closely correlated with poor prognosis of cancer patients. Whether attributed to the hypoxia, or above-mentioned the stimulation of growth factors or the activation of oncogenes, or the inactivation of tumor suppressors, such as pVHL, the cancer cells are
- HEF-I activated, HEF-I induces the expression of various genes , encoding, for example, hexokinase 2, glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGF, MMP-2, uPAR, MDRl, etc., leading to improvement in apoptosis resistance, angiogenesis, cell proliferation, and invasiveness, thereby resulting in the malignant transformation of cancer cells.
- HIF Because it plays a pivotal role in the growth, proliferation and malignant transformation of cancer, in particular, solid cancer, HIF has become a major target of many anticancer agents, and active and extensive research has been conducted thereon[Cancer Res.
- HEF-I can be used as a valid target for novel anticancer therapeutics.
- Angiogenesis factors which are derived by an activated HEF-I in hypoxia condition, such as VEGF, are associated with the progress of diabetic retinopathy and arthritis as well as cancer. Accordingly, the compounds that inhibit an activated HEF-I from hypoxia condition can also be used as novel therapeutics for the diseases comprising diabetic retinopathy and rheumatoid arthritis[Eiji Eceda, Pathology International, 2005, VoI 55, 603-610]. However, this field is still in its infancy.
- An object of the present invention is to provide a compound having inhibition activity against the transcription factor HEF- 1.
- Still a further object of the present invention is to provide a pharmaceutical composition for the treatment of diabetic retinopathy and arthritis.
- the above objects of the present invention could be accomplished by the provision of a compound represented by Chemical Formula IA or IB as defined below.
- the compound functions to selectively suppress the growth and metastasis of tumor cells, thereby showing potent anticancer activity with little or no side effects.
- the compound is useful in the treatment of diabetic retinopathy and arthritis through the inhibitory mechanism against HDDF-I activity.
- Ia accordance with another object provided are a method for preparing the compound and a pharmaceutical composition containing the compound. . .
- the compound of the present invention shows anticancer activity not through general cytotoxicity, but through inhibition activity of FHF-I activity, particularly through dose-dependent inhibition activity against BQF- l ⁇ accumulation in hypoxia. Having selective inhibition activity, the compound of the present invention is effective for suppressing tihe expression of the genes involved in the malignant transformation of cancer, thereby preventing the growth and metastasis of cancer.
- the compound of the present invention serving as an FHF-I inhibitor, is useful in the treatment of various cancers, including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vaginal cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, and CNS tumors.
- various cancers including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vaginal cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer,
- the compound of the present invention has selective inhibition activity against VEGF, a target gene of HIF-I, and thus can be used as an ingredient of therapeutics for diabetic retinopathy and arthritis, which are aggravated upon FHF-1-mediated VEGF expression in hypoxia.
- FIG. 1 shows the inhibition activity of the compounds of the invention against FHF-l ⁇ accumulation in hypoxia
- FIG. 2 shows the inhibition activity of the compounds of the invention against VEGF expression in hypoxia
- FIG.3 shows the in vivo anticancer activity of the compounds of the invention in nude mice.
- X and Y are each C or N, preferably with the proviso that when X is C, Y is C or N and when Y is N, ' Xis C orN;
- Z is O or NH
- Ri is selected from a group consisting of H, OH and COORa where Ra is H or Ci-C 2 alkyl;
- R 3 is selected from a group consisting of H, COORa and SO 2 NH 2 , the Ra being H or Ci-C 2 alkyl;
- Ri is selected from a group consisting of H, COORa and CONRbRc, the Ra being H or Ci-C 2 alkyl, the Rb and the Rc being independently selected from a group consisting OfC]-C 3 alkyl substituted with a C 3 -C 5 heteroaryl or heterocyclic group containing N, O and/or S;
- R 5 is selected from a group consisting of H, Cr-Qo alkyl, phenyl, halogen, nitro and acetyl;
- R 6 , R. 7 are Rio are independently selected from a group consisting of H and halogen;
- R 8 is a substituent located at the C 5 or Ce position on the benzooxazole or benzoimidazole, selected from a group consisting of H, COORa, CONRbRc and SO 2 NH 2 , the Ra being selected from H and Ci-C 2 alkyl, the Rb and the Rc being independently selected from Ci-C 5 alkyl substituted with a C 3 ⁇ C 5 heteroaryl or heterocyclic group containing N, O and/or S; Ci-C 5 alkyl substituted with an amino group or with a Ci ⁇ C 3 alkyl- substituted amino group; amino; H; and Ci-C 3 alkyl; and
- R 9 is selected from a group consisting of Ci-Ci 0 alkyl, halogen and nitro group.
- the present invention pertains to a method for preparing the compounds of Chemical Formula IA and IB.
- Representative compounds of the present invention can be synthesized according to Reaction Schemes- 1 to 6, which are the mother models from which all of the compounds of the present invention can be derived by modifying reaction conditions, including reagents, solvents, the order of the reaction steps, and the like.
- the coupling reaction starts with phenoxyacetic acid (2a) and an amine compound (3).
- the coupling agent useful in the present invention is selected from a group consisting of l-[3 ⁇ dimemylamino)propyl]-3-emylcarbodiimide hydrochloride. (EDC), 0-benzotriazole-
- HHlSr ⁇ -tetramethyl-uronium-hexafluoro-phosphate HBTU
- 1-hydroxybenzotriazole HOBt
- benzotriazol-1-yl-o5c ⁇ -1ris-pyiTOlidino-phosphonium hexafluorophosphate PyBOP
- l-hydroxy-7-azabenz ⁇ triazole HAAt
- a preferable organic solvent is dimethyUbrmamide (DMF) or methylenechloride
- the compound of Chemical Formula IAa can be reacted with an inorganic base in a mixture of an organic solvent and water to synthesize the corresponding carboxylic acid compound of Chemical Formula IAb.
- the organic solvent useful for this reaction may be tetrahydrofuran, dioxane, methanol or ethanol, and the inorganic base may be selected from among sodium lithianide? and sodium hydroxide. This reaction is preferably conducted at 25 ⁇ 5O 0 C.
- the compound of Chemical Formula IAb can be converted into a corresponding amide compound of Chemical Formula IAc through reaction with ammonium chloride or alkyl amine in the presence of a Hunig base and a coupling agent in an organic solvent at room temperature (25°C) or under a flux condition.
- the coupling agent useful for this reaction is selected from among EDG, HOBt, PyBOP and combinations thereof. DIPEA or TEA is useful as the Hunig base.
- the organic solvent is preferably DMF.
- a phenoxy acetic acid (2a) is reacted with an amine compound (4) in the presence of a coupling agent in an organic solvent to yield a carboxylic acid ester compound (IAd).
- a coupling agent selected from among PyBOP, EDC, HOBt, 4-dimethylaminopyridine (DMAP), and combinations thereof. This reaction is preferably conducted at , 25 0 C, with DMF.serving as an organic solvent.
- the compound of Chemical Formula IAg falls into the range of compounds of Chemical Formula IA. ⁇ Reaction Scheme 4> - .
- the compound of Chemical Formula IB can be prepared by reacting the phenoxy acetic .acid (2b), which is commercially available or can_be readily prepared using a well know method, with a compound (6), which can be synthesized using a known method, at an equivalent ratio in the presence of triethylsilyl polyphosphate (PPSE). This reaction is preferably conducted at 140-16O 0 C for 2 ⁇ 4 hours.
- PPSE triethylsilyl polyphosphate
- An ester compound (IBa) is hydrolyzed into a corresponding carboxylic acid compound (IBb) in the presence of aluminum bromide and dimethyl sulfide, with CH 2 CI 2 serving as a solvent This hydrolysis is preferably carried out at 25°C for 2 ⁇ 3 hours. Alternatively, the conversion of the ester compound (IBa) into the acid compound (IBb) may be achieved in the presence of an acid under flux.
- ester compound (IBa) and the carboxylic acid compound (IBb) can be used to prepare a corresponding amide compound (IBc).
- a solution of commercially available alkyl amine in anhydrous toluene is stirred in the presence of triethyl aluminum (2M Hexane solution) at room temperature, preferably for
- the compound (IBc) may be synthesized through the reaction of the compound (IBb) with an amine compound selected from among ammonium chloride, hydrazine and alkyl amine at room temperature (25 0 C) in the presence of a coupling agent and a Hunig base in DMF.
- the coupling agent is selected from among EDC, HOBt,
- the present invention pertains to an anticancer pharmaceutical composition
- an anticancer pharmaceutical composition comprising the compound of Chemical Formula IA or IB, or a pharmaceutically acceptable salt as an active ingredient for the inhibition of HIF-I activity.
- the compound of Chemical Formula IA or IB, or a related pharmaceutical composition exhibits 15. anticancer activity not through generalxytotoxicity, but through selective cytotoxicity characterized by .inhibition activity against the transcription factor HEF-I, which plays a pivotal role in the growth and metastasis of cancer cells.
- inhibittion activity against HEF-I means inhibiting all of the transcription of an HIF-I gene, the expression of HIF-I protein, and the accumulation of HEF-I 20 protein.
- the compounds of the present invention were found to have excellent inhibition activity against HEF-I transcription as measured in assays for HEF-1-mediated transcription in hypoxia. Therefore, the compounds of the present invention can also have an inhibitory effect on the HEF-I related expression of the genes involved in the malignant transformation of cancer, thereby suppressing the growth and metastasis of cancer. Consequently, the
- 25 compounds of the invention can be used as active ingredients useful in the treatment and prevention of cancer.
- the compounds of the present invention can inhibit the expression of the HEF-l ⁇ protein in a dose-dependent manner in hypoxia without influencing the production of topoisomerase-1 (TOPO-I).
- the compounds of the present invention do not function through general cytotoxicity for anticancer activity, but show dose-dependent inhibition of the 30 accumulation of HEF-l ⁇ protein, thereby suppressing the growth and metastasis of cancer with the minimal concomitant production of side effects.
- the compounds of the present invention can inhibit the expression of VEGF in a dose-dependent manner in hypoxia with no effect on the expression of the control gene GAPDH. Accordingly, the compounds of the present invention can be used for cancer therapy thanks to the ability thereof to suppress the growth and metastasis of cancer through selective inhibition activity against VEGF, a target gene of EDDF-l, . as well.
- the pharmaceutical composition of the present invention comprising the compound of Chemical Formula IA and IB or a pharmaceutically acceptable salt thereof can be used as a therapeutic for various cancerous disorders, including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vagina cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, and CNS tumors.
- the ability of the compound of Chemical Formula IA or IB, or a pharmaceutically acceptable salt thereof for inhibiting HIF-I activity ensures that the pharmaceutical composition can be effectively used in the treatment of diabetic retinopathy and arthritis.
- the term "inhibition. of EDDF-I activity" or a phrase equivalent thereto means inhibiting all of the transcription of an HEF-I gene, the expression of HIF-I protein, and the accumulation of EDDF-I protein.
- _ . .EDDF-I can.be_a target of drugs for the treatment of disorders which, devebp through .angi ⁇ genesis. ,
- the angiogenesis factors such as VEGF
- EDDF-I stimulated by EDDF-I
- EDDF-I which is activated in hypoxia
- angiogenesis factors such as VEGF
- EDDF-I stimulated by EDDF-I
- EDDF-I which is activated in hypoxia
- VEGF angiogenesis factor
- EDDF-I stimulated by EDDF-I
- EDDF-I which is activated in hypoxia
- compounds capable of inhibiting the activity of EDDF-I which is activated in hypoxia, can be used as therapeutics for diabetic retinopathy or arthritis ((Eiji Ikeda, Pathology International, 2005, VoI 55, 603-
- the compounds of the present invention can- inhibit the expression of VEGF in a dose-dependent manner in hypoxia without influencing the expression of the control
- the compounds of the present invention are useful as active ingredients for the treatment of diabetic retinopathy or arthritis, which is aggravated upon the expression of VEGF because they can selectively inhibitEQF-l, which plays a pivotal role in the expression of VEGF in hypoxia
- the pharmaceutical composition of the present invention may be formulated into oral or non-oral dosage forms.
- oral dosage forms include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc.
- ⁇ ese forms may include diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,, and/or glycin), and/or lubricants (for example, silica, talc, stearic acid or magnesium of calcium salts thereof, and/or polyethylene glycol) in addition to the active ingredient Tablets may also include binders, such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and optionally disintegrants, such as starch, agar, alginic acid or sodium salt thereof, a boiling mixture, and/or absorbents, colorants, flavoring agents, and sweeteners.
- diluents for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,, and/or glycin
- lubricants for example
- the composition may be formulated into subcutaneous, intravenous, intramuscular, or intrathoracic injections.
- the compound of Chemical Formula IA or IB or a pharmaceutically acceptable salt thereof may be mixed with a stabilizer or a buffer in water so as to afford a solution or a suspension which is then packaged into ampule or vial units.
- the composition is sterilized and/or may contain an auxiliary agent, such as a preservative, a stabilizer, a wettable agent, an emulsifier, an osmotic pressure-controlling salt and a buffer, and/or other therapeutically effective materials. They may be mixed, granulized, or coated according to a method well known in the.art.
- an auxiliary agent such as a preservative, a stabilizer, a wettable agent, an emulsifier, an osmotic pressure-controlling salt and a buffer, and/or other therapeutically effective materials.
- auxiliary agent such as a preservative, a stabilizer, a wettable agent, an emulsifier, an osmotic pressure-controlling salt and a buffer, and/or other therapeutically effective materials.
- They may be mixed, granulized, or coated according to a method well known in the.art.
- the compound of Chemical Formula IA or IB may be administered once or many times to mammals
- Example 4 ⁇ 3-[2-(4-Adamantan-l-yl-phenoxy)-acetylarnino]-phenyl ⁇ -acetic acid methyl ester
- the present example was performed in the same manner to give 3-[2-(4-fe/Y-bu1yl-phenoxy)- 0 acetylaminoj-benzoic acid methyl ester as a light yellow solid (185 mg, 100% yield).
- the present example was performed in the same manner from 4-[2-(4-tert-butyl-phenoxy)- ⁇ 15 acetylaminoj-benzoic acid methyl ester to give 4-[2-(4-tert-butyl-phenoxy)-acetylamino]-benzoic acid as a white solid (68.7 mg, 65.7% yield).
- the present example was performed in the same manner from 3-[2-(4-chloro-phenoxy)-acerylamino]- benzoic acid methyl ester to give 3-[2-(4-chloro-phenoxy)-acetylamino]-ben2oic acid as a white solid (70.3 mg, 74.2% yield).
- the present example was performed in the same manner from 3-[2-(2,4-dichloro-phenoxy)- acetylaminoj-benzoic acid methyl ester to give S-P ⁇ ' Michloro-phenoxyyacetylaminoj-benzDic acid 3-[2-(2,4- dichloro-phenoxy)-acetylamino]-benzoic acid as a white solid (583.7 mg, 85.8% yield).
- the present example was performed in the same manner from 3-[2-(4-bromo-phenoxy)-acetylamino]- benzoic acid methyl ester to give 3-[2-(4-bromo-phenoxy)-acetylamino]-benzoic acid as a white solid (44.6 mg,
- the present example was performed in the same manner from 3-[2-(4-iodo-phenoxy)-acetylamino]- benzoic acid methyl ester to give 3-[2-(4-iodo-phenoxy)-ace ⁇ ylamino]-benzoic acid as a white solid (64.4 mg, 67.7% yield).
- N-(3-cyano-phenyl)-2-(2,4-dichloro-phenoxy)-acetamide(70.0 mg, 0.22 mmol), sodium azide (42.9 mg, 0.66 mmol) and triethylamine hydrochloride (45.4 mg, 0.33 mmol) in N-methylpyrrolidone (6 ml) (NMP) was stirred at 150 ° C under nitrogen overnight After cooling, the reaction mixture was diluted with water, acidified to PH 1 with 10% v/v hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated.
- Sulfamoyl chloride was prepared by the dropwise addition of formic acid (0.03 mL, 0.80 mmol) to neat chlorosulfonyl isocyanate (0.07 mg, 0.80 mmol) at 0 ° C with rapid stirring. Gas was evolved during the addition process. The viscous mixture was stirred for 5 min at 0 ° C. during which time it solidified. Dichloromethane (0.2 mL) was added and the solution of the 2-(2,4-Dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide (100 mg, 0.32 mmol) and pyridine (0.26 mL, 3.2 mmol)in dichloromethane (0.3 mL) was added dropwise.
- furfuryl amine(6.8 mg, 0.07 mmol, 0.07 ml) in anhydrous toluene 1 ml was treated with trimethyl aluminium(in 2.0 M Hexane, 0.15 ml, 0.31 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan- l-yl-phenoxy)-acetyl amino]- ⁇ hydroxy-berizoic acid methyl ester(30.1 mg, 0.07 mmol) in toluene 8 ml. The mixture was stirred for 3 h at 80 "C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate.
- HATU(68.5 mg, 0.18 mmol) in DMF 3.0 ml was added N-(aminopropyl)mo ⁇ holine(0.18 mmol, 0.03 ml) and DIEEA(0.03 ml, 0.18 j ⁇ mol) at room temperature.
- the .reaction mixture .was separated witbi ethyl .acetate and sodium bicarbonate.
- the organic phase was dried (MgSCv t anh), and concentrated.
- Example 70 >3-[2-(4-adamantan-l-yl ⁇ henoxy)-acetylarnino]-N-(4 ⁇ Uoro-phenyl)-berizarnide
- Reaction mixture was diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over MgSO ⁇
- Example 82 >3-[2-(2,4 ⁇ iicMorc)-phenoxy)-ace1ylamino]-N-(2-piperidine-l-yl-ethyl)-be ⁇ zamide
- N-(3-mo ⁇ holine-4-yl-propyl)-benzamide as a colorless solid (0.185g, 60% yield).
- Example 106 2-[2 ⁇ 4-adamantan-l-yl-phenoxy)-acelylamino]-N-(2-pvri ⁇ %e ⁇ -yl-ethyl)-isomcotinarm
- furfurylamine 28.2 mg, 0.29 mmol, 0.03 ml was dissolved in dry toluene (3 ml) and treated with trimethylaluminium (2.0 M in hexane) (0.64 ml. 1.28 mmol) with stirring under argon. After 0.25h, a solution of the 2-(2,4-Dichloro-phenoxymethy)-benzooxazole-5-carboxylic acid methyl ester (100.2 mg, 0.29 mmol) in toluene (9 ml) was added. The mixture was then stirred at 80 oC for Ih, the reaction mixture was allowed to cool and was treated with dilute HCl, until no more effervescence took place.
- Example 155 2 ⁇ 4-adamantan-l-yl-phenoxymeft ⁇ yl)-lH-benzDimidazole-5-carboxylic acid (3-imidazole-l-yl- propyl)-amide
- Formulations comprising the compound are prepared as follows.
- Lactose Ig These components were mixed and filled in an airtight sac to prepare a powder agent ⁇ FORMULA ⁇ N EXAMPLE 2> Tablet Fo ⁇ nulation Cpd.
- a powder agent ⁇ FORMULA ⁇ N EXAMPLE 2> Tablet Fo ⁇ nulation Cpd.
- lOOmg Of Chemical Formula IA or IB lOOmg
- EXPERIMENTAL EXAMPLE 1 Assay for Inhibition of HIF-Mediated Transcriptional Activity (BKE Reporter Assay)
- HRE Hydrophila Responsive Element, 5'-ACGTG-3'
- a human VEGF gene Six tandem repeats of HRE (Hypoxia Responsive Element, 5'-ACGTG-3'), which is present in a human VEGF gene, was inserted into the multi-cloning region of a pGL3-basic vector (Promega) containing a luciferase gene as a reporter gene to produce a recombinant pGL3-HRE-luciferase vector which was then used to assay the compounds prepared in the above Examples for inhibition activity against HIF-mediated transcriptional activity.
- pGL3-basic vector Promega
- HepG2 or Hep3B both available from ATCC (American Type Culture Collection), and the gastric carcinoma cell line AGS, available from ATCC, were grown at 70% confluency in culture dishes and co-transfected with an internal control vector (pRL-CMV, Promega) and the recombinant pGL3-HRE-luciferase vector using Lipofectamine Plus Reagent (Tnvitrogen).
- pRL-CMV internal control vector
- Tnvitrogen Lipofectamine Plus Reagent
- HepG2 and AGS cells were treated with the compound of Chemical Formula IA while Hep3B and AGS cells were treated with the compound of Chemical Formula IB.
- the compound of Chemical Formula IA was used in a concentration of 10 ⁇ M for HepG2 or AGS cells.
- the compound of Chemical Formula IB was used in a concentration of 30 ⁇ M for Hep3B and in a concentration of 10 ⁇ M for AGS cells. After culture for 48 hours, the compounds of Examples were applied to respective cells which were then incubated for 16 hrs in hypoxia (1% O 2 , 94% N 2 , and 5% CO 2 ).
- the compounds prepared in Examples above were assayed for inhibition activity against HIF-I by measuring the activity of the luciferase, induced in hypoxia, using a Dual-luciferase reporter assay system (Promoga). In this regard, the luciferase activity was measured for 10 sec using a Microlumat Plus luminometer (EGScG Berthold). In the meanwhile, the renilla luciferase activity from the control vector pRL-CMV (Promega) was measured to normalize the data obtained.
- Hep3B The hepatocellular carcinoma cell line Hep3B, available from ATCC (American Type Culture
- the compounds of the present invention in particular the compounds prepared in Experimental Examples 18, 23, 44, 48, 113 or 126, were found to show excellent inhibition activity against the transcription mediated by HIF-I, which is induced in hypoxia. Therefore, the compounds of the present invention are useful as active ingredients for cancer therapy because tiiey can inhibit the expression of the genes implicated in the malignant transformation of cancer, thereby suppressing the growth and metastasis of cancer.
- Experimental Example 1 were assayed for HIF-l ⁇ accumulation inhibition in the gastric carcinoma cell line AGS and the hepatocellular carcinoma cell line Hep3B or HepG2.
- the compounds prepared in Examples 18 and 126 were used to measure the inhibition of HDDF-l ⁇ accumulation in the hepatocellular carcinoma cell line HepG2 as follows. _
- BOGF-l ⁇ accumulation inhibition of the compounds prepared in Experimental Examples 18, 23, 44, 48, 113 or 126 was assayed in the hepatocellular carcinoma cell line Hep3B as follows.
- the inhibitory effect of the compound prepared in Example 18, 23, 44, 48, 113 or 126 on HEF-l ⁇ protein production induced in hypoxia was assayed using a Western blotting method.
- the hepatocellular carcinoma cell line HepG2 American Type Culture Collection
- DMSO alone was used as a control (expressed as 'DMSO' in FIG. 1).
- the hepatocellular carcinoma cell line was then incubated for 12 hrs in hypoxia (1% O 2 , 94% N 2 , and 5% CO 2 , expressed as '1% O 2 ' in FIG.
- HIF- l ⁇ protein was prepared using an anti-HIF-l ⁇ antibody (R&D System) and a secondary antibody labeled with horseradish peroxidase (HRP).
- the compounds prepared in the present invention were found to inhibit the production of HIF-l ⁇ protein in a dose-dependent manner in hypoxia with no influence on the production of topoisomerase-1 (TOPO-I) or HDF-l ⁇ .
- TOPO-I topoisomerase-1
- HDF-l ⁇ topoisomerase-1
- the inhibition of these compounds against HIF-I -mediated transcriptional activity in hypoxia is attributed to the suppression of the HIF-l ⁇ expression induced upon hypoxia HIF-l ⁇ , as a constituent of HQF-I, plays an important role in the expression of target genes of HEF-I. Therefore, the compounds of the present invention are useful as active ingredients for cancer therapy because they can inhibit the expression of the EQT-l ⁇ protein responsible for the growth and metastasis of cancer in a dose-dependent manner.
- Hep3B hepatocellular carcinoma cell lines
- ATrC American Type Culture Collection
- the compounds prepared in the present invention inhibits the accumulation of HF-l ⁇ playing a pivotal role in the growth and metastasis of cancer depending on time, thereby inhibiting the growth and metastasis of cancer, so it can be used as an effective ingredient for anticancer agent
- the inhibitory effect of the compounds of the present invention on HDF-I activity was confirmed by assaying the compounds prepared in Examples for inhibition activity on the expression of EPO or VEGF, a representative target gene of HtF-I through an analysis of RT-PCR(reverse transcriptase polymerase chain reaction).
- VEGF a target gene of FHF-I, encodes an angiogenesis factor playing a pivotal role in the growth and metastasis of cancer
- EPO is a hematosis hormone gene, and both genes have been known for being deeply related to the development and the aggravation of cancer.
- the compounds of the present invention were measured for inhibition of VEGF expression in AGS, Hep3B and HepG2 cells.
- the hepatocellular carcinoma cell line Hep3B was treated with compounds prepared in Examples 18 and 126 as follows.
- HepG2 cells (American Type Culture Collection) were treated with various concentrations (0 ⁇ M, 1 ⁇ M, 3 ⁇ M and 10 ⁇ M) of compounds prepared in Examples 18, 44, 113 or 126 and incubated for 12 hrs in hypoxia (1% O 2 , 94% N 2 , and 5% CO 2 , expressed as '1% O 2 ' in HG. 2).
- Total RNA was isolated using an RNA Mini kit (Qiagen). From the total RNA (2 ⁇ g) thus obtained, cDNA was synthesized using an RT-PCR kit (Thvitrogen), and was used to amplify EPO or VEGF by 5 PCR in the presence of EPO or VEGF-specific primers.
- EPO or VEGF expression was quantitatively analyzed by running the PCR products on agarose gel.
- GAPDH was simultaneously amplified so as to analyze the selective inhibition of each compound for VEGF.
- Base sequences of primers used for the amplification of EPO, VEGF and GAPDH used in the present invention were as follows.
- the compounds of the present invention are useful as active ingredients for cancer therapy because they can selectively inhibit the expression of VEGF, an angiogenesis factor playing an important role in the malignant transformation of cancer, or the expression of EPO a hematosis5 hormone gene, a thereby suppressing the growth and metastasis of cancer.
- the compounds of the present invention can be used as an active ingredient for the treatment of diabetic retinopathy or arthritis, which is aggravated upon HIF-1-mediated VEGF expression in hypoxia
- the compounds prepared in Examples 18, 95 or 126 were measured for in vivo anticancer activity in mice.
- mice Female nude mice 5-6 weeks old (Crj:BALB/c nu/nu, Charles River) were bred in germ-free breeding rooms maintained at constant temperature and humidity. The nude mice were anesthetized before incision of the chest skin. The metastatic breast carcinoma cell line MDA-MB-435, obtained from DR. D.R. Welch, Univ. Alabama, was implanted at a count of 10 6 cells/mouse into the mammary gland fat pad, and the incisions were then closed with surgical clips. The nude mice were divided into test groups and a control group, each consisting of 6 mice.
- the compounds prepared in Example 18, 95 or 126 were administered at various concentrations.
- the compounds were dissolved at concentrations of 20mg/kg and 50 mg/kg in a solvent containing 94.5% of physiological saline, 0.5% of DMSO and 5% of Tween 20 (hereinafter referred to as 'Solvent A 1 ), the concentration of the compounds prepared in Experimental Examples 18, 95 or 126 was adjusted at 20mg/kg or 50mg/kg and administered once to the experimental groups at a dose of 100 ⁇ l a day per individual.
- Solution A alone was used at a dose of 100 ⁇ l once a day.
- tumor volumes and body weights were measured once a week. Tumor volumes were calculated according to the following Mathematic Formula 1.
- Tumor Volume (mm 3 ) (Length of Long Axis, mm)x(Length of Short Axis, mm) 2 x 0.5 . .
- the compounds prepared in Examples 18 and 126 were observed to further inhibit the growth of the cancer cells by 64.6% and 58.6%, respectively, compared to the control.
- the growth of the cancer cells was inhibited by a further 46.5% and 53%, respectively, compared to the control.
- the growth of the cancer cells was inhibited by 4.3%
- the growth of the cancer cells was inhibited by 36.5%, compared to the control.
- the extracted cancer cells of the test groups became smaller, compared to that of the control. No dead were observed in six mice of each group which were administered with the concentration of 50mg/kg of the compounds prepared in Examples 18, 95 or 126.
- mice of the test groups did not appear different from those of the control in terms of body weight and feed intake. Therefore, the compounds of the present invention were very effective active ingredients for anticancer agents, thanks to the in vivo anticancer activity and the lack of general cellular toxicity thereof, as demonstrated by experiments on mice.
- mice An acute cytotoxicity assay was conducted with five-week-old SPF C57BL/6 mice (Samtako BioKorea) as follows.
- the compounds prepared in Examples 18 and 126 were suspended in a solvent comprising 94.5% of physiological saline, 0.5% of DMSO and 5% of Tween 80, and 0.5 mL of each of the suspensions was orally administered once into five mice at a dose of 300mg/kg.
- the mice were observed for death, clinical syndromes, and body weight and then autopsied for the observation of abdominal and thoracic organs with the naked eye. No noteworthy clinical syndromes were found, no mice died, and no changes due to toxicity were observed with respect to body weight or during the autopsy. Consequently, the compounds prepared in Examples 18 and 126 are safe with a minimal lethal dose of at least 300 mg/kg for oral administration, as demonstrated by the observation of no toxicity up to a dose of 300 mg/kg.
- the compounds in accordance with the present invention have anticancer activity not through general cytotoxicity, but through selective inhibition of HIF- 1 activity.
- the compounds of the present invention can be effectively used to suppress the growth and metastasis of cancer because they inhibit the HOF-1-mediated expression of the genes implicated in the malignant transformation of cancer.
- the. anticancer activity of compounds.of the present invention is not attributed to general cytotoxicity,.. but to dose-dependent inhibition of the accumulation of HIF-l ⁇ protein.
- the compounds of the present invention can be effectively used in the treatment of various cancerous diseases, including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vaginal cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, and CNS tumors.
- various cancerous diseases including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vaginal cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer,
- the compounds of the present invention can be also used as active ingredients of therapeutics for diabetic retinopathy or arthritis, which is aggravated upon HF-1-mediated VEGF expression.
- SEQ ID NO: 1 is a sense primer of an EPO gene
- SEQ ID NO: 2 is a antisense primer of an EPO gene
- SEQ ID NO: 3 is a sense primer of a VEGF gene
- SEQ ID NO: 4 is an antisense primer of a VEGF gene
- SEQ ID NO: 5 is a sense primer of a GAPDH gene
- SEQ ID NO: 6 is an antisense primer of a GAPDH gene.
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Abstract
Disclosed herein are an HIF-1 inhibitor, a method for the preparation thereof, and a pharmaceutical composition comprising the same as an active ingredient The HIF-1 inhibitor shows anticancer activity thanks to the inhibition activity against HIF-1, a transcription factor which plays an important role in the growth and metastasis of cancer, but not to general cytotoxicity. Thus, the HIF inhibitor and a pharmaceutically acceptable salt thereof can be used as a therapeutic for various cancers such as liver cancer, stomach cancer and breast cancer. Also, the compound having inhibition activity against HIF-1 is useful in the treatment of diabetic retinopathy and arthritis, which are aggravated by HIF-1-mediated VEGF expression.
Description
COMPOUNDS TEAT INHIBIT HIF-I ACTIVITY, THE METHOD FOR PREPARATION THEREOF AND THE PHARMACEUTICAL COMPOSITION CONTAINING THEM AS AN
EFFECTIVE COMPONENT
[TECHNICALFIELD]
The present invention relates to compounds that inhibit HEF-I activity, the method for preparation thereof and a pharmaceutical composition containing the same as an active ingredient
[BACKGROUNDART] In spite of extensive efforts conducted for decades all over the world, cancer still remains one of the most incurable diseases. Recently, with great and brilliant advances in all sorts of sciences comprising cancer biology and medicinal chemistry, anticancer agents such as Gleevec, which have innovative mechanisms, have been developed. Since the completion of the Human Genome Project, new molecules that are targets of anticancer agents have been discovered. HIF-l(Hypoxia Inducible Factor-1) is a heterodimeric transcription factor composed of two subunits: HIF- lα subunit, an oxygen-dependent decomposition domain;,.and HEF-lβ subunit a constitutively expressed domain[Cancer Metastasis Rev., 17, 187-195, 1998; Trends MoI. Med., 7, 345- 350, 2001].
Under normal oxygen concentrations, the HEF-lα protein is hydroxylated depending on the oxygen at proline residues 402 and 564, thereby it will be ubiquitinated by interacting the tumor suppressor pVHL(von Hippel-Lindau) and decomposed by proteasome. In hypoxia, however, these consecutive reactions are inhibited, so that the HEF-lα protein is accumulated and translocated as a dimeric complex associated with the preexisting BQOF-lβ protein into the nucleusfScience 292, 468472, 2001; Science 292, 468-472, 2001]. The stability of HEF- Ia depends not only on partial oxygen pressure but also on factors involved in an oxygen sensing pathway, including transition metal ions, iron chelators, and antioxidants. In addition, the HIF- lα protein can accumulate irrespective of oxygen concentrations by activation of growth factors, such as epidermal growth factor, heregulin, insulin-like growth factor-I, insulin-like growth factor- H, etc., or of oncogenes, such as ErbB2, etc.. When these growth factors bind to respective receptors, it is increase that HIF-lα protein is synthesized by activating the PBK- AKT or MAPK signal transduction pathway, with the result that the HEF-I α protein accumulates.
Within a nucleus, HJDF is associated with an HRE(Hypoxia Responsive Element, 5 -ACGTG-3') on the promoter of a target gene to induce the expression of the gene. There are about 60 genes that have been known to be regulated by HIF, including a vascular endothelial growth factor(VEGF) geae[Nat. Rev. Cancer 2, 3847, 2002; J. Biol. Cliein. 278, 19575-19578, 2003; Nat, Med 9, 677-684, 2003; Biochein. Pharmacol 64, 993-998, 2002].
Hypoxia is usual in cancer, in particular solid cancer. Because solid cancer cells are adapted to a low
oxygen condition after being subjected to various genetic alterations, they become more malignant and resistant to anticancer agents. In fact, hypoxia is known to play an important role in malignant cancer in over 70% of all cancer lypesENature 386, 403, 1997; Hockel M and Vaupel P, Semin. Oncol. 28, 36-41, 2001, Nature Med. 6,
1335, 2000; Bos et al. Cancer 2003, 97, 1573-1581]. HIF-I is one of ώe most important molecules regulating the adaptation of cancer cells to hypoxia, and the amount of HEF-lα protein is closely correlated with poor prognosis of cancer patients. Whether attributed to the hypoxia, or above-mentioned the stimulation of growth factors or the activation of oncogenes, or the inactivation of tumor suppressors, such as pVHL, the cancer cells are
. activated, HEF-I induces the expression of various genes , encoding, for example, hexokinase 2, glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGF, MMP-2, uPAR, MDRl, etc., leading to improvement in apoptosis resistance, angiogenesis, cell proliferation, and invasiveness, thereby resulting in the malignant transformation of cancer cells. Because it plays a pivotal role in the growth, proliferation and malignant transformation of cancer, in particular, solid cancer, HIF has become a major target of many anticancer agents, and active and extensive research has been conducted thereon[Cancer Res. 62, 4316, 2002; Nat Rev Drug Discovery 2, 1, 2003; Semenza et al. Nature Reviews Cancer 2003, 3, 721-732]. Recently, a significant number of „ . preexisting anticancer agents, such as taxol, xafamycin and 17-AAG(17-allylaminogeldanamycin), or small molecular compound YC-l(3-(5'-hydroxymethyl-2'-fiιryl)-l-benzyUndazDle) are undergoing various clinical demonstrations for use as HEF-I inliibitorsfJohnson et al Nature Reviews Drug Discovery 2003, 2, 1-9; Semenza et al. Nature Reviews Cancer 2003, 3, 721-732; JNCI 95, 516, 2003], and cell based reporter assays for screening HIF-I inhibitors of new structures are being actively conducted by taking advantage of HRE[Cancer Res 65, 4918, 2005; Cancer Cell 6, 33, 2004; Cancer Res. 62, 4316, 2002). However, these are in the early stage of drug discovery.
HEF-I can be used as a valid target for novel anticancer therapeutics. Angiogenesis factors which are derived by an activated HEF-I in hypoxia condition, such as VEGF, are associated with the progress of diabetic retinopathy and arthritis as well as cancer. Accordingly, the compounds that inhibit an activated HEF-I from hypoxia condition can also be used as novel therapeutics for the diseases comprising diabetic retinopathy and rheumatoid arthritis[Eiji Eceda, Pathology International, 2005, VoI 55, 603-610]. However, this field is still in its infancy.
[DISCLOSURE] [TECHNICALPROBLEM]
An object of the present invention is to provide a compound having inhibition activity against the transcription factor HEF- 1.
Another object of the present invention is to provide a method for preparing an inhibitor of HEF-I activity.
Further object of the present invention is to provide a pharmaceutical composition for the treatment of various cancers, comprising the compound as an active ingredient useful in the suppression of the growth and metastasis of cancer.
Still a further object of the present invention is to provide a pharmaceutical composition for the treatment of diabetic retinopathy and arthritis.
[TECHNICAL SOLUTION]
In accordance with an object, the above objects of the present invention could be accomplished by the provision of a compound represented by Chemical Formula IA or IB as defined below. The compound functions to selectively suppress the growth and metastasis of tumor cells, thereby showing potent anticancer activity with little or no side effects. Also, the compound is useful in the treatment of diabetic retinopathy and arthritis through the inhibitory mechanism against HDDF-I activity.
Ia accordance with another object, provided are a method for preparing the compound and a pharmaceutical composition containing the compound. . .
[ADVANTAGEOUS EFFECT]
The compound of the present invention shows anticancer activity not through general cytotoxicity, but through inhibition activity of FHF-I activity, particularly through dose-dependent inhibition activity against BQF- lα accumulation in hypoxia. Having selective inhibition activity, the compound of the present invention is effective for suppressing tihe expression of the genes involved in the malignant transformation of cancer, thereby preventing the growth and metastasis of cancer.
Therefore, the compound of the present invention, serving as an FHF-I inhibitor, is useful in the treatment of various cancers, including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vaginal cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, and CNS tumors.
In addition, the compound of the present invention has selective inhibition activity against VEGF, a target gene of HIF-I, and thus can be used as an ingredient of therapeutics for diabetic retinopathy and arthritis, which are aggravated upon FHF-1-mediated VEGF expression in hypoxia.
[DESCRIPTION OF DRAWINGS]
FIG. 1 shows the inhibition activity of the compounds of the invention against FHF-lα accumulation in hypoxia,
FIG. 2 shows the inhibition activity of the compounds of the invention against VEGF expression in hypoxia, and
FIG.3 shows the in vivo anticancer activity of the compounds of the invention in nude mice.
[BESTMODE]
In accordance with an embodiment of the present invention, provided is a compound represented by the following Chemical Formula IA or IB, or a pharmaceutically available salt thereof. <Chemical Formula 1A>
IA
<Chemical Formula 1B>
(wherein,
X and Y are each C or N, preferably with the proviso that when X is C, Y is C or N and when Y is N, ' Xis C orN;
Z is O or NH;
Ri is selected from a group consisting of H, OH and COORa where Ra is H or Ci-C2 alkyl;
R2 is selected from a group consisting of H, OH, CN, CF3, C1-C2 alkyl, COORa, CH2COORa, CONRbRc, SO2NH2, SO2CH3, SO2CH2OH, 0(C=O)NH2, OSO2NH2, tettazøle, C1-C3 alkyl-substituted tetrazole, and benzoyl, the Ra being H or Ci-C2 alkyl, the Rb and the Rc being independently selected from a group consisting OfC3-C5 heteroaryl containingN, O and/or S; Ci-C5 alkyl substituted with a C3-C5 heteroaryl or heterocyclic group containing N, O and/or S; Ci-C3 alkyl substituted with OH and/or phenyl; phenyl substituted with halogen and/or trihalomethyl; naphthyl; H; and Ci-C3 alkyl;
R3 is selected from a group consisting of H, COORa and SO2NH2, the Ra being H or Ci-C2 alkyl; Ri is selected from a group consisting of H, COORa and CONRbRc, the Ra being H or Ci-C2 alkyl, the Rb and the Rc being independently selected from a group consisting OfC]-C3 alkyl substituted with a C3-C5 heteroaryl or heterocyclic group containing N, O and/or S; Q-Cs alkyl substituted with an amino group or a Ci~C2alkyl-substituted amino group; H; and Ci-C2 alkyl;
R5 is selected from a group consisting of H, Cr-Qo alkyl, phenyl, halogen, nitro and acetyl;
R6, R.7 are Rio are independently selected from a group consisting of H and halogen;
R8 is a substituent located at the C5 or Ce position on the benzooxazole or benzoimidazole, selected from a group consisting of H, COORa, CONRbRc and SO2NH2, the Ra being selected from H and Ci-C2 alkyl, the Rb and the Rc being independently selected from Ci-C5 alkyl substituted with a C3~C5 heteroaryl or heterocyclic group containing N, O and/or S; Ci-C5 alkyl substituted with an amino group or with a Ci~C3 alkyl- substituted amino group; amino; H; and Ci-C3 alkyl; and
R9 is selected from a group consisting of Ci-Ci0 alkyl, halogen and nitro group.)
. Concrete examples of the compounds represented by Chemical Formula IA and IB, according to the present invention, are given in Table 1, below.
STABLE 1>
Representative compounds of the present invention can be synthesized according to Reaction Schemes- 1 to 6, which are the mother models from which all of the compounds of the present invention can be derived by modifying reaction conditions, including reagents, solvents, the order of the reaction steps, and the like.
The synthesis of compounds of Chemical Formula IA can be achieved through the coupling reaction shown in Reaction Scheme 1. - .
<Reaction Scheme 1> .
(wherein Ri-R7, X, and Y are each as defined in Chemical Formula IA.)
In more detail, the coupling reaction starts with phenoxyacetic acid (2a) and an amine compound (3).
These starting materials are condensed into the compound of Chemical Formula IA in the presence of a Hunig base with the aid of a coupnhg agent in an organic solvent. Diisopropylamine (DIPEA) or triethylamine (TEA) may be used as a Hunig base for this reaction. The coupling agent useful in the present invention is selected from a group consisting of l-[3^dimemylamino)propyl]-3-emylcarbodiimide hydrochloride. (EDC), 0-benzotriazole-
HHlSr^-tetramethyl-uronium-hexafluoro-phosphate (HBTU), 1-hydroxybenzotriazole (HOBt), benzotriazol-1-yl-o5c^-1ris-pyiTOlidino-phosphonium hexafluorophosphate (PyBOP), l-hydroxy-7-azabenzόtriazole (HOAt) and combinations thereof. A preferable organic solvent is dimethyUbrmamide (DMF) or methylenechloride
(CH2Cl2). . .
When the R4 moiety of Chemical Formula IA is COORa in Reaction Scheme 1,. it can be further modified, as seen in Reaction Scheme 2.
In Reaction Scheme 2, compounds of Chemical Formula IAa, IAb and IAc all correspond to those of Chemical Formula IA.
<Reaction Scheme 2>
(wherein RHR.3, Rr-R7, X, Y, Ra, Rb and Rc are each as defined in Chemical Formula IA.) Below, a more detailed description is given of the reactions of Reaction Scheme 2.
1) The compound of Chemical Formula IAa can be reacted with an inorganic base in a mixture of an organic solvent and water to synthesize the corresponding carboxylic acid compound of Chemical Formula IAb. The organic solvent useful for this reaction may be tetrahydrofuran, dioxane, methanol or ethanol, and the inorganic base may be selected from among sodium lithianide? and sodium hydroxide. This reaction is preferably conducted at 25 ~ 5O0C.
2) The compound of Chemical Formula IAb can be converted into a corresponding amide compound of Chemical Formula IAc through reaction with ammonium chloride or alkyl amine in the presence of a Hunig base and a coupling agent in an organic solvent at room temperature (25°C) or under a flux condition. The coupling agent useful for this reaction is selected from among EDG, HOBt, PyBOP and combinations thereof. DIPEA or TEA is useful as the Hunig base. The organic solvent is preferably DMF.
When the R2 moiety of Chemical Formula IA is COORa or CONRbRc in Reaction Scheme 1, it can be synthesized according to Reaction Scheme 3, below.
In Reaction Scheme 3, the compounds of Chemical Formula IAd, IAc and IAf all correspond to those of Chemical Formula IA. .
<Reaction Scheme 3>
(wherein, Ri5R3-R7, X, Y, Ra, Rb and Rc are each as defined in Chemical Formula IA.) Detailed reaction steps are described as follows.
1) A phenoxy acetic acid (2a) is reacted with an amine compound (4) in the presence of a coupling agent in an organic solvent to yield a carboxylic acid ester compound (IAd). Suitable is a coupling agentselected from among PyBOP, EDC, HOBt, 4-dimethylaminopyridine (DMAP), and combinations thereof. This reaction is preferably conducted at ,250C, with DMF.serving as an organic solvent.
2) The carboxylic acid ester compound (IAd) is converted into a corresponding carboxylic acid compound (IAe) in the presence of lithium iodide in an organic solvent, such as pyridine, CH2Cl2 or DMF, under reflux. ' ' ■ '
3) The compound (IAe) is reacted with ammonium chloride or alkyl amine using a coupling agent in DMF at room temperature (25°C) or under reflux, thereby producing an amide compound (IAf). Useful is a coupling agent selected from among DMAP, PyBOP, EDC, HOBt and combinations thereof.
In the case that the R2 moiety of Chemical Formula IA is CONH2, synthesis thereof can be achieved via the route shown in Reaction Scheme 4, below.
The compound of Chemical Formula IAg falls into the range of compounds of Chemical Formula IA. <Reaction Scheme 4> - .
(wherein R1, R3-R7, X and Y are each as defined in Chemical Formula IA.)
In more detail, a phenoxy acetic acid (2a) is reacted with an amine compound (5) in the presence of a coupling agent in an organic solvent to yield a compound (IAg). PyBOP or DMAP is preferably used as the coupling agent DMF is a preferable solvent for this reaction, and a temperature of 25°C may be set to elicit the desired reaction result. The compound of Chemical Formula IB can be synthesized according to Reaction Scheme 5, below.
<Reactioή Scheme 5>
(wherein, Z, R8, R9 and Rio are each as defined in Chemical Formula IB.)
In more detail, the compound of Chemical Formula IB can be prepared by reacting the phenoxy acetic .acid (2b), which is commercially available or can_be readily prepared using a well know method, with a compound (6), which can be synthesized using a known method, at an equivalent ratio in the presence of triethylsilyl polyphosphate (PPSE). This reaction is preferably conducted at 140-16O0C for 2~4 hours.
Rs of COORa in Reaction Scheme 5 could be obtained via the route of Reaction Scheme 6, below. Compounds IBa, IBb and IBc of Reaction Scheme 6 are within the range of Chemical Formula IB.
(wherein, Z, R9, Rio, Ra, Rb and Rc are each as defined in Chemical Formula IB.) A detailed description is given of Reaction Scheme 6, below.
1) An ester compound (IBa) is hydrolyzed into a corresponding carboxylic acid compound (IBb) in the presence of aluminum bromide and dimethyl sulfide, with CH2CI2 serving as a solvent This hydrolysis is preferably carried out at 25°C for 2~3 hours. Alternatively, the conversion of the ester compound (IBa) into the
acid compound (IBb) may be achieved in the presence of an acid under flux.
2) Either of the ester compound (IBa) and the carboxylic acid compound (IBb) can be used to prepare a corresponding amide compound (IBc). A solution of commercially available alkyl amine in anhydrous toluene is stirred in the presence of triethyl aluminum (2M Hexane solution) at room temperature, preferably for
5 approximately 30 min. To this mixture is added a solution of the compound (IBa) in toluene^ followed by fluxing at 800C to yield the compound (IBc). The reaction time is preferably set at 1 to 2 hours. Alternatively, the compound (IBc) may be synthesized through the reaction of the compound (IBb) with an amine compound selected from among ammonium chloride, hydrazine and alkyl amine at room temperature (250C) in the presence of a coupling agent and a Hunig base in DMF. The coupling agent is selected from among EDC, HOBt,
10 HATU, HBTU, and combinations thereof, and the Hunig base is DIPEA.
In accordance with a further embodiment, the present invention pertains to an anticancer pharmaceutical composition comprising the compound of Chemical Formula IA or IB, or a pharmaceutically acceptable salt as an active ingredient for the inhibition of HIF-I activity.
The compound of Chemical Formula IA or IB, or a related pharmaceutical composition, exhibits 15. anticancer activity not through generalxytotoxicity, but through selective cytotoxicity characterized by .inhibition activity against the transcription factor HEF-I, which plays a pivotal role in the growth and metastasis of cancer cells.
As used herein, the term "inhibition activity against HEF-I" or a phrase equivalent thereto means inhibiting all of the transcription of an HIF-I gene, the expression of HIF-I protein, and the accumulation of HEF-I 20 protein.
The compounds of the present invention were found to have excellent inhibition activity against HEF-I transcription as measured in assays for HEF-1-mediated transcription in hypoxia. Therefore, the compounds of the present invention can also have an inhibitory effect on the HEF-I related expression of the genes involved in the malignant transformation of cancer, thereby suppressing the growth and metastasis of cancer. Consequently, the
25 compounds of the invention can be used as active ingredients useful in the treatment and prevention of cancer.
As will be understood in Experimental Example 2, below, the compounds of the present invention can inhibit the expression of the HEF-lα protein in a dose-dependent manner in hypoxia without influencing the production of topoisomerase-1 (TOPO-I). En other words, the compounds of the present invention do not function through general cytotoxicity for anticancer activity, but show dose-dependent inhibition of the 30 accumulation of HEF-lα protein, thereby suppressing the growth and metastasis of cancer with the minimal concomitant production of side effects.
In addition, as will be understood in Experimental Example 3, below, the compounds of the present invention can inhibit the expression of VEGF in a dose-dependent manner in hypoxia with no effect on the expression of the control gene GAPDH. Accordingly, the compounds of the present invention can be used for
cancer therapy thanks to the ability thereof to suppress the growth and metastasis of cancer through selective inhibition activity against VEGF, a target gene of EDDF-l,.as well.
Having inhibition activity against EDDF-I, therefore, the pharmaceutical composition of the present invention comprising the compound of Chemical Formula IA and IB or a pharmaceutically acceptable salt thereof can be used as a therapeutic for various cancerous disorders, including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vagina cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, and CNS tumors. . Also, the ability of the compound of Chemical Formula IA or IB, or a pharmaceutically acceptable salt thereof for inhibiting HIF-I activity, ensures that the pharmaceutical composition can be effectively used in the treatment of diabetic retinopathy and arthritis.
As used herein, the term "inhibition. of EDDF-I activity" or a phrase equivalent thereto means inhibiting all of the transcription of an HEF-I gene, the expression of HIF-I protein, and the accumulation of EDDF-I protein. _ . .EDDF-I can.be_a target of drugs for the treatment of disorders which, devebp through .angiόgenesis. ,
Particularly, the angiogenesis factors, such as VEGF, stimulated by EDDF-I, which is activated in hypoxia, are implicated in the development of diabetic retinopathy or arthritis, such as rheumatoid arthritis. Diabetic retinopathy or arthritis can be aggravated as the expression of VEGF increases with the activation of HIF-I in hypoxia. Accordingly, compounds capable of inhibiting the activity of EDDF-I, which is activated in hypoxia, can be used as therapeutics for diabetic retinopathy or arthritis ((Eiji Ikeda, Pathology International, 2005, VoI 55, 603-
,610).
As will be shown in Experimental Example 3, the compounds of the present invention can- inhibit the expression of VEGF in a dose-dependent manner in hypoxia without influencing the expression of the control
' gene GAPDH. Accordingly, the compounds of the present invention are useful as active ingredients for the treatment of diabetic retinopathy or arthritis, which is aggravated upon the expression of VEGF because they can selectively inhibitEQF-l, which plays a pivotal role in the expression of VEGF in hypoxia
The pharmaceutical composition of the present invention may be formulated into oral or non-oral dosage forms. Examples of oral dosage forms include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc. Ηαese forms may include diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,, and/or glycin), and/or lubricants (for example, silica, talc, stearic acid or magnesium of calcium salts thereof, and/or polyethylene glycol) in addition to the active ingredient Tablets may also include binders, such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and optionally disintegrants, such as starch, agar, alginic acid or sodium salt thereof, a boiling mixture, and/or absorbents, colorants, flavoring agents, and sweeteners.
Also, the pharmaceutical composition comprising the compound of Chemical Formula IA or IB or a pharmaceutically acceptable salt thereof in accordance with the present invention may be administered via non- oral routes. For this, the composition may be formulated into subcutaneous, intravenous, intramuscular, or intrathoracic injections. Si order to obtain such non-oral dosage forms, the compound of Chemical Formula IA or IB or a pharmaceutically acceptable salt thereof may be mixed with a stabilizer or a buffer in water so as to afford a solution or a suspension which is then packaged into ampule or vial units.
Further, the composition is sterilized and/or may contain an auxiliary agent, such as a preservative, a stabilizer, a wettable agent, an emulsifier, an osmotic pressure-controlling salt and a buffer, and/or other therapeutically effective materials. They may be mixed, granulized, or coated according to a method well known in the.art. As an active ingredient, the compound of Chemical Formula IA or IB may be administered once or many times to mammals including humans, at a dose of 0.1 to 500 mg/kg (body weight) a day, and preferably at a dose of 0.5 to 100 mg/kg (body weight), via an oral or nbn-oral route.
[MODE FORMVENTION] _A better.understanding of the present invention may be.obtained through the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.
<Example l>2-(4-Adamantan-l-yl-phenoxy)-N-(3-mefliane-Sulfonyl-phenyl)-acetamide
1H NMR (CDCl3, 300 MHz) 8.59(1H, s, CONH), 8.09(1H, m, aromatic), 8.05 (IH, d, J=7.8 Hz, aromatic), 7.7(1H, d, J=SA Hz, aromatic), 7.54(1H, m, aromatic), 7.33(2H, m, aromatic), 6.94(2H, m, aromatic), 4.61(2H, s, -OCH2), 3.05(3H, s, -SO2CH3), 2.09(3H, brs, adamanryl), 1.88(6H, d,J=2.4 Hz, adamanryl), 1.76(6H, m, adamantyl). . ,
<Example 2> 3-[2-(4-Adaman-l-yl-phenoxy)-acetylainiαo]-benzoic acid methyl ester
To a solution of the (4-adamantan-l-yl-phenoxyl)-acetic acid (140 mg, 0.5 mmol) and 3-aminobenzoic acid methyl ester (110 mg, 0.75 rnmol) in DMF (5.0 mL) were added l-[3-(dimethyamino)propyl]-3- ethylcarbodiimide hydrochloride (EDC) (144.0 mg, 0.75 mmol), 1-hdroxylbenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and NN-diisopropylethylamine (DIPEA) (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography («-Hexane : Ethyl acetat : MeOH = 15 : 3: 1) gave 3-[2-(4-Adamant-l-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (160 mg, 76% yield). 1H-MdR (DMSO-d&JOOHz). .10.31(lH, s, NH), 8.3.4(1H, m, aromatic), 7.89 (IH, m, aromatic),.
7.67(1H, m, aromatic), 7.47(1H, ps t, .£=7.8 Hz, aromatic), 7.28(2H5 m, aromatic), 6.93(2H, m, aromatic), 4.62(2H, s, OCH2CO), 3.85(3H, s, OCH3), 2.03(3H, m, adamantyl), 1.81-1.82(6H, m, adamantyl), 1.71(6H, m, adamantyl).
<Example 3> 3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-benzoic acid ethyl ester
To a mixture of [4-(l-damantyl)-phenoxyl]acetic acid (143.2 mg, 0.5 mmol), 3-aminobenzoic acid ethyl ester (123.9 mg, 0.5 mmol), ,Ν-(3-dimethylaminopropyl>ΝI-ethyl carbodiimideHCl (EDC) (143.8 mg,
0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (6 mL) was added N, N- dϋsopropylethyamine, redistilled (DIPEA) (97.0 mg, 0.13 mL, 0.75 mmol). The mixture was stirred overnight, and then, partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried
(MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n- Hexane:Eihyl acetatMeOH = 6:3:1) to give 3-[2^4-adamantan-l-yl-phenoxy)-acetylamino]-benzoic acid ethyl ester as a white solid (194.4 mg, 89.7% yield).
1H-NMR (CDCB, 300Hz) 8.42(1H, s, NH), 8.02-8.06(2H m, aromatic), 7.82-7.85(1H, m, aromatic), 7.44(1H, ps-t, J=8.1 Hz, aromatic), 7.32-7.37 (2H, m, aromatic), 6.93-6.98(2H, m, aromatic), 4.59(2H,
s, CH2), 4.37(2H, q, J =7.2 Hz, aromatic), 2.08(3H, m, adamaniyl), 1.88(6H, m, adamaniyl), 1.70-1.80(6H, m, adamantyl), 1.39(3H, t, J=7.5 Hz, CH3).
<Example 4> {3-[2-(4-Adamantan-l-yl-phenoxy)-acetylarnino]-phenyl}-acetic acid methyl ester
To a solution of the (4-adamantan-l-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and (3-amino- phenyl>acetic acid methyl ester (LMJ-I-57) (124 mg, 0.75 mmol) in DMF (5.0 mL) were added l-[3- (dimemyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (144 mg, 0.75 mmol), 1-hdroxylbenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and NJv[-diisopropylethylamine (DIPEA) (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine.
The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (CH2Cl2 : MeOH = 4O-: l),gave. {3-[2-(4-adamantan-l-yl-phenoxy)τacetylamino]-phenyl}.-acetic.acid.methyl . ester as a white solid (208.8 mg, 99.9% yield).
1H-MdR (CDCl3, 300Hz) 8.27(1H, s, NH), 7.51(2H, m, aromatic), 7.23-7.35(3H, m, aromatic), 7.04(1H, d, J=7.2 Hz, aromatic), 6.91(2H m, aromatic), 4.55(2H, s, OCH2CO), 3.66(3H, s, COCH3), 3.60(2H, s,
CH2COOCH3), 2.06(3H, m, adamantyl), 1.86(6H, m, adamantyl), 1.68-1.78(6H, m, adamantyl).
<Example 5> 4-[2-(4-Adamantan-l-yl-phenoxy)-acerylamino]-beπzoic acid methyl ester
1HNMR (CDCl3, 300 Hz) 8.46 (IH s, NH), 8.04 (2H, d, J = 21.3 Hz, aromatic-H), 7.69 (2H, d, J =
9.3 Hz, aromatic-H), 7.34 (2H, d, J = 8.7 Hz, aromatic-H), 6.94 (2H, d, J = 8.7 Hz, aromatic-H), 4.61 (2H, s, CH2), 3.90 (3H, s, CH3), 1.75-2.09 (15H, m, adamantiy-H).
<Example 6> 2-[2-(4-adamantan-l-yl-phenoxy)-acetylatnino]-benzoic acid methyl ester
To a mixture of [4-(l-damantyl)-phenoxyl]acecic acid (85.9 mg, 0.30 mmol), 2- amino-benzoic acid methyl ester (0.07 mL, 0.54 mmol), N-(3-dimethylaminopropyl>N1-ethyl carbodiimideHCl (EDC) (103.5 mg, 0.54 mmol) and l-hydroxybenzo1riazole (HOBt) (73.0 mg, 0.54 mmol) in DMF (3.6 mL) was added N, N- dϋsopropylethyamine, redistilled (DIPEA) (69.8 mg, 0.10 mL, 0.54 mmol). The mixture was stirred overnight, 10 and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated: The residue was purified by silica gel flash column chromatography (n- _ . . . JHexanerEfhyl acetat:MeOH .=.12:3:1) . to give 2-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]rbenzoic- acid.. methyl ester as a white solid (46.4 mg, 36.9% yield).
' 1HNMR (CDCI3^OO HZ) 12.1 (IH, s,NH), 8.79 (UL d, J = 8.7 Hz, aromatic-H), 8.05 (IH, dd, J = 15 7.8 & 1.8 Hz, aromatic-H), 7.54 - 7.60 (IH, m, aromatic-H), 7.31 - 7.35 (2H, m, aromatic-H), 7.12 - 7.16 (2H, m, aromatic-H), 7.03 - 7.07 (2H, m, aromatic-H), 4.62 (2H, s, CH2), 3.93 (3H, s, CH3), 2.08 (3H, m, adamantly-H), 1.88 (6H,m,adamanύy-H), 1.70 1.80(6H,m, adamantly-H).
<Example 7> 5-[2-(4-Adamantan-l-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester
To a mixture of (4-adamantan-l-yl-ρhenoxy)-acetic acid (143.2mg, 0.50 mmol), 5-aminoisophthalic acid dimethyl ester (156.9 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N'-ethyl carbodiimideHCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) inDMF (5mL) was added N, N-diisopropylethyamine, redistilled (DIPEA) (0.13 mL, 0.75 mmol). The mixture was stirred overnight, and
25 then partitioned between ethyl acetate and 10% HCl. The organic phase washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl
acetatMeOH = 9:3 : 1) to give 5-[2-(4-Adamantan-l-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester as a light yellow, solid (195.6 mg, 81.92% yield).
1H-NMR (CDCl3, 300 Hz) 8.47 - 8.48 (4H, m, aromatic-H, NH), 7.34 - 7.36 (2H, m, aromatic-H), 6.94 - 6.97 (2H, m, aromatic-H), 4.63 (2H, s, CH2), 3.96 (6H, s, CH3), 2.10 (3H, m, adamantly-H), 1.90 (6H5 m, adamantly-H), 1.77 (6H, m, adamantly-H) .
<Example 8> 3-[2^4-^t-bu1yl-phenoxy)-acetyl-amino]-beπzoic acid methyl ester
The present example was performed in the same manner to give 3-[2-(4-fe/Y-bu1yl-phenoxy)- 0 acetylaminoj-benzoic acid methyl ester as a light yellow solid (185 mg, 100% yield).
1HNMR (CDCl3, 300Hz) 8.40(1H, s, NH), 7.99-8.08(2H, m, aromatic-H), 7.82-7.84(1H, m, aromatic-H), 7.45(lH,.ps-t, J=7.8 Hz,-aromatioH), 7.34- 7382BL, m, aromatic-H), 6.91.-6.96(2H, m,:aromatic- .
H), 4.61(2H, s, CH2), 3.93 (3H, s, CH3), 1.32(9H, s, CH3).
5 <Example 9> 3-[2-(4-FluorcHphenoxy)-acetylamino]-benzoic acid methyl ester
To 4-Fluoro-acetic acid (150.1 mg, 0.88 mmol), the amine 5 (199.6 mg, 1.32 mmol), EDCHCl (253.1 mg, 1.32 mmol) and HOBt (179.7 mg, 1.32 mmol) in DMF (8 mL) was added DIPEA (0.23 mL, 1.32 mmol).
; ' The mixture was stirred overnight, and then partitioned between Ethyl acetat and 10% HCl. The organic phase 0 was washed with brine, dried (anhydrous MgSCU), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane : Ethyl acetat : MeOH = 6 : 3 : 1) to give 3-[2-(4-Fluoro-phenoxy)- acetylaminoj-benzoic acid methyl ester as a white solid (236.1 mg, 88.5% yield).
1H-NMR (CDCl3) 8.37 (IH, s, NH), 8:07 (IH, m, aromatic-H), 7.99 8.02 (IH, m, aromatic-H), 7.83 (IH, d, J = 7.8 Hz, aromatic-H), 7.44 (IH, ps-t, J = 7.8 Hz, aromatic-H), 7.02 7.08 (2H, m, aromatic-H),5 6.93 6.97 (2H, m, aromatic-H), 4.59 (2H, s, CH2), 3.92 (3H, s, CH3).
<Example 10> 3-[2-(4-Chloro-phenoxy)-acetylamino]-benzoic acid methyl ester
The present example was performed in the same manner to give 3-[2-(4-Chloro-phenoxy)- acetylamino]-benzoic acidmethyl esteras awhite solid(135.2 mg, 84.5% yield).
1H-NMR (CDCl3) 8.321H, s, NH), 8.06(1H, s, aromatic-H), 8.00(1H, d, J =8.4 Hz, aromatic-H), 7.83 (IH, d, J=8.2 Hz, arpmatic-H), 7.45(1H, ps-t, J= 7.8 Hz, aromatic-H), 729-73'4(2H5 m, aromatic-H), 6.91- 6.97(2H, m, aromatic-H), 4.60(2H, s, CH2), 3.92(3H, s, CH3).
<Example 11> 3-[2-(2,4-diChloro-phenoxy)-ace1ylamino]-benzoic acid methyl ester
(701.2 mg, 99.0% yield).
1H-NMR(CDCl3) 8.63 (IH, s, NH), 8.14 (IH, m, aromatic-H), 7.93 - 7.96 (IH, m, aromatic-H), 7.84 - 7.86 (IH, m, aromatic-H), 7.43 - 7.48 (2H, m, aromatic-H), 7.25 - 7.29 (IH, m, aromatic-H), 6.91 (IH, d, J= 9.0 Hz, aromatic-H), 4.66 (2H, s, CH2), 3.93 (3H, s, CH3). • • ' • '
To (2,4-dichloro-phenoxy)-acetic acid (110.6 mg, 0.5 mmol), 2-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol), and benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (520.3 g, 1.0 mmol) in DMF (5 mL) was added N, N-dϋsopropylethyamine, redistilled (DPEA) (0.17 mL, 1.0 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was
washedwith brine, dried (MgSC>4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetatMeOH = 6:3:1) to give 2-[2-(2,4-diChloro-phenoxy)-ace1ylamino]- benzoic acid metliyl ester as a white solid (118.0 mg, 66.6% yield).
1H-NMR (CDCl3, 300 Hz) 11.84 (IH, s, NH), 8.73 (IH5 d, J = 8.1 Hz, aromatic-H), 8.05 (IH, dd, J = 8.1 & 1.8 Hz, aromatic-H), 7.57 (IH, m, aromatic-H), 7.44 (IH, d, J = 2.4 Hz, aromatic-H), 7.13 7.22 (2H, m, aromatic-H), 6.92 (IH, d, J = 8.4 Hz, aromatic-H), 4.69 (2H, s, CH2), 3.90 (3H, s, CH3).
<Example 13> 4-[2-(2,4-diChloro-phenoxy)-acetylamino]-benzoic acid methyl ester
1H-NMR(CD3OD) 7.96 7.99 (2H, m, aromatic-H), 7.64 7.71 (2H5 m, aromatic-H), 7.41 (IH, d, J = 2.4 Hz, aromatic-H), 7.21 7.25 (IH, m, aromatic-H), 7X)I (IH, d, J = 8.4 Hz, aromatic-H), 4.71 (2H5 s, CH2),
•
<Example 14> S-P^ΛS-triCUoro-phenoxy^acetylarninoJ-berizoic acid methyl ester
• overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-
Hexane:Ethyl acetatMeOH = 6:3:1) to give 3-[2-(2,4,5-triCMoro-phenoxy)-acerylamino]-benzoic acid methyl
esterasawhite solid(166.4mg, 85.6% yield).
1H-NMR (CDGl3) 8.55 (IH, s, NH)5 8.13 (IH5 s5 aromatic-H), 7.95 (IH, d, J = 7.8 Hz, aromatic-H)5 7.85 (IH5 d, J= 7.2 Hz, aromatic-H), 7.56 (IH5 s, aromatic-H)57.46 (IH5 ps-t, J= 7.8 Hz, aromatic-H), 7.08 (IH5 S5 aromatic-H)54.65 (2H5 s, CH2), 3.93 (3H5 s, CH3). <Example 15> 3-[2-(4-bromo-phenoxy)-acetylamino]-benzoic acid methyl ester
To a solution of the 4-bromophenoxy acetic acid (139 mg, 0.6 mmol) and amine (76 mg, 0.5 mmol) in DMF (5.0 mL) were added EDCHCl (144 mg, 0.75 mmol), HOBT (101 mg, 0.75 mmol), and DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetat and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane : Ethyl acetat : MeOH = 12 : 3: 1) gave 3-[2-(4-bromo-phenoxy)- acerylamino]-benzoic acid methyl ester as a white solid (138 mg, 76% yield). :. . 1H-NMR (CDCl3,.300Hz). . 8.32 (IH5 S5MI)5 8.06 (IH5 m, aromatic)5-7.99 (IH5 m5 aromatic), 7.84.
(IH5 m, aromatic), 7.42-7.47 (3H5 m, aromatic), 6.89 (2H, m, aromatic), 4.59 (2H, s, OCH2CO), 3.92 (3H, s, OCH3).
<Example 16> 3-[2-(4-iodo-phenoxy)-acetylamino]-benzoic acid methyl ester
Ηie present example was performed in the same manner to give 3-[2-(4-iodo-phenoxy)-acerylamino]- benzoic acid methyl ester as a white solid (199.0. mg, 97.0% yield).
1H-NMR (CDCl3) 8.31 (IH, s, NH), 8.06 (IH5 S5 aromatic-H)5 8.00 (IH5 d, J = 8.1 Hz, aromatic-H), 7.83 (IH, d, J = 7.8 Hz3 aromatic-H), 7.61 - 7.66 (2H, m, aromatic-H), 7.44 (IH5 ps-t, J = 7.8 Hz, aromatic-H), 6.76 - 6.81 (2H, m, aromatic-H), 4.59 (2H S5 CH2), 3.92 (3H5 S5 CH3).
<Example l7>3-[2-(4-acetyl-phenoxy)-ace1ylamino]-benzoic acid methyl ester
1H-NMR (CDCl3, 300Hz) 8.32(1H, s, NH), 8.07(1H, m, aromatic), 7.97-8.01(3H, m, aromatic), 7.83(1H, d, J=7.8 Hz, aromatic), 7.45 (IH, ps t, J= 7.8 Hz, aromatic), 7.05(2H, m, aromatic), 4.69(2H, s, OCH2CO), 3.92(3H, s, OCH3), 2.58(3H, s, COCH3).
10 <Example 18>3-[2-(4-Adamantan-l-yl-phenoxy)-aceryl-amino]-4-hydroxy-benzoic acidmethyl ester
15 mmol) and pyridine (0.05 mL) were added, and the resulting. Solution was stirred at room temperature overnight^ and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSθ4 anh), and concentrated. The residue was purified by (n-Hexane:Ethyl acetatMeOH = 6:3: 1) to give 3-[2- (4-Adamantan-l-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester as a white solid (1832 mg, 84.1% yield). ■ ' ■
20 1H-NMR (DMSO-dg, 300 Hz) 11.10 (IH, s, OH), 9.24 (IH, s,NH), 8.69 (IH, m, aromatic-H), 7.60 -
7.64 (IH, m, aromatic-H), 7.30 (2H, d, J = 8.4 Hz, aromatic-H), 6.94 - 6.99 (3H, m, aromatic-H), 4.74 (2H, s, CH2), 3.79 (3H, s, CH3), 2.04 (3H, m, adamantly-H), 1.83 (6H, m, adamantly-H), 1.72 (6H, m, adamantly-H). <Example 19> 3-[2-(44ert-buryl-phenoxy)-acetyl-arnino]-4-hydroxy-benzoic acid methyl ester
, 25 (4-tert-butyl-phenoxy)-acetic acid (200 mg, 0.96 mmol) and 3-amino-4-hydroxy-benzoic acid methyl ester (240.7 mg,' 1.44 mmol) were dissolved in PPSE (3 mL), and reacted for 2.5h at 140 "C. After saturated sodium bicabonate aqueous solution was added, organic phase was washed with 10% HCl and brine. The organic phase was dried (MgSOt anh), and concentrated. The residue was purified by silica gel column
ckomatography(n-Hexane:Ethyl acetatMeOH = 15:3:1) to give 3-[2-(4-tert-butyl-phenoxy)-acetyl-amino]-4- hydroxy-benzoic acid methyl ester as an orange solid (350 mg, 89% yield).
1H-NMR(CD3OD, 300Hz) 8.79(1H, d, J=2.4 Hz, aromatic), 7.68(1H, dd, J==8.7&1.8 Hz, aromatic), 7.35(2H, m, aromatic), 6.89-6.99(3H, m, aromatic), 4.66(2H, s, OCH2), 3.85(3H, s, CH3), 1.29(9H, s, (CH3)3)
<Example 20> 3-(2-biphenyl-4-yl-aceryl-amino)-benzoic acid methyl ester
To a solution of the 4-biphenyl acetic acid (106.1 mg, 0.50 mmol), 3-amino benzoic acid methyl ester
(113.4 mg, 0.75 mmol), EDCHCl (143.8 mg, 0.75 mmol) and HOBT (101.4 mg, 0.75 mmol) were dissolved in DMF (5.0 mL), and DIPEA (0.13 mL, 0.75 mmol) were added. The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetat. and brine. The. organic phase was dried .(anhydrous MgSO4),. and .concentrated. Purification Jay. silica gel. column chromatography (n-Hexane. :. Ethyl. acetat : MeOH = 6 : 3: 1) gave 3-(2-biphenyl4-yl-acetyl-amino)-benzoic acid methyl ester as a white solid (174
' mg, 100% yield). 1H-NMR (CDCl3, 300 Hz) 7.88-7.91(2H, m, aromatic-H), 7.77(1H, d, J= 7.8 Hz, aromatic-H), 7.61-
7.66(4 H, m, aromatic-H), 7.36-7.49(6H, m, aromatic-H), 7.18(1H, s,NH), 3.90(3H," s, CH3), 3.81(2H, s, CH2).
<Example 21> 4-[2-(4-Adamantan-l-yl-phenoxy)acetyl-amino]-isophtalic acid dimethyl ester
1H-NMR (CDCl3, 300Hz) 12.00(1H, s, NH), 9.40(1H, d, J=I .8 Hz, aromatic), 8.12(1H, d, J=7.8 Hz, aromatic), 7.78(1H, dd, J=8.1 & 1.8 Hz, aromatic), 7.33(2H, m, aromatic), 7.03(2H5 m, aromatic), 4.65(2H, s,
OCH2CO), 3.97(3H, s, OCH3), 3.95(3H, s, OCH3), 2.09(3H, m, adamantyl),. 1.89-1.90(6H, m, adamantyl), 1.72- 1.82(6H, m, adamanty).
<Example 22> 3-[2-(4-nitrophenoxy)acetyl-amino]-benzoic acid methyl ester
To a solution of the 4-nitrophenoxy acetic acid (100 mg, 0.5 nxtnol), 3-amino benzoic acid methyl ester (115 mg, 0.76 mmol), HOBt (102.81 mg, 0.76 mmol) and DIPEA (98.34 mg, 0.76 mmol) in DMF (4.0 mL) were added EDC (145.86 mg, 0.76 mmol) at room temperature. After reaction terminated, the reaction mixture in cool water was diluted with Ethyl acetat The organic phase was washed with aqueous sodium bicarbonate and dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (Ethyl acetat : Hexane =
1:9 ~ 1:1) gave 3-[2-(4-ni1ro-phenoxy)aceryl-amino]-benzoic acid methyl ester as a white solid (150 mg, 89% yield). . .. ' _.. . ' . . " - .- ■ _ .- ' . . .
1H NMR (DMSO-dg, 300 MHz) 8.35(1H, s, CONH), 8.24(2H, m, aromatic), 8.08(1H, t, J=1.8 Hz, aromatic), 7.97(1H, d, J=S.1 Hz, aromatic), 7.82(1H5 d, J=7.8 Hz, aromatic), 7.43(1H, t, J=7.8 Hz, aromatic), 7.09 (2H, m, CONH2), 4.72(2H, s, OCH2), 3.90(3H, s, OCH3).
<Example 23> 3-[2^4-Adamantan-l-yl-pheno}^)aceryl-arriino]-benzamide
To a solution of the 4-adamantan-l-yl-phenoxy acetic acid (114.6 mg, 0.40 mmol) and 3-amino benzamide (81.7 mg, 0.60 mmol) ware disolved in DMF (4.0 mL), and were added EDCHCl (115.1 mg, 0.60 mmol), HOBt (81.1 mg, 0.60 mmol) and DIPEA (0.15 mL, 0.60 mmol). The reaction mixture was stirred overnight, and then partitioned between Ethyl acetat and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane : Ethyl acetat : MeOH =
9:3: 1) gave 3-[2-(4-Adamantan-l-yl-phenoxy)acetyl-amino]-benzamide as a white solid (145.0 mg, 89.6% yield). 1H-NMR (CD3OH) 8.08(1H, m, aromatic-H), 7.80-7.80(1H, m, aromatic-H), 8.57(1H, d, J=8.4 Hz, aromatic-H), 7.43(1H, m, aromatic-H), 7.30-7.33(2H, m, aromatic-H), 7.00(2H, m, aromatic-H), 4.65(2H, s,
CH2), 2.06(3H, m, adamantyl-H), 1.90(6H m, adamantiy-H), 1.80(6H, m, adamantly-H).
<Example 24> 3-[2-(2,4-diGhloro-phenoxy)acetyl-amiαo]-benzamide
To a solution of the 4-biphenyl acetic acid (106.1 mg, 0.50 mmol), 3-amino benzoic acid methyl ester (113.4 mg, 0.75 mmol), EDCHCl (143.8 mg, 0.75 mmol) and HOBT (101.4 mg, 0.75 mmol) were dissolved in DMF (5.0 mL), and DIPEA (0.13 mL, 0.75 mmol) were added. The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetat and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane : Ethyl acetat : MeOH = 6 : 3: 1) gave 3-(2-biphenyl4-yl-aceryl-amino)-ben2X3ic acid methyl ester as a white solid (174 mg, 100% yield).. ■
<Example25>3-[2-(2,4,5-tricUoro-phenoxy)acetyl-arnino]-benzamide ■
To a solution of the 2,4,5-irichloro-phenoxy acetic acid (76.7 mg, 0.3 mmol), 3-amino benzamide (61.3 mg, 0.45 mmol), EDC (86.3 mg, 0.45 mmol) and HOBt (61.3 mg, 0.45 mmol) were dissolved in DMF (3 mL), and DIPEA (0.08 mL, 0.45 mmol) were added. The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetat and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (CH2Ck : MeOH = 6 : 3: 1) gave 3-[2-(2,4,5- tricMoro-phenoxy)acetyl-amino]-benzamide as a white solid (95.2 mg, 84.9% yield). 1H-NMR (CDCl3) 10.31(1H, s, NH)5 8.06(1H, s, aromatic-H), 795QH, s, NH2), 7.85(1H, s, aromatioH), 7.75(1H3 d, J=7.8 Hz, aromatic-H), 7.58(1H5 d, J=7.8 Hz, aromatic-H), 7.47(1H3 s, aromatic-H), 7.36-7.42(2H, m, aromatic-H, NH2), 4.95(2H, s, CH2).
<Example 26> 3-[2-(4-bromo-phenoxy)aceryl-amino]-benzamide
3.0 mmol), N<3-dimethylaminopropyl)-N'-etiiyl carbodiimideHCl (EDC) (517.6 mg, 2.7 mmol) and 1- hydroxybenzotriazole (HOBt) (365.3 mg, 2.7 mmol) in DMF (18 mL) was added N, N-dϋsopropylefhyamine, redistilled (DIPEA) (0.47 ml, 2.7 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization fi"om the mixture of Ethyl acetate and MeOH to give 3-[2-(4-bromo- phenoxy)acetyl-amino]-benzamide as a white solid (134.9 mg, 21.52% yield).
1HNMR (DMSO-dg) 10.21 (IH, s, NH), 8.09 (IH, s, aromatic-H), 7.94 (IH, s, MH2), 7.79 (IH, d, J =
8.1 Hz5 aromatic-H), 7.35 - 7.59 (5H, m, aromatic-H, NH2), 6.99 (2H, d, J = 9.3 Hz, aromatic-H), 4.72 (2H, s, CH2).
<Example 27> 3-[2-(4-bromo-2-cUorc>-phenoxy)acetyl-arnino]-benzaiτiide
A mixture of 4-bromo-2-chloro-phenol (2.0 g, 9.64 mmol) and anhydrous potassium carbonate (4.0 g, 28.92 mmol) in dry DMF (30 ml) was heated at 60oC for Ih under Ar atmosphere. The mixture was then cooled to room temperature and ethyl chloroacetate (1.24 ml, 11.57 mmol) was added through septum using syringe. The mixture was stirred overnight at room temperature and poured into water with stirring. Stirring continued for 10 min, and then partitioned between ethyl acetat and water. The organic phase washed with brine, dried (anhydrous MgSO4), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane : Ethyl acetat : MeOH = 15 : 3 : 1) to give (4-Bromo-2-chloro-phenoxy)-acetic acid ethyl ester as a colorless oil
(2.98(2.83) g, >100% yield). To (4-boromo-2-chloro-phehoxy)-acetic acid (132.8 mg, 0.5 mmol), 3-amino- benzamide (102.2 mg, 0.75 mmol), N-(3-dimethylaminopropyl>N'-ethyl carbodiimideHCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 ml) was added N, N- diisopropylethyamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washedwith brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:Me0H = 10:1) to give 3-[2-(4-bromo-2-chloro-phenoxy)aceryl-amino]-benzamide as a white solid (181.4 mg, 94.6% yield).
1H-NMR (DMSO-de) 10.30 (IH, s, NH), 8.06 (IH, s, aromatic-H), 7.94 (IH, s, NH2), 7.70 7.77 (2H, m, aromatic-H), 7.57 (IH, d, J = 7.2 Hz, aromatic-H), 7.48 (IH, dd, J = 16.2 & 2.4 Hz, aromatic-H), 7.35 7.42 (2H, m, aromatic-H, NH2), 7.06 (IH, d, J= 9 Hz, arόmatic-H), 4.87 (2H, s, CH2).
<Example 28> 3-[2-(4-iodo-phenoxy)acetyl-amino]-benzamide
To (4-iodo-phenoxy)-acetic acid (83.5 mg, 0.3 mmol), 3-aminobeπzamide (61.3 mg, 0.45 mmol), N- (3-dimethylaminopropyl)-N-ethyl carbodϋmideHCl (EDC) (86.3 mg, 0.45 mmol) and 1-hydroxybenzotriazole (HOBt) (61.3 mg, 0.45 mmol) in DMF (3 ml) was added N, N-dϋsopropylethyamine, redistilled (DIPEA) (0.08 ml, 0.45 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washedwith brine, dried (MgSC>4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CHkMeOH = 6: 1) to give 3-[2-(4-iodo-phenoxy)acetyl-amino]-benzamide as a white solid (105.1 mg, 88.4% yield). 1H-NMR (DMSOKI6) 10.22 (IH, s, NH), 8.09 (IH, s, aromatic-H), 7.94(1H, s, NH2), 7.79 (IH, d, J =
8.1 Hz, aromatic-H), 7.56 - 7.64 (3H, m, aromatic-H), 7.35 - 7.41 (2H, m, aromatic-H, NH2), 6.86 (2H, d, J= 8.7 Hz, aromatic-H), 4.71 (2H5 S3 CH2)., .. . . . .
<Exaraple 29> 3-(2-phenoxy-aceryl-amino)-benzamide
To a solution of phenoxy-acetic acid (100 mg, 0.65 mmol), 3-amino benzamide (178.9 mg, 1.31 mmol), HOBt (177.7 mg, 1.31 mmol) and DIPEA (170 mg, 1.31 mmol) in DMF (6 ml) was added EDC (252 mg, 1.31 mmol) at room temperature and'the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH : MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH : MC = 1:9 ~ 2:8) to afford of 3-(2-phenoxy- aceryl-amino)-benzamide as a colorless solid (146 mg, 82% yield).
. 1H NMR (DMSO-d6, 300 MHz) 10.19(1H, s, CONH), 8.09(1H, s, aromatic), 7.93(1H, s, aromatic), 7.80(1H, d, J=9.0 Hz, aromatic), 7.56(1H, d, J = 7.5 Hz, aromatic), 7.35(4H, m, CONH2, aromatic), 6.98(3H, m, aromatic), 4.70(2H, s, OCH2).
<Example 30> 3-[2-(4-tert-butyl-phenoxy)-aceryl-amino]-benzamide
To a solution of (44ert-butyl-phenoxy)-acetic acid (125 mg, 0.6 mmol), 3-amino benzamide (163.5 mg, 1.2 mmol), HOBT (162 mg, 1.2 mmol) and DIPEA (155 mg, 1.2 mmol) in DMF (6 ml) was added EDC (230.05 mg, 1.2 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH : MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH : MC = 1 :9 ~ 2:8) to' afford of 3-[2-(4-tert- butyl-phenoxy)-acetylamino]-benzamide as a colorless solid (168 mg, 85.75% yield). 1HNMR <T>MSO-dfo.300 MHz) 10.67 (IH, s, CONH), 8.44 (IH, d, J = 5.1 Hz1 CONH2), 8.41 (IH, s, CONH2), 8.20 (IH, brs, pyridine), 7.68 (IH, brs, pyridine), 7.49 (IH, d, J= 1.5, 5.1 Hz, pyridine), 7.16-7.11 (2H, m, aromatic), 7.01-6.97 (2H, m, aromatic), 4.80 (2H, s, OCH2).
<Example 31> 3-(2-p-tolyloxy-acetyl-amino)-benzamide
To a solution of (4-methyl-phenoxy)-acetic acid (100 mg, 0.6 mmol), 3-amino benzamide (163.86 mg, 12' mmol), HOBT (162 mg, 1.2 mmol) and DJJPEA (155 mg, 1.2 mmol) in DMF (6 ml) was added EDC (230.8 mg, 1.2 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH : MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH : MC = 1 :9 ~ 2:8) to afford of 3-[2-(4-tert-buryl- phenoxy)-acetylamino]-benzamide as a colorless solid (133 mg, 78% yield).
1H NMR (DMSO-d6, 300 MHz) 10.16(1H, s, CONH), 8.09(1H, s, aromatic), 7.93(1H, s, aromatic), 7.80(1H, d, J=8.1 Hz, aromatic), 7.56(1H, d, J=8.1 Hz, aromatic), 7.37(2H, m, CONH2), 7.10(2H, d, J=8.7 Hz, aromatic), 6.90(2H, d, J =8.4 Hz, aromatic), 4.65(1H, s, OCH2), 2.23(3H, s, CH3).
<Example 32> 3-[2^4-nitrcHphenoxy)-aceryl-amino)-benzamide
To a solution of (4-nitro-phenoxy)-acetic acid (100 mg, 0.5 mmol), 3-amino benzamide (103.5 mg, 0.76 mmol), HOBt (102.81 mg, 0.76 mmol) and DIPEA (98.34 mg, 0.76 mmol) in DMF (2 ml) was added EDC (145.86 mg, 0.76 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mixture of MeOH : MC
(10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH : MC = 1:9 ~ 2:8) to afford of 3-[2-(4-tert- butyl-phenoxy)-acetylamino]-ben2arnide as a colorless solid (135 mg, 81% yield). 1H NMR (DMSO-ds, 300 MHz) 10.32(1H, s, CONH), 8.24(1H, d, J=9.3 Hz, aromatic), 8.08(1H5 s, aromatic), 7.94(1H, s, aromatic), 7.78(1H, d, J=8.1 Hz, aromatic), 7.58(1H, d, J=7.2 Hz, aromatic), 7.39(2H, m, CONH2), 7.21(2H, d,J=9.3 Hz, aromatic), 4.92(2H, s, OCH2). .
<Example 33> 2^4-Adamantyl-l-yl-phenoxyl)-N-(3-sulfamoyl-phenyl)-ace1amide
The mixture of [4-(l-damantyl)-phenoxyl]acetic acid (80.7 mg, 0.28 mmol), 3-amino- benzenesulfonamide (72.3 mg, 0.42 mmol), N, N-diisopropylethyamine, redistilled (DPEA) (0.1 ml, 0.56 mmol) and benzDtriazole-1-yl-oxy-tris-pyrrolidino-phosphoniurh hexafluorophosphate (pybop) (291.4 mg, 0.56 mmol) in DMF (5 mL) was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by Prep-TLC (n-
Hexane:EtoAc:MeOH = 6:3:1) to give 2-(4-Adamantyl-l-yl-phenoxyl)-N-(3-sulfamoyl-phenyl)-acetamide as a white solid (23.1 mg, 18.7% yield). .
1H-NMR (DMSO-d6, 300 Hz) 10.39 (IH, s, NH), 8.23 (IH, s, aromatic-H), 7.79 7.82 (IH, m, aromatic-H), 7.51 7.53 (2H, m, aromatic-H), 7.37 (2H, s, NH2), 7.28 (2H, d, J = 8.7 Hz, aromatie-H), 6.93 (2H, d, J = 8,7 Hz, aromatic-H), 2.04 (3H, m, adamantly-H), 1.83 (6H, m, adamantly-H), 1.72 (6H m, adamantly-H).
<Example 34> 2-(4-Adamantyl-l-yl-phenoxyl)-N-(4-sulfamoyl-phenyl)-acetamide
To a solution of the (4-adamantan-l-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and 4-amino- benzenesulfonamide (103 mg, 0.6 mmol) in DMF (5.0 mL) were added benzotriazol-1-yl-N-oxy- tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (390 mg, 0.75 mmol), and A- dimethylaminopyridine (DMAP) (92 mg, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (CH2C12 : MeOH = 40 : 1) gave 2-(4- Adamantan-l-yl-phenoxy)-N-(4-sulfamoyl-phenyl)-acetamide as a white solid (78.9 mg, 35.8% yield).
1H-NMR (DMSO-d6, 300Hz) 10.40 (IH, s, NH), 7.75-7.83 (4H, m, aromatic), 7.27-7.30 (4H, m, • aromatic), 6.92 (2H, m, aromatic), 4.70 (2H, s, OCH2CO), 2.04 (3H, m, adamantyl), 1.80-1.83 (6H, m, . adamantyl), 1.67-1.75 (6H, m, adamantyl).
<Example 35> 2-(4-Adamanτyl-l-yl-phenoxyl)-N-(3-cyano-phenyl)-acetamide
To 2-(4-Adamantan-l-yl-phenoxy)-acetic acid (200.0 mg, 0.70 mmol), 3-amino-benzonitrile (124.1 mg, 1.05 mmol), N-(3-dimethylaminopropyl)-N'-ethyl carbodϋmideHCl (EDC) (201.3 mg, 1.05 mmol) and 1- hydroxybenzotriazole (HOBt) (142.9 mg, 1.05 mmol) in DMF (10 mL) was added N, N-diisopropylethyamine, redistilled (DIPEA) (131.5 mg, 0.18 ml, 1.05 mmol). The mixture wasstirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtoAc:MeOH =
6:3:1) to give 2-(4-Adamantyl-l-yl-phenoxyl)-N-(3-cyano-phenyl)-acetamide as a yellow solid (222.8 mg, 82.6% yield).
1H-NMR (CDCl3, 300 Hz) 8.41(1H, s, NH), 8.03 (IH, s, aromatic-H), 7.78 - 7.81 (IH, m, aromatic- H), 7.42 7.49 (2H, m, aromatic-H),- 7.32 7.37 (2H, m, aromatic-H), 6.91 6.97 (2H, m, aromatic-H), 4.62 (2H, s, CH2), 2.09 (3H, m, adamantly-H),1.89 (6H, m, adamantly-H), 1.77 (6H, m, adamantly-H).
<Example 36>N-(3-Cyano-phenyl)-2-(2,4-dichloro-phenoxy)-acetamide
To (2,4-dichloro-phenojiy)-acetic acid (300.0 mg, 1.36 mmol), 3-amino-benzonitrile (241.0 mg, 2.04 mmol), N-(3-dimethylaminopropyl>]Sr-ethyl carbodϋmideHCl (EDC) (391.1 mg, 2.04 mmol) and 1- hydroxybenzotriazDle (HOBt) (277.7 mg, 2.04 mmol) in DMF (18 mL) was added N, N-diisopropylethyamine, redistilled (DIPEA) (0.35 ml, 2.04 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSCvt anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtoAc:MeOH = 6:3:1) to give AC- 147 as a white solid (353.7 mg, 81.3% yield).
1H-NMR (DMSO-4 300 Hz) 7SO(IH, s, NH), 7.26 (IH, s, aromatic-H), 6.97 - 7.01 (IH, m, aromatic-H), 6.65 - 6.71 (3H, m, aromatic-H), 6.47 - 6.50 (IH, m, aromatic-H), 6.12 (IH, d, J = 8.7 Hz, aromatic- H), 4.86 (2H, s, CH2). ■ ' '
<Example 37> 2-(4-Adamantan-l-yl-phenoxy)-N-(3-trffluoromethyl-phenyl)-acetarnide
1H NMR (CDCl3, 300 MHz) 8.44 (IH, s, CONH), 7.89 (IH, s, aromatic), 7.83 (IH, d, J = 7.8 Hz, aromatic), 7.50-7.32 (4H, m, aromatic), 6.95 (2H, d, J = 8.7 Hz, aromatic), 4.61 (2H, s, OCH2), 2.10 (3H, brs, adamantyl), 1.90 (6H, d, J = 2.4 Hz, adamanτyl), 1.77 (6H1 m, adamantyl).
<Example 38> 2-(4-Adaman1an-l-yl-phenoxy)-N-(3-hydroxyl-phenyl)-acetamide
To a solution of the (4-adamantan-l-yl-phenoxy)-acetic acid (85.9 mg, 0.3 mmol) and 3-amino-phenol (65.5 mg, 0.6 mmol) in DMF (5.0 mL) were added benzotriazol-l-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (312.2 mg, 0.6 mmol), and N^-diisopropylethylamine (DIPEA) (0.11ml,. 0.6 mmol). The reaction mixture was stirred atroom temperature overnight and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated Purification by silica gel column chromatography (n-Hexane : EtOAc : MeOH = 15 : 3: 1 ) gave 2-(4-Adamantan-l-yl-phenoxy)-N-(3-hydroxyl- phenyl)-acetamide as a white solid (67.6 mg, 59.7% yield).
1H-NMR (CD3OD, 300Hz) 7.28-7.32 (2H5 m, aromatic), 7.19-7.21 (IH, m, aromatic), 7.09-7.14 (IH, m, aromatic), 6.93-7.00 (3H5 m, aromatic), 6.56 (IH, dd, J = 7.8 Hz & 1.8 Hz, aromatic), 4.60 (2H, s, OCH2CO), 2.06 (3H5 m, adamantyl), 1.90-1.91 (6H5 m, adamantyl), 1.75-1.86 (6H5 m, adamantyl).
<Example 39> 2-(2,4-dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide
To a solution of the (2,4-dichloro-phenoxy)-acetic acid (600 mg, 2.71 mmol) and 3-amino-phenol (592 mg, 5.43 mmol) in DMF (20.0 mL) were added benzotriazol-l-yl-N-oxy-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBOP) (2.8 g, 5.43 mmol), and N,N-diisopropylethylamine (DIPEA) (0.95 ml, 5.43 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4anh), and concentrated. Purification by silica gei column chromatography (n-Hexane : EtOAc : MeOH = 10 : 3 : 1) gave 2-(2,4-Dichloro-phenoxy)-N-(3-hydroxy-phenyl)- acetamide as a white solid (837 mg, 99% yield)
1H-NMR (CD3OD, 300Hz) 7.47(1H, d, J=2.4 Hz, aromatic), 7.28(1H, m, aromatic), 7.19(1H, ps t, J=1.8 Hz, aromatic), 7.10(2H, m, aromatic), 6.97 (IH, m, aromatic), 6.57(1H, dd, J=8.1 &2.4 Hz, aromatic), 4.73(2H5 S5 OCH2CO).
<Example 40> 2-(2,4-dichloro-phenoxy)-N-(3-methanesulfonyl-phenyl)-acetamide
To 2,4-dichloφhenoxyacetic acid (110.6 mg, 0.5 mmol), 3-methylsulphonylaniline (128.4 mg, 0.75 mmol), N<3-dimethylaminopropyl>N'-ethyl carbodiimideHCl (EDC). (143.8 mg, 0.75 mmol) and 1- hydroxybenzotriazole (HOBt) (102.1 mg, 0.75 mmol) in DMF (5mL) was added N, N-diisopropylethyamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSCvt anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2MeOH = 15:1) to give 2-(2,4-dichloro- phenoxy)-N-(3-memanesutfonyl-phenyl)-acetamide as a white solid (103.0 mg, 55.02% yield).
IH-NMR (CD3OD and DMSO-d6, 300 Hz) 8.41 (IH, m, aromatic-H), 7.99 - 8.03 (IH5 m, aromatic- H), 7.66 - 7.79 (3H5 m, aromatic-H), 7.45 (IH, dd, J = 9.0 & 2.4 Hz, aromatic-H), 7.24 (IH5 d, J = 9.0 Hz5 aromatic-H), 4.30 (ZH, s, CH2), 3.27 (3H5 s, CH3).
<Example 41> 2-(254-dichloro-pheno>^)-N-[3-(2-hydroxy-ethanesuhOnyl)-phenyl]-acetamide
Cl <
OH
To 2,4-dichlorphenoxyacetic acid (110.6 mg, 0.5 mmol), 2-(3-amino-benzenesulfonyl)-ethanol (151.0 mg, 0.75 mmol), N-(3-dimelhylaminopropyl>N'-e%l carbodiimideHCl (EDC) (143.8 mg, 0.75 mmol) and 1- hydroxybenzotriazole (HOBt) (102.1 mg, 0.75 mmol) in DMF (5mL) was added N5 N-dϋsopropylethyamine5 redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSCvi anh)5 and concentrated. The residue was purified by preparative (CH2CH2MeOH = 30: 1) to give 2-(254-dichloro-phenoxy)-N-[3-(2-hydroxy- ethanesuh°onyl)-phenyl]-acetamide as ayell foam (21.5 mg, 10.6% yield).
1H-NMR (CDCl3, 75 Hz) 8.78 (IH, s, NH), 8.20 (IH5 s, aromatic-H), 7.89 7.92 (IH, m5 aromatic- H), 7.73 (IH, d, J = 7.8 Hz5 aromatic-H), 7.59 (IH ps-t, J = 7.8 Hz5 aromatic-H), 7.45 (IH5 d, J = 2.4 Hz5 aromatic-H), 7.247.28 (IH5 m, aromatic-H), 6.91 (IH5 d, J = 9.0 Hz, aromatic-H), 4.66 (2H5 s, CH2), 4.03 (2H51, J =4.8 Hz, CH2), 3.39 (2H51, J=4.8 Hz5 CH2).
<Example 42> 2-(4-Adamantan-l-yl-phenoxyl)-N-(3-beπzoyl-phenyl)-acetamide
To a solution of the (4-adamantan-i-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and (3-amino- phenyl)-phenyl-methanone (148 mg, 0.75 mmol) in DMF (5.0 mL) were added l-[3-(dimethyamino)propyl]-3- ethylcarbodϋmide hydrochloride (EDC) (144.0 mg, 0.75 mmol), 1-hdroxylbenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and N,N-diisopropylethylamine (DIPEA) (0.13 ml, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane : EtOAc :
MeOH = 12 : 3: 1) gave 2^4-Admnaitan-l-yl-phenoxy)-N-(3-benzDyl-phenyl)-acetamide as a white solid (173.1 mg, 74.3% yield).
1H-NMR(CDCl3, 300Hz) 8.44 (IH, s, NH), 8.02 (IH, dd, J=7.8 & 1.2 Hz aromatic), 7.81- 7.89 (3H, m, aromatic), 7.45-7.7.63 (5H, m, aromatic), 7.34 (2H, m, aromatic), .6.94 (2H, m, aromatic), 4.61 (2H, s, . OCH2CO), 2.10 (3H, m, adamantyl), 1.89-1.90 (6H, m, adamantyl), 1.72-1.82 (6H, m, adamanryl).
<Example 43> 2-[2-(4-Adamantan-l-yl-pheno5^)-acerylamino]-benzoic acid
A solution of 2-[2-(ΦAdamantan-l-yl-phenoxy)-ace1ylamino]-benzoic acid methyl ester (30.5 ing, 0.07 mmol) in l,4-dioxane/H2O (3:1, 3 mL) added LiOHH2O (8.4 mg, 0.2 mmol) at room temperature. The resulting mixture was stirred overnight, and then acidified with 10% HCl to PH 2. Ethyl acetate was added and the organic layer was separated. The organic layer was washed with water, and dried (MgSO4 anh), and concentrated.
The residue was purified by silica gel flash column chromatography (n-Hexane : EtOAc : MeOH = 6 : 3: 1) to gave 2-[2-(4-Adamant-l-yl-phenoxy)-acerylamino]-benzoic acid as a white solid (18.5 mg, 62.5% yield).
1H-NMR (DMSO-d6, 300 Hz) 8.57(1H, d, J=8.4 Hz, aromatic-H), 8.01-8.04 (IH, m, aromatic-H), 7.32-7.37(1H, m, aromatic-H), 7.26(2H, d, J=8.4 Hz, aromatic-H), 7.00-7.05(3H, m, aromatic-H), 4.58(2H, s, CH2), 2.03(3H, m, adamantly-H), 1.81(6H, m, adamantly-H), 1.71(6H, m, adamantly-H).
<Example 44> 3-[2-(4-Adamantan-l-yl-phenoxy)-acerylamino]-benzoic acid
A solution of methyl ester (306 mg, 0.72 mmol) in THF/H2O/l,4-dioxane (1:1:1, 300 mL) added LiOHH2O (60 mg, 1.44 mmol) at room temperature. The resulting mixture was stirred overnight^ and then acidified with 10% HCl to PH 2. Ethyl acetate was added and the organic layer was separated. After concentration, the residue was purified by silica gel flash column chromatography (n-Hexane : EtOAc : MeOH =
15 : 3: 1) to gave 3-[2-(4-Adamant-l-yl-phenoxy)-acetylamino]-benzoic acid as a white solid (152 mg, 43% yield).
1H-NMR (DMSO-de, 300Hz) 10.31 (IH, s, NH), 8.27 (IH, s, aromatic), 7.84 (IH, d, J = 8.7 Hz, aromatic), 7.67 (IH, d, J = 8.1 Hz, aromatic), 7.38 (IH, ps t, J = 7.8 Hz, aromatic), 7.27 (2H, m, aromatic), 693 (2H, m, aromatic), 4.68 (2H, s, OCH2CO), 2.03 (3H, m, adamantyl), 1.81-1.82 (6H, m, adamantyl), 1.71 (6H, m, adamantyl).
<Example 45> S-P^Adamantan-l-yl-phenoxy^acetylaminoJ-phenylJ-acetic acid
7.29 (3H, m, aromatic), 6.90-6.98 (3H, m, aromatic), 4.65 (2H, s, OCH2CO), 3.53 (2H, s, CH2COOH), 2.03 (3H, m, adamantyl), 1.82-1.83 (6H, m, adamantyl), 1.71 (6H, m, adamantyl).
<Example 46> 4-[2-(4-Adamantan-l-yl-phenoxy)-acetylamino]-benzoic acid
1H-NMR(DMSO-O6, 300Hz) 10.34 (IH, s, NH), 7.89 (ZH, d, J= 8.4 Hz, aromatic-H), 7.73 (2IL d3 J = 8.7 Hz, aromatic-H), 7.27 7.30 (2H, m, aromatic-H), 6.90 6.93 (2H, m, aromatic-H), 4.69 (2H, s, CH2), 2.04 10 (3H, m, adamantyl-H), 1.82(6H, m, adamantylτH), 1.72 (6H, m, adamantyl-H).
<Example 47> 4-[2-(4-tert-butyi-phenoxy)-acetylamino]-benzoic acid
The present example was performed in the same manner from 4-[2-(4-tert-butyl-phenoxy)- ■ 15 acetylaminoj-benzoic acid methyl ester to give 4-[2-(4-tert-butyl-phenoxy)-acetylamino]-benzoic acid as a white solid (68.7 mg, 65.7% yield).
1H-NMR (CDCl3) 8.41(1H1 s, NH), 8.03-8.11(2H, m, aromatic-H), 7.87 (IH, d, J=7.5 Hz, aromatic- H), 7.45(1H, m, aromatic-H), 7.36 (2H, d, J=8.7 Hz, aromatic-H), 6.92(2H, m, aromatic-H), 4.60(2H, s, CH2), 1.31(9H, s, CH3). 20
<Example 48> 3-[2-(4-Adaman1an-l-yl-phenoxy)-acetylamirlo]4-hydroxy-benzoic acid
3-[2-(4-Adamantan-l-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester (151.8 mg, 0.35 mmol) in l,4-dioxane/H2O (10 ml) was treated with KOH (290.7 mg, 5.18 mmol) at 60 "C for 3h. The reaction
25 mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSθ4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2MeOH = 4:1) to give 3-[2-(4-Adamantan-l-yl-phenoxy)-
acetylamino]-4-hydroxy-benzoic acid as a white solid (110.4 mg, 75.10% yield).
1H-NMR (DMSO-Cl6, 300 Hz) 9.26 (IH, s, NH), 8.64 (IH5 s, aromatic-H), 7.56 (IH, d, J = 8.7 Hz, aromatic-H), 7.29 (2H, d, J = 8.4 Hz, aromatic-H), 6.90 6.96 (3H, m, aromatic-H), 4.71 (2H, s, CH2), 2.03 (3H, m, adarnantly-H), 1.72 1.82 (12H, m, adamantly-H).
<Example 49> 3-[2-(4-tert-buryl-pheno)^)-acetylamiiio]-4-hydroxy-benzoic acid
A 3-[2-(4-Adamantan-l-yl-pheno^)-arøtylamino]4-hydroxy-benzoic acid methyl ester (151.8 mg, 0.35 mmol) in l,4-dioxane/H2O (10 ml) was treated with KOH (290.7 mg, 5.18 mmol) at 60 °C for 3h. The ■ reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue .was purified by silica gel flash column chromatography (CH2CH2MeOH = 4: 1) to give 3-[2-(4-ten>butyl-phenoxy)-acetylamino]- 4-hydroxy-benzoic acid as a white solid (110.4 mg, 75.10% yield).
1H-NMR (DMSO-O6, 300 Hz) 9.26 (IH, s, NH), 8.64 (IH9 s, aromatic-H), 7.56 (IH, d, J = 8.7 Hz5 aromatic-H), 7.29 (2H, d, J = 8.4 Hz, aromatic-H), 6.90 6.96 (3H, m, aromatic-H), 4.71 (2H, s, CH2), 2.03 (3H, m, adamantly-H), 1.72 1.82 (12H, m, adamantly-H).
<Example 50> 3-[2-(4-Adamantan-l-yl-phenoxy)-ace1ylamino]-isophtalic acid
1H-NMR (CD3OD, 300 Hz) 8.52(2H, m, aromatic-H), 8.40(1H, m, aromatic-H), 7.30-7.33(2H, m,
aromatic-H), 6.97-7.00(2H, m, aromatic-H), 4.67(2H, s, CH2), 2.06(3H, m, adamanuy-H), 1.90(6H, m, adamantiy-H), 1.80(6H, m, adamantly-H).
<Examρle 51> 3-[2-(4-fluoro-phenoxy)-ace(ylamino]-benzoic acid
0.90 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2CH2MeOH = 6: 1) to give 3-[2~ (4-fluoro-phenoxy)-acetylamino]-benzoic acid as a white solid (108.3 mg, 83.24% yield). 1H-NMR (DMSO-de) 10.31(1H, s, NH), 8.27(1H, s, aromatic-H), 7.84(1H, d, J=8.7 Hz, aromatic-H), 7.67(1H, d, J=8.1 Hz, aromatic-H), 7.41(1H, ps-t, J =7.8 Hz, aromatic-H), 7.12-7.18(2H, m, aromatic-H), 7.01- .7.05(2H, m, aromatic-H),.4.71(2H, s, CH2). .
<Example 52> 3-[2-(4-chloro-phenoxy)-acerylamino]-benzoic acid
The present example was performed in the same manner from 3-[2-(4-chloro-phenoxy)-acerylamino]- benzoic acid methyl ester to give 3-[2-(4-chloro-phenoxy)-acetylamino]-ben2oic acid as a white solid (70.3 mg, 74.2% yield).
1H-NMR pMSO-ds) 10.30(1H, s, NH), 8.26(1H, s, aromatic-H), 7.83(1H, d, J=7.8 Hz, aromatic-H), 7.66(1H, d, J=7.2 Hz, aromatic-H), 7.44(1H, ps-t, J =7.8 Hz, aromatic-H), 7.33-7.36(2H, m, aromatic-H), 7.01-
7.04(2H, m, aromatic-H), 4.72(2H, s, CH2).
<Example 53> 3-[2-(2,4-dicUoro-phenoxy)-acetylamino]-benzoic acid
1H-NMR (CD3OD) 8.25(1H, s, aromatic-H), 7.78-7.86(2H, m, aromatic-H), 7.41-7.48(2H, m, aromatic-H), 7.29(1H, dd, J=9.0&2.4 Hz, aromatic-H), 7.10 (IH, d, J=9.3 Hz, aromatic-H), 4.77(2H5 s, CH2).
<Examρle 54> 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid
2-[2-(2,4-dicMoro-pheno>^)-ac^1ylamino]-benzoic acid methyl ester(94.6 mg, 0.27 mmol) in THF/H2O(3:1, 25 mL) was treated with LiOHH2O(22.7 mg, 0.54 mmol) at room temperature. The reaction mixture was then acidified with 10.% HCl to PH 2, and added ethyl.acetate and brine..The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography(CH2Cl2:MeOH=6:l) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid as a white solid (81.7 mg, 88.9% yield).
1H-NMR (DMSOd6, 300 Hz) 12.64(1H, s, NH), 8.59(1H, d, J=8.7 Hz, aromatic-H), 8.02(1H, dd, J=8.1 & 1.2 Hz, aromatic-H), 7.61(1H, d, J=3.0 Hz, aromatic-H), 7.53(1H, m, aromatic-H), 7.37(1H, dd,
J=8.7&2.4 Hz, aromatic-H), 7.11-7.20(2H, m, aromatic-H), 4.86(2H3 s, CH2).
<Example 55> 4-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid
THF/H2O(3:1, 9 mL) was treated with LiOHH2O(30.2 mg, 0.72 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, and added ethyl acetate and brine. The organic phase was washed with water, dried (MgSθ4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2MeOH=^ 1) to give 4-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid as a white solid(86.4 mg, 70.6% yield).
1H-NMR pMSO-d& 300 Hz) 10.44(1H, s, NH), 7.88(2H, d, J=8.4 Hz, arømatic-H), 7.58-7.64(3H, m, aromatic-H), 7.33-7.37(1H, m, aromatic-H), 7.09 (IH, d, J=9.3 Hz, aromatic-H), 4.87(2H, s, CH2).
<Example 56> 3-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-benzDic acid
The present' example was performed in the same manner from 3-[2-(2,4,5-tricMoro-phenoxy)- acetylamino]-benzoic acid methyl ester to give 3-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-benzoic acid as a white solid (89.3 mg, 77.2% yield).
1H-NMR (DMSO-Cl6) 10.56(1H, s, NH), 8.25(1H, s, aromatic-H), 7.83(1H, s, aromatic-H), 7.77(1H, d, J=7.8 Hz, aromatic-H), 7.70(1H, d, J=7.8 Hz, aromatic-H), 7.47(1H5 s, aromatic-H), 7.32(1H, ps-t, J=^7.8 Hz5 aromatic-H), 4.98(2H, s, CH2). . _.. .. .. .
<Example 57> 3-[2-(4-bromo-phenoxy)-acerylamino]-beπzoic acid
51% yield).
1H-NMR (CD3OD, 300Hz) 8.26(1H, m, aromatic), 7.86(1H5 m, aromatic), 7.79(1H, d, J=8.1 Hz, aromatic), 7.41-7.46(3H, m, aromatic), 6.99(2H, m, aromatic), 4.68(2H5 s, OCH2CO).
<Example 58> 3-[2-(4-iodo-prienoxy)-acetylamino]-benzoic acid
The present example was performed in the same manner from 3-[2-(4-iodo-phenoxy)-acetylamino]- benzoic acid methyl ester to give 3-[2-(4-iodo-phenoxy)-aceτylamino]-benzoic acid as a white solid (64.4 mg,
67.7% yield).
1H-NMR (DMSO-ds) 10.15(1H, s, NH), 8.25(1H, s, aromatic-H), 7.85(1H, d, J=8.1 Hz, aromatic-H), 7.60-7.67(3H, m, aromatic-H), 7.43(1H, ps-t, J=8.1 Hz, aromatic-H), 6.86(2H, d, J=8.7 Hz, aromatic-H), 4.72(2H, s, CH2).
<Example 59> 3-(2-biphenyl-4-yl-acetylamino)-benzoic acid
3-(2-biphenyl-4-yl-acetylarnino)-benzoic acid methyl ester(133.6 mg, 0.39 mmol) in THF/H2O(1:1, 4 mL) was treated with LiOHH2O(32.7mg, 0.78 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2. Resulting mixture was collected by filteration, and recrystaUized with mixture of
CH2Cl2 and MeOH to give 3-(2-biphenyl-4-yl-ace1ylamino>benzoic acid as a white solid (74.4 mg, 58.1% yield). . 1H-NMR (DMSO-dg, 300 Hz) 12.96(1H, s, CQ2H), 10.44(1H5. s, NH), 8.26 (IH, s, aromatic-H),. 7.86(1H, d, J=8.7 Hz, aromatic-H), 7.61-7.66(5H, m, aromatic-H), 7.43-7.48(5H, m, aromatic-H), 7.32-7.40(1H, m, aromatic-H), 3.71(2H, s, CH2).
<Example 60> 3-[2-(4-aceryl-phenoxy)-acetylammo]-benzoic acid
Methyl ester(113 mg, 0.35 mmol) in THF/H2O(1:1, 14 mL) was treated with LiOHH2O (29 mg,
0.69 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, added EtoAC, and an organic layer was separated. After concentrated, The residue was purified by silica gel column chromatography (CH2Cl2:Me0H=15:l) to give 3-[2-(4-acetyl-phenoxy)-acetylamino]-benzoic acid as a white solid (73 mg, 67% yield).
1H-NMR (CD3OD, 300Hz) . 8.26(1H, m, aromatic), 8.00(2H, m, aromatic), 7.86(1H, m, aromatic), 7.79(1H, d, J=8.1 Hz, aromatic),. 7.43(1H, ps t, J=8.1 Hz, aromatic), 7.14(2H, m, aromatic), 4.79(2H, s, OCH2CO), 2.55(3H, s, COCH3).
<Example 61> 2-(4-adamantan-l-yl-phenoxy)-N-[3-(lH-tetrazole-5-yl) phenyl]-acetamide
A mixture of l^-Adamantan-l-yl-phenojQ'^N-CS-cyano-phenyl^acetamide (165.9 mg, 0.43 mmol), sodium azide (83.9 mg, 1.29 mmol) and triethylamine hydrochloride (89.5 mg, 0.65 mmol) in N- methylpyrrolidone (6 ml) (NMP) was stirred at 150 "C under nitrogen overnight After cooling, the reaction mixture was diluted with water, acidified to PH 1 with 10% v/v hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CHaCBkMeOH = 6:1) to give 2-(4-adamantan-l-yl-phenoxy)-N-[3- (lH-tetrazole-5-yl) phenylj-acetamide as a solid (30.3 mg, 16.3% yield).
1H-NMR (DMSO-d6, 300 Hz) ' 10.36(1H, s, NH), 8.46(1H, s, aromatic-H), 7.81(1H, d, J=8.1 Hz, aromatic-H), 7.73(1H, d, J=7.8 Hz, aromatic-H), 7.55 (IH, ps-t, J=8.1 Hz5 aromatic-H), 7.29(2H, d, J=8.7 Hz, aromatic-H,), 6.94 (2H, d, J=9.3 Hz5 aromatic-JH), 4.71(2H, s, CH2), 2.03(3H, on, adamantly-H), 1.83(6H, m, adamantly-H), 1.71(6H, m, adamantiy-H).
<Example 62> 2-(2,4-dichloro-phenoxy)-N-[3-(lH-tetrazole-5-yl)-phenyl]-acetamide
A mixture of N-(3-cyano-phenyl)-2-(2,4-dichloro-phenoxy)-acetamide(70.0 mg, 0.22 mmol), sodium azide (42.9 mg, 0.66 mmol) and triethylamine hydrochloride (45.4 mg, 0.33 mmol) in N-methylpyrrolidone (6 ml) (NMP) was stirred at 150 °C under nitrogen overnight After cooling, the reaction mixture was diluted with water, acidified to PH 1 with 10% v/v hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2MeOH = 3:1) to give 2-(2,4-dichloro-phenoxy>N-[3-(lH-tetrazole-5-yl)-phenyl]- acetamide as a solid (57.2 mg, 71.6% yield).
1H-NMR (DMSO-dg, 300 Hz) 10.31(1H, s, NH), 8.21(1H, s, aromatic-H), 7.64-7.72(2H, m, aromatic-H), 7.61(1H, d,- J=2.4 Hz, aromatic-H), 7.34-7.40(2H, m, aromatic-H), 7.13(1H, d, J=9.0 Hz, aromatic- H), 4.89(2H, s, CH2).
<Example 63> carbamic acid 3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-phenylester
To a stirred solution of mixture of 2-(2,4-Dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide (95.2 mg, 0.3 mmol) in CH2CI2 (1.0 mL) was added trishloroacetyl (0.09 ml, 0.76. mmol) at 0 °C and the solution was stirred at room temperature until the reaction was complete, as judged by TLC. The reaction mixture was added aluminum oxide and CH2Ct(IO mL) and then stirred at room temperature for 0.5 h. The aluminum oxide was removed by filtration and the filtrate was concentrated in vacuo. Purification by preparative TLC (n-Hexane : EtOAc : MeOH = 6 : 3 : 1) gave Carbamic acid 3-[2-(4-Adamantan-l-yl-phenoxyl)-acetylamino]-phenyl ester as a white solid (42.0 mg, 39.4% yield). 1H-NMR pMSO-ds, 300Hz) 10.27(1H, s, NH), 7.60(1H, d, J=2.4 Hz, aromatic), 7.45(1H, m, aromatic), Z27-7.38(3H,.m, aromatic), 7.16(1H, brs, NH2), 7.10(1H, d, J=8.7 H^.aromatic), 6.91(1H, brs, NH2), . 6.81(1H d, J=8.1 Hz; aromatic), 4.86(2H, s, OCH2CO).
<Example 64> sulfamic acid 3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-phenyl ester
Sulfamoyl chloride was prepared by the dropwise addition of formic acid (0.03 mL, 0.80 mmol) to neat chlorosulfonyl isocyanate (0.07 mg, 0.80 mmol) at 0 °C with rapid stirring. Gas was evolved during the addition process. The viscous mixture was stirred for 5 min at 0 °C. during which time it solidified. Dichloromethane (0.2 mL) was added and the solution of the 2-(2,4-Dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide (100 mg, 0.32 mmol) and pyridine (0.26 mL, 3.2 mmol)in dichloromethane (0.3 mL) was added dropwise. The reaction mixture was warmed 25 Cand stirred for 18h. The reaction was quenched by the successive addition of ethyl acetate (5 mL).and H2O (3 mL). The biphaseic mixture was poured into ethyl acetate (10 mL) and H2O (5 mL) and the organic layer was separated. After concentration, the residue was purified by preparative TLC (n-Hexane : EtOAc : MeOH = 6 : 3 : 1) to gave Sulfamic acid 3-[2-(4-Adamantan-l-yl-phenoxyl)-acetylamino]-phenyl ester as a white solid (19.3 mg, 15.4% yield).
1H-NMR (CD3OD, 300 Hz) 7.70(1H, m, aromatic), 7.47(2H, m, aromatic), 7.38(2H, m, aromatic), 7.28(2H, m, aromatic), 7.09(2H, m, aromatic), 4.76(2H, m, OCH2CO).
<Example 65> 3-[2^4-adamantan-l-yl-pheno3cy)-acetylatnino]-4-hydroxy-benzamide
Ammonium chloride(6.5 mg, 0.12 mmol) in anhydrous toluene 2 ml was treated with trimethyl aluminium(in 2.0 M Hexane, 0.26 ml, 0.51 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan- l-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester(50.1 mg, 0.12 mmol) in toluene 4 ml. The mixture was stirred for 3 h at 80 "C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was washed by brine, dried (MgSU4 anh), and concentrated. The residue was purified by preparative TLC(CH2Cl2MeOH=IS: 1) to give 3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-4-hydroxy-benzarnide as a white solid (12.9_mg, 25.6% yield). . . . _ ..
1H-NMR (CDCl3 + CD3OD, 300 Hz) 8.26(1H, d, J=2.4 Hz, aromatic-H), 7.23 (IH, d, J=2.1 Hz, aromatic-H), 6.99(2H, d, J=9.3 Hz, aromatic-H), 6.64(2H, d, J=9.3 Hz, aromatic-H), 6.59 (IH, d, J=8.7 Hz, aromatic-H), 4.25 (2H, s, CH2), 1.75(3H, m, adamantly-H), 1.56(6H, m, adamantly-H), 1.44(6H, m, adamantiy- H).
<Example 66> 3-[2^4-adamantan-l-yl-phenoxy)-acerylamino]-4-hydroxy-N,N^imethyl-benzamide
Dimethyl amine(0.06 ml, 0.12 mmol) in anhydrous toluene 2 ml was treated with trimethyl aluminium(in 2.0 M Hexane, 0.15 ml, 0.31 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan- l-yl-phenoxy)-acerylamino]-4-hydroxy-benzoic acid methyl ester(30.1 mg, 0.07 mmol) in toluene 4 ml. The mixture was stirred for 3 h at 80 "C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was washed by brine, dried (MgSθ4 anh), and concentrated. The residue was purified by preparative TLC(Hexane:EtoAC:MeOH=15:3:l) to give 3-[2-(4-admnan1an-l-yl-phenoxy)-ace1ylamino]-4-hydroxy-N,N- dimethyl-benzamide as a white solid (10.4 mg, 23.2% yield).
1H-NMR (CDCl3, 300 Hz) 8.85(1Ii s, NH), 7.70(1H, s, aromatic-H), 7.32 (2H, d, J=8.4 Hz,
aromatic-H), 7.03-7.05(1H, m, aromatic-H), 6.93(2H, d, J = 8.7 Hz, aromatic-H), 6.85(1H, d, J=7.2 Hz, aromatic- H), 4.61(2H, s, CH2), 3.07 (6H, s, CH3), 2.09(3H, m, adamantly-H), 1.89(6H5 m, adamantly-H), 1.76(6H5 m, adamantly-H)/
<Example 67> 3-[2-(4-adamantan-l-yl-phenoxy)-acetylan^
furfuryl amine(6.8 mg, 0.07 mmol, 0.07 ml) in anhydrous toluene 1 ml was treated with trimethyl aluminium(in 2.0 M Hexane, 0.15 ml, 0.31 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan- l-yl-phenoxy)-acetyl amino]-Φhydroxy-berizoic acid methyl ester(30.1 mg, 0.07 mmol) in toluene 8 ml. The mixture was stirred for 3 h at 80 "C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase . was washed by brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative TLC(CH2Cl2:Me0H=15:l) to give 342-(4-adamantan-l-yl-phenoxy>acerylamino]-N-furan-2-ylmethyl-4- hydroxy-benzamide as a white solid (15.4 mg, 44.0% yield). 1H-NMR (CDCl3, 300 Hz) 8.71(1H, s, NH), 7.76(1H, s, aromatic-H), 7.48 (IH, d, J=9.0 Hz, aromatic-H), 7.33-7.38(3H, m, aromatic-H), 7.04(1H, d, J= 8.1 Hz, aromatic-H), 6.95(2H, d, J=9.0 Hz, aromatic- H), 6.44(1H, s, NH), 6.32 (2H, d, J=8.7 Hz, aromatic-H), 4.62-4.69(4H, m, CH2), 2.10(3H, m, adamantly-H), 1.90(6H, m, adamantly-H), 1.77(6H, m, adamantly-H).
<Example 68> 3-[2-(4-adamantan-l-yl-phenoxy)-acerylamino]-N-(2-dimethylamino-ethyl)-4-hydroxy- benzamide
3-[2-(4-adamantan-l-yl-phenoxy)acetylamino]-4-hydroxy-benzoic acid(60.1 mg, 0.14 mmol) and
PyBOP(148.3 mg, 0.29 mmol) in DMF 3.0 ml was added N,N-dimetliylethylenediamine(25.1 mg, 0.29 mmol, 0.03 ml) and DIPEA(0.05 ml, 0.29 mmol) at room temperature. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by preparative TLC(CH2Cl2:Me0H=7:l) to give 3-[2-(4-adamantan-l-yl-phenoxy)-acerylamino]-N-(2-
dimethylaminoethyl)-4-hydroxy-benzamide as a yellow solid (20.2 mg, 28.7% yield).
1H-NMR (MEOD, 300 Hz) 8.26(1H, m, aromatic), 7.85(1H, dd, J=1.8&9.0 Hz, aromatic-H), 7.45- 7.47(1H, m, aromatic-H), 7.36(2H, d, J=9.0 Hz, aromatic-H), 7.02(2H, d, J==6.6 Hz, aromatic-H), 4.73(2H, s, CH2), 3.63(2H5 1, J=6.6 Hz, CH2), 2.93(2H, t, J=6.6 Hz, CH2), 2.60(6H, s, CH3), 2.08(3H, m, adamanily-H), 1.91(6H, m, adamantly-H), 1.81(6H, ni, adamantly-H).
<Example 69> 3-[2-(4-adamantan-l-yl-phenoxy)-ace1ylammo]4-hydroxy-N-(3-moφholine-4-yl-propyl)- benzamide
HATU(68.5 mg, 0.18 mmol) in DMF 3.0 ml was added N-(aminopropyl)moφholine(0.18 mmol, 0.03 ml) and DIEEA(0.03 ml, 0.18 jήmol) at room temperature. The .reaction mixture .was separated witbi ethyl .acetate and sodium bicarbonate. The organic phase was dried (MgSCvt anh), and concentrated. The residue was purified by preparative TLC(CH2Cl2:Me0H=15:l) to give 3-[2-(4-adamantan-l-yl-phenoxy>acerylamino]-N-(2- dimemylamino-ethyl)-4-hydroxy-benzamide as a yellow solid (9.5 mg, 14.5% yield).
1H-NMR (MEOD, 300 Hz) 8.57(1H, d, J=2.4 Hz, aromatic), 7.51(1H, dd, J =2.4&8.7 Hz, aromatic- H), 7.33(2H, d, J=8.7 Hz, aromatic-H), 6.98(2H, d, J= 8.7 Hz, aromatic-H), 6.92(1H, d, J=8.7 Hz, aromatic-H), 4.67(2H, s, CH2), 3.76-3.81(4H, m, aUpliatic), 6.92(2H, t, J=6.9 Hz, aHphatic), 2.71-2.79(6H, m, aHphatic), 2.07(3H, m, adamantly-H), 1.91(8H, m, adamantly-Hand aliphatic), 1.80 (6H, m, adamantly-H).
<Example 70>3-[2-(4-adamantan-l-yl^henoxy)-acetylarnino]-N-(4^Uoro-phenyl)-berizarnide
To a solution of 3-[2-(4-adamantan-l-yl-phenoxy)-acetylarnino]-benzoic acid (20 mg, 0.049 mmol), 4- chloro aniline (9.4 mg, 0.073 mmol) and DIPEA (9.56 mg, 0.073 mmol) in DMF (5 mL) was added EDC (14.18 mg, 0.073 mmol) and HOBt (9.99 mg, 0.073 mmol) at room temperature and continued stining for 16 h at room temperature. Reaction mixture was diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over MgSO^ The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by column chromatography on silica gel
(EtoAC:Hexane=l:5) to give S-P^Φadamantan-l-yl-phenoxy^acetylammoJ-N^Φ-chloro-phenyl^benzamide as a colorless crystals(15 mg, yield: 59 %).
1HNMR (DMSOd5, 300 MHz) 10.39(1H3 s, OCH2CONH), 10.27(1H, s, PhCONHPh), 8.16(1H9 s, aromatic), 7.89(1H, d, J=8.7 Hz, aromatic), 7.80(2H5 d, J=9.0 Hz, aromatic), 7.66(1H, d, J=7.8 Hz, aromatic), 7.45(3H, m, aromatic), 7.28(2H, d, J=8.4 Hz, aromatic), 6.93(2H, d, J=8.4 Hz, aromatic), 4.69(2H, s, OCH2), 2.03(3H, s, adamantyl), 1.83(6H, s, adamantyl), 1.71(6H, s, adamanryl).
<Example 7l> 3-[2-(4-adaman1an-l-yl-ρhenoxy)-acetylamώ^^
1H-NMR (CDCl3, 300 Hz) 8.47(1H, s, NH), 8.13-8.16(2H, m, aromatic-H), 7.96(1H, s, NH), 7.89(1H3 d, J=7.8 Hz, aromatic-H), 7.79-7.81(1H, m, aromatic-H), 7.67(1H, d, J=7.8 Hz, aromatic-H), 7.46- 7.52(2H, m, aromatic-H), 7.40-7.43(1H, m, aromatic-H), ?.32-7.36(2H, m, aromatic-H), 6.95(2H, d, J= 8.7 Hz, aromatic-H), 4.62(2H, s, CH2), 2.10(3H, m, adamantly-H), 1.72-1.90 (12H, m, adamanuy-H).
<Example 72>3-[2-(4-adamantan-l-yl-phenoj^)-acerylamino]-N-naphtalene-2-yl-beπzamide
To a solution of 3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-benzoic acid(20 mg, 0.049 mmol), 2- naphtylamine(10.59 mg, 0.073 mmol) and DIPEA(9.56 mg, 0.073 mmol) in DMF 1 mL was added EDC(Kl 8 mg, 0.073 mmol) and HOBt(9.99 mg, 0.073 mmol) at room temperature and continued stirring for 16 h at room temperature. . Reaction mixture was diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over MgSOψ The solvent was filtered arid evaporated under reduced
pressure to afford a crude solid, which was purified by column chromatography on silica gel (n- Hexane:EtoAC=l:9~4:6) to give 3-[2-(4-adamantan-l-yl-phenoxy)-ac^tylairimo]-N-naphtalene-2-yl-benzamide as a colorless crystals(16 mg, 61.53% yield).
1HNMR (DMSOd6 300 MHz) 10.39(1H, s, OCH2CONH), 10.27(1H, s, PhCONHPh), 8.16(1H, s, aromatic), 7.89(1H, d, J=8.7 Hz, aromatic), 7.80(2H, d, J=9.0 Hz, aromatic), 7.66(1H, d, J=7.8 Hz, aromatic), 7.45(3H, m, aromatic), 7.28(2H, d, J=8.4Hz, aromatic), 6.93(2H, d, J=8.4 Hz, aromatic), 4.69(2H, s, OCH2), 2.03(3H, s, adamantyl), 1.83(6H, s, adamantyl), 1.71(6H, s, adamantyl).
<Example 73> S-P^-adamaniHi-l-yl-pheno^^acerylamino-N-furan^-ylmethyl -benzamide
To a solution of 3r[2^4.-adamantanJ-yl-pheno>^)-acerylamino]-berizoic acid(60.0 mg, 0.15 mmol), furfuryl amine(21.9 mg, 0.03 ml, 0.23 mmol), EDQ43.1 mg, 0.23 mmol) and HOBt(34.5 mg, 0.23 mmol) in DMF 1.5 mL was added DIPEA(0.04 ml, 0.20 mmol). Reaction mixture was stirred, and separated by ethyl acetate and 10% HCl. It was sequentially washed with brine and water, and dried over MgSO^ The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel flash column chromatography (n-Hexane:EtoAC:MeOH= 6:3:1) to give 3-[2-(4-adamantan-l-yl-phenoxy)- acerylarnino-N-furan-2-ylmethyl -benzamide as a yellow solid (79.5 mg, 100% yield).
1HNMR (CDCl3, 300 MHz) 8.47(3H, m, 2xCONH, aromatic), 7.97(1H, s, aromatic), 7.75(1H, d, J=8.1 Hz, aromatic), 7.48(1H, d, J=7.2 Hz, aromatic), 7.33(3H, m, aromatic), 7.13(2H, d, J=5.4 Hz, aromatic), 6.90(2H, d, J=9.0 Hz, aromatic), 6.78(IH, brs, aromatic), 4.55(2H, s, OCH2CO), 3.68(2H, q, J=6.75 Hz,
NHCH2CH2), 2.91(2H, t, J=6.9 Hz, NHCH2CH2), 2.08(3H, s, adamantyl), 1.87 (6H, s, adamantyl), 1.75(6H, m, adamantyl).
<Example 74> 3-[2-(4-adamantan-l-yl-phenoxy)-acerylainino]-N-(2-pyridine4-yl-ethyl)-berjzamide
To a solution of 3-[2-(4-adamantan-l-yl-phenoxy)-acerylamino]-benzoic acid(50 mg, 0.123 mmol), 4- (2-aminoethyl)pyridine(22.59 mg, 0.184 mmol) and DIPEA(23.90 mg, 0.184 mmol) in DMF 1 mL was added
EDC(35.45 mg, 0.184 mmol) and HOBt(24.99 mg, 0.184 mmol) at room temperature and continued stirring for 16 h at room temperature. Reaction mixture was diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by column chromatography on silica gel (n- Hexane: EtoAC=l:5) to give 3-[2-(4-adamantan-l-yl-pheno^)-acetylainino]rlSr-(2-pyridine-4-yl-ethyl)- benzamide as a colorless crystal(25 mg, 40% yield).
1HNMR (CDCl3, 300 MHz) 8.47(3H, m, 2χCONH, aromatic), 7.97(1H, s, aromatic), 7.75(1H, d,
J=8.1 Hz, aromatic), 7.48(1H, d, J=7.2 Hz, aromatic), 7.33(3H, m, aromatic), 7.13(2H, d, J=5.4 Hz, aromatic),
6.90(2H, d, J=9.0 Hz, aromatic), 6.78(1H, brs, aromatic), 4.55(2H, s, OCH2CO), 3.68(2H5 q, J=6.75 Hz, NHCH2CH2), 2.91(2H, t, J=6.9 Hz, NHCH2CH2), 2.08(3H, s, adamanryl), 1.87 (6H, s, adamantyl), 1.75(6H, m, adamantyl).
<Example 75> 3-[2-(2,4-dicMoro-phenoxy)-acetylamino]-N,N-dimethyl-benzamide
1H-NMR (CD3OD, 300Hz) 7.74(1H, ps t, J=1.8 Hz, aromatic), 7.64(1H, m, aromatic), 7.45(2H, m, aromatic), 7.28(1H, dd, J=9.0&2.4 Hz, aromatic), 7.18 (IH, m, aromatic), 7.09(1H, d, J=9.3 Hz, aromatic), 4.77(2H, s, OCH2CO), 3.09 (3H, s, NCH3), 3.00(3H, s, NCH3).
<Example 76> 3-[2-(2,4-dicMoro-phenoxy)-acetylamino]-N-ethyl-benzairiide
To solution of 3-[2-(2,4-dichloro-plienoxy)-ace1ylamino]-benzoic acid(150 mg, 0.44 mmol), ethylamine (0.034 ml, 0.66 mmol) in DMF 3.0 mL was added EDC(126.5 mg, 0.66 mmol), HOBt (89.2 mg, 0.66
mmol) and DIPEA(O-Il ml, 0.66 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2CkMeOH=I 5:1) to give 3-[2-(2,4^cWoro-phenoxy)-acetylamino]-N-ethyl- benzamide as a white solid (144.6 mg, 90% yield).
1H-NMR (DMSO-dβ, 300Hz) 10.31(1H, s, NH), 8.45(1H, ps t, J=5.7 Hz, aromatic), 8.04(1H, s, aromatic), 7.74(1H, m, aromatic), 7.55(2H, m, aromatic), 7.39(2H, m, aromatic), 7.12(1H, d, J=9.0 Hz, aromatic), 4.88(2H, s, OCH2CO), 3.27(2H, m, NHCH2CH3), 1.10(3H, t, J=7.2 Hz, NHCH2CH3).
<Example 77> S-P^^dichlororphenoxy^acetylarriinoj-N-fiπan^-ylmethyl-benzainide
10
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid(100.3 mg, 0.3 mmol), furfuryl
. ..amine(58.3 mg, 0.06 ml, 0.6. mmol), 4-dimethylaminopyridine(73.4 mg, 0.6 mmol) and PyBOP(312.3 mg, J.O.. mmol) in DMF 5.0 mL was stirred. Reaction mixture was separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography 15 (CH2Cl2MeOH=IO: 1) to give 3-[2-(2,4-dicUoro-phenoxy)-acetylamino]-N-furan-2-ylmethyl-benzainide as a white solid (144.6 mg, 90% yield).
1H-NMR (DMSO-ds, 300 Hz) 10.34(1H, s, NH), 8.97(1H, 1, J=5.4 Hz, NH-CH2), 8.05(1H3 s, aromatic-H), 7.73-7.76(1H, m, aromatic-H), 7.55-7.59(3H, m, aromatic-H), 7.34-7.43(2H, m, aromatic-H), 7.10(1H, d, J=9.3 Hz, aromatic-H), 6.37-6.39(1H, m, aromatic-H), 6.26(1H, d, J=3.0 Hz, aromatic-H), 4.86(2H, s, 20. 0-CH2-CO), 4.86(2H, d, J=5.7 Hz,, NH-CH2-furan).
< Example 78>3-[2-(2,4-dicWoro-phenoxy)-acetylamino]-N-furan-2-ylmeώyl-4-hydroxy-benzarnide
furfuryl amine(28.2 mg, 0.29 mmol, 0.03 ml) in anhydrous toluene 3 ml was treated with trimethyl
25 aluminium(in 2.0 M Hexane, 0.64 ml. 1.28 mmol) under nitrogea After 0.25 h, It was added 2-(2,4-dichloro- phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester(100:2 mg, 0.29 mmol) in toluene 9 ml. The mixture was stirred for 1 h at 80 "C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was
washed by brine, dried (MgSθ4 anh), and concentrated. The residue was purified by. preparative TLC(CH2Cl2:Me0H=15:l) to give 3-[2^2,4-dicMorcHphenoxy)-a∞lylmnino]-N-furan-2-ylme%l-4- a. yellow soUd (10.4 mg, 23.2% yield).
1R-NMR (CD3OD, 300 Hz) 8.64(1H, m, aromatic-H), 7.49-7.54(2H, m, aromatic-H), 7.41(1H, m, aromatic-H), 7.30-7.33(1H, m, aromatic-H), 7.14(1H, d, J=9.3 Hz, aromatic-H), 6.91(1H, d, J=8.7 Hz, aromatic- H), 6.33-6.35(1H, m, aromatic-H), 6.27-6.28(1H, m, aromatic-H), 5.77(2H, s, CH2), 4.53(2H, s, CH2).
<Example 79> N-berizyl-3-[2-(2,4-dicUoro-phenoxy)-acerylammo]-berizamide
To solution of 3-[2-(2,4-dichloro-phenoxy)-acerylamino]-benzoic acid(68 mg, 0.2 mmol), benzylamine
(0.032 ml, 0.3 mmol) in DMF 3.0 mL was added EDC(57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and πiPEA(Q.O52 ml, 0.3 mmol). Reaction.mixture was stirred at room temperature, and separated by EtoAC, and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtoAC:MeOH=15:3:l) to give N-benzyl-3-[2-(2,4-dichloro-phenoxy)-acerylamino]- benzamide as a white solid (12 mg, 14% yield).
1H-NMR (CD3OD, 300Hz) 7.99(1H, ps t, J=1.8Hz, aromatic), 8.08(1H, dd, J=7.5&1.2 Hz, aromatic), 7.61(2H, m, aromatic), 7.19-7.44(7H, m, aromatic), 7.01(1H, d, J=1.8Hz, aromatic), 4.56(2H, s, OCH2CO), 3.34(2H, s, NHCH2Ph).
<Example 80> 3-[2-(2,4-dicMorcHpheno^)-ace1ylaniino]-N-pyridine4-y]rnethyl-benzamide
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid(68 mg, 0.2 mmol), 4- aminomethyl pyridine(0.024 ml, 0.24 mmol) in DMF 3.0 mL was added EDC(57.5 mg, 0.3 mmol), HOBt(40.6 mg, 0.3 mmol) and DIPEA(0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:l) to give 3-[2-(2,4-dichloro-phenoxy)- acerylamino]-N-pyridine-4-ylmethyl-benzamide as a white solid (60.6 mg, 70% yield).
1H-NMR (DMSO-dg, 300Hz) 10.35(1H, s, NH), 9.12(1H, t, J=5.4 Hz, NH), 8.50(2H, m, aromatic),
8.11(1H, m, aromatic), 7.78(1H, dd, J=8.1 &1.2 Hz aromatic), 7.61(2H, m, aromatic), 7.44(1H, ps t, J=7.8 Hz, aromatic), 7.38 (IH, dd, J=8.6&2.4 Hz aromatic), 7.29(2H, m, aromatic), 7.12(1H, d, J=9.0 Hz, aromatic), 4.88(2H5 s, OCH2CO), 4.49(2H, d, J=5.4 Hz, NHCH2).
<Example 81> S-P^^KJichlorcπpheno^yaceiylarmnoj-N-pyridine-S-ylmethyl-benzamide
To solution of 3-[2-(2,4κHcUoro-pheno5^)-ace1ylamino]-benzoic acid(102 mg, 0.3 mmol), 3- aminome%l pyridine(0.036 ml, 0.36 mmol) in DMF 3.0 mL was added EDC(86.3 mg, 0.45 mmol), HOBt(60.8 mg, 0.45 mmol) and DIPEA(0.078 ml, 0.45 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:l) to give 3-[2-(2,4-dichloro-phenoxy)- acerylamino]-Nrpyridine-3--ylmethyl-benzamide as awhitejsolid (7.1.4 mg, 55%_ yield)
1H-NMR (DMSO-ds, 300Hz) 10.34(1H, s, MH), 9.09(1H, t, J=6.0 Hz, NH), 8.54(1H, d, J=2.1 Hz, aromatic), 8.45(1H, m, aromatic), 8.09(1H, s, aromatic), 7.72(2H, m, aromatic), 7.60(2H, m, aromatic), 7.33- 7.45(3H, m, aromatic), 7.11(1H, d, J=9.0 Hz, aromatic), 4.88(2H, s, OCH2CO), 4.48(2H, d, J =6.0 Hz3NHCH2).
<Example 82>3-[2-(2,4κiicMorc)-phenoxy)-ace1ylamino]-N-(2-piperidine-l-yl-ethyl)-beπzamide
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid(68 mg, 0.2 mmol), l-(2- aminoethyl)-piperidine(0.043 ml, 0.3 mmol) in DMF 3.0 mL was added EDC(57.5 mg, 0.3 mmol), HOBt(40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSOt anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:l) to give 3-[2-(2,4-dichloro-phenoxy)- a(^tylarnmo]-N-pyridine-3-ylmethyl-benzamide as a white solid (60.6 mg, 70% yield). 1H-NMR (CD3OD, 300Hz) 8.09(1H, ps t, J=I.8 Hz, aromatic), 7.75(1H, dd, J=7.8&1.2 Hz, aromatic),
7.58(1H, d, J=7.8 Hz, aromatic), 7.45(2H, m, aromatic), 7.28(1H, dd, J-8.7&24 Hz, aromatic), 7.09(1H, d, J=8.7 Hz, aromatic), 4.78(2H, s, OCH2CO), 3.59(2H, m, aUphatic), 2.73-2.80(6H, m, aliphatic), 1.65-1.73(4H, m, aliphatic), 1.55(2H, m,,aliphatic).
<Example 83> 3-[2^2,4<licMoro-phenoxy)-acet^^^
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzDic acid(68 mg, 0.2 mtnol) and 2- morpholine4-yl-ethylamine(0.039 ml, 0.3 mmol) in DMF 3.0 mL was added EDC(57.5 mg, 0.3 mmol), HOBt(40.6 mg, 0.3 mmol) and DIPEA(0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:l) to give 3-[2-(2,4-dichloro-phenoxy)- acetylamino]-N-pyridine-3-ylmethyl-benzarnide as a white solid (34.1mg, 38% yield). 1H-NMDR. (CD3OD, 300 Hz) 8.02(1H, m, aromatic), 7.78(1H, m, aromatic), 7.57(1H, m, aromatic),
7.41(ZBt m, aromatic), 72AQH, dd, J=9.0&2.4 Hz, aromatic), 7.05(1H, d, J=8.4 Hz, aromatic), 4.74(2H, s, OCH2COX3.70-3.73 (4H, m, aliphatic), 3.54(ZH, t, J=6.6.Hz, aHphatic), 2.57-2.66(6H, m, aliphatic). . . .
<Example 84> 3-[2^2,4-dicMorcHphenoxy)-acetylammo]-N-(2-hydroxy-emyl)-berizarnide
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid(150 mg, 0.44 mmol) and ethanolamine(0.04 ml, 0.66 mmol) in DMF 3.0 mL was added EDC(126.5 mg, 0.66 mmol), HOBt (89.2 mg, 0.66 mmol) and DIPEA(0.11 ml, 0.66 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:Me0H=15:l) to give 3-[2-(2,4-dichloro-phenoxy)-acerylamino]-N-
(2-hydroxy-ethyl)-benzamide as a white solid (135 mg, 80% yield).
1H-NMR (DMSO-dδ, 300Hz) 10.32(1H, s, NH), 8.40(1H, ps t, J=5.4 Hz, NH), 8.05(1H, s, aromatic), 7.7GQH, d, 3=7.8 Hz, aromatic), 7.58 (ZH, m, aromatic), 7.39(2H, m, aromatic), 7.12(1H, d, J=8.4 Hz, aromatic), 4.88(2H, s, OCH2CO), 4.72(1H, t, J=6.0 Hz, OH), 3.51(2H, m, aliphatic), 3.33(2H, m, aliphatic).
<Example 85>3-[2^2,4-dicUoro-phenoxy)-acerylarriino]-N-(3-moφholine-4-yl-propyl)-benzamide
3-[2-(2,4-dichloro-phenoxy)-ace1ylamino]-ben2oic acid(200 mg, 0.59 minol) and N- (aminopropyl)moφholine(0.17 ml, 1.18 mmol) in DMF 3.0 mL was added EDC(168.7 mg, 0.88 mmol), HOBt(118.9 mg, 0.88 mmol) and DIPEA(0.15 ml, 0.88 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:Me0H=15:l) to give 3-[2-(2,4-dichloro- phenoxy)-acetylamino]-N-(3-moφholine-4-yl-propyl)-ben2amide as ayellow solid (56.7 mg, 20% yield).
1H-NMR (CD3OD, 300Hz) 8.05(1H, m, aromatic), 7.73(1H, m, aromatic), 7.54(1H5 m, aromatic), 7.44(2H, m, aromatic), 7.26(IH, dd, J=9.0&3.0 Hz, aromatic), 7.08(1H, d, J=8.7 Hz, aromatic), 4.76(2H, s, OCH2CO), 3.65-3.68 (4H, m, aliphatic), 3.41(2H, m, aliphatic), 2.41-2.48(6H, m, aliphatic), 1.81 (2H, m, aliphatic).
<Example 86> 2-[2-(4-adamantan-l-yl-pheno^)-acetylamino]-isoriicotinic acid methyl ester
1H NMR (DMSO-d6, 300 MHz) 9.06(1H, s, CONH), 8.80(1H, s, pyridine), 8.45(1H, d, J=5.1 Hz, pyridine), 7.65(1H, d, J=5.4 Hz, pyridine), 7.33(2H, d, J=8.4 Hz, aromatic), 6.95(2H, d, J=9.3 Hz, aromatic), 4.64(2H, s, OCH2), 3.97 (3H, s, OCH3), 2.09(3H, brs, adamantyl), 1.88(6H, s, adamaniyl), 1.76(6H, m, adamantyl).
<Example 87> 5-[2-(4-adamantan-l-yl-phenoxy)-acerylarαino]-nicotinic acid methyl ester
To solution of (4-adamantan-l-yl-phenoxy)-acetic acid(125 mg, 0.438 mmol), 5-amino nicotinic acid methyl ester(100 mg, 0.654 mmol) and DIPEA(84.62 mg, 0.654 mmol) in DMF 1 mL was added EDC(125.5 mg, 0.654 mmol), HOBt(88.47 mg, 0.654 mmol). Reaction mixture was stirred at room temperature, poured onto ice cold water, extracted with ethyl acetate, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC: Hexane=l:9~l:l) to give 3-[2-(2,4-dichloro-phenoxy)-ace1ylamino]-N-(3-moφhohne- 4-yl-propyl)-benzamide as a colorless solid (0.125g, 68% yield).
1HNMR (CDCl3, 300 MHz) 9.01(2H, brs, CONH, pyridine), 8.67(1H, s, pyridine), 8.53(1H, s, pyridine), 7.34(2H, d, J=9.3 Hz, aromatic), 6.95(2H, d, J=8.7 Hz, aromatic), 4.65(2H, s, OCH2), 3.96(3H, s,
OCH3), 2.09(3H,.brs, adamantyl),J^9(6H, d,J=3.0 Hz, adamanryl), 1.76(6H, m, adamanryl). . ._
<Example 88> 5-[2-(2,4-dichloro-phenoxy)-acetylamino]-nicotinic acid methyl ester
N-(3-moφholine-4-yl-propyl)-benzamide as a colorless solid (0.185g, 60% yield).
1H NMR (CDCl3, 300 MHz) 8.98(2H, d, J=14.7 Hz, CONH, pyridine), 8.75 (IH, s, pyridine), 8.65(1H, s, pyridine), 7.45(1H, d, J=2.4 Hz, aromatic) 7.26(1H, dd, J=3.0&7.8 Hz, aromatic), 6.91(1H, d, J=8.4 Hz, aromatic), 4.68 (2H, s, OCH2), 3.96(3H, s, OCH3).
<Example 89>2-(4-adamantan-l-yl-phenoxy)-N-(4-methyl-pyridine-2-yl)-acetamide
To solution of (4-adamantan-l-yl-phenoxy)-acetic acid(50 mg, 0.17 mmol), 5-amino-4-picoline(28.32 mg, 0.26 mmol) and DEPEA(33.85 mg, 0.26 mmol) in DMF 1 mL was added EDC(50.2 mg, 0.26 mmol) and HOBt(35,39 mg, 0.26 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was extracted with ethyl acetate, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=l:9~2:8) to give 2-(4-adamantan-l-yl- phenoxy)-N-(4-methyl-pyridine-2-yl)-acetamide as a colorless solid (0.033g, 50% yield).
1H NMR (CDCl3, 300 MHz) 8.92(1H, brs, CONET), 8.16(1H, d, J=5.4 Hz, aromatic), 8.12(1H, s, aromatic), 7.31(2H, m, aromatic), 6.94(3H, m, pyridine), 4.60(2H, s, OCH2), 2.39(3H, s, CH3), 2.08(3H, brs, adamantyl), 1.88 (6H, d, J=3.0 Hz, adamantyl), 1.76(6H, m, adamantyl).
<Example 90> 2^2,4κiicMoro-phenoxy)-N-(4-methyl-pyridine-2-yl)-acetamide
1H NMR (CDCl3, 300 MHz) 9.19(1H, brs, CONH), 8.18(1H, d, J=4.8 Hz, aromatic), 8.11(1H, s, aromatic), 7.43(1H, d, J=3.0 Hz, aromatic), 7.22(1H, dd, J=2.7, 9.0 Hz, aromatic), 6.94-6.88(2H, m, aromatic), 4.65(2H, s, OCH2), 2.40(3H, s, CH3).
<Example 91> 2-[2-(2,4-dicUorcHphenoxy)-acetylamino]-isonicotinic acid metliyl ester
α
To solution of (2,4-dichloro-phenoxy)-acetic acid(0.200 g, 0.9 mmol), 2-ainino isonicotinic acid methyl ester(207 mg, 1.36 mmol) and DMAP(0.222 g, 1.81 mmol) in DMF 13 mL was added PyBOP(946 mg, 1.81mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSC>4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=l:9~4:6) to give 2-[2-(2,4-dichloro- phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.229 g, 71% yield).
1H NMR (DMSOd6, 300 MHz) 10.87(1H, s, CONH), 8.53(2H, d, J=4.8 Hz, pyridine), 7.58(m, 2H, aromatic), 7.35(1H, dd, J=1.8&9.0 Hz, pyridine), 7.11 (IH, d, J=8.4 Hz, aromatic), 4.98(2H, s, OCH2), 3.88(3H5 s, OCH3).
<Example 92> 2-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester
1H NMR pMSO-ds, 300 MHz) 10.89(1H, s, CONH), 8.54(2H, d, J=5.4 Hz, pyridine), 7.85(s, IH, aromatic), 7.58(1H, dd, J=1.35&4.95 Hz, pyridine), 7.48(1H, s, aromatic), 5.05(2H, s, OCH2), 3.89(3H, s, OCH3).
<Example 93> 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester
To solution of (4-bromo-2-cMorcHphenoxy)-acetic acid(100 nig, 0.378 mmol), 2-amino isonicotinic acid methyl ester(86.42 mg, 0.568 mmol) and DMAP(69.43 mg, 0.568 mmol) in DMF 2 mL was added PyBOP(295 mg, 0.568 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=4:9~4:6) to give 2-[2-(4-bromo- 2-chloro-phenoxy)-acerylamino]-isonicotinic acid methyl ester as a colorless solid (0.084 g, 56% yield).
1H NMR (CDCl3, 300 MHz) 92QH, s, CONH), 8.77(1H, s, pyridine), 8.47 (IH, d, J=4.8 Hz, pyridine), 7.66QH9 dd, J=1.2&4.8 Hz, pyridine), 759QH, d, J=2.4 Hz, aromatic), 7.38(1H, dd, J=2.25&8.85 Hz, aromatic), 6.85(1H, d, J=8.4 Hz, aromatic), 4.67(2H5 s, OCH2), 3.96(3H, s, OCH3).
<Example 94> 2-[2-(4-tert-buryl-phenoxy)-acerylamino]-isonicotinic acid methyl ester
<Example 95> 2-[2-(2,4-dicUorc)-phenoxy)-acelylaniino]-isonicotinic acid
1H NMR (DMSOd6, 300 MHz) 10.55(1H, s, CQNH), 8.44(1H, s, pyridine), 8.32(1H, d, J=3.9 Hz, pyridine), 7.59(1H5 d, J=2.1 Hz, pyridine), 7.52(1H, dd, J=0.9&3.75 Hz, aromatic), 7.36(1H, dd, J=1.95&6.75 Hz, aromatic), 7.12 (IH, d, J=6.6 Hz, aromatic), 4.96(2H, s, OCH2), COOHnot detected.
<Example 96> 5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-iiicotinic acid
A solution of 5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-nicotinic acid methyl ester(50 mg, 0.11 mmol) and lithium Iodide(l 89 mg, 1.11 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resultant crude product was purified by HPLC (MeOHZMC=I 0%) to afford 5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-nicotinic acid as a colorless solid (0.015 g, 30% yield).
1H NMR (CD3OD + CDCl3, 300 MHz) 8.95(1H, d, J=1.8 Hz, pyridine), 8.84 (IH, s, pyridine), 8.44(1H, s, pyridine), 7.28(2H, d, J=8.4 Hz, aromatic), 6.94(2H, d, J=9.0 Hz, aromatic), 4.62(2H, s, OCH2), 2.04(3H, brs, adamantyl), 1.86(6H, d, J=3.0 Hz, adamantyl), 1.74(6H, m, adamantyl), COOH and CONH not detected.
<Example 97> 5-[2-(2,4-dichloro-phenoxy)-acetylamino]-nicotinic acid
A solution of 5-[2-(2,4-dichloro-phenoxy)-acetylamino]-nicotinic acid methyl ester(50 mg, 0.14mmol)
and lithium Iodide(189 mg, 1.41 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSC>4, filtered and concentrated under reduced pressure. The resultant crude product was purified by HPLC (MeOHMC=I 0%) to afford 5-[2-(4-adamantan-l-yl-phenoxy)-acerylamino]-nicotinic acid as a colorless solid (0.022 g, 45% yield).
1H NMR (DMSOd6, 300 MHz) 10.70(1H, s, CONH), 8.77(2H, d, J=15.9 Hz, pyridine), 8.46(1H, s, pyridine), 7.60(1H, d, J=2.4 Hz, aromatic), 7.36(1H, dd, J=2.4&8.4 Hz5 aromatic), 7.13(1H, d, J=9 Hz, aromatic), 4.93(2H, s, OCH2), COOH not detected. ■ " ■
<Example 98> 2-[2-(4-adamantan-l-yl-phenoxy)-acerylarnino]-isonicotinic acid
A solution of 2-[2-(4-adamaiitan-l-yl-phenoxy)-acetylarnino]-isonicotiriic acid methyl ester(50 mg, O.l lmmol) and lithium Iodide(159 mg, 1.11 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSOt, filtered and concentrated under reduced pressure. The resultant crude product was purified by HPLC (MeOH/MC=10%) to afford 2-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]- isonicotinic acid as a colorless solid (0.039 g, 81% yield). 1H NMR (DMSOA 300 MHz) 10.29(1H, s, CONH), 8.39(1H, s, pyridine), 8.26(1H, d, J=5.1 Hz, pyridine), 7.45(1H, d, J=5.1 Hz, pyridine), 7.27(2H, d, J=8.7 Hz, aromatic), 6.90(2H, d, J=8.4 Hz, aromatic), 4.74(2H, s, OCH2), 2.03 (3H,brs, adamanryl), 1.82(6H, d, J=1.8 Hz, adamantyl), 1.71(6H, s, adamantyl), COOH not detected.
<Example 99> 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]-isonicotiriic acid
BYYCI H y
A solution of 2-[2-(4-bromo-2κ;MorcHphenoxy)-acetylamino]-isonicotinic acid methyl ester(50 mg,
0.125mmol) and lithium Iodide(189 mg, 1.25 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSθ4, filtered and concentrated under reduced pressure. The resultant crude 5 product was purified by HPLC (MeQHMC==10%) to afford 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]- isonicotinic acid as a colorless solid (0.012 g, 25% yield).
1H NMR (DMSOd6, 300 MHz) 10.29(1H, s, CONH)5 8.33(1H, s, pyridine), 8.21(1H, d, J=5.1 Hz, pyridine), 7.71(1H, d, J=2.4 Hz, pyridine), 7.49(1H, dd, J=2.4&8.4 Hz, aromatic), 7.41(1H, d, J=4.8 Hz, aromatic), 7.06(1H, d, J =8.7 Hz, aromatic), 4.92(2H, s, OCH2), COOH not detected. • 10
<Example lOO>2-[2^4-tert-bu1yl-phenoxy)-ace1ylaniino]-isonicotinic acid
To solution of 2-[2-(4-tert-butyl-phenoxy)-ace1ylamiαo]-isonicotinic acid methyl ester(51.8 mg, 0.15 mmol) in pyridine 6 ml was added lithium Iodide(12.6 mg, 0.30 mmol), and stirred at 125 °C. Reaction mixture 15 was concentrated, and purified by Prep-TLC(CH2Cl2:Me0H = 10: 1) to give as a colorless solid (39.4 mg, 77.94% yield).
1H-NMR (DMSO-d6, 300 Hz) 10.63(1H, s, NH), 8.53(1H, s, aromatic-H), 8.45(1H, d, J=5.1 Hz, aromatic-H), 7.55(1H, d, J=4.8 Hz, aromatic-H), 7.31 (2H, d, J=8.4 Hz, aromatioH), 6.88(2H, d, J=8.7 Hz, aromatic-H), 4.78(2H, s, CH2), 1.25(9H, s, CH3). 20
<Example 101> 5-[2χ4-adaman1an-l-ylφhenoxy)-acetylairi^
To solution of S-p^adamantan-l-ylφhenoxy^acetylaminoJ-rjicotinic acid(40 mg, 0.098 mmol), furfuryl amine(19.11 mg, 0.196 mmol) and DMAP(24.06 mg, 0.196 mmol) in DMF was added PyBOP(102.4
25 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was
purified by PLC (MeOH:MC=l:9) to afford 5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-N-furan-2- ylmethyl-nicotinamide as a colorless solid (5 rag, 25.3% yield).
1H NMR (DMSOd5, 300 MHz) 10.74(1H, s, OCH2CONH), 9.25(1H5 1, J=5.85 Hz3 CH2CONH), 8.46(1H, d, J=4.8 Hz, pyridine), 8.41(1H, s, pyridine), 7.61 (IH5 d, J=3.0 Hz, pyridine), 7.58(1H, s, fiiran), 7.51- 7.49(1H, m, fiiran), 7.37(1H, dd, J=2.4&8.4 Hz, furan), 7.11(1H, d, J=8.7 Hz, aromatic), 6.39 (IH, t, J=2.4 Hz3 aroamatic), 6.28(1H3 d, J=3 Hz3 aromatic), 4.97(2H, s, OCH2), 4.45(2H, d, J=5.4 Hz, CONHCH2).
<Example 102> 5-[2-(4-adamantan-l-yl-pheno>^)-acetylarnmo]-N-(2-pyridine-4-yl-ethyl) nicotinamide
1H NMR (DMSO-dfo 300 MHz) 8.83-8.74(3H, m, 2xCONH, pyridine), 8.44 (3H, m, pyridine), 7.31(2H3 d, J=8.4 Hz, pyridine), 7.22(3H, m, pyridine, aromatic), 6.90(2H, d, J=9.0 Hz3 aromatic), 4.59(2H, s, OCH2), 3.73(2H, q, J = 5.85 Hz3 CONHCH2CH2), 2.97(2H, t, J=6.6 Hz, CONHCH2CH2), 2.07(3H, brs, adamantyl), 1.86(6H, d, J=I .8 Hz3 adamantyl), 1.81-1.69(6H, m, adamanτyl).
<Example 103> S-P^adamantan-l-yl-phenoxy^ac^iylarninoJ-N^S-irmdazole-l-yl-propyl^ricoώ
To solution of 5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), 1-
(3-aminopropyl)-unidazole(24.65 mg, 0.196 mmol) and DMAP(24.06 mg, 0.196 ramol) in DMF was added PyBOP(102.47 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOHMC=I :9) to afford 5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]- N-(3-imidazole-l-yl-propyl)-nicotinamide as a colorless solid (37 mg, 49% yield).
1H NMR (DMSOKI6, 300 MHz) 10.45(1H5 s, OCH2CONH), 8.92(1H, d, J=1.8 Hz, pyrazole),
8.72(2H, d, J=1.8 Hz, pyrazole), 8.47(1H, t, J=2.1 Hz, CH2CONH), 7f65(lH, s, pyridine), 7.28(2H5 d, J=9.3 Hz, aromatic), 7.20(1H, s, pyridine), 6.94(2H, d, J=9.3 Hz, aromatic), 6.88(1H, s, pyridine), 4.72(2H, S5OCH2), 4.02(2H, t, J=6.75 Hz5 NCH2), 3.24(2H, q, J=6.75 Hz5 CH2CH2CH2), 2.03 (3H5 brs, adamaniyl), 3.24(2H, t,
J=6.75 Hz, CONHCH2CH2), 1.82(6H5 s, adamantyl), 1.71(6H, m, adamantyl).
<Example 104> 2-[2-(4-adamanten4-yl-phenoxy)-acetylamm^^
4-chloroaniline(25.12 mg, 0.196 mmol) and DMAP(21.65 mg, 0.17 mmol) in DMF was added PyBOP(92.22 mg, 0.17 mmol), and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSθ4, and concentrated. The resultant crude product was purified by PLC (MeOHrMC=I :9) to afford 2-[2-(4-admnantan-l-yl-phenoxy)-acerylammo]-N-(4-cWoro-phenyl)-isonicotinarnide as a colorless solid (49 mg, 98% yield).
1H NMR (DMSO-d6, 300 MHz) 10.74(1H, s, OCH2CONH), 9.25(1H, t, J=5.85 Hz, CH2CONH), 8.46(1H5 d, J=4.8 Hz, pyridine), 8.41(1H5 s, pyridine), 7.61 (IH5 d, J=3.0 Hz, pyridine), 7.58(1H5 s, furan), 7.51- 7.49(1H, m, furan), 7.37(1H5 dd, J=2.4&8.4 Hz, furan), 7.11(1H, d, J=8.7 Hz, aromatic), 6.39 (IH, t, J=2.4 Hz, aroamatic), 6.28(1H, d, J=3 Hz, aromatic), 4.97(2H, s, OCH2), 4.45(2H, d, J=5.4 Hz5 CONHCH2).
<Example 105> 2-[2^4-adamantan-l-yl-phenoxy)-a^
1H NMR (DMSOd6, 300 MHz) 10.74(1H, s, OCH2CONH), 9.25(1H, t, J=5.85 Hz, CH2CONH), 8.46(1H, d, J=4.8 Hz, pyridine), 8.41(1H, s, pyridine), 7.61 (IH, d, J=3.0 Hz, pyridine), 7.58(1H, s, furan), 7.51- 7.49(1H, m, furan), 7.37(1H, dd, J=2.4&8.4 Hz, furan), 7.11(1H, d, J=8.7 Hz, aromatic), 6.39 (IH, t, J=2.4 Hz, aroamatic), 6.28(1H, d, J=3 Hz, aromatic), 4.97(2H, s, OCH2), 4.45(2H, d, J=5.4 Hz, CONHCH2)
<Example 106> 2-[2^4-adamantan-l-yl-phenoxy)-acelylamino]-N-(2-pvriα%e^-yl-ethyl)-isomcotinarm
4-(2-aminoemyl) pyridine(24.06 mg, 0.196 mmol) and DMAP(24.06 mg, 0.196 mmol) in DMF was added PyBOP(102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOHMC=I :9) to afford 2-[2-(4-adamantan-l-yl-phenoxy)-acerylamino]- N-(2-pyridine-4-yl-ethyl)-isonicotinamide as a colorless solid (42.7 mg, 84% yield).
1H NMR (DMSO-de, 300 MHz) 10.74(1H, s, OCH2CONH), 9.25(1H, t, J=5.85 Hz, CH2CONH), 8.46(1H, d, J=4.8 Hz, pyridine), 8.41(1H, s, pyridine), 7.61 (IH, d, J=3.0 Hz, pyridine), 7.58(1H, s, furan), 7.51- 7.49(1H, m, furan), 7.37(1H, dd, J=2.4&8.4 Hz, furan), 7.11(1H, d, J=8.7 Hz, aromatic), 6.39 (IH, t, J=2.4 Hz, aroamatic), 6.28(1H, d, J=3 Hz, aromatic), 4.97(2H, s, OCH2), 4.45(2H, d, J=5.4 Hz, CONHCH2).
<Example 107> 2-[2-(4-adaman1an-l-yl-phenoxy)-acetyla^
1HNMR (DMSO-dfo 300 MHz) 10.66(1H, s, pyridine), 8,78(1H, t, J=5.55 Hz, pyrazole), 8.46(1H, d,
J=4.8 Hz, pyridine), 8.41(1H, s, pyrazole), 7.83 (IH, brs, OCH2CONH), 7.49-7.46(1H, m, pyrazole), 7.27(3H, d, J=9.3 Hz, aromatic, pyridine), 7.0(1H, brs, CONHCH2), 6.89(2H, d, J=9.0 Hz, aromatic), 4.78(2H, s, OCH2),
4.03(2H, t, J=7.05 Hz, N-CH2), 3.23(2H, q, J=6.3 Hz5 CONHCH2CH2), 2.03(3H, s, adamantyl), 1.96(2H, m,
CH2CH2CH2), 1.82(6H, d, J=2.4 Hz, adamantyl), 1.71(6H, s, adamantyl).
<Example 108> 2-[2-(2,4-dicMoro-phenoxy)-ace(ylarriino]-N,N-dimemyl-isomαDtinarnide
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (100.0 mg, 0.31 mmol), dimethylamine(0.24 ml, 0.47 mmol, in 2.0 M tetrahydrofuran), EDC(90.1 mg, 0.47 mmol) and HOBt(63.5 mg,
-. 0.47 mmol) in DMF 4ml was added DIPEA(60.8 mg, 0.08 ml, 0.47 mmol), and stirred. Reaction mixture was then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried over anhydrous MgSO4, . and concentrated. The residue was purified by preparative-TLC(n-
Hexane:EtoAC:MeOH=6:3:l) to afford 2-[2-(2,4κlicUorcHphenoxy)-acetylamino]-N,N-dimethyl- isonicotinamide as a yellow solid (52.9 mg, 46.5 % yield).
1HNMR (CDCl3, 300 Hz) 8.46(1H, s, NH), 8.30-8.42(2H, m, aromatic-H), 7.45(1H, d, J=2.4 Hz, aromatic-H), 7.22-7.26(1H, m, aromatic-H), 7.13(1H, m, aromatic-H), 6.89(1H, d, J=9.3 Hz, aromatic-H), 4.66(2H, s, CH2), 3.12(3H, s, CH3), 2.97(3H, s, CH3).
<Example 109> 2-[2-(2,4-dicMoro-phenoxy)-acerylammo]-N-furan-2-ylmethyl-isonicotinamide
To solution of 2-[2^2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (16 mg, 0.047 mmol), fbrfuryl amine(9.1 mg, 0.094 mmol) and DMAP(8.6 mg, 0.07 mmol) in DMF 4ml was added PyBOP(36 mg, 0.07 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO^ and concentrated. The resultant crude product was purified by PLC (MeOH:MC=l :9) to afford 2-[2<2,4^licUorc)-phenoxy>ace1ylarnino]-N-furan-2-ylmethyl- isonicotinamide as a colorless solid (5 mg, 25.3 % yield).
1H NMR (DMSO-4 300 MHz) 10.74(1H, s, OCH2CONH), 9.25(1H, t, J=5.85 Hz, CH2CONH), 8.46(1H, d, J=4.8 Hz, pyridine), 8.41(1H, s, pyridine), 7.61 (IH, d, J=3.0 Hz, pyridine), 7.58(1H, s, ruran), 7.51- 7.49(1H, m, furan), 7.37(1H, dd, J=2.4&8.4 Hz, furan), 7.11(1H, d, J=8.7 Hz, aromatic), 6.39 (IH, i, J=2.4 Hz, aroamatic), 6.28(1H, d, J=3 Hz, aromatic), 4.97(2H, s, OCH2), 4.45(2H, d, J=5.4 Hz, CONHCH2).
<Example 110> 2-[2-(2,4^icUoro-phenoxy)-acetylamino]-N^2φirjeridine-l-yl-emyl)-isonicotinamide
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (80.0 mg, 0.24 mmol), 2- piperidine-l-yl-ethylamine(46.2 mg, 0.05 ml, 0.36 mmol), EDC(69.0 mg, 0.36 mmol) and HOBt(48.7 mg, 0.36 mmol) in DMF 4ml was added DIPEA(46.5 mg, 0.06 ml, 0.36 mmol), and stirred. Reaction mixture was then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried over anhydrous MgSθ4, and concentrated. The residue was purified by preparative-TLC(n-Hexane:EtoAC:MeOH=6:3:l) to afford 2-[2-(2,4-dicWoro-phenoxy)-acetylainmo]-N-(2-piperidine-l-yl-emyl)-isomcotinamide as a yellow solid (14.3 mg, 13.3 % yield).
1HNMR (CDCl3, 300 Hz) 9.1O(1H, s, NH), 8.80(1H, m, NH), 8.67(1H, s, aromatic-H), 8.46(1H, d, J=4.8 Hz, aromatic-H), 7.75(1H, m, aromatic-H), 7.44-7.46(1H, m, aromatic-H), 7.22-7.26(1H, m, aromatic-H), 6.89(1H, d, J= 9.3 Hz, aromatic-H), 4.66(2H, s, CH2), 3.82-3.87(2H, m, CH2), 3.07(6H, m, CH2), 1.99(4H, m,
CH2), 1.65(2H, m, CH2), 3.90(3H, s, CH3).
<Example 111> 2-[2^2,4-dicUorcHphenoxy)-acetylammo]-N-(3-moφholme4-yl-propyl)-isonicotinamide
To solution of 2-[2-(2J4-dichloro-phenoxy)-aceftylamino]-isonicotinic acid (100 mg, 0.31 mmol), 3- morpholine4-propylamine(67.8 mg, 0.07 ml, 0.47 mmol), EDC(90.1 mg, 0.47 mmol) and HOBt(63.4 mg, 0.47 mmol) in DMF 4ml was added DIPEA(60.7 mg, 0.08 ml, 0.47 mmol), and stirred. Reaction mixture was then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by preparative-TLC(CH2Cl2:Me0H=6:l) to afford 2-[2-(2,4- dicMoro-pheno^)-acetylamiiio]-N-(3-moφholine-4-yl-propyl)-isomcotinamide as awhite solid (31.3 mg, 21.7 % yield). 1HNMR (CDCl3, 300 Hz) 9.15(1H, s, NH), 8.57(1H, s, aromatic-H), 8.45 (IH, d, J=5.1 Hz, aromatic-
H), 8.29(1H, s, NH), 7.57-7.58(1H, m, aromatic-H), 7.45(1H, d, J=2.4 Hz, aromatic-H), 7.23-7.26(1H, m, aromatic-H), 6.90(1H, d, J=8.4 Hz, aromatic-H), 4.66(2H, s, CH2), 3.86(4H, m, CH2), 3.60-3.65 (2H, m, CH2), 2.79(6H, m, CH2), 2.00(2H, m, CH2).
<Example 112> 5-[2-(4-adamantan-l-yl-phenoxy)-arørylamino]-nicotinarnide
To solution of (4-adamantan-l-yl-phenoxy)-acetic acid(50 mg, 0.17 mmol), 5-amino nicotinamide(47.89 mg, 0.34 mmol) and DMAP(42.71 mg, 0.34 mmol) in DMF 5 ml was added PyBOP(181 mg, 0.34 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by preparative-TLC(CH2Cl2:Me0H=6:l) to afford 5-[2-(4-adamantaii-l-yl-phenoxy)-acetylammo]-nicotinamide as a colorless solid (42.48 mg, 60 % yield).
1H NMR (DMSO-d& 300 MHz) 10.41(1H, s, CONH), 8.91(1H, d, J=2.4 Hz, pyridine), 8.75(1H, d, J=2.4 Hz, pyridine), 8.49-8.47(1H, m, pyridine), 8.15 (IH, s, CONH2), 7.59(1H, s, CONH2), 7.29(2H, d, J=8.7
Hz, aromatic), 6.94(2H, d, J=2.4 Hz, adamantyl), 1.71(6H, s, adamantyl).
<Example 113> 2-[2-(4-adamantan-l-yl-phenoxy)-ace1ylamino]-isonicotinaniide
To solution of (4-adamantan-l-yl-phenoxy)-acetic acid(70 mg, 0.24 mmol), 2-amino nicotinamide(50.28 mg, 0.36 mmol) and DMAP(59.77 mg, 0.48 mmol) in DMF 5 ml was added PyBOP(452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC(EtoAC:Hexane:MeOH=3:6: 1-2:4:1) to afford 2-[2-(4-adamantan-l-yl-phenoxy)-acerylamino]- isonicotinamide as a colorless solid (0.05g, 50 % yield). 1H NMR CDMSO-d6, 300 MHz) 10.62(1H, s, CONH), 8.43(2H, m, CONH2), 8.19 (IH, s, pyridine),
7.67(1H, s, pyridine), 7.49.(1H, d, J=5.1 Hz, pyridine), 7.26(2H, d, J=9.3 Hz, aromatic), 6.89(2H, d, J=8.4 Hz, aromatic), 4.78(2H, s, OCH2), 2.03(3H, brs, adamantyl), 1.82(6H, s, adamantyl), 1.71(6H, s, adamantyl).
<Example 114> 2-[2-(4-fluoro-phenoxy)-ace1ylamino]-isonicotinamide
To solution of (4-fluoro-phenoxy)-acetic acid(100 mg, 0.43 mmol), 2-amino nicotinamide(89.39 mg,
0.65 mmol) and DMAP(106 mg, 0.86 mmol) in DMF 5 ml was added PyBOP(452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%).
The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by
PLC(EtoAC:Hexane:MeOH=3:6: 1-2:4:1) to afford 2-[2-(4-fluorcHphenoxy)-ace1ylamino]-isonicotinarnide as a colorless solid (0.08g, 59 % yield).
1H NMR (DMSO-dβ, 300 MHz) 10.67(1H, s, CONH), 8.44(1H, d, J=5.1 Hz, CONH2), 8.41(1H, s,
CONH2), 8.20(1H, brs, pyridine), 7.68(1H, brs, pyridine), 7.49(1H, d, J=1.5&5.1 Hz, pyridine), 7.16-7.11(2H, m, aromatic), 7.01-6.97 (2H, m, aromatic), 4.80(2H, s, OCH2).
<Example 115> 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isoriicotinarriide
To solution of (2,4-dichloro-phenoxy)-acetic acid(51 mg, 0.23 mmol), 2-amino isonicotinamide(47.66 mg, 0.34 mmol) and DMAP(56.6 mg, 0.46mmol) in DMF 4 ml was added PyBOP(236 mg, 0.46 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSC>4, and concentrated. The residue was purified by PLC(EtoAC:Hexane:MeOH=3:6:l~2:4:l) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.06g, 77 % yield).
1H NMR (DMSO-dg, 300 MHz) 10.70(1H, s, CONH), 8.45-8.41(2H, m, CONH2), 8.19(1H5 brs, pyridine), 7.67(1H, brs, pyridine), 7.61(1H, d, J=2.4 Hz, pyridine), 7.50(1H, d, J=5.1 Hz, aromatic), 7.37(1H, dd, J=2.85&8.85 Hz, aromatic), 7.11(1H, d, J=8.4 Hz, aromatic), 4.97(2H, s, OCH2).
<Example 116> 2-[2-(2,4,5-tricMoro-phenoxy)-acerylamino]-isonicotinamide
1H NMR (DMSO-ds, 300 MHz) 10.72(1H, s, CONH), 8.45(1H, d, J=4.8 Hz, CONH2), 8.40(1H, s, CONH2), 8.20(1H, brs, pyridine), 7.85(1H, s, pyridine), 7.68(1H, brs, pyridine), 7.51-7.48(2H, m, aromatic), 5.04(2H, s, OCH2).
<Example 117> 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinainide
To solution of (4-bromo-phenoxy)-acetic acid(100 mg, 0.43 mmol), 2-amino isonicotinamide(89.39 mg, 0.65 mmol) and DMAP(106 mg, 0.86 mmol) in DMF 5 ml was added PyBOP(452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSθ4, and concentrated. The residue was purified by PLC(EtoAC:Hexane:MeOH=3:6: 1-2:4:1) to afford 2-[2-(4-bromo-phenoxy)-ace1ylamino]-isonicotinamide as a colorless solid (0.083g, 55 % yield).
1H NMR (DMSO-dfo 300 MHz) 10.72(1H5 s, CONH), 8.44(1H, d, J=3.0 Hz, CONH2), 8.40(1H, s, CONH2), 8.19(1H, brs, pyridine), 7.67(1H, brs, pyridine), 7.50-7.44(3H, m, pyridine, aromtic), 6.97-6.92(2H, m, aromatic), 4.83(2H, s, OCH2).
<Example 118> 2-[2^4-bromo-2-cUoro-phenoxy)-acerylarnino]-isonicotinamide
1H NMR (DMSO-dg, 300 MHz) 10.71(1H, s, CONH), 8.43(2H, m, CONH2), 8.19 (IH, s, pyridine), 7.69(2H, m, pyridine), 7.49(2H, m, aromatic), 7.06(1H5 d, J=9 Hz, aromatic), 4.97(2H, s, OCH2).
<Example 119> 2-[2^44ert-bu1yl-phenoxy)-acetylamino]-isonicotinamide ■
A solution of 4-tert-butylphenoxy acetic acid(60.1 mg, 0.29 mmol), 2-amino isonicotinatnide(60.3 mg,
0.44 mmol), DBPEA(0.1 ml, 0.58 mmol) and PyBOP(301.8 mg, 0.58 mmol) in DMF 4.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC(n-Hexane:EtoAc:MeOH=6:3:l) to give 2-[2-
(44ert-butyl-phenoxy)-a∞tylarnino]-isonicotinamide as a white solid (53.6 mg, 56.5% yield).
1H-NMR (DMSO-dfo 300 Hz) 10.64(1H, s, NH), 8.42-8.46(2H, m, aromatic-H), 8.20(1H, s, NH2), 7.68(1H, s, NH2), 7.49-7.51(1H, m, aromatic-H), 7.28-7.32(2H, m, aromatic-H), 6.86-6.91(2H, m, aromatic-H), 4.78(2H, s, CH2), 1.24 (9H, s, CH3).
<Example 120>2-(2-p-tolyloxy-acerylamino)-isonicotinamide
A solution of 4 p-tolyloxy-acetic acid(60.1 mg, 0.36 mmol), 2-amino-isonicotinamide(74.1 mg, 0.54 mmol), DIPEA(0.12 ml, 0.72 mmol) and PyBOP(374.4 mg, 0.72 mmol) in DMF 5.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by Prep-TLC(CH2Cl2:Me0H= 10:1) to give 2-(2-p-tolyloxy- acetylamino)-isonicotinamide as a white solid (68.5 mg, 66.8% yield).
1H-NMR (DMSO-dβ, 300 Hz) 10.61(1H, s, NH), 8.42-8.45(2H, m, aromatic-H), 8.20(1H, s, NH2), 7.68(1H, s, NH2), 7.49-7.51(1H, m, aromatic-H), 7.10 (2H, d, J=8.7 Hz, aromatic-H), 6.85-6.88(2H, m, aromatic- H), 4.76(2H, s, CH2), 2.23(3H, s, CH3).
<Example 121> 2-(2-phenoxy-acetylamino)-isonicotinamide
To solution of (phenoxy-acetic acid(100 mg, 0.65 minol), 2-amino isonicotinamide(180 mg, 1.31
mmol) and DMAP(160 mg, 1.31 mmol) in DMF 5 ml was added PyBOP(684 mg, 1.31 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSθ4, and concentrated. The residue was purified by PLC(EtOAc:n-Hexanes:MeOH=l:2:l~l:2:2) to afford 2-(2-phenoxy-acetylamino)-isonicotinamide as a colorless solid (0.105g, 58.9 % yield).
1H NMR (DMSO-ds, 300 MHz) 10.65(1H, s, CONH), 8.45-8.42(2H, m, CONH2), 8.19(1H, s, pyridine-H), 7.67(1H, s, pyridine-H), 7.49(1H, dd, J=1.5&5.1 Hz, pyridine-H), 7.33-7.28(2H, m, aromatic), 6.98- 6.94(3H, m, aromatic), 4.81 (2H, s, OCH2).
<Example 122>2-[2-(4-nitro-phenoxy)-acetylamino]-isoriicotinamide
To solution of (4-nitro-phenoxy)-acetic acid(50 mg, 0.25 mmol), 2-amino isonicotinamide(52 mg, 0.37 mmol) and DMAP(62 mg, 0.5 mmol) in DMF 6 ml was added PyBOP(684 mg, 1.31 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtOAc:n-Hexane:MeOH=l:2: 1-1:2:2) to afford 2-[2^4-nitro-phenoxy)-aceιtylamino]-isonicotinamide as a colorless solid (0.04g, 50 % yield). „
1HNMR(DMSOA 300 MHz) 10.87(1H, s, CONH), 8.46(1H, d, J=5.4 Hz, CONH2), 8.24-8.19(3H, m, CONH2, pyridine-H), 7.67(1H, s, pyridine), 7.50(1H, J =5.7 Hz, pyridine), 7.19(2H, d, J=9.0 Hz5 aromatic), 5.02(2H, s, OCH2).
<Example 123> 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester
A mixture of 3-amino-4-hydroxy-benzoic acid methyl ester (105.7 mg, 0.63 mmol) and 2,4- dichlorophenoxyacetic acid (100 mg, 0.45 mmol) in PPSE (1.5 mL) was heated at 160 °C for 4 h. At the end of the reaction period, the mixture was taken to 3 mL dichloromethane and neutralized with 4.5 mL 1 N NaOH
solution. The organic layer was separated and the aqueous solution extracted with 3 x 3 mL portions of dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and 1he solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (EtOAc : hexanes = 1 : 1) to afford 2-(2,4-diclilorophenoxymethyl)-ben2DxazDle-5-carboxylic acid methyl ester as a colorless powder (0.115 g, 52% yield).
1H NMR (CDCl3, 300 MHz) 8.45 (IH, d, J = 1.2 Hz, aromatic), 8.14 (IH, dd, J =1.5, 9.0 Hz5 aromatic), 7.60 (IH, d, J = 8.4 Hz, aromatic), 7.40 (IH, d, J = 2.7 Hz5 aromatic), 7.19 (IH5 dd, J = 2.4, 8.4 Hz, aromatic), 7.07 (IH, d, J= 9.3 Hz, aromatic), 5.39 (2H, s, OCH2), 3.96 (3H, s, OCH3).
<Example 124> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester
A mixture of (4-adamantan-l-yl-phenoxymethyl)-acetic acid(200.0 mg, 0.70 mmol) and 3-amino-4- hydroxy-benzoic acid methyl ester(164.3 mg, 0.98 mmol) in PPSE (3 mL) was heated at 140 "C for 2 h. At the end of the reaction period, the mixture was taken to dichloromethane and neutralized with 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtoAc:MeOH=6:3 : 1) to afford 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester as a white solid (187.3 mg, 64.1% yield). 1H-NMR (CDCl3, 300 Hz) 8.45(1H, m, aromatic-H), 8.11-8.14(1H, m, aromatic-H), 7.59(1H, d,
J=9.3 Hz, aromatic-H), 7.28-7.33(2H, m, aromatic-H), 6.99-7.03(2H, m, aromatic-H), 5.32(2H, s, CH2), 3.96(3H, s, CH3), 2.08(3H, m, adamantly-H), 1.87(6H, m, adamantly-H), 1.76(6H, m, adamantly-H).
<Example 125> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester
A mixture of (4-adamantan-l-yl-phenoxymethyl)-acetic acid(200.0 mg, 0.70 mmol) and 4-amino-3- hydroxy-benzoic acid methyl ester(l 64.3 mg, 0.98 mmol) in PPSE (3 mL) was heated at 140 °C for 2 h. At the
end of the reaction period, the mixture was taken to dichloromethane and neutralized with 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtoAc:MeOH=6:3:l) to afford 2-(4-adamantan-l-yl-phenoxymethyl)-ben2oxazole-6-carboxylic acid methyl ester as a white solid (184.0 mg, 63.0% yield).
1H-NMR (CDCl3, 300 Hz) 8.25(1H, s, aromatic-H),8.08-8.11(1H, m, aromatic-H), 7.79(1H3 d, J=8.4 Hz, aromatic-H), 7.30(2H, d, J=9.3 Hz5 aromatic-H), 7.01(2H, d, J=9.3 Hz, aromatic-H), 5.33(2H, s, CH2), 3.96(3H, s, CH3), 2.08(3H, m, adamantiy-H), 1.87(6H, m, adamantly-H), 1.75(6H3 m, adamantiy-H).
<Example 126> 2-(4-adamantan-l-yl-phenoxymetiiyl)-lH-benzoimidazole-5-carboxylic acid methyl ester
A mixture of (4-adamantan-l-yl-phenoxymethyl)-acetic acid(200.0 mg, 0.70 mmol) and 4-amino-3- hydroxy-benzoic acid methyl ester(164.3 mg, 0.98 mmol) in PPSE (2.4 mL) was heated at 140 "C for 4 h. At the end of the reaction period, the mixture was taken to ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer was separated and the aqueous solution extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (EtOAc:Hexane=l :9~4:6 to afford 2^4-adamantan-l-yl-phenoxymemyl)-lH-benzoimidazole-5-carboxylic acid methyl ester as a colorless powder (0.282g, 90% yield).
1HNMR (CDCl3, 300 MHz) 8.35(1H, s, aromatic), 7.98(1H, dd, J=I .8 & 8.7 Hz, aromatic), 7.59(1H, d, J=8.4 Hz, aromatic), 7.19(2H, m, aromatic), 6.84 (2H, m, aromatic), 5.34(2H, s, OCH2), 3.91(3H, s, OCH3), 2.04(3H, s, adamantyl), 1.81-1.66(12H, m, adamantyl), NH not detected
<Example 127> 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester
1H-NMR (CDCl3, 300 Hz) 8.26(1H, s, aromatic-H), 8.07-8.12(1H, m, aromatic-H), 7.79(1H, d, J=8.4 Hz, aromatic-H), 7.40(1H, d, J=2.7 Hz, aromatic-H), 7.17-7.21(1H, m, aromatic-H), 7.06(1H, d, J=9.3 Hz, aromatic-H), 5.40(2H, s, CH2), 3.96(3H, s, CH3).
<Example 128> 2-(2,4-dicMorcκphenoxymethyl)-lH-benzoimidazole-5-carboxy]ic acid methyl ester
1HNMR (CDCl3, 300 MHz) 8.35(1H, s, aromatic), 8.01(1H, dd, J=1.2&8.4 Hz, aromatic), 7.64(1H, brs, NH), 7.39(1H, d, J=2.4 Hz, aromatic), 7.19(1H, dd, J=2.4&8.4 Hz, aromatic), 6.97(1H, d, J=8.4 Hz, ' aromatic), 5.43(2H, s, OCH2), 3.94(3H, s, OCH3).
<Example 129> 2-(2,4-tert-buryl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester
1H-NMR (CDCl3, 300 Hz) 8.25(1H, s, aromatic-H), 8.08-8.11(1H, m, aromatic-H), 7.79(1H, d, J=8.4 Hz, aromatic-H), 7.31-7.36(2H, m, aromatic-H), 6.97-7.02(2H, m, aromatic-H), 5.33(2H, s, CH2), 3.96(3H, s, CH3), 1.29(9H, s, CH3).
<Example 130> 2-(2,4-tert-butyl-phenoxymemyl)-lH-benzoimidazole-5-carboxylic acid methyl ester
1HNMR(CDCl3, 300 MHz) 8.39(1H s, aromatic), 8.03(1H, d, J=8.1 Hz, aromatic), 7.66(1H, d, J=7.8 Hz, aromatic), 7.27(2H, d, J=8.4 Hz, aromatic), 6.88(2H d, J=8.7 Hz, aromatic), 5.43(2H, s, OCH2), 3.95(3H, s, OCH3), 1.27 (9H, s, t-butyl), NH not detected.
<Example 131> 2-(4-nitro-phenoxymethyl)-lH-benzoimidazole-5-carboxylic acid methyl ester
A mixture of (4-nitro-butyl-phenoxy)-acetic acid(50 mg, 0.25 mmol) and 3,4-diaminobenzoic acid methyl ester(59 mg, 0.35 mmol) in PPSE was heated at 160 °C for 4 h. At the end of the reaction period, the mixture was taken to ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer was separated and the aqueous solution extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (MeOH:MC=0.5:9.5) to afford 2-(4-nitro-phenoxymethyl)-lH- benzoimidazole-5-carboxylic acid methyl ester as a colorless powder (66.4 mg, 80% yield).
1H NMR (DMSO-dg, 300 MHz) 13.13(1H, brs, NH), 8.27-8.19(3H, m, aromatic), 7.85(1H, dd, J=1.5&8.4 Hz, aromatic), 7.65(1H, d, J=8.4 Hz, aromatic), 7.34-7.29(2H, m, aromatic), 6.88(2H, d, J=8.7 Hz, aromatic), 5.55 (2H, s, OCH2), 3.86(3H, s, OCH3).
<Example 132> 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-5-sulfonic acid amide
A mixture of ((2,4-dichloro-phenoxy)-acetic acid(66.3 mg, 0.3 mmol) and 4-amino-3-hydroxy-benzoic acid methyl ester(79 mg, 0.42 mmol) in PPSE 1 mL was heated at 120 °C for 2 h. At the end of the reaction period, the mixture was taken to dichloromethane and neutralized with aqueous sodium bicarbonate. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:MeOH=30:l) to afford 2-(2,4-dichloro- phenoxymethyl)-benzoxazole-5-sulfonic acid amide as a white solid (12 mg, 11% yield).
1H-NMR (CD3OD, 300Hz) 8.26(1H, d, J=1.8 Hz, aromatic), 8.00(1H, dd, J =8.7&1.8 Hz, aromatic), 7.81(1H, d, J=8.4 Hz, aromatic), 7.45(1H, d, J=2.4 Hz, aromatic), 7.25(2H, m, aromatic), 5.50(2H, s, OCH2).
<Example 133> 2-(2,4-dichloro-phenoxymetliyl)-benzoxazole-5-carboxylic acid
To a solution of 2-(2,4-dichloro-phenoxymethyl)-benzDoxazole-5-carboxylic acid methyl ester (60.0 mg, 0.17 mmol) in dimethyl sulfide (5 ml) and dichloromethane (5 ml) was added aluminum bromide (725.5 Mg, 2.72 mmol). The reaction mixture was stirred at room temperaturefor 2.5h, after which water and 10% HCl were added. After stirring at room temperature for Ih, the miture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSQi anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2MeOH = 4:1) to give 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-5- carboxylic acid as a white solid (42.0 mg, 72.9% yield).
1H-NMR (CDCI3+CD3OD, 300 Hz) 8.25(1H, s, aromatic-H), 8.07-8.10(1H, m, aromatic-H), 7.74(1H, d, J=SJHz, aromatic-H), 7.38(1H, d, J=2.4 Hz, aromatic-H), 7.18-7.22(1H, m, aromatic-H), 7.12(1H, d, J=8.4 Hz, aromatic-H), 5.42(2H, s, CH2).
<Example 134> 2-(4-adamantan-l-yl-pheno5cymethyl)-benzoxazole-5-carboxylic acid
1H-NMR (CD3OD, 300 Hz) 8.40(1H, m, aromatic-H), 8.08-8.11(1H9 m, aromatic-H), 7.58(1H, d, J=8.4Hz, aromatic-H), 7.37(1H, s, aromatic-H), 7.23-7.29(2H, m, aromatic-H), 6.93-6.98(2H, m, aromatic-H), 5.29(2H, s, CH2), 2.03 (3H, m, adamantiy-H), 1.83(6H, m, adamantly-H), 1.71(6H, m, adamantiy-H).
<Example 135> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid
To a solution of 2-(4-adamantan-l-yl-pheno)Qαnethyl)-benzoxazole-6-carboxylic acid methyl ester(110 mg, 0.26 mmol) in dimethyl sulfide (10 ml) and dichlorometfiane (10 ml) was added aluminum bromide (1.13 g, 4.22 mmol). The reaction mixture was stirred at room temperaturefor 2.5h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the miture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2MeOH = 4:1) to give 2-(4-adamantan-l-yl- phenoxymethyl)-benzoxazole-6-carboxylic acid as a white solid (81.6 mg, 76.8% yield).
1H-NMR (DMSO-dg, 300 Hz) 8.25(1H, s, aromatic-H), 8.02(1H, d, J=7.8 Hz, aromatic-H), 7.82(1H5 d, J=8.7 Hz, aromatic-H), 7.28(2H, d, J=8.7 Hz5 aromatic-H), 7.01(2H, d, J=8.4 Hz, aromatic-H), 5.46(2H, s, CH2), 2.02(3H, m, adamantiy-H), 1.81(6H, m, adamantiy-H), 1.70(6H, m, adamantly-H).
<Example 136> 2-(4-adamantan-l-yl-phenoxymethyl)-lH-benzoirnidazole-5-carboxylic acid
(200 mg, 0.48 mmol), acetic acid (130 mL) and coned HCl (100 mL) was heated under reflux for 3 h. At the end of the reaction period, the mixture was cooled to 10 °C, neutralized with aqueous sodium bicarbonate solution, filtered, washed with ethyl acetate (10 mL), water (50 mL) and dried to afford 2-(4-adamantan-l-yl- phenoxymethyl)-lH-benzoimidazole-5-carboxylic acid as a colorless powder (0.162 g, 84% yield). 1H NMR (CDCl3, 300 MHz) 8.27(1H, s, aromatic), 8.0(1H, d, J=8.4 Hz), 7.8(1H, α\ J=8.7 Hz),
7.31(2H, d, J=8.4 Hz), 7.06(2H, d, J=9 Hz), 5.5(2H, s, OCH2), 2.03(3H, s, adamantyl), 1.81(6H, d, J=3.3 Hz, adamanryl), 1.71(6H, m, adamantyl), COOH and NH not detected.
<Example 137> 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-6-carboxylic acid
To a solution of 2-(2,4-dichloro-phenoxymethyl)-benzDxazole-6-carboxylic acid methyl ester(100 mg, 0.29 mmol) in dimethyl sulfide (8 ml) and dichloromethane (58 ml) was added aluminum bromide (1.24 g, 4.64 mmol). The reaction mixture was stirred at room temperaturefor 2.5h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the miture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSθ4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2MeOH = 4:1) to give 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-6- carboxylic acid as a white solid (59.15 mg mg, 61.2% yield).
1H-NMR (DMSOd6, 300 Hz) 13.22(1H, s, COOH), 8.28(1H, s, aromatic-H), 8.00-8.03(1H, m, aromatic-H), 7.88(1H, d, J=8.4Hz, aromatic-H), 7.64-7.65 (IH, m, aromatic-H), 7.34-7.43(2H, m, aromatic-H), 5.66(2H s3 CH2). . . . .
<Example 138> 2-(2,4-dichloro-pheno5Qτnethyl)-lH-benzoimidazole-5-carboxylic acid
A mixture of 2-(2,4-dicUorophenoxyme1hyl)-lH-ben2oirnidazole-5-carboxylic acid methyl ester(l 10 mg, 0.31 mmol), acetic acid (60 mL) and coned HCl (60 mL) was heated under reflux for 3 h. At the end of the reaction period, the mixture was cooled to 10 °C, neutralized with aqueous sodium bicarbonate solution, filtered, washed with ethyl acetate (10 mL), water (50 mL) and dried to afford 2-(2,4-dichloro-phenoxymethyl)-lH- benzoimidazole-5-carboxylic acid as a colorless powder (0.099 g, 94.28% yield). 1HNMDR. (CDCl3, 300 MHz) 13.16(2H, brs, COOH5NET), 8.27(1H, s, aromatic), 7.99(1H, d, J=9.0 Hz, aromatic), 7.79(1H, d, J=8.7 Hz, aromatic), 7.65(1H, d, J=1.8 Hz, aromatic), 7.41(2H, m, aromatic), 5.64(2H, s, OCH2).
<Example 139> 2-(4-tert-butyl-phenoxymethyl)-benzoxazole-6-carboxylic acid
To a solution of 2-(4-tert-butyl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester(67.8 mg, 0.20 mmol) in dimethyl sulfide (3 ml) and dichloromethane (3 ml) was added aluminum bromide (533.4 g, 2.0 mmol). The reaction mixture was stirred at room temperaturefor 2.5h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the miture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSC>4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtoAc:MeOH=6:3:l) to give 2-(4-tert-butyl-phenoxymethyl)- benzoxazole-6-carboxylic acid as a white solid (50.5 mg, 77.7% yield).
1H-IvMR (DMSOd6, 300 Hz) 8.27(1H, s, aromatic-H), 8.01(1H, d, J= 8.4Hz, aromatic-H), 7.86(1H, d, J=8.7Hz, aromatic-H), 7.31-7.34(2H, m, aromatic-H), 6.99-7.02(2H, m, aromatic-H), 5.47(2H, s, CH2), 1.24(9H5 S3 CH3).
<Example 140> 2-(4-tert-butyl-phenoxymethyl)-lH-beπzDimidazole-5-carboxylic acid
A mixture of 2-(4-tert-butyl-phenoxymethyl)-lH-benzoimidazole-5-carboxylic acid methyl ester(150 mg, 0.44 mmol), acetic acid (30 mL) and coned HCl (39 mL) was heated under reflux for 3 h. At the end of the reaction period, the mixture was cooled to 10 °C, neutralized with aqueous sodium bicarbonate solution, filtered, washed with ethyl acetate (10 mL), water (50 mL) and dried to afford 2-(4-tert-buryl-phenoxymethyl)-lH- benzoimidazole-5-carboxylic acid as a colorless powder (0.13 g, 90% yield). • 1H NMR (DMSOd5, 300 MHz) 8.24(1H, s, aromatic), 8.02(1H, d, J=8.4 Hz, aromatic), 7.82(1H, d,
J=8.4 Hz, aromatic), 7.35(2H, d, J=8.4Hz, aromatic), 7.05(2H, d, J=9.3 Hz, aromatic), 5.57(2H, s, OCH2), 1.25(9H, s, C(CH3)3), COOH andNH not detected.
<Example 141> 2-(4-mtro-phenoxymeUiyl)-lH-benzoirnidazole-5-carboxylic acid
A mixture of 2^4-nitro-phenoxymethyl)-lH-benzDirnidazole-5-carboxylic acid methyl ester(90 mg,
0.27 mmol), acetic acid (15 mL) and coned HCl (20 mL) was heated under reflux for 3 h. At the end of the reaction period, the mixture was cooled to 10 °C, neutralized with aqueous sodium bicarbonate solution, filtered, washed with ethyl acetate (10 mL), water (50 mL) and dried to afford 2-(4-nitro-phenoxymethyl)-lH- benzoimidazole-5-carboxylic acid as a colorless powder (0.078 g, 90% yield).
1H NMR (DMSOd6, 300 MHz) 8.29-8.25(3H, m, aromatic), 8.02-7.99(1H, m, aromatic), 7.83- 7.81(1H, m, aromatic), 7.37(2H, d, J=9.0 Hz, aromatic), 7.65 (IH, d, J=I.8 Hz3 aromatic), 7.41(2H, m, aromatic), 5.77(2H s, OCH2), COOH andNH not detected.
<Example 142> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid amide
To solution of 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid(72.1 mg, 0.18 mmol), ammonium chloride(19.1 mg, 0.36 mmol) in DMF 4.0 mL was added HBTU(136.53 mg, 0.36 mmol) and DIPEA(O.O63 ml, 0.36 mmol). After stirring at room temperature, the miture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2MeOH=ISrI) to give 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole- 5-carboxylic acid amide as a yellow solid (2.7 mg, 4% yield).
1H-NMR (DMSO-d6,300Hz) 10.54(1H, s, NH), 8.81(1H, s, aromatic), 8.65 (IH, s, aromatic), 8.53(1H, s, aromatic), 8.44(1H, s, aromatic), 8.02-8.12 (4H, m, aromatic), 7.84(1H, m, aromatic), 7.62-7.76(5H, m, aromatic), 7.41-7.49(3H, m, aromatic), 7.26(1H, m, aromatic).
<Example 143> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid dimethylamide
To solution of 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxa2ole-5-carboxylic acid(60.4 mg, 0.15 mmol), dimethyl amine(0.030 ml, in 2M THF) in DMF 5.0 mL was added HBTU(113.8 mg, 0.30 mmol) and DIPEA(0.052 ml, 0.30 mmol). After stirring at room temperature, the miture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSC>4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc:MeOH=15:3:l) to give 2-(4-adamantan-l-yl-phenoxymethyl)- benzDxazole-5-carboxylic acid dimethylamide as a white solid (37.9 mg, 59 % yield).
1H-NMR (CD3OD, 300Hz) 7.79(1H, d, J=1.2 Hz, aromatic), 7.71(1H, d, J= 8.4 Hz, aromatic), 7.49(1H, dd, J=8.4&1.2 Hz, aromatic), 7.28(2H, m, aromatic), 6.98(2H, m, aromatic), 5.36(2H, s, OCH2CO), 3.12(3H, s, CH3), 3.00 (3H, s, CH3), 2.05(3H, m, adamantyl), 1.88-1.89(fiH, m, adamantyl), 1.74-1.83 (6H, m, adamantyl)
<Example 144> 2-(4-adamantan-l-yl-phenoxymethyl)-beπzoxazole-5-carboxylic acid (furan-2-ylmethyl)-amide
1H-NMR (CDCl3, 300 Hz) 8.15(1H, m, aromatic-H), 7.86-7.89(1H, m, aromatic-H), 7.59(1H, d, J=8.7 Hz, aromatic-H), 7.39(1H, m, aromatic-H), 7.28-7.31(2H, m, aromatic-H), 6.99-7.01(2H, m, aromatic-H), 6.42(1H, s, NH), 6.32-6.37(2H, m, aromatic-H), 5.31(2H, s, CH2), 4.67(2H, d, J=5.7 Hz, CH2), 2.08(3H, m, adamantiy-H), 1.87(6H, m, adamantly-H), 1.76(6H, m, adamantly-H).
<Example 145> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (2-dimethylamino-ethyl)- amide
To solution of 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazDle-5-carboxylic acid(57.7 mg, 0.14 mmol) and3-morpholine4-yl-propylamine(0.031 ml, 0.29 mmol) in DMF 4.0 mL was added HBTU (109.98 mg, 0.29 mmol) and DlPEA(0.051 ml, 0.29 mmol). After stirring at room temperature, the miture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2MeOH=IO: 1) to give 2-(4-adamantan-l-yl- phenoxymethyl)-benzDxazole-5-carboxylic acid (2-dimethylamino-ethyl)-amide as a white solid (38.2mg, 58% yield).
1H-NMR (CD3OD, 300Hz) 8,21(1H, d, J=1.8 Hz, aromatic), 7.94(1H, dd, J =8.7&1.8 Hz5 aromatic), 7.69(1H5 d, J=8.4 Hz, aromatic), 7.27(2H, m, aromatic), 6.97(2H, m, aromatic), 5.35(2H, s, OCH2CO)53.60(2H, % J=6.6 Hz, aUphatic), 2.79(2H, t, J=6.6 Hz, aHphatic), 2.48(6H, s, N(CHs)2), 2.04(3H, m, adamanryl), 1.83-1.90(6H, m, adamantly), 1.73-1.78(6H, m, adamantly).
<Example 146> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (2-piperidine-l-yl-ethyl)- amide
To solution of 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carbθjgΗc acid(70.2 mg, 0.17 mmol) and 2-piperidine-l-yl-ethylamine(0.049 ml, 0.35 mmol) in DMF 5.0 mL was added HBTU(132.7 mg,
0.35 mmol) and DIPEA(0.061 ml, 0.35 mmol). After stirring at room temperature, the miture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:l) to give 2-(4-adamantan-l-yl- phenoxymethyl)-benzoxazole-5-carboxylic acid (2-piperidine-l-yl-ethyl)-amide as a white foam (18.9 mg, 22 % yield).
1H-NMR (CD3OD, 300Hz) 8.22(1H, d, J=1.2 Hz, aromatic), 7.96(1H, dd, J =8.7&1.8, aromatic),
7.71(1H, d, J=8.4 Hz, aromatic), 7.27(2H, m, aromatic), 6.97(2H, m, aromatic), 5.36(2H, s, OCH2CO), 3.74(2H, t, 3=6.0 Hz, aliphatic), 3.03-3.19(6H, m, aliphatic), 2.04(3H, m, adamantyl), 1.73-1.88(16H, m, adamantly, aliphtic), 1.64(2H, m, aliphtic)
<Example 147> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (3-morpholine-4-yl- propyl)-amide
To solution of 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-5-carbθ5cylic acid(73.9 mg, 0.18 mmol) and 3-morpholine-4-yl-propylamine(0.053 ml, 0.37 mmol) in DMF 4.0 mL was added HATU (54.8 mg, 0.37 mmol) and DIPEA(0.064 ml, 0.37 mmol). After stirring at room temperature, the miture was partitioned between.ethyl acetate and. brine..The organiophase was dried (MgSO4 anh), and concentrated. The.residue was purified by silica gel column chromatography (CH2Cl2MeOH=IO: 1) to give 2-(4-adamantan-l-yl- phenoxymethyl)-benzoxazole-5-carboxylic acid (3-morpholine-4-yl-propyl)-amide as a white foam (11.9 mg, 13% yield). 1H-NMR(CD3OD, 300Hz) 8.18(1H, d, J=1.8 Hz, aromatic), 7.91(1H, dd, J=9.0&1.2 Hz, aromatic),
7.69(1H, d, J=8.4 Hz, aromatic), 7.27(2H, m, aromatic), 6.97(2H, m, aromatic), 5.35(2H, s, OCH2CO), 3.69(4H, m, aliphatic), 3.45(2H, % J=6.9 Hz, aliphatic), 2.47-2.52(6H, m, aHphatic), 2.04(3H, m, adamantyl), 1.82-1.88(8H5 m, adamantly, aliphtic), 1.73-1.78(6H, m, adamantyl)
<Example 148> 2-(2,4-dichloro-pheno5QΗiethyl)-benzoxazole-5-carboxylic acid (furan-2-ylmethyl)-amide
1H-NMR (DMSOd6, 300 Hz) 9.09(1H, t, J=5.4 Hz, NH), 8.30(1H, s, aromatic-H), 7.98-8.02(1H, m, aromatic-H), 7.86(1H, d, J=8.7 Hz, aromatic-H), 7.63(1H, d, J=2.4 Hz, aromatic-H), 7.58(1H, s, aromatic-H), 7.35-7.43(2H, m, aromatic-H), 6.40-6.41(1H, m, aromatic-H), 6.30-6.31(1H, m, aromatic-H), 5.63(2H, s, CH2), 4.49(2H, d,J=5.7 Hz, CH2).
<Example 149> 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (furan-2-ylmethyl)-amide
. To solution of 2-(4-^damantan-l-yl-phenoxymethyl).-benzoxazole-6-carboxylic acid(30.1mg, 0.08 mmol), furfuryl amin<11.0 mg, 0.12 mmol, 0.01 ml), EDC(21.7 mg, 0.12 mmol) and HOBt(15.4 mg, 0.12 mmol) in DMF 3.0 mL was added DIPEA(14.2 mg, 0.12 mmol, 0.02 ml). After stirring at room temperature, the miture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc:MeOH=6:3:l) to give 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (furan-2-yrmethyl)-amide as a white solid (6.3 mg, 17.4% yield).
1H-NMR (CDCI3+CD3OD, 300 Hz) 8.25(1H, d, J=8.7 Hz, aromatic-H), 7.60 (IH, s, aromatic-H), 7.28-7.35(4H3 m, aromatic-H), 6.92-6.97(2H, m, aromatic-H), 6.24-6.31(2H, m, aromatic-H), 4.61(2H, s, CH2), 4.51(2H5 s, CH2), 2.05 (3H, m, adamantiy-H), 1.86(6H, m, adamantiy-H), 1.75(6H, m, adamantiy-H).
<Example 150> 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-6-carboxylic acid (furan-2-ylmethyl)-amide
To solution of 2-(4-adamantan-l-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid(30.0mg, 0.09 mmol), furfuryl amine(13.0 mg, 0.14 mmol, 0.013 ml), EDC(25.7 mg, 0.14 mmol) and HOBt (18.24 mg, 0.14 mmol) in DMF 3.0 mL was added DIPEA(16.8 mg, 0.14 mmol, 0.02 ml). After stirring at room temperature, the
miture was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n- Hexane:EtOAc:MeOH=6:3:l) to give 2-(2,4-diclτloro-phenoxymethyl)-benzoxazole-6-carboxylic acid (furan- 2-ylmethyl)-amide as a white solid (14.7 mg, 37.9% yield). 1H-NMR (DMSO-(I6, 300 Hz) 9.10(lH, t, J=6.0 H2, NH), 8.26(lH, s, aromatic-H), 7.94-7.97(lH, m, aromatic-H), 7.86(1H, d, J=8.7 Hz, aromatic-H), 7.64(1H, d, J=2.4 Hz, aromatic-H), 7.59(1H5 s, aromatic-H), 7.34-7.43(2H3 m, aromatic-H), 6.40-6.41(1H, m, aromatic-H), 6.30-6.31(1H, m, aromatic-H), 5.65 (2H, s, CH2), 4.50(2H, d, J=5.7 Hz, CH2).
<Example 151> 2-(4-adamantan-l-yl-phenoxymethyl)-3H-benzoimidazole-5-carboxylic acid amide
0.11 mmol), ammonium chloride(11.8 mg, 0.22 mmol), EDC(32.6 mg, 0.17 mmol) and HOBt (23.0 mg, 0.17 mmol) in DMF 3.0 mL was added DIPEA(0.03 ml, 0.17 mmol). After stirring at room temperature, the miture was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2MeOH=O: 1) to give 2-(4-adamantan-l-yl-phenoxyme1hyl)-3H-ben2X)irnidazDle-5-carbojQ'lic acid amide as a white solid (16.8 mg, 37.5% yield).
1HNMR (CDCl3, 300 Hz) 8.13(1H, s, aromatic-H), 7.80(1H, d, J=8.7 Hz, aromatic-H), 7.62(1H, d, J=8.1 Hz, aromatic-H), 7.26(2H, d, J=8.7 Hz, aromatic-H), 6.95(2H, d, J=8.4 Hz, aromatic-H), 5.32(2H, s, CH2),
2.03(3H, m, adamantiy-H), 1.83(6H, m, adamantiy-H), 1.72(6H, m, adamantly-H).
<Example 152> 2^4-adamantan-l-yl-phenoxymerhyl)-3H-benzoimidazole-5-carboxylic acid dimethylamide
0.11 mmol), dimeihyl amine(10.4 mg, 0.23 mmol), EDC(44.1 mg, 0.23 mmol) and HOBt(31.3 mg," 0.23 mmol) in DMF 4.0 mL was added DIPEA(28.8 mg, 0.23 mmol, 0.04 ml). After stirring at room temperature, the miture
was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSC>4 anh), and concentrated. The residue was purified by Prep-TLC(n-Hexane:EtoAc:MeOH=6:3:l) to give 2-(4- adamantan-l-yl-phenoxymethyl)-3H-benzoimidazDle-5-carboxylic acid diethylamide as a yellow solid (27.8 mg, 54.0% yield) 1H-NMR (CDCl3, 300 Hz) 7.71(1H5 s, aromatic-H), 7.57(1H, d, J=8.7 Hz, aromatic-H), 7.19-
7.28(3H, m, aromatic-H), 6.87(2H, d, J=8.7 Hz, aromatic-H), 5.33(2H, s, CH2), 3.11(3H, s, CH3), 2.97(3H, s, CH3), 2.06(3H, m, adamantly-H), 1.83(6H, m, adamantly-H), 1.68-1.79(6H, m, adamanuy-H).
<Example 153> 2-(4-adamantan-l-yl-phenoxvmethyl)-lH-benzoimidazole-5-carboxylic acid (furan-2-ylmethyl)- amide
To a solution of 2-(4-adamantan-l-yl-phenojQαnethyl)-lH-benzoimidazole-5-carboxylic acid (50 mg, 0.124 mmol), fMurylamine (18 mg, 0.186 mmol) and DMAP (22.78 mg, 0.186 mmol) inDMF (1 mL) was added PyBOP (97 mg, 0.186 mmol) at room temperature. The mixture was stirred for 16 h at room temperature and then poured into water (150 mL). The resulting solid was extracted with a mixture of methanol : MC (10%), washed with brine, aqueous sodium bicarbonate and water, dried over anhydrous MgSO4, filtered and concentrated under reducued pressure. The resulted crude product was purified by PLC (methanol : MC = 0.5 : 9.5) to afford 2-(4-adamantan-l-yl-phenoxymethyl)-lH-berizoimidazole-5-carboxylic acid (furan-2-ylmethyl)- amide as a colorless solid (43.2 mg, 72% yield). 1HNMR (CDCI3^OO MHZ) 8.08(1H, S, CONH), 7.59(ffl, d, J=8.4 Hz, furan), 7.46QH d, J=8.7 Hz, furan), 7.29(1H s, aromatic), 7.15(2H, d, J= 8.4 Hz, aromatic), 7.07(1H, m, furan), 6.79(2H, d, J=8.4 Hz, aromatic), 6.24 (2H, d, J=12.3 Hz, aromatic), 5.21(2H, s, OCH2), 4.59(2H, d, J=4.8 Hz, &ran-CH2NH), 2.02(3H, s, adamantyl), 1.76-1.65(12H m, adamantyl), benzoimidazole NH not detected.
<Example 154> 2-(4-adaman1an-l-yl-phenoxymethyl)-lH-benzoimidazole-5-carboxy]ic acid (2- dimethylamino-ethyl)-amide
1H-MVIR (CDCI3+CD3OD, 300 Hz) 8.39(1H, s, aromatic-H), 8.03(1H, d, J= 8.7 Hz, aromatic-H), 7.72-7.74(1H, m, aromatic-H), 7.29(2H, d, J=9.0 Hz, aromatic-H), 6.97(2H, d, J=9.3 Hz, aromatic-H), 5.45(2H, s, CH2), 3.79(2H, m, CH2), 3.37(2H, m, CH2), 2.93(6H, m, CH3), 2.04(3H, m, adamantly-H), 1.83(6H, m, adamantly-H), 1.66-1.77(6H, m, adamantly-H).
<Example 155> 2^4-adamantan-l-yl-phenoxymeftιyl)-lH-benzDimidazole-5-carboxylic acid (3-imidazole-l-yl- propyl)-amide
0.18 mmol), 3-imidazole-l-yl-propylamine(33.8 mg, 0.27 mmol, 0.03 ml) and HBTU(136.5 mg, 0.36 mmol) in DMF 4.0 mL was added DIPEA(46.5 mg, 0.36 mmol, 0.06 ml). After stirring at room temperature, the miture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by Prep-TLC(CH2Cl2:MeOH=10:l) to give 2-(4-adamantan-l-yl-phenoxymethyl>lH- benzoimidazole-5-carboxylic acid (2-dimetliylamino-ethyl)-amide as ayellow solid (30.9 mg, 33.7% yield).
1H-MvIR (CDCI3+CD3OD, 300 Hz) 8.28(1H, s, NH), 8.03-8.10(2H, m, aromatic-H), 7.70-7.73(1H, m, aromatic-H), 7.56(1H, d, J=8.7 Hz, aromatic-H), 7.23-7.26(4H, m, aromatic-H), 7.11(1H, s, NH), 6.92- 6.96(2H, m, aromatic-H), 5.27(2H, s, CH2), 4.16(2H, m, CH2), 3.42(2H, m, CH2), 2.14(2H, m, CH2), 2.02 (3H, m, adamantly-H), 1.81(6H, m, adamantly-H), 1.65-1.75(6H, m, adamantly-H).
<Example 156> 2-(2,4-dichloro-phenoxymethyl)-lH-benzoimidazole-5-carboxylic acid hydrazide
The resultant crude was filtered and concentrated under reduced pressure to afford 2-(2,4-dichloro- phenoxymeihyl^lH-benzoimidazole-S-carboxylic acid hydrazide as a solid (3 mg, 15% yield).
1H NMR (DMSO-dg, 300 MHz) 12.9(1H, brs, benzoimidazole NH), 9.73(1H, s, CONH), 8.14- 7.99(1H, m, aromatic), 7.73-7.52(3H, m, aromatic), 7.42-7.34 (2H, m, aromatic), 5.44(2H, s, OCH2), 4.47(2H, brs, NH2).
<Example 157> 2^2,4HdicMoro-phenoxymemyl)-3H-benzormidazole-5-carboxylic acid (foran-2- ylmethyl)-amide
To solution of 2^2,4-dicUoro-phenoxymethyl)-3H-beπzoirnidazole-5-carboxy]ic acid(22.2mg, 0.07 mmol), furfuryl amine(10.7 mg, 0.11 mmol, 0.01 ml), EDC(21.1 mg, 0.11 mmol) and HOBt(14.9 mg, 0.11 mmol) in DMF 3.0 mL was added DIPEA(14.2 mg, 0.11 mmoL, 0.02 ml). After stirring at room temperature, the miture was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by Prep-TLC(n-Hexane:EtoAc:MeOH = 6:3:1) to give 2-(2,4-dicMoro-phenoxymethyl)-3H-benzoimidazole-5-carboxylic acid (furan-2-ylmethyl)-amide as a white solid (14.7 mg, yield: 37.92 %). 1H-NMR (DMSOd6, 300 Hz) 8.12(1H, s, NH), 8.01(1H, s, aromatic-H), 7.70(1H, d, J=8.1 Hz, aromatic-H), 7.62(1H, d, J=8.4 Hz, aromatic-H), 7.37-7.40(2H, m, aromatic-H), 7.16-7.20(1H, m, aromatic-H), 7.02(1H3 d, J=9.3 Hz, aromatic-H), 6.57(1H, m, NH), 6.30-6.35(2H, m, aromatic-H), 5.42(2H, s, CH2), 4.67(2H, d, J=4.8 Hz, CH)
Formulations comprising the compound are prepared as follows.
<FORMULAΗON EXAMPLE 1> Powder Formulation
Cpd. Of Chemical Formula IA or IB 2g
Lactose Ig These components were mixed and filled in an airtight sac to prepare a powder agent
<FORMULAπθN EXAMPLE 2> Tablet Foπnulation Cpd. Of Chemical Formula IA or IB lOOmg
Corn Starch lOOmg Lactose lOOmg
Mg Stearate 2mg
These components were mixed and subjected to a conventional tabletting process to produce a tablet.
<FORMULATION EXAMPLE 3> Capsule Foπnulation Cpd. Of Chemical Formula IA or IB lOOmg
Corn starch lOOmg
Lactose lOOmg
Mg Stearate 2mg
These components were mixed and loaded into a gelatin capsule according to a conventional method to prepare a capsule dosage form. _ . • . . . . ..
EXPERIMENTAL EXAMPLE 1> Assay for Inhibition of HIF-Mediated Transcriptional Activity (BKE Reporter Assay)
Six tandem repeats of HRE (Hypoxia Responsive Element, 5'-ACGTG-3'), which is present in a human VEGF gene, was inserted into the multi-cloning region of a pGL3-basic vector (Promega) containing a luciferase gene as a reporter gene to produce a recombinant pGL3-HRE-luciferase vector which was then used to assay the compounds prepared in the above Examples for inhibition activity against HIF-mediated transcriptional activity.
<!-!> Assay of HCF activation level
The hepatocellular carcinoma cell line HepG2 or Hep3B, both available from ATCC (American Type Culture Collection), and the gastric carcinoma cell line AGS, available from ATCC, were grown at 70% confluency in culture dishes and co-transfected with an internal control vector (pRL-CMV, Promega) and the recombinant pGL3-HRE-luciferase vector using Lipofectamine Plus Reagent (Tnvitrogen). HepG2 and AGS cells were treated with the compound of Chemical Formula IA while Hep3B and AGS cells were treated with the compound of Chemical Formula IB. The compound of Chemical Formula IA was used in a concentration of 10 μM for HepG2 or AGS cells. The compound of Chemical Formula IB was used in a concentration of 30 μM for Hep3B and in a concentration of 10 μM for AGS cells. After culture for 48 hours, the compounds of
Examples were applied to respective cells which were then incubated for 16 hrs in hypoxia (1% O2, 94% N2, and 5% CO2). The compounds prepared in Examples above were assayed for inhibition activity against HIF-I by measuring the activity of the luciferase, induced in hypoxia, using a Dual-luciferase reporter assay system (Promoga). In this regard, the luciferase activity was measured for 10 sec using a Microlumat Plus luminometer (EGScG Berthold). In the meanwhile, the renilla luciferase activity from the control vector pRL-CMV (Promega) was measured to normalize the data obtained.
The results are given in Table 1.
On the basis of the renila luciferase activity, the HF activity % remaining after treatment with the compounds was corrected.
<l-2> Assay of IGn
The hepatocellular carcinoma cell line Hep3B, available from ATCC (American Type Culture
Collection), and the gastric carcinoma cell line AGS, available from ATCC, were seeded in a density of 5x104 cell/well and were incubated for 48hrs at 37°C, 5% CO2 in culture dishes and co-transfected with an internal control vector (pRL-CMV, Promega) and the recombinant pGL3-HRE-luciferase vector using Lipofectamine Plus Reagent (bivitrogen). Compounds of Formula 1 dissolved in DMSO were placed in Hie incubated cell lines and were treated in various concentrations from 0.01 to 100 μM for 16 hrs and after then the number of survival cell lines at each concentration of compound was shown by a graph and a concentration of IC50 at which 50% cells of the compounds were survived was assayed. The results are given in Table 1.
Also, with respect to the compounds prepared in Experimental Examples 86, 87, 98, 102-107, 112 and 113, a concentration of IC50 was assayed in the same manner as stated with cell line SK-Hep-1, available from ATCQAmerican Type Culture Collection), and the result was given in Table 2.
[Table 2]
As a control compound, YC-I, commercially available from AG Scientific Inc. San Diego, CA, was
used in the same manner as above, and the results are shown in Table 1.
As apparent from data of Table 1 and Table 2 above, the compounds of the present invention, in particular the compounds prepared in Experimental Examples 18, 23, 44, 48, 113 or 126, were found to show excellent inhibition activity against the transcription mediated by HIF-I, which is induced in hypoxia. Therefore, the compounds of the present invention are useful as active ingredients for cancer therapy because tiiey can inhibit the expression of the genes implicated in the malignant transformation of cancer, thereby suppressing the growth and metastasis of cancer.
EXPERIMENTAL FXAMPT, F, 2> Assay for Inhibition of Accumulation of HIF-lα in Hypoxia The compounds identified to show excellent inhibition of HDF-mediated transcription activity in
Experimental Example 1 were assayed for HIF-lα accumulation inhibition in the gastric carcinoma cell line AGS and the hepatocellular carcinoma cell line Hep3B or HepG2. In this regard, the compounds prepared in Examples 18 and 126 were used to measure the inhibition of HDDF-lα accumulation in the hepatocellular carcinoma cell line HepG2 as follows. _
<2-l> Assay of HIF-lα accumulation inhibition at each concentration
BOGF-lα accumulation inhibition of the compounds prepared in Experimental Examples 18, 23, 44, 48, 113 or 126 was assayed in the hepatocellular carcinoma cell line Hep3B as follows.
The inhibitory effect of the compound prepared in Example 18, 23, 44, 48, 113 or 126 on HEF-lα protein production induced in hypoxia was assayed using a Western blotting method. The hepatocellular carcinoma cell line HepG2 (American Type Culture Collection) was grown to 70% confluency in culture dishes and treated with various concentrations of the compounds of Examples 18, 23, 44, 48, 113 or 126 in DMSO. DMSO alone was used as a control (expressed as 'DMSO' in FIG. 1). The hepatocellular carcinoma cell line was then incubated for 12 hrs in hypoxia (1% O2, 94% N2, and 5% CO2, expressed as '1% O2' in FIG. 1), followed by preparing a nuclear extract with an NE-PER reagent (Pierce). Approximately 30 μg of protein was obtained from each of the nuclear extracts using SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), and was then transferred onto a polyvinylidene fluoride (PVDF) membrane. Quantitative analysis for HIF- lα protein was conducted using an anti-HIF-lα antibody (R&D System) and a secondary antibody labeled with horseradish peroxidase (HRP). In order to confirm the existence of the same quantity of the nuclear extracts on respective PVDF membranes, they were deprived of the HEF-lα antibody using a buffer containing 2- mercaptoethanol and quantitatively measured for FflF-lβ topoisomerase-1 using HEF-lβ or anti-topoisomerase-1 antibody (expressed as TOPO-I' in FIG. 1) (Santa Cruz).
The results are given in FIG. 1.
As seen in FIG. 1, the compounds prepared in the present invention were found to inhibit the production of HIF-lα protein in a dose-dependent manner in hypoxia with no influence on the production of topoisomerase-1 (TOPO-I) or HDF-lβ. The inhibition of these compounds against HIF-I -mediated transcriptional activity in hypoxia is attributed to the suppression of the HIF-lα expression induced upon hypoxia HIF-lα, as a constituent of HQF-I, plays an important role in the expression of target genes of HEF-I. Therefore, the compounds of the present invention are useful as active ingredients for cancer therapy because they can inhibit the expression of the EQT-lα protein responsible for the growth and metastasis of cancer in a dose-dependent manner.
<2-2> Assay of HIF-lα accumulation inhibition at each time
While One of the hepatocellular carcinoma cell lines Hep3B, available from ATrC(American Type Culture Collection), was incubated in hypoxia for 4, 8, 12 and 16 hrs, the amounts of HEF-lα and topoisomerase-1 (TOPO-I) were assayed and the result was given in Fig.2.
As shown in Fig. 2, in case the compounds prepared in the present invention were not added, the amount of HDF-Ia increased as time went on but in case the compounds were added, the.amount of MF-lα decreased rapidly and then it was not detected after 12 hrs. The amount of topoisomerase-1 (TOPO-I) was nearly regular regardless of addition of the compounds.
Accordingly, the compounds prepared in the present invention inhibits the accumulation of HF-lα playing a pivotal role in the growth and metastasis of cancer depending on time, thereby inhibiting the growth and metastasis of cancer, so it can be used as an effective ingredient for anticancer agent
<EXPERIME]NTAL EXAMPLE 3> Effect on Expression of EPO or VEGF, Target Genes of HIF-I, in Hypoxia
The inhibitory effect of the compounds of the present invention on HDF-I activity was confirmed by assaying the compounds prepared in Examples for inhibition activity on the expression of EPO or VEGF, a representative target gene of HtF-I through an analysis of RT-PCR(reverse transcriptase polymerase chain reaction). VEGF, a target gene of FHF-I, encodes an angiogenesis factor playing a pivotal role in the growth and metastasis of cancer and EPO is a hematosis hormone gene, and both genes have been known for being deeply related to the development and the aggravation of cancer. The compounds of the present invention were measured for inhibition of VEGF expression in AGS, Hep3B and HepG2 cells. In this regard, the hepatocellular carcinoma cell line Hep3B was treated with compounds prepared in Examples 18 and 126 as follows.
After being grown to 70% confluency in culture dishes, HepG2 cells (American Type Culture
Collection) were treated with various concentrations (0 μM, 1 μM, 3 μM and 10 μM) of compounds prepared in Examples 18, 44, 113 or 126 and incubated for 12 hrs in hypoxia (1% O2, 94% N2, and 5% CO2, expressed as '1% O2' in HG. 2). Total RNA was isolated using an RNA Mini kit (Qiagen). From the total RNA (2 μg) thus obtained, cDNA was synthesized using an RT-PCR kit (Thvitrogen), and was used to amplify EPO or VEGF by 5 PCR in the presence of EPO or VEGF-specific primers. EPO or VEGF expression was quantitatively analyzed by running the PCR products on agarose gel. As an internal control, GAPDH was simultaneously amplified so as to analyze the selective inhibition of each compound for VEGF. Base sequences of primers used for the amplification of EPO, VEGF and GAPDH used in the present invention were as follows.
0 EPO; 5'-CACnTCCGCAAACTCTTCCG-S1 (sense),
5'-GTCACAGCTTGCCACCTAAG-S' (antisense). VEGF; 5'-GCTCTACCTCCACCATGCCAA-S' (sense),
5'-TGGAAGATGTCCACCAGGGTC-3l (antisense). GAPDH; 5'-ACCACAGTCCATGCCATCAC^1 (sense), 5 5'-TCCACCACCCTGTTGCTGTA-S' (antisense).
The results are given in FIG.3.
As seen in FIG. 3, neither the compound of Example 18 nor that of Example 126 had effects on the expression of the internal control GAPDH in hypoxia. It was observed, however, that both the compounds O prepared in the present invention showed dose-dependent inhibition of EPO or VEGF expression in hypoxia.
Accordingly, the compounds of the present invention were found to selectively inhibit the expression of
EPO or VEGF, a target gene of HEF-I. Therefore, the compounds of the present invention are useful as active ingredients for cancer therapy because they can selectively inhibit the expression of VEGF, an angiogenesis factor playing an important role in the malignant transformation of cancer, or the expression of EPO a hematosis5 hormone gene, a thereby suppressing the growth and metastasis of cancer.
Having the selective inhibition of the expression of the FHF-I target VEGF, the compounds of the present invention can be used as an active ingredient for the treatment of diabetic retinopathy or arthritis, which is aggravated upon HIF-1-mediated VEGF expression in hypoxia
O EXPERIMENTAL EXAMPLE 4> Assay for in vivo Anticancer Activity in Mouse
The compounds prepared in Examples 18, 95 or 126 were measured for in vivo anticancer activity in mice.
Female nude mice 5-6 weeks old (Crj:BALB/c nu/nu, Charles River) were bred in germ-free breeding rooms maintained at constant temperature and humidity. The nude mice were anesthetized before incision of the
chest skin. The metastatic breast carcinoma cell line MDA-MB-435, obtained from DR. D.R. Welch, Univ. Alabama, was implanted at a count of 106 cells/mouse into the mammary gland fat pad, and the incisions were then closed with surgical clips. The nude mice were divided into test groups and a control group, each consisting of 6 mice. When the transplanted breast cancer had grown to a size of about 50 mm3 as measured using a caliper, the compounds prepared in Example 18, 95 or 126 were administered at various concentrations. In more detail, the compounds were dissolved at concentrations of 20mg/kg and 50 mg/kg in a solvent containing 94.5% of physiological saline, 0.5% of DMSO and 5% of Tween 20 (hereinafter referred to as 'Solvent A1), the concentration of the compounds prepared in Experimental Examples 18, 95 or 126 was adjusted at 20mg/kg or 50mg/kg and administered once to the experimental groups at a dose of 100 μl a day per individual. For the control group, Solution A alone was used at a dose of 100 μl once a day. Thereafter, tumor volumes and body weights were measured once a week. Tumor volumes were calculated according to the following Mathematic Formula 1.
<Mathematic Formula 1> Tumor Volume (mm3)=(Length of Long Axis, mm)x(Length of Short Axis, mm)2 x 0.5 . .
The results are given in FIG. 4. Also, the cancer cell was extracted from the mouse 35 days later and was represented in Fig. 5.
When used at a concentration of 50 mg/kg, as seen in FIG. 3, the compounds prepared in Examples 18 and 126 were observed to further inhibit the growth of the cancer cells by 64.6% and 58.6%, respectively, compared to the control. In the test groups administered with a concentration of 20 mg/kg of the compounds of
Examples 18 and 126, the growth of the cancer cells was inhibited by a further 46.5% and 53%, respectively, compared to the control. In the test groups administered with a concentration of 20 mg/kg of the compound of Example 95, the growth of the cancer cells was inhibited by 4.3%, in the test groups administered with a concentration of 50mg/kg, the growth of the cancer cells was inhibited by 36.5%, compared to the control. Also, as shown in Fig. 5, the extracted cancer cells of the test groups became smaller, compared to that of the control. No dead were observed in six mice of each group which were administered with the concentration of 50mg/kg of the compounds prepared in Examples 18, 95 or 126. Also, the mice of the test groups did not appear different from those of the control in terms of body weight and feed intake. Therefore, the compounds of the present invention were very effective active ingredients for anticancer agents, thanks to the in vivo anticancer activity and the lack of general cellular toxicity thereof, as demonstrated by experiments on mice.
EXPERIMENTAL EXAMPLE 5> Cytotoxicity Assay
An acute cytotoxicity assay was conducted with five-week-old SPF C57BL/6 mice (Samtako BioKorea) as follows.
The compounds prepared in Examples 18 and 126 were suspended in a solvent comprising 94.5% of physiological saline, 0.5% of DMSO and 5% of Tween 80, and 0.5 mL of each of the suspensions was orally administered once into five mice at a dose of 300mg/kg. The mice were observed for death, clinical syndromes, and body weight and then autopsied for the observation of abdominal and thoracic organs with the naked eye. No noteworthy clinical syndromes were found, no mice died, and no changes due to toxicity were observed with respect to body weight or during the autopsy. Consequently, the compounds prepared in Examples 18 and 126 are safe with a minimal lethal dose of at least 300 mg/kg for oral administration, as demonstrated by the observation of no toxicity up to a dose of 300 mg/kg.
[INDUSTRIAL APPLICABILITY]
As described in the foregoing, the compounds in accordance with the present invention have anticancer activity not through general cytotoxicity, but through selective inhibition of HIF- 1 activity. Thus, the compounds of the present invention can be effectively used to suppress the growth and metastasis of cancer because they inhibit the HOF-1-mediated expression of the genes implicated in the malignant transformation of cancer. Particularly, the. anticancer activity of compounds.of the present invention is not attributed to general cytotoxicity,.. but to dose-dependent inhibition of the accumulation of HIF-lα protein.
Having inhibition activity against HIF-I, therefore, the compounds of the present invention can be effectively used in the treatment of various cancerous diseases, including liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, periproctic cancer, oviduct cancer, endometrial cancer, cervical cancer, vulva cancer, vaginal cancer, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, and CNS tumors.
Thanks to selective inhibition of the expression of the HIF-I target gene VEGF, the compounds of the present invention can be also used as active ingredients of therapeutics for diabetic retinopathy or arthritis, which is aggravated upon HF-1-mediated VEGF expression.
[SEQUENCE LIST PRETEXT]
SEQ ID NO: 1 is a sense primer of an EPO gene, SEQ ID NO: 2 is a antisense primer of an EPO gene, SEQ ID NO: 3 is a sense primer of a VEGF gene,
SEQ ID NO: 4 is an antisense primer of a VEGF gene, SEQ ID NO: 5 is a sense primer of a GAPDH gene, SEQ ID NO: 6 is an antisense primer of a GAPDH gene.
Claims
[CLAIMS]
[Claim 1)
A compound, represented by the following Chemical Formula IA or IB. <Chemical Formula 1 A>
IA
<Chemical Formula 1B>
X and Y are each C or N, preferably with a proviso that when X is C, Y is C or N and when Y is N, X . is C orN;
Z is O or ISlH;
R1 is selected from a group consisting of H, OH and COORa where Ra is H or Ci-C2 alkyl; 5 R2 is selected from a group consisting of H, OH, CN, CF3, C1-C2 alkyl, COORa, CH2COORa,
CONRbRc, SO2NH2, SO2CH3, SO2CH2OH, 0(C=O)NH2, OSO2NH2, tetrazole, Cj-C3 alkyl-substituted tetrazole, and Ci-C3 alkyl-substituted benzoyl, Ra being H or C]-C2 alkyl, Rb and Rc being independently selected from a group consisting of C3-C5 heteroaryl containing N, O and/or S; Ci-C5 alkyl substituted with a C3-C5 heteroaryl or heterocyclic group containing N, O and/or S; Ci-C3 alkyl substituted with OH and/or phenyl; O phenyl substituted with halogen and/or trihalomethyl; naphthyl; H; and Ci-C3 alkyl;
R3 is selected from a group consisting of H, COORa and SO2NH2, the Ra being H or Ci-C2 alkyl; R4 is selected from a group consisting of H, COORa and CONRbRc, the Ra being H or Ci-C2 alkyl, the Rb and the Rc being independently selected from a group consisting of Ci-C3 alkyl substituted with a C3-C5 heteroaryl or heterocyclic group containing N, O and/or S; Ci-C5 alkyl substituted with an amino group or a5 Ci~C2alkyl-substiruted amino group; H; and Ci-C2 alkyl;
R5 is selected from a group consisting of H, Ci-Ci0 alkyl, phenyl, halogen, nitro and acetyl; R& R7 are R]0 are independently selected from a group consisting of H and halogen;
R8 is a substituent located at a C5 or C6 position on the benzooxazole or benzoimidazole, selected from a group consisting of H, COORa, CONRbRc and SO2NH2, the Ra being selected from H and Ci-C2 alkyl, the Rb and the Rc being independently selected from Ci-C5 alkyl substituted with a C3-C5 heteroaryl or heterocyclic
5 group containing N, O and/or S; Ci-C5 alkyl substituted with an amino group or with a Ci-C3 alkyl-substituted amino group; amino; H; and Ci-C3 alkyl; and
R9 is selected from a group consisting of Q-Cio alkyl, halogen and nitro group.
[Claim 2] 0 The compound as set forth in claim 1, wherein the compound is selected from a group consisting of:
2-(4-adamantan-l-yl-phenoxy)-N-(3-memanesulfonyl-phenyl)-acetamide;
3-[2-(4-adamantan-l-yl-pheno^)-ace1ylarnino]-benzoic acid methyl ester,
3-[2-(4-adaman1an-l-yl-phenoj^)-acerylarnino]-benzoic acid ethyl ester;
S-P^adammαtan-l-yl-phenoxy^acetylarninoj-phenyl-acetic acid methyl ester, 5 4-[2^4-adamantan-l-yl-pheno^)-ace1ylamino]-benzoic acid methyl ester,
2-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-benzoic acid methyl ester,
5-[2-(4-adamantan-l-yl-phenoxy)-ace1ylarnino]-isophthalic acid dimethyl ester,
3-[2-(4-tert-butyl-phenoxy)-ace1ylamino-benzDic acid methyl ester,
3-[2-(4-fluoro-phenoxy)-acetylamino]-ben2oic acid methyl ester, O 3-[2-(4-chloro-phenoxy)-acetylamino]-ben2Dic acid methyl ester,
3-[2-(2,4-dichloro-phenoxy)-ace1ylamino]-benzDic acid methyl ester,
2-[2-(2,4-dichloro-phenoxy)-acerylamino]-benzoic acid methyl ester,
4-[2-(2,4-dichloro-phenoxy)-acerylamino]-benzoic acid methyl ester,
3-[2-(2, 4, S-trichloro-phenoxy^-aceτylaminoJ-benzoic acid methyl ester; 5 3-[2-(4-bromo-pheno^)-acerylamino]-benzoic acid methyl ester,
3-[2-(4-iodo-phenoxy)-acetylamino]-benzDic acid methyl ester, 3-[2-(4-aceryl-phenoxy)-acetylamino]-benzDic acid methyl ester; 3-[2^4-adaman1an-l-yl-pheno>^)-acerylarnino]-4-hydroxy-benzoic acid methyl ester, 3-[2-(4-tert-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester, O 3-(2-biphenyl-4-yl-acetylamino)-benzoic acid methyl ester,
4-[2-(4-adamantan-l-yl-phenoxy)-ace1ylarnino]-isophthalic acid dimethylester, 3-[2-(4-nitro-phenoxy)-acetylamino]-benzoic acid methyl ester, 3-[2^4-adamantan-l-yl-phenoxy)-ace1ylarnino]-benzamide; 3-[2-(2, 4-dichloro-phenoxy)-acetylamino]-benzamide; 3-[2-(2, 4, 5-trichloro-phenoxy)acetylamino]-benzamide;
3-[2-(4-bromo-phenoxy)-acetylamino]-benzamide;
3-[2-4-omo-2-chloro-phenoxy)-acetylalnino]-benzainide;
3-[2-(4-iodo-pheno)iy)-acetylamino]-benzamide; 3-(2-phenoxy-acetylamino)-benzamide;
3-[2-(44ert-butyl-phenoxy)-acetylamino]-benzamide;
3-(2-p-tolyoxy-acetylamino)-benzamide;
3-[2-(4-nitro-phenoxy)-acetylamino]-benzamide;
2-(4-adamantan-1-yl-phenoxy)-N-(3-sulphamoyl-phenyl)-acetamide;
2-(4-adamantan-1-yl-phenoxy)-N-(4-sulphamoyl-phenyl)-acetainide;
2-(4-adamantan-1-yl-phenoxy)-N-(3-cyano-pb.enyl)-acetamide;
N^-cyanophenyl^^Φdichloro-phenoxyyacetamide;
2-(4-adamantan-l-yl-pheno^)-Ν^3-1rifluoromethyl-ρhenyl)acetamide;
2-(4-adamantan-l-yl-pb.enoxy)-N-(3-hydroxy-phenyl)-acetamide; 2-(2,4-dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide; 2-(2,4-dichloro-phenoxy) -N-(3-methanesu]fonyl-phenyl)-acetainide; 2-(2,4-dichloro-phenoxy) -Ν-[3^2-hydroj^-ethanesulfonyl)phenyl]-ace1aniide;
2-(4-adamantan-1-yl-phenoxy)-N- (3-benzoyl-phenyl)-acetamide;
2-(4-adamantan-1-yl-phenoxy) -acetylanώio]-benzoic acid; 3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-benzoicacid;
3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-phenyl-aceticacid;
4-[2-(4-adamantan-l -yl-phenoxy)-acetylamino]-benzoic acid;
3-[2-(4-tert-butyl-phenoxy)-acetylamino-benzoic acid;
3-[2-(4-adamantan-l -yl-phenoxy)-ace1ylainino]4-hydroxy-benzoic acid; 3-[2-(4-tert-butyl-phenoxy)-acetylainino]-4-liydro)ςy-benzoic acid;
5-P^Φadamantan-l-yl-phenoxy^ac^tylaminoJ-isophthalic acid; 3-[2-(4-fluoro-phenoxy)-acetylamino]-benzoic acid; 3-[2-(4-chloro-phenoxy)-acefylamino]-benzoic acid; 3-[2-(2, 4-dichloro-phenoxy)-acetylamino]-benzoic acid; 2-[2-(2, 4-dichloro-phenoxy)-acetylamino]-benzoic acid;
4-[2-(2, 4-dichlorophenoxy)-acetylamino]-benzDic acid; 3-[2-(2, 4, 5-tricliloro-phenoxy^acetylaminoJ-benzoic acid; 3-[2-(4-bromo-phenoxy)-acetylamino]-beixzDic acid; 3-[2-(4-iodo-phenoxy)-acetylainiαo]-benzoic acid; 3-(2-biphenyl-4-yl-acetylamino)-benzoic acid;
3-[2-(4-acetyl-phenoxy)-acetylamino]-benzoic acid;
2-4-adamantan-l-yl-phenoxy)^N-[3-(lH-tetrazol-5-yl)phenyl]-acetamide;
2-2,4-dichloro-phenoxy)-N-[3-(lH-tetrazol-5-yl)-phenyl]-acetainide; Carbamic acid 3-[2-(4-adamantan-l-yl-phenoxy)-ace1ylamino]-phenylester;
Sulfamic acid 3-[2-(4-adamantan-l-yl-pheno5^)-acetylamino]-phenyl ester,
3-[2-4-adamantan-l-yl-phenoxy)-a(^lamino]-4-h.ydro>^-benzamide;
3-[2-4adamantan-l-yl-phenoxy)-acetylambo]4-hydroxy-N, N-dimethyl-benzamide;
3-[2-(4-adamantan4-yl-pheno>sy)-acetylam^ 3-[2-(4-adamantan4-yl-phenoxy)-ace1ylamino]^
3-[2-4-adamantan-l-yl-phenoxy)-aretylamino]-4-h^
3-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-Ν-(4κiUoro-phenyl)-benzainide;
3-[2-(4-adamantan-l-yl-pheno^)-ace1ylainino]-N^3-ttffluoromethyl-phenyl)-benzamide;
3-[2-(4-adamantan-l-yl-pheno5ςy)-a∞1ylamino]-Ν-naphthalen-2-yl-benzamide; 3-[2-(4-adamantan-l-yl-phenoxy)race1ylanm^
3-[2-(4-adamantan-l-yl-phenoxy)-acetylamno]-N-(2-pyridin^-yl-ethyl)-benzamide;
3-[2-2, 4-dichloro-phenoxy)-a∞tylamino]-N,N-dimethyl-benzamide;
3-[2-(2,4-dichloro-phenoxy)-a<xtylamiiio]-N-ethyl-benzamide;
3-[2-2,4-dichloro-phenoxy)-acetylamino]-N-furan-2-ylmethyl-benzamide; 3-[2-(2,4-cWor(>pheno?^)-a∞1ylamino]-N-furan-2-y]methy1 -4-hydroxy-beiizamide;
N-benzyl-3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzamide;
3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-pyridin4-ylme1hyl-benzaniide;
3-[2-(2,4-dichloro-phenoxy)-acetylamino] -N-pyridin-3-ylmethyl-benzamide;
3-[2-(2,4-dichloro-phenoxy)-acetylamino] -N-(2-piperidin-l-yl-ethyl)-ben2amide;
3-[2-(2,4-dichloro-phenoxy)-acetylamino] -N-(2-morpholin-4-yl^1liyl)-benzamide;
3-[2-(2,4-dichloro-phenoxy)-acetylamino] -N-(2-hydroxy-ethyl)-benzamide; 3-[2-(2, 4-dicUoro-phenoxy)-acetylarnino]-N-(3-morpholin-4-yl-propyl)-benzamide; 2-[2-(4-adamantan-l-yl-phenoxy )-acetylamino]-isonicotinic acid methyl ester; 5-[2-(4-adamantan-l-yl-phenoxy)-ace1ylamino]-nicotinic acid metiiyl ester, 5-[2-(2, 4-dichloro-phenoxy)-acetylamino]-nicotinic acid methyl ester,
2-(4-adamantan-l-yl-phenoxy)-N-(4-methyl-pyridin-2-yl)-acetamide; 2-(2, 4-dichloro-phenoxy)-N-(4-methyl-pyridin-2-yl)-acetamide; 2-[2-(2, 4-dichlorophenoxy)-acetylamino]-isonicotinic acid methyl ester, 2-[2-(2, 4, 5-trichloro-phenoxy)-acetylamino]-isoiiicotinic acid methyl ester, 2-[2-(4-bromo-2-chloro-phenojQ')-acetylaπώio]-isonicotinic acid methyl ester,
2-[2-(4-tert-butyl-phenoxy)-acetylamino]-isonicotinic acid methyl ester,
2-[2-(2, 4-dichloro-phenoxy)-acetylainino]-isonicotinic acid;
5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-nicotinic acid; 5-[2-(2, 4-dichloro-phenoxy)-acetylainino]-nicotinic acid;
2-[2-(4-adamantan-l-yl-phenoxy)-aceiylamino]-isonicotinic acid
2-[2-(4-bromo-2-cUoro-phenoxy)-acetylamino]-isonicotinic acid;
2-[2-(4-tert-butyl-henoxy)-acetylamino]-isonicotinicacid;
5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-N-mran-2-ylmethyl-nicothamide; 5-[2-(4-adamantan- 1 -yl-phenoxy)-ace1ylamino]-N^2-pyridin-4-yl-ethyl)nicotinamide;
5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-N^3-imidazol-l-yl-propyl)-niα)tinamide;
2-[2-(4-adamntan -1-yl-phenoxy)-ace1ylamino]-N-(4κ;Moro-phenyl)-isonicotinamide;
2-[2-(4-adamantan-l-yl-pheno^)-acetylamino]-N-flκBn-2-y]methyl-isonicx)tinamide
2-[2-(4-adaman1an-l-yl-phenoxy)-a∞1ylammo]rN^2-pyridh4-yl-e1hyl)-isomcotmamide; 2-[2-(4-adamantan-.l-yl-phenoxy)-acetylamko]-N-(3-imidazol-l-yl-propyl)-isomcx)tinamide;
2-[2-(2, 4-dichloro-phenoxy)-a∞tylamino]-N^-dimethyl-isonicotinamide;
2-[2-(2, 4-dichloro-phenoxy)-a∞tylamino]-Ν-furan-2-y]memyl-isonicotinamide;
2-[2-(2, 4-dichloro-phenoxy)-acetylamino]-N-(2-piperidin-l -yl-ethyl)-isonicotinamide;
2-[2-(2, 4-dichloro-phenoxy)-ac«1ylambo]τN-(3-moφhQlin^-yl-propyl)-isonicotinamide; 5-[2-(4-adamantan-l-yl-phenoxy)-acetylamino]-nicotinamide;
2-[2-(4-adamantan- 1 -yl-phenoxy^-acetylaminoj-isonicotinamide;
2-[2-(4-fluoro-pheno^)-ace1ylamino]-isonicotinainide;
2-[2-(2, 4^cUoro-phenoxy)-a∞tylamino]-isonicotinamide;
2-[2-(2,4,5-tricMoro-pheno^)-acetylainino]-isonicotinamide; 2-[2-(4-bromo-phenoxy)-acetylaitιino]-isonicotiiiamide;
2-[2-(4-bromo-2κ;Uoro-phenoxy)-ace1ylamino]-isonicotinamide; 2-[2-(44ert-butyl-phenoxy)-ace1ylamiiio]-isoriicotinamide; 2-(2-/?-tolyoxy-acetylamino)-isonicotinamide; 2-{2-phenoxy-acetylammo)-isomcotoamide; 2-[2^4-nitro-phenoxy)-acetylamino]-isonicotinamide;
2-(2, 4-dichloro-phenoxymethyl)-benzooxazol-5-carboxylic acidmethyl ester, 2-(4-adamantan-l-yl-pheno5QΗiethyl)-benzooxazol-5-carboxylic acidmethyl ester; 2-(4-adamantan-l-yl-phenoxymethyl)-benzOθxazol-6-carbθ5Q'lic acid methyl ester, 2-(4-adamaniHn-l-yl-phenoxymethyl)-lH-berizoiinidazol-5-carboxylic acid methyl ester, 2-(2, 4-dichlorophenoxymethyl)-benzooxazol-6-carboxyJlic acid methyl ester, 2-(2, 4-dichloro-phenoxymethyl)-lH-benzoimidazol-5-carboxylic acid methyl ester; 2-(2, 4tert-butyl-phenoxymethyl)-benzooxazDl-ό-carboxylic acid methyl ester, 2-(2, 4-tert-butyl-phenoxymethyl)-lH-ben2oimidazDl-5-carboxylic acid methyl ester, 2-(4-nitro-phenoxymethyl)-lH-benzoimidazol-5-carboxylic acid methyl ester, 2-(2, 4-dichloro-phenoxymethyl)-benzDoxazDl-5-sulfonic acid amide; 2-(2, 4-dichlorophenoxymethyl)-benzooxazDl-5-carboxylic acid; 2-(4-adamantan-l-yl-phenoxymetliyl)-benzooxazol-5-carboxylic acid; 2-(4-adamantan-l-yl-phenoxymethyl)-benzooxazol-6-carboxylic acid; 2-4-adamantan-l-yl-phenoxymethyl)-lH-benH)imidazol-5-carboxylic acid; 2-(2, 4-dichlorophenoxymethyl)-benzooxa2ol-6-carboxylic acid; 2-(2, 4-dichlorophenoxymethyl)- lH-benzoimidazol-5-carboxyilic acid; 2-(4-tert-butyl-phenoxymethyl)-benzooxazol-6-carboxylic acid; 2-(4-tBrt-butyl-phenoxymethyl)-lH-beπzoimidazol-5-carboxylic acid;
2-4-nitrθrphenoxymethyl)-lH-benzDimidazDl^5-carboxylic acid;
2-4-adamantan-l-yl-phenoxymethyl)-benzooxa2ϋl-5-carboxylic acidamide; 2-(4-adamantan-l-yl-pheno>Qτnethyl)-benzooxazol-5-carboxylic aciddimethylamide 2-4-adamantan-l-yl-phenoxymemyl)-benzooxazol-5-carboxyUc acid(fiHBn-2-ylmethyl)^ 2-(4-adamantan-l-yl-phenoxyme1iiyl)-benzooxazol-5^arboxyHc acid(2-dimemylanώ 2-(4-adamantan-l-yl-phenoxymethyl)-benzDOxazol-5-carbo5^Uc acid(2-piperidin-l-yl-emyl)-ai^ 2-(4-adamantan-l-yl-phenoxymethyl)-benzooxazDl-5-carboxylic acid(3-morpholin-4-yl-propyl)- amide;
2-(2, 4-dichloro-phenoxymethyl)-benzooxazol-5-carboxylic acid(fύran-2-ylmethyl)-amide; 2-(4-adamantan-l-yl-phenoxymethyl)-benzooxazol-6-carboxylic acid (fiiran-2-ylmethyl-amide; 2-(2, 4-dichloro-phenoxymethyl)-benzooxazol-6-carboxylic acid (furan-2-ylmethyl)-amide; 2-(4-adamantan-l-yl-phenoxymethyl)-3H-benzDimidazol-5-carboxylic acid amide; 2-4-adamantan-l-yl-phenoxymetliyl)-3H-benzDimidazol-5-carboxylic acid dimethylamide; 2-{4-adamantan-l-yl-phenoxymemyl)-lΗ-benzOimidazDl-5-carboxyΗc acid(fiΗ-an-2-ylmeth^^ 2-(4-adamantan-l-yl-phenoxymethyl)-lH-benzoimidazol-5-carboxylic acid(2-dimethylamino-e&yl)- amide;
2-(4-adamantan-l-yl-phenoxymetliyl)-lH-beπzoimidazol-5-carboxylic acid (3-imidazol-l-yl-propyl)- amide;
2-(2, 4-dichloro-phenoxymethyl)-lΗ-benzoimidazDl-5-carboxylic acid hydrazide; and
2-{2, 4-dichloro-phenoxymethyl)-3H-benzoiimidazol-5-carboxylic acid (furan-2-ylmethyl)-ainide. [Claim 3]
The compound as set forth in claim 1, wherein the compound is selected from a group consisting of 3- [2-(4-adamantan-l-yl-phenoxy)-acetylamino]-4-hydroxy-ben2oic acid methyl ester and 2-(4-adamantan-l-yl- phenoxymethyl)-lH-benzoimidazol-5-carboxylic acid methyl ester.
[Claim 4]
A method for preparing a compound represented by Chemical Formula IA of claim 1 according to the following Reaction Scheme 3, in which a compound (IAd) is converted into a compound (IAe) in the presence of lithium iodide in an organic solvent selected from among pyridine, CBkCl2 and DMF. <Reaction Scheme 3>
(wherein R1, Rr-R?, X, Y, Ra, Rb and Rc are each as defined in Chemical Formula IA.)
[Claim 5]
A method for preparing a compound of Chemical Formula IB of claim 1 according to the following Reaction Scheme 6, in which a compound (IBa) is hydrolyzed into a corresponding carboxylic acid compound (IBb) in the presence of aluminum bromide and dimethyl sulfide with CH2Cl2 serving as a solvent
<Reaction Scheme 6>
1Bfo (wherein, Z, R9, R10, Ra, Rb and Rc are each as defined in Chemical Formula IB.)
[Claim 6] An HIF-I inhibitor, comprising a compound of one of claims 1 to 3 as an active ingredient.
[Claim 7] .
A pharmaceutical composition for the treatment of cancer, comprising a compound of one of claims 1 to 3 as an active ingredient
[Claim 8]
The pharmaceutical composition as set forth in claim 7, wherein the cancer is selected from liver cancer, stomach cancer and breast cancer.
[Claim 9]
A pharmaceutical composition for the treatment of diabetic retinopathy, comprising the compound of one of claims 1 to 3 as an active ingredient
[Claim 10] A pharmaceutical composition for the treatment of rheumatoid arthritis, comprising the compound of one of claims 1 to 3 as an active ingredient.
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| US12/306,319 US8394799B2 (en) | 2006-07-04 | 2007-07-03 | Compounds that inhibit HIF-1 activity, the method for preparation thereof and the pharmaceutical composition containing them as an effective component |
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| KR1020060062722A KR100787131B1 (en) | 2006-07-04 | 2006-07-04 | Compounds that inhibit hif-1 activity the method for preparation thereof and the pharmaceutical composition containing them as an effective component |
| KR10-2006-0062722 | 2006-07-04 |
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| Country | Link |
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| US (1) | US8394799B2 (en) |
| KR (1) | KR100787131B1 (en) |
| WO (1) | WO2008004798A1 (en) |
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Also Published As
| Publication number | Publication date |
|---|---|
| US8394799B2 (en) | 2013-03-12 |
| KR100787131B1 (en) | 2007-12-21 |
| WO2008004798A8 (en) | 2009-08-13 |
| US20090306078A1 (en) | 2009-12-10 |
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